Lab Markers

A/G Ratio

Marker Name: A/G Ratio

REFERENCE RANGES FOR A/G RATIO:

Laboratory reference range: 1.1–2.5

Functional reference range: 1.5–2.0

DESCRIPTION:

Blood contains two major classes of circulating proteins: albumin and globulins.¹ The mathematical ratio of albumin to globulin in the serum is the A/G ratio.² Under normal conditions, 60 percent of plasma protein in a given sample is albumin, while the remaining 40 percent is globulins.³ Plasma globulins and albumin are synthesized by the liver, while immunoglobulins are synthesized by cells of the immune system.⁴

Albumin performs several functions in the intravascular space. It provides osmotic pressure, which helps retain water in the vasculature. It also acts as a carrier protein for a number of substances including calcium, unconjugated bilirubin, thyroid hormones, and a multitude of pharmaceutical drugs.^4,5 Globulins are a heterogeneous assortment of circulating proteins that includes enzymes, proteins of the complement system, clotting factors, and immunoglobulins.^1,3,6 Immunoglobulins make up a substantial fraction of the total globulin content in blood.^1,6 As such, albumin and immunoglobulin levels drive much of the A/G ratio.

Levels of albumin and globulin are regulated in separate ways. Albumin is synthesized at a constant rate by the liver and has a long half-life compared to other proteins, especially in tissues.⁷ Immunoglobulin levels in blood are constant in the absence of an active immune response. This immune response can be a reaction to an acute infection or chronic autoimmune inflammation. Immunoglobulin levels can also be elevated from a neoplastic conversion of immune cells (e.g., plasma cells in multiple myeloma).⁸

The A/G ratio is a calculation based on a directly measured level, albumin, and a calculated level, globulin. Total protein is the combined quantity of albumin and globulins in serum, but it is not measured as the sum of two measured substances. Instead, total protein is the quantity of all molecules in a serum sample that contain peptide bonds. In other words, total protein and albumin are directly measured in a standard liver panel and globulins are not.³ Globulin levels are calculated by subtracting the albumin level from the total protein level. The albumin level divided by the calculated globulin level provides the A/G ratio.²

An elevated A/G ratio could theoretically signify abnormally high levels of albumin or abnormally low levels of globulins. In practice, however, an elevated A/G ratio virtually always signifies a deficiency in one or more types of globulins.³ With the exception of extremely rare clinical situations (e.g., hepatocellular carcinoma that increases albumin biosynthesis), albumin production by the liver is either normal or inappropriately low.^3,9 Albumin levels can increase during periods of dehydration and relative hemoconcentration; however, globulin levels will also increase in periods of decreased intravascular water. Therefore, the ratio of albumin to globulin would remain unchanged. Most often, a high A/G ratio reflects underproduction of immunoglobulins.^10,11

An abnormally low A/G ratio indicates either albumin deficiency or globulin excess in serum. Albumin levels may be abnormally low because of lack of production by the liver (e.g., cirrhosis) or from protein wasting (e.g., nephrotic syndrome).⁴ Importantly, hypoalbuminemia due to renal protein loss must be greater than globulin loss to appreciably lower the A/G ratio. Globulin levels may increase in serum from inflammation or infection, or the increase could reflect hematologic cancer, such as Waldenstrom macroglobulinemia.⁴

A standard liver panel includes total protein, albumin, alanine aminotransferase (ALT), acetate aminotransferase (AST), alkaline phosphatase, and bilirubin.¹² The report may also provide a calculated A/G ratio.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^10,11

Immunoglobulin deficiency (e.g., agammaglobulinemia, chronic lymphocytic leukemia)

Low in:⁴

Albumin deficiency
- Liver cirrhosis
- Nephrotic syndrome
- Analbuminemia
Globulin excess
- Acute infection/inflammation
- Chronic inflammatory disease (e.g., tuberculosis, syphilis)
- Hematological neoplasm
  - Multiple myeloma
  - Monoclonal gammopathy of undetermined significance
  - Lymphoma
  - Leukemia
  - Macroglobulinemia (e.g., Waldenstrom macroglobulinemia)

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source – Kresser Institute

Albumin

Marker Name: Albumin

REFERENCE RANGES FOR ALBUMIN:

Laboratory reference range: 3.5–5.5 g/dL

Functional reference range: 4–5 g/dL

DESCRIPTION:

Albumin is the most abundant protein found in the blood. It comprises approximately 60 percent of the proteins in plasma.¹ Albumin contributes to the osmotic pressure within blood vessels, which is important for fluid balance in peripheral tissues.² The plasma protein acts as a carrier for various molecules including calcium, unconjugated bilirubin, thyroid hormones, long-chain fatty acids, toxic heavy metal ions, and many drugs.^2,3

Albumin is synthesized by the liver.² Biosynthesis of albumin requires sufficient amounts of essential amino acids (i.e., histidine, leucine, isoleucine, lysine, phenylalanine, methionine, threonine, tryptophan, and valine).⁴ In healthy individuals, the rate of albumin synthesis roughly equals the rate at which protein is utilized, catabolized, or excreted.¹ Compared to other proteins, albumin has a relatively long half-life and remains reasonably constant.² The intravascular half-life of albumin is 16 hours, but the half-life in tissues is 19 days.^5-7

Albumin levels are relatively constant, even during early phases of nutritional deficiency or liver disease. Therefore, the serum marker is not a sensitive indicator of these conditions. Prealbumin proteins such as transthyretin, retinol-binding protein, and coagulation factors have shorter half-lives and are faster to herald the onset of nutritional or biosynthetic abnormality.² Low serum albumin levels strongly correlate with morbidity and mortality; every 10 g/L decrease in serum albumin is associated with a 137 percent increase in mortality risk and an 89 percent increase in morbidity risk.⁵

Hyperalbuminemia, or the abnormal elevation of albumin in the blood, generally reflects dehydration and hemoconcentration.⁸ Mild elevations in albumin may be caused by high-protein diets, though the clinical consequence of this is negligible.⁹ Hepatocellular carcinoma could theoretically stimulate the synthesis of albumin resulting in elevated levels in the serum, but this is exceedingly rare.¹⁰

It is much more common for albumin levels to be abnormally low (i.e., hypoalbuminemia). Hypoalbuminemia can be caused by dilution from relative increases in intravascular fluids. Low serum albumin levels usually indicate impaired biosynthesis in the liver, insufficient protein intake, increased tissue catabolism of protein, impaired protein absorption, or protein loss from renal excretion.³ Albumin levels may be abnormally low in patients with acute inflammation, shock, or protein-wasting enteropathy.⁸ An extremely rare autosomal recessive condition called analbuminemia results in a complete lack of circulating albumin.¹¹ Curiously, this condition generally results in nothing more serious than edema.^2,11

Albumin is a standard component of the liver panel, which includes alanine aminotransferase (ALT), acetate aminotransferase (AST), alkaline phosphatase, bilirubin, and total protein.¹²

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^8-10

Hemoconcentration
- Inadequate water intake
- Excessive diuresis
High-protein diet with protein supplementation (rare)
Hepatocellular carcinoma (rare)

Low in:^2,13-16

Hemodilution
- Intravenous fluids
- Advanced congestive heart failure
- Polydipsia
Protein malnutrition
Protein malabsorption
Liver failure
Advanced liver disease
Renal failure
Nephrotic syndrome
Inflammation
Protein-losing enteropathy
- Primary gastrointestinal mucosal diseases (e.g., ulcerative colitis)
- Increased interstitial pressure or lymphatic obstruction (e.g., sarcoidosis)
- Non-erosive upper gastrointestinal diseases (e.g., celiac sprue)
Analbuminemia

FUNCTIONAL RANGE INDICATIONS:

High in:

Dehydration (hematocrit, hemoglobin, and red blood cells will also often be elevated in functional range)

Low in:

Impaired liver function
Inflammation

References:

Source: Kresser Institute

Alkaline Phosphatase

Marker Name: Alkaline phosphatase

REFERENCE RANGES FOR ALKALINE PHOSPHATASE:

Laboratory reference range: 39–117 IU/L

Functional reference range: 42–107 IU/L

DESCRIPTION:

Alkaline phosphatase refers to the family of related zinc metalloenzymes present in liver, bone, kidney, and placenta.^1-3 The biological importance of alkaline phosphatase in humans is largely unknown, although the enzyme appears to play a role in bone mineralization and fat absorption.^4-6 While the enzymatic function of alkaline phosphatase is of comparatively little clinical importance, the level of alkaline phosphatase in the blood is an important biomarker of disease.⁴

Serum alkaline phosphatase levels predominantly increase in one of two circumstances, either due to biliary stasis or increased osteoblastic activity in bone.³ In both cases, the expression of alkaline phosphatase in the respective tissues is stimulated by some inciting event. In hepatobiliary disease, serum alkaline phosphatase biosynthesis is stimulated by bile acids retained in the hepatobiliary system.^7,8 Increased synthesis plus liver cell destruction subsequent to hepatobiliary disease leads to regurgitation and leaking of alkaline phosphatase into the blood, which is detected by laboratory assay.

In diseases of the bone, alkaline phosphatase activity is stimulated by increased osteoblastic activity. In fact, alkaline phosphatase is the principal glycosylated protein found in bone, where it is bound to the cell surface of osteoblasts.⁹ Normal physiologic processes or diseases that stimulate bone growth reflexively increase osteoblastic activity and, by extension, alkaline phosphatase activity. Since alkaline phosphatase levels vary depending on osteoblastic activity, levels of the enzyme are generally higher in children and adolescents since these are periods of rapid bone growth.⁴ Moreover, diseases that result in increased bone turnover, such as Paget’s disease, can increase alkaline phosphatase levels in blood.¹⁰

Elevated alkaline phosphatase levels are also noted in other non-disease states.¹¹ Alkaline phosphatase levels may also increase to a lesser degree in the third trimester of normal pregnancy. This increase is presumably due to an influx of the placental alkaline phosphatase into the serum.⁴ Curiously, individuals with O or B blood types may have transient elevations in serum alkaline phosphatase after consuming a fatty meal.^4,11 Regardless of the tissue source, alkaline phosphatase is cleared from the serum at a steady rate regardless of the functional capacity of the liver or health of the bile ducts.¹² It has a half-life in the serum of seven days.¹³

Elevations in serum alkaline phosphatase are usually a more pressing clinical concern than abnormally low levels.¹⁴ Nevertheless, several disease processes can reduce serum alkaline phosphatase below the normal range. Decreased alkaline phosphatase activity in the serum occurs in greater than 50 percent of patients who had cardiac surgery requiring a cardiac bypass pump.¹⁴ This may be due at least in part to magnesium deficiency, since deficient levels of this element can directly decrease alkaline phosphatase levels.¹⁵ Zinc deficiency is probably the most well-known cause of low alkaline phosphatase levels, although this may not be a common cause in Western countries.¹⁴ Anemia and various endocrine disturbances can lower serum alkaline phosphatase levels.

Alkaline phosphatase is one of the core measurements in a standard liver panel, which also includes alanine aminotransferase (ALT), acetate aminotransferase (AST), bilirubin, albumin, and total protein.¹⁶ Gamma-glutamyl transpeptidase (GGT) may be ordered to confirm that elevated alkaline phosphatase levels come from a hepatobiliary source.¹² GGT levels correlate with alkaline phosphatase levels in hepatobiliary disease (i.e., both are elevated).¹⁷ Bone-specific alkaline phosphatase may be used to monitor treatment in individuals with Paget’s disease, osteoporosis, or osteomalacia.¹⁸

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:¹¹

Pregnancy (normal in third trimester)
Endocrine disease
- Hyperthyroidism
- Hyperparathyroidism
Hepatic cholestasis
Biliary cholestasis
Bone disease
- Vitamin D insufficiency
- Rickets
- Healing bone fracture
- Paget’s disease
- Osteomalacia
- Malignancy involving bone
Fatty meal (B and O blood groups only)
Drugs
- Estrogens
- Androgens
- Albumin
- Phenothiazines
- Erythromycin
- Oral hypoglycemic agents

Low in:^{11,14,15,19,20}

Severe anemia
Pernicious anemia
Malnutrition
Nutrient imbalance
- Phosphate deficiency
- Zinc deficiency
- Magnesium deficiency
- Vitamin C deficiency
- Hypervitaminosis D
Wilson disease
Hypothyroidism
Hypoparathyroidism
Celiac disease
Estrogen replacement therapy
Cardiac surgery (especially with cardiac bypass pump use)
Large-volume blood transfusions
Milk-alkali syndrome

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications, and:
Folate deficiency
Vitamin B6 deficiency

References:

Source: Kresser Institute

ALT

Marker Name: ALT

REFERENCE RANGES FOR ALT:

Laboratory reference range: 0–44 IU/L

Functional reference ranges:¹⁸

Male: 0–26 IU/L

Female: 0–20 IU/L

DESCRIPTION:

Alanine aminotransferase (ALT), formerly called serum glutamate-pyruvate transaminase (SGPT),¹is an enzyme found predominantly in hepatocytes that catalyzes the transfer of an amino group from alanine to alpha-ketoglutarate, yielding pyruvate and glutamate. Serum ALT levels are routinely measured to detect and characterize diseases of the liver.²

ALT is a sensitive and somewhat specific indicator of liver cell injury.³ While the highest activity of ALT is in the liver, lesser amounts can be detected in skeletal muscle and kidney.⁴ ALT is found exclusively in the cytoplasm and spilled into the bloodstream when cells are injured.⁵ Thus, virtually any disease that destroys hepatocytes will increase serum levels of ALT.⁶Aminotransferases are cleared from the circulation by sinusoidal cells in the liver.⁷ While the half-life of ALT in the circulation is approximately two days, massive liver injury may cause prolonged ALT elevations.³

An elevated level of ALT in the serum may manifest before clinical symptoms of liver disease. When interpreting serum ALT levels, it is important to use age- and gender-specific reference limits; normal values of ALT in men are 25 to 30 percent higher than they are in women of the same age.^8,9

The extent of ALT elevations in the blood may provide a clue to the etiology of liver damage. The causes of liver injury from highest serum ALT elevation to lowest are as follows: ischemic or toxic liver injury, acute viral hepatitis, autoimmune hepatitis, alcoholic liver disease, chronic hepatitis, and liver cirrhosis.⁷ The rate and degree to which ALT increases and subsequently returns to normal also varies by etiology. Acute ischemic hepatitis causes extremely high increases in serum ALT with a relatively rapid return to normal. On the other hand, acute viral hepatitis rises more slowly and does not usually reach the same levels as would occur in acute ischemic hepatitis. Likewise, serum levels of ALT return to normal relatively slowly in acute viral hepatitis compared to ischemic liver injury.⁷

Aminotransferase levels, including ALT, are abnormally low in patients on hemodialysis.¹⁰ This is likely, but not necessarily, due to vitamin B6 deficiency.¹¹ Abnormally low ALT levels, in isolation, are not usually a cause for concern.^3,7

ALT is measured with aspartate aminotransferase (AST) as part of a standard liver function panel.¹²Examining the ratio of AST to ALT can provide some additional clues to the mechanism of hepatic injury. ALT is higher than AST in most diseases of the liver, such as viral or autoimmune hepatitis.¹³On the other hand, alcoholic liver disease, liver cirrhosis, acute bile duct obstruction, and early hepatitis will elevate AST greater than ALT in the serum.^14,15 Gamma-glutamyl transpeptidase (GGT) is also routinely measured with ALT and may be superior to AST and ALT levels in detecting alcohol abuse or alcoholic liver disease.^16,17

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^7,19

Muscle injury (e.g., rhabdomyolysis)
Hypervitaminosis A
Liver disease resulting in hepatocellular injury
- Liver cirrhosis
- Chronic hepatitis
- Alcoholic liver disease
- Nonalcoholic fatty liver disease
- Autoimmune hepatitis
- Acute viral hepatitis
- Hepatobiliary obstruction
- Ischemic liver injury
- Liver carcinoma
Renal cell injury
Hemolysis
Drugs and toxins (e.g., acetaminophen, halothane, carbon tetrachloride, lead)

Low in:^10,11,20

Vitamin B6 deficiency
Hemodialysis

FUNCTIONAL RANGE INDICATIONS:

High in:

Metabolic dysfunction (dysglycemia, insulin resistance, etc.)
Iron overload
Nonalcoholic fatty liver disease
Viral infections
Autoimmune liver disease

Low in:

Same as conventional indications
Impaired liver function

References:

Source: Kresser Institute

AST

Marker Name: AST

REFERENCE RANGES FOR AST:

Laboratory reference range: 0–40 IU/L

Functional reference range:¹²

Male: 0–25 IU/L

Female: 0–23 IU/L

DESCRIPTION:

Aspartate aminotransferase (AST) reversibly catalyzes the transfer of an alpha amino group between aspartate and glutamate. In this conversion, α-ketoglutarate is also converted to oxaloacetate. As with other transaminases, AST requires pyridoxal 5ʹ-phosphate (vitamin B6) as a cofactor for catalysis, while the reverse reaction requires pyridoxamine 5′-phosphate.¹ AST, also known as serum glutamic oxaloacetic transaminase (SGOT), catabolizes amino acids so that they may enter the citric acid cycle and help produce energy.²

AST is found in two isozymes, one in the cytosol and the other in the mitochondria.^3,4 Cytosolic AST is found in red blood cells and heart tissue, while mitochondrial AST is found in highest concentrations in the liver. AST is also found in the skeletal muscle, pancreas, spleen, lung, kidney, and brain.⁴ In general, mild tissue injury liberates AST from the cytoplasm, while severe tissue damage additionally spills AST from the mitochondria into the serum.⁵ Currently, there is no clinical basis for distinguishing between cytosolic or mitochondrial AST in the serum.⁴

Elevated AST in the serum occurs in any disease that destroys liver cells (hepatocytes). The degree to which AST levels are increased may suggest the etiology of liver damage. Chronic liver diseases such as liver cirrhosis and chronic hepatitis result in a moderate increase in AST levels, approximately five to 10 times above the upper limit of normal.² AST levels that exceed 10 times the upper reference limit (marked elevation) usually indicate an acute hepatic injury such as liver ischemia or toxic liver injury.² Aminotransferase levels may exceed 75 times the upper limit of normal in shock liver hepatotoxic drug overdose.

Mild elevations in AST commonly occur in clinical settings.² Elevated AST may come from extrahepatic sources such as heart disease but most commonly reflects chronic alcohol use or nonalcoholic fatty liver disease.⁶ Mild serum AST excess may be due to chronic hepatitis B, hepatitis C, autoimmune disease, hemochromatosis, or abnormalities in copper metabolism (Wilson’s disease).² Since AST is present in various tissues other than liver, an elevated AST is not necessarily specific for liver damage. Vigorous exercise, skeletal muscle injury, heart muscle injury (e.g., myocardial infarction) or acute pancreatitis can raise serum AST levels.

For reasons that are not fully understood, AST levels are decreased in patients with uremia and undergoing hemodialysis.^7,8 This may be related to deficiency in vitamin B6.

AST is measured in the context of a liver function panel and GGT.⁹ ALT is higher than AST in most diseases of the liver. Infectious hepatitis or inflammatory diseases affecting the liver, for example, will elevate ALT higher than AST, making the AST/ALT ratio less than or equal to one.⁵ Conversely, alcoholic liver disease generally raises AST levels to twice that of ALT in the serum (i.e., AST/ALT ratio ≥2).¹⁰ Cirrhosis, acute bile duct obstruction, and early hepatitis will elevate AST greater than ALT in the serum.¹¹

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:²

Vigorous exercise
Rhabdomyolysis
Liver disease resulting in hepatocellular injury
- Liver cirrhosis
- Chronic hepatitis
- Alcoholic liver disease
- Nonalcoholic fatty liver disease
- Autoimmune hepatitis
- Acute viral hepatitis
- Hepatobiliary obstruction
- Ischemic liver injury
- Liver carcinoma
Heart muscle injury (e.g., myocardial infarction)
Acute pancreatitis
Drugs (e.g., acetaminophen, halothane)

Low in:^7,13

Vitamin B6 deficiency
Hemodialysis
Uremia

FUNCTIONAL RANGE INDICATIONS:

High in:

Metabolic dysfunction (dysglycemia, insulin resistance, etc.)
Iron overload
Nonalcoholic fatty liver disease
Viral infections
Autoimmune liver disease

Low in:

Same as conventional indications
Impaired liver function

References:

Source: Kresser Institute

B12, serum

Marker Name: B12, serum

REFERENCE RANGES FOR SERUM VITAMIN B12:

Laboratory reference range: 211–946 pg/mL

Functional reference range: 450–2000 pg/mL

DESCRIPTION:

Vitamin B12 (cobalamin) is one of the water-soluble B vitamins.¹ Vitamin B12 is essential for DNA synthesis, as it is required for synthesis of the purine and pyrimidine nucleotide bases.² Vitamin B12 is particularly important for the formation of morphologically normal and functional red blood cells, and it plays an important role in nervous system development and neurological function.³

Vitamin B12 is a cofactor for the enzymes methionine synthase and L-methylmalonyl-CoA mutase.⁴ Methionine synthase transfers a methyl group from methyltetrahydrofolate to homocysteine, which forms the amino acid methionine and tetrahydrofolate (THF). L-methylmalonyl-CoA mutase, on the other hand, produces succinyl-CoA from L-methylmalonyl-CoA. Succinyl-CoA is a key intermediate in the citric acid cycle.

Vitamin B12 is not a single molecule, but rather several related cobalt-containing molecules (corrinoids) that have vitamin B12 activity in the body.³ The principal forms of vitamin B12 active in the human body are methylcobalamin and 5-deoxyadenosylcobalamin.³

Since humans cannot synthesize vitamin B12, it must be obtained from dietary sources or supplementation. Orally consumed vitamin B12 requires acid-pepsin and pancreatic proteases to free cobalamin from proteins and ligands, respectively.⁵ Simultaneously, ingested vitamin B12 must be protected from acid and enzymatic degradation. Intrinsic factor, a substance secreted by parietal cells in the stomach, provides this protection for vitamin B12.⁵ Intrinsic factor binds to vitamin B12 and essentially shuttles it to the terminal ileum, where it is absorbed into the portal circulation and carried to the liver.³ Intrinsic factor is essential for vitamin B12 absorption in the terminal ileum.⁶

Most vitamin B12 is transported in the blood bound to plasma binding proteins, specifically, transcobalamins. Approximately 80 percent of circulating vitamin B12 is bound to transcobalamin I, though transcobalamin II is the principal plasma binding protein responsible for delivering B12 to tissues.⁷

Half of circulating vitamin B12 is taken up by the liver, and the other half is transported to tissues. The portion of B12 taken up by the liver enters the biliary system, and vitamin B12 is continually secreted in the bile. Intrinsic factor may bind to secreted B12 in the bile for reuptake in the terminal ileum, thereby preserving total body vitamin B12 levels.^3,7 Vitamin B12 is not reabsorbed by the intestine, it is passed in the feces.

Laboratories currently measure total cobalamin blood assays of vitamin B12; however, many groups have argued that holotranscobalamin, or “active B12,” more accurately reflects the level of bioavailable vitamin B12 in the blood.^8-10Holotranscobalamin is the portion of circulating vitamin B12 that is bound to transcobalamin proteins. While holotranscobalamin carries only 6 to 20 percent of total plasma B12,¹⁰it delivers the majority of usable B12 to tissues, which is why holotranscobalamin is also known as “active B12.” Although holotranscobalamin is a better indicator of early vitamin B12 deficiency than total serum B12 levels, few clinical laboratories routinely measure holotranscobalamin.⁹

Hypercobalaminemia is an abnormally high serum vitamin B12 level. Since vitamin B12 is a water-soluble vitamin, it has been long assumed that an elevated B12 level is both uncommon and of little clinical importance.¹¹ Within the last decade, however, new research has revealed that hypercobalaminemia is more common than previously realized and may have deleterious effects for patients.^11-13 Interestingly, elevated vitamin B12 levels may indicate functional vitamin B12 deficiency.¹¹ Excessive intake of vitamin B12 is likely the most common cause of hypercobalaminemia. This is most often caused by excess oral supplementation or excessive parenteral administration of vitamin B12.¹¹ Various solid and blood cancers can cause abnormally high levels of circulating vitamin B12. Some solid tumors can cause hypercobalaminemia, especially cancers of the gastrointestinal organs. Inflammatory conditions, liver disease, and kidney disease may also cause abnormally elevated vitamin B12 levels in the blood.¹¹

An abnormally low serum vitamin B12 level is hypocobalaminemia. Insufficient consumption of vitamin B12 in the diet, gastric diseases, and malabsorption are the main causes of hypocobalaminemia.^2,5 Pernicious anemia is a major cause of vitamin B12 deficiency among white and black adults, but it is much less frequently seen in Hispanics or Asians.¹⁴ Pernicious anemia results from a defect in the activity of intrinsic factor, which is thought to be caused by autoimmunity against intrinsic factor or gastric parietal cells.¹⁵ Other reasons for malabsorption of vitamin B12 and subsequent hypocobalaminemia include reduced gastric acid secretion, failure of the exocrine pancreas, chronic alcoholism, H. pylori infection, the effect of certain drugs, and gastrointestinal surgeries (e.g., gastric bypass).^5,16

Serum vitamin B12 is virtually always measured with folate. Investigations of vitamin B12 deficiency may include holotranscobalamin, homocysteine, and/or methylmalonic acid assays.^17,18

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^3,11

Excessive intake (especially parenteral)
Paradoxical functional vitamin B12 deficiency
Inflammatory disease (e.g., lupus, rheumatoid arthritis)
Renal failure
Liver disease (e.g., acute hepatitis, liver cirrhosis, alcoholic liver disease)
Blood disorder
- Chronic myeloid leukemia
- Polycythemia vera
- Primary myelofibrosis
- Acute leukemia
- Primary hypereosinophilic syndrome
Solid neoplasm
- Hepatocellular carcinoma
- Breast cancer
- Colon cancer
- Gastric cancer
- Pancreatic cancer

Low in:^5,19

Insufficient dietary intake
Gastrointestinal conditions
- Pernicious anemia
- Gastrectomy/bariatric surgery
- Gastritis
- Crohn’s disease
- Malabsorption (e.g., tropical sprue)
- Small bowel disease
- Ileal resection
- Pancreatic insufficiency
- Pancreatitis
- Tapeworm infestation
Inherited transcobalamin II deficiency
Drugs
- Metformin
- Proton pump inhibitors (e.g., omeprazole)
- Histamine receptor antagonists

FUNCTIONAL RANGE INDICATIONS:

High in:

B12 supplementation
Impaired B12 metabolism

Low in:

Functional B12 metabolism
GI conditions impairing B12 absorption

References:

Source: Kresser Institute

Basophils

Marker Name: Basophils

REFERENCE RANGES FOR BASOPHILS:

Functional reference range: 0–3%

DESCRIPTION:

Basophils are the least abundant leukocytes (white blood cells) in the circulation. Under normal circumstances, they comprise less than 0.5 percent of circulating blood cells.¹ Mature basophils are found near the marginal zone in the red pulp of the spleen, in the lamina propria of the small intestine, and within lung parenchyma.² Once basophil cells are activated, they promote an increase in eosinophil numbers and participate in the differentiation of macrophages in the lung.²Basophils play an important role in the expulsion of parasites from the intestine and provide detective immunity against parasites that typically gain entry through the skin.^3,4 New research has revealed the important roles that basophils play in protective immunity, immediate-type allergy, and delayed-type allergy.⁵

While found in low numbers in the circulation, basophil numbers can expand rapidly in bone marrow in response to inflammatory signals. Granulocyte-myeloid precursor cells differentiate into basophils when exposed to hematopoietic cytokines, interleukin-3, and thymic stromal lymphopoietin.^4,6 Basophils can be quickly mobilized to the bloodstream, spleen, lung, and liver, including various lymphoid or nonlymphoid tissues.¹ The typical lifespan of a basophil is about 60 hours.² Interestingly, this lifespan does not appear to be lengthened during infection, as it is with some other types of leukocytes.² Thus, increases in basophil levels within the blood are the result of de novo production.⁴

An abnormally high number of basophils is called basophilia or basophilic leukocytosis. Basophilic leukocytosis is an uncommon clinical condition and is most often associated with acute or chronic leukemia.⁷ Causes of basophilia include myeloproliferative disorders, hypersensitivity or inflammatory reactions, and hypothyroidism (myxedema).^7,8

Basopenia is an abnormally low basophil count in the blood. Low basophil counts likely represent increased migration of basophils into tissues or decreased production by the bone marrow. Basopenia is rarely clinically important in isolation, but this laboratory result could prompt further testing.

A basophil count is reported within the results of a complete blood count (CBC) with automated differential.⁹ A manual differential or peripheral blood smear may be ordered separately to quantify basophils and to look for morphologic abnormalities.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^5,7,8,10,11

Hypersensitivity reactions
Inflammatory conditions
- Inflammatory bowel disease
- Chronic dermatitis
- Chronic sinusitis
- Asthma
Hypothyroidism (especially myxedema)
Infection (e.g., helminths, varicella, tuberculosis)
Myeloproliferative disorders (e.g., polycythemia vera, myelofibrosis, essential thrombocytosis)
Acute or chronic leukemia
Drugs
- Estrogen administration

Low in:^11-15

Ovulation
Normal pregnancy
Cigarette smoking
Acute allergic reaction
Chronic spontaneous urticaria
Stress reactions (e.g., blood loss, thermal trauma, acute radiation exposure)
Hyperthyroidism
Thymoma
Drugs
- Chronic corticosteroid use

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

Bilirubin, total

Marker Name: Bilirubin, total

REFERENCE RANGES FOR TOTAL BILIRUBIN:

Laboratory reference range: 0–1.2 mg/dL

Functional reference range: 0.1–1.2 mg/dL

DESCRIPTION:

Bilirubin is the waste product of heme catabolism.¹ Bilirubin may be found in the bloodstream, in the liver, within bile, or in the intestines as it makes its way from a red blood cell degradation byproduct to eventual elimination in the feces.¹ Under physiologic concentrations, bilirubin may serve as an antioxidant.² Moreover, the pigmented molecule is responsible for the characteristic color of bile and feces.^3,4 However, elevated bilirubin levels may be toxic to cells and intracellular organelles.^1,5 Markedly elevated serum bilirubin concentrations in neonates may cause neurological disturbances or even death.^6,7

Approximately 80 percent of bilirubin comes from hemoglobin, with the remaining 20 percent derived from other heme-containing molecules including myoglobin, cytochromes, catalases, and peroxidases.¹ Heme is converted into biliverdin by heme oxygenase, which is then converted to bilirubin by biliverdin reductase.⁹

Bilirubin levels are controlled by complex physiologic mechanisms that keep bilirubin from reaching toxic levels under normal circumstances.^1,8 These mechanisms include uptake and storage in the liver, conjugation with glucuronic acid, binding to serum proteins, and enzymatic degradation in the gastrointestinal tract.¹

Bilirubin is fairly insoluble in water, so it is usually carried by albumin in the blood. The bilirubin-albumin complex shuttles bilirubin to the liver, where it is taken up by hepatocytes.¹ Within liver cells, bilirubin is conjugated with glucuronide, rendering it water soluble.¹⁰ Conjugated bilirubin is then excreted into the bile. Bacteria within the intestines further metabolize conjugated bilirubin into urobilinogens, which are either reabsorbed by the ileum and large intestine (20 percent) or excreted in the feces (80 percent). Reabsorbed urobilinogen is either metabolized by the liver and again excreted in the bile, or excreted in the urine. When this excretory system is dysfunctional, the kidney may excrete between 50 and 90 percent of conjugated bilirubin.¹¹

As the name implies, total bilirubin provides a measure of all bilirubin molecules in the serum. This includes both conjugated and unconjugated forms of bilirubin. Unconjugated bilirubin is very poorly soluble in water and must be bound to protein within blood. Unconjugated bilirubin binds to albumin and, to a lesser extent, to lipoproteins as it is secreted by the liver.¹ Very little unconjugated bilirubin is free (i.e., unbound to protein) in blood under normal conditions. Nevertheless, excessive amounts of unconjugated bilirubin can exceed the binding capacity of albumin and circulate freely in the blood. All known toxic effects of bilirubin are associated with elevations in the unconjugated form.¹

Laboratories may report direct and indirect bilirubin rather than conjugated and unconjugated. Direct bilirubin is a measure of water-soluble forms of bilirubin and is essentially equivalent to the conjugated bilirubin in the sample.¹² Total bilirubin minus direct bilirubin yields indirect bilirubin (i.e., unconjugated bilirubin).

The etiology of elevated total bilirubin (hyperbilirubinemia) can be understood based on whether bilirubin accumulated before or after conjugation. Unconjugated hyperbilirubinemia is due to increased bilirubin production, impaired hepatic bilirubin uptake, or impaired bilirubin conjugation.^13,14 Conjugated hyperbilirubinemia, on the other hand, is due to either extrahepatic cholestasis (i.e., biliary obstruction) or intrahepatic cholestasis. Elevated total bilirubin is usually due to elevated unconjugated (i.e., direct) bilirubin.¹² Almost every neonate develops a level of plasma/serum bilirubin that exceeds adult normal levels, though few experience clinical issues from bilirubin toxicity. Severe neonatal hyperbilirubinemia, however, can cause long-term neurological complications and death.

Little work has been done to explore the causes of low total serum bilirubin. However, bilirubin levels may be decreased in patients with nephrotic syndrome in the context of generalized protein wasting in the urine.¹⁵ The molecule may also be a prognostic indicator for other conditions such as albuminuria in type 2 diabetes or chronic kidney disease.^16,17

Bilirubin is one of the six components of the standard liver panel, which includes alanine aminotransferase (ALT), acetate aminotransferase (AST), alkaline phosphatase, albumin, and total protein.¹⁸

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^13,14

Unconjugated hyperbilirubinemia
- Increased bilirubin production (e.g., hemolysis, extravasation of blood)
- Impaired hepatic bilirubin uptake
  - Heart failure
  - Portosystemic shunt
  - Drugs (e.g., rifampin, probenecid)
- Impaired bilirubin conjugation
  - Crigler-Najjar syndrome types I and II
  - Gilbert syndrome (most common cause of bilirubin elevation)
  - Neonates (normal in most neonates, very high levels can be dangerous)
  - Hyperthyroidism
  - Chronic liver disease
  - Ethinyl estradiol
- Conjugated hyperbilirubinemia
  - Extrahepatic cholestasis
    - Biliary atresia
    - Choledocholithiasis
    - Tumor (e.g., cholangiocarcinoma)
    - Primary sclerosing cholangitis
    - AIDS cholangiopathy
    - Acute and chronic pancreatitis
    - Parasites (e.g., Ascaris lumbricoides, liver flukes)
  - Intrahepatic cholestasis
    - Hepatitis (e.g., viral, alcoholic, nonalcoholic, neonatal)
    - Primary biliary cholangitis
    - Drugs/toxins (e.g., alkylated steroids, chlorpromazine, arsenic)
    - Sepsis
    - Shock
    - Infiltrative diseases (e.g., amyloidosis, lymphoma, sarcoidosis)
    - Total parenteral nutrition
    - Postoperative cholestasis
    - Hepatic crisis in sickle cell disease
    - Pregnancy
    - End-stage liver disease

Low in:¹⁵

Nephrotic syndrome

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

BUN

Marker Name: BUN

REFERENCE RANGES FOR BUN:

Laboratory reference range: 6–24 mg/dL

Functional reference range: 13–18 mg/dL

DESCRIPTION:

Urea is a water-soluble end product of protein metabolism suitable for excretion in the urine.¹BUN, or blood urea nitrogen, is the quantity of urea nitrogen in the blood. Urea provides no known physiologic benefit in humans other than as a waste product. Nevertheless, BUN is a clinically useful laboratory test that is measured in essentially every person who receives an order for routine blood work.^2,3

Urea is created by the urea cycle, also known as the ornithine cycle.⁴ The liver is the primary source of urea production, but some urea production also takes place in the kidneys and intestines. Nitrogen found in urea may derive from ingested proteins or muscle catabolism.¹ Each molecule of urea contains two nitrogen atoms, one from ammonia and one from aspartate, combined by the enzyme arginase.⁵ Urea cycle function is dependent on activation of carbamoyl phosphate synthase by N-acetylglutamate.⁶ After it is synthesized, urea passively diffuses across cell membranes and is found in the bloodstream.⁷ Urea is excreted by the kidney or, to a smaller degree, in sweat. BUN levels increase approximately 50 percent from infancy to adulthood, and BUN levels tend to be slightly higher in men than in women.^8,9

BUN varies inversely with glomerular filtration rate. That is, increases in BUN correlate with decreases in kidney function.¹⁰ However, BUN is not a precise measure of glomerular filtration rate for two reasons.¹⁰ First, the rate of urea production is not constant and may increase substantially in patients who consume high-protein diets or in the context of increased tissue catabolism. Conversely, a low-protein diet or liver disease may decrease BUN apart from kidney function. Second, roughly half of filtered urea by the glomerulus is passively absorbed in the proximal tubules. Thus, BUN will vary as sodium and water reabsorption rates change. For these reasons, creatinine levels in blood are a far more accurate measure of glomerular filtration rate and overall kidney function.

As a clinical tool, BUN is most useful when interpreted in the context of blood creatinine levels. Under normal conditions, the ratio of BUN to creatinine is between 10:1 and 20:1. If the BUN-to-creatinine ratio exceeds 20:1, it indicates prerenal injury and, most often, decreased renal perfusion.^11,12

BUN is also useful for estimating glomerular filtration rate in advanced kidney failure.¹³ In advanced kidney disease, creatinine clearance overestimates kidney function while urea clearance underestimates it. Therefore, glomerular filtration rate can be more accurately estimated in advance kidney failure by averaging clearance rates of both molecules.¹⁴

functional-biomarker-bun_kll-google-docs-2016-10-09-18-04-18

Elevated levels of urea in the blood may be referred to as uremia or azotemia. Uremia generally reflects a more severe clinical state in which various blood electrolytes are abnormal beyond BUN. Uremia is often used interchangeably with end-stage renal disease or advanced kidney failure.¹⁵ Azotemia, on the other hand, reflects a broad set of etiologies for mild to moderate BUN elevations. Azotemia is sometimes used interchangeably with the term prerenal disease, or, simply prerenal azotemia.¹⁶ The most common causes of elevated BUN include decreased renal perfusion, acute or chronic kidney disease, or medications. In fact, a large number of medications across various drug classes may increase BUN.^8,10

An abnormally low BUN in isolation is rarely a cause for concern. While decreased BUN may occur in the context of severe liver disease, this state is usually obvious from other clinical and laboratory evidence. BUN may also be low from excessive hydration (e.g., primary polydipsia, iatrogenic). A low BUN usually reflects a low-protein diet or is a side effect from drugs such as chloramphenicol and streptomycin.

BUN is always measured with creatinine, and these two values are the primary ways to estimate glomerular filtration rate and kidney function.¹⁰ BUN is measured as part of the basic metabolic panel or complete metabolic panel. Depending on the clinical situation, BUN may also be measured with blood ammonia levels and urinalysis.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^8,17-19

Hypovolemia/dehydration
High-protein diet
Total parenteral nutrition
Gastrointestinal hemorrhage
Ketoacidosis
Kidney diseases
- Glomerulonephritis (acute or chronic)
- Pyelonephritis
- Acute tubular necrosis
- Interstitial nephritis
- End-stage renal disease
Ureteral obstruction
Shock
Congestive heart failure
Thermal burn injury
Recent heart attack
Drugs
- Diuretics (e.g., furosemide, hydrochlorothiazide)
- Antibiotics (e.g., tetracyclines)
- Anti-gout medications (e.g., allopurinol, probenecid)
- Chemotherapeutics (e.g., cisplatin)

Low in:⁸

Low-protein diet
Malnutrition
Excessive fluid administration
Polydipsia
Drugs
- Streptomycin
- Chloramphenicol

FUNCTIONAL RANGE INDICATIONS:

High in:

Low in:

References:

Source: Kresser Institute

BUN/Creatinine Ratio

Marker Name: BUN/Creatinine Ratio

REFERENCE RANGES FOR BUN/CREATININE RATIO:

Laboratory reference range:¹

BUN:Cr	Urea:Cr	Location	Mechanism
>20:1	>100:1	Prerenal (before the kidney)	BUN reabsorption is increased. BUN is disproportionately elevated relative to creatinine in serum. Dehydration or hypoperfusion is suspected.
10-20:1	40-100:1	Normal or Postrenal (after the kidney)	Normal range. Can also be postrenal disease. BUN reabsorption is within normal limits.
<10:1	<40:1	Intrarenal (within kidney)	Renal damage causes reduced reabsorption of BUN, therefore lowering the BUN:Cr ratio.

Functional reference range: same as conventional range

DESCRIPTION:

Urea is the water-soluble byproduct of protein metabolism through the urea cycle (ornithine cycle).² Blood urea nitrogen (BUN) is a measure of nitrogen incorporated within urea molecules. Creatinine is a water-soluble waste product of protein catabolism, specifically muscle proteins. Neither BUN nor creatinine has a known physiological action in the body; however, these biomarkers are routinely measured in clinical settings.^3,4 The ratio of BUN to creatinine can provide useful clinical information about blood volume and renal perfusion.²

Muscles produce creatinine at a constant rate, proportional to overall muscle mass.^5,6 Virtually all creatinine in the blood is completely filtered by the kidneys and not reabsorbed.⁵ Creatinine varies inversely with glomerular filtration rate (GFR) and is a useful biomarker for estimating GFR. BUN production, on the other hand, is not constant.^7,8 Once urea is formed, it is filtered by the kidney.⁹ However, roughly half of filtered urea is passively reabsorbed in the proximal tubule of the kidney.² While BUN and creatinine vary inversely with GFR, BUN levels may increase without concomitant renal disease.¹⁰ For these reasons, creatinine is usually a better measure of GFR than BUN. The exception is advanced kidney disease, in which GFR is more accurately estimated by averaging clearance rates of both BUN and GFR.^11,12

The BUN/creatinine ratio is mainly used to detect prerenal injury, as occurs from reduced blood flow to the kidneys.¹³ As intravascular volume decreases, the proximal tubule of the kidney retains sodium and water to compensate.¹³ This is accompanied by an increase in urea reabsorption by the kidney and elevations in the blood.² Creatinine levels, on the other hand, stay relatively stable in this state. Consequently, a BUN/creatinine ratio of 20 or greater most often indicates prerenal disease. There may be other causes of an abnormally high BUN/creatinine ratio, however. Gastrointestinal bleeding may result in a disproportionately large increase in BUN relative to creatinine.^11,14 Corticosteroid treatment may also disproportionately elevate BUN levels.¹⁴ In fact, a large number of medications may increase BUN without appreciably affecting creatinine.^2,5Conversely, muscle wasting may reduce creatinine production to the point that the BUN/creatinine ratio is abnormally high despite a normal BUN level.¹¹

Normal and abnormally low BUN/creatinine ratio results must be considered within the clinical context and are often not clinically useful.¹³ For instance, prerenal disease may exist in a patient with a normal BUN/creatinine ratio if urea production is abnormally low for some reason. Likewise, an abnormally low BUN/creatinine ratio is usually caused by decreased BUN in the context of normal creatinine.¹⁵ This may be due to liver failure, diminished protein intake, or severe polyuria/polydipsia.¹⁵ Massive increases in creatinine could also result in an abnormally low BUN/creatinine ratio, such as myositis, rhabdomyolysis, or other severe muscle trauma.¹⁵Cephalosporins, vitamin C, and flucytosine can spuriously increase serum creatinine levels without affecting measured BUN levels, decreasing the BUN/creatinine ratio.¹⁵

Creatinine and BUN are routinely measured as part of the basic metabolic panel or complete metabolic panel.⁵

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^13,15

Prerenal injury
- Hypovolemia
- Hypotension
- Congestive heart failure
- Nephrotic syndrome
Gastrointestinal hemorrhage
Muscle wasting
Drugs
- Diuretics (e.g., furosemide, hydrochlorothiazide)
- Antibiotics (e.g., tetracyclines)
- Anti-gout medications (e.g., allopurinol, probenecid)
- Chemotherapeutics (e.g., cisplatin)

Low in:¹⁵

Low protein intake
Liver failure
Severe polyuria/polydipsia
- Diabetes insipidus
- Diabetes mellitus (uncontrolled)
- Cushing’s disease
Muscle injury
- Myositis
- Rhabdomyolysis

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

Calcitriol

Marker Name: Calcitriol

REFERENCE RANGES FOR SERUM CALCITRIOL:

Laboratory reference range: 19.9–79.3 pg/mL

Functional reference range: Same as conventional range

DESCRIPTION:

Calcitriol, also known as 1,25-dihydroxyvitamin D, is the most biologically active form of vitamin D.¹It is tightly regulated by PTH and is directly responsible for increasing the intestinal absorption of calcium, increasing the resorption rate of bone, and decreasing the excretion of calcium and phosphate by the kidneys.¹ These three functions of calcitriol work to increase the level of calcium in the blood.² As such, vitamin D is important for the regulation of normal calcium levels. Normal calcium levels, regulated by the action of vitamin D, promote bone formation during development and prevent bone demineralization in older individuals.^1,2^,³ Adequate vitamin D is required for normal function of muscle tissue, nervous tissue, and cells of the immune system.⁴ Vitamin D deficiency, on the other hand, is associated with high blood pressure, heart attack, and cancer.⁴

Vitamin D may be ingested and absorbed from dietary sources and supplements. Generally, these forms of vitamin D, namely ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) are biologically inactive. A third inactive form of vitamin D, 7-dehydrocholesterol, may be converted into vitamin D3 by UV light striking the skin.¹^,³ These forms of vitamin D must be metabolized by enzymes in the liver to produce the weakly active form of vitamin D, 25-hydroxyvitamin D (calcidiol).³ 25-hydroxyvitamin D may act directly in the body or be converted to 1,25-dihydroxyvitamin D (calcitriol) by enzymes in the kidney.^1,5 Calcitriol has a short half-life in the body, approximately four hours.³ Calcitriol is inactivated by the liver and excreted with the bile in the gastrointestinal tract.¹^,⁶

While 1,25-dihydroxyvitamin D (calcitriol) is the most biologically active form of vitamin D, it is not the routine test for vitamin D status. Serum 25-hydroxyvitamin D is the routine test and may be a good indicator of a person’s vitamin D status in many circumstances.^3,7 However, for the most complete picture of functional vitamin D status, it is best to test serum 25-hydroxyvitamin D along with serum calcitriol, serum PTH, serum calcium, and serum phosphorus. This will also help clarify vitamin D status in people with chronic renal failure, rickets, or those taking therapeutic calcitriol.⁸Calcitriol measurements may also be useful in determining the cause of disorders of calcium or phosphorus metabolism.⁸

Abnormally high calcitriol levels usually reflect an elevated serum 25-hydroxyvitamin D level. Excess serum 25-hydroxyvitamin D is usually caused by excess intake of vitamin D.²It is possible that calcitriol levels could be increased due to deficient activity of degradative enzymes, particularly hepatic 24-hydroxylase; however, this is quite rare.⁹

Since vitamin D status is usually determined by measuring 25-hydroxyvitamin D levels, we know much more about what causes low 25-hydroxyvitamin D than calcitriol, specifically. Nonetheless, 25-hydroxyvitamin D levels are a useful surrogate in this case, given the well-characterized regulation of these vitamin D molecules. It is important to note, however, that calcitriol is more tightly regulated than calcidiol. Inadequate consumption, absorption, or synthesis of vitamin D may cause low calcitriol levels.^1,3,10,11 On the other hand, low serum calcitriol may result from increased liver metabolism and excretion, or, to a much lesser extent, excessive excretion from the kidneys.^1,3,10 Certain drugs can cause abnormally low calcitriol levels as well. The most well-known are anticonvulsant drugs, but certain antimicrobials and corticosteroids can cause low calcitriol levels.¹¹ The most common cause of low calcitriol levels, specifically, is chronic kidney disease.¹¹

If calcitriol is being measured, it usually means 25-hydroxyvitamin D levels are also being considered.^8,12 To clarify diagnosis, parathyroid hormone, serum calcium, and serum phosphorus should also be tested.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^2,10

Excessive intake
Hyperparathyroidism
Sarcoidosis
Hematological malignancy
Solid organ malignancy
Certain infections (mycobacterium, histoplasmosis)
Other granulomatous conditions

Low in:^2,11

Chronic kidney disease
Renal failure
Nephrotic syndrome
Normal pregnancy
Breastfeeding infants
Inadequate sunlight exposure
Obesity
Fat malabsorption
Hypoparathyroidism
Secondary hyperparathyroidism
Small bowel disease
Gastric bypass surgery
Pancreatic insufficiency
Advanced liver disease
Thermal burn injury with extensive skin damage
Hereditary vitamin D-resistant rickets (vitamin D-dependent rickets, type 2)
Cystic fibrosis
Drugs
- Anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin)
- Isoniazid
- Rifampin
- Corticosteroids
- Theophylline

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

Calcium

Marker Name: Serum Calcium

REFERENCE RANGES FOR SERUM CALCIUM:

Laboratory reference range: 8.7–10.2 mg/dL

Functional reference range: 9.2–10.1 mg/dL

DESCRIPTION:

Calcium is a divalent ion that plays an important role in cell signaling, blood clotting, muscle contraction, and nerve function.^1,2 Virtually all calcium in the body is found within the bones and teeth.¹ A relatively small amount of calcium can be found extracellularly (i.e., within the serum) and within cells. Because of the potentially toxic effects of free intracellular calcium, calcium within cells is kept within membrane-bound organelles and released only under specific circumstances, such as muscle contraction or neurotransmitter release.³

Total body calcium levels are regulated by a complex interplay of factors that take place within the intestines, kidneys, and bone.⁴ Calcium homeostasis is regulated by parathyroid hormone (PTH), vitamin D, fibroblast growth factor 23 (FGF-23), calcitonin, and estrogen.^4,5 Calcium levels are chiefly governed by the parathyroid gland, which relies on calcium-sensing receptors to detect blood calcium levels and respond with appropriate changes in PTH secretion.⁵ Serum PTH and serum calcium are usually inversely correlated.⁶

PTH acts rapidly to increase blood calcium levels through multiple mechanisms, including increased bone resorption, increased reabsorption of calcium by the kidneys, increased vitamin D levels in the blood, and in turn, increased absorption of calcium in the small intestine. As serum calcium levels increase, PTH levels decrease.⁵ FGF-23 generally acts in opposition to PTH by lowering phosphate and vitamin D levels and by inhibiting PTH secretion itself.^4,5

Calcium in the serum exists in one of three forms: 40 percent is bound to albumin, 15 percent is bound to organic and inorganic anions (e.g., sulfate, phosphate, lactate, citrate), and the remaining 45 percent is ionized, or “free,” calcium.⁷ Total serum calcium concentration is generally a good reflection of total calcium, with exceptions of hypoalbuminemia, acid-base disorders, and chronic kidney disease.^4,7 In the presence of hypoalbuminemia, the true calcium level can be estimated by correcting for albumin using the following equation:⁷

Corrected [Ca] = Measured Total [Ca] + (0.8 (4.0 -[Alb]))

Hypercalcemia may be due to an abnormality in the action or regulation of PTH. For example, hypercalcemia and elevated PTH may co-occur in primary hyperparathyroidism due to impaired PTH negative feedback in the parathyroid gland. Hypercalcemia of malignancy may or may not be related to PTH.⁸ Calcium intake alone is rarely the cause of elevated serum calcium; however, excess vitamin D supplementation can give rise to hypercalcemia.⁹ Renal failure results in a state called tertiary hyperparathyroidism and, consequently, hypercalcemia.⁹

As with elevated serum calcium, hypocalcemia may or may not be related to abnormalities in PTH. Magnesium deficiency is a common cause of minor hypocalcemia; it can occur in the context of high, low, or normal PTH levels, since it can reduce PTH secretion or interfere with PTH function.¹⁰

Serum PTH is the most useful test for distinguishing among etiologies of hypocalcemia.¹¹ Serum magnesium, creatinine, phosphate, vitamin D metabolites (primarily 25-hydroxyvitamin D), and alkaline phosphatase can also provide helpful information.¹¹ An albumin level may be required to identify and correct for hypoalbuminemia.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^12-14

Nutrient imbalances
- Excessive vitamin D
- Excessive vitamin A
- Excessive calcium intake (rare)
Primary hyperparathyroidism
Hyperthyroidism
Adrenal insufficiency
Parenteral nutrition
Milk alkali syndrome
Familial hypocalciuric hypercalcemia
Familial isolated hyperparathyroidism
Acromegaly
Renal failure (tertiary hyperparathyroidism)
Multiple endocrine neoplasia
Pheochromocytoma
Malignancy
Chronic granulomatous disease
Immobility
Drugs
- Thiazide diuretics
- Lithium
- Theophylline

Low in:^10,11

States of low PTH (hypoparathyroidism)
- Hypomagnesemia with reduced PTH secretion
- Post-surgical (e.g., thyroidectomy, parathyroidectomy, radical neck dissection)
- Hungry bone syndrome (post-parathyroidectomy)
- Autoimmune (e.g., autoimmune polyglandular syndrome)
- Infiltration of the parathyroid gland (granulomatous, iron overload, metastases)
- Isolated hypoparathyroidism due to activating antibodies to calcium-sensing receptor
- Radiation-induced destruction of parathyroid glands
- Various genetic disorders
- HIV infection
States of high PTH (secondary hyperparathyroidism in response to hypocalcemia)
- Vitamin D deficiency or resistance
- Parathyroid hormone resistance
- Hypomagnesemia with parathyroid hormone resistance
- Renal disease
- Loss of calcium from the circulation
  - Hyperphosphatemia
  - Tumor lysis
  - Acute pancreatitis
  - Osteoblastic metastases
  - Acute respiratory alkalosis
  - Sepsis or acute severe illness
- Drugs
  - Fluoride poisoning
  - Calcium chelators (EDTA, citrate, phosphate)
  - Inhibitors of bone resorption (e.g., bisphosphonates, calcitonin)
  - Cinacalcet
  - Foscarnet
  - Phenytoin

FUNCTIONAL RANGE INDICATIONS:

High in:¹³

Dehydration (causing mild or transient hypercalcemia)
Excessive vitamin D supplementation
Excessive calcium
Immobility
Drugs (e.g., lithium)

Low in:¹⁵

Dietary factors: caffeine, phosphates (found in soda), high intake of phytate
Vitamin D deficiency
Magnesium deficiency
Low stomach acid
Chronic renal failure
Alcoholism
Medications (bisphosphonates, diuretics, antibiotics, estrogen replacement therapies, insulin, excessive laxative use)

References:

Source: Kresser Institute

Chloride

Marker Name: Serum Chloride

REFERENCE RANGES FOR SERUM CHLORIDE:

Laboratory reference range: 97–108 mmol/L

Functional reference range: 100–106 mmol/L

DESCRIPTION:

Chloride is one of the body’s main electrolytes. The anion is found throughout the body, although the blood contains particularly high levels. Cellular processes keep extracellular concentrations of chlorine higher than intracellular concentrations.¹ With sodium, chloride maintains osmotic pressure and water balance and contributes to serum osmolality.^2,3 Chloride also participates in acid–base homeostasis, acting as a buffer and maintaining the proper electrical gradient across cell membranes.^3-5

Substantial amounts of chloride are consumed in the diet. Chloride is freely absorbed by the gut and freely filtered by the kidney.⁵ Like sodium, most chloride is reabsorbed by the kidney.⁶ As such, the level of chloride in blood usually moves in the same direction and in proportion to sodium.⁴ In pathological conditions, however, such as acid–base disorders, chloride levels can change independently from sodium.⁴ Bicarbonate–chloride transporters and chloride channels in renal tubules change serum levels of chloride in response to acid–base disturbances.⁶

Hyperchloremia, which is an abnormally high concentration of chloride in the blood, may occur in several conditions.⁷ Hyperchloremia often occurs with hypernatremia, but concomitant elevations do not always occur. Excess ingestion (e.g., saltwater drowning) or administration of sodium chloride (e.g., hypertonic saline infusion) can cause hyperchloremia and hypernatremia, as can free water loss or hypotonic dehydration (e.g., diabetes insipidus).⁷ Hypernatremia itself may drive hyperchloremia. Hyperchloremia without hypernatremia is often caused by an acid–base disturbance, usually hyperchloremic metabolic acidosis. Hyperchloremic metabolic acidosis has multiple causes, from early kidney failure to severe diarrhea. Various drugs, including carbonic anhydrase inhibitors, are known to cause hyperchloremic metabolic acidosis.

Hypochloremia is an abnormally low serum chloride level. The etiology of hypochloremia is often grouped into renal and extrarenal causes.⁷ Renal chloride losses may occur from diuretic abuse, interstitial nephritis, chronic renal failure, and adrenal insufficiency. Extrarenal causes of hypochloremia may be caused by total body chloride depletion, dilution, and acid–base abnormalities. Chloride may be depleted by inadequate intake or excessive losses. Serum chloride is diluted by a relative increase in other substances, such as free water. Dilutional causes of hypochloremia include states such as nephrosis, syndrome of inappropriate antidiuretic hormone (SIADH), and pathological polydipsia (excess water consumption). Metabolic acidosis can result in decreased serum chloride, as can compensated respiratory acidosis.

Serum chloride is virtually always measured along with other components of the basic metabolic panel or comprehensive metabolic panel.⁸ Chloride may also be measured in the urine or on the arm, as part of a chloride sweat test.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^2,10

Dehydration
Kidney disease
- Early renal failure
- Interstitial renal disease
- Nephrotic syndrome
- Renal tubular acidosis
Acid–base disturbance
- Metabolic acidosis
- Bicarbonate loss (e.g., small bowel diarrhea)
- Hypernatremia
- Respiratory alkalosis
Hormonal conditions
- Diabetes insipidus
- Mineralocorticoid deficiency
- Hyperparathyroidism
Saltwater ingestion
Hypertonic saline administration
Drugs
- Acetazolamide
- Ammonium chloride
- Androgens
- Arginine or lysine hydrochloride
- Bromine intoxication
- Estrogens
- Hydrochlorothiazide
- Iodine intoxication
- Salicylate intoxication

Low in:^2,¹²

Inadequate NaCl intake
Acid–base abnormalities
- Compensated respiratory acidosis
- Metabolic alkalosis (e.g., vomiting, nasogastric suctioning)
Hormonal conditions
- Adrenal insufficiency
- Hypothyroidism
- Syndrome of inappropriate antidiuretic hormone (SIADH)
Congestive heart failure
Liver cirrhosis
Nephrotic syndrome
Interstitial nephritis
Small bowel fistulas
Hyperglycemia (early)
Pathological polydipsia
Drugs
- Barbiturates
- Chlorpropamide
- Clofibrate
- Diuretic abuse
- Morphine
- Nicotine
- Tricyclics

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

Cholesterol, total

Marker Name: Cholesterol, Total

REFERENCE RANGES FOR TOTAL CHOLESTEROL:

Laboratory reference range:
Male and female: 100–199 mg/dL

Functional reference ranges:
Male: 150–220 mg/dL
Female: 150–230 mg/dL

DESCRIPTION:

Cholesterol is the major lipid in the circulation and is a prominent component of cell membranes throughout the body. Cholesterol provides structural integrity to the phospholipid bilayer within cell membranes and increases cell membrane permeability.¹ Cholesterol is also the structural precursor to various steroid molecules including bile acids, vitamin D, cortisol, corticosteroid, aldosterone, and sex steroids.²

As a lipid, cholesterol is insoluble in water, and, by extension, insoluble in plasma.³ Instead, cholesterol can circulate in the bloodstream by attaching to lipoproteins. The five major lipoproteins in plasma are chylomicrons, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), intermediate-density lipoproteins, and high-density lipoproteins (HDL).³ LDL is the major carrier of cholesterol, and VLDL is the major carrier of triglycerides.³ HDL also carries cholesterol.

Cholesterol may be generated and transported through three major pathways: the exogenous pathway, the endogenous pathway, and the reverse cholesterol transport pathway.⁴ In the exogenous pathway of lipid metabolism, dietary cholesterol and fatty acids are absorbed from the gastrointestinal tract and cholesterol is esterified.⁵ Triglycerides and cholesterol combine to form chylomicrons, which enter the circulation and travel throughout the body. Remnants of these chylomicrons form HDL.

In the endogenous pathway, VLDL is created in the liver from triglycerides and cholesterol esters. VLDL undergoes several changes, ultimately being incorporated into LDL. LDL, which primarily contains cholesterol esters, is internalized in the liver and other tissues. LDL in the liver is converted into bile acids and secreted into the intestines. LDL in other tissues may be used as a steroid precursor molecule, used in cell membrane synthesis, or stored for future use.⁵

The reverse cholesterol transport pathway removes cholesterol from the tissues and returns it to the liver.⁴ HDL is the primary lipoprotein in this pathway. Mature HDL is formed from nascent HDL particles that have been secreted by the liver and intestine.⁴ During this maturation process, known as the HDL cycle, maturing HDL particles attract free cholesterol and cholesterol from cell membranes into the growing HDL particle.⁶

Total cholesterol is measured directly from serum samples, as are HDL and triglycerides.³ LDL cholesterol is determined by mathematical calculation of measured cholesterol. While many clinicians still insist on fasting determination of total cholesterol, studies indicate that differences between fasting and non-fasting total cholesterol values are negligible.⁷

An abnormally high total cholesterol level in the blood is called hypercholesterolemia.⁸ Since total cholesterol includes HDL cholesterol, LDL cholesterol, and other lipids, abnormally high levels of total cholesterol may also be called hyperlipidemia. Strictly speaking, however, hypercholesterolemia is not precisely synonymous with hyperlipidemia, since hyperlipidemia also describes abnormally elevated triglyceride levels, and triglycerides are not a form of cholesterol. Hypercholesterolemia may be the result of a primary or secondary disorder. Primary hypercholesterolemia is due to a heritable condition such as familial hypercholesterolemia or polygenic hypercholesterolemia.⁹ While von Gierke disease is heritable, it is considered a secondary cause of hypercholesterolemia. Secondary causes of hypercholesterolemia may be due to endocrine disturbances, such as diabetes or hypothyroidism; diseases of the kidney or liver; the effect of various stressors, such as cigarette smoking; or the effect of various drugs.¹⁰

Hypocholesterolemia is the name given to abnormally low circulating levels of total cholesterol.¹¹As with hyperlipidemia, hypolipidemia and hypocholesterolemia are used interchangeably, although this is imprecise.¹² The causes of hypocholesterolemia can also be categorized as primary and secondary. Abetalipoproteinemia and hypobetalipoproteinemia are the most common primary causes of hypocholesterolemia.¹³ Malnutrition and malabsorption are unfortunately common causes of hypocholesterolemia, although abnormally low levels of cholesterol may occur in chronic inflammatory diseases and chronic liver diseases, which are also common. Blood disorders such as anemia, sickle cell disease, and hematologic malignancy may also reduce circulating levels of cholesterol. Supratherapeutic doses of statins may lead to abnormally low levels of circulating cholesterol.

Total cholesterol is measured as part of the standard serum lipid profile. The serum lipid profile includes total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. This report may also provide calculated estimates of VLDL cholesterol, non-HDL cholesterol, and the cholesterol/HDL ratio.¹⁴

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS: High in:^9,10,15,16

Primary disorders of cholesterol metabolism
- Familial hypercholesterolemia
- Familial combined hypercholesterolemia
- Familial hyperapobetalipoproteinemia
- Polygenic hypercholesterolemia
Diabetes mellitus
Hypothyroidism
Obesity
Cigarette smoking
Excessive alcohol consumption
Anorexia nervosa
Nephrotic syndrome
Renal failure
Obstructive liver disease
Hepatitis
Acute intermittent porphyria
Systemic lupus erythematosus
Von Gierke disease
Drugs
- Adrenal steroids
- Beta-blockers
- Isotretinoin
- Thiazides
- Anticonvulsants
- Protease inhibitors
- Oral estrogens

Low in:^11,12,17

Primary disorders of cholesterol metabolism
- Abetalipoproteinemia
- Hypobetalipoproteinemia
- Chylomicron retention disease
Anemia
Chronic inflammation
Infection (acute or chronic)
Hyperthyroidism
Chronic liver disease
Sickle cell disease
Malabsorption and undernutrition (e.g., critical illness)
Gaucher type I disease
Malignancy
Drugs
- Statins

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications
Poor thyroid function
Intestinal permeability
Chronic infections
Heavy metal toxicity (and possibly presence of other toxins such as mold)

Low in:

Same as conventional indications

References:

Source: Kresser Institute

CO2 (Carbon Dioxide)

Marker Name: CO₂ (Carbon Dioxide)

REFERENCE RANGES FOR CO2:

Laboratory reference range: 18–29 mmol/L

Functional reference range: 25–30 mmol/L

DESCRIPTION:

Carbon dioxide (CO₂) is the waste product of cellular respiration, either aerobic respiration or fermentation. Chemoreceptors in the carotid bodies and aortic bodies and on the ventral lateral surface of the medulla oblongata sense carbon dioxide.¹ The relative level of carbon dioxide detected by these chemoreceptors can influence respiration rate.¹ A molecule closely related to carbon dioxide, bicarbonate (HCO₃), is an important buffer in blood. Physiologic mechanisms alter the function of the lungs and the kidneys to tightly regulate pH in the blood through changes in carbon dioxide and bicarbonate levels.²

The major buffer system in blood comprises bicarbonate and carbonic acid. In other words, hydrogen ion concentration (pH) in the blood may be affected by changes in circulating bicarbonate levels or carbonic acid levels.² Carbonic acid maintains an equilibrium with carbon dioxide and water. Thus, increases or decreases in carbon dioxide levels, as may occur through decreased or increased respiration, respectively, can drive levels of carbonic acid up or down. Carbonic acid is also converted into bicarbonate and hydronium ions. In the kidneys and lungs, the enzyme carbonic anhydrase catalyzes this reaction.³

functional-biomarker-co2_kll-google-docs-2016-10-09-18-08-01

An elevated partial pressure of carbon dioxide in arterial blood is called hypercapnia. An elevation in venous blood CO₂ is not necessarily hypercapnia, since elevated venous CO₂ could correspond to either alkalosis or acidosis. Venous bicarbonate is a surrogate measure of CO₂.²Thus, an elevated bicarbonate level in the blood suggests an acid-base disturbance of some sort, either a metabolic alkalosis or a compensatory respiratory acidosis.

CO₂ levels in blood may be abnormally high when the lungs cannot exhale sufficient amounts of carbon dioxide produced by metabolically active tissue. Examples include chronic obstructive pulmonary disease (COPD) and severe asthma. Restrictive lung diseases, such as interstitial lung disease and sarcoidosis, may also cause elevated CO₂ levels. Extensive vomiting is a common cause of metabolic alkalosis and accompanying elevations in blood CO₂ levels.

An abnormally low carbon dioxide level in the venous blood may be caused by metabolic acidosis or respiratory alkalosis. Metabolic acidosis usually involves a problem with the kidneys, such as renal tubular acidosis, or some acidification of the blood as may be caused by drugs or intoxicants.² The chief concern of respiratory alkalosis is hyperventilation, which can be related to a medical or mental health condition (e.g., panic disorder, generalized anxiety disorder).

CO₂ is measured in venous blood along with the other components of the basic metabolic panel or complete metabolic panel. It is not possible to accurately diagnose an acid-base disturbance from an isolated total CO₂ measurement.² An acid-base disturbance can be determined if one has knowledge of pH, partial pressure of carbon dioxide (PaCO₂), total CO₂, sodium, and chloride levels.² Sodium and chloride are used to determine the anion gap. The causes of acidosis are different depending on whether the anion gap is normal or increased.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^2,4,5

Obstructive airway disease (e.g., COPD, severe asthma)
Restrictive airway disease (e.g., interstitial lung disease, sarcoidosis)
Metabolic alkalosis
- Chronic vomiting
- Conn syndrome
- Hyperaldosteronism
- Cushing syndrome
- Hypokalemia
- Volume contraction
- Diuretics
- Excessive licorice ingestion

Low in:^2,4,5

Respiratory alkalosis (e.g., hyperventilation)
Metabolic acidosis
- Kidney failure
- Renal tubular acidosis (Types I, II, IV)
- Ketoacidosis
- Lactic acidosis
- Protracted diarrhea
- Addison disease
Drugs and toxins
- Ethylene glycol poisoning
- Methanol poisoning
- Alcohol intoxication
- Salicylate intoxication (e.g., aspirin overdose)
- Paraldehyde
- Acetazolamide

FUNCTIONAL RANGE INDICATIONS:

High in:

Emphysema
Diuretic use
Aldosteronism
Hyperemesis

Low in:

Functional dysglycemia (check other markers of dysglycemia)
Salicylate and diuretic use
Fasting or malnutrition

References:

Source: Kresser Institute

Copper

Marker Name: Copper

REFERENCE RANGES FOR SERUM COPPER CONCENTRATION:

Laboratory reference range: 72–166 µg/dL

Functional reference range: 81–157 µg/dL

DESCRIPTION:

Copper is an essential trace element for metalloenzymes involved in cellular respiration, neurotransmitter synthesis, decomposition of superoxides, collagen cross-linking, bone formation, production of melatonin and melanin, and thrombosis.^1,2 The copper-containing protein ceruloplasmin transports copper from the liver to peripheral tissues, but it also acts as an acute phase reactant.² Copper is present in all tissues but is particularly concentrated in the liver and brain.^3-5

Humans absorb approximately 1 mg of copper in the diet, while secreting and reabsorbing between 4 and 5 mg of copper in the digestive tract, each day.⁶ Copper is absorbed in the stomach and proximal small intestine.⁷ At low levels of copper intake, energy-requiring (i.e., “active”) transporters shuttle copper across the wall of the gastrointestinal tract.^1,7 When copper intake is high, the mineral can passively diffuse into the portal circulation. Once copper is absorbed, it is carried by albumin and amino acids to the liver.^1,8

Once copper enters the liver, it has one of three fates: it is stored in the liver bound to the protein metallothionein, it enters the bloodstream bound mainly to the protein ceruloplasmin, or it is excreted in the bile.⁶ Excretion of copper into the gastrointestinal tract is one of the main ways in which total body copper is regulated.^9,10

An elevated serum copper level (hypercupremia) may be caused by a number of diseases and disorders, most notably Wilson disease, but also hyperthyroidism, hemochromatosis, primary biliary cirrhosis, and primary sclerosing cholangitis.¹¹ Wilson disease is a rare genetic condition in which copper is not effectively incorporated into ceruloplasmin, nor is it properly excreted from the liver into the bile.¹² As an acute phase reactant, copper levels can be transiently elevated subsequent to infection, trauma, infarction, inflammatory arthritis, and certain forms of cancer.^2,13 A mild elevation of copper is normal during pregnancy, and serum copper levels may exceed three times the upper limit of normal in the third trimester.¹³

Conditions that cause decreased absorption of copper such as bariatric surgery or inflammatory bowel disease can also cause copper deficiency. In fact, gastric surgery is the most common cause of acquired copper deficiency.¹⁴ Menkes disease is a rare genetic disease that disrupts the transport proteins that mediate copper uptake from the intestine, thus reducing copper absorption.¹ Excessive consumption of zinc or iron can interfere with copper homeostasis and lower copper levels in the serum.¹⁵ Since copper is bound to proteins in the portal and systemic vasculature, disorders that diminish carrier protein levels will also diminish serum copper levels (e.g., nephrotic syndrome, protein malnutrition, aceruloplasminemia, etc.).^14,16,17

To determine the etiology of abnormal serum copper, it is useful to evaluate related markers such as ceruloplasmin, iron, and zinc.¹ Care should be taken to distinguish between copper and iron deficiency, which may present similarly.¹⁹ Since these nutrients compete for absorption, supplementation with iron could exacerbate copper deficiency, and vice versa.¹

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^{1,11-13,20,21}

Normal pregnancy
Excessive copper intake
Hyperthyroidism
Hemochromatosis
Wilson disease
Ceruloplasmin (acute phase reactant) elevation
- Infarction
- Coronary artery disease
- Infection
- Inflammation
- Neoplastic disease (e.g., leukemia)
- Trauma
- Renal failure
Primary biliary cirrhosis
Primary sclerosing cholangitis
Drugs
- Oral contraceptives
- Estrogens
- Carbamazepine
- Phenobarbital

Low in:^1,15-18,20

Menkes disease
Nutrient imbalances
- Excessive zinc ingestion
- Excessive iron ingestion
Gastrointestinal malabsorption
- Post-gastrectomy
- Post-gastric bypass surgery
- Celiac disease
- Inflammatory bowel disease
- Chronic diarrhea
- Cystic fibrosis
Hypoproteinemia
- Malnutrition
- Nephrotic syndrome
Chronic dialysis (hemodialysis, peritoneal dialysis)
Prolonged total parenteral nutrition
Aceruloplasminemia
Drugs
- Clioquinol
- Tetrathiomolybdate
- Corticosteroids

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

Creatinine

Marker Name: Creatinine

REFERENCE RANGES FOR CREATININE:

Laboratory reference range:
Male and female: 0.76–1.27 mg/dL

Functional reference range:
Male: 0.85–1.1 mg/dL
Female: 0.7 – 1.0 mg/dL

DESCRIPTION:

Creatinine is a soluble waste product of muscle catabolism. While creatinine has no known physiological action, measurement of creatinine in the blood and urine is a useful means of assessing kidney function. Since creatinine is formed at a relatively constant rate and is almost completely filtered by the kidneys, levels of the molecule in blood provide a reasonable estimate of glomerular filtration rate (GFR).¹

Adenosine triphosphate (ATP) is an important carrier of cellular energy in all human cells, but it is especially important in skeletal muscle cells. ATP utilization can change dramatically between muscle fibers at rest and during active contraction.² The creatine kinase enzyme in muscle fibers can use creatine phosphate to phosphorylate adenosine diphosphate (ADP), forming ATP.³ The eventual waste product is creatinine, which can be formed from either creatine or creatine phosphate.

Approximately 98 percent of endogenous creatinine comes from skeletal muscle.⁴ Creatinine is both created and excreted at a relatively constant rate under normal conditions. The urinary creatinine excretion rate is proportional to muscle mass; roughly one gram of creatinine is excreted every 24 hours for every 17 to 22 kilograms of muscle.^4,5 Creatinine is freely filtered in the kidneys by the glomerulus and is not reabsorbed, secreted, or metabolized by the nephron.⁶As such, the serum creatinine concentration can be used to approximate the glomerular filtration rate—serum levels of creatinine rise as glomerular filtration rate decreases.⁷ GFR is even more precisely estimated by combining information about serum creatinine level, age, gender, and ethnicity of the patient.⁸

An elevated level of creatinine in the blood is called hypercreatininemia, though this term is rarely used clinically. Transient elevations in creatinine may be due to hypovolemia or dehydration, which occurs in the context of an elevated blood urea nitrogen (BUN) (e.g., prerenal azotemia).¹Short-term elevations in serum creatinine may be due to an acute kidney issue such as acute interstitial nephritis, obstructive nephropathy, or acute tubular necrosis.⁹ Long-term elevations usually reflect chronic kidney disease, such as nephrosclerosis.⁹ Not all elevations in blood creatinine levels indicate problems with the kidneys. Rhabdomyolysis, for example, may increase creatinine levels in the blood by increasing release of creatinine from ruptured muscle cells. However, rhabdomyolysis can cause acute renal failure from increased urinary myoglobin.¹⁰Certain medications may interfere with laboratory methods used to measure serum creatinine. Cefoxitin and flucytosine can spuriously increase serum creatinine levels if the laboratory uses the alkaline picrate method.¹¹ Moreover, acetoacetate produced during diabetic ketoacidosis can also erroneously increase creatinine levels measured by this method.¹¹

Abnormally low levels of serum creatinine could theoretically be due to abnormally increased glomerular filtration rate; however, this is not a clinically important issue in practical terms.¹² Low creatinine levels generally reflect reduced muscle mass and, by extension, decreased body-wide creatinine production by skeletal muscle.¹² Severe protein malnutrition and advanced liver disease may decrease blood creatinine levels.

Creatinine is routinely measured as part of the basic metabolic panel or complete metabolic panel.¹ Creatinine may also be measured as part of the creatinine clearance test, which will also include a measurement of creatinine in the urine.¹³ The gold standard creatinine clearance test is usually determined from a 24-hour urine collection.¹⁴

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^9,11,12,15

Increased muscle mass
Dehydration/hypovolemia
Kidney diseases
- Nephrosclerosis
- Interstitial nephritis (acute and chronic)
- Prerenal azotemia
- Obstructive nephropathy
- Renal vascular disease
- Glomerulonephritis (acute or chronic)
- Pyelonephritis
- Acute tubular necrosis
- Interstitial nephritis
- End-stage renal disease
Ureteral obstruction
Rhabdomyolysis
Congestive heart failure
Hepatorenal syndrome
Thrombotic thrombocytopenic purpura
Shock
Drugs
- Trimethoprim
- Cimetidine
- Cobicistat

Low in:^12,16-18

Low muscle mass
Severe protein malnutrition
Advanced liver disease
Guillain-Barré syndrome

FUNCTIONAL RANGE INDICATIONS:

High in:

Strenuous exercise (especially weight lifting; creatinine is released during muscle breakdown)
Mild dehydration (BUN, hemoglobin, hematocrit, and red blood cells may also be elevated)
Enlarged prostate
Pregnancy
Many other pathological conditions involving muscle catabolism

Low in:

Decreased muscle mass (observed in the elderly and/or those with chronic illness)
Inadequate dietary protein intake (observed in vegetarians and vegans)
Impaired protein digestion
Impaired liver function (albumin and aminotransferases will also often be abnormal)

References:

Source: Kresser Institute

CRP-hs

Marker Name: CRP-hs

REFERENCE RANGES FOR CRP-hs:

Laboratory reference range: 0–3 mg/L

Functional reference range: 0–1 mg/L

DESCRIPTION:

CRP-hs stands for high sensitivity C-reactive protein. C-reactive protein is an acute phase reactant, which is the name given to proteins that enter the bloodstream in large numbers in response to inflammation and tissue injury.¹ C-reactive protein elevations following pneumococcal pneumonia was the first instance of an acute phase reactant described in man.² C-reactive protein can participate in several stages of inflammation, and it has both pro- and anti-inflammatory functions.³ One of the major functions of C-reactive protein is to find a phosphocholine, which is present on foreign pathogens and damaged cells.⁴ Thus, C-reactive protein improves recognition and elimination of pathogens and necrotic and apoptotic cells.³ C-reactive protein can also activate monocytes and the complement system, which is a key component of the innate (non-adaptable) immune system. Interaction with complement proteins and monocytes may exacerbate tissue damage in pro-inflammatory settings.^3,5 C-reactive protein may also be an early predictor of cardiovascular disease and occult atherosclerosis, though this is unsettled in the literature.^6-8

Hepatocytes are the main source of acute phase reactants, including C-reactive protein.³Interleukin-6 (IL-6) is the main driver of C-reactive protein, though IL-1 beta, tumor necrosis factor-alpha, and interferon gamma also stimulate production of the protein.⁹ These cytokines may have inhibitory or synergistic effects on C-reactive protein and other acute phase reactants depending on the specific inflammatory state and the local milieu.¹ The system is regulated so tightly that virtually any form of tissue injury, infection, inflammation, or non-physiological stressors can cause CRP to be synthesized and released.^8,10 Levels of C-reactive protein can vary in the blood by a thousand-fold or more.^1,11 The half-life of C-reactive protein is approximately 19 hours, and the sole determinant of C-reactive protein concentration is the synthesis rate.^12,13 CRP is cleared from the plasma and catabolized by hepatocytes.¹⁴

C-reactive protein is a biological entity, and high sensitivity describes the sensitivity with which the assay measures the biological entity. There is nothing fundamentally different between the C-reactive protein measured with traditional and high sensitivity assay methods; the high sensitivity C-reactive protein is simply intended to measure relatively low levels of normal C-reactive protein.^3,8

CRP-hs is, indeed, a highly sensitive assay for C-reactive protein, and concentrations in the blood of 0.3 mg/dL and higher may indicate some form of inflammation. In general, values greater than 1 mg/dL are considered a sign of clinically significant inflammation.¹⁵ CRP values between 0.3 and 1 mg/dL may indicate cigarette smoking, hypertension, obesity, or another relatively minor inflammation.³ Infection often causes markedly elevated levels of CRP ( i.e., > 50 mg/dL.)¹⁶ Even though C-reactive protein is an “acute” phase reactant, elevated levels of C-reactive protein can be found in both acute and chronic inflammatory states.³ Likewise, elevated C-reactive protein may be found after trauma or infarction and during the course of certain cancers. Virtually any stressor can raise C-reactive protein levels.⁸ CRP is a sensitive indicator of inflammation but almost completely nonspecific.³

The “normal” level of CRP is unknown, such that any detectable CRP may reflect a clinical abnormality, however minor.³ Therefore, no clinical state exists in which CRP is considered abnormally low.

When C-reactive protein is used to assess inflammation, it may be ordered with erythrocyte sedimentation rate (ESR). The high sensitivity assay for C-reactive protein is often used to calculate cardiovascular risk and is usually measured with other markers, such as a lipid panel and hemoglobin A1c.¹⁷

It is important to note that CRP-hs has high intraindividual variability, meaning levels can vary substantially from reading to reading in a single person with no pathological changes. Therefore, a single measurement of CRP-hs may not reflect an individual’s typical CRP-hs level. Repeat measurements may be required to establish an individual’s true mean CRP-hs concentration.^18-21

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS: High in:^{1,11,12,22,23}

Low in:^1,10,15

Not clinically relevant

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

eGFR

Marker Name: eGFR

REFERENCE RANGES FOR eGFR:

Laboratory reference range: >59 mL/min/1.73

DESCRIPTION:

eGFR stands for estimated glomerular filtration rate. The overall glomerular filtration rate equals the sum of filtration rates from each functioning nephron. The precise measurement of glomerular filtration rate is complex, time-consuming, and impractical to perform in routine clinical practice.¹Moreover, an exact GFR is not needed for most clinical scenarios. Therefore, an approximate glomerular filtration rate is estimated from routine laboratory testing. Levels of creatinine in the blood are the most commonly used method to estimate GFR.¹

Almost all endogenous creatinine comes from skeletal muscle and is produced at a constant rate.² Creatinine is freely filtered by the glomerulus and is not reabsorbed, secreted, or metabolized by the nephron.³ In most circumstances, an increase in serum levels of creatinine reflects a decrease in glomerular filtration rate, and vice versa.⁴

Since the 1970s, clinicians have estimated GFR from serum creatinine using the Cockcroft-Gault equation.⁵

egfr

Because women generally have less lean muscle mass than men, the result of the equation is multiplied by 0.85 when estimating GFR in women. While the Cockcroft-Gault equation was the main means of estimating GFR from serum creatinine, authors of the MDRD study published a revised equation that apparently provides a more accurate estimate.⁶ The mathematics of the MDRD equation are more complex than Cockcroft-Gault, thus it is more convenient to use an online calculator.⁷ In people with chronic kidney disease, a separate equation, called the CKD- EPI, is more accurate.⁸

A more precise but still estimated GFR can be determined by using urinary excretion of inulin. Inulin is physiologically inert, freely filtered at the glomerulus, and not secreted, reabsorbed, or metabolized by the kidney.⁹ As such, it is the ideal molecule for estimating GFR. Unfortunately, inulin is rather expensive and difficult to assay and is rarely used clinically.¹ Urine creatinine clearance is often used as a surrogate, since creatinine nearly fulfills the same criteria.¹⁰ Urinary creatinine times the total volume of urine produced in 24 hours divided by serum creatinine provides a reasonably accurate estimate of GFR.¹¹

Cystatin C is a low-molecular-weight protein that is filtered by the glomerulus but not reabsorbed. While some researchers and clinicians have tried to find ways to use serum cystatin C as a more accurate means to estimate GFR, attempts have been limited, since cystatin C is partially metabolized in the renal tubules.¹

Glomerular filtration rates that exceed normal limits are rarely a clinical problem by themselves. Abnormally high eGFR may represent low muscle mass, since little creatinine is being created by muscle.¹² Protein malnutrition and advanced liver disease may lead to lower creatinine levels, and, by extension, elevated eGFR.

Low eGFR occurs in a wide range of clinical conditions. Reduced glomerular filtration rates are usually caused by conditions that directly or indirectly affect the kidney. The main indirect cause of reduced GFR is poor blood flow to the kidney, whether due to hypovolemia, congestive heart failure, or some other cardiovascular condition. Chronic elevations in eGFR usually reflect primary disease of the kidney. In fact, eGFR plays a key role in staging chronic kidney disease.¹³ The five stages of chronic kidney disease are stratified by progressively increasing ranges of eGFR.

eGFR is now automatically calculated from serum creatinine and presented in the results of each basic metabolic panel or complete metabolic panel.¹ There are usually two results listed, one calculated assuming the patient is African-American and the other assuming the patient is not, since race affects the normal range for GFR.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:¹²

Low muscle mass
Liver failure
Protein malnutrition

Low in:^14-16

Hypovolemia/dehydration
Shock
Chronic kidney disease
- Glomerular (e.g., Goodpasture syndrome)
- Vascular (e.g., hypertensive nephrosclerosis)
- Tubulointerstitial (e.g., urinary tract infection, renal calculi)
- Cystic (e.g., polycystic kidney disease)
- Diabetic (e.g., diabetic nephropathy)
- Transplant (e.g., rejection, anti-rejection drug toxicity)
Acute interstitial nephritis
Acute glomerulonephritis
Prerenal azotemia
Acute tubular necrosis
Metabolic acidosis
Diabetic ketoacidosis
Alcoholic ketoacidosis
Gastrointestinal bleeding
Sickle cell anemia
Rhabdomyolysis
Multiple myeloma

FUNCTIONAL RANGE INDICATIONS:

High in:

No functional range

Low in:

No functional range

References:

Source: Kresser Institute

Eosinophils

Marker Name: Eosinophils

REFERENCE RANGES FOR EOSINOPHILS:

Laboratory reference range:
Relative 0–5%
Absolute 0.0–0.4 x10³/µL

Functional reference range:
Relative 0–3%
Absolute 0.0–0.4 x10³/µL

DESCRIPTION:

Eosinophils are one of the five major types of leukocytes (white blood cells), along with neutrophils, basophils, lymphocytes, and monocytes. Eosinophils are granulocytes, along with basophils and neutrophils.¹ Eosinophils are drawn to areas of inflammation through chemotaxis, at which point they activate and release substances contained within their granules. This degranulation adds substantially to the inflammatory response. These white blood cells secrete enzymes, growth factors, lipid mediators, and cytokines at sites of inflammation or infection, depending on the local milieu.² Eosinophils also release a number of reactive oxygen species and granule proteins that can destroy microbes.³ Unfortunately, these substances can also damage local tissues and cause excessive inflammation.^3,4

Development and maturation of eosinophils takes place within the bone marrow.² Upon maturation, eosinophils are released into the circulation; however, eosinophil numbers are relatively low in the vasculature. They are usually found in tissues surrounding the gut or occasionally in the lung.⁵ Eosinophils in the tissues can outnumber blood eosinophils by several hundred times.⁶ Eosinophils live for approximately eight to 18 hours within the circulation or between three to four days in tissues.⁷ At the end of their lifecycle, eosinophils undergo apoptosis. However, pro-inflammatory markers within tissues may delay programmed cell death and prolong the eosinophil’s lifespan.⁵

The absolute eosinophil count may be determined by multiplying the total WBC count by the percentage of eosinophils.² However, this approach can be problematic due to wide variations in absolute neutrophil counts among different ethnic groups.⁸ Moreover, eosinophil counts can vary within the same person at different times of the day or across different days.⁹ Importantly, eosinophil counts using peripheral blood may not correlate to tissue levels. While absolute eosinophil counts greater than 1,500 per microliter strongly suggest risk to organs and tissues, tissue damage may occur at lower blood eosinophil counts.¹⁰

An abnormally high eosinophil count in the blood is called eosinophilia. The causes of eosinophilia may be grouped into seven broad categories: infection, allergy, neoplasm, lung disorders, skin disorders, and miscellaneous conditions. Eosinophilia is most often associated with helminth parasite infections or infestations, though specific bacterial, fungal, and viral infections may also raise eosinophil counts in the blood.¹¹ Skin and lung disorders associated with eosinophilia are usually related to atopy or allergic hypersensitivity reactions. Hypersensitivity to virtually any prescription medication, nonprescription medication, dietary supplement, or herbal remedy can cause eosinophilia.¹² Very high eosinophil counts may denote a hypereosinophilic syndrome.¹³

Eosinopenia, or an abnormally low eosinophil count in the blood, is rather uncommon. It occurs most commonly in the context of an elevated neutrophil count during an acute infection.^14,15 Acute inflammation may also cause transient eosinopenia as eosinophils rapidly migrate from the blood to tissues.¹⁴ Corticosteroids, adrenergic drugs, and certain chemotherapeutics may decrease eosinophil counts. Erythropoietin deficiency, which is rare, may cause eosinopenia.^15,16

An eosinophil count is reported within the results of a complete blood count (CBC). In most cases, a standard CBC order includes an automated differential, which provides counts of the five main types of leukocytes, including eosinophils.¹⁷ A manual differential or peripheral blood smear may be ordered separately to quantify eosinophils along with other white blood cells. This test is performed manually by clinical staff.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^10,12,13

Infections
- Parasitic (most common)
- Bacterial
- Fungal
- Viral
Allergy and atopy
- Bronchial asthma
- Hay fever
- Urticaria
Drug hypersensitivity
Skin disorders
- Psoriasis
- Pemphigus
- Dermatitis herpetiformis
- Urticaria
- Angioedema
- Atopic dermatitis
Lung diseases
- Eosinophilic pneumonia
- Loeffler’s syndrome
- Churg–Strauss syndrome
- Tropical pulmonary eosinophilia
Hypereosinophilic syndrome
Systemic mastocytosis
Hypoadrenalism
Cholesterol embolization
Radiation exposure
Neoplastic
- Hodgkin lymphoma
- Chronic eosinophilic leukemia
- Lymphocytic leukemia
- Myelogenous leukemia
- Adenocarcinoma of various solid organs

Low in:^14-16

Acute infection (usually with concurrent neutrophilia)
Acute inflammation
Acute stress
Erythropoietin deficiency
Drugs
- Corticosteroids
- Adrenergic agents
- Chemotherapy

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

Ferritin

Marker Name: Ferritin

REFERENCE RANGES FOR SERUM FERRITIN:

Laboratory reference ranges:
Male: 30–400 ng/mL
Female: 15–150 ng/mL

Functional reference ranges:
Male: 30–200 ng/mL
Female: 30–100 ng/mL

DESCRIPTION:

Ferritin is the storage protein for iron. Each large ferritin protein has a spherical cavity that can hold up to 4,500 iron atoms as a crystalline solid.^1,2Ferritin stores and slowly releases iron in a non-toxic and controlled way, which helps protect against iron deficiency and iron overload.²Much of the iron in ferritin can be readily released for metabolic use. For example, in red cell precursors, ferritin plays a key role in providing iron for heme synthesis.¹

Biosynthesis of ferritin is partially controlled by the concentration of iron in the cell. Specifically, iron regulatory proteins 1 and 2 (IRP1, IRP2) sense cytoplasmic iron concentration and regulate translation of ferritin mRNA accordingly.^3,4 Iron is stored in its ferric form (Fe³⁺) and released in its ferrous form (Fe²⁺), but mechanistic details of iron uptake and release from ferritin remain unclear.⁴

Ferritin is also an acute-phase reactant that may help protect against oxidative stress and inflammation.¹ A wide variety of acute and chronic inflammatory conditions involve the production of cytokines that upregulate ferritin synthesis.⁵ Endotoxin, a toxic molecule found in gram-negative bacteria, stimulates a particularly strong increase in ferritin production.⁶

Ferritin is found in most tissues; the vast majority is inside cells as an iron storage protein, and a small amount is in plasma as an iron carrier.⁷ Circulating ferritin is most often in the form of apoferritin, which does not contain iron.¹ A separate form of ferritin, m-ferritin, is found in mitochondria and likely protects against oxidative damage.¹

In an otherwise healthy individual, serum ferritin is an excellent indirect marker of total body iron stores. This is no longer true in states of inflammation, as ferritin plays the dual roles of iron storage protein and acute-phase reactant. Therefore, normal serum ferritin may either indicate a healthy iron level or a state of simultaneous iron deficiency and inflammation. High ferritin may indicate iron overload, inflammation, or both. Many conditions involving blood loss are also inflammatory, in which case ferritin may be low, normal, or high. As a general rule, inflammation elevates ferritin concentration approximately threefold.⁸ Conditions causing relatively consistent ferritin changes are reviewed here.

High serum ferritin concentration (hyperferritinemia) can be caused by conditions of iron overload or inflammation (acute or chronic). A list of specific conditions that can cause hyperferritinemia is provided below.

Low serum ferritin concentration (hypoferritinemia) is exclusively caused by iron deficiency, which can in turn be caused by various conditions and drugs listed below.

For a full evaluation of iron status, serum ferritin should be considered with related markers, including a complete blood count (CBC), serum iron, TIBC, UIBC, and iron saturation. If etiology of high ferritin is unclear from patient history, tests for relevant genetic mutations and other acute-phase reactants, such as C-reactive protein (CRP); erythrocyte sedimentation rate (ESR); and plasma fibrinogen can help distinguish between iron overload and underlying inflammation.^8,9

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^9,10

Low in:^8,22

Pregnancy
- Direct iron loss to fetus during pregnancy
- Blood loss during delivery
- Lactation
Inadequate dietary intake
- Diet low in meat
Gastrointestinal malabsorption
- Achlorhydria or hypochlorhydria
- Gastritis (e.g., atrophic gastritis, autoimmune metaplastic atrophic gastritis, Helicobacter pylori gastritis)²³
- Celiac disease²⁴
- Post-gastric bypass surgery²⁵
Blood loss (depending on level of associated inflammation, ferritin can also be high or normal in these conditions)²⁶
- Obvious bleeding (e.g., external wound, melena, hematemesis, hemoptysis, gross hematuria)
- Heavy menstrual bleeding
- Gastrointestinal bleeding (e.g., hemorrhoids, fissures)
- Repeated blood donations
- Intraluminal neoplasms (e.g., malignancies of the gastrointestinal tract)^18,27
- Lasthénie de Ferjol syndrome
Treatment with erythropoietin (EPO)²⁸
Drugs²⁹
- Proton pump inhibitors
- H₂ receptor blockers
- Certain antibiotics (e.g., quinolones, tetracycline)
- Excessive calcium supplementation

FUNCTIONAL RANGE INDICATIONS:

High in:

Functional iron overload
Functional liver problems
Insulin resistance and metabolic dysfunction

Low in:

Functional iron deficiency
Malabsorption
Blood loss
Pregnancy

References:

Source: Kresser Institute

Folate

Marker Name: Folate

REFERENCE RANGES FOR SERUM FOLATE:

Laboratory reference range: > 3 μg/L

Functional range: > 8 μg/L

DESCRIPTION:

Folate is a coenzyme that participates in single-carbon transfers during nucleic acid and amino acid metabolism.¹ Specifically, folate is a cofactor in purine biosynthesis, thymidylate biosynthesis, and synthesis of methionine from homocysteine.² Folate also generates the single-carbon molecule formate, which participates in various one-carbon reactions. Folate converts various amino acids (e.g., histidine) to glutamate.¹ Taken together, folate is a critical cofactor in the synthesis of DNA and protein metabolism.

Folate is sometimes used interchangeably with the term folic acid; however, this is not technically accurate. Folic acid is the most oxidized form of folate and is often found in supplements, but it occurs rarely in food.¹ Folate is a broad term that applies to many molecules that have folate-like activity.

Humans derive folate from dietary sources. Naturally occurring “food” folates have up to six additional glutamate molecules in a peptide polymer linkage.³ These food folates are hydrolyzed to form monoglutamate prior to absorption in the gut.¹ The resulting monoglutamate is further reduced to form either methyl- or formyl-tetrahydrofolate, though the main form of folate in the plasma is 5-methyltetrahydrofolate.⁴ Folate is freely filtered by the glomerulus, but most is reabsorbed in the proximal tubule of the nephron.¹ Whole-body folate turnover occurs via catabolism into cleavage products.¹

Enzymatic processes that use folate are intimately related to those that use vitamin B12. In fact, vitamin B12 deficiency can be masked by sufficient levels of folate. In vitamin B12 deficiency, folate levels tend to accumulate in the serum and decrease the enzymatic activity of vitamin B12-dependent methyltransferases.⁵ One way to distinguish between folate and vitamin B12 deficiency is to simultaneously assay serum concentrations of homocysteine and methylmalonic acid. Serum homocysteine and methylmalonic acid levels will be elevated in vitamin B12 deficiency, whereas folate deficiency will only increase homocysteine levels in the serum, not methylmalonic acid levels.⁶

High serum folate levels usually represent excessive dietary consumption, usually through consumption of fortified foods and supplements. There are no known negative clinical consequences of an abnormally high folate level, and maximum daily intake is unlikely to cause adverse events.^1,4,7 On the other hand, an abnormally high serum folate level may indicate the presence of disease, such as vitamin B12 deficiency or pernicious anemia. In the setting of vitamin B12 deficiency, for example, abnormally high serum folate can worsen anemia and cognitive disturbances in some individuals.⁸

A low serum folate level is usually due to decreased intake or absorption of the vitamin.⁹Decreased intake usually results from overcooking food, which can destroy folate, or in the context of general malnutrition. Normal pregnancy and lactation increase metabolic demands on the mother, which can lead to lower folate levels when intake isn’t properly increased. Diseases affecting the intestines, such as celiac sprue and inflammatory bowel disease, can interfere with the absorption of folate. Several genetic conditions may lead to chronically low folate levels; perhaps most notable among these is methylenetetrahydrofolate reductase (MTHFR) deficiency.⁹Methotrexate, trimethoprim, and phenytoin are well known to reduce serum folate levels.

Folate is measured with serum vitamin B12. A workup of folate deficiency may include a serum homocysteine level and a serum methylmalonic acid level.⁶ Serum folate is quite sensitive to recent dietary intake and thus may be inadequate to determine chronic folate deficiency. The folate found within red blood cells, however, provides a better estimate of long-term body folate status.^4,6

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^3,5

Excessive intake
Vitamin B12 deficiency
Pernicious anemia

Low in:^9,10

Normal pregnancy
Normal lactation
Nutritional deficiency
- Poor dietary intake
- Overcooked foods
- Alcohol
- Substance abuse
Malabsorption
- Celiac disease
- Inflammatory bowel disease
- Infiltrative bowel disease
- Short bowel syndrome
Chronic hemolysis
Exfoliative dermatitis
Genetic causes
- Methylenetetrahydrofolate reductase (MTHFR) deficiency
- Hereditary folate malabsorption
- Glutamate formiminotransferase deficiency
- Functional methionine synthase deficiency
Drugs
- Methotrexate
- Trimethoprim
- Phenytoin
- Pyrimethamine
- Alcohol

FUNCTIONAL RANGE INDICATIONS:

High in:

N/A

Low in:

Folate deficiency

References:

Source: Kresser Institute

Free Thyroxine Index

Marker Name: Free Thyroxine Index

REFERENCE RANGE FOR FREE THYROXINE INDEX:

Laboratory reference range: 1.2–4.9

DESCRIPTION:

The free thyroxine index (free T4 index; FTI; T7) is one of the tests used to estimate free thyroxine (T4) hormone levels.¹ Since FTI includes T3 resin uptake in its calculation, FTI can also “correct” or normalize total T4 values by accounting for potential abnormalities in thyroid hormone-binding protein levels in the serum.^1,2

FTI is calculated using the following equation:³

free-thyroxine-index

The FTI relies on two measured values: total T4 and T3 resin uptake. Total T4 is technically a measure of both bound and unbound T4 in the serum. However, approximately 99.98 percent of T4 in the serum is bound, so total T4 is effectively a measure of bound T4 and is unaffected by small differences in free T4 concentrations.¹ The T3 resin uptake test detects and quantifies potential binding protein abnormalities. T3 resin uptake is a complex marker that is directly proportional to the saturation of thyroid hormone molecules on serum-binding proteins.

When thyroxine-binding proteins are present in normal concentrations in the serum, an elevated FTI usually indicates hyperthyroidism, since FTI reflects free T4 levels. In T4 toxicosis, free T4 may be elevated without an associated increase in T3, though TSH will be abnormally low.⁴ This pattern of laboratory findings may also be present in individuals with hyperthyroidism and concurrent non-thyroidal illness, amiodarone-induced thyroid dysfunction, or exogenous estrogen.⁵ Uncommonly, an elevated free T4 (i.e., FTI) may be caused by a TSH-producing pituitary tumor. Increased levels of thyroxine-binding globulin (TBG), such as during a normal pregnancy, will elevate the FTI by increasing T3 resin uptake.³

Conversely, low free T4 levels in the context of normal TBG concentrations in serum usually indicate hypothyroidism. TBG-deficient individuals will also have a lower-than-normal FTI due to decreased T3 resin uptake. There are various reasons someone would be deficient in TBG, but these are usually due to decreased protein synthesis or increased protein excretion by the kidney.

Given that FTI is a calculation of measured values, it can only be determined from measurements of total T4 and T3 resin uptake. When FTI is reported, total T4 measurements are also provided, which is important for interpretation.¹ Clinical laboratories also provide the thyroid hormone-binding ratio or index (THBR or THBI) with FTI results.¹ FTI is also measured with other indices of thyroid function, such as thyroid-stimulating hormone (TSH), total T3, free T3, and reverse T3.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^1,6-8

Pregnancy
Hyperthyroidism
T4 toxicosis
Euthyroid hyperthyroxinemia
TSH-mediated hyperthyroidism
Acute thyroiditis
Familial dysalbuminemic hyperthyroxinemia
Drugs
- Drugs that increase TBG (e.g., estrogens, tamoxifen, opioids)
- Drugs that decrease T4 conversion to T3 (e.g., amiodarone)

Low in:^1,6,9

Hypothyroidism
Chronic thyroiditis
Subacute thyroiditis
Congenital thyroid agenesis, dysgenesis, or defects in hormone synthesis
Nephrosis
Drugs
- Synthetic triiodothyronine treatment
- Drugs that decrease TBG (e.g., anabolic steroids, glucocorticoids)
- Drugs that increase T4 clearance (e.g., phenytoin, carbamazepine, phenobarbital)
- Drugs that inhibit T4 synthesis/release (e.g., thionamides, lithium, perchlorate)

FUNCTIONAL RANGE INDICATIONS:

High in:

No functional range; same as conventional indications

Low in:

No functional range; same as conventional indications

References:

Source: Kresser Institute

GGT

Marker Name: GGT

REFERENCE RANGES FOR GGT:

Laboratory reference range:
Male and female: 0–65 IU/L

Functional reference ranges:¹⁴Male: 0–29 IU/L
Female: 0–21 IU/L

DESCRIPTION:

Gamma-glutamyl transpeptidase (GGT) is an enzyme that transfers a gamma-glutamyl moiety to an amino acid acceptor. It is an enzyme in the gamma-glutamyl cycle, which participates in glutathione drug detoxification and amino acid transport.^1,2 Glutathione is the most abundant substrate for GGT.³

GGT is primarily found in the hepatobiliary tract, kidney, pancreas, and liver.^4,5 The enzyme is also present in the spleen, heart, brain, and seminal vesicles to a lesser extent.⁶ The highest concentration of GGT in the body is in the kidneys, but the enzyme present in serum is primarily produced by the liver.^7,8

Like alkaline phosphatase, GGT levels increase in the blood subsequent to hepatobiliary obstruction.⁵ Unlike alkaline phosphatase, however, GGT is not found in appreciable levels in bone. Therefore, it can be used to clarify the source of increased alkaline phosphatase levels in blood.^4,9 That is, elevated alkaline phosphatase and GGT levels in the serum indicate hepatobiliary disease, while alkaline phosphatase without a corresponding increase in GGT suggests a disease affecting the bone.¹⁰

Certain forms of gammopathy (e.g., type IgM Waldenstrom’s macroglobulinemia) may interfere with the performance of the clinical assay.⁷ GGT is a sensitive test; it is abnormal in virtually all patients with liver disease regardless of cause.³ On the other hand, GGT has poor sensitivity, since it is increased in many conditions.

Increased GGT is believed to result from spillage from cell membranes when the source tissue is damaged (e.g., liver injury subsequent to excessive alcohol intake) or from increased enzyme production (e.g., induction by anticonvulsants).³ The highest levels of serum GGT tend to occur in cases of hepatobiliary obstruction.¹⁰ Anticonvulsants of various drug classes are well known to create serum GGT elevations.¹¹ Drug-induced elevations in GGT are believed to be induced by relative decreases in glutathione levels in the liver. As the liver attempts to detoxify and excrete various drugs, especially anticonvulsants, glutathione needs increase. Interestingly, when glutathione levels are normalized through cysteine supplementation, the offending drugs do not induce a rise in GGT levels.¹²

Abnormally low levels of GGT in the serum are generally not of clinical concern. Protein malnutrition, particularly a deficiency in amino acids that contain sulfur, could lower serum GGT levels, as has been shown experimentally in rodents.¹³ Even under these conditions, however, GGT levels return to normal after protein has been restored.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^3,15

Diabetes
Obesity
Excessive alcohol intake
Smoking
Biliary obstruction
Liver disease
Liver injury
Pancreatitis
Cardiovascular disease (e.g., hypertension, congestive heart failure)
Genetic abnormality (rare)
Drugs
- Phenytoin
- Carbamazepine
- Barbiturates (e.g., phenobarbital)
- NSAIDs
- Statins
- Antibiotics/antifungals
- H₂ histamine receptor antagonists

Low in:³

Low-protein diet
Genetic GGT deficiency (rare)
Drugs
- Clofibrate
- Oral contraceptives

FUNCTIONAL RANGE INDICATIONS:

High in:

Iron overload
Metabolic dysfunction (dysglycemia, insulin resistance, etc.)

Low in:

Same as conventional indications

References:

Source: Kresser Institute

Globulin

Marker Name: Globulin

REFERENCE RANGES FOR GLOBULIN:

Laboratory reference range: 1.5–4.5 g/dL

Functional reference range: 2.4–2.8 g/dL

DESCRIPTION:

In the context of laboratory assessment and biomarkers, globulins are any plasma proteins other than albumin. Globulins make up 40 percent of plasma proteins and include carrier proteins, enzymes, complement, clotting factors, and immunoglobulins.^1-3 Globulins play many different physiological roles in the body according to type. Immunoglobulins and complement play important roles in the adaptive and innate immune systems, for example. With the exception of immunoglobulins, virtually all globulins are synthesized in the liver.⁴

Circulating immunoglobulins (i.e., antibodies), as opposed to membrane-bound immunoglobulins, are primarily produced by activated plasma cells.^5,6 Their production is stimulated by exposure to antigens. After antigen exposure, antibodies are housed in memory B cells, which are long-lived cells that can respond rapidly to future provocations by antigens.⁶ Barring a disease of the immune system, additional antigen exposures result in a short-lived and relatively intense increase in circulating immunoglobulins. Other circulating globulins are held at rather constant levels in the blood under normal conditions, balanced between synthesis and degradation, utilization and excretion.

Serum globulins are usually estimated from other directly measured substances on a liver panel, namely total protein and albumin. Since circulating plasma proteins are either albumin or globulins, serum globulin level is estimated by subtracting albumin from total protein.³ While elevated globulin levels may be apparent from this calculation from measured values, decreased globulin levels may be less apparent, especially when deficiencies in relatively minor globulins exist.

Serum proteins can be further separated by electrophoresis, which separates albumin from globulins. Globulin fractions migrate into four bands on electrophoresis gel: α₁, α₂, β, and γ.^1,3Immunoglobulins tend to migrate to and cluster in the γ band on electrophoresis and, as such, are sometimes referred to as gamma globulins.¹ Elevated immunoglobulin levels can be further characterized by immunoelectrophoresis, establishing if the increase is composed of one immunoglobulin type (i.e., monoclonal) or several types (i.e., polyclonal).³

Elevated globulin levels in the serum generally reflect overproduction. For example, multiple myeloma is a neoplastic proliferation of plasma cells that results in substantial elevations in monoclonal immunoglobulin.⁷ Autoimmune diseases can also increase the level of circulating globulins.² Likewise, acute inflammation can cause a transient increase in serum globulin levels. Hemoconcentration, or a relative lack of intravascular water, can result in relative hyperglobulinemia.

Decreased globulin levels are usually the result of the underproduction of immunoglobulins.² This may be due to genetic abnormality (e.g., X-linked agammaglobulinemia) or hematologic malignancy (chronic lymphocytic leukemia). There is a normal period of hypogammaglobulinemia in neonates within the first six months of life; however severe deficits in gamma globulin levels or prolonged hypogammaglobulinemia is abnormal.⁸

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^4,9,10

Hemoconcentration
- Inadequate water intake
- Excessive diuresis
Acute infection
Acute inflammation
Chronic inflammatory disease
Hematological neoplasm
- Multiple myeloma
- Monoclonal gammopathy of undetermined significance
- Lymphoma
- Leukemia
- Macroglobulinemia (e.g., Waldenstrom macroglobulinemia)

Low in:^4,8,11-16

Hemodilution
- Intravenous fluids
- Advanced congestive heart failure
- Polydipsia
Inflammation
Protein malnutrition
Protein malabsorption
Liver failure
Advanced liver disease
Renal failure
Nephrotic syndrome
Protein-losing enteropathy
- Primary gastrointestinal mucosal diseases (e.g., ulcerative colitis)
- Increased interstitial pressure or lymphatic obstruction (e.g., sarcoidosis)
- Non-erosive upper gastrointestinal diseases (e.g., celiac sprue)
Primary humoral immunodeficiency (e.g., agammaglobulinemia)
Transient hypogammaglobulinemia of infancy (normal and pathological)

FUNCTIONAL RANGE INDICATIONS:

High in:

Hypochlorhydria (protein malabsorption)
Inflammation and oxidative stress

Low in:

Hypochlorhydria
Inflammation
Anemias
Blood loss (hemorrhage, dysmenorrhea, etc.)

References:

Source: Kresser Institute

Glucose

Marker Name: Glucose

REFERENCE RANGES FOR GLUCOSE:

Laboratory reference range: 65–99 mg/dL

Functional reference range: 75–85 mg/dL

DESCRIPTION:

Glucose is a monosaccharide sugar with the molecular formula C6H12O6. Glucose is the primary energy source of most living cells across the five kingdoms of living organisms. The molecule is a substrate for energy production via aerobic respiration, anaerobic respiration, and fermentation.¹Glucose may be obtained from the diet directly, or more commonly, from the breakdown of disaccharides (e.g., sucrose, lactose) and larger carbohydrates (e.g., starch) consumed in the diet. In gluconeogenesis, glucose can be synthesized from non-carbohydrate precursors such as lactate and pyruvate.¹ Glucose may also be converted into glycogen, which is a large, branched polymer of glucose molecules.² Glycogen is stored in the liver and is available to rapidly release glucose into the bloodstream when needed.

Glucose levels in the bloodstream are hormonally regulated by insulin and, to a lesser extent, by glucagon.³ Circulating glucose, which increases after a meal, is taken up by pancreatic beta cells via glucose transporters.⁴ In response, these pancreatic beta cells release insulin into the bloodstream. Initially, there is a rapid burst of insulin that reaches a peak within three to five minutes and then subsides within 10 minutes.⁵ Additional insulin is released by the pancreas if glucose levels in the blood remain elevated.³ Circulating insulin then binds to cells throughout the body, permitting cellular uptake of glucose. As glucose enters the cells, levels drop in the bloodstream. If circulating glucose levels drop too low, glucagon and epinephrine stimulate cells in the liver to breakdown glycogen molecules to form glucose.⁶ In healthy individuals, these opposing hormones keep circulating glucose levels within normal limits.

An elevated glucose level is called hyperglycemia. Healthy individuals have transient increases in blood glucose, but because of tight hormonal regulation, these levels usually do not exceed 200 mg/dL.⁷ Hyperglycemia often occurs in the context of diabetes mellitus. The main types of diabetes mellitus are type 1, type 2, and gestational diabetes, though there are several less common varieties. Hyperglycemia may occur in people who do not have a diagnosis of diabetes, but even in these cases, the affected person most likely has some degree of insulin insensitivity or insulin deficiency. Infection and various drugs that cause increases in circulating blood glucose are more likely to affect people with diabetes or prediabetes.^8,9 Hyperglycemia may be caused by various endocrine system disturbances, such as Cushing syndrome or hyperthyroidism.⁸ Diseases that affect the exocrine function of the pancreas, such as pancreatitis and cystic fibrosis, can also cause hyperglycemia.⁸

Hypoglycemia indicates an abnormally low blood glucose level. As with hyperglycemia, hypoglycemia is more likely to occur in individuals with diabetes, especially those individuals who have poorly controlled diabetes or “brittle” diabetes, which is prone to rapid blood glucose fluctuations.¹⁰ Insulin and several classes of oral type 2 diabetes medications are associated with hypoglycemia. Moreover, various prescription medications can cause hypoglycemia, usually in people with diabetes.¹¹ Hypoglycemia may indicate a primary endocrine disorder other than diabetes, such as glucagon deficiency, pheochromocytoma, or Addison’s disease. Starvation and malnutrition may overcome the body’s ability to provide glucose from glycogen stores, which can cause hypoglycemia.

Handheld blood glucose meters can provide rapid and reasonably accurate blood glucose measurements at the bedside.¹² Glucose is measured as part of the basic metabolic panel or complete metabolic panel.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^8,9,13

Diabetes mellitus
- Type 1
- Type 2
- Gestational
- Latent autoimmune diabetes in adults
- Maturity onset diabetes of the young
- Neonatal
Genetic defects in insulin action (e.g., type A insulin resistance)
Diseases of the exocrine pancreas (e.g., pancreatitis, cystic fibrosis)
Endocrinopathies (e.g., acromegaly, Cushing syndrome, hyperthyroidism)
Infections (e.g., cytomegalovirus, rubella)
Drugs
- Antibiotics (e.g., quinolones)
- Atypical antipsychotics (e.g., clozapine, olanzapine)
- Beta-blockers (e.g., metoprolol, propranolol)
- Corticosteroids
- Calcineurin inhibitors (e.g., cyclosporine, tacrolimus)
- Protease inhibitors
- Thiazide diuretics

Low in:^11,14,15

Diabetes mellitus
Liver disease
Endocrine disorders (e.g., glucagon deficiency, Addison’s disease)
Malnutrition
Alcohol abuse
Substance abuse
Jamaican vomiting sickness
Gastric surgery
Excessive muscular activity
Diarrhea (childhood)
Drugs
- Antibiotics (e.g., quinolones, chloramphenicol, pentamidine)
- ACE inhibitors (e.g., enalapril, lisinopril)
- Beta-blockers (e.g., metoprolol, propranolol)
- Salicylates (e.g., aspirin)
- Diabetes treatments
  - Insulin
  - Sulfonylureas
  - DPP-4 inhibitors
  - SGLT2 inhibitors
  - Alpha-glucosidase inhibitors
- Chloroquine
- Clofibrate
- Disopyramide

FUNCTIONAL RANGE INDICATIONS:

High in:

Early stages of impaired glucose tolerance and insulin resistance
Active stress response

Low in:

Reactive hypoglycemia
Hypoglycemia (may still be present when glucose is above 65)
Impaired liver function

References:

Source: Kresser Institute

HDL

Marker Name: HDL

REFERENCE RANGES FOR HDL CHOLESTEROL:

Laboratory reference range: 39+ mg/dL

Functional reference range: 50–85 mg/dL

DESCRIPTION:

HDL, or high-density lipoprotein, is one of the five major lipoproteins in plasma. Unlike other lipoproteins, HDL primarily shuttles fatty acids from adipocytes and other fat-containing cells to the liver for eventual excretion in the feces.^1,2 HDL also transfers cholesterol to steroidogenic tissues such as the ovaries, testes, and adrenal glands to serve as precursors for steroid-containing hormones.³ HDL also appears to play a role in removing cholesterol from lipid-laden macrophages (i.e., foam cells) in atherosclerotic plaques.⁴

HDL primarily participates in the reverse cholesterol transport pathway.⁵ The liver synthesizes HDL, which is secreted as flattened spherical particles of apolipoproteins and phospholipids.^4,6 As a lipoprotein with both fatty and proteinaceous components, HDL can associate itself in a micelle structure, with hydrophobic ends on its interior and hydrophilic ends on its exterior.⁷ With this structure, HDL serves as a carrier of water-insoluble lipids such as cholesterol and triglycerides within plasma.

Nascent HDL particles attract free cholesterol and cholesterol from cell membranes into the growing HDL particle.⁵ During this maturation process, known as the HDL cycle, maturing HDL particles attract free cholesterol by interacting with the ATP-binding cassette transporter A1.^8,9Free cholesterol is enzymatically converted into cholesterol esters that migrate to the core of the growing lipoprotein particle. HDL particles deposit cholesterol in target tissues by interacting with specific HDL receptors, such as scavenger receptor BI.³ HDL degradation and catabolism take place largely in the liver.⁴

While laboratory reports list the test by the name “HDL,” what is actually reported and what is actually of clinical interest is HDL-C, or HDL cholesterol. HDL-C reflects HDL particles that contain cholesterol. Strictly speaking, HDL refers only to the lipoprotein. Modern laboratories are currently transitioning from older to newer methods for measuring HDL and other cholesterol levels in blood samples.¹⁰ Some inherent limitations to these methods remain, including heterogeneity of LDL and HDL particle size and composition.¹¹

Abnormally high levels of HDL are uncommonly referred to in the literature as hyperalphalipoproteinemia. This term can be confusing since there are heritable causes of elevated HDL that are commonly called hyperalphalipoproteinemia.¹² Other, secondary causes of elevated HDL are virtually never called hyperalphalipoproteinemia (though they could be, strictly speaking). HDL-C levels can be increased by regular physical activity, weight loss, and certain drugs.^13,14 On the other hand, very high levels of HDL may increase the risk of cardiovascular events, such as heart attack.¹⁵ This may be because excess HDL at the levels described becomes dysfunctional.¹⁶

As with elevated HDL, the term hypoalphalipoproteinemia is usually reserved for familial cases of low HDL. Several rare genetic disorders cause decreased circulating HDL.¹⁷ Other metabolic abnormalities can lower HDL levels (e.g., elevated cholesteryl ester transfer protein activity, lipoprotein lipase deficiency, elevated hepatic triglyceride lipase activity).¹⁸ Obesity and lifestyle issues such as smoking and physical inactivity are associated with low HDL-C levels. Acute infection, inflammation, and certain chronic diseases can lower HDL as well.⁶

HDL cholesterol is measured as part of the standard serum lipid profile. The serum lipid profile includes total cholesterol, LDL cholesterol, and triglycerides. This report may also provide calculated estimates of VLDL cholesterol, non-HDL cholesterol, and the cholesterol/HDL ratio.¹⁹

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS: High in:^3,13,15,18

Cholesteryl ester transfer protein deficiency
Familial hyperalphalipoproteinemia
Drugs
- Bile acid sequestrants
- Fibrates
- Nicotinic acid (niacin)
- Omega-3 fatty acids
- PCSK9 inhibitors
- Statins

Low in:^17,18

Insulin resistance
Uncontrolled diabetes mellitus
Malnutrition
Cigarette smoking
Acute infection
Inflammation
Hepatocellular disease
Cholestasis
Chronic renal failure
Primary causes
- Familial primary hypoalphalipoproteinemia
- Non-familial hypoalphalipoproteinemia
- Familial hypoalphalipoproteinemia with hypertriglyceridemia
Elevated cholesteryl ester transfer protein activity
Lipoprotein lipase deficiency
Elevated hepatic triglyceride lipase activity
Gammopathy (artifact)
Drugs
- Beta blockers
- Benzodiazepines
- Anabolic steroids

FUNCTIONAL RANGE INDICATIONS:

High in:

Inflammation

Low in:

Insulin resistance and metabolic dysfunction
Inflammation
Impaired liver function
Numerous chronic disease states

References:

Source: Kresser Institute

Hematocrit

Marker Name: Hematocrit

REFERENCE RANGES FOR HEMATOCRIT:

Laboratory reference range:
Male and Female: 37.5–51%

Functional reference ranges:
Male: 40–48%
Female: 37–44%

DESCRIPTION:

Hematocrit (Hct) is the percentage of red blood cells, by volume, in the blood. Thus, hematocrit provides information about the relative amount of red blood cells per unit of blood volume. The main function of a red blood cell (erythrocyte) is to deliver oxygen to tissues throughout the body. Its unique torus shape is ideal for gas diffusion, and it is flexible enough to pass through small capillaries in peripheral tissues.¹ Red blood cells are also important for the removal of carbon dioxide from the tissues and can help buffer the pH of the blood.

Erythropoiesis, or the production of new red blood cells, takes place in the bone marrow.² Red blood cells are only one possible cell type that may be formed from pluripotent stem cells; the stem cells also give rise to all of the white blood cells and platelets. Erythropoiesis requires the coordination of numerous cytokines and hormones. Perhaps the most important hormone for red cell production is erythropoietin, which is produced in the kidney.³ Immature red blood cells called reticulocytes move from the bone marrow into the vasculature, where they take about one week to mature into fully functional erythrocytes.² A mature red blood cell circulates in the blood stream for approximately 120 days, after which it is removed from the bloodstream by macrophages.^4,5

Modern instruments calculate hematocrit (Hct) by directly counting the number of red blood cells in a sample and multiplying it by the mean corpuscular volume (MCV) using the following equation:

hematocrit

A high hematocrit is called erythrocytosis or polycythemia. A high hematocrit may be due to an increased number of red blood cells (true erythrocytosis) or a normal number of red blood cells in blood with an elevated mean corpuscular volume.⁶ Since hematocrit is the volume of packed red blood cells per unit of blood volume, it may be elevated when there are too many red blood cells or too little plasma. An elevated hematocrit caused by too many red blood cells may be congenital polycythemia, primary polycythemia (also known as polycythemia vera), secondary polycythemia, or idiopathic erythrocytosis. Causes of secondary polycythemia range from simple hypoxia to certain forms of cancer, such as leukemia. Less commonly, elevated hematocrit may be caused by an abnormally low plasma volume. This condition most commonly occurs in people who smoke.

A low hematocrit is synonymous with anemia. A low hematocrit may occur through one of four ways: blood loss, decreased red blood cell production, increased red blood cell destruction, or an increase in plasma volume. Some people may have a chronically low hematocrit from birth, as is the case in glucose-6 phosphate dehydrogenase deficiency. Blood loss may be rapid, such as after severe trauma with hemorrhage, or it may be slow, such as chronic gastrointestinal bleeding. Various forms of cancer are the most common cause of decreased red blood cell production. Red blood cells may be destroyed by parasites (as seen in malaria) or as a consequence of genetic disease (e.g., sickle cell anemia).

Hematocrit is measured as a part of a complete blood count (CBC), which includes hemoglobin, hematocrit, a red blood cell (RBC) count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red cell distribution width (RDW).⁷ The complete blood count may also include a reticulocyte count. It is often measured with related iron markers, including TIBC, UIBC, iron saturation, serum iron, and ferritin.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^8-14

Dehydration
Decreased plasma volume in relation to red blood cells (hemoconcentration)
- Smoker’s polycythemia
- Gaisbock’s disease (stress erythrocytosis)
Polycythemia vera (primary polycythemia)
Idiopathic erythrocytosis
Secondary polycythemia
- Hypoxia
- Obstructive sleep apnea
- Pulmonary fibrosis
- Chronic obstructive pulmonary disease (COPD)
- Erythropoietin-secreting tumor (e.g., hepatocellular carcinoma, renal cell carcinoma, hemangioblastoma, pheochromocytoma, uterine myomata)
Congenital polycythemia
Treatment with erythropoietin

Low in:^7,15,16

First and second trimesters of normal pregnancy
Nutrient imbalance
- Iron deficiency
- Folate deficiency
- Vitamin B12 deficiency
- Vitamin B6 deficiency
- Copper deficiency
Heavy menstrual periods
Serial phlebotomy
Excessive fluid intake (polydipsia)
Excessive fluid administration (iatrogenic; dilution anemia)
Chronic inflammation (e.g., chronic infection, malignancy, rheumatologic disorders, inflammatory bowel disease, chronic immune activation)
Sideroblastic anemia
Hemorrhage
- Internal
- External
Red blood cell destruction
- Sickle cell anemia
- Thalassemia
- Autoimmune hemolytic anemia
- Evans syndrome
- Malaria
- Bartonella
- Leptospirosis
Bone marrow suppression
Primary bone marrow failure
Certain cancers
- Leukemia
- Gastric adenocarcinoma
- Adenocarcinoma of the cecum
Certain genetic conditions
- Glucose-6 phosphate dehydrogenase deficiency
Drugs
- Cephalosporins
- Chemotherapeutic agents

FUNCTIONAL RANGE INDICATIONS:

High in:

Dehydration
Erythrocytosis
Polycythemia

Low in:

Functional anemia

References:

Source: Kresser Institute

Hemoglobin

Marker Name: Hemoglobin

REFERENCE RANGES FOR HEMOGLOBIN:

Laboratory reference range:
Male and Female: 12.6–17.7 g/dL

Functional reference ranges:
Male: 14–15 g/dL
Female: 13.5–14.5 g/dL

DESCRIPTION:

Hemoglobin (Hb or Hgb) is the iron-containing metalloprotein in red blood cells (RBCs) that carries oxygen from the lungs to tissues throughout the body and gives red blood cells their characteristic color.^1,2 In red blood cells, hemoglobin also transports about 10 percent of the body’s carbon dioxide and is thought to play a role in nitric oxide delivery and regulation of vasomotor tone.^3,4 Hemoglobin is the main constituent of RBCs and makes up approximately 96 percent of RBC dry weight. Abnormal hemoglobin structure can affect RBC shape, which can impair function and flow through blood vessels.⁵ Outside of red blood cells, hemoglobin functions as an antioxidant and plays a role in iron metabolism.⁶

Hemoglobin is a tetrameric protein composed of two pairs of globin chains; most normal adult hemoglobin (HbA) consists of two alpha chains and two beta chains (α₂β₂).⁷ Within each globin chain is a central heme molecule that contains iron, which is the site of oxygen binding.⁸ Fully deoxygenated hemoglobin is slow to bind the first oxygen molecule. However, due to a phenomenon called cooperativity, each additional oxygen molecule bound increases the affinity of remaining binding sites for oxygen.⁴ Hemoglobin can bind up to four oxygen molecules.⁹

Hemoglobin exists in a taut form (T) and a relaxed form (R). The taut form has low oxygen affinity and releases bound oxygen; it is favored by conditions typically found in respirating tissue such as low pH, high CO₂concentration, high 2,3-BPG concentration, and high temperature. The relaxed form has high oxygen affinity and is favored by the inverse conditions, which are typically found in lung alveoli. Therefore, hemoglobin generally binds oxygen in lungs and releases oxygen in respirating tissues where it is needed.^4,10 Hemoglobin oxygen binding can be impaired by competitive inhibitors such as carbon monoxide and hydrogen sulfide.^4,11

High hemoglobin can be caused by dehydration, high-altitude living, smoking, cor pulmonale, certain lung conditions, states of increased RBC production, and certain genetic disorders. A complete list of conditions that can cause increased hemoglobin levels is below.

Low hemoglobin can be caused by normal pregnancy, certain nutrient imbalances (e.g., iron deficiency, lead poisoning), ineffective erythropoiesis, hemolytic anemia, hypothyroidism, chronic kidney disease, liver disease, chronic inflammation, certain bone marrow disorders, porphyria, vasculitis, hypopituitarism, hypogonadism, and certain drugs. A full list of conditions and drugs that can cause decreased hemoglobin levels is provided below.

To determine the etiology of abnormal hemoglobin concentration, related iron markers should be considered, including serum iron, ferritin, TIBC, UIBC, iron saturation, and other markers in the complete blood count (CBC).

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^12,13

Dehydration
High-altitude living
Smoking
Cor pulmonale
Severe lung conditions
- Pulmonary fibrosis
- Chronic obstructive pulmonary disease (COPD)
- Emphysema
States of increased red blood cell production
- Treatment with erythropoietin (EPO)
- Polycythemia vera
- Renal neoplasm (e.g., renal cell carcinoma)
Certain genetic disorders that cause:
- Altered oxygen sensing¹⁴
- Abnormal hemoglobin oxygen affinity¹⁵

Low in:^12-13,16-18

Normal pregnancy
Nutrient imbalances
- Folate deficiency
- Vitamin B6 deficiency
- Vitamin B12 deficiency
- Copper deficiency
- Lead poisoning¹⁹
- Iron deficiency^20-23
  - Inadequate dietary intake
  - Gastrointestinal malabsorption
  - Blood loss
- Ineffective erythropoiesis (e.g., hereditary sideroblastic anemias, severe alpha and beta thalassemia, myelodysplastic syndrome (MDS) variants)^24-27
- Hemolytic anemia (e.g., autoimmune hemolytic anemia, sickle cell anemia, malaria, etc.)
- Hypothyroidism²⁸
- Chronic kidney disease
- Liver disease²⁹
- Chronic inflammation (e.g., chronic infection, malignancy, rheumatologic disorders, inflammatory bowel disease, chronic immune activation)
- Certain bone marrow disorders (e.g., leukemia, lymphoma, multiple myeloma, aplastic anemia)
- Porphyria
- Vasculitis³⁰
- Hypopituitarism
- Hypogonadism
- Drugs³¹
  - Proton pump inhibitors
  - H₂ receptor blockers
  - Certain antibiotics (e.g., quinolones, tetracycline)
  - Excessive calcium supplementation
  - Chemotherapeutic agents
  - Antiretroviral drugs for HIV infection (e.g., azidothymidine)

FUNCTIONAL RANGE INDICATIONS:

High in:

Dehydration

Low in:

Functional (early-stage) anemias

References:

Source: Kresser Institute

Hemoglobin A1c

Marker Name: Hemoglobin A1c

REFERENCE RANGES FOR HEMOGLOBIN A1c:

Laboratory reference range: 4.8–5.6%

Functional reference range: 4.6–5.3%

DESCRIPTION:

Hemoglobin A1c is a subtype of hemoglobin that is non-enzymatically glycosylated by circulating glucose. The action of hemoglobin A1c is indistinguishable from other subtypes of hemoglobin; however, measuring levels of hemoglobin A1c in the blood is useful for estimating average levels of blood glucose over a three-month period. Therefore, hemoglobin A1c can be used to inform diabetes mellitus diagnosis and monitor the efficacy of exercise, dietary management, and treatment of diabetes.¹

Hemoglobin in newly formed red blood cells contains negligible amounts of covalently bound glucose, yet glucose can freely permeate the cell membranes of red blood cells.¹ Thus, glucose can freely interact with hemoglobin molecules within red blood cells. The N-terminus of the beta chain of hemoglobin non-covalently interacts with glucose, then proceeds through a Schiff base and Amadori rearrangement to form a covalent bond between glucose and hemoglobin.² Over the following weeks, these Amadori rearrangement products transition to intermediate and advanced glycosylation endproducts.^3,4 These reactions are irreversible and persist for the life of the red blood cell.

This non-enzymatic covalent bonding of glucose and hemoglobin takes place in a dose-dependent fashion, such that greater amounts of circulating glucose correspond to higher levels of glycosylated hemoglobin, or hemoglobin A1c. The typical lifespan of a red blood cell is 120 days, with approximately 1 percent of the entire erythrocyte population degrading and replenishing itself daily.^1,5 Taken together, this indicates that any spot assessment of hemoglobin A1c level in the blood provides an average circulating glucose level for the previous three months.²

Estimated average glucose (eAC) is calculated from the measured hemoglobin A1c level and is included in most laboratory reports with hemoglobin A1c.⁶ While hemoglobin A1c reflects mean blood glucose over the previous 120 days, commercially available assays of glycated hemoglobin actually correlate best with mean blood glucose over the previous eight to 12 weeks.^2,6 In other words, blood glucose levels within the past 30 to 90 days have a greater effect on the hemoglobin A1c measurement than those in the preceding months.^1,7

Importantly, modern hemoglobin A1c assay equipment can vary as much as 0.5 percent from the actual value in the blood.⁸ Moreover, there appears to be a high degree of inter- and intra-personal variability in hemoglobin A1c measurements over time.⁷ Finally, since the hemoglobin A1c assay specifically quantifies a fraction of hemoglobin A, people with a predominance of other forms of hemoglobin (e.g., HbF, HbS, HbE, HbD, Hb Fukuoka, Hb Philadelphia, and Hb Raleigh) may have reported hemoglobin A1c levels that are difficult to interpret clinically.^9,10

Under normal circumstances, an elevated hemoglobin A1c reflects higher-than-normal circulating glucose levels for the preceding three months.⁵ This is consistent with a diagnosis of diabetes mellitus. Various nonwhite racial and ethnic groups may have higher hemoglobin A1c levels after adjusting for many factors that may affect glycemia. Therefore, the normal range of hemoglobin A1c may need to be interpreted in context of the patient’s ethnicity or race.^1,11 Any circumstance that increases the lifespan of red blood cells such as polycythemia or splenectomy can artificially elevate hemoglobin A1c levels.

Other than chronic hypoglycemia, the clinical significance of an abnormally low hemoglobin A1c level is unclear. Any condition that shortens the lifespan of a red blood cell can result in a lower-than-expected level of hemoglobin A1c. For example, glucose-6-phosphate dehydrogenase deficiency, sickle cell disease, thalassemia, pernicious anemia, and hemolytic anemia can change the rate at which hemoglobin and red blood cells are produced and removed from circulation, i.e., the red blood cell turnover rate.¹² Any condition that increases red blood cell turnover rate and, by extension, increases the production of new red blood cells, will make hemoglobin A1c underestimate the true level of circulating glucose. The same is true for blood donation, hemolysis, or hemorrhage within the three months prior to the hemoglobin A1c test. Some studies suggest that low A1c (< 5.0 percent) may be interpreted as a general marker of poor health and may occur in disease states such as cancer.¹³

If there is reason to believe that hemoglobin A1c may be an inaccurate measure of average circulating glucose levels, a fructosamine assay can be used to determine intermediate-term blood glucose averages (previous two to three weeks).⁷

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^1,6,10,11

Diabetes mellitus
Polycythemia
Post-splenectomy
Certain variant forms of hemoglobin
Non-white ethnicity (may be normal)

Low in:^6,10,13-16

Chronic hypoglycemia
Anemia
- Iron deficiency
- Vitamin B12 deficiency
- Folate deficiency
- Autoimmune hemolytic anemia
Blood transfusion
Blood donation
Chronic renal failure
Hemolysis
Hemorrhage
Certain variant forms of hemoglobin
Cancer

FUNCTIONAL RANGE INDICATIONS:

High in:

Impaired glucose tolerance and insulin resistance
Non-pathological (A1c may be high or high-normal in individuals with increased red blood cell survival time)

Low in:

General marker of ill health

References:

Source: Kresser Institute

Homocysteine

Marker Name: Homocysteine

REFERENCE RANGES FOR HOMOCYSTEINE:

Laboratory reference range: 0–15 µmol/L

Functional reference range: < 7 µmol/L DESCRIPTION:

Homocysteine does not appear to play any positive biological role other than as an amino acid intermediate in the methionine and folate cycles.¹ However, elevated levels of homocysteine are associated with several disease states, including vascular diseases and cognitive disorders.²Homocysteine auto-oxidizes in plasma to form biologically reactive products, namely homocysteine, homocysteine-mixed disulfides, and homocysteine thiolactone.³ Homocysteine and these related molecules may injure the vascular endothelium directly or by first interacting with low-density lipoproteins (LDL).⁴ Homocysteine may also be prothrombotic, especially in the context of acute coronary syndromes, increasing platelet accumulation and aggregation.^5,6

Homocysteine and methyltetrahydrofolate (methyl-THF) are substrates for methionine synthase, a vitamin B12-dependent enzyme that forms tetrahydrofolate (THF) and methionine.² Homocysteine can also enter the transsulfuration pathway, where it is converted to cystathionine and then cysteine and glutathione through vitamin B6-dependent enzymes.⁷ Thus, a deficiency in folate (a precursor of methyl-THF) and/or vitamin B12 (a cofactor for methionine synthase) can interfere with methionine synthase activity, resulting in increased homocysteine, decreased methionine, and increased metabolism through the transsulfuration pathway.⁸

homocysteine

Hyperhomocysteinemia is an abnormally high level of homocysteine in the blood, as measured by plasma homocysteine. For reasons described above, the level of circulating homocysteine is inversely correlated with levels of folate, vitamin B12, and vitamin B6.⁹ Therefore, deficiencies in these vitamins, especially folate, may cause plasma levels of homocysteine to rise. Homocysteine levels also rise in response to diminished hormone levels, namely thyroid hormone and estrogen. Consequently, hyperhomocysteinemia has been noted in hypothyroidism and menopause.²Plasma homocysteine levels tend to rise in patients with end-stage renal disease. Genetic diseases of impaired homocysteine metabolism, such as thermolabile methylenetetrahydrofolate reductase (MTHFR) deficiency, may raise plasma homocysteine levels.¹⁰

Plasma homocysteine may be measured with assays of serum vitamin B12, folate, and vitamin B6. A methylmalonic acid test may help distinguish between vitamin B12 or folate deficiencies.¹² In folate deficiency, homocysteine levels in the serum will be abnormally high but methylmalonic acid levels will be normal. In vitamin B12 deficiency, both serum homocysteine and methylmalonic acid levels will be elevated.¹²

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^1,2,10,13,14

Nutrient imbalances
- Vitamin B12 deficiency
- Vitamin B6 deficiency
- Folate deficiency
Hypothyroidism
Menopause
Impaired homocysteine metabolism (e.g., methylenetetrahydrofolate reductase (MTHFR) mutation, cystathionine-beta-synthase deficiency)
End-stage renal disease

Low in:

Not applicable

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

Iron

Marker Name: Iron

REFERENCE RANGES FOR SERUM IRON:

Laboratory reference range: 40–155 µg/dL

Functional reference range: 40–135 µg/dL

DESCRIPTION:

Most of the body’s iron (Fe) is found in hemoglobin proteins of red blood cells, where it plays the crucial role of transporting oxygen to tissues throughout the body.¹A small but important portion of iron is found in metalloenzymes needed for tyrosine, dopamine, serotonin, and noradrenaline synthesis and is used as a cofactor for enzymes involved in gluconeogenesis, energy production, and DNA and RNA synthesis.²

Iron homeostasis is achieved by a complex balance of intestinal absorption, iron recycling from red blood cells, release of iron stores from ferritin in the mononuclear phagocyte system, and iron loss through sweat, shed skin cells, minor gastrointestinal losses, and menstruation in women.^3,4Research suggests that the protein hepcidin plays a major role in iron balance by adjusting the rate of iron absorption in the gastrointestinal tract and iron export from macrophages in response to many signals, such as body iron levels, inflammation, infection, endotoxin, p53, hypoxia, anemia, and erythropoiesis (red blood cell production) rate. Gastrointestinal absorption of iron is tightly regulated, since there is no innate way to upregulate iron excretion if too much is absorbed. Iron is primarily absorbed in the duodenum of the small intestine, though many mechanistic details remain unclear.³

When iron is absorbed from food, it is transported through plasma by the protein transferrin. Transferrin carries iron throughout the body and primarily delivers it to bone marrow, where red blood cell precursors incorporate the iron into hemoglobin during erythropoiesis. The many biological functions of iron involve its ability to readily change oxidation states, cycling between Fe²⁺and Fe³⁺. However, this reactivity can also produce harmful free radicals, so the vast majority of iron in the body is bound to proteins. Most iron circulating in plasma is bound to transferrin; the remaining trace amount is usually chelated to amino acids or citrate and promptly taken up by the liver.²

The serum iron (SI) test effectively measures the concentration of iron in transit, bound to transferrin.⁵

For high serum iron, consider hereditary hemochromatosis, massive iron intake, liver disease, and ineffective erythropoiesis. A full list of conditions that can cause elevated iron concentration is below.^6,7

For low serum iron, consider blood loss, low dietary intake, gastrointestinal malabsorption, chronic inflammatory disease, pregnancy, certain genetic conditions, and certain drugs (e.g., proton pump inhibitors, certain antibiotics). A complete list of conditions and drugs that can cause low iron concentration is provided below.^1,8,9-15

Serum iron concentration is a useful measure of circulating iron, but it should be considered with other iron markers, including a complete blood count (CBC), ferritin, TIBC, UIBC, and iron saturation.¹⁶

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:⁶

Increased iron absorption from a normal diet
- Hereditary hemochromatosis (HH)
  - Human hemochromatosis protein (HFE)-related
    - C282Y homozygosity
    - C282Y/H63D compound heterozygosity
    - Other mutations of HFE
  - Other gene mutations
    - Juvenile hemochromatosis (mutations in hemojuvelin or hepcidin)
    - Ferroportin mutations
    - Transferrin receptor 2 mutation (rare)
  - Multiple infusions of iron-containing agents
    - Red cell transfusion
    - Multiple infusions of intravenous iron
    - Intravenous hemin/hematin
  - Massive increase in oral intake
    - High-dose iron supplementation
    - Medications containing iron
    - Diet
  - Liver disease
    - Hepatitis B or C
    - Alcohol-induced liver disease
    - Porphyria cutanea tarda
    - Steatohepatitis (fatty liver disease)
    - Neonatal or perinatal iron overload, due to gestational alloimmune liver disease
  - Wilson’s disease (aceruloplasminemia)
  - Ineffective erythropoiesis
    - Hereditary sideroblastic anemias
    - Severe alpha and beta thalassemia
    - Myelodysplastic syndrome (MDS) variants, such as refractory anemia with ringed sideroblasts (RARS)
  - Insulin resistance (considered once other causes are ruled out)⁷

Low in:^1,9

Inadequate dietary intake
- Diet low in meat
Gastrointestinal malabsorption
- Achlorhydria or hypochlorhydria
- Inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis)
- Gastritis
  - Atrophic gastritis
  - Autoimmune metaplastic atrophic gastritis
  - Helicobacter pylori gastritis
- Celiac disease
- Post-gastric bypass surgery¹⁰
Chronic inflammatory disease¹¹
- Multiple causes (e.g., infections, malignancy, diabetes mellitus, acute and chronic immune activation, etc.)
Pregnancy
- Fluid expansion during pregnancy
- Direct iron loss to fetus during pregnancy
- Blood loss during delivery
- Lactation
Blood loss⁸
- Obvious bleeding
  - Trauma
  - Melena
  - Hematemesis
  - Hemoptysis
  - Gross hematuria
- Heavy menstrual bleeding
- Gastrointestinal bleeding
  - Multiple causes (e.g., hemorrhoids, fissures, inflammatory bowel disease, infection, diverticulitis)¹²
- Repeated blood donations
- Surgery
- Hemodialysis¹³
- Intraluminal neoplasms (e.g., malignancies of the gastrointestinal or genitourinary tract)¹⁴
- Intravascular hemolysis, with accompanying hemoglobinuria and hemosiderinuria
- Pulmonary hemosiderosis (as seen in anti-glomerular basement membrane antibody disease)
- Lasthénie de Ferjol syndrome
Treatment with erythropoietin (EPO)
Congenital iron deficiencies
- Iron-refractory iron deficiency anemia (IRIDA)
- Mutations in the iron transporter gene DMT1
Drugs¹⁵
- Proton pump inhibitors
- H₂ receptor blockers
- Certain antibiotics (e.g., quinolones, tetracycline)
- Excessive calcium supplementation

FUNCTIONAL RANGE INDICATIONS:

High in:

Functional iron overload
Functional liver problems
Insulin resistance

Low in:

Functional iron deficiency
Celiac disease and other GI conditions that cause malabsorption
Blood loss
Pregnancy
Chronic inflammatory conditions

References:

Source: Kresser Institute

Iron Saturation

Marker Name: Iron Saturation

REFERENCE RANGES FOR IRON SATURATION:

Laboratory reference range: 15–55%

Functional reference range: 17–45%

DESCRIPTION:

Iron saturation, also referred to as transferrin saturation (TSAT), is the percent of iron-binding sites on plasma proteins occupied by iron. Since transferrin carries the majority of plasma iron, iron saturation approximates the percent of transferrin bound by iron. To know the exact transferrin-specific saturation, direct measurement of transferrin would be required. Iron saturation is typically calculated from serum iron (SI) and total iron-binding capacity (TIBC) or unsaturated iron-binding capacity (UIBC) using one of the equations below.¹

iron-saturation

Iron saturation depends on serum iron and transferrin concentration and is therefore affected by the same variables: iron homeostasis, nutritional status, inflammation, liver function, pregnancy, certain genetic conditions, and certain drugs. For information on how these factors alter plasma transferrin and iron content, see TIBC and iron reference sheets. Note that when more than one of these health variables is simultaneously abnormal, iron saturation can be unpredictable.² For example, a patient with concomitant protein and iron deficiency may present with normal, low, or high iron saturation.³

Iron saturation follows a diurnal rhythm, with higher values in the morning and lower values at night; however, these variations are not typically large enough to change diagnosis outcome.^4,5When iron saturation exceeds 80 percent, non-transferrin bound iron (NTBI) is found in plasma, which produces reactive oxygen species (ROS) and causes cellular damage.^6,7

High iron saturation can be caused by hereditary hemochromatosis, multiple infusions of iron-containing agents, massive increase in oral iron intake, hypotransferrinemia, pernicious anemia, ineffective erythropoiesis, and some cases of hemolytic anemia, hemosiderosis, and chronic liver disease.^8-21 A list of specific conditions that can cause high iron saturation is provided below.

Low iron saturation can be caused by iron deficiency, pregnancy, states of increased erythropoiesis, certain drugs, states of acute inflammation, and some cases of chronic inflammation.^8-11,22-30 A full list of conditions and drugs that can cause low iron saturation is found below.

To determine the etiology of abnormal iron saturation, related iron markers should be considered, including a complete blood count (CBC), serum iron, ferritin, TIBC, and UIBC.⁸

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^8-11

Hereditary hemochromatosis (HH)^12,13
- Human hemochromatosis protein (HFE)-related
  - C282Y homozygosity
  - C282Y/H63D compound heterozygosity
  - Other mutations of HFE
- Other genetic mutation
  - Juvenile hemochromatosis (mutations in hemojuvelin or hepcidin)
  - Transferrin receptor 2 mutation (rare)
- Multiple infusions of iron-containing agents
  - Red cell transfusion
  - Multiple infusions of intravenous iron
  - Intravenous hemin/hematin
- Massive increase in oral iron intake
  - High-dose iron supplementation
  - Medications containing iron
  - Diet
- Hypotransferrinemia
  - Hereditary atransferrinemia
  - Nephrotic syndrome
- Pernicious anemia¹⁴
- Ineffective erythropoiesis
  - Hereditary sideroblastic anemias¹⁵
  - Severe alpha and beta thalassemia^16,17
  - Myelodysplastic syndrome (MDS) variants, such as refractory anemia with ringed sideroblasts (RARS)¹⁸
- Hemolytic anemia (can be high, but sometimes normal)
  - Autoimmune hemolytic anemia
  - Sickle cell anemia
- Hemosiderosis (can be high, but sometimes normal)
  - Pulmonary hemosiderosis (as seen in anti-glomerular basement membrane antibody disease)
  - Chronic hemolysis
- Chronic liver disease (can be high, but sometimes normal)
  - Hepatitis B or C
  - Alcohol-induced liver disease¹⁹
  - Porphyria cutanea tarda²⁰
  - Steatohepatitis (fatty liver disease)²¹

Low in:^8-11,22,23

Normal pregnancy (in the absence of iron deficiency)
Iron deficiency
- Inadequate dietary intake (e.g., diet low in meat)
- Gastrointestinal malabsorption
  - Hypochlorhydria
  - Gastritis (e.g., atrophic gastritis, autoimmune metaplastic atrophic gastritis, Helicobacter pylori gastritis)
  - Celiac disease
  - Post-gastric bypass surgery²⁴
- Blood loss²⁵
  - Obvious bleeding (e.g., external wound, melena, hematemesis, hemoptysis, gross hematuria)
  - Heavy menstrual bleeding
  - Gastrointestinal bleeding (e.g., hemorrhoids, fissures)
  - Repeated blood donations
  - Intraluminal neoplasms (e.g., malignancies of the gastrointestinal tract)²⁶
  - Lasthénie de Ferjol syndrome
- States of increased red blood cell production
  - Treatment with erythropoietin (EPO)²⁷
  - Polycythemia vera²⁸
- States of acute inflammation, as seen in:
  - Myocardial infarction
  - Sepsis
- Chronic inflammation (can be low, but often normal)²⁹
  - Multiple causes (e.g., chronic infection, malignancy, rheumatologic disorders, inflammatory bowel disease, acute and chronic immune activation, etc.)
- Drugs³⁰
  - Oral contraceptives
  - Proton pump inhibitors
  - H₂ receptor blockers
  - Certain antibiotics (e.g., quinolones, tetracycline)
  - Excessive calcium supplementation

FUNCTIONAL RANGE INDICATIONS:

High in:

Functional iron overload
Functional liver problems

Low in:

Functional iron deficiency
Chronic inflammation

References:

Source: Kresser Institute

LDH

Marker Name: LDH

REFERENCE RANGES FOR LDH:

Laboratory reference range: 121–224 IU/L

Functional reference range: 140–180 IU/L

DESCRIPTION:

Lactate dehydrogenase (LDH) reversibly produces NADH and pyruvate from lactate and NAD⁺. The enzyme plays a key role in glycolysis, gluconeogenesis, and anaerobic metabolism.¹ In addition, LDH is critical for the oxygenation of long-chain fatty acids in liver peroxisomes.² LDH is a cytosolic enzyme that is found in virtually every cell, though levels are highest in heart, liver, muscle, kidney, lung, and red blood cells.³ When cells are injured, the LDH-containing cytosol is spilled into the serum. Therefore, serum LDH levels are a marker for tissue or cellular damage.⁴

LDH is a tetramer of two major subunits, the H type and the M type.⁵ The H type is primarily found in heart muscle, while the M type is found in skeletal muscle and liver.¹ These subunits form five types of tetramers: H₄, H₃M₁, H₂M₂, H₁M₃, and M₄.¹ The H₄ tetramer preferentially oxidizes lactate to pyruvate and is allosterically inhibited by high levels of pyruvate.¹ The M₄ tetramer, on the other hand, preferentially catalyzes the opposite reaction, pyruvate to lactate, allowing LDH to operate in anaerobic conditions. Tetramers containing both H and M type subunits share properties of the pure tetramers, according to the ratio of subtypes present.¹

The subunit composition and tissue location of LDH determine its primary physiological role. During aerobic exercise when the oxygen levels within cells are relatively low, LDH liberates NAD⁺so that the molecule can participate in glycolysis.¹ This reaction also produces lactic acid, which tends to accumulate in muscle during anaerobic metabolism. Conversely, LDH can use lactate to produce pyruvate and NADH for glycolysis or gluconeogenesis.¹ However, since skeletal muscle LDH preferentially converts pyruvate to lactate, lactate that accumulates in skeletal muscle under anaerobic conditions must be shuttled to other tissues to recycle it into pyruvate and NADH. The shuttling system is known as the Cori cycle.

An elevation in serum LDH is a nonspecific indicator of tissue damage. Nevertheless, serum LDH levels can be clinically useful in certain circumstances.⁴ Serum LDH levels may be used to monitor chronic hematologic disorders, such as hemolytic anemia or megaloblastic anemia.^4,6 Serum LDH can be used to monitor treatment progress in individuals with germ cell line tumors who initially experienced increased LDH levels prior to treatment.^4,7,8 LDH levels will rise and exceed normal limits approximately 10 hours after the onset of myocardial infarction, peak within one to two days, and remain elevated for up to eight days.^9,10

Some individuals may have lactate dehydrogenase deficiency caused by an autosomal recessive mutation in one of the genes that code for an LDH protein subunit.⁵ Individuals with a deficiency in the M type subunit will have muscle stiffness after strenuous exercise, poor exercise capacity, and the presence of myoglobin in the urine.¹¹ A deficiency in the H type subunit of LDH has no discernible clinical consequences.⁵ Deficiency in the M type or H type subunits may or may not be reflected in the serum LDH levels.⁵ Excessive vitamin C ingestion may cause a false decrease in LDH levels; however, this is a laboratory artifact rather than a true reduction in serum LDH.¹²

It is quite common for LDH to be measured with a comprehensive metabolic panel, complete blood count, or liver function tests.⁴ Serum LDH levels may be ordered in the diagnosis of myocardial infarction; however, current recommendations suggest using cardiac troponins since they are a more specific indicator of heart muscle damage and cardiac ischemia.^9,13 In rare instances, individual lactate dehydrogenase isoenzymes may be measured in the serum for specific purposes.¹⁴ These isoenzymes are formed from various H and M subunits of LDH.⁹ The usefulness of LDH isozyme testing is very limited and not widely available.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:¹⁵

Cardiac
- Myocyte injury (e.g., ischemia, trauma)
- Infection (e.g., myocarditis, rheumatic fever)
- Heart failure
Pregnancy
- Preeclampsia
- Adnexal mass in pregnancy
- HELLP syndrome
Rhabdomyolysis
Endocrine
- Hypothyroidism
- Acromegaly
- Cushing’s syndrome
Gastrointestinal
- Intestinal obstruction
- Early acute hepatitis
- Ischemic hepatitis
- Acute pancreatitis
Hematologic
- Folate deficiency
- Iron deficiency
- Pernicious anemia
- Hemolytic anemia
- Inherited hematologic conditions (e.g., spherocytosis, sickle cell disease)
- Ineffective erythropoiesis
- Primary myelofibrosis
Infection
- Pneumocystis pneumonia (late)
- Tuberculosis
- Malaria
- Parasitic
- Legionnaire’s disease
- Histoplasmosis
- Toxoplasmosis
Central nervous system disorders
- Bacterial meningitis
- Cerebral hemorrhage
- Cerebral venous thrombosis
Malignancy
- Leukemias
- Lymphomas
- Solid tumors (e.g., germ cell tumors)
- Tumor lysis syndrome
Neuromuscular
- Myopathies (inherited, acquired, drug)
- Periodic paralyses
Pulmonary
- Pulmonary embolism, infarction
- Pulmonary alveolar proteinosis
Rheumatologic
- Dermatomyositis
- Rheumatoid arthritis
- Scleroderma
- Sjögren’s syndrome
- Systemic lupus erythematosus
- Polyarteritis nodosa
- Eosinophilic granulomatosis with polyangiitis (Churg-Strauss vasculitis)
- Granulomatosis with polyangiitis (Wegener’s)
- Behçet’s syndrome
- Sarcoidosis
- Vasculitis
Renal infarction
Carbon monoxide exposure
Idiosyncratic LDH elevation
Drugs
- Chemotherapy
- Neuroleptic agents (neuroleptic malignant syndrome)
- Withdrawal from L-dopa or dopamine agonist
- Serotonin syndrome
- Malignant hyperthermia in response to anesthesia
- Recreational drugs (e.g., cocaine, methysergide, alcohol)
- Glucocorticoids
- Statins
- Colchicine
- Antimalarials

Low in:⁵

LDH deficiency

FUNCTIONAL RANGE INDICATIONS:

High in:

Early stages of conditions listed above
Non-pathological

Low in:

Hypoglycemia (if serum glucose below conventional reference range)
Reactive hypoglycemia (consider if serum glucose normal or below functional reference range)

References:

Source: Kresser Institute

LDL

Marker Name: LDL

REFERENCE RANGES FOR LDL:

Laboratory reference range: 0–99 mg/dL

Functional reference range: 0–140 mg/dL

DESCRIPTION:

Low-density lipoprotein (LDL) is one of the five major lipoproteins; it is the major carrier of cholesterol (as cholesterol esters), and it may also carry triglycerides and phospholipids.^1,2 LDL provides cholesterol to the liver for the creation of bile acids and to non-liver tissue for the synthesis of hormones, incorporation into cell membranes, and storage.^3,4 Delivery of cholesterol esters in liver and non-liver tissues takes place through receptor-mediated endocytosis.⁵ Strictly speaking, LDL refers to the lipoprotein rather than the cholesterol. The cholesterol particle is LDL cholesterol (LDL-C). In clinical settings, LDL and LDL-C are used interchangeably, however, and both refer to LDL cholesterol.

LDL may enter the bloodstream through dietary intake or de novo synthesis in the liver. Ingested lipids are initially incorporated into chylomicrons, which deliver triglycerides to tissues.¹Chylomicrons that have been depleted of their triglycerides become chylomicron remnants and are taken up by the liver. The liver then uses these remnants to form very-low-density lipoproteins (VLDLs), which become intermediate-density lipoproteins (IDLs) in the bloodstream. A portion of VLDLs and IDLs are then converted into LDL particles.^1,3 The majority of cholesterol is synthesized by the body, mostly in liver and, to a lesser degree, in the intestines.⁵ LDL contains apolipoprotein B-100 (Apo B-100) and apolipoprotein C-III (Apo C-III).^1,2 Apo B-100 is a ligand for the LDL receptor in the liver, and Apo C-III inhibits triglyceride hydrolysis by lipoprotein lipase and hepatic lipase.^1,6,7

Total cholesterol, HDL cholesterol, and triglycerides are measured directly from serum or plasma samples, while LDL cholesterol is determined by mathematical calculation using measured values.^2,8 The Friedewald formula is used to calculate the LDL level in blood:⁹

LDL

Direct measurement of LDL is more accurate than using the Friedewald formula, but considerably more expensive.^8,10 In most clinical situations, a mathematical estimate is sufficient. In some patients, however, such as people with very high triglyceride levels (>400 mg/dL or >4.516 mmol/L), estimation is far too inaccurate, which usually necessitates direct measurement of LDL. Fortunately, a new calculation method that scales measurements based on the triglyceride-to-VLDL ratio may permit accurate LDL estimation in all patients without the increased expense of direct LDL measurements.¹¹

When LDL cholesterol is elevated due to a primary genetic disorder, it may be referred to as hyperbetalipoproteinemia.¹² Non-familial causes of elevated LDL cholesterol do not typically share this moniker. Causes of high LDL cholesterol that are potentially modifiable through behavioral change include sedentary lifestyle, obesity, and excessive alcohol use. LDL cholesterol levels, as well as all other lipid levels, can be expected to increase in later stages of normal pregnancy to meet increased energy demands of the mother and the fetus.¹³ Certain diseases of the kidney and liver can elevate LDL cholesterol levels. Endocrine diseases such as hypothyroidism and diabetes mellitus, especially type 2 diabetes, may raise LDL cholesterol levels. Various prescription and nonprescription drugs have been shown to cause elevated LDL cholesterol in some individuals.

A low LDL cholesterol level in the blood is sometimes referred to as hypobetalipoproteinemia; however, this term is usually reserved for primary causes of low LDL cholesterol, such as abetalipoproteinemia and familial hypobetalipoproteinemia. Secondary causes of low LDL cholesterol are far more common than primary causes.¹⁴ Acute and chronic infections as well as chronic inflammatory states can lower levels of circulating LDL. Severe nutritional deficits, anemia, and neutropenia may also lower LDL cholesterol. Iatrogenic causes of low LDL cholesterol include supratherapeutic doses of statins, bile acid sequestrants, or ezetimibe.

LDL cholesterol is measured as part of the standard serum lipid profile. The serum lipid profile includes total cholesterol, HDL cholesterol, and triglycerides. This report may also provide calculated estimates of VLDL cholesterol, non-HDL cholesterol, and the cholesterol/HDL ratio.¹⁵

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS: High in:^13,16

Primary causes
- Heterozygous familial hypercholesterolemia
- Homozygous familial hypercholesterolemia
- Polygenic hypercholesterolemia
- Primary hyperlipoproteinemia type 1
Normal pregnancy (third trimester)
Obesity
Sedentary lifestyle
Alcohol abuse
Diabetes mellitus
Hypothyroidism
Chronic kidney disease
Nephrotic syndrome
Cholestatic liver diseases
Drugs
- Anabolic steroids
- Thiazides
- Beta-blockers
- Retinoids
- Glucocorticoids
- Highly active antiretroviral agents
- Oral estrogens
- Anti-rejection drugs

Low in:¹⁴

Primary causes
- Abetalipoproteinemia
- Hypobetalipoproteinemia
- Chylomicron retention disease
Infection
- Chronic (e.g., hepatitis C)
- Acute
Hyperthyroidism
Anemia
Malnourishment
- Anorexia
- Malabsorption
- Poor diet
Neutropenia
Advanced, non-cholestatic liver disease
Malignancy
Drugs
- Statins
- Bile acid sequestrants
- Ezetimibe

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications
Poor thyroid function
Intestinal permeability
Chronic infections
Heavy metal toxicity (and possibly presence of other toxins such as mold)

Low in:

Same as conventional indications

References:

Source: Kresser Institute

Lymphocytes

Marker Name: Lymphocytes

REFERENCE RANGES FOR LYMPHOCYTES:

Laboratory reference range:
Relative 26–46%
Absolute: 0.7–3.1 x103/µL

Functional reference range:
Relative 25–40%
Absolute: N/A

DESCRIPTION:

Lymphocytes make up one of two major categories of white blood cells. The three main types of lymphocytes are B lymphocytes, T lymphocytes, and natural killer (NK) cells;¹ each type of lymphocyte plays several roles in the immune system. B lymphocytes, once they have been activated to form plasma cells, are the sole site of antibody synthesis in the body.² B cells also act as antigen-presenting cells, regulate dendritic cell function, participate in wound healing, produce cytokines, and participate in tumor immunity and transplant rejection.³

The primary tissues that produce B and T lymphocytes are the bone marrow and thymus gland, respectively. Various secondary lymphoid tissue such as lymph nodes, tonsils, spleen, and mucosal surfaces in the gastrointestinal tract and lungs also participate in lymphocyte production. B cells develop through several stages, including B progenitor cell (pre-pro-B cell), the pro-B cell, the pre-B cell, the naïve B cell, and the mature B cell.⁴ Activated B cells include antigen-activated B cells, plasma cells, and memory cells. B lymphocytes play a primary role in humoral immunity and a supporting role in cell-mediated immunity.^3,5

T lymphocytes, on the other hand, are the prime players in cell-mediated immunity.⁶ The main types of T lymphocytes are cytotoxic, helper, and memory T cells. Cytotoxic T cells seek out and destroy “infected” cells, which are cells bearing foreign antigen molecules on their cell membranes.⁴ Helper T cells, also called modulatory T cells, participate in inflammation, promote immune tolerance, and promote tumor immunity.⁷ Unfortunately, helper T cells may also participate in autoimmune disorders, allergy, hypersensitivity reactions, anaphylaxis, and perhaps tissue and organ rejection.⁸

Natural killer (NK) cells are part of the innate immune system. They can bind to and destroy certain tumor cells or virus-infected cells, presumably without prior antigen exposure. Natural killer cells can also regulate immune responses through interactions with dendritic cells, macrophages, endothelial cells, and T lymphocytes.⁹

When an absolute lymphocyte count (ALC) or lymphocyte percentage is reported on a complete blood count (CBC) with differential, it reflects the quantity of B lymphocytes, T lymphocytes, and natural killer cells.¹⁰ The absolute lymphocyte count can be calculated from a lymphocyte percentage and a total white blood cell count using the following equation:

Lymphocytes equation

An abnormally high number of lymphocytes in the blood is called lymphocytosis. There are several specific causes of lymphocytosis, but they can be broadly grouped as either reactive or clonal lymphocytosis. Reactive lymphocytosis may be caused by infections, especially viral infections, or a variety of noninfectious stressors such as drugs, stress, or surgery. Clonal lymphocytosis can be caused by monoclonal B cell lymphocytosis, which is premalignant, or a blood cancer, including chronic lymphocytic leukemia, non-Hodgkin lymphoma, or acute lymphoblastic leukemia.¹¹

An abnormally low lymphocyte count is called lymphocytopenia. Lymphocytopenia may occur in one or more of three general ways:¹² too few lymphocytes are produced, lymphocytes are destroyed faster than they can be replenished, or lymphocytes are sequestered in the spleen or within the lymph nodes. Lymphocytopenia may be genetic or acquired. The acquired causes of lymphocytopenia include infection, autoimmune disorder or its treatment, cancer or its treatment, and various stressors, such as nutritional deficiency or alcohol abuse.

A basic complete blood count (CBC) simply provides quantities of circulating cells in the bloodstream, including red blood cells, white blood cells, and platelets. To obtain a lymphocyte count, the CBC must be ordered with a differential, which tells the laboratory to provide a count of individual white blood cell types.¹⁰ A peripheral blood smear may be ordered as a follow-up test to investigate the morphology of lymphocytes.¹³ The presence of certain abnormal lymphocytes can help guide the precise diagnosis of lymphocyte abnormalities.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:¹⁰

Infections
- Viral (e.g., EBV, CMV, HIV, mononucleosis)
- Bacterial (e.g., pertussis)
- Parasitic (e.g., babesiosis)
- Protozoal (e.g., toxoplasmosis)
- Rickettsial
Stressors (e.g., cigarette smoking, trauma, splenectomy)
Hyperthyroidism
Rheumatoid arthritis
Leukemias
Lymphomas
Serum sickness
Autoimmune lymphocytosis
Malignant thymoma
Monoclonal B cell lymphocytosis
Drugs
- Chemotherapeutics
- High-dose niacin supplementation

Low in:^10,14

Zinc deficiency
Protein malnutrition
Alcohol abuse
Infection
- Bacterial
- Viral
- Fungal
- Parasitic
Autoimmune disorders (e.g., lupus, rheumatoid arthritis)
Trauma
Genetic immunodeficiency disorders
Immunosuppressive therapy
Cancer (e.g., lymphoma)
Aplastic anemia
Cushing’s syndrome
Cancer treatment
- Chemotherapy
- Radiation therapy

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications
Viral infections

Low in:

Same as conventional indications
Bacterial infections

References:

Source: Kresser Institute

Magnesium

Marker Name: Magnesium

REFERENCE RANGES FOR SERUM MAGNESIUM:

Laboratory reference range: 1.6–2.6 mg/dL

Functional reference range: 2.0–2.6 mg/dL

DESCRIPTION:

Magnesium (Mg) is a cofactor for more than 300 enzymes, a constituent of bones and teeth, and needed by every cell. Magnesium is necessary for all enzymes that use and synthesize ATP and for enzymes involved in synthesis of RNA, DNA, proteins, and glutathione. Every cell uses magnesium for active transport of calcium and potassium ions across cell membranes, which is important for muscle and nerve function and normal heart rhythm. It helps regulate blood pressure, blood glucose, and levels of other nutrients including calcium, vitamin D, potassium, zinc, and copper.^1-4

Assessing magnesium status is challenging because less than 1 percent of total magnesium is in blood serum—the rest is in bones and cells.^3,5Serum magnesium concentration is the most commonly used magnesium test, but this test is flawed because magnesium in blood serum is tightly regulated, and does not correlate well with overall magnesium status.⁶ Magnesium status is also evaluated by magnesium loading (tolerance) tests; total magnesium concentration in erythrocytes (RBCs), saliva, and urine; or total ionized magnesium concentration in blood, plasma, and serum. However, there is no single sufficient testing method for magnesium status; a better functional biomarker is needed.^7,8

Magnesium balance is achieved primarily by small intestinal absorption and renal excretion and reabsorption. Unlike other ions, hormones do not substantially regulate urinary magnesium excretion, and magnesium content of bone is not readily mobilized into circulating magnesium. Instead, low plasma magnesium concentration triggers the kidney to lower magnesium excretion and prevent further depletion.⁹

High magnesium is uncommon but can be caused by insufficient renal function or very high magnesium intake. Slightly elevated magnesium can be caused by primary hyperparathyroidism, diabetic ketoacidosis, tumor lysis syndrome, drugs such as lithium, milk-alkali syndrome, adrenal insufficiency, and familial hypocalciuric hypercalcemia.^10,11

Low magnesium is common. The primary cause of magnesium deficiency is low dietary intake; the vast majority of Americans consume well under their estimated average requirements (EAR).¹² For low magnesium, also consider hyperthyroidism, heavy menstrual periods, excessive sweating, chronic stress, hungry bone syndrome, gastrointestinal magnesium loss (diarrhea, malabsorption, pancreatitis), renal magnesium loss (diabetes mellitus type 2, primary aldosteronism, hypercalcemia, renal tubular dysfunction, leptospirosis), certain drugs (proton pump inhibitors, diuretics), various genetic disorders, surgery, and other dietary factors (ketogenic diet, coffee, alcohol).^9,10,13-15

For treatment of low magnesium, note that magnesium supplements list the amount of elemental magnesium per serving in the Supplement Facts panel, not the total weight of magnesium-containing compounds.¹

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^10,11

Renal insufficiency
Excessive magnesium ingestion
- Parenteral magnesium treatment for severe preeclampsia or eclampsia in pregnant women
- Very high dose ingestion of Epsom salt (magnesium sulfate)
- Catharsis with magnesium-containing drugs (especially in children, the elderly, and those with gastrointestinal disease)
- Magnesium enemas
- Dead Sea water poisoning
Mild hypermagnesemia
- Diabetic ketoacidosis
- Tumor lysis syndrome
- Lithium ingestion
- Milk-alkali syndrome
- Adrenal insufficiency
- Familial hypocalciuric hypercalcemia
- Some cases of primary hyperparathyroidism (though this condition can also result in low magnesium)

Low in:^9,10,12-15

Inadequate dietary intake
Dietary factors (e.g., ketogenic diet, coffee, soda, alcohol, excessive sodium)
Hyperthyroidism
Heavy menstrual periods
Excessive sweating
Prolonged stress
Hungry bone syndrome (post parathyroidectomy)
States of gastrointestinal magnesium loss
- Diarrhea
- Malabsorption
- Steatorrhea
- Small bowel bypass surgery
- Acute pancreatitis
States of renal magnesium loss
- Chronic extracellular fluid volume expansion
  - Primary aldosteronism
- Alcoholism
- Diabetes mellitus type 2, especially if uncontrolled
- Hypercalcemia
  - Primary hyperparathyroidism
- Renal magnesium wasting due to tubular dysfunction
  - Recovery from acute tubular necrosis
  - Following renal transplantation
  - During a postobstructive diuresis
- Leptospirosis
States of intravascular magnesium chelation
- Following surgery
- During liver transplantation
Genetic disorders
- Mutation in the TRPM6 gene, which causes both primary intestinal hypomagnesemia and renal magnesium wasting
- Familial primary renal magnesium wasting, a rare diagnosis of exclusion
  - Gitelman syndrome is the most common, caused by mutations in the SLC12A3gene, which codes for the thiazide-sensitive sodium chloride cotransporter (NCC)
  - Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), most often caused by mutations in the CLDN16 gene (also known as HOMG3or PCLN1) and occasionally caused by mutations in the CLDN19 gene
  - Various less common genetic disorders
- Drugs
  - Proton-pump inhibitors (e.g., omeprazole), especially when used for more than one year or when used concurrently with diuretics
  - Loop and thiazide diuretics
  - Aminoglycoside antibiotics
  - Amphotericin B
  - Cisplatin
  - Pentamidine
  - Cyclosporine
  - Antibodies targeting the epidermal growth factor (EGF) receptor (cetuximab, panitumumab, matuzumab)
  - Foscarnet therapy of cytomegalovirus chorioretinitis

FUNCTIONAL RANGE INDICATIONS:

High in:

Hypothyroidism
Impaired kidney function
Use of antacids with magnesium
Excessive supplementation with magnesium
Addison’s disease/adrenal insufficiency

Low in:

Magnesium deficiency
Malabsorption
Fluid loss
Many other disease states

References:

https://ods.od.nih.gov/factsheets/Magnesium-HealthProfessional/#en7
https://www.nap.edu/read/5776/chapter/1
Rude RK. Magnesium. In: Coates PM, Betz JM, Blackman MR, Cragg GM, Levine M, Moss J, White JD, eds. Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare; 2010:527-37.
Rude RK. Magnesium. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Modern Nutrition in Health and Disease. 11th ed. Baltimore, Mass: Lippincott Williams & Wilkins; 2012:159-75.
Volpe SL. Magnesium. In: Erdman JW, Macdonald IA, Zeisel SH, eds. Present Knowledge in Nutrition. 10th ed. Ames, Iowa; John Wiley & Sons, 2012:459-74.
Gibson, RS. Principles of Nutritional Assessment, 2nd ed. New York, NY: Oxford University Press, 2005.
http://www.ncbi.nlm.nih.gov/pubmed/22064327?dopt=Abstract
http://www.tandfonline.com/doi/abs/10.1080/07315724.2004.10719418#.Ve8-sM44Is
http://www.uptodate.com/contents/regulation-of-magnesium-balance
http://www.uptodate.com/contents/causes-of-hypomagnesemia
http://www.uptodate.com/contents/causes-and-treatment-of-hypermagnesemia
https://www.ars.usda.gov/ARSUserFiles/80400530/pdf/0506/usual_nutrient_intake_vitD_ca_phos_mg_2005-06.pdf
http://acb.sagepub.com/content/51/2/179
http://ckj.oxfordjournals.org/content/5/Suppl_1/i25
http://umm.edu/health/medical/altmed/supplement/magnesium

Source: Kresser Institute

MCH

Marker Name: MCH

REFERENCE RANGES FOR MCH:

Laboratory reference range: 26.6–33 pg/cell

Functional reference range: 27.7–32 pg/cell

DESCRIPTION:

Mean corpuscular hemoglobin (MCH) is the mass of hemoglobin in the average red blood cell,¹though in practice the test provides limited information about hemoglobin within red blood cells.

MCH is not measured directly; it is calculated from hemoglobin concentration and red blood cell count.

MCH formula

MCH is an indication of average values and may not precisely account for variability within mixed populations of red blood cells.² For example, iron-deficiency anemia may result in decreased mean corpuscular volume (MCV) and MCH, while megaloblastic anemia may result in increased MCV and MCH.

The laboratory value of MCH may be incorrectly high or low when hemoglobin concentration and red blood cell count cannot be accurately measured. For example, people with exceptionally high levels of circulating lipids will have a high degree of plasma turbidity.³ This plasma turbidity will artificially increase measured hemoglobin and will consequently deliver a falsely elevated MCH. Thus, MCH can be useful for suggesting a possible spurious hemoglobin lab result.

In the context of anemia, a high MCH signifies hyperchromic anemia.⁴ Conversely, a low MCH signifies hypochromic anemia.⁴ These diagnoses can only be definitively made, however, in conjunction with mean corpuscular volume. This is because red blood cell volume affects the concentration of hemoglobin within each cell, which is reported as MCHC. Thus, MCH can vary in parallel to MCV under physiological circumstances.^5,6

MCH is always measured as part of a complete blood count (CBC).⁷ MCH is of little clinical significance in isolation and must be considered in conjunction with hemoglobin, RBC count, MCV, and RDW.¹

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS: High in:^5,7

Macrocytosis

Low in:^5,7

Iron deficiency
Thalassemia

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

MCHC

Marker Name: MCHC

REFERENCE RANGES FOR MCHC:

Laboratory reference range: 31.5–35.7 g/dL

Functional reference range: 32–35 g/dL

DESCRIPTION:

Mean corpuscular hemoglobin concentration (MCHC) is the average concentration of hemoglobin in a sample of red blood cells.¹ MCHC supplies a ratio of hemoglobin mass to red cell volume. MCHC provides some information about hemoglobin, the main transport molecule for oxygen in the blood.

MCHC is not particularly useful for modern clinical diagnosis; however, it is important for clinical laboratory quality control, since it is quite stable.¹ Like mean corpuscular hemoglobin (MCH), MCHC is calculated rather than measured directly. MCHC is calculated from hemoglobin concentration and hematocrit.²

MCHC formula

MCHC can be erroneously elevated or decreased in situations where hemoglobin, hematocrit, or both are distorted within a sample. For instance, laboratory analysis of plasma samples subject to autoagglutination may underestimate hematocrit while overestimating hemoglobin. This distorts MCHC accordingly.

A high MCHC signifies hyperchromic anemia.³ A high MCHC not due to a spurious laboratory result may indicate autoimmune hemolytic anemia or a hemoglobin abnormality, such as homozygous hemoglobin C disease or sickle cell disease. MCHC may be elevated in people who have sustained significant burns. Blood samples from patients with hereditary spherocytosis, a rare genetic condition, will return with a consistently elevated MCHC.

A low MCHC is consistent with hypochromic anemia. It may be present in iron-deficiency anemia or thalassemia.²

MCHC is always measured as part of a complete blood count (CBC).⁴ MCHC is of little clinical significance, but it can be used to isolate spurious laboratory results.¹

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS: High in:^4,5

Low in:^4,5

Iron-deficiency anemia
Thalassemia

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

MCV

Marker Name: MCV

REFERENCE RANGES FOR MCV:

Laboratory reference range: 79–97 fL

Functional reference range: 85–92 fL

DESCRIPTION:

Mean corpuscular volume (MCV) is one of the standard indices used to describe red blood cells. As the name implies, MCV provides an average volume of red blood cells. MCV is important for the differential diagnosis of anemia,¹ which is often defined as an abnormally low hematocrit or hemoglobin level.² An abnormally high MCV is called macrocytosis, while an abnormally low MCV is microcytosis. As such, diagnoses of anemia can be qualified as microcytic anemia, normocytic anemia, or macrocytic anemia, depending on MCV.³

MCV is reported as a single number, and it represents the mean volume across all red blood cells. For various diagnostic purposes, it is important to know whether the red blood cells are similar in volume or represent a wide range of volumes. For example, a normal MCV could reflect a collection of red blood cells that share a similar volume within the normal range or, just as easily, equal numbers of red blood cells that have abnormally low volumes and abnormally high volumes.

To determine the distribution of volumes in a sample, the MCV is evaluated with another measurement called the red blood cell distribution width, or RDW. The RDW can be either normal or elevated, as no biological state routinely results in an RDW that is lower than normal.⁴ A normal RDW generally means that the red blood cells in a sample have a similar volume, while a high RDW indicates red blood cells with varying volumes.

The volume of a red blood cell is determined by the amount of hemoglobin, ions, and water contained within it. As with other cells in the body, protein pumps regulate cationic and anionic content in red blood cells. Under normal conditions, red blood cells contain low sodium, high potassium, and very low calcium levels. If these protein pumps are dysfunctional, it can change the ion content within the cells and subsequently, the volume of red blood cells.⁵ Free water can move passively into and out of red blood cells through osmosis to areas of relatively high solute concentration. Alternatively, red blood cells contain specific water channels called aquaporins that can actively move water across the cell membrane.⁶

In certain cases, macrocytosis, or an elevated MCV, may occur without the presence of anemia. For example, pregnant women, newborns, and infants may have macrocytosis without anemia.⁷Macrocytic anemia usually falls into one of four major categories: a nutritional deficiency, the adverse effect of a drug, a primary bone marrow disorder (e.g., leukemia, myelodysplastic disorder), or a chronic illness other than cancer. A wide array of medications and drug classes can cause macrocytosis, including antivirals, chemotherapeutic agents, anticonvulsants, and antimicrobials.^7,8

The most common cause of microcytic anemia is iron-deficiency anemia.⁹ Iron-deficiency anemia, in turn, is due to decreased iron intake, decreased absorption, chronic disease, or bleeding. The other major causes of microcytic anemia are thalassemia, sideroblastic anemia (either hereditary or acquired), and anemia of chronic disease.¹⁰ Certain drugs, nutritional deficiencies, and metal poisoning may also cause microcytic anemia.

Mean corpuscular volume is always measured in conjunction with other red blood cell indices such as mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red cell distribution width (RDW).¹¹ Likewise, red blood cell indices are virtually always measured with a total red blood cell count, hemoglobin, and hematocrit, along with a reticulocyte count in some cases.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS: High in:^7,8,12

Aging
Pregnancy
Infancy
Nutrient imbalances
- Vitamin B12 deficiency
- Folate deficiency
Aplastic anemia
Hemolytic anemia
Reticulocytosis
Megaloblastic anemia
Liver disease
Excessive alcohol intake
Hypothyroidism
Leukemia
Multiple myeloma
Myelodysplastic syndrome (MDS) variants
Drugs
- Oral contraceptives
- Proton pump inhibitors
- Histamine H₂ receptor blockers
- Nitrous oxide
- Metformin
- Colchicine
- Triamterene
- Sulfasalazine
- Antimicrobials (e.g., pyrimethamine, sulfamethoxazole, trimethoprim, valacyclovir)
- Antiviral treatment of HIV infection (e.g., zidovudine, stavudine)
- Chemotherapeutic agents (e.g., hydroxyurea, cyclophosphamide, busulfan, methotrexate, azathioprine, mercaptopurine, cladribine, etc.)
- Anticonvulsants (e.g., phenytoin, valproic acid, primidone)

Low in:^9,10,13,14

Alpha and beta thalassemia
Sideroblastic anemia
Nutrient imbalances
- Iron deficiency
- Vitamin B6 deficiency
- Copper deficiency
- Lead poisoning
- Zinc poisoning
Chronic inflammation (e.g., chronic infection, malignancy, rheumatologic disorders, inflammatory bowel disease, chronic immune activation, and other inflammatory disorders)
Hemoglobinopathies
Inherited microcytic anemia
Hypothermia
Drugs
- Chloramphenicol
- Isoniazid
- Busulfan
- Penicillamine
- Linezolid

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

MMA

Marker Name: Methylmalonic acid (MMA)

REFERENCE RANGES FOR SERUM MMA:

Laboratory reference range: 0–378 nmol/L

Functional reference range: < 300 nmol/L DESCRIPTION:

Methylmalonic acid is a small molecule formed from the catabolism of the amino acids isoleucine, methionine, threonine, and valine, as well as cholesterol and odd-chain fatty acids.^1,2 Beyond its role as an intermediate in these metabolic reactions, methylmalonic acid is not known to play a direct role in cellular or tissue function. Nevertheless, excessive levels of methylmalonic acid may cause a metabolic acidosis, ketosis, and hyperammonemia.^2,3

Methylmalonic acid is a key component of the methylmalonyl-CoA pathway.² Through this pathway, isoleucine, methionine, threonine, valine, thymidine, uracil, cholesterol, and odd-chain fatty acids are catabolized to form succinyl-CoA for use in the citric acid cycle. The isomerization of methylmalonyl-CoA to succinyl-CoA requires the vitamin B12-dependent enzyme methylmalonyl-CoA mutase. Thus, elevations in circulating methylmalonic acid are usually either due to mutations in this enzyme or a lack of the cofactor, vitamin B12.²

Since mutations in methylmalonyl-CoA mutase are rare (roughly one in 48,000) and come to clinical attention in the neonatal period, accumulations of methylmalonic acid in adults usually reflect vitamin B12 deficiency.⁴ In fact, methylmalonic acid is an extremely sensitive indicator of vitamin B12 deficiency and is considered the gold standard for confirmation of this diagnosis.⁵

An elevated plasma methylmalonic acid level is called methylmalonic acidemia. Methylmalonic acidemia is an umbrella term that is applied to a number of inherited errors of methylmalonic acid metabolism, but it also may be applied to transient elevations in plasma methylmalonic acid.²While genetic causes of methylmalonic acidemia result in large increases in plasma methylmalonic acid, the most common cause of elevated methylmalonic acid in plasma is vitamin B12 deficiency. Methylmalonic acid levels may also increase during pregnancy, renal insufficiency, and in a portion of otherwise healthy elderly individuals.^3,6

A low plasma methylmalonic acid does not appear to reflect any clinical disease or disorder. In fact, clinical laboratories may not include lower boundaries for normal serum methylmalonic acid ranges.³

Methylmalonic acid is commonly measured during investigation of suspected vitamin B12 or folate deficiency. Therefore, plasma methylmalonic acid may be measured with vitamin B12, folate, and homocysteine.⁷ In vitamin B12 deficiency, both serum homocysteine and methylmalonic acid levels will be elevated, but methylmalonic acid levels will be normal in folate deficiency.⁷

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^2,6,8

Normal pregnancy
Vitamin B12 deficiency
Pernicious anemia
End-stage renal disease
Genetic disorders impairing methylmalonic acid metabolism

Low in:³

Not clinically relevant

FUNCTIONAL RANGE INDICATIONS:

High in:

Functional B12 deficiency
Pregnancy

Low in:

Not clinically relevant

References:

Source: Kresser Institute

Monocytes

Marker Name: Monocytes

REFERENCE RANGES FOR MONOCYTES:

Laboratory reference range:
Relative 2–12%
Absolute 0.1–0.9 x10³/µL

Functional reference range:
Relative 4–7%
Absolute N/A

DESCRIPTION:

Monocytes are one of the two main types of agranulocytes, along with lymphocytes. The prototypical monocyte is larger than other white blood cells and has a single, lobed, kidney-shaped nucleus.¹ Normally, monocytes make up less than 10 percent of circulating white blood cells. While monocytes are produced from precursor cells in the bone marrow, approximately half of all monocytes can be found in the spleen at any one time. Monocytes play important roles in inflammation and in the innate immune system response pathogens, but they may also exacerbate certain inflammatory diseases, such as atherosclerosis.²

In the absence of infection or inflammation (i.e., steady state), monocytes do not proliferate; rather, they maintain a stable number in various pools throughout the body.² When monocytes encounter an antigen, they activate, signal to other monocytes using chemokines, and rapidly move from the blood to the tissues.³ During inflammation, monocytes can become macrophages or inflammatory dendritic cells.³ These cells can phagocytose, or consume microbes.⁴ Macrophages, and especially dendritic cells, help coordinate the actions of B and T lymphocytes.⁴ Endogenous factors called lipid mediators can stop acute inflammation by monocytes and macrophages.^5,6

Monocytosis is an abnormally high number of monocytes in the circulation. Monocytosis is either reactive or clonal. Reactive monocytosis occurs during certain stresses encountered by the affected individual, such as chronic infection, inflammatory diseases, and severe trauma.⁷ Clonal monocytosis reflects a cancerous state and is most often associated with the myelomonocytic or monocytic subtypes of acute myeloid leukemia.^8,9

An abnormally low number of circulating monocytes is called monocytopenia. Until recently, monocytopenia was not believed to be a distinct entity.¹⁰ Monocytopenia was considered in the context of neutropenia or general leukopenia. However, people with mutations in the GATA2gene may be chronically deficient in or completely lack monocytes. These individuals are particularly susceptible to certain infections, such as nontuberculous mycobacterial infection, molluscum contagiosum, and Epstein-Barr virus infections.^11,12 People with the GATA2 mutation are also prone to develop acute myelogenous leukemia and chronic myelomonocytic leukemia.¹³

A monocyte count is reported as part of a CBC with differential. The standard differential is an automated count of the main leukocyte types: monocytes, lymphocytes, eosinophils, basophils, and neutrophils.¹⁴

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^1,7,8,15-17

Acute stress
Myeloproliferative disorders
Chronic infections
- Tuberculosis
- Brucellosis
- Bacterial endocarditis
- Typhoid
- Protozoal infections
- Rickettsial diseases
- Malaria
Noninfectious inflammation
- Rheumatoid arthritis
- Inflammatory bowel disease
- Temporal arteritis
- Systemic lupus erythematosus
- Collagen vascular disease
Hematologic cancers
- Hodgkin lymphoma
- Chronic myeloid leukemia
- Acute myeloid leukemia (myelomonocytic, monoblastic)

Low in:^13,18-21

Mutations of the hematopoietic transcription factor gene GATA2
Infection
Aplastic anemia
Severe thermal injury
Hematologic cancers
- Acute myeloid leukemia
- Hairy cell leukemia
- Chronic lymphocytic leukemia
Drugs (e.g., chemotherapy, corticosteroids)

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications
Inflammation

Low in:

Same as conventional indications

References:

Source: Kresser Institute

Neutrophils

Marker Name: Neutrophils

REFERENCE RANGES FOR NEUTROPHILS:

Lab reference range:
Relative: 49–74%
Absolute: 1.4 – 7.0 x103/µL

Functional reference range:
Relative: 40–60%
Absolute: N/A

DESCRIPTION:

A neutrophil is one of the white blood cells that circulates in the bloodstream. It is also a type of granulocyte, which is a cell that releases enzymes during the immune response to infection or allergen. Granulocytes include neutrophils, eosinophils, and basophils and are distinguished from lymphoid white blood cells, namely B and T lymphocytes, plasma cells, and natural killer cells.¹

Neutrophils are the most common phagocyte, which is a cell that ingests foreign particles or cells (e.g., microorganisms).² As such, neutrophils are integral components of the innate immune system and are the first cells recruited to sites of infection or inflammation.³ They are attracted to these sites through a variety of cytokines, chemokines, and other chemotactic factors. Once at the site of infection, neutrophils internalize and destroy foreign microbes. As neutrophils move towards their microbial targets, they release neutrophil extracellular traps (NETs), which can themselves capture and kill microbes.⁴ Ideally, NETs should protect tissue from destruction by localizing the effect of proteases; neutrophils can mediate tissue damage in several inflammatory disorders.⁵

White blood cells—including neutrophils—red blood cells, and platelets are formed from multipotent stem cells within the bone marrow. Granulocyte colony-stimulating factor (G-CSF) stimulates the proliferation, maturation, and function of neutrophils, with virtually no effect on other granulocytes or monocytes.⁵ Neutrophils normally spend four to five days in the last stage of cell division before entering the bloodstream.⁶ Once in the bloodstream, human neutrophils survive for approximately five days.⁷ At that time, they undergo spontaneous apoptosis and neutrophil senescence, which renders them unable to respond to chemoattractants.⁸

An abnormally high number of neutrophils in the blood is called neutrophilia. The most common cause of neutrophilia is an acute bacterial infection, especially certain bacteria including Pneumococcus, Staphylococcus, and Clostridium species.⁹ Certain viruses, fungi, and parasites can also increase the number of neutrophils in the bloodstream. Inflammatory conditions, such as rheumatoid arthritis and inflammatory bowel disease, are often associated with increased neutrophil counts. Conversely, anti-inflammatory drugs, specifically glucocorticoids (e.g., prednisone) may increase the absolute neutrophil count.¹⁰ Many physiological stressors have been shown to cause elevated neutrophil levels from trauma, thermal injury, and myocardial infarction to vigorous exercise and cigarette smoking.⁹

An abnormally low neutrophil count is called neutropenia. Neutropenia may occur during a severe infection or soon afterwards. It may be caused by certain cancers or by cancer treatment (e.g., chemotherapeutic agents). A number of drugs from a wide assortment of drug classes have been shown to diminish neutrophil counts. Certain cancers, myelodysplastic syndrome, and aplastic anemia also cause neutropenia.¹¹

A basic complete blood count (CBC) simply provides quantities of circulating cells in the bloodstream including red blood cells, white blood cells, and platelets. To obtain a neutrophil count, the CBC must be ordered with a differential, which tells the laboratory to provide a count of individual white blood cell types. If a manual differential is ordered, the lab will also report the number of segmented neutrophils and banded neutrophils.¹²

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^13-15

Normal pregnancy
Transient elevation during labor and delivery
Normal infancy
Cigarette smoking
Acute infection (especially bacterial but also certain viral and fungal infections)
Noninfectious inflammation
- Gouty arthritis
- Acute glomerulonephritis
- Rheumatic fever
- Anaphylaxis
- Collagen-vascular diseases
Acute stress
- Severe burns
- Intestinal obstruction
- Myocardial infarction
- Cardiopulmonary bypass surgery
- Severe asthma attack
Myeloproliferative disorders
Metabolic disorders
- Diabetic ketoacidosis
- Preeclampsia
- Uremia
Poisoning (e.g., lead, mercury, turpentine, insect venom)
Acute hemorrhage
Cancers of the blood (e.g., chronic myeloid leukemia, polycythemia vera)
Solid tumor cancers (e.g., squamous cell cancers)
Drugs
- Glucocorticoids
- Recombinant granulocyte colony-stimulating factor
- Catecholamines
- Lithium

Low in:^16-18

Nutritional deficiency (e.g., vitamin B12, folate, copper)
Congenital neutropenia (e.g., benign ethnic neutropenia)
Infection (e.g., HIV, sepsis)
Post-infectious neutropenia
Autoimmune neutropenia
- Primary autoimmune
- Secondary autoimmune
- Felty syndrome
Myelodysplastic syndromes
Cancers of the blood (e.g., acute myeloid leukemia, lymphoma)
Aplastic anemia
Paroxysmal nocturnal hemoglobinuria
Drugs
- Chemotherapy
- Atypical antipsychotics (e.g., clozapine, olanzapine)
- Antibiotics (e.g., penicillin)
- Anticonvulsants (e.g., phenytoin)
- Sulfasalazine
- Thionamides (e.g., methimazole, propylthiouracil, carbimazole)
- Ticlopidine
- Rituximab

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications
Bacterial infection

Low in:

Same as conventional indications
Viral infection

References:

Source: Kresser Institute

Phosphorus

Marker Name: Phosphorus

REFERENCE RANGES FOR SERUM PHOSPHORUS:

Laboratory reference range: 2.5–4.5 mg/dL

Functional reference range: 3.0–4.0 mg/dL

DESCRIPTION:

Phosphorus (P) is a primary constituent of bones and teeth, which contain about 85 percent of total body phosphorus as hydroxyapatite. Remaining phosphorus is found primarily inside cells as a crucial component of adenosine triphosphate (ATP), phospholipids in cell membranes, and the structural framework of DNA and RNA. Phosphorus also helps regulate use of certain vitamins and minerals such as vitamin D, iodine, magnesium, and zinc.^1,2 A relatively small amount of phosphorus is found in the plasma as phospholipids, ester phosphates, and inorganic phosphate anions.³

Regulation of phosphorus homeostasis involves intestinal absorption and secretion, renal excretion and reabsorption, and bone formation and resorption. These regulatory processes involve a complex interplay of parathyroid hormone (PTH), calcitonin, fibroblast growth factor 23 (FGF23) and its cofactor Klotho, and possibly estrogens. Dietary deficiency is rare, as intake and absorption of dietary phosphate in the small intestine are normally high and proceed with minimal regulation by calcitriol, while a relatively small amount of phosphate is excreted in the colon. Bone resorption can raise plasma phosphate concentration and is regulated by PTH, calcitriol, and possibly FGF23. The kidneys play the most important role in phosphorus balance, as renal phosphate reabsorption can vary widely and responds to dietary phosphate consumption, serum phosphate level, PTH, FGF23, other phosphatonins, and calcitriol.³

High serum phosphorus concentration (hyperphosphatemia) can be caused by tissue breakdown, movement of phosphate out of cells, vitamin D toxicity, decreased renal excretion, pseudohyperphosphatemia (due to a laboratory artifact), or certain drugs. A complete list of conditions and drugs that can cause hyperphosphatemia is provided below.²

Low serum phosphorus concentration (hypophosphatemia) can be caused by alcoholism, vitamin D deficiency or resistance, decreased intestinal absorption, redistribution of phosphate from extracellular fluid into cells (as seen in hungry bone syndrome), renal replacement therapies, increased urinary phosphate excretion, and certain drugs. A full list of conditions and drugs that can cause low serum phosphorus is below.^4,5

If the etiology of abnormal serum phosphorus is unclear from patient history, it can be useful to measure vitamin D.⁶

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:²

Vitamin D toxicity
Cell lysis
- Tumor lysis syndrome
- Rhabdomyolysis
Cellular shift of phosphate out of cells
- Lactic acidosis
- Ketoacidosis
- Severe hyperglycemia
Decreased renal excretion
- Reduced glomerular filtration rate
  - Acute kidney injury
  - Chronic kidney disease
- Increased tubular reabsorption
  - Hypoparathyroidism
  - Pseudohypoparathyroidism (renal resistance to PTH)
  - Acromegaly
  - Familial tumoral calcinosis
- Pseudohyperphosphatemia (laboratory artifact)
  - Hyperglobulinemia
    - Multiple myeloma
    - Waldenström’s macroglobulinemia
    - Monoclonal gammopathy
  - Hyperlipidemia
  - Hemolysis
  - Hyperbilirubinemia
  - Sample contamination with certain medications
    - High-dose liposomal amphotericin B
    - Heparin
    - Recombinant tissue plasminogen activator
  - Drugs
    - Bisphosphonates (e.g., etidronate)
    - Phosphate-containing laxatives
    - Fosphenytoin

Low in:^4,5

Vitamin D deficiency or resistance
Alcoholism
Decreased intestinal absorption
- Inadequate intake (rare)
- Steatorrhea
- Chronic diarrhea
- Inflammatory bowel disease (e.g., Crohn’s disease, celiac disease)¹
Redistribution of phosphate from extracellular fluid into cells
- Increased insulin secretion
  - Treatment of diabetic ketoacidosis or nonketotic hyperglycemia
  - Refeeding of malnourished patients
  - Patients receiving hyperalimentation
- Acute respiratory alkalosis
- Hungry bone syndrome
  - Post-parathyroidectomy
  - Post-thyroidectomy in patients with preexisting osteopenia
- Renal replacement therapies
- Increased urinary phosphate excretion
  - Primary and secondary hyperparathyroidism
  - Osmotic diuresis
  - Intravenous iron administration (especially formulations containing carbohydrate moieties)
  - Post renal transplantation
  - Post partial hepatectomy
  - Hereditary hypophosphatemic rickets
  - Tumor-induced osteomalacia
  - Fibrous dysplasia (rare)
  - McCune-Albright syndrome (rare)
  - Fanconi syndrome, as seen in:
    - Multiple myeloma
    - Cystinosis
    - Wilson’s disease
    - Hereditary fructose intolerance
  - Drugs
    - Thiazide diuretics with carbonic anhydrase inhibitory activity (e.g., metolazone)
    - Antacids containing aluminum or magnesium
    - Cinacalcet treatment
    - Tenofovir
    - Acetazolamide
    - Imatinib mesylate

FUNCTIONAL RANGE INDICATIONS:

High in:

Excessive vitamin D supplementation
Impaired kidney function (check BUN, creatinine, and other markers of kidney function)
Recent broken bone
Many other disease states

Low in:

Vitamin D deficiency
Hypochlorhydria
Fluid loss
Many other disease states

References:

Source: Kresser Institute

Platelets

Marker Name: Platelets

REFERENCE RANGES FOR PLATELETS:

Laboratory reference range: 150–379 x 10³/µL

Functional reference range: 150–379 x 10³/µL

DESCRIPTION:

Platelets are small, disc-shaped cells that are integral to the repair of damaged blood vessels. In the presence of injured vascular endothelium, platelets initiate and coordinate clot formation by adhering to the injured blood vessel, aggregating to form a platelet plug, and secreting factors that initiate the coagulation cascade.^1-3 Platelets can also recruit white blood cells and progenitor cells to sites of vascular injury.⁴

Platelets bind to proteins in the extracellular matrix that are exposed during blood vessel injury. Binding to these exposed proteins (e.g., collagen) activates the platelets, causing them to secrete various molecules, including thromboxane A2 and ADP. These molecules stimulate other platelets in the vicinity, which in turn activate those platelets. Activated platelets bind to circulating fibrinogen and enhance the action of thrombin; fibrinogen and thrombin are two major proteins involved in coagulation.⁵ Thrombin is also an extremely potent activator of platelets, which further enhances hemostasis.¹

Platelets are the direct products of megakaryocytes. Like all blood cell lines, megakaryocytes are produced from multipotent stem cells within the bone marrow.⁶ Megakaryocytes are released from the bone marrow and travel to the lung, where they are transformed into platelets.⁷Megakaryocytes respond to the body’s need for platelets by altering their number and size, increasing or decreasing based on relative need.⁶ Platelet formation and megakaryocyte production are controlled by the hematopoietic cytokine thrombopoietin.⁸ The body attempts to regulate platelet mass rather than platelet number through megakaryocyte production and maturation, as well as thrombopoietin levels.⁶

The standard laboratory test for platelets is a platelet count, which reports total platelet number.⁹Platelet morphology can be evaluated by a peripheral blood smear. Certain aspects of platelet function can be assessed by various studies including platelet aggregometry, bleeding time, thromboelastography, platelet-mediated thrombin generation, and platelet activation measurement.¹⁰ These tests can be used to evaluate platelet dysfunction or to monitor antiplatelet therapies.

Thrombocytosis is an abnormally high number of platelets in the blood.⁹ Thrombocytosis can occur in a variety of medical conditions. Elevated platelet counts are most commonly seen in the course of hematologic conditions, both cancer (e.g., lymphoma) and non-cancer disorders (e.g., iron-deficiency anemia). Various acute and chronic inflammatory conditions may increase platelet counts. These inflammatory conditions may be the result of a chronic infection or primary rheumatologic condition, such as rheumatoid arthritis.¹¹ Thrombocytosis may be a reaction to bodily injury such as thermal burns, severe trauma, or major surgery.¹² Drugs in several drug classes can also increase platelet counts.

Thrombocytopenia is a condition in which platelet count is below normal.⁹ A low platelet count occurs in three broad circumstances: the bone marrow is not making enough platelets, platelets are being destroyed in the bloodstream, or the liver or spleen is removing platelets from circulation.⁹ Decreased production of platelets in the bone marrow may be due to myelodysplastic disorders, hematologic malignancies, aplastic anemia, metastatic cancer to bone marrow, or even treatment for cancer (chemotherapy, radiation).¹³ Platelets may be destroyed in various immune (e.g., heparin-induced thrombocytopenia) and nonimmune (e.g., disseminated intravascular coagulation) conditions. Five percent of women will have thrombocytopenia as part of normal pregnancy without any known sequelae. On the other hand, a fraction of pregnant women will develop a very serious condition called the HELLP syndrome, which stands for hemolysis, elevated liver function, and low platelets.¹⁴

A platelet count is a standard component of a complete blood count (CBC).¹⁵ Thus, a platelet count is determined along with a red blood cell count, a white blood cell count, hemoglobin and hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). A peripheral blood smear should be used to confirm and investigate thrombocytosis or unexplained thrombocytopenia.¹²

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS: High in:^9,12,16

Nonmalignant hematologic conditions
- Acute blood loss
- Acute hemolytic anemia
- Iron-deficiency anemia
- Treatment of vitamin B12 deficiency
Acute and chronic inflammatory conditions, including:
- Inflammatory bowel disease
- Celiac disease
- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes)
- Rheumatologic disorder
- Vasculitis
- Chronic infections (e.g. ,tuberculosis)
Cancer (e.g., lymphoma)
Primary thrombocythemia
Tissue damage (e.g., severe trauma, severe burn, myocardial infarction, major surgery)
Asplenia (surgical or functional)
Spurious laboratory result
- Mixed cryoglobulinemia
- Pseudohyperkalemia
- Cytoplasmic fragments
Drug-induced thrombocytosis (e.g., vincristine, enoxaparin, thrombopoietin)

Low in:^13,14

Nutrient deficiencies (e.g., vitamin D, vitamin B12, folate, copper)
Pregnancy-related thrombocytopenia
- Normal pregnancy
- HELLP syndrome (hemolysis, elevated liver function, and low platelets)
- Preeclampsia
Autoimmune disorders and rheumatologic diseases
- Rheumatoid arthritis
- Antiphospholipid antibody syndrome
- Systemic lupus erythematosus
Infection (e.g., HIV, hepatitis C, Epstein-Barr virus, intracellular parasites, sepsis)
Aplastic anemia
Dilution (polydipsia, IV fluid administration)
Primary bone marrow disorder
Bone marrow infiltration by cancer
Hypersplenism or chronic liver disease
Congenital platelet disorders
Disseminated intravascular coagulation
Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome
Idiopathic thrombocytopenic purpura
Paroxysmal nocturnal hemoglobinuria
Cardiac bypass
Post-transfusion purpura
Drug-induced thrombocytopenia
- Antiplatelet drugs (e.g., GPIIb/IIIa inhibitor, clopidogrel)
- Heparin
- NSAIDs
- Antibiotics (e.g., vancomycin, ampicillin)
- Chemotherapeutics

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

Potassium

Marker Name: Potassium

REFERENCE RANGES FOR SERUM POTASSIUM:

Laboratory reference range: 3.5–5.2 nmol/L

Functional reference range: 4.0–4.5 nmol/L

DESCRIPTION:

Potassium (K) is an electrolyte that contributes to the resting membrane potential across all cell membranes, which is needed for nerve, muscle, and heart function.¹ Potassium is important for blood pressure control, gastrointestinal motility, acid-base homeostasis, glucose metabolism, renal function, and fluid and electrolyte balance.^2-4 Potassium homeostasis involves the intestines and kidneys and is regulated by aldosterone, which acts by enhancing urinary potassium secretion. Approximately 98 percent of potassium ions are inside cells; this chemical gradient is maintained by energy-intensive Na+/K+-ATPase pumps, insulin receptors, and beta-2-adrenergic receptors. Serum potassium concentration is a common test for evaluating potassium status.^5,6

High serum potassium concentration (hyperkalemia) is uncommon in patients with normal urinary potassium excretion due to a process called potassium adaptation: as potassium intake increases, the extent and efficiency of urinary excretion also increase. Reduced urinary potassium excretion can, however, be caused by several health conditions and drugs listed below. Increased potassium release from cells can also cause high serum potassium; in these cases, hyperkalemia typically only persists when renal insufficiency is also present. Often, high potassium indicates pseudohyperkalemia rather than true hyperkalemia, as repeated fist clenching or trauma during blood draw can cause increased potassium release from cells near the draw site.¹

Low serum potassium concentration (hypokalemia) is common. It can be caused by inadequate dietary intake, certain drugs, dialysis, plasmapheresis, increased potassium entry into the cells, decreased potassium exit from cells, and increased losses in the urine, gastrointestinal tract, or sweat. A specific list of conditions and drugs that cause these states is below.⁷

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:¹

Reduced urinary potassium excretion
- Acute and chronic kidney disease
- Hypoaldosteronism
- Voltage-dependent renal tubular acidosis, seen in:
  - Urinary tract obstruction
  - Lupus nephritis
  - Sickle cell disease
  - Renal amyloidosis
- Effective arterial blood volume depletion
  - True blood volume depletion
  - Heart failure
  - Cirrhosis
- Rare causes
  - Familial pseudohypoaldosteronism type 1
  - Familial pseudohypoaldosteronism type 2 (Gordon’s syndrome)
  - Ureterojejunostomy
- Increased potassium release from cells, especially with concurrent renal insufficiency
  - Pseudohyperkalemia: potassium elevation in sample because of blood draw complication
    - Mechanical trauma
    - Repeated fist clenching
    - In patients with thrombocytosis
    - In patients with chronic lymphocytic leukemia
    - In patients with familial hyperkalemia
  - Fasting
  - Metabolic acidosis
  - Hyperglycemia
  - Insulin deficiency, especially in uncontrolled diabetes mellitus
  - Increased tissue catabolism, seen in:
    - Tumor lysis syndrome
    - Rhabdomyolysis
    - Trauma
    - Severe accidental hypothermia
  - Rare causes
    - Familial hyperkalemic periodic paralysis
    - Overdose of certain plants (digitalis, related digitalis glycosides)
    - Red cell transfusion, especially in infants with massive transfusions
    - Administration of succinylcholine, in patients with neuromuscular disease, burns, severe trauma, prolonged immobilization, or chronic infection
    - Administration of arginine hydrochloride
  - Drugs
    - Nonsteroidal anti-inflammatory drugs (aspirin, ibuprofen, naproxen)
    - Potassium-sparing diuretics (spironolactone, eplerenone, amiloride, triamterene)
    - Somatostatin or somatostatin agonist (octreotide)
    - Beta blockers, especially non-selective beta blockers (e.g., propranolol, labetalol)
    - Angiotensin-converting enzyme (ACE) inhibitors
    - Angiotensin II receptor blockers (ARBs)
    - Aminocaproic acid
    - Heparin
    - Activators of ATP-dependent potassium channels
      - Calcineurin inhibitors (e.g., cyclosporine, tacrolimus)
      - Diazoxide
      - Minoxidil
      - Some volatile anesthetics (e.g., isoflurane)

Low in:⁷

Inadequate dietary intake
Low-calorie diet
Increased sweat losses
Dialysis
Plasmapheresis
Increased potassium entry into cells
- Elevated beta-adrenergic activity (e.g., from high stress)
- Metabolic or respiratory alkalosis
- Acute increase in blood cell production
- Hypothermia
- Hypokalemic periodic paralysis
Decreased potassium exit from cells
- Barium intoxication
- Cesium intoxication
Increased gastrointestinal potassium loss
- Vomiting
- Chronic diarrhea
- Laxative abuse
- Clay ingestion
- Ogilvie’s syndrome
Increased urinary potassium loss
- Primary mineralocorticoid excess (e.g., primary aldosteronism)
- Hypomagnesemia
- Renal tubular acidosis
- Polyuria
- Liddle’s syndrome
- Salt-wasting nephropathies
  - Bartter’s syndrome
  - Gitelman’s syndrome
  - Tubulointerstitial diseases (as seen in Sjögren’s syndrome)
  - Hypercalcemia
  - Tubular injury (as seen in leukemia)
- Drugs
  - Diuretics (especially carbonic anhydrase inhibitors, loop diuretics, thiazide-type diuretics)
  - Amphotericin B
  - Cisplatin
  - Chloroquine
  - Certain antipsychotics (risperidone, quetiapine)
  - Theophylline
  - High-dose penicillin
  - Beta-adrenergic agonists
    - Albuterol
    - Terbutaline
    - Dobutamine
  - Sympathomimetics
    - Pseudoephedrine
    - Ephedrine
  - Heroin

FUNCTIONAL RANGE INDICATIONS:

High in:

Functional dysglycemia
HPA axis dysfunction
Impaired kidney function
Pseudohypoaldosteronism

Low in:

Functional dysglycemia
HPA axis dysfunction
Malabsorption and malnutrition
Alcoholism
Medications such as antibiotics or diuretics
Many other disease states

References:

http://www.uptodate.com/contents/causes-and-evaluation-of-hyperkalemia-in-adults
ID, Linus S, Wingo CS. Disorders of potassium metabolism. In: Freehally J, Johnson RJ, Floege J, eds. Comprehensive clinical nephrology. 5th ed.St. Louis: Saunders, 2014:118-118
Malnic G, Giebisch G, Muto S, Wang W, Bailey MA, Satlin LM. Regulation of K+ excretion. In: Alpern RJ, Caplan MJ, Moe OW, eds. Seldin and Giebisch’s the kidney: physiology and pathophysiology. 5th ed. London: Academic Press, 2013:1659-1716
Mount DB, Zandi-Nejad K. Disorders of potassium balance. In: Taal MW, Chertow GM, Marsden PA, Skorecki KL, Yu ASL, Brenner BM, eds. The kidney. 9th ed. Philadelphia: Elsevier, 2012:640-688
http://www.uptodate.com/contents/clinical-manifestations-of-hyperkalemia-in-adults
http://www.uptodate.com/contents/clinical-manifestations-and-treatment-of-hypokalemia-in-adults
http://www.uptodate.com/contents/causes-of-hypokalemia-in-adults

Source: Kresser Institute

Protein, total

Marker Name: Protein, Total

REFERENCE RANGES FOR TOTAL PROTEIN:

Laboratory reference range: 6–8.5 g/dL

Functional reference range: 6.9–7.4 g/dL

DESCRIPTION:

Total protein is the quantity of circulating proteins per unit volume of serum. Blood contains a variety of circulating proteins, but they can be grouped into two major classes: albumin and globulins.¹ Serum albumin makes up 60 percent of total protein, and serum globulins make up the remaining 40 percent.² Globulins include immunoglobulins (i.e., antibodies), clotting factors, enzymes, and peptide hormones, among other proteins.^1,2 Plasma proteins perform a number of critical functions in blood such as providing osmotic pressure to maintain fluid balance between the vasculature and tissues, carrying small molecules and ions, and acting as an amino acid repository for tissues.²

Albumin and most globulin proteins are synthesized by the liver.³ One notable exception is immunoglobulins, which are synthesized by mononuclear cells in the bone marrow, lymph nodes, and spleen.⁴ The liver is capable of synthesizing all amino acids except for the so-called essential amino acids, which need to be consumed in the diet. This synthesis assumes, however, that the liver has a steady supply of dietary proteins for biosynthesis reactions. In healthy individuals, the rate of protein synthesis roughly equals the rate at which protein is used, catabolized by cells, or excreted. Thus, total protein levels in the serum are relatively stable.²

Total protein measurement is a relatively inexpensive way to quantify albumin and globulins in the blood. Most modern laboratories use a simple colorimetric assay to detect protein levels. Divalent copper reacts with peptide bonds within proteins to form a purple biuret complex.^1,5 Importantly, this reaction detects all peptide linkages, so total protein cannot distinguish between albumin or individual types of globulins.¹ Since albumin comprises roughly 60 percent of total serum protein, a decrease in albumin levels may be sufficient to reduce total protein quantity without altering other serum protein levels.^2,4 Additional testing is required to determine abnormalities in specific serum proteins.

Hyperproteinemia is an abnormally high level of proteins in the blood. Almost all cases of hyperproteinemia can be explained by one of two causes: either total water in the plasma is abnormally low, resulting in hemoconcentration, or the rate of protein synthesis is abnormally high (e.g., inflammation, monoclonal gammopathy).^2,4,6 Elevated total protein levels should be considered in the context of dehydration, either due to a lack of water intake or excessive water loss. In the absence of dehydration, one must consider inflammatory processes or hematological neoplasm. Tests for polyclonal and monoclonal immunoglobulins can help distinguish the former from the latter.

An abnormally low total serum protein level is called hypoproteinemia. Hemodilution or relative abundance of water in the plasma may cause relative hypoproteinemia. Hemodilution commonly occurs subsequent to intravenous fluid administration and in advanced congestive heart failure, but may also occur in polydipsia.^7-9 Aside from hemodilution, hypoproteinemia is either due to decreased protein production or increased protein loss. Decreased protein production may be due to protein malnutrition, which deprives the liver of amino acids and peptides required for biosynthetic pathways. Liver disease may result in decreased protein synthesis even in the context of adequate protein intake. While healthy kidneys do not excrete plasma proteins, people with nephrotic syndrome may experience considerable protein wasting in the urine, which can lead to hypoproteinemia.^3,10

Total protein is virtually always measured as part of a liver panel, which also includes alanine aminotransferase (ALT), acetate aminotransferase (AST), alkaline phosphatase, bilirubin, and albumin.¹¹ Some liver function tests also include gamma-glutamyl transferase (GGT) and lactate dehydrogenase. Since hemodilution and hemoconcentration can directly affect the interpretation of total serum protein, a basic or complete metabolic panel is also ordered to obtain measures of blood urea nitrogen (BUN) and creatinine.²

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^3,4,6

Hemoconcentration
- Inadequate water intake
- Excessive diuresis
Acute inflammation
Acute infection
HIV/AIDS
Amyloidosis
Hematological neoplasm
- Multiple myeloma
- Monoclonal gammopathy
- Lymphoma
- Leukemia
- Macroglobulinemia (e.g., Waldenström macroglobulinemia)

Low in:^3,7-9,12

Hemodilution
- Excessive IV fluid administration
- Advanced congestive heart failure
- Polydipsia
- Protein malnutrition
Protein malnutrition
Advanced liver disease
Renal failure
Nephrotic syndrome
Protein-losing enteropathy
- Primary gastrointestinal mucosal diseases (e.g., ulcerative colitis)
- Increased interstitial pressure or lymphatic obstruction (e.g., sarcoidosis)
- Non-erosive upper gastrointestinal diseases (e.g., celiac sprue)
Hypogammaglobulinemia

FUNCTIONAL RANGE INDICATIONS:

High in:

Hypochlorhydria
Gout

Low in:

Protein malabsorption (due to hypochlorhydria or impaired liver function)

References:

Source: Kresser Institute

PTH

Marker Name: PTH

REFERENCE RANGES FOR PTH:

Laboratory reference range: 15–65 pg/mL

Functional reference range: 15–30 pg/mL (PTH levels >30 pg/mL may be indicative of biological vitamin D deficiency when 25(OH)D levels are low.)

DESCRIPTION:

Parathyroid hormone (PTH) is one of the two hormones, along with calcitriol, that governs calcium and phosphate homeostasis.¹ Under normal circumstances, PTH maintains serum calcium levels within a narrow range. The hormone does this by stimulating calcium resorption in the kidneys and bone resorption.¹ PTH also indirectly helps increase serum calcium by stimulating the production of enzymes in the kidney that convert 25-hydroxyvitamin D to its more active form, 1,25-dihydroxyvitamin D (calcitriol).¹ Calcitriol then increases intestinal absorption of calcium, increases resorption rate of bone, and decreases excretion of calcium and phosphate by the kidneys.² PTH is the main hormone responsible for maintaining serum phosphate levels, which it does by altering renal reabsorption of phosphate and liberating phosphate through bone resorption.³

Calcium in the blood regulates the release, synthesis, and degradation of PTH.¹ Parathyroid cells possess sensitive calcium-sensing surface receptors.¹ Once these receptors sense a drop in serum calcium, parathyroid cells release PTH through exocytosis.⁴ Hypocalcemia, by acting at calcium-sensing receptors on parathyroid cells, can prompt acute and chronic effects of PTH. In addition to exocytosis of PTH, which takes seconds to minutes, hypocalcemia may stimulate PTH gene expression and the proliferation of additional parathyroid cells over the course of days to weeks. Conversely, increases in plasma calcium inhibit PTH secretion. In this way, adequate vitamin D can suppress PTH levels by reducing the need for PTH to increase serum calcium.

PTH is an 84-amino acid polypeptide (PTH (1-84)) that is synthesized, stored, and secreted by the parathyroid glands.¹ However, it is initially produced as a 115-amino acid peptide and cleaved into a 90-amino acid peptide before being cleaved to its most active 84-amino acid form.⁵ Once secreted, the PTH (1-84) is cleared from the bloodstream within two to four minutes, by uptake into the liver and kidney or, to a lesser extent, through proteolytic degradation.¹^,⁶ The 84-amino acid peptide may be further broken down into smaller C-terminal and N-terminal fragments that may be mildly bioactive.⁵ C-terminal fragments have a five- to tenfold longer half-life. As such, the amount of PTH (1-84) may only represent 5 to 30 percent of circulated PTH.

The existence of C- and N-terminal fragments may have implications for PTH hormone assays.⁵PTH assays are primarily done by two-site immunometric assays, whereas they were formerly measured through radioimmunoassay. Second-generation two-site immunometric assays are called “intact” PTH assays and measure PTH (1-84) and other large C-terminal PTH fragments. Third-generation two-site immunometric assays are called “bioactive” PTH assays and only measure PTH (1-84), not C-terminal PTH fragments.⁵ For most purposes, “intact” and “bioactive” PTH assays provide virtually the same clinical information.⁴ However, there may be instances when third-generation “bioactive” assays may be clinically superior. Examples include PTH measurement in patients with renal failure, intraoperative PTH monitoring, PTH carcinoma, and for patients that have inappropriately “normal” serum PTH concentrations by “intact” PTH assays.⁵

Increased levels of PTH are a normal response to hypocalcemia. However, in a healthy state, the changes in PTH and calcium should rapidly reach equilibrium, driving both values into the normal range. Severe hypocalcemia that cannot be corrected through homeostatic mechanisms, as seen in vitamin D deficiency and chronic kidney failure, may lead to chronic elevations in PTH.¹ This condition is called secondary hyperparathyroidism. Elevated PTH without a concomitant decrease in serum calcium suggests primary hyperparathyroidism.⁷ Primary hyperparathyroidism occurs when the parathyroid glands secrete too much PTH, perhaps due to a nodule in one of the glands itself. Tertiary hyperparathyroidism follows from chronic hypocalcemia and long-standing secondary hyperparathyroidism; hyperplasia in the parathyroid glands leads to increased PTH secretion.⁸

PTH levels should decrease in states of hypercalcemia as a normal homeostatic response.¹

However, chronically elevated calcium will result in decreased PTH secretion as the parathyroid glands attempt to compensate for the hypercalcemia.⁷ If PTH is not responding correctly, such as happens in hypoparathyroidism, both calcium and PTH levels may be abnormally low.⁷ Severe hypomagnesemia causes hypocalcemia by impairing PTH release in hypocalcemic states.^9,10

PTH is virtually always measured along with serum calcium and is often measured along with phosphate, magnesium, 25-hydroxyvitamin D, or 1,25-dihydroxyvitamin D.⁷

Finally, recent research suggests that PTH may be used to determine whether 25(OH)D levels that are borderline low are indicative of biological vitamin D deficiency. According to a meta-analysis studying the suppressive effect of vitamin D on PTH, the effect was greatest with PTH levels over 49 (PTH was suppressed by 21 pg/mL), less significant with PTH levels between 38 and 49 pg/mL (PTH was suppressed by 17 pg/mL), and very small with PTH levels <38 pg/mL (PTH was suppressed by 2 pg/mL).¹¹ These data suggest that PTH levels >30 pg/mL should corroborate concerns about low 25(OH)D in proportion to its upward divergence from 30 pg/mL.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^7,8

Primary hyperparathyroidism
PTH-secreting tumor
Hypocalcemia (secondary hyperparathyroidism)
- Vitamin D deficiency
- Chronic kidney failure
Tertiary hyperparathyroidism (chronic hypocalcemia and parathyroid gland hyperplasia)
Drugs
- Lithium
- Calcimimetic drugs (e.g., Norcalcin, cinacalcet)
- Non-hypercalcemic vitamin D analogs (e.g., oxacalcitriol, paricalcitol, 1-alpha-hydroxyvitamin D2)

Low in:^7,9,10

Hypercalcemia
Hypoparathyroidism
Congenital hypoparathyroid disorders
Hypomagnesemia

FUNCTIONAL RANGE INDICATIONS:

High in:

Vitamin D deficiency

Low in:

Same as conventional indications

References:

Source: Kresser Institute

RBC

Marker Name: RBC

REFERENCE RANGES FOR RBC COUNT:

Laboratory reference range: 4.14–5.80 x 106/µL

Functional reference range: 4.40–4.90 x 106/µL

DESCRIPTION:

Red blood cells (RBCs), also known as erythrocytes, deliver oxygen to cells throughout the body. They also absorb and carry carbon dioxide from tissues to the lungs to be expired and can help buffer blood pH. The most numerous cells in the body, RBCs make up about 40 to 45 percent of blood by volume; a healthy person contains about 600 RBCs for every white blood cell.¹

Oxygen in RBCs is carried by hemoglobin, a large protein molecule with four iron atoms at its center to which oxygen is loosely attached. Oxygenated hemoglobin is red, giving blood its characteristic color. When RBCs lose their oxygen, however, the shape of the hemoglobin molecule changes such that, when viewed through the skin, deoxygenated blood traveling through the veins appears blue.²

Red blood cell function is enhanced by its distinct biconcave disc shape, which adds valuable surface area for the exchange of O₂ and CO₂ without adding volume to the cell. Similarly, RBCs are one of the only cells in the body without a nucleus, which allows them to maximize hemoglobin content while further minimizing volume. RBCs are also highly flexible, enabling them to squeeze through even the smallest-diameter capillaries.¹

Red blood cell production, or erythropoiesis, occurs in the bone marrow and is regulated by a complex array of cytokines and hormones. One key hormone is erythropoietin, produced in the kidneys. Erythropoietin cooperates with other growth factors to stimulate development of red blood cells from multipotent progenitors.³ Once mature, the average lifespan of a red blood cell is 120 days. In order to produce red blood cells at an adequate rate, healthy levels of many key nutrients are needed.^4,5

High red blood cell count (erythrocytosis) can be caused by dehydration, states of decreased oxygen availability, myeloproliferative disorders, states of elevated erythropoietin, certain drugs, and other conditions. A full list of conditions and drugs that can cause high red blood cell count is provided below.^6-13

Low red blood cell count (often defined as anemia) can be caused by normal pregnancy, certain nutrient imbalances, chronic inflammation, bone marrow disorders, certain anemias, endocrine disorders, chronic kidney disease, certain inherited disorders, and specific drugs. A full list of conditions and drugs that can cause low red blood cell count is below.^14-16

To determine the etiology of abnormal RBC level, related markers should be considered, including hemoglobin, serum iron, ferritin, TIBC, UIBC, iron saturation, and other markers in the complete blood count (CBC).

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:⁶

Dehydration⁸
Smoking
Chronic carbon monoxide poisoning
High-altitude living
Congenital heart disease
Myeloproliferative disorders
- Polycythemia vera
- Essential thrombocytosis
- Primary idiopathic myelofibrosis (myelosclerosis)
- Chronic myelogenous leukemia
Erythropoietin-producing neoplasms (e.g., renal cell carcinoma, hepatocellular carcinoma, haemangioblastoma, etc.)⁷
Certain genetic conditions causing:
- Altered oxygen sensing
- Abnormal hemoglobin oxygen release
Post renal transplant⁹
Autologous blood transfusions
States of hypoxemia¹⁰
- Sleep apnea¹²
- Massive obesity
- Pulmonary fibrosis
- Emphysema
- Hypoventilation
  - Muscle-wasting diseases (e.g., myasthenia gravis)
  - Neurodegenerative diseases
  - Congenital central hypoventilation syndrome
- Right-to-left cardiac shunts
- Ventilation perfusion abnormality
Drugs
- Androgens or anabolic steroids¹¹
- Morphine
- Diuretics¹³

Low in:^14,16

Normal pregnancy
Nutrient imbalances^4,5
- Folate deficiency
- Iron deficiency
- Copper deficiency
- Vitamin B2 deficiency
- Vitamin B3 deficiency
- Vitamin B6 deficiency
- Vitamin B12 deficiency
- Vitamin E deficiency
- Lead poisoning
Chronic inflammation (e.g., chronic infection, malignancy, rheumatologic disorders, inflammatory bowel disease, chronic immune activation, and other inflammatory disorders)
Certain bone marrow disorders (e.g., preleukemia, myeloid leukemia, aplastic anemia, erythroleukemia)
Sideroblastic anemia¹⁵
Alpha and beta thalassemia
Hemolytic anemia (e.g., autoimmune hemolytic anemia, sickle cell anemia, malaria, etc.)¹⁵
Myelophthistic anemia
Endocrine disorders
- Hypothyroidism
- Adrenal corticosteroid deficiency
- Gonadal deficiency
Chronic renal disease
Congenital disorders of DNA synthesis
Drugs
- Isoniazid
- Pyrazinamide
- Chloramphenicol

FUNCTIONAL RANGE INDICATIONS:

High in:

Dehydration
Erythrocytosis
Polycythemia

Low in:

Functional anemia

References

Source: Kresser Institute

RDW

Marker Name: RDW

REFERENCE RANGES FOR RDW:

Laboratory reference range: 12.3–15.4%

Functional reference range: 11.5–15%

DESCRIPTION:

Red cell distribution width (RDW) describes the variation in sizes of red blood cells in the bloodstream. Red cell distribution width is measured with mean corpuscular volume (MCV), since each of the two values can only be fully interpreted with knowledge of the other. MCV represents the mean volume across all red blood cells, but it does not provide information about red blood cell volume variability in a sample. RDW, on the other hand, indicates whether red blood cells are roughly the same volume or have a wide range of volumes. It is expressed as the coefficient of variation, that is, as a percentage.¹

Modern laboratories measure RDW using automated hematology instruments. These instruments only report RDW, but they have the ability to generate a histogram of red blood cell widths. Typically, the distribution of red blood cell widths is symmetrical, similar to a normal distribution.²Most red blood cells will have a width near the mean with fewer blood cells on either end of the distribution (small widths and large widths). However, abnormalities in this distribution curve could suggest the presence of certain disease states.²

If there is a “shoulder” on the right side of the curve, this indicates the presence of very large red blood cells in the sample. These red blood cells could be macrocytes or reticulocytes. Conversely, a “shoulder” on the left side of the curve indicates the presence of very small red blood cells such as microspherocytes, schistocytes, large platelets (macrothrombocytocytes), or platelet clumps.

The results of this histogram are not reported on standard lab results. Instead, a single mean value, the RDW, is reported. As such, RDW can be either normal or elevated; there is no medical condition that causes a consistently low RDW.¹ A normal RDW generally means that the red blood cells in a sample have a similar volume, while a high RDW indicates red blood cells with varying volumes. Importantly, a normal RDW does not necessarily mean that the red blood cells are themselves a normal size. A normal RDW could simply mean that a large portion of red blood cells are abnormally large or small.¹ For this reason, mean corpuscular volume (MCV) must be measured concurrently.

The pattern of elevated RDW and low MCV is associated with iron deficiency and sickle cell-β-thalassemia. If MCV is normal but RDW is high, it could indicate early iron, vitamin B12, or folate deficiency. This pattern may also occur in sickle cell disease, chronic liver disease, and myelodysplastic syndrome. When both RDW and MCV are high, it could also indicate folate or vitamin B12 deficiency, chronic liver disease, or myelodysplastic syndrome, but it may also reflect the administration of cytotoxic chemotherapeutic agents.

RDW and MCV are always measured together, as are the other red blood cell indices, mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC).³ These tests are virtually always performed along with a total red blood cell count, hemoglobin, and hematocrit, and, in some cases with a reticulocyte count. If it was not measured initially, abnormalities in RDW are usually confirmed and elaborated with a peripheral blood smear test.⁵

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS: High in:^5-8

Nutrient imbalances
- Iron deficiency (especially early deficiency)
- Folate deficiency (especially early deficiency)
- Vitamin B12 deficiency (especially early deficiency)
Immune hemolytic anemia
Cytotoxic chemotherapy
Chronic liver disease
Myelodysplastic syndrome
Sickle cell disease
Sickle cell-β-thalassemia
Chronic liver disease
Cardiovascular diseases
- Peripheral artery disease
- Atrial fibrillation
- Heart failure
- Hypertension
- Acute myocardial infarction
- Acute stroke

Low in:¹

Laboratory error
Error during blood withdrawal or blood handling

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

Sodium

Marker Name: Sodium

REFERENCE RANGES FOR SERUM SODIUM:

Laboratory reference range: 134–144 nmol/L

Functional reference range: 135–140 nmol/L

DESCRIPTION:

Most of the body’s sodium (Na) is found in plasma, where it is the main extracellular cation. Sodium plays a key role in regulating extracellular fluid volume (ECF), blood pressure, osmotic equilibrium, and acid-base balance, and it contributes to the resting membrane potential across all cell membranes, which is important for muscle and nerve function.^1,2 Approximately 30 percent of sodium is found in nonexchangeable locations such as bone, but serum sodium concentration is a useful representation of total body sodium.³

Sodium cannot freely diffuse across cell membranes, but water can. When serum sodium concentration changes, water moves in and out of cells to maintain osmotic equilibrium between intracellular and extracellular fluid. Because of this phenomenon, abnormal serum sodium concentration primarily indicates a disorder of water balance (dehydration or overhydration), as opposed to a disorder of total plasma sodium. These changes in water balance do not cause a disorder in ECF volume (hypervolemia or hypovolemia) until the condition is extreme, because approximately two-thirds of water is intracellular and only one-third is extracellular.⁴

Serum sodium homeostasis involves the kidneys, intestines, and hypothalamus. It is primarily maintained by thirst and antidiuretic hormone (ADH, also referred to as vasopressin), which regulate water consumption and urinary water conservation, respectively.⁴

High serum sodium concentration (hypernatremia) is a disorder of too little water, or dehydration. It is most often caused by unreplaced loss of fluid that is hypotonic to plasma; that is, loss of fluid that has a concentration of osmotically active electrolytes (i.e., sodium plus potassium) that is lower than the concentration of sodium in plasma. Hypernatremia can also be caused by sodium overload or excessive glycogen breakdown. A complete list of specific conditions that can cause high serum sodium is provided below. Water intake corrects hypernatremia, so prolonged hypernatremia requires either impaired thirst, which is most often caused by hypothalamic lesions or mental illness, or lack of independent access to water, which most often occurs with infants and the elderly.³

Low serum sodium concentration (hyponatremia) is a disorder of too much water, or overhydration. It can be caused by advanced renal failure, malnourishment, primary polydipsia (increased thirst), reduced effective arterial blood volume, syndrome of inappropriate ADH secretion (SIADH), certain endocrine disorders (adrenal insufficiency, hypothyroidism), pregnancy, extreme exercise, hyperglycemia, absorption of irrigant solutions during surgery, and many drugs. Pseudohyponatremia can occur when the plasma water fraction is decreased by abnormally high serum protein or fat content. Hyponatremia is unusual if the ability to dilute urine is intact, because the maximum attainable urine volume in normal circumstances is over 10 L/day, while normal water intake is under 2.5 L/day. A complete list of disorders that can cause hyponatremia is provided below.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:³

Dehydration due to unreplaced loss of fluid that is hypotonic to plasma. Effect is transient, unless thirst or water access is inhibited.
- Water losses (insensible, sweat)
- Gastrointestinal water losses (vomiting, osmotic diarrheas)
- Urinary water losses
  - Central or nephrogenic diabetes insipidus
  - Osmotic diuresis, due to:
    - High glucose (as seen in uncontrolled diabetes mellitus)
    - Urea (as seen in high-protein tube feedings)
    - Mannitol therapy
  - Hypothalamic lesions impairing thirst or osmoreceptor function
    - Adipsic diabetes insipidus
    - Primary hypodipsia
    - Primary mineralocorticoid excess
  - Sodium overload (effect is transient, unless thirst or water access is inhibited)
    - Intake or administration of hypertonic sodium solutions
    - Sodium poisoning
  - Water loss into cells due to glycogen breakdown (effect is transient)
    - Extreme exercise
    - Seizures
  - Drugs
    - Loop diuretics⁴

Low in:⁵

FUNCTIONAL RANGE INDICATIONS:

High in:

Functional dysglycemia (check other markers of glycemic dysregulation)
HPA axis dysregulation (more likely hyperfunction)
Cushing’s disease
Mild dehydration

Low in:

Functional dysglycemia
Hypothyroidism
HPA axis dysregulation (more likely hypofunction)
Addison’s disease or glucocorticoid-induced adrenal insufficiency

References:

Source: Kresser Institute

T3, free

Marker Name: Free T3

REFERENCE RANGES FOR SERUM FREE T3 (TRIIODOTHYRONINE):

Laboratory reference range: 2.0–4.4 pg/mL

Functional reference range: 2.5–4.0 pg/mL

DESCRIPTION:

Triiodothyronine (T3) is the most biologically active thyroid hormone in humans.¹ T3 modifies gene transcription in virtually every cell, which alters the rate of protein synthesis and substrate turnover.² Thyroid hormone is critical for the development of brain and other tissues in fetuses and infants and sets the “metabolic tone” of cells in adults. As such, the synthesis and secretion of thyroid hormone is tightly regulated through several feedback mechanisms.³

The synthesis and secretion of T4 and T3 by the thyroid gland is under direct control of thyroid-stimulating hormone (TSH, also called thyrotropin). Thyroid-stimulating hormone is produced by the pituitary gland in response to elevations in thyrotropin-releasing hormone (TRH) produced in the hypothalamus.³ As levels of T4 and T3 increase in the blood, they exert negative feedback signals on both the hypothalamus and the pituitary gland to reduce secretion of TRH and TSH, respectively.

t3-free-a

t3-free-b

While T4 production takes place solely within the thyroid gland, approximately 80 percent of T3 is produced from T4 in peripheral tissues by deiodinase enzymes.³ The remaining 20 percent is synthesized and secreted by the thyroid gland.³ Two major forms of thyroxine-5′-deiodinase enzymes (type I and type II) are responsible for converting free T4 into the more active thyroid hormone, T3.³ Type I thyroxine-5′-deiodinase is a plasma membrane-bound enzyme present mostly in liver, kidney, and thyroid tissue. Type II thyroxine-5′-deiodinase is a microsomal enzyme found in muscle, brain, pituitary, skin, and placental tissue.

The action of type I thyroxine-5′-deiodinase is increased during hyperthyroidism, but decreased in hypothyroidism, starvation, diabetes mellitus, uremia, or treatment with propylthiouracil, amiodarone, or propranolol.³ Type II thyroxine-5′-deiodinase is increased in hypothyroidism and decreased in hyperthyroidism. Amiodarone also decreases the action of type II thyroxine-5′-deiodinase.³

Elevated free T3 levels may indicate hyperthyroidism, thyroid hormone resistance syndrome, or T3 toxicosis.^4,⁵ Serum T3 levels can be expected to increase during normal pregnancy.⁶ Free T3 is generally more accurate in cases of hyperthyroidism than it is for diagnosing hypothyroidism.

Decreased free T3 levels in the serum usually indicate hypothyroidism or chronic or subacute thyroiditis. Drugs that interfere with the conversion of T4 to T3 will decrease free T3 levels, with a reflexive increase in T4 levels. Amiodarone, for example, can inhibit the conversion of T4 to T3.⁷Free T3 is actually less useful as an indicator of thyroid function than T4.^1,8 Free T3 may be normal in hypothyroidism, when TSH levels are high and free T4 levels are low. Furthermore, any serious illness can interfere with the activity of type I thyroxine-5′-deiodinase and lower free T3 levels.⁹

Clinical laboratories do not directly measure free T3.^10,11 Free T3 is estimated from Total T3 and thyroid hormone-binding index.¹⁰ Thus, free T3 is not measured without total T3. Free T3 is usually also measured with serum TSH, total T4, and free T4. An abnormal free T3 may be followed by tests to identify autoimmune causes of thyroid disease including thyroid peroxidase (TPO), thyroglobulin (Tg), and the TSH receptor antibody studies.¹⁰

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^6,7,10,12

Pregnancy
Hyperthyroidism (e.g., Graves’ disease)
Acute thyroiditis (e.g., postpartum thyroiditis)
T3 toxicosis
Thyroid hormone resistance syndrome

Low in:^9,10,12

Hypothyroidism
Chronic thyroiditis
Subacute thyroiditis
Critical, non-thyroidal illness
Drugs that impair deiodination (i.e., conversion from T4 to T3)
- Amiodarone
- Glucocorticoids
- Contrast agents
- Propylthiouracil
- Propranolol
- Nadolol

FUNCTIONAL RANGE INDICATIONS:

High in:

Hyperthyroidism
Facetious hyperthyroidism

Low in:

Hypothyroidism
Inflammation

References:

Source: Kresser Institute

T3, reverse

Marker Name: Reverse T3

REFERENCE RANGE FOR REVERSE T3 (TRIIODOTHYRONINE):

Laboratory reference range: 9.2–24.1 ng/dL

DESCRIPTION:

Reverse triiodothyronine (reverse T3; rT3) does not stimulate nuclear thyroid hormone receptors and, as such, is considered an inactive thyroid hormone. While rT3 possesses no direct thyroid hormone effect, the molecule is a competitive inhibitor of enzymatic conversion of T4 to T3.¹

reverse-t3a

reverse-t3b

Reverse T3 may also play several minor biological roles.² For example, rT3 potently initiates actin polymerization in astrocytes, which means it plays a potentially critical role in brain development.³Reverse T3 also inhibits the release of free fatty acids normally stimulated by dexamethasone or adrenaline.⁴

Serum rT3 levels do not increase in response to TSH, as T3 and T4 levels do, suggesting that thyroid secretion of rT3 is negligible. Conversion of T4 to rT3 in peripheral tissues is the main way rT3 is synthesized.⁵ Two major forms of thyroxine-5′-deiodinases (type I and type II) are responsible for converting free T4 into the more active thyroid hormone, T3.⁶ While type I can also convert T4 into rT3, a third thyroxine-5′-deiodinase (type III) is primarily responsible for this enzymatic conversion.^6-8 Type III thyroxine-5′-deiodinase is found in virtually every peripheral tissue except the pituitary gland. The enzyme is particularly important during fetal development, but it is normally undetectable in adult tissues.⁹ However, recent work with sensitive assays shows that type III is also present in adult tissues, especially neurons, and increases dramatically after tissue injury or during severe illness.^7,9

Type III thyroxine-5′-deiodinase activity is increased during hyperthyroidism and decreased during hypothyroidism, leading to relative increases and decreases in rT3 levels, respectively. This deiodinase is induced in tissues that have been injured or are suffering from hypoxia.⁹Conversely, growth hormone and glucocorticoids reduce the activity of this enzyme. In addition to converting T4 into rT3, type III thyroxine-5′-deiodinase also inactivates T3, converting it into 3,3′-diiodothyronine (T2).⁷ Both type I and type II thyroxine-5′-deiodinases convert rT3 into T2.¹⁰

Most causes of elevated rT3 are due to changes in the activity of type III thyroxine-5′-deiodinase.^11,12 Any serious illness can induce the activity of this enzyme, but hypoxia and ischemia appear to be particularly potent.¹³ Type III thyroxine-5′-deiodinase activity increases as does the level of serum rT3 in protein calorie malnutrition, carbohydrate deprivation, chronic renal failure, cirrhosis, and uncontrolled diabetes. Non-thyroidal illness syndrome (i.e., euthyroid sick syndrome) is recognized by low T3 and T4 concentrations with elevated rT3 levels in the context of inappropriately low or unchanged thyroid-stimulating hormone (TSH) levels.¹⁴

Any state that suppresses the action of type III thyroxine-5′-deiodinase would, in turn, decrease serum rT3 levels. In practical terms, this only occurs in patients with hypothyroidism or those being treated with growth hormones or glucocorticoids.⁷ Individuals with a rare genetic defect called X-linked monocarboxylate transporter 8 deficiency effectively have reduced type III thyroxine-5′-deiodinase activity and low rT3 levels.^11,15

Serum rT3 levels are most useful in a clinical setting as a means of distinguishing between nonthyroidal illness and a primary thyroid disease.¹² In patients with central hypothyroidism, rT3 levels are low because of reduced amounts of substrate, namely T4. On the other hand, Type III thyroxine-5′-deiodinase activity is induced by severe illness, especially hypoxia or ischemia, which will increase serum rT3 levels.

Thyroxine sulfate levels may also be measured with rT3; thyroxine sulfate is elevated in severe nonthyroidal illness.¹⁶ Serum rT3 levels are usually only measured in the context of a thyroid function work-up including total T3, total T4, free T4, TSH, etc.^12,17,18

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^{5,11,14,19,20}

Carbohydrate deprivation
Malnutrition
Hyperthyroidism
Non-thyroidal illness syndrome (i.e., euthyroid sick syndrome)
Inflammation
Cirrhosis
Chronic renal failure
Acute febrile illness
Uncontrolled diabetes mellitus
Drugs
- Amiodarone

Low in:^12,13,15

Central hypothyroidism
X-linked monocarboxylate transporter 8 deficiency
Drugs
- Growth hormone
- Glucocorticoids

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

T3, total

Marker Name: Total T3

REFERENCE RANGES FOR TOTAL T3 (TRIIODOTHYRONINE):

Laboratory reference range: 71–180 ng/dL

Functional reference range: 100–180 ng/dL

DESCRIPTION:

Triiodothyronine (T3) is the major biologically active thyroid hormone.¹ Thyroid hormone alters the rate of protein synthesis and substrate turnover of essentially every cell in the body by directly driving gene transcription.² Thyroid hormone is critical for early human development and cellular activity throughout life. Serious and long-term developmental delays can occur if insufficient thyroid hormone is available to a developing fetus, neonate, or child. Likewise, too much or too little circulating thyroid hormone causes various health issues in adults.^3,4 Therefore, several physiological mechanisms exist to tightly control the synthesis and secretion of thyroid hormone.⁵

Approximately 20 percent of T3 is synthesized and secreted by the thyroid gland, while the remaining 80 percent comes from the enzymatic conversion of T4 (thyroxine) to T3 in peripheral tissues.⁵ Thyroid-stimulating hormone (TSH, also called thyrotropin) controls virtually every step of thyroid hormone synthesis and secretion in the thyroid gland and drives peripheral conversion of T4 to T3. T4 is converted to T3 by several thyroxine-5′-deiodinase enzymes.⁵ Factors that influence thyroxine-5′-deiodinase activity include the presence of thyroid hormone, nutritional status, and acute illness.

t3-total-a

t3-total-b

T3 acts at nuclear receptors to alter gene transcription. It is thought that only free T3 (i.e., T3 that is not bound to serum proteins) can be taken up by cells and affect nuclear thyroid hormone receptors. Therefore, only free T3 is considered biologically active at any moment. A mere 0.5 percent of T3 in the serum is in this active state. The remaining 99.5 percent of T3 in the serum is bound to serum proteins; 80 percent is bound to thyroxine-binding globulin (TBG), 5 percent is bound to transthyretin (TTR), and 15 percent is bound to albumin and lipoprotein.⁵

Changes in the concentration of serum-binding proteins can have a substantial effect on total T3 concentrations in the blood.⁵ Increased TBG concentrations (e.g., from estrogens, hepatitis, etc.) will increase total T3, while abnormally low levels of TBG (e.g., from anabolic steroids, nephrotic syndrome, etc.) will lower total T3.⁶ Under most circumstances, serum-binding protein levels do not alter free T3 hormone concentrations or the absolute rate of T3 metabolism.^5,6 Consequently, serum total T3 concentrations may vary substantially based on serum protein concentrations but do not necessarily change free T3 concentrations in the blood.⁶

Elevated total T3 levels usually indicate hyperthyroidism or a euthyroid state in which serum protein levels are increased.^4,6,7 Drugs that increase TBG levels will increase total T3 levels.⁶Thyroid physiology changes during the course of normal pregnancy to meet the needs of the mother and the fetus. Consequently, total T3 concentrations rise during the first 20 weeks of gestation, reaching a new plateau level for the remainder of the pregnancy.⁸

Decreased total T3 levels in the serum may be present in individuals with hypothyroidism or chronic thyroiditis. Deficiency in serum-binding proteins will also result in decreased total T3 levels. This may occur in patients with nephrotic syndrome, who may pass substantial amounts of serum proteins in the urine, consequently lowering TBG and total T3 levels.⁹ High levels of circulating androgens, glucocorticoids, cortisol, or growth hormone can also lower TBG levels, and therefore total T3 levels.^6,10

Total T3 is often ordered with other thyroid markers, including TSH, total T4, free T3, and free T4.^11-13

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^6,8,14-16

Normal pregnancy
Hyperthyroidism
Euthyroid hyperthyroxinemia
T3 toxicosis
Acute thyroiditis
Familial dysalbuminemic hyperthyroxinemia
Drugs that increase TBG (e.g., estrogens, tamoxifen, opioids)
Synthetic triiodothyronine treatment

Low in:^6,14,15

Hypothyroidism
Chronic thyroiditis
Subacute thyroiditis
Nephrotic syndrome
Endocrine disorders that decrease TBG
- Cushing syndrome
- Acromegaly
- Uncontrolled diabetes mellitus
Drugs that decrease TBG (e.g., anabolic steroids, glucocorticoids)

FUNCTIONAL RANGE INDICATIONS:

High in:

Hyperthyroidism
Facetious hyperthyroidism (excess thyroid hormone replacement)

Low in:

Hypothyroidism
Inflammation

References:

Source: Kresser Institute

T3 uptake

Marker Name: T3 uptake

REFERENCE RANGES FOR T3 (TRIIODOTHYRONINE) UPTAKE:

Laboratory reference range:
Male and Female: 24–39%

Functional reference ranges:
Male: 30–38%
Female: 28–35%

DESCRIPTION:

Triiodothyronine (T3) uptake, or T3 resin uptake, estimates the saturation of thyroid hormone molecules on serum-binding proteins (mostly thyroxine-binding globulin, or TBG).^1,2 T3 uptake was developed to determine whether abnormal thyroxine (T4) levels are due to differences in free thyroid hormone levels or abnormal TBG levels.¹

According to the free hormone hypothesis, only free hormone (i.e., hormone that is not bound to serum proteins) can be taken up by cells and affect nuclear thyroid hormone receptors.^1,4 Less than 0.5 percent of serum T3 is “free”; 80 percent of T3 is bound to TBG, 15 percent is bound to albumin and lipoproteins, and 5 percent is bound to transthyretin (TTR).³ Given that the majority of thyroid hormone is bound, the levels of serum proteins can have a substantial effect on bound thyroid hormone levels, and therefore total thyroid hormone levels in blood.^1,3 Importantly, serum protein levels do not alter free hormone concentrations or the absolute rates of thyroid hormone metabolism.³ While total and free thyroid hormone levels can often provide an accurate picture of thyroid function, total thyroid hormone levels are decidedly inaccurate if serum-binding proteins are deficient or present in excess.^1,5 The T3 uptake test can provide clarity in these cases.

Utility of the T3 resin uptake test can be best understood through clinical examples. A person with an abnormally high T4 level may either have true hyperthyroidism or an elevated serum TBG level.⁶ The T3 resin uptake test can distinguish between the two clinical situations; uptake will be high in hyperthyroidism or low in a state of TBG excess. The converse is also true. A low T4 level may indicate hypothyroidism or diminished TBG. In hypothyroidism, T3 uptake will also be low. However, if TBG levels are abnormally low, T3 uptake will be abnormally high.⁶

Clinical Status	Total T4	T3 resin uptake
Hyperthyroidism	High	High
Hypothyroidism	Low	Low
High TBG	High	Low
Low TBG	Low	High

Any illness that depletes TBG levels will increase T3 uptake.⁶ This depletion of TBG may be due to a lack of serum protein production (e.g., liver cirrhosis) or through protein excretion by the kidney (e.g., nephrotic syndrome). Any serious illness can reduce TBG levels and increase T3 uptake. TBG levels are sensitive to the presence of other circulating hormones either in the context of disease (e.g., acromegaly, Cushing syndrome) or from exogenous administration (e.g., corticosteroids, androgens).

An increase in TBG in serum will decrease T3 uptake.⁶ While liver disease is usually associated with a drop in serum proteins (e.g., albumin), hepatitis and porphyria actually increase TBG levels.^7,8 Normal pregnancy may result in an increase in serum TBG. TBG levels are also related to circulating estrogens, including pharmacological doses of estrogens such as those found in oral contraceptives.

T3 resin uptake is only meaningful in the context of other thyroid function testing, particularly T4 levels. Therefore, it is essential to measure T3 uptake, T4 levels, and TSH levels together or temporally near each other.^1,5,6

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^5,10

Hyperthyroidism
Cushing disease
Acromegaly
Serious illness (i.e., reduced TBG)
Diabetic ketoacidosis
Cirrhosis
Nephrotic syndrome
X-linked decreased thyroid-binding globulin
Drugs
- Corticosteroids (e.g., prednisone)
- Androgens (e.g., anabolic steroids)
- Salicylates
- Asparaginase
- Danazol
- Niacin

Low in:^5,7,9

Pregnancy
Hypothyroidism
Hepatitis
Primary biliary cirrhosis
Malnutrition
Porphyria
X-Linked increased thyroid-binding globulin
Drugs
- Estrogens (e.g., oral contraceptives)
- Perphenazine
- Fluorouracil
- Clofibrate

FUNCTIONAL RANGE INDICATIONS:

High in:

Testosterone replacement
PCOS
Salicylate use
Heparin therapy

Low in:

Estrogen replacement
Heparin therapy

References:

Source: Kresser Institute

T4, free

Marker Name: Free T4

REFERENCE RANGES FOR FREE T4 (THYROXINE):

Laboratory reference range: 0.82–1.77 ng/dL

Functional reference range: 1.0–1.5 ng/dL

DESCRIPTION:

Free T4 is the portion of the total thyroid hormone T4 (thyroxine) pool that is not bound to serum proteins. T4 is the molecular precursor of T3 (triiodothyronine), which is an order of magnitude more potent than T4 at thyroid hormone-responsive receptors.¹ The thyroid gland is the only source of T4 synthesis in the body.² The terms T4 and T3 indicate four and three iodine atoms bound to the core thyroid hormone molecule, respectively.

t4-free-a

t4-free-b

A substantial amount of T4 is stored within the thyroid gland. Within this gland, most T4 is bound to the protein thyroglobulin within thyroid follicles.² Thyroid-stimulating hormone stimulates the thyroid gland to hydrolyze thyroglobulin and release free T4, along with other actions that promote thyroid hormone synthesis and secretion.³

Secreted free T4 quickly binds to serum proteins; greater than 99 percent of circulating T4 is bound to a serum protein.⁴ Approximately 75 percent of T4 in the bloodstream is bound to thyroxine-binding globulin (TBG), 12 percent is bound to albumin, 10 percent is bound to transthyretin, and 3 percent is bound to lipoproteins.^2,4 The remaining 0.02 percent of unbound T4, or free T4, is the biologically active portion of serum T4.²

Four different tests are available to estimate free T4. Two of them are routinely used by clinical laboratories, and none of them actually measures free T4 in the serum.⁵ The first free T4 estimate in common use is the “Free T4 index.” The Free T4 index estimates free T4 from total T4 and the thyroid hormone binding index, which is measured by determining T3 resin uptake. “Direct” free T4 assays estimate free T4 using various methodologies, none of which is a direct measurement.⁶The only true direct measurement of free T4 is by equilibrium dialysis, which is only available in reference laboratories and is not routinely used in clinical laboratories because of its cost.⁵ The major drawback of each of the four laboratory clinical assays is that if the patient has a serum-binding protein abnormality, results are significantly inaccurate.⁵

Since free T4 is often estimated rather than directly measured, there is a risk that abnormalities in total T4 may be due to abnormalities in TBG levels, rather than true hyperthyroidism or hypothyroidism. When total T4 levels are abnormal, a normal free T4 value suggests an abnormality in TBG levels.^5,7 True hyper- or hypothyroidism will be accompanied by elevated or reduced levels of free T4, respectively. In some cases, T4 levels may be abnormally high in the absence of TSH abnormalities or overt signs of hyperthyroidism (e.g., euthyroid hyperthyroxinemia).⁸Decreased free T4 levels in the serum usually indicate hypothyroidism or chronic or subacute thyroiditis.

Free T4 may be measured with serum TSH to determine the degree of hypothyroidism or hyperthyroidism.⁵ Combining the measurement of serum TSH and serum free T4 increases the sensitivity and specificity of thyroid function testing.⁹ Free T4 may also be measured with total T3, free T3, or reverse T3 in certain circumstances. Patients with suspected autoimmune thyroiditis may be tested for the presence of antibodies against thyroid peroxidase (TPO), thyroglobulin (Tg), and the TSH receptor, along with serum free T4 levels.⁵

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^5,10-12

Pregnancy
Hyperthyroidism
Euthyroid hyperthyroxinemia
TSH-mediated hyperthyroidism
Acute thyroiditis
Familial dysalbuminemic hyperthyroxinemia
Drugs that increase TBG (e.g., estrogens, tamoxifen, opioids)
Drugs that decrease T4 conversion to T3 (e.g., amiodarone)

Low in:^5,10,13

Hypothyroidism
Chronic thyroiditis
Subacute thyroiditis
Nephrosis
Congenital thyroid agenesis, dysgenesis, or defects in hormone synthesis
Synthetic triiodothyronine treatment
Drugs that decrease TBG (e.g., anabolic steroids, glucocorticoids)
Drugs that increase T4 clearance (e.g., phenytoin, carbamazepine, phenobarbital)
Drugs that inhibit T4 synthesis/release (e.g., thionamides, lithium, perchlorate)

FUNCTIONAL RANGE INDICATIONS:

High in:

Hyperthyroidism
Facetious hyperthyroidism

Low in:

Hypothyroidism
T3 replacement therapy

References:

Source: Kresser Institute

T4, total

Marker Name: Total T4

REFERENCE RANGES FOR TOTAL T4 (THYROXINE):

Laboratory reference range: 4.5–12 µg/dL

Functional reference range: 6–12 µg/dL

DESCRIPTION:

T4 (thyroxine) is one of two biologically active thyroid hormones.¹ T4 is the molecular precursor of T3 (triiodothyronine), which is the substantially more potent thyroid hormone; T3 binds to thyroid hormone-responsive receptors with 10 to 15 times greater affinity than T4.² Given this difference in potency, T4 may be considered a prohormone to T3. The abbreviations T4 and T3 reflect the number of iodine atoms found in the respective thyroid hormone molecules.

t4-total-a

t4-total-b

T4 is produced solely by the thyroid gland and is stored in large quantities within the gland.¹ T4 is bound to thyroglobulin within the thyroid gland, mostly within the lumen of thyroid follicles.¹Thyroid-stimulating hormone (TSH) acting on the thyroid gland causes T4 to be released into the bloodstream.³

T4 is enzymatically converted to T3 in the peripheral tissues. In fact, roughly 80 percent of T3 is produced by deiodination of T4 outside of the thyroid gland. This deiodination is performed by thyroxine-5′-deiodinases found largely in the liver and kidney, but also present in muscle, brain, pituitary, skin, and placenta.⁴ Interestingly, the deiodinases are selenoproteins (selenium-containing proteins), and selenium deficiency exacerbates autoimmune thyroid disease and endemic cretinism.⁵

Greater than 99 percent of T4 circulating in the bloodstream is bound to a serum protein.⁶ Three-quarters of circulating T4 is bound to thyroxine-binding globulin (TBG), 12 percent is bound to albumin, and 10 percent is bound to transthyretin.^1,6 Less than one-tenth of 1 percent of serum T4 is not bound to proteins, yet only the unbound portion of T4 is biologically active. The laboratory assay “total T4” measures both bound and unbound T4. T4 that is not bound to any serum protein is “free T4.” The relative levels of these serum proteins can make a considerable difference on thyroid function status. Total T4 provides a better estimate of thyroid function when TBG levels are normal.⁷

Elevated total T4 levels may occur in patients with hyperthyroidism but do not necessarily define hyperthyroidism. For instance, euthyroid hyperthyroxinemia is a condition in which T4 levels are elevated in the absence of abnormal TSH levels or clinical signs of hyperthyroidism.⁸ Drugs that increase TBG levels will also tend to increase total T4 levels, as this state creates additional binding sites for thyroxine in the blood. Iodine-containing drugs such as amiodarone can inhibit the conversion of T4 to T3, causing a relative increase in the prohormone T4.⁹ Normal pregnancy changes thyroid physiology; total T4 concentrations rise during the first half of pregnancy and reach a new steady state at approximately 20 weeks of gestation.¹⁰

Decreased total T4 levels in the serum usually indicate hypothyroidism or chronic or subacute thyroiditis. Conditions that affect serum protein levels will also affect total T4 concentrations. For instance, nephrotic syndrome is a protein wasting condition in which thyroid hormone bound to serum proteins can be filtered and excreted in the urine, causing overall reductions in total T4.¹¹The same is true for drugs that increase T4 clearance, mainly antiepileptic drugs. Likewise, any drug that can inhibit the synthesis or release of thyroxine will lower total T4 levels. Importantly, these conditions may or may not alter TSH levels.¹²Overt hyperthyroidism with high T4 and low TSH is rare during pregnancy; it occurs in 0.1 to 0.4 percent of all pregnancies.¹⁰

Total T4 is primarily used to monitor treatment with synthetic hormones or antithyroid drugs, such as thiouracil.⁷ While free T4 is used more often than total T4 to evaluate thyroid function, no clinical laboratories offer a truly direct measure of free T4.^12,13 Instead, serum free T4 is calculated from total T4 and other indices. Therefore, any free T4 level involves measurement of total T4 and either TBG or T3 resin uptake. Total T4 may also be measured with serum TSH, total T3, free T3, reverse T3, or markers for thyroid antibodies.¹²

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^7,9,10,12

Normal pregnancy
Hyperthyroidism
Euthyroid hyperthyroxinemia
TSH-mediated hyperthyroidism
Acute thyroiditis
Familial dysalbuminemic hyperthyroxinemia
Drugs that increase TBG (e.g., estrogens, tamoxifen, opioids)
Drugs that decrease T4 conversion to T3 (e.g., amiodarone)

Low in:^7,12

Hypothyroidism
Chronic thyroiditis
Subacute thyroiditis
Congenital thyroid agenesis, dysgenesis, or defects in hormone synthesis
Nephrosis/nephrotic syndrome
Synthetic triiodothyronine treatment
Drugs that decrease TBG (e.g., anabolic steroids, glucocorticoids)
Drugs that increase T4 clearance (e.g., phenytoin, carbamazepine, phenobarbital)
Drugs that inhibit T4 synthesis/release (e.g. thionamides, lithium, perchlorate)

FUNCTIONAL RANGE INDICATIONS:

High in:

Hyperthyroidism
Facetious hyperthyroidism (excess thyroid hormone replacement)
Hepatitis

Low in:

Hypothyroidism
T3 replacement therapy

References:

Source: Kresser Institute

Tg antibodies

Marker Name: Tg antibodies

REFERENCE RANGES FOR SERUM TG ANTIBODIES:

Laboratory reference range: 0–0.9 IU/mL

DESCRIPTION:

Thyroglobulin (Tg) antibodies are autoantibodies directed against epitopes contained within the thyroglobulin protein. The presence of Tg antibodies in the blood is abnormal. Tg antibodies in the blood often indicate chronic autoimmune thyroiditis.¹

Thyroglobulin is a glycoprotein composed of two identical subunits that are noncovalently bound together.² Thyroglobulin is integral to thyroid hormone formation, which takes place within the lumen of thyroid follicles. It is the principal storage form of thyroid hormones within the thyroid gland. Approximately 25 mg of thyroglobulin is hydrolyzed each day to yield 100 µg of thyroxine (T4).³ A relatively minute quantity, 100 µg, of thyroglobulin is released from the thyroid daily.²Thyroglobulin is the major protein in the thyroid gland, by weight, and is the principal component of colloid, where thyroid hormone is stored within the thyroid gland.²

The mechanism by which the immune system produces autoantibodies against Tg is unknown, but leading hypotheses believe that an initial insult initiates the autoimmune process. A viral illness is considered the most common cause, but injury to the thyroid gland, pregnancy, and excessive iodine intake may also trigger this process.^1,4-7 B cells and T cells respond inappropriately to a similar epitope on a virus particle or recognize “self” HLA class II molecules as foreign when presented to them by thyroid follicle cells.^1,8,9

Tg antibodies are usually detected in the same clinical situations as TPO antibodies. Tg and TPO antibodies are present in roughly 90 percent of people with Hashimoto’s thyroiditis and 50 to 80 percent of people with Graves’ disease.¹⁰ Tg antibodies, like TPO antibodies, may be present in subclinical hypothyroidism, indicating an elevated risk of progressing to overt hypothyroidism.¹¹Laboratory tests used to detect Tg antibodies are less sensitive and only as specific as those used to detect thyroid peroxidase (TPO) antibodies. Therefore, Tg antibody tests are often considered a secondary test for autoimmune hypothyroidism after TPO antibodies.^12,13

Thyroglobulin levels (not Tg antibodies) are used to monitor patients treated for differentiated thyroid carcinoma.^14,15 However, if patients have autoantibodies directed against the thyroglobulin molecule (i.e., Tg antibodies), the use of thyroglobulin levels as a tumor biomarker may be compromised.¹³ Tg antibodies are in fact elevated in 20 percent of patients with thyroid cancer.^16,17Thus, in patients with treated thyroid cancer, both thyroglobulin and Tg antibodies are measured together. Changes in Tg antibodies may be a more rapid indicator of recurrent disease than changes in thyroglobulin levels.

Women with pregnancy-related thyroiditis or postpartum thyroiditis who also have elevated Tg antibodies are at greater risk of developing permanent autoimmune hypothyroidism.¹³ As with TPO antibodies, Tg antibodies can be passed across the placenta to fetuses, which may transiently disrupt thyroid function (i.e., cause hypothyroidism) during the neonatal period.^18,19

The Tg antibodies test may be ordered in conjunction with TPO antibodies and other thyroid markers (e.g., serum TSH, total T3, and free T4 levels).²⁰

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^1,17,21-23

Hashimoto’s thyroiditis/chronic autoimmune hypothyroidism
- Goitrous autoimmune thyroiditis
- Atrophic autoimmune thyroiditis
Graves’ disease
Differentiated thyroid carcinoma
Subclinical hypothyroidism
Pregnancy (abnormal)
Neonatal period (transient)
Postpartum thyroiditis
Painless (silent) thyroiditis

Low in:

Not applicable

FUNCTIONAL RANGE INDICATIONS:

High in:

No functional range

Low in:

No functional range

References:

Source: Kresser Institute

TIBC

Marker Name: TIBC

REFERENCE RANGES FOR TIBC:

Laboratory reference range: 250–450 µg/dL

Functional reference range: 275–425 µg/dL

DESCRIPTION:

Total iron-binding capacity (TIBC), also known as transferrin iron-binding capacity, measures the blood’s capacity to carry iron. Since transferrin (Trf) binds and transports the majority of plasma iron, TIBC is used as an approximate indirect marker of transferrin concentration. However, proteins other than transferrin do contribute to TIBC.^1-3

Transferrin-bound iron only constitutes approximately 0.1 percent of total body iron, but it is a vital and dynamic iron pool.⁴ The main biological function of transferrin is to bind one or two ferric iron ions (Fe³⁺) and transport them from macrophages and absorption sites in the small intestine to all tissues, especially bone marrow, where red blood cell production occurs.^3-5 The vast majority of iron in the body is bound to proteins such as transferrin, which minimizes circulation of reactive free iron that could otherwise produce harmful free radicals.^3-5 Iron deficiency significantly upregulates transferrin production by unknown mechanisms, making TIBC an indirect marker for iron status.^3,6

Transferrin is also a negative acute-phase reactant, meaning that its production decreases in states of inflammation.⁷ This transferrin downregulation serves to decrease iron available to pathogens that need iron to survive and contributes to anemia of chronic inflammation.^7,8Similarly, transferrin sequesters iron in intestinal mucosa to impede bacterial survival as part of the innate immune system.⁹

Transferrin synthesis occurs throughout the body but is particularly prevalent in the liver.¹⁰Because of this, TIBC can reflect liver function. Overall, TIBC can reflect iron status, inflammation, liver function, or a combination of the three; this complicates interpretation of TIBC level.

High TIBC can be caused by iron deficiency, pregnancy, states of increased red blood cell production, certain acute liver conditions, and certain drugs (e.g., oral contraceptives).^6,11-21 A list of specific conditions and drugs that can cause high TIBC is provided below.

Low TIBC can be caused by hereditary hemochromatosis, hereditary atransferrinemia, multiple infusions of iron-containing agents, massive increase in oral iron intake, pernicious anemia, hypoproteinemia, chronic liver disease, chronic inflammatory conditions, and some cases of ineffective erythropoiesis, hemolytic anemia, and hemosiderosis.^{8,11-15,22-25} A list of specific conditions that can cause low TIBC is below.

TIBC is a useful marker for iron status but is less sensitive than serum ferritin and inconclusive on its own. Related markers should be considered, including a complete blood count (CBC), serum iron, ferritin, UIBC, and iron saturation.¹¹ To determine if low TIBC is due to an underlying inflammatory condition, measuring other acute-phase reactants such as C-reactive protein, erythrocyte sedimentation rate, and plasma fibrinogen can be helpful.⁶

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^6,16

Iron deficiency
- Inadequate dietary intake
  - Diet low in meat
- Gastrointestinal malabsorption
  - Achlorhydria or hypochlorhydria
  - Gastritis
    - Atrophic gastritis
    - Autoimmune metaplastic atrophic gastritis
    - Helicobacter pylori gastritis¹⁷
  - Celiac disease
  - Post-gastric bypass surgery¹⁸
- Chronic blood loss (if associated inflammation is high, TIBC can also be low or normal in these conditions)¹⁹
  - Obvious bleeding
    - External wound
    - Melena
    - Hematemesis
    - Hemoptysis
    - Gross hematuria
  - Heavy menstrual bleeding
  - Gastrointestinal bleeding (e.g., hemorrhoids, fissures)
  - Repeated blood donations
  - Intraluminal neoplasms (e.g., malignancies of the gastrointestinal tract)²⁰
  - Lasthénie de Ferjol syndrome
- Normal pregnancy (in the absence of iron deficiency)⁶
- States of increased red blood cell production
  - Treatment with erythropoietin (EPO)
  - Polycythemia vera
- Certain acute liver conditions, including:
  - Acute viral hepatitis
  - Acute hepatic necrosis
- Drugs²¹
  - Oral contraceptives⁶
  - Proton pump inhibitors
  - H₂ receptor blockers
  - Certain antibiotics (e.g., quinolones, tetracycline)
  - Excessive calcium supplementation

Low in:^11-15

Hereditary hemochromatosis (HH)^22,23
- Human hemochromatosis protein (HFE)-related
  - C282Y homozygosity
  - C282Y/H63D compound heterozygosity
  - Other mutations of HFE
- Other genetic mutation
  - Juvenile hemochromatosis (mutations in hemojuvelin or hepcidin)
  - Ferroportin mutations
  - Transferrin receptor 2 mutation (rare)
- Hereditary atransferrinemia
- Multiple infusions of iron-containing agents
  - Red cell transfusion
  - Multiple infusions of intravenous iron
  - Intravenous hemin/hematin
- Massive long-term increase in oral iron intake
  - High-dose iron supplementation
  - Medications containing iron
  - Diet
- Pernicious anemia
- Hypoproteinemia, as seen in:
  - Malnutrition (e.g., kwashiorkor)
  - Nephrotic syndrome
- Chronic liver disease
  - Hepatitis B or C
  - Alcohol-induced liver disease
  - Porphyria cutanea tarda
  - Steatohepatitis (fatty liver disease)
  - Neonatal or perinatal iron overload, due to gestational alloimmune liver disease²⁴
- Chronic inflammation^8,25
  - Multiple causes (e.g., chronic infection, malignancy, rheumatologic disorders, inflammatory bowel disease, acute and chronic immune activation, etc.)
- Ineffective erythropoiesis (can be mildly decreased, but often normal)
  - Hereditary sideroblastic anemias
  - Severe alpha and beta thalassemia
  - Myelodysplastic syndrome (MDS) variants, such as refractory anemia with ringed sideroblasts (RARS)
- Hemolytic anemia (can be mildly decreased, but often normal), such as:
  - Autoimmune hemolytic anemia
  - Sickle cell anemia
- Hemosiderosis (can be mildly decreased, but sometimes normal)
  - Pulmonary hemosiderosis (as seen in anti-glomerular basement membrane antibody disease)
  - Chronic hemolysis

FUNCTIONAL RANGE INDICATIONS:

High in:

Functional iron deficiency
Pregnancy

Low in:

Functional iron overload
Functional liver problems
Chronic inflammation

References:

Source: Kresser Institute

Total Cholesterol/HDL Ratio

Marker Name: Total Cholesterol/HDL Ratio

REFERENCE RANGES FOR TOTAL CHOLESTEROL/HDL RATIO:

Laboratory reference range: 0–5

Functional reference range: 0–3

DESCRIPTION:

The total cholesterol/HDL ratio is the mathematical ratio of total cholesterol to HDL cholesterol in the blood. It is also known as the atherogenic or Castelli index.¹ HDL is an acronym for high-density lipoprotein, and, as listed in this ratio, it specifically refers to HDL cholesterol (HDL-C). The total cholesterol/HDL ratio more accurately predicts coronary heart disease risk than LDL cholesterol alone.^2-5

HDL is one of the five major lipoproteins in plasma and one of the cholesterol types that combine to provide a total cholesterol measurement. Cholesterol provides structural integrity to cell membranes throughout the body and is a precursor to various steroid molecules.^6,7 HDL carries fatty acids from fat-containing cells to the liver for eventual excretion in the feces—the so-called reverse cholesterol transport pathway.^8-10 Importantly, HDL also removes cholesterol from lipid-filled macrophages in atherosclerotic plaques.¹¹

Nascent HDL particles are synthesized de novo by the liver and small intestine.¹² They draw free cholesterol molecules from atherosclerotic plaques and fat-containing cells to form a mature HDL particle.⁸ At the end of the particle’s lifespan, the liver catabolizes senescent HDL particles and HDL remnants.^11,13

Other components of total cholesterol are generated via the exogenous or endogenous pathways.⁸ In the exogenous pathway, dietary cholesterol and fatty acids are absorbed from the gastrointestinal tract.⁹ Triglycerides and cholesterol combine to form chylomicrons, which enter the circulation and travel throughout the body. Remnants of these chylomicrons form HDL. In the endogenous pathway, VLDL is created in the liver from triglycerides and cholesterol esters and is eventually incorporated into LDL.⁹

The total cholesterol-to-HDL cholesterol ratio is higher than normal if total cholesterol is proportionally higher than HDL cholesterol. This could be due to an excess of total cholesterol, the relative lack of HDL cholesterol, or both. As such, abnormal elevations in the total cholesterol-to-HDL cholesterol ratio are caused by the same conditions that increase total cholesterol and/or decrease HDL cholesterol. Increased total cholesterol may be due to endocrine disturbances, such as diabetes or hypothyroidism, diseases of the kidney or liver, the effect of various stressors, such as cigarette smoking, or the effect of various drugs.¹⁴ On the other hand, obesity and lifestyle issues such as smoking and physical inactivity are associated with abnormally low HDL-C levels. Acute infection, inflammation, and certain chronic diseases can lower HDL cholesterol levels, thus raising the total-to-HDL cholesterol ratio.¹⁵

Relative reductions in total cholesterol and elevations in HDL cholesterol are generally considered healthy.¹⁶

Total cholesterol and HDL cholesterol are measured in a standard serum lipid profile.¹⁷

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS: High in:^14,18-22

Primary disorders of cholesterol metabolism
- Familial hypercholesterolemia
- Familial combined hypercholesterolemia
- Familial hyperapobetalipoproteinemia
- Polygenic hypercholesterolemia
- Familial primary hypoalphalipoproteinemia
- Non-familial hypoalphalipoproteinemia
- Familial hypoalphalipoproteinemia with hypertriglyceridemia
Obesity
Sedentary lifestyle
Cigarette smoking
Excessive alcohol consumption
Diabetes mellitus
Hypothyroidism
Nephrotic syndrome
Renal failure
Obstructive liver disease
Hepatitis
Acute intermittent porphyria
Anorexia nervosa
Systemic lupus erythematosus
Von Gierke disease
Elevated cholesteryl ester transfer protein activity
Lipoprotein lipase deficiency
Elevated hepatic triglyceride lipase activity
Drugs
- Adrenal steroids
- Beta-blockers
- Benzodiazepines
- Isotretinoin
- Thiazides
- Anticonvulsants
- Protease inhibitors
- Anabolic steroids
- Oral estrogens

Low in:

Not clinically relevant

FUNCTIONAL RANGE INDICATIONS:

High in:

Early stages of conventional indications above

Low in:

Impaired liver function
Not clinically significant

References:

Source: Kresser Institute

TPO antibodies

Marker Name: TPO antibodies

REFERENCE RANGES FOR SERUM TPO ANTIBODIES:

Laboratory reference range: 0–34 IU/mL

DESCRIPTION:

TPO stands for thyroid peroxidase, which is an enzyme that is integral to thyroid hormone synthesis in the thyroid gland.¹ Unfortunately, this enzyme can also become an antigen in autoimmune thyroid disease. The consequence of the ensuing autoimmune response is the production of antibodies directed against TPO. TPO antibodies detected in blood help determine the cause of thyroid dysfunction.²

The presence of antibodies directed against TPO is abnormal. While the precise cause is unknown, several hypotheses have been put forward to explain this flaw in immune system function.² In general, these hypotheses include an inciting cause followed by a process that mediates the autoimmune process. Possible inciting causes include viral illness, genetic predisposition, thyroid injury (e.g., infection, radiation, drug action), changes in circulating sex steroids, changes occurring during pregnancy, and excessive iodine intake.^2-6

Regardless of cause, antibodies directed against TPO cause lymphocytes to infiltrate the thyroid gland, destroying thyroid follicles. This may lead to fibrosis and areas of follicle hyperplasia. Moreover, TPO antibodies can destroy thyroid cells and may inhibit the activity of TPO directly.^7,8These processes often lead to progressive hypothyroidism.²

Greater than 90 percent of people with Hashimoto’s thyroiditis (i.e., chronic autoimmune thyroiditis) have high concentrations of TPO antibodies in their blood.⁹ More than half of individuals with Graves’ disease have TPO antibodies. TPO antibodies may be detectable in people with subclinical hypothyroidism; their presence indicates an increased risk of developing overt hypothyroidism.¹⁰ Hypothyroidism occurs in approximately 1 to 2 percent of all pregnancies, and the most common cause of hypothyroidism in this patient population is Hashimoto’s thyroiditis.¹¹ TPO antibodies are able to cross the placenta, thus these antibodies may be present in fetuses born to mothers with circulating TPO antibodies.¹¹

TPO antibody levels may be measured in conjunction with other thyroid function tests (e.g., TSH, free T4) when an autoimmune mechanism is suspected. TPO antibodies are usually measured with other autoantibodies that would affect thyroid function, namely antibodies directed against thyroglobulin (Tg), thyroid-stimulating immunoglobulin (TSI), and the TSH receptor (TRAb).^12,13

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^2,9-11,14-16

Hashimoto’s thyroiditis/chronic autoimmune hypothyroidism
- Goitrous autoimmune thyroiditis
- Atrophic autoimmune thyroiditis
Graves’ disease
Subclinical hypothyroidism
Pregnancy (abnormal)
Neonatal period (transient)
Postpartum thyroiditis
Painless (silent) thyroiditis

Low in:

Not applicable

FUNCTIONAL RANGE INDICATIONS:

High in:

No functional range

Low in:

Not applicable

References:

Source: Kresser Institute

Triglycerides

Marker Name: Triglycerides

REFERENCE RANGES FOR TRIGLYCERIDES:

Laboratory reference range: 0–149 mg/dL

Functional reference range: 50–100 mg/dL

DESCRIPTION:

A triglyceride is the combination of a glycerol molecule and three fatty acids connected through ester linkages.¹ Triglycerides are one of the major lipids found in the serum and are a major component of fat cells (adipocytes). Triglycerides are the primary energy storage molecule; they can enter the bloodstream from dietary sources or can be released from adipocytes to act as a rapid energy source.^2,3 The ability to store triglycerides and release this energy when food is scarce is important for survival.²

Triglycerides can be synthesized within intestinal cells from the enzymatic combination of free fatty acids and glycerol.⁴ Triglycerides join cholesterol to form chylomicrons, which can travel to various tissues throughout the body. Chylomicrons can release free fatty acids as an immediate energy source or transfer fatty acids to adipocytes for storage.⁴ Very low-density lipoproteins (VLDL) may also shuttle triglycerides released from the liver to peripheral tissues or for storage in adipocytes.⁵

Blood triglyceride levels may increase as much as five- to tenfold after a meal, which is why most clinicians order triglycerides in fasting patients. Non-fasting triglycerides may be more representative of typical circulating triglyceride levels; however, it is unclear how to interpret non-fasting triglyceride levels at this point.³ If tissues demand a source of energy between meals, triglycerides can be liberated through lipolysis. Lipolysis, or the hydrolysis of triglycerides, occurs predominantly in adipocytes.⁵Lipolysis is under tight hormonal regulation and is affected by insulin and circulating catecholamines, particularly epinephrine and norepinephrine.⁵

An abnormally high level of circulating triglycerides is called hypertriglyceridemia. It may be due to a primary genetic disorder such as familial hypertriglyceridemia or, more often, a secondary cause.⁶ Secondary causes of hypertriglyceridemia include obesity, insufficient physical activity, and excessive alcohol consumption.⁷ Certain endocrine diseases such as diabetes mellitus and hypothyroidism can cause an elevation in triglycerides. Kidney disease, particularly uremia and glomerulonephritis, can elevate triglyceride levels. High triglyceride levels are noted in otherwise healthy women in the third trimester of pregnancy, which is considered a normal biological response to pregnancy.⁸ Several drugs can increase triglycerides in the blood, including corticosteroids, oral estrogens, certain blood pressure medications, and certain antipsychotics.⁵

An abnormally low triglyceride level is called hypotriglyceridemia. Hypotriglyceridemia is associated with certain genetic conditions such as hereditary abetalipoproteinemia, hypobetalipoproteinemia, and Williams-Beuren syndrome.^9,10Certain chronic infections such as hepatitis B, hepatitis C, and HIV/AIDS can cause prolonged hypertriglyceridemia. Various autoimmune conditions are associated with low triglyceride levels, and hypotriglyceridemia may herald the onset of some autoimmune conditions.¹¹ Exercise and severe malnutrition will also lower circulating triglycerides.^12,13

Triglycerides are reported as part of a serum lipid profile or lipid panel. The serum lipid profile includes total cholesterol, HDL cholesterol, and LDL cholesterol. This report may also provide calculated estimates of VLDL cholesterol, non-HDL cholesterol, and the cholesterol/HDL ratio.¹⁴

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS: High in:^6-8

Primary hypertriglyceridemia
- Chylomicronemia
- Familial hypertriglyceridemia
- Familial combined hyperlipidemia
- Familial dysbetalipoproteinemia
- Hypertriglyceridemia and serum cholesterol
Normal pregnancy (third trimester)
Obesity
Insufficient physical activity
Alcohol consumption
Diabetes mellitus
Hypothyroidism
Renal disease (e.g., uremia, glomerulonephritis)
Autoimmune conditions (e.g., systemic lupus erythematosus)
Drugs
- Corticosteroids
- Oral estrogens
- Tamoxifen
- Beta-blockers
- Thiazides
- Isotretinoin
- Bile acid binding resins
- Cyclophosphamide
- Antiretrovirals
- Phenothiazines
- Atypical antipsychotics

Low in:^9-13,15

Heritable conditions
- Hereditary abetalipoproteinemia
- Hypobetalipoproteinemia
- Williams-Beuren syndrome
Autoimmune conditions
Hyperthyroidism
Malnutrition and undernutrition
Alcohol consumption
HIV/AIDS
Hepatitis (chronic, active hepatitis B, hepatitis C)
Drugs
- Fibrates
- Statins
- Nicotinic acid

FUNCTIONAL RANGE INDICATIONS:

High in:

Non-fasted state (make sure patient was fasting)
Early insulin resistance
Hypothyroidism

Low in:

Malabsorption
Hyperthyroidism
Autoimmune disease (some clinicians have empirically noted low triglyceride levels in patients with autoimmune disease)

References:

Source: Kresser Institute

Triglycerides/HDL Ratio

Marker Name: Triglycerides/HDL Ratio

REFERENCE RANGES FOR TRIGLYCERIDE/HDL RATIO:

Laboratory reference range: 0–3.8

Functional reference range: 0–2

DESCRIPTION:

The ratio between triglycerides and HDL cholesterol (triglycerides/HDL ratio) can be used to help predict the atherogenicity of plasma.^1-3 The ratio of triglycerides to HDL tends to correlate with myocardial infarction risk.⁴ Moreover, this ratio can be used to estimate atherogenic dyslipidemia and its associated residual cardiovascular risk in patients with type 2 diabetes mellitus.⁵ The prevalence of macroangiopathy, insulin resistance, loss of pancreatic beta cell function, and non-LDL related macrovascular risk can also be estimated using this ratio.⁵

Triglycerides can be absorbed from dietary sources or synthesized by intestinal cells from free fatty acids and glycerol.^6-8 Triglycerides can also be liberated by adipocytes via lipolysis as a rapid source of energy.⁹ Lipolysis is tightly regulated by circulating insulin, epinephrine, and norepinephrine.⁹

HDL primarily participates in the reverse cholesterol transport pathway.¹⁰ HDL is synthesized by the liver and collects cholesterol from adipocytes and atherosclerotic plaques.¹⁰ The nascent HDL particle matures as cholesterol is enzymatically esterified and incorporated into the lipoprotein particle.¹⁰ In fact, the triglyceride/HDL ratio correlates with both cholesterol esterification rate and lipoprotein particle size.³ At the end of the particle’s lifespan, HDL is degraded and metabolized by the liver, and excess cholesterol is excreted in the bile.¹¹

Blood triglyceride levels may increase by an order of magnitude after a meal. Thus, the triglyceride/HDL ratio is only clinically relevant when it is measured in the plasma of fasting individuals.¹²

The triglyceride/HDL cholesterol ratio is usually elevated in cases of abnormally high triglyceride levels and/or abnormally low HDL cholesterol levels in the blood. Presumably, any state that would alter lipid levels in these ways could elevate this ratio. The ratio has been studied most extensively as a marker for cardiovascular risk and, as such, has been shown to be elevated in conditions that are associated with elevated cardiovascular risk such as obesity, hypertension, diabetes mellitus, hypothyroidism, and smoking.^1,2,5,6,13 For reasons that are not entirely clear, elevations in this ratio have also been correlated to certain mental health illnesses such as major depression and bipolar disorder.⁴

Since the triglyceride/HDL ratio is a means to assess atherogenic potential, the ratio cannot be too low. Relative reductions in total cholesterol and elevations in HDL cholesterol are considered healthy.¹³

Triglycerides and HDL cholesterol are directly measured in a standard serum lipid profile. The ratio is calculated from these two measured values.¹⁴

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS: High in:^2,4,5,15-17

Low in:

Not clinically relevant

FUNCTIONAL RANGE INDICATIONS:

High in:

Early stages of indications listed in conventional range section

Low in:

Inflammation (with very high HDL) and/or autoimmune disease (with very low triglycerides)

References:

Source: Kresser Institute

TSH

Marker Name: TSH

REFERENCE RANGES FOR SERUM TSH:

Laboratory reference range: 0.45–4.5 µIU/mL

Functional reference range: 0.5–2.0 µIU/mL

DESCRIPTION:

TSH stands for thyroid-stimulating hormone, although it is sometimes called thyrotropin or thyrotropic hormone. TSH stimulates the thyroid gland to produce thyroid hormone. Thyroid hormone, in turn, is critical for the proper function of virtually every type of cell in the human body.¹

TSH is a glycoprotein that consists of alpha and beta subunits. The alpha subunit is virtually identical to that of some gonadotropins, while the beta subunit is unique to TSH.² TSH is secreted from the anterior pituitary gland as separate alpha and beta subunits. The secretion of these subunits by the pituitary is dependent on the presence of thyroid-releasing hormone (TRH), which is secreted by the hypothalamus.³ TRH-stimulated cells in the anterior pituitary secrete TSH into the bloodstream. The circulating TSH binds to and activates the TSH receptor, located predominantly on thyroid follicular cells.⁴ TSH receptor activation stimulates the production and release of thyroid hormone from the thyroid gland.¹

TRH release from the hypothalamus and TSH release from the pituitary gland are under negative feedback control from circulating thyroid hormone levels.⁵ In other words, rising levels of thyroid hormone decrease the release of TRH and TSH. Conversely, decreased levels of thyroid hormone stimulate the hypothalamus and pituitary gland to release more TRH and TSH, respectively.

There is considerable controversy regarding the upper limit of normal for serum TSH.⁵ There is general agreement that age-based normal ranges for serum TSH should be used, given the wide variability of normal levels across the lifespan.⁶

High levels of circulating TSH are usually caused by primary hypothyroidism or subclinical hypothyroidism.^5,7 This is in contrast to secondary hypothyroidism, which usually results in normal or low TSH levels in the presence of low serum T4 and T3 concentrations. Some cases of secondary hypothyroidism may result in slightly elevated levels of functionally abnormal TSH.⁷That is, serum levels of TSH appear high, but the hormone does not exert an appropriate biological effect. Many cases of elevated TSH are due to transient hypothyroidism, perhaps due to thyroiditis or therapy with radioiodine. Primary deficiencies in the thyroid gland that lead to decreased thyroid hormone production can cause reflexive elevations in TSH. In rare instances, a TRH-secreting tumor can cause excessive secretion of TSH by the pituitary gland, even in the context of normal circulating thyroid levels.

As with elevated levels of TSH, abnormally low levels of circulating TSH are usually caused by primary hyperthyroidism or subclinical hyperthyroidism. Graves’ disease is the most common cause of hyperthyroidism, though Hashimoto thyrotoxicosis (i.e. Hashitoxicosis) is also quite common.^8,9 Certain forms of thyroiditis may also cause low TSH levels in the blood. Amiodarone is well known to cause low TSH levels. Not all causes of low TSH are related to increases in circulating thyroid hormones. For example, euthyroid sick syndrome may lower blood TSH levels along with decreased thyroxine or triiodothyronine levels.^10,11

Several tests are used in addition to serum TSH levels to evaluate thyroid function, including total thyroxine (T4), total triiodothyronine (T3), free T4, free T3, and reverse T3 concentrations in the serum.⁵ Suspected autoimmune thyroiditis may be investigated by examining the blood for the presence of antibodies against thyroid peroxidase (TPO), thyroglobulin (Tg), and the TSH receptor.⁵

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:⁷

Transient hypothyroidism
- Painless thyroiditis
- Subacute granulomatous thyroiditis
- Postpartum thyroiditis
- Subtotal thyroidectomy
- Radioiodine therapy
Chronic autoimmune thyroiditis
Thyroidectomy
Fibrous thyroiditis
Congenital thyroid agenesis, dysgenesis, or defects in hormone synthesis
Generalized thyroid hormone resistance
Iodine deficiency or excess
External beam radiation therapy
Sarcoidosis
Hemochromatosis
Drugs
- Thionamides
- Lithium
- Amiodarone
- Interferon-alpha
- Interleukin-2
- Perchlorate
- Tyrosine kinase inhibitors

Low in:^9,10

Graves’ disease
Hashitoxicosis
Thyroiditis (e.g., postpartum thyroiditis, de Quervain’s thyroiditis)
Euthyroid sick syndrome
Excessive thyroid hormone replacement therapy
Iodine-induced hyperthyroidism
Autoimmune hypopituitarism
Toxic nodular goiter
Struma ovarii
Amiodarone

FUNCTIONAL RANGE INDICATIONS:

High in:

Hypothyroidism
Iodine, selenium, or zinc deficiency
Functional iron overload

Low in:

Facetious hyperthyroidism (excessive thyroid hormone replacement)
Pituitary hypofunction

References:

Source: Kresser Institute

TSI antibodies

Marker Name: TSI antibodies

REFERENCE RANGE FOR TSI ANTIBODY ACTIVITY:

Laboratory reference range: 0–139% of basal activity

DESCRIPTION:

TSI stands for thyroid-stimulating immunoglobulin. Unlike thyroid peroxidase or thyroglobulin, there is no biological structure called thyroid-stimulating immunoglobulin. Instead, TSI antibodies are autoantibodies that recognize and bind to epitopes on the thyroid-stimulating hormone receptor (TSHR). In general, anti-TSHR antibodies may activate, block, or have no effect on the receptor.¹ TSI antibodies, specifically, are autoantibodies that activate the TSH receptor, thereby increasing the synthesis and secretion of thyroid hormones.

TSI antibodies are not affected by the normal feedback mechanisms that regulate thyroid-releasing hormone (TRH), thyroid-stimulating hormone (TSH), and thyroid hormone levels. Increases in the thyroid hormones triiodothyronine (T3) and thyroxine (T4) would normally provide negative feedback to the hypothalamus and pituitary glands, thereby decreasing the release of TRH and TSH, respectively.^2,3 TSI antibodies, however, continue to interact with thyroid tissue independent of hormone levels.

Anti-TSHR antibodies are present in virtually every form of autoimmune thyroid condition, whether it results in hypothyroidism, hyperthyroidism, or a euthyroid state. In fact, stimulating, neutral, and inhibiting anti-TSHR antibodies may be present in the same individual (e.g., an individual with Graves’ disease).⁴ These antibodies may counteract the action of one another such that relative levels of stimulating and inhibiting antibodies may predict overall thyroid function at a given time.¹

In fact, modern tests of TSI antibodies do not necessarily detect the mere presence of TSI antibodies, but rather quantify their net activity on the TSHR. Specifically, the modern test is typically an activity assay that observes the overall effect of any stimulating, inhibitory, and neutral antibodies present.⁵

The presence of anti-TSHR antibodies and increased TSI activity indicates Graves’ disease.⁷Testing is also used to monitor remission or relapse in patients treated for Graves’ disease.⁶ TSI antibodies may also be used to quantify risk for neonatal and/or gestational thyrotoxicosis in pregnant women with Graves’ disease.

The TSI antibodies test is typically measured after or with other thyroid function testing (e.g., TSH, total T3, free T4, TPO antibodies, Tg antibodies).

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^1,5,7

Graves’ disease
Hashitoxicosis
Gestational thyrotoxicosis
Neonatal thyrotoxicosis
Silent thyroiditis

Low in:

Not applicable

FUNCTIONAL RANGE INDICATIONS:

High in:

No functional range

Low in:

No functional range

References:

Source: Kresser Institute

UIBC

Marker Name: UIBC

REFERENCE RANGES FOR UIBC:

Laboratory and functional reference range: 175–350 µg/dL

DESCRIPTION:

Unsaturated iron-binding capacity (UIBC) measures how much additional iron the blood could potentially carry.¹ Since transferrin carries the majority of circulating iron, UIBC represents the approximate concentration of apotransferrin, or transferrin not bound by iron.² UIBC can be measured directly. However, it is typically calculated from total iron-binding capacity (TIBC), which is an indirect estimate of transferrin concentration, and serum iron concentration (SI) using the following formula:^1,3

uibc

Since UIBC varies with TIBC and SI, it is affected by the same health variables; these include iron homeostasis, nutritional status, inflammation, liver function, pregnancy, certain genetic conditions, and certain drugs. For a discussion of how these factors influence serum transferrin and serum iron concentrations, see TIBC and iron reference sheets.

High UIBC can be caused by iron deficiency, pregnancy, states of increased red blood cell production, and certain drugs (e.g., oral contraceptives, proton pump inhibitors, and tetracycline antibiotics).^4-12 A complete list of conditions and drugs that can cause high UIBC is provided below.

Low UIBC can be caused by hereditary hemochromatosis, hereditary atransferrinemia, multiple infusions of iron-containing agents, massive increase in oral iron intake, hypoproteinemia, chronic liver disease, and some cases of chronic inflammation, pernicious anemia, ineffective erythropoiesis, hemolytic anemia, and hemosiderosis.^13-24 A full list of conditions that can cause low UIBC is below.

Since several factors can simultaneously influence UIBC, the test is not conclusive on its own. UIBC should be considered with related iron markers, including a complete blood count (CBC), serum iron, ferritin, TIBC, and iron saturation.¹³

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^4,5

Iron deficiency
- Inadequate dietary intake
  - Diet low in meat
- Gastrointestinal malabsorption
  - Achlorhydria or hypochlorhydria
  - Gastritis
    - Atrophic gastritis
    - Autoimmune metaplastic atrophic gastritis
    - Helicobacter pylori gastritis⁶
  - Celiac disease
  - Post-gastric bypass surgery⁷
- Blood loss⁸
  - Obvious bleeding
    - External wound
    - Melena
    - Hematemesis
    - Hemoptysis
    - Gross hematuria
  - Heavy menstrual bleeding
  - Gastrointestinal bleeding (e.g., hemorrhoids, fissures)
  - Repeated blood donations
  - Surgery
  - Hemodialysis
  - Intraluminal neoplasms (e.g., malignancies of the gastrointestinal tract)⁹
  - Lasthénie de Ferjol syndrome
- Normal pregnancy (in the absence of iron deficiency)⁴
- States of increased red blood cell production
  - Treatment with erythropoietin (EPO)¹⁰
  - Polycythemia vera¹¹
- Drugs¹²
  - Oral contraceptives⁴
  - Proton pump inhibitors
  - H₂ receptor blockers
  - Certain antibiotics (e.g., quinolones, tetracycline)
  - Excessive calcium supplementation

Low in:^13-15

Hereditary hemochromatosis (HH)^16-18
- Human hemochromatosis protein (HFE)-related
  - C282Y homozygosity
  - C282Y/H63D compound heterozygosity
  - Other mutations of HFE
- Other genetic mutation
  - Juvenile hemochromatosis (mutations in hemojuvelin or hepcidin)
  - Ferroportin mutations
  - Transferrin receptor 2 mutation (rare)
- Hereditary atransferrinemia
- Multiple infusions of iron-containing agents
  - Red cell transfusion
  - Multiple infusions of intravenous iron
  - Intravenous hemin/hematin
- Massive increase in oral iron intake
  - High-dose iron supplementation
  - Medications containing iron
  - Diet
- Hypoproteinemia, as seen in:
  - Malnutrition (e.g., kwashiorkor)
  - Nephrotic syndrome
- Chronic liver disease
  - Hepatitis B or C
  - Alcohol-induced liver disease
  - Porphyria cutanea tarda
  - Steatohepatitis (fatty liver disease)
  - Neonatal or perinatal iron overload, due to gestational alloimmune liver disease¹⁹
- Chronic inflammation (can be low, but sometimes normal)²⁰
  - Multiple causes (e.g., chronic infection, malignancy, rheumatologic disorders, inflammatory bowel disease, acute and chronic immune activation, etc.)
- Pernicious anemia (can be low, but sometimes normal)²¹
- Ineffective erythropoiesis (can be low, but sometimes normal)
  - Hereditary sideroblastic anemias²²
  - Severe alpha and beta thalassemia²³
  - Myelodysplastic syndrome (MDS) variants, such as refractory anemia with ringed sideroblasts (RARS)²⁴
- Hemolytic anemia (can be low, but sometimes normal), such as:
  - Autoimmune hemolytic anemia
  - Sickle cell anemia
- Hemosiderosis (can be low, but sometimes normal)
  - Pulmonary hemosiderosis (as seen in anti-glomerular basement membrane antibody disease)
  - Chronic hemolysis

FUNCTIONAL RANGE INDICATIONS:

High in:

Functional iron deficiency
Pregnancy

Low in:

Functional iron overload
Functional liver problems
Chronic inflammation

References:

Source: Kresser Institute

Uric Acid

Marker Name: Uric acid

REFERENCE RANGES FOR URIC ACID:

Laboratory reference range: 3.7–8.6 mg/dL

Functional reference range:

Male: 3.7–6 mg/dL

Female: 3.2–5.5 mg/dL

DESCRIPTION:

Uric acid is the end product of purine metabolism, where it serves as a relatively soluble molecule for the excretion of purine molecules in urine. Negligible amounts of uric acid are consumed in the diet; however, consumption of uric acid precursors in the form of purine molecules is substantial.¹ Uric acid may also function as an antioxidant and free radical scavenger.² Historically, uric acid was viewed as a relatively innocuous waste product that only contributed to human disease if the molecule precipitated as uric acid crystals, as seen in gout and urolithiasis. More recently, however, uric acid is believed to contribute to inflammation and oxidative stress.³

Healthy adult men have a total uric acid pool of around 1.2 g, which is about twice the amount that adult women have.⁴ This is presumably due to increased clearance, reduced reabsorption, and a greater number of active renal urate transporters in women versus men. Approximately 60 percent of the total uric acid pool is replaced each day through production and elimination under steady-state conditions.⁴

Most uric acid is produced in the liver from the metabolism of consumed purines, or, to a lesser extent, of purines synthesized by the body. The purine bases guanine and hypoxanthine are metabolized to xanthine, which is, in turn, irreversibly oxidized to uric acid by the xanthine oxidase enzyme. Non-liver tissues produce negligible amounts of uric acid via nonspecific metabolic enzymes.⁴ Two-thirds of uric acid is eliminated from the body through the urine, while the remaining one-third is expelled in the gastrointestinal tract.⁵

Uric acid may be measured in blood or urine. An elevated uric acid level in the blood is called hyperuricemia, while an elevated uric acid level in the urine is called hyperuricosuria. In most cases, uric acid levels in blood will mirror urinary uric acid levels. However, if a person has decreased renal excretion of uric acid, this could cause abnormally high uric acid levels in the blood and abnormally low uric acid levels in the urine. Normally, uric acid levels in the blood are assumed to reflect total body levels of uric acid. Nonetheless, patients with deposits of uric acid crystals and tophi within joints may have more total body uric acid than is reflected in blood samples.

While there is a clear association between blood uric acid levels and the risk of gout, not all patients with elevated blood uric acid levels will develop gout or uric acid crystal deposits.^6,7Conversely, some patients with gout may not have consistently elevated levels of uric acid in the blood.⁸

Primary hyperuricemia is supersaturated uric acid levels in the presence of an offending drug or coexisting disease that directly elevates uric acid.⁹ Secondary hyperuricemia, on the other hand, may be due to excessive uric acid production, reduced renal clearance of uric acid, or both. Secondary hyperuricemia may be the result of an identifiable genetic disorder, drug, supplement, or environmental insult.¹⁰ The list of causes of secondary hyperuricemia is extensive. Numerous medications, inherited disorders, acquired conditions, and lifestyle diseases may increase blood uric acid levels. While hyperuricemia is clearly associated with chronic kidney disease, hypertension, cardiovascular disease, and insulin resistance, it is not clear whether these elevated uric acid levels are causative or correlative.⁸

An abnormally low level of uric acid in the blood is called hypouricemia; the causes of hypouricemia are almost as numerous as the causes of hyperuricemia. Hypouricemia may be caused by decreased uric acid production, decreased reabsorption in the kidney, or increased oxidation secondary to drug treatment (e.g., rasburicase).¹¹ It may also be the result of various inherited or acquired diseases. Many medications can reduce uric acid levels in the blood either as their primary desired clinical effect (e.g., allopurinol) or as an unintended side effect (e.g., losartan).¹¹

While elevated blood uric acid levels are sufficient to diagnose hyperuricemia, clinical correlation via history and physical examination are required to make a definitive diagnosis of gout.¹² Other diseases related to uric acid require additional diagnostic testing.^13,14

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^8,15-18

Alcohol abuse
Decreased renal clearance
Renal failure
Hypothyroidism
Alcoholic ketoacidosis
Diabetic ketoacidosis
Diabetes insipidus
Hemolytic anemia
Tumor lysis syndrome
Rhabdomyolysis
Inherited disorders
- HGPRT deficiency (e.g., Lesch–Nyhan syndrome)
- PRPP synthetase superactivity
- Hereditary fructose intolerance
- Glycogen storage diseases (Types Ia, III, V, VII)
- Glucose-6-phosphate deficiency
- Down syndrome
Excessive consumption of purines
Myeloproliferative disorders
Lymphoproliferative disorders
Essential thrombocytosis
Hypoxemia
Drugs
- Loop diuretics
- Thiazide diuretics
- Cyclosporine
- Pyrazinamide
- Ethambutol

Low in:^6,9-11,19,20

Inflammation
Normal pregnancy
Total parenteral nutrition
Severe hepatocellular injury
Fanconi syndrome
Extracellular fluid expansion
- Excess intravenous fluid administration
- Primary polydipsia
- Syndrome of inappropriate antidiuretic hormone
Intracranial disease
Multiple sclerosis
AIDS
Malignancies (e.g., Hodgkin lymphoma)
Inherited disorders
- Hereditary xanthinuria
- Nucleosidase phosphorylase deficiency
- Familial renal hypouricemia
Drugs
- Aspirin
- Oral estrogens
- Ampicillin
- Calcium channel blockers
- Allopurinol
- Probenecid
- Febuxostat
- Enalapril
- Captopril
- Losartan
- Isoniazid
- Trimethoprim-sulfamethoxazole
- Rifampin
- Fenofibrate
- Atorvastatin
- Sulindac
- Rasburicase

FUNCTIONAL RANGE INDICATIONS:

High in:

Functional dysglycemia

Low in:

Deficiency of B12, folate, or molybdenum (these nutrients are cofactors for uric acid synthase; if MCV, MCH, and/or MCHC are elevated, this interpretation is more likely)

References:

Source: Kresser Institute

Vitamin D, 25-hydroxy

Marker Name: Vitamin D, 25-hydroxy

REFERENCE RANGES FOR SERUM 25-HYDROXYVITAMIN D:

Laboratory reference range: 30–100 ng/mL

Functional reference range: 35–60 ng/mL

DESCRIPTION:

25-hydroxyvitamin D, also known as calcidiol or calcifediol, is one of the two main biologically active forms of vitamin D.¹ Biologically active vitamin D has several important functions. It facilitates calcium absorption in the gastrointestinal tract and maintains calcium and phosphate levels in the blood.² Adequate vitamin D levels are important for bone formation in children and adolescents and to prevent bone demineralization in older individuals.^1,3 Adequate vitamin D is required for normal function of muscle tissue, nervous tissue, and cells of the immune system.⁴Research suggests that deficiencies in vitamin D may contribute to hypertension, cardiovascular events, and cancer.⁴ Likewise, inadequate vitamin D levels may contribute to the etiology of both type 1 and type 2 diabetes and can interfere with normal pregnancy outcomes.⁴

Three of the five forms of vitamin D are biologically inert: vitamin D2 (ergocalciferol), vitamin D3 (cholecalciferol), and 7-dehydrocholesterol. In fact, the forms of vitamin D derived from dietary sources, supplements, and skin exposure to UV light are all biologically inert. Vitamin D is found in limited amounts in most foods; when present, it is most often in the form of vitamin D3.² Vitamin D2 and vitamin D3 are obtained from vitamin D-fortified foods and vitamin D supplements. Ultraviolet light striking the skin non-enzymatically converts circulating 7-dehydrocholesterol into vitamin D3.¹Vitamin D2 and vitamin D3 are converted to 25-hydroxyvitamin D, an active form of the vitamin, in the liver. 25-hydroxyvitamin D can then act on tissues in the body or be converted to 1,25-hydroxyvitamin D, another active form of the vitamin, in the kidney.^1,5 Both 1,25-hydroxyvitamin D and 25-hydroxyvitamin D are enzymatically degraded and excreted with the bile in the gastrointestinal tract.⁶ The half-life of 25-hydroxyvitamin D is three to four weeks, while the half-life of 1,25-hydroxyvitamin D is roughly four hours.³

1,25-dihydroxyvitamin D (calcitriol) is more biologically active than 25-hydroxyvitamin D; however, serum 25-hydroxyvitamin D is the most abundant active form of vitamin D in the blood and the best indicator of a person’s vitamin D status in most circumstances.^2,3,7 Serum 25-hydroxyvitamin D may not accurately reflect true vitamin D status in people with chronic renal failure or type 1 vitamin D rickets or in those taking therapeutic calcitriol.⁷ There is wide variability in reported 25-hydroxyvitamin D levels between laboratories and between assay methods, which could impact clinical decision-making.⁷

The most common cause of elevated serum 25-hydroxyvitamin D levels is excess intake of vitamin D. Excess sun exposure does not lead to increased 25-hydroxyvitamin D levels, since sustained heating of the skin will photodegrade the vitamin and its precursor.²Hyperparathyroidism greatly affects calcium levels but does not usually increase 25-hydroxyvitamin D levels. In fact, secondary hyperparathyroidism can paradoxically lower 25-hydroxyvitamin D levels in some cases.⁸

Low vitamin D levels may be characterized as insufficiency or deficiency, the latter reflecting lower 25-hydroxyvitamin D levels than the former.^3,9 Low 25-hydroxyvitamin D arises from decreased consumption of vitamin D, inadequate synthesis of precursors in the skin, decreased synthesis in the liver, increased breakdown, or loss from the kidneys.¹ Certain drugs, most notably anti-epileptic drugs, can cause abnormally low 25-hydroxyvitamin D levels. Since vitamin D is fat soluble, obese individuals may have a relative lack of bioavailable 25-hydroxyvitamin D because it is sequestered in fatty tissue.⁷ Likewise, obese individuals undergoing bariatric surgery may not be able to absorb adequate amounts of vitamin D through the gut.¹⁰

25-hydroxyvitamin D is often the sole test used to initially diagnose vitamin D deficiency. 1,25-dihydroxyvitamin D may be assayed to explore possible reasons for vitamin D deficiency.¹¹ When abnormalities in 1,25-dihydroxyvitamin D are being considered, parathyroid hormone, serum calcium, and serum phosphate may be tested.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:²

Excessive intake

Low in:^2,10

Normal pregnancy
Breastfeeding infants
Inadequate sunlight exposure
Obesity
Fat malabsorption
Hypoparathyroidism
Secondary hyperparathyroidism
Small bowel disease
Gastric bypass surgery
Pancreatic insufficiency
Advanced liver disease
Nephrotic syndrome
Thermal burn injury with extensive skin damage
Hereditary vitamin D-resistant rickets (vitamin D-dependent rickets, type 2)
Cystic fibrosis
Drugs
- Anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine)
- Isoniazid
- Corticosteroids
- Theophylline
- Rifampin

FUNCTIONAL RANGE INDICATIONS:

High in:

Excessive intake

Low in:

Nonpathological in some nonwhite populations (must check PTH and 1,25D to determine true biological vitamin D activity)

References:

Source: Kresser Institute

WBC

Marker Name: WBC

REFERENCE RANGES FOR WBC COUNT:

Laboratory reference range: 3.4–10.8 x 10³/µL

Functional reference range: 5.0–8.0 x 10³/µL

DESCRIPTION:

White blood cells (WBCs), also known as leukocytes, are the major cell type of the immune system. Unlike red blood cells and platelets, white blood cells have a nucleus. Five main types of leukocytes circulate in the bloodstream: basophils, neutrophils, eosinophils, monocytes, and lymphocytes. Lymphocytes can be further characterized as B lymphocytes, T lymphocytes, and natural killer (NK) cells. Monocytes and neutrophils have the ability to phagocytose, or consume microbes. Basophils and eosinophils participate in allergic responses, although eosinophils primarily respond to parasitic infections.

White blood cells are primarily produced in the bone marrow. Lymphocytes may also be produced in the lymphoid tissue, such as the spleen and lymph nodes. The bone marrow contains a mitotic pool, a maturation pool, and a storage pool of neutrophils. Leukocytes in the vasculature are either circulating or in the marginal pool; leukocytes attached to blood vessel walls at the tissue-capillary interface make up the marginal pool. Leukocytes may also cross from the circulation into the tissue pool in various tissues throughout the body. An increase in white blood cell count usually means an increase in neutrophils;¹ however, an increase in WBC count may also be due to an increase in eosinophils, monocytes, lymphocytes, or (uncommonly) basophils.²

WBC levels may increase due to infection, inflammatory disorders, hematologic cancer (e.g., leukemia), corticosteroids, and stress.³ During acute inflammation, the mitotic pool grows, while the maturation and storage pools within bone marrow shrink. This decrease reflects increased release of neutrophils into the circulation.⁴ The number of neutrophils in the tissue pool also increases. Stress or corticosteroid administration causes neutrophils to move from the marginal pool to the circulating pool, while bone marrow pools remain unaffected. In chronic disorders such as myeloproliferative disorders or chronic myelogenous leukemia, neutrophilia is caused by increased production and release of cells.⁵

An elevated white blood cell count, or leukocytosis, is usually the result of a reactive leukocytosis, which means leukocyte numbers increase in response to an infection, stress, or inflammation. Conversely, leukocytosis may be clonal, which means leukocytes are being created along one cell line, as would occur during leukemia. In both reactive and clonal leukocytosis, one type of white blood cell usually predominates.³ For example, a parasitic infection may cause eosinophils to increase.⁶ Likewise, acute lymphocytic leukemia may cause a large increase in the absolute lymphocyte count.⁷

An abnormally low WBC count is called leukopenia. As with leukocytosis, leukopenia often refers to a change in the number of neutrophils, the major leukocyte. In fact, leukopenia is often used interchangeably with neutropenia.⁸ However, leukopenia may be due to specific reductions in leukocytes other than or in addition to neutrophils. Leukopenia may occur when white blood cells are depleted by infection or cancer treatment (e.g., chemotherapy, radiation therapy). It may also occur due to ineffective production or maturation of leukocytes in the bone marrow, which may occur in myelodysplastic syndrome or leukemia.⁸ White blood cells may be sequestered within the spleen, a condition called hypersplenism.

A white blood cell count or WBC is often measured in the context of a complete blood count (CBC) with differential. This includes individual counts of the five main leukocytes: neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Unless a different test has been specifically ordered, a standard CBC with differential is performed using an automated cell counting device. Physicians may also order a manual differential in which laboratory personnel create a slide of the patient’s blood and manually count populations of blood cells under a microscope.^9,10 This may also be called a peripheral blood smear.¹⁰

A white blood cell count may be requested in fluids other than blood. It is considered routine for cerebral spinal fluid collected during a lumbar puncture to be sent for a white blood cell count with differential.^11,12 Likewise, the WBC is measured in fluid removed from the pleural space after thoracentesis, the joint space after arthrocentesis, and the abdominal cavity after paracentesis, among others.

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^13-15

Normal pregnancy
Transient elevation during labor and delivery
Normal infancy
Cigarette smoking
Acute infection (especially bacterial, but also certain viral and fungal infections)
Inflammation
Chronic inflammatory conditions (e.g., rheumatoid arthritis, Crohn’s disease, ulcerative colitis, vasculitis)
Acute stress
Myeloproliferative disorders
Hematologic and neoplastic diseases
- Acute lymphocytic leukemia
- Chronic lymphocytic leukemia
- Chronic myelogenous leukemia
- Large granular lymphocytic leukemia
- Thymoma
Metabolic disorders
- Diabetic ketoacidosis
- Preeclampsia
- Uremia
Certain genetic abnormalities
Drugs
- Glucocorticoids
- Recombinant granulocyte colony-stimulating factor
- Catecholamines
- Lithium

Low in:^16-18

Nutritional deficiency (e.g., vitamin B12, folate, copper)
Congenital neutropenia (e.g., benign ethnic neutropenia)
Infection (e.g., HIV, sepsis)
Post-infectious neutropenia
Autoimmune neutropenia
Myelodysplastic syndromes
Hematologic and neoplastic diseases
Aplastic anemia
Paroxysmal nocturnal hemoglobinuria
Drugs
- Chemotherapy
- Atypical antipsychotics (e.g., clozapine, olanzapine)
- Antibiotics (e.g., penicillin)
- Anticonvulsants (e.g., phenytoin)
- Sulfasalazine
- Thionamides (e.g., methimazole, propylthiouracil, carbimazole)
- Ticlopidine
- Rituximab

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

Zinc

Marker Name: Zinc

REFERENCE RANGE FOR PLASMA OR SERUM ZINC CONCENTRATION:

Laboratory reference range: 56–134 µg/dL

Functional reference range: 81–157 µg/dL

DESCRIPTION

Zinc is a trace element that is essential for the proper function of approximately 250 proteins, at least 200 of which are enzymes.¹ Zinc is a cofactor for carbonic anhydrase, alkaline phosphatase, and DNA polymerase, among many others.² The mineral plays a vital role in cell growth and replication, immune system function, protein synthesis, DNA synthesis, bone and joint health, wound healing, and thyroid function.^1-4 A steady supply of zinc is required for normal growth and development.⁵ Moreover, zinc is integral to the sense of taste and smell.^4,6

A normal adult human contains between 1.5 and 3 grams of zinc at any given time.^5,7 Roughly 60 percent of zinc in the body is contained within bone and muscle,⁷ though there is no specialized zinc storage system.⁴ Zinc undergoes very slow turnover; only 0.1 percent of total body zinc is replenished each day.⁵ The element is mainly absorbed in the upper small intestine and, to a lesser extent, in the lower small intestine and colon.⁸ Likewise, zinc is mainly excreted via the gastrointestinal tract, though 10 percent of circulating zinc may be secreted in the urine.⁷

Pancreatic enzymes release dietary zinc, which then forms complexes with organic acids, amino acids, and phosphates.⁹ Zinc homeostasis is mainly controlled by metallothionein, a metalloprotein found in gastrointestinal tract cells.^7,10 Metallothionein binds not only to zinc, but also to other biologically important divalent ions, such as iron and copper. In fact, excess zinc intake can inhibit copper absorption by metallothionein.^7,10

In the serum, 80 percent of zinc is carried by albumin, while most of the other 20 percent is shuttled by alpha-2-macroglobulin; the mineral is loosely bound to the former and tightly bound to the latter.¹ Consequently, states of hypoalbuminemia can result in a higher-than-normal portion of zinc binding to macroglobulin, rendering it functionally unavailable (i.e., it is too tightly bound to dissociate for biological uses).¹ Intracellular zinc may be bound to carrier molecules within cells. For example, metallothionein acts as a storage molecule for zinc in the liver.⁷

Elevated zinc (hyperzincemia) can occur through over-supplementation, by consuming contaminated foods, or through prolonged use of denture adhesives. Direct zinc toxicity from excess zinc consumption is rarely a clinical concern because of multiple homeostatic mechanisms. That is, excess ingested zinc is not absorbed by metallothionein in the gut, and excess zinc may be secreted by the gut into the intestinal lumen or by the kidney into the urine.¹⁰Excessive zinc intake may be of concern when it causes hypocupremia, an abnormally low level of copper in the blood.¹⁰ Exposure to ZnO fumes, which may occur in galvanized metal welders, may lead to inhalation of enough zinc to cause acute toxicity.¹¹

Low zinc levels (hypozincemia) can result from inadequate intake of zinc, zinc malabsorption, impaired zinc transport, or increased zinc loss. Inadequate intake of zinc may not be due to decreased consumption, but rather due to increased requirements for zinc (e.g., pregnancy, prolonged breast-feeding).¹² Numerous drugs across many drug classes can cause zinc depletion.⁶

Plasma or serum levels are generally regarded as an acceptable indicator of zinc status in healthy individuals.^5,10 During acute inflammatory states, however, plasma zinc is not a useful measurement, since plasma levels deplete.¹³ In these cases, zinc status can be accurately obtained by measuring zinc within red blood cells.¹³ Albumin and copper levels in the serum can provide critical information when evaluating serum zinc levels.^10,12 Since erythrocytes carry appreciable amounts of zinc, hemolysis can cause serum zinc level to be falsely elevated.²Gadolinium, iodine, and barium are known to interfere with serum metal testing.¹²

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^11,14-17

Excess zinc supplementation
Inhalation of ZnO fumes
Prolonged use of denture adhesives
Familial hyperzincemia

Low in:^8,9,12,18,19

Dietary inadequacy
- Malnutrition
- Vegetarian diets
- Total parenteral nutrition (TPN) with inadequate zinc
- Sickle cell anemia
- Pregnancy
- Prolonged breast-feeding
- Severe burns
Decreased absorption
- High-phytate diets
- Inflammatory bowel disease
- Bowel surgery
- Chronic diarrhea
- Necrotizing enterocolitis in pre-term infants
- Acrodermatitis enteropathica
States of hypoalbuminemia (e.g., cirrhosis, nephrotic syndrome)
Drugs
- Oral contraceptives
- Antacids
- Histamine H₂ antagonists
- Anti-inflammatories
- Diuretics
- Angiotensin-converting enzyme (ACE) inhibitors
- Anticonvulsants
- Antiretrovirals

FUNCTIONAL RANGE INDICATIONS:

High in:

Same as conventional indications

Low in:

Same as conventional indications

References:

Source: Kresser Institute

Zinc/Copper Ratio

Marker Name: Zinc / Copper ratio

REFERENCE RANGE FOR ZINC/COPPER RATIO:

Functional reference range: 0.85–1.2

DESCRIPTION:

Zinc and copper are trace elements that are essential to the function of hundreds of proteins in humans. Zinc is a cofactor for RNA and DNA polymerase, carbonic anhydrase, alkaline phosphatase, and approximately 200 other enzymes.¹ Zinc is essential for cell signaling, growth and development, lipid metabolism, and nervous system and immune system function.² Copper is an integral component of numerous metalloenzymes involved in cellular respiration, collagen cross-linking, neurotransmitter synthesis, bone formation, and thrombosis, among others.^3,4

Zinc and copper can be found throughout the body, but 50 to 60 percent of total body stores of these minerals is held within bone and muscle.^3,5 In humans, total body copper content is between 50 and 120 mg, while zinc content is two orders of magnitude higher, between 1.5 and 3 grams.^3,6

Zinc and copper homeostasis are closely related; intestinal absorption of copper is inhibited by zinc within the gastrointestinal tract and vice versa.^1,7 Metallothionein, a metalloprotein that binds to various divalent ions, is responsible for copper and zinc absorption in the intestine.⁸Metallothionein regulates zinc homeostasis, yet copper binds to the metalloprotein in gut enterocytes more avidly than zinc does.³ Moreover, metallothionein acts as a storage molecule for both zinc and copper in the liver.³

Both elements are transported in the blood by carrier proteins; albumin and macroglobulin carry zinc, while ceruloplasmin carries most copper.³ The same cytokines that increase the cellular uptake of zinc also enhance the production of ceruloplasmin in the liver.⁹

As a ratio, any etiology of increased serum zinc or decreased serum copper will necessarily increase the zinc/copper ratio. Further exacerbating this imbalance is the manner in which these divalent cations are absorbed in the gut; excess of one decreases the absorption of the other.^1,7Conversely, the ratio may be abnormally low if zinc levels diminish, copper levels increase, or both changes occur.

Importantly, copper can be transiently elevated during acute inflammation, infection, or trauma, while serum levels of zinc may decrease.^4,10-12 Consequently, the zinc-to-copper ratio would decrease substantially. Under these clinical conditions, a more accurate assessment of copper and zinc can be gathered by assessing erythrocytes levels of each trace mineral.¹⁰

Zinc and copper may be measured within a trace minerals panel.¹³ Albumin and ceruloplasmin levels can provide important diagnostic information when evaluating zinc and copper abnormalities.^8,14

FUNCTIONAL RANGE INDICATIONS:

High in:^3,15-24

Excess zinc
- Megadose zinc supplementation
- Inhalation of ZnO fumes
- Prolonged use of denture adhesives
- Familial hyperzincemia
Decreased copper
- Menkes disease
- Excessive iron ingestion
- Chronic dialysis (hemodialysis, peritoneal dialysis)
- Prolonged total parenteral nutrition
- Aceruloplasminemia
- Gastrointestinal malabsorption
  - Post-gastrectomy
  - Post-gastric bypass surgery
  - Celiac disease
  - Inflammatory bowel disease
  - Chronic diarrhea
  - Cystic fibrosis
- Hypoproteinemia
  - Malnutrition
  - Nephrotic syndrome
- Drugs
  - Corticosteroids
  - Clioquinol
  - Tetrathiomolybdate

Low in:^{3,11,14,20,25-31}

Excess copper
- Wilson disease
- Normal pregnancy
- Excessive copper intake
- Hyperthyroidism
- Hemochromatosis
- Primary biliary cirrhosis
- Primary sclerosing cholangitis
- Drugs
  - Oral contraceptives
  - Estrogens
  - Carbamazepine
  - Phenobarbital
- Decreased zinc
  - States of hypoalbuminemia (e.g., cirrhosis, nephrotic syndrome)
  - Dietary inadequacy
    - Malnutrition
    - Strict vegetarian diets
    - Total parenteral nutrition (TPN) with inadequate zinc
    - Sickle cell anemia
    - Pregnancy (normal or abnormal)
    - Prolonged breastfeeding
    - Severe burns
  - Decreased absorption
    - High-phytate diets
    - Inflammatory bowel disease
    - Bowel surgery
    - Chronic diarrhea
    - Necrotizing enterocolitis in preterm infants
    - Acrodermatitis enteropathica
  - Drugs
    - Antacids
    - Histamine H₂ antagonists
    - Oral contraceptives
    - Anti-inflammatories
    - Diuretics
    - Angiotensin-converting enzyme (ACE) inhibitors
    - Anticonvulsants
    - Antiretrovirals
  - Increased copper and decreased zinc
    - Infarction
    - Coronary artery disease
    - Infection
    - Inflammation
    - Neoplastic disease (e.g., leukemia)
    - Trauma
    - Renal failure

References:

Source: Kresser Institute

DESCRIPTION:

References:

What is Functional Medicine?

Functional Medicine Testing

Functional Lab Charts

Lab Markers