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LIVER FUNCTION TESTS

Aspartate Aminotransferase

Reference Range: 0–35 units/L or 0–0.58 µkat/L

The aspartate aminotransferase (AST) enzyme is abundant in heart and liver tissue

and moderately present in skeletal muscle, kidney, and pancreas. In cases of acute

cellular injury to the heart or liver, the enzyme is released into the blood from the

damaged cells. In practice, AST determinations have been used to evaluate

myocardial injury and to diagnose and assess the prognosis of liver disease resulting

from hepatocellular injury. The serum AST level is increased in more than 95% of

patients after an MI. However, the increase in AST does not occur until 4 to 6 hours

after the onset of myocardial injury. Peak AST concentrations are seen in the serum

after 24 to 36 hours, returning to the normal range in about 4 to 5 days.

Serum AST values are elevated significantly in patients with acute hepatic

necrosis, whether caused by viral hepatitis or a hepatotoxin (e.g., carbon

tetrachloride). In these situations, the serum concentrations of both AST and alanine

aminotransferase (ALT) will be increased, even before the appearance of clinical

symptoms (e.g., jaundice). The AST and ALT serum concentrations can be increased

by as much as 100 times the usual upper limits of normal in the presence of

parenchymal liver disease. Patients with intrahepatic cholestasis, posthepatic

jaundice, or cirrhosis usually experience more moderate elevations of AST,

depending on the extent of cell necrosis. The AST serum concentration is usually

higher than that of ALT in patients with cirrhosis, and the AST increase is usually

about four to five times greater than the upper limit of normal.

Alanine Aminotransferase

Reference Range: 0–35 units/L or 0–0.58 µkat/L

The ALT enzyme is found in essentially the same tissues that have high

concentrations of AST. However, elevations in serum ALT are more specific for

liver-related injuries or diseases. Although ALT is relatively more abundant in

hepatic tissue versus cardiac tissue than AST, the liver still contains 3.5 times more

AST than ALT. Serum concentrations of both AST and ALT increase when disease

processes affect liver cell structure, but ALT concentrations are not significantly

increased as a result of an acute MI. Evaluating the ratio of ALT to AST can be

potentially useful, particularly in the diagnosis of viral hepatitis. The ALT/AST ratio

frequently exceeds 1.0 with alcoholic cirrhosis, chronic liver disease, or hepatic

cancer. However, ratios less than 1.0 tend to be observed with viral hepatitis or

acute hepatitis, which can be useful when diagnosing liver disease.

Alkaline Phosphatase

Reference Range: 20–130 units/L or 0.33–2.17 µkat/L

The alkaline phosphatases (ALPs) constitute a large group of isoenzymes that play

important roles in the transport of sugar and phosphate. These isoenzymes of ALP

have different physiochemical properties and originate from different tissues (e.g.,

liver, bone, placenta, and intestine). In normal adults, ALP is derived primarily from

liver and bone. Although only small amounts of ALP are present in the liver, this

enzyme is secreted into the bile, and substantially elevated ALP serum concentrations

can be seen with mild intrahepatic or extrahepatic biliary obstruction. Thus, the

presence of early bile duct abnormalities can result in elevated ALP before increases

in the serum bilirubin are observed. Drug-induced cholestatic jaundice (e.g.,

chlorpromazine or sulfonamides) can increase serum ALP concentrations. In mild

cases

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of acute liver cell damage, ALP levels are seldom elevated. Even in cirrhosis,

ALP concentrations are variable and depend on the degree of hepatic

decompensation and obstruction.

The osteoblasts in bone produce large amounts of ALP, and marked serum

elevations can be seen in Paget disease of the bone, hyperparathyroidism, osteogenic

sarcoma, osteoblastic cancer metastatic to bone, and other conditions of pronounced

osteoblastic activity. The serum ALP is increased during periods of rapid bone

growth (e.g., infancy, early childhood, and healing bone fractures) and during

pregnancy because of the contributions of the placenta and fetal bones.

Gamma-Glutamyl Transferase

Reference Range: male 9–50 units/L, female 8–40 units/L

Although the enzyme γ-glutamyl transferase (GGT) is found in the kidney, liver,

and pancreas, its major clinical value is in the evaluation of hepatobiliary disease.

An increase in the serum concentration of GGT parallels the increase of ALP in

obstructive jaundice and infiltrative disease of the liver. However, increased ALP in

the presence of a normal GGT is more suggestive of muscular or bone-related issues.

GGT is one of the more sensitive liver enzymes for identifying biliary obstruction

and cholecystitis. Because GGT is a hepatic microsomal enzyme, tissue

concentrations increase in response to microsomal enzyme induction by alcohol and

other drugs (e.g., carbamazepine, phenobarbital, and phenytoin). As a result, GGT is

a sensitive indicator of recent or chronic alcohol exposure.

Bilirubin

Total Bilirubin—Reference Range: 0.1–1.0 mg/dL or 2–18 µmol/L Direct

(Conjugated) Bilirubin—Reference Range: 0–0.2 mg/dL or 0–4 µmol/L

Bilirubin is primarily a breakdown product of Hgb and is formed in the

reticuloendothelial system (Fig. 2-1, step 1). It is then transferred into the blood (step

2), where it is almost completely bound to serum albumin (step 3). When bilirubin

arrives at the sinusoidal surface of the liver cells, the free fraction is rapidly taken up

into the cell (step 4) and converted primarily to bilirubin diglucuronide (step 5). A

monoglucuronide is also formed that is metabolized predominantly to the

diglucuronide. The conjugated bilirubin diglucuronide is then excreted into the bile

(step 6) and appears in the intestine, where bacteria convert most of it to

urobilinogen (step 7). The majority of urobilinogen is destroyed or excreted in the

feces (step 13), but a small portion is reabsorbed into the blood (step 8) and either

reabsorbed into the liver (step 9) and subsequently excreted into the bile (step 12) or

excreted into the urine (step 10). Urobilinogen is responsible for the straw color of

the urine and the yellowish-brown color of the feces. The mechanism by which

conjugated bilirubin in the liver cell is transferred to the blood (step 14) is not well

understood. However, in many types of liver disease, conjugated (direct) bilirubin is

present in increased concentrations in the blood. When this concentration exceeds 0.2

to 0.4 mg/dL, bilirubin will begin to appear in the urine (step 11). Unconjugated

(indirect) bilirubin is water insoluble and is highly bound to serum albumin; both

factors account for its lack of excretion in the urine.

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MISCELLANEOUS TESTS

Amylase and Lipase

Amylase (reference range: 35–118 units/L or 0.58–1.97 μkat/L) and lipase

(reference range: 10–160 units/L or 0–2.67 μkat/L) are enzymes produced by the

pancreas and secreted into the duodenum to assist in the digestive process. Small

amounts of both enzymes are also found in the saliva and stomach. Significantly

elevated levels of either enzyme are suggestive of pancreatic damage.

Figure 2-1 Bilirubin metabolism.

Amylase is responsible for breaking down complex carbohydrates into simple

sugars. Significant elevations in serum amylase are observed in patients with acute

pancreatitis or pancreatic duct obstruction. Amylase levels tend to rise 6 to 48 hours

after onset of the disease and usually return to normal 3 days after the acute event. In

chronic pancreatitis or obstruction, amylase levels may remain elevated for longer

periods. Other nonpancreatic conditions (e.g., bowel perforation, biliary disease,

perforated peptic ulcer, ectopic pregnancy, and mumps) can be associated with

elevated serum amylase levels.

Lipase is responsible for breaking down triglycerides into fatty acids. Elevated

serum lipase levels are also suggestive of pancreatic disease and tend to be more

specific for pancreatic disease than amylase. Nonpancreatic conditions such as

gallbladder disease or biliary cirrhosis can also lead to elevated lipase levels. The

onset of lipase elevation is similar to amylase; however, lipase typically remains

elevated for 5 to 7 days and can be useful in diagnosing patients in later stages of

pancreatic disease. Narcotics (e.g., morphine) can constrict the sphincter of Oddi and

increase serum concentrations of both amylase and lipase.

Prostate-Specific Antigen

Reference Range: 0–4 ng/mL or 0–4 mcg/L

Prostate-specific antigen (PSA) is a protease glycoprotein produced almost

exclusively by prostate epithelial cells. Large quantities of PSA are carried in semen;

only low levels are found in the blood. Serum concentrations of PSA are increased

when

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the normal prostate glandular structure is disrupted by benign or malignant tumor

or inflammation (prostatitis). More than half of men with benign prostatic hyperplasia

(BPH) have elevated serum PSA concentrations. PSA is also a valuable parameter

for staging and monitoring the progression and response to therapy of prostate

cancer.

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The prostate gland increases in size with age; therefore, it is expected that older

men will have higher PSA levels compared with younger men. PSA serum

concentrations can also increase after prostatic manipulation such as digital rectal

examination (DRE), catheter placement, transrectal ultrasound, cystoscopy, or biopsy

of the prostate. In addition, serum PSA will increase 24 to 48 hours after ejaculation.

Although elevated serum concentrations of PSA can occur in men with BPH,

concentrations tend to be higher and encountered more often in men with cancer. Men

with PSA levels between 4 and 10 ng/mL should be evaluated further for potential

prostate cancer.

The serum half-life of PSA is 2 to 3 days, but serum PSA concentrations can

remain high for several weeks after manipulation of the prostate. Circulating serum

PSA is bound to plasma proteins, and the capability exists to measure both total and

free (unbound) PSA concentrations. Increased risk of prostate cancer has been

observed in men with a free PSA to total PSA ratio of less than 0.25.

31 An aggressive

approach to localize prostate cancer for men with life expectancies more than 10

years is now favored.

30,32

Thyroid-Stimulating Hormone

Reference Range: 0.5–4.7 µunits/mL or munits/L

Thyroid-stimulating hormone (TSH, also known as thyrotropin) is secreted by the

pituitary gland to stimulate the thyroid gland to produce the thyroid hormones T4 and

T3

. TSH is measured, often in conjunction with the thyroid hormones, to diagnose

thyroid disorders and to monitor exogenous thyroid supplementation therapy. The

reader is referred to Chapter 52, Thyroid Disorders, as it provides a more detailed

discussion of the clinical implications of altered thyroid laboratory findings.

Procalcitonin

Procalcitonin is a precursor for calcitonin and is typically undetectable in healthy

individuals. Elevations in procalcitonin occur in patients with inflammation

secondary to bacterial infections; however, a similar increase is not observed in

patients with inflammation secondary to viral infections or noninfectious conditions.

Interestingly, increases in calcitonin are not seen in patients with elevated

procalcitonin. In patients with sepsis or sepsis syndrome, procalcitonin levels <0.5

ng/mL have been associated with a low risk of progression to severe sepsis and

levels >2.0 ng/mL represent a high risk for severe sepsis. Trials involving lower

respiratory tract infections have suggested that antibiotic therapy should be

discouraged in patients with procalcitonin levels <0.25 ng/mL, but encouraged for

those with levels ≥0.5 ng/mL. These criteria have also been used as a guide for

discontinuing therapy as infections resolve; however, the exact role for the use of

procalcitonin levels has not been clearly characterized. Additional trials will help to

accurately define the role of procalcitonin testing.

Cholesterol and Triglycerides

A detailed discussion of hypercholesterolemia and lipid disorders is provided in

Chapter 8, Dyslipidemias, Atherosclerosis, and Coronary Heart Disease. For

convenience, the current range of desired values for total cholesterol (TC), lowdensity lipoproteins (LDLs), high-density lipoproteins (HDLs), and fasting

triglycerides (TGs) has been incorporated in Table 2-2.

HEMATOLOGY

There are several different hematologic cell types that originate from the

hematopoietic stem cell. Each cell line has a defined role and unique contribution to

the overall homeostatic process and may be found in the bone marrow, lymph system,

or blood. Typically, routine clinical laboratory testing involves measuring

concentrations of mature myeloid cells found in the blood. Figure 2-2 illustrates the

various lineages derived from the hematopoietic stem cell.

33 The cells derived from

the myeloid linage are the focus of the following discussion. Readers are encouraged

to refer to Section 16, Hematology and Oncology, to gain further understanding of the

clinical relevance of lymphoid and myeloid cells (Fig. 2-2).

Complete Blood Count

The complete blood count (CBC) is one of the most commonly ordered clinical

laboratory tests. A CBC measures the RBCs, Hgb, hematocrit (Hct), mean cell

volume (MCV), mean cell Hgb concentration (MCHC), and total white blood cells

(WBCs). Depending on the laboratory, an order for a CBC may also include

platelets, reticulocytes, or leukocyte differential. An abbreviated method of noting

hematologic parameters in clinical practice is noted in the following figure.

Red Blood Cells (Erythrocytes)

Males—Reference Range: 4.3–5.9 × 10

6

/µL or 4.3–5.9× 10

12

/L

Females—Reference Range: 3.5–5 × 10

6

/µL or 3.5–5 × 10

12

/L

Erythrocytes or RBCs are produced in the bone marrow, released into the

peripheral blood, circulated for approximately 120 days, and cleared by the

reticuloendothelial system. The primary function of RBCs is to transport oxygen

linked to Hgb from the lungs to tissues. The concentration of RBCs in the blood can

be measured to detect anemia, calculate RBC indices, or calculate the Hct. Hct and

Hgb concentrations are generally used to monitor quantitative changes in RBCs.

Hematocrit

Males—Reference Range: 40.7%–50.3%or 0.4–0.503

Females—Reference Range: 36%–44.6%or 0.36–0.446

Hct (packed cell volume) is the percentage of RBCs to the total blood volume and

is determined by centrifuging a capillary tube of whole blood and comparing the

height of the settled RBCs to the height of the column of whole blood. A decrease in

Hct may result from bleeding, the bone marrow suppressant effects of drugs, chronic

diseases, genetic alterations in RBC morphology, or hemolysis. An increase in Hct

may result from hemoconcentration, polycythemia vera, or polycythemia secondary to

chronic hypoxia.

Hemoglobin

Males—Reference Range: 13.8–17.5 g/dL or 138–175 g/L

Females—Reference Range: 12.1–15.3 g/dL or 121–153 g/L

Hgb is the major oxygen-carrying compound contained in RBCs. Therefore, total

Hgb concentration primarily depends on the number of RBCs in the blood sample. As

mentioned with Hct, medical conditions that impact the number of RBCs will also

affect Hgb concentration. As discussed previously, glycosylated Hgb (A1c

) is a

related test used to monitor diabetes mellitus.

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Figure 2-2 Hematopoietic stem cell lineage. (Adapted with permission from Greer JP et al, eds. Wintrobe’s

Clinical Hematology. 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:80.)

Red Blood Cell Indices

RBC indices (also known as Wintrobe indices) are useful in the classification of

anemias. These indices include the MCV, the mean cell Hgb (MCH), and the MCHC.

These indices are calculated in Equations 2-9 to 2-11:

MEAN CELL VOLUME

The MCV detects changes in cell size. A decreased MCV indicates a microcytic cell,

which can result from iron-deficiency anemia or

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