Chapter 1 Assessment of liver function and diagnostic studies

Paul Martin, MD, FRCP, FRCPI, Lawrence S. Friedman, MD

1 Reflecting the liver’s diverse functions, the colloquial term liver function tests (LFTs) includes true tests of hepatic synthetic function (e.g., serum albumin), tests of excretory function (e.g., serum bilirubin), and tests that reflect hepatic necroinflammatory activity (e.g., serum aminotransferases) or cholestasis (e.g., alkaline phosphatase).

2 Abnormal liver biochemistry test results are often the first clues to liver disease. The widespread inclusion of these tests in routine blood chemistry panels uncovers many patients with unrecognized hepatic dysfunction.

3 Normal or minimally abnormal liver biochemical test levels do not preclude significant liver disease, even cirrhosis.

4 Laboratory testing can assess the severity of liver disease and its prognosis; sequential testing may allow assessment of the effectiveness of therapy.

5 Liver biopsy remains the gold standard for assessing the severity of liver disease, as well as for confirming the diagnosis for some causes. Newer diagnostic noninvasive modalities including serum markers of fibrosis and transient elastography may complement the use of liver biopsy.

6 Various imaging studies are useful in detecting focal hepatic defects, the presence of portal hypertension, and abnormalities of the biliary tract.

Routine Liver Biochemical Tests

Serum bilirubin

1. Jaundice

Often the first evidence of liver disease

Clinically apparent when serum bilirubin exceeds 3 mg/dL; patient may notice dark urine or pale stool before conjunctival icterus

2. Metabolism

Bilirubin is a breakdown product of hemoglobin and, to a lesser extent, heme-containing enzymes; 95% of bilirubin is derived from senescent red blood cells.

Following red blood cell breakdown in the reticuloendothelial system, heme is degraded by the enzyme heme oxygenase in the endoplasmic reticulum.

Bilirubin is released into blood and tightly bound to albumin; free or unconjugated bilirubin is lipid soluble, is not filtered by the glomerulus, and does not appear in urine.

Unconjugated bilirubin is taken up by the liver by a carrier-mediated process, attaches to intracellular storage proteins (ligands), and is conjugated by the enzyme uridine diphosphate (UDP)–glucuronyl transferase to form a diglucuronide and, to a lesser extent, a monoglucuronide.

Conjugated bilirubin is water soluble and thus appears in urine.

When serum bilirubin glucuronides are elevated, some binding to albumin occurs (delta bilirubin), leading to absence of bilirubinuria despite conjugated hyperbilirubinemia; this phenomenon explains delayed resolution of jaundice during recovery from acute liver disease until catabolism of albumin-bound bilirubin occurs.

Conjugated bilirubin is excreted by active transport across the canalicular membrane into bile.

Bilirubin in bile enters the small intestine; in the distal ileum and colon, bilirubin is hydrolyzed by beta-glucuronidases to form unconjugated bilirubin, which is then reduced by gut bacteria to colorless urobilinogens; a small amount of urobilinogen is reabsorbed by the enterohepatic circulation and mostly excreted in the bile, with a smaller proportion undergoing urinary excretion.

Urobilinogens or their colored derivatives urobilins are excreted in feces.

4. Classification of hyperbilirubinemia

a. Unconjugated (bilirubin nearly always less than 7 mg/dL)

Overproduction (presentation to liver of bilirubin load that exceeds hepatic capacity for uptake and conjugation): hemolysis, ineffective erythropoiesis, resorption of hematoma

Defective uptake and storage of bilirubin: Gilbert’s syndrome (idiopathic unconjugated hyperbilirubinemia)

b. Conjugated

Hereditary: Dubin–Johnson and Rotor’s syndromes, bile transport protein defects

Cholestasis (bilirubin is not a sensitive test of hepatic dysfunction)

– Intrahepatic: cirrhosis, hepatitis, primary biliary cirrhosis, drug-induced

– Extrahepatic biliary obstruction: choledocholithiasis, stricture, neoplasm, biliary atresia, sclerosing cholangitis

c. Very high bilirubin levels

Higher than 30 mg/dL: usually signifies hemolysis plus parenchymal liver disease or biliary obstruction; urinary excretion of conjugated bilirubin may help prevent even higher levels of hyperbilirubinemia; renal failure contributes to hyperbilirubinemia

Higher than 60 mg/dL: seen in patients with hemoglobinopathies (e.g., sickle cell anemia) who develop obstructive jaundice or acute hepatitis

Serum aminotransferases (Table 1.1)

2. Clinical usefulness

Normal levels of ALT are up to 30 U/L in men and up to 19 U/L in women.

Levels increase with body mass index and may correlate with the risk of coronary artery disease and mortality.

Levels may rise acutely with a high caloric meal or ingestion of acetaminophen 4 g/day; coffee appears to lower levels.

Aminotransferase elevations are often the first biochemical abnormalities detected in patients with viral, autoimmune, or drug-induced hepatitis; the degree of elevation may correlate with the extent of hepatic injury but is generally not of prognostic significance.

In alcoholic hepatitis, the serum AST is usually no more than 2 to 10 times the upper limit of normal, and the ALT is normal or nearly normal with an AST:ALT ratio greater than 2; relatively low ALT levels may result from a deficiency of pyridoxal 5-phosphate, a necessary cofactor for hepatic synthesis of ALT. In contrast, in nonalcoholic fatty liver disease, ALT is typically higher than AST until cirrhosis develops.

Aminotransferase levels may be higher than 3000 U/L in acute or chronic viral hepatitis or drug-induced liver injury; in acute liver failure or ischemic hepatitis (shock liver), even higher values (higher than 5000 U/L) may be found.

Mild to moderate elevations of aminotransferase levels are typical of chronic viral hepatitis, autoimmune hepatitis, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson disease, and celiac disease.

In obstructive jaundice, aminotransferase values are usually lower than 500 U/L; rarely, values may reach 1000 U/L in acute choledocholithiasis or 3000 U/L in acute cholecystitis, followed by a rapid decline to normal.

3. Approach to the patient with an elevated ALT is shown in Fig. 1.1.

4. Approach to the patient with mild diffuse liver test abnormalities is shown in Fig. 1.2.

5. Abnormally low aminotransferase levels have been associated with uremia and chronic hemodialysis; chronic viral hepatitis in this population may not result in aminotransferase elevation.

TABLE 1.1 Causes of elevated serum aminotransferase levels ^∗

Mild elevation (<5× normal)	Marked elevation (>15× normal)
Hepatic: ALT predominant	Acute viral hepatitis (A–E, herpes)
Chronic viral hepatitis	DILI
Acute viral hepatitis (A–E, EBV, CMV)	Ischemic hepatitis
NAFLD	Autoimmune hepatitis
Hemochromatosis	Wilson disease
DILI	Acute bile duct obstruction
Autoimmune hepatitis	Acute Budd–Chiari syndrome
Alpha-1 antitrypsin deficiency	Hepatic artery ligation
Wilson disease
Celiac disease
Hepatic: AST predominant
Alcohol-related liver injury (AST:ALT >2:1)
Cirrhosis
Nonhepatic
Strenuous exercise
Hemolysis
Myopathy
Thyroid disease
Macro-AST

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CMV, cytomegalovirus; DILI, drug-induced liver injury; EBV, Epstein-Barr virus; NAFLD, nonalcoholic fatty liver disease.

∗ Almost any liver disease may be associated with ALT levels 5 times to 15 times normal.