Laboratory Measurement of Hepatic Function

Markers of Cellular Injury

The serum aminotransferases AST and ALT catalyze the reversible transfer of the α-amino group of the amino acids aspartic acid and alanine, respectively, to the α-keto group of α-ketoglutaric acids, forming oxaloacetic acid and pyruvic acid, respectively. These enzymes are present in the serum at low levels in the blood (usually up to 35 to 60 IU/L, depending on the laboratory reference values) and are released into the blood whenever hepatocyte plasma membrane damage occurs. ALT is found primarily in the cytoplasm of liver cells and is relatively a more specific indicator of liver damage than the AST, which can be found in the mitochondria of the skeletal and cardiac muscles, kidney, pancreas, red blood cells, and brain. Small rises of ALT can occasionally also be seen in muscle injury.

Although serum levels of aminotransferases are elevated to some degree in almost all liver diseases, the highest levels are seen with acute viral hepatitis, toxin-induced hepatic necrosis, and ischemic liver injury. Mild cases of viral hepatitis are accompanied by elevations in the few hundreds, and values greater than 1000 IU/mL are usually seen only in patients who develop jaundice from acute viral hepatitis. Values greater than 3000 IU/mL are more typical of acetaminophen-induced toxic injury or severe cases of ischemic hepatitis. The degree of elevation has little prognostic significance because it does not reflect the integrity of the remaining viable hepatocytes and the ability of the liver to recover. The remaining synthetic function of the liver is more accurately measured by the prothrombin time, which serves as the best tool for predicting hepatic outcome.

In cases of mild to moderate aminotransferase elevations up to 300 IU/mL, a ratio of AST to ALT of greater than 2 is suggestive of alcoholic liver disease (ALD). Cases of nonalcoholic fatty liver disease (NAFLD) or viral hepatitis typically have a higher serum ALT level than the AST, whereas hypoxic or toxic injury has a higher AST than ALT. The serum AST has a shorter mean plasma half-life (17 hours) as compared with the ALT (47 hours), so it declines more rapidly than the serum ALT, allowing the serum ALT to become higher than the serum AST in the recovery phase of the illness. If the serum AST is significantly elevated out of proportion to a normal or minimally elevated serum ALT, extrahepatic sources of the serum AST should be considered, such as myocardial infarction, rhabdomyolysis, strenuous exercise, or hemolysis.

An acute elevation of the serum aminotransferases may represent a recent onset of injury from ischemia, drug or toxins, acute viral infection, or, in some cases, choledocholithiasis, whereas a chronic elevation of 6 months or longer may represent chronic viral hepatitis, autoimmune hepatitis (AIH), or metabolic diseases of the liver.

Markers of Bile Secretion and Flow

Alkaline phosphatase is a group of zinc metalloenzymes that hydrolyze organic phosphate esters. It is found in the canalicular membrane of hepatocytes, as well as in a variety of other tissues, including bone, intestine, placenta, kidney, and leukocytes. Normal serum levels are highly dependent on age, with high levels in childhood and puberty correlating with active bone growth and a second elevation during older age correlating with bone resorption. In liver disease the enzyme apparently increases by virtue of new protein synthesis, probably induced by certain bile acids. Although modest elevations are seen in many forms of hepatocellular disease, values that are threefold or more above normal range are indicative of bile duct obstruction or intrahepatic cholestasis.

Another enzyme used to evaluate cholestasis, γ-glutamyl transpeptidase (GGT), is present in the liver and in other organs, such as the small intestine, kidney, testes, pancreas, spleen, heart, and brain. This enzyme catalyzes the transfer of γ-glutamyl groups from glutathione and other peptides to other amino acids. Serum GGT is a sensitive, but nonspecific, test for detecting biliary tract disease. It is highly inducible by alcohol and drugs and may be elevated in certain medical conditions such as diabetes mellitus, renal failure, myocardial infarction, and chronic obstructive pulmonary disease. Its main value in the clinical setting is in determining if an elevated alkaline phosphatase level is due to liver disease or not and perhaps in monitoring alcohol abstinence in a patient with normal serum AST and ALT.

Acute cholestasis may be due to an acute obstruction in the bile duct, which may result from the passage of a gallstone into the common bile duct or from a rapidly growing malignancy. It may also result from hepatotoxicity from certain drugs, such as macrolide antibiotics and azole class of antifungal agents, or as a consequence of sepsis, parenteral nutrition (PN), or other complications of critical illness. Drug-induced cholestasis may linger to become chronic, but other causes of chronic cholestasis include chronic bile duct obstruction from a benign biliary stricture or a slower growing malignancy, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), immunoglobulin G4 (IgG4)-associated cholangitis (IAC), and hepatic sarcoidosis. Infiltrative diseases of the liver often also lead to an increase in serum alkaline phosphatase levels.

Markers of Bilirubin Metabolism

Unconjugated bilirubin is the by-product of hemoglobin degradation in the spleen. It binds to serum albumin and is brought to the liver, where it is taken up by the hepatocyte to undergo conjugation, and conjugated bilirubin is excreted in bile. Serum unconjugated bilirubin levels increase in disorders that result in overproduction of unconjugated bilirubin or in disorders of the conjugation process. Serum conjugated bilirubin is commonly elevated in most liver diseases, including conditions in which there is hepatocellular injury, bilirubin transport disorders, or bile duct diseases. In the evaluation of hyperbilirubinemia, it is important to attempt to identify the type of bilirubin that is elevated to allow for the identification of the pathologic step in bilirubin metabolism.

Measures of Synthetic Function

Albumin is the most abundant serum plasma protein synthesized by the liver. It has a half-life of approximately 20 days, which limits its utility as a synthetic marker during acute liver disease. It is also insensitive to mild degrees of hepatic injury, but a significant decline signals a prolonged, and usually major, insult to the liver. Other factors that may affect the serum albumin levels include nutrition and losses through the gastrointestinal and renal systems. In patients with edema and ascites, the volume of distribution for albumin may be expanded, leading to a reduction in the measured serum levels.

The liver synthesizes six coagulation factors: factor I (fibrinogen), II (prothrombin), V, VII, IX, and X. The prothrombin time measures the rate of conversion of prothrombin to thrombin in the test serum with added thromboplastin and calcium and indirectly assesses for the availability of the coagulation factors. Prolongation of the prothrombin time may be due to inadequate factor synthesis by the liver in cases of severe liver dysfunction, but dietary vitamin K deficiency, antibiotic administration, vitamin K malabsorption, disseminated intravascular coagulation, and drugs (such as warfarin) are other causes. Administration of parenteral vitamin K may aid in differentiation of vitamin K deficiency from synthetic dysfunction of the liver.