2. Cholestatic enzymes (GGT, AP, Bilirubin, Cholyglycine)

3. Measures of hepatic synthetic function (albumin, cholesterol, prothrombin time)

Hepatocellular enzymes are actually better measures of liver cell injury than function. Alanine aminotransferase (ALT, SGPT) and aspartate arninotransferase (AST, SGOT) are hepatocellular enzymes. Significantly abnormal liver enzymes are over 1.5 times the upper limit of normal. Typically AST will be higher than ALT in ethanol induced liver disease (often greater than twice the ALT) while non-alcoholic liver disease frequently presents with a higher ALT. Very high elevations such as over twenty times normal will often be due to severe necrosis such as tylenol overdose, shock, or acute viral hepatitis. Uncommonly the new onset of biliary obstruction will present with elevated AST and ALT. Extrahepatic etiologies such as muscle injury have uncommonly been noted. Milder elevations (over 1.5 times normal) are typically due to chronic liver disease.

Unfortunately hepatocellular enzymes are not specific or sensitive tests. Frequently chronic liver disease, such as hepatitis C, will have fluctuating AST and ALT. One month they will be normal, then twice normal the next. Such fluctuation is common and the clinician should not be lulled into a sense of security that all is well. Likewise the degree of elevation does not correlate well with the degree of chronic injury. Patients with mild viral hepatitis may have the same degree of elevation as those with cirrhosis. Cirrhotic patients frequently have only mildly normal hepatocellular enzymes. Hepatocellular enzymes should be considered as normal or abnormal. The degree of elevation beyond 1.5 times the upper limit of normal is important but of little diagnostic value in asymptomatic patients with chronic liver disease.

Cholestatic enzymes are measures of impairment of bile flow. This may be due to either hepatic or extrahepatic obstruction. Alkaline Phosphatase (AP), Gamma-glutamyl transpeptidase (GGT) and serum cholyglycine and bilirubin are increased with impaired bile flow. Significantly abnormal cholestatic enzymes are over 1.5 times the upper limit of normal. Frequently they are simultaneously elevated.

Isolated elevation of bilirubin in an asymptomatic patient may be due to hemolysis or genetic impairments in bilirubin excretion such as the common Gilbert' s syndrome. Gilbert' s syndrome frequently presents with an isolated unconjugated bilirubin in the 2-3 mg/dL range in the absence of hemolysis and is often worsened with fasting. Some have estimated that Gilbert's syndrome may be present is as high as 10% of the population. Additional hepatic evaluation of those with Gilbert's syndrome is not required.

An isolated elevation of alkaline phosphatase in the absence of cholestasis may be due to bone injury such as metabolic or metastatic bone disease. Chronic renal failure and diabetes are associated with increased alkaline phosphatase. Increased alkaline phosphatase is normal during pregnancy, the neonatal period, and adolescent growth spurts.

An isolated elevation of GGT is common in healthy populations. GGT elevation can occur with enzyme induction rather than injury or cholestasis. Multiple medications (such as dilantin), ethanol and other chemical exposure can cause an increased GGT. Additional hepatic evaluation of an elevated GGT is not required. Often avoiding ethanol or simple changes in medications will resolve the GGT abnormality.

Measures of Hepatic Synthetic function include albumin, total protein, prothrombin time (PT, INR) and cholesterol. Albumin, protein and cholesterol are clearly influenced by diet, ethanol abuse, nephrotic syndrome and overall health. Prothrombin time reflects hepatic synthesis of factors I, II, V, VII, and X. Prolongation of prothrombin time may be due to clotting factor deficiency, vitamin K malabsorption, chronic cholestasis with fat malabsorption,or hepatocellular dysfunction. Critically ill patients can have a rapid drop in albumin and protein in the absence of liver failure. These measures often remain normal until severe hepatic injury. They are neither sensitive or specific. Never the less these imperfect measures are the best available "function tests." Unfortunately there is no liver equivalent of the creatinine clearance and multiple measures to quantify liver function by drug metabolism have had significant limitations.