Overall Bottom Line

A detailed medical history is the single most important step in the evaluation of a patient with abnormal liver tests.
Evaluation of liver enzyme elevation can be categorized into hepatocellular injury, cholestatic injury, or mixed injury based on patterns of relative elevation of different liver enzymes.
Serum chemistries which are used to diagnose liver disease can be divided into laboratories which evaluate liver function (INR, albumin), those which primarily evaluate integrity of hepatocytes (AST, ALT) and those which predominantly assess abnormalities of bile ducts and bile flow (bilirubin, AP, GGT).
The differential diagnosis of abnormal liver tests is broad and includes infectious (viral hepatitis), metabolic (NAFLD, Wilson disease, hemochromatosis, alpha-1 antitrypsin deficiency), toxin- and drug-induced (alcohol, herbal products), immunologic (autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, overlap syndromes), infiltrative, vascular and neoplastic diseases.
Non-hepatic causes of elevated liver enzymes, such as congestive hepatopathy, shock liver, muscle diseases, thyroid disorders, celiac disease, or adrenal insufficiency must be excluded.

Section 1: Background

Definition of disease

Tests which are used to assess for liver injury and liver function

	Normal function	Significance of abnormal value
Tests of liver injury:
ALT, formerly SGOT	Catalyzes transfer of amino groups of alanine	Elevated in: Hepatocellular injury
AST, formerly SGPT	Catalyzes transfer of amino groups of L-aspartic acid	Elevated in: Hepatocellular injury Myocyte injury (rhabdomyolysis, exercise, myocardial infarction)
AP	Enzyme found on canalicular membrane of hepatocytes, function unknown. Also found in bone, small intestine, placenta	Elevated in: Cholestatic liver disease of various etiology (biliary obstruction, biliary injury, drug induced) Infiltrative diseases of the liver (sarcoidosis, amyloidosis) Neoplastic diseases of the liver Congestive hepatopathy Bone disorders, normal bone growth, pregnancy
GGT	Found in cell membranes of many tissues (liver, kidney, pancreas, spleen)	Sensitive but non-specific indicator of hepatobiliary injury. An elevated GGT is not specific for alcohol use. Clinical utility is in differentiating origin of AP elevation (GGT elevated in liver disease, normal in bone disease)
Tests of liver function:
Total bilirubin	Normal breakdown product of heme	Elevated in biliary obstruction, disorders of bilirubin metabolism, hepatitis, cirrhosis and acute liver failure
Indirect bilirubin	Unconjugated form of bilirubin which is insoluble in plasma and converted to excretable conjugated form by hepatocytes	Elevated in: Increased heme breakdown (i.e. hemolysis) Inherited disorders of bilirubin metabolism (Gilbert’s disease)
Direct bilirubin	Conjugated form of bilirubin which is excreted by hepatocytes across canalicular membrane into bile	Elevated in: Obstruction of bile ducts Impaired hepatocyte function (chronic liver disease, cirrhosis, liver failure) Genetic syndromes (Rotor syndrome, Dubin–Johnson syndrome)
PT	Measurement of clotting time	Elevated in disease states causing impaired liver function and decreased hepatic production of clotting proteins (cirrhosis, acute liver failure)
Albumin	Protein synthesized by hepatocytes	Decreased in hepatocellular dysfunction/chronic liver disease

ALT and AST are enzymes found in hepatocytes. High serum levels reflect hepatocellular injury. AST is found in other cells including in the heart, skeletal muscle, brain and other organs. In contrast, ALT is found mostly in liver which makes it a more specific marker of liver injury compared with AST. Revised upper limits of ALT have been proposed (30 IU/L for men and 19 IU/L for women) after excluding individuals with probable NASH and hepatitis C from the “normal” population used to determine range limits.
Normal ALT serum levels have a high negative predictive value (>90%) in excluding a clinically significant liver disease.
GGT is present in decreasing quantities in the kidneys, liver, pancreas and intestine. It is a sensitive indicator of hepatobiliary disease, but lacks specificity. GGT levels are increased in cholestatic liver diseases, NAFLD, space-occupying liver lesions and venous hepatic congestion. GGT may be induced by many drugs and alcohol.
- GGT is not a marker of alcoholic liver disease.
  - Decreasing enzyme activities during abstinence from alcohol are diagnostically more helpful than the presence of an elevated GGT per se.
- Normal GGT levels have a high negative predictive value (>90%) in excluding hepatobiliary disease.
- An isolated elevation of GGT should not lead to an exhaustive work-up for liver disease.
Liver AP is a sensitive indicator of cholestasis of various etiologies, but AP does not discriminate between intra- and extrahepatic cholestasis. Elevation in 5′nucleotidase, GGT and liver isoenzyme fractionation of AP can be used to confirm hepatic origin of AP.
Mild elevations of serum AP levels may be found in viral hepatitis, drug induced, granulomatous and neoplastic liver disease.
Bilirubin is formed from breakdown of heme. It is carried bound to albumin to hepatocytes where UGT1A1 (bilirubin-UDP-glucuronosyltransferase) conjugates bilirubin. The conjugated bilirubin is then exported through a transporter into bile canaliculi and excreted through bile ducts. Transport of bilirubin through the canalicular membrane into the canaliculus is the rate limiting step (“bottle neck”) of bilirubin excretion. Causes of hyperbilirubinemia include excess heme breakdown, disorders of conjugation and bilirubin transport, hepatocellular damage and obstruction of bile ducts.
- Increases in conjugated bilirubin are highly specific for hepatobiliary disease.

Disease classification

Enzyme patterns of liver injury

Enzyme pattern	ALT:AP ratio^a
Hepatocellular	≥5
Cholestatic	≤2
Mixed	>2 to <5

^a All enzymes expressed as multiples of ULN

Etiology

See “Definition of disease.”

Pathology/pathogenesis

See “Definition of disease.”

Section 2: Prevention

Not applicable for this topic.

Section 3: Diagnosis

Bottom Line/Clinical Pearls

A detailed history is the key to the correct interpretation of abnormal liver tests. History taking should include information including alcohol use, recent use of acetaminophen, herbal products or other medications, and risk factors for viral hepatitis transmission.
Physical examination should include assessment for jaundice and encephalopathy which can indicate acute liver failure in a patient with no prior history of underlying liver disease. Stigmata of cirrhosis (spider angiomata, ascites, muscle wasting, Dupuytren’s contracture, splenomegaly) should be noted on physical examination.
Elevated INR and bilirubin in a patient with encephalopathy and no underlying liver disease indicates acute liver failure and should prompt consideration of referral to a transplant center.
Further laboratory investigations and imaging to diagnose the cause of elevated liver tests should be driven by clinical history and the pattern of liver test elevation (see Table: Enzyme patterns of liver injury and algorithms shown in Algorithm 1.1 and Algorithm 1.2).