General Discussion

The first step in the evaluation of transaminase elevation is to repeat the test to confirm the result. Both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are released into the blood in increasing amounts when the liver cell membrane is damaged. However, necrosis of liver cells is not required for the release of the aminotransferases, and correlation between the level of the aminotransferases and the degree of liver cell damage is poor.

The initial evaluation includes a detailed history, review of medications, and a physical examination. The history should include an assessment of the patient’s risk factors for liver disease with attention directed toward family history, medications, vitamins, herbal supplements, alcohol consumption, drug use, history of blood-product transfusions, and symptoms of liver disease. Signs of liver disease are outlined below.

Common causes of elevated aminotransferase levels are alcohol-related liver injury, hepatitis B and C, autoimmune hepatitis, fatty infiltration of the liver, nonalcoholic steatohepatitis (NASH), hemochromatosis, Wilson’s disease, alpha₁-antitrypsin deficiency, and celiac disease. Alcohol-related liver injury is a common cause of elevated aminotransferase levels and must be considered in any child or adolescent who may be drinking.

The term NASH was first used in 1980 in describing 20 nonalcoholic patients with liver biopsy changes compatible with alcoholic hepatitis. NASH may be considered part of a larger spectrum of nonalcoholic fatty liver disorders (NAFLD) that extends from simple steatosis through NASH. Liver biopsy is necessary for definitive diagnosis of NASH, which is characterized by fatty change with lobular inflammation, hepatocellular injury, and Mallory’s hyaline, with or without fibrosis, in the absence of excessive alcohol consumption. In contrast, simple fatty liver is characterized histologically by hepatic steatosis without inflammation, ballooning degeneration, necrosis, fibrosis, or cirrhosis.

Recent studies suggest that NASH may not be rare in children, especially in obese children, and severe fibrosis may be found at an early age. Therefore, NASH should be considered in obese children with elevated aminotransferase levels. Liver biopsy is the gold standard for the diagnosis of NAFLD/NASH to confirm the diagnosis and establish severity of fibrosis and the presence of cirrhosis. Liver biopsy also excludes other coexisting conditions that can result in hepatic steatosis.

Medications That May Cause Transaminase Elevation

Causes of Transaminitis

Key Historical Features

Key Physical Findings

Suggested Work-up

ALT, AST

AST:ALT ratio >2 suggests alcohol abuse AST:ALT ratio <1 suggests NASH

Total and direct bilirubin, alkaline phosphatase, gamma-glutamyl transpepditase (GGT) To evaluate biliary excretion Prothrombin time To assess hepatic synthetic function Albumin To assess hepatic synthetic function Complete blood count (CBC) To evaluate for infection, neutropenia, thrombocytopenia Fasting serum glucose and insulin level To evaluate for insulin resistance Fasting lipid panel To evaluate for hyperlipidemia Hepatitis C antibody To evaluate for hepatitis C infection Hepatitis B surface antigen, surface antibody, and core antibody To evaluate for hepatitis B infection Serum iron, ferritin, and total iron-binding capacity Iron overload suggests hemochromatosis Serum ceruloplasmin Decreased level suggests Wilson disease α₁-antitrypsin phenotyping To evaluate for α₁-antitrypsin deficiency Gliadin and endomesial antibodies Immunoglobulin A (IgA) antibodies to both gliadin and endomysium are 95% sensitive and specific for the diagnosis of celiac disease Urine organic acids and serum amino acids To evaluate for inborn errors of metabolism (particularly important in children who are not obese and are presenting at a younger age)

Additional Work-up (May Be Indicated If Above Tests Are Normal)

Chloride sweat test	If cystic fibrosis is suspected
Hepatitis A immunoglobulins	If hepatitis A infection is suspected on the basis of history and physical examination
Cytomegalovirus (CMV) immunoglobulins	If CMV infection is suspected
Epstein-Barr virus immunoglobulins	If Epstein-Barr virus is suspected
Acetaminophen and aspirin levels	If toxicity or overdose is suspected
Quantitative hepatitis C virus ribonucleic acid (RNA)	If hepatitis C antibody is positive
Liver ultrasonography	To evaluate for hepatic steatosis, cholelithiasis, cholecystitis evidence of cirrhosis, or a liver mass
Liver biopsy	May be indicated to exclude other diseases and to help make a specific diagnosis