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Most Common Causes of Elevated Liver Enzymes

Elevated levels of hepatic enzymes are commonly detected in clinical practice. Overall, the most common causes of liver enzyme elevation are alcohol toxicity, medication overdose and, fatty liver. The pattern of enzyme elevation allows the physician to classify liver diseases into cholestatic disorders and hepatocellular injury. Hepatocellular injury increases circulating levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Cholestatic disorders usually elevates alkaline phosphatase, bilirubin, and gamma-glutamyl transferase (GGT).

The most common causes of hepatocellular injury are:

  • Alcoholic liver disease
  • Autoimmune hepatitis
  • Chronic viral hepatitis
  • Hemochromatosis
  • Medication toxicity
  • Nonalcoholic fatty liver disease

Less common causes are alpha-1 antitrypsin deficiency and Wilson disease.

Alcohol is primarily metabolized by the liver and hepatocellular injury probably occurs during metabolism. AST elevations are usually higher than ALT elevations because alcohol toxicity causes hepatic deficiency of pyridoxal 5 ́-phosphate, a cofactor of the enzymatic activity of ALT. A ratio of AST to ALT of 2 or higher is indicative of alcohol abuse.

Risk factors for viral hepatitis should be evaluated, including intravenous drug use, unprotected sexual contact, healthcare provider exposure, blood transfusion, organ transplant, and travel.

Medications and herbs responsible for hepatocellular injury include:

  • Acetaminophen
  • Allopurinol
  • Azathioprine
  • Chaparral
  • Diclofenac
  • Hydralazine
  • Isoniazid
  • Methotrexate
  • Methyldopa
  • Mistletoe
  • Nitrofurantoin
  • Quinidine
  • Statins

The most common causes of cholestatic liver disease are:

  • Biliary obstruction
  • Drug hepatotoxicity
  • Cancer
  • Primary biliary cirrhosis
  • Primary sclerosing cholangitis

Less common causes are autoimmune cholangiopathy and sarcoidosis.

Drugs and herbs that cause cholestatic abnormalities include:

  • Amoxicillin clavulanate
  • Anabolic steroids
  • Captopril
  • Carbamazepine
  • Chlorpromazine
  • Erythromycin estolate
  • Estrogens
  • Kava
  • Phenytoin
  • Sulfa drugs

If laboratory results are consistent with cholestatic liver disease, it should be further subclassified as extrahepatic or intrahepatic. Common causes of extrahepatic cholestasis include biliary tree obstruction due to stones or malignancy. Common causes of intrahepatic cholestasis include viral and alcoholic hepatitis, nonalcoholic steatohepatitis, alkylated steroids, herbal supplements, and infiltrative diseases such as amyloid, sarcoid, lymphoma, and tuberculosis, and primary biliary cholangitis.

Alkaline phosphatase is present in bone, kidney, intestine and placenta. It can be elevated during pregnancy, adolescence, and after fatty meals due to intestinal release. Isolated elevations of alkaline phosphatase should be further evaluated by measuring GGT or 5-nucleotidase, which are more specific for liver disease. If these enzymes are within normal limits, nonhepatic sources of alkaline phosphatase should be considered.


Agganis B, Lee D and Sepe T. Liver Enzymes: No trivial elevations, even if asymptomatic. Cleveland Clinic J Med 2018;85:612-17.

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