Liver enzymes: No trivial elevations, even if asymptomatic

Author and Disclosure Information


Primary care physicians are at the forefront in screening for abnormal levels of liver enzymes and investigating the likely causes by obtaining a detailed history and physical examination, followed by appropriate laboratory and diagnostic workup. This review outlines common causes for the two main mechanisms of liver injury—cholestasis and hepatocellular insult—and explores the associated risk factors, methods of diagnosis, and management, with a focus on nonalcoholic fatty liver disease, one of the most often encountered causes of abnormal liver enzyme levels.


  • Disorders of hepatocellular injury tend to elevate levels of aminotransferases, whereas cholestatic disorders cause elevations of alkaline phosphatase and bilirubin.
  • The three most common causes of liver enzyme elevation are alcohol toxicity, medication overdose, and fatty liver disease.
  • Other disorders of liver dysfunction include hereditary hemochromatosis, viral hepatitis, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and alpha-1 antitrypsin disease.
  • Nonhepatic causes of elevated “liver enzymes” also need to be considered. For instance, rhabdomyolysis causes elevations in aminotransferase levels.



Elevated levels of circulating enzymes that are frequently of hepatic origin (aminotransferases and alkaline phosphatase) and bilirubin in the absence of symptoms are common in clinical practice. A dogmatic but true statement holds that there are no trivial elevations in these substances. All persistent elevations of liver enzymes need a methodical evaluation and an appropriate working diagnosis.1

Here, we outline a framework for the workup and treatment of common causes of liver enzyme elevations.


Liver disease and associated liver enzyme elevations

Based on the pattern of elevation, causes of elevated liver enzymes can be sorted into disorders of cholestasis and disorders of hepatocellular injury (Table 1).1

Cholestatic disorders tend to cause elevations in alkaline phosphatase, bilirubin, and gamma-glutamyl transferase (GGT).

Hepatocellular injury raises levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).


When approaching liver enzyme elevations, the clinician should develop a working differential diagnosis based on the medical and social history and physical examination.

Think about alcohol, drugs, and fat

The most common causes of liver enzyme elevation are alcohol toxicity, medication overdose, and fatty liver disease.

Alcohol intake should be ascertained. “Significant” consumption is defined as more than 21 drinks per week in men or more than 14 drinks per week in women, over a period of at least 2 years.2

The exact pathogenesis of alcoholic hepatitis is incompletely understood, but alcohol is primarily metabolized by the liver, and damage likely occurs during metabolism of the ingested alcohol. AST elevations tend to be higher than ALT elevations; the reason is ascribed to hepatic deficiency of pyridoxal 5´-phosphate, a cofactor of the enzymatic activity of ALT, which leads to a lesser increase in ALT than in AST.

Alcoholic liver disease can be difficult to diagnose, as many people are initially reluctant to fully disclose how much they drink, but it should be suspected when the ratio of AST to ALT is 2 or greater.

In a classic study, a ratio greater than 2 was found in 70% of patients with alcoholic hepatitis and cirrhosis, compared with 26% of patients with postnecrotic cirrhosis, 8% with chronic hepatitis, 4% with viral hepatitis, and none with obstructive jaundice.3 Importantly, the disorder is often correctable if the patient is able to remain abstinent from alcohol over time.

Hepatotoxicity of selected drugs

A detailed medication history is important and should focus especially on recently added medications, dosage changes, medication overuse, and use of nonprescription drugs and herbal supplements. Common medications that affect liver enzyme levels include statins, which cause hepatic dysfunction primarily during the first 3 months of therapy, nonsteroidal anti-inflammatory drugs, antiep­ileptic drugs, antibiotics, anabolic steroids, and acetaminophen (Table 2).1 Use of illicit drugs and herbal remedies should be discussed, as they may cause toxin-mediated hepatitis.

Although inflammation from drug toxicity will resolve if the offending agent is discontinued, complete recovery may take weeks to months.4

A pertinent social history includes exposure to environmental hepatotoxins such as amatoxin (contained in some wild mushrooms) and occupational hazards (eg, vinyl chloride). Risk factors for viral hepatitis should be evaluated, including intravenous drug use, blood transfusions, unprotected sexual contact, organ transplant, perinatal transmission, and a history of work in healthcare facilities or travel to regions in which hepatitis A or E is endemic.

The medical and family history should include details of associated conditions, such as:

  • Right heart failure (a cause of congestive hepatopathy)
  • Metabolic syndrome (associated with fatty liver disease)
  • Inflammatory bowel disease and primary sclerosing cholangitis
  • Early-onset emphysema and alpha-1 antitrypsin deficiency.

The physical examination should be thorough, with emphasis on the abdomen, and search for stigmata of advanced liver disease such as hepatomegaly, splenomegaly, ascites, edema, spider angiomata, jaundice, and asterixis. Any patient with evidence of chronic liver disease should be referred to a subspecialist for further evaluation.

Next Article:

The bias of word choice and the interpretation of laboratory tests

Related Articles