When and how to evaluate mildly elevated liver enzymes in apparently healthy patients
ABSTRACTBecause 1% to 9% of people without symptoms have elevated liver enzymes, extensive evaluation of all abnormal test results would expose many patients to undue risks and expenses. On the other hand, failure to evaluate minor liver enzyme elevations could mean missing the early diagnosis of potentially treatable disorders. This review discusses likely causes of elevated aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase levels and provides algorithms for evaluating high liver enzyme values in apparently healthy patients in the primary care setting.
KEY POINTS
- Nonalcoholic fatty liver disease is the most common cause of asymptomatic elevated aminotransferase levels.
- Suspect alcoholic liver disease when the aminotransferases are elevated and the aspartate aminotransferase level is two to three times higher than the alanine aminotransferase level, especially when gamma-glutamyl transferase levels are elevated.
- If medications or alcohol is a suspected cause of elevated aminotransferase levels, remeasure the levels after 6 to 8 weeks of abstinence.
Wilson disease
Prevalence. The estimated prevalence of Wilson disease is 1 in 40,000 to 1 in 100,000. It has been reported in most populations worldwide.
Risk factors. Anyone under age 40 with abnormal liver enzyme levels (including mild elevations) should be evaluated for Wilson disease, even in the absence of neurologic or ocular findings. However, such routine screening is rarely helpful in patients over age 50. Genetic testing is of limited value because of the large number of potential mutations of the ATP7B gene, the gene responsible for Wilson disease. However, if a a person is known to have Wilson disease, genetic screening of family members is useful.
Comments. Effective therapy is available (ie, d-penicillamine, trientine, zinc). For Wilson disease, alpha-1-antitrypsin deficiency, and genetic hemochromatosis, establishing the diagnosis is not only important to the individual patient; it also may prompt the screening of asymptomatic members of the proband’s family.10–12
Alpha-1-antitrypsin deficiency
Prevalence. Alpha-1-antitrypsin deficiency is present in 1 of every 1,600 to 1,800 live births.11
Risk factors. Patients with emphysema or with a young sibling with liver failure should undergo an investigation for alpha-1-antitrypsin deficiency, consisting of a measurement of the alpha-1-antitrypsin level and an assessment for the PiZZ genotype (the most severe form, because homozygous for the abnormal Z allele).
Comments. Although alpha-1-antitrypsin deficiency is a common cause of liver disease in the very young, it is important to remember that a small number of these patients develop end-stage liver disease in adulthood. Liver transplantation is the only effective treatment for end-stage liver disease associated with alpha-1-antitrypsin deficiency.
Primary biliary cirrhosis
Prevalence. In one study of urban-dwelling women in northeast England, the prevalence of primary biliary cirrhosis was estimated at 0.10%.13
Risk factors. Like autoimmune hepatitis, primary biliary cirrhosis mainly affects women and can be associated with other autoimmune disorders.
Comments. A cholestatic pattern of injury is predominant in primary biliary cirrhosis. Treatment of primary biliary cirrhosis with the cytoprotective agent ursodeoxycholic acid improves liver enzyme levels, may lead to histologic improvement and increased survival, and may also delay the need for liver transplantation. 9,13
Drug- and toxin-related liver diseases
Nonsteroidal anti-inflammatory drugs and penicillin-derived antibiotics are the drugs that most commonly cause abnormal serum liver enzyme levels. The mechanisms of druginduced liver disease include induction of hepatic enzymes (antiepileptic drugs), allergic reactions, autoimmunity (nitrofurantoin [Furadantin, Macrobid]), idiosyncratic reactions, and veno-occlusive injury.14 Drugs that are potentially hepatotoxic are listed in Table 2 and are classified as causing hepatocellular damage, cholestatic damage, or steatosis.
MILD ENZYME ELEVATIONS AS INDICATORS OF SPECIFIC DISEASES
Mildly elevated liver enzymes are common and potentially important, yet very few welldesigned prospective studies have addressed the issue of what should be done once they are identified. Most current data are from small retrospective studies that lack accurate information on the important causes of liver diseases such as hepatitis C and nonalcoholic steatohepatitis.
Despite these shortcomings, the literature delineates the three patterns of mild liver enzyme elevations discussed earlier: hepatocellular injury pattern (elevated ALT or AST), cholestatic pattern (elevated alkaline phosphatase or GGT, or both), and mixed pattern (elevation of ALT, AST, and alkaline phosphatase). The following paragraphs focus on the causes of elevation of specific liver enzymes.
AMINOTRANSFERASE ELEVATION
Causes
Aminotransferases are commonly used markers of hepatocyte injury. AST is present in blood cells and many tissues, including liver, muscle, brain, pancreas, and lung. ALT is a cytosolic enzyme found primarily in hepatocytes, making it a more specific indicator of liver disease.
Acute viral hepatitis, toxins, and liver ischemia can markedly raise serum aminotransferase levels (often into the thousands of units per liter). On the other hand, these enzymes are only mildly elevated (< 300 U/L) in nonalcoholic steatohepatitis, chronic hepatitis, cholestatic liver conditions, drug-induced hepatotoxicity, and liver tumors.
Because AST is a mitochondrial enzyme and is affected by alcohol ingestion, an AST level more than twice that of the ALT suggests hepatic damage due to alcohol.
Of note, aminotransferase elevation can also be due to nonhepatic causes. For example, muscle necrosis can result in mild elevation of these enzymes, especially AST, and an elevated creatine kinase can help confirm that the source is muscle tissue.
Undiagnosed celiac disease has been associated with abnormal liver enzyme levels when all other causes have been ruled out, but the mechanism is not yet understood. In this situation, ALT and AST levels typically return to normal with a gluten-free diet.15
