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.
ALKALINE PHOSPHATASE ELEVATION
Causes
Alkaline phosphatase is active in many organs, mainly the liver and bones, but is also found in the small bowel, kidneys, and placenta. Diseases of the hepatobiliary system can cause moderate to marked elevations of alkaline phosphatase. Conditions with bone involvement, such as Paget disease of the bone, sarcoma, metastatic disease, hyperparathyroidism, and rickets, can raise alkaline phosphatase levels. Elevated GGT in conjunction with elevated alkaline phosphatase usually points to hepatobiliary injury. Clinically, isoenzyme fractionation of alkaline phosphatase may help distinguish the source of the elevation, but this is often not needed if the GGT is also elevated.
Hepatobiliary causes of alkaline phosphatase elevation can be divided into four categories:
- Chronic inflammation involving the bile ducts (eg, as in primary biliary cirrhosis and primary sclerosing cholangitis)
- Infiltrative process (eg, neoplasm, tuberculosis, sarcoidosis)
- Cholestatic disorders (eg, drug hepatotoxicity)
- Biliary obstruction (eg, in neoplasia or cholelithiasis).
Only a few studies have investigated the significance of a mild, isolated elevation of alkaline phosphatase. Lieberman and Phillips20 evaluated 87 patients and found that the abnormality resolved completely in less than 3 months in 28 patients, and resolved in 3 to 12 months in another 17 patients. Of the other 42 patients, 24 did not undergo further evaluation because they had significant coexisting disease. Of the remaining 18 patients, 5 had phenytoin-related hepatotoxicity, 3 had congestive heart failure, 3 had metabolic bone disease, 2 had hepatobiliary disease, and 1 had metastatic bone disease; in 4 patients, no explanation was determined. Follow-up was 1.5 to 3 years.
Workup of alkaline phosphatase elevation
An isolated elevated alkaline phosphatase level should always be confirmed and a hepatic origin suspected if the GGT level is also elevated (Figure 2).
A history of recent drug exposure usually points to drug hepatotoxicity as the source of this abnormality. Similarly, other information from the history can point to a potential underlying pathologic process causing the rise in alkaline phosphatase. For example, a history of ulcerative colitis suggests primary sclerosing cholangitis, and a history of previous cancer or sarcoidosis suggests liver involvement.
As part of the initial evaluation, an imaging study (eg, ultrasonography) can exclude biliary obstruction or suggest an infiltrative process.
If a drug is the suspected cause, the alkaline phosphatase level should be repeated after the patient has abstained from the drug for 6 to 8 weeks. If the initial examination suggests a specific disease, disease-specific markers (eg, antimitochondrial antibody for primary biliary cirrhosis, or viral serology) can confirm the suspected diagnosis. If the disease-specific markers are negative and the alkaline phosphatase level does not return to normal, further studies should be considered, including liver biopsy and endoscopic retrograde cholangiopancreatography or magnetic resonance cholangiopancreatography. Given the invasive nature of biopsy and pancreatography, an expert consultation should be done before ordering these tests.
GGT ELEVATION
GGT is a membrane enzyme that is a marker of hepatobiliary disease. Elevations usually parallel the elevation of alkaline phosphatase, confirming a hepatic source for the latter. GGT is the most sensitive marker of biliary tract disease but is not very specific. Alcohol and drugs (eg, phenytoin, phenobarbital) induce GGT. In one study,21 GGT was elevated in 52% of patients without known liver disease. The GGT level can be used to monitor abstinence from alcohol in patients with alcoholic liver disease.21
Workup of GGT elevation
Because GGT lacks specificity as a marker and is highly inducible, an extensive evaluation of an isolated GGT elevation in an otherwise asymptomatic patient is not warranted.
WHEN TO CONSULT
Many of the evaluations discussed in this paper and elsewhere22–27 can be carried out by primary care providers following a systematic approach. Input from a gastroenterologist or hepatologist can be valuable if the initial workup fails to establish the diagnosis, as well as in assuring that the most effective therapy for a specific disease is initiated. Reassurance, patient education, and a systematic approach for evaluating these abnormalities can identify most treatable causes of liver disease in the most cost-effective and efficient manner.
