A small proportion of U.S. patients thought to have drug-induced liver injury actually has hepatitis E infection, and testing for this infection should be considered under certain circumstances, reported Dr. Timothy J. Davern and his colleagues in the November issue of Gastroenterology.
In a study of serum samples and medical records from 318 cases in the Drug-Induced Liver Injury Network (DILIN), 50 cases (16%) tested positive for anti-HEV IgG (indicating previous hepatitis E infection), including 9 (3% of total cases) that were also positive for anti-HEV IgM (indicating more recent hepatitis E infection), wrote Dr. Davern of the department of transplantation at California Pacific Medical Center, San Francisco, and his associates.
The diagnosis of drug-induced liver damage is often challenging because there are no specific biomarkers for it, and the clinical features are nonspecific. "In essence, the diagnosis requires exclusion of a wide array of other causes of liver injury, including viral and autoimmune hepatitis, bile duct obstruction, sepsis, hepatic ischemia, and metabolic disorders," the investigators wrote (Gastroenterology 2011 [doi:10.1053/j.gastro.2011.07.051]).
Testing for hepatitis A, B, and C is routinely done in cases of suspected drug-induced liver injury, but hepatitis E is rarely considered in the differential diagnosis in the United States, mainly because this type of hepatitis is believed to be rare in developed countries unless the patient has recently traveled to an endemic area such as Asia, northeast Africa, the Middle East, or Mexico. However, indigenous cases of acute hepatitis E recently have been reported in the United States, Europe, Japan, and New Zealand, and recent population-based surveys have shown that 20% or more of American adults have serologic evidence of past HEV infection.
Moreover, two potential reservoirs in Western societies have been proposed: farm and wild animals, particularly swine and game, and chronically immunosuppressed patients, who can carry high viral loads.
Given these new developments, clinicians now should consider testing for HEV in the following scenarios: when the clinical presentation of the liver damage is unusual; when the pattern of injury resembles acute viral hepatitis even though hepatitis A, B, and C have been ruled out; and especially when the drug that is suspected to have caused the liver injury is critically important to the patient (such as antiretrovirals or antituberculosis agents), Dr. Davern and his colleagues said.
They assessed serum samples from the first 318 patients enrolled in the DILIN in 2004-2009, which drew subjects from San Francisco, Indiana, Connecticut, and North Carolina.
Fifty cases (16%) were found to be reactive for IgG anti-HEV, indicating remote or resolved infection, and nine cases (3%) were also reactive for IgM anti-HEV, indicating more active or recent infection.
These nine cases were similar to those with no evidence of HEV infection in initial and peak serum bilirubin levels, alanine aminotransferase levels, alkaline phosphatase levels, the distribution pattern of serum enzyme elevations, and liver damage severity scores. None of the nine cases reported exposures to farm animals or raw pork, and none had a history of travel to an endemic area.
Eight of the nine cases had major comorbidities including HIV infection, chronic obstructive pulmonary disease, asthma, alcoholism, obesity, tuberculosis, diabetes, atherosclerosis, and lymphoma.
After a careful reanalysis of these cases, most were thought to result from hepatitis E infection, although some were still considered more likely to be related to drug hepatotoxicity. "Coincidental, subclinical hepatitis E may have preceded the acute liver injury caused by the implicated medication" in some cases, the researchers said.
The study findings suggest that HEV infection should be considered when drug-induced liver injury is suspected. In addition, immunosuppressed patients with chronic unexplained liver disease should be tested for HEV infection.
Currently, there are no FDA-approved assays for anti-HEV with proven specificity and sensitivity. "Research testing results can be obtained from the Centers for Disease Control and Prevention or by special arrangements with research laboratories," Dr. Davern and his associates said.
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, with additional support from the National Cancer Institute. Dr. Davern’s associates reported ties to Teva Pharmaceuticals, KaroBio, Johnson & Johnson, Salix, Gilead Sciences, Eli Lilly, Genentech, Bristol-Myers Squibb, GlaxoSmithKline, and Medtronic.