Potential conflict of interest: Nothing to report.
Editors' Note: PERSPECTIVES IN CLINICAL HEPATOLOGY aims to engage experts with opinions supporting differing perspectives on the management of a case. Typically, the case represents an area of debate or evolving practice in clinical hepatology.
The patient presented below gives us the opportunity to discuss challenges in the diagnosis of drug-induced liver injury in an era of increasing awareness of hepatitis E. (HEPATOLOGY 2012;)
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ALT: alanine aminotransferase; AST, aspartate aminotransferase; DILI, drug-induced liver injury; DILIN, Drug-Induced Liver Injury Network; HEV, hepatitis E virus; INR, international normalized ratio; RUCAM, Roussel Uclaf Causality Assessment Method.
Drs. Emerson Y. Chen, Karl Baum, William Collins, Michael Merz, and William M. Lee: Case Presentation
A 41-year-old man with relapsing-remitting multiple sclerosis who was enrolled in the extension phase of a phase 3 clinical trial using fingolimod, a sphingosine-l-phosphate receptor modulator, presented for an unscheduled study visit with a 3-day history of jaundice, fatigue, exhaustion, light-colored stools, and dark urine. He was started on fingolimod in September 2008, after a 1-year course of interferon-β-1a, and received 2 months of treatment, followed by a 7-month interruption due to moderate liver enzyme elevations (peak aspartate aminotransferase [AST] 83 and alanine aminotransferase [ALT] 246 U/L). Fingolimod was restarted in June 2009 and continued without interruption until March 2010, at which time the medication dose was reduced for all patients by a protocol modification. In April 2010, his co-workers noticed his “yellow appearance,” and so he presented to the clinic for evaluation. Study visits during the 10-month period had been unremarkable. The patient did not have any recent travels, or a personal history or risk factors for liver disease, except that his female partner was infected with chronic hepatitis C. Recent medications included antacids for heartburn and a household remedy, holy thistle. He did not take any acetaminophen.
On the day of presentation, his liver chemistry tests were: AST 1,466 U/L, ALT 2,787 U/L, gamma-glutamyl transpeptidase 292 U/L, alkaline phosphatase 218 U/L, and total bilirubin 10.3 mg/dL (Fig. 1). Prothrombin ratio (international normalized ratio [INR]) during his subsequent 1-week hospitalization ranged between 1.01 and 1.08. Serum creatinine, amylase, electrolytes, and glucose were all within normal limits. There was no evidence of hepatitis A, B, or C, autoimmune hepatitis, primary biliary cirrhosis, or metabolic diseases such as α1-antitrypsin deficiency, hemochromatosis, nonalcoholic steatohepatitis, or Wilson's disease. Other viral hepatitis such as Epstein-Barr virus, cytomegalovirus, herpes simplex virus, and human immunodeficiency virus (HIV) were also excluded. Abdominal ultrasound revealed a normal-sized liver with smooth contour and homogeneous echogenicity, but moderate splenomegaly was noted. Intrahepatic vessels and gallbladder were normal. His clinical condition improved, and he was discharged from the hospital. The initial presumptive diagnosis was drug-induced liver injury (DILI) due to fingolimod. However, stored serum samples available from study visits at 8 months, 5 months, and 3 weeks before, as well as on the day of his clinical presentation, disclosed that hepatitis E virus (HEV) RNA was detectable at high levels 3 weeks prior to the illness and on the day of presentation; HEV antibodies, immunoglobulins M and G, were first detected on the day of presentation. One month after hospital discharge the patient's liver enzymes returned to his baseline.
Dr. Lee and Colleagues' Perspective
DILI was initially suspected considering the previous liver enzyme elevations shortly after beginning fingolimod. However, the second incident occurring with a relatively long latency of 10 months after restarting the same medication made DILI somewhat less likely. Three hepatologists with experience in hepatotoxicity were asked to adjudicate this case for likelihood of DILI using a previously described expert opinion process.1 With the knowledge of the serologic and HEV polymerase chain reaction (PCR) results, all scored the case as either possible or unlikely to be DILI. Lacking the HEV data, however, the scoring would have supported DILI with a greater degree of confidence; that is, either possible or probable likelihood of DILI. Upon questioning, the patient informed the study investigator that he enjoyed eating beef tartare and, on occasion, undercooked liver.
DILI is often suspected when liver test abnormalities occur during clinical trials or following release of a new medication. The causality assessment process to identify DILI involves recognition of the likely causative drug and exclusion of other causes for liver injury, including hepatitis viruses; alcohol, metabolic, genetic, and inherited disease; as well as gallstones and other structural or anatomic processes. Although several scoring systems for causality assessment have been in use for more than two decades, none is used widely on a day-to-day basis by clinicians. The Drug-Induced Liver Injury Network (DILIN) in the United States involves eight sites that collect well-characterized instances of apparent drug toxicity observed in these clinical referral centers.1 Over the initial years of the study, the group thought of utilizing the most commonly referred scoring system, the Roussel Uclaf Causality Assessment Method (RUCAM), for this purpose. Developed by a small international consensus group, RUCAM awards points for the temporal relationship and for factors associated with higher risk such as use of alcohol, older age, and pregnancy, and subtracts points for incomplete data and unknown DILI potential of the putative agent.2, 3 The DILIN has spent considerable effort perfecting an expert opinion process that is a useful exercise, with some advantages over RUCAM,4 but this process cannot easily be applied by clinicians. In the current case, both RUCAM and DILIN expert opinion would likely have failed because neither system specifically requires hepatitis E in the evaluation.
Hepatitis E is a well-recognized but relatively infrequent cause of acute hepatitis that has been associated with chronic hepatitis in post-transplant patients in Europe and the United States.5 Isolated HEV cases, specifically HEV genotype 3 found in Europe and the United States, have been linked to consumption of raw or undercooked pork and game meat.6 The clinical presentation is usually benign compared to HEV genotypes 1 and 2 found in Africa and South Asia, where hepatic failure has occurred. Recently, HEV genotype 3 infection has been observed in presumed DILI cases by the U.S. DILIN.7 Both anti-HEV IgM and HEV RNA are helpful in diagnosing acute infection, as HEV RNA typically becomes undetectable around 2 weeks after the onset of symptoms.8 In this patient who had an initial enzyme elevation within 2 months of starting a new agent, DILI was suspected but the long latency during the second period of drug exposure pointed to an alternative cause.
In summary, hepatitis E should be considered in any acute hepatitis picture and for instances of apparent DILI when the more common etiologies have been excluded. The availability of archived sera was important in confirmation of the diagnosis. Hepatitis E testing should become essential going forward for all DILI causality evaluations to exclude this “new” arrival on the scene.
Dr. Björnsson and Colleagues' Perspective
Acute hepatitis E has recently been reported to be the cause of some cases of liver disease that were first suspected to be DILI.7 DILI is an important issue in the field of clinical hepatology, as it can present as acute hepatitis. Hepatotoxicity is frequently a differential diagnostic consideration in patients presenting with elevated liver tests. The current case highlights the importance of exclusion of other possible causes of liver disease before a drug is firmly stated to be causative of abnormal liver tests. The authors conclude that “hepatitis E should be considered in any acute hepatitis picture and for instances of apparent DILI when the more common etiologies have been excluded.” However, the situation is somewhat more complex, as the necessity for specific diagnostic tests depends on clinical suspicion as well as the known epidemiology of HEV. The patient presented with ALT of 2,787 U/L, which is an extremely high value. The authors state that there was “no evidence of primary biliary cirrhosis, or metabolic diseases such as α1-antitrypsin deficiency, hemochromatosis, nonalcoholic steatohepatitis, or Wilson's disease.” Probably, none of the above-mentioned diseases need to be specifically ruled out in this case, as markedly elevated levels (>1,000 U/L) typically occur with acute hepatocellular injury caused by viruses, drugs, or ischemia. Also, the decision to perform HEV testing should be based on the clinical presentation.
With regard to HEV epidemiology, the incidence and prevalence of infection in various geographical locations ought to have an impact on the performance of testing. In some parts of the world HEV might not exist or the likelihood of this infection may be very low. We are currently collecting data on the seroprevalence of HEV antibodies in the Icelandic population. The results of these studies will be used to assess the necessity for HEV testing in suspected DILI cases and included in our clinical guidelines for the diagnosis of liver disease.
The threshold prevalence used to decide testing would probably need to be very low. For comparison, although the prevalence of hepatitis C is less than 1% in the Nordic countries, it is routinely ruled out in suspected DILI cases in this area. RUCAM, the most commonly used causality assessment instrument in clinical research on DILI,9 was developed more than 20 years ago, before HEV was known to exist in the Western world. Thus, clinical judgment based on expert opinion is of importance in this context.
In summary, we agree with the authors of this interesting case report that testing for HEV should be performed in many patients with acute hepatitis when other common etiologies have been excluded. However, this is also dependent on the clinical context and the geographical location of the case.
The authors thank those involved in this clinical trial, as well as Dr. John Senior, US Food and Drug Administration, for thoughtful encouragement.