James H. Lewis

Hepatic Injury Associated With Ketoconazole Therapy: Analysis of 33 Cases

Ketoconazole has only recently been recognized as a cause of hepatic injury, with most reports coming from outside the United States. In order to characterize more fully the U.S. experience, we undertook an analysis of 54 reports of alleged ketoconazole-induced liver injury submitted to the Food and Drug Administration from the time of initial marketing in 1980. Thirty-three reports were considered likely instances of ketoconazole-induced hepatitis. The majority of these cases occurred in women more than 40 yr of age. Jaundice was recorded in 27 individuals after therapy of 11-168 days with an average daily dose of 200 mg. Anorexia, malaise, nausea, and vomiting accompanied liver injury in one-third of cases. No instances of rash or eosinophilia were recorded. Serum transaminase and alkaline phosphatase values were consistent with acute hepatocellular injury in 18 patients, with primarily cholestatic injury in 5 patients, and with a mixed pattern in 9 individuals. Only one death seemed attributable to ketoconazole. In that patient, the drug was continued after the appearance of clinical and biochemical evidence of hepatic injury and massive hepatocellular necrosis was present at autopsy. The incidence of symptomatic, potentially serious hepatic injury appears to be very low, perhaps 1 in 15,000 exposed individuals. The presumed mechanism of injury is metabolic idiosyncrasy, although hypersensitivity has not been completely dismissed in some cases reported in the literature. The incidence of mild, asymptomatic, reversible elevations in serum transaminases occurring in ketoconazole recipients has been estimated to be 5%-10%. Periodic biochemical testing and monitoring for symptoms of hepatitis during ketoconazole therapy is recommended to help prevent the development of serious or fatal hepatic injury.

Drug-induced liver disease.

Purpose of review To summarize the pertinent case reports, case series and clinical studies that described clinical, histological, epidemiological and mechanistic features of drug-induced liver disease in 2005. Recent findings Acetaminophen, highly active antiretroviral therapy and drugs for tuberculosis retained their preeminent position as the most commonly reported agents causing drug-induced liver disease, with acetaminophen continuing to be the leading cause of acute liver failure in the USA. While the frequency of drug-induced liver disease remains low, a large case-series of acute drug-induced liver disease from Spain and Sweden supported the observation that acute hepatocellular jaundice from a drug is associated with death or the need for transplant in at least 10% (known as Hys Law). With respect to using potentially hepatotoxic medications in patients with underlying liver disease, statins and second-generation thiazolidinediones were shown to be safe when used in patients with elevated baseline alanine aminotransferase or aspartate aminotransferase levels. Summary Drug-induced liver disease remains an important cause of acute liver failure, and research efforts by the National Institutes of Health and others are underway to better determine the risk factors and other host susceptibilities that will allow for the safer use of drugs in the future.

Enflurane Hepatotoxicity: A Clinicopathologic Study of 24 Cases

Analysis of 24 cases of enflurane anesthesia-associated hepatic injury shows that the clinical, biochemical, and histologic features are similar to those seen with halothane- and methoxyflurane-related hepatitis. Postoperative fever was the presenting symptom in 19 patients. Jaundice occurred in 19 patients after a mean latent period of 8 days. Sixteen patients had been previously exposed to enflurane or halothane, and the latent period from exposure to the onset of symptoms or jaundice was shortened in these patients. There were five fatalities among the entire group. Liver biopsy most characteristically showed centrilobular necrosis, occasionally with ballooning degeneration and fatty change. The presumed mechanism of injury is metabolic idiosyncracy, and prior exposure to a haloalkane anesthetic may increase the risk of hepatic injury after enflurane administration.

Drug-induced liver injury in 2007.

Purpose of review To summarize the pertinent literature on the causes, epidemiology, prevalence, clinical features, evaluation and mechanisms of drug-induced liver injury reported during 2007. Recent findings Although the frequency of drug-induced liver injury remains low, new data from the Centers for Disease Control and Prevention confirm that of the approximately 1600 new acute liver failure cases annually, acetaminophen hepatotoxicity accounts for 41%; among children with acute liver failure, acetaminophen was the second most common cause. Antimicrobials lead the list of non-acetaminophen causes of drug-induced liver injury. In Asia, herbal compounds are the most common causes of the condition. Pravastatin was shown to be safe in patients with nonalcoholic fatty liver disease or chronic hepatitis C. The US Food and Drug Administration issued a draft guidance document on the premarketing clinical evaluation and stopping rules of drug-induced liver injury signals, including Hys Law cases in clinical trials. Summary The year 2007 brought with it several reminders of the importance of drug-induced liver injury in the clinical trial as well as the clinical practice setting. There is additional evidence that statin drugs may be used safely in patients with chronic liver disease. Comments received by the US Food and Drug Administration to finalize their guidance document are eagerly awaited.

Turcot's syndrome evidence for autosomal dominant inheritance

A case of Turcots syndrome (colonic polyposis plus a malignant central nervous system tumor) occurring in a kindred with autosomal dominant colonic polyposis is presented. It is proposed that Turcots syndrome patients can be classified into Type I where only siblings are affected and Type II where two or more generations have colonic polyposis. A third nonfamilial group cannot be classified into Type I or II based on available information. Evidence is presented suggesting Turcots syndrome is best considered an additional phenotype of familial polyposis and is most likely inherited in an autosomal dominant manner.

Drug-induced liver disease in 2006.

Purpose of review To identify the key publications of 2006 dealing with drug-induced liver injury. Recent findings When given in therapeutic doses over 14 days, acetaminophen produced significant asymptomatic elevations in alanine aminotransferase among healthy volunteers, suggesting that subclinical injury may be more common than previously thought. Acute liver failure in children was shown to differ in several important respects from that seen in adults, notably a much lower incidence of acetaminophen toxicity with nearly half of all cases being indeterminate in origin. The first cases of hepatotoxicity with telithromycin, a new class of ketolide antibiotic, were described along with reports suggesting liver injury from ezetimibe among other agents. The potential for chronic injury to develop after acute drug-induced liver injury was analyzed in a large Swedish database; 5–6% of cases were judged to become chronic, with drugs causing cholestatic injury predominating. Among well described hepatotoxins, new reports appeared with highly active antiretroviral therapy agents, herbal therapies and several antibiotics. Finally, the safe use of pravastatin and pioglitazone was demonstrated in patients with chronic liver disease in controlled clinical trials. Summary Drug-induced liver injury remains an important concern for many existing drugs as well as for agents in development.

Oncologists and hepatitis B: a survey to determine current level of awareness and practice of antiviral prophylaxis to prevent reactivation.

Background/Aims: The risk of chronic hepatitis B virus reactivation under the influence of chemotherapy or immunosuppression is being increasingly recognized. However, many oncologists either have not observed this complication or are not aware of current recommendations for hepatitis B prophylaxis. Our aims were to determine the awareness of the reactivation risk and to understand the screening and prevention practices among oncologists. Methods: A questionnaire survey was administered to oncologists in the Washington, D.C., area. Results: Responses from 131 practitioners to the 10 questions were received. Nearly 80% of respondents were aware of reactivation, but only 30% had seen a case and only 56% were aware of prophylactic therapy. Fourteen percent of oncologists screened all patients, whereas 86% screened selectively based on risk factors. Most (76%) would use prophylaxis in a patient with active hepatitis B virus, but only about half would treat chronic carriers or those with resolved infection. Regarding choice of prophylaxis, nearly half (48%) were unsure of which agent to use. Conclusions: Improving awareness of hepatitis B virus reactivation and antiviral prophylaxis in the oncology community seems warranted.

Drug-induced liver disease 2004.

Purpose of review To summarize the salient reviews, studies and case reports and series that dealt with clinical, pathological, methodological, and epidemiological descriptions of drug-induced liver disease in the calendar year 2004. Recent findings While no new causes of drug-induced liver injury were reported for 2004, several new reports of previously recognized hepatotoxins, including herbal products, were published. These include the antiretroviral drugs for HIV and agents to manage tuberculosis. Acetaminophen (APAP) retained its preeminent position as the leading cause of drug-induced acute liver failure, currently accounting for nearly 50% of cases according to the latest figures from the U.S. Acute Liver Failure Study Group. Not surprisingly, APAP also heads the list of drugs and toxins leading to liver transplantation for acute hepatic failure. Efforts to reduce the number of cases of intentional APAP poisonings by restricting the number of tablets sold at any one time in the UK are ongoing, but the success of the program may be lessening, as was pointed out this year. The use of potentially hepatotoxic medications in patients with underlying liver disease was examined with the statins, and they emerged as a safe class for use in this setting. Summary Given the apparent increasing incidence of acute liver failure attributable to APAP in the US, additional efforts are still needed to better define the risks associated with its use and to further reduce the incidence of severe liver injury from this widely used agent.

Predicting and preventing acute drug-induced liver injury: what's new in 2010?

Importance of the field: The field of drug-induced liver injury (DILI) continues to expand in terms of global registries and with new agents added every year. Given the need to improve on our current methods of preclinical testing and monitoring for DILI during both clinical trials and in the post-approval setting, there is increasing research aimed at better understanding why injury occurs and who is most susceptible. To this end, the active pursuit of biomarkers that will predict injury prior to its occurrence and genetic testing that can identify individuals at risk of DILI continue to be at the forefront. Areas covered in this review: While alanine aminotransferase (ALT) testing remains the workhorse of biochemical monitoring, it only detects hepatic injury after it has occurred and, therefore, is not a true predictor. The utility and shortcomings of ALT and other liver tests are reviewed along with a synopsis of several other candidate biomarkers that are being studied. In addition, we review the recent data supporting testing for genetic predisposition to DILI and how identifying clinical risk factors may translate into better means for preventing DILI. What the reader will gain: We update the basis on which age and gender are considered risk factors for DILI, and review the latest reports detailing the association of several candidate genes and the development of DILI in a susceptible patient. Human leukocyte antigen-B*5701 is closely linked to the hypersensitivity reaction seen with abacavir, and such screening has been successfully incorporated into HIV treatment around the globe and offers the promise that testing for other genetic markers will soon become a routine part of clinical practice. At present, candidate genes conferring specific susceptibility to DILI have been identified for a relatively few agents (e.g., flucloxacillin, amoxicillin–clavulanate, ximelagatran and isoniazid), but many more are under study. Preventing DILI often comes down to avoiding the use of potentially hepatotoxic drugs in certain situations, and we review the clinical scenarios in which this is most relevant. Take home message: Given the number and range of studies aimed at identifying predictors of DILI, the focus of this review is to summarize what we consider to be the most relevant new information published on the topics of clinical and genetic factors that predispose to DILI, the use of biomarkers as predictors of acute DILI, along with advances in prevention strategies.

Dermatologists' awareness of and screening practices for hepatitis B virus infection before initiating tumor necrosis factor-α inhibitor therapy.

Objective The aim of the study was to assess dermatologists’ awareness of available guidelines and drug package insert information on the screening for and management of hepatitis B (HBV) infection in patients receiving tumor necrosis factor-&agr; inhibitor (TNF-&agr;I) drug therapies for dermatological disorders. Materials and Methods An electronic descriptive cross-sectional questionnaire was administered to a random, nationwide sample of physician members of the American Academy of Dermatology. Each participating physician answered 8 questions regarding his or her awareness of the risk of HBV reactivation. Results More than half of the dermatologists surveyed (52%) were aware of guidelines regarding TNF-&agr;I use in dermatological disorders. Dermatologists who were aware of the guidelines performed universal screening 81% of the time versus 3% of those who were unaware. Approximately 30% of the dermatologists were aware of drug manufacturers’ package insert warnings for risk of HBV reactivation with TNF-&agr;Is. Screening in their high-risk patients was highly variable because >90% performed screening in patients with a history of hepatitis or with elevated liver-associated enzymes. Most (73%) screened appropriately with HB surface antigen. One case of HBV reactivation was observed with infliximab use for psoriasis treatment. Conclusions Based on this survey, improving education among dermatologists regarding the risks of HBV reactivation and its prevention for patients receiving TNF-&agr;I seems warranted. More specific consensus guidelines are recommended to achieve universal screening as the standard of care in these patients.