Gordon D. Benson

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.

Alcohol Oxidation in Rats Inhibited by Pyrazole, Oximes, and Amides

Pyrazole, previously reported to inhibit ethanol oxidation in the rat, also effectively blocks the in vivo metabolism of methanol, propanol, isopropanol, n-butanol, and isobutanol. A variety of oximes and amides are also effective inhibitors of ethanol metabolism. These various inhibitors may prove important in the elucidation of several facets of alcohol metabolism and also may have application in the treatment of methanol poisoning and in the reduction of the sequelae of the disulfiram-ethanol reaction syndrome in man.

Geographic clusters of primary biliary cirrhosis

Genetic and environmental factors have been widely suggested to contribute to the pathogenesis of primary biliary cirrhosis (PBC), an autoimmune disease of unknown etiology leading to destruction of small bile ducts. Interestingly, epidemiologic data indicate a variable prevalence of the disease in different geographical areas. The study of clusters of PBC may provide clues as to possible triggers in the induction of immunopathology. We report herein four such unique PBC clusters that suggest the presence of both genetic and environmental factors in the induction of PBC. The first cluster is represented by a family of ten siblings of Palestinian origin that have an extraordinary frequency of PBC (with 5/8 sisters having the disease). Second, we describe the cases of a husband and wife, both having PBC. A family in which PBC was diagnosed in two genetically unrelated individuals, who lived in the same household, represents the third cluster. Fourth, we report a high prevalence of PBC cases in a very small area in Alaska. Although these data are anedoctal, the study of a large number of such clusters may provide a tool to estimate the roles of genetics and environment in the induction of autoimmunity.

Serial Analysis of Antimitochondrial Antibody in Patients with Primary Biliary Cirrhosis

Antimitochondrial antibodies (AMAs) are the classic serologic marker in primary biliary cirrhosis (PBC). However, there have been only limited attempts to study changes in titer or isotype analysis of such AMAs in patients followed for long periods of time We took advantage of stored sera from well-characterized patients with PBC followed for a period of 7-28 years (mean duration of 13.5 years). Immunoblot and enzyme-linked immunosorbant assays were performed against PDC-E2, BCOADC-E2 and OGDC-E2 as well as isotype analysis of antigen-specific IgG, IgA and IgM antibodies against each of these mitochondrial autoantigens. Sera were analyzed for total IgG, IgA and IgM by radial immunodiffusion. The sera titer of AMAs was significantly higher in younger patients with PBC. Indeed, age of onset of clinical PBC was a significant predictor for the highest values of sera AMAs. In contrast, the AMA titer did not significantly change over time in this prolonged longitudinal study. The total sera levels of the individual immunoglobulins did not show a time-dependent change, when based on age of onset of the disease. Higher titers of AMAs were noted in the younger patients. Furthermore, despite this long follow-up, there was no evidence for a significant change in AMA levels; also, levels were not influenced by drug therapy used during the period of observation.

Quality of Life and Everyday Activities in Patients with Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is generally a slowly progressive disease that may lead to cirrhosis and liver failure. However, patients with PBC often suffer from a variety of symptoms long before the development of cirrhosis that include issues of daily living that have an impact on their work environment and their individual quality of life. We therefore examined multiple parameters by taking advantage of the database of our cohort of 1032 patients with PBC and 1041 matched controls. The data were obtained from patients from 23 tertiary referral centers throughout the United States and from rigorously matched controls by age, sex, ethnicity, and random‐digit dialing. The data showed that patients with PBC were more likely than controls to have significant articular symptoms, a reduced ability to perform household chores, and the need for help with routine activities. Patients with PBC rated their overall activity similar or superior to that of controls; however, more of them reported limitations in their ability to carry out activities at work or at home and difficulties in everyday activities. PBC cases also more frequently reported limitations in participating in certain sports or exercises and pursuing various hobbies; however, they did not report significant limitations in social activities. In a multivariable analysis, household income, a diagnosis of systemic lupus erythematosus, limitations in work activities, a reduction in work secondary to disability, and church attendance were independently increased in PBC cases with respect to controls. Conclusion: Our data indicate that the quality of life of patients with PBC in the United States is generally well preserved. Nevertheless, patients with PBC suffer significantly more than controls from a variety of symptoms that are beyond the immediate impact of liver failure and affect their lifestyle, personal relationships, and work activities. (HEPATOLOGY 2008.)

Prolonged Jaundice Following Ketoconazole-Induced Hepatic Injury

Two patients developed prolonged and progressive jaundice associated with ketoconazole-induced hepatic injury although the drug was discontinued before or shortly after the onset of symptoms of hepatic toxicity. One patient, who had been jaundiced for eight weeks and was not improving, showed prompt clinical improvement and progressive resolution of jaundice following therapy with prednisolone. Liver biopsy before therapy showed marked cholestasis in all acinar zones and moderately severe fibrosis in the space of Disse. The other patient, who was less severely jaundiced, showed spontaneous resolution although he remained jaundiced for 11 weeks. Liver biopsy performed three weeks after onset of symptoms showed a moderate degree of cholestasis in acinar zone 3 and collagen deposition about the terminal hepatic venules and within the space of Disse. These cases are reported because of the unique clinical course, documentation of the morphologic features, and experience with corticosteroid therapy.

Prolonged halothane hepatitis: Prompt resolution of severe lesion with corticosteroid therapy

SummaryPrevious reports on halothane-induced injury have included patients treated with corticosteroids. Therapy has often been initiated before there has been the opportunity for spontaneous resolution of the process. The patient reported here developed typical acute halothane hepatitis following the second exposure to the anesthetic; she remained ill and failed to show evidence of improvement during a five-week period. Clinical improvement was noted shortly after therapy with prednisone. The laboratory studies returned to normal, and the severe morphological lesion resolved. This experience supports the use of corticosteroids in halothane-induced liver injury in the absence of prompt spontaneous resolution, since therapy appears to decrease the morbidity and hasten resolution of the process.