Mucosal immunity and primary biliary cirrhosis: presence of antimitochondrial antibodies in urine.

We have shown that IgA-class antimitochondrial autoantibodies (AMA) can be detected in the bile and saliva of patients with PBC, suggesting that AMA are secreted into the luminal fluid across bile ducts and salivary glands. These data prompted us to determine whether AMA of the IgA isotype may be transported across other epithelial mucosa. Therefore, we tested for the presence of AMA in the urine specimens of 83 patients with PBC and 58 non-PBC controls including healthy individuals and patients with other liver diseases. Patients enrolled in this study had no history of renal disease, and we confirmed there was less than 50 microgram/mL of protein in each of the urine specimens. Interestingly, we found that AMA were present in the urine of 71/83 (86%) of all patients with PBC and in 71/78 (91%) of patients with PBC that were serum AMA positive. In contrast, AMA were not detected in any of the 58 control urine specimens. Of particular interest, AMA of the IgA isotype was present in 57/83 (69%) of patients with PBC, and in 52 of these 57, we found secretory-type IgA. In a nested random subgroup of urine samples, the prevalence of the IgA2 AMA was 6/18 (33%), significantly lower than in matched serum samples, 13/16 (81%, P =.007). These data show that AMA of the IgA isotype is secreted into urine from the uroepithelium of patients with PBC, and support the thesis that PBC originated from either a mucosal challenge or a loss of mucosal tolerance.

Penetration and co-localization in MDCK cell mitochondria of IgA derived from patients with primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease of unknown etiology characterized by high-titer anti-mitochondrial antibodies. The major autoantigen has been identified as the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). The fact that PDC-E2 is present in all nucleated cells, but autoimmune damage is confined to biliary epithelial cells, prompted us to investigate the possibility that mucosally-derived IgA may be pathogenic for biliary epithelial cells. Serum IgA was purified from six patients with PBC and its localization and ability to penetrate cells was studied using Madine-Darby canine kidney (MDCK) cells transfected with the human IgA receptor (MDCK-pIgR). The potential of IgA to be transported through the cells was studied by a combination of immunohistochemistry and dual color fluorescent microscopy. Interestingly, IgA from all PBC patients co-localized with PDC-E2 (the major autoantigen of PBC) inside the cells; this was demonstrated by dual staining with anti-human IgA and a mouse monoclonal antibody directed to PDC-E2. In contrast, no co-localization was observed for IgA controls. Furthermore, dual staining of liver sections from PBC patients demonstrated co-localization of IgA and PDC-E2, both cytoplasmically and at the apical surface. We postulate that there may be a direct effect of these autoantibodies on the mitochondrial function of biliary epithelial cells.

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.

Previous 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.

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.

Hepatotoxicity following the therapeutic use of antipyretic analgesics.

The potential for hepatic injury associated with the therapeutic use of salicylates and acetaminophen has recently attracted considerable attention. About 300 cases have been reported in which elevated transaminase levels or other evidence of hepatic injury developed following treatment with salicylates. Review of the spectrum of abnormalities reveals a group of patients (4 percent) with symptomatic liver damage in whom progressive or chronic liver disease is a possibility with continued use of the drug. In a few patients in this group, jaundice developed; several had abnormal prothrombin times; 11 (70 percent) had transaminase values in excess of 500 units; and five patients (30 percent) had encephalopathy and/or Reye's syndrome. In several reports liver damage has also been associated with the use of acetaminophen in therapeutic or near-therapeutic dosages. Of 18 patients, nine appeared to have ingested acetaminophen in amounts approaching overdose. Of the remaining nine patients, six were alcoholics. In the entire group, only five patients did not have a history of alcohol abuse; in three, glutathione depletion was suggested as a possible explanation for hepatotoxicity. The association with alcoholism or glutathione depletion suggests that host susceptibility may play a critical role. In two patients, long-term use of acetaminophen resulted in liver injury suggestive of chronic active hepatitis, possibly on the basis of an idiosyncratic reaction. In a study of chronic liver disease, acetaminophen half-life was prolonged (168 percent) without accumulation at 4 g a day over five days. In a double-blind, two-week, cross-over study, no clinical or laboratory evidence of adverse effects was found. There is, therefore, no evidence that chronic liver disease increases the risk of hepatotoxicity following the administration of acetaminophen in therapeutic doses. Thus, acetaminophen is the preferred antipyretic analgesic in patients with liver disease. Salicylates should be avoided since many of the adverse effects associated with these drugs are similar to the complications of chronic liver disease.

Acetaminophen in chronic liver disease.

The safety of acetaminophen in therapeutic doses was evaluated in subjects with stable chronic liver disease. Six subjects with chronic liver disease were given 4.0 gm daily for 5 days. Although the mean half-life (t 1/2) acetaminophen was 3.42 hr, there was no evidence of drug cumulation or hepatotoxicity. A double-blind, two-period crossover design was also used to evaluate acetaminophen in 20 subjects. Acetaminophen, at a dose of 4.0 gm daily for 13 days, was well tolerated by these subjects with stable chronic liver disease. One subject developed symptoms, which worsened and were associated with deterioration in the results of laboratory studies, while taking acetaminophen. Subsequent challenges with 4.0 gm acetaminophen daily for periods of 10 and 14 days were well tolerated, which indicates that the deterioration was not related to the drug. During this study there were no abnormalities indicative of an adverse reaction to acetaminophen. There is, therefore, no contraindication to the use of acetaminophen in therapeutic doses in the presence of stable chronic liver disease.

Copper chelating agents. A comparison of cupruretic responses to various tetramines and D-penicillamine.

Toxic or hypersensitivity reactions occur frequently with D-penicillamine therapy. Therefore there is a need for effective, well-tolerated alternative chelating agents to control the copper accumulation which occurs in Wilson's disease and some other chronic liver diseases. A group of tetramines (linear and macrocyclic) was surveyed for cupruretic activity and compared to D-penicillamine. 2,3,2-Tetramine was the most effective agent when given either by gavage or intravenously. It was more effective than 2,2,2-tetramine (trien) or D-penicillamine and, in addition, induced a more prolonged cupruresis. Despite their higher formation constants for copper, the macrocyclic tetramines did not induce a significant cupruresis. In this study, the 2,3,2-tetramine was the most effective agent for inducing a cupruresis in both normal and copper-loaded rats. If well tolerated by humans, it could become a useful agent for management of disorders characterized by copper accumulation.

Hepatic copper accumulation in primary biliary cirrhosis.

Hepatic copper accumulation is a regular feature of primary biliary cirrhosis (PBC). The levels are directly related to the clinical stage of the disease. Since the copper values in PBC are comparable to Wilson's disease, there is the potential for copper toxicity, although this is speculative since the two diseases differ in the binding, distribution, and intracellular localization of the copper. The involvement of copper toxicity in the progression of PBC is supported by the observation that the highest values occur in association with the hepatic failure that occurs in the advanced stage.Corticosteroid therapy appears to decrease hepatic copper levels in PBC. Although this therapy does not invariably lower the hepatic Cu content in patients with PBC, it does so in many individuals. Therapeutic trials with d-penicillamine are in progress. When results are available they will guide us in the management of individual patients with PBC. In the meantime, dietary copper should be restricted as is done in management of Wilson's disease.

Cryoprotein complexes and peripheral neuropathy in a patient with chronic active hepatitis.

A cryoprotein complex was isolated and characterized from a patient with chronic active hepatitis and a severe peripheral neuropathy. This cryoprotein was composed of IgM, IgG, and hepatitis B surface antigen (HBsAg) and had a concentration of approximately 36 mg per 100 ml of serum. Electron microscopic examination of the cryoprotein demonstrated aggregates of Dane particles in close association with the antigenically related tubular and spherical forms of HBsAg. HBsAg, IgM, and IgG were detected by immunofluorescent staining in the intima of small arteries and veins. The association of a high serum level of cryoprotein and deposition of the cryoprotein components in small blood vessels suggests a role for the cryoprotein in the pathogenesis of peripheral neuropathy in this patient with chronic active hepatitis.

Alcohol oxidation in rate 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.