Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a case of ticlopidine-induced prolonged cholestasis in a 60-year-old man with no previous hepatobiliary disease who presented with sudden right upper abdominal pain, jaundice and pruritus three months after starting ticlopidine therapy. Other drugs taken by the patient were not considered probable causes. The diagnostic evaluation showed no biliary obstruction and other possible causes of intra-hepatic cholestasis were excluded. The liver biopsy showed a cholestatic hepatitis with bile duct damage. The disease ran a severe and protracted course, but symptoms and jaundice eventually subsided five months after drug withdrawal. More than a year later, relevant abnormalities of liver function tests consistent with anicteric cholestasis still persist, fulfilling criteria for a minor form of drug-induced prolonged cholestasis. This syndrome has been reported infrequently in relation to several drugs, mainly chlorpromazine, and only once with ticlopidine.
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PMID:Ticlopidine-induced prolonged cholestasis: a case report. 1041 41

To assess epidemiological and clinical significance of drug hepatotoxicity in the setting of liver diseases consultation, ten thousand and three hundred forty two prospectively designed clinical records from patient cared for in our Liver Unit in the period 1988-1998 were incorporated into the study; 58 out of 10,342 (prevalence = 5.6%) fulfilled at least the first three of the following causality requirements: 1.--Liver injury associated in time to drug exposition; 2.--Negative evaluation of more common other etiologies; (alcohol, viruses, immunologic, metabolic, etc) 3.--Favourable response to drug withdrawal (ALT < 50% of baseline in 8 to 30 days in acute hepatitis type, and alkaline phosphatase and/or total bilirubin < 50% of baseline up to 6 months, in acute cholestasis) 4.--Inadverted or rarely prescribed positive challenge. Acute hepatitis type of injury were considered when serum ALT rise 8 times or more above normal superior level with alkaline phosphatase (APh) below 3 times; "pure" cholestasis when APh rise 3 times or more above normal with ALT below 8 times; mixed acute injury or cholestatic hepatitis when both ALT and APh were elevated above 8 and 3 times respectively, and indeterminate type when both enzymes were below the referred levels. Chronic injury were considered when six or more month of evolution and compatible liver histology happens. Clinical severity were expressed as mild (absence of major clinical complications, serum bilirubin < 5 mg/dl and prothrombin concentration > 75%), moderate (presence of clinical complications, bilirubin > 5 mg/dl and prothrombin concentration between 50-75%), and severe (major clinical complications with bilirubin > 5 mg/dl and prothrombin concentration < 50%). Female/male ratio was 1.4:1, with age average 39 years (R = 15-77) and major concentration of cases above 40. More than 50% of cases received 2 or more drugs. Jaundice was present in 60.4%, and systemic manifestations of hypersensibility (fever, adenomegalies, rush, mononucleosis like syndrome, eosinophilia) in 29.3%. Acute injury represented 91.4% of the cases: 41.4% acute hepatitis, 15.5% "pure" cholestasis, 24.1% cholestatic hepatitis, and 10.3% indeterminate type. Four patients (4.5% of acute injury cases) were presented as severe acute liver failure, leading to liver transplant in one of them, drug association (INH-rifampicin and carbamazepine-phenobarbital) and inadverted challenge (sulphonamides and pemoline) were associated to clinical severity. Chronic injury were found in five patient (8.6%), four of them associated to chronic hepatitis and the other one to a ductopenic syndrome. Six drugs represented 53.4% of our cases; oral contraceptives (7 cases), INH alone or combined with rifampicin (6 cases), sulfonamides and clorpropamida (5 cases each), carbamazepine and amiodarone (4 cases each). Normalization of liver enzymes after drug suppression took 2 to 8 weeks in acute hepatitis type (X = 4 weeks), 4 to 20 in "pure" cholestasis (X = 12 weeks) and 8 to 24 weeks in cholestatic hepatitis or mixed type (X = 16 weeks). Two cases of chronic hepatitis normalize the histological activity index in 20 and 18 month respectively, one case remains as chronic hepatitis at 10 month and the other one progress to cirrhosis; the ductopenic syndrome normalize histology in 19 months receiving urso-deoxicolic acid, 10 mg/k/day.
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PMID:[Clinic-epidemiological significance of drug hepatotoxicity in liver disease consultation]. 1092 31

A 66 year-old obese woman with arthrosis, self-medicated with oral nimesulide, 200 mg daily. After 6 weeks she developed nausea, jaundice and dark urine. Two weeks later she had recurrent hematemesis and was hospitalized. Besides obesity and anemia her physical examination was unremarkable. An upper GI endoscopy revealed 3 acute gastric ulcers and a 4th one in the pyloric channel. Abdominal ultrasonogram showed a slightly enlarged liver with diffuse reduction in ecogenicity; the gallbladder and biliary tract were normal. Blood tests demonstrated a conjugated hyperbilirubinemia (maximal total value: 18.4 mg/dl), ALAT 960 U/l, ASAT 850 U/l, GGT 420 U/l, alkaline phosphatases mildly elevated, pro-time 49% and albumin 2.7 mg/dl. Serum markers for hepatitis A, B and C viruses were negative. ANA, AMA, anti-SmA, were negative. Ceruloplasmin was normal. A liver biopsy showed bridging necrosis and other signs of acute toxic liver damage. Gastric ulcers healed after conventional treatment and hepatitis subsided after 2 months leaving no signs of chronic liver damage. The diagnosis of toxic hepatitis due to nimesulide was supported by the time-course of drug usage, sex, age, absence of other causes of liver disease, a compatible liver biopsy and the improvement after drug withdrawal. Peptic ulcers or toxic hepatitis have been previously described as independent adverse reactions in patients taking nimesulide or other NSAIDs but their simultaneous occurrence in a single patient is a unique event that deserves to be reported.
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PMID:[Bleeding gastric ulcers and acute hepatitis: 2 simultaneous adverse reactions due to nimesulide in a case]. 1122 44

The L-nucleoside analog beta-L-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine (beta-L-Fd4C) was first shown to exhibit potent activity against hepatitis B virus (HBV) in tissue culture and then to significantly inhibit viral spread during acute infection in the duck HBV model (F. Le Guerhier et al., Antimicrob. Agents Chemother. 44:111-122, 2000). We have therefore examined its antiviral activity in a mammalian model of chronic HBV infection, the woodchuck chronically infected with woodchuck hepatitis virus (WHV). Side-by-side comparison of beta-L-Fd4C and lamivudine administered intraperitoneally during short-term and long-term protocols demonstrated a more profound inhibition of viremia in beta-L-Fd4C-treated groups. Moreover, beta-L-Fd4C induced a marked inhibition of intrahepatic viral DNA synthesis compared with that induced by lamivudine. Nevertheless, covalently closed circular (CCC) DNA persistence explained the lack of clearance of infected hepatocytes expressing viral antigens and the relapse of WHV replication after drug withdrawal. Liver histology showed a decrease in the inflammatory activity of chronic hepatitis in woodchucks receiving beta-L-Fd4C. An electron microscopy study showed the absence of ultrastructural changes of hepatic mitochondria, biliary canaliculi, and bile ducts. However, a loss of weight was observed in all animals, whatever the treatment, as was a transient skin pigmentation in all woodchucks during beta-L-Fd4C treatment. There was no evidence that lamivudine or beta-L-Fd4C could prevent the development of hepatocellular carcinoma with the protocols used. These results indicate that beta-L-Fd4C exhibits a more potent antiviral effect than lamivudine in the WHV model but was not able to eradicate CCC DNA and infected cells from the liver at the dosage and with the protocol used.
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PMID:Antiviral activity of beta-L-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine in woodchucks chronically infected with woodchuck hepatitis virus. 1125 17

Administration of either lamivudine (2'-deoxy-3'-thiacytidine) or L-FMAU (2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil) to woodchucks chronically infected with woodchuck hepatitis virus (WHV) induces a transient decline in virus titers. However, within 6 to 12 months, virus titers begin to increase towards pretreatment levels. This is associated with the emergence of virus strains with mutations of the B and C regions of the viral DNA polymerase (T. Zhou et al., Antimicrob. Agents Chemother. 43:1947-1954, 1999; Y. Zhu et al., J. Virol. 75:311-322, 2001). The present study was carried out to determine which of the mutants that we have identified conferred resistance to lamivudine and/or to L-FMAU. When inserted into a laboratory strain of WHV, each of the mutations, or combinations of mutations, of regions B and C produced a DNA replication-competent virus and typically conferred resistance to both nucleoside analogs in cell culture. Sequencing of the polymerase active site also occasionally revealed other mutations, but these did not appear to contribute to drug resistance. Moreover, in transfected cells, most of the mutants synthesized viral DNA nearly as efficiently as wild-type WHV. Computational models suggested that persistence of several of the WHV mutants as prevalent species in the serum and, by inference, liver for up to 6 months following drug withdrawal required a replication efficiency of at least 10 to 30% of that of the wild type. However, their delayed emergence during therapy suggested replication efficiency in the presence of the drug that was still well below that of wild-type WHV in the absence of the drug.
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PMID:Mutations of the woodchuck hepatitis virus polymerase gene that confer resistance to lamivudine and 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil. 1177 97

This review addresses recent advances in specific mechanisms of hepatotoxicity. Because of its unique metabolism and relationship to the gastrointestinal tract, the liver is an important target of the toxicity of drugs, xenobiotics, and oxidative stress. In cholestatic disease, endogenously generated bile acids produce hepatocellular apoptosis by stimulating Fas translocation from the cytoplasm to the plasma membrane where self-aggregation occurs to trigger apoptosis. Kupffer cell activation and neutrophil infiltration extend toxic injury. Kupffer cells release reactive oxygen species (ROS), cytokines, and chemokines, which induce neutrophil extravasation and activation. The liver expresses many cytochrome P450 isoforms, including ethanol-induced CYP2E1. CYP2E1 generates ROS, activates many toxicologically important substrates, and may be the central pathway by which ethanol causes oxidative stress. In acetaminophen toxicity, nitric oxide (NO) scavenges superoxide to produce peroxynitrite, which then causes protein nitration and tissue injury. In inducible nitric oxide synthase (iNOS) knockout mice, nitration is prevented, but unscavenged superoxide production then causes toxic lipid peroxidation to occur instead. Microvesicular steatosis, nonalcoholic steatohepatitis (NASH), and cytolytic hepatitis involve mitochondrial dysfunction, including impairment of mitochondrial fatty acid beta-oxidation, inhibition of mitochondrial respiration, and damage to mitochondrial DNA. Induction of the mitochondrial permeability transition (MPT) is another mechanism causing mitochondrial failure, which can lead to necrosis from ATP depletion or caspase-dependent apoptosis if ATP depletion does not occur fully. Because of such diverse mechanisms, hepatotoxicity remains a major reason for drug withdrawal from pharmaceutical development and clinical use.
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PMID:Mechanisms of hepatotoxicity. 1181 20

Prednisone alone or a lower dose in combination with azathioprine is effective in improving symptoms, resolving laboratory and histologic features, and prolonging survival in patients with autoimmune hepatitis. The combination regimen of prednisone and azathioprine is preferred because of its lower frequency of corticosteroid-related side effects. Only patients with severe inflammatory activity have absolute indications for therapy. Treatment must be individualized in patients with mild-to-moderate disease. Medication should be continued at fixed daily maintenance levels until a remission, treatment failure, drug intolerance, or incomplete response has been established. Histologic examination before drug withdrawal ensures remission when symptoms and laboratory tests are normal or near normal. Treatment failure warrants high-dose therapy, whereas drug toxicity and incomplete response compel regimens that are modified individually according to response. Low-dose prednisone or indefinite azathioprine therapy are indicated in patients who have relapsed multiply. Empiric nonsteroidal treatments include ursodeoxycholic acid, cyclosporine, mycophenolate mofetil, and tacrolimus, and they have been used in limited studies to treat recalcitrant disease or corticosteroid intolerance. Investigational therapies promise to target critical pathogenic mechanisms affecting immunocyte activation, autoantigen recognition, cytokine interactions, and regenerative activity.
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PMID:Treatment strategies in autoimmune hepatitis. 1236 82

Autoimmune hepatitis is a well-established chronic liver disease. It primarily affects women, is characterized by circulating autoantibodies and elevated gammaglobulins and is associated with extrahepatic immune-mediated syndromes. Treatment regimens have remained unchanged for a number of years because of the high efficacy of steroid monotherapy, or combination therapy of azathioprine and steroids. In approximately 90% of patients remission of the disease is reached by medical therapy, which is usually administered lifelong because long-term remission after drug withdrawal is achieved in only 17% of patients. In 10% of patients treatment failure is observed. The challenge of remission induction involves the use of transplant immunosuppressants such as cyclosporine, mycophenolate moffetil, and tacrolimus. The challenge of maintenance therapy minimizing steroid side-effects involves the evaluation of topical steroids and the use of azathioprine monotherapy. Overlap syndromes occur in approximately 20% of autoimmune liver diseases. The diagnosis is broadly based on serological, biochemical, clinical and histological parameters. Most common are the overlap of autoimmune hepatitis and primary biliary cirrhosis, as well as autoimmune hepatitis with primary sclerosing cholangitis. These yet incompletely defined syndromes are an important differential diagnosis in the difficult-to-treat patient with autoimmune hepatitis.
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PMID:Autoimmune hepatitis and overlap syndromes. 1247 69

Our aims were to determine the frequency and prognostic implications of antibodies to chromatin in autoimmune hepatitis. Three hundred seventy-one serum samples from 172 patients were tested by enzyme-linked immunosorbent assay. Sixty-seven patients (39%) had antibodies to chromatin. Percent positivity was greater in men than women (58% vs 34%, P = 0.008), and seropositivity was associated with higher serum levels of gamma-globulin and immunoglobulin G. Antibodies to chromatin disappeared in 25 of 60 patients who were tested successively (42%), and they were more common in samples obtained during active than inactive disease (32% vs 19%, P = 0.01). Relapse after drug withdrawal occurred more often in seropositive patients (91% vs 66%, P = 0.002). We conclude that antibodies to chromatin occur commonly in autoimmune hepatitis, and they are associated with disease activity. Percent positivity is greater in men than women, and seropositivity identifies individuals who commonly relapse after drug withdrawal.
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PMID:Frequency and significance of antibodies to chromatin in autoimmune hepatitis. 1292 65

Prednisone alone or a lower dose of prednisone in combination with azathioprine induces remission and enhances survival in autoimmune hepatitis. Treatment failure, incomplete response, drug-induced side effects, and relapse after drug withdrawal are unsatisfactory outcomes that justify the search for new therapies. Potent new drugs promise greater blanket immunosuppression than current regimens, and insights into the pathogenic mechanisms of the disease make site-specific interventions possible. Cyclosporine and tacrolimus are calcineurin inhibitors that impair the transcription of interleukin 2, reduce the expression of cytokines, and diminish T lymphocyte proliferation. Mycophenolate mofetil antagonizes the synthesis of purines and depletes stores of guanine nucleotides necessary for DNA synthesis and expansion of T cell clones. Controlled clinical trials are warranted to establish the role of these new drugs in the treatment of autoimmune hepatitis. Promising site-specific therapies include peptides that competitively block autoantigen presentation, agents such as cytotoxic T lymphocyte antigen 4 that inhibit the second co-stimulatory signal of immunocyte activation, T cell vaccination, oral tolerance therapy, and cytokine manipulation with monoclonal antibodies and recombinant supplements. Confident animal models of experimental autoimmune hepatitis are necessary to mature these interventions. In conclusion, promising immunosuppressive agents that alter cytokine expression and T lymphocyte proliferation may be of value in the treatment of autoimmune hepatitis. Critical mechanisms of immunocyte activation, cytotoxic T cell expansion, and cytokine modulation are the targets of site-specific interventions.
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PMID:Emerging treatments for autoimmune hepatitis. 1456 Nov 79


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