Gastric protection by misoprostol against 1,300 mg of aspirin. An endoscopic dose-response study.

Misoprostol at a dose of 200 micrograms inhibits gastric acid secretion and protects the gastric mucosa against the injurious effects of a single 1,300-mg dose of aspirin. The purpose of this study was to determine whether lower subantisecretory doses of misoprostol protect the gastric mucosa in this single-dose aspirin model. Protection was defined as no more than 10 hemorrhagic spots and no more than two hemorrhagic streaks. A total of 140 men participated in the two phases of the study. In the first phase, groups of 10 subjects each received placebo or misoprostol in doses of 200 micrograms, 100 micrograms, 50 micrograms, or 25 micrograms in a double-blind design. All misoprostol doses protected 50 to 70 percent of subjects as compared with 20 percent of subjects in the placebo group. To expand the number of observations, 90 additional subjects in groups of 30 each were evaluated after receiving misoprostol 50 micrograms or 25 micrograms or placebo. Misoprostol 50 micrograms protected 14 of 30 subjects (47 percent), 25 micrograms protected 11 of 30 (37 percent), and placebo protected six of 30 (20 percent). The dose-response trend was statistically significant (p less than 0.05). It is concluded that misoprostol protects the gastric mucosa against a single 1,300-mg dose of aspirin and that there is a significant dose-response relationship.

Preliminary studies on the detection, isolation and partial characterization of Clq-containing IgM immune complexes in sera of patients with primary biliary cirrhosis.

The complement system is activated in primary biliary cirrhosis (PBC) and this activated state may be medicated by immunoreactive IgM. To identify and further characterize the relationship between the complement (Clq) and IgM in PBC sera, we developed an anti-Clq ELISA method which allowed detection of Clq-containing circulating immune-like complexes. Utilizing this technique, sera from 3 out of 5 patients with PBC revealed circulating immune-like complexes. Moreover, when serum samples were specifically examined for the presence of IgM containing Clq complexes, four of four samples examined were positive. Additional experiments indicated that these immune-like complexes could be removed from PBC sera by means of an anti-Clq immunoadsorbent. Upon subsequent isolation and characterization, these immune-like complexes demonstrated polypeptide chains corresponding to both human Clq and human IgM. Our experimental studies establish that Clq-containing IgM-like complexes can occur in the serum of patients with PBC, and provide additional support for the proposal that immunoreactive IgM can contribute to the activated complement system observed in PBC.

Initial rate of sodium taurocholate uptake in isolated elutriated hepatocytes from untreated and phenobarbital-treated rats.

The initial rate of sodium taurocholate uptake was measured in rat hepatocytes separated by centrifugal elutriation into five cell fractions whose difference in size was verified by flow cytometry. The hepatocytes were prepared from untreated and phenobarbital-treated rats. For untreated animals, the initial rate of taurocholate uptake at concentrations of 5 or 50 microM was the same for hepatocytes prior to fractionation and for each of the five elutriated fractions. Treatment of the animals with phenobarbital was associated with a significant increase in hepatocyte size in all fractions and caused a significant increase in the initial uptake rate. The extent of the rate increase in hepatocytes prior to fractionation was similar to that observed for each of the five hepatocyte subpopulations. Our observation indicates that phenobarbital causes a significant increase in the initial rate of sodium taurocholate uptake and suggests that large and small hepatocytes possess no inherent differences controlling the initial uptake process.

Heterogeneous distribution of drug metabolism in elutriated rat hepatocytes.

Centrifugal elutriation was used to separate isolated rat hepatocytes into five fractions containing cells of different sizes. These fractions were compared with regard to cell size, morphology and function. Analyzed by flow cytometry, the small cells were found to be enriched in fraction 1 and the large cells in fraction 5. Evaluation by light and electron microscopy indicated that the fractions contained single hepatocytes of normal structure. The cytochrome P-450 content and the 7-ethoxycoumarin O-deethylase activity were assessed in hepatocytes from untreated animals, those treated with phenobarbital, and those treated with phenobarbital plus allylisopropylacetamide. In both untreated and phenobarbital-treated animals, cytochrome P-450 content and 7-ethoxycoumarin O-deethylase activity rose significantly from fraction 1 to fraction 5. The P-450 content gradually rose up to 2-fold. The enzyme activity rose 5-fold, and it increased steeply between fractions 2 and 3. The cytochrome P-450 content in phenobarbital-plus-allylisopropylacetamide-treated animals was decreased in all fractions but more extensively in fraction 5 than in fraction 1.

The benefit of long-term interferon alfa therapy for symptomatic mixed cryoglobulinemia (cutaneous vasculitis/membranoproliferative glomerulonephritis) associated with chronic hepatitis C infection.

The efficacy of long-term interferon therapy for chronic hepatitis C infection with symptomatic mixed cryoglobulinemia has not clearly been defined. We describe a patient with chronic hepatitis C, symptomatic mixed cryoglobulinemia (cutaneous vasculitis), and membranoproliferative glomerulonephritis (MPGN) who responded clinically, biochemically, and virologically to a 1-year course of interferon therapy. Interferon side effects were minimal. Relapse occurred when interferon was discontinued, and suppressive maintenance interferon therapy was required for clinical, biochemical, and virologic remission. During the 5th year of maintenance therapy, she developed potential side effects that necessitated discontinuation of interferon treatment. After treatment stoppage, a clinical, biochemical, and virologic remission was maintained for more than 1 year. However, the potential side effects, which included eye irritation, arthralgias, myalgias, fatigue, insomnia, memory loss, and depression, persisted. Ophthalmologic, rheumatologic, and neurologic evaluations were nondiagnostic. Psychometric testing revealed dementia and mood disorder. Because the disabling symptoms persisted after 9 months, a health-related quality of life assessment was carried out with the SF-36 survey. Compared with healthy individuals and patients with chronic hepatitis C, our case had a lower health-related quality of life assessment on six out of seven scales and on four out of seven scales of the SF-36 survey, respectively. This case report indicates that long-term maintenance interferon therapy was effective in the treatment of symptomatic mixed cryoglobulinemia and its renal complications and resulted in a clinical, biochemical, and virologic sustained response. It is postulated that the side effects of long-term interferon therapy in this setting may be problematic.

Splenic abscess. A rare complication of Crohn's colitis.

This report describes a patient with Crohn's disease of the colon who presented with a rare extraintestinal complication: splenic abscess. Additional features of this case were the association of multiple extraintestinal manifestations of Crohn's disease, including iritis, ankylosing spondylitis, and pericholangitis, and polymicrobial bacteremia. This report emphasizes the cryptic nature of splenic abscess presentation, the more frequent association of extraintestinal manifestations of Crohn's disease with intraabdominal complications, and the association of polymicrobial anaerobic bacteremia with obstructive gastrointestinal complications.

Experimental hepatic injury: the sequential changes in drug metabolizing enzyme activities after administration of acetaminophen.

Experimental hepatic necrosis was induced in phenobarbital pretreated rats by means of the intraperitoneal administration of an acetaminophen-dimethyl sulfixide (DMSO) mixture. Cytochrome P-450 content and the specific activities of aminopyrine demethylase, aniline hydroxylase and bilirubin glucuronyl transferase diminished over the three-day study period, as compared with control animals. The reductions, however, were generally modest; not uniform for all the enzymes assayed; and correlated poorly with histologic necrosis and standard liver function tests. It is concluded that in acute liver disease changes in the hepatic in vitro drug metabolizing enzyme capacity may not be closely related to cellular necrosis, per se, and the degree of change in enzyme activities will vary from one enzyme system to another. These findings may explain, in part, the often inconsistent alterations in the disposition and elimination of drugs described in associated liver disease.

The concentration and temporal relationships of acetaminophen-induced changes in intracellular and extracellular total glutathione in freshly isolated hepatocytes from untreated and 3-methylcholanthrene pretreated Sprague-Dawley and Fischer rats.

Fischer rats are more sensitive to acetaminophen-induced hepatotoxicity than Sprague-Dawley rats, however, the mechanisms for this enhanced sensitivity remain unclear. The susceptibility to hepatotoxicity is determined largely by the balance between acetaminophen toxification and detoxification. Since glutathione plays a critical role in the detoxification process, it would be of interest to compare the effects of acetaminophen on hepatic glutathione homeostasis in the Sprague-Dawley and Fischer rat, and relate these effects to cytotoxicity. To this end, we measured the sequential changes of intracellular and extracellular total glutathione in freshly isolated hepatocytes from untreated and 3-methylcholanthrene pretreated Fischer and Sprague-Dawley rats, both in the absence (basal) and presence of acetaminophen. In the basal state, the intracellular total glutathione content was significantly (P less than 0.01) increased in hepatocytes from untreated Fischer rats. Nevertheless, the sequential release of total glutathione into the medium and the sequential depletion of intracellular total glutathione were quantitatively similar in hepatocytes from untreated Fischer and Sprague-Dawley rats. Following exposure to acetaminophen, there was a striking dose and time associated depletion of intracellular total glutathione in untreated hepatocytes from both rat strains, and quantitatively the depletion was similar in untreated hepatocytes from both rat strains. This degree of depletion of intracellular total glutathione was not associated with acetaminophen-induced cytotoxicity in Sprague-Dawley hepatocytes, whereas significant (P less than 0.05) cytotoxicity was demonstrated in Fischer hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxmetidine (H2 receptor antagonist) induced cytotoxicity in isolated rat hepatocytes.

Oxmetidine, a new and more potent analogue of the H2 receptor antagonist, cimetidine, was recently withdrawn from clinical trials because of associated hepatotoxicity. We investigated the potential hepatotoxicity of the drug in vitro and in vivo in the rat. In addition, we investigated, in in vitro experiments, the potential hepatoxicity of other gastric acid inhibitory drugs (cimetidine, ranitidine, omeprazole and nolinium bromide). In in vitro experiments, oxmetidine, at various concentrations, was added to isolated hepatocyte incubations and cytotoxicity was assayed by trypan blue exclusion. In in vivo experiments, oxmetidine was administered both i.p. and orally, and hepatotoxicity was assessed by serum biochemical measures (transaminases, alkaline phosphatase, 5' nucleotidase, gamma glutamyl transpeptidase) and liver histopathology. In the in vitro studies, the addition of oxmetidine to the hepatocyte incubations was associated with significant (P less than 0.001) dose and time dependent cytotoxicity. However, the in vivo experiments revealed no significant changes in serum biochemistry and no significant alterations in liver histopathology up to 72 h following the administration three different dosages of oxmetidine. Of the other gastric acid inhibitory drugs, only nolinium bromide was associated with significant (P less than 0.001) in vitro cytotoxicity. Our in vitro observations establish that oxmetidine is cytotoxic to isolated rat hepatocytes and suggest that nolinium bromide be further evaluated for potential hepatotoxicity.

Chlorpromazine, administered in vivo and in vitro, inhibits the efflux of bile acids in freshly isolated rat hepatocytes.

Although it has been speculated that chlorpromazine may alter the transhepatic movement of bile acids from plasma to bile, the effect of chlorpromazine on various determinants of bile acid transport in isolated rat hepatocytes remains incompletely defined. In particular, there is little information about the effect of chlorpromazine on the release of bile acids from freshly isolated hepatocytes. Therefore, we examined the effect of chlorpromazine, administered in vivo and in vitro, on the efflux rate of radiolabeled bile acids in freshly isolated rat hepatocytes. In an isolated haptocyte system, it is not possible to distinguish the sinusoidal plasma membrane function of efflux (back diffusion) from the canalicular plasma membrane function of excretion. Therefore, efflux, as used in this manuscript, reflects both back diffusion and excretion. In vitro, chlorpromazine produced a rapid dose dependent significant (P less than 0.05) decrease of the bile acid efflux rate in freshly isolated hepatocytes. This decrease in bile acid efflux was observed at chlorpromazine concentrations which did not alter hepatocyte plasma membrane permeability (viability), as measured by intracellular potassium content, release of lactate dehydrogenase, and trypan blue exclusion. Moreover, in freshly isolated hepatocytes from chlorpromazine pretreated rats, a significant (P less than 0.05) decrease in the bile acid efflux rate was also observed, and this decrease in efflux was similar in magnitude to the decrease in bile acid efflux observed following exposure of freshly isolated hepatocytes to chlorpromazine in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term interferon alpha maintenance therapy for chronic hepatitis C infection in a patient with common variable immune deficiency.

A 46-year-old woman with common variable immune deficiency acquired acute non-A, non-B hepatitis from contaminated intravenous gamma globulin in 1983. For 6 years she had fluctuating elevations of her serum aminotransferase levels. In 1990 her serum was documented to be hepatitis C virusribonucleic acid positive by polymerase chain reaction, and her liver biopsy revealed chronic hepatitis with early cirrhosis (Knodell score, 15 points). Hepatitis C virus genotyping indicated that she had been infected with the type 3 genotype. She subsequently underwent treatment with interferon alpha (IFN-alpha) for 1 year and experienced biochemical, virologic, and histologic (Knodell score, 9) suppression. She was continued on maintenance therapy for an additional 7 years, with sustained biochemical and virologic suppression. During the sixth year of therapy, complications of portal hypertension were noted with mild ascites and eventually bleeding esophageal varices. This case report documents a favorable biochemical, virologic, and histologic response to IFN-alpha therapy in this setting; supports the notion that the natural progression of hepatitis C virus infection may be more aggressive in patients with common variable immune deficiency; and, although complications of portal hypertension eventually occurred, the suppressive maintenance IFN therapy may have delayed their onset. The future establishment of the long-term effects of IFN therapy on important clinical outcomes is necessary to understand better its therapeutic benefit in chronic hepatitis C infection.

A comparison of hepatocyte size distribution in untreated and phenobarbital-treated rats as assessed by flow cytometry.

Flow cytometric analysis of narrow forward angle light scatter was used to examine the effect of phenobarbital treatment on hepatocyte size. Light scatter analysis of freshly isolated hepatocytes and of hepatocytes separated by means of centrifugal elutriation into five subpopulations (fractions 1-5) was performed on both untreated and phenobarbital-treated rats. The frequency distribution histogram of forward scatter intensity produced by freshly isolated hepatocytes from untreated rats was used as the baseline. This histogram was arbitrarily divided into four regions; referred to as region 1 (small cells) to region 4 (large cells). Subsequent analysis of the light scatter histograms derived from elutriated fractions of both untreated and phenobarbital-treated animals was performed using these baseline regions. Analysis showed that small cells were enriched in elutriated fraction 1, and large cells in elutriated fraction 5. Phenobarbital treatment was associated with a uniform shift to a higher intensity light scatter (relative increase in cell size) within each of the four selected regions. Our findings suggest that phenobarbital does not have a selective hypertrophic effect on these subpopulations of rat hepatocytes.

Liver support systems: the low clearance of model hepatic excretory anions by charcoal hemoperfusion.

The removal of cholephilic anions (unconjugated bilirubin, bromosulfophthalein, and indocyanine green) by charcoal hemoperfusion was assessed in normal dogs. None of these model excretory compounds was effectively removed by the charcoal columns. In vitro studies suggested that poor removal of the anions was related to albumin binding in that, when the anions were in molecular solution, their extraction by the charcoal column was high; however, when albumin was added, their extraction was negligible. Therefore, if the removal from plasma of strongly bound toxins is important in the treatment of acute hepatitic failure, additional support devices may have to be encompassed into the ultimately hepatic support system.

Reduction of absorption of paracetamol by activated charcoal and cholestyramine: a possible therapeutic measure.

The absorption of an oral 2-g dose of paracetamol was markedly reduced by the simultaneous oral administration of either activated charcoal or cholestyramine but was only slightly reduced when the adsorbents were given 60 minutes after the paracetamol. Since the absorption of a larger dose of the drug will probably be slow, the administration of adsorbents may be of value even when delayed several hours.

Mesenteric vein thrombosis. Four cases and review of the literature.

Mesenteric vein thrombosis, an uncommon but important clinical entity, can cause ischemia or infarction of the small intestine. Mesenteric vein thrombosis was first described nearly a century ago, but diagnosis remains difficult because it can affect young individuals without any known predisposing disorder and because patients often present with nonspecific abdominal symptoms. We report 4 cases of small intestinal ischemia secondary to superior mesenteric vein thrombosis. Three were due to hypercoagulable states (protein-S deficiency, factor-VII abnormalities) and one was idiopathic. In recent years, the development of modern imaging techniques (particularly ultrasonography, duplex scanning, and computed tomography) have enabled early recognition of this disease. Anticoagulation is therapeutic acutely unless there are signs of peritonitis which necessitate surgical resection of the infarcted bowel.

Benign cartilaginous tumor (chondroma) of the liver.

A 44-year-old woman with a large benign cartilaginous tumor (chondroma) of the liver is presented. After being followed up by computed tomography for 6 years and with imagining evidence for a recent increase in its size, this asymptomatic tumor was successfully removed at surgery. The resected tumor proved to be chondroma, a benign cartilaginous tumor. A review of the literature showed no previous reports of this type of hepatic neoplasm.

Ursodeoxycholic acid treatment of refractory chronic graft-versus-host disease of the liver.

OBJECTIVE: To determine the safety and efficacy of ursodeoxycholic acid treatment in patients with chronic graft-versus-host disease (GVHD) of the liver. DESIGN: Open-label study in which each patient served as his or her own control. SETTING: Private practice and a university bone marrow transplant center. PATIENTS: Twelve patients with refractory chronic GVHD of the liver were studied after allogeneic bone marrow transplantation. INTERVENTIONS: After baseline data collection, patients were given ursodeoxycholic acid (UDCA, 10 to 15 mg/kg body weight per day) for 6 weeks. After discontinuation of the drug, patients were followed for an additional 6 weeks. Doses of immunosuppressive drugs were unchanged for these 12 weeks. MEASUREMENTS: Signs, symptoms, Karnofsky performance scores, hematocrit, total leukocyte count, absolute neutrophil count, platelet count, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyltransferase (GGT), total serum bilirubin, prothrombin time, serum creatinine, and blood urea nitrogen were assessed. RESULTS: Serum tests of cholestatic liver injury measured at 2, 4, and 6 weeks showed improvement compared with baseline. At 6 weeks, the percent decrease from baseline in total serum bilirubin was 33% (P less than 0.005); in alkaline phosphatase the decrease was 32% (P less than 0.038); and in AST the decrease was 37% (P less than 0.007). After discontinuation of UDCA therapy, 11 patients were followed for 6 additional weeks. All showed significant worsening in liver function test results. Symptom scores were unchanged throughout the study. One patient with pruritus improved while receiving therapy with UDCA. No adverse effects were observed. CONCLUSION: Therapy with UDCA was safe, well-tolerated, and efficacious in the short-term treatment of refractory chronic GVHD of the liver. Further investigation is needed to evaluate the long-term effects of UDCA therapy.

Serum hepatic biochemical activity in two populations of workers exposed to styrene.

OBJECTIVE: To determine whether hepatic biochemical changes, as measured by routinely available tests indicative of hepatocellular necrosis, cholestasis, or altered hepatic clearance of bilirubin, occur in association with low to moderate exposure to styrene commonly experienced in industrial production. METHODS: Two independent cross sectional studies were performed comparing serum hepatic transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), cholestatic enzymes (alkaline phosphatase (AP) and gamma glutamyl transpeptidase (GGT)), and bilirubin in (a) 47 workers of fibreglass reinforced plastics who were exposed to styrene and (b) 21 boat and tank fabricators, with separate referent groups of unexposed workers. Exposure to styrene was assessed in air by dosimetry, and in venous blood by headspace analysis. Hepatic biochemical variables were assessed across strata of exposure to styrene defined as 25 ppm in air, or 0.275 mg/l in blood, adjusting for age, sex, body mass index, and ethanol consumption. RESULTS: A consistent and significant linear trend for increasing direct bilirubin and direct/total bilirubin ratio was found in association with increasing exposure to styrene, by both air and blood monitoring, in both studies. Mean direct bilirubin concentrations increased from 0.05-0.08 mg% in referents to 0.12-0.19 in workers exposed above 25 ppm, with a significant exposure-response trend (p<0.005). Significantly increased direct/total bilirubin ratios, ranging from 0.22 to 0.35 were associated with exposure to styrene (p<0.001), indicating diminished hepatic clearance of conjugated bilirubin. Also, a significant linear association between the hepatic transaminases ALT and AST and exposure to styrene was found in pooled regression analyses, with an increase in AP of about 10 IU/ml in workers exposed above 25 ppm air or 0.275 mg/l blood styrene in pooled analyses from both studies. CONCLUSIONS: The consistent finding of increased direct bilirubin and AP concentrations in these two independent studies provides evidence for diminished hepatic clearance of conjugated bilirubin with associated cholestasis in workers exposed to styrene. The finding of a significant linear association between hepatic transaminase concentrations and exposure to styrene in pooled analyses is consistent with mild hepatic injury and associated metabolic dysfunction.