Mesalamine capsules for the treatment of active Crohn's disease: results of a 16-week trial. Pentasa Crohn's Disease Study Group.

BACKGROUND: Mesalamine is released from sulfasalazine in the colon and benefits colonic Crohn's disease. The mesalamine used in this study releases the drug throughout the small bowel and colon. Therefore, this study was designed to detect benefit for Crohn's disease involving the small bowel alone or both the colon and small bowel. METHODS: This double-blind, randomized, multicenter prospective controlled trial compared placebo and three daily doses of mesalamine in 310 patients. The primary outcome criterion was change in the Crohn's Disease Activity Index (CDAI) from baseline to final study visit. RESULTS: Patients taking 4 g/day mesalamine experienced a decrease of 72 CDAI points compared with 21 points in the placebo group (P < 0.01). Remission occurred in 43% of the 4-g group and 18% of the placebo group. Patients with ileum-only disease showed a 93-point improvement on 4 g mesalamine, compared with a 2-point improvement in similar patients on placebo. Mesalamine in this trial was not associated with clinically significant toxicity. CONCLUSIONS: This controlled-release mesalamine preparation is safe and effective at 4 g/day as a single agent in treatment of active Crohn's disease of the ileum and colon.

Prevalence of non-A,non-B hepatitis/hepatitis C virus antibody in human immunoglobulins.

Human intravenous immunoglobulins prepared by the cold ethanol fractionation technique of Cohn are considered safe with respect to infectivity. However, there have been several instances of transmission of both hepatitis B and non-A,non-B hepatitis viruses after administration of intravenous immunoglobulins. To determine the prevalence of hepatitis C virus antibody in intravenous immunoglobulins and protein preparations, 30 commercially available products were tested. Using the Abbott enzyme immunoassay for hepatitis C virus antibody, 27 of 30 (90%) immunoglobulins tested positive. The Ortho immunoassay showed that 28 of 30 (93%) were positive, with one discordant result between the Ortho and Abbott assays. An antigen-blocking or neutralization test (Abbott) confirmed the results of the Ortho assay. Bovine, sheep, goat, and horse sera also were tested before and after isolation of animal immunoglobulins. All results on the animal sera were negative, indicating that the fractionation process did not produce false-positive results. The high prevalence rate of hepatitis C virus antibody in intravenous immunoglobulins has important implications for follow-up of recipients, selection of serum donors, and implementation of anti-hepatitis C virus testing.

Prevalence of non-A, non-B hepatitis/hepatitis C virus antibody in laboratory quality-assurance sera.

Quality-assurance sera (QAS) are prepared from pooled sera composed of thousands of individual donations. Previous studies documented that a substantial percentage of individual QAS test positive for viral disease markers, including antibodies to human immunodeficiency virus and to hepatitis B surface antigen. We tested 239 QAS from various proficiency programs and commercial sources to determine the prevalence of hepatitis C virus (HCV) antibody. We tested samples for anti-HCV by using an enzyme immunoassay (EIA; Abbott Labs.) and an enzyme-linked immunosorbent assay (ELISA; Ortho Diagnostics). We observed an overall positive rate of 49% by one or both assays in all categories of sera tested. In addition, we found a greater rate of positivity (58%) in proficiency program samples than in commercial samples (43%). We found discrepant results between the two assays for 15 of 239 samples (6%). In the discrepant samples, the EIA result was positive, whereas the ELISA result was negative. Anti-HCV positivity in QAS has important implications for laboratory personnel handling these samples.

An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis.

A specific assay has been developed for a blood-borne non-A, non-B hepatitis (NANBH) virus in which a polypeptide synthesized in recombinant yeast clones of the hepatitis C virus (HCV) is used to capture circulating viral antibodies. HCV antibodies were detected in six of seven human sera that were shown previously to transmit NANBH to chimpanzees. Assays of ten blood transfusions in the United States that resulted in chronic NANBH revealed that there was at least one positive blood donor in nine of these cases and that all ten recipients seroconverted during their illnesses. About 80 percent of chronic, post-transfusion NANBH (PT-NANBH) patients from Italy and Japan had circulating HCV antibody; a much lower frequency (15 percent) was observed in acute, resolving infections. In addition, 58 percent of NANBH patients from the United States with no identifiable source of parenteral exposure to the virus were also positive for HCV antibody. These data indicate that HCV is a major cause of NANBH throughout the world.

Histological response and antigen transmission in the lymph nodes of athymic nu/nu mice inoculated with Crohn's disease tissue filtrates.

Lymph node histology and antigen transmission in the nu/nu mouse in response to animal inoculation with Crohn's disease tissue filtrates were re-evaluated. We found that a hyperplastic lymph node response in nu/nu mice occurred with Crohn's disease (CD), ulcerative colitis (UC), or other intestinal disease (OID) tissue inoculations. In addition, antigen transmission to lymph nodes as detected by indirect immunofluorescence using CD sera was observed in all inoculation groups. The immunofluorescent reaction also occurred independently of lymph node histology. Thus, we confirm that CD sera recognize an antigen(s) expressed in lymph nodes of athymic mice inoculated with CD tissue filtrates. The antibody (or antibodies) in CD sera was not specific for this 'CD antigen or antigens', however, as tested in the nu/nu mouse system, because the CD sera antibodies also recognised antigens in UC inoculated and OID inoculated animals.

Hepatitis B vaccine: low postvaccination immunity in hospital personnel given gluteal injections.

Although other investigators have found excellent response rates to the hepatitis B vaccine, we report here an unusually low rate of seroconversion following hepatitis B vaccination in a group of apparently healthy medical center personnel. Only 67% of these individuals developed adequate postvaccination antibodies to HBsAg, in contrast to 85 to 96% in other studies. A significant decrease in seroconversion with increasing age was noted with a 54% seroconversion rate in vaccines over the age of 40; all of whom had received gluteal injections. Employees at another facility had been given deltoid injections from the same vaccine lot and had an overall seroconversion rate of 90%. Subsequently, nonresponders from the first group were revaccinated. Seven of the ten individuals tested developed anti-HBs. We believe the relatively low rate of seroconversion in individuals above the age of 40 may have been related to gluteal injection of the hepatitis B vaccine, and further investigation is warranted.

Non-A, non-B posttransfusion hepatitis--a decade later.

We have followed up 69 patients who developed non-A, non-B posttransfusion hepatitis in 1972-1978. Chronic hepatitis, defined by biochemical criteria, was observed in 46 patients (67%), the majority of whom subsequently failed to resolve the abnormalities. Chronic hepatitis was a sequela of non-A, non-B posttransfusion hepatitis less often after the blood bank changed to a policy of all volunteer donors. (However, this association may be explained by other coexistent factors.) The alanine aminotransferase level was more likely to be abnormal than the aspartate aminotransferase level during the chronic phase of non-A, non-B posttransfusion hepatitis. By actuarial means it was calculated that the probability of developing normal enzymes after 6-10 yr was 0.47. However, in spite of this high incidence of biochemical disease, virtually all of the patients have remained asymptomatic. Histologic evidence of cirrhosis has been obtained in 4 of these patients, but in only 2 patients at most has clinical evidence of hepatic failure supervened.

Clinical and pathologic findings of the liver in the acquired immune deficiency syndrome (AIDS).

Clinical data and histologic sections of the liver, including immunohistochemical studies for hepatitis B surface and core antigens, were reviewed in 42 autopsy cases of the acquired immune deficiency syndrome (AIDS). Hepatomegaly, elevation of serum transaminases, and mild elevation of alkaline phosphatase were commonly observed clinical and biochemical abnormalities. Mildly elevated alkaline phosphatase and normal bilirubin levels were present in patients with Mycobacterium avium-intracellulare (MAI) infection, cytomegalovirus (CMV) infection, and Kaposi's sarcoma (KS). Histologic sections demonstrated liver involvement by MAI in eight cases; KS in six cases; cryptococcus in three cases; and CMV in two cases. One case of MAI infection was associated with marked central vein sclerosis, a finding previously unreported. Thirty-two (76%) of 42 cases had serologic or pathologic evidence of hepatitis exposure. Two patients had histologic evidence of chronic active hepatitis. The pathologic processes involving the liver appeared to be secondary to the infections and neoplasms for which this population is susceptible and did not significantly contribute to morbidity or mortality. No findings specific or pathognomic for AIDS were identified in the liver.

A histologic comparison of hepatitis B with non-A, non-B chronic active hepatitis.

The histopathologic aspects of 62 cases of chronic active hepatitis (CAH) were examined to compare hepatitis B surface antigen (HBsAg)-positive with HBsAg-negative (non-A, non-B) cases. Epidemiologically, the two groups were distinct. Homosexuals and young, male users of intravenous drugs accounted for most of the cases of hepatitis B CAH, whereas older men and women with a history of blood transfusions represented a large percentage of the HBsAg-negative cases. However, there were no pathologic differences between the two diseases, in severity of inflammatory activity, degree of architectural damage, appearance of the bile ducts, or prevalence of cirrhosis. In a population of hospitalized patients, these two diseases cannot be distinguished microscopically unless hepatocytes that contain HBsAg are demonstrated. Although our current understanding of non-A, non-B CAH is limited, the disease not necessarily remit spontaneously, and progression to cirrhosis can be expected in some cases.

Chronic active hepatitis of hepatitis B and non-A, non-B etiology.

Sixty-six consecutive liver biopsies demonstrating chronic hepatitis (CAH) were stained for the presence of HBsAg using the three-step peroxidaseantiperoxidase technique. Only cases of CAH thought to be attributable to either hepatitis B or non-A, non-B hepatitis were included in this series. Twenty-three of 30 biopsies taken from 24 patients with HBsAg-positive serum stained positively. None of the HBsAg sero-negative cases stained postively. Hepatocytes staining positively for HBsAg were generally few in number and randomly distributed within the liver lobules. Three cases of membranous staining were noted. After grading both the degree of inflammatory activity and the amount of HBsAg staining, we found that a statistically significant inverse relationship exists. The biopsies of six of the GBsAg sero-positive patients who had received steroid therapy for their liver disease did not stain differently from the biopsies of the remaining 18 HGsAg sero-positive patients. Stains for HBsAg may help in distinguishing acute hepatitis B (HB) superimposed on preexisting liver disease from hepatitis B-CAH (CAHB). This distinction may be possible because tissue staining almost always is negative in acute HB, whereas it often is focally positive in CAHB. This application of immunoperoxidase may be especially useful in patients who are drug addicts.

Clinical value of serum bile acid levels in chronic hepatitis.

A prospective study was undertaken to determine if individual serum bile acid (SBA) levels are clinically useful in differentiating patients with asymptomatic chronic active hepatitis (CAH) from patients with chronic persistent hepatitis (CPH). Fasting and postprandial SBA levels were obtained from 16 patients with CAH, 12 with CPH, and 18 control subjects. Levels of cholylglycine (CG) and total cholic acid conjugates (CCA) were determined by radioimmunoassay. Alanine aminotransferase (ALT) levels were also obtained from each subject. There were no significant differences in the mean fasting and 3-hr postprandial CG or CCA levels between the CPH group and the control subjects. The mean fasting and 3-hr CG and CCA levels were significantly higher for the CAH group than the CPH group (P less than 0.05 for each comparison). A combination of the 3-hr postprandial CG and CCA levels with the ALT levels resulted in a better separation of the two groups. All patients with CAH had either a 3-hr CCA level of 200 micrograms/dl, a 3-hr CG level of 170 microgram/dl, or an ALT level of 120 IU/liter. Using these values, only patients with CPH were misclassified as having CAH, and no control subject reached any of these levels. Although the differences obtained were statistically significant, the separation based on a combination of CG, CCA, or ALT levels may have been fortuitous. Nevertheless, these data suggest that postprandial serum bile acid levels may have clinical utility in identifying patients with asymptomatic chronic hepatitis who are likely to have CAH.

The long-term course of non-A, non-B post-transfusion hepatitis.

Patients with non-A, non-B post-transfusion hepatitis were followed from the onset of their disease until their blood tests normalized, until they died, or until the present time. Of 66 patients, 30 had a spontaneous resolution of their biochemical disease. Ten patients died or were begun on immunosuppressive therapy with transaminases still abnormal. The remaining 26 patients had abnormal transaminase levels when last seen. By actuarial analysis, only 54% of hepatitis patients are predicted to develop s spontaneous biochemical remission within 3 yr. No further resolutions have occurred after that time, Icteric and anicteric acute disease may be equally likely to progress to chronic disease. Initial and follow-up liver biopsy specimens have revealed both chronic persistent and chronic active hepatitis. Two patients showed histologic evidence of cirrhosis, and a third developed a hepatic coagulopathy and sphenomegaly. No other patient to date, however, has veveloped overt evidence of hepatocellular failure or portal hypertension. Thus, non-A, non-B post-transfusion hepatitis frequently results in biochemical evidence of chronic liver disease, and in a few patients cirrhosis may develop slowly and in a clinically inapparent fashion.

Chronic active hepatitis. Who meets treatment criteria?

In order to ascertain the proportion of patients with biopsy-proven chronic active hepatitis who meet currently accepted criteria for immunosuppressive treatment, an analysis of 86 patients seen between 1973 and 1978 carrying this diagnosis was undertaken. Only 66 could be confirmed to have this lesion on blind histologic review. Nine of these 66 were on concomitant immunosuppressive therapy, four had inadequate documentation of chronicity, five consumed more than two ounces of alcohol daily, five had concurrent malignancy, two were prepubertal, and one had oxyphenisatin-induced disease. None of the remaining 40 patients met the biochemical criteria for disease activity. The disease was predominantly seen in asymptomatic middle-aged males and was of viral etiology. A small subgroup of elderly female patients was also identified whose disease was apparently nonviral. In conclusion, the vast majority of chronic active hepatitis seen at a large university center occurs in individuals for whom treatment guidelines have not been established.

HBe-Antigen in the course and prognosis of hepatitis B infection: a prospective study.

The prognostic significance of the HBe-antigen (HBeAg) in the course and outcome of type B hepatitis was studied prospectively in 71 susceptible oncology patients. The patients had been exposed to tumor cell vaccines inadvertently contaminated with hepatitis B surface antigen (HBsAg)-containing plasma. Forty-five patients (63%) were infected. These 45 showed three types of acute seroresponse: HBsAg and HBeAg, 28 patients (62%); HBsAg alone, 8 patients (18%); and a primary antibody to HBsAg (anti-HBs) response, 9 patients (20%). There was no significant difference in acute course and outcome between the two HBs-antigenemic groups. All primary anti-HBs responders had asymptomatic infections. Seventeen patients receiving chemotherapy during the period of hepatitis B exposure were significantly more prone to symptomatic infection with acute HBs-antigenemia, and 2 of these patients developed chronic active hepatitis. The HBeAg is common early in acute hepatitis B among solid tumor patients and at this stage in disease has no prognostic significance independent of HBsAg.