A prospective trial of colchicine for primary biliary cirrhosis.

We entered 60 patients with primary biliary cirrhosis in a double-blind randomized controlled trial to determine whether colchicine is therapeutically effective. Thirty patients had early disease (Stages 1 and 2), and 30 had advanced disease (Stages 3 and 4). Fifteen patients with early disease and 15 with advanced disease received colchicine (0.6 mg twice daily), and the remainder received placebo. Patients were studied about every two months; those remaining in the blind phase at two years underwent repeat liver biopsy and were then placed on open-label colchicine (0.6 mg twice daily). With a few exceptions, the results in patients with early disease were similar to those in patients with advanced disease; hence, data on patients in all stages were combined in the main analysis. During the two-year study period the colchicine-treated patients, as compared with the placebo-treated patients, had improvement in levels of serum albumin, serum bilirubin, alkaline phosphatase, cholesterol, and aminotransferases. However, there was no such improvement in the severity of symptoms or physical findings; moreover, there was no significant difference in the histologic changes noted at liver biopsy in the two treatment groups. At four years after entry, the cumulative mortality from liver disease was 21 percent in patients given colchicine and 47 percent in those given placebo (P = 0.05). The only side effect of colchicine was diarrhea, noted in three patients. The consistent and significant improvement in a number of markers of liver disease and the apparent decreased mortality from liver disease suggest that colchicine may provide some long-term clinical benefit in patients with primary biliary cirrhosis. However, the failure of colchicine to reduce hepatic inflammation and fibrosis leaves uncertain the effect of the drug on the longterm outcome of this disease.

Increased incidence of hypothyroidism in primary biliary cirrhosis.

We examined the thyroid status of 58 patients with primary biliary cirrhosis (PBC) using total serum thyroxin, thyroid hormone binding ratio, free thyroxin index, serum TSH, antithyroglobulin, and antimicrosomal antibodies. Seven patients were known to be hypothyroid prior to the diagnosis of PBC. Six additional patients were found to have biochemical evidence of hypothyroidism. The prevalence of hypothyroidism was 12% if we include only those six PBC patients with newly diagnosed hypothyroidism or 22% if we include all 13 patients. Five of the 58 patients had evidence for an elevation of thyroid hormone binding capacity. Three hypothyroid patients had normal total thyroxins with low thyroid hormone binding ratios. Two euthyroid patients had elevated total T4s with low thyroid hormone binding ratio and normal FTI. The prevalence of positive antimicrosomal antibodies was 34%, including 11 euthyroid PBC patients. The prevalence of positive antithyroglobulin antibodies was 20% including five euthyroid patients. There was no association between HLA DR3 or DR5 and the patients with hypothyroidism and/or antithyroid antibodies. Because fatigue, lethargy, and anorexia as well as hypercholesterolemia are common features of both hypothyroidism and PBC, patients with PBC should be screened for evidence of thyroid dysfunction. Thyroid disease may precede the diagnosis of PBC by several years. Therefore, the development of cholestatic liver disease in a patient with known autoimmune thyroiditis should arouse suspicion of PBC.

Increased oxidation of a chemical carcinogen, benzo(a)pyrene, by colon tissue biopsy specimens from patients with ulcerative colitis.

Colonic biopsy specimens from patients with ulcerative colitis and normal subjects were studied for the ability to metabolize an environmental carcinogen, benzo(a)pyrene. Approximately 73% of 30 colonic biopsy specimens from 7 ulcerative colitis patients could metabolize benzo(a)pyrene to oxidized products, with an average production of 11.6 nmol/mg biopsy protein. In contrast, 39% of 23 biopsy specimens from 5 normal persons showed metabolic activity, with an average of 2.79 nmol benzo(a)pyrene metabolites/mg biopsy protein. Thus, benzo(a)pyrene oxidation activity in colonic tissue from colitis patients was, on the average, fourfold greater than that in normal subjects. This elevated metabolic activity appeared to be unrelated to the state of inflammation in the biopsy section. There was a tendency toward increased metabolic activity in the distal colon. Although there is no evidence that benzo(a)pyrene itself is "the colon carcinogen," this chemical belongs to a broad class of environmental carcinogens, the polycyclic aromatic hydrocarbons. Our findings suggest that the colonic mucosa of patients with ulcerative colitis has a greater ability than that of normal subjects to oxidize such chemicals possibly to electrophiles with higher mutagenic potential.

Genetic abnormalities of immunoregulation in primary biliary cirrhosis.

Patients with primary biliary cirrhosis have an abnormality of lymphocyte suppressor cell function that could play a role in the pathogenesis of their disease. To investigate this possibility, suppressor cell function in patients with primary biliary cirrhosis, in their healthy first-degree relatives, in unrelated household contacts, in patients with other types of cirrhosis, and in normal control subjects was studied. The method used is based on the finding that the in vitro addition of concanavalin A to pokeweed mitogen-stimulated lymphocytes activates suppressor cells, which in turn inhibit immunoglobulin synthesis. Thirteen of 16 patients with primary biliary cirrhosis and six of 23 healthy relatives had significant impairment of IgG suppression. All six of these relatives were female. No abnormal suppression was found in unrelated household contacts of patients with primary biliary cirrhosis, in patients with other types of cirrhosis, or in healthy control subjects. There was no correlation between results of the IgG suppressor cell assay and the disease activity in patients with primary biliary cirrhosis. These data suggest that the abnormal suppressor cell function is not a direct cause of primary biliary cirrhosis; however, it may be a genetic marker for susceptibility to this disease.

Portasystemic shunts in primary biliary cirrhosis: survival is the same as in patients with Laennec's cirrhosis and postnecrotic cirrhosis.

There is little information regarding survival of patients with primary biliary cirrhosis (PBC) who undergo portasystemic shunt operations. The few published reports suggest that survival may be better in this group than in patients with other types of cirrhosis who undergo this procedure. Therefore, we reviewed our experience with 17 patients with PBC who underwent portasystemic shunts and compared their survival with 100 patients with Laennec's and postnecrotic cirrhosis, using the life-table method. We find that survival rates are the same in patients with PBC, Laennec's cirrhosis, and postnecrotic cirrhosis following portasystemic anastomosis.