E. R. Dickson

Trial of Penicillamine in Advanced Primary Biliary Cirrhosis

A total of 227 patients with histologically advanced primary biliary cirrhosis entered a double-blind, randomized, controlled trial to determine whether penicillamine (1 g per day) was therapeutically effective; 111 patients received the drug, and 116 received placebo. The two groups were highly comparable at entry with regard to clinical, biochemical, and histologic features. Penicillamine therapy did not result in an overall improvement in survival as compared with placebo. Clinical symptoms and serial hepatic laboratory values reflected the progressive nature of the disease and were similar in both groups. There were no substantial differences between treatment groups in the morphologic features of sequential biopsy specimens. The development of major side effects led to permanent discontinuation of penicillamine in 22 per cent of the patients taking the drug. We conclude that penicillamine is not useful for patients with histologically advanced primary biliary cirrhosis. The trial is being continued in patients with early histologic disease whose better prognosis necessitates longer follow-up.

Diagnosis of Wilson's Disease Presenting as Fulminant Hepatic Failure

The clinical course, results of standard laboratory tests, parameters of copper metabolism, and hepatic morphology in 9 cases (3 of our own and 6 from the literature) of Wilsons disease presenting as fulminant hepatic failure were compared with the findings in 5 cases of idiopathic fulminant hepatic failure. Patients with Wilsons disease were usually younger, and 7 of the 9 patients had Kayser-Fleischer rings. Patients with idiopathic fulminant hepatic failure had elevated 24-h urinary copper, decreased ceruloplasmin, and low or normal serum copper. Fulminant hepatic failure with Wilsons disease differed from idiopathic fulminant hepatic failure by the following biochemical findings: (a) higher copper levels in serum, urine and liver; (b) less pronounced elevations of transaminase levels; (c) higher concentrations of total bilirubin; and (d) lower hemoglobin values. Serum copper was the most useful biochemical test in diagnosing Wilsons disease before death. At autopsy, only hepatic copper concentrations clearly separated the two groups. Serial serum copper levels (antemortem) and quantitative analysis of hepatic copper (after recovery or postmortem) in patients with fulminant hepatic failure should help to exclude Wilsons disease.

Immunohistochemical Characterization of Hepatic Lymphocytes in Primary Biliary Cirrhosis in Comparison With Primary Sclerosing Cholangitis and Autoimmune Chronic Active Hepatitis

We analyzed the immunophenotypes of hepatic cellular infiltrates by quantitative immunohistochemical methods in biopsy specimens from 20 patients with primary biliary cirrhosis (PBC), 19 with primary sclerosing cholangitis, and 11 with autoimmune chronic active hepatitis. Specifically, we sought to identify activated T cells, interferon-gamma-producing cells, and natural killer cells. The portal cellular infiltrate in PBC contained a preponderance of CD4 cells in comparison with CD8 cells, with a CD4/CD8 ratio of 2.45:1. The cellular infiltrate in areas of piecemeal necrosis contained mostly CD8 cells. Infiltrating CD8 cells in PBC had the surface phenotype of cytotoxic (CD8-positive, CD11b-negative) cells. Approximately 4% of T cells expressed interleukin 2 receptors. Interferon-gamma-staining cells were rarely identified (in less than 2%). Cells that expressed the natural killer cell markers CD16, CD56, or CD57 were infrequent, constituting approximately 5% of the cellular infiltrate. The composition of the infiltrates was similar in patients with PBC and chronic active hepatitis. Natural killer cells were twice as common in patients with primary sclerosing cholangitis (P < 0.05) as in those with PBC. The inflammatory infiltrates in areas of piecemeal necrosis were similar in the three diseases and differed from those found within the portal area, in that CD8 cells were preponderant. In all three liver diseases, almost 90% of bile ducts expressed class II HLA antigens. These findings support the hypothesis that cytotoxic T cells of either the CD4 or CD8 immunophenotype but not natural killer cells may be involved in the pathogenesis of PBC and chronic active hepatitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterisation of patients with a complete biochemical response to ursodeoxycholic acid.

Ursodeoxycholic acid (UDCA) leads to biochemical and clinical improvement in many patients with primary biliary cirrhosis (PBC); although, the response is variable. This study compared UDCA treated patients with complete normalisation of biochemical functions to those without such improvement. Of the 65 patients receiving UDCA, 12 (19%) showed normalisation of liver biochemical functions at two years. The remaining 53 patients showed a less complete response. Mean (SD) alkaline phosphatase and total serum bilirubin values were significantly lower at entry in the patients whose liver biochemistry tests normalised (912 (732) U/l v 1417 (1021) U/l, p = 0.003, and 0.7 (12.1 (5.2) mumol/l v 38.9 (48.5) mumol/l, p = 0.0002, respectively), and percentage of UDCA in biliary bile acid was higher (56.3 (9.5)% v 38.3 (21.1)%, p = 0.03). Patients with biochemically and histologically less severe disease, and greater enrichment of biliary bile with UDCA, are more likely to respond favourably to the drug. The main objective of continued study will be to find out if normal liver biochemical functions can retard disease progression. The association of greater UDCA enrichment with complete biochemical responses suggests that higher doses of UDCA should be evaluated.

Relationship between biliary and serum bile acids and response to ursodeoxycholic acid in patients with primary biliary cirrhosis

Objective:Ursodeoxycholic acid (UDCA) improves liver biochemistries and enriches the bile with UDCA in patients with primary biliary cirrhosis. The aim of this study was to determine whether the degree of enrichment of bile correlated with that of serum and whether either of these measures correlated with improvement in measures of liver disease.Methods:In a randomized study, biliary and serum bile acid analyses were performed at entry and after 2 yr of UDCA or placebo.Results:The percentage of ursodeoxycholic acid in bile increased by 42% in the UDCA group (n = 61) compared with 8% in the placebo group (n = 57) (p < 0.0001). Measurement of serum bile acids in 32 patients (18 ursodeoxycholic acid, 14 placebo) indicated that at 2 yr, ursodeoxycholic acid comprised 65% of serum bile acids in the treated group and 7% in the placebo group. Agreement between bile and serum was fair (r= 0.75, p≤ 0.00002) because in some patients, plasma but not biliary bile acids were enriched with UDCA. Changes in biliary ursodeoxycholic acid correlated significantly but weakly with the changes in serum alkaline phosphatase, AST, bilirubin, and in Mayo risk score. Correlations between changes in serum bile acid composition and biochemical measures of disease activity were even weaker.Conclusion:The measurement of biliary bile acids is superior to that of serum bile acids for assessing the compliance and changes in the circulating bile acids in patients receiving ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Furthermore, measures to further increase the proportion of ursodeoxycholic acid in circulating bile acids should be explored.

Autoimmune conditions associated with primary biliary cirrhosis: response to ursodeoxycholic acid therapy.

Objectives:A variety of autoimmune conditions occur in association with primary biliary cirrhosis. Among these conditions are sicca syndrome, Raynauds phenomenon, arthritis, and Hashimotos thyroiditis. Information is sparse regarding the prevalence and natural history of these conditions when associated with primary biliary cirrhosis and their response to ursodeoxycholic acid treatment. We evaluated the prevalence, natural history, and response to ursodeoxycholic acid therapy of these conditions coassociated with primary biliary cirrhosis.Methods:One hundred-eighty patients with primary biliary cirrhosis, enrolled in a prospective randomized controlled trial of ursodeoxycholic acid (13–15 mg/kg/day), were included. Patients were assessed at study entry and annually.Results:At entry, 77/180 patients (43%) had one of the four conditions, and 18/180 patients (10%) had two or more conditions. Sicca syndrome was the most common, occurring in 58/180 patients (32%). After 2 yr, there was no difference between the treatment groups with regard to resolution or spontaneous onset of these autoimmune features. Sicca syndrome was the most common spontaneously developing condition (9% per yr). Sicca syndrome was the most common associated autoimmune condition, present in one-third of our patients. The associated conditions tended to improve over time, with a low rate of spontaneously developing these conditions. Although ursodeoxycholic acid therapy leads to improvement in the underlying liver disease, it did not appear to influence either the development or resolution of these autoimmune features.Conclusions:Although ursodeoxycholic acid is beneficial in the treatment of primary biliary cirrhosis, it had no measurable effect on the autoimmune conditions coassociated with the disease.

Is routine cholangiography useful in men with suspected primary biliary cirrhosis

The aim of this study was to assess the diagnostic value of cholangiography in men with chronic cholestasis and positive antimitochondrial antibody (AMA) titers who were suspected of having primary biliary cirrhosis (PBC). The authors reviewed retrospectively the records of men who had positive AMA titers over a 16-month period to determine the results of cholangiography. They also reviewed the records of 102 patients with primary sclerosing cholangitis (PSC) from 1989 to 1995 who had undergone cholangiography and testing for AMA. Of 35 men with positive tests for serum AMA, 12 of these patients were referred for cholangiography (11 endoscopic and 1 transhepatic). All completed cholangiograms were normal. A diagnosis of PBC was made in nine patients and atypical autoimmune hepatitis in one. Conversely, only two PSC patients had positive AMA titers (1:20 and 1:80). Both of these patients had coexisting inflammatory bowel disease and cholangiograms diagnostic of PSC. Cholangiography was negative in the male patients with positive AMA titers who were suspected of having PBC. In men with cholestatic liver biochemistries and strongly positive AMA titers, especially in the absence of associated inflammatory bowel disease, routine cholangiography does not add to the diagnostic evaluation.