P.J. Scheuer

Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology.

Twenty-nine patients with primary sclerosing cholangitis were reviewed. Males predominated (2:1). Seventy-six per cent presented with cholestasis and cholangitis, 17% with cirrhosis and portal hypertension, and 7% were asymptomatic, presenting with a raised serum alkaline phosphatase. The serum immunoglobulin IgM concentration was raised in 45% of the patients, but no patient had serum mitochondrial antibody present. Seventy-two per cent had ulcerative proctocolitis. There was no relationship between either duration or severity of ulcerative proctocolitis and the development of primary sclerosing cholangitis. Four patients were not benefited by colectomy. None of the patients ahd Crohns disease. The prognosis was variable. Corticosteriods and azathioprine were ineffective. Eleven patients (38%) had died with a mean survival time of seven years from diagnosis. Three patients with ulcerative proctocolitis developed bile duct carcinoma. The cholangiograms and liver biopsies were reported without reference to clinical information together with 41 patients with other biliary diseases. Cholangiography was diagnostic in 18/22 (82%). Hepatic histology was diagnostic in 8/22 (36%). Ten showed features of large bile duct disease and three were misdiagnosed as primary biliary cirrhosis. Reduced numbers of bile ducts, ductular proliferation, portal inflammation, and substantial copper deposition, in combination with piecemeal necrosis, are commonly seen in primary sclerosing cholangitis and indicate the need for cholangiography.

The Presentation and Diagnosis of 100 Patients with Primary Biliary Cirrhosis

PRIMARY biliary cirrhosis1 , 2 (chronic nonsuppurative destructive cholangitis)3 was formerly diagnosed only in its late, icteric stage. One or more laparotomies had usually been performed to exclu...

CHRONIC LIVER DISEASE AND PRIMARY LIVER-CELL CANCER WITH HEPATITIS-ASSOCIATED (AUSTRALIA) ANTIGEN IN SERUM

Abstract Seventeen patients, all males, are Summary described with chronic liver disease and a positive serological test for hepatitis-associated (H.A.) Australia antigen. Two came from the U.K., eight from Greece, three from North or South America, one from Belgium, one from Italy, and two from Africa. Seven presented during follow-up of a severe attack of virus hepatitis. All had received corticosteroid therapy. The other ten had no past history of the acute disease. Liver biopsy was done in sixteen patients. One patient showed only evidence of a recent viral hepatitis, and four showed persistent hepatitis or inactive post-necrotic scarring. These five patients are symptom-free and the prognosis is considered good. Six patients showed histological features of chronic aggressive hepatitis and in four there was also cirrhosis. They differed from classic active chronic (lupoid) hepatitis in being males of an older age-group. Serum bilirubin, aspartate transaminase, and globulin levels tended to be lower. The smooth-muscle antibody was absent from the serum or present only in low titre. Hepatic histological differences were not absolute although three of the H.A. group showed evidence of a recent acute hepatitis. Five patients had primary liver cancer, and in four of these, underlying cirrhosis was demonstrated. Serum-α-fetoprotein was present in two of these five patients. These observations suggest, but do not prove, that acute hepatitis with positive H.A. antigen may be followed by chronic liver disease and cirrhosis and that this can proceed to liver-cell cancer.

Hepatobiliary fibropolycystic diseases: a clinical and histological review of 51 patients

The clinical, radiological and hepatic histological features of 51 patients with hepatobiliary fibropolycystic disease were reviewed. Many of the patients had more than one of the diseases; the combination of both congenital hepatic fibrosis (CHF) and Carolis disease was most striking. Twelve patients with CHF (50% male) presented at 6 +/- 2 years of age (mean +/- SEM) with hepatosplenomegaly or variceal bleeding. Their main problems were recurrent variceal bleeds and renal disease. Polycystic kidneys and renal stones were present in 79% and chronic renal failure in 30%. Six of the 8 patients with Carolis disease were male (75%) and presented later (aged 37 +/- 8 years) with hepatomegaly or cholangitis. Recurrent cholangitis developed in most (7/8) and 2 had polycystic kidneys. Twelve patients had a combination of CHF and Carolis disease presenting with hepatosplenomegaly, bleeding or cholangitis. As in Carolis disease, most (83%) were male, but the age of presentation (15 +/- 4 years), and the incidence of polycystic kidneys (42%) and renal failure (8%) was intermediate between CHF and Carolis disease. In these patients, bleeds always predated cholangitis. Histologically, acute cholangitis was superimposed on the changes of CHF. Adult polycystic liver disease (10 patients) presented later (43 +/- 3 years) in females (90%) with pain, a mass or incidentally; polycystic kidneys were present in 33%. Microhamartomas (10 patients), which were usually incidental findings, were diagnosed latest (50 +/- 6 years). Three choledochal cysts were seen. The hazard of cancer in these diseases was reflected by 2 bile duct cancers and 1 pancreatic cancer (incidence 6%). This study has confirmed that hepatobiliary fibropolycystic diseases form part of a family and are often associated together. However, the diseases are of greatly differing severity and the prognosis in an individual patient is determined by the fibropolycystic diseases present.

Studies in alcoholic liver disease in Britain. I. Clinical and pathological patterns related to natural history.

A group of 258 patients with various forms of alcoholic liver disease—steatosis, mild and severe hepatitis, and cirrhosis—has been studied. Severity of disease as judged histologically did not correlate very well with clinical presentation although signs of hepatocellular failure were certainly commoner in severe hepatitis and cirrhosis. Fever, pigmentation, and clubbing were also pointers to these two conditions. Alcoholic hepatitis is probably precirrhotic and carries a poor prognosis and the best laboratory indicators of this are moderate elevation of white cell count and bilirubin. Prognosis in alcoholic liver disease is significantly improved by abstinence from alcohol.

Presentation and Course of Asymptomatic Primary Biliary Cirrhosis

Twenty patients without symptoms of hepatobiliary disease were diagnosed as having asymptomatic primary biliary cirrhosis. In every patient liver histology was diagnostic of, suggestive of, or compatible with the diagnosis. Eighteen had a positive serum mitochondrial antibody, 18 had raised serum immunoglobulin M, and 17 had markedly raised serum alkaline phosphatase values. A mean of 4.5 years after diagnosis, 10 of the patients had not developed hepatobiliary symtoms; 4 of these 10 patients have survived 6 to 10 years. Ten patients developed symptoms after a mean of 2.2 years from initial diagnosis; 7 are still alive but 3 have died of liver failure. The development of symptoms could not be predicted by either serum biochemical tests or hepatic histology. It is concluded that the diagnosis of asymptomatic primary biliary cirrhosis is compatible with 10 or more asymptomatic years.

NATURAL HISTORY OF HEPATITIS-ASSOCIATED ANTIGEN-POSITIVE CHRONIC LIVER DISEASE

Abstract A clinical and pathological study of 59 patients with hepatitis-associated antigen (H.A.A.)-positive chronic liver disease is reported. 55 patients were male. 56 were referred from outside the United Kingdom. The predominant age range at the onset of symptoms or diagnosis was thirty to fifty years. 12 of the patients were doctors. Liver biopsy demonstrated the changes of chronic persistent (9), lobular (1), or aggressive (24) hepatitis, cirrhosis (19), or primary liver-cell carcinoma (6). In 30 patients chronic disease followed clear evidence of unresolved acute hepatitis. In 29 the condition presented as established chronic liver disease or as primary liver-cell carcinoma. Clinical evaluation and liver-function tests in the different groups of patients reflected the severity of the underlying hepatic lesion. The serum bilirubin, aspartate transaminase, and γ-globulin levels were rarely very high. Corticosteroids had often been used during the attack of acute hepatitis, and this seemed to predispose to relapses and chronicity. After chronic liver disease was established corticosteroid therapy produced clinical and biochemical improvement. The progression of H.A.A.-positive liver disease was slow, and, of 33 without primary liver-cell carcinoma who had been followed for an average of two years, only 5, all with established cirrhosis, showed evidence of clinical or biochemical deterioration. 3 of these patients died—2 with primary liver-cell carcinoma and 1 with hepatocellular failure.

Is mitochondrial antibody diagnostic of primary biliary cirrhosis

In a series of 218 patients diagnosed as having primary biliary cirrhosis only nine exhibited a negative serum mitochondrial antibody. On examining additional specimens from these patients, seven were found to be positive, giving a final incidence of greater than 99%. The two patients whose sera remained negative for the mitochondrial antibody had liver histology compatible with the diagnosis of primary biliary cirrhosis, but a firm diagnosis could not be reached. Three additional mitochondrial antibody positive subjects who were asymptomatic and exhibited normal serum alkaline phosphatase were shown on liver biopsy to have stage I primary biliary cirrhosis. The presence of a positive serum mitochondrial antibody in a patient with or without abnormalities in liver function tests strongly suggests the diagnosis of primary biliary cirrhosis.

Impaired delayed hypersensitivity in primary biliary cirrhosis.

Abstract Primary biliary cirrhosis is a granulomatous disease. Intrahepatic granulomas were found in 29 out of 69 patients, and in 5 of these patients granulomas were found in lymph-nodes from various sites. This indicates that the granulomatous response can be widespread. Skin testing revealed a high incidence of Mantoux negatives in primary biliary cirrhosis compared with controls. Delayed hypersensitivity could be induced with dinitrochlorobenzene in only 46% of patients compared with 94% of controls. Most patients had impaired in-vitro lymphocyte transformation in response to phytohaemagglutinin. These findings indicate that in primary biliary cirrhosis there may be impairment of the normal mechanisms of delayed hypersensitivity. It is suggested that this is a result of the disease process rather than an aetiological factor.

D-PENICILLAMINE TREATMENT IMPROVES SURVIVAL IN PRIMARY BILIARY CIRRHOSIS

The copper-chelating, immunological, and antifibrotic effects of D-penicillamine indicated that it might be suitable for the treatment of primary biliary cirrhosis (PBC). In a randomised clinical trail, 55 PBC patients received penicillamine (600 mg daily), and 32 received a placebo. Drug reactions developed in 16 patients on penicillamine. All deaths occurred in patients with stage 3 or 4 (late stage) liver histology on entry to the study. 5 (14%) of 37 penicillamine-treated patients and 10 (43%) of 23 placebo patients have died (p less than 0.01). Improvement in survival only became evident after 18 months. Survivors in the penicillamine group demonstrated a significant fall in serum aspartate transaminase, serum immunoglobulins, and liver copper concentrations. On follow-up liver biopsy 12-72 months (median 33) after joining the study, 21% of penicillamine-treated patients had less pronounced inflammation and piecemeal necrosis, whereas there had been no improvement in patients on placebo (p less than 0.02). Penicillamine did not retard the histological evolution of the liver disease from the early prefibrotic stages to the late fibrotic or cirrhotic stages. Both the copper-chelating and immunological effects of penicillamine are probably important in improving survival. The excellent prognosis of patients with PBC in its early histological stages, and the failure of penicillamine to prevent histological progression from early to late stages, suggests that penicillamine treatment should not be given to patients with PBC in the early (stage 1 or 2) histological phase of the disease. Penicillamine treatment is recommended in patients once liver biopsy has demonstrated histological results typical of late stage 3 or 4 PBC.