Treatment and prognosis of primary biliary cirrhosis.
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Biomedical subjects
Publications and source records attributed to S Sherlock.
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The incidence of macrocytosis, defined as a mean corpuscular volume (MCV) of greater than 95 fl and large red cells on peripheral blood film, was determined in 303 alcoholics with liver disease (95 females: 208 males), 60 non-alcoholics with chronic liver disease (44 females: 16 males) and 35 control subjects (15 females: 20 males). Macrocytosis was found in 70.3% (213/303) of alcoholics with liver disease and in 23.3% (14/60) of non-alcoholics with liver disease, P less than 0.001. MCV values greater than 100 fl were seen in 49.5% (150/303) of alcoholics, but in only 3.3% (2/60) of non-alcoholics, P less than 0.001. Macrocytosis was more frequent in female, 86.3% (82/95) than in male alcoholics 63.0% (131/208), P less than 0.001. Serum folate values less than 3 microgram/l were found in 14.5% (44/303) of alcoholics and in 11.7% (7/60) of non-alcoholics. Low serum folate values were found in 18.3% (39/213) of alcoholics with macrocytosis and in 35.9% (28/78) of those with macrocytic anaemia. Twenty alcoholics with pre-cirrhotic liver disease were followed over three months. Macrocytosis was present in 85.0% (17/20) at the outset and in 40% (8/20) 3 months later. The changes in MCV were independent of alcohol intake and serum folate values. Macrocytosis is a useful diagnostic indicator of alcoholism. MCV values greater than 100 fl in patients with liver disease almost invariably indicate alcohol-related disease. In the short-term, changes in MCV are of little use in monitoring alcohol intake.
Two cases of hepatic paraneoplastic manifestations of carcinoma of the kidney are presented. In one, hepatosplenomegaly and abnormal liver function tests resolved following removal of the tumour. In the other, pruritus as a symptom of cholestasis was the presenting feature. Post-operatively a full blown cholestatic syndrome developed. Although their clinical presentations differed they may represent a spectrum of the same disease.
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A young Caucasian woman is described in whom obstructive jaundice was caused by a granular cell myoblastoma of the common bile duct. She was treated by percutaneous transhepatic biliary drainage for 10 days, before radical removal. Granular cell myoblastomas are benign lesions of disputed histogenesis, rare among biliary neoplasms, the excision of which is curative.
Ten cases are reported of short incubation (one to four weeks) non-A, non-B hepatitis occurring after infusion of various preparations of factor VIII concentrates into patients with coagulation disorders. Five patients were symptomatic and, in all, serum transaminase levels were increased for at least six months. These cases of chronic hepatitis exhibited none of the features of autoimmune chronic hepatitis: autoantibodies were negative and serum immunoglobulins were normal. Hepatic histology confirmed acute hepatitis in two cases biopsied early in the illness, and chronic active hepatitis (three) of chronic persistent hepatitis (two) in five cases studied later. Lobular inflammation was a prominent feature in all cases. Other features not commonly associated with type A or B hepatitis included fatty change and damaged bile ducts.
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.
The association of finger clubbing and periostitis has been reported in primary biliary cirrhosis and, more rarely, in other forms of chronic liver disease. The prevalence of periostitis and its relationship to finger clubbing is unknown. In this prospective study, we have determined the prevalence of periostitis and finger clubbing in 74 patients with primary biliary cirrhosis and 54 with other forms of chronic liver disease. Clubbing was present in 24% of patients with primary biliary cirrhosis, 29% with HBsAg negative chronic active hepatitis, and 23% in the group of miscellaneous liver diseases. Symmetrical periostitis affecting the tibiae and fibulae occurred in 35% of patients with primary biliary cirrhosis, 29% with chronic, active hepatitis and 40% of patients in the miscellaneous group. The distal radii and ulnae were affected in only eight patients (6%). In primary biliary cirrhosis, the presence of finger clubbing was strongly associated with periostitis (P less than 0.01), but this association was uncommon in other forms of chronic liver disease. In all forms of chronic liver disease periostitis commonly occurs in the absence of finger clubbing. Marked tenderness over the distal leg bones is a reliable sign of underlying periostitis, but this sign is present in only a third of affected patients. This study indicates that periostitis affecting the lower leg bones is common in patients with chronic liver disease, and its presence should be sought whether or not the patient has finger clubbing.
Twenty-five patients with primary biliary cirrhosis undergoing portal decompression have been followed up for a mean of 51 months. Five patients with decompensated cirrhosis died postoperatively. Overall five year survival of 66% is comparable with that for other forms of cirrhosis but none of the long-term survivors, including three patients with a precirrhotic stage of primary biliary cirrhosis at the time of surgery, developed significant portal-systemic encephalopathy. The results suggest that portal decompression may be the therapy of choice for patients with well-compensated primary biliary cirrhosis who suffer recurrent variceal haemorrhage.
In primary biliary cirrhosis (PBC) liver copper retention occurs as a complication of cholestasis. By analogy with Wilson's disease, it has been suggested that copper retention is hepatotoxic in PBC, and this has been the rationale for the use of D-penicillamine in this disease. The hypothesis that copper is hepatotoxic in PBC has not been tested and in this study we have evaluated the role of liver copper retention in the pathogenesis of PBC. Sixty-four patients with PBC have been studied. Fifty-four had increased liver copper concentrations. Liver cell synthetic function was well preserved. All the patients had normal prothrombin times, and only two had subnormal serum albumin concentrations. There was no correlation between liver copper concentrations and the degree of liver cell damage assessed biochemically (aspartate transaminase), and histologically. Electron microscopy was performed on liver biopsies from five patients with markedly increased liver copper concentrations. The liver cell ultrastructure was compatible with cholestasis. Liver cells contained electron dense lysosomes, which were shown to contain copper and sulphur by x-ray probe microanalysis. The characteristic organelle changes associated with copper toxicity in Wilson's disease were not observed. The biochemical, histological, and histochemical differences between PBC complicated by liver copper retention, and Wilson's disease, indicates that there are differences in the handling of copper in these disease. In this study we could find no evidence to suggest that copper plays an important role in the pathogenesis of liver dysfunction in PBC.
Twelve serologically proven cases of non-A, non-B (NANB) hepatitis have been described. The clinical course was mild in 11 patients. One patient, however, presented in portal systemic encephalopathy and required steroid treatment. Nine of the 12 patients continued to exhibit raised transaminase (AST) activities six or more months after the onset of the acute hepatitis. In these immunoglobulin concentrations were normal and autoantibodies were not present in significant titre. Four patients had evidence of previous hepatitis B infection, suggesting that the route of transmission of NANB might be similar to that of hepatitis B virus. A further four patients gave a history which suggests a possible parenteral mode of transmission. Liver biopsies were carried out both in the acute (8 cases) and chronic (6 cases) phases of the disease. Histological findings in liver biopsies covered the whole spectrum of acute and chronic hepatitis and 1 patient had cirrhosis. One notable feature in these biopsies was the presence of fatty changes.
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Erythrocyte transketolase activity and its stimulation in vitro by the addition of thiamine pyrophosphate (TPP effect) was measured in 64 normally nourished alcoholics with well-compensated liver disease and in 20 control subjects. Biochemical evidence of thiamine deficiency as judged by low transketolase activity was found in 19 alcoholics (29.7%). In 5 of these 19 patients the TPP effect was abnormally high, indicating depleted thiamine stores. IN the other 13 patients the TPP effect was either normal or low, suggesting a deficiency or an inability to use the transketolase apoenzyme, probably as a result o long-standing thiamine deficiency or the presence of liver disease. a further eight patients (12.5%) had normal transketolase activity but a low TPP effect, perhaps reflecting failure of hte coenzyme TPP to recombine with the transketolase apoenzyme in the presence of normal thiamine stores. There was no relationship between transketolase activity and the daily alcohol consumption, the duration of alcoholism, or the histological severity of the liver disease. Thiamine should be given routinely to alcoholics even if their diet appears adequate and their liver disease is minimal or well compensated.
A controlled trial has been undertaken to evaluate adenine arabinoside in the treatment of hepatitis B surface antigen-positive chronic liver disease. Thirteen patients (7 hepatitis B virus DNA polymerase and hepatitis B e antigen-positive, 6 DNA polymerase negative and hepatitis B e antibody-positive) were treated with adenine arabinoside. Eleven comparable patients served as controls, and follow-up was for 6 mo. In the 7 hepatitis B e antigen-positive patients, adenine arabinoside produced a fall in DNA polymerase activity during treatment. When this effect was sustained, it was followed by a loss of e antigen (3 patients). Hepatitis B surface antigen concentrations and aspartate transaminase levels fell significantly at 6 mo (p less than 0.05) in the treated group compared with controls. In the hepatitis B e antibody-positive patients, adenine arabinoside treatment produced no significant change in hepatitis B surface antigen concentrations or aspartate transaminase levels at 6 mo as compared with controls. Adenine arabinoside would appear to reduce either transiently or permanently, hepatitis B virus replication, and it may therefore be useful in reducing the infectivity of some carriers of this virus. In the dose used, adenine arabinoside was ineffective in clearing hepatitis B surface antigen from the serum and eradicating hepatitis B virus from the liver, but combination with other antiviral or immunostimulant agents may enhance its therapeutic effectiveness.
One hundred and forty-one attempts at percutaneous transhepatic variceal obliteration were made in 116 patients with portal hypertension complicated by variceal hemorrhage. Varices were successfully obliterated in 80% of procedures and included 37 patients with continuous, acute variceal hemorrhage. Hemorrhage ceased immediately in these patients. Sixty-five percent of patients rebled a mean of 4.6 mo after successful transhepatic variceal obliteration. A randomized controlled trial against conventional medical therapy (29 treatment, 25 control) failed to show a significant reduction in death rate after transhepatic sclerotherapy, although the onset of further variceal hemorrhage was delayed. Follow-up portography in 50 patients demonstrated new vessel formation in 38 patients and recanalization of previously occluded varices in 5 patients. Complications arose in 29 of 141 procedures. There was one death but all the other complications responded to conservative management. Transhepatic variceal obliteration is an excellent, safe emergency treatment for variceal hemorrhage, especially in patients with decompensated liver disease. A high incidence of rebleeding is a long-term disadvantage and means that transhepatic variceal obliteration should not be used for the prophylaxis of variceal hemorrhage. Successful emergency treatment of variceal hemorrhage should be followed by elective portal decompression in suitable patients.
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To evaluate the significance of granulomas in primary biliary cirrhosis, 295 liver biopsy specimens from 100 patients with primary biliary cirrhosis were reviewed. Granulomas were found in specimens from 54 patients and were less frequent as histologic stage increased. They often persisted in multiple specimens from individual patients. Granulomas did not correlate with clinical presentation or biochemical values, but were associated with better survival since of the 18 patients who died, only 2 showed granulomas on biopsy. To test this finding in patients at a uniform stage of progression, patients with late primary biliary cirrhosis were evaluated separately. Patients with and without granulomas were closely matched in clinical, laboratory, and histologic features. Although 23 of these 57 patients showed granulomas, they were present in only 1 of 14 patients who died. Thus, the presence of granulomas in primary biliary cirrhosis seems to be of prognostic significance, independent of previously reported prognostic indicators.