P. J. Johnson

Hepatitis C virus antibodies in chronic active hepatitis: pathogenetic factor or false-positive result?

An enzyme immunoassay (Ortho-HCV ELISA) for antibodies against the hepatitis C virus (HCV) was used to test 143 serum samples from 53 patients with autoimmune chronic active hepatitis (AI-CAH). Optical density (OD) values in the assay correlated closely with serum globulin (r = 0.8846, p much less than 0.0005) and IgG (r = 0.6281, p less than 0.0005) concentrations but not with immunosuppressant therapy. OD values were positive in 20 (65%) of 31 with active disease and in only 1 (5%) of 22 in remission (p less than 0.0005). The association between positive results and active disease and high serum globulin levels was confirmed by serial studies in 6 of the patients. In contrast, none of 31 patients with primary biliary cirrhosis and only 2 of 24 with non-hepatic disorders associated with high IgG concentrations were positive, and these controls showed no correlation between OD values and serum globulins or IgG. The findings suggest that serum from AI-CAH patients may contain a component that gives false-positive results in the assay.

Antibodies to hepatitis C virus in autoimmune liver disease: evidence for geographical heterogeneity

To resolve conflicting reports about the occurrence of antibodies against hepatitis C virus (HCV) in patients with autoimmune chronic active hepatitis (AI-CAH), sera from UK and Italian patients were tested with the original anti-HCV assay (Ortho) and a novel anti-HCV assay (UBI) based entirely on synthetic HCV peptides. 28 (60%) of 47 Italian patients with type-1 AI-CAH were anti-HCV-positive by Ortho ELISA, 25 of whom were also strongly positive by the UBI assay. 15 (60%) of 25 UK patients with type-1 AI-CAH were HCV-positive by Ortho ELISA but only 2 were positive by the UBI assay. Similarly, 29 (88%) of 33 Italian patients with type-2 AI-CAH, but 0 of 10 UK patients, were very strongly anti-HCV-positive with the UBI assay. Italian patients with AI-CAH appear to have a high frequency of genuine exposure to HCV, whereas seropositivity by the Ortho HCV ELISA in UK patients is likely to represent a false-positive result. These findings indicate important geographical and/or genetic influences in autoimmune liver disease among different populations.

Hepatocellular carcinoma in Great Britain: influence of age, sex, HBsAg status, and aetiology of underlying cirrhosis.

An analysis of 294 patients who died with cirrhosis showed that 24% had developed hepatocellular carcinoma. Haemochromatosis and HBsAg positive chronic active hepatitis were high risk groups (36% and 42% respectively) and the frequency was lowest in primary biliary cirrhosis and HBsAg negative chronic active hepatitis (3% and 11% respectively). Those with hepatocellular carcinoma showed a striking male preponderance (11:1) and further analysis has shown that the proportion developing this tumour in each group was closely related to the proportion of males in that group (r=0.97). Age was the only other significant factor, malignant change occurring more commonly in those over the age of 50 years than those below (30% and 7% respectively, P less than 0.005). The indluence of HBsAg was largely accounted for by the known predisposition of males to carry HBsAg. The group of patients who had developed this tumour without cirrhosis were younger (mean age 39 years) and had a lower male to female ratio of 1.1:1 and the place of contraceptive-related tumour within this group is dicussed.

INDUCTION OF REMISSION IN HEPATOCELLULAR CARCINOMA WITH DOXORUBICIN

Doxorubicin (60 mg/m2 at 3-weekly intervals to a maximum total of 550 mg/m2) induced clinical remission in 14 (32%) of 44 patients with hepatocellular carcinoma. In 3 of those who responded, hepatic arteriography showed clearing of the previously extensive tumour circulation, and in a 4th there was disappearance of the tumour on serial ultrasound examinations. A fall in serum-alpha-fetoprotein level after the initial injection of doxorubicin predicted a favourable clinical response, whereas the level continued to rise in patients who did not respond.

Etiologic and Clinical Characteristics of Peripheral and Hilar Cholangiocarcinoma

A 20‐year experience with 112 patients with cholangiocarcinoma was reviewed with reference to the demographic, etiologic, and clinical features and prognosis in the following two types: peripheral (originating from the intrahepatic small duct radicles) and hilar (originating from the major hepatic ducts at or near the junction of the right and left hepatic ducts). Seventy of the 112 patients were in the hilar group, and 42 were in the peripheral group. Prolonged high alcohol consumption was a prominent feature in both categories (45% and 37%, respectively). Among the women, 35% of those with the peripheral tumor had used oral contraceptive preparations. The major identifiable etiologic factor among the hilar tumors was ulcerative colitis, with or without sclerosing cholangitis, which was documented in 20 of 70 cases (28.6%), with an additional 4 patients having Crohns disease. The hilar group mainly had obstructive jaundice initially, whereas abdominal pain and weight loss were the predominant symptoms in the peripheral type. Tumor recurrence was frequent in those undergoing resection or transplantation, and none of those undergoing chemotherapy or radiation therapy showed any objective evidence of response. Overall median survival time was poor in both groups at 12 months.

Induction of remission in hepatocellular carcinoma: A comparison of VP 16 with adriamycin

Following a pilot study of VP‐16.213 (180 mg/m2 on 3 consecutive days at 2 weekly intervals) in the treatment of patients with hepatocellular carcinoma, the efficacy of the drug was compared with that of adriamycin in another 35 patients in a randomized crossover trial. Each drug gave a similar response rate (18 and 28%, respectively) but the duration of response was significantly longer in those receiving Adriamycin. Some patients who had not responded to treatment with Adriamycin had worthwhile remission with VP 16.

Hepatic sarcomas in adults: a review of 25 cases.

Twenty-five patients with an apparently primary sarcoma of the liver are reviewed. Presenting complaints were non-specific, but hepatomegaly and abnormal liver function tests were usual. Use of the contraceptive pill (four of 11 women) was identified as a possible risk factor; one patient had previously been exposed to vinyl chloride monomer. Detailed investigation showed that the primary tumour was extrahepatic in nine of the 25 patients. Distinguishing features of the 15 patients with confirmed primary hepatic sarcoma included a lower incidence of multiple hepatic lesions and a shorter time from first symptoms to diagnosis, but the most valuable discriminator was histology. Angiosarcomas and undifferentiated tumours were all of hepatic origin, epithelioid haemangioendotheliomas (EHAE) occurred as primary and secondary lesions and all other differentiated tumours arose outside the liver. The retroperitoneum was the most common site of an occult primary tumour and its careful examination therefore crucial: computed tomography scanning was found least fallible in this respect in the present series. Where resection (or transplantation), the best treatment, was not possible, results of therapy were disappointing, prognosis being considerably worse for patients with primary hepatic tumours. Patients with EHAE had a better overall prognosis regardless of primary site.

Response to cyproterone acetate treatment in primary hepatocellular carcinoma is related to fall in free 5α-dihydrotestosterone

The male preponderance in cirrhotic patients with primary hepatocellular carcinoma (HCC) and the presence of androgen receptors in tumour tissue suggest possible benefit from anti-androgenic therapy. Twenty-five cirrhotic patients with irresectable HCC (23 male) were treated with cyproterone acetate (CPA) 300 mg daily. Hepatic ultrasound, alpha-fetoprotein and total and free sex steroid levels were monitored. Five patients had an objective response to therapy with a median duration of 8 weeks and survival in excess of 29 weeks. Median survival for all patients was 14 weeks. Apart from transient paranoia in two cases, side-effects were minimal. Total androgen levels (measured in 13 patients) had fallen significantly at 10 weeks, but free 5 alpha-dihydrotestosterone (DHT) which had fallen by 4.8 pM (median) in five responders, had risen by 5.05 pM in eight non-responders: P less than 0.025. The apparent correlation of response with reduction in free DHT suggests that hormonal manipulation may be effective in HCC if free DHT is reliably reduced. This has been achieved in other conditions by the combination of CPA with low dose oestrogen or with LHRH agonists.

Hepatitis C virus infection in the development of hepatocellular carcinoma in cirrhosis

BACKGROUND/AIMS The role of hepatitis C virus replication and different genotypes in the progression of cirrhosis to hepatocellular carcinoma is examined on the basis of a prospective follow-up of 1438 patients with histologically proven cirrhosis. METHODS The presence of HCV RNA, anti-HCV and characterisation of virus genotypes were determined in 72 cases who developed hepatocellular carcinoma after a median follow-up of 5.3 years (range 1 to 16) and compared to 72 controls who had cirrhosis only, after a median follow-up of 4.8 years (range 1 to 16). Patients in the hepatocellular carcinoma group and controls were matched, one to one, for age, sex, nationality, HBsAg seropositivity, duration of follow-up and aetiology of cirrhosis. RESULTS HCV RNA was detected in 31 of 72 (44%) patients who developed hepatocellular carcinoma, significantly more frequently than in 17 of 72 (23%) controls with cirrhosis (odds ratio 2.4, 95% confidence interval 1.2 to 5.0; p = 0.013). When cirrhosis of different aetiologies was analysed, hepatitis C virus replication was more frequently detected in patients developing hepatocellular carcinoma in association with cryptogenic cirrhosis (p = 0.007), alcoholic cirrhosis (p = 0.043) and hepatitis B virus seronegative cirrhosis (p = 0.05). Hepatitis C virus genotypes 1b and 4 were the most prevalent; they were found in 53% and 25%, respectively, of the patients studied, but were equally distributed between cirrhosis progressing to hepatocellular carcinoma and controls. CONCLUSIONS Persistent hepatitis C virus replication is closely associated with hepatocellular carcinoma development in cirrhosis, and there is no preferential role of individual hepatitis C virus genotypes.

Clinical efficacy and toxicity of standard dose adriamycin in hyperbilirubinaemic patients with hepatocellular carcinoma: relation to liver tests and pharmacokinetic parameters

A standard dose of Adriamycin (60 mg m-2) was administered to 30 patients with inoperable hepatocellular carcinoma, 16 of whom were hyperbilirubinaemic (18-37 mumol l-1). The hyperbilirubinaemic patients experienced marked myelosuppression, but only minor symptomatic side-effects. The degree of neutropenia was directly related to the serum bilirubin concentration, but not to any other standard liver test, presence or absence of cirrhosis, or any pharmacokinetic parameter studied including the area under the Adriamycin or adriamycinol concentration-time curve to 48 h or infinity, or the terminal half-life of Adriamycin. The area under the log concentration-time curve was significantly greater for both Adriamycin and adriamycinol in patients who were hyperbilirubinaemic compared to those with normal bilirubin. Whilst hyperbilirubinaemic patients may tolerate a full dose of Adriamycin, we found no evidence that this was associated with a better response rate, which was disappointingly low at only 18%.