Hepatitis G infection: role in cryptogenic chronic liver disease and primary liver cell cancer in the UK. Trent Hepatitis C virus Study Group.

Hepatitis G virus (HGV) is a flavivirus that can cause acute hepatitis and persistent infection but its role in chronic liver disease or primary liver cancer is unproven. In this study we have examined the prevalence of HGV RNA in the serum of patients with hepatitis C virus (HCV) infection and in patients with cryptogenic chronic liver disease, including non-alcoholic steatohepatitis (NASH), and in patients with HCV-related hepatocellular carcinoma (HCC) and HCC arising in patients with cryptogenic liver disease. One-hundred and thirty patients who were positive for antibody to HCV (anti-HCV), 54 patients with cryptogenic chronic liver disease (including 17 patients with NASH) and 46 patients with hepatitis C-related (n = 27) or cryptogenic liver disease-related HCC (n = 19) were studied. HGV RNA was detected using nested reverse transcriptase-polymerase chain reaction (RT-PCR) and was found in 16.1% of patients with HCV infection. HGV RNA was not detected in any patient with cryptogenic liver disease. In patients with HCC, 7/34 samples were positive for HGV RNA and six out of seven HGV-positive subjects also had HCV infection. Only one patient with HCC in cryptogenic liver disease was positive for HGV RNA. Hence, cryptogenic liver disease in the UK is not caused by HGV/GBVc infection. It seems unlikely that HGV plays a significant role in hepatocarcinogenesis.

Peanut ingestion increases rectal proliferation in individuals with mucosal expression of peanut lectin receptor.

BACKGROUND & AIMS: The Thomsen-Friedenreich blood group antigen (galactose beta 1,3-N-acetyl galactosamine alpha-) acts as an oncofetal antigen in the colonic epithelium, with low expression in normal adult epithelia but increasing to fetal levels of expression in hyperplasia or malignancy. Peanut lectin is one of the commonest dietary lectins that binds this antigen. The aim of this study was to determine whether peanut ingestion can alter rectal epithelial proliferation. METHODS: Thirty-six patients with normal colonic mucosa consumed 100 g of peanuts each day for 5 days. Rectal mitotic index was measured before and after ingestion, and changes in proliferation were correlated with immunohistochemical detection of lectin receptor expression by colonocytes and fecal lectin activity as measured by hemagglutination assay. RESULTS: Peanut ingestion caused a 41% increase in rectal mucosal proliferation in individuals with macroscopically normal mucosa who express TF antigen in their rectal mucosae (10 of 36 patients studied). The proliferative response correlated with fecal hemagglutinating activity, and peanut lectin could be shown immunohistochemically within the rectal mucosa. CONCLUSIONS: The common expression of galactose beta 1,3-N-acetyl galactosamine alpha- by hyperplastic and neoplastic epithelia may therefore be functionally important because it allows interaction with mitogenic dietary lectins. This could be an important mechanism for the association between diet and colorectal cancer.

Use of specific ELISA for the detection of antibodies directed against p53 protein in patients with hepatocellular carcinoma.

AIMS: To analyse the significance of antibodies to p53 protein as a serological marker for changes in p53 gene expression in patients with hepatocellular carcinoma. METHODS: Thirty eight patients with hepatocellular carcinoma, 19 showing accumulation of p53 protein by immunohistochemistry and 19 having no accumulation, were studied. The presence of anti-p53 was tested using a novel ELISA utilising a recombinant p53 protein as a capture system and verified by western blotting. p53 gene mutations were sought by single strand conformational polymorphism and DNA sequencing analyses. RESULTS: Of 19 patients with p53 protein accumulation in tumour tissue, 10 (52%) had antibodies to p53 in serum by ELISA. Four patients with p53 negative immunohistochemistry also had detectable anti-p53. Western blot analysis confirmed the specificity of the ELISA positive serum samples. The presence of anti-p53 was independent of serum alpha-fetoprotein and was detected in 50% of small tumours while only 8% were alpha-fetoprotein positive. Mutations affecting exons 5 and 6 seem to be more frequently associated with development of anti-p53, than mutations in exons 7 or 8. CONCLUSIONS: The ELISA for anti-p53 is a convenient and specific tet for the detection of humoral response to alterations in p53 gene expression and could be of value in the diagnosis and characterisation of patients with hepatocellular carcinoma.

p53 Protein overexpression in cholangiocarcinoma arising in primary sclerosing cholangitis.

The protein encoded by the p53 tumour suppressor gene plays an important part in the regulation of cell growth. Abnormalities of this gene represent one of the most common genetic changes in the development of human cancers. This study investigated the expression of p53 protein in cholangiocarcinoma arising in association with primary sclerosing cholangitis (PSC). Of the 14 patients with cholangiocarcinoma studied, 13 had underlying PSC. The expression of p53 protein was detected immunohistochemically in paraffin wax embedded liver specimens, after microwave pretreatment. The expression of p53 protein was shown in the cholangiocarcinoma tissue of 11 of 14 (78.5%) patients. In five of 10 patients, the accumulation of p53 protein highlighted the presence of neoplastic cells in biliary tissue separate from the main tumour. These cells were mainly located in the septal bile ducts or in the accessory glands, or both, but occasionally also in large portal areas at the periphery of nerves and lymphatics, and in one case in the mucosa of an extrahepatic bile duct. No p53 protein was detectable in liver tissue obtained at the time of transplantation in 15 patients with PSC but not cholangiocarcinoma. These results show that cholangiocarcinoma development in PSC is commonly associated with abnormalities of p53 and that these occur at a late stage in the development of the malignant process. Staining for p53 protein could represent an additional criterion for the diagnosis of cholangiocarcinoma development in patients with PSC.

Chemoembolisation with lipiodol and doxorubicin: applicability in British patients with hepatocellular carcinoma.

Chemoembolisation has been extensively used as primary treatment for unresectable hepatocellular carcinoma (HCC). In this unit, 185 patients with a new diagnosis of HCC not amenable to surgery were seen between 1988 and 1991. Intended therapy for these patients was chemoembolisation with doxorubicin (60 mg/m2) and lipiodol, repeated at six week intervals until it was technically no longer possible or until complete tumour response had been obtained. Chemoembolisation was possible in 67 of the 185 (37%). Reasons for exclusion were portal vein occlusion (n = 36), decompensated cirrhosis (n = 44), distant metastases (n = 5), diffuse tumour or unsuitable anatomy (tumour or vasculature) (n = 11), patient refusal (n = 11), and other (n = 11). Patients excluded from treatment survived for a median of 10 weeks (range 3 days-19 months). In patients treated, 18 had small HCC (< 4 cm) and 49 had large or multifocal HCC. Chemoembolisation was carried out a median of two sessions for small and three sessions for large tumours. Ten of 18 patients with small HCC showed a 50% or greater reduction in tumour size. Five of 49 patients with large or multifocal tumours showed a response to treatment. Median overall survival for treated patients was 36 weeks (range 3 days-4 years). One patient has subsequently undergone liver transplantation with no recurrence and minimal residual disease at transplantation. Two other patients are alive three years after chemoembolisation, one with no evidence of recurrent disease. No patient was thought suitable for surgery after their response to chemoembolisation. Chemotherapy related complications were seen in 22%. Complications were significantly more common in patients with larger tumours and poor liver reserve. Five patients died as a result of chemotherapy related complications. In conclusion, only one third of UK patients with unresectable HCC are treatable by chemoembolisation. Results with small tumours are encouraging, with a high response rate and the possibility of surgical intervention in previously inoperable disease. Large tumours, however, show a poor response and a significant incidence of side effects, suggesting that this treatment offers little benefit in advanced disease.

Hepatocellular carcinoma complicating autoimmune hepatitis: role of hepatitis C virus.

The risk of hepatocellular carcinoma in autoimmune hepatitis is low, even in patients with long-standing cirrhosis. Because of the increasing recognition of an association of hepatitis C virus (HCV) with autoimmune hepatitis, at least in some geographical areas, and with hepatocellular carcinoma (HCC) (hepatoma), we have examined eight cases (4 male, 4 female) who presented between 1985 and 1993 with hepatoma complicating autoimmune hepatitis. All had steroid-responsive autoimmune hepatitis with serum anti-smooth muscle and anti-nuclear autoantibodies. Median duration of disease was 17.1 years, and all patients had biopsy-proven cirrhosis. One patient had a history of intravenous drug abuse, and four had previously received blood transfusions. Serum samples (stored at -20 degrees C from up to 9 years before diagnosis of hepatoma) were tested for anti-hepatitis C virus antibodies by a second-third-generation assay and for HCV RNA by the polymerase chain reaction method using primers from the 5'noncoding region. Tissue from liver adjacent to tumor areas was subjected to polymerase chain reaction along with tissue from previous liver biopsy specimens (taken up to 19 years before diagnosis of hepatoma) in all patients. Six patients had evidence of HCV infection: four seropositive for HCV RNA (two of whom were also anti-HCV positive) and two seronegative for HCV RNA and anti-HCV but with HCV RNA in liver tissue at presentation with hepatoma. Retrospective testing showed probable acquisition of HCV through blood transfusion in the four transfused patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Experience of orthotopic liver transplantation and hepatic resection for hepatocellular carcinoma of less than 8 cm in patients with cirrhosis.

Fifteen patients with cirrhosis underwent orthotopic liver transplantation for small hepatocellular carcinoma (HCC) and 12 patients with cirrhosis underwent hepatic resection for similar HCC. All tumours were of the non-fibrolamellar variant. The majority of the patients in the transplant group had Child's grade B or C cirrhosis. Median follow-up was 37 months with a minimum of 18 months. Eleven of 12 patients in the resection group had Child's grade A cirrhosis. Median follow-up was 29 months with a minimum of 16 months. Actuarial survival rates at 1 and 3 years for the transplanted patients were 80 and 63 per cent and all were tumour free. Tumour recurrence rate was 15 per cent. The overall 1- and 3-year tumour-free survival rates for patients in the resection group were 61 and 33 per cent. Tumour recurrence rate was 45 per cent. The results show orthotopic liver transplantation to be an important surgical option in cirrhotic patients with small HCC, particularly in those with moderate to severe hepatic decompensation.

Accuracy of radiology in detection of hepatocellular carcinoma before liver transplantation.

BACKGROUND/AIMS: Recurrence of hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT) depends on tumor size and number; the accuracy of radiology in detecting HCC is uncertain. This study compared tumor size at radiological and pathological examination in 30 patients with HCC who underwent OLT. METHODS: Pre-OLT radiology included ultrasonography (US), computerized tomography (CT), and hepatic angiography (HA). Sensitivity of radiology was calculated by comparison with pathology. RESULTS: Radiology missed HCC in two patients but showed five with small (< 4 cm) and eight with large (> 4 cm) lesions. Multicentricity was shown in 15 cases at radiological examination and 24 at pathological examination, including one incidental and 4 of 5 radiologically small HCC. Mean tumor bulk was 3.4, 74, 338, and 1375 cm3, respectively, in patients with incidental, small, large, and multicentric HCC at radiology. Sensitivities of US, CT, and HA in detection of HCC (and multicentricity) were 80% (16.6%), 86.6% (58.3%), and 90% (58.3%). No recurrence was found in patients with incidental or small HCC; even when multicentric. CONCLUSIONS: US, CT, and HA identified patients with small or large tumor bulk, but sensitivity in detecting satellites was poor; their finding in patients with radiologically small or incidental tumors does not affect outcome. The failure of US, CT, and HA to detect satellites must be considered in patients undergoing partial hepatectomy for HCC.

Prophylactic sclerotherapy in high-risk cirrhotics selected by endoscopic criteria. A multicenter randomized controlled trial.

Controlled trials of sclerotherapy for the prevention of the first variceal hemorrhage in cirrhotics have given conflicting results. In the present study, 106 cirrhotics were randomized to sclerotherapy (55 patients) or control group (51 patients). Admission criteria were no history of previous variceal bleeding and the presence of high-risk varices, i.e., a variceal score less than or equal to 0 according to Beppu et al. Sclerotherapy sessions were performed at time zero, 7 days, 30 days, and then monthly until eradication. Follow-up endoscopies were performed at 6-month intervals thereafter. Control patients underwent repeat endoscopy at 6-month intervals. Bleeding episodes were treated by sclerotherapy in both groups, whenever possible. Mean follow-up was 24 months. Analysis of the results was performed by the intention-to-treat method. Variceal bleeding occurred in 19 sclerotherapy patients (34.5%) and in 17 controls (35.4%, P = NS). Overall mortality was 34.5% in sclerotherapy patients and 50% in controls (P = NS). Seven of the 19 sclerotherapy patients (36.8%) and 11 of the 17 controls (64.7%) who bled died of hemorrhage (P less than 0.05, log-linear model). It is concluded that prophylactic sclerotherapy does not reduce the incidence of first variceal bleeding in cirrhotics. However, there seems to be a trend toward a lower bleeding-related mortality in sclerotherapy patients than in controls.