P. C. Wu

A one year trial of Lamivudine for chronic hepatitis B

BACKGROUND AND METHODS In preliminary trials, lamivudine, an oral nucleoside analogue, has shown promise for the treatment of chronic hepatitis B. We conducted a one-year, double-blind trial of lamivudine in 358 Chinese patients with chronic hepatitis B. The patients were randomly assigned to receive 25 mg of lamivudine (142 patients), 100 mg of lamivudine (143), or placebo (73) orally once daily. The patients underwent liver biopsies before entering the study and after completing the assigned treatment regimen. The primary end point was a reduction of at least two points in the Knodell necroinflammatory score. RESULTS Hepatic necroinflammatory activity improved by two points or more in 56 percent of the patients receiving 100 mg of lamivudine, 49 percent of those receiving 25 mg of lamivudine, and 25 percent of those receiving placebo (P<0.001 and P=0.001, respectively, for the comparisons of lamivudine treatment with placebo). Necroinflammatory activity worsened in 7 percent of the patients receiving 100 mg of lamivudine, 8 percent of those receiving 25 mg, and 26 percent of those receiving placebo. The 100-mg dose of lamivudine was associated with a reduced progression of fibrosis (P=0.01 for the comparison with placebo) and with the highest rate of hepatitis B e antigen (HBeAg) seroconversion (loss of HBeAg, development of antibody to HBeAg, and undetectable HBV DNA) (16 percent), the greatest suppression of HBV DNA (98 percent reduction at week 52 as compared with the base-line value), and the highest rate of sustained normalization of alanine aminotransferase levels (72 percent). Ninety-six percent of the patients completed the study. The incidence of adverse events was similar in all groups, and there were few serious events. CONCLUSIONS In a one-year study, lamivudine was associated with substantial histologic improvement in many patients with chronic hepatitis B. A daily dose of 100 mg was more effective than a daily dose of 25 mg.

Clinical features of hepatocellular carcinoma: review of 211 patients in Hong Kong.

A retrospective study of 211 patients with proven hepatocellular carcinoma (HCC) was made. The commonest symptoms were anorexia and malaise (73%). Five patients (2.5%) had near‐normal biochemical tests despite the presence of massive tumors. Diagnostic yield from angiography, percutaneous peritoneoscopic biopsy, or scintiscanning was 87–98%. Three percent of the patients had resectable tumors. Median survival for patients with untreated disease was 3.5 weeks. Apart from histology, the total serum bilirubin level was the only factor of prognostic value. Only 12 patients had preexisting symptomatic cirrhosis. When compared with 80 patients with symptomatic postnecrotic cirrhosis without malignancy, patients with HCC had higher SGOT:SGPT ratio, higher serum albumin levels, and higher platelet counts. There was only minimal overlap of patients with symptomatic postnecrotic cirrhosis and those with HCC. The authors conclude that their patients with HCC appeared late for treatment. A probable difference in the development of symptomatic postnecrotic cirrhosis and of HCC with asymptomatic postnecrotic cirrhosis is suggested.

Expression of c-Myc, c-Fos, and c-jun in hepatocellular carcinoma.

Increased expression of the proto‐oncogene c‐myc is a common phenomenon in hepatocellular carcinoma (HCC). The proto‐oncogenes c‐fos and c‐jun are involved in cell cycle progression and cellular proliferation.

Histologic prognostic indicators in hepatocellular carcinoma

Survival and histologic features were studied in 80 patients with proven hepatocellular carcinoma (HCC). The overall survival was 50% at 3.5 weeks with a statistically significant drop in mortality rate after 8.5 weeks. Patients with diffuse clear‐cell pattern, focal clear‐cell pattern, and no clear cells in their tumors had a 50% survival rate at 14 weeks, 6 weeks, and 3 weeks respectively; the differences in survival rates were statistically significant between any pair (p < 0.001). No correlation was found between survival and (1) cytologic differentiation, (2) histologic architecture, (3) degree of pleomorphism, or (4) presence of bile production, proteinaceous secretion, giant cells, or cytoplasmic hyaline bodies. Eosinophilic HCC with lamellar fibrosis was not observed in any of our materials. We concluded that the presence of clear cells was the only histologic feature of prognostic significance in our patients.

Recombinant α2 interferon is superior to doxorubin for inoperable hepatocellular carcinoma: A prospective randomised trial

In a prospective trial of 75 Chinese patients with histologically proven inoperable hepatocellular carcinoma (HCC), 25 patients were randomised to receive doxorubicin 60-75 mg m-2 intravenously once every 3 weeks, 25 to receive recombinant alpha 2 interferon (rIFN) (Roferon) 9-18 x 10(6) IU m-2 intramuscularly (i.m.) daily and 25 to receive rIFN 25-50 x 10(6) IU m-2 i.m. three times weekly. Patients were switched to the other drug if: (a) there was progressive disease after 12 weeks, (b) unacceptable toxicity developed and (c) they had received a total of 500 mg m-2 of doxorubicin. Six patients had switching over of therapy, three on doxorubicin and three on rIFN. In the remaining 69 patients on single drug therapy, the median survival rate of patients on doxorubicin and rIFN was 4.8 and 8.3 weeks respectively (P = ns.). rIFN induced tumour regression of 25-50% in 12% of patients and of over 50% in 10% of patients. When compared with doxorubicin, rIFN was associated with more tumour regression (P = 0.00199) and less progressive tumours (P = 0.00017). It caused less prolonged and less severe marrow suppression (P = 0.01217), and had significantly less fatal complications than doxorubicin (P = 0.01383). Doxorubicin caused fatal complications due to cardiotoxicity and neutropenia in 25% of patients. rIFN was associated with fatal complications due to dementia and renal failure in 3.8% of patients. In the treatment of inoperable HCC, rIFN is superior to doxorubicin in causing more tumour regression, less serious marrow suppression and less fatal complications.

Clear cell carcinoma of liver. An ultrastructural study

A light microscopic and ultrastructural study of ten consecutive cases each of the clear cell type and nonclear cell type of hepatocellular carcinoma (HCC) showed important differences between the two groups which may help to explain their different biological behavior. The clear cells contained substantial quantities of glycogen and lipid which partly substitute the usual cytoplasmic constituents. An analogy was made between these tumor cells with clear cytoplasm and the clear cells which occurred in the intermediary stages of hepatocellular carcinogenesis in animals in an attempt to explain the better outcome of clear cell HCC.

Female Children Respond to Recombinant Hepatitis B Vaccine with a Higher Titre than Male

One-hundred and eighty Chinese children [age range 5 months to 12 years, seronegative for all hepatitis B virus (HBV) markers] of parents seropositive for HBV surface antigen (HBsAg) were randomized to receive doses of either 10 or 20 micrograms of recombinant yeast-derived HBV vaccine at intervals of 0, 1, and 6 months. Six children defaulted and three other children (1.7 per cent) seroconverted to anti-HBc positivity without detectable HBsAg in the serum. All other children attained an anti-HBs titre of > 10 mlU/ml after three doses. Both 10 and 20 micrograms/dose regime gave a similar geometric mean titre (GMT) of anti-HBs. Children aged 0-4 responded with a similar titre compared with children aged > 4. Female children responded with a significantly higher GMT than male children and this was due to a high proportion of female children with higher peak titres. No major side-effects were encountered. We conclude that recombinant HB vaccine is highly immunogenic, well tolerated and equally effective with doses of both 10 and 20 micrograms and that girls responded with a higher anti-HBs titre compared with boys.

Subclinical hepatocellular carcinoma in Hong Kong Chinese.

Of the 208 Chinese patients with histologically proven hepatocellular carcinoma (HCC) seen during a 5-year period, 191 patients presented with symptomatic HCC and 17 patients with asymptomatic HCC (subclinical HCC, SCHCC) being picked up by alpha-fetoprotein (AFP) screening. Compared with the patients with symptomatic HCC, patients with SCHCC had a better performance status (p less than 0.01), higher serum albumin levels (p less than 0.05) and lower alkaline phosphatase levels (p less than 0.01). In those patients with symptomatic HCC, 4.7% were operable and only 2 patients had a tumour diameter of less than 5 cm. In contrast, patients with SCHCC had a higher operability rate (76.5%, p less than 0.0001) and all had a tumour of less than 5 cm in diameter (p less than 0.0001). Patients with SCHCC, most of whom had their tumour resected, had a better long-term survival (p less than 0.0001). We conclude that patients with SCHCC picked up by AFP serosurveillance have a better performance status, higher operability and better prognosis.

Clinicopathological Features of Hepatitis C Virus Antibody Negative Fatal Chronic Hepatitis C after Renal Transplantation

Clinical course and serial liver histology of a patient who developed fatal chronic active hepatitis C after renal transplantation are presented. This patient developed persistently deranged liver biochemistry 3 months after transplantation, despite normal liver enzyme values during the preceding 3 years on hemodialysis. In addition to increased parenchymal enzyme concentrations, the levels of ductal enzymes were also markedly elevated, with peak levels of alanine aminotransferase and gamma-glutamyl transpeptidase 7 and 100 times, respectively, the normal upper limit. The patient was persistently seronegative for hepatitis C virus (HCV) antibodies, but positive for HCV RNA. Treatment with alpha-interferon for 6 months, initiated after the development of early cirrhosis, resulted in no improvement, and the patient died from liver failure 36 months after renal transplantation. Serial liver histology, examined four times from 11 months to 36 months after transplantation, showed progressive deterioration from chronic active hepatitis to cirrhosis. This patient illustrates the uncommon complication of rapidly progressive and ultimately fatal liver disease due to HCV infection after renal transplantation. Early recognition with anti-HCV and HCV RNA assays as well as histologic assessment are crucial for the identification of patients with a poor prognosis who might benefit from therapeutic intervention before irreversible liver damage.

Variations of hepatitis B virus core gene sequence in Western patients with chronic hepatitis B virus infection

Summary. Heterogeneity of the hepatitis B virus (HBV) core gene has been reported to be associated with the presence of active liver disease in Japanese patients with chronic HBV infection. This study evaluated the significance of HBV core gene heterogeneity in Western patients with chronic HBV infection. The hepatitis B virus precore/core gene from 45 patients (inactive:active liver disease ratio 16:29) was amplified from serum by polymerase chain reaction (PCR). Gel electrophoresis was employed to detect large deletions. The PCR amplicons from 13 patients (all HBV serotype adw but with a different spectrum of liver disease) were cloned and sequenced. Hepatitis B surface antigen (HBsAg) serotypes were tested by enzyme immunoassay (EIA) and hepatic expression of HBV antigens was assessed by immunohistochemistry. The HBV core gene was amplified from the serum of all 45 patients. Three patients had mixed infection with both precore mutant and wild‐type HBV and all three had active liver disease. No patient had a large deletion of the HBV core gene. Hepatitis B virus core gene sequence variations were more common in the midcore region and there was no difference in the number of silent and missense substitutions between those with inactive and active liver disease. There was no correlation between the nucleotide or encoded amino acid substitutions and the clinical and biochemical parameters, including the subsequent response to interferon‐α therapy (n= 37) or hepatic HBV antigen expression. Variation of the HBV core gene was not found to be preferentially associated with active liver disease in Western patients with chronic HBV infection. The pattern of hepatitis B core gene variation is in accord with the genomic organization of HBV.