Shinji Nakatani

Randomised trial of effects of interferon-α on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis

Patients with chronic active hepatitis C and cirrhosis often develop hepatocellular carcinoma. Interferon (IFN) seems to be effective in some patients but whether it prevents carcinogenesis is unknown. In a prospective randomised controlled trial, we evaluated the effects of IFN-alpha in cirrhotic patients with HCV infection because of their high risk of hepatocellular carcinoma. 90 patients with compensated chronic active hepatitis C with cirrhosis were randomly allocated to receive IFN-alpha (6 MU three times weekly for 12-24 weeks) (45 patients) or symptomatic treatment (45 controls), and were followed up for 2-7 years. In nine controls, alanine aminotransferase (ALT) decreased to less than 80 IU/L but did not stay in the normal range. In 19 patients given IFN-alpha, ALT decreased to less than 80 IU/L (in seven patients, it became and stayed normal; p = 0.011, Wilcoxon rank-sum test). However, the mean change in ALT was not significantly different between the two groups. The mean change in peak alpha-fetoprotein values was smaller in patients given IFN-alpha than in controls (p = 0.021). The mean change in the serum albumin level was higher in the IFN-alpha group (p < 0.001). The histological activity index in the 12 IFN-alpha patients undergoing a second biopsy after therapy was improved (p = 0.031). Hepatitis C viral RNA disappeared in seven (16%) of the 45 IFN-alpha patients (95% CI, 7-29%) and in none of the 45 controls (0-8%; p = 0.018). Hepatocellular carcinoma was detected in two (4%, 1-15%) IFN-alpha patients and 17 (38%, 24-54%) controls (p = 0.002, Wilcoxon signed-rank test). The risk ratio of IFN-alpha treatment versus symptomatic treatment was 0.067 (0.009-0.530; p = 0.010 Coxs proportional hazards). IFN-alpha improved liver function in chronic active hepatitis C with cirrhosis, and its use was associated with a decreased incidence of hepatocellular carcinoma.

Prevention of hepatocellular carcinoma in patients with chronic active hepatitis C and cirrhosis.

In a prospective randomised controlled study, 90 patients with chronic active hepatitis C and compensated cirrhosis were assigned symptomatic treatment or interferon alfa (IFN-alpha). We report data on decompensation, detection of hepatocellular carcinoma, and mortality rates. IFN-alpha gave a sustained response in only a small proportion of patients, but worsening of compensated cirrhosis was prevented and development of hepatocellular carcinoma was inhibited, increasing the survival rate. The risk ratio of IFN-alpha versus symptomatic treatment decreased by 0.250 for progression to Child-Pugh grade B, 0.256 for detection of hepatocellular carcinoma, and 0.135 for a fatal outcome.

Effect of oral supplementation with branched-chain amino acid granules on serum albumin level in the early stage of cirrhosis: a randomized pilot trial

We designed a randomized pilot trial to examine whether increase or preservation of serum albumin levels was attained with earlier administration of branched-chain amino acid (BCAA) granules for cirrhosis in grade A according to Child-Pugh classification using branched-chain tyrosine ratio (BTR) as an indicator. Forty patients with HCV-related cirrhosis in grade A with serum albumin level between 3.5 and 3.9 g/dl were enrolled in this study. Half of the patients were randomly assigned to receive 14.3 g/day of BCAA granules orally, and half were assigned to a control. Patients were evaluated at entry and at 1-year interval for at least 2 years. For patients whose BTR was less than 4.0, mean change in serum albumin in the BCAA group was significantly higher than that in the control group after 1 and 2 years of treatment. However, for patients whose BTR was more than 4.0, mean change in serum albumin in the BCAA group was not significantly higher than that in the control group after 1 and 2 years of treatment. In conclusion, early oral supplementation of BCAA for HCV-related cirrhosis with serum albumin level between 3.5 and 3.9 g/dl and BTR less than 4.0, improves serum albumin levels and thus might improve prognosis.

Relationship between branched-chain amino acid to tyrosine ratio (BTR) and porto-systemic shunt in the Child-Pugh grade A cirrhosis determined by per-rectal portal scintigraphy

We examined the difference between early cirrhotic patients with lower branched-chain amino acids (BCAA) to tyrosine ratio (BTR) (<4) and higher BTR (>4) in portal circulation using per-rectal portal scintigraphy with technetium-99m pertechnetate. Forty patients with Child-Pugh grade A cirrhosis and serum albumin level between 3.5 and 3.9 g/dl were enrolled in this study. Sixteen patients were infected with HBV and 24 with HCV. Thirteen patients had BTR<4.0 and 27 had BTR>4.0. Shunt index (SI) obtained through per-rectal portal scintigraphy was significantly correlated with BTR (r=-0.558, P<0.0002). ICGR-15 was most strongly correlated with BTR among six parameters representing liver reserve capacity. The mean SI of patients with BTR less than 4 (38.4+/-28.0%) was significantly higher than that of patients with BTR greater than 4 (17.3+/-14.3%) (P=0.0388). The mean concentration of serum BCAA did not significantly differ between the two groups, but the mean concentration of serum tyrosine in the patients with BTR<4 was significantly higher than that in the patients with BTR>4 (P=0.0081). These results suggested that the increase in porto-systemic shunt caused tyrosine passing through liver and stagnating in the serum, as a result of which BTR fall in early cirrhosis. In conclusion, decrease of blood flow through liver and increase in porto-systemic shunt might be partly responsible for deterioration of BTR in early cirrhosis.

Use of Interferon-α for Prevention of Hepatocellular Carcinoma in Patients with Chronic Active Hepatitis C with Cirrhosis

Hepatitis C virus (HCV) is a more important factor associated with hepatocellular carcinoma than hepatitis B virus (HBV) in Japan and certain Western countries [1–3]. Some patients who contracted chronic non-A, non-B hepatitis after blood transfusion and hepatocellular carcinoma many years later have been studied in detail [4–6]. These studies proved that patients with chronic HCV infection often develop hepatocellular carcinoma [7]. The cumulative incidence of hepatocellular carcinoma in patients who had blood transfusions and were negative for hepatitis B surface antigen (HBsAg) was 53% (13/26) during 6 years of observation [8]. All of these patients had HCV antibodies. The mechanism by which hepatocellular carcinoma develops in the presence of HCV is unknown.