Keiji Kita

Limitation of combination therapy of interferon and ribavirin for older patients with chronic hepatitis C

In contrast to the United States, Japanese patients with chronic hepatitis C currently treated with interferon are generally 10 to 15 years older. Older patients, however, tend to experience more frequent adverse events. This study was conducted to clarify the effect of patient age on the efficacy and safety of combination therapy. We consecutively enrolled 208 patients with naïve chronic hepatitis C. Patients were classified into three groups according to age: younger than 50 years of age (n = 52); 50 to 59 years old (n = 83); and 60 years of age or older (n = 73). Interferon alpha‐2b therapy was administered daily for 2 weeks, followed by 3 times per week for 22 weeks, while ribavirin was administered daily. Of the 208 study patients, discontinuation of therapy or dose reduction was required in 116 (56%) and was more frequent in older patient groups: 38%, 48%, and 77% for the <50, 50–59, and ≥60‐year‐old patient groups, respectively (P < .001). Multivariate analysis showed patient age to be independently associated with adherence to therapy. A sustained virological response was achieved in 77 (37%) patients, with genotype, viral load, and adherence to therapy associated with this achievement. A tendency toward a lower sustained virological response rate was seen in the older patients. In conclusion, patient age is an important factor contributing to the safety of combination therapy. Thus, treatment schedule should be modified, or other therapeutic modalities should be considered for older patients with chronic hepatitis C. (HEPATOLOGY 2006;43:54–63.)

Risk factors for hepatocellular carcinoma in Hepatitis C patients with sustained virologic response to interferon therapy

Abstract: Background: Although a variety of papers demonstrated inhibited hepatocarcinogenesis with interferon (IFN) therapy for chronic hepatitis C, a small number of hepatocellular carcinomas (HCCs) were still observed even in sustained virologic responders.

New prognostic scoring model for liver transplantation in patients with non-acetaminophen-related fulminant hepatic failure.

Background. Many patients with fulminant hepatic failure die before receiving liver transplantation because of the difficulty of pinpointing the suitable timing for liver transplantation. The revised Kings College criteria are useful for patients with acetaminophen-related fulminant hepatic failure; however, in those with non-acetaminophen-related fulminant hepatic failure, a new prognostic system that can accurately identify the suitable timing for liver transplantation is required. Methods. Using the first sample consisted of eighty patients with fulminant hepatic failure, we examined 2-week poor prognostic parameters at the time of diagnosis of fulminant hepatic failure (day 1) and on days 4, 8, and 15, respectively, and a 2-week prognostic scoring model was constructed. To confirm the accuracy of this model, validation was performed in the second sample consisting of 26 patients. Results. Cause of fulminant hepatic failure (hepatitis B virus or indeterminate), hepatic coma grade (III or IV), systemic inflammatory response syndrome (yes) and ratio of total to direct bilirubin (> 2.0) were associated with 2-week outcomes during days 1-15. Each of these four parameters was valued at +1. The 2-week survival rate in patients scoring <3 was ≥80% in contrast to less than 30% in patients scoring ≥3. When this scoring model was applied to the second sample, the sensitivity, specificity, and positive and negative predictive values were 87.5%, 90.0%, 93.3%, and 81.8%, respectively. Conclusions. This scoring model may be useful for predicting 2-week outcomes and determining the suitable timing for liver transplantation in patients with non-acetaminophen-related fulminant hepatic failure.

Peritoneoscopy of the liver stained by intravenous injection of indocyanine green-experimental and clinical studies.

SummaryLiver surface patterns were observed by peritoneoscopy after intravenous injection of indocyanine green (ICG). The normal rat liver was diffusely stained dark greenish-brown 5 minutes after the injection of ICG 25 mg/kg body weight into the tail vein. Green spots persisted longer in the centrolobular area, clearly revealing lobular markings. This regional difference in hepatocyte staining suggested differing abilities of hepatocytes to take up or excrete ICG. This dyeing technique was applied to liver disease patients. The liver was diffusely stained light greenish-brown 5 minutes after the injection of ICG 5 mg/kg body weight. In patients, especially those with obscure lobular markings before ICG injection, lobules were clearly demarcated by reddish terminal portal veins against a green background. This simplified detection of lobular distortions. Prenodular patches (Kalk’s Bunteflecke) on the liver surface were stained green more intensely than surrounding areas, which supports the hypothesis that patches are composed of active hepatocytes.

Photodynamic therapy of rat liver cancer: Protection of the normal liver by indocyanine green

SummaryThe application of photodynamic therapy (PDT) to hepatocellular carcinoma (HCC) has been difficult because hematoporphyrin derivatives (HpD) accumulate not only in cancer cells but also in normal hepatocytes and, hence, laser irradiation causes injuries in both tissues. Protection of the normal liver tissue from laser phototoxicity was demonstrated using indocyanine green (ICG) as a protective agent. In vitro, argon laser irradiation decolored the green tint of ICG much faster in solutions containing HpD than those without, suggesting that ICG captured singlet oxygen from HpD. Degeneration of Chang hepatocytes induced by HpD and laser irradiation was prevented by an addition of ICG into the medium. In vivo, laser irradiation of the rat liver surface caused hyperemia when HpD was injected two days before, while the hyperemia was much milder in rats additionally receiving ICG injection 10 minutes before the irradiation. ICG injected into rat HCC accumulated only in the normal liver tissue. Laser irradiation of rat HCC preinjected with both HpD and ICG destroyed only the cancer tissue, while the surrounding liver tissue was preserved.Both in vitro and in vivo results suggest that ICG has a scavenger effect against excited oxygen and it might be used as a protective agent in PDT of HCC.

Detection of hepatitis B virus DNA in the liver and serum of patients with hepatitis B surface antigen and hepatitis C virus antibody negative chronic liver disease.

To elucidate the positive frequency of hepatitis B virus (HBV) DNA in patients with hepatitis B surface antigen (HBsAg) and antibody to hepatitis C virus (HCVAb) negative (NBNC) chronic liver disease, we detected serum HBV-DNA using the real-time detection polymerase chain reaction method (RTD-PCR) in comparison with HBsAg and HCVAb negative individuals with normal alanine aminotransferase (ALT). We also revealed the nucleotide sequence of the X-pre-C gene-coding region of intrahepatic HBV-DNA. Serum HBV-DNA was detected in 12 of 36 NBNC patients (five of 22 chronic hepatitis, three of eight liver cirrhosis and four of six hepatocellular carcinoma), whereas none of 31 control individuals were positive for serum HBV-DNA (P<0.01). Serum antibody to hepatitis B core antigen (HBcAb) was positive in nine of 36 in patients with NBNC patients and was positive in nine of 31 in control individuals (n.s). Five of six NBNC patients with serum HBV-DNA positive by RTD-PCR were also positive for intrahepatic HBV-DNA. Analysis of the nucleotide sequence of the X-pre-C coding region of HBV-DNA in the liver showed similar mutation sites of 1677, 1679, 1709, 1753, 1762, 1764. These findings suggested that serum HBV-DNA was more frequently detected in NBNC patients than normal individuals and the presence of low levels of serum HBV-DNA was correlated to the 1677--1764 X-pre-C mutations.

Observation of microvascular casts of human hepatocellular carcinoma by scanning electron microscopy

SummaryThe microcirculation of hepatocellular carcinomas (HCCs) and surrounding tissue was observed three-dimensionally by scanning electron microscopy of vascular casts made from 10 livers at autopsy. The livers were perfusion-washed and cast with resin through both the hepatic artery and portal vein branches. The HCCs observed ranged from several millimeters to 3 cm in size. A vascular plexus proliferated around the HCC nodules in all cases. Both portal vein and hepatic artery branches proliferated markedly to form the plexus in 5 patients. These vessels communicated directly with the blood sinuses of the HCCs as feeder vessels. HCC cells replaced normal cells while maintaining the liver’s trabecular structure in 2 cases. At the borders of these HCCs, there was direct communication between the hepatic sinusoids and the tumor blood sinuses. Efferent vessels of the tumors were generally difficult to identify but vessels resembling hepatic vein branches were detected in one 4-mm HCC nodule after microdissection. Thus, HCC was demonstrated to be supplied not only by the hepatic artery but also by the portal vein and hepatic sinusoids. This may be one of the reasons why cancer cells survive in the tumor margins and daughter nodules after transcatheter arterial embolization of HCC.