Kunihide Ishii

Effect of interferon treatment on serum 2',5'-oligoadenylate synthetase levels in hepatitis C-infected patients.

Interferon (IFN) is widely used for patients with hepatitis C. Less than half of treated patients respond to IFN therapy, however, and increased resistance to IFN is particularly observed in genotype 1b patients. Recently, genotype 1b patients with the wild type sequence in the NS5A gene were shown to be resistant to therapy, suggesting that the NS5A protein may be involved to IFN resistance. Thus, we investigated the serum 2′,5′‐oligoadenylate synthetase (2′,5′‐OAS) levels before and during IFN treatment. In addition, other biochemical markers and NS5A mutations were also examined in 30 HCV genotype 1b‐positive patients. Before IFN treatment, 2′,5′‐OAS activity in sera was significantly lower in wild type patients than in mutant type patients. All patients were subsequently enrolled in IFN therapy, and 2′,5′‐OAS activity was elevated both in wild and mutant type patients, irrespective of the number of mutations in NS5A. Logistic regression analysis revealed that clearance of serum HCV RNA was independently related to the pretreatment viral load and NS5A mutations, but not to serum 2′,5′‐OAS activity. We concluded that the NS5A protein, that is associated with the outcome of IFN therapy, affects the kinetics of IFN‐induced molecules, such as 2′,5′‐OAS. 2′,5′‐OAS activity does not, however, seem to be related to long‐term virological response to IFN therapy. J. Med. Virol. 62:185–190, 2000.

Erythropoietic protoporphyria with fatal liver failure.

Abstract: A 33-year-old woman with a history of photosensitivity, persistent abdominal pain, and liver dysfunction was admitted to our department because of abdominal pain and progression of liver dysfunction. On admission, levels of protoporphyrin and coproporphyrin within erythrocytes were markedly increased. Autofluorescent erythrocytes were also detected, leading to a diagnosis of erythropoietic protoporphyria. A liver biopsy specimen revealed cirrhosis with dark brown granules filling hepatocytes, bile canaliculi, and bile ductules. Transfusion of washed erythrocytes, hemodialysis, and administration of cholestyramine and beta-carotene transiently improved levels of porphyrins and liver function. The patient died of rupture of esophageal varices followed by multiple organ failure. However, the treatments were believed to have extended survival.

Severe alcoholic hepatitis successfully treated by leukocytapheresis: a case report.

BACKGROUND The prognosis of severe alcoholic hepatitis is poor, and there is no established method for a cure. METHODS A 34-year-old man was admitted to Kurume University Hospital because of severe liver dysfunction due to excess alcohol intake. He was treated with prednisolone and two sessions of granulocyte and monocyte adsorption apheresis (GCAP) using an Adacolumn, which removes leukocytes--especially granulocytes and monocytes--from the peripheral blood. We evaluated the changes in the serum levels of interleukin-6, interleukin-8, tumor necrosis factor-alpha, and soluble intercellular adhesion molecule-1, as well as the conventional liver tests and peripheral white blood cell count. RESULTS Prednisolone was effective in the short term but resulted in an increase in C-reactive protein (CRP), peripheral leukocytes, and serum total bilirubin. GCAP performed on the 34th and 41st hospital days produced decreases in the white blood cell count, total bilirubin, and intercellular adhesion molecule-1. The patient survived, despite the expected poor prognosis on admission. CONCLUSIONS GCAP is recommended as a potential therapeutic option for severe alcoholic hepatitis.

Evaluation of Resistance-Associated Substitutions in NS5A Using Direct Sequence and Cycleave Method and Treatment Outcome with Daclatasvir and Asunaprevir for Chronic Hepatitis C Genotype 1.

Background The aim of this study was to evaluate the efficacy of daclatasvir plus asunaprevir therapy in patients infected with hepatitis C virus and determine its relevance to resistant variants. Methods A total of 629 consecutive patients infected with hepatitis C virus genotype 1 were assessed. Daclatasvir (60 mg/day) plus asunaprevir (200 mg/day) was given for 24 weeks. The virological responses and resistance-associated substitutions of hepatitis C virus mutants were examined by the direct sequence and cycleave methods were evaluated. Results Overall, 89.4% (555/621) of patients exhibited a sustained virological response (SVR). The SVR rates in the patients with wild type, mixed, and mutant type Y93 by direct sequencing were 92.5% (520/562), 70.3% (26/37), and 42.9% (9/21), respectively. The SVR rates in the patients with 100%, 90%, 80%-30%, and 20%-0% Y93 wild by the cycleave method were 93.4% (456/488), 88.2%(30/34), 56.0%(14/25), and 36.8%(7/19), respectively. In contrast, the SVR rates for the wild type and mixed/mutant type L31 by direct sequencing were 90.2% (534/592) and 72.4% (21/29), respectively. In the multivariate analyses, the wild type Y93, no history of simeprevir therapy, the wild type L31, and low HCV RNA level were independent factors of SVR. Conclusion NS5A resistance-associated substitutions, especially Y93H, were major factors predicting the SVR. Although direct sequencing can predict the SVR rate, the cycleave method is considered to be more useful for predicting the SVR when used in combination.

Gender difference in alcoholic liver disease in Japan : an analysis based on histological findings

Abstract Gender difference in alcoholic liver disease was evaluated in histologically-proven, hepatitis C virus-negative Japanese patients. The mode of drinking and cumulative alcohol intake were compared according to histological groups. Daily amount of alcohol did not differ between men and women. Mean duration of drinking was shorter and cumulative alcohol intake was smaller in women. However, the mean daily alcohol consumption was greater in women and cumulative alcohol intake did not differ in both gender when alcohol amount was adjusted to body weight. A significant predominance in female patients was shown by analysis on contingency tables in histologically-matched patient group with cumulative alcohol intake less than 500 kg for alcoholic hepatitis, less than 600 kg for hepatic fibrosis and less than 800 kg for liver cirrhosis. In conclusion, women are at risk of developing alcoholic liver disease with fewer cumulative alcohol intake compared with men in hepatitis C virus-negative patients.

Selection of Prognostic Factors of Acute Hepatitis Type Non-a, Non-B for Patient Listing for Liver Transplantation

The aim of this study was to select prognostic factors from information available on admission in order to list patients for liver transplantation before the onset of hepatic encephalopathy in patients with fatal hepatitis type non-A, non-B. Information regarding patient profile and biochemical data obtained on admission was analyzed by multiple stepwise logistic regression, and independent prognostic factors related to death were selected. Four parameters were selected as independent prognostic factors. Patient age (over 50 years), serum total bilirubin level (over 10 mg/dl), peripheral leukocyte count, and prothrombin time were independently related to death. Positive predictive value, negative predictive value, and predictive accuracy were 0.86, 0.79, and 0.84, respectively. Our model is able to predict a patients fatal outcome much earlier than other currently used models. It will be helpful for early referral to a transplant center.

The Role of Neutrophils in Liver Cell Injury in Alcoholic Hepatitis

We describe the role of neutrophils in the pathogenesis of alcoholic hepatitis (AH). Endotoxemia, leukocytosis in the peripheral blood, and infiltration of the liver by neutrophils are common features in patients with AH.

Significance of prognostic prediction and cost-benefit-analysis in intensive therapy in fulminant hepatitis.

最近3年間に当施設で経験した劇症肝炎12例の総医療費について調べ, さらに予後予測と実際の予後との見直しを行い, 予後判定の有用性の有無や社会的問題点などについて検討した. 非A非B非C型の劇症肝炎亜急性型の8例はすべて死亡した. 予後予測による予後判定では, 高橋らのLogistic analysisおよび肝移植適応ガイドライン案では全例に転帰の一致をみた. 60日以上延命できたが肝不全のために死亡した亜急性型の3症例では, 総医療費も膨大となった. 平均15日の治療期間で, 1日あたりの医療費が40万円を超える例が5例 (42%) に認められた. 劇症肝炎の集中治療においては, 1カ月に約1000万の医療費が必要と考えられた. 以上より劇症肝炎亜急性型で死亡が予測された症例では, 早期に肝移植を考慮すべきであり, 十分なインフォームドコンセントのもとに家族の同意を得た治療法を選択する必要がある.

Serum type III procollagen N paptide(PIIIP) and laminin levels and hepatic immunohistochemical study in patients with various liver diseases.

各種肝疾患95例における血清タイプIIIプロコラーゲンNペプチド(PIIIP)やラミニン値の変動と肝生検組織における肝線維化,細胞浸潤および巣状壊死の程度,タイプIIIコラーゲンやラミニンの分布およびその産生細胞を観察し,さらに血清PIIIP,ラミニン値が肝線維化のマーカーになり得るか否かを検討した.血清PIIIPは活動性の肝病変を呈する疾患で高値を呈し,肝細胞障害に伴なうタイプIIIコラーゲンの形成を反映するものと思われた.また,血清ラミニンは肝線維化の高度な肝疾患例で高値を呈し,基底膜形成の増加をよく反映するものと思われ,血清PIIIPとラミニンを同時に測定することは,肝疾患の活動性,線維化の形成および程度の判定に有用と思われた.また,タイプIIIコラーゲンは伊東細胞,肝細胞,内皮細胞や線維芽細胞,ラミニンは内皮細胞,伊東細胞,肝細胞および胆管上皮細胞などにより産生されることが示唆された.

Study of liver disease in alcoholic patients.

常習飲酒家肝障害200症例の組織学的分類を行い,各病型別に,断酒後の肝機能の推移・背景因子・個々の組織所見・アルコールで変化した肝細胞膜に対する血中抗体(以下,ア-肝細胞膜抗体)の出現頻度などについて比較検討した.常習飲酒家肝障害で組織学的に慢性肝炎の像を呈した例(以下,常習飲酒家慢性肝炎)のうち,特に活動型の症例は,断酒後血清トランスアミナーゼ値の異常が持続する頻度が高く,病歴上,肝炎ウイルスの関与した症例が多い.組織学的にもpiecemeal necrosis・円形細胞浸潤などウイルス性慢性肝炎を思わせる所見が,有意に高頻度で認められた.また,常習飲酒家慢性肝炎例では他の常習飲酒家肝障害と比べて1日の平均飲酒量は少なく,断酒早期の血清中のア-肝細胞膜抗体の出現頻度も10例中3例30%と最も低く,その成因として,免疫学的機序の関与よりもむしろ,肝炎ウイルス関与の可能性が強く示唆された.