今日の臨床サポート

急性肝不全

著者: 持田智 埼玉医科大学 消化器内科・肝臓内科

監修: 金子周一 金沢大学大学院

著者校正/監修レビュー済:2021/03/31
参考ガイドライン:
  1. Sugawara K, Nakayama N, Mochida S. Acute liver failure in Japan: definition, classification, and prediction of the outcome. J Gastroenterol. 2012 Aug;47(8):849-61.
  1. Nakao M, Nakayama N, Uchida Y, Tomiya T, Ido A, Sakaida I, Yokosuka O, Takikawa Y, Inoue K, Genda T, Shimizu M, Terai S, Tsubouchi H, Takikawa H, Mochida S. Nationwide survey for acute liver failure and late-onset hepatic failure in Japan. J Gastroenterol. 2018 Jun;53(6):752-769.
患者向け説明資料

概要・推奨   

  1. 正常肝ないし肝予備能が正常と考えられる肝に肝障害が生じ、初発症状出現から8週以内に、高度の肝機能障害に基づいてプロトロンビン時間が40%以下ないしはINR値1.5以上を示すものを「急性肝不全」と診断する。
  1. 急性肝不全昏睡型のうち、成因がウイルス性、自己免疫性、薬物アレルギーなどで、肝炎を伴う症例が劇症肝炎に相当し、劇症肝炎は急性肝不全に含まれる疾患単位である。
  1. 肝炎症例では内科的集学的治療を実施して、死亡が予測される場合は肝移植の適応を検討する。成因に対する治療および肝庇護療法は、肝性脳症を発症する前から、可及的速やかに実施する。昏睡Ⅱ度以上の肝性脳症が出現した場合は、血漿交換とOn-line HDFなどの血液濾過透析による人工肝補助を行う。肝炎以外の症例では、原疾患に対する治療が最も重要である。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
持田智 : 講演料(AbbVie GK,Gilead Sciences Inc.,大塚製薬(株),東レ(株),エーザイ(株),MSD(株),大日本住友製薬(株),あすか製薬(株)),研究費・助成金など(EPSインターナショナル(株),ギリアドサイエンシズ,AbbVie GK),奨学(奨励)寄付など(AbbVie GK,EAファーマ(株),あすか製薬(株),エーザイ(株),大日本住友製薬(株),東レ(株))[2021年]
監修:金子周一 : 研究費・助成金など(バイエル薬品株式会社,株式会社キュービクス,アボットジャパン合同会社,日東電工株式会社,株式会社スギ薬局,株式会社サイトパスファインダー),奨学(奨励)寄付など(小野薬品工業株式会社,エーザイ株式会社,株式会社ツムラ,アッヴィ合同会社,大日本住友製薬株式会社,ゼリア新薬工業株式会社,塩野義製薬株式会社,大塚製薬株式会社,アステラス製薬株式会社,田辺三菱製薬株式会社,マイランEPD合同会社,EAファーマ株式会社,大鵬薬品工業株式会社,中外製薬株式会社,協和キリン株式会社,持田製薬株式会社,日本ケミファ株式会社,LifeScan Japan株式会社)[2021年]

改訂のポイント:
  1.  

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 正常肝ないし肝予備能が正常と考えられる肝に肝障害が生じ、初発症状出現から8週以内に、高度の肝機能障害に基づいてプロトロンビン時間が40%以下ないしはINR値1.5以上を示すものを「急性肝不全」と診断する。
  1. 病型および成因によって分類する。
  1. 病型分類:
  1. 「非昏睡型」肝性脳症が認められない、ないしは昏睡度がⅠ度までの症例
  1. 「昏睡型」 昏睡Ⅱ度以上の肝性脳症を呈する症例で、初発症状発現から昏睡Ⅱ度以上の肝性脳症が出現するまでの期間で、「急性型」と「亜急性型」に分類
  1. 「急性型」 初発症状発現から10日以内に昏睡Ⅱ度以上の肝性脳症を呈する症例
  1. 「亜急性型」初発症状発現から11日以降に昏睡Ⅱ度以上の肝性脳症を呈する症例
  1. 成因分類:
  1. 肝炎症例
  1. ウイルス性(A型、B型[急性感染例、キャリア例]、C型、E型、その他)
  1. 自己免疫性
  1. 薬物性(アレルギー)
  1. 成因不明例
  1. 肝炎以外の症例
  1. 薬物性(中毒)
  1. 代謝性(Wilson病など)
  1. 循環不全
  1. 悪性腫瘍の肝浸潤
  1. その他
  1. 急性肝不全昏睡型のうち、成因がウイルス性、自己免疫性、薬物アレルギーなどで、肝炎を伴う症例が劇症肝炎に相当し、劇症肝炎は急性肝不全に含まれる疾患単位である。
  1. プロトロンビン時間が40%以下ないしはINR値1.5以上で、初発症状出現から8週以降24週以内に昏睡Ⅱ度以上の脳症を発現する症例は「遅発性肝不全」と診断し、「急性肝不全」の類縁疾患として扱う。
  1. わが国における劇症肝炎の推定患者数は年間450例であり、急性肝不全の症例数は年間約1,000~1,200例と推定される。
  1. 類縁疾患であるLOHFは希少疾患であり、年間の患者数は30例程度と考えられている。
  1. 病理組織学的には、急性型は広汎肝壊死、亜急性型は亜広汎肝壊死を呈することが多い。
 
劇症肝炎の剖検所見、病理組織所見

a:剖検肝
b:剖検肝(割面)
c:肝組織像

出典

img1:  著者提供
 
 
 
  1. 全身性炎症反応症候群(systemic inflammatory response syndrome: SIRS)の病態を呈し、多臓器不全(multiple organ failure: MOF)を併発して予後不良の症例が多い。
問診・診察のポイント  
  1. 初発症状の出現時期を特定することが病型分類のために重要である。発熱、食欲不振、全身倦怠感などの発症日を本人ないし家族に確認する。

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文献 

著者: Satoshi Mochida, Yasuhiro Takikawa, Nobuaki Nakayama, Makoto Oketani, Takafumi Naiki, Yoshiyuki Yamagishi, Takafumi Ichida, Hirohito Tsubouchi
雑誌名: Hepatol Res. 2011 Sep;41(9):805-12. doi: 10.1111/j.1872-034X.2011.00860.x.
Abstract/Text The diagnostic criteria of fulminant hepatitis in Japan are different from those of acute liver failure in Europe and the United States, both in regard to the histological features in the liver and the cutoff values of the prothrombin time. Thus, the Intractable Hepato-Biliary Disease Study Group established novel diagnostic criteria for "acute liver failure" in Japan based on the demographic and clinical features of the patients. Patients showing prothrombin time values of 40% or less of the standardized values or international normalized ratios of 1.5 or more caused by severe liver damage within 8 weeks of onset of the symptoms are diagnosed as having "acute liver failure", where the liver function prior to the current onset of liver damage is estimated to be normal. Acute liver failure is classified into "acute liver failure without hepatic coma" and "acute liver failure with hepatic coma," depending on the severity of the hepatic encephalopathy; the latter is further classified into two types, the "acute type" and the "subacute type", in which grade II or more severe hepatic coma develops within 10 days and between 11 and 56 days, respectively, after the onset of disease symptoms. Patients without histological findings of hepatitis, such as those with liver damage caused by drug toxicity, circulatory disturbance or metabolic disease, are also included in the disease entity of "acute liver failure", while acute-on-chronic liver injuries, such as liver injury caused by alcohol, are excluded. A nationwide survey of "acute liver failure" in Japan based on the novel criteria is proposed.

© 2011 The Japan Society of Hepatology.
PMID 21884340  Hepatol Res. 2011 Sep;41(9):805-12. doi: 10.1111/j.1872・・・
著者: Kayoko Sugawara, Nobuaki Nakayama, Satoshi Mochida
雑誌名: J Gastroenterol. 2012 Aug;47(8):849-61. doi: 10.1007/s00535-012-0624-x. Epub 2012 Jul 24.
Abstract/Text Acute liver failure is a clinical syndrome characterized by hepatic encephalopathy and a bleeding tendency due to severe impairment of liver function caused by massive or submassive liver necrosis. Viral hepatitis is the most important and frequent cause of acute liver failure in Japan. The diagnostic criteria for fulminant hepatitis, including that caused by viral infections, autoimmune hepatitis, and drug allergy induced-liver damage, were first established in 1981. Considering the discrepancies between the definition of fulminant hepatitis in Japan and the definitions of acute liver failure in the United States and Europe, the Intractable Hepato-Biliary Disease Study Group established the diagnostic criteria for "acute liver failure" for Japan in 2011, and performed a nationwide survey of patients seen in 2010 to clarify the demographic and clinical features and outcomes of these patients. According to the survey, the survival rates of patients receiving medical treatment alone were low, especially in those with hepatic encephalopathy, despite artificial liver support, consisting of plasma exchange and hemodiafiltration, being provided to almost all patients in Japan. Thus, liver transplantation is inevitable to rescue most patients with hepatic encephalopathy. The indications for liver transplantation had, until recently, been determined according to the guideline published by the Acute Liver Failure Study Group in 1996. Recently, however, the Intractable Hepato-Biliary Disease Study Group established a scoring system to predict the outcomes of acute liver failure patients. Algorithms for outcome prediction have also been developed based on data-mining analyses. These novel guidelines need further evaluation to determine their usefulness.

PMID 22825549  J Gastroenterol. 2012 Aug;47(8):849-61. doi: 10.1007/s0・・・
著者: S Mochida, M Arai, A Ohno, F Yamanobe, K Ishikawa, A Matsui, I Maruyama, H Kato, K Fujiwara
雑誌名: Hepatology. 1999 May;29(5):1532-40. doi: 10.1002/hep.510290533.
Abstract/Text Activated Kupffer cells provoke massive liver necrosis after endotoxin stimulation through microcirculatory disturbance caused by sinusoidal fibrin deposition in rats undergoing 70% hepatectomy. In these rats, serum activities of purine nucleoside phosphorylase (PNP) and alanine transaminase (ALT) were increased at 1 and 5 hours, respectively, following endotoxin administration. When 70% resected liver was perfused with Dulbecco's modified Eagle medium (DMEM) containing heat-inactivated fetal calf serum, the increase in both enzyme activities was not affected by addition of endotoxin during perfusion, suggesting that activated Kupffer cells injured neither sinusoidal endothelial cells nor hepatocytes. The activity of tissue factor, an initiator of blood coagulation cascade, was much higher in Kupffer cells isolated from partially hepatectomized rats than in those from normal rats. In contrast, mRNA expressions of tissue factor pathway inhibitor (TFPI) as well as thrombomodulin were almost undetectable in normal and partially resected livers. When recombinant human TFPI was injected intravenously in 70% hepatectomized rats, TFPI was markedly stained on the surfaces of sinusoidal endothelial cells and microvilli of hepatocytes on immunohistochemistry. In these rats, endotoxin-induced liver injury was significantly attenuated compared with rats given no TFPI. Similar attenuation was also found in rats receiving recombinant human thrombomodulin. These results suggest that fibrin deposition developing in 70% hepatectomized rats after endotoxin administration may be caused by deranged blood coagulation in the hepatic sinusoids through increasing tissue factor activity in Kupffer cells and minimal TFPI and thrombomodulin in endothelial cells. The destruction of sinusoidal endothelial cells as well as hepatocytes may occur as a result of microcirculatory disturbance caused by such sinusoidal fibrin deposition.

PMID 10216139  Hepatology. 1999 May;29(5):1532-40. doi: 10.1002/hep.51・・・
著者: Kenji Fujiwara, Satoshi Mochida, Atsushi Matsui, Nobuaki Nakayama, Sumiko Nagoshi, Gotaro Toda, Intractable Liver Diseases Study Group of Japan
雑誌名: Hepatol Res. 2008 Jul;38(7):646-57. doi: 10.1111/j.1872-034X.2008.00322.x. Epub 2008 Mar 5.
Abstract/Text AIM: A nationwide survey was performed to clarify the present state of fulminant hepatitis and late onset hepatic failure (LOHF) between 1998 and 2003 in Japan.
METHODS: Three hundred and sixteen, 318 and 64 patients, respectively, with acute and subacute types of fulminant hepatitis and LOHF, in which grade II or more severe hepatic encephalopathy occurred within 10 days, between 11 days and 8 weeks and between 8 and 24 weeks, respectively, after the onset of disease symptoms, were analyzed.
RESULTS: Complications such as metabolic syndrome were underlying in 41.5% of patients with subacute fulminant hepatitis and 51.6% of patients with LOHF, and most of such patients had received daily medications. The etiology of fulminant hepatitis was viral infection in 71.2% of the acute type and 31.8% in the subacute type. Hepatitis B virus (HBV) infection was found in most of these patients; transient infection prevailed in the acute type; and HBV carrier prevailed in the subacute type. The etiology was unknown in 42.8% and 53.1% of the subacute type and LOHF, respectively. Autoimmune hepatitis and drug allergy-induced liver injury were found in 10.7% and 11.3%, respectively, of the subacute type. Artificial liver support with plasma exchange and/or hemodiafiltration took place in more than 90% of all patients. The survival rates of the patients without liver transplantation were 53.7% in the acute and 24.4% in the subacute type, and 11.5% in LOHF. The prognosis was especially poor in HBV carriers and patients with autoimmune hepatitis. The survival rates of those who underwent liver transplantation were 56.3%, 39.3% and 23.4% in the acute type, subacute type and LOHF, respectively.
CONCLUSION: The etiology and prognosis differed in patients with fulminant hepatitis and LOHF depending on the disease types in Japan, and liver transplantation improved the prognosis of the patients irrespective of the disease type and etiology.

PMID 18328067  Hepatol Res. 2008 Jul;38(7):646-57. doi: 10.1111/j.1872・・・
著者: Makoto Oketani, Akio Ido, Nobuaki Nakayama, Yasuhiro Takikawa, Takafumi Naiki, Yoshiyuki Yamagishi, Takafumi Ichida, Satoshi Mochida, Saburo Onishi, Hirohito Tsubouchi, Intractable Hepato-Biliary Diseases Study Group of Japan
雑誌名: Hepatol Res. 2013 Feb;43(2):97-105. doi: 10.1111/j.1872-034X.2012.01105.x.
Abstract/Text AIM: To summarize the annual nationwide survey on fulminant hepatitis (FH) and late-onset hepatic failure (LOHF) between 2004 and 2009 in Japan.
METHODS: The annual survey was performed in a two-step questionnaire process to detail the clinical profile and prognosis of patients in special hospitals.
RESULTS: Four hundred and sixty (n = 227 acute type; n = 233 subacute type) patients had FH and 28 patients had LOHF. The mean age of patients with FH and LOHF were 51.1 ± 17.0 and 58.0 ± 14.4 years, respectively. The causes of FH were hepatitis A virus in 3.0%, hepatitis B virus (HBV) in 40.2%, other viruses in 2.0%, autoimmune hepatitis in 8.3%, drug allergy-induced in 14.6% and indeterminate etiology in 29.6% of patients. HBV reactivation due to immunosuppressive therapy was observed in 6.8% of FH patients. The short-term survival rates of patients without liver transplantation (LT) were 48.7% and 24.2% for the acute and subacute type, respectively, and 13.0% for LOHF. The prognosis was poor in patients with HBV reactivation. The implementation rate for LT in FH patients was equivalent to that in the previous survey. The short-term survival rates of total patients, including LT patients, were 54.2% and 40.8% for the acute and subacute type, respectively, and 28.6% for LOHF.
CONCLUSION: The demographic features and etiology of FH patients has gradually changed. HBV reactivation due to immunosuppressive therapy is problematic. Despite advances in therapeutic approaches, the prognosis of patients without LT has not improved.

© 2013 The Japan Society of Hepatology.
PMID 23409848  Hepatol Res. 2013 Feb;43(2):97-105. doi: 10.1111/j.1872・・・
著者: Satoshi Mochida, Masamitsu Nakao, Nobuaki Nakayama, Yoshihito Uchida, Sumiko Nagoshi, Akio Ido, Toshihide Mimura, Masayoshi Harigai, Hiroshi Kaneko, Hiroko Kobayashi, Tetsuya Tsuchida, Hiromichi Suzuki, Nobuyuki Ura, Yuichi Nakamura, Masami Bessho, Kazuo Dan, Shigeru Kusumoto, Yasutsuna Sasaki, Hirofumi Fujii, Fumitaka Suzuki, Kenji Ikeda, Kazuhiko Yamamoto, Hajime Takikawa, Hirohito Tsubouchi, Masashi Mizokami
雑誌名: J Gastroenterol. 2016 Oct;51(10):999-1010. doi: 10.1007/s00535-016-1168-2. Epub 2016 Feb 1.
Abstract/Text BACKGROUND: The significance of HBV reactivation during immunosuppressive therapy was evaluated in three nationwide cohorts including patients with previously resolved HBV (prHBV) infection.
METHODS: The clinical features of 1061 patients with acute liver failure (ALF) or late-onset hepatic failure (LOHF) were retrospectively examined, focusing on those who experienced HBV reactivation. Additionally, 420 patients with prHBV infection were prospectively enrolled: 203 received immunosuppressive therapies immediately after enrollment, while the remaining 217 were enrolled after having received immunosuppressive therapies without the occurrence of HBV reactivation. The serum HBV-DNA levels were prospectively monitored every month, and the incidences of HBV reactivation, defined as a serum HBV-DNA level of 1.3 log IU/ml or more, were evaluated.
RESULTS: In the retrospective study, persistent HBV infection was found in 90 patients, and HBV reactivation was responsible for liver injuries in 50 patients including 23 receiving immunosuppressive therapies (26 with HBs-antigen positivity, 7 with prHBV infection). None of seven patients with prHBV infection were rescued. In the prospective studies, HBV reactivation occurred in ten patients, but preemptive entecavir administration prevented liver injury. The cumulative reactivation rate was 3.2 % at 6 months, and the increase of the rate compared to that at 6 months was +1.5 % at 48 months.
CONCLUSIONS: HBV reactivation during immunosuppression was responsible for liver injuries in a quarter of the ALF/LOHF patients with persistent HBV infection. Early serum HBV-DNA monitoring may improve patient prognosis, since HBV reactivation typically occurs within 6 months of the start of immunosuppressive therapies in patients with prHBV infection.

PMID 26831356  J Gastroenterol. 2016 Oct;51(10):999-1010. doi: 10.1007・・・
著者: Masamitsu Nakao, Nobuaki Nakayama, Yoshihito Uchida, Tomoaki Tomiya, Akio Ido, Isao Sakaida, Osamu Yokosuka, Yasuhiro Takikawa, Kazuaki Inoue, Takuya Genda, Masahito Shimizu, Shuji Terai, Hirohito Tsubouchi, Hajime Takikawa, Satoshi Mochida
雑誌名: J Gastroenterol. 2018 Jun;53(6):752-769. doi: 10.1007/s00535-017-1394-2. Epub 2017 Oct 13.
Abstract/Text BACKGROUND: A nationwide survey was performed to clarify the recent status of acute liver failure (ALF) and late-onset hepatic failure (LOHF) in Japan.
METHODS: Two-step surveys for patients with ALF and LOHF meeting the Japanese diagnostic criteria were performed annually in 782 hospitals. The clinical features of the patients were then compared to those reported in previous surveys.
RESULTS: In total, 1554 and 49 patients with ALF and LOHF, respectively, who were seen between 2010 and 2015 were enrolled. The subjects were classified into 1280 patients with hepatitis (642 non-comatose and 638 comatose) and 323 patients without hepatitis (190 non-comatose and 133 comatose). Compared with patients seen between 1998 and 2009, an older patient age and a higher percentage of underlying extrahepatic disease were observed. Although hepatitis virus infection was the most frequent etiology, the percentage of patients with this etiology had decreased, compared with previous cohorts, while the percentages of patients with drug-induced liver injuries, autoimmune hepatitis, and an indeterminate etiology had increased. Liver transplantation was performed in 170 patients (10.6%), whereas artificial liver support with plasmapheresis and/or hemodiafiltration were performed for most of the comatose patients. The outcomes of comatose patients were unfavorable, similar to previous surveys, especially the outcomes of hepatitis B virus carriers, including those with de novo hepatitis B (survival rate of 5.4% without liver transplantation).
CONCLUSION: Although the clinical features, including the etiologies, of patients with ALF and LOHF have changed, the outcomes of patients have not improved in recent years.

PMID 29030713  J Gastroenterol. 2018 Jun;53(6):752-769. doi: 10.1007/s・・・
著者: Nobuaki Nakayama, Hayato Uemura, Yoshihito Uchida, Tomoaki Tomiya, Akio Ido, Kazuaki Inoue, Takuya Genda, Yasuhiro Takikawa, Isao Sakaida, Shuji Terai, Osamu Yokosuka, Masahito Shimizu, Hajime Takikawa, Satoshi Mochida
雑誌名: Hepatol Res. 2018 Mar;48(4):303-312. doi: 10.1111/hepr.13064.
Abstract/Text AIM: To establish diagnostic criteria for acute-on-chronic liver failure (ACLF) in Japan, a multicenter pilot survey was carried out to examine the usefulness of overseas criteria in patients with chronic liver diseases manifesting acute decompensation.
METHODS: Patients fulfilling the Asian-Pacific Association for the Study of the Liver (APASL), European Association for the Study of the Liver (EASL), or Chinese Medical Association (CMA) criteria for decompensation were enrolled from eight institutions in Japan, and the clinical features were evaluated.
RESULTS: Among 112 patients, 109 patients (97.3%) fulfilled the APASL criteria for decompensation; 7 patients were excluded because the decompensation had been provoked by gastrointestinal bleeding. Consequently, 102 patients (91.1%) were diagnosed as having ACLF according to the APASL definition. Among the patients who fulfilled the APASL criteria for decompensation, the etiologies of the underlying liver diseases were alcohol abuse in 59 cases (54.1%) and hepatitis B or hepatitis C virus infection in 24 (22.0%). The acute insults were alcohol abuse in 50 (45.9%), bacterial infection in 26 (23.9%), and exacerbation of underlying liver disease in 14 (12.8%). Fifty-four patients (49.5%) satisfied the CMA criteria, but the survival rates were similar between patients who did and those who did not meet the criteria. When 84 patients with underlying cirrhosis were classified according to the EASL-Chronic Liver Failure (Clif) Consortium criteria, the survival rates differed according to grade: 67.6% (23/34) for patients without ACLF, and 41.2% (14/34) and 18.8% (3/16) for those with grade 1/2 and grade 3 ACLF, respectively.
CONCLUSION: The APASL definition was suitable for screening Japanese patients with ACLF, including those whose conditions were triggered by gastrointestinal bleeding, and the EASL-Clif Consortium criteria were useful for predicting outcome.

© 2018 The Japan Society of Hepatology.
PMID 29341357  Hepatol Res. 2018 Mar;48(4):303-312. doi: 10.1111/hepr.・・・
著者: Satoshi Mochida, Nobuaki Nakayama, Akio Ido, Kazuaki Inoue, Takuya Genda, Yasuhiro Takikawa, Isao Sakaida, Shuji Terai, Osamu Yokosuka, Masahito Shimizu, Hajime Takikawa
雑誌名: Hepatol Res. 2018 Mar;48(4):219-224. doi: 10.1111/hepr.13066.
Abstract/Text To establish diagnostic criteria for acute-on-chronic liver failure (ACLF) in Japan, the Intractable Hepato-Biliary Disease Study Group of Japan undertook a multicenter pilot survey for patients fulfilling the Asian Pacific Association for the Study of the Liver (APASL), Association for the Study of the Liver-Chronic Liver Failure (EASL-Clif) Consortium, or Chinese Medical Association (CMA) diagnostic criteria for ACLF. The APASL criteria were suitable for screening Japanese patients with ACLF when patients whose conditions were triggered by gastrointestinal bleeding were included within the disease entity, and the EASL-Clif Consortium criteria were useful for classifying the severity of the patients' conditions. Based on these observations, the Study Group proposed the following diagnostic criteria for ACLF in Japan: patients with cirrhosis and a Child-Pugh score of 5-9 should be diagnosed as having ACLF when a deterioration of liver function (serum bilirubin level ≥5.0 mg/dL and prothrombin time value ≤40% of the standardized values and/or international normalization rate ≥1.5) caused by severe liver damage develops within 28 days after acute insults, such as alcohol abuse, bacterial infection, gastrointestinal bleeding, or the exacerbation of underlying liver diseases. The severities of the patients can be classified into four grades depending on the extent of the deterioration in organ functions, including kidney, cerebral, blood coagulation, circulatory and respiratory functions, as well as liver function. The usefulness of these novel criteria should be validated prospectively in a large-scale cohort in the future.

© 2018 The Japan Society of Hepatology.
PMID 29361652  Hepatol Res. 2018 Mar;48(4):219-224. doi: 10.1111/hepr.・・・
著者: Satoshi Mochida, Nobuaki Nakayama, Atsushi Matsui, Sumiko Nagoshi, Kenji Fujiwara
雑誌名: Hepatol Res. 2008 Oct;38(10):970-9. doi: 10.1111/j.1872-034X.2008.00368.x. Epub 2008 May 7.
Abstract/Text AIM: The indications for liver transplantation in cases of fulminant hepatitis are currently determined according to the Guideline of the Acute Liver Failure Study Group of Japan in 1996, which is based on assessment of the prognosis of the patients at the onset of hepatic encephalopathy and reassessed 5 days later. This Guideline was prepared based on the clinical findings in patients seen between 1988 and 1992, and showed a predictive accuracy of 82% in the patients seen between 1993 and 1995. In this study, the usefulness of the Guideline was re-evaluated, since the therapeutic strategies for fulminant hepatitis have advanced remarkably over the last 10 years.
METHODS: The predictive accuracy of the Guideline was assessed in 698 patients with fulminant hepatitis and late onset hepatic failure (LOHF) between 1998 and 2003. The time-point in the course of the disease at which physicians considered liver transplantation was examined.
RESULTS: The accuracy in patients not receiving liver transplantation was 68% and 78% in acute and subacute types, respectively, of fulminant hepatitis, and 84% among LOHF cases. The values did not improve following the reassessment. The sensitivity and specificity of the assessment in patients with acute and subacute types, respectively, were extremely low. Liver transplantation was considered in 42% of LOHF patients at 8 or more days before encephalopathy development.
CONCLUSION: The Guideline should be modified to improve its accuracy. The Guideline should also be made adoptable for the assessment of LOHF patients before hepatic encephalopathy onset.

PMID 18462374  Hepatol Res. 2008 Oct;38(10):970-9. doi: 10.1111/j.1872・・・
著者: Nobuaki Nakayama, Makoto Oketani, Yoshihiro Kawamura, Mie Inao, Sumiko Nagoshi, Kenji Fujiwara, Hirohito Tsubouchi, Satoshi Mochida
雑誌名: J Gastroenterol. 2012 Jun;47(6):664-77. doi: 10.1007/s00535-012-0529-8. Epub 2012 Mar 9.
Abstract/Text BACKGROUND: We established algorithms to predict the prognosis of acute liver failure (ALF) patients through a data-mining analysis, in order to improve the indication criteria for liver transplantation.
METHODS: The subjects were 1,022 ALF patients seen between 1998 and 2007 and enrolled in a nationwide survey. Patients older than 65 years, and those who had undergone liver transplantation and received blood products before the onset of hepatic encephalopathy were excluded. Two data sets were used: patients seen between 1998 and 2003 (n=698), whose data were used for the formation of the algorithm, and those seen between 2004 and 2007 (n=324), whose data were used for the validation of the algorithm. Data on a total of 73 items, at the onset of encephalopathy and 5 days later, were collected from 371 of the 698 patients seen between 1998 and 2003, and their outcome was analyzed to establish decision trees. The obtained algorithm was validated using the data of 160 of the 324 patients seen between 2004 and 2007.
RESULTS: The outcome of the patients at the onset of encephalopathy was predicted through 5 items, and the patients were classified into 6 categories with mortality rates between 23% and89%. When the prognosis of the patients in the categories with mortality rates greater than 50% was predicted as "death", the accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the algorithm were 79, 78, 81, 83, and 75%, respectively. Similar high values were obtained when the algorithm was employed in the patients for validation. The outcome of the patients 5 days after the onset of encephalopathy was predicted through 7 items, and a similar high accuracy was found for both sets of patients.
CONCLUSIONS: Novel algorithms for predicting the outcome of ALF patients may be useful to determine the indication for liver transplantation.

PMID 22402772  J Gastroenterol. 2012 Jun;47(6):664-77. doi: 10.1007/s0・・・
著者: Satoshi Mochida, Nobuaki Nakayama, Akio Ido, Yasuhiro Takikawa, Osamu Yokosuka, Isao Sakaida, Hisataka Moriwaki, Takuya Genda, Hajime Takikawa
雑誌名: Hepatol Res. 2016 Mar;46(5):369-71. doi: 10.1111/hepr.12626. Epub 2016 Jan 19.
Abstract/Text In 2011, the Intractable Liver Diseases Study Group of Japan, established novel diagnostic criteria for "acute liver failure ", and published the classification criteria for the etiologies of acute liver failure and late-onset hepatic failure (LOHF) in 2013. According to this classification, HBV carriers showing acute hepatitis exacerbation were divided into 3 subgroups; asymptomatic or inactive HBV carriers without drug exposure, asymptomatic or inactive HBV carriers developing HBV reactivation during and after immunosuppressive therapies and/or antineoplastic chemotherapies and those with previously resolved HBV infection showing iatrogenic HBV reactivation. In an annual nationwide survey in 2013, however, a patient with previously resolved HBV infection was enrolled, in whom LOHF developed as a result of HBV reactivation despite in the absence of immunosuppressive therapies and/or antineoplastic chemotherapies. Thus, the study group revised the classification criteria in 2015; HBV carriers developing acute hepatitis exacerbation were classified into asymptomatic or inactive HBV carriers and patients with previously resolved HBV infection, and both groups were further sub-classified into those receiving immunosuppressive therapies and/or antineoplastic chemotherapies and those without such drugs exposure.

© 2015 The Japan Society of Hepatology.
PMID 26615003  Hepatol Res. 2016 Mar;46(5):369-71. doi: 10.1111/hepr.1・・・
著者: Noriyo Yamashiki, Yasuhiko Sugawara, Sumihito Tamura, Nobuaki Nakayama, Makoto Oketani, Koji Umeshita, Shinji Uemoto, Satoshi Mochida, Hirohito Tsubouchi, Norihiro Kokudo
雑誌名: Liver Transpl. 2012 Sep;18(9):1069-77. doi: 10.1002/lt.23469.
Abstract/Text Nationwide surveys of acute liver failure (ALF) are conducted annually in Japan, and 20% of patients with ALF undergo liver transplantation (LT). We extracted data for 212 patients who underwent LT for ALF from the nationwide survey database of the Intractable Liver Diseases Study Group of Japan. After the exclusion of 3 patients who underwent deceased donor LT, 209 recipients of living donor liver transplantation (LDLT) were analyzed. ALF patients were placed into 3 subgroups according to the time from the onset of the disease to the occurrence of encephalopathy: patients who presented with encephalopathy within 10 days of the disease's onset were classified as having acute ALF, patients who presented within 11 to 56 days were classified as having subacute ALF, and patients who presented within 9 to 24 weeks were classified as having late-onset hepatic failure (LOHF). Long-term follow-up data were obtained from the registry of the Japanese Liver Transplantation Society. The 2 data sets were merged, and descriptive and survival data were analyzed. A Cox regression analysis was performed to define factors predicting overall mortality, short-term mortality (≤90 days after LT), and long-term mortality (>90 days after LT). One hundred ninety of the analyzed patients (91%) were adults (age ≥ 18 years); 70 patients (34%) were diagnosed with acute ALF, 124 (59%) were diagnosed with subacute ALF, and 15 (7%) were diagnosed with LOHF. Hepatitis B virus was the most common cause of acute ALF (61%), whereas autoimmune hepatitis (14%) and drug allergy-induced hepatitis (14%) were more frequent in patients with subacute ALF or LOHF. The cumulative patient survival rates 1, 5, and 10 years after LT were 79%, 74%, and 73%, respectively. Patient age was associated with short- and long-term mortality after LT, whereas ABO incompatibility affected short-term mortality, and donor age affected long-term mortality. In conclusion, the long-term outcomes of LDLT for ALF in this study were excellent, regardless of the etiology or classification. The majority of the donors were living donors. Increasing the deceased donor pool might be an urgent necessity.

Copyright © 2012 American Association for the Study of Liver Diseases.
PMID 22577093  Liver Transpl. 2012 Sep;18(9):1069-77. doi: 10.1002/lt.・・・
著者: Masamitsu Nakao, Nobuaki Nakayama, Yoshihito Uchida, Tomoaki Tomiya, Makoto Oketani, Akio Ido, Hirohito Tsubouchi, Hajime Takikawa, Satoshi Mochida
雑誌名: Hepatol Res. 2019 Aug;49(8):844-852. doi: 10.1111/hepr.13345. Epub 2019 May 29.
Abstract/Text AIM: A nationwide survey of acute liver failure (ALF) and late-onset hepatic failure (LOHF) has revealed that the outcomes of recent patients whose diseases were caused by infection with hepatitis A virus (HAV) have worsened, compared with those of previously reported patients. The factors associated with this deterioration were evaluated.
METHODS: A total of 83 patients with HAV infection seen between 1998 and 2015 were enrolled. All the patients had a prothrombin time-international normalized ratio of 1.5 or more and hepatic encephalopathy of grade 2 or more severe. The demographic and clinical features of 45 patients seen prior to 2003 (cohort 1) and 38 patients seen during 2004 and thereafter (cohort 2) were compared.
RESULTS: Three and four patients in cohort 1 and cohort 2, respectively, received liver transplantations; the survival rates among the remaining patients were 56% for cohort 2 and 79% for cohort 1 (P < 0.05). The mean age (±standard deviation) of the patients was higher in cohort 2 than in cohort 1 (58 ± 11 vs. 48 ± 13 years; P < 0.01). The percentages of patients with underlying metabolic diseases were 22% in cohort 1 and 61% in cohort 2 (P < 0.01). Diabetic mellitus was more common among deceased patients than among rescued patients (29% vs. 8%; P < 0.05) among patients who did not receive liver transplantations, and a multivariate analysis revealed that patient age and disease type were significantly and independently associated with the outcome.
CONCLUSION: The outcomes of recent patients with ALF or LOHF caused by HAV infection have recently worsened mainly because of an increase in underlying metabolic diseases as a consequence of aging.

© 2019 The Japan Society of Hepatology.
PMID 30957325  Hepatol Res. 2019 Aug;49(8):844-852. doi: 10.1111/hepr.・・・
著者: Takeji Umemura, Kendo Kiyosawa
雑誌名: Intern Med. 2006;45(12):747-8. Epub 2006 Jul 18.
Abstract/Text
PMID 16847362  Intern Med. 2006;45(12):747-8. Epub 2006 Jul 18.
著者: Makoto Oketani, Akio Ido, Hirofumi Uto, Hirohito Tsubouchi
雑誌名: Hepatol Res. 2012 Jul;42(7):627-36. doi: 10.1111/j.1872-034X.2012.00998.x.
Abstract/Text With the increasing use of potent immunosuppressive therapy, reactivation of hepatitis B virus (HBV) in endemic regions is becoming a clinical problem requiring special attention. A recent annual nationwide survey clarified that HBV reactivation related to immunosuppressive therapy has been increasing in patients with malignant lymphoma, other hematological malignancies, oncological or rheumatological disease. In the survey, rituximab plus steroid-containing chemotherapy was identified as a risk factor for HBV reactivation in hepatitis B surface antigen (HBsAg) negative patients with malignant lymphoma. In this setting, HBV reactivation resulted in fatal fulminant hepatitis regardless of the treatment of nucleoside analog. The Intractable Hepatobiliary Disease Study Group and the Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis jointly developed guidelines for preventing HBV reactivation. The essential features of the guideline are as follows. All patients should be screened for HBsAg by a sensitive method before the start of immunosuppressive therapy. Second, hepatitis B core antigen (HBcAb) and hepatitis B surface antibody (HBsAb) testing should be performed in HBsAg negative patients, especially those receiving intensive immunosuppressive therapy. Prophylaxis with nucleoside analogs is essential for preventing HBV reactivation in HBsAg positive patients. In contrast, HBsAg negative with HBcAb and/or HBsAb positive patients should be monitored monthly for an increase in serum HBV DNA during and 12 months after completion of chemotherapy. Nucleoside analogs should be administrated immediately when HBV DNA becomes positive during this period. This strategy facilitates commencement of nucleoside analogs at an early stage of HBV reactivation and results in prevention of severe hepatitis.

© 2012 The Japan Society of Hepatology.
PMID 22686858  Hepatol Res. 2012 Jul;42(7):627-36. doi: 10.1111/j.1872・・・
著者: Shigeru Kusumoto, Yasuhito Tanaka, Ritsuro Suzuki, Takashi Watanabe, Masanobu Nakata, Hirotaka Takasaki, Noriyasu Fukushima, Takuya Fukushima, Yukiyoshi Moriuchi, Kuniaki Itoh, Kisato Nosaka, Ilseung Choi, Masashi Sawa, Rumiko Okamoto, Hideki Tsujimura, Toshiki Uchida, Sachiko Suzuki, Masataka Okamoto, Tsutomu Takahashi, Isamu Sugiura, Yasushi Onishi, Mika Kohri, Shinichiro Yoshida, Rika Sakai, Minoru Kojima, Hiroyuki Takahashi, Akihiro Tomita, Dai Maruyama, Yoshiko Atsuta, Eiji Tanaka, Takayo Suzuki, Tomohiro Kinoshita, Michinori Ogura, Masashi Mizokami, Ryuzo Ueda
雑誌名: Clin Infect Dis. 2015 Sep 1;61(5):719-29. doi: 10.1093/cid/civ344. Epub 2015 May 1.
Abstract/Text BACKGROUND: There is no standard management of reactivation of hepatitis B virus (HBV) infection in HBV-resolved patients without hepatitis B surface antigen (HBsAg), but with antibodies against hepatitis B core antigen and/or antibodies against HBsAg (anti-HBs).
METHODS: We conducted a prospective observational study to evaluate the occurrence of HBV reactivation by serial monthly monitoring of HBV DNA and to establish preemptive therapy guided by this monitoring in B-cell non-Hodgkin lymphoma (B-NHL) treated with rituximab plus corticosteroid-containing chemotherapy (R-steroid-chemo). The primary endpoint was the incidence of HBV reactivation defined as quantifiable HBV DNA levels of ≥ 11 IU/mL.
RESULTS: With a median HBV DNA follow-up of 562 days, HBV reactivation was observed in 21 of the 269 analyzed patients. The incidence of HBV reactivation at 1.5 years was 8.3% (95% confidence interval, 5.5-12.4). No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were between 11 and 432 IU/mL. An anti-HBs titer of <10 mIU/mL and detectable HBV DNA remaining below the level of quantification at baseline were independent risk factors for HBV reactivation (hazard ratio, 20.6 and 56.2, respectively; P < .001). Even in 6 patients with a rapid increase of HBV due to mutations, the monthly HBV DNA monitoring was effective at preventing HBV-related hepatitis.
CONCLUSIONS: Monthly monitoring of HBV DNA is useful for preventing HBV reactivation-related hepatitis among B-NHL patients with resolved HBV infection following R-steroid-chemo (UMIN000001299).

© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
PMID 25935551  Clin Infect Dis. 2015 Sep 1;61(5):719-29. doi: 10.1093/・・・
著者: Hideaki Takahashi, Masafumi Ikeda, Takashi Kumada, Yukio Osaki, Shunsuke Kondo, Shigeru Kusumoto, Kazuyoshi Ohkawa, Seijin Nadano, Junji Furuse, Masatoshi Kudo, Kiyoaki Ito, Masahiro Yokoyama, Takuji Okusaka, Masanori Shimoyama, Masashi Mizokami
雑誌名: Hepatol Res. 2015 Dec;45(12):1220-7. doi: 10.1111/hepr.12496. Epub 2015 Mar 2.
Abstract/Text AIM: The purpose of this multicenter cooperative study was to elucidate the clinical features of hepatitis B virus (HBV) reactivation by chemotherapeutic agents and the patient outcomes after HBV reactivation by a retrospective review of accumulated patients' medical records.
METHODS: Records of a total of 27 patients (hematological malignancy, 14 patients; solid tumor, 13 patients) from 11 institutions who were diagnosed between June 2005 and October 2010 as having HBV reactivation following chemotherapy were reviewed.
RESULTS: Of the 27 patients with reactivation, 16 patients were hepatitis B surface antigen (HBsAg) positive and 11 were HBsAg negative prior to the commencement of chemotherapy. Of the 11 patients who were HBsAg negative prior to the chemotherapy, 10 had hematological malignancies and one had a solid tumor. Of the 14 patients with hematological malignancies with HBV reactivation enrolled in the study, the reactivation occurred more than 12 months after the completion of chemotherapy in five patients (36%); on the other hand, none of the patients (0%) with solid tumors developed HBV reactivation more than 12 months after the completion of chemotherapy. Of the 24 patients who had acute liver dysfunction at the diagnosis of HBV reactivation, nine (38%) had severe hepatitis and seven (29%) died of liver failure.
CONCLUSION: Most of the patients with HBV reactivation who were HBsAg negative prior to the chemotherapy had underlying hematological malignancies. Furthermore, patients with hematological malignancies often developed late-onset HBV reactivation. The prognosis of patients who develop acute liver dysfunction as a complication of HBV reactivation is extremely dismal.

© 2015 The Japan Society of Hepatology.
PMID 25627550  Hepatol Res. 2015 Dec;45(12):1220-7. doi: 10.1111/hepr.・・・
著者: Nobuaki Nakayama, Makoto Oketani, Yoshihiro Kawamura, Mie Inao, Sumiko Nagoshi, Kenji Fujiwara, Hirohito Tsubouchi, Satoshi Mochida
雑誌名: J Gastroenterol. 2011 Sep;46(9):1127-35. doi: 10.1007/s00535-011-0420-z. Epub 2011 May 21.
Abstract/Text BACKGROUND: Patients with acute liver failure are classified according to the interval between the onset of hepatitis symptoms and the development of hepatic encephalopathy. We examined the validity of such classifications.
METHODS: The subjects were 1,022 patients enrolled in a nationwide survey in Japan. The intervals between the onset of the hepatitis symptoms and the development of encephalopathy were 10 days or less in 472 patients (group-A), between 11 and 56 days in 468 patients (group-B), and longer than 56 days in 82 patients (group-C). Data on a total of 104 items collected from the patients were subjected to clustering using a self-organizing map.
RESULTS: The patients were classified into three clusters. The first cluster consisted of 411 patients (group-A: 57%, group-B: 39%, group-C: 4%). Their incidence of complications was low; 34% underwent liver transplantation (LT), and their survival rate was 90%, while 94% of those treated without transplant were rescued. The second cluster consisted of 320 patients (21, 65, and 14% groups A, B, and C, respectively), who showed a high incidence of complications; the survival rate was 7% in the patients treated conservatively without LT. Sixteen percent underwent LT and survival rate of these patients was 52%. There was a third cluster, of 291 patients (59, 34, and 7% groups A, B, and C, respectively). Without LT, 81% of the patients died. Seven percent were treated by LT and their survival rate was 60%.
CONCLUSIONS: Clustering revealed that patients with acute liver failure could be classified into three clusters independent of the interval between the onset of disease symptoms and the development of encephalopathy. This technique may be useful, since the outcomes of the patients differed markedly among the clusters.

PMID 21603944  J Gastroenterol. 2011 Sep;46(9):1127-35. doi: 10.1007/s・・・
著者: Keiichi Fujiwara, Osamu Yokosuka, Kazuaki Inoue, Shin Yasui, Ryuzo Abe, Shigeto Oda, Shinju Arata, Yasuhiro Takikawa, Akio Ido, Satoshi Mochida, Hirohito Tsubouchi, Hajime Takikawa, Intractable Hepato-Biliary Disease Study Group of Japan
雑誌名: Hepatol Res. 2016 Jan;46(1):10-2. doi: 10.1111/hepr.12543.
Abstract/Text
PMID 26096326  Hepatol Res. 2016 Jan;46(1):10-2. doi: 10.1111/hepr.125・・・

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