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劇症肝炎、LOHFのうち肝炎症例の治療体系

急性肝不全、LOHF(肝炎症例)の治療体系
出典
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1: 著者提供

急性肝不全の診断基準

[ID0603]:急性肝不全の成因分類
出典
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1: 持田智、滝川康裕ほか:我が国における「急性肝不全」の概念,診断基準の確立:厚生労働省科学研究費補助金(難治性疾患克服研究事業)「難治性の肝・胆道疾患に関する調査研究」班,ワーキンググループ-1,研究報告: 肝臓 2011: 52(6): p395, Table 1

劇症肝炎の診断基準

出典
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1: 持田智:劇症肝炎:わが国における問題点: 肝臓 2009: 50(9): p498, Table 1

急性肝不全の成因分類

出典
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1: 厚生労働省「難治性の肝・胆道疾患に関する調査研究」班:急性肝不全の成因分類 2015年改訂版.

急性肝不全、LOHFの成因(2010~2015年:1,603例)

出典
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1: Nationwide survey for acute liver failure and late-onset hepatic failure in Japan.
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.
J Gastroenterol. 2018 Jun;53(6):752-769. doi: 10.1007/s00535-017-1394-...

急性肝不全、LOHFの背景成因と予後(2010~2015年の発症例)

出典
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1: Nationwide survey for acute liver failure and late-onset hepatic failure in Japan.
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.
J Gastroenterol. 2018 Jun;53(6):752-769. doi: 10.1007/s00535-017-1394-...

劇症肝炎の肝移植適応ガイドライン(新)

劇症肝炎、LOHFのスコアリングシステムによる予後予測。
出典
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1: 厚生労働省「難治性の肝・胆道疾患に関する調査研究」班:劇症肝炎の肝移植適応ガイドライン・スコアリングシステム, 2009年.

急性肝不全(肝炎症例)の治療(2010~2015年の発症例)

急性肝不全、LOHFのうち肝炎の1,280症例に対する各種治療法の実施頻度(%)
出典
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1: Nationwide survey for acute liver failure and late-onset hepatic failure in Japan.
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.
J Gastroenterol. 2018 Jun;53(6):752-769. doi: 10.1007/s00535-017-1394-...

急性肝不全およびLOHFの合併症(2010~2015年の発症例)

急性肝不全、LOHFに見られる合併症の頻度(%)
出典
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1: Nationwide survey for acute liver failure and late-onset hepatic failure in Japan.
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.
J Gastroenterol. 2018 Jun;53(6):752-769. doi: 10.1007/s00535-017-1394-...

免疫抑制・化学療法により発症するB型肝炎対策ガイドライン

補足:血液悪性疾患に対する強力な化学療法中あるいは終了後に、HBs抗原陽性あるいはHBs抗原陰性例の一部においてHBV再活性化によりB型肝炎が発症し、その中には劇症化する症例があり、注意が必要である。また、血液悪性疾患または固形癌に対する通常の化学療法およびリウマチ性疾患・膠原病などの自己免疫疾患に対する免疫抑制療法においてもHBV再活性化のリスクを考慮して対応する必要がある。通常の化学療法および免疫抑制療法においては、HBV再活性化、肝炎の発症、劇症化の頻度は明らかでなく、ガイドラインに関するエビデンスは十分ではない。また、核酸アナログ投与による劇症化予防効果を完全に保証するものではない。
注1) 免疫抑制・化学療法前に、HBVキャリアおよび既往感染者をスクリーニングする。HBs抗原、HBc抗体およびHBs抗体を測定し、HBs抗原が陽性のキャリアか、HBs抗原が陰性でHBs抗体、HBc抗体のいずれか、あるいは両者が陽性の既往感染かを判断する。HBs抗原・HBc抗体およびHBs抗体の測定は、高感度の測定法を用いて検査することが望ましい。また、HBs抗体単独陽性(HBs抗原陰性かつHBc抗体陰性)例においても、HBV再活性化は報告されており、ワクチン接種歴が明らかである場合を除き、ガイドラインに従った対応が望ましい。
注2) HBs抗原陽性例は肝臓専門医にコンサルトすること。また、すべての症例において核酸アナログの投与開始ならびに終了にあたって肝臓専門医にコンサルトするのが望ましい。
注3) 初回化学療法開始時にHBc抗体、HBs抗体未測定の再治療例および既に免疫抑制療法が開始されている例では、抗体価が低下している場合があり、HBV DNA定量検査などによる精査が望ましい。
注4) 既往感染者の場合は、リアルタイムPCR法によりHBV DNAをスクリーニングする。
注5)
a. リツキシマブ・オビヌツズマブ(±ステロイド)、フルダラビンを用いる化学療法および造血幹細胞移植:既往感染者からのHBV再活性化の高リスクであり、注意が必要である。治療中および治療終了後少なくとも12か月の間、HBV DNAを月1回モニタリングする。造血幹細胞移植例は、移植後長期間のモニタリングが必要である。
b. 通常の化学療法および免疫作用を有する分子標的治療薬を併用する場合:頻度は少ないながら、HBV再活性化のリスクがある。HBV DNA量のモニタリングは1~3か月ごとを目安とし、治療内容を考慮して間隔および期間を検討する。血液悪性疾患においては慎重な対応が望ましい。
c. 副腎皮質ステロイド薬、免疫抑制薬、免疫抑制作用あるいは免疫修飾作用を有する分子標的治療薬による免疫抑制療法:HBV再活性化のリスクがある。免疫抑制療法では、治療開始後および治療内容の変更後(中止を含む)少なくとも6か月間は、月1回のHBV DNA量のモニタリングが望ましい。なお、6か月以降は3か月ごとのHBV DNA量測定を推奨するが、治療内容に応じて高感度HBs抗原測定(感度 0.005IU/mL)で代用することを考慮する。
注6) 免疫抑制・化学療法を開始する前、できるだけ早期に核酸アナログ投与を開始する。ことに、ウイルス量が多いHBs抗原陽性例においては、核酸アナログ予防投与中であっても劇症肝炎による死亡例が報告されており、免疫抑制・化学療法を開始する前にウイルス量を低下させておくことが望ましい。
注7) 免疫抑制・化学療法中あるいは治療終了後に、HBV DNA量が20IU/ml(1.3LogIU/mL)以上になった時点で直ちに核酸アナログ投与を開始する(20IU/mL未満陽性の場合は、別のポイントでの再検査を推奨する)。また、高感度HBs抗原モニタリングにおいて1IU/mL未満陽性(低値陽性)の場合は、HBV DNAを追加測定して20IU/mL以上であることを確認した上で核酸アナログ投与を開始する。免疫抑制・化学療法中の場合、免疫抑制薬や免疫抑制作用のある抗腫瘍薬は直ちに投与を中止するのではなく、対応を肝臓専門医と相談する。
注8) 核酸アナログは薬剤耐性の少ないETV、TDF、TAFの使用を推奨する。
注9) 下記の①か②の条件を満たす場合には核酸アナログ投与の終了が可能であるが、その決定については肝臓専門医と相談した上で行う。
 ①スクリーニング時にHBs抗原陽性だった症例では、B型慢性肝炎における核酸アナログ投与終了基準を満たしていること。
②スクリーニング時にHBc抗体陽性またはHBs抗体陽性だった症例では、(1)免疫抑制・化学療法終了後、少なくとも12か月間は投与を継続すること。(2)この継続期間中にALT(GPT)が正常化していること(ただしHBV以外にALT異常の原因がある場合は除く)。(3)この継続期間中にHBV DNAが持続陰性化していること。(4)HBs抗原およびHBコア関連抗原も持続陰性化することが望ましい。
注10) 核酸アナログ投与終了後少なくとも12か月間は、HBV DNAモニタリングを含めて厳重に経過観察する。経過観察方法は各核酸アナログの使用上の注意に基づく。経過観察中にHBV DNA量が20IU/mL(1.3 LogIU/mL)以上になった時点で直ちに投与を再開する。
出典
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1: 日本肝臓学会 肝炎診療ガイドライン作成委員会 編「B型肝炎治療ガイドライン(第3.4版)」2021年5月, P78-80, 図8             https://www.jsh.or.jp/medical/guidelines/jsh_guidlines/hepatitis_b(2022年1月参照)

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
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1: 著者提供

肝性脳症の昏睡度分類(犬山シンポジウム:1972年)

出典
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1: 厚生労働省「難治性の肝・胆道疾患に関する調査研究」班編:我が国における「急性肝不全」の概念、診断基準の確立, 肝臓, 2011; 52(6), p61:395, table 2.

小児肝性昏睡の分類 (第5回小児肝臓ワークショップ:1988年)

出典
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1: 厚生労働省「難治性の肝・胆道疾患に関する調査研究」班編:我が国における「急性肝不全」の概念、診断基準の確立, 肝臓, 2011; 52(6), p62:396, table 3.

わが国におけるacute-on chronic liver failure(ACLF)の重症度分類

出典
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1: 持田智,中山伸朗,寺井崇二,吉治仁志,清水雅仁,井戸章雄,井上和明,玄田拓哉,滝川康裕,高見太郎,加藤直也,阿部雅則,安部隆三,乾あやの,大平弘正,笠原群生,茶山一彰,長谷川潔,田中 篤.わが国におけるacute-on-chronic liver failure(ACLF)とその関連病態の診断基準: 肝臓 2022; 63 (5): 219-223.

決定木法による急性肝不全、LOHF(肝炎症例)の予後予測

出典
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1: Algorithm to determine the outcome of patients with acute liver failure: a data-mining analysis using decision trees.
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.
J Gastroenterol. 2012 Jun;47(6):664-77. doi: 10.1007/s00535-012-0529-8...

劇症肝炎、LOHFのうち肝炎症例の治療体系

急性肝不全、LOHF(肝炎症例)の治療体系
出典
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1: 著者提供

急性肝不全の診断基準

[ID0603]:急性肝不全の成因分類
出典
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1: 持田智、滝川康裕ほか:我が国における「急性肝不全」の概念,診断基準の確立:厚生労働省科学研究費補助金(難治性疾患克服研究事業)「難治性の肝・胆道疾患に関する調査研究」班,ワーキンググループ-1,研究報告: 肝臓 2011: 52(6): p395, Table 1