今日の臨床サポート

門脈圧亢進

著者: 入江真1) 福岡大学西新病院

著者: 向坂彰太郎2) 福岡大学 医学科消化器内科学

監修: 金子周一 金沢大学大学院

著者校正/監修レビュー済:2021/02/03
参考ガイドライン:
  1. 日本消化器病学会:肝硬変診療ガイドライン2015 (改訂第2版)
患者向け説明資料

概要・推奨   

  1. 肝硬変患者の意識障害は、肝性脳症を念頭に置いて検査をすることが勧められる(推奨度1)
  1. 肝硬変患者の吐下血は、食道静脈瘤破裂を念頭に置いて速やかに検査をすることが勧められる(推奨度1)
  1. 肝硬変患者の発熱、腹痛、腹満感は、特発性細菌性腹膜炎を念頭に置いて検査をすることが勧められる(推奨度1)
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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:
入江真 : 特に申告事項無し[2021年]
向坂彰太郎 : 特に申告事項無し[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. 定期レビューを行い、門脈圧亢進症治療について改訂を行った。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 門脈圧亢進症は、門脈系のいずれかの部位で血流が障害され、門脈圧亢進を来すことにより生じる臨床症状群を総称するものである。
  1. 門脈圧亢進症を来す基礎疾患は、肝硬変症、特発性門脈圧亢進症、原発性肝癌、肝外門脈閉塞症、Budd-Chiari症候群などがある。
 
門脈圧亢進症の分類

門脈うっ滞の原因を肝前性、肝内性、肝後性に分類した。

 
  1. 臨床症状群の主たるものに、脾腫ならびに脾機能亢進症、食道・胃静脈瘤をはじめとする門脈-大循環側副血行路、肝性脳症、肝性腹水などがある。
  1. 特発性門脈圧亢進症は指定難病であり、門脈血行異常症の診断と治療のガイドライン(2013年)における特発性門脈圧亢進症重症度分類を用いて重症度III度以上の場合などでは、申請し認定されると、保険料の自己負担分の一部が公費負担として助成される。([平成27年1月施行])
  1.  難病法に基づく医療費助成制度 
問診・診察のポイント  
  1. 食道・胃静脈瘤破裂(問診、バイタル測定、上部内視鏡検査)

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文献 

著者: Pere Ginès, Andrés Cárdenas, Vicente Arroyo, Juan Rodés
雑誌名: N Engl J Med. 2004 Apr 15;350(16):1646-54. doi: 10.1056/NEJMra035021.
Abstract/Text
PMID 15084697  N Engl J Med. 2004 Apr 15;350(16):1646-54. doi: 10.1056・・・
著者: Yasutoshi Muto, Shunichi Sato, Akiharu Watanabe, Hisataka Moriwaki, Kazuyuki Suzuki, Akinobu Kato, Masahiko Kato, Teiji Nakamura, Kiyohiro Higuchi, Shuhei Nishiguchi, Hiromitsu Kumada, Long-Term Survival Study Group
雑誌名: Clin Gastroenterol Hepatol. 2005 Jul;3(7):705-13.
Abstract/Text BACKGROUND & AIMS: Nutritional intervention with branched-chain amino acid (BCAA) is reported to increase serum albumin concentration in patients with decompensated cirrhosis. However, a definite conclusion on whether it can improve patients' survival has not yet been reached. The present study aimed to test possibilities of improving survival of patients with decompensated cirrhosis by using a BCAA preparation that is suitable for long-term oral administration.
METHODS: A multicenter, randomized, and nutrient intake-controlled trial on the comparative effects of BCAA orally administered at 12 g/day for 2 years versus diet therapy with defined daily food intake (1.0-1.4 g protein kg(-1) day(-1) including BCAA preparation and 25-35 kcal kg(-1) day(-1)) was conducted in 646 patients with decompensated cirrhosis. The primary end point was a composite of death by any cause, development of liver cancer, rupture of esophageal varices, or progress of hepatic failure (event-free survival). The secondary end points were serum albumin concentration and health-related quality of life (QOL) measured by Short Form-36 questionnaire.
RESULTS: The incidence of events comprising the primary end point significantly decreased in the BCAA group as compared with the diet group (hazard ratio, 0.67; 95% confidence interval, 0.49-0.93; P = .015; median observation period, 445 days). Serum albumin concentration increased significantly in the BCAA group as compared with the diet group (P = .018). The "general health perception" domain in Short Form-36 measures was also improved (P = .003). Patients' adherence to the prescription was favorable.
CONCLUSIONS: Oral supplementation with a BCAA preparation that can be administered for a long period improves event-free survival, serum albumin concentration, and QOL in patients with decompensated cirrhosis with an adequate daily food intake.

PMID 16206505  Clin Gastroenterol Hepatol. 2005 Jul;3(7):705-13.
著者: Giulio Marchesini, Giampaolo Bianchi, Manuela Merli, Piero Amodio, Carmine Panella, Carmela Loguercio, Fillipo Rossi Fanelli, Roberto Abbiati, Italian BCAA Study Group
雑誌名: Gastroenterology. 2003 Jun;124(7):1792-801.
Abstract/Text BACKGROUND & AIMS: The role of oral supplementation with branched-chain amino acids (BCAA) in advanced cirrhosis is far from settled. A nutritional approach might prevent progressive liver failure and improve nutritional parameters and quality of life.
METHODS: A multicenter, randomized study comparing 1-year nutritional supplementation with BCAA against lactoalbumin or maltodextrins was performed in 174 patients with advanced cirrhosis. Primary outcomes were the prevention of a combined end point (death and deterioration to exclusion criteria), the need for hospital admission, and the duration of hospital stay. Secondary outcomes were nutritional parameters, laboratory data and Child-Pugh score, anorexia, health-related quality of life, and need for therapy.
RESULTS: Treatment with BCAA significantly reduced the combined event rates compared with lactoalbumin (odds ratio, 0.43; 95% confidence interval, 0.19-0.96; P = 0.039) and nonsignificantly compared with maltodextrins (odds ratio, 0.51; 95% confidence interval, 0.23-1.17; P = 0.108). The average hospital admission rate was lower in the BCAA arm compared with control treatments (P = 0.006 and P = 0.003, respectively). In patients who remained in the study, nutritional parameters and liver function tests were, on average, stable or improved during treatment with BCAA and the Child-Pugh score decreased (P = 0.013). Also, anorexia and health-related quality of life (SF-36 questionnaire) improved. Long-term compliance with BCAA was poor.
CONCLUSIONS: In advanced cirrhosis, long-term nutritional supplementation with oral BCAA is useful to prevent progressive hepatic failure and to improve surrogate markers and perceived health status. New formulas are needed to increase compliance.

PMID 12806613  Gastroenterology. 2003 Jun;124(7):1792-801.
著者: B A Runyon
雑誌名: Hepatology. 1998 Jan;27(1):264-72. doi: 10.1002/hep.510270139.
Abstract/Text Ascites is the most common of the major complications of cirrhosis. The development of ascites is an important landmark in the natural history of cirrhosis and has been proposed as an indication for liver transplantation. The initial evaluation of a patient with ascites should include a history, physical evaluation, and abdominal paracentesis with ascitic fluid analysis. Treatment should consist of abstinence from alcohol, sodium restricted diet, and diuretics. This regimen is effective in approximately 90% of patients. The treatment options for the diuretic-resistant patients include serial therapeutic paracenteses, liver transplantation, and peritoneovenous shunting.

PMID 9425946  Hepatology. 1998 Jan;27(1):264-72. doi: 10.1002/hep.510・・・
著者: P Ginès, M Guevara, D De Las Heras, V Arroyo
雑誌名: Aliment Pharmacol Ther. 2002 Dec;16 Suppl 5:24-31.
Abstract/Text Renal function abnormalities and ascites in cirrhosis are the final consequence of a circulatory dysfunction characterized by marked splanchnic arterial vasodilation. This causes a reduction in effective arterial blood volume and the homoeostatic activation of vasoconstrictor and sodium-retaining systems. Albumin is very effective in preventing renal failure associated with large-volume paracentesis and spontaneous bacterial peritonitis, conditions that are known to cause an impairment of circulatory function in patients with cirrhosis and ascites. Moreover, albumin administration improves survival in patients with spontaneous bacterial peritonitis. In patients with hepatorenal syndrome the administration of vasoconstrictor drugs in combination with albumin improves circulatory and renal function markedly and survival slightly. By contrast, the administration of albumin without vasoconstrictors has marginal or no effects on renal function in this setting.

PMID 12423450  Aliment Pharmacol Ther. 2002 Dec;16 Suppl 5:24-31.
著者: Isao Sakaida, Seiji Kawazoe, Kozo Kajimura, Takafumi Saito, Chiaki Okuse, Koichi Takaguchi, Mitsuru Okada, Kiwamu Okita, ASCITES-DOUBLEBLIND Study Group
雑誌名: Hepatol Res. 2014 Jan;44(1):73-82. doi: 10.1111/hepr.12098. Epub 2013 Apr 3.
Abstract/Text AIM: Hepatic edema is manifested by ascites, lower limb edema and intolerable symptoms. Some patients insufficiently respond to the conventional diuretic therapy. Therefore, a novel therapeutic option is required. We conducted a phase 3 study to confirm therapeutic effect of tolvaptan on hepatic edema associated with liver cirrhosis.
METHODS: In our multicenter, randomized, double-blind, placebo-controlled trial, liver cirrhosis patients who showed insufficient response to conventional diuretics were randomly assigned to 7-day administration of either tolvaptan at 7.5 mg/day or placebo as an add-on therapy to conventional diuretics. The primary outcome was change in bodyweight from baseline.
RESULTS: Of 164 eligible patients, 84 were assigned to tolvaptan and 80 to placebo. Change in bodyweight from baseline on the final dosing day was -0.44 kg (standard deviation [SD], 1.93) in the placebo group and -1.95 kg (SD, 1.77) in the tolvaptan group (P < 0.0001). Improvement rates for lower limb edema and ascites-related clinical symptoms were higher with tolvaptan than with placebo. Even in patients with low serum albumin (<2.5 g/dL), decrease in bodyweight was greater with tolvaptan than with placebo (P = 0.0163). In addition, tolvaptan significantly increased serum sodium concentration from baseline.
CONCLUSION: Add-on therapy with tolvaptan was effective for the treatment of hepatic edema and ascites-related clinical symptoms. Furthermore, tolvaptan is expected to improve low serum sodium concentration and to exert its effect regardless of serum albumin level. Add-on therapy with tolvaptan is therefore considered to be a novel therapeutic option for hepatic edema.

© 2013 The Japan Society of Hepatology.
PMID 23551935  Hepatol Res. 2014 Jan;44(1):73-82. doi: 10.1111/hepr.12・・・
著者: Nathan M Bass, Kevin D Mullen, Arun Sanyal, Fred Poordad, Guy Neff, Carroll B Leevy, Samuel Sigal, Muhammad Y Sheikh, Kimberly Beavers, Todd Frederick, Lewis Teperman, Donald Hillebrand, Shirley Huang, Kunal Merchant, Audrey Shaw, Enoch Bortey, William P Forbes
雑誌名: N Engl J Med. 2010 Mar 25;362(12):1071-81. doi: 10.1056/NEJMoa0907893.
Abstract/Text BACKGROUND: Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established.
METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy.
RESULTS: Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events.
CONCLUSIONS: Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.)

2010 Massachusetts Medical Society
PMID 20335583  N Engl J Med. 2010 Mar 25;362(12):1071-81. doi: 10.1056・・・
著者: Juan Carlos Garcia-Pagán, Jaime Bosch
雑誌名: Nat Clin Pract Gastroenterol Hepatol. 2005 Nov;2(11):526-35. doi: 10.1038/ncpgasthep0323.
Abstract/Text The evidence that endoscopic band ligation (EBL) has greater efficacy and fewer side effects than endoscopic injection sclerotherapy has renewed interest in endoscopic treatments for portal hypertension. The introduction of multishot band devices, which allow the placement of 5-10 bands at a time, has made the technique much easier to perform, avoiding the use of overtubes and their related complications. EBL sessions are usually repeated at 2 week intervals until varices are obliterated, which is achieved in about 90% of patients after 2-4 sessions. Variceal recurrence is frequent, with 20-75% of patients requiring repeated EBL sessions. According to current evidence, nonselective beta-blockers are the preferred treatment option for prevention of a first variceal bleed, whereas EBL should be reserved for patients with contraindications or intolerance to beta-blockers. Nonselective beta-blockers, probably in association with the vasodilator isosorbide mononitrate, and EBL are good treatment options to prevent recurrent variceal rebleeding. The efficacy of EBL might be increased by combining it with beta-blocker therapy. Patients who are intolerant, have contraindications or bled while receiving primary prophylaxis with beta-blockers must be treated with EBL. In the latter situation, EBL should be added to rather than replace beta-blocker therapy. EBL, in combination with vasoactive drugs, is the recommended form of therapy for acute esophageal variceal bleeding; however, endoscopic injection sclerotherapy can be used in the acute setting if EBL is technically difficult.

PMID 16355158  Nat Clin Pract Gastroenterol Hepatol. 2005 Nov;2(11):52・・・
著者: Jaime Bosch, Annalisa Berzigotti, Juan Carlos Garcia-Pagan, Juan G Abraldes
雑誌名: J Hepatol. 2008;48 Suppl 1:S68-92. doi: 10.1016/j.jhep.2008.01.021. Epub 2008 Feb 12.
Abstract/Text Variceal bleeding is the last step in a chain of events initiated by an increase in portal pressure, followed by the development and progressive dilation of varices until these finally rupture and bleed. This sequence of events might be prevented - and reversed - by achieving a sufficient decrease in portal pressure. A different approach is the use of local endoscopic treatments at the varices. This article reviews the rationale for the management of patients with cirrhosis and portal hypertension, the current recommendations for the prevention and treatment of variceal bleeding, and outlines the unsolved issues and the perspectives for the future opened by new research developments.

PMID 18304681  J Hepatol. 2008;48 Suppl 1:S68-92. doi: 10.1016/j.jhep.・・・
著者: M S Khuroo, N S Khuroo, K L C Farahat, Y S Khuroo, A A Sofi, S T Dahab
雑誌名: Aliment Pharmacol Ther. 2005 Feb 15;21(4):347-61. doi: 10.1111/j.1365-2036.2005.02346.x.
Abstract/Text BACKGROUND: The treatment effects of primary prophylactic endoscopic variceal ligation are unclear.
AIM: To compare the treatment effects of endoscopic variceal ligation and beta-blockers for primary prophylaxis of oesophageal variceal bleeding. In addition, a subgroup analysis was done with the purpose to delineate differences in the effects of intervention that were biologically based.
METHODS: We performed a literature search for randomized controlled trials, which compared the treatment effects of endoscopic variceal ligation with beta-blockers for primary prophylaxis of oesophageal variceal bleeding. Of the 955 articles screened, eight randomized-controlled trials including 596 subjects (285 with endoscopic variceal ligation and 311 with beta-blockers) were analysed. Outcomes measures evaluated were first gastrointestinal bleed, first variceal bleed, all-cause deaths, bleed-related deaths and severe adverse events. The measure of association employed was relative risk; with heterogeneity and sensitivity analyses.
RESULTS: Variceal obliteration was obtained in 261 (91.6%) patients and target beta-blockers therapy was achieved in 294 (94.5%) patients (P = 0.19). Endoscopic variceal ligation compared with beta-blockers significantly reduced rates of first gastrointestinal bleed by 31% (RR, 0.69; 95% CI: 0.49-0.96; P = 0.03; NNTB = 15) and first variceal bleed by 43% (RR, 0.57; 95% CI: 0.38-0.85; P = 0.0067; NNTB = 11). All-cause deaths and bleed-related deaths were unaffected (RR, 1.03; 95% CI: 0.79-1.36; P = 0.81 and RR, 0.84; 95% CI: 0.44-1.61; P = 0.60 respectively). Severe adverse events were significantly less in endoscopic variceal ligation compared with beta-blockers (RR, 0.34; 95% CI: 0.17-0.69; P = 0.0024; NNTB = 28). Sensitivity analysis of five trials published in peer review journals and four trials with high quality showed results similar to those seen in the primary analysis of all the eight trials, confirming stability of conclusions. Following variceal obliteration with endoscopic variceal ligation, oesophageal varices recurred in 83 (29.1%) patients. Seven (28.1%) patients bled with one fatal outcome. In subgroup analyses, endoscopic variceal ligation had significant advantage compared wtih beta-blockers in trials including < or =30% patients with alcoholic cirrhosis, >30% patients with Child Class C cirrhosis and >50% patients with large varices.
CONCLUSIONS: In patients with cirrhosis with moderate to large varices and who have not bled, endoscopic varices ligation compared with beta-blockers significantly reduced bleeding episodes and severe adverse events, but had no effect on mortality.

PMID 15709985  Aliment Pharmacol Ther. 2005 Feb 15;21(4):347-61. doi: ・・・

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