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アルコール性肝障害

著者: 竹井謙之 三重大学大学院 医学系研究科 消化器内科

監修: 金子周一 金沢大学大学院

著者校正/監修レビュー済:2020/06/10
患者向け説明資料

概要・推奨   

  1. アルコール性肝炎を疑うときは肝生検が推奨される(推奨度2)
  1. 重症型アルコール性肝炎は予後不良であり、その重症度はスコア化で判定する(推奨度1)
  1. アルコール性肝障害では厳格な禁酒が強く推奨される(推奨度1)
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となりま
  1. 閲覧にはご契約が必要となります。閲覧にはご契 約が必要となり ます。閲覧にはご契約が必要となります。閲覧には
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります
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:
竹井謙之 : 講演料(大塚製薬(株),大日本住友製薬(株),ギリアド・サイエンシズ(株)),研究費・助成金など(極東製薬工業(株),シスメックス(株),アストラゼネカ(株)),奨学(奨励)寄付など(MSD(株),アッヴィ(同),エーザイ(株),大塚製薬(株),ギリアド・サイエンシズ(株),大日本住友製薬(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. 定期レビューを行い、現状では変更なしだが、新規治療薬等新しいエビデンスを含め改訂準備中。

病態・疫学・診察

疾患情報(疫学・病態)  
まとめ:
  1. 飲酒は個人の生活習慣を形成している重要な因子であり、過度の飲酒が引き起こすアルコール性肝障害はアルコール関連生活習慣病である。
  1. アルコールの過剰摂取は脂肪肝から肝線維症、肝硬変、肝癌に至る慢性肝障害、また肝細胞壊死が前景に出るアルコール性肝炎を惹起する。
 
アルコール性肝障害の進展様式

アルコールの過剰摂取は脂肪肝から肝線維症、肝硬変、肝癌に至る慢性肝障害、さらに炎症・肝細胞壊死が前景に出るアルコール性肝炎を惹起する。 わが国のアルコール性肝障害の特徴として炎症や壊死を経ずに肝線維化から肝硬変に進展する肝線維症が多い。

出典

img1:  著者提供
 
 
 
アルコール性肝障害の発症機序

アルコール性肝障害は過剰飲酒に伴う肝障害であり、多くはアルコール換算60g/日以上の飲酒を5年以上継続することによって発症する。アルコール依存者のなかから肝硬変に進展する率は20~30%であることからもわかるように、アルコールに対する肝障害の感受性には個人差が大きく、性差、年齢、栄養状態、アルデヒド脱水素酵素(ALDH)などの遺伝的素因、免疫機能などにより決定される。アルコール性肝障害の発症および進展には下記に示す多くの因子が複合的に関連し肝病変が進展すると考えられている。
  1. アルコール代謝に伴うほかの代謝系への負荷
  1. アルコールや代謝産物であるアセトアルデヒド自体による肝毒性
  1. 腸内細菌由来エンドトキシンによる肝Kupffer細胞活性化とそれより産生される障害性メディエータ群の関与
  1. 鉄過剰やミクロソームエタノール酸化系(MEOS)活性などによる酸化ストレスの増大
  1. アルコールによる肝微小循環障害

出典

img1:  著者提供
 
 
 
  1. 女性はアルコール性肝障害への感受性が高い。
 
女性とアルコール関連問題

アルコールへの感受性には性差があり、女性はより少量の飲酒で肝障害を発症する。女性では男性に比べて約2/3の飲酒量で肝障害が出現し、約半分の飲酒期間(10年程度)で肝硬変にまで進展するとされている。アルコールは水溶性であるため、脂肪含有率の高い女性にとっては、体格差と相まって、同量の飲酒でも組織に分布するアルコール量がより高くなる。また女性ホルモンであるエストロゲンによるADHやCYP2E1活性の抑制作用が報告されており、女性ではアルコール分解効率が低下している。さらにはエストロゲンによるエンドトキシンの腸管透過性亢進やKupffer細胞活性化も知られ、肝障害進展における性差発現に関与している。女性のほうがアルコール依存症になりやすいとの報告もある。

出典

img1:  Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study.
 
 Hepatology. 1996 May;23(5):1025-9. doi: ・・・
 
  1. 平均アルコール摂取量150ml以上の大量飲酒者は約240万人と推測されている。特に若年女性の大量飲酒者は急激な増加を示しており、将来への影響が危惧される。
  1. 重症型アルコール性肝炎は発熱、黄疸、腹水など肝不全症状に加え、脳症や消化管出血、感染症、腎不全などを合併しやすく、重篤な経過をたどる病態である。(表<図表>
  1. アルコール性肝障害は内科的領域にとどまらず、アルコール依存や社会経済的問題など飲酒関連問題が介在することに留意しなければならない。
 
  1. 女性はアルコール性肝障害を発症しやすく、男性より少量の飲酒量で発症する。
  1. アルコールへの感受性には性差があり、女性はより少量の飲酒で肝障害を発症し、より重篤な肝障害に進展しやすいことが多くの研究で実証されている[1]。一例を挙げるとBeckerらの検討では、週当たりの飲酒量が7単位(1単位はエタノール約10g)を超えると女性は肝障害の発症が有意に高く、約2倍のリスクがあるとされている。肝硬変への進展リスクも同様に週当たりの飲酒量が7~41単位では男性の約2倍のリスクが認められた[2]。また別の研究では、女性は男性に比べて約2/3の飲酒量で肝障害が出現し、約半分の飲酒期間(10年程度)で肝硬変にまで進展するとされている[3]。これらは欧米のデータであるが、わが国ではALDH2の多型によるpoor metabolizerが約60%を占め、日本人女性のアルコール感受性はより高いと考えられる。また若年女性の大量飲酒者は急激な増加を示しており(健康・栄養情報研究会編:「国民栄養の現状 平成14年度厚生労働省国民栄養調査」)、女性のアルコール性肝障害が将来急増するのではないかと危惧される。女性のほうがアルコール依存症になりやすいとの報告もある。
 
アルコール健康障害対策基本法:
  1. 国際的にアルコール関連問題がますます重要性を増していることを受けて、WHO(世界保健機関)は2010年に「アルコールの有害事象に対する世界的な治療戦略」を策定した。わが国でも2013年12月、「アルコール健康障害対策基本法」が成立し、2016年5月、内閣府によりアルコール健康障害対策推進基本計画が発表された。
  1. 内閣府HP:[ https://www.mhlw.go.jp/stf/seisakunitsuite/bunya/0000176279.html アルコール健康障害対策]
問診・診察のポイント  
  1. 最も重要なことは正確な飲酒歴の聴取を行うことである。アルコール多飲者は飲酒期間、飲酒量ともに過小申告する傾向にあり、特にアルコール依存者では飲酒自体を否定することもまれではない。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: Jürgen Rehm, Benjamin Taylor, Satya Mohapatra, Hyacinth Irving, Dolly Baliunas, Jayadeep Patra, Michael Roerecke
雑誌名: Drug Alcohol Rev. 2010 Jul;29(4):437-45. doi: 10.1111/j.1465-3362.2009.00153.x.
Abstract/Text INTRODUCTION AND AIMS: Alcohol is an established risk factor for liver cirrhosis. It remains unclear, however, whether this relationship follows a continuous dose-response pattern or has a threshold. Also, the influences of sex and end-point (i.e. mortality vs. morbidity) on the association are not known. To address these questions and to provide a quantitative assessment of the association between alcohol intake and risk of liver cirrhosis, we conducted a systematic review and meta-analysis of cohort and case-control studies.
DESIGN AND METHODS: Studies were identified by a literature search of Ovid MEDLINE, EMBASE, Web of Science, CINAHL, PsychINFO, ETOH and Google Scholar from January 1980 to January 2008 and by searching the references of retrieved articles. Studies were included if quantifiable information on risk and related confidence intervals with respect to at least three different levels of average alcohol intake were reported. Both categorical and continuous meta-analytic techniques were used to model the dose-response relationship.
RESULTS: Seventeen studies met the inclusion criteria. We found some indications for threshold effects. Alcohol consumption had a significantly larger impact on mortality of liver cirrhosis compared with morbidity. Also, the same amount of average consumption was related to a higher risk of liver cirrhosis in women than in men.
DISCUSSION AND CONCLUSIONS: Overall, end-point was an important source of heterogeneity among study results. This result has important implications not only for studies in which the burden of disease attributable to alcohol consumption is estimated, but also for prevention.

PMID 20636661  Drug Alcohol Rev. 2010 Jul;29(4):437-45. doi: 10.1111/j・・・
著者: U Becker, A Deis, T I Sørensen, M Grønbaek, K Borch-Johnsen, C F Müller, P Schnohr, G Jensen
雑誌名: Hepatology. 1996 May;23(5):1025-9. doi: 10.1002/hep.510230513.
Abstract/Text The association between self-reported alcohol intake and the risk of future liver disease was studied in a large population-based prospective cohort with 12-year follow-up. Alcohol intake was assessed in 13,285 men and women aged 30 to 79 years by a self-administered questionnaire. Diagnoses indicating alcohol-induced liver disease (n = 261) or alcohol-induced cirrhosis (n = 124) were obtained from death certificates and the hospital discharge register, and data were analyzed by multiplicative Poisson regression models. The total cumulated observation time was 130,558 person-years. The overall incidence rates of alcohol-induced cirrhosis were 0.2% per year in men and 0.03% per year in women. The nadir of the estimated relative risk of developing liver disease was observed at an alcohol intake of 1 to 6 beverages per week, and above this level a steep increase in relative risk was observed. The risk function was independent of age and stable over time. The level of alcohol intake above which the relative risk was significantly greater than 1 was observed at 7 to 13 beverages per week for women and 14 to 27 beverages per week for men. Women had a significantly higher relative risk of developing alcohol-related liver disease than men for any given level of alcohol intake. We observed a dose-dependent increase in relative risk of developing alcohol-induced liver disease for both men and women, with the steepest increase among women. In the general population, self-reported current alcohol intake is a good predictor of the future risk of alcohol-induced liver disease.

PMID 8621128  Hepatology. 1996 May;23(5):1025-9. doi: 10.1002/hep.510・・・
著者: J B Saunders, M Davis, R Williams
雑誌名: Br Med J (Clin Res Ed). 1981 Apr 4;282(6270):1140-3.
Abstract/Text The sudden increase in alcoholic liver disease among women in the past 10 years has caused much speculation that they may be more susceptible to the hepatotoxic effects of alcohol than men. Women tend to present with more severe liver disease, particularly alcoholic hepatitis, and do so after a shorter period of excessive drinking and at a lower daily alcohol intake. Differences in body size and composition are partly responsible for the greater susceptibility of women, but differences in immune reactivity between the sexes may also play a part. Greater emphasis must be placed on designing abstinence programmes specifically for female patients, on earlier detection of liver disease, and on educating women about hazardous drinking levels.

PMID 6786474  Br Med J (Clin Res Ed). 1981 Apr 4;282(6270):1140-3.
著者: G L Bird
雑誌名: Baillieres Clin Gastroenterol. 1993 Sep;7(3):663-82.
Abstract/Text In heavy drinkers with clinical evidence of liver disease, routine investigations should exclude the possibility of other chronic liver diseases of non-alcoholic aetiology requiring specific therapy--these include chronic viral hepatitis, autoimmune diseases of the liver, Wilson's disease and genetic haemochromatosis. If abnormalities in liver biochemistry persist despite abstinence, or if the diagnosis of alcoholic liver disease is in doubt, a liver biopsy should be carried out. Studies evaluating the role of liver biopsy in alcoholic liver disease suggest that without histological confirmation the diagnosis will be inaccurate in 10-20% of patients. Serum biochemistry and the currently available imaging modalities have severe limitations in determining the relative contributions of fatty liver, alcoholic hepatitis and cirrhosis to the overall picture in alcoholic liver disease. Histological examination is therefore of additional value in determining the prognosis, which is worst in patients with a combination of alcoholic hepatitis and cirrhosis. There are a number of indices available, based on clinical and laboratory information, for evaluating the short-term prognosis, but these can only be used with accuracy if the histological pattern of damage has initially been evaluated.

PMID 8219405  Baillieres Clin Gastroenterol. 1993 Sep;7(3):663-82.
著者: D R Harris, R Gonin, H J Alter, E C Wright, Z J Buskell, F B Hollinger, L B Seeff, National Heart, Lung, and Blood Institute Study Group
雑誌名: Ann Intern Med. 2001 Jan 16;134(2):120-4.
Abstract/Text BACKGROUND: Although concomitant alcoholism is widely believed to enhance liver disease progression in persons with hepatitis C virus (HCV) infection, this relationship has not been well quantified.
OBJECTIVE: To quantify the relationship of transfusion-associated HCV infection and history of heavy alcohol abuse to development of cirrhosis.
DESIGN: Retrospective cohort study.
SETTING: Liver clinics in university and government hospitals.
PATIENTS: Extended follow-up of 1030 patients in prospective investigations of transfusion-associated viral hepatitis conducted in the United States between 1968 and 1980.
MEASUREMENTS: Development of cirrhosis and history of heavy alcohol abuse were determined from review of interviews with patients or their proxies, medical records, death certificates, and autopsy and biopsy reports. Logistic regression was used to estimate the risk for cirrhosis associated with transfusion-associated HCV infection and history of heavy alcohol abuse.
RESULTS: The absolute risk for cirrhosis was 17% among patients with transfusion-associated HCV; 3.2% among patients with transfusion-associated non-A, non-B, non-C hepatitis; and 2.8% among controls. Patients with transfusion-associated HCV were more likely than controls to develop cirrhosis (odds ratio, 7.8 [95% CI, 4.0 to 15.1]). A history of heavy alcohol abuse was associated with a fourfold increased risk for cirrhosis. Hepatitis C virus infection plus a history of heavy alcohol abuse led to a substantial increase in risk for cirrhosis (odds ratio, 31.1 [CI, 11.4 to 84.5]) compared with controls without such a history.
CONCLUSIONS: Heavy alcohol abuse greatly exacerbates the risk for cirrhosis among patients with HCV infection. This finding emphasizes the need to counsel such patients about their drinking habits.

PMID 11177315  Ann Intern Med. 2001 Jan 16;134(2):120-4.
著者: E H Forrest, C D J Evans, S Stewart, M Phillips, Y H Oo, N C McAvoy, N C Fisher, S Singhal, A Brind, G Haydon, J O'Grady, C P Day, P C Hayes, L S Murray, A J Morris
雑誌名: Gut. 2005 Aug;54(8):1174-9. doi: 10.1136/gut.2004.050781.
Abstract/Text INTRODUCTION: Alcoholic hepatitis is associated with a high short term mortality. We aimed to identify those factors associated with mortality and define a simple score which would predict outcome in our population.
METHODS: We identified 241 patients with alcoholic hepatitis. Clinical and laboratory data were recorded on the day of admission (day 1) and on days 6-9. Stepwise logistic regression was used to identify variables related to outcome at 28 days and 84 days after admission. These variables were included in the Glasgow alcoholic hepatitis score (GAHS) and its ability to predict outcome assessed. The GAHS was validated in a separate dataset of 195 patients.
RESULTS: The GAHS was derived from five variables independently associated with outcome: age (p = 0.001) and, from day 1 results, serum bilirubin (p<0.001), blood urea (p = 0.019) and, from day 6-9 results, serum bilirubin (p<0.001), prothrombin time (p = 0.002), and peripheral blood white blood cell count (p = 0.001). The GAHS on day 1 had an overall accuracy of 81% when predicting 28 day outcome. In contrast, the modified discriminant function had an overall accuracy of 49%. Similar results were found using information at 6-9 days and when predicting 84 day outcome. The accuracy of the GAHS was confirmed by the validation study of 195 patients The GAHS was equally accurate irrespective of the use of the international normalised ratio or prothrombin time ratio, or if the diagnosis of alcoholic hepatitis was biopsy proven or on the basis of clinical assessment.
CONCLUSIONS: Using variables associated with mortality we have derived and validated an accurate scoring system to assess outcome in alcoholic hepatitis. This score was able to identify patients at greatest risk of death throughout their admission.

PMID 16009691  Gut. 2005 Aug;54(8):1174-9. doi: 10.1136/gut.2004.05078・・・
著者: M R Teli, C P Day, A D Burt, M K Bennett, O F James
雑誌名: Lancet. 1995 Oct 14;346(8981):987-90.
Abstract/Text "Pure" alcoholic fatty liver has been widely assumed to be "benign" with very low risk of progression to cirrhosis. Studies thus far have included either patients with coexisting recognised precursor lesions of cirrhosis or have been restricted to short-term histological follow-up. We have followed 88 patients, first seen between 1978 and 1985, with a histological diagnosis of pure alcoholic fatty liver and no evidence of fibrosis or alcoholic hepatitis, for a median of 10.5 years, to determine any factors predictive of disease progression. Of the 88, at follow-up nine had developed cirrhosis and a further seven fibrosis. Eight of nine patients with cirrhosis had continuing alcohol consumption of more than 40 units per week at follow-up; in the other patients, consumption was unknown. Independent histological predictors of progression on index biopsy were: presence of mixed macro/microvesicular fat, and presence of giant mitochondria. We can no longer regard alcoholic fatty liver as benign. In the presence of continuing high alcohol consumption the above histological features identified those at high risk (47-61%) of disease progression. Therefore, patients with these features should be counselled intensively regarding their alcohol consumption.

PMID 7475591  Lancet. 1995 Oct 14;346(8981):987-90.
著者: S A Borowsky, S Strome, E Lott
雑誌名: Gastroenterology. 1981 Jun;80(6):1405-9.
Abstract/Text Survival of 64 male chronic alcoholic cirrhotics with first-onset ascites discharged from a gastrointestinal convalescent service was examined over a 32-mo period of study. Of 54 patients discharged as improved, 23 (43%) remained abstinent for a mean time of 14.0 mo and 15 (28%) resumed heavy drinking (greater than 2 g/kg/day). Twelve of 15 heavy drinkers died in a mean time of 7.2 mo, while all but one abstainer were alive. Differences in survival were statistically significantly different (p less than 0.001) when examined by the life-table method. Survival of 16 "moderate or binge" drinkers was not significantly different from abstainers. However, the number of rehospitalizations for liver disease was increased in this group. The study indicates that continued heavy drinking is associated with poor survival of alcoholic cirrhotics.

PMID 6971772  Gastroenterology. 1981 Jun;80(6):1405-9.
著者: F Pessione, M J Ramond, L Peters, B N Pham, P Batel, B Rueff, D C Valla
雑誌名: Liver Int. 2003 Feb;23(1):45-53.
Abstract/Text AIM: To evaluate 5-year survival predictive factors in hospitalised patients with excessive alcohol intake and cirrhosis, including in a multivariate analysis the severity of the liver disease, gastrointestinal bleeding, concomitant viral B or C infection, smoking status, presence of alcoholic hepatitis at inclusion and abstinence from alcohol during follow-up.
METHODS: In a non-concurrent cohort study, 122 patients with excessive alcohol intake and cirrhosis were followed up at least five years or till death. Two patients were lost to follow-up.
RESULTS: The 5-year survival rates were 43% in the 122 patients and 66%, 50% and 25% in Child-Pugh class A, B and C patients, respectively. In multivariate analysis, age (P = 0.01), Child-Pugh score (P = 0.0001), gastrointestinal bleeding (P = 0.01), presence of HBs Ag and/or anti-HCV (P = 0.03), smoking (P = 0.01), absence of histologically proven alcoholic hepatitis (P = 0.05) and persistent alcohol intake (P = 0.002) were associated with significantly increased risk ratios of death.
CONCLUSIONS: In hospitalised patients with excessive alcohol intake and cirrhosis: (1) age, liver failure, gastrointestinal bleeding, concomitant viral B or C infection and persistent alcohol intake are independent poor prognostic markers, (2) smoking may contribute to the aggravation of cirrhosis, and (3) alcoholic hepatitis, being a potentially reversible cause of liver failure, has a favourable prognostic significance.

PMID 12640727  Liver Int. 2003 Feb;23(1):45-53.
著者: A Chedid, C L Mendenhall, P Gartside, S W French, T Chen, L Rabin
雑誌名: Am J Gastroenterol. 1991 Feb;86(2):210-6.
Abstract/Text Two hundred eighty-one alcoholic patients were prospectively evaluated by clinical, biochemical, and histologic parameters during a 4-yr period to assess their prognosis. They were stratified into four categories of injury: 1) fatty liver (26 patients), 2) acute alcoholic hepatitis (106), 3) cirrhosis (39), and 4) cirrhosis with superimposed alcoholic hepatitis (111). The rate of survival and variables correlating with survival varied according to the group. At 48 months, 70% of the patients with fatty liver were alive, 58% in the alcoholic hepatitis group, 49% in cirrhosis, and 35% in alcoholic hepatitis superimposed upon cirrhosis. Within group one, deaths were due to causes unrelated to liver disease. In the alcoholic hepatitis group, factors significantly correlating with survival were ascites, alanine amino-transferase levels, grams of alcohol consumed, continuation of alcohol intake, and clinical severity of disease. Survival in patients of group three correlated significantly with prothrombin time and histologic severity score. Patients with combined cirrhosis and alcoholic hepatitis exhibited the worst prognosis, with the most significant predictors of survival being age, grams of alcohol consumed, the ratio of serum aminotransferases (AST:ALT) and the histologic and clinical severity of the disease. Although a different pattern of correlates was observed for each pathologic level of injury, knowledge of the various correlates aids in prognostic assessment.

PMID 1992635  Am J Gastroenterol. 1991 Feb;86(2):210-6.
著者: J T Galambos
雑誌名: Gastroenterology. 1972 Dec;63(6):1026-35.
Abstract/Text
PMID 4639358  Gastroenterology. 1972 Dec;63(6):1026-35.
著者: Yoshinori Horie, Yoshiyuki Yamagishi, Hirotoshi Ebinuma, Toshifumi Hibi
雑誌名: Clin Res Hepatol Gastroenterol. 2011 Nov;35(11):738-44. doi: 10.1016/j.clinre.2011.07.005. Epub 2011 Aug 15.
Abstract/Text BACKGROUND AND AIMS: Severe alcoholic hepatitis (SAH) is an inflammatory response with multiple morbidity factors like leucocytosis, hepatomegaly, renal failure, hepatic encephalopathy, endotoxemia, and has a high mortality rate. Accordingly, identifying therapeutic interventions that can support prognosis is the goal of research.
METHODS: Questionnaires were sent to 1234 medical institutions asking for information on patients with SAH during 2004 to 2008 including patients' demography, disease profile and the therapeutic interventions patients had received during hospitalization.
RESULTS: Twenty-nine hospitals had treated SAH patients, and provided full demographic data on 62 patients. Twenty-seven patients had received no treatment, 10 patients had received granulocytes/monocytes apheresis (GMA) to deplete elevated myeloid linage leucocytes, the rest had received one or more of the following treatments, corticosteroids, plasma exchange (PE) and haemodialysis (HD). Further, 23 patients had died and 39 had survived within 100 days of hospitalization. Serum creatinine (Cr) was higher in patients who had died vs patients who had survived (P=0.026). Likewise, patients with white blood cells (WBC) ≥ 10(4)/μL had higher mortality rate vs patients with WBC<10(4)/μL (P=0.039). GMA in patients with WBC ≥ 10(4)/μL showed 100% prognosis vs patients with WBC ≥ 10(4)/μL who did not receive GMA (P=0.0007). Corticosteroids, PE and HD did not significantly impact prognosis of SAH patients.
CONCLUSIONS: Our perception is that, patients with elevated myeloid leucocytes benefit most from GMA, while PE appears to support patients with coagulation deficiency or high plasma bilirubin and HD has indication in patients with high Cr.

Copyright © 2011 Elsevier Masson SAS. All rights reserved.
PMID 21840788  Clin Res Hepatol Gastroenterol. 2011 Nov;35(11):738-44.・・・
著者: A Rambaldi, H H Saconato, E Christensen, K Thorlund, J Wetterslev, C Gluud
雑誌名: Aliment Pharmacol Ther. 2008 Jun;27(12):1167-78. doi: 10.1111/j.1365-2036.2008.03685.x. Epub 2008 Mar 20.
Abstract/Text BACKGROUND: Glucocorticosteroids versus placebo or no intervention for patients with alcoholic hepatitis have been evaluated for more than 35 years. However, the results of randomized trials and meta-analyses differ substantially.
AIM: To review all randomized clinical trials of glucocorticosteroids vs. placebo or no intervention for patients with alcoholic hepatitis.
METHODS: We searched for randomized trials published before July 2007. The trials were assessed for risk of bias.
RESULTS: We included 15 trials with a total of 721 randomized patients. The overall mortality rate was 39.5%. Twelve of the fifteen trials were at risk of bias. Glucocorticosteroids did not statistically reduce mortality compared with placebo or no intervention (relative risk 0.83, 95% CI 0.63-1.11). Glucocorticosteroids significantly reduced mortality in the subgroup of trials with patients with Maddrey's score of at least 32 or hepatic encephalopathy and with low-bias risk. In all analyses, heterogeneity was significant and substantial. Trial sequential analyses using heterogeneity-adjusted information size demonstrated no significant effect of glucocorticosteroids on mortality. Weighted logistic regression analyses taking prognostic factors at randomization into consideration found no significant effect of glucocorticosteroids on mortality.
CONCLUSIONS: The current evidence base of mainly heterogeneous with high bias risk trials does not support the use of glucocorticosteroids in alcoholic hepatitis. Large, low-bias risk placebo-controlled randomized trials are needed.

PMID 18363896  Aliment Pharmacol Ther. 2008 Jun;27(12):1167-78. doi: 1・・・
著者: F Stickel, B Hoehn, D Schuppan, H K Seitz
雑誌名: Aliment Pharmacol Ther. 2003 Aug 15;18(4):357-73.
Abstract/Text Chronic alcohol consumption may lead to primary and secondary malnutrition. In particular, protein energy malnutrition not only aggravates alcoholic liver disease but also correlates with impaired liver function and increased mortality. Therefore, in these patients, adequate nutritional support should be implemented in order to improve their prognosis. Clinical trials addressing this issue have shown that nutritional therapy either enterally or parenterally improves various aspects of malnutrition, and there is increasing evidence that it may also improve survival. Therefore, malnourished alcoholics should be administered a diet rich in carbohydrate- and protein-derived calories preferentially via the oral or enteral route. Micronutrient deficiencies typically encountered in alcoholics, such as for thiamine and folate, require specific supplementation. Patients with hepatic encephalopathy may be treated with branched-chain amino acids in order to achieve a positive nitrogen balance. Fatty liver represents the early stage of alcoholic liver disease, which is usually reversible with abstinence. Metadoxine appears to improve fatty liver but confirmatory studies are necessary. S-adenosyl-L-methionine may be helpful for patients with severe alcoholic liver damage, since various mechanisms of alcohol-related hepatotoxicity are counteracted with this essential methyl group donor, while a recent large trial showed that the use of polyenylphosphatidylcholine is of limited efficacy.

PMID 12940921  Aliment Pharmacol Ther. 2003 Aug 15;18(4):357-73.
著者: E Cabré, P Rodríguez-Iglesias, J Caballería, J C Quer, J L Sánchez-Lombraña, A Parés, M Papo, R Planas, M A Gassull
雑誌名: Hepatology. 2000 Jul;32(1):36-42. doi: 10.1053/jhep.2000.8627.
Abstract/Text Steroids are recommended in severe alcohol-induced hepatitis, but some data suggest that artificial nutrition could also be effective. We conducted a randomized trial comparing the short- and long-term effects of total enteral nutrition or steroids in these patients. A total of 71 patients (80% cirrhotic) were randomized to receive 40 mg/d prednisolone (n = 36) or enteral tube feeding (2,000 kcal/d) for 28 days (n = 35), and were followed for 1 year or until death. Side effects of treatment occurred in 5 patients on steroids and 10 on enteral nutrition (not significant). Eight enterally fed patients were prematurely withdrawn from the trial. Mortality during treatment was similar in both groups (9 of 36 vs. 11 of 35, intention-to-treat) but occurred earlier with enteral feeding (median 7 vs. 23 days; P =.025). Mortality during follow-up was higher with steroids (10 of 27 vs. 2 of 24 intention-to-treat; P =. 04). Seven steroid patients died within the first 1.5 months of follow-up. In contrast to total enteral nutrition (TEN), infections accounted for 9 of 10 follow-up deaths in the steroid group. In conclusion, enteral feeding does not seem to be worse than steroids in the short-term treatment of severe alcohol-induced hepatitis, although death occurs earlier with enteral nutrition. However, steroid therapy is associated with a higher mortality rate in the immediate weeks after treatment, mainly because of infections. A possible synergistic effect of both treatments should be investigated.

PMID 10869286  Hepatology. 2000 Jul;32(1):36-42. doi: 10.1053/jhep.200・・・
著者: M Plauth, E Cabré, O Riggio, M Assis-Camilo, M Pirlich, J Kondrup, DGEM (German Society for Nutritional Medicine), P Ferenci, E Holm, S Vom Dahl, M J Müller, W Nolte, ESPEN (European Society for Parenteral and Enteral Nutrition)
雑誌名: Clin Nutr. 2006 Apr;25(2):285-94. doi: 10.1016/j.clnu.2006.01.018. Epub 2006 May 16.
Abstract/Text Enteral nutrition (EN) by means of oral nutritional supplements (ONS) and tube feeding (TF) offers the possibility to increase or to insure nutrient intake in case of insufficient oral food intake. The present guideline is intended to give evidence-based recommendations for the use of ONS and TF in patients with liver disease (LD). It was developed by an interdisciplinary expert group in accordance with officially accepted standards and is based on all relevant publications since 1985. The guideline was discussed and accepted in a consensus conference. EN by means of ONS is recommended for patients with chronic LD in whom undernutrition is very common. ONS improve nutritional status and survival in severely malnourished patients with alcoholic hepatitis. In patients with cirrhosis, TF improves nutritional status and liver function, reduces the rate of complications and prolongs survival. TF commenced early after liver transplantation can reduce complication rate and cost and is preferable to parenteral nutrition. In acute liver failure TF is feasible and used in the majority of patients.

PMID 16707194  Clin Nutr. 2006 Apr;25(2):285-94. doi: 10.1016/j.clnu.2・・・
著者: G R Swart, M C Zillikens, J K van Vuure, J W van den Berg
雑誌名: BMJ. 1989 Nov 11;299(6709):1202-3.
Abstract/Text OBJECTIVE: To assess whether a late evening meal would improve nitrogen balance in patients with cirrhosis of the liver.
DESIGN: Randomised crossover study of meal schedules comparing three meals a day with four or six meals a day, the four and six meal schedules both including a late evening meal (2300).
SETTING: Metabolic ward.
PATIENTS: Seven men and two women aged 34-66 with cirrhosis of the liver (Child's grade B).
INTERVENTIONS: Patients spent two seven day periods in the ward. For five days of each period they received, in random order, isonitrogenous isocaloric diets supplied in three meals a day and in four or six meals a day.
MAIN OUTCOME MEASURE: Nitrogen balance, calculated as the difference between dietary intake and the total of urinary, faecal, and integumental nitrogen loss.
RESULTS: Faecal nitrogen loss was no different between three meals a day and four or six meals a day. On both four and six meals a day, however, patients had nitrogen balances that were more positive (or less negative) than on three meals a day (1.26 (SD 2.1) g/24 h v 0.26 (2.2) g/24 h, p less than 0.01). Six meals a day did not produce significantly better improvements in nitrogen balance than four meals a day.
CONCLUSIONS: A late evening meal seemed to improve the efficiency of nitrogen metabolism, but longer term studies are needed to assess whether this leads to a better nutritional state.

PMID 2513050  BMJ. 1989 Nov 11;299(6709):1202-3.

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