今日の臨床サポート

脂肪肝(NAFLD)

著者: 今一義 順天堂大学 消化器内科学

著者: 渡辺純夫 順天堂大学 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:2021/04/14
参考ガイドライン:
  1. 日本消化器病学会日本肝臓学会:NAFLD/NASH診療ガイドライン2020 改訂第2版
患者向け説明資料

概要・推奨   

  1. 肥満を有するNAFLD患者には、まず食事・運動療法を行うことが勧められる(推奨度2)
  1. NAFLDに対する薬物療法は、NASHの診断が確定した場合か、線維化の進行が疑われる場合に推奨される(推奨度2
  1. NAFLDによって肝疾患関連死および心血管イベントが増加し、特に線維化進展例ではいずれのリスクも増加する
  1. 難治性の高度の肥満(BMI 35 kg/m2 以上)があり、糖尿病・高血圧・脂質異常症・睡眠時無呼吸症候群のいずれかを伴うNAFLDに対しては肥満手術が有効である(推奨度3)。
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:
今一義 : 特に申告事項無し[2021年]
渡辺純夫 : 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. NAFLD/NASH診療ガイドライン2020に基づき診断、治療について改訂を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 非アルコール性脂肪性肝疾患(NAFLD)は、非アルコール性脂肪肝(NAFL)と非アルコール性脂肪肝炎(NASH)を含む疾患概念である。
  1. NAFLDの診断は、有意な飲酒歴がないことを確認し、ウイルス性肝炎など他の肝機能障害を来す疾患を除外し、画像診断で肝臓に脂肪沈着があることを確認して下す。
  1. 有病率は近年の肥満の増加に伴い増加傾向にあり、成人の29.7~32.2%%にNAFLDを認める。
  1. 予後には肝障害に伴うものだけではなく、糖尿病、脳心血管イベントが関与してくる。
  1. 治療としては食事・運動療法が第1選択であり、薬剤療法はまだ確立されたものがない。
 
  1. NAFLDによって肝疾患関連死、心血管イベントが増加する。NAFLDがあると糖尿病の発症率が増加する(推奨度2M)(参考文献:[1]
  1. NAFLD全体でみた場合とNASHでみた場合とで、予後に関する影響が異なる。
  1. NAFLDにより死亡率がオッズ比1.5で増加する。肝疾患関連死、心血管イベントの発症率も増加し、糖尿病の発症率が2倍になる。NAFLと比較して、NASHではより高い肝疾患関連死が認められる(オッズ比5.71)。
  1. よって、NAFLD患者の予後を考慮する際は全体の合併症の推移も検討する必要がある。
 
問診・診察のポイント  
  1. 基本的に無症状である。

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文献 

著者: Giovanni Musso, Roberto Gambino, Maurizio Cassader, Gianfranco Pagano
雑誌名: Ann Med. 2011 Dec;43(8):617-49. doi: 10.3109/07853890.2010.518623. Epub 2010 Nov 2.
Abstract/Text BACKGROUND. NAFLD ranges from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH). The natural history of NAFLD and the optimal strategy to identify subjects with progressive liver disease are unclear. Objectives. To assess the evidence in: (1) natural history of NAFLD; and (2) non-invasive methods to differentiate NAFLD histological subtypes. DESIGN AND SETTING. Among 4185 articles published on MEDLINE, Cochrane Library, EMBASE, Pubmed, national and International meeting abstracts through July 2010, 40 articles assessing the natural history of NAFLD and 32 articles evaluating the diagnostic accuracy of non-invasive tests against liver biopsy (LB) were included. MEASUREMENTS. Two reviewers retrieved articles and evaluated study quality by appropriate scores. Main outcomes were pooled using random- or fixed-effects models. RESULTS. NAFLD has an increased overall mortality (OR: 1.57, 95% CI: 1.18-2.10), deriving from liver-related and cardiovascular disease, and a 2-fold risk of diabetes. Compared to SS, NASH has a higher liver-related (OR for NASH: 5.71, 2.31-14.13; OR for NASH with advanced fibrosis: 10.06, 4.35-23.25), but not cardiovascular mortality (OR: 0.91, 0.42-1.98). Three non-invasive methods received independent validation: pooled AUROC, sensitivity and specificity of cytokeratin-18 for NASH are 0.82 (0.78-0.88), 0.78 (0.64-0.92), 0.87 (0.77-0.98). For NASH with advanced fibrosis, pooled AUROC, sensitivity and specificity of NAFLD fibrosis score and Fibroscan are 0.85 (0.80-0.93), 0.90 (0.82-0.99), 0.97 (0.94-0.99) and 0.94 (0.90-0.99), 0.94 (0.88-0.99) and 0.95 (0.89-0.99). CONCLUSIONS. NAFLD warrants screening for cardio-metabolic risk and for progressive liver disease. The combination of three noninvasive tests with LB may optimally individuate patients with NASH, with or without advanced fibrosis.

PMID 21039302  Ann Med. 2011 Dec;43(8):617-49. doi: 10.3109/07853890.2・・・
著者: F M Finucane, S J Sharp, L R Purslow, K Horton, J Horton, D B Savage, S Brage, H Besson, E De Lucia Rolfe, A Sleigh, H J Martin, A Aihie Sayer, C Cooper, U Ekelund, S J Griffin, N J Wareham
雑誌名: Diabetologia. 2010 Apr;53(4):624-31. doi: 10.1007/s00125-009-1641-z. Epub 2010 Jan 6.
Abstract/Text AIMS/HYPOTHESIS: We sought to determine the effect of an aerobic exercise intervention on clustered metabolic risk and related outcomes in healthy older adults in a single-centre, explanatory randomised controlled trial.
METHODS: Participants from the Hertfordshire Cohort Study (born 1931-1939) were randomly assigned to 36 supervised 1 h sessions on a cycle ergometer over 12 weeks or to a non-intervention control group. Randomisation and group allocation were conducted by the study co-ordinator, using a software programme. Those with prevalent diabetes, unstable ischaemic heart disease or poor mobility were excluded. All data were collected at our clinical research facility in Cambridge. Components of the metabolic syndrome were used to derive a standardised composite metabolic risk score (zMS) as the primary outcome. Trial status: closed to follow-up.
RESULTS: We randomised 100 participants (50 to the intervention, 50 to the control group). Mean age was 71.4 (range 67.4-76.3) years. Overall, 96% of participants attended for follow-up measures. There were no serious adverse events. Using an intention-to-treat analysis, we saw a non-significant reduction in zMS in the exercise group compared with controls (0.07 [95% CI -0.03, 0.17], p = 0.19). However, the exercise group had significantly decreased weight, waist circumference and intrahepatic lipid, with increased aerobic fitness and a 68% reduction in prevalence of abnormal glucose metabolism (OR 0.32 [95% CI 0.11-0.92], p = 0.035) compared with controls. Results were similar in per-protocol analyses.
CONCLUSIONS/INTERPRETATION: Enrolment in a supervised aerobic exercise intervention led to weight loss, increased fitness and improvements in some but not all metabolic outcomes. In appropriately screened older individuals, such interventions appear to be safe.
TRIAL REGISTRATION: Controlled-trials.com ISRCTN60986572
FUNDING: Medical Research Council.

PMID 20052455  Diabetologia. 2010 Apr;53(4):624-31. doi: 10.1007/s0012・・・
著者: Alexis St George, Adrian Bauman, Amanda Johnston, Geoffrey Farrell, Tien Chey, Jacob George
雑誌名: J Gastroenterol Hepatol. 2009 Mar;24(3):399-407. doi: 10.1111/j.1440-1746.2008.05694.x. Epub 2008 Dec 2.
Abstract/Text BACKGROUND AND AIM: Non-alcoholic fatty liver disease associated with insulin resistance is the most common cause of abnormal liver tests in clinical practice. To date, practical and effective strategies to improve the metabolic profile of this large group of patients have not been well characterised. We sought to assess the effect at 3 months of a behavior change-based lifestyle intervention on the metabolic profile of patients characterised by elevated liver enzymes.
METHODS: A total of 152 patients with elevated liver enzymes, central obesity and a range of metabolic risk factors were randomised to either a moderate- (6 sessions/10 weeks) or low-intensity (3 sessions/4 weeks) lifestyle counselling intervention or control group.
RESULTS: There was improvement in all metabolic risk factors in the moderate-intensity group, versus a smaller number of changes in the low-intensity intervention group and no change in any metabolic risk factors in control subjects. Reduction in liver enzymes was greatest in the moderate-intensity intervention group and least in the control group. The likelihood of elevated alanine aminotransferase (ALT) levels in both the moderate and low-intensity groups was reduced by over 70% compared to controls. The proportion of subjects achieving weight loss (>or= 2%) was significantly higher in the moderate-intensity intervention group (66%) versus the low-intensity intervention group (39%; P < 0.05) and controls (29%; P < 0.001).
CONCLUSIONS: Moderate and even low-intensity lifestyle counselling interventions targeting improvement in physical activity and nutritional behaviors and modest weight loss are a practical and effective method for improving the health of patients with elevated liver enzymes and a range of metabolic risk factors.

PMID 19067776  J Gastroenterol Hepatol. 2009 Mar;24(3):399-407. doi: 1・・・
著者: Lijun Peng, Jiyao Wang, Feng Li
雑誌名: Cochrane Database Syst Rev. 2011 Jun 15;(6):CD003619. doi: 10.1002/14651858.CD003619.pub3. Epub 2011 Jun 15.
Abstract/Text BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming a wide spread liver disease. The present recommendations for treatment are not evidence-based. Some of them are various weight reduction measures with diet, exercise, drug, or surgical therapy.
OBJECTIVES: To assess the benefits and harms of intended weight reduction for patients with NAFLD.
SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, PubMed, EMBASE, Science Citation Index Expanded, Chinese Biomedicine Database, and ClinicalTrials.gov until February 2011.
SELECTION CRITERIA: We included randomised clinical trials evaluating weight reduction with different measures versus no intervention or placebo in NAFLD patients.
DATA COLLECTION AND ANALYSIS: We extracted data independently. We calculated the odds ratio (OR) for dichotomous data and calculated the mean difference (MD) for continuous data, both with 95% confidence intervals (CI).
MAIN RESULTS: The review includes seven trials; five on aspects of lifestyle changes (eg, diet, physical exercise) and two on treatment with a weight reduction drug 'orlistat'. In total, 373 participants were enrolled, and the duration of the trials ranged from 1 month to 1 year. Only one trial on lifestyle programme was judged to be of low risk of bias. We could not perform meta-analyses for the main outcomes as they were either not reported or there were insufficient number of trials for each outcome to be meta-analysed. We could meta-analyse the available data for body weight and body mass index only. Adverse events were poorly reported.
AUTHORS' CONCLUSIONS: The sparse data and high risk of bias preclude us from drawing any definite conclusion on lifestyle programme or orlistat for treatment of NAFLD. Further randomised clinical trials with low risk of bias are needed to test the beneficial and harmful effects of weight reduction for NAFLD patients. The long-term prognosis of development of fibrosis, mortality, and quality of life should be studied.

PMID 21678341  Cochrane Database Syst Rev. 2011 Jun 15;(6):CD003619. d・・・
著者: Rajasekhara R Mummadi, Krishna S Kasturi, Swapna Chennareddygari, Gagan K Sood
雑誌名: Clin Gastroenterol Hepatol. 2008 Dec;6(12):1396-402. doi: 10.1016/j.cgh.2008.08.012. Epub 2008 Aug 19.
Abstract/Text BACKGROUND & AIMS: Weight loss in overweight or obese individuals results in marked improvement or resolution of hypertension, diabetes mellitus, and hyperlipidemia. However, the overall effect of weight loss on nonalcoholic fatty liver disease (NAFLD) remains unclear. This systematic review and meta-analysis is an effort to explore the effect of weight loss after bariatric surgical procedures on NAFLD.
METHODS: We performed an electronic literature search of published articles on bariatric surgery and liver histology since inception to September of 2007. Primary outcome measures were improvement and/or resolution in the 3 components of NAFLD (steatosis, steatohepatitis, and fibrosis) after bariatric surgery-induced weight loss. A pooled proportion of patients with improvement or resolution was calculated for steatosis, steatohepatitis, and fibrosis using a random effects model. Heterogeneity among the studies was assessed using the I(2) (inconsistency) statistic and subgroup analyses.
RESULTS: A total of 15 studies (766 paired liver biopsies) were selected for final data extraction. The percentage reduction in mean body mass index after bariatric surgeries ranged from 19.11 to 41.76. The pooled proportion of patients with improvement or resolution in steatosis was 91.6% (95% confidence interval [CI], 82.4%-97.6%), in steatohepatitis was 81.3% (95% CI, 61.9%-94.9%), in fibrosis was 65.5% (95% CI, 38.2%-88.1%), and for complete resolution of nonalcoholic steatohepatitis was 69.5 (95% CI, 42.4%-90.8%).
CONCLUSIONS: Steatosis, steatohepatitis, and fibrosis appear to improve or completely resolve in the majority of patients after bariatric surgery-induced weight loss.

PMID 18986848  Clin Gastroenterol Hepatol. 2008 Dec;6(12):1396-402. do・・・

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