今日の臨床サポート

非アルコール性脂肪肝炎(NASH)

著者: 伊藤義人 京都府立医科大学大学院 医学研究科

監修: 金子周一 金沢大学大学院

著者校正/監修レビュー済:2021/04/14
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. ALTが持続高値を示す原因として最も頻度が高いのは非ウイルス性非アルコール性肝疾患である。内臓脂肪型肥満を伴うことが多く、腹部CTや超音波検査で脂肪肝を伴うのが特徴。NASHの確定診断ができれば、すぐに治療を始める必要がある。
  1. 肥満を伴うNASHの患者には体重の減量が有効である。適度の有酸素運動とともにカロリーコントロールの指導を行うことが強く推奨される(推奨度1)
  1. インスリン抵抗性を合併するNASHを中心とした検討ではピオグリタゾンは比較的短期間の投与で肝機能および組織像を改善する(推奨度2)
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が
  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
  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
  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
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:
伊藤義人 : 講演料(ギリアド・サイエンシズ(株),アッヴィ合同会社,大日本住友製薬(株)),研究費・助成金など(日産化学工業(株),ギリアド・サイエンシズ(株),MSD(株),ブリストル・マイヤーズスクイブ(株),ノボノルディスクファーマ(株)),奨学(奨励)寄付など(アッヴィ合同会社,バイエル(株),武田薬品工業(株)),企業などが提供する寄付講座(ニチニチ製薬)[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に基づき主に治療について改訂を行なった。 

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 非アルコール性脂肪肝炎(NASH)の診断は、脂肪肝を伴う慢性肝疾患から既知の慢性肝疾患を除外した後に肝生検を行い、その病理学的所見に基づいて下す。
  1. NASHには肥満を背景とする原発性NASH以外に、消化器の外科治療後症例、原因の明らかでない代謝疾患に基づく症例など二次性NASHが知られている。
 
Ludwigによる脂肪肝炎の分類

脂肪肝炎はアルコール性肝炎に伴う症例と非アルコール性脂肪肝炎とに大別される。非アルコール性脂肪肝炎は原因の晃間症例(二次性)と主に肥満を誘因とする原発性症例に分類される。二次性非アルコール性脂肪肝炎のうち、薬剤により誘発された症例は薬物性肝障害に含まれる。

出典

 
  1. 疾患の頻度は高く、2009~2010年の検診受診者非飲酒者5,075名をもとにした推計では、肝臓の線維化が進展したNASH症例だけでも受診者の1.9~2.7%を占めるとされる[1]
  1. NASHは進行性の肝疾患であり、肝硬変や肝細胞癌の発生母地と考えられている。
  1. 肥満を背景とするNASHでは、食事制限と運動により減量を行えば病期の進展を止めることができると考えられており、早期に診断して治療を開始することが勧められる。
 
  1. NASHの有病率は全世界的に3~5%と推定されている(推奨度2)
  1. まとめ:NASHの頻度はこれまで人口の1~3%と予測されてきた。しかし、最近では3~5%と推定されるようになっている[2][3][4][5]
  1. 代表事例の説明:年齢分布は、わが国では男性は中年層、女性は高齢層に多いと推定される[6][1][7]
  1. 結論:NASHの有病率はどの国や地域においてもいまだ正確には把握されていない。
  1. 追記:NASHおよびNASH肝硬変の有病率および年齢分布については、肝生検患者のセレクションバイアスの問題のために、正確な調査が行われていない。
問診・診察のポイント  
  1. 肥満、脂肪肝の病歴、生活習慣病の罹患・治療歴を確認する。

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: Yuichiro Eguchi, Hideyuki Hyogo, Masafumi Ono, Toshihiko Mizuta, Naofumi Ono, Kazuma Fujimoto, Kazuaki Chayama, Toshiji Saibara, JSG-NAFLD
雑誌名: J Gastroenterol. 2012 May;47(5):586-95. doi: 10.1007/s00535-012-0533-z. Epub 2012 Feb 11.
Abstract/Text BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing. This study aimed to assess the recent prevalence of NAFLD and to predict the prevalence of nonalcoholic steatohepatitis (NASH) with liver fibrosis using established scoring systems in the general population.
METHODS: A cross-sectional study was conducted among 8352 subjects who received health checkups from 2009 to 2010 in three health centers in Japan. Subjects with an intake over 20 g of alcohol/day or with other chronic liver diseases were excluded. Fatty liver was detected by ultrasonography. The probability of NASH with advanced fibrosis was calculated according to the body mass index, age, ALT, and triglyceride (BAAT) and FIB-4 (based on age, aspartate aminotransferase and alanine aminotransferase levels, and platelet counts) indices.
RESULTS: A total of 5075 subjects were enrolled. The overall prevalence of NAFLD was 29.7%. There was a significant threefold difference in the mean prevalence between males (41.0%) and females (17.7%). This prevalence showed a linear increase with body mass index, triglycerides, and low-density lipoprotein cholesterol regardless of threshold values, even without obesity. The estimated prevalence of NASH according to the BAAT index ≥3 was 2.7%, and according to the FIB-4 index it was 1.9%.
CONCLUSIONS: The prevalence of NAFLD has increased in the general population, especially in males. There is a linear relationship between the prevalence of NAFLD and various metabolic parameters, even in nonobese subjects. The prevalence of NASH with advanced fibrosis is estimated to be considerably high in subjects with NAFLD.

PMID 22328022  J Gastroenterol. 2012 May;47(5):586-95. doi: 10.1007/s0・・・
著者: Christopher D Williams, Joel Stengel, Michael I Asike, Dawn M Torres, Janet Shaw, Maricela Contreras, Cristy L Landt, Stephen A Harrison
雑誌名: Gastroenterology. 2011 Jan;140(1):124-31. doi: 10.1053/j.gastro.2010.09.038. Epub 2010 Sep 19.
Abstract/Text BACKGROUND & AIMS: Prevalence of nonalcoholic fatty liver disease (NAFLD) has not been well established. The purpose of this study was to prospectively define the prevalence of both NAFLD and nonalcoholic steatohepatitis (NASH).
METHODS: Outpatients 18 to 70 years old were recruited from Brooke Army Medical Center. All patients completed a baseline questionnaire and ultrasound. If fatty liver was identified, then laboratory data and a liver biopsy were obtained.
RESULTS: Four hundred patients were enrolled. Three hundred and twenty-eight patients completed the questionnaire and ultrasound. Mean age (range, 28-70 years) was 54.6 years (7.35); 62.5% Caucasian, 22% Hispanic, and 11.3% African American; 50.9% female; mean body mass index (BMI) (calculated as kg/m(2)) was 29.8 (5.64); and diabetes and hypertension prevalence 16.5% and 49.7%, respectively. Prevalence of NAFLD was 46%. NASH was confirmed in 40 patients (12.2% of total cohort, 29.9% of ultrasound positive patients). Hispanics had the highest prevalence of NAFLD (58.3%), then Caucasians (44.4%) and African Americans (35.1%). NAFLD patients were more likely to be male (58.9%), older (P = .004), hypertensive (P < .00005), and diabetic (P < .00005). They had a higher BMI (P < .0005), ate fast food more often (P = .049), and exercised less (P = 0.02) than their non-NAFLD counterparts. Hispanics had a higher prevalence of NASH compared with Caucasians (19.4% vs 9.8%; P = .03). Alanine aminotransferase, aspartate aminotransferase, BMI, insulin, Quantitative Insulin-Sensitivity Check Index, and cytokeratin-18 correlated with NASH. Among the 54 diabetic patients, NAFLD was found in 74% and NASH in 22.2%.
CONCLUSION: Prevalence of NAFLD and NASH is higher than estimated previously. Hispanics and patients with diabetes are at greatest risk for both NAFLD and NASH.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID 20858492  Gastroenterology. 2011 Jan;140(1):124-31. doi: 10.1053/・・・
著者: G Vernon, A Baranova, Z M Younossi
雑誌名: Aliment Pharmacol Ther. 2011 Aug;34(3):274-85. doi: 10.1111/j.1365-2036.2011.04724.x. Epub 2011 May 30.
Abstract/Text BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease, and its worldwide prevalence continues to increase with the growing obesity epidemic. This study assesses the epidemiology of NAFLD in adults based on clinical literature published over the past 30 years.
AIM: To review epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults based on clinical literature published over the past 30 years.
METHODS: An in-depth search of PubMed (1980-2010) was based on five search terms: 'non-alcoholic fatty liver disease' OR 'non-alcoholic steatohepatitis' OR 'fatty liver' OR 'steatosis' AND 'incidence' [MeSH Terms] OR 'prevalence' [MeSH Terms] OR 'natural history'. Studies of paediatric cohorts were excluded. Articles were categorised by topic and summarised, noting generalisations concerning their content.
RESULTS: Four study categories included NAFLD incidence, prevalence, risk factors and natural history. Studies related to NAFLD prevalence and incidence indicate that the diagnosis is heterogeneous and relies on a variety of assessment tools, including liver biopsy, radiological tests such as ultrasonography, and blood testing such as liver enzymes. The prevalence of NAFLD is highest in populations with pre-existing metabolic conditions such as obesity and type II diabetes. Many studies investigating the natural history of NAFLD verify the progression from NASH to advanced fibrosis and hepatocellular carcinoma.
CONCLUSIONS: Non-alcoholic fatty liver disease is the most common cause of elevated liver enzymes. Within the NAFLD spectrum, only NASH progresses to cirrhosis and hepatocellular carcinoma. With the growing epidemic of obesity, the prevalence and impact of NAFLD continues to increase, making NASH potentially the most common cause of advanced liver disease in coming decades.

© 2011 Blackwell Publishing Ltd.
PMID 21623852  Aliment Pharmacol Ther. 2011 Aug;34(3):274-85. doi: 10.・・・
著者: Ji Cheol Bae, Yong Kyun Cho, Won Young Lee, Hyun Il Seo, Eun Jung Rhee, Se Eun Park, Cheol Young Park, Ki Won Oh, Ki Chul Sung, Byung Ik Kim
雑誌名: Am J Gastroenterol. 2010 Nov;105(11):2389-95. doi: 10.1038/ajg.2010.275. Epub 2010 Jul 13.
Abstract/Text OBJECTIVES: A cross-sectional analysis was conducted in healthy, nondiabetic Korean adults to assess the prevalence of nonalcoholic fatty liver disease (NAFLD), to compare the prevalence of NAFLD across different glycemic ranges as assessed by glycosylated hemoglobin (HbA1c), and to examine the impact of NAFLD on insulin resistance in relation to HbA1c levels.
METHODS: After rigorous exclusion criteria, the final number of subjects who participated in a comprehensive health status checkup program was 99,969. All subjects were classified into four categories with respect to HbA1c level (≤4.9, 5.0-5.4, 5.5-5.9, and 6.0-6.4%). We estimated the odds ratio (OR) for prevalence of NAFLD according to the categorized level of HbA1C and evaluated the association of NAFLD with the homeostatic model assessment of insulin resistance (HOMA-IR) in relation to the HbA1c level.
RESULTS: Twenty-eight percent (n=28,130, 40.2% of the men, 10.3% of the women) of the study subjects had NAFLD. Men had a 5.83-fold (95% confidence interval 5.63-6.05) increased risk for having NAFLD than did women. The risk for NAFLD increased with increasing level of HbA1c (OR 1.44, 2.62, and 7.18) when compared with the lowest quartile (HbA1C≤4.9%). HOMA-IR increased in the NAFLD subjects as the level of HbA1c increased. The magnitude of association of HOMA-IR with HbA1c level was greater in NAFLD subjects than in non-NAFLD subjects (P<0.001 for interaction). These associations were consistent even after adjustment for body mass index and other metabolic components.
CONCLUSIONS: NAFLD had an association with HbA1c level and insulin resistance in nondiabetic individuals, and these associations were independent of obesity and other metabolic components.

PMID 20628364  Am J Gastroenterol. 2010 Nov;105(11):2389-95. doi: 10.1・・・
著者: Kausik Das, Kshaunish Das, Partha S Mukherjee, Alip Ghosh, Sumantra Ghosh, Asit R Mridha, Tapan Dhibar, Bhaskar Bhattacharya, Dilip Bhattacharya, Byomkesh Manna, Gopal K Dhali, Amal Santra, Abhijit Chowdhury
雑誌名: Hepatology. 2010 May;51(5):1593-602. doi: 10.1002/hep.23567.
Abstract/Text UNLABELLED: There is a paucity of community-based epidemiological data on nonalcoholic fatty liver (NAFL) among nonaffluent populations in developing countries. Available studies are radiological and/or biochemical and lack histological assessment, limiting their strength. We conducted a prospective epidemiological study comprising a 1:3 subsample of all adult (>18 years) inhabitants of a rural administrative unit of West Bengal, India. Subjects positive for hepatitis B virus and/or hepatitis C virus infection and consuming any amount of alcohol were excluded. Diagnosis of NAFL was by dual radiological screening protocol consisting of ultrasonographic and computed tomographic examination of the liver. Transient elastographic examination and liver biopsy were performed in a subset to identify significant liver disease. The risk factors of having NAFL were analyzed. A total of 1,911 individuals were analyzed, 7% of whom were overweight and 11% of whom had abdominal obesity. The prevalence of NAFL, NAFL with elevated alanine aminotransferase, and cryptogenic cirrhosis was 8.7%, 2.3%, and 0.2%, respectively. Seventy-five percent of NAFL subjects had a body mass index (BMI) <25 kg/m(2), and 54% were neither overweight nor had abdominal obesity. The subjects with the highest risk of having NAFL were those with a BMI >25 kg/m(2) (odds ratio 4.3, 95% confidence interval 1.6-11.5). Abdominal obesity, dysglycemia (fasting plasma glucose >100 mg/dL or elevated homeostatic model assessment of insulin resistance), and higher income were the other risk factors. Even having a normal BMI (18.5-24.9 kg/m(2)) was associated with a 2-fold increased risk of NAFL versus those with a BMI <18.5 kg/m(2).
CONCLUSION: There is a significant prevalence of NAFL and potentially significant liver disease, including cryptogenic cirrhosis, in this predominantly nonobese, nonaffluent population in a developing country. NAFL will be a major determinant of future liver disease burden in countries of the developing world.

PMID 20222092  Hepatology. 2010 May;51(5):1593-602. doi: 10.1002/hep.2・・・
著者: Etsuko Hashimoto, Katsutoshi Tokushige
雑誌名: J Gastroenterol. 2011 Jan;46 Suppl 1:63-9. doi: 10.1007/s00535-010-0311-8. Epub 2010 Sep 16.
Abstract/Text We provide an update review on the prevalence, gender, ethnic variations, and prognosis of nonalcoholic steatohepatitis (NASH). According to annual health checks, 9-30% of Japanese adults have nonalcoholic fatty liver disease (NAFLD) by ultrasonography (US) and prevalence of NASH is estimated to be 1-3%. These conditions are strongly associated with the presence of obesity and lifestyle-related diseases. NAFLD and NASH exhibit age and gender differences in both prevalence and severity. Among younger patients, these conditions are more common in men (2-3 times); however, after 60 years of age, the prevalence of NASH is higher in women. According to a systemic analysis of histological findings for NASH, 37.6% of patients had progressive fibrosis, 20.8% improved, and 41.6% remained stable over a mean duration of follow-up of 5.3 years. Age and presence of inflammation on initial biopsy were independent predictors of progression to advanced fibrosis. The frequencies of development of cirrhosis in NASH are 5-25% during around 7-year follow-up periods. Survival in NASH is lower than the expected survival of the matched general population due to the higher prevalence of cardiovascular and liver-related death. In patients with cirrhotic NASH, hepatocellular carcinoma (HCC) and liver failure are the main causes of morbidity and mortality (5-year cumulative HCC development rate 11.3%, 5-year survival rate 75.2%, respectively). The cumulative rate of recurrence of HCC at 5 years was 72.5%. Regular screening for complications of liver cirrhosis and HCC is extremely important for cirrhotic NASH patients.

PMID 20844903  J Gastroenterol. 2011 Jan;46 Suppl 1:63-9. doi: 10.1007・・・
著者: Satoru Yatsuji, Etsuko Hashimoto, Maki Tobari, Katsutoshi Tokushige, Keiko Shiratori
雑誌名: Hepatol Res. 2007 Dec;37(12):1034-43. doi: 10.1111/j.1872-034X.2007.00156.x. Epub 2007 Jul 4.
Abstract/Text Aim: Nonalcoholic steatohepatitis (NASH) is considered to be a manifestation of metabolic syndrome. Because prevalence and severity of metabolic syndrome are different according to ages, gender and ethnic group, it is speculated that the clinicopathological features of NASH may also vary in relation to these factors. The present study was performed to clarify the influence of age and gender on the development of Japanese NASH. Subjects: One hundred 93 biopsy-proven NASH patients (86 women and 107 men) were included in this cross-sectional study. The patients were separately analyzed by generation; a younger group (<55 years old) and an older group (>/=55 years old). These groups were compared for their clinical and histological features. Independent risk factors for advanced fibrosis were also analyzed. Results: Comparison of our younger and older groups showed that older patients had much more advanced fibrosis than the younger ones (advanced fibrosis: 23.8%; youngergroup vs. 54.3%; older group, P < 0.001). Women were predominant in the older group (23.8%; younger group vs. 67.4%; older group, P < 0.001). According to the multivariate analysis for risk factors for advanced fibrosis, age (P = 0.007) and BMI (P = 0.028) were independent predictors of advanced fibrosis in the younger group. In contrast, the absence of hyperlipidemia (P = 0.042) was the only significant independent predictor of advanced fibrosis in the older group. Gender was not a risk factor for the severity of NASH. Conclusions: Clinicians need to be aware of age- and gender-specific differences when assessing the characteristics of NASH, and the findings may be useful for prevention and treatment of this disease.

PMID 17610504  Hepatol Res. 2007 Dec;37(12):1034-43. doi: 10.1111/j.18・・・
著者: Naga Chalasani, Zobair Younossi, Joel E Lavine, Michael Charlton, Kenneth Cusi, Mary Rinella, Stephen A Harrison, Elizabeth M Brunt, Arun J Sanyal
雑誌名: Hepatology. 2018 Jan;67(1):328-357. doi: 10.1002/hep.29367. Epub 2017 Sep 29.
Abstract/Text
PMID 28714183  Hepatology. 2018 Jan;67(1):328-357. doi: 10.1002/hep.29・・・
著者: European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO)
雑誌名: J Hepatol. 2016 Jun;64(6):1388-402. doi: 10.1016/j.jhep.2015.11.004. Epub 2016 Apr 7.
Abstract/Text
PMID 27062661  J Hepatol. 2016 Jun;64(6):1388-402. doi: 10.1016/j.jhep・・・
著者: Arun J Sanyal, American Gastroenterological Association
雑誌名: Gastroenterology. 2002 Nov;123(5):1705-25.
Abstract/Text
PMID 12404245  Gastroenterology. 2002 Nov;123(5):1705-25.
著者: Vincent Wai-Sun Wong, Wah-Kheong Chan, Shiv Chitturi, Yogesh Chawla, Yock Young Dan, Ajay Duseja, Jiangao Fan, Khean-Lee Goh, Masahide Hamaguchi, Etsuko Hashimoto, Seung Up Kim, Laurentius Adrianto Lesmana, Yu-Cheng Lin, Chun-Jen Liu, Yen-Hsuan Ni, Jose Sollano, Simon Kin-Hung Wong, Grace Lai-Hung Wong, Henry Lik-Yuen Chan, Geoff Farrell
雑誌名: J Gastroenterol Hepatol. 2018 Jan;33(1):70-85. doi: 10.1111/jgh.13857.
Abstract/Text
PMID 28670712  J Gastroenterol Hepatol. 2018 Jan;33(1):70-85. doi: 10.・・・
著者: J Ludwig, T R Viggiano, D B McGill, B J Oh
雑誌名: Mayo Clin Proc. 1980 Jul;55(7):434-8.
Abstract/Text Nonalcoholic steatohepatitis is a poorly understood and hitherto unnamed liver disease that histologically mimics alcoholic hepatitis and that also may progress to cirrhosis. Described here are findings in 20 patients with nonalcoholic steatohepatitis of unknown cause. The biopsy specimens were characterized by the presence of striking fatty changes with evidence of lobular hepatitis, focal necroses with mixed inflammatory infiltrates, and, in most instances, Mallory bodies; Evidence of fibrosis was found in most specimens, and cirrhosis was diagnosed in biopsy tissue from three patients. The disease was more common in women. Most patients were moderately obese, and many had obesity-associated diseases, such as diabetes mellitus and cholelithiasis. Presence of hepatomegaly and mild abnormalities of liver function were common clinical findings. Currently, we know of no effective therapy.

PMID 7382552  Mayo Clin Proc. 1980 Jul;55(7):434-8.
著者: C A Matteoni, Z M Younossi, T Gramlich, N Boparai, Y C Liu, A J McCullough
雑誌名: Gastroenterology. 1999 Jun;116(6):1413-9.
Abstract/Text BACKGROUND & AIMS: The spectrum of nonalcoholic fatty liver disease ranges from fatty liver alone to nonalcoholic steatohepatitis. Most previous studies have short follow-up and have not carefully delineated different histological types when determining clinical outcomes. The aim of this study was to compare clinical characteristics and outcomes of patients with different types of nonalcoholic fatty liver.
METHODS: All liver biopsy specimens from 1979 to 1987 with fat accumulation were assessed for inflammation, ballooning degeneration, Mallory hyaline, and fibrosis. Biopsy specimens were also assessed for histological iron and hepatitis C RNA. Outcomes were cirrhosis, mortality, and liver-related mortality.
RESULTS: Of 772 liver biopsy specimens, complete data were available in 132 patients. Fatty liver (type 1) did not differ from the other three types combined with respect to gender, race, age, or obesity. Cirrhosis was more common in the other types combined (22%) than fatty liver alone (4%; P CONCLUSIONS: The outcome of cirrhosis and liver-related death is not uniform across the spectrum of nonalcoholic fatty liver. These poor outcomes are more frequent in patients in whom biopsies show ballooning degeneration and Mallory hyaline or fibrosis.

PMID 10348825  Gastroenterology. 1999 Jun;116(6):1413-9.
著者: Nila Rafiq, Chunhong Bai, Yun Fang, Manirath Srishord, Arthur McCullough, Terry Gramlich, Zobair M Younossi
雑誌名: Clin Gastroenterol Hepatol. 2009 Feb;7(2):234-8. doi: 10.1016/j.cgh.2008.11.005. Epub 2008 Nov 7.
Abstract/Text BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of conditions ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH) convincingly. NASH is the only subtype of NAFLD that has been shown to progress relatively, although these findings were reported from studies with short follow-up periods. We assessed the long-term outcomes of a NAFLD cohort.
METHODS: Patients with NAFLD established by biopsy were identified in databases and categorized as NASH or non-NASH. Mortality data and causes of death were obtained from National Death Index Plus. The nonparametric Kaplan-Meier method with log-rank test and multivariate analyses with a Cox proportional hazard model were used to compare different NAFLD subtypes and to identify independent predictors of overall and liver-related mortality.
RESULTS: Of 173 NAFLD patients (age at biopsy, 50.2 +/- 14.5 y; 39.9% male; 80.8% Caucasian; 28.9% with type II diabetes), 72 (41.6%) had NASH and 101 (58.4%) had non-NASH NAFLD. Over the follow-up period, the most common causes of death were coronary artery disease, malignancy, and liver-related death. Although overall mortality did not differ between the NAFLD subtypes, liver-related mortality was higher in patients with NASH (P < .05). Independent predictors of liver-related mortality included histologic NASH, type II diabetes, older age at biopsy, lower albumin levels, and increased levels of alkaline phosphatase (P < .05).
CONCLUSIONS: This long-term follow-up evaluation of NAFLD patients confirms that NASH patients have increased liver-related mortality compared with non-NASH patients. In addition, patients with NAFLD and type II diabetes are especially at risk for liver-related mortality.

PMID 19049831  Clin Gastroenterol Hepatol. 2009 Feb;7(2):234-8. doi: 1・・・
著者: Paul Angulo, David E Kleiner, Sanne Dam-Larsen, Leon A Adams, Einar S Bjornsson, Phunchai Charatcharoenwitthaya, Peter R Mills, Jill C Keach, Heather D Lafferty, Alisha Stahler, Svanhildur Haflidadottir, Flemming Bendtsen
雑誌名: Gastroenterology. 2015 Aug;149(2):389-97.e10. doi: 10.1053/j.gastro.2015.04.043. Epub 2015 Apr 29.
Abstract/Text BACKGROUND & AIMS: Histologic analysis of liver biopsy specimens allows for grading and staging of nonalcoholic fatty liver disease (NAFLD). We performed a longitudinal study to investigate the long-term prognostic relevance of histologic features for patients with NAFLD.
METHODS: We performed a retrospective analysis of 619 patients diagnosed with NAFLD from 1975 through 2005 at medical centers in the United States, Europe, and Thailand. Patients underwent laboratory and biopsy analyses, and were examined every 3-12 months after their diagnosis. Outcomes analyzed were overall mortality, liver transplantation, and liver-related events. Cumulative outcomes were compared by log-rank analysis. Cox proportional-hazards regression was used to estimate adjusted hazard ratios (HRs). Time at risk was determined from the date of liver biopsy to the date of outcome or last follow-up examination.
RESULTS: Over a median follow-up period of 12.6 years (range, 0.3-35.1 y), 193 of the patients (33.2%) died or underwent liver transplantation. Features of liver biopsies significantly associated with death or liver transplantation included fibrosis stage 1 (HR, 1.88; 95% confidence interval [CI], 1.28-2.77), stage 2 (HR, 2.89; 95% CI, 1.93-4.33), stage 3 (HR, 3.76; 95% CI, 2.40-5.89), and stage 4 (HR, 10.9; 95% CI, 6.06-19.62) compared with stage 0, as well as age (HR, 1.07; 95% CI, 1.05-1.08), diabetes (HR, 1.61; 95% CI, 1.13-2.30), current smoking (HR, 2.62; 95% CI, 1.67-4.10), and statin use (HR, 0.32; 95% CI, 0.14-0.70). Twenty-six patients (4.2%) developed liver-related events; fibrosis stage 3 (HR, 14.2; 95% CI, 3.38-59.68) and stage 4 (HR, 51.5; 95% CI, 9.87-269.2) compared with stage 0, were associated significantly with the events. Patients with fibrosis, regardless of steatohepatitis or NAFLD activity score, had shorter survival times than patients without fibrosis.
CONCLUSIONS: In a longitudinal study of patients with NAFLD, fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver-related events.

Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID 25935633  Gastroenterology. 2015 Aug;149(2):389-97.e10. doi: 10.1・・・
著者: Kittichai Promrat, David E Kleiner, Heather M Niemeier, Elizabeth Jackvony, Marie Kearns, Jack R Wands, Joseph L Fava, Rena R Wing
雑誌名: Hepatology. 2010 Jan;51(1):121-9. doi: 10.1002/hep.23276.
Abstract/Text UNLABELLED: Nonalcoholic steatohepatitis (NASH) is a chronic progressive liver disease that is strongly associated with obesity. Currently, there is no approved therapy for NASH. Weight reduction is typically recommended, but efficacy data are lacking. We performed a randomized controlled trial to examine the effects of lifestyle intervention using a combination of diet, exercise, and behavior modification, with a goal of 7% to 10% weight reduction, on clinical parameters of NASH. The primary outcome measure was the change in NASH histological activity score (NAS) after 48 weeks of intervention. Thirty-one overweight or obese individuals (body mass index [BMI], 25-40 kg/m(2)) with biopsy-proven NASH were randomized in a 2:1 ratio to receive intensive lifestyle intervention (LS) or structured education (control). After 48 weeks of intervention, participants assigned to LS lost an average of 9.3% of their weight versus 0.2% in the control group (P = 0.003). A higher proportion of participants in the LS group had a reduction of NAS of at least 3 points or had posttreatment NAS of 2 or less as compared with the control group (72% versus 30%, P = 0.03). NAS improved significantly in the LS group (from 4.4 to 2.0) in comparison with the control group (from 4.9 to 3.5) (P = 0.05). Percent weight reduction correlated significantly with improvement in NAS (r = 0.497, P = 0.007). Participants who achieved the study weight loss goal (>or=7%), compared with those who lost less than 7%, had significant improvements in steatosis (-1.36 versus -0.41, P < 0.001), lobular inflammation (-0.82 versus -0.24, P = 0.03), ballooning injury (-1.27 versus -0.53, P = 0.03) and NAS (-3.45 versus -1.18, P < 0.001).
CONCLUSION: Weight reduction achieved through lifestyle intervention leads to improvements in liver histology in NASH.

PMID 19827166  Hepatology. 2010 Jan;51(1):121-9. doi: 10.1002/hep.2327・・・
著者: Mariana Lazo, Steven F Solga, Alena Horska, Susanne Bonekamp, Anna Mae Diehl, Frederick L Brancati, Lynne E Wagenknecht, F Xavier Pi-Sunyer, Steven E Kahn, Jeanne M Clark, Fatty Liver Subgroup of the Look AHEAD Research Group
雑誌名: Diabetes Care. 2010 Oct;33(10):2156-63. doi: 10.2337/dc10-0856. Epub 2010 Jul 27.
Abstract/Text OBJECTIVE: Weight loss through lifestyle changes is recommended for nonalcoholic fatty liver disease (NAFLD). However, its efficacy in patients with type 2 diabetes is unproven.
RESEARCH DESIGN AND METHODS: Look AHEAD (Action for Health in Diabetes) is a 16-center clinical trial with 5,145 overweight or obese adults with type 2 diabetes, who were randomly assigned to an intensive lifestyle intervention (ILI) to induce a minimum weight loss of 7% or a control group who received diabetes support and education (DSE). In the Fatty Liver Ancillary Study, 96 participants completed proton magnetic resonance spectroscopy to quantify hepatic steatosis and tests to exclude other causes of liver disease at baseline and 12 months. We defined steatosis >5.5% as NAFLD.
RESULTS: Participants were 49% women and 68% white. The mean age was 61 years, mean BMI was 35 kg/m(2), mean steatosis was 8.0%, and mean aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were 20.5 and 24.2 units/l, respectively. After 12 months, participants assigned to ILI (n = 46) lost more weight (-8.5 vs. -0.05%; P < 0.01) than those assigned to DSE and had a greater decline in steatosis (-50.8 vs. -22.8%; P = 0.04) and in A1C (-0.7 vs. -0.2%; P = 0.04). There were no significant 12-month changes in AST or ALT levels. At 12 months, 26% of DSE participants and 3% (1 of 31) of ILI participants without NAFLD at baseline developed NAFLD (P < 0.05).
CONCLUSIONS: A 12-month intensive lifestyle intervention in patients with type 2 diabetes reduces steatosis and incident NAFLD.

PMID 20664019  Diabetes Care. 2010 Oct;33(10):2156-63. doi: 10.2337/dc・・・
著者: D A de Luis, R Aller, O Izaola, M Gonzalez Sagrado, R Conde
雑誌名: Nutr Hosp. 2010 Sep-Oct;25(5):730-5.
Abstract/Text OBJECTIVE: The aim of our study was to examine the changes in hypertransaminasemia after weight reduction in obese patients with and without NAFLD and the relation with insulin resistance.
RESEARCH METHODS: A population of 162 obese patients was randomly allocated to two groups: a) diet I (low fat) and b) diet II (low carbohydrate), dieting along 3 months. Patients were classified as group I (n=112) when serum ALT activity was normal or group II (NAFLD, n=30) when serum ALT activity was (>or=43 UI/L).
RESULTS: In control group with diet I, BMI, weight, fat mass, waist to hip ratio, waist circumference, systolic pressure, total cholesterol, LDL cholesterol, HOMA and insulin levels decreased. In NAFLD group with diet I improved the same parameters and glucose, triglycerides, ALT, AST, gamaglutamine transferase levels, too. In control group with diet II, BMI, weight, fat mass, waist to hip ratio, waist circumference, systolic pressure, total cholesterol, LDL cholesterol, HOMA and insulin levels decreased. In NAFLD group with diet II improved the same parameters and glucose, triglycerides, ALT and gamaglutamine transferase levels, without statistical changes in AST.
CONCLUSION: We showed that weight reduction secondary to two hypocaloric diets was associated with improvement in hipertransaminasemia and insulin resistance in NAFLD patients.

PMID 21336428  Nutr Hosp. 2010 Sep-Oct;25(5):730-5.
著者: D Enette Larson-Meyer, Bradley R Newcomer, Leonie K Heilbronn, Julia Volaufova, Steven R Smith, Anthony J Alfonso, Michael Lefevre, Jennifer C Rood, Donald A Williamson, Eric Ravussin, Pennington CALERIE Team
雑誌名: Obesity (Silver Spring). 2008 Jun;16(6):1355-62. doi: 10.1038/oby.2008.201. Epub 2008 Apr 10.
Abstract/Text OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) and its association with insulin resistance are increasingly recognized as major health burdens. The main objectives of this study were to assess the relation between liver lipid content and serum lipids, markers of liver function and inflammation in healthy overweight subjects, and to determine whether caloric restriction (CR) (which improves insulin resistance) reduces liver lipids in association with these same measures.
METHODS AND PROCEDURES: Forty-six white and black overweight men and women (BMI = 24.7-31.3 kg/m(2)) were randomized to "control (CO)" = 100% energy requirements; "CR" = 25%; "caloric restriction and increased structured exercise (CR+EX)"= 12.5% CR + 12.5% increase in energy expenditure through exercise; or "low-calorie diet (LCD)" = 15% weight loss by liquid diet followed by weight-maintenance, for 6 months. Liver lipid content was assessed by magnetic resonance spectroscopy (MRS) and computed tomography (CT). Lipid concentrations, markers of liver function (alanine aminotransferase (ALT), alkaline phosphatase (ALK)), and whole-body inflammation (tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP)) were measured in fasting blood.
RESULTS: At baseline, increased liver lipid content (by MRS) correlated (P < 0.05) with elevated fasting triglyceride (r = 0.52), ALT (r = 0.42), and hsCRP (r = 0.33) concentrations after adjusting for sex, race, and alcohol consumption. With CR, liver lipid content was significantly lowered by CR, CR+EX, and LCD (detected by MRS only). The reduction in liver lipid content, however, was not significantly correlated with the reduction in triglycerides (r = 0.26; P = 0.11) or with the changes in ALT, high-density lipoprotein (HDL)-cholesterol, or markers of whole-body inflammation.
DISCUSSION: CR may be beneficial for reducing liver lipid and lowering triglycerides in overweight subjects without known NAFLD.

PMID 18421281  Obesity (Silver Spring). 2008 Jun;16(6):1355-62. 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: Rex T Wang, Ronald L Koretz, Hal F Yee
雑誌名: Am J Med. 2003 Nov;115(7):554-9.
Abstract/Text PURPOSE: To assess the evidence supporting the efficacy of weight reduction for patients with nonalcoholic fatty liver.
METHODS: Potentially relevant studies were identified by a computerized search of databases and a manual search of abstracts from scientific meetings. Studies were included if they reported histology, serum aminotransferase levels, or radiological imaging of the liver in obese adult patients who had undergone weight reduction. Weight reduction regimens included diet, exercise, antiobesity medications, gastric bypass, gastroplasty, or any combination of these interventions. Studies involving jejunoileal or small bowel bypass surgery were excluded.
RESULTS: We identified 517 potentially relevant studies, of which 15 met the inclusion criteria: one randomized controlled trial (in abstract form), two nonrandomized controlled trials, nine case series, one retrospective review, and two case reports. Three studies included more than 50 patients, whereas nine studies had 25 or fewer patients. Twelve studies used behavioral, dietary, or pharmacologic therapy for weight reduction, and three studies used surgical interventions. Although all 15 studies demonstrated overall improvement in the measurements of liver outcome after weight reduction, more than half did not report histologic results.
CONCLUSION: Despite general acceptance that weight reduction is an effective therapy for nonalcoholic fatty liver, this systematic review found little data to support or refute this recommendation.

PMID 14599635  Am J Med. 2003 Nov;115(7):554-9.
著者: Arun J Sanyal, Naga Chalasani, Kris V Kowdley, Arthur McCullough, Anna Mae Diehl, Nathan M Bass, Brent A Neuschwander-Tetri, Joel E Lavine, James Tonascia, Aynur Unalp, Mark Van Natta, Jeanne Clark, Elizabeth M Brunt, David E Kleiner, Jay H Hoofnagle, Patricia R Robuck, NASH CRN
雑誌名: N Engl J Med. 2010 May 6;362(18):1675-85. doi: 10.1056/NEJMoa0907929. Epub 2010 Apr 28.
Abstract/Text BACKGROUND: Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease.
METHODS: We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance.
RESULTS: Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P=0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P=0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P=0.005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P=0.02 for vitamin E and P=0.004 for pioglitazone) but not with improvement in fibrosis scores (P=0.24 for vitamin E and P=0.12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups.
CONCLUSIONS: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT00063622.)

2010 Massachusetts Medical Society
PMID 20427778  N Engl J Med. 2010 May 6;362(18):1675-85. doi: 10.1056/・・・
著者: Ken Sato, Masahiko Gosho, Takaya Yamamoto, Yuji Kobayashi, Norimitsu Ishii, Tomohiko Ohashi, Yukiomi Nakade, Kiyoaki Ito, Yoshitaka Fukuzawa, Masashi Yoneda
雑誌名: Nutrition. 2015 Jul-Aug;31(7-8):923-30. doi: 10.1016/j.nut.2014.11.018. Epub 2014 Dec 24.
Abstract/Text OBJECTIVES: Vitamin E is often used in the treatment of nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH); however, the magnitude of treatment response associated with vitamin E in improving liver function and histology in NAFLD/NASH has not, to our knowledge, been quantified systematically. Thus, we conducted a meta-analysis of randomized controlled trials (RCTs) using vitamin E in the treatment of NAFLD/NASH.
METHODS: PubMed, Medline, and Cochrane Library Full Text Database, and Japan Medical-Literature Database (Igaku Chuo Zasshi) were searched until March 2014, and five RCTs were identified for meta-analysis.
RESULTS: According to a random effect model analysis of the five studies, vitamin E significantly reduced aspartate transaminase (AST) by -19.43 U/L, alanine aminotransferase (ALT) by -28.91 U/L, alkaline phosphatase (ALP) by -10.39 U/L, steatosis by -0.54 U/L, inflammation by -0.20 U/L, and hepatocellular ballooning by -0.34 U/L compared with the control group. Vitamin E treatment with NASH adult patients showed obvious reductions in not only AST of -13.91 U/L, ALT by -22.44 U/L, steatosis of -0.67 U/L, inflammation of -0.20 U/L, but also fibrosis of -0.30 U/L compared to the control treatment.
CONCLUSIONS: Vitamin E significantly improved liver function and histologic changes in patients with NAFLD/NASH.

Copyright © 2015 Elsevier Inc. All rights reserved.
PMID 26059365  Nutrition. 2015 Jul-Aug;31(7-8):923-30. doi: 10.1016/j.・・・
著者: Renata Belfort, Stephen A Harrison, Kenneth Brown, Celia Darland, Joan Finch, Jean Hardies, Bogdan Balas, Amalia Gastaldelli, Fermin Tio, Joseph Pulcini, Rachele Berria, Jennie Z Ma, Sunil Dwivedi, Russell Havranek, Chris Fincke, Ralph DeFronzo, George A Bannayan, Steven Schenker, Kenneth Cusi
雑誌名: N Engl J Med. 2006 Nov 30;355(22):2297-307. doi: 10.1056/NEJMoa060326.
Abstract/Text BACKGROUND: No pharmacologic therapy has conclusively proved to be effective for the treatment of nonalcoholic steatohepatitis, which is characterized by insulin resistance, steatosis, and necroinflammation with or without centrilobular fibrosis. Pioglitazone is a thiazolidinedione that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus.
METHODS: We randomly assigned 55 patients with impaired glucose tolerance or type 2 diabetes and liver biopsy-confirmed nonalcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet (a reduction of 500 kcal per day in relation to the calculated daily intake required to maintain body weight) plus pioglitazone (45 mg daily) or a hypocaloric diet plus placebo. Before and after treatment, we assessed hepatic histologic features, hepatic fat content by means of magnetic resonance spectroscopy, and glucose turnover during an oral glucose tolerance test ([14C]glucose given with the oral glucose load and [3H]glucose given by intravenous infusion).
RESULTS: Diet plus pioglitazone, as compared with diet plus placebo, improved glycemic control and glucose tolerance (P<0.001), normalized liver aminotransferase levels as it decreased plasma aspartate aminotransferase levels (by 40% vs. 21%, P=0.04), decreased alanine aminotransferase levels (by 58% vs. 34%, P<0.001), decreased hepatic fat content (by 54% vs. 0%, P<0.001), and increased hepatic insulin sensitivity (by 48% vs. 14%, P=0.008). Administration of pioglitazone, as compared with placebo, was associated with improvement in histologic findings with regard to steatosis (P=0.003), ballooning necrosis (P=0.02), and inflammation (P=0.008). Subjects in the pioglitazone group had a greater reduction in necroinflammation (85% vs. 38%, P=0.001), but the reduction in fibrosis did not differ significantly from that in the placebo group (P=0.08). Fatigue and mild lower-extremity edema developed in one subject who received pioglitazone; no other adverse events were observed.
CONCLUSIONS: In this proof-of-concept study, the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis. Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone. (ClinicalTrials.gov number, NCT00227110 [ClinicalTrials.gov] .).

Copyright 2006 Massachusetts Medical Society.
PMID 17135584  N Engl J Med. 2006 Nov 30;355(22):2297-307. doi: 10.105・・・
著者: Guruprasad P Aithal, James A Thomas, Philip V Kaye, Adam Lawson, Stephen D Ryder, Ian Spendlove, Andrew S Austin, Jan G Freeman, Linda Morgan, Jonathan Webber
雑誌名: Gastroenterology. 2008 Oct;135(4):1176-84. doi: 10.1053/j.gastro.2008.06.047. Epub 2008 Jun 25.
Abstract/Text BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease for which there is limited therapy available. Insulin sensitizing, anti-inflammatory, and antifibrotic properties of thiazolidinediones support their use in treating NASH. We have evaluated pioglitazone in the treatment of nondiabetic patients with NASH.
METHODS: We randomized 74 nondiabetic patients (45 men; median age, 54 y) with histologically proven NASH to 12 months of standard diet, exercise, and either placebo or pioglitazone (30 mg/day). Sixty-one patients (30 placebo, 31 pioglitazone) had liver biopsies both at the beginning and the end of the study.
RESULTS: Compared with placebo, pioglitazone therapy was associated with an increase in weight (mean change, -0.55 vs +2.77 kg; P = .04) and a reduction in glucose (+0.4 vs -0.1 mmol/L; P = .02), HbA1c (+0.16% vs -0.18%; P = .006), insulin C peptide level (+42 vs -78 pmol/L; P = .02), alanine aminotransferase level (-10.9 vs -36.2 u/L; P = .009), gamma-glutamyltransferase level (-9.4 vs -41.2 u/L; P = .002), and ferritin (-11.3 vs -90.5 microg/L; P = .01). Histologic features including hepatocellular injury (P = .005), Mallory-Denk bodies (P = .004), and fibrosis (P = .05) were reduced in patients treated with pioglitazone compared with those in the placebo group.
CONCLUSIONS: Pioglitazone therapy over a 12-month period in nondiabetic subjects with NASH resulted in improvements in metabolic and histologic parameters, most notably liver injury and fibrosis. Larger extended trials are justified to assess the long-term efficacy of pioglitazone in this patient group.

PMID 18718471  Gastroenterology. 2008 Oct;135(4):1176-84. doi: 10.1053・・・
著者: Lauren N Bell, Jiangxia Wang, Sriya Muralidharan, Sadhana Chalasani, Allison M Fullenkamp, Laura A Wilson, Arun J Sanyal, Kris V Kowdley, Brent A Neuschwander-Tetri, Elizabeth M Brunt, Arthur J McCullough, Nathan M Bass, Anna Mae Diehl, Aynur Unalp-Arida, Naga Chalasani, Nonalcoholic Steatohepatitis Clinical Research Network
雑誌名: Hepatology. 2012 Oct;56(4):1311-8. doi: 10.1002/hep.25805. Epub 2012 Aug 21.
Abstract/Text UNLABELLED: The PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis [NASH]) trial demonstrated that pioglitazone and vitamin E improved liver histology to varying degrees, but the mechanisms are unknown. We conducted a study to examine the changes in adipose tissue insulin resistance (Adipo-IR) during the PIVENS trial and its relationship to histological endpoints. Adipo-IR (fasting nonesterified fatty acids [NEFAs] × fasting insulin) was calculated at baseline and after 16 and 96 weeks of therapy. Compared to placebo, the baseline Adipo-IR was not different in either the vitamin E group (P = 0.34) or the pioglitazone group (P = 0.29). Baseline Adipo-IR was significantly associated with fibrosis score (P = 0.02), but not with other histological features or nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 16 weeks, compared to placebo, the pioglitazone group had a significant reduction in Adipo-IR (-15.7 versus -1.91; P = 0.02), but this effect did not persist at 96 weeks (-3.25 versus -4.28; P = 0.31). Compared to placebo, Adipo-IR in the vitamin E group did not change significantly either after 16 weeks (P = 0.70) or after 96 weeks (P = 0.85). Change in Adipo-IR at week 16 was not associated with changes in any histological parameters at week 96, but improvement in Adipo-IR at week 96 was significantly associated with improvement in ballooning (P = 0.03), fibrosis (P = 0.004), and NAS (P = 0.01).
CONCLUSION: Vitamin E improved liver histology independent of changes in Adipo-IR, and pioglitazone treatment acutely improved Adipo-IR, but this was not sustained. Changes in Adipo-IR were associated with changes in liver histology, including fibrosis.

Copyright © 2012 American Association for the Study of Liver Diseases.
PMID 22532269  Hepatology. 2012 Oct;56(4):1311-8. doi: 10.1002/hep.258・・・
著者: Kenneth Cusi, Beverly Orsak, Fernando Bril, Romina Lomonaco, Joan Hecht, Carolina Ortiz-Lopez, Fermin Tio, Jean Hardies, Celia Darland, Nicolas Musi, Amy Webb, Paola Portillo-Sanchez
雑誌名: Ann Intern Med. 2016 Sep 6;165(5):305-15. doi: 10.7326/M15-1774. Epub 2016 Jun 21.
Abstract/Text BACKGROUND: The metabolic defects of nonalcoholic steatohepatitis (NASH) and prediabetes or type 2 diabetes mellitus (T2DM) seem to be specifically targeted by pioglitazone. However, information about its long-term use in this population is limited.
OBJECTIVE: To determine the efficacy and safety of long-term pioglitazone treatment in patients with NASH and prediabetes or T2DM.
DESIGN: Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT00994682).
SETTING: University hospital.
PARTICIPANTS: Patients (n = 101) with prediabetes or T2DM and biopsy-proven NASH were recruited from the general population and outpatient clinics.
INTERVENTION: All patients were prescribed a hypocaloric diet (500-kcal/d deficit from weight-maintaining caloric intake) and then randomly assigned to pioglitazone, 45 mg/d, or placebo for 18 months, followed by an 18-month open-label phase with pioglitazone treatment.
MEASUREMENTS: The primary outcome was a reduction of at least 2 points in the nonalcoholic fatty liver disease activity score in 2 histologic categories without worsening of fibrosis. Secondary outcomes included other histologic outcomes, hepatic triglyceride content measured by magnetic resonance and proton spectroscopy, and metabolic parameters.
RESULTS: Among patients randomly assigned to pioglitazone, 58% achieved the primary outcome (treatment difference, 41 percentage points [95% CI, 23 to 59 percentage points]) and 51% had resolution of NASH (treatment difference, 32 percentage points [CI, 13 to 51 percentage points]) (P < 0.001 for each). Pioglitazone treatment also was associated with improvement in individual histologic scores, including the fibrosis score (treatment difference, -0.5 [CI, -0.9 to 0.0]; P = 0.039); reduced hepatic triglyceride content from 19% to 7% (treatment difference, -7 percentage points [CI, -10 to -4 percentage points]; P < 0.001); and improved adipose tissue, hepatic, and muscle insulin sensitivity (P < 0.001 vs. placebo for all). All 18-month metabolic and histologic improvements persisted over 36 months of therapy. The overall rate of adverse events did not differ between groups, although weight gain was greater with pioglitazone (2.5 kg vs. placebo).
LIMITATION: Single-center study.
CONCLUSION: Long-term pioglitazone treatment is safe and effective in patients with prediabetes or T2DM and NASH.
PRIMARY FUNDING SOURCE: Burroughs Wellcome Fund and American Diabetes Association.

PMID 27322798  Ann Intern Med. 2016 Sep 6;165(5):305-15. doi: 10.7326/・・・

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