今日の臨床サポート

肝機能障害(AST,ALT上昇)

著者: 横江正道 名古屋第二赤十字病院 総合内科

監修: 野口善令 豊田地域医療センター 総合診療科

著者校正/監修レビュー済:2021/06/23
参考ガイドライン:
日本肝臓学会:B型肝炎治療ガイドライン(第3.3版) 2021年1月 
日本肝臓学会:C型肝炎治療ガイドライン(第8版)2020年7月
日本消化器病学会:NAFLD/NASH診療ガイドライン2014
日本消化器病学会:NAFLD/NASH診療ガイドライン2020
患者向け説明資料

概要・推奨   

  1. 肝逸脱酵素の正常値の2倍以上を認める場合は、肝炎などの疾患を検索することが推奨される。しかし、肝逸脱酵素の慢性的な軽度上昇は必ずしも重篤な疾患の存在を意味しないため、必ずしも肝生検を行う必要はない(推奨度2)。
  1. 症状のない肝機能障害患者の多くは、NASHや脂肪肝である(推奨度2)。
  1. AST/ALTの上昇のレベルから疾患の推測をする(推奨度2)。
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:
横江正道 : 特に申告事項無し[2021年]
監修:野口善令 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行い、NAFLD/NASHについて加筆修正を行った。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 肝逸脱酵素は、検診や、通常の診療でよく測定される検査である。
  1. 多くの場合が無症状である(肝機能障害単独の場合)。
  1. AST、ALTの上昇は、測定者の約5~10%の異常として認められる。
  1. 原因のよくわからない肝機能異常の患者に肝生検を行って確定診断をつけた研究では、その66~84%が脂肪変性や脂肪肝、脂肪肝炎(NAFLD)であったと報告されている[1][2]
  1. 非肥満NAFLD/NASHはアジアに多く、PNPLA3遺伝子多型がNAFLD/NASH発症および・病態進展に関与していることが明らかなとなり、PNPLA3GGホモ変異は日本人の一般事項の約20%に存在することから日本人はNAFLD/NASHを発症しやすいと考えられている[3]
 
原因不明の肝機能障害を肝生検で診断した354例の結果

66%はNASH、脂肪肝

出典

img1:  Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology.
 
 J Hepatol. 2001 Aug;35(2):195-9.
 
  1. 特に重篤な疾患を認めない、正常値2倍程度の軽度のAST、ALTの上昇は、ほとんどの場合、アルコール性肝障害か、脂肪肝であるため、原因となるような薬剤、食事を中止し、脂肪肝の治療である、食事指導(カロリー制限)、節酒、運動指導を行い、1月後に値をフォローアップする。改善傾向を認めない場合は、鑑別疾患を考え直す。
  1. なかには全身倦怠感を自覚する患者さんもいるが、高度の肝機能障害を伴う場合を除いて、どこまで直接、因果関係があるかは実臨床上、言い切れないと思われる。
  1. 黄疸を伴う場合には、ウイルス性肝炎、閉塞性黄疸、悪性腫瘍、アルコール性肝障害などの除外診断を進める。
  1. 発熱を伴う場合には、ウイルス性肝炎、伝染性単核球症、急性胆管炎、などを考えるきっかけになる。
  1. 薬剤性肝障害は頻度の高い原因である。最近、使い始めた薬や、⼀時的に飲んだ薬などを確認する。
問診・診察のポイント  
問診:
  1. 自覚症状(全⾝倦怠感、易疲労感、腹痛、発熱、咽頭痛、関節痛、筋⾁痛など)の有無と持続期間を確認する。
  1. 薬物使用歴を確認する。

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文献 

著者: M M Skelly, P D James, S D Ryder
雑誌名: J Hepatol. 2001 Aug;35(2):195-9.
Abstract/Text BACKGROUND/AIMS: The significance of abnormal liver function tests in the absence of diagnostic serology is unclear. The aim of this study was to report liver biopsy findings in a large group of patients with unexplained abnormal liver biochemistry.
METHODS: Histological findings were examined in 354 patients who underwent liver biopsy to investigate abnormal liver function tests.
RESULTS: Six percent of patients had a normal liver biopsy while 26% were found to have some degree of fibrosis and 6% were cirrhotic. Thirty four and 32% of biopsies suggested non-alcoholic steatohepatits or fatty liver respectively. Other diagnoses included cryptogenic hepatitis, drug toxicity, primary and secondary biliary cirrhosis, autoimmune hepatits, alcohol-related liver disease, primary sclerosing cholangitis, haemochromatosis, amyloid and glycogen storage disease. Patient management was directly altered in 18% of patients due to liver biopsy findings and three families were entered into screening programmes for inheritable liver disease.
CONCLUSIONS: The finding of abnormal liver function tests in the absence of diagnostic serology may indicate significant liver disease. Liver biopsy yields a range of liver diseases of diverse nature and extent. Liver diseases may be uncovered for which specific treatment is indicated.

PMID 11580141  J Hepatol. 2001 Aug;35(2):195-9.
著者: S Daniel, T Ben-Menachem, G Vasudevan, C K Ma, M Blumenkehl
雑誌名: Am J Gastroenterol. 1999 Oct;94(10):3010-4. doi: 10.1111/j.1572-0241.1999.01451.x.
Abstract/Text OBJECTIVES: It is currently recommend to perform a liver biopsy for patients with chronically elevated liver function tests (LFT) of unknown etiology (marker negative). The necessity and benefits of these recommendations are unknown. The aims of this study were to determine the prevalence of marker-negative LFT in patients referred for evaluation of chronically elevated LFT; to determine the prevalence of diseases that may be associated with marker-negative abnormal LFT; and to assess whether a liver biopsy alters the management of such patients.
METHODS: We conducted a prospective observational study of 1124 adults referred for evaluation of chronically elevated LFT. Patients who consented to a liver biopsy were eligible. Marker-negative abnormal LFT was defined as the absence of accepted serum markers for infectious, metabolic, autoimmune, or hereditary liver disease, the absence of a history of alcohol or hepatotoxic drug use, and the absence of signs of chronic liver disease.
RESULTS: Eighty-one of 1124 eligible patients were marker-negative. Liver biopsies in the 81 marker-negative patients revealed: normal histology (eight), steatosis (41), steatohepatitis (26), fibrosis (four), and cirrhosis (two). All 73 abnormal liver biopsies had some degree of steatosis. There were no significant associations between histological findings and the presence of obesity (p = 0.13), hyperlipidemia (p = 0.4), or diabetes (p = 0.9). There were no significant associations when classifying patients by gender or by symptoms.
CONCLUSION: In the setting of marker-negative elevated LFT, the most likely histological diagnosis is fatty metamorphosis of the liver with occasional associated fibrosis.

PMID 10520861  Am J Gastroenterol. 1999 Oct;94(10):3010-4. doi: 10.111・・・
著者: Kenichi Nishioji, Naomi Mochizuki, Masao Kobayashi, Mai Kamaguchi, Yoshio Sumida, Takeshi Nishimura, Kanji Yamaguchi, Hiroshi Kadotani, Yoshito Itoh
雑誌名: PLoS One. 2015;10(10):e0140427. doi: 10.1371/journal.pone.0140427. Epub 2015 Oct 20.
Abstract/Text Non-alcoholic fatty liver disease (NAFLD) in non-obese individuals is inadequately elucidated. We aim to investigate the impact of known genetic polymorphisms on NAFLD and the interaction between genetic risks and weight gain on NAFLD in obese and non-obese Japanese individuals. A total of 1164 participants who received health checkups were included. Participants with excessive alcohol consumption, with viral hepatitis or other inappropriate cases were excluded. Fatty liver was diagnosed by ultrasonography. Participants with a body mass index (BMI) of <18.5 kg/m2, 18.5-22.9 kg/m2, 23.0-24.9 kg/m2 and ≥25 kg/m2 were classified underweight, normal weight, overweight and obese, respectively. Self-administered questionnaire for lifestyle was assessed and a total of 8 previously reported genetic polymorphisms were chosen and examined. In all, 824 subjects were enrolled. The overall prevalence of NAFLD was 33.0%: 0% in underweight, 15.3% in normal weight, 41.1% in overweight and 71.7% in obese individuals. The prevalence of NAFLD is more affected by the G allele of patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 in normal weight (odds ratio (OR) 3.52; 95%-CI: 1.42-8.71; P = 0.0063) and in overweight individuals (OR 2.60; 95%-CI: 1.14-5.91; P = 0.0225) than in obese individuals (not significant). Moreover, the G allele of PNPLA3 rs738409 and weight gain ≥10 kg after age 20 had a joint effect on the risk of NAFLD in the normal weight (OR 12.00; 95% CI: 3.71-38.79; P = 3.3×10-5) and the overweight individuals (OR 13.40; 95% CI: 2.92-61.36; P = 0.0008). The G allele of PNPLA3 rs738409 is a prominent risk factor for NAFLD and the interaction between the PNPLA3 rs738409 and weight gain ≥10 kg after age 20 plays a crucial role in the pathogenesis of NAFLD, especially in non-obese Japanese individuals.

PMID 26485523  PLoS One. 2015;10(10):e0140427. doi: 10.1371/journal.po・・・
著者: L W Kundrotas, D J Clement
雑誌名: Dig Dis Sci. 1993 Dec;38(12):2145-50.
Abstract/Text The purpose of this study was to determine the etiology of elevated alanine aminotransferase (ALT) in a population of asymptomatic volunteer blood donors. Subjects with an ALT value > 2.25 sd above norm (> 55 IU/liter) from the donated unit, were prospectively evaluated over a six-week interval. The subjects consisted of blood donors (78% male, 22% female) beginning basic military training at Lackland Air Force Base. Of 44,160 individuals screened, 19,877 (45%) voluntarily donated blood, 99 (0.5%) of which had confirmed ALT elevation. Of these (90 male/9 female), an associated condition or explanation was made in 12%: four with acute hepatitis B, four positive for anti-HCV, two with autoimmune disease, one with cholelithiasis and one associated with acute appendicitis. In 87 the ALT elevation could not be explained using available testing methods but may represent individual variation from a non-Gaussian distribution, be of nonhepatic origin (muscle), or of hepatic disease not detected by the diagnostic algorithm used. To increase the diagnostic yield, it is suggested that at least two elevated ALT values be established in this population over a period of time (yet undefined), before an extensive hepatic investigation is pursued.

PMID 8261813  Dig Dis Sci. 1993 Dec;38(12):2145-50.
著者: R Hultcrantz, H Glaumann, G Lindberg, L H Nilsson
雑誌名: Scand J Gastroenterol. 1986 Jan;21(1):109-13.
Abstract/Text The accidental finding of raised levels of serum aminotransferase levels may lead to extensive investigations of the liver in apparently healthy people. To identify diagnostic groups and their need for investigations, we have evaluated the results of all investigative procedures carried out in 149 asymptomatic patients with persistently raised serum levels of aminotransferases. Fatty liver was found in 64%. These patients often had a high body weight. A high alcohol intake and diabetes mellitus were also noted. Chronic active or persistent hepatitis was found in 20% of the patients. Six per cent had cirrhosis, 4% had alpha 1-antitrypsin deficiency, and 3.5% had hemochromatosis. Apart from ferritin, alpha 1-antitrypsin, and markers for hepatitis B, blood tests were of little value for distinguishing among different diagnostic groups. This was the case also for the imaging procedures, and neither liver scintigraphy nor ultrasonography was a reliable source of diagnostic information. The results of our study indicate that diagnosis in this group of patients cannot be made without liver biopsy.

PMID 3952445  Scand J Gastroenterol. 1986 Jan;21(1):109-13.
著者: Edoardo G Giannini, Roberto Testa, Vincenzo Savarino
雑誌名: CMAJ. 2005 Feb 1;172(3):367-79. doi: 10.1503/cmaj.1040752.
Abstract/Text Isolated alterations of biochemical markers of liver damage in a seemingly healthy patient can present a challenge for the clinician. In this review we provide a guide to interpreting alterations to liver enzyme levels. The functional anatomy of the liver and pathophysiology of liver enzyme alteration are briefly reviewed. Using a schematic approach that classifies enzyme alterations as predominantly hepatocellular or predominantly cholestatic, we review abnormal enzymatic activity within the 2 subgroups, the most common causes of enzyme alteration and suggested initial investigations.

PMID 15684121  CMAJ. 2005 Feb 1;172(3):367-79. doi: 10.1503/cmaj.10407・・・
著者: Michael Krier, Aijaz Ahmed
雑誌名: Clin Liver Dis. 2009 May;13(2):167-77. doi: 10.1016/j.cld.2009.02.001.
Abstract/Text Traditionally, the constellation of biochemistry tests including liver enzymes, total bilirubin, and hepatic synthetic measures (prothrombin time (PT) and serum albumin level) are referred to as liver function tests (LFTs). Abnormal LFTs can be encountered during primary health care visits, routine blood donation, and insurance screening. A reported 1% to 4% of asymptomatic patients exhibit abnormal LFTs, leading to a sizeable number of annual consultations to a gastroenterology and/or hepatology practice. A cost-effective and systematic approach is essential to the interpretation of abnormal LFTs. A review of pattern of abnormal LFTs, detailed medical history, and a comprehensive physical examination help establish a foundation for further individualized testing. Further investigation often involves biochemical testing for disease-specific markers, radiographic imaging, and even consideration of a liver biopsy. In the following account, markers of hepatic injury are reviewed followed by a discussion on an approach to various patterns of abnormal LFTs in an asymptomatic patient.

PMID 19442912  Clin Liver Dis. 2009 May;13(2):167-77. doi: 10.1016/j.c・・・
著者: Paul T Giboney
雑誌名: Am Fam Physician. 2005 Mar 15;71(6):1105-10.
Abstract/Text Mild elevations in liver chemistry tests such as alanine transaminase and aspartate transaminase can reveal serious underlying conditions or have transient and benign etiologies. Potential causes of liver transaminase elevations include viral hepatitis, alcohol use, medication use, steatosis or steatohepatitis, and cirrhosis. The history should be thorough, with special attention given to the use of medications, vitamins, herbs, drugs, and alcohol; family history; and any history of blood-product transfusions. Other common health conditions, such as diabetes, heart disease, and thyroid disease, can cause or augment liver transaminase elevations. The recent American Gastroenterological Association guideline regarding the evaluation and management of abnormal liver chemistry tests proposes a practical, algorithmic approach when the history and physical examination do not reveal the cause. In addition to liver chemistries, an initial serologic evaluation includes a prothrombin time; albumin; complete blood count with platelets; hepatitis A, B, and C serologies; and iron studies. Depending on the etiology, management strategies may include cessation of alcohol use, attention to medications, control of diabetes, and modification of lifestyle factors such as obesity. If elevations persist after an appropriate period of observation, further testing may include ultrasonography and other serum studies. In some cases, biopsy may be indicated.

PMID 15791889  Am Fam Physician. 2005 Mar 15;71(6):1105-10.

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