Takyar Varun, Nath Anand, Beri Andrea, Gharib Ahmed M, Rotman Yaron
Liver & Energy Metabolism Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Department of Medicine, Medstar Washington Hospital Center, Washington, DC.
Hepatology. 2017 Sep;66(3):825-833. doi: 10.1002/hep.29247. Epub 2017 Jul 27.
Healthy volunteers are crucial for biomedical research. Inadvertent inclusion of subjects with nonalcoholic fatty liver disease (NAFLD) as controls can compromise study validity and subject safety. Given the rising prevalence of NAFLD in the general population, we sought to identify its prevalence and potential impact in volunteers for clinical trials. We conducted a cross-sectional study of subjects who were classified as healthy volunteers between 2011 and 2015 and had no known liver disease. Subjects were classified as presumed NAFLD (pNF; alanine aminotransferase [ALT] level ≥ 20 for women or ≥ 31 for men and body mass index [BMI] > 25 kg/m ), healthy non-NAFLD controls (normal ALT and BMI), or indeterminate. A total of 3160 subjects participated as healthy volunteers in 149 clinical trials (1-29 trials per subject); 1732 of these subjects (55%) had a BMI > 25 kg/m and 1382 (44%) had abnormal ALT. pNF was present in 881 subjects (27.9%), and these subjects were older than healthy control subjects and had higher triglycerides, low-density lipoprotein cholesterol, and HbA1c and lower high-density lipoprotein cholesterol (P < 0.001 for all). The 149 trials included 101 non-interventional, 33 interventional, and 15 vaccine trials. The impact on study validity of recruiting NAFLD subjects as controls was estimated as likely, probable, and unlikely in 10, 41, and 98 trials, respectively. The proportion of pNF subjects (28%-29%) did not differ by impact. Only 14% of trials used both BMI and ALT for screening. ALT cutoffs for screening were based on local reference values. Grade 3-4 ALT elevations during the study period were rare but more common in pNF subjects than in healthy control subjects (4 versus 1).
NAFLD is common and often overlooked in volunteers for clinical trials, despite its potential impact on subject safety and validity of study findings. Increased awareness of NAFLD prevalence and stricter ALT cutoffs may ameliorate this problem. (Hepatology 2017;66:825-833).
健康志愿者对生物医学研究至关重要。不经意间将非酒精性脂肪性肝病（NAFLD）患者纳入对照组可能会损害研究的有效性和受试者安全。鉴于普通人群中NAFLD的患病率不断上升，我们试图确定其在临床试验志愿者中的患病率及其潜在影响。我们对2011年至2015年间被归类为健康志愿者且无已知肝脏疾病的受试者进行了一项横断面研究。受试者被分为推定NAFLD（pNF；女性丙氨酸氨基转移酶[ALT]水平≥20或男性≥31且体重指数[BMI]>25kg/m²）、健康非NAFLD对照组（ALT和BMI正常）或不确定组。共有3160名受试者作为健康志愿者参与了149项临床试验（每位受试者参与1 - 29项试验）；其中1732名受试者（55%）BMI>25kg/m²，1382名（44%）ALT异常。881名受试者（27.9%）存在pNF，这些受试者比健康对照组受试者年龄更大，甘油三酯、低密度脂蛋白胆固醇和糖化血红蛋白（HbA1c）更高，高密度脂蛋白胆固醇更低（所有P<0.001）。这149项试验包括101项非干预性试验、33项干预性试验和15项疫苗试验。将NAFLD受试者招募为对照组对研究有效性的影响在10项、41项和98项试验中分别估计为可能、很可能和不太可能。pNF受试者的比例（28% - 29%）在不同影响程度的试验中无差异。只有14%的试验同时使用BMI和ALT进行筛查。筛查的ALT临界值基于当地参考值。研究期间3 - 4级ALT升高很少见，但在pNF受试者中比健康对照组受试者更常见（分别为4例和1例）。
尽管NAFLD对受试者安全和研究结果的有效性有潜在影响，但在临床试验志愿者中很常见且常被忽视。提高对NAFLD患病率的认识和采用更严格的ALT临界值可能会改善这一问题。（《肝脏病学》2017年；66:825 - 833）
