Rastogi Archana, Rath Indira, Varadarajan Annapoorani, Ramakrishna Gayatri, Bihari Chhagan, Maiwall Rakhi
Institute of Liver & Biliary Sciences, D-1 Vasant Kunj, Delhi 110070, India.
Pathol Res Pract. 2022 Oct;238:154112. doi: 10.1016/j.prp.2022.154112. Epub 2022 Sep 7.
Non-alcoholic fatty liver disease is one of the most common causes of chronic liver diseases and occurs even in lean individuals having normal or low body mass index (BMI). Crucial issue is understanding the clinical, pathobiologic and metabolic characteristics in comparison to obese patients. Very few studies have compared clinicopathological characteristics between lean and obese. Published literature is generally in a small cohort of patients, rarely included over-weight as separate category, and most often had non-standardized use of BMI criteria with discordant conclusions. There is very sparse published literature on liver biopsy-confirmed cohort and that to from Asia; also, none had explored the role of mediators such as stellate cells, progenitor cells and macrophages.
To evaluate the prevalence of NAFLD in lean patients in a large cohort of histology-confirmed NAFLD, and explore clinico-pathological spectrum of lean NAFLD in comparison to over-weight and obese. Also, to investigate role of hepatic stellate cells, macrophage polarization and their relation to hepatic progenitor cells, in particular the relation to fibrosis and to different BMI categories.
Prospective analysis of eleven-year retrospective cross-sectional data of all consecutive patients of NAFLD diagnosed in the period between the year 2011 and 2021. All histologically confirmed cases of NAFLD fulfilling inclusion and exclusion criteria were stratified to three groups according to BMI based on Asian criteria. Demographic, lab, metabolic, and histological comparisons between lean and overweight-obese patients were performed. Histological grading and staging of NAFLD components were performed by NAS-CRN score. Immunohistochemical and image analysis-based assessment and quantification of stellate cells, progenitor cells, and macrophage polarization was performed. Appropriate statistical methods were applied, and study was approved by the Institutional ethics committee.
Lean patients with biopsy-proven diagnosis constituted 21 % (n = 267) of total NAFLD (n = 1273). Other groups were-over-weight patients (232;18.2 %), and the highest were obese patients (774; 60.8 %). 13.9 % of the lean patients with NAFLD were under-weight with BMI<18.5 kg/m. Lean patients had significantly lower BMI and waist circumference along with lesser fasting glucose levels in comparison to the other groups. Rest of the metabolic parameters were nearly similar. Lean patients showed higher serum ALT levels, and histological characteristics such as ballooning of hepatocytes and steatosis were also more marked in comparison to other groups. Lobular inflammation and advanced fibrosis were significantly less common in lean patients with NASH related cirrhosis found in only 20.9 % of them. Immunophenotypic studies revealed the inter-relationship of HPCs, HSCs, and macrophages was influenced by the stage of fibrosis and not by the BMI.
Prevalence of NAFLD in lean individuals in a histological-confirmed patient cohort was 21 %. (n = 267/1273). Major strengths of this study are large cohort of lean individuals from a single center, inclusion of only histology-confirmed cases, Asia specific BMI criteria usage, comparative clinical, metabolic, immune-morphologic and image analysis-based characterization, inclusion of over-weight in addition to obese patients, and investigating cross-talk of principal patho-physiologic markers.
非酒精性脂肪性肝病是慢性肝病最常见的病因之一，甚至在体重指数（BMI）正常或较低的瘦人中也会发生。关键问题在于了解与肥胖患者相比，其临床、病理生物学和代谢特征。很少有研究比较瘦人和肥胖患者的临床病理特征。已发表的文献通常基于一小群患者，很少将超重单独列为一类，而且大多数情况下BMI标准使用不规范，结论也不一致。关于肝活检确诊队列的已发表文献非常稀少，来自亚洲的更是如此；此外，尚无研究探讨星状细胞、祖细胞和巨噬细胞等介质的作用。
评估在大量经组织学确诊的非酒精性脂肪性肝病患者队列中瘦人非酒精性脂肪性肝病的患病率，并与超重和肥胖患者相比，探讨瘦人非酒精性脂肪性肝病的临床病理谱。此外，研究肝星状细胞、巨噬细胞极化的作用及其与肝祖细胞的关系，特别是与纤维化及不同BMI类别的关系。
对2011年至2021年期间诊断的所有连续性非酒精性脂肪性肝病患者的11年回顾性横断面数据进行前瞻性分析。所有经组织学确诊且符合纳入和排除标准的非酒精性脂肪性肝病病例，根据亚洲标准按BMI分为三组。对瘦人与超重 - 肥胖患者进行人口统计学、实验室检查、代谢和组织学比较。采用NAS - CRN评分对非酒精性脂肪性肝病各成分进行组织学分级和分期。通过免疫组织化学和基于图像分析的方法对星状细胞、祖细胞和巨噬细胞极化进行评估和定量。应用适当的统计方法，本研究经机构伦理委员会批准。
经活检证实诊断的瘦人患者占非酒精性脂肪性肝病患者总数的21%（n = 267），总病例数为1273例。其他组为超重患者（232例；18.2%），肥胖患者最多（774例；60.8%）。13.9%的瘦人非酒精性脂肪性肝病患者体重过轻，BMI < 18.5 kg/m²。与其他组相比，瘦人患者的BMI和腰围显著更低，空腹血糖水平也更低。其余代谢参数几乎相似。瘦人患者血清ALT水平较高，肝细胞气球样变和脂肪变性等组织学特征也比其他组更明显。小叶性炎症和晚期纤维化在瘦人患者中明显较少见，NASH相关肝硬化仅在20.9%的瘦人患者中发现。免疫表型研究显示，肝祖细胞、肝星状细胞和巨噬细胞之间的相互关系受纤维化阶段影响，而非BMI影响。
在经组织学确诊患者队列中，瘦人非酒精性脂肪性肝病的患病率为21%（n = 267/1273）。本研究的主要优势在于来自单一中心的大量瘦人队列、仅纳入经组织学确诊的病例、使用亚洲特定的BMI标准、基于比较临床、代谢、免疫形态学和图像分析的特征描述、除肥胖患者外还纳入超重患者，以及研究主要病理生理标志物的相互作用。
