Department of Pathophysiology and Transplantation, Unit of Metabolic and Internal Medicine, University of Milan, Milan, Italy.
Biomedical Department of Internal and Specialistic Medicine (Dipartimento Biomedico di Medicina Interna e Specialistica), Gastroenterological and Hepatological Unit, University of Palermo, Palermo, Italy.
Clin Gastroenterol Hepatol. 2017 Oct;15(10):1604-1611.e1. doi: 10.1016/j.cgh.2017.04.045. Epub 2017 May 26.
BACKGROUND & AIMS: Lean nonalcoholic fatty liver disease (NAFLD) is defined as NAFLD that develops in patients with a body mass index (BMI) less than 25 kg/m. We investigated the differences between lean NAFLD and NAFLD in overweight and obese persons, factors associated with the severity of liver and cardiovascular disease, and the effects of visceral obesity.
We performed a retrospective cohort study of 669 consecutive patients with biopsy-proven NAFLD seen at 3 liver centers in Italy. We collected anthropometric, clinical, and biochemical data, as well as information on carotid atherosclerosis (artery intima-media thickness and plaque), liver histology (nonalcoholic steatohepatitis [NASH] and fibrosis), insulin resistance, and diabetes. Overweight was defined as a BMI of 25 to 29.9 kg/m, and obese was defined as a BMI of 30 kg/m or greater. Patients were assigned to groups based on waist circumference, a marker of visceral obesity (low: men, <94 cm, women <80 cm; medium: men, 94-102 cm, women 80-88 cm; or high: men >102 cm, women >88 cm). DNA samples were analyzed for the rs738409 C>G (I148M in PNPLA3), the rs58542926 C>T (E167K in TM6SF2), and single-nucleotide polymorphisms. Variables in men and women were analyzed using chi-squared analysis and the Mann-Whitney or Kruskal-Wallis tests. Multiple linear or logistic regression analyses were adjusted for all the variables of clinical relevance or statistically significant at univariate analyses. The primary outcome was the difference in liver and cardiovascular disease between lean NAFLD and NAFLD in overweight and obese persons. Secondary outcomes were effects of visceral obesity, based on waist circumference, on hepatic, vascular, and metabolic features.
Significantly lower proportions of patients with lean NAFLD (143 patients; 43 women; mean age, 46 ± 13 y) had hypertension (P = .001), diabetes (P = .0001), and metabolic syndrome (P = .0001) than overweight or obese patients with NAFLD (526 patients; 149 women; mean age, 49 ± 12 y). Significantly lower proportions of patients with lean NAFLD had NASH (17% vs 40% of obese or overweight patients with NAFLD; P = .0001), fibrosis of F2 or higher (17% vs 42%; P = .0001), or carotid plaques (27% vs 39%; P = .03). Patients with lean NAFLD had significantly thinner carotid intima-media (0.74 ± 0.1 mm) than obese or overweight patients with NAFLD (0.84 ± 0.3 mm; P = .0001). There was no significant difference in the proportions of patients with rs738409 C>G in PNPLA3, but a significantly greater proportion of patients with lean NAFLD carried rs58542926 C>T in TM6SF2 (4%) than obese or overweight individuals with NAFLD (0.3%; P = .001). Of the 143 patients with lean NAFLD, 27 had grade 3 steatosis, 24 had a lobular inflammation score greater than 2, 10 had a ballooning score of 2, and 25 had a fibrosis score of 2 or higher. In patients with lean NAFLD, the only variable associated independently with NASH and a fibrosis score of 2 or higher was rs738409 C>G in PNPLA3. Patients with lean NAFLD and a medium waist circumference had a significantly higher risk of diabetes (odds ratio, 11; 95% confidence interval [CI], 1.2-106; P = .03) than overweight or obese patients with a similar waist circumference (odds ratio, 1.3; 95% CI, 0.4-4.2; P = .6). Lean and overweight or obese patients with high waist circumferences had significant increases in risk compared with patients with low and medium circumference and diabetes, hypertension, and fibrosis scores of 2 or higher.
In a retrospective study of patients with lean NAFLD vs obese or overweight persons with NAFLD, we found 20% of patients with lean NAFLD to have NASH, fibrosis scores of 2 or higher, and carotid atherosclerosis. Lean patients with rs738409 C>G in PNPLA3 should be monitored for liver disease progression; studies including large series of patients with lean NAFLD will clarify the possible role of TM6SF2 polymorphisms.
瘦型非酒精性脂肪性肝病（NAFLD）定义为体质量指数（BMI）＜25 kg/m²的患者发生的 NAFLD。我们研究了瘦型 NAFLD 与超重和肥胖者中 NAFLD 的差异、与肝和心血管疾病严重程度相关的因素，以及内脏肥胖的影响。
我们对意大利 3 个肝脏中心连续就诊的 669 例经活检证实的 NAFLD 患者进行了回顾性队列研究。我们收集了人体测量、临床和生化数据，以及颈动脉粥样硬化（动脉内膜-中层厚度和斑块）、肝组织学（非酒精性脂肪性肝炎[NASH]和纤维化）、胰岛素抵抗和糖尿病信息。超重定义为 BMI 为 25 至 29.9 kg/m²，肥胖定义为 BMI 为 30 kg/m²或更高。根据腰围（一种内脏肥胖的标志物，男性＜94 cm，女性＜80 cm；中值：男性 94-102 cm，女性 80-88 cm；高值：男性＞102 cm，女性＞88 cm）将患者分配到不同的组。对 rs738409 C>G（PNPLA3 中的 I148M）、rs58542926 C>T（TM6SF2 中的 E167K）和单核苷酸多态性进行 DNA 分析。采用卡方检验和 Mann-Whitney 或 Kruskal-Wallis 检验分析男性和女性的变量。对所有有临床意义或单变量分析有统计学意义的变量进行多元线性或逻辑回归分析。主要结局是瘦型 NAFLD 与超重和肥胖者中 NAFLD 的肝和心血管疾病差异。次要结局是基于腰围的内脏肥胖对肝脏、血管和代谢特征的影响。
与超重或肥胖的 NAFLD 患者（526 例；149 名女性；平均年龄 49 ± 12 岁）相比，瘦型 NAFLD 患者（143 例；43 名女性；平均年龄 46 ± 13 岁）高血压（P =.001）、糖尿病（P =.0001）和代谢综合征（P =.0001）的比例显著较低。与超重或肥胖的 NAFLD 患者相比，瘦型 NAFLD 患者 NASH（17% vs. 40%；P =.0001）、纤维化 F2 或更高（17% vs. 42%；P =.0001）或颈动脉斑块（27% vs. 39%；P =.03）的比例显著较低。瘦型 NAFLD 患者的颈动脉内膜-中层厚度明显较薄（0.74 ± 0.1 mm），而超重或肥胖的 NAFLD 患者（0.84 ± 0.3 mm；P =.0001）。PNPLA3 中的 rs738409 C>G 比例没有显著差异，但瘦型 NAFLD 患者携带 TM6SF2 中的 rs58542926 C>T（4%）的比例显著高于超重或肥胖的 NAFLD 患者（0.3%；P =.001）。在 143 例瘦型 NAFLD 患者中，27 例有 3 级脂肪变性，24 例有肝小叶炎症评分＞2，10 例有气球样变评分 2，25 例有纤维化评分 2 或更高。在瘦型 NAFLD 患者中，唯一与 NASH 和纤维化评分 2 或更高相关的变量是 PNPLA3 中的 rs738409 C>G。腰围处于中等水平的瘦型和超重或肥胖 NAFLD 患者患糖尿病的风险明显较高（比值比，11；95%置信区间 [CI]，1.2-106；P =.03），而腰围相似的超重或肥胖患者（比值比，1.3；95% CI，0.4-4.2；P =.6）。与低和中腰围以及糖尿病、高血压和纤维化评分 2 或更高的患者相比，高腰围的瘦型和超重或肥胖患者的风险显著增加。
在一项对瘦型 NAFLD 患者与超重或肥胖者中 NAFLD 患者的回顾性研究中，我们发现 20%的瘦型 NAFLD 患者有 NASH、纤维化评分 2 或更高，以及颈动脉粥样硬化。携带 PNPLA3 中 rs738409 C>G 的瘦型患者应监测肝病进展；包括大量瘦型 NAFLD 患者的研究将阐明 TM6SF2 多态性的可能作用。
