Liver and Cardiovascular Damage in Patients With Lean Nonalcoholic Fatty Liver Disease, and Association With Visceral Obesity
Liver and Cardiovascular Damage in Patients With Lean Nonalcoholic Fatty Liver Disease, and Association With Visceral Obesity
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DOI：
10.1016/j.cgh.2017.04.045
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发表时间：
2017-10-01
影响因子：
12.6
通讯作者：
Fargion, Silvia
中科院分区：
文献类型：
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作者：
Fracanzani, Anna Ludovica;Petta, Salvatore;Fargion, Silvia
背景与目的：瘦型非酒精性脂肪性肝病（NAFLD）被定义为在体重指数（BMI）小于25 kg/m的患者中发生的NAFLD。我们调查了超重和肥胖人群中瘦型NAFLD和NAFLD的差异，与肝脏和心血管疾病严重程度相关的因素，以及内脏性肥胖的影响。方法：我们对意大利3个肝脏中心的669例连续活检证实的NAFLD患者进行了回顾性队列研究。我们收集了人体测量学、临床和生化数据，以及颈动脉粥样硬化（动脉内膜-中膜厚度和斑块）、肝脏组织学（非酒精性脂肪性肝炎[NASH]和纤维化）、胰岛素抵抗和糖尿病的信息。超重定义为BMI在25 - 29.9 kg/m(2)之间，肥胖定义为BMI在30 kg/m(2)或更高。患者根据腰围（内脏肥胖的标志）分组（低：男性，< 94厘米，女性< 80厘米；中：男性，94-102厘米，女性80-88厘米；高：男性bb10 -102厘米，女性bb10 -88厘米）。对DNA样本进行rs738409 C > G （PNPLA3中为I148M）、rss58542926 C > T （TM6SF2中为E167K）和单核苷酸多态性分析。使用卡方分析和Mann-Whitney或Kruskal-Wallis检验对男性和女性的变量进行分析。多元线性或逻辑回归分析对所有临床相关变量或单变量分析有统计学意义的变量进行调整。主要结局是超重和肥胖人群中瘦型NAFLD和NAFLD在肝脏和心血管疾病方面的差异。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。结果：瘦型NAFLD患者（143例，女性43例，平均年龄46 +/- 13岁）合并高血压（P = 0.001）、糖尿病（P = 0.0001）和代谢综合征（P = 0.0001）的比例显著低于超重或肥胖NAFLD患者（526例，女性149例，平均年龄49 +/- 12岁）。瘦型NAFLD患者发生NASH （17% vs 40%的肥胖或超重NAFLD患者，P = 0.0001）、F2或更高级别纤维化（17% vs 42%, P = 0.0001）或颈动脉斑块（27% vs 39%, P = 0.03）的比例明显较低。瘦型NAFLD患者颈动脉内膜-中膜明显薄于肥胖或超重NAFLD患者（0.84 +/- 0.3 mm, P = 0.0001） （0.74 +/- 0.1 mm）。PNPLA3中携带rs738409 C > G的患者比例差异无统计学意义，但消瘦型NAFLD患者携带TM6SF2中rs58542926 C > T的比例（4%）明显高于肥胖或超重NAFLD患者（0.3%,P = .001）。143例瘦型NAFLD患者中，27例为3级脂肪变性，24例小叶炎症评分大于2,10例球囊评分为2,25例纤维化评分为2或更高。在瘦型NAFLD患者中，唯一与NASH和纤维化评分2分或更高独立相关的变量是PNPLA3中的rs738409 C > G。瘦型NAFLD和中等腰围患者患糖尿病的风险明显高于腰围相似的超重或肥胖患者（优势比为1.3,95% CI为0.4-4.2,P = 0.6）（优势比为11,95%可信区间[CI]为1.2-106,P = 0.03）。与低、中腰围、糖尿病、高血压和纤维化评分为2分或更高的患者相比，瘦弱、超重或肥胖的高腰围患者的风险显著增加。结论：在一项对瘦型NAFLD患者与肥胖或超重NAFLD患者的回顾性研究中，我们发现20%的瘦型NAFLD患者患有NASH，纤维化评分为2分或更高，并伴有颈动脉粥样硬化。PNPLA3中rs738409 C > G的精益患者应监测肝脏疾病进展；包括大量瘦型NAFLD患者的研究将阐明TM6SF2多态性的可能作用。
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(2). 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.METHODS: 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(2), and obese was defined as a BMI of 30 kg/m(2) 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.RESULTS: 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 obesepatients 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.CONCLUSIONS: 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.