肥胖与非酒精性脂肪肝研究进展

doi:10.3877/cma.j.issn.2095-9605.2024.02.007

全球肥胖发病率逐年增长，与其密切相关的代谢性疾病非酒精性脂肪性肝病（NAFLD）发病率亦与日俱增，是慢性肝病的最常见病因之一，其机制可能与胰岛素抵抗、脂代谢紊乱、氧化应激、菌群失调和细胞自噬等有关。目前NAFLD确诊依赖肝活检，相对无创方便的血清学及影像学诊断方法也愈发成熟。研究表明减重可改善NAFLD肝脏组织学特征以及血脂等生化指标，目前减重的基本方法是干预改变生活方式，针对减重研发的药物也越来越丰富。同时，减重代谢手术对NAFLD获益确切，NAFLD或可成为减重代谢手术适应证之一。

关键词: 肥胖, 非酒精性脂肪肝病, 发病机制, 分型, 治疗, 减重代谢手术

The global incidence of obesity increases year by year, and the incidence of nonalcoholic fatty liver disease (NAFLD), a metabolic disease closely related to obesity, is also increasing day by day. NAFLD is one of the most common causes of chronic liver disease. Its mechanism may be related to insulin resistance, lipid metabolism disorder, oxidative stress, flora disorder and autophagy and so on. Diagnosis for NAFLD is currently dependent on liver biopsy, but relatively non-invasive and convenient serological and imaging diagnostic methods are also being more sophisticated. Studies have shown that weight loss can improve liver histological features and biochemical indicators such as blood lipids in NAFLD. At present, the basic method of weight loss is to change lifestyle, but drugs developed for weight loss are becoming increasingly diverse. At the same time, weight loss metabolic surgery has definite benefits for NAFLD, which may be one of the new indications for weight loss metabolic surgery in the future.

Key words: Obesity, Non-alcoholic fatty liver disease, Pathogenesis, Classification, Treatment, Metabolic bariatric surgery

表1 NAS评分系统和SAF评分系统的比较^[14]

NAS评分系统	SAF评分系统
脂肪变性等级	脂肪变性等级
肝细胞大泡性脂肪变性（包括大、小液滴）的百分比	S0：没有
肝细胞大泡性脂肪变性（包括大、小液滴）的百分比	S1：5%~33%
0：<5%	S2：34%~66%
1：5%~33%	S3：>66%
2：34%~66%
3：>66%
小叶（腺泡）炎症	小叶（腺泡）炎症
每20×物镜视野下计数	0：无
0：无	1：每20倍物镜视野≤2个病灶
1：<2个病灶	2：每20倍物镜视野>2个病灶
2：2~4个病灶
3：>4个病灶
气球样变	气球样变
0：无	0：无
1：少量	1：圆形、淡染、胞质疏松的肝细胞簇
2：大量	2：圆形、淡染、胞质疏松的肝细胞簇，且肝细胞增大（大于2倍正常肝细胞体积）
NAS（0~8）	活动等级（A，0~4级）
脂肪变性+小叶炎症+气球样变评分之和	小叶炎症和气球样变分数的总和
	A1：A＝1，轻度活动
	A2：A＝2，中度活动
	A3和A4：A>2，重度活动
纤维化分期	纤维化分期
0：无纤维化	F0：无纤维化
1a：轻微的（需要马松三色染色法辨认）小叶中央肝细胞周围纤维化	F1A：轻度3区窦周纤维化
1a：轻微的（需要马松三色染色法辨认）小叶中央肝细胞周围纤维化	FlB：中度3区窦周纤维化
1b：明显（苏木精和伊红染色可见）小叶中央肝细胞周围纤维化	F1C：仅汇管区纤维化
1b：明显（苏木精和伊红染色可见）小叶中央肝细胞周围纤维化	F2：3区和汇管区周围窦周纤维化
1c：汇管区细胞周围纤维化	F3：桥接纤维化
2：小叶中央和汇管区细胞周围纤维化	F4：肝硬化
3：桥接纤维化
4：肝硬化
SAF得分
S_0-3 A_0-4 F_0-4

表1 NAS评分系统和SAF评分系统的比较^[14]

NAS评分系统	SAF评分系统
脂肪变性等级	脂肪变性等级
肝细胞大泡性脂肪变性（包括大、小液滴）的百分比	S0：没有
肝细胞大泡性脂肪变性（包括大、小液滴）的百分比	S1：5%~33%
0：<5%	S2：34%~66%
1：5%~33%	S3：>66%
2：34%~66%
3：>66%
小叶（腺泡）炎症	小叶（腺泡）炎症
每20×物镜视野下计数	0：无
0：无	1：每20倍物镜视野≤2个病灶
1：<2个病灶	2：每20倍物镜视野>2个病灶
2：2~4个病灶
3：>4个病灶
气球样变	气球样变
0：无	0：无
1：少量	1：圆形、淡染、胞质疏松的肝细胞簇
2：大量	2：圆形、淡染、胞质疏松的肝细胞簇，且肝细胞增大（大于2倍正常肝细胞体积）
NAS（0~8）	活动等级（A，0~4级）
脂肪变性+小叶炎症+气球样变评分之和	小叶炎症和气球样变分数的总和
	A1：A＝1，轻度活动
	A2：A＝2，中度活动
	A3和A4：A>2，重度活动
纤维化分期	纤维化分期
0：无纤维化	F0：无纤维化
1a：轻微的（需要马松三色染色法辨认）小叶中央肝细胞周围纤维化	F1A：轻度3区窦周纤维化
1a：轻微的（需要马松三色染色法辨认）小叶中央肝细胞周围纤维化	FlB：中度3区窦周纤维化
1b：明显（苏木精和伊红染色可见）小叶中央肝细胞周围纤维化	F1C：仅汇管区纤维化
1b：明显（苏木精和伊红染色可见）小叶中央肝细胞周围纤维化	F2：3区和汇管区周围窦周纤维化
1c：汇管区细胞周围纤维化	F3：桥接纤维化
2：小叶中央和汇管区细胞周围纤维化	F4：肝硬化
3：桥接纤维化
4：肝硬化
SAF得分
S_0-3 A_0-4 F_0-4

图1 NAFLD的病理学特征（HE染色，20倍物镜）。1A：脂肪变性，细胞质充满大脂滴，周围呈小滴状大泡性脂肪变性；1B：气球样变，可见增大的气球样变肝细胞；1C：轻度小叶炎症；1D：中度小叶炎症

[1]	WHO. Obesity and overweight [EB/OL]. [2024-03-01] URL
[2]	Chen K, Shen Z, Gu W, et al. Prevalence of obesity and associated complications in China: A cross-sectional, real-world study in 15.8 million adults [J]. Diabetes Obes Metab, 2023, 25(11): 3390-3399.
[3]	Stergios A, Polyzos,Ilias D, et al. Sarcopenia, sarcopenic obesity and nonalcoholic fatty liver disease [J]. Metabolism, 2023, 147: 155676.
[4]	Lee HH, Lee HA, Kim EJ, et al. Metabolic dysfunction-associated steatotic liver disease and risk of cardiovascular disease [J]. Gut, 2024, 73(3): 533-540.
[5]	Marin-Alejandre BA, Abete I, Cantero I, et al. The metabolic and hepatic impact of two personalized dietary strategies in subjects with obesity and nonalcoholic fatty liver disease: the fatty liver in obesity (FLiO) randomized controlled trial [J]. Nutrients, 2019, 11(10): 2543.
[6]	James OF, Day CP. Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance [J]. J Hepatol, 1998, 29(3): 495-501.
[7]	Smith GI, Shankaran M, Yoshino M, et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease [J]. J Clin Invest, 2020, 130(3): 1453-1460.
[8]	Szukiewicz D. Molecular Mechanisms for the vicious cycle between insulin resistance and the inflammatory response in obesity [J]. Int J Mol Sci, 2023, 24(12): 9818.
[9]	Zeng H, Qin H, Liao M, et al. CD36 promotes de novo lipogenesis in hepatocytes through INSIG2-dependent SREBP1 processing [J]. Mol Metab, 2022, 57: 101428.
[10]	Rochette L, Dogon G, Rigal E, et al. Lipid peroxidation and iron metabolism: two corner stones in the homeostasis control of ferroptosis [J]. Int J Mol Sci, 2022, 24(1): 449.
[11]	Hu J, Wang H, Li X, et al. Fibrinogen-like protein 2 aggravates nonalcoholic steatohepatitis via interaction with TLR4, eliciting inflammation in macrophages and inducing hepatic lipid metabolism disorder [J]. Theranostics, 2020, 10(21): 9702-9720.
[12]	Fang J, Yu CH, Li XJ, et al. Gut dysbiosis in nonalcoholic fatty liver disease: pathogenesis, diagnosis, and therapeutic implications [J]. Front Cell and Infect Mi, 2022, 12: 997018.
[13]	Kloska A, Węsierska M, Malinowska M, et al. Lipophagy and lipolysis status in lipid storage and lipid metabolism diseases [J]. Int J Mol Sci, 2020, 21(17): 6113.
[14]	Schild MH, Guy CD. Nonalcoholic steatohepatitis: histopathology basics within a broader context [J]. Surgical Pathology Clinics, 2018, 11(2): 267-285.
[15]	Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease [J]. Hepatology, 2005, 41(6): 1313-1321.
[16]	Castera L, Friedrich-Rust M, Loomba R. Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease [J]. Gastroenterology, 2019, 156(5): 1264-1281.e4.
[17]	Wiafe YA, Anyitey-Kokor IC, Nmai RA, et al. Diagnostic performance of greyscale ultrasound in detecting fatty liver disease in a type 2 diabetes population using fibroscan as the reference standard [J]. Cureus, 2023, 15(6): e40756.
[18]	Ferraioli G, Wong VW-S, Castera L, et al. Liver ultrasound elastography: an update to the world federation for ultrasound in medicine and biology guidelines and recommendations [J]. Ultrasound Med Biol, 2018, 44(12): 2419-2440
[19]	Ekstedt M, Hagström H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up [J]. Hepatology, 2015, 61(5): 1547-1554.
[20]	Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention [J]. Nat Rev Gastro Hepat, 2020, 18(4): 223-238.
[21]	Chooi YC, Zhang QA, Magkos F, et al. Effect of an Asian-adapted Mediterranean diet and pentadecanoic acid on fatty liver disease: the TANGO randomized controlled trial [J]. Am J Clin Nutr, 2024, 119(3): 788-799.
[22]	Ezpeleta M, Gabel K, Cienfuegos S, et al. Effect of alternate day fasting combined with aerobic exercise on non-alcoholic fatty liver disease: a randomized controlled trial [J]. Cell Metab, 2023, 35(1): 56-70.e3.
[23]	Montemayor S, Bouzas C, Mascaró CM, et al. Effect of dietary and lifestyle interventions on the amelioration of NAFLD in patients with metabolic syndrome: The FLIPAN Study [J]. Nutrients, 2022, 14(11): 2223.
[24]	Younossi ZM, Corey KE, Lim JK. AGA Clinical Practice Update on Lifestyle Modification Using Diet and Exercise to Achieve Weight Loss in the Management of Nonalcoholic Fatty Liver Disease: Expert Review [J]. Gastroenterology, 2021, 160(3): 912-918.
[25]	Stine JG, Soriano C, Schreibman I, et al. Breaking down barriers to physical activity in patients with nonalcoholic fatty liver disease [J]. Digest Dis Sci, 2020, 66(10): 3604-3611.
[26]	Kaplan LM, Golden A, Jinnett K, et al. Perceptions of barriers to effective obesity care: results from the national action Study [J]. Obesity, 2017, 26(1): 61-69.
[27]	Bril F, Biernacki DM, Kalavalapalli S, et al. Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial [J]. Diabetes Care, 2019, 42(8): 1481-1488.
[28]	Bai YW, Li TQ, Liu JC, et al. Aerobic exercise and vitamin E improve high-fat diet-induced NAFLD in rats by regulating the AMPK pathway and oxidative stress [J]. Eur J Nutr, 2023, 62(6): 2621-2632.
[29]	Cho Y, Rhee H, Kim Y-E, et al. Ezetimibe combination therapy with statin for non-alcoholic fatty liver disease: an open-label randomized controlled trial (ESSENTIAL study) [J]. BMC Med, 2022, 20(1): 93.
[30]	Wang X, Zhao B, Sun H, et al. Effects of sitagliptin on intrahepatic lipid content in patients with non-alcoholic fatty liver disease [J]. Front Endocrinol, 2022, 13: 866189.
[31]	Newsome PN, Buchholtz K, Cusi K, et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis [J]. N Engl J Med, 2021, 384(12): 1113-1124.
[32]	Zhu W, Yan M, Cao H, et al. Effects of clostridium butyricum capsules combined with rosuvastatin on intestinal flora, lipid metabolism, liver function and inflammation in NAFLD patients [J]. Cell Mol Biol, 2022, 68(2): 64-69.
[33]	Zhuo L, Xu J, You N, et al. Study on the new strategy and key techniques for accurate prevention and treatment of nonalcoholic steatohepatitis based on intestinal target bacteria [J]. Medicine, 2020, 99(50): e22867.
[34]	Androutsakos T, Nasiri-Ansari N, Bakasis A-D, et al. SGLT-2 inhibitors in NAFLD: expanding their role beyond diabetes and cardioprotection [J]. Int J Mol Sci, 2022, 23(6): 3107.
[35]	Shih P-H, Shiue S-J, Chen C-N, et al. Fucoidan and fucoxanthin attenuate hepatic steatosis and inflammation of NAFLD through modulation of leptin/adiponectin axis [J]. Mar Drugs, 2021, 19(3): 148.
[36]	Verrastro O, Panunzi S, Castagneto-Gissey L, et al. Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial [J]. Lancet, 2023, 401(10390): 1786-1797.
[37]	Głuszyńska P, Łukaszewicz A, Diemieszczyk I, et al. The Effect of Laparoscopic Sleeve Gastrectomy on the Course of Non-Alcoholic Fatty Liver Disease in Morbidly Obese Patients during One Year of Follow Up [J]. J Clin Med, 2023, 12(12): 4122.
[38]	Lassailly G, Caiazzo R, Ntandja-Wandji L-C, et al. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis [J]. Gastroenterology, 2020, 159(4): 1290-1301.e5.
[39]	Bower G, Athanasiou T, Isla AM, et al. Bariatric surgery and nonalcoholic fatty liver disease [J]. Eur J Gastroenterol Hepatol, 2015, 27(7): 755-768.
[40]	Klebanoff MJ, Corey KE, Chhatwal J, et al. Bariatric surgery for nonalcoholic steatohepatitis: a clinical and cost-effectiveness analysis [J]. Hepatology, 2017, 65(4): 1156-1164.

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Research progress in the relationship between obesity and non-alcoholic fatty liver disease

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Research progress in the relationship between obesity and non-alcoholic fatty liver disease