To view enhanced content for this article go to http://www.medengine.com/Redeem/2128F060377C0C79.
Stefano Ballestri and Fabio Nascimbeni contributed equally and are joint first authors.
Nonalcoholic fatty liver disease (NAFLD) spans steatosis through nonalcoholic steatohepatis, cirrhosis, and hepatocellular carcinoma (HCC) associated with striking systemic features and excess cardiovascular and liver-related mortality. The pathogenesis of NAFLD is complex and multifactorial. Endocrine derangements are closely linked with dysmetabolic traits. For example, in animal and human studies, female sex is protected from dysmetabolism thanks to young individuals’ ability to partition fatty acids towards ketone body production rather than very low density lipoprotein (VLDL)-triacylglycerol, and to sex-specific browning of white adipose tissue. Ovarian senescence facilitates both the development of massive hepatic steatosis and the fibrotic progression of liver disease in an experimental overfed zebrafish model. Consistently, estrogen deficiency, by potentiating hepatic inflammatory changes, hastens the progression of disease in a dietary model of nonalcoholic steatohepatitis (NASH) developing in ovariectomized mice fed a high-fat diet. In humans, NAFLD more often affects men; and premenopausal women are equally protected from developing NAFLD as they are from cardiovascular disease. It would be expected that early menarche, definitely associated with estrogen activation, would produce protection against the risk of NAFLD. Nevertheless, it has been suggested that early menarche may confer an increased risk of NAFLD in adulthood, excess adiposity being the primary culprit of this association. Fertile age may be associated with more severe hepatocyte injury and inflammation, but also with a decreased risk of liver fibrosis compared to men and postmenopausal status. Later in life, ovarian senescence is strongly associated with severe steatosis and fibrosing NASH, which may occur in postmenopausal women. Estrogen deficiency is deemed to be responsible for these findings via the development of postmenopausal metabolic syndrome. Estrogen supplementation may at least theoretically protect from NAFLD development and progression, as suggested by some studies exploring the effect of hormonal replacement therapy on postmenopausal women, but the variable impact of different sex hormones in NAFLD (i.e., the pro-inflammatory effect of progesterone) should be carefully considered.
Brunt EM. Nonalcoholic fatty liver disease: pros and cons of histologic systems of evaluation. Int J Mol Sci 2016;17.
Ballestri S, Nascimbeni F, Romagnoli D, et al. The independent predictors of non-alcoholic steatohepatitis and its individual histological features. Insulin resistance, serum uric acid, metabolic syndrome, alanine aminotransferase and serum total cholesterol are a clue to pathogenesis and candidate targets for treatment. Hepatol Res. 2016;46:1074–87. PubMedCrossRef
Non-Alcoholic Fatty Liver Disease Study Group, Lonardo A, Bellentani S, et al. Epidemiological modifiers of non-alcoholic fatty liver disease: focus on high-risk groups. Dig Liver Dis. 2015;47:997–1006. CrossRef
Lee YH, Kim SH, Kim SN, et al. Sex-specific metabolic interactions between liver and adipose tissue in MCD diet-induced non-alcoholic fatty liver disease. Oncotarget. 2016;7:46959–46971.
Ludwig J, Viggiano TR, McGill DB, et al. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434–8. PubMed
McKenzie J, Fisher BM, Jaap AJ, et al. Effects of HRT on liver enzyme levels in women with type 2 diabetes: a randomized placebo-controlled trial. Clin Endocrinol (Oxf). 2006;65:40–4. CrossRef
Li H, Wang YJ, Tan K, et al. Prevalence and risk factors of fatty liver disease in Chengdu, Southwest China. Hepatobiliary Pancreat Dis Int. 2009;8:377–82. PubMed
Younossi ZM, Stepanova M, Negro F, et al. Nonalcoholic fatty liver disease in lean individuals in the United States. Medicine (Baltimore). 2012;91:319–27. CrossRef
Yan J, Xie W, Ou WN, et al. Epidemiological survey and risk factor analysis of fatty liver disease of adult residents, Beijing, China. J Gastroenterol Hepatol. 2013;28:1654–9. PubMed
Schneider AL, Lazo M, Selvin E, et al. Racial differences in nonalcoholic fatty liver disease in the US population. Obesity (Silver Spring). 2014;22:292–9. CrossRef
Martinez-Alvarado Mdel R, Juarez-Rojas JG, Medina-Urrutia AX, et al. Association of fatty liver with cardiovascular risk factors and subclinical atherosclerosis in a Mexican population. Rev Invest Clin. 2014;66:407–14. PubMed
Huang X, Xu M, Chen Y, et al. Validation of the fatty liver index for nonalcoholic fatty liver disease in middle-aged and elderly Chinese. Medicine (Baltimore). 2015;94:e1682. CrossRef
Gutierrez-Grobe Y, Ponciano-Rodriguez G, Ramos MH, et al. Prevalence of non alcoholic fatty liver disease in premenopausal, posmenopausal and polycystic ovary syndrome women. The role of estrogens. Ann Hepatol. 2010;9:402–9. PubMed
Calzadilla Bertot L, Adams LA. The natural course of non-alcoholic fatty liver disease. Int J Mol Sci 2016;17. doi: 10.3390/ijms17050774.
Hossain N, Afendy A, Stepanova M, et al. Independent predictors of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2009;7:1224-9, 1229 e1-2.
Tapper EB, Krajewski K, Lai M, et al. Simple non-invasive biomarkers of advanced fibrosis in the evaluation of non-alcoholic fatty liver disease. Gastroenterol Rep (Oxf). 2014;2:276–80. CrossRef
Yang JD, Abdelmalek MF, Guy CD, et al. Patient sex, reproductive status, and synthetic hormone use associate with histologic severity of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2017;15:127–131.e2.
Villa E. Role of estrogen in liver cancer. Womens Health (Lond). 2008;4:41–50. CrossRef
Acikel M, Sunay S, Koplay M, et al. Evaluation of ultrasonographic fatty liver and severity of coronary atherosclerosis, and obesity in patients undergoing coronary angiography. Anadolu Kardiyol Derg. 2009;9:273–9. PubMed
Sun L, Lu SZ. Association between non-alcoholic fatty liver disease and coronary artery disease severity. Chin Med J (Engl). 2011;124:867–72.
Jepsen P, Vilstrup H, Mellemkjaer L, et al. Prognosis of patients with a diagnosis of fatty liver—a registry-based cohort study. Hepatogastroenterology. 2003;50:2101–4. PubMed
Lu J, Zhang J, Du R, et al. Age at menarche is associated with the prevalence of NAFLD later in life. J Diabetes. 2017;9:53–60.
Mueller NT, Pereira MA, Demerath EW, et al. Earlier menarche is associated with fatty liver and abdominal ectopic fat in midlife, independent of young adult BMI: the CARDIA study. Obesity (Silver Spring). 2015;23:468–74. CrossRef
Laitinen J, Power C, Jarvelin MR. Family social class, maternal body mass index, childhood body mass index, and age at menarche as predictors of adult obesity. Am J Clin Nutr. 2001;74:287–94. PubMed
Kavanagh K, Espeland MA, Sutton-Tyrrell K, et al. Liver fat and SHBG affect insulin resistance in midlife women: the Study of Women’s Health Across the Nation (SWAN). Obesity (Silver Spring). 2013;21:1031–8. CrossRef
Feingold K, Brinton EA, Grunfeld C. The effect of endocrine disorders on lipids and lipoproteins. In: De Groot LJ, Chrousos G, Dungan K, et al, editors. South Dartmouth: Endotext; 2000.
Morita A, Ishigaki Y. Gender-difference in diabetes mellitus. Nihon Rinsho. 2015;73:606–10. PubMed
Corradi PF, Corradi RB, Greene LW. Physiology of the hypothalamic pituitary gonadal axis in the male. Urol Clin N Am. 2016;43:151–62. CrossRef
Dakin RS, Walker BR, Seckl JR, et al. Estrogens protect male mice from obesity complications and influence glucocorticoid metabolism. Int J Obes (Lond). 2015;39:1539–47.
Candia R, Riquelme A, Baudrand R, et al. Overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in visceral adipose tissue and portal hypercortisolism in non-alcoholic fatty liver disease. Liver Int. 2012;32:392–9. PubMed
Garaulet M, Perez-Llamas F, Baraza JC, et al. Body fat distribution in pre-and post-menopausal women: metabolic and anthropometric variables. J Nutr Health Aging. 2002;6:123–6. PubMed
Kvist H, Chowdhury B, Grangard U, et al. Total and visceral adipose-tissue volumes derived from measurements with computed tomography in adult men and women: predictive equations. Am J Clin Nutr. 1988;48:1351–61. PubMed
Italian Association for the Study of the Liver, Lonardo A, Nascimbeni F, et al. AISF position paper on nonalcoholic fatty liver disease (NAFLD): updates and future directions. Dig Liver Dis. 2017;49:471–483.
Yoon M. PPARalpha in obesity: sex difference and estrogen involvement. PPAR Res. 2010. doi: 10.1155/2010/584296.
McCarty MF, DiNicolantonio JJ. An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly. Age (Dordr). 2015;37:96. CrossRef
Syn WK, Jung Y, Omenetti A, et al. Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease. Gastroenterology. 2009;137(1478–1488):e8.
Varlamov O, Bethea CL, Roberts CT Jr. Sex-specific differences in lipid and glucose metabolism. Front Endocrinol (Lausanne). 2014;5:241.
Suzuki A, Abdelmalek MF. Nonalcoholic fatty liver disease in women. Womens Health (Lond). 2009;5:191–203. CrossRef
Besse-Patin A, Leveille M, Oropeza D, et al. Estrogen signals through peroxisome proliferator-activated receptor-gamma coactivator 1alpha to reduce oxidative damage associated with diet-induced fatty liver disease. Gastroenterology 2017;152:243–256.
Lemieux C, Phaneuf D, Labrie F, et al. Estrogen receptor alpha-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene. Int J Obes (Lond). 2005;29:1236–44. CrossRef
Buchman AL, Dubin MD, Moukarzel AA, et al. Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology. 1995;22:1399–403. PubMed
Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149(367–78):e5 (quiz e14-5).
Hashida R, Kawaguchi T, Bekki M, et al. Aerobic vs. resistance exercise in non-alcoholic fatty liver disease: A systematic review. J Hepatol. 2017;66:142–152.
- NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk
- Springer Healthcare
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
e.Med Kampagnen-Visual, Mail Icon II