Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Diabetology & Metabolic Syndrome
Published in: Diabetology & Metabolic Syndrome 1/2020

01-12-2020 | Obesity | Review

NAFLD as a continuum: from obesity to metabolic syndrome and diabetes

Authors: Amélio F. Godoy-Matos, Wellington S. Silva Júnior, Cynthia M. Valerio

Published in: Diabetology & Metabolic Syndrome | Issue 1/2020

Login to get access

Abstract

Background

The prevalence of non-alcoholic fatty liver disease (NAFLD) has been increasing rapidly. It is nowadays recognized as the most frequent liver disease, affecting a quarter of global population and regularly coexisting with metabolic disorders such as type 2 diabetes, hypertension, obesity, and cardiovascular disease. In a more simplistic view, NAFLD could be defined as an increase in liver fat content, in the absence of secondary cause of steatosis. In fact, the clinical onset of the disease is a much more complex process, closely related to insulin resistance, limited expandability and dysfunctionality of adipose tissue. A fatty liver is a main driver for a new recognized liver-pancreatic α-cell axis and increased glucagon, contributing to diabetes pathophysiology.

Main text

This review will focus on the clinical and pathophysiological connections between NAFLD, insulin resistance and type 2 diabetes. We reviewed non-invasive methods and several scoring systems for estimative of steatosis and fibrosis, proposing a multistep process for NAFLD evaluation. We will also discuss treatment options with a more comprehensive view, focusing on the current available therapies for obesity and/or type 2 diabetes that impact each stage of NAFLD.

Conclusion

The proper understanding of NAFLD spectrum—as a continuum from obesity to metabolic syndrome and diabetes—may contribute to the early identification and for establishment of targeted treatment.
Literature
1.
Buzzetti E, Pinzani M, Tsochatziz EA. The multiple-hit pathogensesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65:1038–48.PubMed
2.
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence and outcomes. Hepatology. 2016;64:73–84.PubMed
3.
Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L. Current guidelines for the management of non-alcoholic fatty liver disease: a systematic review with comparative analysis. World J Gastroenterol. 2018;24:3361–73.PubMedPubMedCentral
4.
Marjot T, Moolla A, Cobbold JF, Hodson L, Tomlinson JW. Nonalcoholic fatty disease in adults: current concepts in etiology, outcomes, and management. Endocrine Rev. 2020;41:66–117.
5.
Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67:328–57.PubMed
6.
European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64:1388–402.
7.
Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis. J Hepatol. 2016;65:589–600.PubMed
8.
Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020;73(1):202–9.
9.
NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet. 2016;387:1377–96.
10.
Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde, Departamento de Análise em Saúde e Vigilância de Doenças não Transmissíveis. Vigitel Brasil 2018: vigilância de fatores de risco e proteção para doenças crônicas por inquérito telefônico: estimativas sobre frequência e distribuição sociodemográfica de fatores de risco e proteção para doenças crônicas nas capitais dos 26 estados brasileiros e no Distrito Federal em 2018. Brasília: Ministério da Saúde, 2019. https://​portalarquivos2.​saude.​gov.​br/​images/​pdf/​2019/​julho/​25/​vigitel-brasil-2018.​pdf.
11.
Pallayova M, Taheri S. Non-alcoholic fatty liver disease in obese adults: clinical aspects and current management strategies. Clin Obes. 2014;4:243–53.PubMed
12.
Perumpail B, Muhammad AK, Yoo ER, Cholankeril G, Kim D, Ahmed A. Clinical epidemiology and disease burden of nonalcoholic fatty liver disease. World J Gastroenterol. 2017;23(47):8263–76.PubMedPubMedCentral
13.
Ross R, Neeland IJ, Yamashita S, Shai I, Seidel J, Magni P, et al. Waist circumference as a vital sign in clinical practice: a consensus statement from the IAS and ICCR working group on visceral obesity. Nat Rev Endocrinol. 2020;16:177–89.PubMedPubMedCentral
14.
Kim D, Chung GE, Kwak MS, Seo HB, Kang JH, Kim W, et al. Body fat distribution and risk of incident and regressed nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2016;14(1):132–8.PubMed
15.
Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365(9468):1415–28.PubMed
16.
Alberti KG, Zimmet P, Shaw J, IDF Epidemiology Task Force Consensus Group. The metabolic syndrome-a new worldwide definition. Lancet. 2005;366:1059–62.PubMed
17.
Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735–52.PubMed
18.
Moore JX, Chaudhary N, Akinyemiju T. Metabolic syndrome prevalence by race/ethnicity and sex in the United States, National Health and Nutrition Examination Survey, 1988–2012. Prev Chronic Dis. 2017;14:160287.
19.
20.
van Vliet-Ostaptchouk JV, Nuotio ML, Slagter SN, Doiron D, Fisher K, Foco L, et al. The prevalence of metabolic syndrome and metabolically healthy obesity in Europe: a collaborative analysis of ten large cohort studies. BMC Endocr Disord. 2014;14:9.PubMedPubMedCentral
21.
Jinjuvadia R, Antaki F, Lohia P, Liangpunsakul S. The association between nonalcoholic fatty liver disease and metabolic abnormalities in United States population. J Clin Gastroenterol. 2017;51:160–6.PubMedPubMedCentral
22.
23.
Cusi K. Time to include nonalcoholic steatohepatitis in the management of patients with type 2 diabetes. Diabetes Care. 2020;43(2):275–9.PubMed
24.
Dai W, Ye L, Liu A, Wen SW, Deng J, Wu X, Lai Z. Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a meta-analysis. Medicine. 2017;96:e8179.PubMedPubMedCentral
25.
Younossi ZM, Golabi P, Avila L, Paik JM, Srishord M, Fukui N, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol. 2019;71:793–801.PubMed
26.
Shulman GI. Ectopic fat in insulin resistance, dyslipidemia and cardiometabolic disease. N Engl J Med. 2014;371:1131–41.PubMed
27.
Virtue S, Vidal-Puig A. It’s not how fat you are, it’s what you do with it that counts. PLoS Biol. 2008;23:6.
28.
Stein DT, Szczepaniak L, Garg A, Malloy C, McGarry JD. Intramuscular lipid is increased in subjects with congenital generalized lipodystrophy (Abstract). Diabetes. 1997;46(Suppl. 1):242A.
29.
Hussain I, Patni N, Ueda M, Sorkina E, Valerio CM, Cochran E, et al. A novel generalized lipodystrophy-associated progeroid syndrome due to recurrent heterozygous LMNA p.T10I mutation. J Clin Endocrinol Metab. 2018;103(3):1005–14.PubMed
30.
Godoy-Matos AF, Valerio CM, Moreira RO, Momesso DP, Bittencourt LK. Pancreatic fat deposition is increased and related to beta-cell function in women with familial partial lipodystrophy. Diabetol Metab Syndr. 2018;10:71.PubMedPubMedCentral
31.
32.
Godoy-Matos AF, Bahia LR, Domingues RC, Tambascia M, Geloneze B, Kraemer-Aguiar LG, et al. Rosiglitazone decreases intra- to extramyocellular fat ratio in obese non-diabetic adults with metabolic syndrome. Diabet Med. 2010;27:23–9.PubMed
33.
Gavrila A, Chan JL, Yiannakouris N, Kontogianni M, Miller LC, Orlova C, et al. Serum adiponectin levels are inversely associated with overall and central fat distribution but are not directly regulated by acute fasting or leptin administration in humans: cross-sectional and interventional studies. J Clin Endocrinol Metab. 2003;88:4823–31.PubMed
34.
Pellegrinelli V, Carobbio S, Vidal-Puig A. Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues. Diabetologia. 2016;59:1075–88.PubMedPubMedCentral
35.
Stefan N, Schick F, Häring HU. Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans. Cell Metab. 2017;26:292–300.PubMed
36.
Lotta LA, Gulati P, Day FR, Payne F, Ongen H, van de Bunt M, et al. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat Genet. 2017;49:17–26.PubMed
37.
Bril F, Barb D, Portillo-Sanchez P, Biernacki D, Lomonaco R, Suman A, et al. Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease. Hepatology. 2017;65(4):1132–44.PubMed
38.
Rotman A, Neuschwander-Tetri BA. Liver fat accumulation as a barometer of insulin responsiveness again points to adipose tissue as the culprit. Hepatology. 2017;65:1090–8.
39.
Younossis Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, prediction, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15:11–20.
40.
Sliz E, Sebert S, Würtz P, Kangas AJ, Soininen P, Lehtimäki T, et al. NAFLD risk alleles in PNPLA3, TM6SF2, GCKR and LYPLAL1 show divergent metabolic effect. Human Mol Gen. 2018;27(12):2214–23.
41.
42.
Knop FK. A gut feeling about glucagon. Eur J Endocrinol. 2018;178:R267–8.PubMed
43.
Holst JJ, Wewer Albrechtsen NJ, Pedersen J, Knop FK. Glucagon and amino acids are linked in a mutual feedback cycle: the liver-α-cell axis. Diabetes. 2017;66(2):235–40.PubMed
44.
Longuet C, Robledo AM, Dean ED, Dai C, Ali S, McGuinness I, et al. Liver-specific disruption of the murine glucagon receptor produces α-cell hyperplasia: evidence for a circulating α-cell growth factor. Diabetes. 2013;62:1196–205.PubMedPubMedCentral
45.
Dean ED, Li M, Prasad N, Wisniewski SN, Von Deylen A, Spaeth J, et al. Interrupted glucagon signaling reveals hepatic alpha cell axis and role for l-glutamine in α cell proliferation. Cell Metab. 2017;25:1362–73.PubMedPubMedCentral
46.
Knop FK, Aaboe K, Vilsbøll T, Vølund A, Holst JJ, Krarup T, Madsbad S. Impaired incretin effect and fasting hyperglucagonemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity. Diab Obes Metabol. 2012;14:500–10.
47.
48.
Junker AE, Gluud L, Holst JJ, Knop FK, Vilsbøll T. Diabetic and nondiabetic patients with nonalcoholic fatty liver disease have an impaired incretin effect and fasting hyperglucagonaemia. J Intern Med. 2016;279(5):485–93.PubMed
49.
Wewer Albrechtsen NJ, Junker AE, Christensen M, Hædersdal S, Wibrand F, Lund AM, et al. Hyperglucagonemia correlates with plasma levels of non-branched-chain amino acids in patients with liver disease independent of type 2 diabetes. Am J Physiol Gastrointest Liver Physiol. 2018;314(1):G91–6.PubMed
50.
Wewer Albrechtsen NJ, Færch K, Jensen TM, Witte DR, Pedersen J, Mahendran Y, et al. Evidence of a liver-alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagon inotropic amino acids. Diabetologia. 2018;61:671–80.PubMed
51.
Lund A, Bagger JI, Albrechtsen NJW, Christensen M, Grøndahl M, Hansen CP, et al. Increased liver fat content in totally pancreatectomized patients. Diabetes. 2017;66:A674–88.
52.
Guzman CB, Zhang XM, Liu R, Regev A, Shankar S, Garhyan P, et al. Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes. Diabetes Obes Metab. 2017;19:1521–8.PubMed
53.
Albrechtsen NJW, Pedersen J, Galsgaard KD, Winther-Sorensen M, Suppli MP, Janah L, et al. The liver-α-cell axis and type 2 diabetes. Endocr Rev. 2019;40(5):1353–66.
54.
Kitade I, Chen G, Ni Y, Ota T. Nonalcoholic fatty liver disease and insulin resistance: new insights and potential new treatments. Nutrients. 2017;9(4):E387.PubMed
55.
Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. Nonalcoholic steatohepatitis: a review. JAMA. 2020;323(12):1175–83.PubMed
56.
Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system. For nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.PubMed
57.
Bedossa P, Poitou C, Veyrie N, Bouillot J-L, Basdevant A, Paradis V, et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology. 2012;56:1751–9.PubMed
58.
Sumida Y, Nakajima A, Itoh Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2014;20(2):475–85.PubMedPubMedCentral
59.
Hernaez R, Lazo M, Bonekamp S, Kamel I, Brancati FL, Guallar E, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology. 2011;54:1082–90.PubMed
60.
Siddiqui MS, Harrison SA, Abdelmalek MF, Anstee QM, Bedossa P, Castera L, Liver Forum Case Definitions Working Group, et al. Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science. Hepatology. 2018;67(5):2001–12.PubMed
61.
Shi KQ, Tang JZ, Zhu XL, Ying L, Li DW, Gao J, et al. Controlled attenuation parameter for the detection of steatosis severity in chronic liver disease: a meta-analysis of diagnostic accuracy. J Gastroenterol Hepatol. 2014;29:1115–49.
62.
Park CC, Nguyen P, Hernandez C, Bettencourt R, Ramirez K, Fortney L, et al. Magnetic resonance elastography vs transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease. Gastroenterology. 2017;152:598–607.PubMed
63.
Petta S, Wong VW, Camma C, Hiriart JB, Wong GL, Vergniol J, et al. Serial combination of non-invasive tools improves the diagnostic accuracy of severe liver fibrosis in patients with NAFLD. Aliment Pharmacol Ther. 2017;46(6):617–27.PubMed
64.
Loomba R, Wolfson T, Ang B, Hooker J, Behling C, Peterson M, et al. Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study. Hepatology. 2014;60:1920–8.PubMed
65.
Xiao G, Zhu S, Xiao X, Yan L, Yang J, Wu G. Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: a meta-analysis. Hepatology. 2017;66(5):1486–501.PubMed
66.
Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317–25.PubMed
67.
Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846–54.PubMed
68.
Castera L, Friedrich-Rust M, Loomba R. Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease. Gastroenterology. 2019;156(5):1264–81.PubMed
69.
Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33.PubMedPubMedCentral
70.
Kotronen A, Peltonen M, Hakkarainen A, Sevastianova K, Bergholm R, Johansson LM, et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology. 2009;137:865–72.PubMed
71.
Lee JH, Kim D, Kim HJ, Lee CH, Yang JI, Kim W, et al. Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease. Dig Liver Dis. 2010;42:503–8.PubMed
72.
Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, et al. Liver fibrosis in overweight patients. Gastroenterology. 2000;118(6):1117–23.PubMed
73.
Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38(2):518–26.PubMed
74.
Altamirano J, Qi Q, Choudhry S, Abdallah M, Singal AK, Humar A, et al. Non-invasive diagnosis: non-alcoholic fatty liver disease and alcoholic liver disease. Transl Gastroenterol Hepatol. 2020;5(5):31.PubMedPubMedCentral
75.
Siddiqui MS, Yamada G, Vuppalanchi R, Natta MV, Loomba R, Guy C, et al. Diagnostic accuracy of noninvasive fibrosis models to detect change in fibrosis stage. Clin Gastroenterol Hepatol. 2019;17(9):1877–85.PubMedPubMedCentral
76.
Polyzos SA, Kountouras J, Mantzoros CS. Obesity and nonalcoholic fatty liver disease: from pathophysiology to therapeutics. Metabolism. 2019;92:82–97.PubMed
77.
Hannah WN Jr, Harrison SA. Effect of weight loss, diet, exercise, and bariatric surgery on nonalcoholic fatty liver disease. Clin Liver Dis. 2016;20:339–50.PubMed
78.
Patel NS, Doycheva I, Peterson MR, Hooker J, Kisselva T, Schnabl B, et al. Effect of weight loss on magnetic resonance imaging estimation of liver fat and volume in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2015;13(3):561–8.PubMed
79.
Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia. 2012;55(4):885–904.PubMed
80.
Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149(2):367–78.PubMed
81.
Brunner KT, Henneberg CJ, Wilechansky RM, Long MT. Nonalcoholic fatty liver disease and obesity treatment. Curr Obes Rep. 2019;8(3):220–8.PubMedPubMedCentral
82.
Ratziu V, Ghabril M, Romero-Gomez M, Svegliati-Baroni G. Recommendations for management and treatment of nonalcoholic steatohepatitis. Transplantation. 2019;103(1):28–38.PubMed
83.
Arendt BM, Comelli EM, Ma DWL, Lou W, Teterina A, Kim T, et al. Altered hepatic gene expression in nonalcoholic fatty liver disease is associated with lower hepatic n-3 and n-6 polyunsaturated fatty acids. Hepatology. 2015;61:1565–78.PubMed
84.
Takeuchi Y, Yahagi N, Izumida Y, Nishi M, Kubota M, Teraoka Y, et al. Polyunsaturated fatty acids selectively suppress sterol regulatory element-binding protein-1 through proteolytic processing and autoloop regulatory circuit. J Biol Chem. 2010;285:11681–91.PubMedPubMedCentral
85.
Anania C, Perla FM, Olivero F, Pacifico L, Chiesa C. Mediterranean diet and nonalcoholic fatty liver disease. World J Gastroenterol. 2018;24:2083–94.PubMedPubMedCentral
86.
Zelber-Sagi S, Salomone F, Mlynarsky L. The Mediterranean dietary pattern as the diet of choice for non-alcoholic fatty liver disease: evidence and plausible mechanisms. Liver Int. 2017;37:936–49.PubMed
87.
Parker HM, Johnson NA, Burdon CA, Cohn JS, O’Connor HT, George J. Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol. 2012;56:944–51.PubMed
88.
Yan J-H, Guan B-J, Gao H-Y, Peng X-E. Omega-3 polyunsaturated fatty acid supplementation and non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Medicine. 2018;97:e12271.PubMedPubMedCentral
89.
Argo CK, Patrie JT, Lackner C, Henry TD, de Lange EE, Weltman AL, et al. Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo controlled trial. J Hepatol. 2015;62:190–7.PubMed
90.
Sanyal AJ, Abdelmalek MF, Suzuki A, Cummings OW, Chojkier M, EPE-A Study Group. No significant effects of ethyleicosapentanoic acid on histologic features of non-alcoholic steatohepatitis in a phase 2 trial. Gastroenterology. 2014;147:377–84.PubMed
91.
Aller R, Izaola O, de la Fuente B, De Luis Román DA. Mediterranean diet is associated with liver histology in patients with non alcoholic fatty liver disease. Nutr Hosp. 2015;32:2518–24.PubMed
92.
Kontogianni MD, Tileli N, Margariti A, Georgoulis M, Deutsch M, Tiniakos D, et al. Adherence to the Mediterranean diet is associated with the severity of non-alcoholic fatty liver disease. Clin Nutr. 2014;33:678–83.PubMed
93.
Ryan MC, Itsiopoulos C, Thodis T, Ward G, Trost N, Hofferberth S, et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol. 2013;59:138–43.PubMed
94.
Misciagna G, Del Pilar DM, Caramia DV, Bonfiglio C, Franco I, Noviello MR, et al. Effect of a low glycemic index Mediterranean diet on non-alcoholic fatty liver disease. A randomized controlled clinici trial. J Nutr Health Aging. 2017;21:404–12.PubMed
95.
Larsen TM, Dalskov S-M, van Baak M, Jebb SA, Papadaki A, Pfeiffer AFH, et al. Diets with high or low protein content and glycemic index for weight-loss maintenance. N Engl J Med. 2010;363:2102–13.PubMedPubMedCentral
96.
Markova M, Pivovarova O, Hornemann S, Sucher S, Frahnow T, Wegner K, et al. Isocaloric diets high in animal or plant protein reduce liver fat and inflammation in individuals with type 2 diabetes. Gastroenterology. 2017;152(571–585):e8.
97.
Arslanow A, Teutsch M, Walle H, Grünhage F, Lammert F, Stokes CS. Short-term hypocaloric high-fiber and high-protein diet improves hepatic steatosis assessed by controlled attenuation parameter. Clin Transl Gastroenterol. 2016;7:e176.PubMedPubMedCentral
98.
Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Obesity Society. Circulation. 2014;129:S102–38.PubMed
99.
Yumuk V, Tsigos C, Fried M, Schindler K, Busetto L, Micic D, et al. European guidelines for obesity management in adults. Obes Facts. 2015;8:402–24.PubMedPubMedCentral
100.
Acosta A, Streett S, Kroh MD, Cheskin LJ, Saunders KH, Kurian M, et al. White paper AGA: POWER -practice guide on obesity and weight management, education, and resources. Clin Gastroenterol Hepatol. 2017;15:631–49.PubMed
101.
Gupta NA, Mells J, Dunham RM, Grakoui A, Handy J, Saxena NK, et al. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology. 2010;51(5):1584–92.PubMed
102.
Armstrong MJ, Hull D, Guo K, Barton D, Hazlehurst JM, Gathercole LL, et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol. 2016;64:399–408.PubMedPubMedCentral
103.
Gastaldelli A, Gaggini M, Daniele G, Ciociaro D, Cersosimo E, Tripathy D, et al. Exenatide improves both hepatic and adipose tissue insulin resistance: a dynamic positron emission tomography study. Hepatology. 2016;64:2028–37.PubMed
104.
Upadhyay J, Polyzos SA, Perakakis N, Thakkar B, Paschou SA, Katsiki N, et al. Pharmacotherapy of type 2 diabetes: an update. Metabolism. 2018;78:13–42.PubMed
105.
Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373(1):11–22.PubMed
106.
Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ, et al. Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA. 2016;315(22):2424–34.PubMedPubMedCentral
107.
Liu Y, Wei R, Hong TP. Potential roles of glucagon-like peptide-1-based therapies in treating non-alcoholic fatty liver disease. World J Gastroentol. 2014;20(27):9090–7.
108.
Wang Y, Parlevliet ET, Geerling JJ, van der Tuin SJ, Zhang H, Bieghs V, et al. Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration. Br J Pharmacol. 2014;171:723–34.PubMedPubMedCentral
109.
Zhang L, Yang M, Ren H, Hu H, Boden G, Li L, Yang G. GLP-1 analogue prevents NAFLD in ApoE KO mice with diet and Acrp30 knockdown by inhibiting c-JNK. Liver Int. 2013;33(5):788–94.
110.
Xu F, Li Z, Zheng X, Liu H, Liang H, Xu H, Chen Z, et al. SIRT1 mediates the effect of GLP-1 receptor agonist exenatide on ameliorating hepatic steatosis. Diabetes. 2014;63(11):3637–46.PubMed
111.
Khoo J, Hsiang J, Taneja R, Law NM, Ang TL. Comparative effects of liraglutide 3 mg vs structured lifestyle modification on body weight, liver fat and liver function in obese patients with non-alcoholic fatty liver disease: a pilot randomized trial. Diabetes Obes Metab. 2017;19:1814–7.PubMed
112.
113.
Assy N, Hussein O, Abassi Z. Weight loss induced by orlistat reverses fatty infiltration and improves hepatic fibrosis in obese patients with non-alcoholic steatohepatitis. Gut. 2007;56(3):443–4.PubMedPubMedCentral
114.
Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA. Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology. 2009;49:80–6.PubMed
115.
Harrison SA, Fincke C, Helinski D, Torgerson S, Hayashi P. A pilot study of orlistat treatment in obese, non-alcoholic steatohepatitis patients. Aliment Pharmacol Ther. 2004;20:623–8.PubMed
116.
Kelley DE, Kuller LH, McKolanis TM, Harper P, Mancino J, Kalhan S. Effects of moderate weight loss and orlistat on insulin resistance, regional adiposity, and fatty acids in type 2 diabetes. Diabetes Care. 2004;27:33–40.PubMed
117.
Zelber-Sagi S, Kessler A, Brazowsky E, Webb M, Lurie Y, Santo M, et al. A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2006;4:639–44.PubMed
118.
Caiazzo R, Lassailly G, Leteurtre E, Baud G, Verkindt H, Raverdy V, et al. Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5-year controlled longitudinal study. Ann Surg. 2014;260:893–9.PubMed
119.
Ruiz-Tovar J, Alsina ME, Alpera MR, OBELCHE Group. Improvement of nonalcoholic fatty liver disease in morbidly obese patients after sleeve gastrectomy: association of ultrasonographic findings with lipid profile and liver enzymes. Acta Chir Belg. 2017;117:363–9.PubMed
120.
Kalinowski P, Paluszkiewicz R, Wróblewski T, Remiszewski P, Grodzicki M, Bartoszewicz Z, et al. Ghrelin, leptin, and glycemic control after sleeve gastrectomy versus Roux-en-Y gastric bypass—results of a randomized clinical trial. Surg Obes Relat Dis. 2017;13:181–8.PubMed
121.
Kalinowski P, Paluszkiewicz R, Ziarkiewicz-Wróblewska B, Wróblewski T, Remiszewski P, Grodzicki M, et al. Liver function in patients with nonalcoholic fatty liver disease randomized to Roux-en-Y gastric bypass versus sleeve gastrectomy: a secondary analysis of a randomized clinical trial. Ann Surg. 2017;266:738–45.PubMed
122.
Fakhry TK, Mhaskar R, Schwitalla T, Muradova E, Gonzalvo JP, Murr MM. Bariatric surgery improves nonalcoholic fatty liver disease: a contemporary systematic review and meta-analysis. Surg Obes Relat Dis. 2019;15(3):502–11.PubMed
123.
124.
Haukeland JW, Konopski Z, Eggesbø HB, von Volkmann HL, Raschpichler G, Bjøro K, et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol. 2009;44(7):853–60.PubMed
125.
Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305:1659–68.PubMedPubMedCentral
126.
Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675–85.PubMedPubMedCentral
127.
Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135(4):1176–84.PubMed
128.
Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern Med. 2017;177(5):633–40.PubMedPubMedCentral
129.
Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142(1):37–46.PubMed
130.
Schürks M, Glynn RJ, Rist PM, Tzourio C, Kurth T. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ. 2010;341:c5702.PubMedPubMedCentral
131.
Abner EL, Schmitt FA, Mendiondo MS, Marcum JL, Kryscio RJ. Vitamin E and all-cause mortality: a meta-analysis. Curr Aging Sci. 2011;4(2):158–70.PubMedPubMedCentral
132.
Sanyal AJ, Harrison SA, Ratziu V, Abdelmalek MF, Diehl AM, Caldwell S, et al. The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials. Hepatology. 2019;70(6):1913–27.PubMed
133.
134.
Chen HP, Shieh JJ, Chang CC, Chen TT, Lin JT, Wu MS, et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut. 2013;62(4):606–15.PubMed
135.
Ravikumar B, Gerrard J, Dalla Man C, Firbank MJ, Lane A, English PT, et al. Pioglitazone decreases fasting and postprandial endogenous glucose production in proportion decrease in hepatic triglyceride content. Diabetes. 2008;57:2288–95.PubMedPubMedCentral
136.
Tang W, Xu Q, Hong T, Tong G, Feng W, Shen S, et al. Comparative efficacy of anti-diabetic agents on nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized and non-randomized studies. Diabetes Metab Res Rev. 2016;32(2):200–16.PubMed
137.
Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355(22):2297–307.PubMed
138.
Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med. 2016;165(5):305–15.PubMed
139.
Bril F, Biernack DM, Kalavalapalli S, Lomonaco R, Subbarayan SK, Lai J, et al. Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial. Diab Care. 2019;42:1481–8.
140.
Silva Júnior WS, Godoy-Matos AF, Kraemer-Aguiar LG. Dipeptidyl peptidase 4: a new link between diabetes mellitus and atherosclerosis? Biomed Res Int. 2015;2015:816164.PubMedPubMedCentral
141.
Silva Júnior WS, Souza MDGC, Kraemer-Aguiar LG. Dipeptidyl peptidase 4 (DPP4), adipose inflammation, and insulin resistance: is it time to look to the hepatocyte? Hepatobiliary Surg Nutr. 2018;7(6):499–500.PubMedPubMedCentral
142.
Itou M, Kawaguchi T, Taniguchi E, Sata M. Dipeptidyl peptidase-4: a key player in chronic liver disease. World J Gastroenterol. 2013;19(15):2298–306.PubMedPubMedCentral
143.
Silva Júnior WS, Souza MDGC, Nogueira Neto JF, Bouskela E, Kraemer-Aguiar LG. Dipeptidyl peptidase 4 activity is related to body composition, measures of adiposity, and insulin resistance in subjects with excessive adiposity and different degrees of glucose tolerance. J Diabetes Res. 2019;2019:5238013.PubMedPubMedCentral
144.
Ghorpade DS, Ozcan L, Zheng Z, Nicoloro SM, Shen Y, Chen E, et al. Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance. Nature. 2018;555(7698):673–7.PubMedPubMedCentral
145.
Macauley M, Hollingsworth KG, Smith FE, Thelwall PE, Al-Mrabeh A, Schweizer A, et al. Effect of vildagliptin on hepatic steatosis. J Clin Endocrinol Metab. 2015;100(4):1578–85.PubMedPubMedCentral
146.
Deng XL, Ma R, Zhu HX, Zhu J. Short article: a randomized-controlled study of sitagliptin for treating diabetes mellitus complicated by nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2017;29(3):297–301.PubMed
147.
Armstrong MJ, Houlihan DD, Rowe IA, Clausen WH, Elbrønd B, Gough SC, et al. Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program. Aliment Pharmacol Ther. 2013;37(2):234–42.PubMed
148.
Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387(10019):679–90.PubMed
149.
Newsome P, Francque S, Harrison S, Ratziu V, Van Gaal L, Calanna S, et al. Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. Aliment Pharmacol Ther. 2019;50(2):193–203.PubMedPubMedCentral
150.
Dokmak A, Almeqdadi M, Trivedi H, Krishnan S. Rise of sodium-glucose cotransporter 2 inhibitors in the management of nonalcoholic fatty liver disease. World J Hepatol. 2019;11(7):562–73.PubMedPubMedCentral
151.
Raj H, Durgia H, Palui R, Kamalanathan S, Selvarajan S, Kar SS, et al. SGLT-2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: a systematic review. World J Diabetes. 2019;10(2):114–32.PubMedPubMedCentral
152.
Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, et al. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT Trial). Diabetes Care. 2018;41(8):1801–8.PubMed
153.
Sattar N, Fitchett D, Hantel S, George JT, Zinman B. Empagliflozin is associated with improvements in liver enzymes potentially consistent with reductions in liver fat: results from randomised trials including the EMPA-REG OUTCOME® trial. Diabetologia. 2018;61(10):2155–63.PubMedPubMedCentral
154.
Shimizu M, Suzuki K, Kato K, Jojima T, Iijima T, Murohisa T, et al. Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease. Diabetes Obes Metab. 2019;21(2):285–92.PubMed
155.
Eriksson JW, Lundkvist P, Jansson PA, Johansson L, Kvarnström M, Moris L, et al. Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study. Diabetologia. 2018;61(9):1923–34.PubMedPubMedCentral
156.
Li B, Wang Y, Ye Z, Yang H, Cui X, Wang Z, et al. Effects of canagliflozin on fatty liver indexes in patients with type 2 diabetes: a meta-analysis of randomized controlled trials. J Pharm Pharm Sci. 2018;21(1):222–35.PubMed
157.
Akuta N, Kawamura Y, Watanabe C, Nishimura A, Okubo M, Mori Y, et al. Impact of sodium glucose cotransporter 2 inhibitor on histological features and glucose metabolism of non-alcoholic fatty liver disease complicated by diabetes mellitus. Hepatol Res. 2019;49(5):531–9.PubMed
158.
Maffioli P, Fogari E, D’Angelo A, Perrone T, Derosa G. Ultrasonography modifications of visceral and subcutaneous adipose tissue after pioglitazone or glibenclamide therapy combined with rosuvastatin in type 2 diabetic patients not well controlled by metformin. Eur J Gastroenterol Hepatol. 2013;25(9):1113–22.PubMed
159.
Feng W, Gao C, Bi Y, Wu M, Li P, Shen S, et al. Randomized trial comparing the effects of gliclazide, liraglutide, and metformin on diabetes with non-alcoholic fatty liver disease. J Diabetes. 2017;9(8):800–9.PubMed
160.
Morita Y, Ueno T, Sasaki N, Tateishi Y, Nagata E, Kage M, et al. Nateglinide is useful for nonalcoholic steatohepatitis (NASH) patients with type 2 diabetes. Hepatogastroenterology. 2005;52(65):1338–43.PubMed
161.
Inui Y, Kawata S, Matsuzawa Y, Tokunaga K, Fujioka S, Tamura S, et al. Inhibitory effect of a new alpha-glucosidase inhibitor on fatty liver in Zucker fatty rats. J Hepatol. 1990;10(1):62–8.PubMed
162.
Nozaki Y, Fujita K, Yoneda M, Wada K, Shinohara Y, Takahashi H, et al. Long-term combination therapy of ezetimibe and acarbose for non-alcoholic fatty liver disease. J Hepatol. 2009;51(3):548–56.PubMed
163.
Rudovich NN, Weickert MO, Machann J, Pfeiffer AF. Combination of acarbose and ezetimibe prevents non-alcoholic fatty liver disease: a break of intestinal insulin resistance? J Hepatol. 2010;52(6):952–3.PubMed
164.
Gentile S, Turco S, Guarino G, Oliviero B, Rustici A, Torella R. Non-insulin-dependent diabetes mellitus associated with nonalcoholic liver cirrhosis: an evaluation of treatment with the intestinal alpha-glucosidase inhibitor acarbose. Ann Ital Med Int. 1999;14(1):7–14.PubMed
165.
Monteiro Júnior FD, Silva Júnior WS, Salgado Filho N, Ferreira PAM, Araújo GF, Mandarino NR, et al. Effects of weight loss induced by bariatric surgery on the prevalence of metabolic syndrome. Arq Bras Cardiol. 2009;92(6):418–56.PubMed
166.
Rubino F, Nathan DM, Eckel RH, Schauer PR, Alberti KGMM, Zimmet PZ, et al. Metabolic surgery in the treatment algorithm for type 2 diabetes: a joint statement by international diabetes organizations. Diabetes Care. 2016;39(6):861–77.PubMed
167.
Cummings DE, Cohen RV. Beyond BMI: the need for new guidelines governing the use of bariatric and metabolic surgery. Lancet Diabetes Endocrinol. 2014;2(2):175–81.PubMedPubMedCentral
168.
Clanton J, Subichin M. The effects of metabolic surgery on fatty liver disease and nonalcoholic steatohepatitis. Surg Clin North Am. 2016;96(4):703–15.PubMed
169.
Aminian A, Chang J, Brethauer SA, Kim JJ, American Society for Metabolic and Bariatric Surgery Clinical Issues Committee. ASMBS updated position statement on bariatric surgery in class I obesity (BMI 30–35 kg/m2). Surg Obes Relat Dis. 2018;14(8):1071–87.PubMed
170.
Berry MA, Urrutia L, Lamoza P, Molina A, Luna E, Parra F, et al. Sleeve gastrectomy outcomes in patients with BMI between 30 and 35–3 years of follow-up. Obes Surg. 2018;28(3):649–55.PubMed
Metadata
Title
NAFLD as a continuum: from obesity to metabolic syndrome and diabetes
Authors
Amélio F. Godoy-Matos
Wellington S. Silva Júnior
Cynthia M. Valerio
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Diabetology & Metabolic Syndrome / Issue 1/2020
Electronic ISSN: 1758-5996
DOI
https://doi.org/10.1186/s13098-020-00570-y

Other articles of this Issue 1/2020

Diabetology & Metabolic Syndrome 1/2020 Go to the issue

Research

Long non-coding RNA CDKN2B-AS1 regulates high glucose-induced human mesangial cell injury via regulating the miR-15b-5p/WNT2B axis

Short report

Melatonin deficiency decreases brown adipose tissue acute thermogenic capacity of in rats measured by 18F-FDG PET

Research

Diagnostic accuracy of the Finnish Diabetes Risk Score for the prediction of undiagnosed type 2 diabetes, prediabetes, and metabolic syndrome in the Lebanese University

Research

The prevalence of metabolic syndrome and its association with body fat distribution in middle-aged individuals from Indonesia and the Netherlands: a cross-sectional analysis of two population-based studies

Research

Association of serum fibroblast growth factor 19 levels with arteriosclerosis parameters assessed by arterial stiffness and atherogenic index of plasma in patients with type 2 diabetes

Review

Dexamethasone in the era of COVID-19: friend or foe? An essay on the effects of dexamethasone and the potential risks of its inadvertent use in patients with diabetes
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits