Hígado graso (parte 1): aspectos generales, epidemiología, fisiopatología e historia natural

Autores/as

DOI:

https://doi.org/10.22516/25007440.952

Palabras clave:

Hígado graso, fisiopatología, Historia Natural

Resumen

El hígado graso no alcohólico (NAFLD) se define por la presencia de grasa o esteatosis en los hepatocitos y abarca un espectro que va desde la esteatosis simple, pasa por la esteatohepatitis no alcohólica (NASH) con inflamación y fibrosis, y finaliza en la cirrosis. Se considera una prevalencia mundial global cercana al 25% en la población general y se diagnóstica entre los 40 y 50 años, con variaciones respecto al sexo predominante y con diferencias étnicas (la población hispana es la más afectada). El hígado graso está asociado al síndrome metabólico (SM), y la obesidad se considera el principal factor de riesgo con su presencia y con su progresión.

El hígado graso es un trastorno complejo y muy heterogéneo en su fisiopatología, que resulta de la interacción de múltiples elementos: factores genéticos, epigenéticos, ambientales, culturales, entre otros. Todo ello en conjunto lleva a incremento paulatino de grasa hepática, resistencia a la insulina y alteraciones hormonales y de la microbiota intestinal, lo que genera un daño hepatocelular a través de la formación de radicales libres de oxígeno y activación de la fibrogénesis hepática.

La historia natural del hígado graso es dinámica: los pacientes con esteatosis simple tienen bajo riesgo de progresión a cirrosis, mientras que en los pacientes con NASH este riesgo se aumenta; sin embargo, el proceso puede ser reversible y algunas personas tendrán una mejoría espontánea. La fibrosis parece ser el determinante de la mortalidad global y de los desenlaces asociados a la enfermedad hepática; se considera que en todos los pacientes la fibrosis empeora una etapa cada 14 años y en NASH empeora en una etapa cada 7 años. Estudios previos concluyen que aproximadamente 20% de los casos de esteatosis simple progresan a NASH y que, de ellos, aproximadamente el 20% progresan a cirrosis, con presencia de hepatocarcinoma (HCC) en el 5% a 10% de ellos.

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Biografía del autor/a

Jhon Edison Prieto-Ortiz, Centro de enfermedades hepáticas y digestivas (CEHYD)

Médico especialista en Medicina interna, Gastroenterología y Hepatología, Universidad Nacional de Colombia, Hospital Clínic de Barcelona, Centro de enfermedades hepáticas y digestivas (CEHYD). Bogotá, Colombia. 

 

Carlos Bernardo Sánchez Luque, Centro de Enfermedades Hepáticas y Digestivas CEHYD.

Médico Especialista en Gastroenterología y Endoscopia Digestiva. Hepatología. Clínica Colsanitas Keralty. Hospital Universitario Fundación Santafé. Bogotá, Colombia.

Rolando Ortega Quiróz MD. MSc. FAASLD, Clínica del Norte

Médico especialista en Medicina interna, Gastroenterología y Hepatología, Universidad de Cartagena, Universidad Nacional de Colombia, Hospital Clínic de Barcelona. Jefe servicio de gastroenterología y Hepatología clínica del Norte, Barranquilla, Colombia.

Referencias bibliográficas

Ayonrinde OT. Historical narrative from fatty liver in the nineteenth century to contemporary NAFLD - Reconciling the present with the past. JHEP Rep. 2021;3(3):100261. https://doi.org/10.1016/j.jhepr.2021.100261

Zelman S. The liver in obesity. AMA Arch Intern Med. 1952;90(2):141-56. https://doi.org/10.1001/archinte.1952.00240080007002

Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55(7):434-8.

Patel V, Sanyal AJ, Sterling R. Clinical Presentation and Patient Evaluation in Nonalcoholic Fatty Liver Disease. Review Clin Liver Dis. 2016;20(2):277-92. https://doi.org/10.1016/j.cld.2015.10.006

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(1):328-357. https://doi.org/10.1002/hep.29367

Eslam M, Sanyal AJ, George J; International Consensus Panel. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology. 2020;158(7):1999-2014.e1. https://doi.org/10.1053/j.gastro.2019.11.312

Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15(1):11-20. https://doi.org/10.1038/nrgastro.2017.109

Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140(1):124-31. https://doi.org/10.1053/j.gastro.2010.09.038

Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34(3):274-85. https://doi.org/10.1111/j.1365-2036.2011.04724.x

Lizardi-Cervera J, Laparra IB, Chávez-Tapia NC, Ostos MER, Uribe Esquivel M. Prevalencia de hígado graso no alcohólico y síndrome metabólico en población asintomática. Rev Gastroenterol México 2006;71(4):453-9.

Riquelme A, Arrese M, Soza A, Morales A, Baudrand R, Pérez-Ayuso RM, et al. Non-alcoholic fatty liver disease and its association with obesity, insulin resis-tance and increased serum levels of C-reactive protein in Hispanics. Liver Int. 2009;29(1):82-8. https://doi.org/10.1111/j.1478-3231.2008.01823.x

Encuesta Nacional de la Situación Nutricional ENSIN 2015. Colombia: Ministerio de Salud y Protección Social; 2015.

Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, Mir H, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol. 2011;9(6):524-530.e1; quiz e60. https://doi.org/10.1016/j.cgh.2011.03.020

Falck-Ytter Y, Younossi ZM, Marchesini G, McCullough AJ. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis. 2001;21(1):17-26. https://doi.org/10.1055/s-2001-12926

Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999;30(6):1356-62. https://doi.org/10.1002/hep.510300604

Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116(6):1413-9. https://doi.org/0.1016/s0016-5085(99)70506-8

Cortez-Pinto H, Camilo ME, Baptista A, De Oliveira AG, De Moura MC. Non-alcoholic fatty liver: another feature of the metabolic syndrome? Clin Nutr. 1999;18(6):353-8. https://doi.org/10.1016/S0261-5614(99)80015-6

Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40(6):1387-95. https://doi.org/10.1002/hep.20466

Arun J, Clements RH, Lazenby AJ, Leeth RR, Abrams GA. The prevalence of nonalcoholic steatohepatitis is greater in morbidly obese men compared to women. Obes Surg. 2006;16(10):1351-8. https://doi.org/10.1381/096089206778663715

Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37(4):917-23. https://doi.org/10.1053/jhep.2003.50161

Weston SR, Leyden W, Murphy R, Bass NM, Bell BP, Manos MM, et al. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology. 2005;41(2):372-9. https://doi.org/10.1002/hep.20554

Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346(16):1221-31. https://doi.org/10.1056/NEJMra011775

Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA. 2015;313(22):2263-73. https://doi.org/10.1001/jama.2015.5370

Younossi ZM, Golabi P, de 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(04):793-801. https://doi.org/10.1016/j.jhep.2019.06.021

Rinella M, Charlton M. The globalization of nonalcoholic fatty liver disease: prevalence and impact on world health. Hepatology. 2016;64(1):19-22. https://doi.org/10.1002/hep.28524

Jarvis H, Craig D, Barker R, Spiers G, Stow D, Anstee QM, et al. Metabolic risk factors and incident advanced liver disease in non-alcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis of population-based observational studies. PLoS Med. 2020;17(4):e1003100. https://doi.org/10.1371/journal.pmed.1003100

Arab JP, Dirchwolf M, Álvares-da-Silva MR, Barrera F, Benítez C, Castellanos-Fernandez M, et al. Latin American Association for the study of the liver (ALEH) practice guidance for the diagnosis and treatment of non-alcoholic fatty liver disease. Ann Hepatol. 2020;19(6):674-690. https://doi.org/10.1016/j.aohep.2020.09.006

Loomba R, Abraham M, Unalp A, Wilson L, Lavine J, Doo E, et al. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology. 2012;56(3):943-51. https://doi.org/10.1002/hep.25772

Ma J, Hwang SJ, Pedley A, Massaro JM, Hoffmann U, Chung RT, et al. Bi-directional analysis between fatty liver and cardiovascular disease risk factors. J Hepatol. 2017;66(2):390-397. https://doi.org/10.1016/j.jhep.2016.09.022

Stepanova M, Younossi ZM. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population. Clin Gastroenterol Hepatol. 2012;10(6):646-50. https://doi.org/10.1016/j.cgh.2011.12.039

Giorgio V, Prono F, Graziano F, Nobili V. Pediatricnon alcoholic fatty liver disease: old and new concepts on development, progression, metabolic insight and potential treatment targets. BMC Pediatr. 2013;13:40. https://doi.org/10.1186/1471-2431-13-40

Anderson EL, Howe LD, Jones HE, Higgins JPT, Lawlor DA, Fraser A. The Prevalence of Non-Alcoholic Fatty Liver Disease in Children and Adolescents: A Systematic Review and Meta-Analysis. PLoS One. 2015;10(10):e0140908. https://doi.org/10.1371/journal.pone.0140908

Yu EL, Golshan S, Harlow KE, Angeles JE, Durelle J, Goyal NP, et al. Prevalence of Nonalcoholic Fatty Liver Disease in Children with Obesity. J Pediatr. 2019;207:64-70. https://doi.org/10.1016/j.jpeds.2018.11.021

Majumdar A, Tsochatzis EA. Changing trends of liver transplantation and mortality from non-alcoholic fatty liver disease. Metabolism. 2020;111S:154291. https://doi.org/10.1016/j.metabol.2020.154291

Younossi ZM, Marchesini G, Pinto-Cortez H, Petta S. Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: Implications for Liver Transplantation. Transplantation. 2019;103(1):22-27. https://doi.org/10.1097/TP.0000000000002484

Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40(12):1461-5. https://doi.org/10.1038/ng.257

Loomba R, Schork N, Chen CH, Bettencourt R, Bhatt A, Ang B, et al. Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study. Gastroenterology. 2015;149(7):1784-93. https://doi.org/10.1053/j.gastro.2015.08.011

Jonas W, Schürmann A. Genetic and epigenetic factors determining NAFLD risk. Mol Metab. 2021;50:101111. https://doi.org/10.1016/j.molmet.2020.101111

Carlsson B, Lindén D, Brolén G, Liljeblad M, Bjursell M, Romeo S, et al. Review article: the emerging role of genetics in precision medicine for patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2020;51(12):1305-1320. https://doi.org/10.1111/apt.15738

Wang Y, Kory N, BasuRay S, Cohen JC, Hobbs HH. PNPLA3, CGI-58, and Inhibition of Hepatic Triglyceride Hydrolysis in Mice. Hepatology. 2019;69(6):2427-2441. https://doi.org/10.1002/hep.30583

Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology. 2011;53(6):1883-94. https://doi.org/10.1002/hep.24283

Krawczyk M, Stokes CS, Romeo S, Lammert F. HCC and liver disease risks in homozygous PNPLA3 p.I148M carriers approach monogenic inheritance. J Hepatol. 2015;62(4):980-1. https://doi.org/10.1016/j.jhep.2014.10.048

Liu YL, Patman GL, Leathart JB, Piguet AC, Burt AD, Dufour JF, et al. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol. 2014;61(1):75-81. https://doi.org/10.1016/j.jhep.2014.02.030

Ehrhardt N, Doche ME, Chen S, Mao HZ, Walsh MT, Bedoya C, et al. Hepatic Tm6sf2 overexpression affects cellular ApoB-trafficking, plasma lipid levels, hepatic steatosis and atherosclerosis. Hum Mol Genet. 2017;26(14):2719-2731. https://doi.org/10.1093/hmg/ddx159

Liu YL, Reeves HL, Burt AD, Tiniakos D, McPherson S, Leathart JB, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun. 2014;5:4309. https://doi.org/10.1038/ncomms5309

Dongiovanni P, Petta S, Maglio C, Fracanzani AL, Pipitone R, Mozzi E, et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology. 2015;61(2):506-14. https://doi.org/10.1002/hep.27490

Caddeo A, Jamialahmadi O, Solinas G, Pujia A, Mancina RM, Pingitore P, et al. MBOAT7 is anchored to endomembranes by six transmembrane domains. J Struct Biol. 2019;206(3):349-360. https://doi.org/10.1016/j.jsb.2019.04.006

Mancina RM, Dongiovanni P, Petta S, Pingitore P, Meroni M, Rametta R, et al. The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent. Gastroenterology. 2016;150(5):1219-1230.e6. https://doi.org/10.1053/j.gastro.2016.01.032

Zain SM, Mohamed Z, Mohamed R. Common variant in the glucokinase regulatory gene rs780094 and risk of nonalcoholic fatty liver disease: a meta-analysis. J Gastroenterol Hepatol. 2015;30(1):21-7. https://doi.org/10.1111/jgh.12714

Luukkonen PK, Tukiainen T, Juuti A, Sammalkorpi H, Haridas PAN, Niemelä O, et al. Hydroxysteroid 17-β dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease. JCI Insight. 2020;5(5):e132158. https://doi.org/10.1172/jci.insight.132158

Yang J, Trépo E, Nahon P, Cao Q, Moreno C, Letouzé E, et al. A 17-Beta-Hydroxysteroid Dehydrogenase 13 Variant Protects From Hepatocellular Carcinoma Development in Alcoholic Liver Disease. Hepatology. 2019;70(1):231-240. https://doi.org/10.1002/hep.30623

Sookoian S, Rosselli MS, Gemma C, Burgueño AL, Fernández Gianotti T, Castaño GO, et al. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter. Hepatology. 2010;52(6):1992-2000. https://doi.org/10.1002/hep.23927

Dongiovanni P, Valenti L, Rametta R, Daly AK, Nobili V, Mozzi E, et al. Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease. Gut. 2010;59(2):267-73. https://doi.org/10.1136/gut.2009.190801

Petersen KF, Dufour S, Hariri A, Nelson-Williams C, Foo JN, Zhang XM, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med. 2010;362(12):1082-9. https://doi.org/10.1056/NEJMoa0907295

Carulli L, Canedi I, Rondinella S, Lombardini S, Ganazzi D, Fargion S, et al. Genetic polymorphisms in non-alcoholic fatty liver disease: interleukin-6-174G/C polymorphism is associated with non-alcoholic steatohepatitis. Dig Liver Dis. 2009;41(11):823-8. https://doi.org/10.1016/j.dld.2009.03.005

Shabgah AG, Norouzi F, Hedayati-Moghadam M, Soleimani D, Pahlavani N, Navashenaq JG. A comprehensive review of long non-coding RNAs in the pathogenesis and development of non-alcoholic fatty liver disease. Nutr Metab (Lond). 2021;18(1):22. https://doi.org/10.1186/s12986-021-00552-5

Tsagakis I, Douka K, Birds I, Aspden JL. Long non-coding RNAs in development and disease: conservation to mechanisms. J Pathol. 2020;250(5):480-495. https://doi.org/10.1002/path.5405

Khalifa O, Errafii K, Al-Akl NS, Arredouani A. Noncoding RNAs in Nonalcoholic Fatty Liver Disease: Potential Diagnosis and Prognosis Biomarkers. Dis Markers. 2020;2020:8822859. https://doi.org/10.1155/2020/8822859

Marra F, Svegliati-Baroni G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J Hepatol. 2018;68(2):280-295. https://doi.org/10.1016/j.jhep.2017.11.014

Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343-51. https://doi.org/10.1172/JCI23621

Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014;146(3):726-35. https://doi.org/10.1053/j.gastro.2013.11.049

Pramfalk C, Pavlides M, Banerjee R, McNeil CA, Neubauer S, Karpe F, et al. Sex-Specific Differences in Hepatic Fat Oxidation and Synthesis May Explain the Higher Propensity for NAFLD in Men. J Clin Endocrinol Metab. 2015;100(12):4425-33. https://doi.org/10.1210/jc.2015-2649

Gastaldelli A, Cusi K, Pettiti M, Hardies J, Miyazaki Y, Berria R, et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology. 2007;133(2):496-506. https://doi.org/10.1053/j.gastro.2007.04.068

van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI, Kench JG, et al. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology. 2008;48(2):449-57. https://doi.org/10.1002/hep.22350

Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120(5):1183-92. https://doi.org/10.1053/gast.2001.23256

Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C, et al. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35(2):373-9. https://doi.org/10.1053/jhep.2002.30692

Willner IR, Waters B, Patil SR, Reuben A, Morelli J, Riely CA. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol. 2001;96(10):2957-61. https://doi.org/10.1111/j.1572-0241.2001.04667.x

Kral JG, Lundholm K, Björntorp P, Sjöström L, Scherstén T. Hepatic lipid metabolism in severe human obesity. Metabolism. 1977;26(9):1025-31. https://doi.org/10.1016/0026-0495(77)90020-8

Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA. Effect of fatty acids on glucose production and utilization in man. J Clin Invest. 1983;72(5):1737-47. https://doi.org/10.1172/JCI111133

Porez G, Prawitt J, Gross B, Staels B. Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease. J Lipid Res. 2012;53(9):1723-37. https://doi.org/10.1194/jlr.R024794

Moschen AR, Kaser S, Tilg H. Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends Endocrinol Metab. 2013;24(11):537-45. https://doi.org/10.1016/j.tem.2013.05.009

Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49(6):1877-87. https://doi.org/10.1002/hep.22848

Boursier J, Mueller O, Barret M, Machado M, Fizanne L, Araujo-Perez F, et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology. 2016;63(3):764-75. https://doi.org/10.1002/hep.28356

Caussy C, Hsu C, Lo MT, Liu A, Bettencourt R, Ajmera VH, et al. Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD. Hepatology. 2018;68(3):918-932. https://doi.org/10.1002/hep.29892

Loomba R, Seguritan V, Li W, Long T, Klitgord N, Bhatt A, et al. Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metab. 2017;25(5):1054-1062.e5. https://doi.org/10.1016/j.cmet.2017.04.001

Rahman K, Desai C, Iyer SS, Thorn NE, Kumar P, Liu Y, et al. Loss of Junctional Adhesion Molecule A Promotes Severe Steatohepatitis in Mice on a Diet High in Saturated Fat, Fructose, and Cholesterol. Gastroenterology. 2016;151(4):733-746.e12. https://doi.org/10.1053/j.gastro.2016.06.022

Cope K, Risby T, Diehl AM. Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology. 2000;119(5):1340-7. https://doi.org/10.1053/gast.2000.19267

Mezey E, Imbembo AL, Potter JJ, Rent KC, Lombardo R, Holt PR. Endogenous ethanol production and hepatic disease following jejunoileal bypass for morbid obesity. Am J Clin Nutr. 1975;28(11):1277-83. https://doi.org/10.1093/ajcn/28.11.1277

Zhao M, Zhao L, Xiong X, He Y, Huang W, Liu Z, et al. TMAVA, a Metabolite of Intestinal Microbes, Is Increased in Plasma From Patients With Liver Steatosis, Inhibits γ-Butyrobetaine Hydroxylase, and Exacerbates Fatty Liver in Mice. Gastroenterology. 2020;158(8):2266-2281.e27. https://doi.org/10.1053/j.gastro.2020.02.033

Miura K, Ohnishi H. Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20(23):7381-91. https://doi.org/10.3748/wjg.v20.i23.7381

Cohen B, Novick D, Rubinstein M. Modulation of insulin activities by leptin. Science. 1996;274(5290):1185-8. https://doi.org/10.1126/science.274.5290.1185

Asilmaz E, Cohen P, Miyazaki M, Dobrzyn P, Ueki K, Fayzikhodjaeva G, et al. Site and mechanism of leptin action in a rodent form of congenital lipodystrophy. J Clin Invest. 2004;113(3):414-24. https://doi.org/10.1172/JCI19511

Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest. 2003;112(1):91-100. https://doi.org/10.1172/JCI200317797

Musso G, Gambino R, Durazzo M, Biroli G, Carello M, Fagà E, et al. Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology. 2005;42(5):1175-83. https://doi.org/10.1002/hep.20896

Satoh H, Nguyen MT, Miles PD, Imamura T, Usui I, Olefsky JM. Adenovirus-mediated chronic «hyper-resistinemia» leads to in vivo insulin resistance in normal rats. J Clin Invest. 2004;114(2):224-31. https://doi.org/10.1172/JCI20785

Keyhani-Nejad F, Barbosa Yanez RL, Kemper M, Schueler R, Pivovarova-Ramich O, Rudovich N, et al. Endogenously released GIP reduces and GLP-1 increases hepatic insulin extraction. Peptides. 2020;125:170231. https://doi.org/10.1016/j.peptides.2019.170231

Dibner C, Gachon F. Circadian Dysfunction and Obesity: Is Leptin the Missing Link? Cell Metab. 2015;22(3):359-60. https://doi.org/10.1016/j.cmet.2015.08.008

Fleet T, Stashi E, Zhu B, Rajapakshe K, Marcelo KL, Kettner NM, et al. Genetic and Environmental Models of Circadian Disruption Link SRC-2 Function to Hepatic Pathology. J Biol Rhythms. 2016;31(5):443-60. https://doi.org/10.1177/0748730416657921

Kettner NM, Voicu H, Finegold MJ, Coarfa C, Sreekumar A, Putluri N, et al. Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis. Cancer Cell. 2016;30(6):909-924. https://doi.org/10.1016/j.ccell.2016.10.007

Yamamoto Y, Moore R, Goldsworthy TL, Negishi M, Maronpot RR. The orphan nuclear receptor constitutive active/androstane receptor is essential for liver tumor promotion by phenobarbital in mice. Cancer Res. 2004;64(20):7197-200. https://doi.org/10.1158/0008-5472.CAN-04-1459

Wahlang B, Beier JI, Clair HB, Bellis-Jones HJ, Falkner KC, McClain CJ, et al. Toxicant-associated steatohepatitis. Toxicol Pathol. 2013;41(2):343-60. https://doi.org/10.1177/0192623312468517

Aron-Wisnewsky J, Minville C, Tordjman J, Lévy P, Bouillot JL, Basdevant A, et al. Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese. J Hepatol. 2012;56(1):225-33. https://doi.org/10.1016/j.jhep.2011.04.022

Benotti P, Wood GC, Argyropoulos G, Pack A, Keenan BT, Gao X, et al. The impact of obstructive sleep apnea on nonalcoholic fatty liver disease in patients with severe obesity. Obesity (Silver Spring). 2016;24(4):871-7. https://doi.org/10.1002/oby.21409

Chen J, Schenker S, Frosto TA, Henderson GI. Inhibition of cytochrome c oxidase activity by 4-hydroxynonenal (HNE). Role of HNE adduct formation with the enzyme subunits. Biochim Biophys Acta. 1998;1380(3):336-44. https://doi.org/10.1016/s0304-4165(98)00002-6

Rensen SS, Slaats Y, Driessen A, Peutz-Kootstra CJ, Nijhuis J, Steffensen R, et al. Activation of the complement system in human nonalcoholic fatty liver disease. Hepatology. 2009;50(6):1809-17. https://doi.org/10.1002/hep.23228

Rensen SS, Slaats Y, Nijhuis J, Jans A, Bieghs V, Driessen A, et al. Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis. Am J Pathol. 2009;175(4):1473-82. https://doi.org/10.2353/ajpath.2009.080999

Sastre J, Pallardó FV, Llopis J, Furukawa T, Viña JR, Viña J. Glutathione depletion by hyperphagia-induced obesity. Life Sci. 1989;45(2):183-7. https://doi.org/10.1016/0024-3205(89)90293-2

Baskol G, Baskol M, Kocer D. Oxidative stress and antioxidant defenses in serum of patients with non-alcoholic steatohepatitis. Clin Biochem. 2007;40(11):776-80. https://doi.org/10.1016/j.clinbiochem.2007.02.006

Ikura Y, Ohsawa M, Suekane T, Fukushima H, Itabe H, Jomura H, et al. Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease: impact on disease progression. Hepatology. 2006;43(3):506-14. https://doi.org/10.1002/hep.21070

Nocito A, Dahm F, Jochum W, Jang JH, Georgiev P, Bader M, et al. Serotonin mediates oxidative stress and mitochondrial toxicity in a murine model of nonalcoholic steatohepatitis. Gastroenterology. 2007;133(2):608-18. https://doi.org/10.1053/j.gastro.2007.05.019

Younossi ZM, Gramlich T, Bacon BR, Matteoni CA, Boparai N, O›Neill R, et al. Hepatic iron and nonalcoholic fatty liver disease. Hepatology. 1999;30(4):847-50. https://doi.org/10.1002/hep.510300407

Mendler MH, Turlin B, Moirand R, Jouanolle AM, Sapey T, Guyader D, et al. Insulin resistance-associated hepatic iron overload. Gastroenterology. 1999;117(5):1155-63. https://doi.org/10.1016/S0016-5085(99)70401-4

Valenti L, Fracanzani AL, Bugianesi E, Dongiovanni P, Galmozzi E, Vanni E, et al. HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology. 2010;138(3):905-12. https://doi.org/10.1053/j.gastro.2009.11.013

Cai J, Zhang XJ, Li H. The Role of Innate Immune Cells in Nonalcoholic Steatohepatitis. Hepatology. 2019;70(3):1026-1037. https://doi.org/10.1002/hep.30506

Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate Immunity and Inflammation in NAFLD/NASH. Dig Dis Sci. 2016;61(5):1294-303. https://doi.org/10.1007/s10620-016-4049-x

Schuster S, Cabrera D, Arrese M, Feldstein AE. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol. 2018;15(6):349-364. https://doi.org/10.1038/s41575-018-0009-6

Parthasarathy G, Revelo X, Malhi H. Pathogenesis of Nonalcoholic Steatohepatitis: An Overview. Hepatol Commun. 2020;4(4):478-492. https://doi.org/10.1002/hep4.1479

Wree A, Holtmann TM, Inzaugarat ME, Feldstein AE. Novel Drivers of the Inflammatory Response in Liver Injury and Fibrosis. Semin Liver Dis. 2019;39(3):275-282. https://doi.org/10.1055/s-0039-1685515

Wree A, Eguchi A, McGeough MD, Pena CA, Johnson CD, Canbay A, et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology. 2014;59(3):898-910. https://doi.org/10.1002/hep.26592

Ekstedt M, Hagström H, Nasr P, Fredrikson M, Stål P, Kechagias S, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61(5):1547-54. https://doi.org/10.1002/hep.27368

Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, Castellanos M, Aller-de la Fuente R, Metwally M, et al. Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients With Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study. Gastroenterology. 2018;155(2):443-457.e17. https://doi.org/10.1053/j.gastro.2018.04.034

Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14(7):397-411. https://doi.org/10.1038/nrgastro.2017.38

Friedman SL. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol. 2010;7(8):425-36. https://doi.org/10.1038/nrgastro.2010.97

Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol. 2021;18(3):151-166. https://doi.org/10.1038/s41575-020-00372-7

Kleiner DE, Brunt EM, Wilson LA, Behling C, Guy C, Contos M, et al. Association of Histologic Disease Activity With Progression of Nonalcoholic Fatty Liver Disease. JAMA Netw Open. 2019;2(10):e1912565. https://doi.org/10.1001/jamanetworkopen.2019.12565

Pais M, Franzén LE, Mathiesen UL, Kechagias S. Low clinical relevance of the nonalcoholic fatty liver disease activity score (NAS) in predicting fibrosis progression. Scand J Gastroenterol 2012;47(1):108-115. https://doi.org/10.3109/00365521.2011.634024

Pais R, Charlotte F, Fedchuk L, Bedossa P, Lebray P, Poynard T, et al. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol. 2013;59(3):550-6. https://doi.org/10.1016/j.jhep.2013.04.027

Wong VW, Wong GL, Choi PC, Chan AW, Li MK, Chan HY, et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut. 2010;59(7):969-74. https://doi.org/10.1136/gut.2009.205088

Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol. 2009;51(2):371-9. https://doi.org/10.1016/j.jhep.2009.03.019

Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643-54.e1-9; quiz e39-40. https://doi.org/10.1016/j.cgh.2014.04.014

Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2015;149(2):389-97.e10. https://doi.org/10.1053/j.gastro.2015.04.043

Younossi ZM, Stepanova M, Rafiq N, Makhlouf H, Younoszai Z, Agrawal R, et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology. 2011;53(6):1874-82. https://doi.org/10.1002/hep.24268

Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology. 1996;24(2):289-93. https://doi.org/10.1002/hep.510240201

Rahman RN, Ibdah JA. Nonalcoholic fatty liver disease without cirrhosis is an emergent and independent risk factor of hepatocellular carcinoma: a population based study. Hepatology. 2012;56:241A.

Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology. 1990;11(1):74-80. https://doi.org/10.1002/hep.1840110114

Dam-Larsen S, Franzmann M, Andersen IB, Christoffersen P, Jensen LB, Sørensen TI, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. 2004;53(5):750-5. https://doi.org/10.1136/gut.2003.019984

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):1913-1927. https://doi.org/10.1002/hep.30664

Loomba R, Adams LA. The 20% Rule of NASH Progression: The Natural History of Advanced Fibrosis and Cirrhosis Caused by NASH. Hepatology. 2019;70(6):1885-1888. https://doi.org/10.1002/hep.30946

Caldwell SH, Crespo DM. The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease. J Hepatol. 2004;40(4):578-84. https://doi.org/10.1016/j.jhep.2004.02.013

Figura 1. Fisiopatología del hígado graso. Fuente: elaboración propia

Publicado

2022-12-21

Cómo citar

Prieto Ortíz, J. E., Sánchez Luque, C. B., & Ortega Quiróz, R. J. (2022). Hígado graso (parte 1): aspectos generales, epidemiología, fisiopatología e historia natural. Revista Colombiana De Gastroenterología, 37(4), 420–433. https://doi.org/10.22516/25007440.952

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