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The Natural History of NAFLD: Environmental vs. Genetic Risk Factors

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Non-Alcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD), now the leading cause of liver damage worldwide, is a potentially progressive condition to advanced hepatic fibrosis, the main risk factor for liver-related events and for hepatocellular carcinoma. In particular, about 10–30% of NAFLD patients can develop nonalcoholic steatohepatitis (NASH), which more frequently progresses to advanced liver disease. However, development of cardiovascular complications and of extra-hepatic neoplasm is a more frequent evolution of this condition, and there is a huge interindividual variability in liver disease susceptibility. Indeed, although the severity of metabolic alterations is the main risk factor for progressive NAFLD, qualitative components of the diet, physical activity, and inherited factors play also an important role. In particular, during the last years, common variants in PNPLA3, TM6SF2, MBOAT7 and GCKR have been shown to contribute to the full spectrum of NAFLD pathology by facilitating hepatic fat compartmentalization in the presence of environmental triggers. In the future, evaluation of genetic risk factors may help stratifying the risk of liver-related vs. extra-hepatic complications of the disease, and to guide pharmacological therapy.

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References

  1. 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(1):73–84.

    Article  PubMed  Google Scholar 

  2. Estes C, Anstee QM, Teresa Arias-Loste M, Bantel H, Bellentani S, Caballeria J, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J Hepatol. 2018;69(4):896–904.

    Article  PubMed  Google Scholar 

  3. Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med. 1999;107(5):450–5.

    Article  CAS  PubMed  Google Scholar 

  4. Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology. 2007;45(6):1366–74.

    Article  CAS  PubMed  Google Scholar 

  5. Mashek DG, Khan SA, Sathyanarayan A, Ploeger JM, Franklin MP. Hepatic lipid droplet biology: getting to the root of fatty liver. Hepatology. 2015;62(3):964–7.

    Article  PubMed  Google Scholar 

  6. 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(6):1313–21.

    Article  PubMed  Google Scholar 

  7. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52(5):1836–46.

    Article  CAS  PubMed  Google Scholar 

  8. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129(1):113–21.

    Article  PubMed  Google Scholar 

  9. Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44(4):865–73.

    Article  CAS  PubMed  Google Scholar 

  10. Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal 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.

    Article  CAS  PubMed  Google Scholar 

  11. Adams LA, Harmsen S, St Sauver JL, Charatcharoenwitthaya P, Enders FB, Therneau T, et al. Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study. Am J Gastroenterol. 2010;105(7):1567–73.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363(14):1341–50.

    Article  CAS  PubMed  Google Scholar 

  13. Fracanzani AL, Tiraboschi S, Pisano G, Consonni D, Baragetti A, Bertelli C, et al. Progression of carotid vascular damage and cardiovascular events in non-alcoholic fatty liver disease patients compared to the general population during 10 years of follow-up. Atherosclerosis. 2016;246:208–13.

    Article  CAS  PubMed  Google Scholar 

  14. Ballestri S, Zona S, Targher G, Romagnoli D, Baldelli E, Nascimbeni F, et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol. 2016;31(5):936–44.

    Article  CAS  PubMed  Google Scholar 

  15. Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology. 2017;65(5):1557–65.

    Article  CAS  PubMed  Google Scholar 

  16. Golabi P, Stepanova M, Pham HT, Cable R, Rafiq N, Bush H, et al. Non-alcoholic steatofibrosis (NASF) can independently predict mortality in patients with non-alcoholic fatty liver disease (NAFLD). BMJ Open Gastroenterol. 2018;5(1):e000198.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 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. Gastroenterology. 2018;155(2):443–457.e17.

    Article  PubMed  Google Scholar 

  18. Bhala N, Angulo P, van der Poorten D, Lee E, Hui JM, Saracco G, et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatology. 2011;54(4):1208–16.

    Article  PubMed  Google Scholar 

  19. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2012;43(8):617–49.

    Article  Google Scholar 

  20. 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.

    Article  PubMed  Google Scholar 

  21. Hagstrom H, Nasr P, Ekstedt M, Hammar U, Stal P, Hultcrantz R, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67:1265.

    Article  PubMed  Google Scholar 

  22. Romero-Gomez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol. 2017;67(4):829–46.

    Article  PubMed  Google Scholar 

  23. 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.

    Article  PubMed  Google Scholar 

  24. McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015;62(5):1148–55.

    Article  PubMed  Google Scholar 

  25. Pelusi S, Petta S, Rosso C, Borroni V, Fracanzani AL, Dongiovanni P, et al. Renin-angiotensin system inhibitors, type 2 diabetes and fibrosis progression: an observational study in patients with nonalcoholic fatty liver disease. PLoS One. 2016;11(9):e0163069.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. 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.

    Article  CAS  PubMed  Google Scholar 

  27. Goldberg D, Ditah IC, Saeian K, Lalehzari M, Aronsohn A, Gorospe EC, et al. Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation. Gastroenterology. 2017;152(5):1090–9.e1.

    Article  PubMed  Google Scholar 

  28. Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol. 2012;56(6):1384–91.

    Article  PubMed  Google Scholar 

  29. Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123(1):134–40.

    Article  PubMed  Google Scholar 

  30. Piscaglia F, Svegliati-Baroni G, Barchetti A, Pecorelli A, Marinelli S, Tiribelli C, et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology. 2016;63(3):827–38.

    Article  PubMed  Google Scholar 

  31. Younossi ZM, Otgonsuren M, Henry L, Venkatesan C, Mishra A, Erario M, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology. 2015;62(6):1723–30.

    Article  CAS  PubMed  Google Scholar 

  32. Ajmera V, Park CC, Caussy C, Singh S, Hernandez C, Bettencourt R, et al. Magnetic resonance imaging proton density fat fraction associates with progression of fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology. 2018;155(2):307–310.e2.

    Article  PubMed  Google Scholar 

  33. Dongiovanni P, Stender S, Pietrelli A, Mancina RM, Cespiati A, Petta S, et al. Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver. J Intern Med. 2018;283(4):356–70.

    Article  CAS  PubMed  Google Scholar 

  34. McPherson S, Pais R, Valenti L, Schattenberg J, Dufour JF, Tsochatzis E, et al. Further delineation of fibrosis progression in NAFLD: evidence from a large cohort of patients with sequential biopsies. J Hepatol. 2017;64:S593.

    Article  Google Scholar 

  35. Jensen T, Abdelmalek MF, Sullivan S, Nadeau KJ, Green M, Roncal C, et al. Fructose and sugar: a major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018;68(5):1063–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mitchell T, Jeffrey GP, de Boer B, MacQuillan G, Garas G, Ching H, et al. Type and pattern of alcohol consumption is associated with liver fibrosis in patients with non-alcoholic fatty liver disease. Am J Gastroenterol. 2018;113:1484.

    Article  PubMed  Google Scholar 

  37. Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J Hepatol. 2018;68(2):268–79.

    Article  CAS  PubMed  Google Scholar 

  38. Makkonen J, Pietilainen KH, Rissanen A, Kaprio J, Yki-Jarvinen H. Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: a study in monozygotic and dizygotic twins. J Hepatol. 2009;50(5):1035–42.

    Article  CAS  PubMed  Google Scholar 

  39. 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.

    Article  PubMed  Google Scholar 

  40. Guerrero R, Vega GL, Grundy SM, Browning JD. Ethnic differences in hepatic steatosis: an insulin resistance paradox? Hepatology. 2009;49(3):791–801.

    Article  PubMed  Google Scholar 

  41. Caussy C, Soni M, Cui J, Bettencourt R, Schork N, Chen CH, et al. Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis. J Clin Invest. 2017;127(7):2697–704.

    Article  PubMed  PubMed Central  Google Scholar 

  42. 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;40:1461–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dongiovanni P, Donati B, Fares R, Lombardi R, Mancina RM, Romeo S, et al. PNPLA3 I148M polymorphism and progressive liver disease. World J Gastroenterol. 2013;19(41):6969–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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. 2013;61(1):75–81.

    Article  CAS  Google Scholar 

  45. Dongiovanni P, Romeo S, Valenti L. Hepatocellular carcinoma in nonalcoholic fatty liver: role of environmental and genetic factors. World J Gastroenterol. 2014;20(36):12945–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mandorfer M, Scheiner B, Stattermayer AF, Schwabl P, Paternostro R, Bauer D, et al. Impact of patatin-like phospholipase domain containing 3 rs738409 G/G genotype on hepatic decompensation and mortality in patients with portal hypertension. Aliment Pharmacol Ther. 2018;48:451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Valenti L, Alisi A, Galmozzi E, Bartuli A, Del Menico B, Alterio A, et al. I148M Patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease. Hepatology. 2010;52(4):1274–80.

    Article  CAS  PubMed  Google Scholar 

  48. 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.

    Article  CAS  PubMed  Google Scholar 

  49. Nobili V, Liccardo D, Bedogni G, Salvatori G, Gnani D, Bersani I, et al. Influence of dietary pattern, physical activity, and I148M PNPLA3 on steatosis severity in at-risk adolescents. Genes Nutr. 2014;9(3):392.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Stender S, Kozlitina J, Nordestgaard BG, Tybjaerg-Hansen A, Hobbs HH, Cohen JC. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat Genet. 2017;49(6):842–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. BasuRay S, Smagris E, Cohen J, Hobbs HH. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology. 2017;66(4):1111–24.

    Article  CAS  PubMed  Google Scholar 

  52. Mitsche MA, Hobbs HH, Cohen JC. Phospholipase domain-containing protein 3 promotes transfers of essential fatty acids from triglycerides to phospholipids in hepatic lipid droplets. J Biol Chem. 2018;293(18):6958–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Donati B, Motta BM, Pingitore P, Meroni M, Pietrelli A, Alisi A, et al. The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage. Hepatology. 2016;63(3):787–98.

    Article  CAS  PubMed  Google Scholar 

  54. Mondul A, Mancina RM, Merlo A, Dongiovanni P, Rametta R, Montalcini T, et al. PNPLA3 1148M variant influences circulating retinol in adults with nonalcoholic fatty liver disease or obesity. J Nutr. 2015;145(8):1687–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pirazzi C, Valenti L, Motta BM, Pingitore P, Hedfalk K, Mancina RM, et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum Mol Genet. 2014;23(15):4077–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Pingitore P, Dongiovanni P, Motta BM, Meroni M, Lepore SM, Mancina RM, et al. PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis. Hum Mol Genet. 2016;25(23):5212–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjaerg-Hansen A, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2014;46(4):352–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 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.

    Article  CAS  PubMed  Google Scholar 

  59. 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.

    Article  CAS  PubMed  Google Scholar 

  60. Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011;7(3):e1001324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Santoro N, Zhang CK, Zhao H, Pakstis AJ, Kim G, Kursawe R, et al. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology. 2011;55:781–9.

    Article  PubMed  CAS  Google Scholar 

  62. 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):1219–30.e6.

    Article  CAS  PubMed  Google Scholar 

  63. Dongiovanni P, Meroni M, Mancina RM, Baselli G, Rametta R, Pelusi S, et al. Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nonalcoholic fatty liver disease. Hepatol Commun. 2018;2(6):666–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Al-Serri A, Anstee QM, Valenti L, Nobili V, Leathart JB, Dongiovanni P, et al. The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case-control and intra-familial allele association studies. J Hepatol. 2012;56(2):448–54.

    Article  CAS  PubMed  Google Scholar 

  65. Fares R, Petta S, Lombardi R, Grimaudo S, Dongiovanni P, Pipitone R, et al. The UCP2 -866 G>A promoter region polymorphism is associated with nonalcoholic steatohepatitis. Liver Int. 2015;35(5):1574–80. https://doi.org/10.1111/liv.12707. Epub 2014 Nov 20.

  66. Petta S, Valenti L, Tuttolomondo A, Grimaudo S, Dongiovanni P, Pipitone RM, et al. IFNL4 rs368234815 δG>TT variant is associated with histological liver damage in patients with non-alcoholic fatty liver disease. Hepatology. 2017;66(6):1885–93.

    Article  CAS  PubMed  Google Scholar 

  67. Petta S, Valenti L, Marra F, Grimaudo S, Tripodo C, Bugianesi E, et al. MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease. J Hepatol. 2016;64(3):682–90.

    Article  CAS  PubMed  Google Scholar 

  68. Abul-Husn NS, Cheng X, Li AH, Xin Y, Schurmann C, Stevis P, et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med. 2018;378(12):1096–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Di Filippo M, Moulin P, Roy P, Samson-Bouma ME, Collardeau-Frachon S, Chebel-Dumont S, et al. Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. J Hepatol. 2014;61(4):891–902.

    Article  PubMed  CAS  Google Scholar 

  70. Donati B, Valenti L. Telomeres, NAFLD and chronic liver disease. Int J Mol Sci. 2016;17(3):383.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Donati B, Pietrelli A, Pingitore P, Dongiovanni P, Caddeo A, Walker L, et al. Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease. Cancer Med. 2017;6(8):1930–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Calado RT, Regal JA, Kleiner DE, Schrump DS, Peterson NR, Pons V, et al. A spectrum of severe familial liver disorders associate with telomerase mutations. PLoS One. 2009;4(11):e7926.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Pericleous M, Kelly C, Wang T, Livingstone C, Ala A. Wolman’s disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency. Lancet Gastroenterol Hepatol. 2017;2(9):670–9.

    Article  PubMed  Google Scholar 

  74. Bruce KD, Cagampang FR, Argenton M, Zhang J, Ethirajan PL, Burdge GC, et al. Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression. Hepatology. 2009;50(6):1796–808.

    Article  CAS  PubMed  Google Scholar 

  75. Breij LM, Kerkhof GF, Hokken-Koelega AC. Accelerated infant weight gain and risk for nonalcoholic fatty liver disease in early adulthood. J Clin Endocrinol Metab. 2014;99(4):1189–95.

    Article  CAS  PubMed  Google Scholar 

  76. Nobili V, Marcellini M, Marchesini G, Vanni E, Manco M, Villani A, et al. Intrauterine growth retardation, insulin resistance, and nonalcoholic fatty liver disease in children. Diabetes Care. 2007;30(10):2638–40.

    Article  PubMed  Google Scholar 

  77. Suomela E, Oikonen M, Pitkänen N, Ahola-Olli A, Virtanen J, Parkkola R, et al. Childhood predictors of adult fatty liver. The cardiovascular risk in young Finns study. J Hepatol. 2016;65:784–90.

    Article  PubMed  Google Scholar 

  78. Valenti L, Romeo S. Destined to develop NAFLD? The predictors of fatty liver from birth to adulthood. J Hepatol. 2016;65(4):668–70.

    Article  PubMed  Google Scholar 

  79. Murphy SK, Yang H, Moylan CA, Pang H, Dellinger A, Abdelmalek MF, et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology. 2013;145(5):1076–87.

    Article  CAS  PubMed  Google Scholar 

  80. Kitamoto T, Kitamoto A, Ogawa Y, Honda Y, Imajo K, Saito S, et al. Targeted-bisulfite sequence analysis of the methylation of CpG islands in genes encoding PNPLA3, SAMM50, and PARVB of patients with non-alcoholic fatty liver disease. J Hepatol. 2015;63(2):494–502.

    Article  CAS  PubMed  Google Scholar 

  81. Cheung O, Puri P, Eicken C, Contos MJ, Mirshahi F, Maher JW, et al. Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression. Hepatology. 2008;48(6):1810–20.

    Article  CAS  PubMed  Google Scholar 

  82. Gerhard GS, DiStefano JK. Micro RNAs in the development of non-alcoholic fatty liver disease. World J Hepatol. 2015;7(2):226–34.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Hsu SH, Wang B, Kota J, Yu J, Costinean S, Kutay H, et al. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J Clin Invest. 2012;122(8):2871–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Csak T, Bala S, Lippai D, Satishchandran A, Catalano D, Kodys K, et al. microRNA-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes and correlates with fibrosis in diet-induced steatohepatitis. Liver Int. 2015;35(2):532–41.

    Article  CAS  PubMed  Google Scholar 

  85. Pirola CJ, Fernandez Gianotti T, Castano GO, Mallardi P, San Martino J, Mora Gonzalez Lopez Ledesma M, et al. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut. 2015;64(5):800–12.

    Article  CAS  PubMed  Google Scholar 

  86. Zarrinpar A, Gupta S, Maurya MR, Subramaniam S, Loomba R. Serum microRNAs explain discordance of non-alcoholic fatty liver disease in monozygotic and dizygotic twins: a prospective study. Gut. 2016;65(9):1546–54.

    Article  CAS  PubMed  Google Scholar 

  87. Valenti L, Bugianesi E, Pajvani U, Targher G. Nonalcoholic fatty liver disease: cause or consequence of type 2 diabetes? Liver Int. 2016;36(11):1563–79.

    Article  CAS  PubMed  Google Scholar 

  88. Stender S, Smagris E, Lauridsen BK, Kofoed KF, Nordestgaard BG, Tybjaerg-Hansen A, et al. Relationship between genetic variation at PPP1R3B and liver glycogen and triglyceride levels. Hepatology. 2018;67(6):2182–95.

    Article  CAS  PubMed  Google Scholar 

  89. Nobili V, Bedogni G, Donati B, Alisi A, Valenti L. The I148M variant of PNPLA3 reduces the response to Docosahexaenoic acid in children with non-alcoholic fatty liver disease. J Med Food. 2013;16(10):957–60.

    Article  CAS  PubMed  Google Scholar 

  90. Scorletti E, West AL, Bhatia L, Hoile SP, McCormick KG, Burdge GC, et al. Treating liver fat and serum triglyceride levels in NAFLD, effects of PNPLA3 and TM6SF2 genotypes: results from the WELCOME trial. J Hepatol. 2015;63(6):1476–83.

    Article  CAS  PubMed  Google Scholar 

  91. Ma J, Hennein R, Liu C, Long MT, Hoffmann U, Jacques PF, et al. Improved diet quality associates with reduction in liver fat, particularly in individuals with high genetic risk scores for nonalcoholic fatty liver disease. Gastroenterology. 2018;155(1):107–17.

    Article  PubMed  Google Scholar 

  92. Donati B, Dongiovanni P, Romeo S, Meroni M, McCain M, Miele L, et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci Rep. 2017;7(1):4492.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Dongiovanni P, Petta S, Mannisto V, Mancina RM, Pipitone R, Karja V, et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol. 2015;63(3):705–12.

    Article  CAS  PubMed  Google Scholar 

  94. Guzman CB, Duvvuru S, Akkari A, Bhatnagar P, Battioui C, Foster W, et al. Coding variants in PNPLA3 and TM6SF2 are risk factors for hepatic steatosis and elevated serum alanine aminotransferases caused by a glucagon receptor antagonist. Hepatol Commun. 2018;2(5):561–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Pillai S, Duvvuru S, Bhatnagar P, Foster W, Farmen M, Shankar S, et al. The PNPLA3 I148M variant is associated with transaminase elevations in type 2 diabetes patients treated with basal insulin peglispro. Pharmacogenomics J. 2018;18(3):487–93.

    Article  CAS  PubMed  Google Scholar 

  96. Eriksson JW, Lundkvist P, Jansson PA, Johansson L, Kvarnstrom 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;61:1923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Valenti L, Dongiovanni P. Mutant PNPLA3 I148M protein as pharmacological target for liver disease. Hepatology. 2017;66(4):1026–8.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

    Luca Valenti & Serena Pelusi

  2. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy

    Luca Valenti & Serena Pelusi

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  1. Luca Valenti
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  2. Serena Pelusi
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Correspondence to Luca Valenti .

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Editors and Affiliations

  1. Department of Medical Sciences, Division of Gastroentrology and Hepatology, University of Turin, Turin, Italy

    Elisabetta Bugianesi

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Valenti, L., Pelusi, S. (2020). The Natural History of NAFLD: Environmental vs. Genetic Risk Factors. In: Bugianesi, E. (eds) Non-Alcoholic Fatty Liver Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-95828-6_7

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  • DOI: https://doi.org/10.1007/978-3-319-95828-6_7

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