Nonalcoholic Fatty Liver Disease: Pathophysiology and Management

Gastroenterology Clinics of North America

Volumn 45, Issue 4, 2016, Pages 639-652

  Carr, Rotonya M ^a   Oranu, Amanke ^a   Khungar, Vandana ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Hepatic steatosis; Lipid droplet; NASH; NASH therapeutics; Nonalcoholic fatty liver disease; Obesity; Perilipins

Indexed keywords

ALPHA TOCOPHEROL; ELAFIBRANOR; HORMONE; OBETICHOLIC ACID; PIOGLITAZONE; GASTROINTESTINAL AGENT;

CARDIOVASCULAR DISEASE; CAUSE OF DEATH; DIAGNOSTIC TEST; DISEASE SEVERITY; HEPATITIS; HEREDITY; HISTOPATHOLOGY; HUMAN; INSULIN RESISTANCE; INTESTINE FLORA; LIFESTYLE MODIFICATION; LIPOTOXICITY; LIVER BIOPSY; LIVER DISEASE; LIVER FIBROSIS; MALIGNANT NEOPLASTIC DISEASE; MORTALITY; NONALCOHOLIC FATTY LIVER; NUTRITION; PATHOPHYSIOLOGY; PATIENT CARE; PATIENT REFERRAL; REVIEW; RISK ASSESSMENT; RISK FACTOR; WEIGHT REDUCTION; MULTIMODALITY CANCER THERAPY; WEIGHT LOSS PROGRAM;

COMBINED MODALITY THERAPY; GASTROINTESTINAL AGENTS; HUMANS; NON-ALCOHOLIC FATTY LIVER DISEASE; RISK FACTORS; WEIGHT REDUCTION PROGRAMS;

EID: 84995403907     PISSN: 08898553     EISSN: 15581942     Source Type: Journal    
DOI: 10.1016/j.gtc.2016.07.003     Document Type: Review

References (85)

1. 1 Chalasani, N., Younossi, Z., Lavine, J.E., et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 55 (2012), 2005-2023.
2. 2 Younossi, Z.M., Koenig, A.B., Abdelatif, D., et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence and outcomes. Hepatology 64 (2015), 73-84.
3. 3 Vernon, G., Baranova, A., Younossi, Z.M., Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 34 (2011), 274-285.
4. 4 Petersen, K.F., Dufour, S., Feng, J., et al. Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men. Proc Natl Acad Sci U S A 103 (2006), 18273-18277.
5. 5 Pan, J.J., Fallon, M.B., Gender and racial differences in nonalcoholic fatty liver disease. World J Hepatol 6 (2014), 274-283.
6. 6 Browning, J.D., Szczepaniak, L.S., Dobbins, R., et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40 (2004), 1387-1395.
7. 7 Fleischman, M.W., Budoff, M., Zeb, I., et al. NAFLD prevalence differs among Hispanic subgroups: the multi-ethnic study of atherosclerosis. World J Gastroenterol 20 (2014), 4987-4993.
8. 8 Kallwitz, E.R., Daviglus, M.L., Allison, M.A., et al. Prevalence of suspected nonalcoholic fatty liver disease in Hispanic/Latino individuals differs by heritage. Clin Gastroenterol Hepatol 13 (2015), 569-576.
9. 9 Saab, S., Manne, V., Nieto, J., et al. Nonalcoholic fatty liver disease in Latinos. Clin Gastroenterol Hepatol 14 (2016), 5-12 [quiz: e9-10].
10. 10 Charlton, M.R., Burns, J.M., Pedersen, R.A., et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the united states. Gastroenterology 141 (2011), 1249-1253.
11. 11 Rafiq, N., Bai, C., Fang, Y., et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol 7 (2009), 234-238.
12. 12 Grundy, S.M., Cleeman, J.I., Daniels, S.R., et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation 112 (2005), 2735-2752.
13. 13 Liu, J., Grundy, S.M., Wang, W., et al. Ethnic-specific criteria for the metabolic syndrome: evidence from china. Diabetes Care 29 (2006), 1414-1416.
14. 14 Marchesini, G., Bugianesi, E., Forlani, G., et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37 (2003), 917-923.
15. 15 Lonardo, A., Ballestri, S., Marchesini, G., et al. Nonalcoholic fatty liver disease: a precursor of the metabolic syndrome. Dig Liver Dis 47 (2015), 181-190.
16. 16 Pelchat, M.L., Johnson, A., Chan, R., et al. Images of desire: food-craving activation during fMRI. Neuroimage 23 (2004), 1486-1493.
17. 17 Kelley, A.E., Bakshi, V.P., Haber, S.N., et al. Opioid modulation of taste hedonics within the ventral striatum. Physiol Behav 76 (2002), 365-377.
18. 18 Page, K.A., Chan, O., Arora, J., et al. Effects of fructose vs glucose on regional cerebral blood flow in brain regions involved with appetite and reward pathways. JAMA 309 (2013), 63-70.
19. 19 Teff, K.L., Elliott, S.S., Tschop, M., et al. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab 89 (2004), 2963-2972.
20. 20 Ahima, R.S., Flier, J.S., Leptin. Annu Rev Physiol 62 (2000), 413-437.
21. 21 Buechler, C., Wanninger, J., Neumeier, M., Adiponectin, a key adipokine in obesity related liver diseases. World J Gastroenterol 17 (2011), 2801-2811.
22. 22 Chitturi, S., Farrell, G., Frost, L., et al. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity?. Hepatology 36 (2002), 403-409.
23. 23 Targher, G., Bertolini, L., Rodella, S., et al. Associations between plasma adiponectin concentrations and liver histology in patients with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf) 64 (2006), 679-683.
24. 24 Armstrong, M.J., Gaunt, P., Aithal, G.P., et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387 (2016), 679-690.
25. 25 Kang, H., Greenson, J.K., Omo, J.T., et al. Metabolic syndrome is associated with greater histologic severity, higher carbohydrate, and lower fat diet in patients with NAFLD. Am J Gastroenterol 101 (2006), 2247-2253.
26. 26 Musso, G., Gambino, R., De Michieli, F., et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 37 (2003), 909-916.
27. 27 Lai, H.S., Lin, W.H., Chen, P.R., et al. Effects of a high-fiber diet on hepatocyte apoptosis and liver regeneration after partial hepatectomy in rats with fatty liver. JPEN J Parenter Enteral Nutr 29 (2005), 401-407.
28. 28 Sullivan, S., Implications of diet on nonalcoholic fatty liver disease. Curr Opin Gastroenterol 26 (2010), 160-164.
29. 29 Festi, D., Schiumerini, R., Eusebi, L.H., et al. Gut microbiota and metabolic syndrome. World J Gastroenterol 20 (2014), 16079-16094.
30. 30 Ouyang, X., Cirillo, P., Sautin, Y., et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol 48 (2008), 993-999.
31. 31 Abid, A., Taha, O., Nseir, W., et al. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome. J Hepatol 51 (2009), 918-924.
32. 32 Mouzaki, M., Comelli, E.M., Arendt, B.M., et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 58 (2013), 120-127.
33. 33 Miele, L., Valenza, V., La Torre, G., et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49 (2009), 1877-1887.
34. 34 Giorgio, V., Miele, L., Principessa, L., et al. Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity. Dig Liver Dis 46 (2014), 556-560.
35. 35 Fu, Z., Gilbert, E.R., Liu, D., Regulation of insulin synthesis and secretion and pancreatic beta-cell dysfunction in diabetes. Curr Diabetes Rev 9 (2013), 25-53.
36. 36 McGarry, J.D., What if Minkowski had been ageusic? An alternative angle on diabetes. Science 258 (1992), 766-770.
37. 37 Gao, B., Tsukamoto, H., Inflammation in alcoholic and nonalcoholic fatty liver disease: friend or foe?. Gastroenterology 150 (2016), 1704-1709.
38. 38 Makkonen, J., Pietilainen, K.H., Rissanen, A., et al. Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: a study in monozygotic and dizygotic twins. J Hepatol 50 (2009), 1035-1042.
39. 39 Jenkins, C.M., Mancuso, D.J., Yan, W., et al. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase a2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J Biol Chem 279 (2004), 48968-48975.
40. 40 He, S., McPhaul, C., Li, J.Z., et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem 285 (2010), 6706-6715.
41. 41 Speliotes, E.K., Butler, J.L., Palmer, C.D., et al. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 52 (2010), 904-912.
42. 42 Romeo, S., Kozlitina, J., Xing, C., et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 40 (2008), 1461-1465.
43. 43 Sookoian, S., Pirola, C.J., 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 53 (2011), 1883-1894.
44. 44 Santoro, N., Kursawe, R., D'Adamo, E., et al. A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology 52 (2010), 1281-1290.
45. 45 Hernaez, R., McLean, J., Lazo, M., et al. Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the third National Health and Nutrition Examination Survey. Clin Gastroenterol Hepatol 11 (2013), 1183-1190.e2.
46. 46 Basantani, M.K., Sitnick, M.T., Cai, L., et al. PNPLA3/adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. J Lipid Res 52 (2011), 318-329.
47. I148M in mouse liver causes hepatic steatosis. J Clin Invest 122 (2012), 4130-4144.
48. 48 Smagris, E., BasuRay, S., Li, J., et al. PNPLA3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 61 (2015), 108-118.
49. 49 Speliotes, E.K., Yerges-Armstrong, L.M., Wu, J., et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet, 7, 2011, e1001324.
50. 50 Palmer, N.D., Musani, S.K., Yerges-Armstrong, L.M., et al. Characterization of European ancestry nonalcoholic fatty liver disease-associated variants in individuals of African and Hispanic descent. Hepatology 58 (2013), 966-975.
51. 51 Fracanzani, A.L., Valenti, L., Bugianesi, E., et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology 48 (2008), 792-798.
52. 52 Verma, S., Jensen, D., Hart, J., et al. Predictive value of ALT levels for non-alcoholic steatohepatitis (NASH) and advanced fibrosis in non-alcoholic fatty liver disease (NAFLD). Liver Int 33 (2013), 1398-1405.
53. 53 Adams, L.A., Lindor, K.D., Angulo, P., The prevalence of autoantibodies and autoimmune hepatitis in patients with nonalcoholic fatty liver disease. Am J Gastroenterol 99 (2004), 1316-1320.
54. 54 Cotler, S.J., Kanji, K., Keshavarzian, A., et al. Prevalence and significance of autoantibodies in patients with non-alcoholic steatohepatitis. J Clin Gastroenterol 38 (2004), 801-804.
55. 55 Loria, P., Lonardo, A., Leonardi, F., et al. Non-organ-specific autoantibodies in nonalcoholic fatty liver disease: prevalence and correlates. Dig Dis Sci 48 (2003), 2173-2181.
56. 56 Lee, S.S., Park, S.H., Kim, H.J., et al. Non-invasive assessment of hepatic steatosis: prospective comparison of the accuracy of imaging examinations. J Hepatol 52 (2010), 579-585.
57. 57 Saadeh, S., Younossi, Z.M., Remer, E.M., et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 123 (2002), 745-750.
58. 58 Feldstein, A.E., Wieckowska, A., Lopez, A.R., et al. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 50 (2009), 1072-1078.
59. 59 Angulo, P., Hui, J.M., Marchesini, G., et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 45 (2007), 846-854.
60. 60 Castera, L., Foucher, J., Bernard, P.H., et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 51 (2010), 828-835.
61. 61 Rinaldi, L., Restivo, L., Guerrera, B., et al. Hepatic steatosis and necro-inflammatory activity overestimate liver stiffness by transient elastography in staging liver fibrosis in chronic hepatitis c. J Hepat Res, 1, 2014, 1012.
62. 62 Myers, R.P., Pomier-Layrargues, G., Kirsch, R., et al. Feasibility and diagnostic performance of the FibroScan XL probe for liver stiffness measurement in overweight and obese patients. Hepatology 55 (2012), 199-208.
63. 63 Imajo, K., Kessoku, T., Honda, Y., et al. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology 150 (2016), 626-637.e7.
64. 64 Rockey, D.C., Caldwell, S.H., Goodman, Z.D., et al. Liver biopsy. Hepatology 49 (2009), 1017-1044.
65. 65 Booth, S.L., Golly, I., Sacheck, J.M., et al. Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status. Am J Clin Nutr 80 (2004), 143-148.
66. 66 Angulo, P., Kleiner, D.E., Dam-Larsen, S., et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149 (2015), 389-397.e10.
67. 67 Carr, R.M., Ahima, R.S., Pathophysiology of lipid droplet proteins in liver diseases. Exp Cell Res 340 (2016), 187-192.
68. 68 Straub, B.K., Gyoengyoesi, B., Koenig, M., et al. Adipophilin/perilipin-2 as a lipid droplet-specific marker for metabolically active cells and diseases associated with metabolic dysregulation. Histopathology 62 (2013), 617-631.
69. 69 Straub, B.K., Stoeffel, P., Heid, H., et al. Differential pattern of lipid droplet-associated proteins and de novo perilipin expression in hepatocyte steatogenesis. Hepatology 47 (2008), 1936-1946.
70. 70 Carr, R.M., Patel, R.T., Rao, V., et al. Reduction of TIP47 improves hepatic steatosis and glucose homeostasis in mice. Am J Physiol Regul Integr Comp Physiol 302 (2012), R996-R1003.
71. 71 Kleiner, D.E., Brunt, E.M., Van Natta, M., et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41 (2005), 1313-1321.
72. 72 Ratziu, V., Charlotte, F., Heurtier, A., et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 128 (2005), 1898-1906.
73. 73 Promrat, K., Kleiner, D.E., Niemeier, H.M., et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 51 (2010), 121-129.
74. 74 Vilar-Gomez, E., Martinez-Perez, Y., Calzadilla-Bertot, L., et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 149 (2015), 367-378.e5 [quiz: e314-65].
75. 75 Paradis, V., Zalinski, S., Chelbi, E., et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 49 (2009), 851-859.
76. 76 Belfort, R., Harrison, S.A., Brown, K., et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 355 (2006), 2297-2307.
77. 77 Chalasani, N.P., Sanyal, A.J., Kowdley, K.V., et al. Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design. Contemp Clin Trials 30 (2009), 88-96.
78. 78 Carr, R.M., Reid, A.E., FXR agonists as therapeutic agents for non-alcoholic fatty liver disease. Curr Atheroscler Rep, 17, 2015, 500.
79. 79 Neuschwander-Tetri, B.A., Loomba, R., Sanyal, A.J., et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385 (2015), 956-965.
80. 80 Clinical trials.Gov. 2016. Available at: https://clinicaltrials.gov/ct2/show/NCT02548351.
81. 81 Ratziu, V., Harrison, S.A., Francque, S., et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150 (2016), 1147-1159.e5.
82. 82 Lassailly, G., Caiazzo, R., Buob, D., et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology 149 (2015), 379-388 [quiz: e315-376].
83. 83 Abu Dayyeh, B.K., Edmundowicz, S.A., Jonnalagadda, S., et al. Endoscopic bariatric therapies. Gastrointest Endosc 81 (2015), 1073-1086.
84. 84 Gorden, A., Yang, R., Yerges-Armstrong, L.M., et al. Genetic variation at NCAN locus is associated with inflammation and fibrosis in non-alcoholic fatty liver disease in morbid obesity. Hum Hered 75 (2013), 34-43.
85. 85 Sookoian, S., Pirola, C.J., Meta-analysis of the influence of TM6SF2 E167K variant on plasma concentration of aminotransferases across different populations and diverse liver phenotypes. Sci Rep, 6, 2016, 27718.