Endocrinol Metab.  2020 Jun;35(2):243-259. 10.3803/EnM.2020.35.2.243.

Noninvasive Evaluation of Nonalcoholic Fatty Liver Disease

Affiliations
  • 1Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver diseases and can progress to advanced fibrosis and end-stage liver disease. Thus, intensive research has been performed to develop noninvasive methods for the diagnosis of nonalcoholic steatohepatitis (NASH) and fibrosis. Currently, no single noninvasive tool covers all of the stages of pathologies and conditions of NAFLD, and the cost and feasibility of known techniques are also important issues. Blood biomarkers for NAFLD may be useful to select subjects who need ultrasonography (US) screening for NAFLD, and noninvasive tools for assessing fibrosis may be helpful to exclude the probability of significant fibrosis and to predict advanced fibrosis, thus guiding the decision of whether to perform liver biopsy in patients with NAFLD. Among various methods, magnetic resonance-based methods have been shown to perform better than other methods in assessing steatosis as well as in detecting hepatic fibrosis. Many genetic markers are associated with the development and progression of NAFLD. Further well-designed studies are needed to determine which biomarker panels, imaging studies, genetic marker panels, or combinations thereof perform well for diagnosing NAFLD, differentiating NASH and fibrosis, and following-up NAFLD, respectively.

Keyword

Evaluation; Non-alcoholic fatty liver disease; Liver steatosis; Fibrosis; Biomarkers

Figure

  • Fig. 1 Diagrams of spectrum obtained by hepatic proton magnetic resonance spectroscopy (1H-MRS). Proton spectra obtained from normal (A) and fatty (B) livers show resonance peaks from water and triglyceride (TG), with boxes highlighting the dominant lipid peaks from the resonance of methyl (−CH3) protons and methylene (−(CH2)n−) in the TG molecule along the frequency domain. ppm, parts per million.

  • Fig. 2 Hepatic magnetic resonance imaging (MRI)-proton density fat fraction (PDFF). Liver MRI-PDFF study in a patient with nonalcoholic fatty liver disease (NAFLD) showing. (A, B) T1-weighted magnetic resonance images showing the automatic capturing of the liver and (C) the summary of results that shows PDFF of the whole liver (13.2%) as well as R2* value (as a marker for liver iron content). R2* values of <126 S−1 are normal at 3T scanner examination [41].

  • Fig. 3 Hepatic magnetic resonance elastography (MRE). Liver MRE study in a patient with nonalcoholic fatty liver disease showing: (A) magnitude image, (B) phase contrast, (C) wave image, (D, E) gray and color scale stiffness maps (elastograms), and (F) color stiffness map with overlayed confidence map.

  • Fig. 4 Algorithm for nonalcoholic fatty liver disease (NAFLD) evaluation. Calculations: NFS=−1.675+0.037×age (yr)+0.094×BMI (kg/m2)+1.13×IFG/DM (yes=1, no=0)+0.99×AST/ALT ratio–0.013×platelet (×109/L)–0.66×albumin (g/dL); FIB-4=(age×AST)/[PLT(×109/L)×(√ALT)]; APRI=[AST (IU/L)/ULN/PLT(×109/L)]×100. MS, metabolic syndrome; IR, insulin resistance; DM, diabetes mellitus; US, ultrasonography; FIB-4, fibrosis-4; NFS, NAFLD Fibrosis Score; APRI, AST to platelet ratio index; ELF, enhanced liver fibrosis; VCTE, vibration-controlled transient elastography; MRE, magnetic resonance elastography. aHigher cutoffs for patients aged >65 years; bAffected by body factors and suggested cutoff values have been variable; cFurther validation is required.


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Reference

1. Allen AM, Therneau TM, Larson JJ, Coward A, Somers VK, Kamath PS. Nonalcoholic fatty liver disease incidence and impact on metabolic burden and death: a 20 year-community study. Hepatology. 2018; 67:1726–36.
Article
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.
Article
3. Park SH, Jeon WK, Kim SH, Kim HJ, Park DI, Cho YK, et al. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol. 2006; 21(1 Pt 1):138–43.
Article
4. Jeong EH, Jun DW, Cho YK, Choe YG, Ryu S, Lee SM, et al. Regional prevalence of non-alcoholic fatty liver disease in Seoul and Gyeonggi-do, Korea. Clin Mol Hepatol. 2013; 19:266–72.
Article
5. Portillo-Sanchez P, Bril F, Maximos M, Lomonaco R, Biernacki D, Orsak B, et al. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab. 2015; 100:2231–8.
Article
6. 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; 140:124–31.
Article
7. 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.
Article
8. 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; 40:1387–95.
Article
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; 44:865–73.
Article
10. Athyros VG, Alexandrides TK, Bilianou H, Cholongitas E, Doumas M, Ganotakis ES, et al. The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement. Metabolism. 2017; 71:17–32.
Article
11. Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2005; 288:E462–8.
Article
12. 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; 65:1132–44.
Article
13. Stefan N, Haring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol. 2019; 7:313–24.
Article
14. Wildman-Tobriner B, Middleton MM, Moylan CA, Rossi S, Flores O, Chang ZA, et al. Association between magnetic resonance imaging-proton density fat fraction and liver histology features in patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis. Gastroenterology. 2018; 155:1428–35.
15. Nasr P, Forsgren MF, Ignatova S, Dahlstrom N, Cedersund G, Leinhard OD, et al. Using a 3% proton density fat fraction as a cut-off value increases sensitivity of detection of hepatic steatosis, based on results from histopathology analysis. Gastroenterology. 2017; 153:53–5.
Article
16. Lee YH, Cho Y, Lee BW, Park CY, Lee DH, Cha BS, et al. Nonalcoholic fatty liver disease in diabetes. Part I: epidemiology and diagnosis. Diabetes Metab J. 2019; 43:31–45.
Article
17. Permutt Z, Le TA, Peterson MR, Seki E, Brenner DA, Sirlin C, et al. Correlation between liver histology and novel magnetic resonance imaging in adult patients with non-alcoholic fatty liver disease: MRI accurately quantifies hepatic steatosis in NAFLD. Aliment Pharmacol Ther. 2012; 36:22–9.
18. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med. 2001; 344:495–500.
Article
19. Wong VW, Chalasani N. Not routine screening, but vigilance for chronic liver disease in patients with type 2 diabetes. J Hepatol. 2016; 64:1211–3.
Article
20. Corey KE, Klebanoff MJ, Tramontano AC, Chung RT, Hur C. Screening for nonalcoholic steatohepatitis in individuals with type 2 diabetes: a cost-effectiveness analysis. Dig Dis Sci. 2016; 61:2108–17.
Article
21. Soderberg C, Stal P, Askling J, Glaumann H, Lindberg G, Marmur J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010; 51:595–602.
Article
22. Rafiq N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009; 7:234–8.
Article
23. Taylor RS, Taylor RJ, Bayliss S, Hagstrom H, Nasr P, Schattenberg JM, et al. Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Gastroenterology. 2020; 158:1611–25.
Article
24. 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; 61:1547–54.
Article
25. 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; 149:389–97.
Article
26. 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; 67:1265–73.
27. Hagstrom H, Nasr P, Ekstedt M, Hammar U, Stal P, Hultcrantz R, et al. Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: a long-term follow-up study. Hepatol Commun. 2017; 2:48–57.
28. Grgurevic I, Podrug K, Mikolasevic I, Kukla M, Madir A, Tsochatzis EA. Natural history of nonalcoholic fatty liver disease: implications for clinical practice and an individualized approach. Can J Gastroenterol Hepatol. 2020; 2020:9181368.
Article
29. Zhou JH, Cai JJ, She ZG, Li HL. Noninvasive evaluation of nonalcoholic fatty liver disease: current evidence and practice. World J Gastroenterol. 2019; 25:1307–26.
Article
30. Bannas P, Kramer H, Hernando D, Agni R, Cunningham AM, Mandal R, et al. Quantitative magnetic resonance imaging of hepatic steatosis: validation in ex vivo human livers. Hepatology. 2015; 62:1444–55.
31. Kechagias S, Nasr P, Blomdahl J, Ekstedt M. Established and emerging factors affecting the progression of nonalcoholic fatty liver disease. Metabolism. 2020; Feb. 14. [Epub]. https://doi.org/10.1016/j.metabol.2020.154183.
Article
32. Gunn NT, Shiffman ML. The use of liver biopsy in nonalcoholic fatty liver disease: when to biopsy and in whom. Clin Liver Dis. 2018; 22:109–19.
33. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980; 55:434–8.
34. 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. Diabetologia. 2016; 59:1121–40.
35. Newsome PN, Cramb R, Davison SM, Dillon JF, Foulerton M, Godfrey EM, et al. Guidelines on the management of abnormal liver blood tests. Gut. 2018; 67:6–19.
Article
36. Bhatia LS, Curzen NP, Calder PC, Byrne CD. Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor? Eur Heart J. 2012; 33:1190–200.
Article
37. Prati D, Colli A, Conte D, Colombo M. Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women. Hepatology. 2005; 42:1460–1.
Article
38. Kwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017; 112:18–35.
Article
39. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018; 67:1560–99.
Article
40. Cotter TG, Rinella M. Nonalcoholic fatty liver disease 2020: the state of the disease. Gastroenterology. 2020; 158:1851–64.
Article
41. Bashir MR, Wolfson T, Gamst AC, Fowler KJ, Ohliger M, Shah SN, et al. Hepatic R2* is more strongly associated with proton density fat fraction than histologic liver iron scores in patients with nonalcoholic fatty liver disease. J Magn Reson Imaging. 2019; 49:1456–66.
Article
42. 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.
Article
43. 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.
Article
44. Bedogni G, Kahn HS, Bellentani S, Tiribelli C. A simple index of lipid overaccumulation is a good marker of liver steatosis. BMC Gastroenterol. 2010; 10:98.
Article
45. Poynard T, Ratziu V, Naveau S, Thabut D, Charlotte F, Messous D, et al. The diagnostic value of biomarkers (SteatoTest) for the prediction of liver steatosis. Comp Hepatol. 2005; 4:10.
46. 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.
Article
47. Kahn HS. The “lipid accumulation product” performs better than the body mass index for recognizing cardiovascular risk: a population-based comparison. BMC Cardiovasc Disord. 2005; 5:26.
Article
48. Zhou YJ, Zhou YF, Zheng JN, Liu WY, Van Poucke S, Zou TT, et al. NAFL screening score: a basic score identifying ultrasound-diagnosed non-alcoholic fatty liver. Clin Chim Acta. 2017; 475:44–50.
Article
49. Kabisch S, Bather S, Dambeck U, Kemper M, Gerbracht C, Honsek C, et al. Liver fat scores moderately reflect interventional changes in liver fat content by a low-fat diet but not by a low-carb diet. Nutrients. 2018; 10:157.
Article
50. Bril F, Ortiz-Lopez C, Lomonaco R, Orsak B, Freckleton M, Chintapalli K, et al. Clinical value of liver ultrasound for the diagnosis of nonalcoholic fatty liver disease in overweight and obese patients. Liver Int. 2015; 35:2139–46.
Article
51. Ryan CK, Johnson LA, Germin BI, Marcos A. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation. Liver Transpl. 2002; 8:1114–22.
Article
52. Chartampilas E. Imaging of nonalcoholic fatty liver disease and its clinical utility. Hormones (Athens). 2018; 17:69–81.
Article
53. Piekarski J, Goldberg HI, Royal SA, Axel L, Moss AA. Difference between liver and spleen CT numbers in the normal adult: its usefulness in predicting the presence of diffuse liver disease. Radiology. 1980; 137:727–9.
Article
54. Park SH, Kim PN, Kim KW, Lee SW, Yoon SE, Park SW, et al. Macrovesicular hepatic steatosis in living liver donors: use of CT for quantitative and qualitative assessment. Radiology. 2006; 239:105–12.
Article
55. Ozturk A, Grajo JR, Dhyani M, Anthony BW, Samir AE. Principles of ultrasound elastography. Abdom Radiol (NY). 2018; 43:773–85.
Article
56. Mikolasevic I, Orlic L, Franjic N, Hauser G, Stimac D, Milic S. Transient elastography (FibroScan(®)) with controlled attenuation parameter in the assessment of liver steatosis and fibrosis in patients with nonalcoholic fatty liver disease: where do we stand? World J Gastroenterol. 2016; 22:7236–51.
57. Caussy C, Alquiraish MH, Nguyen P, Hernandez C, Cepin S, Fortney LE, et al. Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis. Hepatology. 2018; 67:1348–59.
Article
58. Karlas T, Petroff D, Sasso M, Fan JG, Mi YQ, de Ledinghen V, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol. 2017; 66:1022–30.
Article
59. Cassinotto C, Boursier J, de Ledinghen V, Lebigot J, Lapuyade B, Cales P, et al. Liver stiffness in nonalcoholic fatty liver disease: a comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatology. 2016; 63:1817–27.
Article
60. Siddiqui MS, Vuppalanchi R, Van Natta ML, Hallinan E, Kowdley KV, Abdelmalek M, et al. Vibration-controlled transient elastography to assess fibrosis and steatosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2019; 17:156–63.
Article
61. Petta S, Ciminnisi S, Di Marco V, Cabibi D, Camma C, Licata A, et al. Sarcopenia is associated with severe liver fibrosis in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2017; 45:510–8.
Article
62. Shen F, Zheng RD, Shi JP, Mi YQ, Chen GF, Hu X, et al. Impact of skin capsular distance on the performance of controlled attenuation parameter in patients with chronic liver disease. Liver Int. 2015; 35:2392–400.
Article
63. Vuppalanchi R, Siddiqui MS, Van Natta ML, Hallinan E, Brandman D, Kowdley K, et al. Performance characteristics of vibration-controlled transient elastography for evaluation of nonalcoholic fatty liver disease. Hepatology. 2018; 67:134–44.
Article
64. Qayyum A. MR spectroscopy of the liver: principles and clinical applications. Radiographics. 2009; 29:1653–64.
Article
65. Dulai PS, Sirlin CB, Loomba R. MRI and MRE for non-invasive quantitative assessment of hepatic steatosis and fibrosis in NAFLD and NASH: clinical trials to clinical practice. J Hepatol. 2016; 65:1006–16.
Article
66. Lee SS, Park SH. Radiologic evaluation of nonalcoholic fatty liver disease. World J Gastroenterol. 2014; 20:7392–402.
Article
67. Noureddin M, Lam J, Peterson MR, Middleton M, Hamilton G, Le TA, et al. Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials. Hepatology. 2013; 58:1930–40.
Article
68. Patel J, Bettencourt R, Cui J, Salotti J, Hooker J, Bhatt A, et al. Association of noninvasive quantitative decline in liver fat content on MRI with histologic response in nonalcoholic steatohepatitis. Therap Adv Gastroenterol. 2016; 9:692–701.
Article
69. Le TA, Chen J, Changchien C, Peterson MR, Kono Y, Patton H, et al. Effect of colesevelam on liver fat quantified by magnetic resonance in nonalcoholic steatohepatitis: a randomized controlled trial. Version 2. Hepatology. 2012; 56:922–32.
70. Capitan V, Petit JM, Aho S, Lefevre PH, Favelier S, Loffroy R, et al. Macroscopic heterogeneity of liver fat: an MR-based study in type-2 diabetic patients. Eur Radiol. 2012; 22:2161–8.
Article
71. Kim KY, Song JS, Kannengiesser S, Han YM. Hepatic fat quantification using the proton density fat fraction (PDFF): utility of free-drawn-PDFF with a large coverage area. Radiol Med. 2015; 120:1083–93.
Article
72. Venkatesh SK, Yin M, Ehman RL. Magnetic resonance elastography of liver: technique, analysis, and clinical applications. J Magn Reson Imaging. 2013; 37:544–55.
Article
73. Ajmera VH, Liu A, Singh S, Yachoa G, Ramey M, Bhargava M, et al. Clinical utility of an increase in magnetic resonance elastography in predicting fibrosis progression in nonalcoholic fatty liver disease. Hepatology. 2020; 71:849–60.
Article
74. Singh S, Venkatesh SK, Loomba R, Wang Z, Sirlin C, Chen J, et al. Magnetic resonance elastography for staging liver fibrosis in non-alcoholic fatty liver disease: a diagnostic accuracy systematic review and individual participant data pooled analysis. Eur Radiol. 2016; 26:1431–40.
Article
75. Kim D, Kim WR, Talwalkar JA, Kim HJ, Ehman RL. Advanced fibrosis in nonalcoholic fatty liver disease: noninvasive assessment with MR elastography. Radiology. 2013; 268:411–9.
Article
76. 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. Version 2. Hepatology. 2014; 60:1920–8.
77. Jayakumar S, Middleton MS, Lawitz EJ, Mantry PS, Caldwell SH, Arnold H, et al. Longitudinal correlations between MRE, MRI-PDFF, and liver histology in patients with non-alcoholic steatohepatitis: analysis of data from a phase II trial of selonsertib. J Hepatol. 2019; 70:133–41.
Article
78. Serai SD, Obuchowski NA, Venkatesh SK, Sirlin CB, Miller FH, Ashton E, et al. Repeatability of MR elastography of liver: a meta-analysis. Radiology. 2017; 285:92–100.
79. 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; 59:550–6.
Article
80. 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; 13:643–54.
Article
81. Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H, et al. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology. 2016; 150:626–37.
Article
82. Loomba R, Sirlin CB, Ang B, Bettencourt R, Jain R, Salotti J, et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology. 2015; 61:1239–50.
Article
83. 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; 155:443–57.
Article
84. Lichtinghagen R, Pietsch D, Bantel H, Manns MP, Brand K, Bahr MJ. The Enhanced Liver Fibrosis (ELF) score: normal values, influence factors and proposed cut-off values. J Hepatol. 2013; 59:236–42.
Article
85. Tada T, Kumada T, Toyoda H, Saibara T, Ono M, Kage M. New scoring system combining the FIB-4 index and cytokeratin-18 fragments for predicting steatohepatitis and liver fibrosis in patients with nonalcoholic fatty liver disease. Biomarkers. 2018; 23:328–34.
Article
86. Krawczyk M, Liebe R, Lammert F. Toward genetic prediction of nonalcoholic fatty liver disease trajectories: PNPLA3 and beyond. Gastroenterology. 2020; 158:1865–80.
Article
87. 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; 149:1784–93.
Article
88. Krawczyk M, Rau M, Schattenberg JM, Bantel H, Pathil A, Demir M, et al. Combined effects of the PNPLA3 rs 738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study. J Lipid Res. 2017; 58:247–55.
89. Koo BK, Joo SK, Kim D, Bae JM, Park JH, Kim JH, et al. Additive effects of PNPLA3 and TM6SF2 on the histological severity of non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2018; 33:1277–85.
Article
90. 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
91. Del Campo JA, Gallego-Duran R, Gallego P, Grande L. Genetic and epigenetic regulation in nonalcoholic fatty liver disease (NAFLD). Int J Mol Sci. 2018; 19:911.
Article
92. Liu DJ, Peloso GM, Yu H, Butterworth AS, Wang X, Mahajan A, et al. Exome-wide association study of plasma lipids in >300,000 individuals. Nat Genet. 2017; 49:1758–66.
93. Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med. 2017; 377:2063–72.
Article
94. Sayiner M, Koenig A, Henry L, Younossi ZM. Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in the United States and the rest of the world. Clin Liver Dis. 2016; 20:205–14.
Article
95. BasuRay S, Smagris E, Cohen JC, Hobbs HH. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Version 2. Hepatology. 2017; 66:1111–24.
96. 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; 61:75–81.
97. 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; 49:842–7.
Article
98. Diogo D, Tian C, Franklin CS, Alanne-Kinnunen M, March M, Spencer CCA, et al. Phenome-wide association studies across large population cohorts support drug target validation. Nat Commun. 2018; 9:4285.
Article
99. Sookoian S, Castano GO, Scian R, Mallardi P, Fernandez Gianotti T, Burgueno AL, et al. Genetic variation in transmembrane 6 superfamily member 2 and the risk of nonalcoholic fatty liver disease and histological disease severity. Hepatology. 2015; 61:515–25.
Article
100. Zhou Y, Llaurado G, Oresic M, Hyotylainen T, Orho-Melander M, Yki-Jarvinen H. Circulating triacylglycerol signatures and insulin sensitivity in NAFLD associated with the E167K variant in TM6SF2. J Hepatol. 2015; 62:657–63.
Article
101. Kahali B, Liu YL, Daly AK, Day CP, Anstee QM, Speliotes EK. TM6SF2: catch-22 in the fight against nonalcoholic fatty liver disease and cardiovascular disease? Gastroenterology. 2015; 148:679–84.
Article
102. Thabet K, Asimakopoulos A, Shojaei M, Romero-Gomez M, Mangia A, Irving WL, et al. MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C. Nat Commun. 2016; 7:12757.
Article
103. Thabet K, Chan HLY, Petta S, Mangia A, Berg T, Boonstra A, et al. The membrane-bound O-acyltransferase domain-containing 7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B. Hepatology. 2017; 65:1840–50.
Article
104. 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; 150:1219–30.
Article
105. Buch S, Stickel F, Trepo E, Way M, Herrmann A, Nischalke HD, et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat Genet. 2015; 47:1443–8.
Article
106. 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; 7:4492.
Article
107. Yamashita A, Hayashi Y, Nemoto-Sasaki Y, Ito M, Oka S, Tanikawa T, et al. Acyltransferases and transacylases that determine the fatty acid composition of glycerolipids and the metabolism of bioactive lipid mediators in mammalian cells and model organisms. Prog Lipid Res. 2014; 53:18–81.
Article
108. D’Souza K, Epand RM. Enrichment of phosphatidylinositols with specific acyl chains. Biochim Biophys Acta. 2014; 1838:1501–8.
109. Luukkonen PK, Zhou Y, Hyotylainen T, Leivonen M, Arola J, Orho-Melander M, et al. The MBOAT7 variant rs641738 alters hepatic phosphatidylinositols and increases severity of non-alcoholic fatty liver disease in humans. J Hepatol. 2016; 65:1263–5.
Article
110. Zarini S, Hankin JA, Murphy RC, Gijon MA. Lysophospholipid acyltransferases and eicosanoid biosynthesis in zebrafish myeloid cells. Prostaglandins Other Lipid Mediat. 2014; 113–115:52–61.
Article
111. Perez-Chacon G, Astudillo AM, Balgoma D, Balboa MA, Balsinde J. Control of free arachidonic acid levels by phospholipases A2 and lysophospholipid acyltransferases. Biochim Biophys Acta. 2009; 1791:1103–13.
112. Brouwers MCGJ, Jacobs C, Bast A, Stehouwer CDA, Schaper NC. Modulation of glucokinase regulatory protein: a double-edged sword? Trends Mol Med. 2015; 21:583–94.
Article
113. Sliz E, Sebert S, Wurtz P, Kangas AJ, Soininen P, Lehtimaki T, et al. NAFLD risk alleles in PNPLA3, TM6SF2, GCKR and LYPLAL1 show divergent metabolic effects. Hum Mol Genet. 2018; 27:2214–23.
Article
114. Danford CJ, Yao ZM, Jiang ZG. Non-alcoholic fatty liver disease: a narrative review of genetics. J Biomed Res. 2018; 32:389–400.
115. Kawaguchi T, Shima T, Mizuno M, Mitsumoto Y, Umemura A, Kanbara Y, et al. Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers. PLoS One. 2018; 13:e0185490.
Article
116. 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; 378:1096–106.
117. Ma Y, Belyaeva OV, Brown PM, Fujita K, Valles K, Karki S, et al. 17-Beta hydroxysteroid dehydrogenase 13 is a hepatic retinol dehydrogenase associated with histological features of nonalcoholic fatty liver disease. Hepatology. 2019; 69:1504–19.
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