Overview of the Pathogenesis, Genetic, and Non-Invasive Clinical, Biochemical, and Scoring Methods in the Assessment of NAFLD
Abstract
:1. Background
2. Pathophysiology of NAFLD
3. Clinical Evaluation of NAFLD
4. Laboratory Evaluation of NAFLD
4.1. Routine Markers of Liver Injury and Metabolic Syndrome
4.2. Markers of Inflammation
4.3. Markers of Oxidative Stress
4.4. Markers of Apoptosis
4.5. Markers of Fibrogenesis
5. Differentiation of Steatosis, Steatohepatitis, and Fibrosis
6. Genetical Evaluation and Multi-Omics Profiles of NAFLD
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Lonardo, A.; Nascimbeni, F.; Targher, G.; Bernardi, M.; Bonino, F.; Bugianesi, E.; Casini, A.; Gastaldelli, A.; Marchesini, G.; Marra, F.; et al. AISF position paper on nonalcoholic fatty liver disease (NAFLD): Updates and future directions. Dig. Liver Dis. 2017, 49, 471–483. [Google Scholar] [CrossRef] [PubMed]
- Lonardo, A.; Nascimbeni, F.; Mantovani, A.; Targher, G. Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence? J. Hepatol. 2018, 68, 335–352. [Google Scholar] [CrossRef] [PubMed]
- 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. 2011, 34, 274–285. [Google Scholar] [CrossRef] [PubMed]
- George, E.S.; Roberts, S.K.; Nicoll, A.J.; Reddy, A.; Paris, T.; Itsiopoulos, C.; Tierney, A.C. Non-alcoholic fatty liver disease patients attending two metropolitan hospitals in Melbourne, Australia: High risk status and low prevalence. Intern. Med. J. 2018, 48, 1369–1376. [Google Scholar] [CrossRef] [PubMed]
- Sanal, M.G. Biomarkers in nonalcoholic fatty liver disease-the emperor has no clothes? World J. Gastroenterol. 2015, 21, 3223–3231. [Google Scholar] [CrossRef] [PubMed]
- Hu, X.Y.; Li, Y.; Li, L.Q.; Zheng, Y.; Lv, J.H.; Huang, S.C.; Zhang, W.; Liu, L.; Zhao, L.; Liu, Z.; et al. Risk factors and biomarkers of non-alcoholic fatty liver disease: An observational cross-sectional population survey. BMJ Open 2018, 8, e019974. [Google Scholar] [CrossRef] [PubMed]
- Mazzoccoli, G.; De Cosmo, S.; Mazza, T. The Biological Clock: A Pivotal Hub in Non-alcoholic Fatty Liver Disease Pathogenesis. Front. Physiol. 2018, 9, 193. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Oikonomou, D.; Georgiopoulos, G.; Katsi, V.; Kourek, C.; Tsioufis, C.; Alexopoulou, A.; Koutli, E.; Tousoulis, D. Non-alcoholic fatty liver disease and hypertension: Coprevalent or correlated? Eur. J. Gastroenterol. Hepatol. 2018, 30, 979–985. [Google Scholar] [CrossRef] [PubMed]
- Harada, P.H.; Bensenõr, I.J.M.; Drager, L.F.; Goulart, A.C.; Mill, J.G.; Lotufo, P.A. Non-alcoholic fatty liver disease presence and severity are associated with aortic stiffness beyond abdominal obesity: The ELSA-Brasil. Atherosclerosis 2019, 284, 59–65. [Google Scholar] [CrossRef]
- Tellez-Plaza, M.; Briongos-Figuero, L.; Pichler, G.; Dominguez-Lucas, A.; Simal-Blanco, F.; Mena-Martin, F.J.; Bellido-Casado, J.; Arzua-Mouronte, D.; Chaves, F.J.; Redon, J.; et al. Cohort profile: The Hortega Study for the evaluation of non-traditional risk factors of cardiometabolic and other chronic diseases in a general population from Spain. BMJ Open 2019, 9, e024073. [Google Scholar] [CrossRef]
- Stinton, L.M.; Loomba, R. Recommendations for liver biopsy evaluation in non-alcoholic fatty liver disease. Minerva. Gastroenterol. Dietol. 2014, 60, 5–13. [Google Scholar] [PubMed]
- Khurana, S.; Butt, W.; Khara, H.S.; Johal, A.S.; West, S.F.; Chen, Z.E.; Berger, A.L.; Diehl, D.L. Bi-lobar liver biopsy via EUS enhances the assessment of disease severity in patients with non-alcoholic steatohepatitis. Hepatol. Int. 2019, 13, 323–329. [Google Scholar] [CrossRef] [PubMed]
- Munsterman, I.D.; van Erp, M.; Weijers, G.; Bronkhorst, C.; de Korte, C.L.; Drenth, J.P.H.; van der Laak, J.A.W.M.; Tjwa, E.T.T.L. A Novel Automatic Digital Algorithm that Accurately Quantifies Steatosis in NAFLD on Histopathological Whole-Slide Images. Cytom. B Clin. Cytom. 2019. [Google Scholar] [CrossRef] [PubMed]
- Golabi, P.; Stepanova, M.; Pham, H.T.; Cable, R.; Rafiq, N.; Bush, H.; Gogoll TYounossi, Z.M. Non-alcoholic steatofibrosis (NASF) can independently predict mortality in patients with non-alcoholic fatty liver disease (NAFLD). BMJ Open Gastroenterol. 2018, 5, e000198. [Google Scholar] [CrossRef] [PubMed]
- Zhou, J.H.; Cai, J.J.; She, Z.G.; Li, H.L. Noninvasive evaluation of nonalcoholic fatty liver disease: Current evidence and practice. World J. Gastroenterol. 2019, 25, 1307–1326. [Google Scholar] [CrossRef] [PubMed]
- Wang, C.C.; Jhu, J.J. On the Application of Clustering and Classification Techniques to Analyze Metabolic Syndrome Severity Distribution Area and Critical Factors. Int. J. Environ. Res. Public Health 2019, 16, 1575. [Google Scholar] [CrossRef] [PubMed]
- Castera, L.; Friedrich-Rust, M.; Loomba, R. Noninvasive Assessment of Liver Disease in Patients with Nonalcoholic Fatty Liver Disease. Gastroenterology 2019, 156, 1264–1281. [Google Scholar] [CrossRef]
- Sheth, H.; Bagasrawala, S.; Shah, M.; Ansari, R.; Olithselvan ALakdawala, M. The HAALT Non-invasive Scoring System for NAFLD in Obesity. Obes. Surg. 2019, 29, 2562–2570. [Google Scholar] [CrossRef] [PubMed]
- Yilmaz, Y.; Ulukaya, E. Toward a biochemical diagnosis of NASH: Insights from pathophysiology for distinguishing simple steatosis from steatohepatitis. Curr. Med. Chem. 2011, 18, 725–732. [Google Scholar] [CrossRef]
- Boursier, J.; Guillaume, M.; Leroy, V.; Irlès, M.; Roux, M.; Lannes, A.; Foucher, J.; Zuberbuhler, F.; Delabaudière, C.; Barthelon, J.; et al. New sequential combinations of non-invasive fibrosis tests provide an accurate diagnosis of advanced fibrosis in NAFLD. J. Hepatol. 2019, 71, 389–396. [Google Scholar] [CrossRef]
- Crossan, C.; Majumdar, A.; Srivastava, A.; Thorburn, D.; Rosenberg, W.; Pinzani, M.; Longworth LTsochatzis, E.A. Referral pathways for patients with NAFLD based on non-invasive fibrosis tests: Diagnostic accuracy and cost analysis. Liver Int. 2019. [Google Scholar] [CrossRef] [PubMed]
- Alswat, K.A.; Fallatah, H.I.; Al-Judaibi, B.; Elsiesy, H.A.; Al-Hamoudi, W.K.; Qutub, A.N.; Alturaify NAl-Osaimi, A. Position statement on the diagnosis and management of non-alcoholic fatty liver disease. Saudi Med. J. 2019, 40, 531–540. [Google Scholar] [CrossRef] [PubMed]
- Önnerhag, K.; Hartman, H.; Nilsson, P.M.; Lindgren, S. Non-invasive fibrosis scoring systems can predict future metabolic complications and overall mortality in non-alcoholic fatty liver disease (NAFLD). Scand. J. Gastroenterol. 2019, 54, 328–334. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jennison, E.; Patel, J.; Scorletti, E.; Byrne, C.D. Diagnosis and management of non-alcoholic fatty liver disease. Postgrad. Med. J. 2019, 95, 314–322. [Google Scholar] [CrossRef] [PubMed]
- Leite, N.C.; Villela-Nogueira, C.A.; Cardoso, C.R.; Salles, G.F. Non-alcoholic fatty liver disease and diabetes: From physiopathological interplay to diagnosis and treatment. World J. Gastroenterol. 2014, 20, 8377–8392. [Google Scholar] [CrossRef] [PubMed]
- Farrell, G.C.; Haczeyni FChitturi, S. Pathogenesis of NASH: How Metabolic Complications of Overnutrition Favour Lipotoxicity and Pro-Inflammatory Fatty Liver Disease. Adv. Exp. Med. Biol. 2018, 1061, 19–44. [Google Scholar] [CrossRef] [PubMed]
- Lonardo, A.; Mantovani, A.; Lugari STargher, G. NAFLD in Some Common Endocrine Diseases: Prevalence, Pathophysiology, and Principles of Diagnosis and Management. Int. J. Mol. Sci. 2019, 20, 2841. [Google Scholar] [CrossRef] [PubMed]
- Marchisello, S.; Di Pino, A.; Scicali, R.; Urbano, F.; Piro, S.; Purrello, F.; Rabuazzo, A.M. Pathophysiological, Molecular and Therapeutic Issues of Nonalcoholic Fatty Liver Disease: An Overview Review Article. Int. J. Mol. Sci. 2019, 20, 1948. [Google Scholar] [CrossRef] [PubMed]
- Buzzetti, E.; Pinzani, M.; Tsochatzis, E.A. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 2016, 65, 1038–1048. [Google Scholar] [CrossRef] [PubMed]
- Ballestri, S.; Nascimbeni, F.; Romagnoli, D.; Lonardo, A. The independent predictors of non-alcoholic steatohepatitis and its individual histological features: Insulin resistance, serum uric acid, metabolic syndrome, alanine aminotransferase and serum total cholesterol are a clue to pathogenesis and candidate targets for treatment. Hepatol. Res. 2016, 46, 1074–1087. [Google Scholar] [CrossRef]
- Borrelli, A.; Bonelli, P.; Tuccillo, F.M.; Goldfine, I.D.; Evans, J.L.; Buonaguro, F.M.; Mancini, A. Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: Current and innovative therapeutic approaches. Redox Biol. 2018, 15, 467–479. [Google Scholar] [CrossRef] [PubMed]
- Gonzalez-Jaramillo, V.; Portilla-Fernandez, E.; Glisic, M.; Voortman, T.; Ghanbari, M.; Bramer, W.; Chowdhury, R.; Nijsten, T.; Dehghan, A.; Franco, O.H. Epigenetics and Inflammatory Markers: A Systematic Review of the Current Evidence. Int. J. Inflam. 2019, 2019, 6273680. [Google Scholar] [CrossRef] [PubMed]
- Kim, S.S.; Cho, H.J.; Kim, H.J.; Kang, D.R.; Berry, J.R.; Kim, J.H.; Yang, M.J.; Lim, S.G.; Kim SCheong, J.Y.; Cho, S.W. Nonalcoholic fatty liver disease as a sentinel marker for the development of diabetes mellitus in non-obese subjects. Dig. Liver Dis. 2018, 50, 370–377. [Google Scholar] [CrossRef] [PubMed]
- Błaszczyk-Bębenek, E.; Piórecka, B.; Płonka, M.; Chmiel, I.; Jagielski, P.; Tuleja, K.; Schlegel-Zawadzka, M. Risk Factors and Prevalence of Abdominal Obesity among Upper-Secondary Students. Int. J. Environ. Res. Public Health 2019, 16, 1750. [Google Scholar] [CrossRef] [PubMed]
- HaGani, N.; Moran, M.R.; Caspi, O.; Plaut, P.; Endevelt, R.; Baron-Epel, O. The Relationships between Adolescents’ Obesity and the Built Environment: Are They City Dependent? Int. J. Environ. Res. Public Health 2019, 16, 1579. [Google Scholar] [CrossRef] [PubMed]
- Lonardo, A.; Ballestri, S.; Marchesini GAngulo PLoria, P. Nonalcoholic fatty liver disease: A precursor of the metabolic syndrome. Dig. Liver Dis. 2015, 47, 181–190. [Google Scholar] [CrossRef] [PubMed]
- Sung, K.C.; Lee, M.Y.; Kim, Y.H.; Huh, J.H.; Kim, J.Y.; Wild, S.H.; Byrne, C.D. Obesity and incidence of diabetes: Effect of absence of metabolic syndrome, insulin resistance, inflammation and fatty liver. Atherosclerosis 2018, 275, 50–57. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Golabi, P.; Paik, J.; Fukui, N.; Locklear, C.T.; de Avilla, L.; Younossi, Z.M. Patients with Lean Nonalcoholic Fatty Liver Disease Are Metabolically Abnormal and Have a Higher Risk for Mortality. Clin. Diabetes 2019, 37, 65–72. [Google Scholar] [CrossRef] [PubMed]
- Lonardo, A.; Loria, P. Apolipoprotein synthesis in nonalcoholic steatohepatitis. Hepatology 2002, 36, 514–515. [Google Scholar] [CrossRef] [PubMed]
- Lonardo, A.; Loria, P.; Argo, C.; Caldwell, S. Perspectives on cellular dysfunction in nonalcoholic steatohepatitis: A case of ‘multiorganelle failure’? Proceedings of a virtual workshop on nonalcoholic steatohepatitis. Expert Rev. Gastroenterol. Hepatol. 2011, 5, 135–139. [Google Scholar] [CrossRef] [PubMed]
- Tarantino, G.; Conca, P.; Pasanisi, F.; Ariello, M.; Mastrolia, M.; Arena, A.; Tarantino, M.; Scopacasa, F.; Vecchione, R. Inflammatory markers help diagnose nonalcoholic steatohepatitis? Eur. J. Gastroenterol. Hepatol. 2009, 21, 504–511. [Google Scholar] [CrossRef] [PubMed]
- Moschen, A.R.; Wieser, V.; Tilg, H. Adiponectin: Key player in the adipose tissue-liver crosstalk. Curr. Med. Chem. 2012, 19, 5467–5473. [Google Scholar] [CrossRef] [PubMed]
- Stojsavljević, S.; Gomerčić Palčić, M.; Virović Jukić, L.; Smrčić Duvnjak, L.; Duvnjak, M. Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease. World J. Gastroenterol. 2014, 20, 18070–18091. [Google Scholar] [CrossRef] [PubMed]
- Stiglund, N.; Strand, K.; Cornillet, M.; Stål, P.; Thorell, A.; Zimmer, C.L.; Näslund, E.; Karlgren, S.; Nilsson, H.; Mellgren, G.; et al. Cell Phenotype and Functionality in Non-alcoholic Fatty Liver Disease. Front. Immunol. 2019, 10, 1255. [Google Scholar] [CrossRef] [PubMed]
- Lonardo, A.; Adinolfi, L.E.; Restivo, L.; Ballestri, S.; Romagnoli, D.; Baldelli, E.; Nascimbeni, F.; Loria, P. Pathogenesis and significance of hepatitis C virus steatosis: An update on survival strategy of a successful pathogen. World J. Gastroenterol. 2014, 20, 7089–7103. [Google Scholar] [CrossRef] [PubMed]
- Machado, M.V.; Cortez-Pinto, H. Gut microbiota and nonalcoholic fatty liver disease. Ann. Hepatol. 2012, 11, 440–449. [Google Scholar] [CrossRef]
- Bertolotti, M.; Lonardo, A.; Mussi, C.; Baldelli, E.; Pellegrini, E.; Ballestri, S.; Romagnoli, D.; Loria, P. Nonalcoholic fatty liver disease and aging: Epidemiology to management. World J. Gastroenterol. 2014, 20, 14185–14204. [Google Scholar] [CrossRef] [PubMed]
- Magee, N.; Zou, A.; Zhang, Y. Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells. BioMed Res. Int. 2016, 2016, 5170402. [Google Scholar] [CrossRef] [PubMed]
- Tiwari-Heckler, S.; Gan-Schreier, H.; Stremmel, W.; Chamulitrat, W.; Pathil, A. Circulating Phospholipid Patterns in NAFLD Patients Associated with a Combination of Metabolic Risk Factors. Nutrients 2018, 10, 649. [Google Scholar] [CrossRef]
- Mazidi, M.; Katsiki, N.; Mikhailidis, D.P.; Banach, M. Link between plasma trans-fatty acid and fatty liver is moderated by adiposity. Int. J. Cardiol. 2018, 272, 316–322. [Google Scholar] [CrossRef]
- Piscaglia, F.; Svegliati-Baroni, G.; Barchetti, A.; Pecorelli, A.; Marinelli, S.; Tiribelli, C.; Bellentani, S. HCC-NAFLD Italian Study Group. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study. Hepatology 2016, 63, 827–838. [Google Scholar] [CrossRef] [PubMed]
- Lonardo, A.; Nascimbeni, F.; Maurantonio, M.; Marrazzo, A.; Rinaldi, L.; Adinolfi, L.E. Nonalcoholic fatty liver disease: Evolving paradigms. World J. Gastroenterol. 2017, 23, 6571–6592. [Google Scholar] [CrossRef] [PubMed]
- Singhal, G.; Kumar, G.; Chan, S.; Fisher, F.M.; Ma, Y.; Vardeh, H.G.; Nasser, I.A.; Flier, J.S.; Maratos-Flier, E. Deficiency of fibroblast growth factor 21 (FGF21) promotes hepatocellular carcinoma (HCC) in mice on a long term obesogenic diet. Mol. Metab. 2018, 13, 56–66. [Google Scholar] [CrossRef] [PubMed]
- Svegliati-Baroni, G.; Ridolfi, F.; Di Sario, A.; Casini, A.; Marucci, L.; Gaggiotti, G.; Orlandoni, P.; Macarri, G.; Perego, L.; Benedetti, A.; et al. Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: Differential effects on signal transduction pathways. Hepatology 1999, 29, 1743–1751. [Google Scholar] [CrossRef] [PubMed]
- Lonardo, A.; Lombardini, S.; Scaglioni, F.; Carulli, L.; Ricchi, M.; Ganazzi, D.; Adinolfi, L.E.; Ruggiero, G.; Carulli, N.; Loria, P. Hepatic steatosis and insulin resistance: Does etiology make a difference? J. Hepatol. 2006, 44, 190–196. [Google Scholar] [CrossRef]
- Speliotes, E.K.; Yerges-Armstrong, L.M.; Wu, J.; Hernaez, R.; Kim, L.J.; Palmer, C.D.; Gudnason, V.; Eiriksdottir, G.; Garcia, M.E.; Launer, L.J.; 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, e1001324. [Google Scholar] [CrossRef]
- Guichelaar, M.M.; Gawrieh, S.; Olivier, M.; Viker, K.; Krishnan, A.; Sanderson, S.; Malinchoc, M.; Watt, K.D.; Swain, J.M.; Sarr, M.; et al. Interactions of allelic variance of PNPLA3 with nongenetic factors in predicting nonalcoholic steatohepatitis and nonhepatic complications of severe obesity. Obesity 2013, 21, 1935–1941. [Google Scholar] [CrossRef]
- Ahmed, M. Non-alcoholic fatty liver disease in 2015. World J. Hepatol. 2015, 7, 1450–1459. [Google Scholar] [CrossRef]
- Targher, G.; Rossini, M.; Lonardo, A. Evidence that non-alcoholic fatty liver disease and polycystic ovary syndrome are associated by necessity rather than chance: A novel hepato-ovarian axis? Endocrine 2016, 51, 211–221. [Google Scholar] [CrossRef]
- Sanyal, A.J. Putting non-alcoholic fatty liver disease on the radar for primary care physicians: How well are we doing? BMC Med. 2018, 16, 148. [Google Scholar] [CrossRef]
- Bortolotto, L.A. Identifying the Impact of Metabolic Syndrome in Hypertensive Patients. Arq. Bras. Cardiol. 2018, 110, 522–523. [Google Scholar] [CrossRef] [PubMed]
- Lee, J.; Lee, Y.; Chung, S.; Cho, H.; Park, B.; Jung, D. Severity of nonalcoholic fatty liver disease is associated with subclinical cerebro-cardiovascular atherosclerosis risk in Korean men. PLoS ONE 2018, 13, e0193191. [Google Scholar] [CrossRef] [PubMed]
- Lonardo, A.; Nascimbeni, F.; Ballestri, S.; Fairweather, D.; Win, S.; Than, T.A.; Abdelmalek, M.F.; Suzuki, A. Sex Differences in NAFLD: State of the Art and Identification of Research Gaps. Hepatology 2019. [Google Scholar] [CrossRef] [PubMed]
- Ballestri, S.; Zona, S.; Targher, G.; Romagnoli, D.; Baldelli, E.; Nascimbeni, F.; Roverato, A.; Guaraldi, G.; Lonardo, A. 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, 936–944. [Google Scholar] [CrossRef] [PubMed]
- Lin, S.Y.; Lin, C.L.; Lin, C.C.; Wang, I.K.; Hsu, W.H.; Kao, C.H. Risk of acute coronary syndrome and peripheral arterial disease in chronic liver disease and cirrhosis: A nationwide population-based study. Atherosclerosis 2018, 270, 154–159. [Google Scholar] [CrossRef] [PubMed]
- Strey, C.B.M.; de Carli, L.A.; Fantinelli, M.; Gobbato, S.S.; Bassols, G.F.; Losekann, A.; Coral, G.P. Impact of Diabetes Mellitus and Insulin on Nonalcoholic Fatty Liver Disease in the Morbidly Obese. Ann. Hepatol. 2018, 17, 585–591. [Google Scholar] [CrossRef] [PubMed]
- Catharina, A.S.; Modolo, R.; Ritter, A.M.V.; Sabbatini, A.R.; Lopes, H.F.; Moreno Junior, H.; Faria, A.P. Metabolic syndrome-Related Features in Controlled and Resistant Hypertensive Subjects. Arq. Bras. Cardiol. 2018, 110, 514–521. [Google Scholar] [CrossRef]
- Katsiki, N.; Anagnostis, P.; Kotsa, K.; Goulis, D.G.; Mikhailidis, D.P. Obesity, Metabolic Syndrome and the Risk of Microvascular Complications in Patients with Diabetes mellitus. Curr. Pharm. Des. 2019. [Google Scholar] [CrossRef]
- Nascimbeni, F.; Pais, R.; Bellentani, S.; Day, C.P.; Ratziu, V.; Loria, P.; Lonardo, A. From NAFLD in clinical practice to answers from guidelines. J. Hepatol. 2013, 59, 859–871. [Google Scholar] [CrossRef] [Green Version]
- Lonardo, A.; Targher, G. NAFLD: Is There Anything New under the Sun? Int. J. Mol. Sci. 2017, 18, 1955. [Google Scholar] [CrossRef]
- Lonardo, A.; Lugari, S.; Ballestri, S.; Nascimbeni, F.; Baldelli, E.; Maurantonio, M. A round trip from nonalcoholic fatty liver disease to diabetes: Molecular targets to the rescue? Acta Diabetol. 2019, 56, 385–396. [Google Scholar] [CrossRef] [PubMed]
- Mantovani, A.; Dauriz, M.; Byrne, C.D.; Lonardo, A.; Zoppini, G.; Bonora, E.; Targher, G. Association between nonalcoholic fatty liver disease and colorectal tumours in asymptomatic adults undergoing screening colonoscopy: A systematic review and meta-analysis. Metabolism 2018, 87, 1–12. [Google Scholar] [CrossRef] [PubMed]
- Arora, A.; Sharma, P. Non-invasive Diagnosis of fibrosis in non.alcoholic fatty liver disease. J. Clin. Exp. Hepatol. 2012, 2, 145–155. [Google Scholar] [CrossRef]
- Schreiner, A.D.; Rockey, D.C. Evaluation of abnormal liver tests in the adult asymptomatic patient. Curr. Opin. Gastroenterol. 2018, 34, 272–279. [Google Scholar] [CrossRef] [PubMed]
- Shirin, D.; Peleg, N.; Sneh-Arbib, O.; Cohen-Naftaly, M.; Braun, M.; Shochat, T.; Issachar, A.; Shlomai, A. The Pattern of Elevated Liver Function Tests in Nonalcoholic Fatty Liver Disease Predicts Fibrosis Stage and Metabolic-Associated Comorbidities. Dig. Dis. 2019, 37, 69–76. [Google Scholar] [CrossRef] [PubMed]
- Hagström, H.; Nasr, P.; Bottai, M.; Ekstedt, M.; Kechagias, S.; Hultcrantz, R.; Stål, P. Elevated serum ferritin is associated with increased mortality in NAFLD after 16 years of follow-up. Liver Int. 2016, 36, 1688–1695. [Google Scholar] [CrossRef]
- Foroughi, M.; Maghsoudi, Z.; Khayyatzadeh, S.; Ghiasvand, R.; Askari, G.; Iraj, B. Relationship between non-alcoholic fatty liver disease and inflammation in patients with non-alcoholic fatty liver. Adv. Biomed. Res. 2016, 5, 28. [Google Scholar] [CrossRef]
- Ustyol, A.; Aycan Ustyol, E.; Gurdol, F.; Kokali, F.; Bekpınar, S. P-selectin, endocan, and some adhesion molecules in obese children and adolescents with non-alcoholic fatty liver disease. Scand. J. Clin. Lab. Invest. 2017, 77, 205–209. [Google Scholar] [CrossRef]
- Dowla, S.; Aslibekyan, S.; Goss, A.; Fontaine, K.; Ashraf, A.P. Dyslipidemia is associated with pediatric nonalcoholic fatty liver disease. J. Clin. Lipidol. 2018, 12, 981–987. [Google Scholar] [CrossRef]
- Tabung, F.K.; Balasubramanian, R.; Liang, L.; Clinton, S.K.; Cespedes Feliciano, E.M.; Manson, J.E.; Van Horn, L.; Wactawski-Wende, J.; Clish, C.B.; Giovannucci, E.L.; et al. Identifying Metabolomic Profiles of Insulinemic Dietary Patterns. Metabolites 2019, 9, 120. [Google Scholar] [CrossRef]
- Chen, H.; Wang, J.; Li, Z.; Lam, C.W.K.; Xiao, Y.; Wu, Q.; Zhang, W. Consumption of Sugar- Sweetened Beverages Has a Dose-Dependent Effect on the Risk of Non-Alcoholic Fatty Liver Disease: An Updated Systematic Review and Dose-Response Meta-Analysis. Int. J. Environ. Res. Public Health 2019, 16, 2192. [Google Scholar] [CrossRef] [PubMed]
- Paquette, M.; Bernard, S.; Hegele, R.A.; Baass, A. Chylomicronemia: Differences between familial chylomicronemia syndrome and multifactorial chylomicronemia. Atherosclerosis 2019, 283, 137–142. [Google Scholar] [CrossRef] [PubMed]
- Targher, G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis 2007, 191, 235–240. [Google Scholar] [CrossRef] [PubMed]
- Wójcik-Cichy, K.; Koślińska-Berkan, E.; Piekarska, A. The influence of NAFLD on the risk of atherosclerosis and cardiovascular diseases. Clin. Exp. Hepatol. 2018, 4, 1–6. [Google Scholar] [CrossRef] [PubMed]
- Fujii, H.; Imajo, K.; Yoneda, M.; Nakahara, T.; Hyogo, H.; Takahashi, H.; Hara, T.; Tanaka, S.; Sumida, Y.; Eguchi, Y.; et al. Japan Study Group of Nonalcoholic Fatty Liver Disease. HOMA-IR: An independent predictor of advanced liver fibrosis in nondiabetic non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 2019. [Google Scholar] [CrossRef]
- Loria, P.; Lonardo, A.; Carulli, N. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology 2004, 39, 1748. [Google Scholar] [CrossRef]
- Amin, R.F.; El Bendary, A.S.; Ezzat, S.E.; Mohamed, W.S. Serum Ferritin level, microalbuminuria and non-alcoholic fatty liver disease in type 2 diabetic patients. Diabetes Metab. Syndr. 2019, 13, 2226–2229. [Google Scholar] [CrossRef]
- Yoneda, M.; Uchiyama, T.; Kato, S.; Endo, H.; Fujita, K.; Yoneda, K.; Mawatari, H.; Iida, H.; Takahashi, H.; Kirikoshi, H.; et al. Plasma Pentraxin3 is a novel marker for nonalcoholic steatohepatitis (NASH). BMC Gastroenterol. 2008, 8, 53. [Google Scholar] [CrossRef]
- Kar, S.; Paglialunga, S.; Jaycox, S.H.; Islam, R.; Paredes, A.H. Assay validation and clinical performance of chronic inflammatory and chemokine biomarkers of NASH fibrosis. PLoS ONE 2019, 14, e0217263. [Google Scholar] [CrossRef]
- Nigro, E.; Scudiero, O.; Monaco, M.L.; Palmieri, A.; Mazzarella, G.; Costagliola, C.; Bianco, A.; Daniele, A. New insight into adiponectin role in obesity and obesity-related diseases. BioMed Res. Int. 2014, 2014, 658913. [Google Scholar] [CrossRef]
- Boyraz, M.; Cekmez, F.; Karaogu, A.; Cinaz, P.; Durak, M.; Bideci, A. Serum adiponectin, leptin, resistin and RBP4 levels in obese and metabolic syndrome children with nonalcoholic fatty liver disease. Biomark Med. 2013, 737–745. [Google Scholar] [CrossRef]
- Lanthier, N.; Horsmans, Y.; leclerq, I.A. The metabolic syndrome how it may influence hepatic stellate cell activation and hepatic fibrosis. Curr. Opin. Clin. Nutr. Metab. Care 2009, 12, 404–411. [Google Scholar] [CrossRef]
- Pacifico, L.; Poggiogalle, E.; Costantino, F.; Anania, C.; Ferraro, F.; Chiarelli, F.; Chiesa, C. Acylated and nonacylated ghrelin levels and their associations with insulin resistance in obese and normal weight children with metabolic synddrome. Eur. J. Endocrinol. 2009, 161, 861–870. [Google Scholar] [CrossRef]
- Dvorak, K.; Stritesky, J.; Petrtyl, J.; Vitek, L.; Sroubkova, R.; Lenicek, M.; Smid, V.; Haluzik, M.; Bruha, R. Use of Non-Invasive Parameters of Non-Alcoholic Steatohepatitis and Liver Fibrosis in Daily Practice–An Exploratory Case–control Study. PLoS ONE 2014, 9, e111551. [Google Scholar] [CrossRef]
- Sánchez-Valle, V.; Chávez-Tapia, N.C.; Uribe, M.; Méndez-Sánchez, N. Role of oxidative stress and molecular changes in liver fibrosis: A review. Curr. Med. Chem. 2012, 19, 4850–4860. [Google Scholar] [CrossRef]
- Cabré, N.; Luciano-Mateo, F.; Fernández-Arroyo, S.; Baiges-Gayà, G.; Hernández-Aguilera, A.; Fibla, M.; Fernández-Julià, R.; París, M.; Sabench, F.; Del Castillo, D.; et al. Laparoscopic sleeve gastrectomy reverses non-alcoholic fatty liver disease modulating oxidative stress and inflammation. Metabolism 2019. [Google Scholar] [CrossRef]
- Shen, J.; Chan, H.L.; Wong, G.L.; Chan, A.W.; Choi, P.C.; Chan, H.Y.; Chim, A.M.; Yeung, D.K.; Yu, J.; Chu, W.C.; et al. Assesment of non-alcoholic fatty liver disease using serum total cell death and apoptosis markers. Aliments Pharmacol. Ther. 2012, 36, 1057–1066. [Google Scholar] [CrossRef]
- Younosssi, Z.M.; Jarrar, M.; Nugent, C.; Randhawa, M.; Afendy, M.; Stepanova, M.; Rafiq, N.; Goodman, Z.; Chandhoke, V.; Baranova, A. A novel diagnostic biomarker panel for obesity–Related nonalcoholic steatohepatitis (NASH). Obes. Surg. 2008, 18, 1430–1437. [Google Scholar] [CrossRef]
- Tarantino, G.; Mazzarella, C.; Tarantino, M.; Di Minno, M.N.; Conca, P. Could high levels of tissue polypeptide specific antigen, a marker of apoptosis detected in nonalcoholic staetohepatitis, improve after weight loss? Dis. Markers 2009, 26, 55–63. [Google Scholar] [CrossRef]
- Markelova, E.V.; Romanchuk, A.L.; Prosekova, E.V.; Krasnikov, V.E.; Beniova, S.N. Assessing the level of matrix metal proteinases 1,8,9, their tissue inhibitor type I, in cases of odontogenic phlegmons. Bratisl. Lek. Listy 2017, 118, 51–55. [Google Scholar] [CrossRef]
- Orasan, O.H.; Ciulei, G.; Cozma, A.; Sava, M.; Dumtrasci, D.L. Hyaluronic acid as a biomarker of fibrosis in chronic liver diseases of different etologies. Clujul Med. 2016, 89, 24–31. [Google Scholar]
- Degertekin, B.; Ozenirler, S.; Elberg, S.; Akyol, G. The serum endothelin-1 level in steatosis and NASH, and its relation with severity of liver fibrosis. Dig. Dis. Sci. 2007, 52, 2622–2628. [Google Scholar] [CrossRef]
- Mahmoud, A.A.; Bakir, A.S.; Shabana, S.S. Serum TGF-β, serum MMP-1, and HOMA-IR as non-invasive predictors of fibrosis in Egyptian patients with NAFLD. Saudi J. Gatroenterol. 2012, 18, 327–333. [Google Scholar] [CrossRef]
- Abdelaziz, R.; Elbasel, M.; Esmat, S.; Essam, K.; Abdelaaty, S. Tissue inhibitors of metalloproteinase-1 and 2 and obesity related non-alcoholic fatty liver disease. Is there a relationship. Digestion 2015, 92, 130–137. [Google Scholar] [CrossRef]
- Lee, Y.H.; Bang, H.; Park, Y.M.; Bae, J.C.; Lee, B.W.; Kang, E.S.; Cha, B.S.; Lee, H.C.; Balkau, B.; Lee, W.Y.; et al. Non-laboratory-based self-assessment screening score for non-alcoholic fatty liver disease: Development, validation and comparison with other scores. PLoS ONE 2014, 9, e107584. [Google Scholar] [CrossRef]
- Ciećko-Michalska, I.; Szczepanek, M.; Wierzbicka-Tutka, I.; Zahradnik-Bilska, J.; Mach, T. Non-invasive diagnosis of steatosis, inflammatory changes and liver fibrosis in patients with non-alcoholic fatty liver diseases. Pilot study. Arch. Med. Sci. Atheroscler. Dis. 2018, 3, e179–e183. [Google Scholar] [CrossRef]
- Siddiqui, M.S.; Yamada, G.; Vuppalanchi, R.; Van Natta, M.; Loomba, R.; Guy, C.; Brandman, D.; Tonascia, J.; Chalasani, N.; Neuschwander-Tetri, B.; et al. NASH Clinical Research Network. Diagnostic Accuracy of Noninvasive Fibrosis Models to Detect Change in Fibrosis Stage. Clin. Gastroenterol. Hepatol. 2019, 17, 1877–1885. [Google Scholar] [CrossRef]
- Huang, X.; Xu, M.; Chen, Y.; Peng, K.; Huang, Y.; Wang, P.; Ding, L.; Lin, L.; Xu, Y.; Chen, Y.; et al. Validation of the fatty liver index for nonalcoholic fatty liver disease in middle aged and elderly. Medicine 2015, 94, e1682. [Google Scholar] [CrossRef]
- Franch-Nadal, J.; Caballeria, L.; Mata-Cases, M.; Mauricio, D.; Giraldez-García, C.; Mancera, J.; Goday, A.; Mundet-Tudurí, X.; Regidor, E.; PREDAPS Study Group. Fatty liver index is a predictor of incident diabetes in patients with prediabetes: The PREDAPS study. PLoS ONE 2018, 13, e0198327. [Google Scholar] [CrossRef]
- Khang, A.R.; Lee, H.W.; Yi, D.; Kang, Y.H.; Son, S.M. The fatty liver index, a simple and useful predictor of metabolic syndrome: Analysis of the Korea National Health and Nutrition Examination Survey 2010–2011. Diabetes Metab. Syndr. Obes. 2019, 12, 181–190. [Google Scholar] [CrossRef]
- Borman, M.A.; Ladak, F.; Crotty, P.; Pollett, A.; Kirsch, R.; Pomier-Layrargues, G.; Beaton, M.; Duarte-Rojo, A.; Elkashab, M.; Myers, R.P. The fatty liver index has limited utility for the detection and quantification of hepatic steatosis in obese patients. Hepatol. Int. 2013, 7, 592–599. [Google Scholar] [CrossRef]
- Cuthbertson, D.J.; Weickert, M.O.; Lythgoe, D.; Sprung, V.S.; Dobson, R.; Shoajee-Moradie, F.; Umpleby, M.; Pfeiffer, A.F.; Thomas, E.L.; Bell, J.D.; et al. External validation of the fatty liver index and lipid accumulation product indices, using 1H-magnetic resonance spectroscopy, to identify hepatic steatosis in healthy controls and obese, insulin-resistant individuals. Eur. J. Endocrinol. 2014, 171, 561–569. [Google Scholar] [CrossRef]
- Lee, J.H.; Kim, D.; Kim, H.J.; Lee, C.H.; Yang, J.I.; Kim, W.; Kim, Y.J.; Yoon, J.H.; Cho, S.H.; Sung, M.W.; et al. Hepatic steatosis index: A simple screening tool reflecting nonalcoholic fatty liver disease. Dig. Liver Dis. 2010, 42, 503–508. [Google Scholar] [CrossRef]
- Wang, J.; Xu, C.; Xun, Y.; Lu, Z.; Shi, J.; Yu, C.; Li, Y. ZJU index: A novel model for predicting nonalcoholic fatty liver disease in a Chinese population. Sci. Rep. 2015, 5, 16494. [Google Scholar] [CrossRef]
- Poynard, T.; Lassailly, G.; Diaz, E.; Clement, K.; Caïazzo, R.; Tordjman, J.; Munteanu, M.; Perazzo, H.; Demol, B.; Callafe, R.; et al. FLIP consortium. Performance of biomarkers FibroTest, ActiTest, SteatoTest, and NashTest in patients with severe obesity: Meta analysis of individual patient data. PLoS ONE 2012, 7, e30325. [Google Scholar] [CrossRef]
- McPherson, S.; Stewart, S.F.; Henderson, E.; Burt, A.D.; Day, C.P. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut 2010, 59, 1265–1269. [Google Scholar] [CrossRef] [Green Version]
- Kruger, F.C.; Daniels, C.R.; Kidd, M.; Swart, G.; Brundyn, K.; van Rensburg, C.; Kotze, M. APRI: A simple bedside marker for advanced fibrosis that can avoid liver biopsy in patients with NAFLD/NASH. S. Afr. Med. J. 2011, 101, 477–480. [Google Scholar]
- Shah, A.G.; Lydecker, A.; Murray, K.; Tetri, B.N.; Contos, M.J.; Sanyal, A.J. Nash Clinical Research Network. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 2009, 7, 1104–1112. [Google Scholar] [CrossRef]
- Pérez-Gutiérrez, O.Z.; Hernández-Rocha, C.; Candia-Balboa, R.A.; Arrese, M.A.; Benítez, C.; Brizuela-Alcántara, D.C.; Méndez-Sánchez, N.; Uribe, M.; Chávez-Tapia, N.C. Validation study of systems for noninvasive diagnosis of fibrosis in nonalcoholic fatty liver disease in Latin population. Ann. Hepatol. 2013, 12, 416–424. [Google Scholar] [CrossRef]
- Raszeja-Wyszomirska, J.; Szymanik, B.; Ławniczak, M.; Kajor, M.; Chwist, A.; Milkiewicz, P.; Hartleb, M. Validation of the BARD scoring system in Polish patients with nonalcoholic fatty liver disease (NAFLD). BMC Gastroenterol. 2010, 10, 67. [Google Scholar] [CrossRef]
- Sun, W.; Cui, H.; Li, N.; Wei, Y.; Lai, S.; Yang, Y.; Yin, X.; Chen, D.F. Comparison of FIB4 index, NAFLD fibrosis score and BARD score for prediction of advanced fibrosis in adult patients with non-alcoholic fatty liver disease: A meta-analysis study. Hepatol. Res. 2016, 46, 862–870. [Google Scholar] [CrossRef]
- Angulo, P.; Hui, J.M.; Marchesini, G.; Bugianesi, E.; George, J.; Farrell, G.C.; Enders, F.; Saksena, S.; Burt, A.D.; Bida, J.P.; et al. The NAFLD fibrosis score: A noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007, 45, 846–854. [Google Scholar] [CrossRef]
- Demir, M.; Lang, S.; Schlattjan, M.; Drebber, U.; Wedemeyer, I.; Nierhoff, D.; Kaul, I.; Sowa, J.; Canbay, A.; Töx, U.; et al. A new inexpensive and non-invasive scoring system to exclude advanced fibrosis in patients with NAFLD. PLoS ONE 2013, 8, e58360. [Google Scholar] [CrossRef]
- Miyaaki, H.; Ichikawa, T.; Nakao, K.; Yatsuhashi, H.; Furukawa, R.; Ohba, K.; Omagari, K.; Kusumoto, Y.; Yanagi, K.; Inoue, O.; et al. Clinicopathological study of nonalcoholic fatty liver disease in Japan: The risk factors for fibrosis. Liver Int. 2008, 28, 519–524. [Google Scholar] [CrossRef]
- Ratziu, V.; Giral, P.; Charlotte, F.; Bruckert, E.; Thibault, V.; Theodorou, I.; Khalil, L.; Turpin, G.; Opolon, P.; Poynard, T. Liver fibrosis in overweight patients. Gastroenterology 2000, 118, 1117–1123. [Google Scholar] [CrossRef]
- Sterling, R.K.; Lissen, E.; Clumeck, N.; Sola, R.; Correa, M.C.; Montaner, J.; SSulkowski, M.; Torriani, F.J.; Dieterich, D.T.; Thomas, D.L.; et al. APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006, 43, 1317–1325. [Google Scholar] [CrossRef]
- Nones, R.B.; Ivantes, C.P.; Pedroso, M.L.A. Can FIB4 and NAFLD fibrosis scores help endocrinologists refer patients with non-alcoholic fat liver disease to a hepatologist? Arch. Endocrinol. Metab. 2017, 61, 276–281. [Google Scholar] [CrossRef] [Green Version]
- Sumida, Y.; Yoneda, M.; Hyogo, H.; Itoh, Y.; Ono, M.; Fujii, H.; Eguchi, Y.; Suzuki, Y.; Aoki, N.; Kanemasa, K.; et al. Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD). Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population. BMC Gastroenterol. 2012, 12, 2. [Google Scholar] [CrossRef]
- Arteaga, I.; Buezo, I.; Expósito, C.; Pera, G.; Rodríguez, L.; Alumà, A.; Auladell, M.A.; Torán, P.; Caballería, L. Non-invasive markers of fibrosis in the diagnosis of non-alcoholic fatty liver disease. Gastroenterol. Hepatol. 2014, 37, 503–510. [Google Scholar] [CrossRef]
- Dixon, J.B.; Bhathal, P.S.; O’Brien, P.E. Nonalcoholic fatty liver disease: Predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001, 121, 91–100. [Google Scholar] [CrossRef]
- Calès, P.; Boursier, J.; Oberti, F.; Hubert, I.; Gallois, Y.; Rousselet, M.C.; Dib, N.; Moal, V.; Macchi, L.; Chevailler, A.; et al. FibroMeters: A family of blood tests for liver fibrosis. Gastroenterol. Clin. Biol. 2008, 32, 40–51. [Google Scholar] [CrossRef]
- Poynard, T.; Munteanu, M.; Deckmyn, O.; Ngo, Y.; Drane, F.; Castille, J.M.; Housset, C.; Ratziu, V.; Imbert-Bismut, F. Validation of liver fibrosis biomarker (FibroTest) for assessing liver fibrosis progression: Proof of concept and first application in a large population. J. Hepatol. 2012, 57, 541–548. [Google Scholar] [CrossRef]
- Poynard, T.; Ratziu, V.; Charlotte, F.; Messous, D.; Munteanu, M.; Imbert-Bismut, F.; Massard, J.; Bonyhay, L.; Tahiri, M.; Thabut, D.; et al. LIDO Study Group; CYTOL study group. Diagnostic value of biochemical markers (NashTest) for the prediction of non alcoholo steato hepatitis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol. 2006, 6, 34. [Google Scholar] [CrossRef]
- Guha, I.N.; Parkes, J.; Roderick, P.; Chattopadhyay, D.; Cross, R.; Harris, S.; Kaye, P.; Burt, A.D.; Ryder, S.D.; Aithal, G.P.; et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: Validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology 2008, 47, 455–460. [Google Scholar] [CrossRef]
- Morra, R.; Munteanu, M.; Imbert-Bismut, F.; Messous, D.; Ratziu, V.; Poynard, T. FibroMAX: Towards a new universal biomarker of liver disease? Expert Rev. Mol. Diagn. 2007, 7, 481–490. [Google Scholar] [CrossRef]
- Palekar, N.A.; Naus, R.; Larson, S.P.; Ward, J.; Harrison, S.A. Clinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonalcoholic fatty liver disease. Liver Int. 2006, 26, 151–156. [Google Scholar] [CrossRef]
- Francque, S.M.; Verrijken, A.; Mertens, I.; Hubens, G.; Van Marck, E.; Pelckmans, P.; Michielsen, P.; Van Gaal, L. Noninvasive assessment of nonalcoholic fatty liver disease in obese or overweight patients. Clin. Gastroenterol. Hepatol. 2012, 10, 1162–1168. [Google Scholar] [CrossRef]
- Nakamura, A.; Yoneda, M.; Sumida, Y.; Eguchi, Y.; Fujii, H.; Hyogo, H.; Ono, M.; Suzuki, Y.; Kawaguchi, T.; Aoki, N.; et al. Modification of a simple clinical scoring system as a diagnostic screening tool for non-alcoholic steatohepatitis in Japanese patients with non-alcoholic fatty liver disease. J. Diabetes Investig. 2013, 4, 651–658. [Google Scholar] [CrossRef] [Green Version]
- Macaluso, F.S.; Maida, M.; Petta, S. Genetic background in nonalcoholic fatty liver disease: A comprehensive review. World J. Gastroenterol. 2015, 21, 11088–11111. [Google Scholar] [CrossRef]
- Armstrong, L.E.; Guo, G.L. Understanding Environmental Contaminants’ Direct Effects on Non-alcoholic Fatty Liver Disease Progression. Curr. Environ. Health Rep. 2019. [Google Scholar] [CrossRef]
- Wang, C.W.; Chuang, H.Y.; Liao, K.W.; Yu, M.L.; Dai, C.Y.; Chang, W.T.; Tsai, C.H.; Chiang, H.C.; Huang, P.C. Urinary thiodiglycolic acid is associated with increased risk of non-alcoholic fatty liver disease in children living near a petrochemical complex. Environ. Int. 2019, 131, 104978. [Google Scholar] [CrossRef]
- Non-alcoholic Fatty Liver Disease Study Group; Lonardo, A.; Bellentani, S.; Argo, C.K.; Ballestri, S.; Byrne, C.D.; Caldwell, S.H.; Cortez-Pinto, H.; Grieco, A.; Machado, M.V.; et al. Epidemiological modifiers of non-alcoholic fatty liver disease: Focus on high-risk groups. Dig. Liver Dis. 2015, 47, 997–1006. [Google Scholar] [CrossRef] [Green Version]
- Romeo, S.; Kozlitina, J.; Xing, C.; Pertsemlidis, A.; Cox, D.; Pennacchio, L.A.; Boerwinkle, E.; Cohen, J.C.; Hobbs, H.H. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 2008, 40, 1461–1465. [Google Scholar] [CrossRef] [Green Version]
- 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 2011, 53, 1883–1894. [Google Scholar] [CrossRef]
- Singal, A.G.; Manjunath, H.; Yopp, A.C.; Beg, M.S.; Marrero, J.A.; Gopal, P.; Waljee, A.K. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: A meta-analysis. Am. J. Gastroenterol. 2014, 109, 325–334. [Google Scholar] [CrossRef]
- Liu, Y.L.; Patman, G.L.; Leathart, J.B.; Piguet, A.C.; Burt, A.D.; Dufour, J.F.; Day, C.P.; Daly, A.K.; Reeves, H.L.; Anstee, Q.M. Carriage of the PNPLA3 rs738409 C & gt; G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J. Hepatol. 2014, 61, 75–81. [Google Scholar] [CrossRef]
- Musso, G.; Cassader, M.; Gambino, R. PNPLA3 rs738409 and TM6SF2 rs58542926 gene variants affect renal disease and function in nonalcoholic fatty liver disease. Hepatology 2015, 62, 658–659. [Google Scholar] [CrossRef]
- Kozlitina, J.; Smagris, E.; Stender, S.; Nordestgaard, B.G.; Zhou, H.H.; Tybjærg-Hansen, A.; Vogt, T.F.; Hobbs, H.H.; Cohen, J.C. Exomewide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 2014, 46, 352–356. [Google Scholar] [CrossRef]
- Dongiovanni, P.; Petta, S.; Maglio, C.; Fracanzani, A.L.; Pipitone, R.; Mozzi, E.; Motta, B.M.; Kaminska, D.; Rametta, R.; Grimaudo, S.; et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 2015, 61, 506–514. [Google Scholar] [CrossRef]
- Liang, N.; Damdimopoulos, A.; Goñi, S.; Huang, Z.; Vedin, L.L.; Jakobsson, T.; Giudici, M.; Ahmed, O.; Pedrelli, M.; Barilla, S.; et al. Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARα. Nat. Commun. 2019, 10, 1684. [Google Scholar] [CrossRef]
- Gallego-Durán, R.; Romero-Goméz, M. Epigenetic mechanism in nonalcoholic fatty liver disease: An emerging field. World J. Hepatol. 2015, 7, 2497–2502. [Google Scholar] [CrossRef] [PubMed]
- Sinton, M.C.; Hay, D.C.; Drake, A.J. Metabolic control of gene transcription in non-alcoholic fatty liver disease: The role of the epigenome. Clin. Epigenet. 2019, 11, 104. [Google Scholar] [CrossRef] [PubMed]
- Salvoza, N.C.; Klinzing, D.C.; Gopez-Cervantes, J.; Baclig, M.O. Association of Circulating Serum miR-34a and miR-122 with Dyslipidemia among Patients with Non-Alcoholic Fatty Liver Disease. PLoS ONE 2016, 11, e0153497. [Google Scholar] [CrossRef] [PubMed]
- Ko, C.J.; Li, C.J.; Wu, M.Y.; Chu, P.Y. Overexpression of LGR-5 as a Predictor of Poor Outcome in Patients with Hepatocellular Carcinoma. Int. J. Environ. Res. Public Health 2019, 16, 1836. [Google Scholar] [CrossRef] [PubMed]
- Pacifico, L.; Andreoli, G.M.; D’Avanzo, M.; De Mitri, D.; Pierimarchi, P. Role of osteoprotegerin/receptor activator of nuclear factor kappa B/receptor activator of nuclear factor kappa B ligand axis in nonalcoholic fatty liver disease. World J. Gastroenterol. 2018, 24, 2073–2082. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Khajehahmadi, Z.; Mohagheghi, S.; Nikeghbalian, S.; Geramizadeh, B.; Khodadadi, I.; Karimi, J.; Ghaffari, M.E.; Tavilani, H. Downregulation of Hedgehog Ligands in Human Simple Steatosis May Protect Against Nonalcoholic Steatohepatitis: Is TAZ a Crucial Regulator? IUBMB Life 2019. [Google Scholar] [CrossRef] [PubMed]
- Younossi, Z.M.; Baranova, A.; Ziegler, K.; Del Giacco, L.; Schlauch, K.; Born, T.L.; Elariny, H.; Gorreta, F.; VanMeter, A.; Younoszai, A.; et al. A genomic and proteomic study of the spectrum of nonalcoholic fatty liver disease. Hepatology 2005, 42, 665–674. [Google Scholar] [CrossRef]
- Bell, L.N.; Theodorakis, J.L.; Vuppalanchi, R.; Saxena, R.; Bemis, K.G.; Wang, M.; Chalasani, N. Serum proteomics and biomarker discovery across the spectrum of nonalcoholic fatty liver disease. Hepatology 2010, 51, 111–120. [Google Scholar] [CrossRef]
- Romeo, S. Notch and Nonalcoholic Fatty Liver and Fibrosis. N. Engl. J. Med. 2019, 380, 681–683. [Google Scholar] [CrossRef]
- Romier, B.; Ivaldi, C.; Sartelet, H.; Heinz, A.; Schmelzer, C.E.H.; Garnotel, R.; Guillot, A.; Jonquet, J.; Bertin, E.; Guéant, J.L.; et al. Production of Elastin-Derived Peptides Contributes to the Development of Nonalcoholic Steatohepatitis. Diabetes 2018, 67, 1604–1615. [Google Scholar] [CrossRef] [Green Version]
- Di Mauro, S.; Scamporrino, A.; Petta, S.; Urbano, F.; Filippello, A.; Ragusa, M.; Di Martino, M.T.; Scionti, F.; Grimaudo, S.; Pipitone, R.M.; et al. Serum coding and non-coding RNAs as biomarkers of NAFLD and fibrosis severity. Liver Int. 2019. [Google Scholar] [CrossRef] [PubMed]
- Kurbatova, I.V.; Topchieva, L.V.; Dudanova, O.P.; Shipovskaya, A.A. Biochemical and molecular-genetic indicators of inflammation and apoptosis in liver cirrhosis as an outcome of the progression of non-alcoholic steatohepatitis. Ter. Arkh. 2019, 91, 21–27. [Google Scholar] [CrossRef] [PubMed]
- Mirea, A.M.; Toonen, E.J.M.; van den Munckhof, I.; Munsterman, I.D.; Tjwa, E.T.T.L.; Jaeger, M.; Oosting, M.; Schraa, K.; Rutten, J.H.W.; van der Graaf, M.; et al. Increased proteinase 3 and neutrophil elastase plasma concentrations are associated with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. Mol. Med. 2019, 25, 16. [Google Scholar] [CrossRef] [PubMed]
- Barchetta, I.; Enhörning, S.; Cimini, F.A.; Capoccia, D.; Chiappetta, C.; Di Cristofano, C.; Silecchia, G.; Leonetti, F.; Melander, O.; Cavallo, M.G. Elevated plasma copeptin levels identify the presence and severity of non-alcoholic fatty liver disease in obesity. BMC Med. 2019, 17, 85. [Google Scholar] [CrossRef] [PubMed]
- Asprouli, E.; Kalafati, I.P.; Sakellari, A.; Karavoltsos, S.; Vlachogiannakos, J.; Revenas, K.; Kokkinos, A.; Dassenakis, M.; Dedoussis, G.V.; Kalogeropoulos, N. Evaluation of Plasma Trace Elements in Different Stages of Nonalcoholic Fatty Liver Disease. Biol. Trace Elem. Res. 2019, 188, 326–333. [Google Scholar] [CrossRef] [PubMed]
- Lonardo, A.; Sookoian, S.; Pirola, C.J.; Targher, G. Non-alcoholic fatty liver disease and risk of cardiovascular disease. Metabolism 2016, 65, 1136–1150. [Google Scholar] [CrossRef] [PubMed]
- Targher, G.; Byrne, C.D.; Lonardo, A.; Zoppini, G.; Barbui, C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis. J. Hepatol. 2016, 65, 589–600. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lonardo, A.; Nascimbeni, F.; Ballestri, S. NAFLD, Hepatotropic Viruses, and Cardiometabolic Risk. Hepatology 2017, 65, 2122–2123. [Google Scholar] [CrossRef] [Green Version]
- Hernaez, R.; Lazo, M.; Bonekamp, S.; Kamel, I.; Brancati, F.L.; Guallar, E.; Clark, J.M. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: A meta-analysis. Hepatology 2011, 54, 1082–1090. [Google Scholar] [CrossRef] [Green Version]
- Ballestri, S.; Romagnoli, D.; Nascimbeni, F.; Francica, G.; Lonardo, A. Role of ultrasound in the diagnosis and treatment of nonalcoholic fatty liver disease and its complications. Expert Rev. Gastroenterol. Hepatol. 2015, 9, 603–627. [Google Scholar] [CrossRef]
- Ballestri, S.; Nascimbeni, F.; Baldelli, E.; Marrazzo, A.; Romagnoli, D.; Targher, G.; Lonardo, A. Ultrasonographic fatty liver indicator detects mild steatosis and correlates with metabolic/histological parameters in various liver diseases. Metabolism 2017, 72, 57–65. [Google Scholar] [CrossRef] [PubMed]
- Ballestri, S.; Nascimbeni, F.; Lugari, S.; Lonardo, A.; Francica, G. A critical appraisal of the use of ultrasound in hepatic steatosis. Expert Rev. Gastroenterol. Hepatol. 2019, 13, 667–681. [Google Scholar] [CrossRef] [PubMed]
- Pu, K.; Wang, Y.; Bai, S.; Wei, H.; Zhou, Y.; Fan, J.; Qiao, L. Diagnostic accuracy of controlled attenuation parameter (CAP) as a non-invasive test for steatosis in suspected non-alcoholic fatty liver disease: A systematic review and meta-analysis. BMC Gastroenterol. 2019, 19, 51. [Google Scholar] [CrossRef] [PubMed]
- Brener, S. Transient Elastography for Assessment of Liver Fibrosis and Steatosis: An Evidence-Based Analysis. Ont. Health Technol. Assess. Ser. 2015, 15, 1–45. [Google Scholar] [PubMed]
- Cocciolillo, S.; Parruti, G.; Marzio, L. CEUS and Fibroscan in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. World J. Hepatol. 2014, 6, 496–503. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tovo, C.V.; Villela-Nogueira, C.A.; Leite, N.C.; Panke, C.L.; Port, G.Z.; Fernandes, S.; Buss, C.; Coral, G.P.; Cardoso, A.C.; Cravo, C.M.; et al. Transient hepatic elastography has the best performance to evaluate liver fibrosis in non-alcoholic fatty liver disease (NAFLD). Ann. Hepatol. 2019, 18, 445–449. [Google Scholar] [CrossRef]
- Jeong, J.Y.; Kim, T.Y.; Sohn, J.H.; Kim, Y.; Jeong, W.K.; Oh, Y.H.; Yoo, K.S. Real time shear wave elastography in chronic liver diseases: Accuracy for predicting liver fibrosis, in comparison with serum markers. World J. Gastroenterol. 2014, 20, 13920–13929. [Google Scholar] [CrossRef] [PubMed]
- Grgurević, I.; Bokun, T.; Mustapić, S.; Trkulja, V.; Heinzl, R.; Banić, M.; Puljiz, Ž.; Lukšić, B.; Kujundžić, M. Real-time two-dimensional shear wave ultrasound elastography of the liver is a reliable predictor of clinical outcomes and the presence of esophageal varices in patients with compensated liver cirrhosis. Croat Med. J. 2015, 56, 470–481. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yoneda, M.; Suzuki, K.; Kato, S.; Fujita, K.; Nozaki, Y.; Hosono, K.; Saito, S.; Nakajima, A. Nonalcoholic fatty liver disease: US-based acoustic radiation force impulse elastography. Radiology 2010, 256, 640–647. [Google Scholar] [CrossRef]
- Liu, H.; Fu, J.; Hong, R.; Liu, L.; Li, F. Acoustic Radiation Force Impulse Elastography for the Non-Invasive Evaluation of Hepatic Fibrosis in Non-Alcoholic Fatty Liver Disease Patients: A Systematic Review & Meta-Analysis. PLoS ONE 2015, 10, e0127782. [Google Scholar] [CrossRef]
- Venkatesh, S.K.; Yin, M.; Ehman, R.L. Magnetic resonance elastography of liver: Technique, analysis, and clinical applications. J. Magn. Reson. Imaging 2013, 37, 544–555. [Google Scholar] [CrossRef] [Green Version]
- Cui, J.; Ang, B.; Haufe, W.; Hernandez, C.; Verna, E.C.; Sirlin, C.B.; Loomba, R. Comparative diagnostic accuracy of magnetic resonance elastography vs. eight clinical prediction rules for non-invasive diagnosis of advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease: A prospective study. Aliments Pharmacol. Ther. 2015, 41, 1271–1280. [Google Scholar] [CrossRef]
- Heba, E.; Hernandez, C.; Haufe, W.; Hooker, J.; Andre, M.P.; Valasek, M.A.; Aryafar, H.; Sirlin, C.B.; Loomba, R. Magnetic resonance elastography is superior to acoustic radiation force impulse for the Diagnosis of fibrosis in patients with biopsy-proven nonalcoholic fatty liverdisease: A prospective study. Hepatology 2016, 63, 453–461. [Google Scholar] [CrossRef]
- Karlas, T.; Petroff, D.; Garnov, N.; Böhm, S.; Tenckhoff, H.; Wittekind, C.; Wiese, M.; Schiefke, I.; Linder, N.; Schaudinn, A.; et al. Non-invasive assessment of hepatic steatosis in patients with NAFLD using controlled attenuation parameter and 1H-MR spectroscopy. PLoS ONE 2014, 9, e91987. [Google Scholar] [CrossRef]
- Kang, B.K.; Yu, E.S.; Lee, S.S.; Lee, Y.; Kim, N.; Sirlin, C.B.; Cho, E.Y.; Yeom, S.K.; Byun, J.H.; Park, S.H.; et al. Hepatic fat quantification: A prospective comparison of magnetic resonance spectroscopy and analysis methods for chemical-shift gradient echo magnetic resonance imaging with histologic assessment as the reference standard. Investig. Radiol. 2012, 47, 368–375. [Google Scholar] [CrossRef]
- Lee, S.S.; Park, S.H. Radiologic evaluation of nonalcoholic fatty liver disease. World J. Gastroenterol. 2014, 20, 7392–7402. [Google Scholar] [CrossRef]
- Besutti, G.; Valenti, L.; Ligabue, G.; Bassi, M.C.; Pattacini, P.; Guaraldi, G.; Giorgi Rossi, P. Accuracy of imaging methods for steatohepatitis diagnosis in non-alcoholic fatty liverdisease patients: A systematic review. Liver Int. 2019. [Google Scholar] [CrossRef]
- Manning, P.; Murphy, P.; Wang, K.; Hooker, J.; Wolfson, T.; Middleton, M.S.; Newton, K.P.; Behling, C.; Awai, H.I.; Durelle, J.; et al. Liver histology and diffusion-weighted MRI in children with nonalcoholic fatty liverdisease: A MAGNET study. J. Magn. Reson. Imaging 2017, 46, 1149–1158. [Google Scholar] [CrossRef]
- Schwimmer, J.B.; Behling, C.; Angeles, J.E.; Paiz, M.; Durelle, J.; Africa, J.; Newton, K.P.; Brunt, E.M.; Lavine, J.E.; Abrams, S.H.; et al. Magnetic resonance elastography measured shear stiffness as a biomarker of fibrosis in pediatric nonalcoholic fatty liver disease. Hepatology 2017, 66, 1474–1485. [Google Scholar] [CrossRef]
- Guo, Y.; Lin, H.; Zhang, X.; Wen, H.; Chen, S.; Chen, X. The influence of hepatic steatosis on the evaluation of fibrosis with non-alcoholic fatty liver disease by acoustic radiation force impulse. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2017, 2017, 2988–2991. [Google Scholar] [CrossRef]
- Vuppalanchi, R.; Siddiqui, M.S.; Van Natta, M.L.; Hallinan, E.; Brandman, D.; Kowdley, K.; Neuschwander-Tetri, B.A.; Loomba, R.; Dasarathy, S.; Abdelmalek, M.; et al. NASH Clinical Research Network. Performance characteristics of vibration-controlled transient elastography for evaluation of nonalcoholic fatty liver disease. Hepatology 2018, 67, 134–144. [Google Scholar] [CrossRef]
- Tovo, C.V.; de Mattos, A.Z.; Coral, G.P.; Branco, F.S.; Suwa, E.; de Mattos, A.A. Noninvasive imaging assessment of non-alcoholic fatty liver disease: Focus onliver scintigraphy. World J. Gastroenterol. 2015, 21, 4432–4439. [Google Scholar] [CrossRef]
- Lee, S.J.; Kim, S.U. Noninvasive monitoring of hepatic steatosis: Controlled attenuation parameter and magnetic resonance imaging-proton density fat fraction in patients with nonalcoholic fatty liver disease. Expert Rev. Gastroenterol. Hepatol. 2019, 523–530. [Google Scholar] [CrossRef]
- Jayakumar, S.; Middleton, M.S.; Lawitz, E.J.; Mantry, P.S.; Caldwell, S.H.; Arnold, H.; Mae Diehl, A.; Ghalib, R.; Elkhashab, M.; Abdelmalek, M.F.; 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, 133–141. [Google Scholar] [CrossRef]
Genes incorporated in Glucose and Lipid Metabolism | |
Apolipoprotein C III | APOC3 rs 2854116, rs 2854117 |
Peroxisome proliferative activated receptor α, γ, peroxisome proliferator-activated receptor γ coactivator 1-α | PPAR α, rs 1800206, PPAR γ, rs1801282, PPARGC1A, rs2290602 |
Fatty acid transport protein | FATP5, rs 56225452 |
Adiponectin | ADIPQ, rs2241766, rs 1501299 |
Leptin receptor | LEPR rs62589000, rs6700986 |
Resistin | RETN rs 3745367 |
Genes incorporated in the pathogenesis of NAFLD | |
TNF-α, TNF-α related apoptosis inducing ligand | TNF-α rs 1800629, rs361525,TRAIL rs6763816, rs4491934 |
Toll like receptor | TLR4 rs4986790 |
Superoxide dismutase 2 | SOD2 rs4880 |
Cytochrome P450 2E1 | CYP2E1 rs2031920 |
Kruppel-like factor 6 | KLP6 rs3750816 |
Transforming growth factor β1 | TGF-β1 rs1800471 |
Angiotensin II, angiotensin II Type receptor | AGII rs699, AGTR1 rs3772622, rs 3772633 |
Method | Field of Detection | Accuracy | Strengths | Advantages and Limitations | Reference |
---|---|---|---|---|---|
Biochemical Methods | |||||
IL-6 | NASH fibrosis | AUROC 0.83 | 95% CI: 0.67;0.98 p = 0.0024 Sensitivity 85% Specificity 86%. | Discrimination between advanced fibrosis patients compared to mild fibrosis patients and no fibrosis patients; p < 0.001. | [89] |
VCAM-1 | NASH fibrosis | AUROC 0.87 0.79 0.53 | 95% CI: 0.75;1.0 p = 0.0005 95% CI: 0.63;0.95 p = 0.0064 95% CI: 0.35;0.71 n.s. | Distinguish between advanced fibrosis and no fibrosis. Distinguish between mild fibrosis from advanced fibrosis. Poor sensitivity for distinguish in no fibrosis compared to mild fibrosis. In children and adolescents is elevated with obesity. | [78] |
HA | NASH fibrosis | AUROC 0.94 | Cut off 25 ug/L sensitivity 90%, specificity 84% CI: 0.59–0.99. | Discrimination between significant liver fibrosis F3 + F4 and mild to moderate, or no fibrosis (F0–F2); p < 0.001. | [94] |
Cytokeratin 18 | NASH fibrosis | M65 AUROC 0.89 | Cut off 750 U/L, sensitivity 80%, specificity 82%, 95% CI: 0.57–0.95. Cut-off 211 U/L, sensitivity 0.79, Specificity 0.76, 95% CI: 0.56–0.93. | Diferentiation of patients with and without NASH. M65 p < 0.014, M30 p < 0.001. Can predict the disease severity in NASH patients. | [94] |
M30 AUROC 0.85 | Cut off 750 U/L, sensitivity 80%, specificity 82%, 95% CI: 0.57–0.95. Cut-off 211 U/L, sensitivity 0.79, Specificity 0.76, 95% CI: 0.56–0.93. | Diferentiation of patients with and without NASH. M65 p < 0.014, M30 p < 0.001. Can predict the disease severity in NASH patients. | [15] |
Method | Field of Detection | Parameters Used for Calculation | Accuracy | Strengths | Advantages and Limitations | Ref. |
---|---|---|---|---|---|---|
Scoring Method | ||||||
Fatty liver index (FLI) | NAFLD | BMI, WC, GGT, triglycerides | AUROC 0.83 AUROC 0.67 | Optimal cut-off point 30 Sensitivity 79.8% Specificity 71.5% 95 % CI:0.825–0.842, p < 0.001. | Low cutoff of 30 is used to rule out NAFLD (negative likelihood ratio 0.2). High cutoff of 60 is used (with a positive likelihood ratio of 4.3). Poorly distinguishes moderate-to severe steatosis from mild steatosis. Limited use in obese patients. | [108] [111] |
Hepatic steatosis index (HSI) | NAFLD | Gender, Diabetes mellitus, BMI, ALT/AST ratio | AUROC 0.81 | Cut-off point 30 p < 0.001 Sensitivity of 93.1% Specificity of 92.4% (95 % CI: 0.81–0.824). | At values of <30, ruled out NAFLD. At values of >36, detected NAFLD. Poorly distinguishes moderate-to severe steatosis from mild steatosis. HSI accuracy decreases in obese children. | [113] [15] |
SteatoTest | Steatosis | apha-2-macroglobulin, apolipoprotein A1, haptoglobin, bilirubin, GGT, ALT, glucose, triglycerides, cholesterol, age, gender, BMI | AUROC 0.71 | At the cut off 0.38: Sensitivity 89.7% Specificity 44.9% PPV 90.9% NPV 41.3% PPV 92.4% for the dg. of steatosis >S0 using 0.38 cut off. NPV 59.3% for the dg. of steatosis >S1 using 0.69 cut off. | [115] | |
NAFL Screening score | NAFLD | Age, glucose, BMI, triglycerides, ALT/AST, uric acid | AUROC 0.87 | At the cut-off 0.24: Sensitivity 92%; NPV 95% At the cut-off 0.44: Specificity 90%; PPV 84% | [15] | |
NAFLD fibrosis score (NFS) | Advanced fibrosis | Age, BMI, impaired fasting glucose and/or diabetes, AST/ALT ratio, platelet count, and albumin | AUROC 0.96 0.83 for cirrhosis 0.73 for advanced fibrosis 0.72 for significant fibrosis | At the cutoff ≤−1.455: Sensitivity 75% Specificity 93% PPV 63%; NPV 96% | Below the lower cutoff (≤−1.455), healthy. Above the cutoff (≥0.676), advanced fibrosis. | [123] |
At the cut- off ≥0.676: Sensitivity 19% Specificity 100% PPV100%; NPV 89% | Can be used to identify those at low or high risk for advanced fibrosis or cirrhosis. | [15] | ||||
APRI | Advanced fibrosis | AST/platelet ratio index | AUROC 0.85 | Optimal cut off 0.98 Sensitivity of 75% Specificity of 86% PPV 54%; NPV 93% | [117] | |
AUROC 0.75 for advanced fibrosis or cirrhosis 0.70 for significant fibrosis | Low specificity to diagnose advanced fibrosis. | [15] | ||||
FIB-4 | Advanced fibrosis | Age, platelet count, ALT, AST | AUROC 0.85 for cirrhosis 0.80 for advanced fibrosis 0.75 for significant fibrosis | At the cut-off 1.3 Sensitivity 85% Specificity 65% PPV 36%; NPV 95% At the cut off 3.25 Sensitivity 26% Specificity 98% PPV 75%; NPV 85% | Can be used to identify patients at low or high risk for advanced fibrosis or cirrhosis. | [15] |
BARD score | Advanced fibrosis | AST, ALT, BMI and diabetes | AUROC 0.70 for cirrhosis 0.73 for advanced fibrosis 0.64 for significant fibrosis | Low specificity to diagnose significant fibrosis and cirrhosis. | [15] | |
Enhanced liver fibrosis (ELF) | Advanced fibrosis Mild fibrosis Fibrosis not present | TIMP1, HA, aminoterminal peptide of pro-colagen III | AUROC 0.90 for severe fibrosis 0.82 for moderate fibrosis 0.76 for no fibrosis | [134] | ||
Hepatic steatosis index (HIS) | Steatosis | Gender, T2DM, BMI, ALT, AST | AUROC 0.81 | Sensitivity of 93.1%, at values of <30 ruled out NAFLD. Specificity of 92.4%, at values of >36 detected NAFLD. | [113] |
Method | Field of Detection | AUROC | Ref. |
---|---|---|---|
Imaging Methods | |||
USG | Steatosis | 0.93 | [169] |
CT | Steatosis | 0.92 | [186] |
MRI | Steatosis | 0.99 | [186] |
TE | Advanced fibrosis | 0.99 | [179] |
ARFI | Advanced fibrosis | 0.97 | [179] |
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Kupčová, V.; Fedelešová, M.; Bulas, J.; Kozmonová, P.; Turecký, L. Overview of the Pathogenesis, Genetic, and Non-Invasive Clinical, Biochemical, and Scoring Methods in the Assessment of NAFLD. Int. J. Environ. Res. Public Health 2019, 16, 3570. https://doi.org/10.3390/ijerph16193570
Kupčová V, Fedelešová M, Bulas J, Kozmonová P, Turecký L. Overview of the Pathogenesis, Genetic, and Non-Invasive Clinical, Biochemical, and Scoring Methods in the Assessment of NAFLD. International Journal of Environmental Research and Public Health. 2019; 16(19):3570. https://doi.org/10.3390/ijerph16193570
Chicago/Turabian StyleKupčová, Viera, Michaela Fedelešová, Jozef Bulas, Petra Kozmonová, and Ladislav Turecký. 2019. "Overview of the Pathogenesis, Genetic, and Non-Invasive Clinical, Biochemical, and Scoring Methods in the Assessment of NAFLD" International Journal of Environmental Research and Public Health 16, no. 19: 3570. https://doi.org/10.3390/ijerph16193570