Non-alcoholic fatty liver disease: Non-invasive investigation and risk stratification

Postgraduate Medical Journal

Volumn 90, Issue 1063, 2014, Pages 254-266

  Dyson, J K ^a   McPherson, S ^a,b   Anstee, Q M ^a,b  

^a FREEMAN HOSPITAL   (United Kingdom)

^b NEWCASTLE UNIVERSITY   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ADIPOCYTOKINE; ALANINE AMINOTRANSFERASE; ASPARTATE AMINOTRANSFERASE; C REACTIVE PROTEIN; CYTOKERATIN 18; FERRITIN; HYALURONIC ACID; INTERLEUKIN 6; INTERLEUKIN 8; KRUPPEL LIKE FACTOR 6; MANGANESE SUPEROXIDE DISMUTASE; PHOSPHATIDYLETHANOLAMINE METHYLTRANSFERASE; TUMOR NECROSIS FACTOR ALPHA;

ALCOHOL CONSUMPTION; APOPTOSIS; ARTICLE; COMPUTER ASSISTED TOMOGRAPHY; ECHOGRAPHY; ELASTOGRAPHY; ENZYME LINKED IMMUNOSORBENT ASSAY; FATTY LIVER; HUMAN; INSULIN RESISTANCE; LIVER BIOPSY; LIVER FIBROSIS; LIVER FUNCTION TEST; NON INVASIVE PROCEDURE; NONALCOHOLIC FATTY LIVER; NONALCOHOLIC FATTY LIVER DISEASE ACTIVITY SCORE; NUCLEAR MAGNETIC RESONANCE IMAGING; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; OBESITY; OXIDATIVE STRESS; PROTON NUCLEAR MAGNETIC RESONANCE; RECEIVER OPERATING CHARACTERISTIC; RISK FACTOR; SENSITIVITY AND SPECIFICITY; STEATOSIS; BIOPSY; COMPLICATION; DIAGNOSTIC IMAGING; DISEASE COURSE; FEMALE; LIVER CIRRHOSIS; MALE; PATHOLOGY; PATIENT SELECTION; PROCEDURES; PROGNOSIS; QUALITY CONTROL; RISK ASSESSMENT;

BENCHMARKING; BIOPSY; DIAGNOSTIC IMAGING; DISEASE PROGRESSION; FATTY LIVER; FEMALE; HUMANS; INSULIN RESISTANCE; LIVER CIRRHOSIS; MALE; NON-ALCOHOLIC FATTY LIVER DISEASE; OXIDATIVE STRESS; PATIENT SELECTION; PROGNOSIS; RISK ASSESSMENT;

EID: 84922392434     PISSN: 00325473     EISSN: 14690756     Source Type: Journal    
DOI: 10.1136/postgradmedj-2013-201620rep     Document Type: Article

References (159)

1. Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nature reviews. Gastroenterol Hepatol 2013;10:330-44.
2. Argo CK, Caldwell SH. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis 2009;13:511-31.
3. Cobbold JF, Anstee QM, Taylor-Robinson SD. The importance of fatty liver disease in clinical practice. Proc Nutr Soc 2010:1-10.
4. Bellentani S, Bedogni G, Miglioli L, et al. The epidemiology of fatty liver. Eur J Gastroenterol Hepatol 2004;16:1087-93.
5. Targher G, Bertolini L, Padovani R, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007;30:1212-18.
6. Jimba S, Nakagami T, Takahashi M, et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet Med 2005;22:1141-45.
7. Williams CD, Stengel J, Asike MI, 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.
8. Williamson RM, Price JF, Glancy S, et al. Prevalence of and risk factors for hepatic steatosis and nonalcoholic Fatty liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes Care 2011;34:1139-44.
9. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640-5.
10. Dixon J, Bhathal P, O'Brian P. Non-alcoholic fatty liver disease: predictors of non-alcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001;121:91-100.
11. Kotronen A, Westerbacka J, Bergholm R, et al. Liver fat in the metabolic syndrome. J Clin Endocrinol Metab 2007;92:3490-7.
12. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology 2011;53:1874-82.
13. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006;44:865-73.
14. Mofrad P, Contos MJ, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 2003;37:1286-92.
15. Anstee QM, McPherson S, Day CP. How big a problem is non-alcoholic fatty liver disease? BMJ 2011;343:d3897.
16. Ratziu V, Bellentani S, Cortez-Pinto H, et al. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010;53:372-84.
17. Anstee QM, Daly AK, Day CP. Genetic modifiers of non-alcoholic fatty liver disease progression. Biochim Biophys Acta 2011;1812:1557-66.
18. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461-5.
19. Valenti L, Al-Serri A, Daly AK, et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2010;51:1209-17.
20. Kotronen A, Johansson LE, Johansson LM, et al. A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans. Diabetologia 2009;52:1056-60.
21. Sookoian S, Castano GO, Burgueno AL, et al. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J Lipid Res 2009;50:2111-16.
22. Kantartzis K, Peter A, Machicao F, et al. Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene. Diabetes 2009;58:2616-23.
23. Rotman Y, Koh C, Zmuda JM, et al. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 2010;52:894-903.
24. Namikawa C, Shu-Ping Z, Vyselaar JR, et al. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. J Hepatol 2004;40:781-6.
25. Al-Serri A, Anstee QM, Valenti L, et al. The SOD2 C47 T polymorphism influences NAFLD fibrosis severity: evidence from case-control and intra-familial allele association studies. J Hepatol 2012;56:448-54.
26. Dong H, Wang J, Li C, et al. The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population. J Hepatol 2007;46:915-20.
27. Song J, da Costa KA, Fischer LM, et al. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). FASEB J 2005;19:1266-71.
28. Narla G, Difeo A, Reeves HL, et al. A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk. Cancer Res 2005;65:1213-22.
29. Miele L, Beale G, Patman G, et al. The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease. Gastroenterology 2008;135:282-91.
30. Anstee QM, Goldin RD. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol 2006;87:1-16.
31. Kerr TA, Davidson NO. Cholesterol and nonalcoholic fatty liver disease: renewed focus on an old villain. Hepatology 2012;56:1995-8.
32. Abdelmalek MF, Suzuki A, Guy C, et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology 2010;51:1961-71.
33. Abu-Shanab A, Quigley EM. The role of the gut microbiota in nonalcoholic fatty liver disease. Nature reviews. Gastroenterol Hepatol 2010;7:691-701.
34. Wigg AJ, Roberts-Thomson IC, Dymock RB, et al. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001;48:206-11.
35. Sabate JM, Jouet P, Harnois F, et al. High prevalence of small intestinal bacterial overgrowth in patients with morbid obesity: a contributor to severe hepatic steatosis. Obes Surg 2008;18:371-7.
36. Henao-Mejia J, Elinav E, Jin C, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012;482:179-85.
37. Tanne F, Gagnadoux F, Chazouilleres O, et al. Chronic liver injury during obstructive sleep apnea. Hepatology 2005;41:1290-6.
38. Tatsumia K, Saibarab T. Effects of obstructive sleep apnoea syndrome on hepatic steastosis and non-alcoholic steatohepatitis. Hepatol Res 2005;33:100-4.
39. Norman D, Bardwell WA, Arosemena F, et al. Serum aminotransferase levels are associated with markers of hypoxia in patients with obstructive sleep apnea. Sleep 2008;31:121-26.
40. Hourigan L, Macdonald G, Purdie D, et al. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 1999;29:1215-19.
41. Sanyal AJ, Contos MJ, Sterling RK, et al. Nonalcoholic fatty liver disease in patients with hepatitis C is associated with features of the metabolic syndrome. Am J Gastroenterol 2003;98:2064-71.
42. Powell EE, Ali A, Clouston AD, et al. Steatosis is a cofactor in liver injury in hemochromatosis. Gastroenterology 2005;129:1937-43.
43. Ekstedt M, Franzen LE, Holmqvist M, et al. Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease. Scand J Gastroenterol 2009;44:366-74.
44. Chalasani N, Younossi Z, Lavine JE, 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 2012;55:2005-23.
45. Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40:1387-95.
46. Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002;137:1-10.
47. Cobbold JF, Anstee QM, Thomas HC. Investigating mildly abnormal serum aminotransferase values. BMJ 2010;341:c4039.
48. Manousou P, Kalambokis G, Grillo F, et al. Serum ferritin is a discriminant marker for both fibrosis and inflammation in histologically proven non-alcoholic fatty liver disease patients. Liver Int 2011;31:730-9.
49. Kowdley KV, Belt P, Wilson LA, et al. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2012;55:77-85.
50. European Association for the Study of the Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol 2010;53:3-22.
51. Adams LA, Lindor KD, Angulo P. The prevalence of autoantibodies and autoimmune hepatitis in patients with nonalcoholic Fatty liver disease. Am J Gastroenterol 2004;99:1316-20.
52. Vuppalanchi R, Gould RJ, Wilson LA, et al. Clinical significance of serum autoantibodies in patients with NAFLD: results from the nonalcoholic steatohepatitis clinical research network. Hepatol Int 2012;6:379-85.
53. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313-21.
54. Ekstedt M, Franzen LE, Mathiesen UL, et al. Low clinical relevance of the nonalcoholic fatty liver disease activity score (NAS) in predicting fibrosis progression. Scand J Gastroenterol 2012;47:108-15.
55. Bedossa P, Poitou C, Veyrie N, et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology 2012;56:1751-9.
56. Guha IN, Parkes J, Roderick P, et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: Validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology 2008;47:455-60.
57. McPherson S, Stewart SF, Henderson E, et al. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut 2010;59:1265-9.
58. Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005;128:1898-906.
59. Yamaguchi K, Yang L, McCall S, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 2007;45:1366-74.
60. Poynard T, Lassailly G, Diaz E, et al. Performance of biomarkers FibroTest, ActiTest, SteatoTest, and NashTest in patients with severe obesity: meta analysis of individual patient data. PloS One 2012;7:e30325.
61. Poynard T, Ratziu V, Naveau S, et al. The diagnostic value of biomarkers (SteatoTest) for the prediction of liver steatosis. Comp Hepatol 2005;4:10.
62. Bedogni G, Bellentani S, Miglioli L, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol 2006;6:33.
63. Musso G, Gambino R, Durazzo M, et al. Noninvasive assessment of liver disease severity with liver fat score and CK-18 in NAFLD: Prognostic value of liver fat equation goes beyond hepatic fat estimation. Hepatology 2010;51:715-7.
64. Kotronen A, Peltonen M, Hakkarainen A, et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology 2009;137:865-72.
65. Bedogni G, Kahn HS, Bellentani S, et al. A simple index of lipid overaccumulation is a good marker of liver steatosis. BMC Gastroenterol 2010;10:98.
66. Schwenzer NF, Springer F, Schraml C, et al. Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. J Hepatol 2009;51:433-45.
67. Ballestri S, Lonardo A, Romagnoli D, et al. Ultrasonographic fatty liver indicator, a novel score which rules out NASH and is correlated with metabolic parameters in NAFLD. Liver Int 2012;32:1242-52.
68. Zardi EM, De Sio I, Ghittoni G, et al. Which clinical and sonographic parameters may be useful to discriminate NASH from steatosis? J Clin Gastroenterol 2011;45:59-63.
69. Myers RP, Pollett A, Kirsch R, et al. Controlled Attenuation Parameter (CAP): a noninvasive method for the detection of hepatic steatosis based on transient elastography. Liver Int 2012;32:902-10.
70. Sasso M, Tengher-Barna I, Ziol M, et al. Novel controlled attenuation parameter for noninvasive assessment of steatosis using Fibroscan (R): validation in chronic hepatitis C. J Viral Hepat 2012;19:244-53.
71. Fishbein M, Castro F, Cheruku S, et al. Hepatic MR for fat quantitation: its relationship to fat morphology, diagnosis, and ultrasound. J Gin Gastroenterol 2005;39:619-25.
72. Charatcharoenwitthaya P, Lindor KD. Role of radiologic modalities in the management of non-alcoholic steatohepatitis. Gin Liver Dis 2007;1137-1154.
73. Joy D, Thava VR, Scott BB. Diagnosis of fatty liver disease: is biopsy necessary? EurJ Gastroenterol Hepatol 2003;15:539-43.
74. Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002;123:745-50.
75. Caldwell SH, Oelsner DH, Iezzoni JC, et al. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999;29:664-9.
76. Szczepaniak LS, Nurenberg P, Leonard D, 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.
77. Petersen KF, Dufour S, Befroy D, et al. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 2005;54:603-8.
78. Thomas EL, Hamilton G, Patel N, et al. Hepatic triglyceride content and its relation to body adiposity: a magnetic resonance imaging and proton magnetic resonance spectroscopy study. Gut 2005;54:122-7.
79. Guiu B, Petit JM, Loffroy R, et al. Quantification of liver fat content: comparison of triple-echo chemical shift gradient-echo imaging and in vivo proton MR spectroscopy. Radiology 2009;250:95-102.
80. Cesbron-Métivier E, Roullier V, Boursier J, et al. Noninvasive liver steatosis quantification using MRI techniques combined with blood markers. Eur J Gastroenterol Hepatol 2010;22:273-82.
81. McPherson S, Jonsson JR, Cowin GJ, et al. Magnetic resonance imaging and spectroscopy accurately estimate the severity of steatosis provided the stage of fibrosis is considered. J Hepatol 2009;51:389-97.
82. Levene AP, Kudo H, Thursz MR, et al. Is oil red-O staining and digital image analysis the gold standard for quantifying steatosis in the liver. Hepatology 2010;51:1859.
83. Malhi H, Gores GJ, Lemasters JJ. Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology 2006;43(2 Suppl 1):S31-S44.
84. Anstee QM, Concas D, Kudo H, et al. Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis. J Hepatol 2010;53:542-50.
85. Farrell GC, Larter CZ, Hou JY, et al. Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression. J Gastroenterol Hepatol 2009;24:443-52.
86. Iredale JP. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Gin Invest 2007;117:539-48.
87. Phillips H, Balart LA. Problems with NASH? HAIR is some help. Am J Gastroenterol 2003;98:500.
88. Palekar NA, Naus R, Larson SP, et al. Clinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonalcoholic fatty liver disease. Liver Int 2006;26:151-6.
89. Tanwar S, Trembling PM, Guha IN, et al. Validation of terminal peptide of procollagen III for the detection and assessment of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease. Hepatology 2013;57:103-11.
90. Shimada M, Kawahara H, Ozaki K, et al. Usefulness of a combined evaluation of the serum adiponectin level, HOMA-IR, and serum type IV collagen 7S level to predict the early stage of nonalcoholic steatohepatitis. Am J Gastroenterol 2007;102:1931-8.
91. Lassailly G, Caiazzo R, Hollebecque A, et al. Validation of noninvasive biomarkers (FibroTest, SteatoTest, and NashTest) for prediction of liver injury in patients with morbid obesity. Eur J Gastroenterol Hepatol 2011;23:499-506.
92. Poynard T, Ratziu V, Charlotte F, et al. 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.
93. Gholam PM, Flancbaum L, Machan JT, et al. Nonalcoholic fatty liver disease in severely obese subjects. Am J Gastroenterol 2007;102:399-408.
94. Yilmaz Y, Ulukaya E, Dolar E. A "biomarker biopsy" for the diagnosis of NASH: promises from CK-18 fragments. Obes Surg 2008;18:1507-8.
95. Younossi ZM, Jarrar M, Nugent C, et al. A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH). Obes Surg 2008;18:1430-7.
96. Younossi ZM, Page S, Rafiq N, et al. A biomarker panel for non-alcoholic steatohepatitis (NASH) and NASH-related fibrosis. Obes Surg 2011;21:431-9.
97. Shen J, Chan HL, Wong GL, et al. Assessment of non-alcoholic fatty liver disease using serum total cell death and apoptosis markers. Aliment Pharmacol Ther 2012;36:1057-66.
98. Feldstein AE, Wieckowska A, Lopez AR, et al. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 2009;50:1072-78.
99. Tamimi TI, Elgouhari HM, Alkhouri N, et al. An apoptosis panel for nonalcoholic steatohepatitis diagnosis. J Hepatol 2011;54:1224-9.
100. Anty R, Iannelli A, Patouraux S, et al. A new composite model including metabolic syndrome, alanine aminotransferase and cytokeratin-18 for the diagnosis of non-alcoholic steatohepatitis in morbidly obese patients. Aliment Pharmacol Ther 2010;32:1315-22.
101. Albano E, Mottaran E, Occhino G, et al. Review article: role of oxidative stress in the progression of non-alcoholic steatosis. Aliment Pharmacol Ther 2005;22(Suppl 2):71-3.
102. Chalasani N, Deeg MA, Crabb DW. Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2004;99:1497-502.
103. Jarrar MH, Baranova A, Collantes R, et al. Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2008;27:412-21.
104. Wong VW, Hui AY, Tsang SW, et al. Metabolic and adipokine profile of Chinese patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2006;4:1154-61.
105. Katja RLM, Parhofer K, Broedl U. Adipokines and insulin resistance. Mol Med 2008;14:741-45.
106. Abiru S, Migita K, Maeda Y, et al. Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis. Liver Int 2006;2006:39-45.
107. Lemoine M, Ratziu V, Kim M, et al. Serum adipokine levels predictive of liver injury in non-alcoholic fatty liver disease. Liver Int 2009;29:1431-8.
108. Baranova A, Gowder SJ, Schlauch K, et al. Gene expression of leptin, resistin, and adiponectin in the white adipose tissue of obese patients with non-alcoholic fatty liver disease and insulin resistance. Obes Surg 2006;16:1118-25.
109. Musso G, Gambino R, Durazzo M, et al. Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology 2005;42:1175-83.
110. Vuppalanchi R, Marri S, Kolwankar D, et al. Is adiponectin involved in the pathogenesis of non-alcoholic steatohepatitis? A preliminary human study. J Clin Gastroenterol 2005;39:237-42.
111. Hui JM, Hodge A, Farrell GC, et al. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 2004;40:46-54.
112. 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 2006;64:679-83.
113. Haukeland JW, Damas JK, Konopski Z, et al. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol 2006;44:1167-74.
114. Feldstein AE, Canbay A, Guicciardi ME, et al. Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice. J Hepatol 2003;39:978-83.
115. Feldstein AE, Canbay A, Angulo P, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 2003;125:437-43.
116. Wieckowska A, Zein NN, Yerian LM, et al. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology 2006;44:27-33.
117. Ratziu V, Sheikh MY, Sanyal AJ, et al. A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis. Hepatology 2012;55:419-28.
118. Bantel H, Ruck P, Gregor M, et al. Detection of elevated caspase activation and early apoptosis in liver diseases. Eur J Cell Biol 2001;80:230-9.
119. Joka D, Wahl K, Moeller S, et al. Prospective biopsy-controlled evaluation of cell death biomarkers for prediction of liver fibrosis and nonalcoholic steatohepatitis. Hepatology 2012;55:455-64.
120. Adams LA, Feldstein AE. Non-invasive diagnosis of nonalcoholic fatty liver and nonalcoholic steatohepatitis. J Dig Dis 2011;12:10-16.
121. Iijima H, Moriyasu F, Tsuchiya K, et al. Decrease in accumulation of ultrasound contrast microbubbles in non-alcoholic steatohepatitis. Hepatol Res 2007;37:722-30.
122. Pinzani M, Vizzutti F, Arena U, et al. Technology Insight: noninvasive assessment of liver fibrosis by biochemical scores and elastography. Nature clinical practice. Gastroenterol Hepatol 2008;5:95-106.
123. Sheth SG, Flamm SL, Gordon FD, et al. AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol 1998;93:44-8.
124. Loaeza-del-Castillo A, Paz-Pineda F, Oviedo-Cardenas E, et al. AST to platelet ratio index (APRI) for the noninvasive evaluation of liver fibrosis. Ann Hepatol 2008;7:350-7.
125. Kruger FC, Daniels CR, Kidd M, et al. APRI: a simple bedside marker for advanced fibrosis that can avoid liver biopsy in patients with NAFLD/NASH. S Afr Med J 2011;101:477-80.
126. Ratziu V, Giral P, Charlotte F, et al. Liver fibrosis in overweight patients. Gastroenterology 2000;118:1117-23.
127. Harrison SA, Oliver D, Arnold HL, et al. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut 2008;57:1441-7.
128. Shah AG, Lydecker A, Murray K, et al. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2009;7:1104-12.
129. Cales P, Laine F, Boursier J, et al. Comparison of blood tests for liver fibrosis specific or not to NAFLD. J Hepatol 2009;50:165-73.
130. Ratziu V, Massard J, Charlotte F, et al. Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol 2006;6:6.
131. Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007;45:846-54.
132. Rosenberg WM, Voelker M, Thiel R, et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology 2004;127:1704-13.
133. Williams AL, Hoofnagle JH. Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis. Gastroenterology 1988;95:734-9.
134. Imperiale TF, Said AT, Cummings OW, et al. Need for validation of clinical decision aids: use of the AST/ALT ratio in predicting cirrhosis in chronic hepatitis C. Am J Gastroenterol 2000;95:2328-32.
135. Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003;38:518-26.
136. Borsoi Viana MS, Takei K, Collarile Yamaguti DC, et al. Use of AST platelet ratio index (APRI Score) as an alternative to liver biopsy for treatment indication in chronic hepatitis C. Ann Hepatol 2009;8:26-31.
137. Qureshi K, Clements RH, Abrams GA. The utility of the "FLD fibrosis score" in morbidly obese subjects with NAFLD. Obes Surg 2008;18:264-70.
138. Wong VW, Wong GL, Chim AM, et al. Validation of the NAFLD fibrosis score in a Chinese population with low prevalence of advanced fibrosis. Am J Gastroenterol 2008;103:1682-8.
139. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43:1317-25.
140. Adams LA. Mortality in nonalcoholic fatty liver disease: clues from the Cremona study. Hepatology 2011;54:6-8.
141. McPherson S, Anstee QM, Henderson E, et al. Are simple noninvasive scoring systems for fibrosis reliable in patients with NAFLD and normal ALT levels? Eur J Gastroenterol Hepatol 2013;25:652-8.
142. Suzuki A, Angulo P, Lymp J, et al. Hyaluronic acid, an accurate serum marker for severe hepatic fibrosis in patients with non-alcoholic fatty liver disease. Liver Int 2005;25:779-86.
143. Yoneda M, Mawatari H, Fujita K, et al. Type IV collagen 7 s domain is an independent clinical marker of the severity of fibrosis in patients with nonalcoholic steatohepatitis before the cirrhotic stage. J Gastroenterol 2007;42:375-81.
144. Lesmana CR, Hasan I, Budihusodo U, et al. Diagnostic value of a group of biochemical markers of liver fibrosis in patients with non-alcoholic steatohepatitis. J Dig Dis 2009;10:201-6.
145. Poynard T, Morra R, Halfon P, et al. Meta-analyses of FibroTest diagnostic value in chronic liver disease. BMC Gastroenterol 2007;7:40.
146. Huwart L, Peeters F, Sinkus R, et al. Liver fibrosis: non-invasive assessment with MR elastography. NMR Biomed 2006;19:173-9.
147. Chen J, Talwalkar JA, Yin M, et al. Early detection of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease by using MR elastography. Radiology 2011;259:749-56.
148. Aguirre DA, Behling CA, Alpert E, et al. Liver fibrosis: noninvasive diagnosis with double contrast material-enhanced MR imaging. Radiology 2006;239:425-37.
149. Lewin M, Poujol-Robert A, Boelle PY, et al. Diffusion-weighted magnetic resonance imaging for the assessment of fibrosis in chronic hepatitis C. Hepatology 2007;46:658-65.
150. Sandrin L, Fourguet B, Hasguenoph JM, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003;29:1705-13.
151. Foucher J, Chanteloup E, Vergniol J, et al. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut 2006;55:403-8.
152. Wong VW, Vergniol J, Wong GL, et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 2010;51:454-62.
153. Castera L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 2010;51:828-35.
154. Myers RP, 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 2012;55:199-208.
155. Myers RP, Pomier-Layrargues G, Kirsch R, et al. Discordance in fibrosis staging between liver biopsy and transient elastography using the fibroscan xl probe. J Hepatol 2012;56(3):564-70.
156. Palmeri ML, Wang MH, Rouze NC, et al. Noninvasive evaluation of hepatic fibrosis using acoustic radiation force-based shear stiffness in patients with nonalcoholic fatty liver disease. J Hepatol 2011;55:666-72.
157. Dahl JJ, Pinton GF, Palmeri ML, et al. A parallel tracking method for acoustic radiation force impulse imaging. IEEE Trans Ultrason Ferroelectr Freq Control 2007;54:301-12.
158. Yoneda M, Suzuki K, Kato S, et al. Nonalcoholic fatty liver disease: US-based acoustic radiation force impulse elastography. Radiology 2010;256:640-7.
159. Musso G, Gambino R, Cassader M, et al. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011;43:617-49.