Diagnosis and Assessment of NAFLD: Definitions and Histopathological Classification

Alastair D. Burt; Carolin Lackner; Dina G. Tiniakos

doi:10.1055/s-0035-1562942

Seminars in Liver Disease, Inhaltsverzeichnis

Semin Liver Dis 2015; 35(03): 207-220
DOI: 10.1055/s-0035-1562942

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Diagnosis and Assessment of NAFLD: Definitions and Histopathological Classification

Alastair D. Burt

¹Faculty of Health Sciences, The University of Adelaide, Level 2, Barr Smith South, North Terrace, Adelaide, Australia

,

Carolin Lackner

²Department of Quantitative Pathomorphology, Institute of Pathology, Medical University of Graz, Graz, Austria

,

Dina G. Tiniakos

³Clinical Senior Lecturer, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom

› Institutsangaben

Abstract

Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of clinical and histopathological changes including “simple” steatosis, steatosis with inflammation, steatohepatitis, cirrhosis, and hepatocellular carcinoma. It was initially described in the context of drug-induced liver injury and acute liver disease following jejunoileal bypass surgery, but since the early 1980s it has been widely acknowledged as the hepatic manifestation of metabolic syndrome. It now represents a burgeoning public health crisis and is fast becoming the main indication for liver transplantation in some parts of the world. Its true incidence and prevalence are unknown, although estimates have been made from large imaging studies. Liver biopsy interpretation is still regarded as the gold standard for making accurate diagnoses in NAFLD, but sampling limitations are recognized. Furthermore, clear definitions for key histopathological components have been lacking, resulting in significant interobserver variations in making a diagnosis of steatohepatitis. In this review the authors consider some aspects of classification and variant forms of NAFLD such as that occurring in children. They provide an update on grading and staging systems and histopathological prognostic factors, and address the role of liver biopsy in contemporary clinical care of patients with NAFLD.

Keywords

nonalcoholic fatty liver disease - steatosis - steatohepatitis - histopathology - metabolic syndrome

Volltext

Referenzen

References
1 MacSween RN, Burt AD. Histologic spectrum of alcoholic liver disease. Semin Liver Dis 1986; 6 (3) 221-232
2 Peters RL. Hepatic morphologic changes after jejunoileal bypass. Prog Liver Dis 1979; 6: 581-594
3 Lewis D, Wainwright HC, Kew MC, Zwi S, Isaacson C. Liver damage associated with perhexiline maleate. Gut 1979; 20 (3) 186-189
4 Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980; 55 (7) 434-438
5 Addison T. Observations on fatty degeneration of the liver. Guys Hosp Rep 1836; 1: 476
6 Rokitansky CA. Skizze der Größen und Formabweichungen der Leber. Bruchstück Med Jahrb des kaisl, königl Österr Staates 1839; Bd 29 oder neueste Folge Bd 20 Wien: 557
7 Bartolow P. Diseases of the liver. In: Pepper W, Starr L, (eds.). A System of Practical Medicine. Vol. II. Philadelphia, PA: Lea Brothers & Co; 1885: 1050
8 Statkewitsch P. Über veränderungen des muskel-und drüsengewebes sowie der herzganglien beim hungern. Arch Exper Path Pharmakol 1894; 33: 415-461
9 Pepper W. Saccharine diabetes. Med Rec 1884; 25: 9-12
10 Connor CL. Fatty infiltration of the liver and the development of cirrhosis in diabetes and chronic alcoholism. Am J Pathol 1938; 14 (3) 347-364 , 9
11 Brunt EM, Neuschwander-Tetri BA, Burt AD. Fatty liver disease: Alcoholic and non-alcoholic. In: Burt AD, Portmann B, Ferrel L, (Eds.). MacSween's Pathology of the Liver. Edinburgh: Churchill Livingstone; 2012: 293-359
12 Dietrich P, Hellerbrand C. Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. Best Pract Res Clin Gastroenterol 2014; 28 (4) 637-653
13 Yeh MM, Brunt EM. Pathological features of fatty liver disease. Gastroenterology 2014; 147 (4) 754-764
14 Tandra S, Yeh MM, Brunt EM , et al; NASH Clinical Research Network (NASH CRN). Presence and significance of microvesicular steatosis in nonalcoholic fatty liver disease. J Hepatol 2011; 55 (3) 654-659
15 Yip WW, Burt AD. Alcoholic liver disease. Semin Diagn Pathol 2006; 23 (3-4) 149-160
16 Sahini N, Borlak J. Recent insights into the molecular pathophysiology of lipid droplet formation in hepatocytes. Prog Lipid Res 2014; 54: 86-112
17 Pawella LM, Hashani M, Eiteneuer E , et al. Perilipin discerns chronic from acute hepatocellular steatosis. J Hepatol 2014; 60 (3) 633-642
18 Smagris E, BasuRay S, Li J , et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 2015; 61 (1) 108-118
19 Choi SS, Diehl AM. Hepatic triglyceride synthesis and nonalcoholic fatty liver disease. Curr Opin Lipidol 2008; 19 (3) 295-300
20 Singhi AD, Jain D, Kakar S, Wu TT, Yeh MM, Torbenson M. Reticulin loss in benign fatty liver: an important diagnostic pitfall when considering a diagnosis of hepatocellular carcinoma. Am J Surg Pathol 2012; 36 (5) 710-715
21 Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999; 94 (9) 2467-2474
22 Kleiner DE, Brunt EM, Van Natta M , et al; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41 (6) 1313-1321
23 Hall AR, Dhillon AP, Green AC , et al. Hepatic steatosis estimated microscopically versus digital image analysis. Liver Int 2013; 33 (6) 926-935
24 Hall AR, Green AC, Luong TV, Burroughs AK, Wyatt J, Dhillon AP. The use of guideline images to improve histological estimation of hepatic steatosis. Liver Int 2014; 34 (9) 1414-1427
25 Karlas T, Petroff D, Garnov N , et al. Non-invasive assessment of hepatic steatosis in patients with NAFLD using controlled attenuation parameter and 1H-MR spectroscopy. PLoS ONE 2014; 9 (3) e91987
26 Schwimmer JB, Middleton MS, Behling C , et al. Magnetic resonance imaging and liver histology as biomarkers of hepatic steatosis in children with nonalcoholic fatty liver disease. Hepatology 2015; 61 (6) 1887-1895
27 Noureddin M, Lam J, Peterson MR , et al. Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials. Hepatology 2013; 58 (6) 1930-1940
28 Idilman IS, Keskin O, Elhan AH, Idilman R, Karcaaltincaba M. Impact of sequential proton density fat fraction for quantification of hepatic steatosis in nonalcoholic fatty liver disease. Scand J Gastroenterol 2014; 49 (5) 617-624
29 Smith K. Liver disease: Kupffer cells regulate the progression of ALD and NAFLD. Nat Rev Gastroenterol Hepatol 2013; 10 (9) 503
30 Harmon RC, Tiniakos DG, Argo CK. Inflammation in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol 2011; 5 (2) 189-200
31 Meli R, Mattace Raso G, Calignano A. Role of innate immune response in non-alcoholic fatty liver disease: metabolic complications and therapeutic tools. Front Immunol 2014; 5: 177
32 Sutti S, Jindal A, Locatelli I , et al. Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH. Hepatology 2014; 59 (3) 886-897
33 Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol 2015; 13 (4) 643-54.e1 , 9, quiz e39–e40
34 McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol 2015; 62 (5) 1148-1155
35 Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD single topic conference. Hepatology 2003; 37 (5) 1202-1219
36 Sanyal AJ, Brunt EM, Kleiner DE , et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 2011; 54 (1) 344-353
37 Matsuda Y, Takada A, Kanayama R, Takase S. Changes of hepatic microtubules and secretory proteins in human alcoholic liver disease. Pharmacol Biochem Behav 1983; 18 (Suppl. 01) 479-482
38 Schaff Z, Lapis K. Fine structure of hepatocytes during the etiology of several common pathologies. J Electron Microsc Tech 1990; 14 (3) 179-207
39 Gores GJ, Herman B, Lemasters JJ. Plasma membrane bleb formation and rupture: a common feature of hepatocellular injury. Hepatology 1990; 11 (4) 690-698
40 Caldwell S, Ikura Y, Dias D , et al. Hepatocellular ballooning in NASH. J Hepatol 2010; 53 (4) 719-723
41 Lackner C, Gogg-Kamerer M, Zatloukal K, Stumptner C, Brunt EM, Denk H. Ballooned hepatocytes in steatohepatitis: the value of keratin immunohistochemistry for diagnosis. J Hepatol 2008; 48 (5) 821-828
42 Zatloukal K, French SW, Stumptner C , et al. From Mallory to Mallory-Denk bodies: what, how and why?. Exp Cell Res 2007; 313 (10) 2033-2049
43 Rangwala F, Guy CD, Lu J , et al. Increased production of sonic hedgehog by ballooned hepatocytes. J Pathol 2011; 224 (3) 401-410
44 Tannapfel A, Denk H, Dienes HP , et al. [Histopathological diagnosis of non-alcoholic and alcoholic fatty liver disease. Grade 2 consensus-based guidelines]. Pathologe 2010; 31 (3) 225-237
45 Farrell GC, Chitturi S, Lau GK, Sollano JD ; Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary. J Gastroenterol Hepatol 2007; 22 (6) 775-777
46 Loria P, Adinolfi LE, Bellentani S , et al; NAFLD Expert Committee of the Associazione Italiana per lo studio del Fegato. Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee. Dig Liver Dis 2010; 42 (4) 272-282
47 Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010; 53 (2) 372-384
48 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 (6) 2005-2023
49 Naveau S, Giraud V, Borotto E, Aubert A, Capron F, Chaput JC. Excess weight risk factor for alcoholic liver disease. Hepatology 1997; 25 (1) 108-111
50 Iturriaga H, Bunout D, Hirsch S, Ugarte G. Overweight as a risk factor or a predictive sign of histological liver damage in alcoholics. Am J Clin Nutr 1988; 47 (2) 235-238
51 Powell EE, Jonsson JR, Clouston AD. Steatosis: co-factor in other liver diseases. Hepatology 2005; 42 (1) 5-13
52 Nalbantoglu IL, Brunt EM. Role of liver biopsy in nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20 (27) 9026-9037
53 Sumida Y, Nakajima A, Itoh Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol 2014; 20 (2) 475-485
54 Younossi ZM, Gramlich T, Liu YC , et al. Nonalcoholic fatty liver disease: assessment of variability in pathologic interpretations. Mod Pathol 1998; 11 (6) 560-565
55 Bedossa P ; FLIP Pathology Consortium. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease. Hepatology 2014; 60 (2) 565-575
56 Guy CD, Suzuki A, Burchette JL , et al; Nonalcoholic Steatohepatitis Clinical Research Network. Costaining for keratins 8/18 plus ubiquitin improves detection of hepatocyte injury in nonalcoholic fatty liver disease. Hum Pathol 2012; 43 (6) 790-800
57 Stumptner C, Fuchsbichler A, Heid H, Zatloukal K, Denk H. Mallory body—a disease-associated type of sequestosome. Hepatology 2002; 35 (5) 1053-1062
58 Ludwig J, McGill DB, Lindor KD. Review: nonalcoholic steatohepatitis. J Gastroenterol Hepatol 1997; 12 (5) 398-403
59 Guy CD, Suzuki A, Zdanowicz M , et al; NASH CRN. Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology 2012; 55 (6) 1711-1721
60 Williams R. Global challenges in liver disease. Hepatology 2006; 44 (3) 521-526
61 Fan JG, Peng YD. Metabolic syndrome and non-alcoholic fatty liver disease: Asian definitions and Asian studies. Hepatobiliary Pancreat Dis Int 2007; 6 (6) 572-578
62 Fan JG, Zhu J, Li XJ , et al. Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J Hepatol 2005; 43 (3) 508-514
63 Pawlik TM, Olino K, Gleisner AL, Torbenson M, Schulick R, Choti MA. Preoperative chemotherapy for colorectal liver metastases: impact on hepatic histology and postoperative outcome. J Gastrointest Surg 2007; 11 (7) 860-868
64 Zorzi D, Laurent A, Pawlik TM, Lauwers GY, Vauthey JN, Abdalla EK. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg 2007; 94 (3) 274-286
65 Gentilucci UV, Santini D, Vincenzi B, Fiori E, Picardi A, Tonini G. Chemotherapy-induced steatohepatitis in colorectal cancer patients. J Clin Oncol 2006; 24 (34) 5467 , author reply 5467–5468
66 Raja K, Thung SN, Fiel MI, Chang C. Drug-induced steatohepatitis leading to cirrhosis: long-term toxicity of amiodarone use. Semin Liver Dis 2009; 29 (4) 423-428
67 Karoui M, Penna C, Amin-Hashem M , et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 2006; 243 (1) 1-7
68 Patel V, Sanyal AJ. Drug-induced steatohepatitis. Clin Liver Dis 2013; 17 (4) 533-546 , vii
69 Ramachandran R, Kakar S. Histological patterns in drug-induced liver disease. J Clin Pathol 2009; 62 (6) 481-492
70 Vauthey JN, Pawlik TM, Ribero D , et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006; 24 (13) 2065-2072
71 Brunt EM, Tiniakos DG. Fatty liver disease. In: Odze RD, Goldblum JR, (Eds.). Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. 3rd ed. Philadelphia, PA: Elsevier; 2014: 1087-1114
72 Thomopoulos KC, Arvaniti V, Tsamantas AC , et al. Prevalence of liver steatosis in patients with chronic hepatitis B: a study of associated factors and of relationship with fibrosis. Eur J Gastroenterol Hepatol 2006; 18 (3) 233-237
73 Machado MV, Oliveira AG, Cortez-Pinto H. Hepatic steatosis in hepatitis B virus infected patients: meta-analysis of risk factors and comparison with hepatitis C infected patients. J Gastroenterol Hepatol 2011; 26 (9) 1361-1367
74 Lonardo A, Adinolfi LE, Restivo L , et al. Pathogenesis and significance of hepatitis C virus steatosis: an update on survival strategy of a successful pathogen. World J Gastroenterol 2014; 20 (23) 7089-7103
75 Vallet-Pichard A, Mallet V, Pol S. Nonalcoholic fatty liver disease and HIV infection. Semin Liver Dis 2012; 32 (2) 158-166
76 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 (7) 1316-1320
77 Yatsuji S, Hashimoto E, Kaneda H, Taniai M, Tokushige K, Shiratori K. Diagnosing autoimmune hepatitis in nonalcoholic fatty liver disease: is the International Autoimmune Hepatitis Group scoring system useful?. J Gastroenterol 2005; 40 (12) 1130-1138
78 Czaja AJ. Autoantibody-negative autoimmune hepatitis. Dig Dis Sci 2012; 57 (3) 610-624
79 Sorrentino P, D'Angelo S, Ferbo U, Micheli P, Bracigliano A, Vecchione R. Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis. J Hepatol 2009; 50 (2) 351-357
80 Híndi M, Levy C, Couto CA, Bejarano P, Mendes F. Primary biliary cirrhosis is more severe in overweight patients. J Clin Gastroenterol 2013; 47 (3) e28-e32
81 Nelson JE, Brunt EM, Kowdley KV ; Nonalcoholic Steatohepatitis Clinical Research Network. Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutations. Hepatology 2012; 56 (5) 1730-1740
82 Brunt EM, Ramrakhiani S, Cordes BG , et al. Concurrence of histologic features of steatohepatitis with other forms of chronic liver disease. Mod Pathol 2003; 16 (1) 49-56
83 Powell EE, Jonsson JR, Clouston AD. Metabolic factors and non-alcoholic fatty liver disease as co-factors in other liver diseases. Dig Dis 2010; 28 (1) 186-191
84 Nelson JE, Wilson L, Brunt EM , et al; Nonalcoholic Steatohepatitis Clinical Research Network. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology 2011; 53 (2) 448-457
85 Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc 2014; 89 (1) 95-106
86 Asselah T, Rubbia-Brandt L, Marcellin P, Negro F. Steatosis in chronic hepatitis C: why does it really matter?. Gut 2006; 55 (1) 123-130
87 Abenavoli L, Masarone M, Peta V , et al. Insulin resistance and liver steatosis in chronic hepatitis C infection genotype 3. World J Gastroenterol 2014; 20 (41) 15233-15240
88 Bedossa P, Moucari R, Chelbi E , et al. Evidence for a role of nonalcoholic steatohepatitis in hepatitis C: a prospective study. Hepatology 2007; 46 (2) 380-387
89 Bugianesi E, Salamone F, Negro F. The interaction of metabolic factors with HCV infection: does it matter?. J Hepatol 2012; 56 (Suppl. 01) S56-S65
90 Machado MV, Cortez-Pinto H. Cell death and nonalcoholic steatohepatitis: where is ballooning relevant?. Expert Rev Gastroenterol Hepatol 2011; 5 (2) 213-222
91 Pais R, Rusu E, Zilisteanu D , et al. Prevalence of steatosis and insulin resistance in patients with chronic hepatitis B compared with chronic hepatitis C and non-alcoholic fatty liver disease. Eur J Intern Med 2015; 26 (1) 30-36
92 Day CP, James OF. Steatohepatitis: a tale of two “hits”?. Gastroenterology 1998; 114 (4) 842-845
93 Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010; 52 (5) 1836-1846
94 Ibrahim SH, Kohli R, Gores GJ. Mechanisms of lipotoxicity in NAFLD and clinical implications. J Pediatr Gastroenterol Nutr 2011; 53 (2) 131-140
95 Yilmaz Y. Review article: is non-alcoholic fatty liver disease a spectrum, or are steatosis and non-alcoholic steatohepatitis distinct conditions?. Aliment Pharmacol Ther 2012; 36 (9) 815-823
96 Burt AD, Mutton A, Day CP. Diagnosis and interpretation of steatosis and steatohepatitis. Semin Diagn Pathol 1998; 15 (4) 246-258
97 Loria P, Lonardo A, Carulli N. Should nonalcoholic fatty liver disease be renamed?. Dig Dis 2005; 23 (1) 72-82
98 Hourigan SK, Torbenson M, Tibesar E, Scheimann AO. The full spectrum of hepatic steatosis in children. Clin Pediatr (Phila) 2015; 54 (7) 635-642
99 Nobili V, Svegliati-Baroni G, Alisi A, Miele L, Valenti L, Vajro P. A 360-degree overview of paediatric NAFLD: recent insights. J Hepatol 2013; 58 (6) 1218-1229
100 Shang XR, Song JY, Liu FH, Ma J, Wang HJ. GWAS-identified common variants with nonalcoholic fatty liver disease in chinese children. J Pediatr Gastroenterol Nutr 2015; 60 (5) 669-674
101 Molleston JP, Schwimmer JB, Yates KP , et al; NASH Clinical Research Network. Histological abnormalities in children with nonalcoholic fatty liver disease and normal or mildly elevated alanine aminotransferase levels. J Pediatr 2014; 164 (4) 707-713.e3
102 Mansoor S, Yerian L, Kohli R , et al. The evaluation of hepatic fibrosis scores in children with nonalcoholic fatty liver disease. Dig Dis Sci 2015; 60 (5) 1440-1447
103 Nobili V, Pinzani M. Alcoholic and non-alcoholic fatty liver in adolescents: a worrisome convergence. Alcohol Alcohol 2011; 46 (5) 627-629
104 Schwimmer JB, Behling C, Newbury R , et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology 2005; 42 (3) 641-649
105 Nobili V, Marcellini M, Devito R , et al. NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice. Hepatology 2006; 44 (2) 458-465
106 Carter-Kent C, Yerian LM, Brunt EM , et al. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology 2009; 50 (4) 1113-1120
107 Takahashi Y, Inui A, Fujisawa T, Takikawa H, Fukusato T. Histopathological characteristics of non-alcoholic fatty liver disease in children: comparison with adult cases. Hepatol Res 2011; 41 (11) 1066-1074
108 Kleiner DE, Brunt EM. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research. Semin Liver Dis 2012; 32 (1) 3-13
109 Suzuki A, Abdelmalek MF, Schwimmer JB , et al; Nonalcoholic Steatohepatitis Clinical Research Network. Association between puberty and features of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2012; 10 (7) 786-794
110 Swiderska-Syn M, Suzuki A, Guy CD , et al. Hedgehog pathway and pediatric nonalcoholic fatty liver disease. Hepatology 2013; 57 (5) 1814-1825
111 Alkhouri N, De Vito R, Alisi A , et al. Development and validation of a new histological score for pediatric non-alcoholic fatty liver disease. J Hepatol 2012; 57 (6) 1312-1318
112 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 (6) 1874-1882
113 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 (5) 1751-1759
114 Nonalcoholic steatohepatitis clinical research network. Hepatology 2003; 37 (2) 244
115 Hjelkrem M, Stauch C, Shaw J, Harrison SA. Validation of the non-alcoholic fatty liver disease activity score. Aliment Pharmacol Ther 2011; 34 (2) 214-218
116 Brunt EM. Grading and staging the histopathological lesions of chronic hepatitis: the Knodell histology activity index and beyond. Hepatology 2000; 31 (1) 241-246
117 Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 116 (6) 1413-1419
118 Sandrini J, Boursier J, Chaigneau J , et al. Quantification of portal-bridging fibrosis area more accurately reflects fibrosis stage and liver stiffness than whole fibrosis or perisinusoidal fibrosis areas in chronic hepatitis C. Mod Pathol 2014; 27 (7) 1035-1045
119 Boursier J, de Ledinghen V, Sturm N , et al; Multicentre group ANRS HC EP23 FIBROSTAR. Precise evaluation of liver histology by computerized morphometry shows that steatosis influences liver stiffness measured by transient elastography in chronic hepatitis C. J Gastroenterol 2014; 49 (3) 527-537
120 Levene AP, Kudo H, Armstrong MJ , et al. Quantifying hepatic steatosis - more than meets the eye. Histopathology 2012; 60 (6) 971-981
121 Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995; 22 (6) 1714-1719
122 Pais R, Pascale A, Fedchuck L, Charlotte F, Poynard T, Ratziu V. Progression from isolated steatosis to steatohepatitis and fibrosis in nonalcoholic fatty liver disease. Clin Res Hepatol Gastroenterol 2011; 35 (1) 23-28
123 Wong VW, Wong GL, Choi PC , et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut 2010; 59 (7) 969-974
124 Ekstedt M, Franzén LE, Mathiesen UL , et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44 (4) 865-873
125 Söderberg C, Stål P, Askling J , et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010; 51 (2) 595-602
126 Brunt EM, Kleiner DE, Wilson LA , et al; NASH Clinical Research NetworkA list of members of the Nonalcoholic Steatohepatitis Clinical Research Network can be found in the Appendix. Portal chronic inflammation in nonalcoholic fatty liver disease (NAFLD): a histologic marker of advanced NAFLD-clinicopathologic correlations from the nonalcoholic steatohepatitis clinical research network. Hepatology 2009; 49 (3) 809-820
127 Gadd VL, Skoien R, Powell EE , et al. The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology 2014; 59 (4) 1393-1405
128 Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis 2004; 24 (1) 3-20
129 Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am J Gastroenterol 2003; 98 (9) 2042-2047
130 Fassio E, Alvarez E, Domínguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology 2004; 40 (4) 820-826
131 Sorrentino P, Tarantino G, Conca P , et al. Silent non-alcoholic fatty liver disease-a clinical-histological study. J Hepatol 2004; 41 (5) 751-757
132 Poonawala A, Nair SP, Thuluvath PJ. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study. Hepatology 2000; 32 (4 Pt 1) 689-692
133 Caldwell SH, Crespo DM. The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease. J Hepatol 2004; 40 (4) 578-584
134 Bugianesi E, Leone N, Vanni E , et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002; 123 (1) 134-140
135 Hashimoto E, Yatsuji S, Tobari M , et al. Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. J Gastroenterol 2009; 44 (Suppl 19): 89-95
136 Ekstedt M, Hagström H, Nasr P , et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015; 61 (5) 1547-1554
137 Torres DM, Harrison SA. Nonalcoholic fatty liver disease: fibrosis portends a worse prognosis. Hepatology 2015; 61 (5) 1462-1464
138 Machado MV, Cortez-Pinto H. Non-alcoholic fatty liver disease: what the clinician needs to know. World J Gastroenterol 2014; 20 (36) 12956-12980
139 Csak T, Ganz M, Pespisa J, Kodys K, Dolganiuc A, Szabo G. Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology 2011; 54 (1) 133-144
140 Guy CD, Suzuki A, Abdelmalek MF, Burchette JL, Diehl AM ; NASH CRN. Treatment response in the PIVENS trial is associated with decreased Hedgehog pathway activity. Hepatology 2015; 61 (1) 98-107
141 Starmann J, Fälth M, Spindelböck W , et al. Gene expression profiling unravels cancer-related hepatic molecular signatures in steatohepatitis but not in steatosis. PLoS ONE 2012; 7 (10) e46584
142 Scuric Z, Stain SC, Anderson WF, Hwang JJ. New member of aldose reductase family proteins overexpressed in human hepatocellular carcinoma. Hepatology 1998; 27 (4) 943-950
143 Yoshitake H, Takahashi M, Ishikawa H , et al. Aldo-keto reductase family 1, member B10 in uterine carcinomas: a potential risk factor of recurrence after surgical therapy in cervical cancer. Int J Gynecol Cancer 2007; 17 (6) 1300-1306
144 Heringlake S, Hofdmann M, Fiebeler A, Manns MP, Schmiegel W, Tannapfel A. Identification and expression analysis of the aldo-ketoreductase1-B10 gene in primary malignant liver tumours. J Hepatol 2010; 52 (2) 220-227
145 Lefkowitch JH, Haythe JH, Regent N. Kupffer cell aggregation and perivenular distribution in steatohepatitis. Mod Pathol 2002; 15 (7) 699-704
146 Park JW, Jeong G, Kim SJ, Kim MK, Park SM. Predictors reflecting the pathological severity of non-alcoholic fatty liver disease: comprehensive study of clinical and immunohistochemical findings in younger Asian patients. J Gastroenterol Hepatol 2007; 22 (4) 491-497
147 Richardson MM, Jonsson JR, Powell EE , et al. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology 2007; 133 (1) 80-90
148 Lonardo A, Ballestri S, Targher G, Loria P. Diagnosis and management of cardiovascular risk in nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2015; 9 (5) 629-650
149 Rafiq N, Bai C, Fang Y , et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol 2009; 7 (2) 234-238
150 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 (6) 1387-1395
151 Bedogni G, Miglioli L, Masutti F , et al. Incidence and natural course of fatty liver in the general population: the Dionysos study. Hepatology 2007; 46 (5) 1387-1391
152 Lonardo A, Bellini M, Tartoni P, Tondelli E. The bright liver syndrome. Prevalence and determinants of a “bright” liver echopattern. Ital J Gastroenterol Hepatol 1997; 29 (4) 351-356
153 Nomura H, Kashiwagi S, Hayashi J, Kajiyama W, Tani S, Goto M. Prevalence of fatty liver in a general population of Okinawa, Japan. Jpn J Med 1988; 27 (2) 142-149
154 Argo CK, Caldwell SH. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis 2009; 13 (4) 511-531
155 Bellentani S, Bedogni G, Miglioli L, Tiribelli C. The epidemiology of fatty liver. Eur J Gastroenterol Hepatol 2004; 16 (11) 1087-1093
156 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 (5) 1212-1218
157 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 (9) 1141-1145
158 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 (1) 124-131
159 Williamson RM, Price JF, Glancy S , et al; Edinburgh Type 2 Diabetes Study Investigators. 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 (5) 1139-1144
160 Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990; 12 (5) 1106-1110
161 Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol 2005; 42 (1) 132-138
162 Dyson JK, Anstee QM, McPherson S. Non-alcoholic fatty liver disease: a practical approach to treatment. Frontline Gastroenterol 2014; 5 (4) 277-286
163 Kwok R, Tse YK, Wong GL , et al. Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease—the role of transient elastography and plasma cytokeratin-18 fragments. Aliment Pharmacol Ther 2014; 39 (3) 254-269
164 Chen J, Talwalkar JA, Yin M, Glaser KJ, Sanderson SO, Ehman RL. Early detection of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease by using MR elastography. Radiology 2011; 259 (3) 749-756
165 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 (4) 846-854
166 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 (7) 1682-1688
167 McPherson S, Stewart SF, Henderson E, Burt AD, Day CP. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut 2010; 59 (9) 1265-1269
168 Dyson JK, Anstee QM, McPherson S. Non-alcoholic fatty liver disease: a practical approach to diagnosis and staging. Frontline Gastroenterol 2014; 5 (3) 211-218
169 Machado MV, Cortez-Pinto H. Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal. J Hepatol 2013; 58 (5) 1007-1019
170 Leandro G, Mangia A, Hui J , et al; HCV Meta-Analysis (on) Individual Patients' Data Study Group. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology 2006; 130 (6) 1636-1642
171 Petta S, Cammà C, Di Marco V , et al. Hepatic steatosis and insulin resistance are associated with severe fibrosis in patients with chronic hepatitis caused by HBV or HCV infection. Liver Int 2011; 31 (4) 507-515
172 Ong JP, Younossi ZM, Speer C, Olano A, Gramlich T, Boparai N. Chronic hepatitis C and superimposed nonalcoholic fatty liver disease. Liver 2001; 21 (4) 266-271
173 Farrell GC, Liddle C. Drugs and the liver updated, 2002. Semin Liver Dis 2002; 22 (2) 109-113
174 Nascimbeni F, Pais R, Bellentani S , et al. From NAFLD in clinical practice to answers from guidelines. J Hepatol 2013; 59 (4) 859-871
175 Boursier J, Chaigneau J, Roullier V , et al; Study group UNAM-METABOL. Steatosis degree, measured by morphometry, is linked to other liver lesions and metabolic syndrome components in patients with NAFLD. Eur J Gastroenterol Hepatol 2011; 23 (11) 974-981