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
1   Faculty of Health Sciences, The University of Adelaide, Level 2, Barr Smith South, North Terrace, Adelaide, Australia
,
Carolin Lackner
2   Department of Quantitative Pathomorphology, Institute of Pathology, Medical University of Graz, Graz, Austria
,
Dina G. Tiniakos
3   Clinical Senior Lecturer, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom
› Author Affiliations
Further Information

Publication History

Publication Date:
17 September 2015 (online)

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.

 
  • 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