Prospects for a better diagnosis and prognosis of NAFLD: a pathologist´s view

Abstract

Despite the development of surrogate non-invasive methods, histological evaluation remains an important tool for reliable classification, grading and staging, as well as prognosis in non-alcoholic fatty liver disease (NAFLD). However, histological evaluation has been criticised because it requires a liver biopsy, its propensity for sampling, and inter-observer variation. This article highlights the future developments in the morphological interpretation of liver biopsy in NAFLD, so as to aid in improving its diagnostic and prognostic utility.

Keywords

Non-alcoholic fatty liver disease / histology / prognosis / grading and staging

References

[1] Eslam M,Sarin SK.A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement.J Hepatol2020;73:202-9

[2] Eslam M,George J.MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease.Gastroenterology2020;158:1999-2014

[3] Younossi ZM,Sanyal A.From NAFLD to MAFLD: implications of a premature change in terminology.Hepatology2020;

[4] Moreno C,Tiniakos D,Mathurin P.EASL Consortium for the Study of Alcohol-related LiVer disease in Europe (SALVE)“Dual aetiology fatty liver disease”: a recently proposed term associated with potential pitfalls.J Hepatol2020;S0168-8278(20)33755

[5] Younossi ZM,Abdelatif D,Henry L.Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology2016;64:73-84

[6] Estes C,Arias-Loste MT.Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030.J Hepatol2018;69:896-904

[7] Cotter TG.Nonalcoholic fatty liver disease 2020: the state of the disease.Gastroenterology2020;158:1851-64

[8] Brunt EM.Nonalcoholic steatohepatitis: pathologic features and differential diagnosis.Semin Diagn Pathol2005;22:330-8

[9] Lackner C.Hepatocellular ballooning in nonalcoholic steatohepatitis: the pathologist’s perspective.Expert Rev Gastroenterol Hepatol2011;5:223-31

[10] Schwabe RF,Pajvani UB.Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis.Gastroenterology2020;158:1913-28 PMCID:PMC7682538

[11] Younossi Z,Sanyal AJ.The conundrum of cryptogenic cirrhosis: Adverse outcomes without treatment options.J Hepatol2018;69:1365-70

[12] Caldwell SH.The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease.J Hepatol2004;40:578-84

[13] Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.J Hepatol2016;64:1388-402

[14] Dulai PS,Patel J.Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis.Hepatology2017;65:1557-65 PMCID:PMC5397356

[15] Vilar-Gomez E,Wai-Sun Wong V.Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.Gastroenterology2018;155:443-57.e17

[16] Leoni S,Napoli L,Ferri S.Current guidelines for the management of non-alcoholic fatty liver disease: a systematic review with comparative analysis.World J Gastroenterol2018;24:3361-73 PMCID:PMC6092580

[17] Kleiner DE,Van Natta M.Nonalcoholic Steatohepatitis Clinical Research NetworkDesign and validation of a histological scoring system for nonalcoholic fatty liver disease.Hepatology2005;41:1313-21

[18] Younossi ZM,Liu YC.Nonalcoholic fatty liver disease: assessment of variability in pathologic interpretations.Mod Pathol1998;11:560-5

[19] Lackner C,Zatloukal K,Brunt EM.Ballooned hepatocytes in steatohepatitis: the value of keratin immunohistochemistry for diagnosis.J Hepatol2008;48:821-8

[20] Rangwala F,Lu J.Increased production of sonic hedgehog by ballooned hepatocytes.J Pathol2011;224:401-10 PMCID:PMC3628812

[21] Starmann J,Spindelböck W.Gene expression profiling unravels cancer-related hepatic molecular signatures in steatohepatitis but not in steatosis.PLoS One2012;7:e46584 PMCID:PMC3468618

[22] Ekstedt M,Nasr P.Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.Hepatology2015;61:1547-54

[23] Taylor RS,Bayliss S.Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.Gastroenterology2020;158:1611-25.e12

[24] Schwabe RF,Pajvani UB.Mechanisms of fibrosis development in nonalcoholic steatohepatitis.Gastroenterology2020;158:1913-28 PMCID:PMC7682538

[25] Bitto N,La Mura V.Coagulation, microenvironment and liver fibrosis.Cells2018;7:85 PMCID:PMC6115868

[26] Jung YK.Reversal of liver cirrhosis: current evidence and expectations.Korean J Intern Med2017;32:213-28 PMCID:PMC5339475

[27] Ellis EL.Clinical evidence for the regression of liver fibrosis.J Hepatol2012;56:1171-80

[28] Marcellin P,Buti M.Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.Lancet2013; 381:468-75

[29] Theise ND,Sun Y,You H.Progression and regression of fibrosis in viral hepatitis in the treatment era: the Beijing classification.Mod Pathol2018;31:1191-200

[30] Sun Y,Wang L.New classification of liver biopsy assessment for fibrosis in chronic hepatitis B patients before and after treatment.Hepatology2017;65:1438-50

[31] Pellicoro A,Ramachandran P.Elastin accumulation is regulated at the level of degradation by macrophage metalloelastase (MMP-12) during experimental liver fibrosis.Hepatology2012;55:1965-75

[32] Pellicoro A,Iredale JP.Reversibility of liver fibrosis.Fibrogenesis Tissue Repair2012;5:S26 PMCID:PMC3368758

[33] Pellicoro A,Iredale JP.Liver fibrosis and repair: immune regulation of wound healing in a solid organ.Nat Rev Immunol2014;14:181-94

[34] Issa R,Constandinou CM.Spontaneous recovery from micronodular cirrhosis: evidence for incomplete resolution associated with matrix cross-linking.Gastroenterology2004;126:1795-808

[35] Wang Y,Yang J.Dual-photon microscopy-based quantitation of fibrosis-related parameters (q-FP) to model disease progression in steatohepatitis.Hepatology2017;65:1891-903 PMCID:PMC5444965

[36] Ishak K,Bianchi L.Histological grading and staging of chronic hepatitis.J Hepatol1995;22:696-9

[37] Bedossa P.An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group.Hepatology1996;24:289-93

[38] Wendum D,Bedossa P.Primary biliary cirrhosis: proposal for a new simple histological scoring system.Liver Int2015;35:652-9

[39] Bedossa P.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.Hepatology2014;60:565-75

[40] Nascimbeni F,Fedchuk L.Clinical validation of the FLIP algorithm and the SAF score in patients with non-alcoholic fatty liver disease.J Hepatol2020;72:828-38

[41] Nascimbeni F,Machado MV.Clinical relevance of liver histopathology and different histological classifications of NASH in adults.Expert Rev Gastroenterol Hepatol2018;12:351-67

[42] Kleiner DE,Wilson LA.Association of histologic disease activity with progression of nonalcoholic fatty liver disease.JAMA Netw Open2019;2:e1912565 PMCID:PMC6784786

[43] Rinella ME,Sanyal AJ.participants of the AASLD/EASL WorkshopReport on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD.J Hepatol2019;71:823-33

[44] Davison BA,Cotter G.Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials.J Hepatol2020;73:1322-32

[45] Hall AR,Luong TV,Wyatt J.The use of guideline images to improve histological estimation of hepatic steatosis.Liver Int2014;34:1414-27

[46] Liu F,Tiniakos D.qFIBS: an automated technique for quantitative evaluation of fibrosis, inflammation, ballooning, and steatosis in patients with nonalcoholic steatohepatitis.Hepatolog71:1953-66

[47] Garcia-Carretero R,Barquero-Perez O.Relevant features in nonalcoholic steatohepatitis determined using machine learning for feature selection.Metab Syndr Relat Disord2019;17:444-51