Steatosis/steatohepatitis: how sustainable is the non-invasive instrumental differential diagnosis in clinical practice?

Abstract

Aim: Simple, rapid, and non-invasive methods for the early diagnosis of non-alcoholic steatohepatitis (NASH) in patients with fatty liver are an unmet need in clinical practice. Transient elastography (TE), commonly used for measuring liver stiffness (LS), which is significantly influenced by both liver fibrosis and inflammation is a promising tool.

Methods: We studied retrospectively the impact of TE in a cohort of 98 consecutive asymptomatic patients with fatty liver who underwent a liver biopsy [21 non-alcoholic fatty liver (NAFL) and 77 NASH] and TE on the same day at the Hepatology Unit of University Hospital of Pisa. Patients positive for HBsAg, anti-HCV, HIV, autoantibodies, drug-induced liver disease, Wilson’s disease, hemochromatosis, alpha-1 antitrypsin deficiency, type 2 diabetes, or neoplasia were excluded.

Results: NAFL patients were younger (42.5 years vs. 47.7 years, P = 0.02) and with lower BMI (25.5 kg/m² vs. 28.8 kg/m², P < 0.001) than NASH patients. TE was higher in NASH than NAFL patients (8.1 kPa vs. 5.4 kPa, P = 0.01). Age, BMI, TE, and total/LDL cholesterol were statistically significantly different between NAFL and NASH patients, but with multivariate analysis only BMI (P = 0.009) and TE (P = 0.031) were independent predictors of NAFL/NASH with AUROCs of 0.771 and 0.754, respectively. A score combining TE and BMI (TE*BMI) showed the best AUROC (0.817, by De Long test, P = 0.01) to differentiate NAFL/NASH (P = 0.005).

Conclusion: Ultrasound based LS measure qualifies as a candidate tool for the early screening of NASH in fatty liver patients provided that its measure is properly standardized and tested in large prospective studies enrolling patients with different clinical and histological features.

Keywords

Non-alcoholic fatty liver disease / NAFL / NASH / liver-stiffness / transient-elastography

References

[1] Williams CD,Asike MI.Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study..Gastroenterology2011;140:124-31

[2] Zelber-Sagi S,Halpern Z.Prevalence of primary non-alcoholic fatty liver disease in a population-based study and its association with biochemical and anthropometric measures..Liver Int2006;26:856-63

[3] 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

[4] Younossi Z,Arrese M.Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis..Hepatology2019;69:2672-82

[5] Eslam M,George J.MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease..Gastroenterology2020;158:1999-2014.e1

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

[7] Adams LA,St Sauver J.The natural history of nonalcoholic fatty liver disease: a population-based cohort study..Gastroenterology2005;129:113-21

[8] Ascha MS,Lopez R,Feldstein AF.The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis..Hepatology2010;51:1972-8

[9] Ertle J,Sowa JP.Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis..Int J Cancer2011;128:2436-43

[10] Baffy G,Caldwell SH.Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace..J Hepatol2012;56:1384-91

[11] Wong RJ,Cheung R.Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States..Gastroenterology2015;148:547-55

[12] 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

[13] White DL,Kanwal F,El-Serag HB.Incidence of hepatocellular carcinoma in all 50 united states, from 2000 through 2012..Gastroenterology2017;152:812-20.e5 PMCID:PMC5346030

[14] Brouwers MC,Cantor RM.Heritability of nonalcoholic fatty liver disease..Gastroenterology2009;137:1536

[15] Lambert JE,Browning JD.Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease..Gastroenterology2014;146:726-35 PMCID:PMC6276362

[16] Schnabl B.Interactions between the intestinal microbiome and liver diseases..Gastroenterology2014;146:1513-24 PMCID:PMC3996054

[17] Brunt EM,Nobili V.Nonalcoholic fatty liver disease..Nat Rev Dis Primers2015;1:15080

[18] Diehl AM.Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis..N Engl J Med2017;377:2063-72

[19] Sandrin L,Hasquenoph JM.Transient elastography: a new noninvasive method for assessment of hepatic fibrosis..Ultrasound Med Biol2003;29:1705-13

[20] Coco B,Maina AM.Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases..J Viral Hepat2007;14:360-9

[21] Millonig G,Adolf S.Liver stiffness is directly influenced by central venous pressure..J Hepatol2010;52:206-10

[22] Millonig G,Friedrich S.Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis..Hepatology2008;48:1718-23

[23] Bonino F,Brunetto MR.Liver stiffness, a non-invasive marker of liver disease: a core study group report..Antivir Ther.2010;15 Suppl 3:69-78

[24] Chapman T,Barr RG.Ultrasound elastography of the liver: what the clinician needs to know..J Ultrasound Med2017;36:1293-304

[25] Angulo P,Marchesini G.The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD..Hepatology2007;45:846-54

[26] Sterling RK,Clumeck N.Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection..Hepatology2006;43:1317-25

[27] Chalasani N,Lavine JE.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..Hepatology2012;55:2005-23

[28] Kleiner DE,Van Natta M.Design and validation of a histological scoring system for nonalcoholic fatty liver disease..Hepatology2005;41:1313-21

[29] Seki E,Osterreicher CH.TLR4 enhances TGF-beta signaling and hepatic fibrosis..Nat Med2007;13:1324-32

[30] Syn WK,Pereira TA.Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease..Hepatology2010;51:1998-2007 PMCID:PMC2920131

[31] Feldstein AE,Angulo P.Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis..Gastroenterology2003;125:437-43

[32] Wolf MJ,Piotrowitz K.Metabolic activation of intrahepatic CD8 + T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes..Cancer Cell2014;26:549-64

[33] Mehal WZ.The inflammasome in liver injury and non-alcoholic fatty liver disease..Dig Dis2014;32:507-15

[34] Kennedy P,Castéra L.Quantitative elastography methods in liver disease: current evidence and future directions..Radiology2018;286:738-63 PMCID:PMC5831316

[35] Ferraioli G.Review of liver elastography guidelines..J Ultrasound Med2019;38:9-14

[36] Tapper EB.Noninvasive imaging biomarker assessment of liver fibrosis by elastography in NAFLD..Nat Rev Gastroenterol Hepatol2018;15:274-82 PMCID:PMC7504909

[37] Lusis AJ,Reue K.Metabolic syndrome: from epidemiology to systems biology..Nat Rev Genet2008;9:819-30 PMCID:PMC2829312

[38] Pouliot M,Lemieux S.Waist circumference and abdominal sagittal diameter: Best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women..Am J Cardiol1994;73:460-8

[39] Petta S,Macaluso FS.The severity of steatosis influences liver stiffness measurement in patients with nonalcoholic fatty liver disease..Hepatology2015;62:1101-10

[40] Lee HW,Kim SU.Discrimination of nonalcoholic steatohepatitis using transient elastography in patients with nonalcoholic fatty liver disease..PLoS One2016;11:e0157358 PMCID:PMC4902201

[41] Castera L,Loomba R.Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease..Gastroenterology2019;156:1264-81.e4 PMCID:PMC7505052

[42] Polyzos SA,Mantzoros CS.Adipokines in nonalcoholic fatty liver disease..Metabolism2016;65:1062-79

[43] Polyzos SA,Zavos C.Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines..Curr Mol Med2009;9:299-314

[44] Mota M,Cazanave SC.Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease..Metabolism2016;65:1049-61 PMCID:PMC4931958

[45] Buzzetti E,Tsochatzis EA.The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)..Metabolism2016;65:1038-48

[46] Nati M,Birkenfeld AL,Chavakis T.The role of immune cells in metabolism-related liver inflammation and development of non-alcoholic steatohepatitis (NASH)..Rev Endocr Metab Disord2016;17:29-39

[47] Boutari C,Mantzoros CS.Association of Adipokines with Development and Progression of Nonalcoholic Fatty Liver Disease..Endocrinol Metab (Seoul)2018;33:33-43 PMCID:PMC5874193

[48] Di Lascio N,Salvati A.Steato-Score: Non-Invasive Quantitative Assessment of Liver Fat by Ultrasound Imaging..Ultrasound Med Biol2018;44:1585-96

[49] Chen J,Yin M,Sanderson SO.Early detection of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease by using MR elastography..Radiology2011;259:749-56 PMCID:PMC3099044

[50] Gallego-Durán R,Gomez-Gonzalez E.Imaging biomarkers for steatohepatitis and fibrosis detection in non-alcoholic fatty liver disease..Sci Rep2016;6:31421 PMCID:PMC4981860

[51] Costa-Silva L,Lima AS,Ferrari TCA.MR elastography is effective for the non-invasive evaluation of fibrosis and necroinflammatory activity in patients with nonalcoholic fatty liver disease..Eur J Radiol2018;98:82-9

[52] Pavlides M,Tunnicliffe EM.Multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease severity..Liver Int2017;37:1065-73 PMCID:PMC5518289

[53] Eddowes PJ,Davies N.Utility and cost evaluation of multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease..Aliment Pharmacol Ther2018;47:631-44

[54] Kim JW,Park YS.Multiparametric MR Index for the Diagnosis of Non-Alcoholic Steatohepatitis in Patients with Non-Alcoholic Fatty Liver Disease..Sci Rep2020;10:2671 PMCID:PMC7021895

[55] Guzmán-Aroca F,Bas A.Detection of non-alcoholic steatohepatitis in patients with morbid obesity before bariatric surgery: preliminary evaluation with acoustic radiation force impulse imaging..Eur Radiol2012;22:2525-32

[56] Fierbinteanu Braticevici C,Panaitescu E.Value of acoustic radiation force impulse imaging elastography for non-invasive evaluation of patients with nonalcoholic fatty liver disease..Ultrasound Med Biol2013;39:1942-50