Noninvasive testing in the diagnosis of metabolic dysfunction-associated steatohepatitis

Lucas M. Marks , Thomas Jensen , Timothy R. DeGrado

Metabolism and Target Organ Damage ›› 2024, Vol. 4 ›› Issue (3) : 28

PDF
Metabolism and Target Organ Damage ›› 2024, Vol. 4 ›› Issue (3) :28 DOI: 10.20517/mtod.2024.44
Review

Noninvasive testing in the diagnosis of metabolic dysfunction-associated steatohepatitis

Author information +
History +
PDF

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) [previously termed nonalcoholic fatty liver disease (NAFLD)] is estimated to be the most common chronic liver disease worldwide, affecting 25% of the world’s population and becoming the leading cause of liver transplant in the US. The progression of MASLD from simple hepatic steatosis to the more severe metabolic dysfunction-associated steatohepatitis (MASH) [previously nonalcoholic steatohepatitis (NASH)] has critically important impacts on clinical outcomes. Early detection and staging of disease severity, along with lifestyle modifications and treatment of comorbid conditions, is the best way to prevent the progression or reverse the course of the disease. Although noninvasive imaging and predictive indices are available for the evaluation of hepatic fibrosis, the only way to diagnose MASH remains liver biopsy despite the risk for complications and being less desired by patients. Hence, there is a need to develop noninvasive tests to aid in both the diagnosis and monitoring of MASH, especially with the recent emergence of liver-directed therapy for “at risk” MASH (MASH with NAS ≥ 4 and Stage ≥ F2 Fibrosis). The goal of the current review is to cover the most recent pathophysiology, current diagnostic methods, and recent advances to aid in the diagnosis of MASH.

Keywords

Metabolic dysfunction-associated steatotic liver disease (MASLD) / nonalcoholic fatty liver disease (NAFLD) / metabolic dysfunction-associated steatohepatitis (MASH) / imaging / fibrosis

Cite this article

Download citation ▾
Lucas M. Marks, Thomas Jensen, Timothy R. DeGrado. Noninvasive testing in the diagnosis of metabolic dysfunction-associated steatohepatitis. Metabolism and Target Organ Damage, 2024, 4(3): 28 DOI:10.20517/mtod.2024.44

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

Rinella ME, Lazarus JV, Ratziu V, et al; NAFLD Nomenclature consensus group. A multisociety Delphi consensus statement on new fatty liver disease nomenclature.Hepatology2023;78:1966-86 PMCID:PMC10653297

[2]

Younossi ZM,Paik JM,Van Dongen C.The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review.Hepatology2023;77:1335-47 PMCID:PMC10026948

[3]

Charlton MR,Pedersen RA,Heimbach JK.Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States.Gastroenterology2011;141:1249-53

[4]

Sumida Y.Current and future pharmacological therapies for NAFLD/NASH.J Gastroenterol2018;53:362-76 PMCID:PMC5847174

[5]

Byrne CD.NAFLD: a multisystem disease.J Hepatol2015;62:S47-64

[6]

Shao T,Liang SH.PET/SPECT molecular probes for the diagnosis and staging of nonalcoholic fatty liver disease.Mol Imaging2019;18:1536012119871455 PMCID:PMC6724487

[7]

Wegrzyniak O,Eriksson O.Recent progress in the molecular imaging of nonalcoholic fatty liver disease.Int J Mol Sci2021;22:7348 PMCID:PMC8306605

[8]

Trujillo MJ,Rubin JM.Non-invasive imaging biomarkers to assess nonalcoholic fatty liver disease: a review.Clin Imaging2021;78:22-34

[9]

Pierantonelli I.Nonalcoholic fatty liver disease: basic pathogenetic mechanisms in the progression from NAFLD to NASH.Transplantation2019;103:e1-13

[10]

Younossi ZM,Pinto-Cortez H.Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: implications for liver transplantation.Transplantation2019;103:22-7

[11]

Ipsen DH,Tveden-Nyborg P.Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease.Cell Mol Life Sci2018;75:3313-27 PMCID:PMC6105174

[12]

Milić S,Štimac D.Non-alcoholic fatty liver disease and obesity: biochemical, metabolic and clinical presentations.World J Gastroenterol2014;20:9330-7 PMCID:PMC4110564

[13]

Ekstedt M,Mathiesen UL.Long-term follow-up of patients with NAFLD and elevated liver enzymes.Hepatology2006;44:865-73

[14]

Singh S,Wang Z,Murad MH.Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.Clin Gastroenterol Hepatol2015;13:643-54 PMCID:PMC4208976

[15]

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

[16]

Yatsuji S,Tobari M,Tokushige K.Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C.J Gastroenterol Hepatol2009;24:248-54

[17]

Iqbal U,Akhtar D,Ahmed A.The epidemiology, risk profiling and diagnostic challenges of nonalcoholic fatty liver disease.Medicines2019;6:41 PMCID:PMC6473603

[18]

Verma S,Hart J.Predictive value of ALT levels for non-alcoholic steatohepatitis (NASH) and advanced fibrosis in non-alcoholic fatty liver disease (NAFLD).Liver Int2013;33:1398-405

[19]

Cusi K,Harrison S.Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease.J Hepatol2014;60:167-74

[20]

Feldstein AE,Lopez AR,Zein NN.Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study.Hepatology2009;50:1072-8 PMCID:PMC2757511

[21]

Kazankov K,Møller HJ.The macrophage activation marker sCD163 is associated with morphological disease stages in patients with non-alcoholic fatty liver disease.Liver Int2016;36:1549-57

[22]

Nielsen MJ,Sun S.The neo-epitope specific PRO-C3 ELISA measures true formation of type III collagen associated with liver and muscle parameters.Am J Transl Res2013;5:303-15 PMCID:PMC3633973

[23]

Tanwar S,Guha IN.Validation of terminal peptide of procollagen III for the detection and assessment of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease.Hepatology2013;57:103-11

[24]

Piazzolla VA.Noninvasive diagnosis of NAFLD and NASH.Cells2020;9:1005 PMCID:PMC7226476

[25]

Lin ZH,Dong QJ.Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis.Hepatology2011;53:726-36

[26]

Rinella ME,Caldwell SH.Controversies in the diagnosis and management of NAFLD and NASH.Gastroenterol Hepatol2014;10:219-27 PMCID:PMC4073533

[27]

Shah AG,Murray K,Contos MJ.Nash Clinical Research NetworkComparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol2009;7:1104-12 PMCID:PMC3079239

[28]

Contreras D,Clark P,Denova-Gutiérrez E.Diagnostic accuracy of blood biomarkers and non-invasive scores for the diagnosis of NAFLD and NASH: systematic review and meta-analysis.Ann Hepatol2023;28:100873

[29]

López IC,Bernal MDF.Utility of the ELF test for detecting steatohepatitis in morbid obese patients with suspicion of nonalcoholic fatty liver disease.Obes Surg2017;27:2347-53

[30]

Ratziu V, Massard J, Charlotte F, et al; LIDO Study Group; CYTOL study group. Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease.BMC Gastroenterol2006;6:6 PMCID:PMC1386692

[31]

Poynard T, Munteanu M, Charlotte F, et al; FLIP Consortium; the FibroFrance-CPAM Group; the FibroFrance-Obese Group. Diagnostic performance of a new noninvasive test for nonalcoholic steatohepatitis using a simplified histological reference.Eur J Gastroenterol Hepatol2018;30:569-77

[32]

Guajardo-Salinas GE.Prevalence of nonalcoholic fatty liver disease (NAFLD) and utility of FIBROspect II to detect liver fibrosis in morbidly obese Hispano-American patients undergoing gastric bypass.Obes Surg2010;20:1647-53

[33]

Iruarrizaga-Lejarreta M,Morrison M.Targeting the NAFLD metabolome and the shaping of precision medicine for patients with NASH.J Hepatol2018;68:S362-3

[34]

Mayo R,Martínez-Arranz I.Metabolomic-based noninvasive serum test to diagnose nonalcoholic steatohepatitis: results from discovery and validation cohorts.Hepatol Commun2018;2:807-20 PMCID:PMC6049064

[35]

Poynard T, Ratziu V, Charlotte F, et al; LIDO Study Group; CYTOL study group. Diagnostic value of biochemical markers (NashTest) for the prediction of non alcoholo steato hepatitis in patients with non-alcoholic fatty liver disease.BMC Gastroenterol2006;6:34 PMCID:PMC1657015

[36]

Dowman JK,Newsome PN.Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.Aliment Pharmacol Ther2011;33:525-40 PMCID:PMC3080668

[37]

Adams LA.Non-invasive diagnosis of nonalcoholic fatty liver and nonalcoholic steatohepatitis.J Dig Dis2011;12:10-6

[38]

Marañón P,Isaza SC.Bone morphogenetic protein 2 is a new molecular target linked to non-alcoholic fatty liver disease with potential value as non-invasive screening tool.Biomark Res2022;10:35 PMCID:PMC9131682

[39]

Neuschwander-Tetri BA.Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference.Hepatology2003;37:1202-19

[40]

Sorrentino P,Conca P.Silent non-alcoholic fatty liver disease-a clinical-histological study.J Hepatol2004;41:751-7

[41]

Fracanzani AL,Bugianesi E.Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes.Hepatology2008;48:792-8

[42]

Xia MF,Bian H.Influence of ethnicity on the accuracy of non-invasive scores predicting non-alcoholic fatty liver disease.PLoS One2016;11:e0160526 PMCID:PMC5007035

[43]

Eddowes PJ,Allison M.Accuracy of fibroscan controlled attenuation parameter and liver stiffness measurement in assessing steatosis and fibrosis in patients with nonalcoholic fatty liver disease.Gastroenterology2019;156:1717-30

[44]

Jang JK,Seo JW.Two-dimensional shear-wave elastography and us attenuation imaging for nonalcoholic steatohepatitis diagnosis: a cross-sectional, multicenter study.Radiology2022;305:118-26

[45]

Thiagarajan P,Aithal GP.Metabolic imaging in non-alcoholic fatty liver disease: applications of magnetic resonance spectroscopy.J Clin Med2021;10:632 PMCID:PMC7915174

[46]

Abrigo JM,Wong VWS.Non-alcoholic fatty liver disease: spectral patterns observed from an in vivo phosphorus magnetic resonance spectroscopy study.J Hepatol2014;60:809-15

[47]

Abdelqader A,Fleisher AS.Extreme esophageal hyperkeratosis presenting as an arachnoid mass.Am J Gastroenterol2016;111:599

[48]

Allen AM,Therneau TM.Multiparametric magnetic resonance elastography improves the detection of NASH regression following bariatric surgery.Hepatol Commun2020;4:185-92 PMCID:PMC6996337

[49]

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

[50]

Andersson A,Imajo K.Clinical utility of magnetic resonance imaging biomarkers for identifying nonalcoholic steatohepatitis patients at high risk of progression: a multicenter pooled data and meta-analysis.Clin Gastroenterol Hepatol2022;20:2451-61.e3

[51]

Papadopoulos V,Guilarte TR.Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function.Trends Pharmacol Sci2006;27:402-9

[52]

Masdeu JC,Fujita M.Imaging neuroinflammation in neurodegenerative disorders.J Nucl Med2022;63:45S-52S

[53]

Xie L,Hatori A.Translocator protein (18 kDa), a potential molecular imaging biomarker for non-invasively distinguishing non-alcoholic fatty liver disease.J Hepatol2012;57:1076-82

[54]

Li Y,Li L.Cholesterol-binding translocator protein TSPO regulates steatosis and bile acid synthesis in nonalcoholic fatty liver disease.iScience2021;24:102457 PMCID:PMC8113880

[55]

Masarone M,Dallio M.Role of oxidative stress in pathophysiology of nonalcoholic fatty liver disease.Oxid Med Cell Longev2018;2018:9547613 PMCID:PMC6016172

[56]

Rokugawa T,Higaki Y.Potential of 99mTc-MIBI SPECT imaging for evaluating non-alcoholic steatohepatitis induced by methionine-choline-deficient diet in mice.EJNMMI Res2014;4:57 PMCID:PMC4452628

[57]

Mather KJ.Imaging of myocardial fatty acid oxidation.Biochim Biophys Acta2016;1861:1535-43 PMCID:PMC5141514

[58]

Giedd KN.Fatty acid imaging of the heart.Curr Cardiol Rep2011;13:121-31

[59]

Fukumoto M,Ogawa Y.In vivo imaging of hepatic fatty acid metabolism in patients with nonalcoholic steatohepatitis using semiquantative 123I-BMIPP liver scan.Hepatol Res2005;33:105-9

[60]

Onishi S.In vivo imaging of hepatic fatty acid metabolism in patients with non-alcoholic steatohepatitis using semiquantitative 123I-labeled branched-chain fatty acid analog.J Gastroenterol Hepatol2006;21:S76-8

[61]

Iozzo P,Takala T.Defective liver disposal of free fatty acids in patients with impaired glucose tolerance.J Clin Endocrinol Metab2004;89:3496-502

[62]

Iozzo P,Roivainen A.Fatty acid metabolism in the liver, measured by positron emission tomography, is increased in obese individuals.Gastroenterology2010;139:846-56.e6

[63]

Abele JT.Effect of hepatic steatosis on liver FDG uptake measured in mean standard uptake values.Radiology2010;254:917-24

[64]

Lin CY,Lin CC,Jeng LB.The negative impact of fatty liver on maximum standard uptake value of liver on FDG PET.Clin Imaging2011;35:437-41

[65]

Abikhzer G,Azoulay L,Rush C.Altered hepatic metabolic activity in patients with hepatic steatosis on FDG PET/CT.AJR Am J Roentgenol2011;196:176-80

[66]

Bural GG,Burke A.Quantitative assessment of the hepatic metabolic volume product in patients with diffuse hepatic steatosis and normal controls through use of FDG-PET and MR imaging: a novel concept.Mol Imaging Biol2010;12:233-9

[67]

Keramida G,Bush J,Dizdarevic S.Accumulation of 18F-FDG in the liver in hepatic steatosis.AJR Am J Roentgenol2014;203:643-8

[68]

Wang G,Olson KA,Sarkar S.Dynamic PET of human liver inflammation: impact of kinetic modeling with optimization-derived dual-blood input function.Phys Med Biol2018;63:155004 PMCID:PMC6105275

[69]

Sarkar S,Spencer B.Dynamic positron emission tomography/computed tomography imaging correlate of nonalcoholic steatohepatitis.Clin Gastroenterol Hepatol2021;19:2441-3 PMCID:PMC10096050

[70]

Diehl AM.Nonalcoholic steatosis and steatohepatitis IV. Nonalcoholic fatty liver disease abnormalities in macrophage function and cytokines.Am J Physiol Gastrointest Liver Physiol2002;282:G1-5

[71]

Duman DG,Akin H.Colloid scintigraphy in non-alcoholic steatohepatitis: a conventional diagnostic method for an emerging disease.Nucl Med Commun2006;27:387-93

[72]

Sodee DB,Noto RB,Alavi A.Gastrointestinal system. In: Early PJ, Sodee DB, editors. Principles and practice of nuclear medicine. 2nd ed. St Louis, MO, USA: Mosby; 1995.

[73]

Subramanian G,Mehter A.ˆ<99m>Tc-stannous phytate: a new in vivo colloid for imaging the reticuloendothelial system.J Nucl Med1973;14:459. (in Japanese)Available from: https://cir.nii.ac.jp/crid/1570854175563339136. [Last accessed on 10 Aug 2024]

[74]

Kikuchi M,Nakahara T.Utility of quantitative 99mTc-phytate scintigraphy to diagnose early-stage non-alcoholic steatohepatitis.Scand J Gastroenterol2009;44:229-36

[75]

Arzoumanian A,Seto H.Clinical comparison of 99mTc-labeled preformed phytate colloid and sulfur colloid: concise communication.J Nucl Med1977;18:118-120

[76]

Doughton JA,Eu P,Williams S.A first-in-human study of 68Ga-nanocolloid PET/CT sentinel lymph node imaging in prostate cancer demonstrates aberrant lymphatic drainage pathways.J Nucl Med2018;59:1837-42

[77]

Toi M,Bando H.Thymidine phosphorylase (platelet-derived endothelial-cell growth factor) in cancer biology and treatment.Lancet Oncol2005;6:158-66

[78]

Yue H,Bicak A.1211-P: the mechanistic role of thymidine phosphorylase in the development of obesity.Diabetes2021;70:1211-P

[79]

Higashikawa K,Tarisawa M.Preclinical investigation of potential use of thymidine phosphorylase-targeting tracer for diagnosis of nonalcoholic steatohepatitis.Nucl Med Biol2020;82-3:25-32

[80]

Harrison SA, Bedossa P, Guy CD, et al; MAESTRO-NASH Investigators. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis.N Engl J Med2024;390:497-509

[81]

Harrison SA,Dubourg J,Alkhouri N.Challenges and opportunities in NASH drug development.Nat Med2023;29:562-73

[82]

Bravo AA,Chopra S.Liver biopsy.N Engl J Med2001;344:495-500

[83]

Newsome PN,Deeks JJ.FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study.Lancet Gastroenterol Hepatol2020;5:362-73 PMCID:PMC7066580

[84]

Noureddin M,Gornbein JA.MRI-based (MAST) score accurately identifies patients with NASH and significant fibrosis.J Hepatol2022;76:781-7

[85]

Jung J,Imajo K.MRE combined with FIB-4 (MEFIB) index in detection of candidates for pharmacological treatment of NASH-related fibrosis.Gut2021;70:1946-53 PMCID:PMC8131405

[86]

Tavaglione F,De Vincentis A.Development and validation of a score for fibrotic nonalcoholic steatohepatitis.Clin Gastroenterol Hepatol2023;21:1523-32.e1

[87]

Harrison SA,Magnanensi J.NIS2+TM, an optimisation of the blood-based biomarker NIS4® technology for the detection of at-risk NASH: a prospective derivation and validation study.J Hepatol2023;79:758-67

[88]

Canivet CM,Qadri S.Validation of the blood test MACK-3 for the noninvasive diagnosis of fibrotic nonalcoholic steatohepatitis: an international study with 1924 patients.Clin Gastroenterol Hepatol2023;21:3097-106.e10

AI Summary AI Mindmap
PDF

111

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/