Semin Liver Dis 2022; 42(03): 313-326
DOI: 10.1055/s-0042-1751081
Review Article

Noninvasive Algorithms for the Case Finding of “At-Risk” Patients with NAFLD

Laurent Castera
1   Université de Paris, UMR1149 (CRI), INSERM, Paris, France
2   Service d'Hépatologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Beaujon, Clichy, France
,
Jérôme Boursier
3   Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, France
4   Laboratoire HIFIH UPRES EA3859, SFR ICAT 4208, Université d'Angers, Angers, France
› Institutsangaben


Abstract

Despite the high prevalence of non-alcoholic fatty liver disease (NAFLD) in primary care (25%), only a small minority (< 5%) of NAFLD patients will develop advanced liver fibrosis. The challenge is to identify these patients, who are at the greatest risk of developing complications and need to be referred to liver clinics for specialized management. The focus should change from patients with abnormal liver tests toward patients “at risk of NAFLD,” namely those with metabolic risk factors, such as obesity and type 2 diabetes. Non-invasive tests are well validated for diagnosing advanced fibrosis. Algorithms using FIB-4 as the first-line test, followed, if positive (≥ 1.3), by transient elastography or a patented blood test are the best strategy to define pathways for “at-risk” NAFLD patients from primary care to liver clinics. Involving general practitioners actively and raising their awareness regarding NAFLD and non-invasive tests are critical to establish such pathways.



Publikationsverlauf

Artikel online veröffentlicht:
14. Juli 2022

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  • References

  • 1 Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64 (01) 73-84
  • 2 Estes C, Anstee QM, Arias-Loste MT. et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J Hepatol 2018; 69 (04) 896-904
  • 3 Haldar D, Kern B, Hodson J. et al; European Liver and Intestine Transplant Association (ELITA). Outcomes of liver transplantation for non-alcoholic steatohepatitis: a European Liver Transplant Registry study. J Hepatol 2019; 71 (02) 313-322
  • 4 Goldberg D, Ditah IC, Saeian K. et al. Changes in the prevalence of hepatitis c virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation. Gastroenterology 2017; 152 (05) 1090-1099.e1
  • 5 Diehl AM, Day C. Nonalcoholic Steatohepatitis. N Engl J Med 2018; 378 (08) 781
  • 6 Blais P, Husain N, Kramer JR, Kowalkowski M, El-Serag H, Kanwal F. Nonalcoholic fatty liver disease is underrecognized in the primary care setting. Am J Gastroenterol 2015; 110 (01) 10-14
  • 7 Albhaisi SAM, Sanyal AJ. New drugs for NASH. Liver Int 2021; 41 (Suppl. 01) 112-118
  • 8 Castera L, Friedrich-Rust M, Loomba R. Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease. Gastroenterology 2019; 156 (05) 1264-1281.e4
  • 9 Angulo P, Bugianesi E, Bjornsson ES. et al. Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2013; 145 (04) 782-9.e4
  • 10 Dulai PS, Singh S, Patel J. et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology 2017; 65 (05) 1557-1565
  • 11 Taylor RS, Taylor RJ, Bayliss S. et al. Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Gastroenterology 2020; 158 (06) 1611-1625.e12
  • 12 Sanyal AJ, Van Natta ML, Clark J. et al; NASH Clinical Research Network (CRN). Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N Engl J Med 2021; 385 (17) 1559-1569
  • 13 Roulot D, Costes JL, Buyck JF. et al. Transient elastography as a screening tool for liver fibrosis and cirrhosis in a community-based population aged over 45 years. Gut 2011; 60 (07) 977-984
  • 14 Koehler EM, Plompen EP, Schouten JN. et al. Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: the Rotterdam study. Hepatology 2016; 63 (01) 138-147
  • 15 Cheng PN, Chiu YC, Chiu HC, Chien SC. The application of liver stiffness measurement in residents without overt liver diseases through a community-based screening program. Medicine (Baltimore) 2016; 95 (12) e3193
  • 16 Caballería L, Pera G, Arteaga I. et al. High prevalence of liver fibrosis among European adults with unknown liver disease: a population-based study. Clin Gastroenterol Hepatol 2018; 16 (07) 1138-1145.e5
  • 17 Abeysekera KWM, Fernandes GS, Hammerton G. et al. Prevalence of steatosis and fibrosis in young adults in the UK: a population-based study. Lancet Gastroenterol Hepatol 2020; 5 (03) 295-305
  • 18 Ciardullo S, Monti T, Perseghin G. Prevalence of liver steatosis and fibrosis detected by transient elastography in adolescents in the 2017-2018 National Health and Nutrition Examination Survey. Clin Gastroenterol Hepatol 2021; 19 (02) 384-390.e1
  • 19 Wong VW, Chu WC, Wong GL. et al. Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography. Gut 2012; 61 (03) 409-415
  • 20 Rao Kondapally Seshasai S, Kaptoge S, Thompson A. et al; Emerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011; 364 (09) 829-841
  • 21 Chen K, Sng WK, Quah JH. et al. Clinical spectrum of non-alcoholic fatty liver disease in patients with diabetes mellitus. PLoS One 2020; 15 (08) e0236977
  • 22 Harman DJ, Ryder SD, James MW. et al. Obesity and type 2 diabetes are important risk factors underlying previously undiagnosed cirrhosis in general practice: a cross-sectional study using transient elastography. Aliment Pharmacol Ther 2018; 47 (04) 504-515
  • 23 Harris R, Card TR, Delahooke T, Aithal GP, Guha IN. Obesity is the most common risk factor for chronic liver disease: results from a risk stratification pathway using transient elastography. Am J Gastroenterol 2019; 114 (11) 1744-1752
  • 24 Petta S, Di Marco V, Pipitone RM. et al. Prevalence and severity of nonalcoholic fatty liver disease by transient elastography: genetic and metabolic risk factors in a general population. Liver Int 2018; 38 (11) 2060-2068
  • 25 Zhang X, Heredia NI, Balakrishnan M, Thrift AP. Prevalence and factors associated with NAFLD detected by vibration controlled transient elastography among US adults: results from NHANES 2017-2018. PLoS One 2021; 16 (06) e0252164
  • 26 Glyn-Owen K, Böhning D, Parkes J, Roderick P, Buchanan R. The combined effect of alcohol and body mass index on risk of chronic liver disease: a systematic review and meta-analysis of cohort studies. Liver Int 2021; 41 (06) 1216-1226
  • 27 Innes H, Crooks CJ, Aspinall E. et al. Characterising the risk interplay between alcohol intake and body mass index on cirrhosis morbidity. Hepatology 2021
  • 28 Mozes FE, Lee JA, Selvaraj EA. et al. Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis. Gut 2021
  • 29 Selvaraj EA, Mózes FE, Jayaswal ANA. et al; LITMUS Investigators. Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: a systematic review and meta-analysis. J Hepatol 2021; 75 (04) 770-785
  • 30 Vali Y, Lee J, Boursier J. et al; LITMUS systematic review team(†). Enhanced liver fibrosis test for the non-invasive diagnosis of fibrosis in patients with NAFLD: a systematic review and meta-analysis. J Hepatol 2020; 73 (02) 252-262
  • 31 Vali Y, Lee J, Boursier J. et al; On Behalf Of The Litmus Systematic Review Team. FibroTest for evaluating fibrosis in non-alcoholic fatty liver disease patients: a systematic review and meta-analysis. J Clin Med 2021; 10 (11) 10
  • 32 Van Dijk AM, Vali Y, Mak AL. et al. Systematic review with meta-analyses: diagnostic accuracy of FibroMeter Tests in patients with non-alcoholic fatty liver disease. J Clin Med 2021; 10 (13) 10
  • 33 Petta S, Wong VW, Cammà C. et al. Serial combination of non-invasive tools improves the diagnostic accuracy of severe liver fibrosis in patients with NAFLD. Aliment Pharmacol Ther 2017; 46 (06) 617-627
  • 34 Anstee QM, Lawitz EJ, Alkhouri N. et al. noninvasive tests accurately identify advanced fibrosis due to NASH: baseline data from the STELLAR Trials. Hepatology 2019; 70 (05) 1521-1530
  • 35 Boursier J, Guillaume M, Leroy V. et al. New sequential combinations of non-invasive fibrosis tests provide an accurate diagnosis of advanced fibrosis in NAFLD. J Hepatol 2019; 71 (02) 389-396
  • 36 American Diabetes Association. 4.. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Medical Care in Diabetes-2021 . Diabetes Care 2021; 44 (Suppl. 01) S40-S52
  • 37 Tsochatzis EA, Newsome PN. Non-alcoholic fatty liver disease and the interface between primary and secondary care. Lancet Gastroenterol Hepatol 2018; 3 (07) 509-517
  • 38 Majumdar A, Campos S, Gurusamy K, Pinzani M, Tsochatzis EA. Defining the minimum acceptable diagnostic accuracy of noninvasive fibrosis testing in cirrhosis: a decision analytic modeling study. Hepatology 2020; 71 (02) 627-642
  • 39 Vilar-Gomez E, Lou Z, Kong N, Vuppalanchi R, Imperiale TF, Chalasani N. Cost effectiveness of different strategies for detecting cirrhosis in patients with nonalcoholic fatty liver disease based on united states health care system. Clin Gastroenterol Hepatol 2020; 18 (10) 2305-2314.e12
  • 40 Crossan C, Majumdar A, Srivastava A. et al. Referral pathways for patients with NAFLD based on non-invasive fibrosis tests: diagnostic accuracy and cost analysis. Liver Int 2019; 39 (11) 2052-2060
  • 41 Srivastava A, Jong S, Gola A. et al. Cost-comparison analysis of FIB-4, ELF and fibroscan in community pathways for non-alcoholic fatty liver disease. BMC Gastroenterol 2019; 19 (01) 122
  • 42 Sterling RK, Lissen E, Clumeck N. et al; APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006; 43 (06) 1317-1325
  • 43 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 (04) 846-854
  • 44 Xiao G, Zhu S, Xiao X, Yan L, Yang J, Wu G. Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: a meta-analysis. Hepatology 2017; 66 (05) 1486-1501
  • 45 Alkayyali T, Qutranji L, Kaya E, Bakir A, Yilmaz Y. Clinical utility of noninvasive scores in assessing advanced hepatic fibrosis in patients with type 2 diabetes mellitus: a study in biopsy-proven non-alcoholic fatty liver disease. Acta Diabetol 2020; 57 (05) 613-618
  • 46 Boursier J, Canivet CM, Costentin C. et al. Impact of type 2 diabetes on the accuracy of non-invasive tests of liver fibrosis with resulting clinical implications. Clin Gastroenterol Hepatol 2022; S1542-3565 (22) 00248-8
  • 47 Patel P, Hossain F, Horsfall LU. et al. A pragmatic approach identifies a high rate of nonalcoholic fatty liver disease with advanced fibrosis in diabetes clinics and at-risk populations in primary care. Hepatol Commun 2018; 2 (08) 893-905
  • 48 McPherson S, Hardy T, Dufour JF. et al. Age as a confounding factor for the accurate non-invasive diagnosis of advanced NAFLD fibrosis. Am J Gastroenterol 2016
  • 49 Drolz A, Wolter S, Wehmeyer MH. et al. Performance of non-invasive fibrosis scores in non-alcoholic fatty liver disease with and without morbid obesity. Int J Obes 2021; 45 (10) 2197-2204
  • 50 Qadri S, Ahlholm N, Lonsmann I. et al. Obesity modifies the performance of fibrosis biomarkers in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2021
  • 51 Alexander M, Loomis AK, Fairburn-Beech J. et al. Real-world data reveal a diagnostic gap in non-alcoholic fatty liver disease. BMC Med 2018; 16 (01) 130
  • 52 Filozof C, Jones S, Connelly M. et al. Liver fibrosis as assessed by the FIB-4 index and metabolic markers in subjects with type 2 diabetes. Hepatology 2017; 66: 1126A
  • 53 Hagström H, Talbäck M, Andreasson A, Walldius G, Hammar N. Ability of noninvasive scoring systems to identify individuals in the population at risk for severe liver disease. Gastroenterology 2020; 158 (01) 200-214
  • 54 Halfon P, Ansaldi C, Penaranda G. et al. Prospective screening of liver fibrosis in a primary care cohort using systematic calculation of fib-4 in routine results. PLoS One 2021; 16 (07) e0254939
  • 55 Lomonaco R, Godinez Leiva E, Bril F. et al. Advanced liver fibrosis is common in patients with type 2 diabetes followed in the outpatient setting: the need for systematic screening. Diabetes Care 2021; 44 (02) 399-406
  • 56 Schonmann Y, Yeshua H, Bentov I, Zelber-Sagi S. Liver fibrosis marker is an independent predictor of cardiovascular morbidity and mortality in the general population. Dig Liver Dis 2021; 53 (01) 79-85
  • 57 Schreiner A, Moran W, Zhang J. et al. The fibrosis-4 index and severe liver disease outcomes in primary care: a stratified Cox analysis. Hepatology 2021; 74: 125A
  • 58 Singh A, Le P, Peerzada MM, Lopez R, Alkhouri N. The utility of noninvasive scores in assessing the prevalence of nonalcoholic fatty liver disease and advanced fibrosis in type 2 diabetic patients. J Clin Gastroenterol 2018; 52 (03) 268-272
  • 59 Sung KC, Johnston MP, Lee MY, Byrne CD. Non-invasive liver fibrosis scores are strongly associated with liver cancer mortality in general population without liver disease. Liver Int 2020; 40 (06) 1303-1315
  • 60 Unalp-Arida A, Ruhl CE. Liver fibrosis scores predict liver disease mortality in the United States population. Hepatology 2017; 66 (01) 84-95
  • 61 Ciardullo S, Muraca E, Perra S. et al. Screening for non-alcoholic fatty liver disease in type 2 diabetes using non-invasive scores and association with diabetic complications. BMJ Open Diabetes Res Care 2020; 8 (01) 8
  • 62 Younossi ZM, Corey KE, Alkhouri N. et al; US Members of the Global Nash Council. Clinical assessment for high-risk patients with non-alcoholic fatty liver disease in primary care and diabetology practices. Aliment Pharmacol Ther 2020; 52 (03) 513-526
  • 63 Hagström H, Talbäck M, Andreasson A, Walldius G, Hammar N. Repeated FIB-4 measurements can help identify individuals at risk of severe liver disease. J Hepatol 2020; 73 (05) 1023-1029
  • 64 Chan WK, Treeprasertsuk S, Goh GB. et al. Optimizing use of nonalcoholic fatty liver disease fibrosis score, fibrosis-4 score, and liver stiffness measurement to identify patients with advanced fibrosis. Clin Gastroenterol Hepatol 2019; 17 (12) 2570-2580.e37
  • 65 Graupera I, Thiele M, Serra-Burriel M. et al; Investigators of the LiverScreen Consortium. Low accuracy of FIB-4 and NAFLD fibrosis scores for screening for liver fibrosis in the population. Clin Gastroenterol Hepatol 2021; S1542-3565 (21) 01358-6
  • 66 Karsdal MA, Daniels SJ, Holm Nielsen S. et al. Collagen biology and non-invasive biomarkers of liver fibrosis. Liver Int 2020; 40 (04) 736-750
  • 67 Sanyal AJ, Shankar S, Yates K. et al. Primary results of the NIMBLE stage-1 NASH-CRN study of circulating biomarkers for nonalcoholic steatohepatitis and its activity and fibrosis stage. Hepatology 2021; 74: 1383A
  • 68 Guillaume M, Moal V, Delabaudiere C. et al. Direct comparison of the specialised blood fibrosis tests FibroMeterV2G and enhanced liver fibrosis score in patients with non-alcoholic fatty liver disease from tertiary care centres. Aliment Pharmacol Ther 2019; 50 (11-12): 1214-1222
  • 69 Eddowes PJ, Sasso M, Allison M. et al. Accuracy of FibroScan controlled attenuation parameter and liver stiffness measurement in assessing steatosis and fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology 2019; 156 (06) 1717-1730
  • 70 Siddiqui MS, Vuppalanchi R, Van Natta ML. et al; NASH Clinical Research Network. Vibration-controlled transient elastography to assess fibrosis and steatosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2019; 17 (01) 156-163.e2
  • 71 Wong VW, Irles M, Wong GL. et al. Unified interpretation of liver stiffness measurement by M and XL probes in non-alcoholic fatty liver disease. Gut 2019; 68 (11) 2057-2064
  • 72 European 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 Hepatol 2016; 64 (06) 1388-1402
  • 73 Srivastava A, Gailer R, Tanwar S. et al. Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease. J Hepatol 2019; 71 (02) 371-378
  • 74 Mofrad P, Contos MJ, Haque M. et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 2003; 37 (06) 1286-1292
  • 75 Armstrong MJ, Marchesini G. Referral pathways for NAFLD fibrosis in primary care - no longer a ‘needle in a haystack’. J Hepatol 2019; 71 (02) 246-248
  • 76 European Association for the Study of the Liver, Clinical Practice Guideline Panel, Chair, EASL Governing Board representative, Panel members. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update. J Hepatol 2021; 75 (03) 659-689
  • 77 Jafarov F, Kaya E, Bakir A, Eren F, Yilmaz Y. The diagnostic utility of fibrosis-4 or nonalcoholic fatty liver disease fibrosis score combined with liver stiffness measurement by fibroscan in assessment of advanced liver fibrosis: a biopsy-proven nonalcoholic fatty liver disease study. Eur J Gastroenterol Hepatol 2020; 32 (05) 642-649
  • 78 Mansour D, Grapes A, Herscovitz M. et al. Embedding assessment of liver fibrosis into routine diabetic review in primary care. JHEP Rep 2021; 3 (04) 100293
  • 79 Younossi ZM, Golabi P, de Avila L. et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol 2019; 71 (04) 793-801
  • 80 Castera L, Vidal-Trecan T, Vallet-Pichard A. et al. High rate of biopsy-proven advanced fibrosis among type 2 diabetes patients screened for NAFLD in diabetes units. Hepatology 2021; 74: 1017A
  • 81 Chalasani N, Younossi Z, Lavine JE. et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018; 67 (01) 328-357
  • 82 Bril F, McPhaul MJ, Caulfield MP. et al. Performance of the SteatoTest, ActiTest, NashTest and FibroTest in a multiethnic cohort of patients with type 2 diabetes mellitus. J Investig Med 2019; Feb; 67 (02) 303-311
  • 83 Bertot LC, Jeffrey GP, de Boer B. et al. Diabetes impacts prediction of cirrhosis and prognosis by non-invasive fibrosis models in non-alcoholic fatty liver disease. Liver Int 2018; 38 (10) 1793-1802
  • 84 Kwok R, Choi KC, Wong GL. et al. Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study. Gut 2016; 65 (08) 1359-1368
  • 85 Lai LL, Wan Yusoff WNI, Vethakkan SR, Nik Mustapha NR, Mahadeva S, Chan WK. Screening for non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus using transient elastography. J Gastroenterol Hepatol 2019; 34 (08) 1396-1403
  • 86 Mikolasevic I, Domislovic V, Turk Wensveen T. et al. Screening for nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus using transient elastography—a prospective, cross sectional study. Eur J Intern Med 2020; 82: 68-75
  • 87 Roulot D, Roudot-Thoraval F, NKontchou G. et al. Concomitant screening for liver fibrosis and steatosis in French type 2 diabetic patients using Fibroscan. Liver Int 2017; 37 (12) 1897-1906
  • 88 Younossi ZM, Ong JP, Takahashi H. et al. A global survey of physicians knowledge about nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2022; Jun; 20 (06) e1456-e1468
  • 89 Lazarus JV, Mark HE, Anstee QM. et al; NAFLD Consensus Consortium. Advancing the global public health agenda for NAFLD: a consensus statement. Nat Rev Gastroenterol Hepatol 2022; 19 (01) 60-78