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An in-depth look at Advanced Fibrosis due to NASH including Impact, Identification and Management

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Identifying Advanced Fibrosis

Noninvasive Tests (NITs)

Types of NITs:








Use of a Second NIT


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NASH, nonalcoholic steatohepatitis; NITs, noninvasive tests; NAFLD, nonalcoholic fatty liver disease; F0–F2, stage 0–2 fibrosis; F2, stage 2 fibrosis; F3, stage 3 fibrosis; F4, stage 4 fibrosis; AASLD, American Association for the Study of Liver Diseases; FIB-4, fibrosis-4; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; NFS, NAFLD fibrosis score; APRI, aspartate aminotransferase/platelet ratio index; US, United States; ELF, enhanced liver fibrosis; NICE, National Institute for Health and Care Excellence; TE, transient elastography; MRE, magnetic resonance elastography; kPa, kilopascal.

From a meta-analysis of 5 multinational cohorts (1,495 NAFLD patients with 17,452 PYF). Liver-related mortality was a secondary outcome and was defined by investigators.1

In a study of patients with histologically confirmed NASH, 48 of 217 (22%) patients with stage 3 fibrosis (F3) progressed to cirrhosis at median follow-up of 29 months. Analysis used data from two large, randomized, placebo-controlled, phase 2b studies of patients with F3 fibrosis and compensated cirrhosis due to NASH in which patients underwent biopsy at screening, Week 48, and Week 96.2

The study investigated interobserver agreement for scores of liver fibrosis in 65 biopsy specimens from patients with mixed liver disease etiologies. Concordance between three pathologists was analysed. Bivariate weighted κ for Ishak staging ranged from 0.57–0.67, and for NASH CRN staging ranged from 0.47–0.59.

FIB-4 test results are based on age, hence the accuracy of the test may vary according to age.

NFS test results are based on age, hence the accuracy of the test may vary according to age.

The study population included patients with histological findings consistent with NAFLD.

In patients with hepatitis C.

Identification of Advanced Fibrosis in patients NAFLD.1

False positives can arise from haemolysis, Gilbert syndrome, cholestasis and inflammation due to increased levels of α2-macroglobulin and haptoglobin.4

Moderate, F1–F2 and F2–bridging fibrosis with few septa.3

Moderate, categorized as mild–advanced fibrosis, ELF scores of 7.7–9.79.

Moderate is classified as patients with fibrosis staging of F2.

MRE image indicates Advanced Fibrosis (F3) – liver stiffness 6.1 kPa. Adapted from Venkatesh SK et al. J Magn Reson Imaging 2013;37:544–555

References:1. 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(5):1557-1565. 2. Sanyal AJ, Harrison SA, Ratziu V, et al. The Natural History of Advanced Fibrosis Due to Nonalcoholic Steatohepatitis: Data From the Simtuzumab Trials. Hepatology. 2019; doi: 10.1002/hep.30664. [epub ahead of print] 3. Pavlides M, Birks J, Fryer E, et al. Interobserver variability in histologic evaluation of liver fibrosis using categorical and quantitative scores. Am J Clin Pathol. 2017;147(4):364-369. 4. European Association for Study of Liver. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol. 2015;63(1):237-264. 5. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD; American Association for the Study of Liver Diseases. Liver biopsy. Hepatology. 2009;49(3):1017-1044. 6. Sumida Y, Nakajima A, Itoh Y. 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Gastroenterol Hepatol (NY). 2016;12(1):33-40. 11. 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(2):371-378. 12. Bewick V, Cheek L, Ball J. Statistics review 13: receiver operating characteristic curves. Crit Care. 2004;8(6):508-512. 13. Fibrosis-4 calculator. Available at: Accessed September 30, 2019. 14. 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(1):328-357. 15. Fibrosis-4 calculator. Available at: Accessed September 30, 2019. 16. 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(1):328-357. 17. Kruger FC, Daniels CR, Kidd M, et al. 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Cost-comparison analysis of FIB-4, ELF and fibroscan in community pathways for non-alcoholic fatty liver disease. BMC Gastroenterol. 2019;19(1):122. 29. Kemp W, Roberts S. FibroScan® and transient elastography. Aust Fam Physician. 2013;42(7):468-471. 30. Mikolasevic I, Orlic L, Franjic N, Hauser G, Stimac D, Milic S. Transient elastography (FibroScan®) with controlled attenuation parameter in the assessment of liver steatosis and fibrosis in patients with nonalcoholic fatty liver disease – Where do we stand? World J Gastroenterol. 2016;22(32):7236-7251. 31. Festi D, Schiumerini R, Marzi L, et al. Review article: the diagnosis of nonalcoholic fatty liver disease—availability and accuracy of non-invasive methods. Aliment Pharmacol Ther. 2013;37(4):392-400. 32. Castera L, Friedrich-Rust M, Loomba R. Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2019;156(5):1264–1281. 33. Atay K, Alan O, Canbakan B, et al. 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US-PP-NAS-0791 10/20