5/24/2013 Linda Ferrell, MD Distinguished Professor LIVER Vice Chair Director of Surgical Pathology Dept of Pathology Update on Staging of Fibrosis and Cirrhosis Stage is more than liver fibrosis Staging and Liver Fibrosis Clinical Modalities to Stage Chronic Liver Disease Two important concepts for consideration: Measurements of liver function and patho- physiology include the following among others: - Stage is more than histologic fibrosis • Transient elastography (Fibroscan ) An integrated clinical/pathophysiologic approach • Clinical scores including Child-Pughs and MELD is needed to accurately stage the disease scores - Cirrhosis is not the “end” of the story: • Serum markers and panels, such as Fibrotest , Histologic scoring may need to evolve to identify Hepascore , FibroSpect , ELF score, AAR, APRI, regression or remodeling of cirrhosis, and evaluate for etc. very advanced nonreversible, or “end-stage” cirrhosis, • Hepatic venous pressure gradient (HVPG) based on degree of fibrosis 1
5/24/2013 Going “Beyond Cirrhosis” Going “Beyond Cirrhosis” Proposal from the International Liver Pathology Proposal: It may be time to put aside the “one- Study Group term-fits-all” approach, and stage liver disease Concept: Cirrhosis has historically implied end- as related to etiology and pathophysiology stage disease with the imminent death of Should we drop the term cirrhosis or at least patient as there was no cure and no treatment recognize different “degree’s of cirrhosis” for a better method of describing advanced liver injury based on But now, many patients remain compensated, etiology and patterns of injury?? and function improves with therapy, particularly notable in chronic viral hepatitis Assessment of Advanced Chronic Liver Disease Adapted from Figs 1, Beyond Cirrhosis (AJCP 2012) Staging and Liver Fibrosis and Exploring Beyond Cirrhosis (Hepatol 2012, 56:779) Patient with chronic liver disease Liver biopsy is still considered an important Clinical workup Liver biopsy with advanced stage of chronic disease • Assessment or reassessment of component of staging -Activity of disease etiology, comorbidities or cofactors -Features of regression • Assessment of severity -Presence of other diseases – Laboratory tests -Risk factors for malignancy Questions: – Transient elastography • How do we use the liver biopsy in the best – HVPG, etc Clinicopathologic correlation way? Final diagnosis as the sum of: • What are the histological aspects we need to Etiology Stage consider? -Advanced stage with no complications Disease activity -Advanced stage with complications -Advanced stage with regression Risk for HCC -End stage 2
5/24/2013 Staging and Liver Fibrosis Adequacy of Biopsy for Grading/Staging Short summary (more details in syllabus) An important starting point is the Current acceptable recommendations adequate biopsy!! • 5 portal areas minimum, probably >11 for optimal value • And/or approx 2 cm core of reasonable width (17 gauge or larger) Staging and Liver Fibrosis: Staging: Histological Aspects Other considerations Etiology related to fibrosis degree and patterns • Etiology of the injury Etiology HBV HCV AIH NASH ASH PBC PSC HHC WD CVOO Fibrosis ranking *13 3 3 3 NA 1 2 2 NA NA NA • Pattern and degree of histological injury Regression or ++ ++ + ++ + + ++ + NA remodel evidence 15 • Treatment effects resulting in Centrizonal or sinusoidal +/- ++ +++ +++ fibrosis prominent pattern Portal-based fibrosis ++ ++ ++ ++ ++ ++ + remodeling, or regression, of fibrosis prominent pattern Fibrosis ranking on explanted liver, 1= most fibrosis, 3= least fibrosis -What changes are reversible? AIH= autoimmune hepatitis; NASH= nonalcoholic steatohepatitis; ASH= alcoholic steatohepatitis; PBC= primary biliary cirrhosis; PSC= primary sclerosing cholangitis; HHC= hereditary hemochromatosis; WD= Wilsons disease; CVOO= primary types of chronic venous outflow obstruction 3
5/24/2013 Histological Aspects Histological Aspects Etiology related to fibrosis degree and patterns Etiology related to fibrosis degree and patterns Etiology HBV HCV AIH NASH ASH PBC PSC HHC WD CVOO Etiology HBV HCV AIH NASH ASH PBC PSC HHC WD CVOO Fibrosis ranking *13 Fibrosis ranking *13 3 3 3 NA 1 2 2 NA NA NA 3 3 3 NA 1 2 2 NA NA NA Regression or ++ ++ + ++ + + ++ + NA Regression or ++ ++ + ++ + + ++ + NA remodel evidence 15 remodel evidence 15 Centrizonal or sinusoidal +/- ++ +++ +++ Centrizonal or sinusoidal +/- ++ +++ +++ fibrosis prominent pattern fibrosis prominent pattern Portal-based fibrosis ++ ++ ++ ++ ++ ++ + Portal-based fibrosis ++ ++ ++ ++ ++ ++ + prominent pattern prominent pattern Fibrosis ranking on explanted liver, 1= most fibrosis, 3= least fibrosis; Fibrosis ranking on explanted liver, 1= most fibrosis, 3= least fibrosis AIH= autoimmune hepatitis; NASH= nonalcoholic steatohepatitis; AIH= autoimmune hepatitis; NASH= nonalcoholic steatohepatitis; ASH= alcoholic steatohepatitis; PBC= primary biliary cirrhosis; ASH= alcoholic steatohepatitis; PBC= primary biliary cirrhosis; PSC= primary sclerosing cholangitis; HHC= hereditary hemochromatosis; PSC= primary sclerosing cholangitis; HHC= hereditary hemochromatosis; WD= Wilsons disease; CVOO= primary types of chronic venous outflow obstruction WD= Wilsons disease; CVOO= primary types of chronic venous outflow obstruction Portal-Based Fibrosis Pattern Patterns of Fibrosis Two major patterns for early scarring of the Major associated lesions liver • Chronic hepatitis – Hepatitis B, C Portal-based Fibrosis – Autoimmune hepatitis Injury begins in periportal area – Alpha-1-antitrypsin and Wilsons disease • Biliary Disease Central-based Fibrosis – PBC, PSC, Chronic obstruction Injury begins in centrilobular zone • Hemochromatosis 4
5/24/2013 Portal-based Fibrosis: Chronic Hepatitis Chronic Hepatitis C: Cirrhosis, rounded nodules Chronic Biliary Disease Chronic Biliary Disease: Jigsaw fibrosis Wider fibrous bands with more ductular reaction can occur in comparison to chronic hepatitis B or C 5
5/24/2013 Fibrosis Scoring of Chronic Hepatitis Commonly used Grading/Staging systems • Scheuer/Batts-Ludwig/Tsui: Practical tips and common problems – Grade and Stage on scale 0-4 – Simple, reproducible, validated clinically • First step: Use a system that is • METAVIR: – Simple – Grade 0-3, Fibrosis 0-4 – Simple, reproducible, validated clinically – Reproducible • Ishak, et al: – Useful in clinical setting – Grades four categories of activity/necrosis, 0-4 or 0-6 • Generally considered too complex, not necessary – Staging 0-6 • Preferred in many clinical trials • Still reproducible and validated clinically Scheuer / Batts-Ludwig / Tsui Grading and Staging Scheuer/Batts,Ludwig/Tsui Fibrosis scoring for Chronic Hepatitis • Simple, reproducible, validated • Essentially same methodology so interchangeable for the most part Stage Description 0 No fibrosis, normal amount of connective tissue • Most commonly used day-to-day in USA and 1 Portal/periportal fibrosis validated for studies as well 2 Septal fibrosis • #1 Recommended for typical usage for 3 Bridging fibrosis with architectural distortion. 4 Cirrhosis, probable cirrhosis grading 6
5/24/2013 METAVIR Ishak, et al: Fibrosis Scoring System 2-letter, 2-number system similar to Scheuer J Hepatol 1995;22:696-9 (Grading system typically not used due to complexity) Used extensively in France 0 No fibrosis F = fibrosis 1 Expansion of some portal areas with or without septa • F0 = no fibrosis 2 Expansion of most portal areas with or without septa • F1 = portal fibrosis without septa 3 Expansion of most portal areas with occasional portal to portal bridging • F2 = portal fibrosis 4 Expansion of portal areas with marked bridging (portal- with rare septa portal and/or portal-central) • F3 = numerous 5 Marked bridging with occasional nodules (incomplete septa, not cirrhosis cirrhosis) 6 Cirrhosis, probable or definitive • F4 = cirrhosi s Portal-Based Fibrosis: Which scoring system to use? • All three systems are reasonable • Scheuer and Batts/Ludwig 0-4 scales works well for chronic hepatitis B and C and is simple – Validated by many studies Limitations: • Doesn’t apply to centrizonal liver disease • Mixed etiologies (Example: Alcohol + HBV) • Doesn’t go “beyond cirrhosis” – No differentiation between early, compensated versus advanced, end-stage decompensated cirrhosis) • Doesn’t evaluate for remodeling/regression From Theise ND, Mod Pathol 2007, 20(supple 1):S3-14; Also published in MacSween’s Pathology of the Liver 7
5/24/2013 Fibrosis: Stage ? CASE EXAMPLES Practice staging using Scale 0-4 Fibrosis: Stage ? Fibrosis Stage? 1. Stage 1 2. Stage 2 3. Stage 3 4. Stage 4 5. Stage 0 55% 27% 16% 1% 0% 1 2 3 4 0 e e e e e g g g g g a a a a a t t t t t S S S S S 8
5/24/2013 Fibrosis: Stage ? Fibrosis stage? 1. Stage 1 2. Stage 2 3. Stage 3 4. Stage 4 5. Stage 0 55% 23% 22% 0% 0% 1 2 3 4 0 e e e e e g g g g g a a a a a t t t t t S S S S S Fibrosis: Stage ? Fibrosis stage? 1. Stage 1 2. Stage 2 3. Stage 3 4. Stage 4 5. Stage 0 52% 48% 0% 0% 0% 1 2 3 4 0 e e e e e g g g g g a a a a a S t S t S t S t S t 9
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