Fibrosis Assessment and Consulting: Abbvie, Contravir, Enanta, - PDF document

1/21/2019 Disclosures Jordan Feld: • Research: Abbott, Abbvie, Gilead, Janssen, Merck Fibrosis Assessment and • Consulting: Abbvie, Contravir, Enanta, Gilead Introduction to Cirrhosis Hemant Shah: • Consulting Fees: Abbvie, Gilead, Merck, Intercept, Hemant Shah MD MScCH Lupin Jordan J Feld MD MPH HPTE Toronto Centre for Liver Disease Sandra Rotman Centre for Global Francis Family Liver Clinic Health @hepatoMD Learning Objectives Outline • Why is cirrhosis important? 1. Understand the importance of staging fibrosis in all liver diseases • Diagnosing cirrhosis – Non-invasive tools 2. Appreciate the utility and caveats of non- – When to consider biopsy invasive tools for assessing fibrosis • Assessing prognosis 3. Understand the importance of cirrhosis and how to assess severity Importance of cirrhosis Cirrhosis matters • Urgency of treatment • Prognosis • Treatment response for HCV, HBV and ?NASH Cirrhosis • Treatment regimen (possibly) Esophageal Jaundice Varices • On-treatment monitoring • Need for follow-up Every patient with liver disease needs a fibrosis assessment, particularly before Hepatic Liver Fluid Retention starting therapy! Encephalopathy Cancer Ascites 1

1/21/2019 Liver disease catches you by surprise Fibrosis not synonymous with cirrhosis Fibrosis staged from 0 (normal) to 4 (cirrhosis) Liver May Look Normal Even with Cirrhosis Tools to Assess Fibrosis • Clinical exam Stages F1- 3 and even early F4 may “look normal” on imaging – Normal until and often with cirrhosis (insensitive) A “normal” liver ultrasound does not exclude fibrosis and may miss cirrhosis – Suggestive findings: spider angiomata, palmar erythema, dilated abdominal veins, splenomegaly – Findings if present, are fairly specific, but very insensitive • Radiology – Normal with F0-F3 and often with cirrhosis (insensitive) – Helpful if shows cirrhosis (fairly specific) • Nodular liver • Enlarged caudate lobe • Enlarged spleen • Enlarged portal vein Tools to Assess Fibrosis Simple Test: APRI • Laboratory tests AST/ULN x 100 • Cirrhosis Platelet count – Liver enzymes (AST/ALT) may be normal even with – Platelets fall advanced fibrosis or cirrhosis – not helpful – AST > ALT (alcohol) – Normal ALT does not mean ‘inactive HCV’ • Limitations – Liver function (bilirubin, albumin, INR) normal until – Must be calculated! advanced cirrhosis – Not great for F1 vs F2/3 – But excellent negative • Tests suggesting advanced fibrosis/cirrhosis predictive value – Platelet count < 150 x 10E9/µl • <0.5 NPV = 98% – AST:ALT ratio > 1 (typically < 1 in HCV) • <1.0 NPV = 93-95% – (Abnormal bilirubin, INR, albumin  late finding) • Very useful test to rule out cirrhosis • Not good for staging, +/- for ruling in cirrhosis (>2) Castera et al. 2005 2

1/21/2019 Similar to APRI: FIB-4 Fibrotest • Age • Gender • GGT • Bilirubin – Indirect may be up • Slightly harder to calculate but online calculators • α 2-Macroglobulin • Age important factor • Haptoglobin • Initially developed for HIV/HCV but validated well in HCV and fairly well – Hemolysis in other liver diseases • Apo-Lipoprotein A1 • >3.25 – likely cirrhosis • <1.45 – very unlikely advanced fibrosis • Very useful – nice to convince your hospital to fund this! • 1.45-3.25 – a bit less helpful • Reasonable for staging Castera et al., Gastro 2005 There are many serum tests and Liver Stiffness by Transient Elastography they perform well (Fibroscan) Ultrasound-based technique 0.8 1.0 15.0 Determines liver “stiffness” 0.8 0.6 Fibrometer 10.0 Fibrotest 0.6 MP3 0.4 5.0 Correlates well with fibrosis 0.4 0.2 0.0 No ceiling, ie, increases with 0.2 worsening cirrhosis → predicts 0.0 0.0 -5.0 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 complications (eg, varices) 12.0 12.0 1.0 10.0 Simple to use – minimal 10.0 Forn’s Score 0.8 Hepascore 8.0 8.0 APRI training 0.6 6.0 6.0 0.4 4.0 Other methods in development 4.0 0.2 2.0 2.0 0.0 0.0 0.0 Caveats: -Fails in up to 20% (especially in obese patients ) – improved with 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 XL probe. • • Good for mild vs. advanced fibrosis Significant overlap across stages -Influenced by inflammation – it falsely elevates measurements • • Cheap, non-invasive May be influenced by other factors Leroy. J Hepatol. 2007;775-82. Liver Stiffness by Transient Elastography An important caveat… Very good for minimal fibrosis (F0-2) vs cirrhosis (F4) • Not widely available • All of these non-invasive tests 2.0 100 Transient Elastometry Measurement (kPa) P < 0.001 Logarithm of Transient Elastometry - Fibroscan, Fibrotest, APRI, FIB-4 etc MUST BE DONE 1.8 63 BEFORE THERAPY! Measurement (log kPa) 1.6 40 - Likely to improve with treatment…but unclear what it 1.4 25 means 1.2 16 - Cannot ‘go back in time’ so if you did not do it before 1.0 10 therapy, very hard to assess fibrosis without a biopsy - If these tests show cirrhosis before 0.8 6.3 treatment…assume cirrhosis forever (even if the 0.6 4.0 tests improve) n = 15 n = 49 n = 26 n = 14 n = 65 0.4 2.5 0 1 2 3 4 Fibrosis Stage Vergera. CID. 2007. 3

1/21/2019 Which would you prefer? Indications for Liver Biopsy 1. Inconclusive, unreliable or unavailable non- invasive tests 2. Diagnostic uncertainty – Etiology of liver disease: Fatty liver, alcohol, autoimmune hepatitis, drug-induced liver injury, other • Non-invasive tests very good for cirrhosis vs minimal fibrosis • High correlation with biopsy especially if they agree • Adequate for most patients with HCV Recognizing Cirrhosis The Spectrum of Cirrhosis: From Subtle to Overt Which one has cirrhosis? Compensated Cirrhosis Decompensated Cirrhosis Diagnosis subtle Diagnosis usually obvious Obvious Not So Obvious Few or no symptoms Complication(s) of cirrhosis - Possibly fatigue - Ascites/edema - Variceal hemorrhage Subtle or no physical exam abnormalities - Encephalopathy - Jaundice - Possibly spider angiomata, palmar erythema, Abnormal liver function splenomegaly, hard liver, - Bilirubin palpable left lobe - Albumin Subtle or no laboratory - INR abnormalities - Low platelet count, AST > ALT What do you call these tests? • ALT • AST • ALP Assessing severity of • GGT cirrhosis Liver enzymes  NOT LFTs 4

1/21/2019 Liver tests/enzymes ≠ LFTs Why? 56 yo man awaiting liver transplant • Liver Function – Clotting factor synthesis  INR ALT 17 AST 27 – Bilirubin conjugation + excretion  Bilirubin GGT 43 – Protein synthesis  Albumin ALP 93 – Gluconeogenesis  Fasting glucose “LFTs” are “Normal”!! – Toxin metabolism  Encephalopathy (clinical exam)/ammonia level – (Renal function)  Creatinine Actually – not true – LFTs VERY abnormal INR 2.4 Bilirubin 98 umol/L Albumin 28 g/L Child-Pugh-Turcotte Child-Pugh Score Assessing Severity of Cirrhosis Lab 1 2 3 INR (N<1.2) <1.7 1.7-2.2 >2.2 Albumin (N>40) >35 28-35 <28 Bilirubin (N<17) <34 34-54 >54 Clinical Ascites none mild severe Encephalopathy none mild severe Child’s CPT score Surgical Mortality Survival A 5-6 ~10% 10-15 yrs B 7-9 ~30% 5 yrs C 10-15 ~80% 2 yrs MELD – Very objective Consequences of Cirrhosis • INR, Bilirubin, Creatinine Baseline 10 Yr MELD Mortality Portal Hypertension Liver Synthetic Dysfunction - Ascites - Protein synthesis 3 month mortality <8 17% - Esophageal varices - albumin, clotting factors 8-10 18% - Encephalopathy - Metabolism - (Hepatic hydrothorax) - Bilirubin, drugs 10-13 32% - (Portopulmonary HTN) >13 66% MELD = (3.8 ln Bili (mg/dL)) + 11.2 (ln INR) + 9.6 (ln Creat (mg/dL)) (or use an online calculator!) Bruno Am J Gastro 2009 5