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

1/21/2019 1

Fibrosis Assessment and Introduction to Cirrhosis

Jordan J Feld MD MPH

Toronto Centre for Liver Disease Sandra Rotman Centre for Global Health

Hemant Shah MD MScCH HPTE

Francis Family Liver Clinic @hepatoMD

Disclosures

Jordan Feld:

• Research: Abbott, Abbvie, Gilead, Janssen, Merck
• Consulting: Abbvie, Contravir, Enanta, Gilead

Hemant Shah:

• Consulting Fees: Abbvie, Gilead, Merck, Intercept,

Lupin

Learning Objectives

• 1. Understand the importance of staging fibrosis

in all liver diseases

• 2. Appreciate the utility and caveats of non-

invasive tools for assessing fibrosis

• 3. Understand the importance of cirrhosis and

how to assess severity

Outline

• Why is cirrhosis important?
• Diagnosing cirrhosis

– Non-invasive tools – When to consider biopsy

• Assessing prognosis

Importance of cirrhosis

• Urgency of treatment
• Prognosis
• Treatment response for HCV, HBV and ?NASH
• Treatment regimen (possibly)
• On-treatment monitoring
• Need for follow-up

Every patient with liver disease needs a fibrosis assessment, particularly before starting therapy!

Cirrhosis matters

Jaundice Fluid Retention Ascites Esophageal Varices Hepatic Encephalopathy Liver Cancer

Cirrhosis

1/21/2019 2

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

Stages F1-3 and even early F4 may “look normal” on imaging A “normal” liver ultrasound does not exclude fibrosis and may miss cirrhosis

Tools to Assess Fibrosis

• Clinical exam

– Normal until and often with cirrhosis (insensitive) – 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

• Laboratory tests

– Liver enzymes (AST/ALT) may be normal even with advanced fibrosis or cirrhosis – not helpful – Normal ALT does not mean ‘inactive HCV’ – Liver function (bilirubin, albumin, INR) normal until advanced cirrhosis

• Tests suggesting advanced fibrosis/cirrhosis

– Platelet count < 150 x 10E9/µl – AST:ALT ratio > 1 (typically < 1 in HCV) – (Abnormal bilirubin, INR, albumin  late finding)

Simple Test: APRI

• Cirrhosis

– Platelets fall – AST > ALT (alcohol)

• Limitations

– Must be calculated! – Not great for F1 vs F2/3 – But excellent negative predictive value

• <0.5 NPV = 98%
• <1.0 NPV = 93-95%

AST/ULN x 100 Platelet count

Castera et al. 2005

• Very useful test to rule out cirrhosis
• Not good for staging, +/- for ruling in cirrhosis (>2)

1/21/2019 3 Similar to APRI: FIB-4

• Slightly harder to calculate but online

calculators

• Age important factor
• Initially developed for HIV/HCV but

validated well in HCV and fairly well in other liver diseases

• >3.25 – likely cirrhosis
• <1.45 – very unlikely advanced

fibrosis

• 1.45-3.25 – a bit less helpful

Fibrotest

• Age
• Gender
• GGT
• Bilirubin

– Indirect may be up

• α2-Macroglobulin
• Haptoglobin

– Hemolysis

• Apo-Lipoprotein A1

Castera et al., Gastro 2005

• Very useful – nice to convince your hospital to fund this!
• Reasonable for staging

There are many serum tests and they perform well

Fibrometer APRI

15.0 10.0 5.0 0.0

• 5.0

12.0 10.0 8.0 6.0 4.0 2.0 0.0 1 2 3 4 4 3 2 1

MP3 Forn’s Score

0.0 0.2 0.4 0.6 0.8 0.0 2.0 4.0 6.0 8.0 10.0 12.0 1 2 3 4 4 3 2 1

Fibrotest Hepascore

0.0 0.2 0.4 0.6 0.8 1.0 1.0 0.8 0.6 0.4 0.2 0.0 1 2 3 4 4 3 2 1

• Leroy. J Hepatol. 2007;775-82.
• Good for mild vs. advanced fibrosis
• Cheap, non-invasive
• Significant overlap across stages
• May be influenced by other factors

Liver Stiffness by Transient Elastography (Fibroscan)

Ultrasound-based technique Determines liver “stiffness” Correlates well with fibrosis No ceiling, ie, increases with worsening cirrhosis → predicts complications (eg, varices) Simple to use – minimal training Other methods in development

Caveats: -Fails in up to 20% (especially in obese patients ) – improved with XL probe.

• Influenced by inflammation – it falsely elevates measurements

Liver Stiffness by Transient Elastography

• Vergera. CID. 2007.
• Very good for minimal fibrosis (F0-2) vs cirrhosis (F4)
• Not widely available

2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 100 63 40 25 16 10 6.3 4.0 2.5 P < 0.001 Logarithm of Transient Elastometry Measurement (log kPa) Transient Elastometry Measurement (kPa) 1 2 3 4

n = 15 n = 49 n = 26 n = 14 n = 65

Fibrosis Stage

An important caveat…

All of these non-invasive tests

• Fibroscan, Fibrotest, APRI, FIB-4 etc MUST BE DONE

BEFORE THERAPY!

• Likely to improve with treatment…but unclear what it

means

• Cannot ‘go back in time’ so if you did not do it before

therapy, very hard to assess fibrosis without a biopsy

• If these tests show cirrhosis before

treatment…assume cirrhosis forever (even if the tests improve)

1/21/2019 4 Which would you prefer?

• Non-invasive tests very good for cirrhosis vs minimal fibrosis
• High correlation with biopsy especially if they agree
• Adequate for most patients with HCV

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

Recognizing Cirrhosis

Which one has cirrhosis?

Obvious Not So Obvious

The Spectrum of Cirrhosis: From Subtle to Overt

Compensated Cirrhosis

Diagnosis subtle Few or no symptoms

• Possibly fatigue

Subtle or no physical exam abnormalities

• Possibly spider angiomata,

palmar erythema, splenomegaly, hard liver, palpable left lobe

Subtle or no laboratory abnormalities

• Low platelet count, AST > ALT

Decompensated Cirrhosis

Diagnosis usually obvious Complication(s) of cirrhosis

• Ascites/edema
• Variceal hemorrhage
• Encephalopathy
• Jaundice

Abnormal liver function

• Bilirubin
• Albumin
• INR

Assessing severity of cirrhosis

What do you call these tests?

• ALT
• AST
• ALP
• GGT

Liver enzymes  NOT LFTs

1/21/2019 5 Why?

56 yo man awaiting liver transplant ALT 17 AST 27 GGT 43 ALP 93

“LFTs” are “Normal”!! Actually – not true – LFTs VERY abnormal

INR 2.4 Bilirubin 98 umol/L Albumin 28 g/L

Liver tests/enzymes ≠ LFTs

• Liver Function

– Clotting factor synthesis  INR – Bilirubin conjugation + excretion  Bilirubin – Protein synthesis  Albumin – Gluconeogenesis  Fasting glucose – Toxin metabolism  Encephalopathy (clinical exam)/ammonia level – (Renal function)  Creatinine

Child-Pugh-Turcotte 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

Child-Pugh Score MELD – Very objective

• INR, Bilirubin, Creatinine

Baseline MELD 10 Yr Mortality <8 17% 8-10 18% 10-13 32% >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 3 month mortality

Consequences of Cirrhosis

Portal Hypertension

• Ascites
• Esophageal varices
• Encephalopathy
• (Hepatic hydrothorax)
• (Portopulmonary HTN)

Liver Synthetic Dysfunction

• Protein synthesis
• albumin, clotting factors
• Metabolism
• Bilirubin, drugs

1/21/2019 6 Stages of Cirrhosis

D’Amico Gastro

Very useful for prognostication

Cirrhosis: Not necessarily a death sentence

91% 5-year and 79% 10-year survival in compensated cirrhosis

Fattovich et al. Gastro 1997;112:463-72.

HCV cirrhosis with a complication Compensated HCV cirrhosis

12 24 36 48 60 72 84 96 108 120 Months A 384 376 342 288 236 165 126 79 52 39 25 B 65 39 21 11 7 4 4 3 3 2 1 Patients at risk 100 80 60 40 20

Survival Probability (%)

Relevance to HCV treatment

• If any signs of decompensation (past or present)

– Ascites, encephalopathy, variceal bleed – Consider referral before treatment – If you do treat – remember a few things

• 1. Protease inhibitors contraindicated
• 2. Ribavirin usually necessary
• 3. May get worse on therapy – warm them!
• Post treatment

– Continue cancer surveillance – even if fibroscan and labs get better!

Is Cirrhosis Irreversible?

Dogma used to be that “fibrosis” and definitely “cirrhosis” are irreversible…but thinking is changing/has changed

• Poynard. Gastroenterology. 2002.
• Maylin. Gastroenterology. 2008.

ONE WAY

• Concept of “Regression of Fibrosis”
• After cure of HCV - fibrosis improves in > 50% AND 33-

67% of cirrhotics are no longer cirrhotic, that is early cirrhosis may be reversible!

What’s the implication of regression?

1 2 3 4 5 6 7 8 9 10 10 20 30

10-year occurence SVR: 1.9% (95%CI 0.0-4.1) non-SVR: 27.4% (95%CI 22.0-32.8)

p<0.001 Follow-up time, years LR-Mortality, % Van de Meer et al JAMA 2012

SVR eliminates liver failure & liver-related death

SVR Non-SVR

10-year occurrence SVR: 1.9 % (95% CI 0.0-4.1) Non-SVR: 27.4% ((5% CI 22.0-32.8)

Liver Related Mortality %

Long-term follow-up of 534 patients with advanced liver damage

Liver Cancer still occurs post-SVR

1 2 3 4 5 6 7 8 9 10 10 20 30

10-year occurence SVR: 5.1% (95%CI 1.3-8.9) non-SVR: 21.8% (95%CI 16.6-27.0)

p<0.001 Follow-up time, years HCC, %

• However – HCC curable if found early
• Surveillance necessary indefinitely – even after SVR

Van de Meer et al JAMA 2012

SVR Non-SVR

10-year occurrence SVR: 5.1 % (95% CI 1.3-8.9) Non-SVR: 21.8% ((5% CI 16.6-27.0)

Long-term follow-up of 534 patients with advanced liver damage

1/21/2019 7 HCC risk after SVR for HCV

• Cirrhosis the key factor
• Cirrhosis – 1.82/100 py (vs 1.1 to 1.39/100 py with IFN)
• No cirrhosis – 0.34/100py
• Can we use pre-treatment FIB4?
• FIB4 > 3.25 – 2.16/100 py  surveillance required
• FIB4 1.45 – 3.25 - 0.45/100 py
• FIB4 < 1.45 – 0.30/100 py

Message: Cirrhosis is the key risk factor for HCC post-SVR

• Can use FIB4 before treatment to determine post-SVR risk – if <3.25 no

surveillance – not cost-effective

Kanwal Gastro 2018, Zangneh Clin Gastro Hep 2018 No surveillance Not cost effective

Summary

• Assessment of fibrosis critical for ALL patients

with HCV and other liver diseases

• Non-invasive tools very useful for almost all

patients but mostly validated in HCV

• Critical to identify cirrhosis BEFORE treatment –

may not be obvious and tests may improve

• Any signs of decompensation should raise alarm

bells

• Once you make the diagnosis…need to find and

ideally reverse the underlying cause