TWHLIVER

CENTREUHN centre of excellence

Liver issues for the Rheumatologist

David Wong, MDUniversity of Torontowww.torontoliver.ca

Disclosures (last 1 year):Research Studies: BMS, Gilead, Johnson & Johnson, VertexAdvisory Boards: Merck, Vertex

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Objectives To understand the sensitivity and

specificity of Fibroscan and Fibrotest for liver monitoring in patients receiving MTX

To understand which patients to refer to a specialist

To consider which labs to monitor when screening for liver problems with DMARDS

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Drug induced liver injury (DILI)

Acute injury ALT/AST

NSAIDS Sulfasalazine

ALP NSAIDS Sulfasalazine Gold salts Azathioprine

Chronic injury Fatty liver

Methotrexate Ductopenia

Azathiprine, Gold salts Nodular regenerative

hyperplasia Azathioprine

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Case of DILI 52 year old woman with HIV

Hepatitis C genotype 3 Poor adherence to meds, did not treat HCV

Previously FTC-TDF-LPV/r Sep 2012 – disseminated MAC

CD4 40 (very low): Treat MAC first with antibiotics Admit to Casey House to monitor treatment

Dec 2012 – start HIV medications FTC-TDF-DRV/r

Jan 2012 – admitted with jaundice, ALT 200s, AST 300s Stop HIV medications

Apr 2013 – re-started HIV medications FTC-TDF-DRV/r

May 2013 – dying of liver failure

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When to worry about DILI?

ALT/AST Height of elevation ~ degree of liver injury

Other considerations? What is liver reserve?

Previously normal liver vs cirrhotic liver? NB not everyone with HBV or HCV has cirrhosis

Hy’s law Jaundice: case fatality rate 10%-50%

Re-introduction of medication can be diagnostic but deadly

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DILI

Guruprasad P Aithal. Nat Rev Rheumatol. 2011;7:139

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Approach to DILI Is there another cause for acute

hepatitis? Is there underlying cirrhosis?

How much liver fibrosis exists? Is fibrosis progressive?

How high is ALT/AST How badly do I need to use this drug? Can I treat through this?

Jaundice is BAD

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HMO in Israel: Psoriasis and RA diagnosed Jan 1998-Jul

2007 Alcohol Fatty liver risks

Dyslipidemia BMI, waist

circumference Fibrosis

assessment

H Amital et al. Rheumatology 2009;48(9):1107

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Methotrexate and the liver

Liver biopsy q1.5 grams? Cirrhosis without abnormal liver

enzymes Monitoring of liver enzymes? Role of ultrasound?

Guruprasad P Aithal. Nat Rev Rheumatol. 2011;7:139

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CasesCase 1 Case 2

History Rheumatoid arthritis treated with MTX at age 40

Disability after back injury at age 40

Liver tests ALT 30-55At age 64 Increasing abdominal distension, found to have ascitesLiver biopsy Lots of scar tissue (cirrhosis), inactive (no

inflammation)Fibrosis is perisinusoidal, Fat 5-10%, Occassional Mallory

Diagnosis Methotrexate toxicity even if trivial MTX even if alcoholic even if diabetic even if BMI >>30

If alcohol: alcoholic cirrhosisIf no alcohol pre-1995: cryptogenic cirrhosisPost 1995, metabolic syndrome: NASH cirrhosis

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Methotrexate and the liver

DILI vs fatty liver?

Guruprasad P Aithal. Nat Rev Rheumatol. 2011;7:139

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How to prevent?MTX Fatty liver

Avoid Don’t use MTX Lose weight, lose diabetesMonitoring Guidelines

AST, ALT, Albumin q4-8 wksLiver biopsy after 1-1.5 gRepeat liver biopsyPIIINPFibroscanFibrotest

Liver biopsy-liver enzymes not informative-ultrasound not informative

Problems Nobody likes biopsy >100,000,000 with fatty liver in the USAInterobserver error for biopsyMost don’t die of cirrhosis

JM Kremer et al. Arthritis Rheum 1994;37:316HH Roenigk et al. J Am Acad Dermatol 1998;38:478

C Paul et al. JEADV 2011;25 (Suppl 2)

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Objectives To understand the sensitivity and

specificity of Fibroscan and Fibrotest for liver monitoring in patients receiving MTX

To understand which patients to refer to a specialist

To consider which labs to monitor when screening for liver problems with DMARDS

TWHLIVER

CENTRE

Typical Referral 52 year old man with psoriatic

arthritis MTX x 5 years Liver biopsy? Fibroscan?

Assessment Risks for fatty liver?

Diabetes, hypertriglyceridemia, central obesity

Alcohol Risks for other liver disease

Viral hepatitis Iron overload Celts

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Fibrosis Assessment Fibroscan

Chest circumference Are the ribs easily palpable Is the rib space adequate

Fibrosis assessment in 3 minutes Fibrotest

Cannot be done if hemolysis Haptoglobin undetectable

Cost for some components Fibrosis assessment in 1-4 weeks

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Acting on Fibrosis Assessment

Concordant results F0-2: continue treatment F3-4: change treatment

Discordant results Ultrasound Liver biopsy

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Hepatitis BWorldwide Problem

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Natural History of Hepatitis B

Importance of immune control

HJ Yim and AS Lok. Hepatology 2006;43:S173

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HBV investigationsHBsAg

anti-HBs, anti-HBc1. Screen for HBV

HBsAg-POS Infected

HBsAg-NEG Not-Infected

Anti-HBc POS Prior infection

Anti-HBc NEG, Anti-HBs NEG No infection, vaccinate

1a. Need for vaccine

High RiskRefer!

Low RiskMonitor ALT

Check HBsAg if ALT

Advanced liver fibrosis? Platelets < 160

Age > 40

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Hepatitis C in OntarioModeled prevalence

MOHLTC integrated Public Health Information System, 4/12/2011

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Challenges in HCV treatment

SVR>90%, minimal side effects

New agents screened against HCV G1b Not as effective against

G1a Most do not work for non-1

Genotype 3?

Other challenges Cirrhosis Monotherapy not

sufficient Treatment experience

Interferon sensitivity (IL28b)

Ribavirin resistance?

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ABT orals + RBV in non-cirrhotics (naïve and nulls)

ABT-450/r PI ABT-267 NS5a inhibitor ABT-333 NN NS5b inhibitor N=451 treated 12-24 weeks

Going ahead with 12 weeks Degree of Difficulty

Excludes cirrhotics Includes 1a (66%), non-CC (81%)

KV Kowdley et al. A3. EASL 2013

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SVR2492 91 90 94 95 93 93 91 95 9494

9894 91 89

97 97 96 93100

KV Kowdley et al. A3. EASL 2013

% S

VR

24

Mal

eFe

mal

e

1a 1b

>7

log

<7

log

F0-F

1F2

-F3

Non

-CC

CC

Mal

eFe

mal

e

1a 1b

>7

log

<7

log

F0-F

1F2

-F3

Non

-CC

CC

Naïve N=159 Null N=88

7881 10850 35124 11342 11544 56 33 55 33 22 66 41 45 85 3

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Salvage for BOC/TPV failures

SOF+DCV+/-RBV x 24 weeks SOF - PolI

Declatasvir (DCV) – NS5A inhibitor Degree of Difficulty

Excludes cirrhotics Includes treatment failures (nulls)

Excludes early DC due to AE 1a: 76-85%, non-CC: 95-100%

MS Sulkowski et al. A1417. EASL 2013

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Week 2 Week 4 EOT SVR4 SVR12

91100 100 100 100

8095 100 100 95

SD SDR

SVR12%

SV

R

21 20 21 20 21 20 21 20 21 20

MS Sulkowski et al. A1417. EASL 2013

1 missed is SVR24

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Hepatitis C diagnosis Anti-HCV antibody: exposed HCV PCR: needed to confirm infection

HCV not greatly affected by immunosuppression

HCV curable

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Summary Immunosuppression

Hepatitis B Vasculitis

Hepatitis C >> Hepatitis B

TWHLIVER

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Objectives To understand the sensitivity and

specificity of Fibroscan and Fibrotest for liver monitoring in patients receiving MTX

To understand which patients to refer to a specialist

To consider which labs to monitor when screening for liver problems with DMARDS

TWHLIVER

CENTRE

Recommendations for Methotrexate or Imuran

Baseline History

Metabolic syndrome Did you ever drink on a

regular or daily basis? Other history of liver

disease Labs

ALT, AST, ALP, CBC Ultrasound if abnormal

tests Especially if Plts <

150 HBsAg

Monitoring Labs

ALT, AST, ALP Look for rising numbers

over the first year that continue to go up rather than just fluctuate

CBC Look for falling patelet

count to < 150 Very concerned if Plts

< 150 and falling by >15% over 2 years

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What to do for your cirrhotics

Stage Clinical Implication1 Asymptomatic 10 year survival > 85-90%2 Esophageal varices Screen with gastroscopy3 History of variceal bleed Beta blockers lower risk4 Ascites Synthesis failure: transplantHepatoma

At any stage Ultrasound surveillance (not AFP)

Plts < 150: suspect cirrhosis Plts < 100: likely will have varices Plts < 70: higher risk of renal failure (hepatorenal

syndrome) No NSAIDS (even with PPI) Tylenol <3-4g/day is much safer

Coffee may be good Alcohol in moderation may be good

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Questions?