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TWH LIVER CENTRE UHN centre of excellence Liver issues for the Rheumatologist David Wong, MD University of Toronto www.torontoliver.ca Disclosures (last.

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Presentation on theme: "TWH LIVER CENTRE UHN centre of excellence Liver issues for the Rheumatologist David Wong, MD University of Toronto www.torontoliver.ca Disclosures (last."— Presentation transcript:

1 TWH LIVER CENTRE UHN centre of excellence Liver issues for the Rheumatologist David Wong, MD University of Toronto www.torontoliver.ca Disclosures (last 1 year): Research Studies: BMS, Gilead, Johnson & Johnson, Vertex Advisory Boards: Merck, Vertex

2 TWH LIVER CENTRE Objectives To understand the sensitivity and specificity of Fibroscan and Fibrotest for liver monitoring in patients receiving MTX 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 understand which patients to refer to a specialist To consider which labs to monitor when screening for liver problems with DMARDS To consider which labs to monitor when screening for liver problems with DMARDS

3 TWH LIVER CENTRE 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

4 TWH LIVER CENTRE Case of DILI 52 year old woman with HIV 52 year old woman with HIV Hepatitis C genotype 3 Hepatitis C genotype 3 Poor adherence to meds, did not treat HCV Poor adherence to meds, did not treat HCV Previously FTC-TDF-LPV/r Previously FTC-TDF-LPV/r Sep 2012 – disseminated MAC Sep 2012 – disseminated MAC CD4 40 (very low): Treat MAC first with antibiotics CD4 40 (very low): Treat MAC first with antibiotics Admit to Casey House to monitor treatment Admit to Casey House to monitor treatment Dec 2012 – start HIV medications Dec 2012 – start HIV medications FTC-TDF-DRV/r FTC-TDF-DRV/r Jan 2012 – admitted with jaundice, ALT 200s, AST 300s Jan 2012 – admitted with jaundice, ALT 200s, AST 300s Stop HIV medications Stop HIV medications Apr 2013 – re-started HIV medications Apr 2013 – re-started HIV medications FTC-TDF-DRV/r FTC-TDF-DRV/r May 2013 – dying of liver failure May 2013 – dying of liver failure

5 TWH LIVER CENTRE When to worry about DILI? ALT/AST ALT/AST Height of elevation ~ degree of liver injury Height of elevation ~ degree of liver injury Other considerations? Other considerations? What is liver reserve? What is liver reserve? Previously normal liver vs cirrhotic liver? Previously normal liver vs cirrhotic liver? NB not everyone with HBV or HCV has cirrhosis NB not everyone with HBV or HCV has cirrhosis Hy’s law Hy’s law Jaundice: case fatality rate 10%-50% Jaundice: case fatality rate 10%-50% Re-introduction of medication can be diagnostic but deadly Re-introduction of medication can be diagnostic but deadly

6 TWH LIVER CENTRE DILI Guruprasad P Aithal. Nat Rev Rheumatol. 2011;7:139

7 TWH LIVER CENTRE Approach to DILI Is there another cause for acute hepatitis? Is there another cause for acute hepatitis? Is there underlying cirrhosis? Is there underlying cirrhosis? How much liver fibrosis exists? How much liver fibrosis exists? Is fibrosis progressive? Is fibrosis progressive? How high is ALT/AST How high is ALT/AST How badly do I need to use this drug? How badly do I need to use this drug? Can I treat through this? Can I treat through this? Jaundice is BAD Jaundice is BAD

8 TWH LIVER CENTRE 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

9 TWH LIVER CENTRE Methotrexate and the liver Liver biopsy q1.5 grams? Liver biopsy q1.5 grams? Cirrhosis without abnormal liver enzymes Cirrhosis without abnormal liver enzymes Monitoring of liver enzymes? Monitoring of liver enzymes? Role of ultrasound? Role of ultrasound? Guruprasad P Aithal. Nat Rev Rheumatol. 2011;7:139

10 TWH LIVER CENTRE Cases Case 1Case 2 HistoryRheumatoid arthritis treated with MTX at age 40 Disability after back injury at age 40 Liver testsALT 30-55 At age 64Increasing abdominal distension, found to have ascites Liver biopsyLots of scar tissue (cirrhosis), inactive (no inflammation) Fibrosis is perisinusoidal, Fat 5-10%, Occassional Mallory DiagnosisMethotrexate toxicity even if trivial MTX even if alcoholic even if diabetic even if BMI >>30 If alcohol: alcoholic cirrhosis If no alcohol pre-1995: cryptogenic cirrhosis Post 1995, metabolic syndrome: NASH cirrhosis

11 TWH LIVER CENTRE Methotrexate and the liver DILI vs fatty liver? Guruprasad P Aithal. Nat Rev Rheumatol. 2011;7:139

12 TWH LIVER CENTRE How to prevent? MTXFatty liver AvoidDon’t use MTXLose weight, lose diabetes Monitoring Guidelines AST, ALT, Albumin q4-8 wks Liver biopsy after 1-1.5 g Repeat liver biopsy PIIINP Fibroscan Fibrotest Liver biopsy -liver enzymes not informative -ultrasound not informative ProblemsNobody likes biopsy>100,000,000 with fatty liver in the USA Interobserver error for biopsy Most don’t die of cirrhosis JM Kremer et al. Arthritis Rheum 1994;37:316 HH Roenigk et al. J Am Acad Dermatol 1998;38:478 C Paul et al. JEADV 2011;25 (Suppl 2)

13 TWH LIVER CENTRE Objectives To understand the sensitivity and specificity of Fibroscan and Fibrotest for liver monitoring in patients receiving MTX 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 understand which patients to refer to a specialist To consider which labs to monitor when screening for liver problems with DMARDS To consider which labs to monitor when screening for liver problems with DMARDS

14 TWH LIVER CENTRE Typical Referral 52 year old man with psoriatic arthritis 52 year old man with psoriatic arthritis MTX x 5 years MTX x 5 years Liver biopsy? Fibroscan? Liver biopsy? Fibroscan? Assessment Assessment Risks for fatty liver? Risks for fatty liver? Diabetes, hypertriglyceridemia, central obesity Diabetes, hypertriglyceridemia, central obesity Alcohol Alcohol Risks for other liver disease Risks for other liver disease Viral hepatitis Viral hepatitis Iron overload Celts Iron overload Celts

15 TWH LIVER CENTRE Fibrosis Assessment Fibroscan Fibroscan Chest circumference Chest circumference Are the ribs easily palpable Are the ribs easily palpable Is the rib space adequate Is the rib space adequate Fibrosis assessment in 3 minutes Fibrosis assessment in 3 minutes Fibrotest Fibrotest Cannot be done if hemolysis Cannot be done if hemolysis Haptoglobin undetectable Haptoglobin undetectable Cost for some components Cost for some components Fibrosis assessment in 1-4 weeks Fibrosis assessment in 1-4 weeks

16 TWH LIVER CENTRE Acting on Fibrosis Assessment Concordant results Concordant results F0-2: continue treatment F0-2: continue treatment F3-4: change treatment F3-4: change treatment Discordant results Discordant results Ultrasound Ultrasound Liver biopsy Liver biopsy

17 TWH LIVER CENTRE Hepatitis B Worldwide Problem

18 TWH LIVER CENTRE Natural History of Hepatitis B Importance of immune control HJ Yim and AS Lok. Hepatology 2006;43:S173

19 TWH LIVER CENTRE HBV investigations HBsAg anti-HBs, anti-HBc 1. 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 Risk Refer! Low Risk Monitor ALT Check HBsAg if ALT  Advanced liver fibrosis? Platelets < 160 Age > 40

20 TWH LIVER CENTRE Hepatitis C in Ontario Modeled prevalence MOHLTC integrated Public Health Information System, 4/12/2011

21 TWH LIVER CENTRE Challenges in HCV treatment SVR>90%, minimal side effects New agents screened against HCV G1b New agents screened against HCV G1b Not as effective against G1a Not as effective against G1a Most do not work for non-1 Most do not work for non-1 Genotype 3? Genotype 3? Other challenges Cirrhosis Monotherapy not sufficient Treatment experience Interferon sensitivity (IL28b) Ribavirin resistance?

22 TWH LIVER CENTRE ABT orals + RBV in non- cirrhotics (naïve and nulls) ABT-450/r PI ABT-450/r PI ABT-267 NS5a inhibitor ABT-267 NS5a inhibitor ABT-333 NN NS5b inhibitor ABT-333 NN NS5b inhibitor N=451 treated 12-24 weeks N=451 treated 12-24 weeks Going ahead with 12 weeks Going ahead with 12 weeks Degree of Difficulty Degree of Difficulty Excludes cirrhotics Excludes cirrhotics Includes 1a (66%), non-CC (81%) Includes 1a (66%), non-CC (81%) KV Kowdley et al. A3. EASL 2013

23 TWH LIVER CENTRE SVR24 KV Kowdley et al. A3. EASL 2013 % SVR24 Male Female 1a 1b > 7 log <7 log F0-F1 F2-F3 Non-CC CC Male Female 1a 1b > 7 log <7 log F0-F1 F2-F3 Non-CC CC Naïve N=159Null N=88 78 81 108 50 35 124 113 42 115 44 56 33 55 33 22 66 41 45 85 3

24 TWH LIVER CENTRE Salvage for BOC/TPV failures SOF+DCV+/-RBV x 24 weeks SOF - PolI SOF - PolI Declatasvir (DCV) – NS5A inhibitor Declatasvir (DCV) – NS5A inhibitor Degree of Difficulty Degree of Difficulty Excludes cirrhotics Excludes cirrhotics Includes treatment failures (nulls) Includes treatment failures (nulls) Excludes early DC due to AE Excludes early DC due to AE 1a: 76-85%, non-CC: 95-100% 1a: 76-85%, non-CC: 95-100% MS Sulkowski et al. A1417. EASL 2013

25 TWH LIVER CENTRE SVR12 % SVR 21 20 21 20 21 20 21 20 21 20 MS Sulkowski et al. A1417. EASL 2013 1 missed is SVR24

26 TWH LIVER CENTRE Hepatitis C diagnosis Anti-HCV antibody: exposed Anti-HCV antibody: exposed HCV PCR: needed to confirm infection HCV PCR: needed to confirm infection HCV not greatly affected by immunosuppression HCV not greatly affected by immunosuppression HCV curable HCV curable

27 TWH LIVER CENTRE Summary Immunosuppression Immunosuppression Hepatitis B Hepatitis B Vasculitis Vasculitis Hepatitis C >> Hepatitis B Hepatitis C >> Hepatitis B

28 TWH LIVER CENTRE Objectives To understand the sensitivity and specificity of Fibroscan and Fibrotest for liver monitoring in patients receiving MTX 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 understand which patients to refer to a specialist To consider which labs to monitor when screening for liver problems with DMARDS To consider which labs to monitor when screening for liver problems with DMARDS

29 TWH LIVER 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 15% over 2 years

30 TWH LIVER CENTRE What to do for your cirrhotics StageClinicalImplication 1Asymptomatic10 year survival > 85-90% 2Esophageal varicesScreen with gastroscopy 3History of variceal bleedBeta blockers lower risk 4AscitesSynthesis failure: transplant HepatomaAt any stageUltrasound surveillance (not AFP) Plts < 150: suspect cirrhosis Plts < 150: suspect cirrhosis Plts < 100: likely will have varices Plts < 100: likely will have varices Plts < 70: higher risk of renal failure (hepatorenal syndrome) Plts < 70: higher risk of renal failure (hepatorenal syndrome) No NSAIDS (even with PPI) No NSAIDS (even with PPI) Tylenol <3-4g/day is much safer Tylenol <3-4g/day is much safer Coffee may be good Coffee may be good Alcohol in moderation may be good Alcohol in moderation may be good

31 TWH LIVER CENTRE Questions?


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