Drug Induced Liver Injury (DILI) Sumita Verma Senior Lecturer Medicine, Hon Consultant Hepatologist Brighton and Sussex Medical School

Transcription

1 Drug Induced Liver Injury (DILI) Sumita Verma Senior Lecturer Medicine, Hon Consultant Hepatologist Brighton and Sussex Medical School

2 Disclosures None pertaining to current talk Research grants from Gilead, Dunhill Medical Trust and NIHR Travel grants from Gilead, Abbvie, BMS

3 DILI leading cause for removing approved medication from market/ issue black box warning Predictable Dose related Short latency (days) Direct toxicity of drug or metabolite Reproducible in animal models Unpredictable (idiosyncratic) Unexpected based on pharmacological action of drug May or may not be dose related Variable latency Lower incidence

4 DILI- CLINICAL SUBTYPES Council for International Organizations of Medical Sciences (CIOMS ) US FDA Drug Hepatotoxicity Steering Committee Hepatocellular (HC): ALT > 3ULN and (ALT/ULN) > 5 (ALP/ULN) Cholestatic: ALP > 2ULN and (ALT/ULN) < 2 (ALP/ULN) Mixed: ALT > 3ULN and ALP > 2ULN and (ALT/ULN) > 2 to < 5 (ALP/ULN)

5 Hy s Law In hepatocellular DILI: bilirubin > 3ULN death/transplant in ~10% FDA: bilirubin > 2ULN with AST/ALT > 3ULN in absence of cholestasis (ALP<2ULN) FDA guidance on DILI Finding one Hy s Law case in the clinical trial database is worrisome; finding two is considered highly predictive that the drug has the potential to cause severe DILI when given to a larger population Zimmerman H 1999 Temple R, Drug Safety 2006, US Food and Drug Administration 2009

6 PATHOGENESIS Drug Dose, duration Hepatic metabolism, Lipophilicity Reactive metabolite Covalent adduct Host DILI Immune response DILI Environment Age, Gender, Ethnicity, Genetic polymorphisms, underlying CLD DILI Metabolic syndrome, Alcohol intake Chronic viral infection Lambert. Hepatol 2008; 2010, Chen Hepatol 2013 Aithal & Larrey. Mann s Pharmacovigilance. 2014

7 Case 1 25 yr old Caucasian male 2012: Two week h/o anorexia and jaundice 5 day use of flucloxacillin for ingrowing toe nail three weeks ago Denied any over the counter drugs Bilirubin 185, peak 614 AST 86, ALT 201, GGT 72, ALP 137, INR 1.1

8 Roussel Uclaf Causality Assessment Method

9 Case 1 Anabolic androgenic steroids (17α alkylated) - Bland Cholestasis - Acute Hepatitis - Loss of bile ducts - Toxicant-associated non-alcoholic fatty liver disease - Hepatic adenomas/hepatocellular carcinoma Flucloxacillin - Cholestatic hepatitis - Older men - > 2 weeks use - HLA B* fold increase- high NPV (88%)

10 Case 1 HLA genotype B12 / B42 Heterozygous for c.2093g>a mutation in ABCB11 Supportive treatment with full recovery Sherrif Y. Liver Int 2011

11 Incidence of DILI Population based Iceland prospective study ( ) - All physicians in Iceland (251,000 >15 yrs) - 3x ULN ALT, > 2x ULN ALP / 100,000/yr - 22% hospitalised, 1% death French prospective study ( ) /100,000/yr - Incidence 16 times greater than reported to French authorities - 12% hospitalised, 6% died Hospital based Spanish prospective study ( ) - 12 hospitals (2.7M population) - ALT>5x ULN,or ALP> 2x ULN + Bil >2.5xULN - 0.8/ 100,000-12% deaths: 0.8/1,000, million hospital admissions in England, (0.35%) coded as drug induced ( ) UK GPRD ( ) - 2.4/100,000/yr Bjronsson E. Gastroenterology 2013 Ibanez. J Hepatol 2002 Sgro C Hepatol 2002 de Abajo, Br J Clin Pharmacol, 2004 Waller P, Br J Clin Pharm, 2005

12 May Bilirubin >2.5 ULN or INR > 1.5 with any liver enzyme elevation Or AST/ALT > 5ULN or ALP > 2ULN - n=1257 of whom 899 adjudicated by panel of expert Hepatologists to have DILI

13 70% jaundiced, 59% women, 54% Hepatocellular 16% > 65 yrs - Cholestatic DILI, men (36% vs 21%), similar frequency of transplant 10% pre existing liver disease - Azithromycin - More severe liver injury - Overall mortality significantly higher (16% vs. 5.2%) but similar liver related mortality 10% died/underwent liver transplant- 44% with severe cutaneous reactions died 17% chronic: more likely with longer drug duration (31% vs. 12.5%, p=0.07)

14 62% AMERICAN DILIN

15 American DILIN Hepatocellular n=484 Cholestatic n=210 Mixed n=205 Age (yrs) Females 65% 51% 50% Latency (days) Fatal liver injury 9% 4% 4% Liver transplant 6.2% 2.9% 0% Chronic DILI 13% 31% 14%

16 In Korea and Singapore HDS account for >70% of all DILI Navarro V Hepatol 2014 Suk K, AJG 2012, Wai C, Liver Int 2007

17 American DILIN Body building HDS N=45 Non-body building HDS N=85 Age Male 100% 35% 37% Hospitalisation 71% 68% 58% Liver transplant 0% 13% 3% Death 0% 4% 7% Days to 50% reduction in bilirubin hepatocellular 42% 71% 53% Conventional drugs N=709 Navarro V Hepatol 2014

18 Andrade R, Gastroenterol 2005 Bjorrnson E, Gastroenterol 2013 Bjornsson N=96 Andrade N=461 Diagnostic criteria ast/alt > 3uln Alt or bili >2ULN Women 56% 49% Hepatocellular 42% 58% Acute Liver Failure Antimicrobials Coamoxyclav Other drugs 37% 22% Diclofenac 6%, azathioprine 4% infliximab 4% nitrofurantoin 4% Herbal 16% 2% chronic 7% 5.7% 4%, HC, jaundice 89% women 32% 12.8%, ATT 5% Ebrotidine 5% NSAIDs 4% Flutamide 4%

19 Frequency of DILI Among Users Bjronsson E. Gastroenterol 2013

20 Age and DILI Bjornsson E, Gastroenterology 2013

21 UK (GPRD) Chlorpromazine amoxicillin-clavulanate Flucloxacillin Tetracyclines Diclofenac Azathioprine Europe (Spain, Iceland) amoxicillin-clavulanate NSAID Azathioprine Infliximab USA (DILIN) amoxicillin-clavulanate INH Nitrofurantoin Co-trimoxazole Minocycline HDS India ATT Antiepileptics Dapsone Co-trimoxazole de Abajo. Br J Clin Pharmacol 2004; Andrade. Gastroenterology 2005; Chalasani. Gastroenterology 2015; Bjornsson. Gastroenterology 2015; Kumar. Hepatology 2010; Devarbhavi. Hepatology 2010

22 DILI Risk Factors Females HC DILI, men cholestatic DILI Age - Older- amoxicillin-clavulanate, nitrofurantoin, flucloxacillin, isoniazid, halothane - Younger- sodium valproate, minocycline Polypharmacy: ATT Drug duration longer in those with morbidity and mortality (135 vs 53 days) Dose: diclofenac, flucloxacillin (>50 mg/day) 81% of DILI leading to transplant > 50 mg/day Chronic liver disease - HBV/HCV infection increases risk of ATT DILI three fold - PBC: Rifampicin hepatotoxicity % Genetic Bjornsson E, Semin Liv Dis, 2014, de Abajo, Br J Clin Pharmacol, 2002 Lammert C, Hepatol 2008, Russo M, Liver Transpl 2004, Ungo J, Am J Res Crit care Med 1998 WU J, Gastroenterol 1990

23 2014: 62 year old female ALT 125, ALP 245 IgG elevated 27 Case 2 Anti smooth muscle antibody positive On exam had stigmata of chronic liver disease Imaging confirmed cirrhosis Simvastatin commenced 1 year ago

24 Histology Rash, eosinophilia DILI Immune-DILI AI-DILI AIH Portal neutrophils, intracellular cholestasis Interphase hepatitis, plasma cells Interphase hepatitis, plasma cells, emperipolesis, rosettes -/ Fibrosis +/ Response to steroids Relapse on steroid withdrawal Case Rechallenge interphase hepatitis, plasma cells, emperipolesis, rosettes Hergue A Gut 2007 (abstract) Bjornnson E, Hepatol 2010 Yeong T, Hep Res 2015

25 Autoimmune DILI (AI-DILI) 9.2%-13.4% of AIH American and Spanish DILIN : 69 with statin DILI - 15% AIH - 50% requiring immunosuppression - Median duration of statin > 6 mths in majority Swedish Registry: 10 yr follow up 23/685 (3.4%) hospitalised - 5 developed AIH Spanish Registry: (n=750): 1.6% AI DILI - 9 recurrent DILI, 44% AI DILI Atovarstatin and fluvasatin, cipro and moxifloxacillin, propafenone and omeprazole, atovarstatin and ezitembe Russo MW Hepatol 2014; Perdices EV, Rev Esp Enferm Dig, 2014 Bjornsson E, J Hepatol, 2009; Lucena M, J Hepatol 2011

26 Case : 55 years Asian male Chronic hepatitis C, chronic hepatitis B (carrier) Non-cirrhotic 4/6months of peginterferon alpha/ribavirin treatment Normal LFTs, HBV DNA and HCV RNA negative Received clarithromycin for URTI for one week 2 weeks later, confused and jaundiced Bilirubin 350, ALT 2000, INR 3 Liver screen unremarkable

27 Case 3 Drug induced acute liver failure (ALF) 4% with DILI develop ALF? Pegylated INF (unlikely)??clarithromycin - Elderly - Cholestatic injury - ALF reported Urgently listed for transplant Extra dural bolt for intracerebral pressure monitoring Unfortunately died before could be transplanted Bjornsson E, Gastroenterol 2013 Robles-Diaz M, Gastroenterol 2014

28 Corticosteroids did not improve overall or spontaneous survival in drug induced, indeterminate or autoimmune ALF and were associated with lower survival in patients with the highest MELD scores Intravenous N-acetyl cysteine improves transplant-free survival in patients with early stage (Gr 1-2 HE) non-acetaminophen related acute liver failure (52% vs. 30%) Lee W, Hepatol 2007

29 Kaiser Permanente healthcare system in California ( ) > 4 million adult members Retrospective, ICD codes for DILI and ALF (INR > 1.5, HE, and bilirubin >5ULN) 62 ALF cases: 32 were drug induced 56% paracetamol, HDS 19%, antimicrobials 6% (co-amoxyclav, INH) Incidence of drug induced ALF 1.91 / 1,000,000 person years (95% CI )

30 Ichai P, et al. Liver Transpl 2008 ETR

31 Importance of Aetiology Survival by aetiology without transplantation Grade III/IV, Kings College Hospital % Percent of patients 80% 60% 40% 20% 0% Died n=72 Survived n=87 Seronegative Malignancy Unknown Viral Drug induced acetaminophen Pregnancy Etiology Data courtesey of Michael Heneghan KCH

32 - 4%-12% of all ALF due to non paracetamol DILI - 70% women, hepatocellular DILI (80%) - Transplant free survival 3-27% - ATT, HDS, sulpa containing drugs, nitrofurantoin, phenytoin, sodium valproate, flutamide and coamoxyclav - Hy s Law 70% specificity to predict ALF - AST > 17.3 ULN, TBL > 6.6 and AST/ALT >1.5 (82% specificity and 80% sensitivity to predict ALF)

33 Case : 55 yr old male ALT 67, AST 64 Psoriasis Methotrexate 5 yrs cumulative dose 2.6gms Alcohol 30 u/week, BMI 29 Fibroscan 10.8kPa

34 10-50 mg/week, intramuscular 21 with cirrhosis of whom - 2 had cirrhosis prior to MTX, - 4 alcohol excess, - 7 had received arsenic, - Most were > 60 yrs, - No mention of obesity, diabetes

35 Methotrexate and Liver Fibrosis in Psoriasis % cases with advanced fibrosis mg: 0% 3000mg: 2.6% 4000mg: 2.6% 5000mg: 8.2% Cummulative methotrexate dose in mg Aithal G, Aliment Pharm Ther 2004

36 Case : 50 yr old male, HIV (truvada, darunavir, ritonavir) Pulmonary tuberculosis HCV positive, GT 3, non cirrhotic (Fibroscan 3.5 kpa) June 2015 ATT (INH, RIF, PZA) commenced- ALT increased from 76 to 577 after three months Restarted sequential ATT Nov 15- ALT increased to 692

37 Kopanoff DE, Am Rev Respir Dis, 1978 Verma S and Kaplowitz N, DILI 2013 Case 5 20% develop abnormal LFTs, 1-4% hepatitis (HC) Risk factors - Older age, - females, pregnancy, - HBV, HCV, HIV, alcohol, - Rifampicin/PZA - N-acetyltransferase 2 and CYP2E1 polymorphisms INH most common cause for non paracetamol ALF

38 Conclusions: DILI Leading cause for ALF: transplant-free survival poor Jaundice bad prognostic sign in HC DILI (Hy s Law) Diagnosis of exclusion: identification of characteristic clinical drug signature and individual susceptibility to DILI Diagnosis difficult: use of concomitant drugs, underlying liver disease Urgent need for diagnostic biomarkers

39