Intrinsic vs. Idiosyncratic DILI

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1 Idiosyncratic Drug Induced Liver Injury Naga Chalasani, MD, FACG Professor & Director Division of GI and Hepatology Indiana University School of Medicine Clarian/IU Digestive Diseases Center ACG PG Course 2010 Intrinsic vs. Idiosyncratic DILI Intrinsic predictable dose-related similar in animals high incidence short latency (hrs) types directly destructive indirect, metabolic Cholestatic Mortality high Idiosyncratic unpredictable not dose-related not seen in animals low incidence, rare variably longer latency types immunoallergic metabolic ( host ) Mortality variable Potential COI Consulting related to drug safety in past 12 months - Karobio - J&J - Lilly - Advanced Life Sciences - Metabasis - Debiovision - Abbott - Phenomix - Salix Potential conflicts due to prior consulting with Merck and Pfizer (makers of lipid lowering agents) Chronic DILI Definition is unclear (? duration,? Level of abnormality) Slowly resolving vs. progressive Incidence was 5.7% in Spanish registry and ~ 14% in the DILIN experience Cholestatic DILI is more likely to cause chronic DILI Rarely, autoimmune hepatitis may be incited Outline Definitions & Epidemiology Prospective Registries Common Causes Risk Factors Causality and Severity Adjudication Treatment? Predisposition to DILI in underlying liver disease Hepatocellular: Cholestatic: Biochemical patterns of DILI Mixed: 2< R < 5 R > 5 and ALT > 2x ULN or baseline R < 2 and Alk P> ULN R= (ALT/ULN)/ (Alk P / ULN) 1

2 Hy s Law Etiology of ALF in the USA Adult Registry (n = 1,321) Hepatocellular injury and jaundice together, predict at least 10% mortality FDA/Industry definition: ALT > 3 ULN and TB > 2 ULN with no other etiology Prognostic significance of Hy s law has been validated in recent studies n % 156 More than half of all US ALF is drug-related 12% 15% APAP Drug 102 Hep B Hep A Autoimm Ischemic Wilson's Budd-Chiari Pregnancy Other Indeterminate Epidemiology Prevalence and incidence poorly defined Data from passive surveillance programs like MEDWATCH only uncover 5-10% Premarketing studies only capture highly selected patients Widely estimated that the risk of hepatotoxicity is one in 10 4 to 10 5 Troglitazone toxicity -1/50,000 Population based estimates 81,300 followed prospectively over 3 years (Northern France ) 95 suspected DILI cases 34 probable DILI cases (2 deaths) Antibiotics (25%), psychotropic (23%), hypolipidemics (13%), NSAID (10%) 80% outpatients 50% diagnosed/ managed by PCP 29% seen by GI Incidence: 14 to 24 per 100,000 (16 X rate of passive surveillance) Translates to 40,000 cases per year in the US (Sgro et al, Hepatology 2002; 36) Major Regulatory Actions ( ) Clinical presentation Withdrawals Second line Safety alerts Bromfenac Pemoline Troglitazone Tolcapone Leflunomide Trovafloxacin Nefazodone Ximelagatrin: Felbamate Nevirapine PZA/Rifampin Terbinafine Valproic acid Zifirlukast Atomoxetine Telethromycin Failure to receive approval Duloxetine (Lipokinex, Kava, hydroxycut) Asymptomatic abnormalities Symptomatic injury Acute hepatitis, liver failure Chronic hepatitis Autoimmune-like Fatty liver, Granulomatous injury Cirrhosis Source: CDER webpage- ( Watkins PB, Toxicologic Pathology

3 Risk Factors VARIABLE EXAMPLE VARIABLE EXAMPLE Age > 60 yrs Children Gender Women Men Obesity Fasting/ Malnutrition INH, Nitrofurantoin Salicylate (Reye s), Valproate Nitrofurantoin, diclofenac INH, Azathioprine Methotrexate, Halothane Chronic Alcoholism Pregnancy HIV infection Underling HCV or HBV Methotrexate Tetracycline INH Sulfonamides Anti-retrovirals INH, NSAIDs Hyperthyroidism Halothane Polypharmacy Anti-tuberculous agents anti-retroviral agents IMPLICATED DRUGS (N = 300) 9/04 12/07 Single prescription drug 73% * Herbal & dietary supp (HDS) 9%** Multiple drugs 18% *Antimicrobials 45% CNS drugs 15% Augmentin (23) Nitrofurantoin (13) Isoniazid (13%) **Muscle building (11) wt loss (8) well being (6) (Green tea, slimquick, hydroxycut, Airborne) Chalasani et al, for the DILIN: Gastroenterology 2008, Dec DILIN OUTCOMES MAYO U MICH Overall N = 300 Single Drug N = 217 HDS N = 28 P-value UCSF USC UTSW IU JEFFERSON/ U PENN UNC DUKE (DCC) Chronic DILI (%) mo mort (%) 8.0 * Transplant (%) *56% of deaths non-liver related Outcomes independent of age, gender, and injury pattern, but worse in diabetics DILIN Prospective Study: Inclusion Criteria Age >2 Within 6 months of DILI onset On 2 consecutive blood draws - AST or ALT > 5 X ULN (baseline) - Alk phos > 2 X ULN (baseline) - T bilirubin > 2.5 mg/dl Chronic HBV, HCV, HIV allowed Unsuspected Pathology Unsuspected acute Hep C (4 out of 300) 1 8 cases of hepatitis E Ig M positivity, 3 positive for HEV PCR 2 Some autoimmune phenotype (nitrofurantoin, minocycline) 3 Several cases following outpatient surgery (?IV cephalosporins) 3 1 Chalasani N et al. Gastroenterology 2008; 2 Davern T et al. Hepatology 2009 (Abstract); 3 Unpublished DILIN data 3

4 DILI Diagnosis High Index of Suspicion!!! Exclude other causes Timing: < 1 to 12 months onset Improvement with cessation/ dechallenge Rechallenge rarely done Prior reports Histology No specific lab or clinical marker Diagnosis of exclusion Flucloxacillin DILI 51 original DILI and 21 replication cases 284 population and 64 drug exposed controls HLA DRB1*5701 was present in > 80% of cases vs. 6.3% controls OR 80.6 ( ), P=8.7 x in individuals with *5701 allele will develop flucloxacillin DILI Daly AK et al on behalf of SAEC: Nature Genetics 2009 Genetic Studies Candidate Gene o CYP2E1/NAT2: INH o MnSOD: INH o UGT1: Diclofenac o BSEP: Bosentan o PLOG: Valproate o HLA-B: Augmentin, diclofenac, anti-tb Genome-wide studies o Ximelagatran o Flucloxacillin o Augmentin Prognosis Depends on severity of injury & timely withdrawal Hepatocellular with jaundice: 10% mortality Cholestatic jaundice: 10% mortality but from non-liver etiology Mixed DILI Lower mortality Continuation after DILI onset is ominous Treatment Prompt discontinuation?steroids? N-acetyl cysteine Liver transplantation 4

5 Isoniazid in chronic HBV Vietnamese immigrants in the US DILI in patients with underlying liver disease sag +/ eag + N=22 sag +/ eag N=33 sag N=103 Completed INH 38% * 81% 88% ALT 48% * 7% 3% INH hepatitis 13% * 0% 0% * P < 0.05 vs eag and sag -. (Patel Am J Gastroenterol 2002) Contraindicated in Liver Disease* Methotrexate Pemoline Tolcapone Valproate Dantrolene Clonazepam Felbamate Tacrine Estrogens Metformin Niacin Gemfibrozil Lovastatin & others * Package Insert Isoniazid in chronic HBV HBsAg + INH rx N=43 HBsAg INH rx N=276 HBsAg + No INH N=86 Age % eag + 21% 20% % abnormal BL ALT 23% 6% 17% % Hepatotoxicity * 35% ^ 9% 8% % Hepatotoxicity ** 23% ^ 9% 2% % Hospitalized 18% ^ 6% 0% * ALT > 1.5 x BL ** anti-hbe conv/ BL ALT removed Age and HBsAg + independent predictors of hepatotoxicity Most episodes of hepatotoxicity associated with HBV DNA ^ p < 0.05 (Wong Hepatology 2000; 31) LFT monitoring recommended Statin hepatotoxicity Amiodarone Flutamide Tretinoin Fluconazole Pemoline Labetalol Disulfiram Methyldopa Diclofenac Carbamazapine Valproic acid Methotrexate Nitrofurantoin Allopurinol Cyclosporine Mercaptopurine Ritonavir Pyrazinamide Isoniazid Mirtazapine Clonazepam Ketaconazole Nicotinic Acid Gemfibrozil Statins Fenofibrate Pioglitazone Rosiglitazone Tamoxifen Normal ALT N=1437 Abn ALT * N=342 Liver dz N=2245 Age Weight Base AST Base ALT Chol (mg/dl) Atorvastatin Simvastatin Fluvastatin 47% 50% 3% 43% 55% 2% * Per package insert * Alcohol, HCV, HBV excluded (Chalasani et al. Gastroenterology 2004) 5

6 Normal ALT Abn. ALT Liver dz Statin duration (yr) 0.48± ±0.08 Statin discontinue 10.7% 11.1% AST/ALT 1-10 xuln 1.7% 4.7% 6.4% AST/ALT >10 xuln Statin hepatotoxicity p=0.002 p= % 0.6% 0.4% p=0.6 p=0.6 Methotrexate chronic exposure Steatosis Zone3 hepatocellular degeneration Kupffer cell hyperplasia Fibrosis Cirrhosis? Universality of steatosis in a dosedependent fashion (Chalasani et al. Gastroenterology 2004) RCT of pravastatin in patients with liver disease Inclusion LDL > 100 mg/dl Chronic liver dz: 64% NAFLD 24% HCV 12% other Pravastatin (n=160) Placebo (n=160) % T cholesterol 20%* 3% % LDL 31% * 3% % ALT > 2X BL 7.5% 12.5% Methotrexate liver injury: Risk factors Alcohol consumption (100 gms/week) Obesity Type2 diabetes Viral hepatitis (B or C) Renal failure Other hepatotoxic compounds, including excessive vitamin A Time to ALT and cumulative % at week 36 similar (Lewis J, Hepatology 2008) DILI due to compounds of interest to GI Methotrexate Azathioprine Biological agents Statins Compounds causing chronic hepatitis minocycline, nitrofurantoin, diclofenac Pre-MTX evaluation: Liver Alcohol consumption Liver chemistries Hepatitis B and C serologies Baseline liver biopsy in those with risk factors 6

7 Monitoring for MTX hepatotoxicity Periodic liver biochemistries Liver biopsy depending on baseline risk and liver tests during the follow-up Suspect DILI Unexplained worsening of liver tests in patients with chronic liver disease (e.g., herbals) Unexplained chronic elevations (e.g., diclofenac, nitrofurantoin, accutane, minocycline) New onset jaundice with negative viral serologies New onset autoimmune liver disease Monitoring for MTX hepatotoxicity Baseline risk F/U Course of action Liver tests Low normal Liver biopsy after 4 gm (~ 3 yrs) Low High* Persistently or severely abnormal Stable or unchanged Liver biopsy Another treatment Liver biopsy after 1 gm High* Worsening Discontinue Liver biopsy at lower threshold Take Home Message Idiosyncratic DILI is rare but can be fatal Prognosis depends on elevated bilirubin, not necessarily aminotransferases Antibiotics, herbals, CNS agents are commonly implicated Pre-existing liver disease may increase susceptibility to selected compounds *Informed consent or explicit documentation of discussions of risk/benefits/alternatives DILI from biological agents Episodes of acute liver injury, including liver failure and death Autoimmune like phenomenon Majority with infliximab, but reported with all agents Worsening of underlying viral liver disease Hepatitis C tailor based on liver histology Hepatitis B need to provide antiviral prophylaxis 7