Debate Drug Induced Liver Disease In The East - Current Status

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1 Debate Drug Induced Liver Disease In The East - Current Status Deepak Amarapurkar Consultant Gastroenterologist and Hepatologist Bombay Hospital & medical Research Centre, & Breach Candy Hospital Mumbai India

2 Drug Induced Liver Disease Price paid for progress More than 1000 drugs can cause hepatic injury Drug induced liver disease can mimic, both clinically and histologically, almost every type of liver disease Over the counter preparations and herbal medications may have significant hepatotoxicity Designer Drugs : Even The Best Design May have a Wardrobe Malfunction FDA Premarketing Clinical Evaluation 2009; Physicians Desk Reference 56th edn 2002; Larrey D et al. Semin Liver Dis. 2002; 22: ; Verma S & Kaplowitz N Gut 2009; 58:

3 Various Patterns Of Hepatotoxicity Acute hepatocellular injury Acute cholestatic injury Chronic cholestatic injury and ductopenia Drug induced autoimmune hepatitis Granulomatous hepatitis Micro and macro vascular steatosis Veno-occlusive disease

4 Levels Of Severity Of DILI 5 Death/Tx 4 Acute liver failure 3 Serious sick, hospitalized 2 Detectable slight functional loss 1 Just enzyme elevations : most people adapt 0 Patients tolerate exposure no adverse effects Increased ALT Jaundice Safe Liver Failure Concept of idiosyncratic DILI Senior JR - Clinical Pharmacology & Therapeutics 2009;85:331-4

5 World Map Illustrating Countries With DILI Incidence Data. Most Of The World Lacks Any Reliable Data On DILI Incidence Ahmad J, Odin JA.. Clin Liver Dis. 2017;21:55-72.

6 National Studies Of Drug-induced Liver Injury Incidence Country Iceland France Korea United Kingdom Spain Sweden Years of study Study type Prospective Prospective Prospective Retrospective Retrospective Retrospective Number of DILI cases Crude DILI incidence rate/100,000 per year Ahmad J, Odin JA.. Clin Liver Dis. 2017;21:55-72.

7 Pattern Of Liver Injury East Vs West Ahmad J, Odin JA.. Clin Liver Dis. 2017;21:55-72

8 Approach To Patients With Drug Induced Liver Disease Step I Establish the list of medication esp herbal medicines tonics and over the counter medication Chronology of each drug with clinical parameter Step II Previous history of adverse effect Immuno allergic manifestation Exclude other causes Step III Comparing patients disease type with signature of hepatotoxicity of drugs consumed Step IV Follow up of patients after withdrawal of drug

9 Risk Factors For DILI Age Drug drug interactions Duration and total dose of drug Enzyme induction Enzyme polymorphism Ethnic and racial factors Gender Nutritional status Pregnancy Renal function Systemic disease Underlying liver disease

10 Candidates Gene Associations In DILI Gene Cytochomes p450(cyp) N acetyltransferase 2 (NAT2) UDP Glucuronosltransferases Drug Transporters Superoxide dismutase Cytokine genes MHC complex genes Daly AK Semin Liver Dis 2009;29:400-11

11 Candidate Gene Analysis For DILI Ahmad J, Odin JA.. Clin Liver Dis. 2017;21:55-72.

12 Monitoring ALT For DILI Sensitivity and specificity of ALT elevations Sensitivity 95% Specificity 85% Accuracy 85.1% Senior JR et al. Clinical Pharmacology & Therapeutics 2009; 85:

13 Significance Of ALT Monitoring In Clinical Trials Some drugs (e.g. statins, tacrine, aspirin) associated with ALT elevations in clinical trials, but are proven safe Others (e.g. bromfenac, troglitazone, trovafloxcin) with elevated ALT in clinical trials have been withdrawn Post drug exposure, some patients with mild DILI exhibit recovery, adaption and tolerance to continued exposure Kaplowtiz N et al. Drug Saf. 2001; 24: ; Zimmerman H Lippinoctt Williams & Willkins 1999; Gupta NK et al. Aliment Pharmacol Ther. 2008; 28: ; Moses P et al. Am J Gastroenterology 1999; 94: ; Chang CY et al. Aliment Pharmacol Ther. 2007; 25: ; Nolan CM et al. JAMA 1999; 281:

14 Conclusion About The ALT Testing ALT testing remains the standard approach in monitoring DILI in spite of its limitations Some cases of DILI (e.g. ATT and DILI associated with genetic markers) may be appropriate for prophylactic testing But as clinicians it is better to educate patients about the warning signs of DILI (abdominal pain, nausea & jaundice) and stop the medication promptly if warning signs are evident Agal S et al. J Gastroenterol Hepatol. 2005; 20: ; Aithal GP et al. Nature Genetics 2010; 42:

15 DILI East Vs West Not studied well in east lack of established registries Consumption of CAM unprescribed is rampant Availability of medicines without prescription Viral hepatitis is rampant Diagnosis of viral hepatitis is presumptive in majority of cases

16 Drug Induced Liver Injury In The WEST

17 Top Ten Therapeutic Classes And Individual Agents To Cause DILI In The DILIN- Prospective Study No Therapeutic classes n No Individual agents n 1 Antimicrobials Amoxicillin-Clavulanate 91 2 Herbal and dietary supplements Isoniazid 48 3 Cardiovascular agents 88 3 Nitrofurantoin 42 4 Central nervous system agents 82 4 Sulfamethoxazole/Trimethoprim 31 5 Anti-neoplastic agents 49 5 Minocycline 28 6 Analgesics 33 6 Cefazolin 20 7 Immunodulatory 27 7 Azithromycin 18 8 Endocrine 20 8 Ciprofloxacin 16 9 Rheumatologic 13 9 Levofloxacin Gastrointestinal Diclofenac 12 N. Chalasani et al Gastroenterology 2015;148:

18 Drug Induced Liver Injury In The EAST

19 Drug In Drug Induced Liver Injury Indian Scenario CHEMO 1% AZORAN 1% STATIN 2% HORMONE 1% NSAID 2% SULFA 1% CNS 1% PCT 1% others 10% (N= 871) ANTIBIO 3% MTX 2% ATT 47% DAPSONE 3% ART 4% AED 7% CAM 13% Dr Harshad Devarbhavi Personal Communication

20 Causes Of All Cases Of Acute Liver Failure (N = 1223) 2% 1% 6% 30% 38% 1% 6% 10% 6% Acute HEV Acute HBV Only Chronic Markers No data available ATT Acute HAV Dual Acute Viral Non-A, Non-E ATT & Viral Ramesh Kumar et al Hepatol 2010;51:

21 Etiology Of Acute Liver Failure In India Agent Adult Children HAV % 10-71% HBV 11-40% 0-10% HDV 0-11% 0-16% HCV 0 7.2% 0-2.5% HEV 23 56% % Mixed Infection 4 22% 10 22% Drugs 0 7.4% % Others 15 62% 0 22% Data pooled from multiple sources

22 DILI in Thailand Population based retrospective study between ,59,061 admissions, 6,516 admissions due to toxic liver injury 33.5% due to acute hepatitis Factors associated with mortality cirrhosis, age > 60, HIV infection, chronic kidney disease, COPD, male gender, malnutrition Acetaminophen 35%, anti-mycobacterial drugs 34.6% 1% of the admission in the hospital is due to DILI Sobhonsliduk et al BMC Gastroenterol 2016;16:13:135-40

23 DILI In Korea A prospective nationwide study from May DILI defined as ALT > 3 upper normal limit or total bilirubin > 2 upper normal limit 371 cases diagnosed as DILI 12/100,000 persons/year causes DILI Herbal Medicines 27.5%, prescription or non prescription medication, health food or dietary suppliement, Medicinal hebrs or plants 9.4%, folk remidies 8.6%, acetaminophen 2.2% Hepatocellular, mixed, cholastatic, 76%, 15% & 9% respectively Suk KT, Am J Gastroenterol ;107:

24 Drug Induced Veno-occlusive Disease This was first described due to toxic injury by pyrrolizidine alkaloids VOD due to herbal medicines has been well described from India Acute stage of disease is associated with painful hepatomegaly, ascites and rarely jaundice Patient may recover completely or go on to develop recurrent ascites or in a 3 rd of them go to chronicity and disease may mimic cirrhosis Currently stem cell transplantation is a commonest cause of VOD worldwide Rolins BJ, Am J Med 1996;81:297

25 Antitubercular Drug-induced Liver Injury Antitubercular treatment (ATT) induced hepatotoxicity is the commonest cause in DILI in India. In 10% of the patients receiving ATT Five to ten percent patients of acute liver failure (ALF) both in adult and paediatric age group are due to ATT ALF due to ATT mimics ALF due to hepatitis viruses and carries mortality up to 70%. Chronic hepatitis B carrier state and associated acute viral hepatitis E is seen in <5% of ATT-induced liver injury. Monitoring during therapy is the best form of preventing serious injury Agal S et al J Gastroenterol Hepatol 2005;20:

26 Incidence Of ATT Induced Hepato-toxicity In China 2.55% - 95% CI 2.04% % In Malaysia 9.7% India 10% Japan 0.5 to 0.59% Shang P PLoSOne 2011;6:e21836 Marzuki OA Singapore Med J 2008;49: Agal S et al J Gastroenterol Hepatol 2005;20: Shigeto E Kakkaku 2007;82:467-73

27 Risk Factors For ATT Induced Liver Injury Advanced age Female sex Poor Nutritional status Pre exiting liver disease Chronic HBV, HCV and HIV infection High alcohol intake Drug interaction Devarbhavi H et al Am J Gastroenterol 2010;105:

28 Hepatitis B And Risk Of Hepatotoxicity HBsAg HBsAg+ve Mortality Mortality carrier in AKT in HBsAg ve rate in induced HBsAg +ve Control Wu et al 15% 35.7% 46% 3% Amarapurkar et al 3.7 % 20.3% 27% 4.8% Hwang SJ et al 10% 26% 1% Wong WM et al 10% 34.9% Amarapurkar DN et al Tubercle & Lung Diseases 1993;24:215-6

29 Role of Acute Viral Hepatitis As A confounding Factor In ATT Induced Hepatotoxicity sera of all patients who developed acute hepatitis during ATT were analyzed for Hepatitis A, B, C & E 15/ % were due to Hep E Later onset of hepatitis (58 (5 133) Vs 26 (3-221) days p = 0.04) Marked elevation of AST, ALT Longer time to normalization Sarda P Indian J Med Res 2009;129:64-7

30 Effect Of Scheduled Monitoring Of Liver Function During AAT In A Retrospective Cohort In China 273 patients developed drug induced toxicity 111 were diagnosed through the scheduled LFT for first two months 162 developed toxicity were not monitored 1.8% in the scheduled group and 11% in the non-scheduled group required hospitalization No death in the scheduled group while 3 deaths in the nonscheduled group Impact on ATT 35.1% in scheduled group 56.8% in non- scheduled group Wu S BMC Public Health 2012;12;454

31 Impact On CRF On ATT Induced Drug Toxicity TB with CRF TB without CRF N Drug Induced Hepatitis % Death during treatment % 16 4 TB with CRF patients are at increased risk of toxicity and death Baghaei P Int J Tuberc Lung Dis 2014;18:352-6

32 The Association Between CYP2E1 Polymorphisms And Hepatotoxicity Due To ATT Drugs : A Meta Analysis Compared with genotype (c1/c1) OR for Pstl/Rsal polymorphism 1.41, (95% CI = P=0.007) Odds ratio for OR Dral 0.78 (95% CI = P = 0.23) NAT2 fast or intermediate acetylator & genotype (c1/c1) Vs NAT2 slow acetylators and high activity of CYP2E1 genotype (c1/c1) had high risk of ATT toxicity Meta-analysis indicates CYP2E1 genotype (c1/c1) has high risk of toxicity and concomitant presence of slow acetylator. NAT2 genotype may further increase the risk Sheng YJ Intect Genel Evol 2014;24:34-40

33 Issues of concern Standardization, Contamination and adulteration Deceptive marketing Efficacy safety claims are not assessed by regulatory authorities

34 Complementary & Alternative Medicine Allopathic & Naturopathic Views On Treatment Western, Scientific, Evidence based Study of defined medical problems of specific etiology Efforts to determine pathogenesis End point related to specific etiology Rigorous scientific proof needed for treatment recommendation Traditional, Natural & Philosophy based Treatment integrative and holistic Aims at general wellness, mind-body concept Employs natural products using natural reparative processes Traditional acceptance of therapies

35 600 commercial herbal formulations are sold world over as hepatoprotective drugs 40 patent polyherbal formulations representing a variety of combinations of 93 Indian herbs from 44 families are sold

36 Drug Induced Liver Injury Due CAM In Korea Incidence of herbal DILI 0.71% Hepatocellular injury 74.7% Cholestatic injury 10.8% Mixed injury 14.5% 21 unique herbal preparations including 11 single species and 10 multiple species Lee WJ Food Chem Toxicol 2015;84;47-54 Oh SJ J Ethnophamarcol 2015;159:253-6

37 Types Of Herbal Products Implicated In DILI Seef LB Gastroenterology ,

38 Trends In Liver Injury From Herbal Products In The DILIN Study Seef LB Gastroenterology ,

39 Complementary & Alternative Medicine Hepatotoxicity Extent of hepatotoxicity from herbal and dietary supplements is probably underestimated Early suspicion of herbal/botanical hepatotoxicity essential since morbidity greatly increased if use continues after enzyme elevation or symptom appears Better surveillance needed for drug reaction

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41 Micro Engineered Liver Tissues For Drug Testing Engineered liver tissue can be used for selecting drugs that are efficacious, safer or personalized for individual patients Khetani SR, J Lab Autom ;20:

42 Pearls And Pitfalls In DILI DILI usually occurs within 90 days Hepatitis viral etiology needs to be executed Cholestatic injury resolve slowly after withdrawal and must be differentiated from biliary obstruction Liver biopsy is of only limited use in diagnosis Difficulty in distinguishing liver damage due to drugs and primary disease, drugs related damage in already existing liver disease Pre treatment LFT is very useful

43 Pearls And Pitfalls In DILI Pin pointing the agent responsible in poly therapy is difficult Diagnostic challenge is potentially dangerous Monitoring liver function tests in the first 2 3 months of therapy With regular monitoring it is reasonable to continue a drug for asymptomatic patient who has upto 2 folds elevation in enzymes A number of drugs which are potent enzyme inducer can produce marked elevation in GGT and ALP. Such change does not necessarily signify hepatic damage

44 Thank You For Your Patient Listening