Debate Drug Induced Liver Disease In The East - Current Status

Deepak AmarapurkarConsultant Gastroenterologist and Hepatologist Bombay

Hospital & medical Research Centre, & Breach Candy Hospital Mumbai India

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; 22:145-155; Verma S & Kaplowitz N Gut 2009; 58:1555−1564.

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

Levels Of Severity Of DILI

5 Death/Tx4 Acute liver failure3 Serious sick, hospitalized2 Detectable slight

functional loss1 Just enzyme elevations :

most people adapt0 Patients tolerate exposure

– no adverse effects

Senior JR - Clinical Pharmacology & Therapeutics 2009;85:331-4

Concept of idiosyncratic DILI

Safe

Liver FailureJaundice

Increased ALT

World Map Illustrating Countries With DILI Incidence Data.

Ahmad J, Odin JA.. Clin Liver Dis. 2017;21:55-72.

Most Of The World Lacks Any Reliable Data On DILI Incidence

National Studies Of Drug-induced Liver Injury Incidence

Country Iceland France Korea United Kingdom

Spain Sweden

Years of study 2010–2011 1997–2000 2005–2007 1994–1999 2004–2009 1995–2005Study type Prospective Prospective Prospective Retrospective Retrospective RetrospectiveNumber of DILI cases

96 34 371 128 57 77

Crude DILI incidence rate/100,000 per year

19.1 13.9 12 2.4 3.01 2.3

Ahmad J, Odin JA.. Clin Liver Dis. 2017;21:55-72.

Pattern Of Liver Injury East Vs West

Ahmad J, Odin JA.. Clin Liver Dis. 2017;21:55-72

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

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

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

Ahmad J, Odin JA.. Clin Liver Dis. 2017;21:55-72.

Candidate Gene Analysis For DILI

Monitoring ALT For DILI

Senior JR et al. Clinical Pharmacology & Therapeutics 2009; 85:331−334.

• Sensitivity and specificity of ALT elevations

– Sensitivity 95%

– Specificity 85%

– Accuracy 85.1%

Significance Of ALT Monitoring In Clinical Trials

Kaplowtiz N et al. Drug Saf. 2001; 24:483−490; Zimmerman H Lippinoctt Williams & Willkins 1999; Gupta NK et al. Aliment Pharmacol Ther. 2008; 28:1021−1041; Moses

P et al. Am J Gastroenterology 1999; 94:1393−1396; Chang CY et al. Aliment Pharmacol Ther. 2007; 25:1135−1151; Nolan CM et al. JAMA 1999; 281:1014−1018.

• 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

Conclusion About The ALT Testing

Agal S et al. J Gastroenterol Hepatol. 2005; 20:1745−1752; Aithal GP et al. Nature Genetics 2010; 42:650−651.

• 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

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

Drug Induced Liver Injury In The WEST

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 408 1 Amoxicillin-Clavulanate 912 Herbal and dietary supplements 145 2 Isoniazid 483 Cardiovascular agents 88 3 Nitrofurantoin 424 Central nervous system agents 82 4 Sulfamethoxazole/Trimethoprim 315 Anti-neoplastic agents 49 5 Minocycline 286 Analgesics 33 6 Cefazolin 207 Immunodulatory 27 7 Azithromycin 188 Endocrine 20 8 Ciprofloxacin 169 Rheumatologic 13 9 Levofloxacin 1310 Gastrointestinal 12 10 Diclofenac 12

N. Chalasani et al Gastroenterology 2015;148:1340-52

Drug Induced Liver Injury In The EAST

ATT47%

CAM13%

AED7%

ART4%

DAPSONE3%

ANTIBIO3%

MTX 2%

NSAID2%

STATIN2%

CNS1%

AZORAN1%

CHEMO1%

PCT1%

SULFA1%

HORMONE1%

others10%

(N= 871)

Dr Harshad Devarbhavi – Personal Communication

Drug InDrug Induced Liver Injury Indian Scenario

30%

6%

6%10%

38%1%

1% 6%2%

Acute HEV Acute HAVAcute HBV Dual Acute ViralOnly Chronic Markers Non-A, Non-ENo data available ATT & ViralATT

Causes Of All Cases Of Acute Liver Failure (N = 1223)

Ramesh Kumar et al Hepatol 2010;51:1665-74

Etiology Of Acute Liver Failure In India

Agent Adult Children

HAV 2-2.5 % 10-71%

HBV 11-40% 0-10%

HDV 0-11% 0-16%

HCV 0 – 7.2% 0-2.5%

HEV 23 – 56% 2.7 – 25%

Mixed Infection 4 – 22% 10 – 22%

Drugs 0 – 7.4% 5.5 – 7.5%

Others 15 – 62% 0 – 22%

Data pooled from multiple sources

DILI in Thailand

• Population based retrospective study between 2009- 2013

• 1,59,061 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

DILI In Korea

• A prospective nationwide study from May 2005-2007

• 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. 2012 ;107:1380-7.

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 3rd 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

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;20:1745-52

Incidence Of ATT Induced Hepato-toxicity

• In China 2.55% - 95% CI 2.04% - 3.06%

• In Malaysia 9.7%

• India 10%

• Japan 0.5 to 0.59%– Shang P PLoSOne 2011;6:e21836

– Marzuki OA Singapore Med J 2008;49:688-93

– Agal S et al J Gastroenterol Hepatol 2005;20:1745-52

– Shigeto E Kakkaku 2007;82:467-73

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;105:2396-404

Hepatitis B And Risk Of Hepatotoxicity

HBsAg HBsAg+ve Mortality Mortalitycarrier in AKT in HBsAg –verate 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

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

• 15/102 – 14.7% 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

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 non-

scheduled group• Impact on ATT 35.1% in scheduled group 56.8% in non- scheduled

group– Wu S BMC Public Health 2012;12;454

Impact On CRF On ATT Induced Drug Toxicity

TB with CRF TB without CRF

N 55 165

Drug Induced Hepatitis % 27 15

Death during treatment % 16 4

TB with CRF patients are at increased risk of toxicity and deathBaghaei P Int J Tuberc Lung Dis 2014;18:352-6

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 = 1.1 – 1.82 P=0.007)

• Odds ratio for OR Dral 0.78 (95% CI = 0.51 – 1.18 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

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

Complementary & Alternative MedicineAllopathic & 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

• 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

Drug Induced Liver InjuryDue 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

Types Of Herbal Products Implicated In DILI

Seef LB Gastroenterology 2015 148, 517-532

Trends In Liver Injury From Herbal Products In The DILIN Study

Seef LB Gastroenterology 2015 148, 517-532

Complementary & Alternative MedicineHepatotoxicity

• 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

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. 2015 ;20:216-50.

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

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

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