Drug induced liver injury ppt

1. Drug-induced Liver Injury (DILI)Drug-induced Liver Injury (DILI)
SURESH GORKASURESH GORKA
Resident GastroenterologyResident Gastroenterology
SKIMSSKIMS

2. IntroductionIntroduction
 Drugs are a relatively common cause of liverDrugs are a relatively common cause of liver
injury:injury:
Earlier definition set the following threshold forEarlier definition set the following threshold for
defining DILI:defining DILI:
elevation ofelevation of TransaminasesTransaminases (either(either
AST and/or ALT) orAST and/or ALT) or BilirubinBilirubin oror AlkalineAlkaline
phosphatasephosphatase >2 ULN>2 ULN (upper limit of normal).(upper limit of normal).

3.  Now cut offNow cut off
elevation in ALT or AST > 5 ULN withoutelevation in ALT or AST > 5 ULN without
symptomssymptoms, or, or
rise inrise in alkaline phosphatase >2 ULNalkaline phosphatase >2 ULN oror
rise inrise in bilirubin >2 ULNbilirubin >2 ULN with any rise in AST andwith any rise in AST and
ALT elevation orALT elevation or
AST or ALT < 5 ULN with symptoms.AST or ALT < 5 ULN with symptoms.

4. EpidemiologyEpidemiology
 Incidence 1:10000 to 1:100000Incidence 1:10000 to 1:100000
 Overall fatality 0.15%Overall fatality 0.15%
 In India contribute 1.4% of all GI admission andIn India contribute 1.4% of all GI admission and
2.5% of Hepatobiliary admissions2.5% of Hepatobiliary admissions

5.  The common drugs causing DILI appearThe common drugs causing DILI appear
geographicalgeographical
 AntimicrobialsAntimicrobials are the commonest causeare the commonest cause
worldwideworldwide,,
 Amoxicillin and FlucloxacillinAmoxicillin and Flucloxacillin common incommon in EuropeEurope,,
 In contrast toIn contrast to AntituberculosisAntituberculosis drugs indrugs in IndiaIndia..

6.  DILI is a leading cause ofDILI is a leading cause of acute liver failure (ALF)acute liver failure (ALF)
in the Western world, within the Western world, with ParacetamolParacetamol being thebeing the
commonest drug followed bycommonest drug followed by antimicrobialsantimicrobials..
 In IndiaIn India AntituberculosisAntituberculosis drugs are thedrugs are the
commonest cause of drug induced ALF in adultscommonest cause of drug induced ALF in adults
and children, contributing to 5.7–22% of all casesand children, contributing to 5.7–22% of all cases
of ALF.of ALF.

7. PresentationsPresentations
 Clinically, DILI may take many forms, varyingClinically, DILI may take many forms, varying
fromfrom asymptomaticasymptomatic, often self-limiting, and, often self-limiting, and
transient elevation in liver biochemical tests totransient elevation in liver biochemical tests to
jaundice and severe life threateningjaundice and severe life threatening acute liveracute liver
failurefailure and rarely toand rarely to chronic liver diseasechronic liver disease..
 Many of the asymptomatic elevation seen inMany of the asymptomatic elevation seen in
individuals exposed to drugs could be theindividuals exposed to drugs could be the
phenomena ofphenomena of adaptation or toleranceadaptation or tolerance, where, where
the liver tests normalize while continuing thethe liver tests normalize while continuing the
drug, a phenomenon seen in approximatelydrug, a phenomenon seen in approximately 5–5–
50%50% of subjects taking drugs.of subjects taking drugs.

8.  Chronic DILIChronic DILI
 Failure of return of liver enzymes or bilirubin toFailure of return of liver enzymes or bilirubin to
pre-DILI baseline, and/or other signs orpre-DILI baseline, and/or other signs or
symptoms of ongoing liver disease (symptoms of ongoing liver disease (e.g., ascites,e.g., ascites,
encephalopathy, portal hypertension, coagulopathyencephalopathy, portal hypertension, coagulopathy)) 6 months6 months
after DILI onset.after DILI onset.
 Chronic DILI occurs in aboutChronic DILI occurs in about 15 – 20 %15 – 20 % of casesof cases
of acute DILI.of acute DILI.

9. Late development toLate development to cirrhosiscirrhosis and itsand its
complications have been observed, but arecomplications have been observed, but are quitequite
rarerare after acute DILI.after acute DILI.
In a study with long follow-up, (mean,In a study with long follow-up, (mean,
11 years), of a total of11 years), of a total of 685685 patients who had DILIpatients who had DILI
associated with jaundice,associated with jaundice, eighteight developeddeveloped
cirrhosiscirrhosis..

10.  Chronic DILIChronic DILI may resemble autoimmune hepatitismay resemble autoimmune hepatitis
and might respond to corticosteroids, providedand might respond to corticosteroids, provided
that serological markers and biopsy findings arethat serological markers and biopsy findings are
suggestive of this diagnosis.suggestive of this diagnosis.
 In a recent Swedish study, of theIn a recent Swedish study, of the 23 patients23 patients
who developedwho developed chronic DILIchronic DILI,, five (23.1%)five (23.1%) werewere
subsequently diagnosed withsubsequently diagnosed with AIHAIH, the suspected, the suspected
drugs being ranitidine, enalapril, oestrogen,drugs being ranitidine, enalapril, oestrogen,
carbamazepine and oestriol.carbamazepine and oestriol.

11. Drug induced Autoimmune liverDrug induced Autoimmune liver
disease (DIAILD)disease (DIAILD)

12.  In 2002, Ohmoto and Yamamoto studiedIn 2002, Ohmoto and Yamamoto studied 6464
patients admitted to their hospital with DILI andpatients admitted to their hospital with DILI and
identifiedidentified 66 with positive ANA.with positive ANA.
 Recently, the Spanish-Latin American DILIRecently, the Spanish-Latin American DILI
Network has published a series ofNetwork has published a series of 7373 DILI cases,DILI cases,
in whichin which 29%29% presented positive autoantibodies,presented positive autoantibodies,
mainly ANA.mainly ANA.

13.  Severe DILISevere DILI
is defined asis defined as
““presence of ascites, encephalopathy and an INRpresence of ascites, encephalopathy and an INR
>1.5” and is the indication of hospitalization.>1.5” and is the indication of hospitalization.

14. Pattern of Drug Induced Liver InjuryPattern of Drug Induced Liver Injury
 Based on the level of elevation of ALT/ALPBased on the level of elevation of ALT/ALP
 Classified into hepatocellular,Classified into hepatocellular,
mixed ormixed or
cholestaticcholestatic

15. R ratioR ratio
 First established by the Council for InternationalFirst established by the Council for International
Organizations of Medical Sciences (CIOMS), andOrganizations of Medical Sciences (CIOMS), and
later modified by the US FDA Drug Hepatotoxicitylater modified by the US FDA Drug Hepatotoxicity
Steering Committee:Steering Committee:
 R =R = (ALT/ ALT ULN) / (ALP/ ALP ULN)(ALT/ ALT ULN) / (ALP/ ALP ULN)
 R ratioR ratio
>5 : Hepatocellular>5 : Hepatocellular
2–5 : Mixed2–5 : Mixed
<2 : Cholestatic<2 : Cholestatic

17.  Cholestatic patternCholestatic pattern of hepatitis hasof hepatitis has
lowest mortalitylowest mortality 1-7.8% (less than hepatocellular-1-7.8% (less than hepatocellular-
10%)10%)
protracted courseprotracted course leading to a longer time forleading to a longer time for
normalization of liver testsnormalization of liver tests..
chronicitychronicity small but definite risk of evolutionsmall but definite risk of evolution

18.  A study by Andrade R J. et al, showed thatA study by Andrade R J. et al, showed that
cholestatic/mixedcholestatic/mixed liver disease were more proneliver disease were more prone
to developing chronic injury (18/194,to developing chronic injury (18/194, 9%9%), than), than
those with thethose with the hepatocellularhepatocellular form (10/ 240,form (10/ 240,
4%4%).).

20. MechanismsMechanisms
 Proposed mechanismsProposed mechanisms
• Intrinsic injuryIntrinsic injury
• Idiosyncratic injuryIdiosyncratic injury
• Mitochondrial toxicityMitochondrial toxicity
• Defect in bile formation or transporterDefect in bile formation or transporter
• Bile Salt Export Pump (BSEP) inhibitionBile Salt Export Pump (BSEP) inhibition

21. Mechanism of DILIMechanism of DILI
Predictable (dose dependent or Intrinsic) hepatotoxicity -
paracetamol toxicity. Paracetamol produces massive hepatocellular
necrosis when consumed in large doses. Its toxic metabolite N-
acetyl-p-benzoquinone imine (NAPQI) depletes the hepatoprotective
glutathione resulting in covalent binding to cellular proteins. This in
turn results in mitochondrial dysfunction and oxidative stress,
culminating in cellular damage and death.
Idiosyncratic DILI mechanism is limited by the lack of
experimental animal models. One of the important concepts in
idiosyncratic DILI is the inflammatory stress hypothesis,
wherein bacterial lipopolysaccharide (LPS) released as a result of
inflammation, in conjunction with drug metabolites has the potential
to precipitate DILI. Inflammagen as a precipitant of liver injury has
been described in animal models involving drugs such as diclofenac,
sulindac, and trovafloxacin.
In addition there is increasing evidence of the important
role of the innate and adaptive immune system through
an interdependent pathway in the pathogenesis of DILI.

22. Generally the drugs or its metabolites are not immunogenic. The
metabolites bind with the cellular proteins such as CYP enzymes to
form hapten which activate the macrophages and the natural killer
cells resident in the liver microvascular/sinusoidal system setting in
motion the major histocompatibility complex (MHC) class II
dependent stimulation of CD4 cells and clonal expansion.

23. Mechanism of DILIMechanism of DILI

24. Types of Idiosyncratic reactionTypes of Idiosyncratic reaction

25. Risk FactorsRisk Factors
 Non-geneticNon-genetic
 Genetic (polymorphism of enzymesGenetic (polymorphism of enzymes
and proteins)and proteins)

28. DiagnosisDiagnosis
 Unlike other causes of hepatitis, DILI is aUnlike other causes of hepatitis, DILI is a
diagnosis ofdiagnosis of exclusionexclusion

29. Algorithm to evaluate suspected
Drug-induced liver injury (DILI)

31. Indication of Liver BiopsyIndication of Liver Biopsy
It should be considered:It should be considered:
IfIf autoimmune hepatitisautoimmune hepatitis remains a competingremains a competing
etiology and if immunosuppressive therapy isetiology and if immunosuppressive therapy is
contemplated.contemplated.
It may be considered in the followingIt may be considered in the following
situations:situations:
If there isIf there is unrelenting riseunrelenting rise in liver biochemistriesin liver biochemistries
or signs of worsening liver functionor signs of worsening liver function despitedespite
stopping the suspected offending agentstopping the suspected offending agent

32.  If the peakIf the peak alanine aminotransferasealanine aminotransferase level haslevel has
not decreased by > 50 % at 30 – 60 daysnot decreased by > 50 % at 30 – 60 days
after the onset in cases of hepatocellular DILI, orafter the onset in cases of hepatocellular DILI, or
if the peakif the peak alkaline phosphatasealkaline phosphatase has not fallen byhas not fallen by
> 50 % at 180 days in cases of cholestatic DILI> 50 % at 180 days in cases of cholestatic DILI
despite stopping the suspected offending agent.despite stopping the suspected offending agent.
 In cases of DILI whereIn cases of DILI where continued use or re-continued use or re-
exposureexposure to the implicated agent is expected.to the implicated agent is expected.
 If liver biochemistry abnormalitiesIf liver biochemistry abnormalities persist beyondpersist beyond
180 days180 days to evaluate for the presence of chronicto evaluate for the presence of chronic
liver diseases (CLDs) and chronic DILI.liver diseases (CLDs) and chronic DILI.

33. Causality Assessment MethodCausality Assessment Method
 Several causality assessment methods haveSeveral causality assessment methods have
been established as tools in the accuratebeen established as tools in the accurate
diagnosis of DILI. These includediagnosis of DILI. These include
 Roussel Uclaf Causality Assessment MethodRoussel Uclaf Causality Assessment Method
(RUCAM),(RUCAM),
 Maria and Victorino (M and V) method andMaria and Victorino (M and V) method and
 DILIN (Drug-Induced Liver Injury Network)DILIN (Drug-Induced Liver Injury Network)
 Digestive disease week-Japan (DDW-J)Digestive disease week-Japan (DDW-J)

34. RUCAMRUCAM::
Established in 1990Established in 1990
Also known as CIOMSAlso known as CIOMS
Goal of causality assessment is to generate aGoal of causality assessment is to generate a
score that reflects thescore that reflects the likelihoodlikelihood that a drugthat a drug
accounts for the injury event.accounts for the injury event.
The RUCAM by contrast can be used byThe RUCAM by contrast can be used by non-non-
expertsexperts and physicians in solo practice.and physicians in solo practice.

35.  RUCAM had an overall better performance andRUCAM had an overall better performance and
waswas more reliable and consistentmore reliable and consistent..
 When RUCAM was compared with M and VWhen RUCAM was compared with M and V
method, RUCAM was more reliable and correlatedmethod, RUCAM was more reliable and correlated
better than expert review.better than expert review.
 RUCAM score has a set ofRUCAM score has a set of 7 domains7 domains whichwhich
include-include-

37.  Total range : -7 to +14Total range : -7 to +14
 Highly probable : >8Highly probable : >8
 Probable : 6 – 8 Unlikely : 1 - 2Probable : 6 – 8 Unlikely : 1 - 2
 Possible : 3 – 5 Excluded : <0Possible : 3 – 5 Excluded : <0

38.  LimitationsLimitations include the allocation ofinclude the allocation of
negative points fornegative points for multiple drugsmultiple drugs and forand for
rechallenge, often resulting in underestimatingrechallenge, often resulting in underestimating
causality eg. In tuberculosis,causality eg. In tuberculosis,
which includes three hepatotoxic drugs namely,which includes three hepatotoxic drugs namely,
isoniazid (INH), rifampicin (RIF), andisoniazid (INH), rifampicin (RIF), and
pyrazinamide (PZA). When given together, it ispyrazinamide (PZA). When given together, it is
impossible to identify the implicated drug in casesimpossible to identify the implicated drug in cases
of hepatotoxicityof hepatotoxicity
None of the causality assessment processes inNone of the causality assessment processes in
use was created specifically foruse was created specifically for HDSHDS
hepatotoxicity.hepatotoxicity.

39. Maria and Victorino scale (M and V scale)Maria and Victorino scale (M and V scale)
alternative to RUCAM. Also called the Clinicalalternative to RUCAM. Also called the Clinical
Diagnostic Scale (CDS)Diagnostic Scale (CDS)

41. PrognosisPrognosis
 In general, outcomes of idiosyncratic DILI areIn general, outcomes of idiosyncratic DILI are
goodgood, only ~, only ~ 10 %10 % reaching the threshold ofreaching the threshold of
ALFALF (coagulopathy and encephalopathy).(coagulopathy and encephalopathy).
 DILI that does evolve toDILI that does evolve to ALFALF carries acarries a poorpoor
prognosisprognosis, with 40 % requiring liver trans-, with 40 % requiring liver trans-
plantation and 42 % dying of the episode.plantation and 42 % dying of the episode.
Advanced coma grade and high MELD scoresAdvanced coma grade and high MELD scores areare
associated with bad outcomes.associated with bad outcomes.

42.  Overall,Overall, survivalsurvival is better foris better for paracetamolparacetamol
induced liver failure than forinduced liver failure than for idiosyncraticidiosyncratic casescases
(spontaneous survival,(spontaneous survival, 62% vs 26%)62% vs 26%)
 Prognostic scoresPrognostic scores to predict outcome for DILIto predict outcome for DILI
reaching the threshold of ALF arereaching the threshold of ALF are poorpoor oror
rudimentary.rudimentary.

43. FDA has adopted Hy’s law as a predictor of severe toxicity during
clinical trials

44. PreventionPrevention
 Rational drugRational drug prescribing is central to minimizingprescribing is central to minimizing
DILI particularly in patients with risk factors suchDILI particularly in patients with risk factors such
as old age, comorbid diseases, HIV status, dailyas old age, comorbid diseases, HIV status, daily
dose of drug >50 mg, or poly pharmacy.dose of drug >50 mg, or poly pharmacy.
 Vigilance for symptomsVigilance for symptoms is the key in the detectionis the key in the detection
of early onset DILI. The suspected drug shouldof early onset DILI. The suspected drug should
be stopped at the slightest suspicion of DILI, inbe stopped at the slightest suspicion of DILI, in
order to prevent progressive liver damage.order to prevent progressive liver damage.

45.  Re-exposure to a drugRe-exposure to a drug that is thought likely tothat is thought likely to
have caused hepatotoxicity ishave caused hepatotoxicity is stronglystrongly
discourageddiscouraged, especially if the initial liver injury, especially if the initial liver injury
was associated with significant aminotransferasewas associated with significant aminotransferase
elevation (for example, > 5xULN, Hy ’ s law,elevation (for example, > 5xULN, Hy ’ s law,
or jaundice). Anor jaundice). An exceptionexception to thisto this
recommendation is in cases ofrecommendation is in cases of life-threateninglife-threatening
situations where there is no suitable alternativesituations where there is no suitable alternative..

46. ManagementManagement
 TheThe hallmarkhallmark of treatment of DILI isof treatment of DILI is withdrawalwithdrawal
of the offending medication,of the offending medication,
 N-acetylcysteine (NAC),N-acetylcysteine (NAC),
 Silymarin,Silymarin,
 Antioxidants,Antioxidants,
 S-adenosine methionine,S-adenosine methionine,
 Ursodeoxycholic acidUrsodeoxycholic acid
 Glucocorticoids, orGlucocorticoids, or
 CombinationCombination
 Liver transplantationLiver transplantation

47.  No definitive therapiesNo definitive therapies are available either forare available either for
DILI with or without ALF.DILI with or without ALF.
 Treatment remainTreatment remain supportivesupportive andand monitoring formonitoring for
the development ofthe development of ALFALF..

48.  N-acetylcysteine (NAC)N-acetylcysteine (NAC) is the treatment ofis the treatment of
choice forchoice for paracetamolparacetamol overdose.overdose.
 The role of NAC inThe role of NAC in non-paracetamolnon-paracetamol-induced liver-induced liver
failure remains unclear. In afailure remains unclear. In a randomisedrandomised
controlled trialcontrolled trial with 177 patients with non-with 177 patients with non-
paracetamol induced ALF, a 72 h infusion ofparacetamol induced ALF, a 72 h infusion of
intravenous NACintravenous NAC did not improve survivaldid not improve survival
compared to placebo.compared to placebo.
 However, in aHowever, in a subgroupsubgroup analysis, patients withanalysis, patients with
grade 1 to 2 encephalopathygrade 1 to 2 encephalopathy had a significantlyhad a significantly
higher ratehigher rate of spontaneousof spontaneous survivalsurvival..

49.  Use ofUse of glucocorticoidsglucocorticoids for immune-mediatedfor immune-mediated
reactions, andreactions, and ursodeoxycholic acid (UDCA)ursodeoxycholic acid (UDCA)
for cholestatic liver injury remain controversialfor cholestatic liver injury remain controversial
therapies.therapies.
 In fact, in two ALF trials (included a total of 104In fact, in two ALF trials (included a total of 104
patients of whom 12 had DILI),patients of whom 12 had DILI), steroids failedsteroids failed toto
show a beneficial effect.show a beneficial effect.
 Similarly, in drug-inducedSimilarly, in drug-induced hepatitis with allergichepatitis with allergic
featuresfeatures, with no improvement after drug, with no improvement after drug
withdrawal, a short course ofwithdrawal, a short course of steroids may besteroids may be
justifiable.justifiable.

50.  Since UDCA has a good safety profile, andSince UDCA has a good safety profile, and
prolonged cholestasisprolonged cholestasis, irrespective of aetiology, irrespective of aetiology
can be fatal, it may be reasonable tocan be fatal, it may be reasonable to
treat prolonged cholestasis due to DILI withtreat prolonged cholestasis due to DILI with
UDCA in a dose ofUDCA in a dose of 13–15 mg/kg13–15 mg/kg..

51. ““King’s College criteriaKing’s College criteria” for liver transplantation in” for liver transplantation in
acute liver failureacute liver failure

52.  This is theThis is the most widely usedmost widely used criteria to listcriteria to list
patients with DILIpatients with DILI for liver transplantation,for liver transplantation,
though they have athough they have a low sensitivity (27%) butlow sensitivity (27%) but
high specificity (90%)high specificity (90%) for death orfor death or
transplantation.transplantation.

53. Take home messageTake home message
 Drug-induced liver injury due to paracetamol andDrug-induced liver injury due to paracetamol and
is theis the leading cause of acute liver failureleading cause of acute liver failure in thein the
UK and USAUK and USA andand 22ndnd
in India after Viral hepatitisin India after Viral hepatitis..
 Consider the possibility of DILI in patient withConsider the possibility of DILI in patient with
unexplainedunexplained acute and chronic liver injury.acute and chronic liver injury.
 Spontaneous recoverySpontaneous recovery fromfrom non-paracetamolnon-paracetamol
drug-induced acute liver failure isdrug-induced acute liver failure is rarerare, and early, and early
referral for liver transplantation is vital.referral for liver transplantation is vital.

54. ReferencesReferences
 Journal of Clinical and Experimental HepatologyJournal of Clinical and Experimental Hepatology
September 2012/ vol.2/ no. 3/ 247-259September 2012/ vol.2/ no. 3/ 247-259
 The American Journal of GastroenterologyThe American Journal of Gastroenterology
17 June 201417 June 2014
 World journal of HepatologyWorld journal of Hepatology
27 April 2014;6(4): 160-16827 April 2014;6(4): 160-168
 GUTGUT
2009;58:1555–15642009;58:1555–1564

55. Thank youThank you