Drug-induced Liver Disease (DILD)Drug-induced Liver Disease (DILD)

Yousif.A QariYousif.A Qari

Consultant GastroenterologistConsultant Gastroenterologist

KAUHKAUH

IncidenceIncidence

10 fold increase in No. of reported cases between 10 fold increase in No. of reported cases between 1964-1973 in Japan1964-1973 in Japan

10% of cases of hepatitis in a major hepatology 10% of cases of hepatitis in a major hepatology center in Francecenter in France

20% of instances of jaundice among geriatric 20% of instances of jaundice among geriatric population in USApopulation in USA

9% of hospitalized patients with AST ≥ 400 IU/L 9% of hospitalized patients with AST ≥ 400 IU/L in a survey in UKin a survey in UK

25%-40% of fulminent hepatic failure25%-40% of fulminent hepatic failure

Drug-induced Liver Disease (DILD)Drug-induced Liver Disease (DILD)

PredictablePredictable• Dose related• Intrinsically hepatotoxic drugs• Acute (hours)• Injury pattern is usually necrosis• Clinically → Fulminant (Acute Hepatitis)• Example: Acetaminophine

UnpredictableUnpredictable• Not dose relatedNot dose related• Rare 0.01-1.0 %Rare 0.01-1.0 %• Weeks to months after ingestion of drugWeeks to months after ingestion of drug• IdiosyncraticIdiosyncratic

Immune mediated idiosyncrasy (Hypersensitivity)Immune mediated idiosyncrasy (Hypersensitivity)• RashRash• FeverFever• ArthragiaArthragia• EosinophiliaEosinophilia• Example: Phenytoin, Sulfonamides, ValproateExample: Phenytoin, Sulfonamides, Valproate

Metabolic idiosyncrasy (Production of toxic metabolites)Metabolic idiosyncrasy (Production of toxic metabolites)• Example: INH, Ketoconazole, and DiclofenacExample: INH, Ketoconazole, and Diclofenac

Overview of Drug induced Liver InjuryOverview of Drug induced Liver Injury

Types of Drug ReactionsTypes of Drug Reactions

Approach to the patientApproach to the patient

Natural HistoryNatural History

Histological ClassificationHistological Classification

Hepatocellular ------› HepatocytesHepatocellular ------› Hepatocytes

Cholestatic -------› Bile ducts or canaliculiCholestatic -------› Bile ducts or canaliculi

MixedMixed

Categorization according to type of reactionCategorization according to type of reaction

Direct toxic reactionsDirect toxic reactions Idiosyncratic reactionsIdiosyncratic reactions Combined toxic/Allergic reactionsCombined toxic/Allergic reactions Allergic hepatitisAllergic hepatitis Cholestatic reactionsCholestatic reactions Granulomatous reactionsGranulomatous reactions Chronic hepatitis and cirrhosisChronic hepatitis and cirrhosis Fatty liver /NASHFatty liver /NASH Veno-Occlusive diseaseVeno-Occlusive disease NeoplasticNeoplastic

Diagnosis of (DILD)Diagnosis of (DILD)

High index of suspicionHigh index of suspicion Abnormalities in hepatic associated enzymesAbnormalities in hepatic associated enzymes Hepatitis like symptomsHepatitis like symptoms JaundiceJaundice Drug historyDrug history

• DoseDose• Duration of therapyDuration of therapy• Time between initiating therapy and the development of Time between initiating therapy and the development of

hepatic injury (latency)hepatic injury (latency) Exclusion of other causes of liver diseasesExclusion of other causes of liver diseases

• Hepatitis BHepatitis B• Hepatitis CHepatitis C• Alcoholic liver diseasesAlcoholic liver diseases• Non alcoholic fatty liver diseasesNon alcoholic fatty liver diseases• HemochromatosisHemochromatosis

2%-5% of general population

Diagnosis of (DILD)Diagnosis of (DILD)

Temporal relationshipTemporal relationship

• Most cases of acute DILD occurring within 1 week to 3 Most cases of acute DILD occurring within 1 week to 3 months of exposuremonths of exposure

• Positive response to discontinuing the agent Positive response to discontinuing the agent (Dechallenge)(Dechallenge)

In acute hepatocelluler injuryIn acute hepatocelluler injury• 50% reduction in hepatic –associated enzymes after 2 weeks50% reduction in hepatic –associated enzymes after 2 weeks• Return to normal by 4 weeksReturn to normal by 4 weeks

In cholestatic injuryIn cholestatic injury• May have prolonged recovery timeMay have prolonged recovery time

Diagnosis of (DILD)Diagnosis of (DILD)

Extrahepatic manifestationsExtrahepatic manifestations

• Hypersensitivity reactionsHypersensitivity reactions FeverFever RashRash ArthralgiasArthralgias EsinopheliaEsinophelia

• Unique clinical syndromesUnique clinical syndromes

Risk Factors For Susceptibility to DILDRisk Factors For Susceptibility to DILD

MethotrexateMethotrexate• AlcoholAlcohol• ObesityObesity• D.MD.M• Chronic hepatitisChronic hepatitis

INHINH• HBV,HCV,HIVHBV,HCV,HIV• AlcoholAlcohol• Older ageOlder age• FemaleFemale

AcetaminophenAcetaminophen• AlcoholAlcohol• FastingFasting• INHINH

ValproateValproate• Young ageYoung age• AnticonvulsantsAnticonvulsants

DiclofenacDiclofenac• FemaleFemale• OsteoarthritisOsteoarthritis

Risk Factors For Susceptibility to DILDRisk Factors For Susceptibility to DILD

SulfonamideSulfonamide• HIVHIV• Slow acetylatorSlow acetylator• Genetic defect in Genetic defect in

defensedefense

AnticonvulsatsAnticonvulsats• Genetic defect in Genetic defect in

detoxificationdetoxification

RifampicinRifampicin• Slow acetylatorsSlow acetylators• INHINH

PyrazinamidePyrazinamide• Slow acetylatorsSlow acetylators• INHINH

Clinical PresentationsClinical Presentations

Asymptomatic elevation in hepatic enzymesAsymptomatic elevation in hepatic enzymes

No progress despiteContinued use of the Medication.

(Drug tolerance)

•INH•Phenytoin•Chlopromazine

Progression to Hepatic injury withContinued use of themedication

AST & ALT 3-5 timesUpper limit of normal

May progress to Hepatic failure

Acute Hepatocelluler InjuryAcute Hepatocelluler Injury(Direct toxic reaction)(Direct toxic reaction)

Characterized byCharacterized by• Marked elevation in ALT and ASTMarked elevation in ALT and AST• Normal or minimally elevated alkaline phosphataseNormal or minimally elevated alkaline phosphatase• Bilirubin variably increased-----›worse prognosis.Bilirubin variably increased-----›worse prognosis.

Comprise 1/3 of all cases of fulminant hepatic Comprise 1/3 of all cases of fulminant hepatic failure in the US.failure in the US.• 20% due to Acetominophen20% due to Acetominophen• 12%-15% due to other drugs 12%-15% due to other drugs

Acute Hepatocelluler InjuryAcute Hepatocelluler Injury(Direct toxic reaction)(Direct toxic reaction)

AlcoholAlcohol• AST is always 2-3 times higher than ALTAST is always 2-3 times higher than ALT• AST remains less than 300 IU.AST remains less than 300 IU.• ALT is almost always less than 100 IU.ALT is almost always less than 100 IU.

Towering elevation of ALT&AST(5000-10000 IU)Towering elevation of ALT&AST(5000-10000 IU)• Drugs (acetaminophen)Drugs (acetaminophen)• Differential:Differential:

Chemical toxinsChemical toxins Toxic MushroomsToxic Mushrooms Shock liverShock liver

• Unusual with other causes of liver diseases including Unusual with other causes of liver diseases including Viral Hepatitis. Viral Hepatitis.

Acute Hepatocelluler InjuryAcute Hepatocelluler Injury(Direct toxic reaction)(Direct toxic reaction)

AnestheticsAnesthetics• HalothaneHalothane• IsofluraneIsoflurane

AntimicrobialsAntimicrobials• INHINH• RifampinRifampin• KetoconazoleKetoconazole• SulfonamidesSulfonamides

AnticonvulsantsAnticonvulsants• PhenytoinPhenytoin• Valproic acidValproic acid• CarbamazipineCarbamazipine

NSAIDS & analgesicsNSAIDS & analgesics• AcetaminophenAcetaminophen• Piroxicam,DiclofenacPiroxicam,Diclofenac• SulindacSulindac

MiscellaneousMiscellaneous• LabetalolLabetalol• Nicotinic acidNicotinic acid• PropylthiouracilPropylthiouracil

Examples

Cholestatic InjuryCholestatic Injury

Definition: Reduction in bile flow due toDefinition: Reduction in bile flow due to• Reduced secretionReduced secretion• ObstructionObstruction

Biochemically:Biochemically:• Elevated Alk phosphataseElevated Alk phosphatase• Elevated GGTElevated GGT• Elevated 5 NTElevated 5 NT

Acute illness that subsides when the offending drug Acute illness that subsides when the offending drug is withdrawn.is withdrawn.

Cholestatic InjuryCholestatic Injury

Clinical presentationClinical presentation

• JaundiceJaundice

• PruritisPruritis

Types of cholestasis resulting from drugsTypes of cholestasis resulting from drugsCanaliculerCanaliculer

(Bland (Bland Jaundice)Jaundice)

Hepato-Hepato-canaliculercanaliculer

(Cholestatic (Cholestatic Jaundice)Jaundice)

DuctulerDuctuler

(Cholan-(Cholan-gioler)gioler)

Cholangio-Cholangio-destructivedestructive

(Vanishing bile (Vanishing bile duct syndduct synd

Cholagio-Cholagio-scleroticsclerotic

(Sclerosing (Sclerosing cholangitis)cholangitis)

Bile castsBile casts ++ ++ ++++++ ++ ++

Portal Portal inflammationinflammation

-- ++ ++ ++ ++

Hepatocellul-Hepatocellul-er necrosiser necrosis

-- ++ +/-+/- ++ ++

Ductal lesionDuctal lesion -- +/-+/- ++ ++++++ ++++++

CholangitisCholangitis -- +/-+/- ++ ++ ++

BilirubinBilirubin ++++++ ++++++ ++++++ +to++++to+++ +to++++to+++

Alk PhosAlk Phos <3X<3X >3X>3X >3X>3X >3X>3X >3X>3X

CholesterolCholesterol +/-+/- ++++ +/-+/- ++++++ ++++++

AST/ALTAST/ALT <5X<5X 2-10X2-10X <5X<5X <5X<5X <5X<5X

ExamplesExamples ContraceptiveContraceptive Anabolic Anabolic steroidessteroides

CChlorpromazinehlorpromazine AugmentinAugmentin ErythromycinErythromycin

Benoxap-Benoxap-rofenrofen

ParaquatParaquat ClorpromazineClorpromazine

FluxuridineFluxuridine ScoliocidesScoliocides

Drugs causing chronic cholestasis Drugs causing chronic cholestasis and the vanishing bile duct syndromeand the vanishing bile duct syndrome

AntibioticsAntibiotics

AmpicillinAmpicillin AugmentinAugmentin ClindamycinClindamycin ErythromycinErythromycin Organic arsenicalsOrganic arsenicals SeptrinSeptrin TetracyclineTetracycline ThiabebdazoleThiabebdazole TroleandomycinTroleandomycin

PsychotropicPsychotropic

AmitriptylineAmitriptyline BarbituratesBarbiturates CarbamazipineCarbamazipine ChlorpromazineChlorpromazine HaloperidolHaloperidol ImipramideImipramide phenothiazinesphenothiazines

Miscellaneous

•Aprindine

• Azathioprine

• Carbutamide

• Ciproheptadine

• Chlorthiazide

• cyamemazine

• Ibuprphen

• Cimetidine

• Prochlorperazine

• Terbinafine

• Terfenadine

• Tolbutamide

• Ticlodipine

• Xenalamine

•Ethenyl estradiol

Comparison between PBC with DICCComparison between PBC with DICCPBCPBC DICCDICC

GenderGender womenwomen bothboth

AgeAge Middle-agedMiddle-aged All agesAll ages

AMAAMA PositivePositive NegativeNegative

OnsetOnset InsiduousInsiduous AcuteAcute

JaundiceJaundice Late featureLate feature Acute featureAcute feature

PruritisPruritis ++ ++

HypercholestremiaHypercholestremia ++ ++

SteatorrheaSteatorrhea ++ ++

XanthomasXanthomas ++ +(transient)+(transient)

VBDSVBDS ++ ++

Portal infiltratesPortal infiltrates ++++++ ++

GranulomasGranulomas ++ - -

PrognosisPrognosis Often progresses to billiary Often progresses to billiary cirrhosiscirrhosis

Jaundice usually resolves after 6-Jaundice usually resolves after 6-76 m;rarely progresses to billiary 76 m;rarely progresses to billiary

cirrhosiscirrhosis

PBC : Primary billiary cirrhosis DICC :Drug induced chronic cholestasis

Granulamatous HepatitisGranulamatous Hepatitis

A form of hepatic injury characterized by :A form of hepatic injury characterized by :

• FeverFever• DiaphoresisDiaphoresis• MalaiseMalaise• AnorexiaAnorexia• JaundiceJaundice• Rt upper quadrant discomfortRt upper quadrant discomfort• Granuloma on liver biopsyGranuloma on liver biopsy• Illness usually occurs within the first 2 months of therapyIllness usually occurs within the first 2 months of therapy

Examples:Examples:

• QuinidineQuinidine• CarbamazipineCarbamazipine• AllopurinolAllopurinol• HydralazineHydralazine• PhenytoinPhenytoin• GoldGold• Mineral oil ingestionMineral oil ingestion• PhenylbutazonePhenylbutazone

Drug induced chronic hepatitisDrug induced chronic hepatitis Can resemble chronic active hepatitis including cirrhosis as well as Can resemble chronic active hepatitis including cirrhosis as well as

a form of chronic autoimmune hepatitisa form of chronic autoimmune hepatitis

Characteristics of drug- induced autoimmune hepatitis Characteristics of drug- induced autoimmune hepatitis

Duration of drug intakeDuration of drug intake ≥ ≥ 2-24 months2-24 months

Female predominanceFemale predominance > 80%> 80%

OnsetOnset Insidious, gradualInsidious, gradual

ClinicalClinical Fatigue, anorexia, wt loss, jaundice, Fatigue, anorexia, wt loss, jaundice, ascites, hepatosplenomegaly, and portal ascites, hepatosplenomegaly, and portal hypertensionhypertension

BiochemicalBiochemical AST, ALT= 5-50 × ULNAST, ALT= 5-50 × ULN

Increased gamma globulin levelIncreased gamma globulin level

SerologySerology

AICH 1AICH 1

AICH 2AICH 2ANA, ASMA, LE factorANA, ASMA, LE factor

Anti-P4501A2, AntiP4502C9Anti-P4501A2, AntiP4502C9

HistologyHistology Very active necro-inflammatory lesionVery active necro-inflammatory lesion Prominent plasma cellsProminent plasma cells

Usual courseUsual course Resolution on withdrawal of drugResolution on withdrawal of drug

Drugs leading to a syndrome resembling Drugs leading to a syndrome resembling type I autoimmune chronic hepatitistype I autoimmune chronic hepatitis

Multiple casesMultiple casesDrugsDrugs Serologic FactorsSerologic Factors

ClometacinClometacin ASMA, Anti-DNAASMA, Anti-DNA

MethyldopaMethyldopa ANA(16%), ASMA(35%)ANA(16%), ASMA(35%)

MinocyclineMinocycline ANA, Anti-DNAANA, Anti-DNA

NitrofurantoinNitrofurantoin ANA(80%), ASMA(72%)ANA(80%), ASMA(72%)

OxyphenisatinOxyphenisatin ANA(67%), ASMA(67%), LE(33%)ANA(67%), ASMA(67%), LE(33%)

Few casesFew casesBenzaroneBenzarone ASMAASMA

DiclofenacDiclofenac ANAANA

FenofibrateFenofibrate ANAANA

PapverinePapverine ANA, ASMAANA, ASMA

PemolinePemoline ANA, Automicrosomal antibodyANA, Automicrosomal antibody

PropylthiouracilPropylthiouracil ANAANA

CaptoprilCaptopril ANA, AntilamininANA, Antilaminin

FlucloxacillinFlucloxacillin AMA,(Anti-M2)AMA,(Anti-M2)

ProcainamideProcainamide ANA, LE factor(50-70%)ANA, LE factor(50-70%)

Vascular injuryVascular injury

May involve all of the vascular components of the liver, May involve all of the vascular components of the liver, including the sinusoids, hepatic veins, and hepatic arteries.including the sinusoids, hepatic veins, and hepatic arteries.

Veno-occlusive disease (VOD):Veno-occlusive disease (VOD):• May be caused by:May be caused by:

Toxic plant alkaloids (certain herbal tea)Toxic plant alkaloids (certain herbal tea) A serious complication complication of bone marrow transplantA serious complication complication of bone marrow transplant

• Azathioprine Azathioprine is probably the calpritis probably the calprit

• Clinically presents asClinically presents as Mild vral-like illness Mild vral-like illness →→ Fulminent hepatic failure→→ Fulminent hepatic failure Rapid weight gainRapid weight gain AscitesAscites JaundiceJaundice Evidance of portal hypertensionEvidance of portal hypertension

Chronic form of VOD may also exist.Chronic form of VOD may also exist.

Neoplastic lesionsNeoplastic lesions Neoplastic lesionsNeoplastic lesions Clinical findingsClinical findings ExamplesExamples

Focal noduler Focal noduler hyperplasiahyperplasia

Hepatic massHepatic mass Contraceptive steroidsContraceptive steroids

AdenomaAdenoma Hepatic massHepatic mass HemoperitoneumHemoperitoneum

Contraceptive steroidsContraceptive steroids Anabolic steroidsAnabolic steroids DanazoleDanazole

Hepatocelluler Hepatocelluler carcinomacarcinoma

Malignant massMalignant mass Anabolic steroidsAnabolic steroids Contraceptive steroidsContraceptive steroids Venyl chlorideVenyl chloride Thorium dioxide Thorium dioxide (Thorotrast)(Thorotrast)

AngiosarcomaAngiosarcoma Malignant massMalignant mass Anabolic steroidsAnabolic steroidsInorganic arsenicalsInorganic arsenicalsThorium Thorium dioxide(Thorotrast)dioxide(Thorotrast)

Natural History and PrognosisNatural History and Prognosis

When recognized promptly and the offending agent is When recognized promptly and the offending agent is discontinued most cases discontinued most cases resolve without chronic sequalaeresolve without chronic sequalae

Mortality principally depend on the Mortality principally depend on the degree of hepatocelluler degree of hepatocelluler injury.injury.

10% mortality for agents causing fulminant hepatitis or 10% mortality for agents causing fulminant hepatitis or toxic steatosis.toxic steatosis.

Agents that cause cholestatic injury rarely , if ever , Agents that cause cholestatic injury rarely , if ever , produce acute fatalitiesproduce acute fatalities

The prognosis is worse whenever jaundice accompanies The prognosis is worse whenever jaundice accompanies hepatocelluler injury.hepatocelluler injury.

Hepatic injury resulting from Hepatic injury resulting from individual agentsindividual agents

AnestheticsAnesthetics