2 DILI- Table of Contents IntroductionEpidemiologyLiver - Drug MetabolismFactors influencing Drug MetabolismMechanisms of Drug-induced HepatotoxicityClinical PresentationDrugs that cause DILIDiagnosisTreatments
3 Introduction Caused by many common drugs AntibioticsOTC medicationsHerbsSupplements0.1 to 3% of hospital admissions1~600 liver transplantations per year in US10% fatality seen in cases with severe ALT elevation and jaundice2Caused by many common drugs prescribed or purchased without regulationAntibiotics-Augmentin, Bactrim, clarithromycin, Cipro, Levaquin, MoxiAnti-TB meds- isoniazid, pyrazinamide> rifampin or ethambutolOTC- ie Tylenol (acetaminophen)Herbs- ie St John’s WartSupplement- weight loss, muscle building, niacinDig Dis Sci 2007;52:Kaplowitz N. Nat Rev Drug Discov 2005;4:
4 EpidemiologyAnnual incidence between 10 and 15 per 10,000 to 100,000 people30% of cases of acute hepatitis10% of consultation by hepatologistsMost common cause of acute liver failure in the USMCC of acute liver failure- acetaminophen being #1 drug to cause it
5 Liver - Drug Metabolism BiotransformationPhase 1- oxidation60 genes code for CYP (family- ie CYP2, subfamily- ie CYP2E1)Hepatic metabolism of exogenous drugs- CYP1, 2, 3, and lesser extent 4CYP3A4- 60% of all hepatic cytochromes, affecting 50% of commonly used drugsEnzyme activity dependent on several exogenous factorsState First- The liver is responsible for the selective uptake, concentration, metabolism, and excretion of the majority of drugs. While some drugs can cause hepatotoxicity prior to biotransformation, it is usually their metabolites that lead to DILI.Biotransformation- group processes by which a drug is metabolized into a more water-soluble form for purpose of excretion; in some cases the excreted metabolite may itself cause injury; while in other cases certain factors can lead to the concentration of metabolites, causing liver injury.Phase 1- transform lipophilic (water-insoluble) molecules into more polar, hydrophilic molecules via oxidation, reduction, or hydrolysis. These are membrane bound hemoproteins composed of an apoprotein and heme group (the oxidizing center).CYP- cytochromie P450 superfamily of mixed function oxidases, and are organized into families and subfamilies. Majority that metabolize drugs are found on the cytoplasmic side of the endoplasmic reticulum membrane.Factors that alter the activity of this group of enzymes have the potential to increase the toxicity of a compound. In some cases, alternate detoxification routes may become overloaded, leading to the development of hepatotoxicity.
6 Liver - Drug Metabolism BiotransformationPhase 2- conjugation(UDP)-glucuronyl transferases (UGT1, & UGT2)SulfotransferasesGlutathione S-transferasesDecreases pharmacologic activityEnhances clearancePhase 2 reactions affect the metabolites of phase 1 rxns in order to make them more hydrophilic for excretion.-These reactions conjugate the drug or metabolite byproducts to highly polar ligands such as glucoronate, sulfate, acetate, glycine, glutathione, or a methyl group.In general, drug conjugates are nontoxic, and phase 2 rxns are considered to be detoxification reactions, however polymorphisms of some of the enzymes may also lead to either decreased or increased activity.
7 Liver - Drug Metabolism BiotransformationPhase 3 – transportABC superfamilyMDR1/ABCB1MRP2/ABCC2MDR3/ABCB4BSEP/ABCB11Altered activity of these transporters can lead to hepatotoxicityPhase 3 rxns lead to the transport of drugs/metabolites across the canalicular membrane and into bile.ABC- adenosine triphosphate (ATP)-binding cassetteMDR- multidrug resistant P-glycoproteinBSEP- bile salt export protein
8 Factors influencing Drug Metabolism PharmacogeneticsPolymorphisms of phase 1, 2, 3 enzymesIe CYP2C9/2C19- warfarin, omeprazole, tolbutamide/mephenytoinIe glutathione S-transferase- acetaminophenHLA- flucloxacillin, augmentinNutritionIe CYP2E1Fasting/malnutritionObesityGrapefruitGenetics- polymorphisms in this setting explains the four-fold or greater differences in rates of metabolism among healthy individuals. Genetic alterations may contribute to diminished metabolism, lack of metabolism, or excessive metabolism of a drug.-polymorphisms of CYP2C9- affects the metabolism of S-warfarin, omeprazole, tolbutamide-polymorphism of CYP2C19- affects the metabolism of S-mephenytoin-polymorphism of glutathione s-transferase can affect metabolism of acetaminophen-HLA (human leukocyte antigen)- association between certain HLA haplotypes and the development of DILI from fluclox-, augmentinNutrition- A person’s nutritional status influences the expression of certain CYPs, both in health and with underlying liver disease. Expression of CYP2E1 is increased by obesity, high fat intake, and fasting-Fasting/malnutrition- may increase risk of DILI from acetaminophen; this is thought to be due to its affect on detoxifying cofactors such as glutathione-obesity- methotrexate, halothane-grapefruit juice- inhibits CYP3A, primarily acting on intestinal form of the enzyme; affecting levels of absorption of several drugs including immunosuppressive meds- cyclosporine and tacrolimus
9 Factors influencing Drug Metabolism Multi-drug effectAge and sexDoseA drug may either inhibit or enhance (inducer) another drugs metabolism. Competitive inhibition of CYP can lead to clinically important drug interactions when there are no alternative pathway for the metabolism of a toxic drug or its metabolite.-Competition for phase 2 reactions such as glucuronidation and sulfation, for example, by phenytoin, may lower the dose threshold for acetaminophen-induced hepatotoxicity.-Phase 3 transporters have also been reported to be inhibited (eg, atorvastatin, carvedilol, clarithromycin, and sertraline) and induced (eg, amiodarone, diltiazem, erythromycin, and St John’s Wart); significantly altering the secretion activity of this group.During adult life, the expression of some CYPs declines by up to 10% with advancing age. Expression of CYP 3A4 and 2E1 seem to be different among men and women, which may explain the enhanced metabolism of certain drugs, however it’s still unclear whether this increases the risk of hepatic drug rxns.Severe DILI rarely occurs from drugs taken at doses less than 10mg; drugs administered at >/= 50mg are more likely to cause DILI.
10 Factors influencing Drug Metabolism Disease-related changes- expression of CYPDMHypothyroidismUnderlying liver diseaseDecreased P450Decreased hepatic clearanceDiseases that alter the expression of CYPs include DM (increased CYP2E1), and hypothyroid (decreased CYP3A4)Cirrhosis is associated with decreased levels of total cytochrome P450 and also reduced hepatic perfusion; results in decreased clearance of such as propranolol, which is usually metabolized rapidly by the liver.
11 Mechanism of DILI Proposed mechanisms Intrinsic injury (direct or indirect injury to hepatocyte)Drug transporter/metabolizing enzyme modulationMitochondrial toxicityBile Salt Export Pump (BSEP) inhibitionModulation of immune reactions (idiosyncratic injury)Histone acetylationIntrinsic injury- direct damage by covalently binding to cellular macromolecules (ie Tylenol, chloroform, carbon tetrachloride, phosphorus)Drug transporters such as BSEP or transporters on the sinusoidal membrane; Drug metabolizing enzymes such as CYP and phase 2 enzymes (ie glucuronidation or sulfation) may be inhibited or induced, essentially increasing the concentration of reactive metabolites within the hepatocyte.Mitochondrial toxicitity- which would essentially deplete the ATP stores, leading to cell death.BSEP- will discuss further in the presentationHistone acetylation- inhibiting cell regeneration by blocking DNA transcription
12 MechanismsDILI can result from reactive drug metabolites; their concentration depends on toxification and detoxification enzymes.
13 MechanismsMost toxic drugs have a direct effect on the hepatocyte, causing necrosis or apoptosis. Mitochondrial toxicity essentially blocks the cells ability to produce ATP, leading to cell death. The toxic drug or metabolite may also directly trigger cell death through the TNF/Fas system. A drug/metabolite maybe recognized by a cytotoxic T-cell to release cytokines, triggering immune-mediated cell death. This is where HLA subtyping plays a role. Histone acetylation by other drugs/metabolites will essentially inhibit the cells ability to regenerate.Some drugs predominately damage the bile ducts, or affect the export proteins (BSEP), leading to cholestasis.While other drugs may cause a mixed injury pattern.
14 MechanismsBSEP- Inhibition of bile acid transporters, such as BSEP (bile acid export pump), results in the accumulation of bile acids within the hepatocyte, causing cell injury through their detergent properties or direct toxic effect on mitochondria.
15 Clinical Presentation Hepatocelluar (cytotoxic) injuryCholestatic injuryMixed injuryMechanism of hepatotoxicityPredictableIdiosyncraticHistologic findings (liver biopsy usually not necessary)HepatitisCholestasisSteatosisType of injury is reflected by the pattern of liver test abnormalities.Hepatocellular injury- 1) aminotransferases are elevated much more than ALP; 2) serum bili may be elevated; 3) test of synthetic function abnmlCholestatic injury- 1) ALP elevated more so than aminotransferases; 2&3 same as aboveAcute DILI- LFTs abnml for less than 3 months; Chronic DILI- abnml for more than 3 months
16 Clinical Presentation Predictable- intrinsic hepatotoxinsPredictably cause dose-dependent hepatocellular necrosisLatent period- brief (hours to a few days)Fairly consistent from person to person and among animal modelsSerum aminotransferases 8 to 500 times normal; ALP less elevatedOften removed from clinical useSome still in use due to known dose-related toxicityHepatotoxic in large doses (ie acetaminophen, iron sulfate)Known dose-effect (ie ethanol, IV tetracycline, L-asparaginase)
17 Clinical Presentation IdiosyncraticUnpredictableSpecies-specific, often cannot be reproduced in animal modelsLatent period- variable, generally 1 to 3 monthsDoses >50mg/day more likely to cause DILI compared to dosing <10mg
18 Clinical Presentation HepatocellularALT/ALP ratio >5~50% of DILI is hepatocellularAST>>ALT- think muscle injury or alcoholic hepatitisNeither above 400CholestaticALP> 2x ULNALT/ALP ratio < 2Mixed5> ALT/ALP ratio > 2Hy’s law- serum bilirubin >2x ULN, aminotransferases >3x ULNAssociated with worse prognosisMortality as high as 14 percentHy’s Law – developed by Hyman Zimmerman
19 * Add slide on Methotrexate monitoring- primo gastro
20 Clinical Presentation Acute DILIMild asymptomatic liver test abnormalitiesCholestasis with pruritisAcute illness with jaundice- resembles viral hepatitisAcute liver failureChronic DILI- may resembleAIHPBCSclerosing cholangitisAlcoholic liver diseaseAsymptomatic abnml liver chemistries- 1/100 to 1/100,000 ; most resolve with drug cessationAcute illness with jaundice- 10 to 14% mortality due to liver failureWill review Acute Liver Failure further in the presentation*Add slides about DILI-like AIH
21 Clinical Presentation SymptomsAcute DILIMalaiseLow-grade feverAnorexiaNausea and VomitingRUQ painJaundiceAcholic stoolsDark uineChronic Dilimay present with signs of cirrhosis or decompensationJaundicePalmer erythemaAscitesHE
22 Acetaminophen Hepatotoxicity Normally metabolized by glucuronidation and sulfationN-hydroxylation (CYP2E1) N-acetyl-p-benzoquinone (NAPQI)NAPQI scavenged by glutathioneOverdose usually >7-10gm (in nonalcoholic patients)Glutathione depleted increased NAPQIhepatotoxicityCYP2E1 induced by fasting, alcohol, Rx (ie INH),TreatmentIpecac- if time of ingestion <4hrsN-acetylcysteine (NAC)- increases level of glutathione
23 Drugs that cause DILI Isoniazid (INH) – 300mg qD MechanismsReactive metabolitesImmunoallergic injury: HLA DQB1*0201Mitochondrial injuryInhibiting histone deacetylasePresents insidiously 4-6 months afterRifampin increases likelihood of INH toxINH can increase acetaminophen toxHx of liver disease- serial monitoring (alternate drug if level >100)Amoxicillin:clavulanate mg qDImmunoallergic injury: Class 1 & 2 HLA DQB1*0602, *1501Cholestatic hepatitis within weeks of first doseValproate (>600mg qD)-Mitochondrial injury-Inhibiting histone deacetylase-Low carnitine levels- increases risk of liver injury
24 Drugs that cause DILI Nitrofurantoin Liver injury usually seen in women taking for >6 monthsLabs- high transaminases; HLA-B8 and ANA are usually positiveSteroids (anabolic, OCP, tamoxifen, glucocorticoids)Cholestatic injuryCanalicular injuryAnesthetic Agents (ie Halothane)Risk increases with more exposure and present within 2 weeksLabs- eosinophilia, AST/ALT IU/LMechanism- reactive metabolites (trifluoroacetyl), and autoanitgensPoor prognosis- age>40, obesity, HE, elevated INR (mortality 80% without OLT)
25 Herbal & Supplements 9-14% of cases of DILI in Western countries Longer exposure before DILI42% in US use some form of alternative therapy69% do not disclose supplement use to health care providers52% use herbal/sup concurrently with prescription medsCommon- Herbalife, Hydroxycut, Chinese herbal, LipoKinetix, Androstenedione, Black cohosh, Green tea extract, Mistletoe, Licorice
29 Diagnosis Obtaining a thorough history Performing blood test to look for other causes on hepatic injurCholestasis- imaging to rule out biliary obstructionReview of drugs exposed preceding the onset of liver injuryUnderlying liver disease is excluded- rule out other causesStopping drug believed to cause injury leads to improvementRechallenge- rapid and severe recurrence; not advised
30 Diagnosis Drug exposure Stop drugs that are commonly known to cause DILIAlways ask about any OTC, herbal and/or supplements takenIf possible review a patient’s pharmacy recordsCheck drugs onCase presentationsDrug-specific liver injury characteristicsDirect link to references and other online recourcesNew cases of DILI welcome
31 Diagnosis Roussel Uclaf Causality Assessment Method (RUCAM) A number of scales have been developed that attempt to categorize causality of drug toxicity-Roussel Uclaf Causality Assessment Method (RUCAM)-Maria & Victorino clinical scale-The Drug-Induced Liver Injury Network (DILIN) developed the DILIN Causality Scoring System- which relies on expert opinionThese scales do not address all risk factors in all patients; and none are used routinely in clinical practice.
32 Diagnosis Drug-induced acute liver failure Most frequent cause of liver failure requiring evaluation for transplantation11th Annual FDA/PhRMA/AASLD Hepatotoxicity ConferenceAcute Liver Failure Study Group ~1700 casesAcetaminophen-induced 46% (n=787)Other drug-induced liver failure 12% (n=202)Acetaminophen-induced- half unintentional narc/aceta overdoseCoagulopathy (INR>1.5)Encephalopathy- day/night confusion, disorientation, sleepinessAcute liver failure is rare- 1-5 per million per year-75% fatality with non-acetaminophen DIL Failure-32% fatality in acetaminophen-ALF
33 Treatment of DILIDiscontinue suspected drug- most cases, liver injury should spontaneously resolveN-Acetylcysteine for acetaminophen liver injuryLiver transplantationLimited use or experimentalIV carnitine for valproate liver injuryUrsodeoxycholic acid for cholestasisCorticosteroids for hypersensitivity casesPlasmapheresis
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