DRUG INDUCED HEPATITIS

DRUG INDUCED HEPATITIS & ITS MANAGEMENT : 

DRUG INDUCED HEPATITIS & ITS MANAGEMENT SPEAKER- ARINDAM PANDE CHAIRPERSON- Prof. B K DEY Prof. S B GANGULY

INTRODUCTION : 

INTRODUCTION MAY FOLLOW INHALATION / INGESTION / PARENTERAL ADMINISTRATION OF— INDUSTRIAL TOXINS BICYCLIC OCTAPEPTIDES PHARMACOLOGICAL AGENTS

INCIDENCE : 

INCIDENCE 1 IN EVERY 10,000 TO 100,000 MAY BE UNDERESTIMATION, DUE TO --UNDERREPORTING --DIFFICULTIES IN DETECTION / DIAGNOSIS --INCOMPLETE OBSEVATION OF EXPOSED PERSONS

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Yearly incidence rate DIH: 14/100 000 inhabitants / year = 8 000 cases / year in France (16-times the number reported to the French Pharmacovigilance Agency) Fatal DIH (0.8/100 000 inhabitants/year) 6% Sgro, Hepatology 2002;36:451.

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B O O E Z D R U G Burger B L O O D Obesity/ diabetes Abnormal liver tests HCV HBV FOURTH CAUSE 9%* *Bagheri, Br J Clin Pharmac 2000;50:479.

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DISPROPORTIONATE ROLE IN FULMINANT HEPATITIS IN THE US AND UK

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Drugs: first cause FULMINANT HEPATITIS in the USA

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Lee WM, Sem Liver Dis, 2003;23:217 FULMINANT HEPATITIS IN THE USA OTHER CAUSES: 48% OTHER DRUGS: 12% PARACETAMOL: 40% DRUGS: 52% Intentional overdoses Self medication with excessive doses in the USA

SIGNIFICANCE…. : 

SIGNIFICANCE…. PREVENTABLE AND CORRECTABLE CAUSE OF ACUTE AND CHRONIC LIVER DISEASES. LOW FREQUENCY(6% of all adverse drug reactions) LEADS TO CASES BEING OVERLOOKED,THUS DIFFICULTY IN ATTRIBUTING CAUSALITY. ROLE OF DRUGS IN SYNERGISTIC HEATOTOXICITY (HIV,TB,NASH,BONE OR ORGAN TR.) LEGAL AND FINANCIAL IMPLICATIONS MOST FREQUENT CAUSE FOR POST MARKETING WITHDRAWAL OF DRUGS (eg. troglitazone).

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Continued treatment ALT 1 ULN 5 ULN DRUG 3. Fulminant hepatitis 1. Adaptation 2. Chronic liver disease FOR THE PHYSICIAN

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DIH: Major cause for drug withdrawal or prescribing restrictions Recent cases: Ximelagatran Troglitazone Bromofenac Felbamate Pemoline Tolcapone Trovafloxacin FOR THE PHARMACEUTICAL INDUSTRY

DEFINITION (FDA, FEB’2001) : 

DEFINITION (FDA, FEB’2001) ALT > 3 times of UNL & Total Bilirubin > 2 times of UNL Further verification through analysis of additional data ↑ serum enzymes ( ALT, AST, ALP)- indicator of liver injury ↑ Total & Conjugatad Bilirubin – measure of overall liver function

PATTERN OF HEPATOTOXICITY : 

PATTERN OF HEPATOTOXICITY PREDICTABLE / DIRECT TOXIC EFFECT (DOSE DEPENDENT) UNPREDICTABLE / IDIOSYNCRATIC (DOSE INDEPENDENT) -- IMMUNO-ALLERGIC TYPE -- METABOLIC IDIOSYNCRASY OTHER

INTRINSIC HEPATOTOXINS : 

INTRINSIC HEPATOTOXINS Acute liver damage after a relatively brief latent period in a predictable, dose-dependent fashion Independent of host susceptibility factors Acetaminophen, CCl4, toxins of Amanita mushroom species

IDIOSYNCRATIC HEPATOTOXINS : 

IDIOSYNCRATIC HEPATOTOXINS An infrequent unpredictable fashion after a variable latent period Variations in the pathways of drug biotransformation, immune mediated hypersensitivity (drug-allergy) Fever, arthralgia, rash and eosinophilia Halothane, isoniazid, phenytoin

CLINICAL CLASSIFICATION : 

CLINICAL CLASSIFICATION wide spectrum from minor nonspecific derangements to fulminant hepatic necrosis Hepatocellular – acute inflammation Cholestatic –biliary obstruction Mixed Fatty liver Fibrosis, chronic hepatitis Granuloma Vascular damage Tumor

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Hepatitis Mixed Cholestasis Hepatocellular Injury and Inflammation Cholestasis & Ductular injury and Inflammation ALT x ULN >5 ← → <2 ALP x ULN ALP ALT

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Navarro V and Senior J. N Engl J Med 2006;354:731-739 Liver Injury and Its Patterns

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Hy’s rule Mortality of drug-induced hepatocellular jaundice: 10% Example: 5 of 1 000 patients have ALT > 10 ULN and bilirubin > 3 ULN in a clinical trial You can expect: 5 deaths with liver failure for 10 000 recipients after marketing

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Lee W. N Engl J Med 2003;349:474-485 Idiosyncratic Drug Reactions and the Cells That Are Affected

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Lee W. N Engl J Med 2003;349:474-485 Effects of Increased or Cumulative Doses of Drugs

Hepatic Drug Metabolism : 

Hepatic Drug Metabolism A schematic of the interplay between drug uptake, metabolism and efflux in the hepatocyte. Uptake Metabolism Efflux (Phase III) Phase I (CYP enz) Phase II (Conjugation)

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METABOLIC ACTIVATION Protein (Low Amounts) Immune reactions Extensive covalent binding  GSH (High Amounts) Direct toxicity Reactive metabolite Drug CYP

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Drugs  Beta- oxidation  Respi- ration Steatosis Cell dysfunction Cell death Lactic acidosis MITOCHONDRIAL DYSFUNCTION

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Lee W. N Engl J Med 2003;349:474-485 Six Mechanisms of Liver Injury

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CLINICAL MANIFESTATIONS OF DRUG INDUCED HEPATITIS

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Navarro V and Senior J. N Engl J Med 2006;354:731-739 Liver-Biopsy Specimens Showing Common Histologic Features of Drug-Related Hepatotoxicity

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HOW CAN THE DIAGNOSIS BE MADE?

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DIAGNOSIS Always consider a possible iatrogenic cause Insistent questioning (Analgesic drugs, illicit drugs, psychoactive drugs, NSAIDs, over-the-counter drugs, herbal remedies) Compatible chronology (DIH may sometimes appear 2 weeks after treatment is stopped)  Fever, rash, eosinophilia (immunoallergic mech.) Similarity to previously reported cases Exclusion of other causes (obesity/diabetes, alcohol, …viral serologies, ultrasonography) Deceleration after withdrawal

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Navarro V and Senior J. N Engl J Med 2006;354:731-739 Diagnosis of Drug-Related Hepatotoxicity

Specific antibodies : 

Specific antibodies Autoantibodies Tienilic acid anti-LKM2 (anti-CYP2C) Beaune, PNAS 1987;84:551 Dihydralazine anti-LM (anti-CYP1A2) Bourdi, JCI 1990;85:1967 Halothane anti-CYP2E1 Eliasson, Mol Pharmacol 1996;50:573 Germander anti-EH de Berardinis, Mol Pharmacol 2000;58:542 Iproniazid anti-M6 (anti-MAO B) Pons, BBRC 1996;218:1118 Anti-metabolite-protein adduct antibodies Halothane anti-TFA-protein Kenna, JPET 1998;245:1103 Tienilic acid anti-TA-protein Robin, JCI 1996;98:1471 Diclofenac anti-Diclof.-protein Aithal, Hepatology 2004;39:1430

Lymphocyte proliferation assay : 

Lymphocyte proliferation assay Mononuclear cells are separated from a patient’s peripheral blood and cultured in medium in the presence of the suspected allergen. A positive result is most easily demonstrated by lymphocyte proliferation (usually measured by the uptake of tritiated thymidine). The ratio of counts per minute in the presence of antigen compared with a control culture in its absence is expressed as the stimulation index. If this value is greater than a cut-off level determined in a set of healthy controls, then the test is considered positive, and evidence of the presence of sensitised lymphocytes. Certain activation markers and adhesion molecules such as CD11a/CD18 (LFA-1), accounts for their rapid reactivation on re-exposure to antigen.

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Lymphocyte proliferation assay 1 2 4 8 16 32 34% 56% 100% 100% 95 pts with DIH 106 controls 35 treated pts without DIH (26% without indo- meth- acin) With/without drug [3H]thymidine incorporation ratio (with indomethacin to prevent inhibitory PGE2 formation) Maria and Victorino, Gut 1997;41:534-540

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Performing a rechallenge for the sake of diagnosis is unethical, and is particularly risky if immunoallergy is suspected (risk of rapid and severe DIH). 2. However, re-introduction may be attempted if: - the drug is required to treat a serious disease; - other drugs are less active; - one suspects direct toxicity (rather than immunoallergy); - one use lower doses (or different co-medications…); - and transaminases are monitored frequently. RECHALLENGE

Management : 

Management Discontinuing the implicated drugs Supportive care for acute hepatitis and hepatic failure Specific pharmacological intervention, e.g. N-acetylcystein for acetoaminophen overdose Carnitine in valproate overdose No established value of - Corticosteroids for drug hepatotoxicity with allergic features - Silibinin for hepatotoxicmushroom poisoning - Ursodeoxycholic acid for cholestatic drug hepatotoxicity

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Drug withdrawal ALT 1 ULN 10 ULN DRUG Few weeks

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Navarro V and Senior J. N Engl J Med 2006;354:731-739 Key Guidelines in the Recognition and Prevention of Hepatotoxicity in Clinical Practice

ACETAMINOPHEN & HEPATOTOXICITY: : 

ACETAMINOPHEN & HEPATOTOXICITY: LEADING CAUSE OF ACUTE LIVER FAILURE IN THE WEST. SINGLE DOSE 15-25g may cause acute liver failure. LIVER INJURY IN 3 PHASES. Role of NAPQI (Phase 1 product), by CYP2E1 Hepatic injury apparent after 24-48 hours FASTING, ALCOHOLISM, CONCURRENT INH, PHENYTOIN are risk factors. ALT 2000-10,000 IU/L, ZONE 3 NECROSIS. Rx: Gastric lavage, activated charcoal (within 30 min) THIOL DONORS - NAC(16hrs), METHIONINE(10hrs) NAC- given if, serum level > 200mg at 4 hr or > 100 mg at 8 hr. 5% oral solution (140mg/kg loading, then 70mg/kg 4hrly for 15-20 doses)

ATDs & HEPATOTOXICITY: : 

ATDs & HEPATOTOXICITY: RISK FACTORS  ^AGE, FEMALE, MALNUTRITION, ALCOHOLISM, NAT ACTIVITY, ACETYLATOR PHENOTYPE. CRITERIA FOR ATD INDUCED H’TOXICITY (ANY ONE) AT > 5 ULN RISE IN SERUM TOTAL BILIRUBIN > 1.5 ANY ^AT WITH ANOREXIA, NAUSEA, VOMITING, JAUNDICE TREATMENT(BTS GUIDELINES): STOP HEPATOTOXIC DRUGS--START ETHAMBUTOL, STREPTOMCIN, QUINOLONES--AFTER COMPLETE RESOLUTION OF TRANSAMINITIS, REINTRODUCE---

ATDs & HEPATOTOXICITY: : 

ATDs & HEPATOTOXICITY: --INH introduced at 50mg/d to 300/d over 2-3 days---After 2-3 days, RFM introduced at 75mg/d to 450m/d--Finally PZN reintroduced at 250 mg/d to 1500mg/day. RECURRENCE OF DIH AFTER RE-INTRODUCTION OF ATDs IS 7-25%

METHOTREXATE & HEPATOTOXICITY: : 

METHOTREXATE & HEPATOTOXICITY: RISK FACTORS….Age >60, Dose(5-15mg/wk), Alcohol, Obesity, Diabetes, Psoriasis, NASH. FEATURES….Non specific, absent until portal hypertension with liver failure develop. MONITORING….Procollagen 3 peptide levels, LFT at 2 months interval, Liver biopsy after cumulative dose of 1.5g(in psoriasis, RA).

VALPROATE & HEPATOTOXICITY: : 

VALPROATE & HEPATOTOXICITY: RISK FACTORS: Exclusively in children < 3yrs..Mitochondrial enzyme def, Friedreich ataxia, Reyes syn. Mediated by metabolite 4 pentenoic acid FEATURES: Nonspecific,4-12 wks after start, Extra hepatic features. Asymptomatic ALT elevation in 45% treated patients MANAGEMENT: Avoid VPA in combination, Significance of warning symptoms in 1st 6 mnth, I.V. L-Carnitine- 50mg/kg/day (if coma, rising ammonia level, valproate level > 450mg/l)

STATINS & HEPATOTOXICITY: : 

STATINS & HEPATOTOXICITY: Very high doses of statins may cause hepatotoxicity, but typical therapeutic doses not associated with significant liver injury. Hepatocellular necrosis from statins is exceptionally rare in humans Asymptomatic elevations in aminotransferases are common but they do not indicate hepatic damage, especially in the setting of normal bilirubin levels. The notion that ezetimibe may have less risk of hepatotoxicity has recently been challenged and it may not be a “safe alternative” to statins in patients with pre-existing liver disease. The anti-hyperlipidemic drug with the highest potential for hepatic injury is the sustained-release formulation of niacin Fenofibrate may very rarely instigate an autoimmune hepatitis-type reaction with resultant ductopenia, chronic hepatitis, and fibrosis, especially when used in combination with statin medications.

OHA & HEPATOTOXICITY: : 

OHA & HEPATOTOXICITY: It is recommended that liver enzymes (ALT) should be monitored in patients with diabetes receiving antidiabetic drugs for which incidences of hepatotoxicity are already reported.

HAART & HEPATOTOXICITY: : 

HAART & HEPATOTOXICITY: NRTI’s: MITOCHONDRIAL TOXICITY(XCEPT LAMIVUDINE) MICRO/MACROVESCICULAR STEATOSIS,LACTIC ACIDOSIS (with shock like state), LFT ABNORMALITY ONSET USUALLY 6 MONTHS AFTER START OF THERAPY NNRTI’s: HEPATITIS AS A PART OF HYPERSENSITIVITY REACTION,WITH EOSINOPHILIA, SKIN RASH, LYMPHADENOPATHY. PROTEASE INHIBITORS: CLINICAL HEPATITIS IS INFREQUENT.

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TRANSAMINASE MONITORING: USEFUL OR USELESS?

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TRANSAMINASE MONITORING Infrequent ALT > 5 ULN Stop treatment Frequent (e.g., tacrine) No jaundice 4 Weeks

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WARN THE PATIENT “ Consult and have liver tests performed if you don’t feel well ” “Stop treatment immediately should you become jaundiced” Rather than infrequent LFT monitoring, it’s best to

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CAN WE PREDICT WHICH PATIENT WILL DEVELOP DIH?

Risk Factors : 

Risk Factors Toxic Potential of Drug Genetic Factors Environmental Factors reactive metabolite mitochondrial effects drug metabolism detoxification transport others other drug ethanol age underlying disease

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Young adults DIH and age High drug consumption Old Children Exceptions: Reye’s syndrome with aspirin and Reye-like syndrome with valproate > > Susceptibility (e.g., isoniazid)

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(Same in females and males before 50) DIH and gender Sgro, Hepatology 2002;36:451 Incidence of DIH: 2.6-fold higher in females than males in persons aged 50 years or more

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CIRRHOSIS - Does not change the incidence of DIH but worsens it outcome (The same degree of liver injury, which is well tolerated in a normal subject, can trigger liver failure, complications and death in patients with an already impaired liver function) DIH in cirrhosis

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DIH and VIRAL INFECTIONS Viral Hepatitis  DIH HAART Anti-tuberculous drugs Paracetamol Varicella, inflenza  Reye Aspirin

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NASH, Alcohol abuse, Viral Infections, Pregnancy, Inborn b-oxidation defects, Mitochondrial cytopathies DRUG(S) + OTHER CONDITION(S) Additively impair mitochondrial function Liver disease ADDITIVE IMPAIRMENT OF MITOCHONDRIAL FUNCTION

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Large doses of paracetamol Hepatitis due to direct toxicity CYP2E1  CYP INDUCTION AND/OR MALNUTRITION CAN INCREASE THE DIRECT TOXICITY OF REACTIVE METABOLITES Large amounts of a reactive metabolite  GSH Susceptibility: Alcohol abuse Malnutrition

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THE N-ACETYL-TRANSFERASE POLYMORPHISM CAN MODULATE AUTOIMMUNE HEPATITIS More frequent hepatitis Dihydralazine Reactive metabolite CYP1A2-metabolite adducts Anti-CYP1A2 autoantibodies CYP1A2 Extensive acetylators NAT2 Dihydralazine Reactive metabolite CYP1A2-metabolite adducts Anti-CYP1A2 autoantibodies CYP1A2 Poor acetylators Uncommon hepatitis Bourdi, Mol Pharmacol 1994;45:1287

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Amoxicillin & Clavulanic Acid- Induced Hepatitis Hautekeete, Gastroenterology 1999;117:1181

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PREVENTION OF RECURRENCE

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Warn the patient and his/her doctors against using the drug again. Give the patient a list of all pharmaceutical specialties containing the drug, in order to avoid inadvertent rechallenge.

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CONCLUSION TWO GOLDEN RULES 1. Always consider the possibility of DIH 2. Immediately withdraw all suspected drugs in severe cases DIH: Difficult to avoid, predict and diagnose Avoid most mishaps

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THANK YOU.