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Drug-induced Liver Disease (DILD)

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Presentation on theme: "Drug-induced Liver Disease (DILD)"— Presentation transcript:

1 Drug-induced Liver Disease (DILD)
Yousif.A Qari Consultant Gastroenterologist KAUH

2 Incidence 10 fold increase in No. of reported cases between in Japan 10% of cases of hepatitis in a major hepatology center in France 20% of instances of jaundice among geriatric population in USA 9% of hospitalized patients with AST ≥ 400 IU/L in a survey in UK 25%-40% of fulminent hepatic failure

3 Drug-induced Liver Disease (DILD)
Predictable Dose related Intrinsically hepatotoxic drugs Acute (hours) Injury pattern is usually necrosis Clinically → Fulminant (Acute Hepatitis) Example: Acetaminophine Unpredictable Not dose related Rare % Weeks to months after ingestion of drug Idiosyncratic Immune mediated idiosyncrasy (Hypersensitivity) Rash Fever Arthragia Eosinophilia Example: Phenytoin, Sulfonamides, Valproate Metabolic idiosyncrasy (Production of toxic metabolites) Example: INH, Ketoconazole, and Diclofenac

4 Overview of Drug induced Liver Injury
Types of Drug Reactions Approach to the patient Natural History

5 Histological Classification
Hepatocellular › Hepatocytes Cholestatic › Bile ducts or canaliculi Mixed

6 Categorization according to type of reaction
Direct toxic reactions Idiosyncratic reactions Combined toxic/Allergic reactions Allergic hepatitis Cholestatic reactions Granulomatous reactions Chronic hepatitis and cirrhosis Fatty liver /NASH Veno-Occlusive disease Neoplastic

7 Diagnosis of (DILD) High index of suspicion
Abnormalities in hepatic associated enzymes Hepatitis like symptoms Jaundice Drug history Dose Duration of therapy Time between initiating therapy and the development of hepatic injury (latency) Exclusion of other causes of liver diseases Hepatitis B Hepatitis C Alcoholic liver diseases Non alcoholic fatty liver diseases Hemochromatosis 2%-5% of general population

8 Temporal relationship
Diagnosis of (DILD) Temporal relationship Most cases of acute DILD occurring within 1 week to months of exposure Positive response to discontinuing the agent (Dechallenge) In acute hepatocelluler injury 50% reduction in hepatic –associated enzymes after 2 weeks Return to normal by 4 weeks In cholestatic injury May have prolonged recovery time

9 Extrahepatic manifestations
Diagnosis of (DILD) Extrahepatic manifestations Hypersensitivity reactions Fever Rash Arthralgias Esinophelia Unique clinical syndromes

10 Risk Factors For Susceptibility to DILD
Methotrexate Alcohol Obesity D.M Chronic hepatitis INH HBV,HCV,HIV Older age Female Acetaminophen Alcohol Fasting INH Valproate Young age Anticonvulsants Diclofenac Female Osteoarthritis

11 Risk Factors For Susceptibility to DILD
Sulfonamide HIV Slow acetylator Genetic defect in defense Anticonvulsats Genetic defect in detoxification Rifampicin Slow acetylators INH Pyrazinamide

12 Clinical Presentations
Asymptomatic elevation in hepatic enzymes No progress despite Continued use of the Medication. (Drug tolerance) Progression to Hepatic injury with Continued use of the medication AST & ALT 3-5 times Upper limit of normal INH Phenytoin Chlopromazine May progress to Hepatic failure

13 Acute Hepatocelluler Injury (Direct toxic reaction)
Characterized by Marked elevation in ALT and AST Normal or minimally elevated alkaline phosphatase Bilirubin variably increased-----›worse prognosis. Comprise 1/3 of all cases of fulminant hepatic failure in the US. 20% due to Acetominophen 12%-15% due to other drugs

14 Acute Hepatocelluler Injury (Direct toxic reaction)
Alcohol AST is always 2-3 times higher than ALT AST remains less than 300 IU. ALT is almost always less than 100 IU. Towering elevation of ALT&AST( IU) Drugs (acetaminophen) Differential: Chemical toxins Toxic Mushrooms Shock liver Unusual with other causes of liver diseases including Viral Hepatitis.

15 Acute Hepatocelluler Injury (Direct toxic reaction)
Examples Anesthetics Halothane Isoflurane Antimicrobials INH Rifampin Ketoconazole Sulfonamides Anticonvulsants Phenytoin Valproic acid Carbamazipine NSAIDS & analgesics Acetaminophen Piroxicam,Diclofenac Sulindac Miscellaneous Labetalol Nicotinic acid Propylthiouracil

16 Cholestatic Injury Definition: Reduction in bile flow due to
Reduced secretion Obstruction Biochemically: Elevated Alk phosphatase Elevated GGT Elevated 5 NT Acute illness that subsides when the offending drug is withdrawn.

17 Clinical presentation
Cholestatic Injury Clinical presentation Jaundice Pruritis

18 Types of cholestasis resulting from drugs
Canaliculer (Bland Jaundice) Hepato-canaliculer (Cholestatic Jaundice) Ductuler (Cholan-gioler) Cholangio-destructive (Vanishing bile duct synd Cholagio-sclerotic (Sclerosing cholangitis) Bile casts + +++ Portal inflammation - Hepatocellul-er necrosis +/- Ductal lesion Cholangitis Bilirubin +to+++ Alk Phos <3X >3X Cholesterol ++ AST/ALT <5X 2-10X Examples Contraceptive Anabolic steroides Chlorpromazine Augmentin Erythromycin Benoxap-rofen Paraquat Clorpromazine Fluxuridine Scoliocides

19 Drugs causing chronic cholestasis and the vanishing bile duct syndrome
Antibiotics Ampicillin Augmentin Clindamycin Erythromycin Organic arsenicals Septrin Tetracycline Thiabebdazole Troleandomycin Psychotropic Amitriptyline Barbiturates Carbamazipine Chlorpromazine Haloperidol Imipramide phenothiazines Miscellaneous Aprindine Azathioprine Carbutamide Ciproheptadine Chlorthiazide cyamemazine Ibuprphen Cimetidine Prochlorperazine Terbinafine Terfenadine Tolbutamide Ticlodipine Xenalamine Ethenyl estradiol

20 Comparison between PBC with DICC
Gender women both Age Middle-aged All ages AMA Positive Negative Onset Insiduous Acute Jaundice Late feature Acute feature Pruritis + Hypercholestremia Steatorrhea Xanthomas +(transient) VBDS Portal infiltrates +++ Granulomas - Prognosis Often progresses to billiary cirrhosis Jaundice usually resolves after 6-76 m;rarely progresses to billiary cirrhosis PBC : Primary billiary cirrhosis DICC :Drug induced chronic cholestasis

21 Granulamatous Hepatitis
A form of hepatic injury characterized by : Fever Diaphoresis Malaise Anorexia Jaundice Rt upper quadrant discomfort Granuloma on liver biopsy Illness usually occurs within the first 2 months of therapy Examples: Quinidine Carbamazipine Allopurinol Hydralazine Phenytoin Gold Mineral oil ingestion Phenylbutazone

22 Drug induced chronic hepatitis
Can resemble chronic active hepatitis including cirrhosis as well as a form of chronic autoimmune hepatitis Characteristics of drug- induced autoimmune hepatitis Duration of drug intake ≥ 2-24 months Female predominance > 80% Onset Insidious, gradual Clinical Fatigue, anorexia, wt loss, jaundice, ascites, hepatosplenomegaly, and portal hypertension Biochemical AST, ALT= × ULN Increased gamma globulin level Serology AICH 1 AICH 2 ANA, ASMA, LE factor Anti-P4501A2, AntiP4502C9 Histology Very active necro-inflammatory lesion Prominent plasma cells Usual course Resolution on withdrawal of drug

23 Drugs leading to a syndrome resembling type I autoimmune chronic hepatitis
Multiple cases Drugs Serologic Factors Clometacin ASMA, Anti-DNA Methyldopa ANA(16%), ASMA(35%) Minocycline ANA, Anti-DNA Nitrofurantoin ANA(80%), ASMA(72%) Oxyphenisatin ANA(67%), ASMA(67%), LE(33%) Few cases Benzarone ASMA Diclofenac ANA Fenofibrate Papverine ANA, ASMA Pemoline ANA, Automicrosomal antibody Propylthiouracil Captopril ANA, Antilaminin Flucloxacillin AMA,(Anti-M2) Procainamide ANA, LE factor(50-70%)

24 Vascular injury May involve all of the vascular components of the liver, including the sinusoids, hepatic veins, and hepatic arteries. Veno-occlusive disease (VOD): May be caused by: Toxic plant alkaloids (certain herbal tea) A serious complication complication of bone marrow transplant Azathioprine is probably the calprit Clinically presents as Mild vral-like illness →→ Fulminent hepatic failure Rapid weight gain Ascites Jaundice Evidance of portal hypertension Chronic form of VOD may also exist.

25 Neoplastic lesions Neoplastic lesions Clinical findings Examples
Focal noduler hyperplasia Hepatic mass Contraceptive steroids Adenoma Hemoperitoneum Anabolic steroids Danazole Hepatocelluler carcinoma Malignant mass Venyl chloride Thorium dioxide (Thorotrast) Angiosarcoma Inorganic arsenicals Thorium dioxide(Thorotrast)

26 Natural History and Prognosis
When recognized promptly and the offending agent is discontinued most cases resolve without chronic sequalae Mortality principally depend on the degree of hepatocelluler injury. 10% mortality for agents causing fulminant hepatitis or toxic steatosis. Agents that cause cholestatic injury rarely , if ever , produce acute fatalities The prognosis is worse whenever jaundice accompanies hepatocelluler injury.

27 THANK YOU

28

29 Hepatic injury resulting from individual agents

30 Anesthetics

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