Drug-induced Liver Disease

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Thank you Andi! I will certainly read this information.

Tom

[ ] Drug-induced Liver Disease

Drug-induced Liver Disease

Mark Swain, MDAssociate Professor of MedicineHepatologistUniversity of Calgary Key Learning Objectives At the end of the session the participants will be able to: · understand the clinical differences in the toxic effects of drugs on the liver· have a reasonable approach to the patient with presumed drug-induced liver disease· understand potential hepatotoxic effects of herbal preparations Abstract Overview of Drug Induced Liver Injury · Types of Drug Reactions· Approach to the Patient· Natural History· Herbal Preparations Types of Drug Reactions Classically drug reactions are classified as hepatocellular, cholestatic, or mixed. Toxicity may target hepatocytes (necrosis), bile ducts or canaliculi (cholestasis) or sinusoidal cells (endothelium, Ito cells). However, a more practical way of categorizing drug reactions is according to the type of reaction observed. a. Direct Toxic Reactions (e.g., acetaminophen, mushrooms, CCI4) · normally acetaminophen undergoes sulfation and glucuronidation for elimination. However, when capacity is exceeded conversion to toxic metabolite which binds to cell components.-- centrilobular necrosis· beware: alcoholic with P450 induction plus glutathione depletion leading to enhanced sensitivity to acetaminophen b. Idiosyncratic Reactions (e.g., INH, PTU, diclofenac) · majority of drug reactions are idiosyncratic or unpredictable· with INH 20% of patients have abnormal LFT's, but 1% have severe hepatic necrosis requiring drug withdrawal· histologically looks like viral hepatitis· toxicity worsened in alcoholics, use of additional medications (e.g., rifampin), elderly, genetic differences (rapid and slow acetylators) c. Combined Toxic/Allergic Reactions (e.g., halothane, isoflurane) · severe halothane hepatitis usually develops after multiple exposures· delay before exposure and hepatotoxicity· liver biopsy: similar to viral hepatitis· protein adducts formed in initial toxic reaction provide the hapten for the formation of antibodies which augments damage on re-exposure d. Allergic Hepatitis (e.g., phenytoin, sulfonamides, augmentin) · systemic allergic reaction characterized by fever, rash, lymphadenopathy, eosinophilia· liver biopsy: hepatocyte necrosis plus cholestasis and eosinophils or granulomas· typically slow resolution clinically e. Cholestatic Reactions (e.g., estradiol, chlorpromazine, erythromycin, captopril, sulfonamides) · main effect on bile flow· jaundice appears early +/- pruritus· liver biopsy: engorgement of canaliculi with bile and minimal hepatocyte necrosis +/- eosinophils f. Granulomatous Reactions (e.g., diltiazem, quinidine, phenytoin, procainamide, allopurinol, carbamazepine) · low grade fever and chronic fatigue and rarely jaundice· liver biopsy: noncaseating granulomas g. Chronic Hepatitis (e.g., methyldopa, nitrofurantoin, INH, trazodone) · indolent, resembles autoimmune hepatitis· increased globulins and ANA positivity may be present· can progress to cirrhosis h. Fatty Liver/NASH (e.g., amiodarone, valproic acid) · typically moderate elevation of ALT/AST· liver biopsy NASH· can progress to cirrhosis in months i. Indolent Cirrhosis (e.g., methotrexate, vitamin A, methyldopa) · toxicity may develop over years without any symptoms or evidence of hepatitis· liver biopsy showing indolent cirrhosis j. Veno-Occlusive Disease (e.g., cyclophosphamide, imuran, Jamaican "Bush Tea") · rapidly progressive occlusive disease of small hepatic venules due to endothelial-cell injury· clinically painful hepatomegaly, jaundice and ascites Approach to the Patient With Drug-induced Liver Disease International Consensus Criteria for Drug-induced Hepatotoxicity4 i. time of drug intake to apparent onset of reaction is "suggestive" (5 to 90 days) or "compatible" (< 5 days or > 90 days from initial drug intake)ii. course of reaction after cessation of drug "very suggestive" (decreased liver enzymes by 50% of excess above ULN within 8 days) or "suggestive" (decrease in liver enzymes by 50% within 30 days for hepatocellular and 180 days for cholestatic)iii. alternative cause of reaction excluded by detailed investigations, including liver biopsyiv. positive response to rechallenge (at least doubling of liver enzymes) when available -- reaction is "drug related" if all of first 3 criteria met, or if 2 of first 3 criteria met with positive re-challenge test. · always make a careful time-line of all drugs ingested and be very suspicious of any potentially hepatotoxic drug begun during the 3 months before the onset of illness· main treatment is drug withdrawal and close observation· acute liver failure due to idiosyncratic drug reactions has poor prognosis· glucocorticoids may by tried in hypersensitivity reactions· give antidote if available (e.g., NAC for acetaminophen - even if ingestion > 36 hours before) Natural History of Drug Induced Liver Disease · in general, drug-induced liver disease is reversible upon drug withdrawal· however, recent study challenges this:3-- 30% from antibiotics, 25% from NSAIDS-- mean follow-up 5 yrs.-- 24% persistent abnormal LFT's. Additional 15% abnormal radioisotope or U/S scans with normal LFT's-- of patients with abnormal LFT's, 60% underwent repeat liver biopsies and 60% showed significant residual pathology including chronic hepatitis, fibrosis and ductopenia-- predictors or presentation associated with persistence or development of chronic liver disease were fibrosis on initial liver biopsy and continued use of offending drug > 6 months after initial biopsy Herbal Induced Liver Disease · growing use of these preparations amongst patients (~ 60% of patients attending GI clinics at University of Calgary)· controlled as food additives, not drugs· often mixtures and can be adulterated by cheaper, more toxic herbs, heavy metals, and Western medicines (acetaminophen, aspirin, steroids) Herbs Known to Cause Hepatotoxicity a. Pyrrolizidine Alkaloids · used for arthritis, gout, infections· brush tea and Comfrey most implicated· cause VOD, clinically manifests as abdominal pain, jaundice and elevated transaminases ± hepatomegaly and ascites· can present as chronic, insidious cirrhosis· usually responds to withdrawal of drug b. Germander · blossoms of germander used for years to treat fever, abdominal complaints, obesity· development of non-specific hepatitis with a benign course manifesting as anorexia, nausea, abdominal pain and jaundice associated with increased ALT/AST· liver biopsy centrilobular necrosis· usually recovery within 2 to 6 months, but FHF and insidious cirrhosis have been described c. Chaparral

· indigenous to southwestern USA· used to treat diarrhea, cramps, chest pain, rheumatism, venereal disease, chronic skin disorders and as a liver tonic· present with acute hepatitis ... nausea, RUQ pain, jaundice, anorexia· marked increase of ALT/AST can be seen· FHF and prolonged cholestasis have been described but usually reversible d. Chinese Herbals i. Jin Bu Huan: used for over 1,000 years as sedative and analgesic· present with acute hepatitis with fever, N/V, fatigue, pruritus, abdominal pain, hepatomegaly, jaundice· ­ ALT/AST· resolves typically over ~ 2 months ii. Ma-Huang: used for centuries for weight loss (active ingredient ephedrine)· present as with Jin Bu Huan· resolves typically over ~ 4 months e. Other · less well characterized valerian, skullcap, mistletoe

Source: http://www.hepnet.com

submitted by: Andi/Liversupport-L

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First principles of Gastroenterology

Chapter 14

Section 7

" Drug-induced Liver Disease " :

http://gastroresource.com/GITextbook/En/Chapter14/14-7.htm

Methotrexate-induced fibrosis/cirrhosis is mentioned.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org