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Drug-Induced Liver Injury Soheil Altafi MD 1/27/15.

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Presentation on theme: "Drug-Induced Liver Injury Soheil Altafi MD 1/27/15."— Presentation transcript:

1 Drug-Induced Liver Injury Soheil Altafi MD 1/27/15

2 DILI- Table of Contents Introduction Epidemiology Liver - Drug Metabolism Factors influencing Drug Metabolism Mechanisms of Drug-induced Hepatotoxicity Clinical Presentation Drugs that cause DILI Diagnosis Treatments

3 Introduction Caused by many common drugs Antibiotics OTC medications Herbs Supplements 0.1 to 3% of hospital admissions 1 ~600 liver transplantations per year in US 10% fatality seen in cases with severe ALT elevation and jaundice 2 1.Dig Dis Sci 2007;52: Kaplowitz N. Nat Rev Drug Discov 2005;4:

4 Epidemiology Annual incidence between 10 and 15 per 10,000 to 100,000 people 30% of cases of acute hepatitis 10% of consultation by hepatologists Most common cause of acute liver failure in the US

5 Liver - Drug Metabolism Biotransformation Phase 1- oxidation 60 genes code for CYP (family- ie CYP2, subfamily- ie CYP2E1) Hepatic metabolism of exogenous drugs- CYP1, 2, 3, and lesser extent 4 CYP3A4- 60% of all hepatic cytochromes, affecting 50% of commonly used drugs Enzyme activity dependent on several exogenous factors

6 Liver - Drug Metabolism Biotransformation Phase 2- conjugation (UDP)-glucuronyl transferases (UGT1, & UGT2) Sulfotransferases Glutathione S-transferases Decreases pharmacologic activity Enhances clearance

7 Liver - Drug Metabolism Biotransformation Phase 3 – transport ABC superfamily MDR1/ABCB1 MRP2/ABCC2 MDR3/ABCB4 BSEP/ABCB11 Altered activity of these transporters can lead to hepatotoxicity

8 Factors influencing Drug Metabolism Pharmacogenetics Polymorphisms of phase 1, 2, 3 enzymes Ie CYP2C9/2C19- warfarin, omeprazole, tolbutamide/mephenytoin Ie glutathione S-transferase- acetaminophen HLA- flucloxacillin, augmentin Nutrition Ie CYP2E1 Fasting/malnutrition Obesity Grapefruit

9 Factors influencing Drug Metabolism Multi-drug effect Age and sex Dose

10 Factors influencing Drug Metabolism Disease-related changes- expression of CYP DM Hypothyroidism Underlying liver disease Decreased P450 Decreased hepatic clearance

11 Mechanism of DILI Proposed mechanisms Intrinsic injury (direct or indirect injury to hepatocyte) Drug transporter/metabolizing enzyme modulation Mitochondrial toxicity Bile Salt Export Pump (BSEP) inhibition Modulation of immune reactions (idiosyncratic injury) Histone acetylation

12 Mechanisms



15 Clinical Presentation Hepatocelluar (cytotoxic) injury Cholestatic injury Mixed injury Mechanism of hepatotoxicity Predictable Idiosyncratic Histologic findings (liver biopsy usually not necessary) Hepatitis Cholestasis Steatosis

16 Clinical Presentation Predictable- intrinsic hepatotoxins Predictably cause dose-dependent hepatocellular necrosis Latent period- brief (hours to a few days) Fairly consistent from person to person and among animal models Serum aminotransferases 8 to 500 times normal; ALP less elevated Often removed from clinical use Some still in use due to known dose-related toxicity Hepatotoxic in large doses (ie acetaminophen, iron sulfate) Known dose-effect (ie ethanol, IV tetracycline, L-asparaginase)

17 Clinical Presentation Idiosyncratic Unpredictable Species-specific, often cannot be reproduced in animal models Latent period- variable, generally 1 to 3 months Doses >50mg/day more likely to cause DILI compared to dosing <10mg

18 Clinical Presentation Hepatocellular ALT/ALP ratio >5 ~50% of DILI is hepatocellular AST>>ALT- think muscle injury or alcoholic hepatitis Neither above 400 Cholestatic ALP> 2x ULN ALT/ALP ratio < 2 Mixed 5> ALT/ALP ratio > 2 Hy’s law- serum bilirubin >2x ULN, aminotransferases >3x ULN Associated with worse prognosis Mortality as high as 14 percent


20 Clinical Presentation Acute DILI Mild asymptomatic liver test abnormalities Cholestasis with pruritis Acute illness with jaundice- resembles viral hepatitis Acute liver failure Chronic DILI- may resemble AIH PBC Sclerosing cholangitis Alcoholic liver disease

21 Clinical Presentation Symptoms Acute DILI Malaise Low-grade fever Anorexia Nausea and Vomiting RUQ pain Jaundice Acholic stools Dark uine Chronic Dili may present with signs of cirrhosis or decompensation Jaundice Palmer erythema Ascites HE

22 Acetaminophen Hepatotoxicity Normally metabolized by glucuronidation and sulfation N-hydroxylation (CYP2E1)  N-acetyl-p-benzoquinone (NAPQI) NAPQI scavenged by glutathione Overdose usually >7-10gm (in nonalcoholic patients) Glutathione depleted  increased NAPQI  hepatotoxicity CYP2E1 induced by fasting, alcohol, Rx (ie INH), Treatment Ipecac- if time of ingestion <4hrs N-acetylcysteine (NAC)- increases level of glutathione

23 Drugs that cause DILI Isoniazid (INH) – 300mg qD Mechanisms Reactive metabolites Immunoallergic injury: HLA DQB1*0201 Mitochondrial injury Inhibiting histone deacetylase Presents insidiously 4-6 months after Rifampin increases likelihood of INH tox INH can increase acetaminophen tox Hx of liver disease- serial monitoring (alternate drug if level >100) Amoxicillin:clavulanate mg qD Immunoallergic injury: Class 1 & 2 HLA DQB1*0602, *1501 Cholestatic hepatitis within weeks of first dose

24 Drugs that cause DILI Nitrofurantoin Liver injury usually seen in women taking for >6 months Labs- high transaminases; HLA-B8 and ANA are usually positive Steroids (anabolic, OCP, tamoxifen, glucocorticoids) Cholestatic injury Canalicular injury Anesthetic Agents (ie Halothane) Risk increases with more exposure and present within 2 weeks Labs- eosinophilia, AST/ALT IU/L Mechanism- reactive metabolites (trifluoroacetyl), and autoanitgens Poor 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 DILI 42% in US use some form of alternative therapy 69% do not disclose supplement use to health care providers 52% use herbal/sup concurrently with prescription meds Common- 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 injur Cholestasis- imaging to rule out biliary obstruction Review of drugs exposed preceding the onset of liver injury Underlying liver disease is excluded- rule out other causes Stopping drug believed to cause injury leads to improvement Rechallenge- rapid and severe recurrence; not advised

30 Diagnosis Drug exposure Stop drugs that are commonly known to cause DILI Always ask about any OTC, herbal and/or supplements taken If possible review a patient’s pharmacy records Check drugs on Case presentations Drug-specific liver injury characteristics Direct link to references and other online recources New cases of DILI welcome

31 Diagnosis Roussel Uclaf Causality Assessment Method (RUCAM)

32 Diagnosis Drug-induced acute liver failure Most frequent cause of liver failure requiring evaluation for transplantation 11 th Annual FDA/PhRMA/AASLD Hepatotoxicity Conference Acute Liver Failure Study Group ~1700 cases Acetaminophen-induced 46% (n=787) Other drug-induced liver failure 12% (n=202) Acetaminophen-induced- half unintentional narc/aceta overdose Coagulopathy (INR>1.5) Encephalopathy- day/night confusion, disorientation, sleepiness

33 Treatment of DILI Discontinue suspected drug- most cases, liver injury should spontaneously resolve N-Acetylcysteine for acetaminophen liver injury Liver transplantation Limited use or experimental IV carnitine for valproate liver injury Ursodeoxycholic acid for cholestasis Corticosteroids for hypersensitivity cases Plasmapheresis

34 The End

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