Drug-Induced Liver InjurySoheil Altafi MD

1/27/15

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

Introduction• Caused by many common drugs • Antibiotics• OTC medications• Herbs• Supplements

• 0.1 to 3% of hospital admissions1

• ~600 liver transplantations per year in US

• 10% fatality seen in cases with severe ALT elevation and jaundice2

1. Dig Dis Sci 2007;52:2463-71 2. Kaplowitz N. Nat Rev Drug Discov 2005;4:489-499

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

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

Liver - Drug Metabolism

• Biotransformation• Phase 2- conjugation• (UDP)-glucuronyl transferases (UGT1, & UGT2)• Sulfotransferases• Glutathione S-transferases

• Decreases pharmacologic activity• Enhances clearance

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

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

Factors influencing Drug Metabolism

• Multi-drug effect• Age and sex• Dose

Factors influencing Drug Metabolism

• Disease-related changes- expression of CYP• DM• Hypothyroidism

• Underlying liver disease• Decreased P450• Decreased hepatic clearance

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

Mechanisms

Mechanisms

Mechanisms

Clinical Presentation

• Clinical Presentation• Hepatocelluar (cytotoxic) injury• Cholestatic injury• Mixed injury

• Mechanism of hepatotoxicity• Predictable• Idiosyncratic

• Histologic findings (liver biopsy usually not necessary)• Hepatitis• Cholestasis• Steatosis

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)

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

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

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

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

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 NAPQIhepatotoxicity

• CYP2E1 induced by fasting, alcohol, Rx (ie INH), • Treatment• Ipecac- if time of ingestion <4hrs• N-acetylcysteine (NAC)- increases level of glutathione

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- 500-3000mg qD• Immunoallergic injury: Class 1 & 2 HLA DQB1*0602, *1501• Cholestatic hepatitis within weeks of first dose

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 500-1000 IU/L• Mechanism- reactive metabolites (trifluoroacetyl), and autoanitgens• Poor prognosis- age>40, obesity, HE, elevated INR (mortality 80% without

OLT)

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

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

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 http://livertox.nih.gov/• Case presentations• Drug-specific liver injury characteristics• Direct link to references and other online recources• New cases of DILI welcome

Diagnosis

• Roussel Uclaf Causality Assessment Method (RUCAM)

Diagnosis• Drug-induced acute liver failure• Most frequent cause of liver failure requiring evaluation for transplantation• 11th 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

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

The End