Transcript Drug-Induced Liver Injury

Drug-Induced Liver Injury
Soheil 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
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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
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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
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Mild asymptomatic liver test abnormalities
Cholestasis with pruritis
Acute illness with jaundice- resembles viral hepatitis
Acute liver failure
• Chronic DILI- may resemble
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AIH
PBC
Sclerosing cholangitis
Alcoholic liver disease
Clinical Presentation
• Symptoms
• Acute DILI
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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 NAPQIhepatotoxicity
• 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
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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)
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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
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IV carnitine for valproate liver injury
Ursodeoxycholic acid for cholestasis
Corticosteroids for hypersensitivity cases
Plasmapheresis
The End