This is your liver. Overview. Functions of the Liver 3/9/2015. This is your liver on Drugs. Drugs and the Liver Drug Induced Liver Injury (DILI)

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1 This is your liver Drugs and the Liver Drug Induced Liver Injury (DILI) Rebecca Duke DNP, MSN, APN-CNP AACN Spring 2015 Transplant Surgery Nurse Practitioner This is your liver on Drugs Overview Over 1000 medications and herbal products have been implicated in DILI 30% of cases of acute hepatitis Cause of jaundice in 50% of patients with new onset jaundice Most common reason for withdrawal of medications The metabolites of compounds are usually the causative factors of DILI Functions of the Liver Liver injury may be produced by a large variety of chemical substances Secretory 1) Bile acid from cholesterol 2)Conjugation of bili Excretory Excretion of exogenous dyes/substa nces Metabolic 1) CHO 2) Lipid 3) Ammonia acid 4) Cholesterol synthesis 5) Mineral 6) Ammonia formation 7) Vitamin 8) Nucleic acid 9) Interconversion of sugars Synthetic Synthesis of 1) Albumin 2) Alpha 1 Gamma globulins 3) Clotting factors 4) Binding proteins 5) Transport Proteins 6) Hormones 7) Cholesterol Detoxification of 1) Xenobiotics 2) Steroids 3) Thyroid hormone 4)Endogenous metabolit es Storage 1) Glycogen 2) B12 3) Vitamin A 4) Copper 5) Iron The type and degree of injury produced is extremely varied, and may mimic the entire spectrum of hepatobiliary disorders The central role played by the liver in the clearance and biotrasnformation of chemicals make the liver susceptible to drug-induced injury. Drugs can initiate progressive chronic liver disease and are the single leading cause of acute liver failure. 1

2 Overview Definitions Type of injury Prescription medications Over the counter Complementary Alternative Medicine (CAM) Illicits Drugs and Disease Drugs in the cirrhotic liver Classification of DILI (drug induced liver injury) Clinical presentation Hepatocellular (cytotoxic) injury Cholestatic injury Mixed injury Mechanisms of hepatotoxicity Intrinsic/Predictable - Tylenol Idiosyncratic only if genetic variable are right Histologic findings Hepatitis Cholestasis Steatosis Hepatocellular Injury AST/ALT elevated Little to no elevation of Alk Phos Ratio helpful ETOH AST:ALT 2:1 Viral hepatitis AST:ALT <1 Common Causes NAFLD/NASH DILI ETOH Hemochromatosis Viral Hepatitis Extrahepatic conditions Cholestatic Injury Lab abnormalities: Alkaline phosphatase, GGT, Total bilirubin elevated Common etiologies Biliary diseases PBC, PSC DILI ETOH hepatitis Hormonal effects on bile flow during pregnancy (cholestasis of pregnancy) Cancer HBV or HCV Cirrhosis (not as common until significant severity) Bile stone/stricture Pancreatic cancer Pharmacology and the Liver Cytochrome P450 system Most drugs are metabolized in the liver Cytochrome P450 system Drug induced pattern Cholestatic, hepatocellular Can cause steatosis Major enzymes involved in drug and bio-activation Inducers and inhibitors Inducers- induces the enzyme Less drug in system Inhibitors inhibits the enzyme More drug in system 2

3 Variables in People for Idiosyncratic DILI Host Factors Environmental Factors Drug-Related Factors Age Smoking Daily Dose Gender Alcohol consumption Metabolic profile Pregnancy Malnutrition Obesity Diabetes Mellitus Co-morbidities including underlying liver disease Indications for therapy Genetics Renal Function Infection and inflammatory episodes Class effect and cross sensitization Drug interactions and polypharmacy Duration of therapy Evaluation of Suspected Idiosyncratic Drug Reactions Hepatitis A, B, C >2 or <5 (mixed) Viral Hepatitis, Autoimmune hepatitis, imaging Abnormal LFTs Thorough H&P Calculate R value >/=5 Hepatocellular Viral Hepatitis, autoimmune hepatitis, imaging </=2 (Cholestatic) Imaging Studies Autoimmune markers: ANA, AMA, SMA Detective Work.Let s put on the hat History is critical Medication history back 2-3 months How long as lab abnormality been noted? How long as jaundice been present Any dark urine? Have they ever been on this medication before? Have they ever had a drug reaction/sensitivity previously? Drugs in same class?? Over the Counters (OTC s) Over the Counter Drugs NSAIDs Acetaminophen Iron supplements Vitamins NSAIDs Those with cirrhosis or advanced liver disease should avoid this class of drugs Hepatitis can occur with variable rates among NSAIDs Diclofenac more common Hepatitis usually resolves after stopping the drug Rare reports of liver failure and chronic liver disease Hepatorenal syndrome Type 1 or type 2 cause renal dysfunction and even renal failure Most common in those with significant hepatic dysfunction/decompensation Block prostaglandins which help with vasodilation Can cause renal problems 3

4 Acetaminophen Okay in liver disease Preferred over NSAIDs No > than 1000 mg/dose No > than 3000 mg/day (FDA says 4000) Conservative dosing recommended no > 2000 mg/day > 3 alcoholic beverages no more than 2000 mg/day Acetaminophen Injury can occur with single dose of 7-10 grams More likely with ingested dosages > 150 mg/kg Children are lower Most recover with supportive measures Need for transplantation Rising INR poor prognostic factor 5% children Therapeutic misadventure More common in elderly, polypharmacy or with OTC combination therapies (cold/uri medication) Iron Supplements Vitamins Hemochromatosis Increased risk for HCC Secondary disease may become exacerbated Those with cirrhosis Overload can cause progression No supplementation unless has IDA Be careful of vitamins with extra iron, prenatal vitamins Vitamin A high doses can be toxic to the liver mild and reversible elevated LFT s Rare liver failure Pre-existing and alcohol = worse Improve with d/c If vitamin deficient Replete and repeat Background In % of U.S. adults reported using natural products Complementary and Alternative Medications (CAM).Herbals etc. Dietary Supplement Health and Education Act (DSHEA) and Final Rule for Dietary Supplement Current Good Manufacturing Practices Does not focus on safety of the ingredients Contains no minimum requirements for quality No responsibility for safety surveillance or reporting to manufacturer 4

5 CAM therapy Reports of acute hepatitis, veno-occlusive disease, fulminant hepatic failure, cirrhosis Interactions more common Not well studied (Traditional FDA trials) Valerian Complementary Alternative Medicine (CAM) Therapies..Not exhaustive in this lecture Black Cohosh Milk Thistle or silymarin Kava Glycyrrhizin (licorice root extract) Diet drugs Hydroxycut, herbalife, Ma Huang liver cleanse Valerian Perennial plant native to Europe Used to treat anxiety, insomnia and nervous restlessness Increases GABA in the brain?? Study found to be no more effective than placebo (14 days) Other studies showed that it can reduce time to fall asleep and improves quality of sleep May effect of drugs in the liver cause toxic levels Statins, antifungal drugs Increase effects of anticonvulsants, barbituates, benzdiazepines, insomnia meds, TCA s and alcohol May effect anesthesia Slows down CNS Black Cohosh Derived from a plant native to N. America Used to treat menopausal symptoms, joint pain, myalgia, bronchitis and obesity Hepatotocixity ranges from autoimmunelike hepatitis to ALF Milk Thistle/Silymarin Anti-oxidant and free-radical scavenger Most commonly utilized for patients in liver disease Thought to have anti-fibrotic activity No side effects Evidence variable Not likely to improve ALT levels JAMA, 2012 Stickel F, Schuppan D. Herbal Medicine in the treatment of liver diseases. Digestive and Liver Disease. 39 (2007)

6 Kava Glycyrrhizin (licorice root extract) Kava root psychotropic remedy in Hawaii, polynesia and the Fiji islands Europe and elsewhere Anxiety disorders Hepatic necrosis or cholestatic hepatitis Can develop fulminant liver failure necessitating liver tx Patients ingesting greater than 250 mg a day of kavalactones are at increased risk Prevents liver injury in animals Anti-oxidant activity Blunts ALT elevations and impedes fibrosis in animals Reported to be beneficial in viral hepatitis Can improve AST/ALT in NAFLD/NASH Single study Comprehensive studies needed Hajiaghamohammadi, A. A., Ziaee, A. and Samimi, R. (2012), The Efficacy of Licorice Root Extract in Decreasing Transaminase Activities in Nonalcoholic Fatty Liver Disease: A Randomized Controlled Clinical Trial. Phytother. Res., 26: doi: /ptr.3728 Diet Drugs Herbalife & Hydroxycut Several case reports of acute liver injury Exact mechanism unknown Necrosis and cholestasis on biopsy Idiosyncratic reaction possible Allergic reaction? Contamination? Hydroxycut 3/8 patients required transplantation No studies done Does not require FDA approval Only case studies Ma Huang ephedra - banned Stickel F, Schuppan D. Herbal Medicine in the treatment of liver diseases. Digestive and Liver Disease. 39 (2007) Chen GC, Ramanathan VS, Law D, Funchain P, Chen GC, French S, Shlopov B, Eysselein V, Reicher S, Pham BV. World J Hepatol November 27; 2(11) ; Am J Gastroenterol 2010;105: ; doi: /ajg ; published online 26 January 2010 Green Tea Extract Dandelion Natural diuretic Stimulates bile flow No evidence for improvement in the liver Used in combo products No proven studies 6

7 Liver Cleanse/Combo CAM Usually combination medications Usually milk thistle Dandelion Other extracts such as artichoke, tumeric etc. Prescription Medications Antibiotics Most reactions are idiosyncratic Tetracyclines and oxypenicillins Usually dose related Erythromycin induced injury usually improves after d/c Sulfamethoxazole Trimethoprim Ampicillin, amoxicillin and Augmentin (amox/clav) Cholestatic and mixed hepatocellular injury Onset of jaundice may be delayed reaction (can happen months after cessation) (Amox/Clav) More Antibiotics Sulfonamides Cholestasis Less common granulomatous hepatitis Hepatocellular necrosis fatal cases Nitrofurantoin Acute and chronic hepatic injury May be immunoallergic or metabolic Fluoroquinolones Macrolides Minocycline Antifungals More common in immunocompromised or on multiple meds Nitrofurantoin Hepatitis Fatigue Fever Muscle and joint aches Poor appetite Nausea/vomiting Weight loss Jaundice Methotrexate At risk populations: Obese Pre-existing liver disease Alcohol Use lower doses Monitor LFT s closely May need to biopsy prior to start of therapy Biopsy may be warranted if half of the monitored LFT s are elevated in one year period Surveillance biopsy after on therapy for a few years 7

8 Tuberculosis Medications Isoniazid % - symptomatic 10-20% elevation of transaminases Histopathology resembles viral hepatitis Resolves 1-4 weeks after d/c Worse with alcohol or concomitant use of acetaminophen or rifampin Rifampin P450 system 1.1% rate of liver toxicity Worse with HCV, HBV, alcoholism Cholestasis, jaundice Tbili up to 30 or more Resolves after d/c Cholestatic injury can take weeks or longer to recover/resolve Statins 0.5-3% have elevated LFT s Can be utilized in those with liver disease CV disease will kill many patients before a mild elevation in their enzymes does anything Monitor LFT s Prior to start of Rx 2-3 months Every 6 months Niacin Anti-Convulsants Can cause mild transaminitis, jaundice and in rare cases liver failure Liver toxicity is dose dependent Toxic doses usually exceed 2 grams per day Worse in those with pre-existing liver disease and alcohol Phenytoin hepatocellular damage rare CYP450 inducer Carbamazepine/Oxcarbazepine liver failure can occur despite d/c Lamotrigine liver failure has been reported in both peds and adults Phenobarbital Valproic acid 20% of patients have elevated LFT s Liver failure more common in children Amiodarone Hydralazine Liver injury ranging from mild transaminase elevations to acute liver failure and cirrhosis Abnormalities usually resolve weeksmonths after stopping meds Significant damage can occur < 1% of patients Used to treat HTN Hepatotoxicity Hypersensitivity-type injury Mixed hepatocellular injury Acute hepatitis Cholestatic jaundice Centrilobular necrosis Reversible after d/c the med 8

9 Illicit Drugs Amphetamines Ecstasy can cause liver failure in severe cases Cocaine ischemic necrosis of the liver Drugs and the Cirrhotic Liver Liver dysfunction causes alterations in clearance May need to adjust dosage Start slow Statins lower doses and monitor LFT s Check enzymes more frequently Anabolic Steroids Not illicit to utilized without indication TPN Drugs and Fatty Liver Disease Methotrexate Tamoxifen Steroids Valprate Amiodarone Questions? Thank you! rduke@nm.org HAART therapy 9