Medications LIver.docx

AST & ALT (aminotransferases) Markers of hepatocellular injury Participate in gluconeogenesis by transferring amino groups ALT: liver specific (cuz it has an “L” for liver) AST: not as liver specific; found in a lot of other cells ALT: 17–63 IU/L AST: 15–37 IU/L ALP (Alkaline Phosphatase) Marker...

AST & ALT (aminotransferases) Markers of hepatocellular injury Participate in gluconeogenesis by transferring amino groups ALT: liver specific (cuz it has an “L” for liver) AST: not as liver specific; found in a lot of other cells ALT: 17–63 IU/L AST: 15–37 IU/L ALP (Alkaline Phosphatase) Marker of of cholestasis (reduction or stoppage of bile flow) Elevated when metabolism is functionally disturbed (e.g. obstructed liver) Damaged liver regurgitates hepatic ALP into serum Can also indicate physiological processes (e.g. growing placenta & growing bone) 50–136 IU/L GGT  (Glycoprotein gamma- glutamyltransferase) Marker of cholestasis Present in many tissues (e.g. liver, kidneys, pancreas, brain, heart) Isolated elevated GGT can indicate alcohol abuse / liver disease XX: 5.0–55.0 IU/L XY: 15.0–85.0 IU/L Bilirubin Urine bilirubin directly reflects hyperbilirubinemia & underlying hepatobiliary disease Reflects balance b/w production & clearance Elevated total serum bilirubin is not a precise indicator but can be due to: Bilirubin overproduction Impaired uptake, conjugation or excretion Backward leakage from damaged hepatocytes or bile ducts Total: 3–17 µmol/L What are some common DILIs? Agent Presentation & Tx Risk Factors Acetaminophen  From suicide attempts or therapeutic misadventures Very common ER presentation Severe transaminitis (ALT > 1,000) Fatal cases involve doses of > 15g (40 pills) 2-6g can be fatal in chronic alcohol users, though ingesting alcohol at the same time can be protective Tx: oral or IV N-acetylcysteine until INR < 1.5 Chronic excessive alcohol ingestion Fasting Concomitant medications (CYP 2E1 or 3A4 promoters) Late presentation Underlying liver disease? Anabolic Steroids Cholestasis w/o hepatitis:  Normal transaminases, ALP, GGT Jaundice, bilirubin levels > 20x ULN! Look well otherwise Tx: reassure bilirubin will normalize but very slowly (months) Common in men, unusual in women Amoxicillin- Clavulanate, Fluroro- quinolones Cholestasis w/ hepatitis:  High transaminases, ALP, GGT Jaundice, high bilirubin Usually looks well Symptom onset can occur several weeks after abx use Methotrexate Regularly monitor long-term methotrexate users w/ fibroscan  Increased risk > 60 years Higher dose = more risk Alcohol consumption Obesity, diabetes Use of NSAIDs, Vit A Immune Check Point Inhibitors Some cases require tx pause Most do not require steroids Still being studied Stimulate immune system, causing autoimmune diseases Doesn’t often affect liver Herbal Products What can cause drug-induced liver injury (DILI)? Too much medication (e.g. acetaminophen) or high risk medication Prescription meds, OTC, natural products, herbal medicine Alcohol use & malnutrition increase the risk What are intrinsic & idiosyncratic DILI? Intrinsic: everyone gets liver injury at a certain dose of drug (e.g. acetaminophen) Idiosyncratic: affects susceptible individuals; exposure & presentation are variable What is non-immune DILI?  Aberrant drug metabolism in susceptible individuals Mechanism: metabolites bind to proteins / lipids / enzymes / DNA, causing oxidative stress Can develop after weeks or months of exposure to drug Can also develop several weeks after drug is discontinued No hypersensitive reaction (e.g. fever, rash) May or may not recur after rechallenge (so weird!) Common culprits: amiodarone, diclofenac, isoniazid What is immune DILI? Reaction is hypersensitive: rash, fever, joint pain, eosinophilia, Stevens-Johnson & toxic epidermal necrolysis  Mechanism: haptenization (drug is covalently bound to proteins, which cause direct toxicity or trigger immune-mediate reactions) Occurs 1-8 weeks after exposure Often preceded by mononucleosis-like syndrome Will recur after rechallenge Common culprits: amoxicillin, diclofenac, phenytoin What is autoimmune DILI? Elevated IgG, ANA, ASMA w/ eosinophilia or granulomatous inflammation on liver biopsies Unlike immune DILI, there is no relapse after drug withdrawal (but don’t expose them to the same drug again!) Responds to corticosteroids Common culprits: minocycline, nitrofurantoin How do hepatocellular & cholestatic injuries present? Hepatocellular: ALT & AST >> ALP; common culprits = acetaminophen, isoniazid, macrolides Cholestatic: ALP >> ALT & AST; common culprits = amoxicillin, chlorpromazine Mixed: Combo of above; common culprits: anabolic steroids, amiodarone What is the R value? R value = (ALT / upper limit)   (ALP / upper limit) R > 5 = hepatocellular R < 2 = cholestatic When would we do a liver biopsy? If no significant improvement after several months Biopsies not that helpful for dx, since several drugs can have the same injury patterns How do we manage DILI? Stop offending drug Look for other causes of Hepatitis (serology and imaging) Supportive care for acute patients Antidotes if available (e.g. N-Acetylcysteine for acetaminophen) Re-challenge is not suggested (especially if severe) What liver disease can chronic alcohol use cause? Fatty liver, cirrhosis, liver cancer, acute hepatitis Acute hepatitis has 30% mortality in severe cases! How is ethanol metabolized by the liver? Alcohol dehydrogenase (ADH): primary enzyme at lower [ ]  CYP 2E1: primary enzyme at higher [ ]  Ethanol → (CYP 2E1) → acetaldehyde → (ADH) → acetate → CO2 + H2O How can alcohol cause injury? Acetaldehyde is toxic to cells Alcohol also causes oxidative stress, mitochondrial dysfunction, hypoxia in hepatocytes (esp. centrilobular area) What are Canadaès low-risk alcohol drinking guidelines? There is no safe dose Women: < 2 drinks / day, < 10 drinks / week,  Men: < 3 drinks / day, < 15 drinks / week How does acute alcohol-related hepatitis present? Hx of alcohol consumption (usually > 100 g / day) RUQ pain AST / ALT elevation (ratio 2:1 - 3:1) AST > 400: usually something else is going on, too Hyperbilirubinemia +/- cirrhosis Hepatic encephalopathy, coagulopathy Leukocytosis: could be secondary to infection; primary reactions associated w/ poor prognosis