drug induced liver injury

things the liver does

cleans the blood, metabolizes stuff, makes coag factors + transport proteins (albumin)

transaminases

AST + ALT

proteins w/ physiologic roles to transfer amine groups w/ during gluconeogenesis

high concentrations in the liver + some other tissues

may be elevated in event of hepatocyte death (transaminitis)

alkaline phosphatase

found in many different tissues including liver

excreted through biliary tree

serum alkaline phosphatase levels may elevate in cholestatic disease

elevated GCT increases the likelihood of ^^

hyperbilirubinemia

any bilirubin value above reference range (2 or higher!)

s/sx of hyperbilirubinemia

jaundice usually develops at >2 mg/dl

scleral ictuerus

pruritis

clay colored stool

what does increased AST/ALT mean

hepatocytes are getting injured

what does increased alkaline phosphatase mean

biliary tract is slowing down

what does increased bilirubin mean

pt may be in trouble → more broad hepatic problem!

causes of liver injury

non-alc fatty liver disease

alc associated hepatitis

viral hepatitis

ischemic hepatitis

autoimmune hepatitis

hepatotoxic meds / DILI

types of DILI

direct hepatotoxins, idiosyncratic rxns, other rxns

direct hepatotoxic DILI

caused by direct hepatotoxins → induces a dose dependent liver injury

can be induced by metabolism of parent drug or its toxic metabolites

occurs rapidly after med administration

what are important drugs that can cause direct hepatotoxic DILI

acetaminophen, methotrexate

idiosyncratic rxn DILI

not dose or duration dependent

variable presentation!, thought to occur through aberrant immune rxns

may occur months after med initiation!

medications that can cause idiosyncratic rxn DILI

abx (amox-clavulanate, cephalosporins, nitrofurantoin), CNS agents, many others!

causes of other DILI

indirect hepatotoxicity

aberrations in ca+ homeostasis

carcinogens

mitochondrial injury

alteration of liver transport protein

dx of DILI

need 2 things:

• other causes must be excluded!

• one of these lab profiles:

  • AST or ALT ≥ 5x ULN

  • alk phos ≥ 2x ULN

  • tbili ≥ 2.5 mg/dl AND either ALT/AST/ alk phos elevated

  • INR ≥ 1.5 AND either ALT/AST/alk phos elevated

sx of DILI

can be completely asymptomatic

s/sx of hepatitis : abd pain, nausea, acholic stool, jaundice

s/sx of cholestasis : jaundice, feeling “foggy”, pruritis (itchy)

acute liver failure, coagulopathy, encephalopathy

labs for DILI presentation

hep A/B/C negative

anti-mitochondrial antibody ≤ 1:5

ceruloplasmin w/in normal range

antinuclear antibody ≤ 1:40

anti-smooth muscle antibody ≤ 1:40

which 2 labs values are different if they have drug-induced autoimmune hepatitis

should be low but if they take drug that causes this, then it can be higher!

antinuclear antibody ≤ 1:40

anti-smooth muscle antibody ≤ 1:40

what questions should be asked when assessing DILI

any new meds in the last 6 months

any new herbals/supplements in last 6 months

when did you start and when did you stop taking

what dose and what frequency

r factor calculations and values

drugs that cause cholestatic DILI

erythromycin, oral contraceptives, amox-clavulanate, enalapril

drugs that cause hepatocellular DILI

acetaminophen, isoniazid, nitrofurantoin, minocycline

drugs that can cause development of drug induced auto-immune hepatitis

nitrofurantoin, minocycline

herbal/OTC supplements that can cause DILI

ashwagandha, green tea extract, garcinia cambogia, polygonum multiflorum, chinese skullcap, scutellaria baicelensis, scutellaria lateriflora, kratom, mitragyna speciosa, anabolic steroids, tumeric/curcumin

what is the main treatment for DILI w/ the drug/herb identified

discontinue the causative drug/herb and give supportive care PRN (antiemetics, antipruritics, fluids)

pruritis supportive care

throught to be d/t increases in serum bile salts

may be treated w/ cholestyramine 4g daily-bid, ursodiol (alt agent)

cholestyramine adrs + interactions

constipation, fat-soluble vitamin deficiency, increases TGs

many absorption interactions, run DDI checker!! but usually separate from other meds by ~4h

ursodiol

alternative agent form pruritis

primary use in gallstone chemodissolution

dosing of ursodiol

10-15mg/kg/d in divided doses

adrs and monitoring for ursodiol

gi distress, dizziness, enteroliths if used >30 ds

no specific monitoring recs

drug induced autoimmune hepatitis

onset, severity, + response distinct from standard autoimmune hepatitis (AIH)

usually use prednisone ~40mg daily after considerations of

• biopsy + dx

• disease not responding to offending drug DC

• severe dx - Hys law

caution glucocorticoid adrs

APAP metabolism

acetaminophen glucuronidation + sulfation → non tox metabolites

acetaminophen CYP2E1 metabolism → toxic NAPQI + glutathione rescue → non toxic metabolites

APAP overdose tx

during APAP overdose glutathione depletion → NAPQI buildup → hepatotoxicity

use activated charcoal! or N-acetyl cysteine (NAC)!

activated charcoal

helps to adsorb APAP

indicated if presenting w/in 4 h of overdose!

1g/kg (max 50g)

contraindications: non-protected airway, gi perforation

N-acetyl cysteine (NAC)

refills hepatic cysteine stores → glutathione → rescues liver from NAPQI

indicated if:

• time/concentration matrix above Rumack-Matthew nomogram line

• any evidence of liver injury present

• detectable acetaminophen in serum >24h after ingestion

• acute APAP ingestion of 150mg/kg or 7.5g(whichever is less) & serum levels cant be obtained w/in 8h of ingestion

NAC adrs

hypersensitivity rxns, pruritis, urticaria, hypotension, N/V (po formulation only)

hypersensitivity adrs are less frequent w/ 2 bag admin method

dosing for NAC

traditional dosing: 150mg/kg/hr IV x 1h → 12.5 mg/kg/hr x 4h → 6.25 mg/kg IV x 16h

2 bag method: 50 mg/kg/hr x 4h → 6.25 mg/kg/hr x16h

PO dosing regimen infrequently used

isoniazid

common abx used in tx of tuberculosis

mech of toxicity not fully understood, may involve metabolite

baseline + monthly monitoring recommended:

• sx check: anorexia, nausea, fatigue, jaundice, abdominal pain

• physical exam

• LFTs

statins

frequently used for ascvd risk reduction

known to cause transaminitis in some pts but true hepatic dysfxn rare!

test LFTs at baseline and as clinically indicated (for abd pain, dark urine, jaundice, fever)