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G32 Gastroenterology
Liver
Toronto Notes 2019
Drug-Induced Liver Disease
Table 17. Classification of Hepatotoxins
Example Dose-Dependence Latent Period Host Factors Predictable
Direct Indirect
Acetaminophen, CCl4 Phenytoin, INH Usual Unusual Hours-days Weeks-months Not important Very important Yes No (idiosyncratic)
Hy’s Law: drug-induced hepatocellular jaundice indicates a mortality of at least 10%
• many different patterns of liver injury (i.e. hepatocellular, cholestatic, mixed, granulomatous, acute liver failure) can be seen in drug-induced liver injury and thus this requires a high index of suspicion.
• see: LiverTox for Information regarding drug-specific risks and patterns of hepatotoxicity (http://
livertox.nih.gov)
Specific Drugs
• acetaminophen
■ metabolized by hepatic cytochrome P450 system
■ can cause ALF (transaminases >1,000 U/L followed by jaundice and encephalopathy)
■ requires 10-15 g in healthy, 4-6 g in alcoholics/anticonvulsant users
■ mechanism: high acetaminophen dose saturates glucuronidation and sulfation elimination
pathways → reactive metabolite is formed → covalently binds to hepatocyte membrane ■ presentation
◆ first 24 h: N/V (usually within 4-12 h of overdose)
◆ 24-48 h: asymptomatic, but ongoing hepatic necrosis resulting in increased transaminases ◆ >48 h: continued hepatic necrosis possibly complicated with ALF or resolution
◆ note: potential delay in presentation in sustained-release products
■ blood levels of acetaminophen correlate with the severity of hepatic injury, particularly if time of ingestion known
■ therapy
◆ gastric lavage/emesis (if <2 h after ingestion)
◆ oral activated charcoal
◆ N-acetylcysteine (NAC, Mucomyst®) can be given PO or IV (most effective within 8-10 h of
ingestion, but should be given no matter when time of ingestion) – promotes hepatic glutathione regeneration
◆ no recorded fatal outcomes if NAC given before increase in transaminases
• chlorpromazine:cholestasisin1%after4wk;oftenwithfever,rash,jaundice,pruritus,andeosinophilia
• INH(isoniazid)
■ 20% develop elevated transaminases but <1% develop clinically significant disease
■ susceptibility to injury increases with age
• methotrexate
■ causes fibrosis/cirrhosis; increased risk in the presence of obesity, DM, alcoholism (i.e. with underlying risk for pre-existing fatty liver)
■ scarring develops without symptoms or changes in liver enzymes, therefore biopsy may be needed in long-term treatment
• amiodarone:cancausesamehistologyandclinicaloutcomeasalcoholichepatitis
• others: azoles, statins, methyldopa, phenytoin, propylthiouracil (PTU), rifampin, sulfonamides,
tetracyclines
• herbs:chaparral,Chineseherbs(e.g.germander,comfrey,bushtea)
Wilson’s Disease
Definition
• autosomalrecessivedefectincoppermetabolism(geneATP7B)
Etiology
• decreasedbiliaryexcretionofcopperplusdecreasedincorporationofcopperintoceruloplasmin
Clinical Features
• liver:acutehepatitis,acuteliverfailure,chronicactivehepatitis,cirrhosis,lowriskofhepatocellular carcinoma
• eyes: Kayser-Fleischer rings (copper deposits in Descemet’s membrane); more common in patients with CNS involvement, present in only 50% of isolated liver involvement
• CNS:basalganglia(wingflappingtremor,Parkinsonism),cerebellum(dysarthria,dysphagia, incoordination, ataxia), cerebrum (psychosis, affective disorder)
• kidneys: Fanconi’s syndrome (proximal tubule transport defects) and stones
• blood:intravascularhemolysis;maybeinitialpresentationinfulminanthepatitis • joints:arthritis,bonedemineralization,calcifications
Clinical Manifestations of Wilson’s Disease
ABCD
Asterixis
Basal ganglia degeneration: suspect if parkinsonian features in the young Ceruloplasmin decreases
Cirrhosis
Corneal deposits (Kayser-Fleischer ring) Copper
Dementia