Acute liver injury Flashcards
Describe the etiology of acute liver failure, and risk factors
- 73% of patients were women (Ostapowicz et al. Ann Intern Med, 2002).
- 39% paracetamol, 2nd most common indeterminate, 13% other drugs
- minor contributors include autoimmune hepatitis, hepatitis B, shock etc
- Risk factors include age, sex (women 80% paracetamol hepatotoxicity, 70% of idiosyncratic), BMI, genetic makeup, other medications, and nutritional status (malnutrition).
Broadly describe how drug metabolism leads to toxicty, and list types of drug indduced heptaotoxicity
- Drug accumulates in cells leading to toxicity
- Metabolism of drug can also play a role: conjugation/PI-II generating toxic metabolites
- affects nucleic acids- carcinogenicity, receptors, transporters, signalling molecules - apoptosis, autologous proteins and hypersensitivity
- Intrinsic or idiosyncratic drug-induced hepatotoxicity.
- Intrinsic: Hepatotoxicity is predictable if dose is high enough.
- Idiosyncratic: Hepatotoxicity results at therapeutic dose of drug. Often fatal if drug use continued - but not always: isoniazid induced liver injury can disappear even with continued use. Dose can still play a role by increasing the likelihood of injury
List the broad mechanisms of hepatocyte injury
- Disrupted Ca2+ homeostasis -> blebbing -> cell death.
- Disruption of actin filaments next to canaliculus, inhibition of transporters eg of bile.
- Covalent binding of drug to cytP-450 - adducts.
- Adducts migrate to plasma membrane - immune response.
- Apoptosis - loss of nuclear chromatin.
- Inhibition of mitochondrial function (loss of ATP and increase in ROS and build-up of fatty acids).
Note also: bile duct epithelium can be damaged by toxic metabolites
List mechanisms of injury in non-heaptocytes
- Kupffer’s cells can activate cytokines amplifying hepatic injury.
- Stellate cells or macrophages can augment injury, produce fibrosis (see also [[Pathology B5 - Lecture 3]]) or form granulomas.
- Sinusoidal endothelial cells can be injured leading to veno-occlusive disease eg chemo drugs and some plant alkaloids.
- Hepatocyte differentiation can lead to benign adenomas or carcinomas.
Describe paracetamol hepatotoxicity
- Risk above 300mg is 90%, between 2-300mg is 30%, is 1-2% less than 200
- Threshold for hepatic injury variable but usually >150mg/kg (>10g).
- Life-threatening hepatotoxicity from overdose is uncommon, fatalities rare.
- Survival is 100% if treatment commences within 8 hours.- usually
- N-acetylcysteine (NAC) is the antidote.
Describe the treatment nomogram
- Data uninterpretable. between 4 hours
- Repeat measurement later.
- Treat if high dose suspected.
- Liver damage highly likely.
- Treat if there is doubt about timing.
- Severe liver damage still possible, treatment should be considered.
Describe the metabolism of paracetamol
Mainly synthesised by phase II conjugation. Will switch to PHS/P450 systems. which generates NAPQI. Usually converted to not harmful metabolite with incorporation of glutathione.
Pathways become saturated and deplete glutathione stores. If glutathione levels drop below 30% normal, NAPQI levels rise and cause damage. Prostaglandin H synthase is a minor pathway. NAC “replaces” glutathione. Is an analog of cysteine.
Describe how NAPQI contributes to toxicity
At least 17 hepatic enzymes are known to be inhibited by NAPQI, likely more.
- Microsomes (1)
- Cytosol (10)
- Mitochondria (4)
- Cell membrane (2)
14 others bind directly to paracetamol but are not yet shown to be inhibited. Cell death likely due to multiple parallel events rather than a single mechanism.
List the three major mechanisms of paracetamol hepatotoxicity
- Uncouples mitochondria - GDH inhibited, inability to produce ATP
- Depletes glutathione further, inhibits glutamylcysteine synhtetase
- Disrupts Ca2+ homeostasis
- Altering gene expression, production of TFs, altered gene expression, protein activity and expression, in addition to…
- Toxic metabolites, GSH depletion, and oxidative stress probably render hepatocytes more susceptible to the innate immune system
- genetic susceptibility (either increased or decreased) identified in animal model KO studies
What are RFs for para-induce hepatotoxcity
- Chronic alcoholism (more than 50g/day)
- alcohol is usually metabolised by CYP450
- induces increased expression of CYP450 nad migration to membrnae
- ethanol out-competes paracetamol hence NAPQI initially low
- as ethanol is metabolised, and there is more P450, hence more NAPQI
- Prolonged fasting
- Other medications (inducers of cytP450 2E1 and 3A4) e.g., isoniazid, rifampicin, carbamazepine. Stimulated cytP450 enzymes & reduced glutathione levels in the liver increase the risk.
- Enzyme inducers can enhance hepatotoxicity, not just ethanol: smoking, phenytoin, phenobarbital.
List some idiosyncratic hepatotoxins
- Allergic and non-allergic reactions can occur.
- allopurinol, diclonfeac eg hepatocellular injury, ACEI cholestatic
- amiodarone hepatocellular, only one cholestatic- terbinafine
What is the major hurdle to getting new drugs on the market?
Hepatotoxicity is the reason why many new drugs never reach the market and is a major reason why drugs are withdrawn from the market. Examples include Bromfenac (NSAID) and Troglitazone (used in type 2 diabetes).
Describe isoniazid
Isoniazid causes elevated aminotransferase levels in 15-20% of patients and severe hepatic necrosis in 1:1000. However, it is still used as a first-line treatment for tuberculosis (for more than 50 years).
Metabolism involves a minimum of 3 3nzymes.
List some troublesome herbal remedies
Some herbal remedies can cause severe hepatotoxicity, including Kava-Kava, Chaparral, Germander, Valerian root, Skullcap, Mistletoe, Senna, and Comfrey.
Describe managemtn of hepatotoxicity (Drug induced)
- Early recognition and discontinuation of the responsible agent.
- Continued monitoring for evidence of acute liver failure (jaundiced, repeated vomiting, nausea, confusion, fever).
- Perform INR ie tiem to clot and LFTs.
- Admit to the hospital if symptoms do not settle or if there are concerns.
- Contact the liver transplant team if INR is prolonged
