Flashcards in Lecture 22: Acute Liver Failure Deck (41):
Acute liver failure: triad
Coagulopathy (INR > 1.5), encephalopathy, jaundice
Two types of acute liver failure
Fulminant and subfulminant (longer jaundice)
Etiologies of acute liver failure: major classes
Viral, drugs/toxins, vascular causes, metabolic, misc (autoimmune, mets)
Viruses of acute liver failure
HAV, HBV, HDV, HEV, HSV, CMV, EBV, VZ, adeno, hemorrhagic fever viruses
Drugs of acute liver failure
Acetaminophen, mushroom poisoning, ecstasy and idiosyncratic
Vascular causes of acute liver failure
Metabolic causes of acute liver failure
Wilson's, acute fatty liver of pregnancy, pediatric diseases
Outcomes of acute liver failure (%)
45% survive, 25% transplant, 30% death
What kind of patients do not do well w/out liver transplant; who does well?
Wilson's, drug-induced, indetermined; acetominophen
Causes of mortality in acute liver failure
Hepatic encephalopathy (number one cause), infection, hypoglycemia, coagulopathy, renal failure
Why do we get hepatic encephalopathy
High serum levels of NH3 (not metabolized into urea) --> crosses BBB + glutamate --> glutamine --> astrocyte accumulation and brain swelling (cerebral edema)
Stages of hepatic encephalopathy
Stage I = subtle changes; stage II = drowsiness, asterixis (hand flapping); stage III = incoherent, sleeping; stage IV = coma w/ cerebral edema
Cerebral edema: clinical signs
Cushing reflex (systemic HTN/bradycardia, end-stage response related to brain herniation), decerebrate rigidity, disconjugate eye movements, loss of pupillary reflexes
Acute liver failure: coagulopathy (why?)
Due to loss of clotting factors, especially Factor V, and platelet abnormalities
Acute liver failure: infection (why, mortality)
Kupffer cell impairment, neutrophil malfunction, decreased compliment levels; NUMBER TWO CAUSE OF MORTALITY
Blood pressure, heart rate, and acidity in acute liver failure
Hypotension, tachycardia, lactic acidosis due to decreased perfusion
Acute liver failure and renal failure
Complicates 50% of cases: can be direct nephrotoxicity (tylenol) or hepatorenal syndrome --> renal vasoconstriction (response to systemic vasodilation) can cause poor perfusion
Acute liver failure and metabolic changes (one word)
ALF: tylenol, give...
ALF: amanita poisoning, give...
ALF: HSV, give...
ALF: autoimmune, give...
ALF: pregnancy, give...
Describe acetaminophen liver failure
Too much --> reactive intermediates (NAPQI), can be metabolized via conjugation with glutathione, which is replaced by cysteine (so give N-Acetylcysteine)
King's college criteria (transplant): acetaminophen
pH less 7.3 (due to high lactic acid) or grade III-IV encephalopathy, high INR, renal failure = 80% mortality
King's college criteria (transplant): non-acetaminophen
High INR or younger than 10, older than 40, bad etiology (Wilson's), high bilirubin, or jaundice greater than 7 days
What is the most common cause of acute liver failure in the US?
Hy's Law (prognosis)
If you have drug induced liver injury with elevations in AST/ALT AND bilirubin, this is worse than AST/ALT alone (JAUNDICE IS WORSE)
What does idiosyncratic drug hepatoxicity mean? (note: these are opposite from predictable hepatoxicity)
Doesn't matter the dose, you can get liver injury, variable duration to injury, may have extrahepatic involvement, but low incidence
Liver drug metabolism: phases
Phase I = oxidation via cytochrome system; Phase II = conjugation via transferases (now hydrophilic); Phase III = excretion
After which phase do you often get a toxic metabolite?
After Phase I, which generates an active metabolite that can cause hepatic injury
Drugs that induce CYP
Rifampin, phenytoin, carbamazepine, phenobarbital, dexamethasone, alcohol
Drugs that inhibit CYP
Grapefruit juice, erythromycin, clarithromycin, ketoconazole, ritonavir
Alcohol and acetaminophen
Heavy drinker w/ alcohol on board: as alcohol leaves bloodstream w/ up-regulated CYP2E1 (due to alcohol) you metabolize tylenol faster, so you have TWO THINGS: DELAYED PRESENTATION AND INCREASED TOXICITY
What can restrict rate of drug elimination?
Depleted cofactors, which can happen during fasting (like an alcoholic who hasn't been eating who takes too much tylenol)
Describe phase III
Takes place in hepatocytes via ATP-binding cassette transport protein (requires energy)
Acetaminophen: minimal hepatotoxic dose, tx
7.5 g (~15 ES tylenol), activated charcoal w/ in 4 hours and NAC w/ in 8 hours
Idiosyncratic hepatotoxins: mechanisms (2)
1. Metabolic idiosyncrasy (genetic differences); 2. Immunoallergy
Isoniazid: mechanism, frequency, latency, % mortality
Metabolic idiosyncrasy with high frequency, hepatitis develops latency w/ 10% mortality
Dilantin: frequency, % mortality, clinical features
Rare, high mortality (up to 40%), features can include fever, rash, immune reaction