Lecture 22: Acute Liver Failure

Question 1

Acute liver failure: triad

Answer 1

Coagulopathy (INR > 1.5), encephalopathy, jaundice

Question 2

Two types of acute liver failure

Answer 2

Fulminant and subfulminant (longer jaundice)

Question 3

Etiologies of acute liver failure: major classes

Answer 3

Viral, drugs/toxins, vascular causes, metabolic, misc (autoimmune, mets)

Question 4

Viruses of acute liver failure

Answer 4

HAV, HBV, HDV, HEV, HSV, CMV, EBV, VZ, adeno, hemorrhagic fever viruses

Question 5

Drugs of acute liver failure

Answer 5

Acetaminophen, mushroom poisoning, ecstasy and idiosyncratic

Question 6

Vascular causes of acute liver failure

Answer 6

Budd-chiari (clot)

Question 7

Metabolic causes of acute liver failure

Answer 7

Wilson’s, acute fatty liver of pregnancy, pediatric diseases

Question 8

Outcomes of acute liver failure (%)

Answer 8

45% survive, 25% transplant, 30% death

Question 9

What kind of patients do not do well w/out liver transplant; who does well?

Answer 9

Wilson’s, drug-induced, indetermined; acetominophen

Question 10

Causes of mortality in acute liver failure

Answer 10

Hepatic encephalopathy (number one cause), infection, hypoglycemia, coagulopathy, renal failure

Question 11

Why do we get hepatic encephalopathy

Answer 11

High serum levels of NH3 (not metabolized into urea) –> crosses BBB + glutamate –> glutamine –> astrocyte accumulation and brain swelling (cerebral edema)

Question 12

Stages of hepatic encephalopathy

Answer 12

Stage I = subtle changes; stage II = drowsiness, asterixis (hand flapping); stage III = incoherent, sleeping; stage IV = coma w/ cerebral edema

Question 13

Cerebral edema: clinical signs

Answer 13

Cushing reflex (systemic HTN/bradycardia, end-stage response related to brain herniation), decerebrate rigidity, disconjugate eye movements, loss of pupillary reflexes

Question 14

Acute liver failure: coagulopathy (why?)

Answer 14

Due to loss of clotting factors, especially Factor V, and platelet abnormalities

Question 15

Acute liver failure: infection (why, mortality)

Answer 15

Kupffer cell impairment, neutrophil malfunction, decreased compliment levels; NUMBER TWO CAUSE OF MORTALITY

Question 16

Blood pressure, heart rate, and acidity in acute liver failure

Answer 16

Hypotension, tachycardia, lactic acidosis due to decreased perfusion

Question 17

Acute liver failure and renal failure

Answer 17

Complicates 50% of cases: can be direct nephrotoxicity (tylenol) or hepatorenal syndrome –> renal vasoconstriction (response to systemic vasodilation) can cause poor perfusion

Question 18

Acute liver failure and metabolic changes (one word)

Answer 18

Hypoglycemia

Question 19

ALF: tylenol, give…

Answer 19

N-Acetylcysteine

Question 20

ALF: amanita poisoning, give…

Answer 20

Penicilli G

Question 21

ALF: HSV, give…

Answer 21

Acyclovir

Question 22

ALF: autoimmune, give…

Answer 22

Steroids (?)

Question 23

ALF: pregnancy, give…

Answer 23

Delivery

Question 24

Describe acetaminophen liver failure

Answer 24

Too much –> reactive intermediates (NAPQI), can be metabolized via conjugation with glutathione, which is replaced by cysteine (so give N-Acetylcysteine)

Question 25

King’s college criteria (transplant): acetaminophen

Answer 25

pH less 7.3 (due to high lactic acid) or grade III-IV encephalopathy, high INR, renal failure = 80% mortality

Question 26

King’s college criteria (transplant): non-acetaminophen

Answer 26

High INR or younger than 10, older than 40, bad etiology (Wilson’s), high bilirubin, or jaundice greater than 7 days

Question 27

What is the most common cause of acute liver failure in the US?

Answer 27

Drug toxicity

Question 28

Hy’s Law (prognosis)

Answer 28

If you have drug induced liver injury with elevations in AST/ALT AND bilirubin, this is worse than AST/ALT alone (JAUNDICE IS WORSE)

Question 29

What does idiosyncratic drug hepatoxicity mean? (note: these are opposite from predictable hepatoxicity)

Answer 29

Doesn’t matter the dose, you can get liver injury, variable duration to injury, may have extrahepatic involvement, but low incidence

Question 30

Liver drug metabolism: phases

Answer 30

Phase I = oxidation via cytochrome system; Phase II = conjugation via transferases (now hydrophilic); Phase III = excretion

Question 31

After which phase do you often get a toxic metabolite?

Answer 31

After Phase I, which generates an active metabolite that can cause hepatic injury

Question 32

Drugs that induce CYP

Answer 32

Rifampin, phenytoin, carbamazepine, phenobarbital, dexamethasone, alcohol

Question 33

Drugs that inhibit CYP

Answer 33

Grapefruit juice, erythromycin, clarithromycin, ketoconazole, ritonavir

Question 34

Alcohol and acetaminophen

Answer 34

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

Question 35

What can restrict rate of drug elimination?

Answer 35

Depleted cofactors, which can happen during fasting (like an alcoholic who hasn’t been eating who takes too much tylenol)

Question 36

Describe phase III

Answer 36

Takes place in hepatocytes via ATP-binding cassette transport protein (requires energy)

Question 37

Acetaminophen: minimal hepatotoxic dose, tx

Answer 37

7.5 g (~15 ES tylenol), activated charcoal w/ in 4 hours and NAC w/ in 8 hours

Question 38

Idiosyncratic hepatotoxins: mechanisms (2)

Answer 38

1. Metabolic idiosyncrasy (genetic differences); 2. Immunoallergy

Question 39

Isoniazid: mechanism, frequency, latency, % mortality

Answer 39

Metabolic idiosyncrasy with high frequency, hepatitis develops latency w/ 10% mortality

Question 40

Dilantin: frequency, % mortality, clinical features

Answer 40

Rare, high mortality (up to 40%), features can include fever, rash, immune reaction

Question 41

Amoxicillin/clavulanic acid (augmentin): frequency, presentation, risk factor

Answer 41

Most frequently reported ab associated with DILI, cholestatitic hepatitis, immunologic idiosyncrasy (HLA haplotype)