Hepatic Encephalopathy

Question 1

dogs and cats, most frequent cause of HE:

up to ___% of affected animals demonstrate neurologic clinical signs

communications are generally:

Answer 1

congenital extrahepatic or intrahepatic portal-to-systemic venous communications

up to 95%

single vessel, but multiple extrahepatic/ntrahepatic can occur

Question 2

Hepatic arteriovenous malformations cause:

young dogs, ddx:

older animals, ddx:

Cats:

Answer 2

portal hypertension
multiple extrahepatic PSS
and ascites

hepatic microvascular dysplasia
rarely, congenital urea cycle deficiencies

PSS secondary to PH secondary to liver dz

hepatic lipidosis

Question 3

pathophysiology of HE is complex
recent work has reemphasized the importance of elevated ______

other substances considered synergistic to ammonia toxicity include:

Answer 3

ammonia

mercaptans, free fatty acids, phenols, bile salts

Question 4

ammonia is produced in the GI by:

then it is absorbed into the:

and rapidly converted to:

in the:

PSS or significant liver disease =

BBB permeability to ammonia increases in HE

how does ammonia decrease excitatory NT in the brain:

Answer 4

1. bacT breakdown of a.a., purine
2. enterocyte metabolism of glutamine
3. bacT breakdown of urea by urease

portal blood

urea or glutamine

liver

high levels of ammonia are present in the systemic circulation

down-regulating the N-methyl-D-aspartate (NMDA, excitatory) receptors

and blocking Cl extrusion from the postsynaptic neuron, decreasing inhibitory neurotransmission

Question 5

brain has no urea cycle; consequently, ammonia in the CNS is removed by:

Answer 5

transamination of glutamate into glutamine in astrocytes

Question 6

glutamine concentrations in the cerebrospinal fluid are elevated in dogs with HE and correlated w.:

Glutamine is exchanged across the blood-brain barrier for ______

tryptophan metabolites:

serotonin NT is…
quinolinate NT is…

glutamine also is transported from astrocytes into neurons, where it is:

overstimulation of the NMDA receptors by:
can cause seizures and neurotoxicity, in part because of:

Answer 6

degree of neuro dysfunct in humans w HE

tryptophan & tryptophan metabolites in CNS

serotonin & quinolinate

inhibitory neurotransmission
excitatory neurotransmission

converted back into glutamate

glutamate and ammonia

free radical formation

Question 7

inhibitory NT:

several different observations implicating “increased GABAergic tone” in HE…

if increased GABA neurotransmission exists in patients with HE, it is due to increased:

what increases the expression of “peripheral-type” benzodiazepine receptors (PTBR) (a heterooligomeric protein complex on the outer mitochondrial membrane of astrocytes):

activation of the PTBR increases mitochondrial cholesterol uptake and synthesis of:

Answer 7

GABA

increased GABA have NOT been found in HE

not GABA itself but…

endogenous GABA ligands:
endogenous benzodiazepines & neurosteroids

ammonia & manganese (also seen in liver disease)

neurosteroids - act on GABA receptors

Question 8

Microglial cell activation =

tx w. N-acetylcysteine and minocycline has been shown to ameliorate CNS inflammation and brain edema in experimental studies

a.a imbalances may play a role in HE
decreased ratio of:

increase in aromatic amino acids
leads to an increased synthesis of:

Normal dogs infused with the aromatic amino acids tryptophan and phenylalanine became:

Answer 8

production of proinflammatory cytokines (TNF-α, IL-1β) - occurs early in HE

branched-chain (valine, leucine, isoleucine): to aromatic (phenylalanine, tyrosine, tryptophan) amino acids

false NT
reduction in synth of dopamine & NE

comatose
addition of branched chain amino acids to the infusion prevented coma

Question 9

CS

Answer 9

depression, dementia, stupor, coma, muscle tremors, motor abnormalities, excessive salivation, and focal or generalized seizures

Question 10

cat CS

dogs PU/PD MoA:

Answer 10

ptyalism is common, and is often only CS

1. secondary to hypercortisolemia
   cortisol inhibits AHD
2. ineffective medullary concentrating bc low urea levels

Question 11

what precipitates CS:

drugs:

Answer 11

high protein meal
GI bleeding
systemic infection
hypoNa, hypoK
hypoglycemia
acidosis & alkalosis
constipation

narcotics and other anesthetic agents

Question 12

Diagnosis
dx or exclusion:

liver function tests:

samples for blood ammonia concentrations are useful only if processed:

rectal portal scintigraphy

liver histopathology

Answer 12

CS + PSS or liver dz
toxin or drug ingestion, intracranial lesions

blood ammonia levels
pre- and postprandial bile acids
sulfobromophthalein (BSP) dye retention

immediately

Question 13

Tx - Seizures:
use of diazepam is controversial because:
can still try and dose

alternatively, the seizure activity may be treated with:

If cerebral edema

AED an attempt to prevent further seizures:

difficulty is:

Answer 13

possibility of > levels of endogenous benzos

propofol (0.5 to 1 mg kg IV bolus, then 0.05 to 0.1 mg/kg/min CRI) although careful respiratory monitoring is essential

Mannitol

KBr is given commonly

Phenobarbital 16 mg/kg IV divided into four doses given on day 1
2 to 4 mg/kg IV q12h

bromide & PB may lead to excessive sedation .:. close monitoring is essential

Question 14

predisposing factors tx:

i.e.if sedated w benzo.

intubation of comatose animals

alkalosis causes

hypokalemia causes

Colloid administration (synthetic or natural/plasma), and potassium and glucose supplementation are often necessary

Answer 14

reverse w. flumazenil (0.02 mg/kg IV)

protect the airway from aspiration and ensure adequate ventilation.\

increases ammonia diffusion into CNS

stimulates renal ammonia production

Question 15

if need RBC what do you use?

Answer 15

FWB or fresh pRBC

bc blood storage increases ammonia

Question 16

lactulose enema:

lactulose (beta galactosidofructose) is a:

Answer 16

1 to 3 ml/10 kg diluted 1 : 1 to 1 : 3 w warm H2O
-minimize ammonia production and absorption

nonabsorbable disaccharide
osmotic cathartic
intestinal bacT hydrolyze lactulose-producing-
-organic acids
-lower colonic pH
-acidification traps ammonia in its NH4+
-preventing absorption by nonionic diffusion and also resulting in the net movement of ammonia from the blood into the bowel lumen.

Question 17

Fulminant hepatic failure (FHF) is

death in humans w FHF often associated w:

assisted MV why?

mannitol, dextrose, FFP, Ab

Answer 17

uncommon

cerebral edema, hemorrhage, and sepsis

prevent hypo- or hyperventilation and minimize changes in intracranial pressure

Question 18

Tx goals:

CS of HE typically can be managed w:

diet:

protein source:

Answer 18

reducing ammonia levels
decreasing GABA
lowering endogenous benzodiazepines

diet modification
oral administration of lactulose
antimicrobial therapy

moderately protein restricted (14% to 17% protein on a dry matter basis in dogs; 30% to 35% protein in cats) and high in CHO

high-quality protein w increased BCAA
branched-chain amino acids

low-residue, easily digestible food to minimize the amount of material reaching the colon

Question 19

Cats, essential a.a necessary for urea:

Answer 19

arginine

Question 20

Lactulose (1 to 3 ml/10 kg BW diluted 1 : 1 to 1 : 3 with warm water q6-8h) is administered orally or rectally, and the dose rate and interval are titrated to:

Answer 20

2-4 moderately soft stools daily

Question 21

Ab 3.

Answer 21

Neomycin sulfate (20 mg/kg PO q6-8h) generally is considered nonabsorbable but should be avoided in animals with concurrent renal disease

Metronidazole (7 to 10 mg/kg PO or IV q12h) is a reasonable alternative, but neurotoxicity may occur more commonly in animals with hepatic disease.

Rifaximin is an oral antimicrobial recently approved for the treatment of humans with hepatic encephalopathy.

Question 22

benefit of combined lactulose and antimicrobial therapy is open to question

Answer 22

therapeutic effect of lactulose depends in part on its metabolism by colonic bacteria,

Although the two treatments often are considered synergistic, oral neomycin inhibits lactulose metabolism in 25% to 30% of human patients

Question 23

liver insufficiency commonly experience gastrointestinal hemorrhage and the digested blood serves as a protein source

Answer 23

recommended that these animals receive gastrointestinal protectant therapy