Hepatic Encephalopathy

Question 1

List 8 factors other than ammonia, implicated in the pathogenesis of HE

Answer 1

• glutamate
• GABA
• aromatic amino acids
• manganese
• endogenous benzos
• endogenous opioids
• mercaptans
• tryptophan-serotonin system alterations

Question 2

Describe the two different types of brain edema. What type is present in HE and which type indicates steroid administration?

Answer 2

cytotoxic - fluid shifts into the cell, e.g., from increased osmotic pull
vasogenic - inflammation and endothelial damage leding to fluid leakage from vasculature (increased vascular permeability)

HE - cytotoxic - glutamine causing osmotic pull (i.e., characterized by abnormal intracellular fluid shift)

Question 3

Why do cats with hepatic lipidosis sometimes develop hyperammonemia? (even in the face of normal hepatic function)

Answer 3

arginine deficiency from anorexia
necessary for the urea cycle

Question 4

What is the chemical formula of ammonia versus ammonium?

Answer 4

NH3, NH4

Question 5

Describe the production of ammonia and ammonium in the GI tract and how they’re absorbed

Answer 5

produced mostly by urease-producing bacteria from dietary protein
ammonia can be freely absored through cell membrane
ammonium cannot pass cell membranes

Question 6

What are the 2 processes by which ammonia is metabolized?

Answer 6

ornithin/urease cycle –> convert ammonia to urea (in the liver, periportal hepatocytes)
transamination –> adds ammonia to glutamate (amination) –> producing glutamine (in the pervenous hepatocytes, brain, skeletal muscles)

Question 7

Describe how ammonia leads to cerebral edema and neurologic injuries

Answer 7

enters astrocytes
binds with glutamate –> forms glutamine –> water pull (osmotically active) –> cytotoxic edema

ammonia also inhibits glutamine release from astrocytes

aquaporine-4 channels inserted into astrocyte’s cell membranes

then glutamine will undergo deamination –> releases glutamate and ammonia –> ROS and RNOS produced –> further cell damage

ammonia may increase BBB permeability

Question 8

What is the mechanism of action by which lactulose helps reduce ammonia levels?

Answer 8

converts NH3 to NH4+ –> trapped in GI tract
osmotic cathartic - faster GI transit time, less time for ammonia absorption

Lactulose, a non-absorbable disaccharide, decreases ammonia production and absorption in the colon by decreasing colonic pH, causing a shift from ammonia to ammonium, with the latter being poorly absorbed by the gastrointestinal mucosa. It also decreases gastrointestinal transit time and inhibits glutaminase activity, decreasing intestinal uptake of glutamine and its metabolism to ammonia

Question 9

What type of bacteria produce ammonia?

Answer 9

urease-forming bacteria

Question 10

List 10 confounding factors worsening/precipitating HE

Answer 10

• hypokalemia
• hyponatremia
• hypoglycemia
• protein-rich meal
• constipaiton
• metabolic alkalosis
• GI bleeding
• dehydration
• renal disease
• diuretic administration

Question 11

How does hypokalemia increase the risk for HE?

Answer 11

• increases renal ammoniagenesis (ammonia production)
• promotes metabolic alkalosis –> increaes ration of NH3:NH4+

Question 12

Explain why PSS should be ligated/occluded slowly

Answer 12

because of risk of forming iatrogenic prehepatic portal hypertension

Question 13

what are the two available devices for delayed PSS occlusion?

Answer 13

ameroid constrictor
cellophane band

Question 14

What is the current evidence for preemptive anti-seizure drug therapy before shunt occlusion surgery?

Answer 14

conflicting, most recent recommend starting levetiracetam early/before surgery

Question 15

How late after shunt attenuation surgery can neurologic complications occur in dogs or cats?

Answer 15

72 hours dog
5 days cat

Question 16

Why is potassium bromide avoided in cats?

Answer 16

induces lower airway disease

Question 17

What are the 3 types of hepatic encephalopathy?

Answer 17

A. Acute liver failure - absence of preexisting liver disease
B. PSS - without intrinsic liver disease
C. liver cirrhosis, portal hypertension, or acquired PSS

Question 18

What are the 2 enteric sources of ammonia?

Answer 18

• urease producing bacteria
• glutaminase activity in enterocytes

Question 19

Do the kidneys produce or metabolize ammonia?

Answer 19

can do both

glutamine synthase and glutaminase present

Question 20

Why can loss of skeletal mass predispose to HE?

Answer 20

skeletal muscles have glutamine synthase –> can act as an ammonia sink

Question 21

How can ammonia affect the immune-system?

Answer 21

• inhibits phagocytic acitivty
• inhibits neutrophil chemotaxis
• causes oxidative burst

Question 22

Which types of HE are most common in SA?

Answer 22

1st Congenital PSS (Class B)
2nd Acquired PCC (Class C)

Class A not common

Question 23

What is the treatment of choice for intra- versus extrahepatic PSS?

Answer 23

extrahepatic:
* ameroid ring
* cellophane band

intrahepatic
* transjugular embolization

aquired - closure contraindicated –> would result in acute exacerbation of portal hypertension

Question 24

What was found in the study by Serrano et al, on CPSS treatment with lactulose, diet, metronidazole in dogs?

Answer 24

diet + lactulose superior to diet alone, or diet + metronidazole

adding metro to diet + lactulose did not improve clinical scores

Question 25

What was found by Carrera et al.’s study on outcome of dogs with post-attenuation seizures after surgical correction of PSS

Answer 25

• 60% of dogs developed post-attenuation seizures
• 40% had neurologic signs other than seizures

of those:
48% signs resolved by discharge
the ones with persisting sings - 70% resolved at home
50% of dogs that had post-attenuation seizures had seizure reoccurence
Os graded high WOL
90% survived > 6 months if they survive at least 30 days