hyperammonemia

Question 1

ammonia plasma concedntration

Answer 1

15-50 uM

Question 2

4 ways ammonia can cross a cell membrane

Answer 2

It can take the place of Potassium in either:

Na/K ATPase
Na K 2Cl symporter

It can replace Hydrogen in the
Na/H antiporter

It can move through Aquaporins at low effeciency

Rhesus glycoproteins, specific ammonia transporters, in the kidney

Question 3

How can ammonia be produced?

Answer 3

De amination of Cytosine, Adenine, or Guanine

De amidation of glutamine or asparagine
Glutaminase

Oxidative de amination of Glutamate
By glutamate dehydrogenase

Oxidative deamination of any amino acid to an alpha-ketoacid

Question 4

Which amino acid is deaminated to make adenosine?

Answer 4

Aspartate, via an adenylosuccinate intermediate

Question 5

What amino acid transports ammonia from the muscle to the liver?

Answer 5

Glutamine and Alanine

Question 6

What are the sources of ammonia for Urea synthesis in the liver

Answer 6

Glutamine and Glutamate (glutamate synthesized from alanine and aKG)

Question 7

What is the essential activator of the urea cycle?

Answer 7

NAG. N acetyl glutamate.

Question 8

What enzyme does the activator of urea synthesis activate?

Answer 8

CPSI

Carbamoyl phosphate synthetase I

Question 9

What are the first two substrates for the urea cycle?

Answer 9

Carbamoyl phosphate and L-Ornithine

Question 10

Where does CPSI catalyze its reaction and what is its product

Answer 10

In the mitochondria

Carbamoyl phosphate

Question 11

Where does the Urea cycle take place?

Answer 11

L-Citrulline synthesis occurs in the mitochondria, by Ornithine transcarbamoylase, and the rest occurs in the cytosol.

Question 12

What amino acid activates the enzyme NAGS

Answer 12

Arginine, indicating that the urea cycle is highly saturated.

Question 13

What protein connects the urea cycle and citrate cycle?

Answer 13

Aspartate Oxaloacetate
converted via asp1artate transaminase
cofactor: alpha-KG Glutamate

Question 14

What happens to most of the ammonia absorbed by the portal vein?

Answer 14

80% is immediately converted to Urea for elmination in urine.

This includes free ammonia as well as glutamine and alanine.

Question 15

How does ammonia excretion change during acidosis?

Answer 15

It increases, becuase there is increased activity of the Proton/Potassium ATPase pump. The tubular fluid is more acidic, there is more protonation of NH3 to NH4, trapping ammonium in the urine and increasing excretion.

Question 16

From what amino acid do renal tubular cells obtain NH3 for excretion?

Answer 16

Glutamine1 or glutamate.

Question 17

How does the ammonia concentration of portal blood compare to systemic blood?

Answer 17

5-10 times higher, highest during the postprandial period.

Ammonia is absorbed from food and from the breakdown of urea by intestinal flora even in a starved state.

Question 18

How does resting muscle affect ammonia levels?

Active muscle?

Answer 18

Resting muscle absorbs low levels of amonia and secretes Glutamine

Active muscle generates and secretes lots of ammonia and alanine

Question 19

How do Kidneys affect ammonia balance

Answer 19

are net ammonia producers, even though they are excreting ammonia. They create more ammonia than they can secrete, and it is up to the liver to generate urea for elimination.

Brain takes up some ammonia, and produces/secretes Glutamine.
Excessive ammonia in the blood will increase brain uptake and generate cerebral edema.

Question 20

How does hyperammonemia affect the brain

Answer 20

Glutamine is taken up by astrocytes 
Increases the synthesis of both
Glutamate
GABA
Chronic/acutely this will cause chronic elevations in both glutamatergic and gabaergic signaling. 

Causes edema of astroglia cells.

Lethargy 
Confusion/strange behavior
Hypotonia
Coma
Seizures

Question 21

What are the causes of neonatal hyperammonemia?

Answer 21

Defective enzymes in the urea cycle

Question 22

What is the most common enzyme deficiency causing neonatal hyperammonemia?

Answer 22

1) OTC, Ornithine transcarbamylase defect

Very High Orotate/Orotic acid in urine

Is DOMINANT mutation, all the rest are recessive.

Blood:
High glutamine, high alanine

Question 23

Second most common ezyme def causing neonatal hyperammonemia?

Answer 23

ASL, Arginosuccinate lyase defeciency

High Arginosuccinate, High citrate

Low Arginine, low Ornithine

High Orotic acid.

Question 24

Third most common ezyme def causing neonatal hyperammonemia?

Answer 24

ASS, Arginossucinate Sythnetase deficiency

Citrulinemia

very high citruline,
high orotic acid
low arginine

Question 25

What does pyruvate carboxylase deficiency cause?

Answer 25

Hypoglycemia, Hyperammonemia, Lactic acidosis, Low glutamate, Low aspartate, impaired myelination.

Inhibits production of oxaloacetate, decreasing availability of Citric Acid Cycle substrates.

Decreased TCA cycle activity causes pyruvate to be shunted towards lactic acid production (like its hypoxia does) causing lactic acidosis.

It also inhibits gluconeogenesis. Pyruvate carboxylase is the first enzyme in gluconeogenesis converting pyrvate to oxaloacetate.
Causes hypoglycemia that affects the brain most severely

Causes low aspartic acid levels, Aspartate is synthesized from oxaloacetate, Aspartate is essential for urea cycle, so there is hyperammonemia too.
Aspartate is a precursor for Glutamate, low brain glutamate levels.

Aspartate is a precursor for myelin, there is low myelination.

Question 26

What is the most common cause of hyperammonemia in adults?

Answer 26

Hepatic encephalopathy.
Liver failure, impaired urea cycle.

Acute: Brain edema and rapid impairment/death
Acetominophen toxicity,
Hepatitis B

Chronic alcoholism, progressive cognitive failures, and mental decline
Hepatitis C

Question 27

What are the 3 vital functions lost during acute liver failure?

Answer 27

1) ammonia detoxification -> hyperammonemia, brain edema

2) gluconeogenesis -> hypoglycemia
hypoglycemia induces hypoinsulinemia.

3) Lactate clearance -> lactic acidosis
The first step in liver gluconeogenesis, lactate -> pyruvate -> oxaloacetate -> PEP

Question 28

How is brain edema treated?

Answer 28

Mannitol. lots of osmotic diuresis.

Question 29

Potential drug targets of hepatic encephalopathy

Answer 29

anti-inflammatory drugs
p38 inhibitors, both to inhibit microglial activation

GABA receptor inhibitors

Question 30

Other ways to prevent hyperammonemia or prevent ammonia absorption

Answer 30

low protein diet

antibiotics to decrease intestinal bacteria

alpha keto acid derivatives of branched chain amino acids

consume lactulose, which will acidify gut lumen, convert NH3 to NH4 and decrease ammonia absorption.

hemodialysis

Question 31

Where do the two nitrogens in urea come from?

Answer 31

One from free ammonia and one from aspartate

Question 32

How do urea cycle defects cause orotic acidemia?

Answer 32

Carbamoyl phosphate is a pyrimidine synthesis precursor, thus excess pyrimidines and degradation products