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Flashcards in hyperammonemia Deck (32)

ammonia plasma concedntration

15-50 uM


4 ways ammonia can cross a cell membrane

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


How can ammonia be produced?

De amination of Cytosine, Adenine, or Guanine

De amidation of glutamine or asparagine

Oxidative de amination of Glutamate
By glutamate dehydrogenase

Oxidative deamination of any amino acid to an alpha-ketoacid


Which amino acid is deaminated to make adenosine?

Aspartate, via an adenylosuccinate intermediate


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

Glutamine and Alanine


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

Glutamine and Glutamate (glutamate synthesized from alanine and aKG)


What is the essential activator of the urea cycle?

NAG. N acetyl glutamate.


What enzyme does the activator of urea synthesis activate?

Carbamoyl phosphate synthetase I


What are the first two substrates for the urea cycle?

Carbamoyl phosphate and L-Ornithine


Where does CPSI catalyze its reaction and what is its product

In the mitochondria
Carbamoyl phosphate


Where does the Urea cycle take place?

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


What amino acid activates the enzyme NAGS

Arginine, indicating that the urea cycle is highly saturated.


What protein connects the urea cycle and citrate cycle?

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


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

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

This includes free ammonia as well as glutamine and alanine.


How does ammonia excretion change during acidosis?

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.


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

Glutamine1 or glutamate.


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

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.


How does resting muscle affect ammonia levels?

Active muscle?

Resting muscle absorbs low levels of amonia and secretes Glutamine

Active muscle generates and secretes lots of ammonia and alanine


How do Kidneys affect ammonia balance

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.


How does hyperammonemia affect the brain

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

Causes edema of astroglia cells.

Confusion/strange behavior


What are the causes of neonatal hyperammonemia?

Defective enzymes in the urea cycle


What is the most common enzyme deficiency causing neonatal hyperammonemia?

#1) OTC, Ornithine transcarbamylase defect

Very High Orotate/Orotic acid in urine

Is DOMINANT mutation, all the rest are recessive.

High glutamine, high alanine


Second most common ezyme def causing neonatal hyperammonemia?

ASL, Arginosuccinate lyase defeciency

High Arginosuccinate, High citrate

Low Arginine, low Ornithine

High Orotic acid.


Third most common ezyme def causing neonatal hyperammonemia?

ASS, Arginossucinate Sythnetase deficiency


very high citruline,
high orotic acid
low arginine


What does pyruvate carboxylase deficiency cause?

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.


What is the most common cause of hyperammonemia in adults?

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


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

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


How is brain edema treated?

Mannitol. lots of osmotic diuresis.


Potential drug targets of hepatic encephalopathy

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

GABA receptor inhibitors


Other ways to prevent hyperammonemia or prevent ammonia absorption

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.



Where do the two nitrogens in urea come from?

One from free ammonia and one from aspartate


How do urea cycle defects cause orotic acidemia?

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