hyperammonemia Flashcards
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
Glutaminase
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?
CPSI
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 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
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.
Blood:
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
Citrulinemia
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.
hemodialysis
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
