URUK STATE UNIVERSITY MEDICINE COLLEGE

Department of Biochemistry

Hyperammonemia

Supervisor by Submitted by
Dr\Shahad Fawzi . ‫نورالهدى حسين الماس‬
Second stage
Group\D
29\6\2020
Introduction about of the Hyperammonemia

Types of Hyperammonemia

Deficiencies of enzymes involved

Signs and symptoms

Diagnosis

Treatment

References
*
Hyperammonemia (or hyperammonaemia) : is a metabolic disturbance
characterised by an excess of ammonia in the blood. It is adangerous condition
that may lead to encephalopathy and death. It may be primary or
secondary.Ammonia is a substance that contains nitrogen.
It is a product of the catabolism of protein. It is converted to the less
toxic substance urea prior to excretion in urine by the kidneys. The
metabolic pathways that synthesize urea are located first in the
mitochondria and then into the cytosol.
The process is known as the urea cycle, which comprises several
enzymes acting in sequence. The disease is split into two types: primary
hyperammonemia and secondary hyperammonemia. Both are caused by a
group of genetic ailments characterized by metabolic dysfunction brought
about by reduced enzyme activity and consequent rise of toxicity. They
are collectively known as inborn errors of metabolism, a phrase coined
by 19th- and 20th-century British physician Archibald Garrod.

*
1 .Primary hyperammonemia: These errors occur in the urea
cycle. An example of its associated disorders is citrullinemia,
which involves the accumulation of ammonia in the blood due to
the deficiency of argininosuccinic acid synthetase.

2.Secondary hyperammonemia : errors occur outside the urea cycle.

Two examples are methylmalonic acidemia and propionic
academia, which belong to a class of amino-acid metabolic
disorders known as organic academia.
Other examples include N-acetylglutamate synthetase deficiency,
ornithine translocase deficiency and arginase deficiency, each of which
is named after the enzyme missing in the urea cycle.

*
*N-Acetylglutamate Synthetase Deficiency (NAGS): N-acetylglutamate

synthetase deficiency affects the body’s ability to make N-Acetylglutamate

(NAG) which is a required cofactor for the function of carbamyl phosphate
synthetase I. Without NAG, CPSI cannot convert ammonia into carbamyl
phosphate. Along with OTC deficiency and CPSI, deficiency of
Nacetylglutamate is the most severe of the urea cycle disorders. Patients with
complete NAGS deficiency rapidly develop hyperammonemia in the newborn
period. A new experimental treatment for this disease is currently under
investigation through the Urea Cycle Disorders Consortium using the compound
carbamyl glutamine.
*Carbamoylphosphate synthetase I deficiency (CPS-I Deficiency):
Carbamylphosphate synthetase I deficiency affects the livers ability to convert
nitrogen to urea. This enzyme takes ammonia and through the use of bicarbonate
and ATP produces carbamyl phosphate. This enzyme requires the presence of its
cofactor nacetylglutamate.. Patients with complete CPSI deficiency rapidly
develop hyperammonemia in the newborn period.
*Ornithine Transcarbamylase (OTC) Deficiency: OTC deficiency is the most
severe of the urea cycle disorders. Patients with complete OTC deficiency
rapidly develop hyperammonemia in the newborn period.
Figure: The urea cycle. CPS-1 cabamoyl phosphate synthetase 1, OTC ornithine
transcarbamylase, ASS argininosuccinic acid synthetase, ASL argininosuccinic acid lyase,
ARG arginase. Hyperammonemia due to urea cycle disorders: a potentially fatal condition in
the intensive care setting.

*
SIGNS
•Initially healthy appearing neonate with decompensation after several days
•Often seen after institution of protein feedings
•Lethargy
•Poor feeding
•Vomiting
•Hypotonia
•Respiratory distress, tachypnea, apnea
•Irritability
•Seizure activity
•Neurologic deterioration leading to coma •Death
Long Term Effects of Neonatal Ammonemia :
•Demonstrated correlation between prolonged neonatal hyperammonemic coma
and brain damage with impaired intellectual functioning
•Did not demonstrate correlation between peak ammonia level and level of
intellectual impairment.

*
*The diagnosis of Hyperammonemia involves identifying the cause of the
condition. Medical examination should include:
*Liver function tests
*Coagulation tests
*Measurement of acetaminophen levels
*Viral serologies
*In case of a suspected IEM, patients should undergo medical tests that evaluate
the levels of organic acid, amino acids and orotic acid in the urine. A liver
biopsy may be considered for confirmation of the diagnosis of the disease.
Quantitative plasma and Carnitine evaluation should also be done. *If an
acute liver failure is suspected due to drug usage, the social history should
be considered and a careful medical treatment has to be carried out.
Abdominal CT scanning may help in an accurate diagnosis.
*The differential diagnosis of Hyperammonemia should aim at distinguishing
the condition from other similar disorders, such as
*Portal vein thrombosis
*Fatty infiltration &
*IEM

*
The treatment of Hyperammonemia aims at restricting the intake of ammonia as
well as increasing its excretion. Physicians make this possible by prescribing
pharmacologic agents like Sodium benzoate and Intravenous Sodium
Phenylacetate. These are commonly used as adjunctive therapy for curing the
condition in patients suffering from deficiency of Urea Cycle Enzyme. In
hyperammonemia ammonia directly affects the CNS .The role of the neurologist
is to provide a basic status evaluation for later reference during follow-up care.
This evaluation is especially useful in the primary genetic entities, in which
recurrence is a virtual certainty and the risk of additional nervous system
compromise exists.

*MANAGEMENT : People suffering from chronic disorders are at a life-long

risk of suffering from Hyperammonemia episodes. For such patients,
management involves long-time follow up and monitoring of the ammonia
levels. A multidisciplinary approach, involving Genetic, Dietary, Metabolic,
Pediatric and Neurological factors, needs to be followed for this disease.
Specific supportive plans need to be used for dealing with acute episodes.
Therapies used for this disorder need to focus on controlling the symptoms and
avoiding its acute episodes.

*
Denise R. Ferrier, phD;Lippincott's Illustrated Reviews:
Biochemistr;Sixth Edition, 2014,P 470-473
DM vasudevan,Sreekumari S and Kannan Vaidyanathan; TEXTBOOK
OF BIOCHEMISTRY For Medical Students; Sixth Edition, 2011,P
179180
Robert K. Murray, MD, PhD & David A. Bender, PhD & Kathleen M.
Botham, PhD, DSc & Peter J. Kennelly, PhD & Victor W. Rodwell, PhD
& P. Anthony Weil, PhD ; Harper’s Illustrated Biochemistry
,TwentyEighth Edition,2009,P 244-250
Vicente Felipo & Santiago Grisolia; Hepatic Encephalopathy,
Hyperammonemia, And Ammonia toxicity ,1st Edition 1994, P 11-18