SN2 SHORT NOTE 5M ★ High-yield

Define hyperammonaemia. Describe its causes, the basis of ammonia toxicity, and its management.

Biochemistry · 1st Professional — Pre-Clinical

Definition

Hyperammonaemia = a raised blood ammonia level, above the normal of 10–80 µg/dL (11–47 µmol/L).

Classification of Causes

Type	Causes
Acquired (secondary)	Hepatic failure and cirrhosis — the commonest; portosystemic shunting; Reye syndrome; valproate; severe sepsis
Inherited (primary)	Urea cycle enzyme defects — OTC deficiency is the commonest; also organic acidaemias and fatty acid oxidation defects

WHY Ammonia Is Toxic to the Brain

↑ Blood NH3 crosses the blood–brain barrier → Fixed by glutamate dehydrogenase → glutamate → Then by glutamine synthetase → glutamine → Two consequences → 1. α-Ketoglutarate is drained from the TCA cycle → ATP production falls → 2. Glutamine accumulates in astrocytes → osmotic swelling → cerebral oedema

Glutamate is also depleted, disturbing neurotransmission; and false neurotransmitters accumulate

Clinical Features

Neonate — poor feeding, vomiting, lethargy, hypotonia, seizures, coma; often mistaken for sepsis
Adult — the four grades of hepatic encephalopathy: altered sleep rhythm → confusion → drowsiness → coma
Flapping tremor (asterixis), constructional apraxia, fetor hepaticus
Respiratory alkalosis — ammonia stimulates the respiratory centre. A valuable clue: urea cycle defects cause alkalosis, organic acidaemias cause acidosis

Management

Measure	Rationale
Stop protein intake temporarily	Removes the nitrogen load
Lactulose	Acidifies the colon → traps ammonia as NH4+; also a laxative
Rifaximin, neomycin	Reduce ammonia-producing gut flora
Sodium benzoate and phenylacetate	Provide alternative routes of nitrogen excretion — conjugate with glycine and glutamine
L-Arginine	Replenishes urea cycle intermediates
Haemodialysis	For severe acute hyperammonaemia
Treat precipitants	GI bleeding, infection, constipation, sedatives, electrolyte disturbance

Applied Aspects

Gastrointestinal bleeding is a classic precipitant — blood in the gut is a large protein load
Blood ammonia must be sent on ice and analysed promptly, or it rises artefactually
Blood urea is low in liver failure — the opposite of what students often expect
Valproate can cause hyperammonaemia even with normal liver function, by depleting carnitine and inhibiting CPS-I

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