Overview
Definition:
Hyperammonemia refers to an abnormally high concentration of ammonia in the blood, exceeding the normal physiological range
It is a critical biochemical abnormality often indicative of an underlying inborn error of metabolism (IEM), most commonly a disorder of the urea cycle, which impairs the body's ability to detoxify ammonia
This can lead to severe neurological dysfunction and is a medical emergency.
Epidemiology:
The incidence of hyperammonemia varies depending on the underlying cause
Urea cycle disorders (UCDs) affect approximately 1 in 30,000 live births
Ornithine transcarbamylase (OTC) deficiency is the most common UCD, accounting for about 50% of cases
Other causes include organic acidemias (e.g., propionic acidemia, methylmalonic acidemia), fatty acid oxidation defects, and certain inherited transport defects
Presentation can occur in neonates, infants, or older children, with neonatal onset often being more severe.
Clinical Significance:
Elevated ammonia levels are neurotoxic, leading to encephalopathy, coma, and potentially irreversible brain damage or death if not managed promptly
Prompt recognition and intervention are crucial for improving neurological outcomes
This condition is a high-yield topic for DNB and NEET SS examinations due to its emergent nature and the need for rapid, evidence-based management.
Clinical Presentation
Symptoms:
Neonatal presentation: Lethargy
Poor feeding
Vomiting
Irritability
Seizures
Jaundice
Hypotonia
Respiratory distress
Older infants/children: Recurrent vomiting
Anorexia
Lethargy
Developmental delay or regression
Behavioral changes
Ataxia
Seizures
Coma.
Signs:
Neurological: Altered mental status ranging from lethargy to deep coma
Seizures (generalized, focal, or myoclonic)
Hypertonia or hypotonia
Irritability
Signs of increased intracranial pressure (bulging fontanelle, papilledema - late)
Hepatic: Hepatomegaly may be present in some underlying conditions
Other: Poor weight gain, recurrent infections, developmental delay.
Diagnostic Criteria:
No single definitive diagnostic criterion exists beyond elevated serum ammonia levels
Diagnosis relies on a combination of clinical suspicion, laboratory findings (elevated ammonia, specific IEM markers), and confirmation with genetic testing
Levels > 150-200 µmol/L in neonates or > 100-150 µmol/L in older children are generally considered significantly elevated and warrant urgent investigation.
Diagnostic Approach
History Taking:
Detailed birth history (gestational age, complications)
Feeding history (vomiting, poor intake)
Developmental milestones
Previous unexplained illnesses or episodes of lethargy/seizures
Family history of unexplained infant deaths, neurological disorders, or known IEMs
Maternal history of consanguinity
Dietary history, especially protein intake
Red Flags: Acute onset of neurological symptoms with metabolic derangement, unexplained lethargy, poor feeding, vomiting, seizures, especially in the neonatal period or in a previously well child.
Physical Examination:
Complete neurological examination: Assess level of consciousness (AVPU, GCS)
Evaluate for focal neurological deficits, seizures, tone abnormalities (hyper/hypotonia)
Assess for signs of increased intracranial pressure
Thorough abdominal examination for hepatomegaly or masses
Assess hydration status and vital signs, including temperature.
Investigations:
Immediate: Serum ammonia (on ice, arterial or venous, no tourniquet, prompt transport)
Blood glucose
Electrolytes, BUN, creatinine
Liver function tests (ALT, AST, bilirubin, albumin, PT/INR)
Arterial blood gas (ABG) to assess for metabolic acidosis
Urine analysis and screen for ketones
Consider: Plasma amino acids (elevated glutamine is common)
Urine organic acids
Serum lactate
Blood acylcarnitines
Ammonia level recheck after initial management to assess response
Diagnostic imaging: Cranial ultrasound or CT/MRI to rule out structural brain lesions or cerebral edema, especially if seizures are present or neurological signs are focal.
Differential Diagnosis:
Sepsis (especially gram-negative)
Hypoglycemia
Hypoxic-ischemic encephalopathy
Intracranial hemorrhage
Inborn errors of metabolism (UCDs, organic acidemias, fatty acid oxidation defects, amino acid disorders)
Portosystemic shunting (e.g., congenital hepatic shunts)
Reye syndrome (historically associated with aspirin use in viral illness)
Certain drug intoxications.
Management
Initial Management:
Immediate reduction of ammonia production and promotion of ammonia excretion
Stop protein intake: Discontinue all oral feeding and administer intravenous fluids with dextrose (10-15%) to provide adequate non-protein calories (120-150 mg/kg/min or 8-10 mg/kg/hr) to prevent catabolism
Intravenous fluids to maintain hydration and urine output
Correct any metabolic derangements (e.g., hypoglycemia, electrolyte imbalances)
Hemodynamic stabilization if shock is present.
Medical Management:
Specific ammonia-lowering agents: Sodium benzoate and sodium phenylacetate (Ammonul®, Buphenyl®/Ravicti®) - these provide alternative pathways for nitrogen excretion
Dosing is critical and weight-based
For example, the standard initial dose for the combination is 250 mg/kg/day for sodium benzoate and 250 mg/kg/day for sodium phenylacetate, divided into 4-6 doses
Continuous infusion may be used in severe cases
Glycerol phenylbutyrate (Ravicti®) is another option, given orally or via NG tube, which is converted to phenylacetate
Dialysis (hemodialysis or peritoneal dialysis): Indicated for severe hyperammonemia (ammonia > 300-500 µmol/L), poor response to medical management, or significant neurological deterioration
Hemodialysis is the most effective method for rapid ammonia reduction
Anticonvulsants: For seizures, use benzodiazepines (e.g., lorazepam) followed by other agents if necessary (e.g., levetiracetam, phenobarbital), avoiding valproic acid, which can be ketogenic.
Surgical Management:
Liver transplantation: Considered for severe, refractory UCDs or when medical management fails to prevent irreversible neurological damage
This is a definitive treatment but is reserved for specific cases and usually after initial stabilization and diagnosis.
Supportive Care:
Close monitoring: Frequent monitoring of ammonia levels (every 4-6 hours initially), electrolytes, glucose, and neurological status
Neurological assessment: Monitor for signs of worsening encephalopathy, seizures, or increased intracranial pressure
Respiratory support: Ensure adequate oxygenation and ventilation, especially if intubated
Nutritional support: Once stable, gradual reintroduction of protein with restriction tailored to the specific IEM, guided by a metabolic specialist
Long-term management: Requires a multidisciplinary team including a metabolic physician, geneticist, dietitian, and neurologist
Genetic counseling is essential.
Complications
Early Complications:
Neurological sequelae (developmental delay, intellectual disability, cerebral palsy)
Seizures refractory to treatment
Cerebral edema and increased intracranial pressure
Coma
Death.
Late Complications:
Long-term neurodevelopmental deficits
Learning disabilities
Behavioral problems
Recurrent episodes of hyperammonemia if adherence to dietary and medication regimens is poor.
Prevention Strategies:
Newborn screening programs can identify some IEMs before symptomatic presentation
Prompt recognition and aggressive management of suspected IEMs in neonates and infants presenting with metabolic encephalopathy
Genetic counseling and prenatal diagnosis for families with known UCDs
Strict adherence to dietary restrictions and medication regimens in diagnosed patients.
Prognosis
Factors Affecting Prognosis:
Severity of hyperammonemia at presentation (peak ammonia level)
Age at onset (neonatal onset generally has a worse prognosis)
Underlying specific IEM and its severity
Rapidity and effectiveness of initial management
Presence and severity of neurological damage at diagnosis
Response to treatment, including dialysis if required
Adherence to long-term management plan.
Outcomes:
With prompt and aggressive management, some individuals can survive and have a reasonable neurodevelopmental outcome, especially if diagnosed early and treated effectively
However, survivors often have some degree of neurocognitive impairment
Untreated or delayed treatment carries a high mortality rate and severe neurological disability.
Follow Up:
Lifelong follow-up is essential for patients diagnosed with IEMs causing hyperammonemia
This includes regular monitoring of ammonia levels, metabolic status, growth, and neurodevelopment
Dietary adjustments and medication management are crucial
Periodic evaluation by a metabolic specialist and dietitian is required
Psychological support for patients and families is important.
Key Points
Exam Focus:
Always suspect IEM in a neonate or infant with unexplained encephalopathy, lethargy, vomiting, or seizures, especially with metabolic acidosis or hyperammonemia
Differentiate between acute ammonia toxicity and the underlying IEM
Understand the rapid management steps: stop protein, give non-protein calories, start ammonia scavengers, and consider dialysis urgently for severe cases.
Clinical Pearls:
Transport blood for ammonia on ice and without delay
Recognize that a normal glucose level does not rule out an IEM causing hyperammonemia
Remember that protein restriction alone is insufficient
aggressive ammonia-lowering strategies are paramount
Liver transplantation is a definitive treatment for UCDs but not a first-line emergency management.
Common Mistakes:
Delaying ammonia measurement or management
Insufficient non-protein caloric support, leading to continued catabolism
Inadequate doses of ammonia scavengers or delaying their initiation
Misattributing symptoms to common conditions like sepsis without considering IEMs
Failing to consider dialysis for refractory hyperammonemia or very high ammonia levels.