What could be causing encephalopathy with a mildly elevated ammonia level?

Differential Diagnosis for Encephalopathy with Mildly Elevated Ammonia (88 μmol/L)

An ammonia level of 88 μmol/L (approximately 150 μg/dL) is only mildly elevated and should prompt investigation for non-hepatic causes of encephalopathy, including partial urea cycle defects, medication effects (particularly valproic acid), organic acidemias, infection, metabolic derangements, and structural brain lesions—while simultaneously treating any precipitating factors. 1, 2

Understanding the Clinical Context

The ammonia level of 88 μmol/L falls into a gray zone that requires careful interpretation:

• Normal ammonia levels are ≤35 μmol/L (≤60 μg/dL), with hyperammonemia defined as ≥50 μmol/L (85 μg/dL) in adults 1
• This level is below the threshold (>150 μmol/L) typically associated with rapidly deteriorating neurological status or cerebral edema 3
• Levels >200 μmol/L (341 μg/dL) are associated with cerebral herniation and poor neurological outcomes, which this patient has not reached 3
• Ammonia levels do not always correlate with encephalopathy severity in cirrhotic patients, and management should not be guided solely by ammonia values 4

Primary Diagnostic Considerations

Partial Urea Cycle Disorders (Most Important to Rule Out)

Adult-onset urea cycle defects can present with encephalopathy at modest ammonia elevations, particularly ornithine transcarbamylase (OTC) deficiency:

• OTC deficiency is the most common urea cycle disorder (1 in 56,500 births) and can manifest for the first time in adulthood 1, 2
• Late-onset presentations include headache, protein avoidance, psychiatric symptoms, lethargy, and episodic encephalopathy triggered by illness, exercise, or pregnancy 1, 2, 5
• Key diagnostic test: Urine orotic acid levels (elevated in OTC deficiency) and plasma amino acid profile 6, 5, 7
• Other UCDs include deficiencies of carbamylphosphate synthase, N-acetylglutamate synthase, argininosuccinate lyase, and arginase 2

Medication-Induced Hyperammonemia

Valproic acid (Depakene) inhibits the urea cycle and is a common cause of hyperammonemia with encephalopathy:

• Review all medications, particularly valproic acid, which can cause hyperammonemia even without liver dysfunction 1
• Discontinuation of the offending agent is critical 1

Organic Acidemias

Methylmalonic acidemia, isovaleric acidemia, and multiple carboxylase deficiency can present with hyperammonemia:

• Incidence approximately 1 in 21,000 births 1
• Diagnostic test: Urine organic acids and plasma acylcarnitine profile 6

Acute Kidney Injury

Impaired renal ammonia excretion can cause modest hyperammonemia:

• Check creatinine, BUN, and assess for acute kidney injury 1
• Acute kidney injury impairs ammonia excretion independent of liver function 1

Infection and Metabolic Precipitants

Common triggers that can unmask underlying ammonia metabolism disorders:

• Infections, dehydration, constipation, electrolyte disorders (particularly alkalosis), and gastrointestinal bleeding can precipitate encephalopathy 6
• Respiratory alkalosis is an important early clue distinguishing hyperammonemia from other causes 1

Structural Brain Lesions

CT or MRI brain imaging is essential to exclude:

• Intracranial hemorrhage, stroke, mass lesions, or cerebral edema 3, 6
• Brain imaging should be performed early, particularly if focal neurological signs are present 3

Immediate Diagnostic Workup

Obtain the following tests urgently:

• Plasma amino acid profile to identify patterns suggestive of urea cycle disorders 6
• Urine orotic acid (elevated in OTC deficiency) 6, 5
• Urine organic acids to identify organic acidemias 6
• Plasma acylcarnitine profile for fatty acid oxidation disorders 6
• Complete metabolic panel including liver function tests, creatinine, electrolytes 6
• Medication review with specific attention to valproic acid 1
• CT or MRI brain to exclude structural lesions 3, 6
• Lactate and pyruvate if mitochondrial disorder suspected 6

Management Approach at This Ammonia Level

Medical Management (Not Dialysis)

At 88 μmol/L, this patient does NOT meet criteria for urgent hemodialysis, which is reserved for:

• Ammonia >150 μmol/L with rapidly deteriorating neurological status 3
• Ammonia >300-400 μmol/L refractory to medical therapy 3, 6
• Moderate to severe encephalopathy (Grade 3-4) with persistently elevated levels 3

Appropriate initial management includes:

• Temporarily stop protein intake to reduce nitrogen load 6, 2
• Administer IV glucose (8-10 mg/kg/min) to prevent catabolism 6
• Provide IV lipids (0.5 g/kg/day, up to 3 g/kg/day) for caloric support 6
• Lactulose 30-45 mL orally or via nasogastric tube every 1-2 hours until bowel movement, then titrate to 2-3 soft stools daily 3, 8
• Identify and treat precipitating factors (infection, constipation, dehydration, medications) 6

Monitoring Requirements

Serial ammonia measurements every 3-4 hours initially:

• Monitor for rising levels that would prompt escalation of therapy 6
• Ensure proper sample collection (free-flowing venous or arterial blood, processed quickly) to avoid false elevations 6
• Continuous neurological assessment using Glasgow Coma Scale or West Haven criteria 6

Critical Pitfalls to Avoid

• Do not assume cirrhotic hepatic encephalopathy without confirming liver disease—adult-onset urea cycle defects can present identically 2, 5
• Do not delay urine orotic acid testing if UCD is suspected, as this is diagnostic for OTC deficiency 5, 7
• Do not continue protein intake if ammonia is rising or encephalopathy worsening 6
• Do not rely solely on ammonia levels to guide lactulose dosing in cirrhotic patients, as levels do not correlate with treatment response 4
• Do not wait for ammonia >200 μmol/L to investigate alternative causes—the diagnosis of partial UCD or medication effect should be made early 1, 2

When to Escalate Therapy

Consider nitrogen scavengers (sodium benzoate) if:

• Ammonia continues to rise despite lactulose and supportive care 2, 7
• Encephalopathy worsens to Grade 3-4 3

Prepare for urgent hemodialysis if:

• Ammonia rises above 300 μmol/L despite medical therapy 3, 6
• Neurological status rapidly deteriorates 3
• Signs of cerebral edema develop 3