What causes episodic encephalopathy or delirium with normal ammonia levels?

Episodic Encephalopathy/Delirium with Normal Ammonia Levels

Normal ammonia levels in a patient with episodic encephalopathy and liver disease essentially rule out hepatic encephalopathy as the primary diagnosis and mandate an immediate search for alternative causes of delirium. 1

Key Diagnostic Principle

A normal blood ammonia level has high negative predictive value for hepatic encephalopathy – if ammonia is normal, the patient lacks sufficient hepatic failure and/or portosystemic shunting to justify a working diagnosis of HE. 1, 2 This finding should trigger a comprehensive differential diagnostic workup for other causes of encephalopathy. 1

Alternative Causes to Investigate When Ammonia is Normal

Metabolic and Toxic Etiologies

• Electrolyte disturbances: Hyponatremia, hypercalcemia, and other imbalances commonly cause episodic confusion 1
• Renal dysfunction: Uremic encephalopathy can mimic HE with similar EEG changes 1
• Medication effects: Benzodiazepines, opioids, anticholinergics, and valproic acid (which can paradoxically cause hyperammonemia without liver disease) 3
• Thiamine deficiency: Wernicke's encephalopathy, particularly in malnourished patients or those with alcohol use disorder 1
• Hypoglycemia or hyperglycemia: Diabetic encephalopathy 1

Infectious Causes

• Septic encephalopathy: Systemic infection without CNS involvement can cause delirium 1
• CNS infections: Meningitis or encephalitis requiring lumbar puncture evaluation 1

Structural Brain Lesions

• Intracranial hemorrhage: Especially in patients with alcohol-related cirrhosis (relative risk >5 for intracerebral bleeding) 1
• Subdural hematoma: Common in elderly or those with falls 1
• Stroke or transient ischemic attacks: Can present with episodic confusion 1

Comorbid Neurodegenerative Conditions

• Mild cognitive impairment (MCI): Significant overlap with covert HE symptoms, particularly in patients >60 years old (prevalence up to 20%) 1
• Dementia: Language is preserved in HE but may be affected in other dementias 1

Other Nonhepatic Hyperammonemia (if ammonia later becomes elevated)

• Hematologic malignancies: Multiple myeloma can cause hyperammonemia without liver failure 3, 4
• Urea cycle disorders: Ornithine carbamoyltransferase (OTC) deficiency can present in adulthood 3
• Malnutrition-related hyperammonemia: Severe nutritional deficiencies can cause hyperammonemia independent of liver disease 5

Recommended Diagnostic Workup

Immediate Laboratory Assessment

• Comprehensive metabolic panel: Sodium, calcium, glucose, renal function 1
• Complete blood count: Evaluate for infection or hematologic malignancy 3
• Medication review: Identify potentially offending agents 1, 3
• Thiamine level: Especially if malnutrition or alcohol use disorder present 1

Brain Imaging

CT scan or MRI should be performed in cases of diagnostic doubt or non-response to treatment (strong recommendation, 96% consensus). 1 This is critical to exclude:

• Intracranial hemorrhage (particularly in alcohol-related liver disease) 1
• Structural lesions 1
• Brain atrophy (related to alcohol or metabolic syndrome rather than HE itself) 1

Important caveat: No cerebral imaging definitively proves HE diagnosis – imaging is used to exclude alternative diagnoses. 1

Additional Testing Based on Clinical Context

• EEG: Can help differentiate causes – would not be altered by diabetes or alcohol disorders but may show changes similar to HE in renal dysfunction, hyponatremia, or septic encephalopathy 1
• Lumbar puncture: If CNS infection suspected 1

Clinical Pitfalls to Avoid

• Do not assume HE based on liver disease alone: The presence of cirrhosis does not mean all encephalopathy is hepatic in origin 1
• Recognize episodic patterns: The fluctuating nature of covert HE differs from the more persistent cognitive impairment of MCI (which is typically noticeable for ≥6 months) 1
• Consider multiple concurrent causes: Patients with cirrhosis, especially elderly, frequently have comorbidities that overlap with HE symptoms 1
• Response to HE therapy as diagnostic tool: If symptoms do not improve with lactulose/rifaximin, this further supports an alternative diagnosis 1

Management Approach

When ammonia is normal, do not treat empirically for hepatic encephalopathy – instead, aggressively pursue and treat the actual underlying cause identified through systematic workup. 1, 2 The episodic nature suggests potentially reversible metabolic, toxic, or structural causes that require specific targeted therapy rather than ammonia-lowering strategies.