What are the causes of acute metabolic encephalopathy?

Causes of Acute Metabolic Encephalopathy

The primary causes of acute metabolic encephalopathy include electrolyte imbalances, hepatic dysfunction with elevated ammonia levels, infections, renal dysfunction, hypo/hyperglycemia, alcohol or drug toxicity, and thiamine deficiency. 1

Definition and Clinical Presentation

• Acute metabolic encephalopathy is characterized by altered level of consciousness, changes in affect, and possible focal neurological signs including speech disorders, seizures, and cranial nerve dysfunctions 1
• Clinical presentation can range from mild executive dysfunction to deep coma with decerebrate posturing 2
• Symptoms typically develop acutely and may fluctuate in severity 1

Major Causes

Hepatic Dysfunction

• Hepatic encephalopathy is a common form of metabolic encephalopathy caused by liver failure and elevated ammonia levels 3
• Alcohol-related liver disease can cause both direct neurotoxicity and hepatic encephalopathy, making it difficult to distinguish between these mechanisms 3
• Metabolic dysfunction-associated fatty liver disease (MAFLD) can impair neurocognitive function even in non-cirrhotic stages 3
• Porto-sinusoidal hypertension can cause encephalopathy due to large portosystemic shunts even without significant liver dysfunction 3

Electrolyte Disturbances

• Hyponatremia is a significant risk factor for encephalopathy, with a critical threshold of <130 mmol/L 3
• Hyponatremia causes cerebral edema with extracellular hypo-osmolality, which synergizes with other metabolic disturbances 3
• Other electrolyte imbalances including dyskalaemia (potassium abnormalities) can precipitate encephalopathy 3, 1

Renal Dysfunction

• Acute kidney injury and chronic kidney disease can cause metabolic encephalopathy through multiple mechanisms 3
• Renal dysfunction leads to protein catabolism, amino acid metabolism abnormalities, and peripheral insulin resistance 3
• Uremic encephalopathy results from accumulation of uremic toxins affecting brain function 3

Medications and Toxins

• Benzodiazepines and opioid analgesics are independently associated with increased risk of encephalopathy in susceptible patients 3
• Proton pump inhibitors (PPIs) can increase the risk of encephalopathy by promoting intestinal dysbiosis and bacterial translocation 3
• Toluene and other solvents can cause toxic leukoencephalopathy 4

Infections

• Systemic infections, particularly urinary tract infections and pneumonia, can precipitate metabolic encephalopathy 3
• Inflammatory markers and bacterial endotoxins can contribute to neuroinflammation and cerebral dysfunction 3

Glucose Abnormalities

• Both hypoglycemia and hyperglycemia can cause acute metabolic encephalopathy 1, 5
• Insulin resistance and abnormal glucose metabolism are common in patients with liver or kidney dysfunction 3

Inherited Metabolic Disorders

• Urea cycle disorders, amino acid metabolism disorders, organic acid metabolism disorders, and fatty acid metabolism disorders can cause acute metabolic encephalopathy 6
• Mitochondrial diseases and mutations in thiamine-transporter genes can lead to metabolic encephalopathy 6

Nutritional Deficiencies

• Thiamine deficiency is a significant cause of metabolic encephalopathy, particularly in alcoholics 3
• Malnutrition can exacerbate metabolic disturbances and contribute to encephalopathy 3

Diagnostic Approach

• Comprehensive evaluation should include blood tests for glucose, electrolytes, inflammatory markers, full blood count, blood alcohol level, and ammonia 3
• Thyroid function tests, brain imaging, screening for psychoactive drugs, and lumbar puncture may be necessary to rule out other causes 3
• Electroencephalogram (EEG) can help exclude non-convulsive seizures and assess severity of brain dysfunction 3, 1

Management Principles

• Identify and treat the underlying cause of metabolic encephalopathy 1, 5
• Correct electrolyte imbalances, particularly sodium disturbances 3, 1
• Avoid medications that can worsen encephalopathy, such as benzodiazepines and opioids in hepatic encephalopathy 3
• Monitor sodium levels in patients with decompensated cirrhosis to prevent hyponatremia-induced encephalopathy 3
• Limit PPI prescriptions to their strict validated indications in patients at risk 3
• Provide supportive care and symptomatic treatment as needed 1, 5

Clinical Pitfalls

• Alternative or additional causes of neuropsychiatric impairment should always be considered in patients with suspected metabolic encephalopathy 3
• Extrahepatic causes for acute encephalopathy are found in 22% of patients with liver disease initially suspected of hepatic encephalopathy 3
• During epidemics or pandemics, focus on infectious causes may lead to missed diagnoses of metabolic encephalopathies 1
• Patients with pre-existing neurological conditions may present atypically 1