What is the appropriate workup and treatment for a patient with suspected hepatic encephalopathy?

Workup for Hepatic Encephalopathy

Immediately initiate a four-pronged approach: assess and protect the airway, systematically exclude alternative causes, identify and treat precipitating factors, and begin empirical ammonia-lowering therapy with lactulose while the workup proceeds. 1

Initial Clinical Assessment

Grade the mental status using the West Haven Criteria (Grade 1: altered sleep/attention; Grade 2: disorientation/asterixis; Grade 3: somnolence/confusion; Grade 4: coma), as this provides standardized severity assessment. 1, 2 For patients with grades 3-4 encephalopathy or significantly altered consciousness, add the Glasgow Coma Scale for more objective measurement. 1, 2

The diagnosis of overt HE remains clinical and based on exclusion—you must detect signs suggestive of HE in a patient with severe liver insufficiency who lacks obvious alternative causes of brain dysfunction. 2 Recognition of precipitating factors (infection, bleeding, constipation) supports the diagnosis. 2

Essential Laboratory Workup

Obtain a plasma ammonia level with proper collection technique immediately—a normal ammonia level has high negative predictive value and essentially excludes hepatic encephalopathy, mandating immediate reevaluation for alternative diagnoses. 1, 3, 2 This is critical: normal ammonia in a patient with episodic encephalopathy and liver disease rules out HE as the primary diagnosis. 3

Obtain a comprehensive metabolic panel including:

• Sodium (hyponatremia is a classical precipitating factor and can cause encephalopathy independently) 2, 3
• Glucose (to exclude hypo/hyperglycemia) 2, 3
• Calcium (hypercalcemia causes confusion) 3
• Renal function (uremic encephalopathy can mimic HE) 2, 3
• Full blood count and inflammatory markers (C-reactive protein) to screen for infection 2

Additional targeted tests:

• Blood alcohol level 2
• Thyroid-stimulating hormone 2
• Thiamine level if malnutrition or alcohol use disorder present 3

Systematic Search for Precipitating Factors

Approximately 90% of HE episodes can be managed by correcting the precipitating factor alone, making this search paramount. 1 All patients have at least one precipitating factor, and 82% have multiple concomitant factors. 4

Screen systematically for:

• Infections (urinary, pneumonia, spontaneous bacterial peritonitis)—present in 64% of cases 4, 2
• Gastrointestinal bleeding—present in 36% of cases 4, 2
• Acute kidney injury—present in 63% of cases 4, 2
• Constipation 2, 4
• Hyponatremia—present in 22% of cases 2, 4
• Dehydration and electrolyte disorders 1, 2
• Medications (benzodiazepines, opioids, proton pump inhibitors)—present in 41% of cases 2, 4, 2
• Non-adherence to ammonia-lowering therapy 4
• Recent TIPS placement 4

The number of concomitant precipitating factors is independently associated with mortality and need for transplantation. 4

Differential Diagnosis Workup

In patients with suspected HE, alternative or additional causes of neuropsychiatric impairment must be identified, as extrahepatic causes for acute encephalopathy occur in 22% of patients with liver disease suspected of HE. 2

When to Obtain Brain Imaging

Brain imaging (CT or MRI) is indicated for:

• First episode of altered mental status 1, 2
• Seizures or new focal neurological signs 1, 2
• Diagnostic doubt or non-response to treatment 3
• Any patient with coagulopathy and risk of intracranial hemorrhage 3

Brain imaging is not routinely necessary in patients with recurrent HE presenting similarly to prior episodes. 1, 2

Additional Diagnostic Tests When Indicated

• EEG: To exclude non-convulsive seizures 2
• Lumbar puncture: If CNS infection (meningitis/encephalitis) suspected 2, 3
• Screening for psychoactive drugs 2

Key Differential Diagnoses to Exclude

When ammonia is normal or diagnosis uncertain, consider:

• Septic encephalopathy (systemic infection without CNS involvement) 3
• Intracranial hemorrhage or subdural hematoma (especially with alcohol-related cirrhosis or falls) 3, 2
• Stroke or transient ischemic attacks 3
• Diabetic encephalopathy (hypoglycemia, ketoacidosis, hyperosmolar state) 2, 3
• Alcohol-related (intoxication, withdrawal, Wernicke encephalopathy) 2
• Neuroinfections 2
• Non-convulsive epilepsy 2
• Uremic encephalopathy (may overlap with HE in end-stage liver disease) 2, 3
• Thiamine deficiency/Wernicke's encephalopathy 3, 2
• Mild cognitive impairment or dementia (especially in patients >60 years—prevalence up to 20%) 2, 3

Empirical Treatment During Workup

Start lactulose immediately while the workup proceeds, unless a clear alternative diagnosis is identified. 1, 5 Lactulose is FDA-approved for prevention and treatment of portal-systemic encephalopathy and reduces blood ammonia levels by 25-50%, with clinical response in about 75% of patients. 5

For patients with recurrent HE despite lactulose, add rifaximin 550 mg twice daily. 6 In the trials for HE, 91% of patients were using lactulose concomitantly. 6

Critical 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. 3
• Do not ignore normal ammonia—this essentially excludes HE and mandates searching for alternative causes. 3, 1
• Do not overlook multiple concomitant precipitating factors—systematic screening for all precipitating factors is essential, as their presence predicts worse outcomes. 4
• If symptoms do not improve with lactulose/rifaximin, this further supports an alternative diagnosis and warrants expanded workup. 3
• Consider comorbidities in elderly patients—those with cirrhosis over age 60 frequently have overlapping conditions (MCI prevalence up to 20%) that mimic covert HE. 2, 3

Post-Diagnosis Management

Refer all patients to a transplant center for evaluation after the first episode of overt HE, as this indicates advanced liver disease. 1 All patients should receive lactulose as secondary prophylaxis after the first episode, titrated to 2-3 bowel movements daily. 1