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

Workup and Management of Suspected Hepatic Encephalopathy

In patients with suspected hepatic encephalopathy, immediately initiate a four-pronged approach: (1) assess and protect airway if altered consciousness is present, (2) systematically exclude alternative causes of encephalopathy through targeted blood tests and selective brain imaging, (3) identify and treat precipitating factors, and (4) begin empirical ammonia-lowering therapy with lactulose while the workup proceeds. 1

Initial Clinical Assessment

Grading Severity

• Use the West Haven Criteria to grade mental status when at least temporal disorientation is present (grades 2-4), as this provides standardized severity assessment 1
• Add the Glasgow Coma Scale for patients with grades 3-4 encephalopathy or significantly altered consciousness 1
• Admit to ICU any patient with grade 3-4 HE, as they are at high risk for aspiration and require intensive monitoring 1

Key Clinical Features to Document

• Orientation status (time, place, person) 2
• Presence of asterixis (flapping tremor) 1, 2
• Recent precipitating events (infection, bleeding, medications, constipation) 1
• Complete neurological examination including cognitive, motor, sensory, and cranial nerve testing 2

Essential Laboratory Workup

Blood Tests (Obtain Immediately)

• Ammonia level with proper collection technique: fasting patient, avoid tourniquet/venous stasis, EDTA tube, place immediately on ice, transport to lab within 60-90 minutes at +4°C 1, 2
  • Critical interpretation: A normal ammonia level essentially excludes HE and mandates reevaluation for alternative diagnoses 1, 2
  • Elevated ammonia alone does NOT confirm HE diagnosis 1, 2
• Electrolytes (especially sodium and calcium) 1, 2
• Glucose 1, 2
• Complete blood count 2
• Renal function (creatinine, BUN) 2
• Inflammatory markers 2
• Coagulation studies 2

Additional Testing Based on Clinical Context

• Blood alcohol level and urine drug screen 1
• Medication levels (benzodiazepines, opioids) if applicable 1
• Blood cultures if infection suspected 1

Brain Imaging Strategy

Do NOT obtain routine brain imaging in patients with recurrent HE presenting similarly to prior episodes 1, 2

Indications for Brain Imaging (CT or MRI, preferably MRI)

• First episode of altered mental status 1, 2
• Seizures or new focal neurological signs 1
• Unsatisfactory response to treatment of precipitating factors and empirical HE therapy 1
• Any diagnostic uncertainty 1

Important caveat: Cirrhotic patients have at least a 5-fold increased risk of intracerebral hemorrhage, making imaging crucial when clinically indicated 1, 2

Systematic Exclusion of Alternative Diagnoses

HE is a diagnosis of exclusion—always rule out these common mimics 1, 2:

Metabolic/Toxic

• Alcohol intoxication or withdrawal (including Wernicke encephalopathy) 1
• Diabetic ketoacidosis or hyperosmolar state 1
• Hypoglycemia 1
• Hyponatremia or hypercalcemia 1, 2
• Drug effects (benzodiazepines, opioids, neuroleptics) 1

Neurological

• Intracranial bleeding or stroke 1
• Nonconvulsive seizures 1
• Structural brain lesions 1, 2

Infectious/Inflammatory

• Meningitis/encephalitis 1
• Sepsis (can coexist with and worsen HE) 1

Other

• Uremic encephalopathy (may overlap in end-stage liver disease) 1
• Psychiatric disorders 1

Identification of Precipitating Factors

Approximately 90% of HE episodes can be managed by correcting the precipitating factor alone 1

Common Precipitants to Actively Seek

• Infections (spontaneous bacterial peritonitis, urinary tract infection, pneumonia) 1
• Gastrointestinal bleeding 1
• Constipation 1
• Dehydration 1
• Electrolyte disorders (especially hypokalemia causing alkalosis) 1
• Acute kidney injury 1
• Medications (sedatives, diuretics) 1
• Under or overuse of lactulose 1

Empirical Treatment (Initiate Immediately)

First-Line Therapy: Lactulose

• Start lactulose immediately while workup proceeds, unless clear alternative diagnosis is identified 1, 3
• Dosing: Titrate to achieve 2-3 soft bowel movements per day 1, 3
• Routes of administration:
  • Oral: preferred if patient can take PO safely 1, 3
  • Nasogastric tube: if unable to take PO (use caution if recent variceal banding) 1
  • Rectal enema: 300 mL lactulose in 700 mL water (total 1 L) for grades 3-4 HE or if ileus present 1
• Monitor: Electrolytes to prevent dehydration and hypernatremia 1
• FDA-approved for prevention and treatment of portal-systemic encephalopathy, reducing blood ammonia by 25-50% with clinical response in ~75% of patients 3

Polyethylene Glycol Alternative

• Consider if patient at risk for ileus or abdominal distention 1

Rifaximin: Role in Acute Setting

• Not routinely recommended as monotherapy in acute overt HE 1
• Role as add-on therapy to lactulose in critically ill patients/ACLF warrants further investigation 1
• FDA-approved for secondary prophylaxis (reducing recurrence risk by 58% and HE-related hospitalizations by 50%) when added to lactulose after recovery 4

Special Considerations for Critically Ill Patients

Airway Management

• Use short-acting sedatives (propofol, dexmedetomidine) if intubation required 1
• Avoid long-acting benzodiazepines 1

Early Empiric Antibiotics

• Reasonable in patients at high risk for infection or when infection is likely precipitant 1

Monitoring Response

• Reassess mental status 2-4 times daily to determine rate of improvement 1
• If no improvement within 24-48 hours despite optimal therapy, reconsider diagnosis and obtain brain imaging 1

Testing for Covert Hepatic Encephalopathy

Only pursue if patient has minimal/no overt symptoms but complaints of cognitive dysfunction, impaired quality of life, or concerns about work performance/driving safety 1, 2

Screening Tools

• Animal Naming Test: Ask patient to name as many animals as possible in 1 minute; <20 animals suggests covert HE 1
• Psychometric Hepatic Encephalopathy Score (PHES): validated paper-pencil battery 2
• Critical Flicker Frequency test: computerized assessment 2

Common Pitfalls to Avoid

• Do not rely on ammonia levels alone for diagnosis—they are variable and can be elevated in non-HE conditions 1, 2
• Do not obtain routine brain imaging in patients with typical recurrent presentations 1, 2
• Do not delay empirical lactulose while waiting for workup completion 1
• Do not miss coexisting causes—infections, electrolyte disorders, and medications can synergize with HE to worsen mental status 1
• Do not forget proper ammonia collection technique—improper handling yields falsely elevated results 1, 2

Secondary Prophylaxis After Recovery

• All patients should receive lactulose as secondary prophylaxis after first episode of overt HE, titrated to 2-3 bowel movements daily 1
• Add rifaximin to lactulose if patient experiences >1 additional episode within 6 months (recurrent HE) 1, 4
• Refer to transplant center for evaluation after first episode of overt HE, as this indicates advanced liver disease 1