Hepatic encephalopathy

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Hepatic encephalopathy refers to brain dysfunction in the presence of underlying liver disease. It is common in patients with cirrhosis. Precipitating factors include infections, gastrointestinal bleeding, and constipation. Pathophysiology is complex and not completely understood, however, the accumulation of ammonia in the blood plays a central role. Clinical features vary and may include confusion, asterixis, and even coma. Diagnosis of overt hepatic encephalopathy is based on the presence of characteristic clinical features but the diagnosis of covert hepatic encephalopathy requires psychometric testing to confirm a diagnosis. Treatment consists of identifying and treating the underlying cause (e.g., GI bleeding) and pharmacotherapy with disaccharide laxatives (e.g., lactulose) and/or rifaximin. Liver transplant is the only curative therapy.

Brain dysfunction (e.g., fluctuations in mental status and cognitive function) in the presence of liver insufficiency (e.g., cirrhosis) ^[2][3]

• 30–40% of patients with cirrhosis will experience overt hepatic encephalopathy at least once during their clinical course ^[2]

Epidemiological data refers to the US, unless otherwise specified.

• Caused by underlying liver dysfunction (e.g., cirrhosis, acute liver failure)
• Precipitating factors include: ^[4]
  • Increased absorption or production of ammonia
    • Infections (e.g., spontaneous bacterial peritonitis, SIRS)
    • Gastrointestinal bleeding
    • Constipation
    • Increased dietary protein intake
    • Hypokalemia
  • Decreased metabolism and clearance of ammonia
    • Renal failure
    • PVT
    • Portosystemic shunts (e.g., after TIPS placement)
    • Hypovolemia (dehydration, diarrhea, vomit)
    • Metabolic alkalosis
    • Diuretic use (hypokalemia, hyponatremia)

• Cirrhosis → ↓ hepatic metabolism and portosystemic shunt → accumulation of neurotoxic metabolites, including ammonia (NH₃) → ammonia crosses blood-brain barrier, is taken up by astrocytes, and converted to glutamine → ↑ osmotic pressure and cellular swelling → cerebral edema and ↑ intracranial pressure → neurological deterioration
• Metabolic effects:
  • Hypokalemia → compensatory shift of K⁺ ions out of the cells and H⁺ ions into the cells to maintain electroneutrality → intracellular acidosis → stimulates tubular cells to produce more ammonia → neurological deterioration
  • Metabolic alkalosis → decreased H⁺ ion availability → decreased conversion of ammonia (NH₃) to ammonium (NH₄⁺) → increased levels of ammonia, which diffuses freely across the blood-brain barrier → neurological deterioration
    
    

Symptoms are usually reversible and may be nonspecific.

• Fatigue, lethargy, apathy
• Altered levels of consciousness, ranging from mild confusion to stupor or coma
• Disoriented
• Irritability
• Memory loss
• Impaired sleeping patterns
• Socially aberrant behavior (e.g., urinating/defecating in public, shouting at strangers)
• Slurred speech
• Asterixis
• Muscle rigidity

Classification is generally based on the following four parameters: ^[2][5]

• Underlying disease
  • Type A: acute liver failure
  • Type B: portosystemic bypassing
  • Type C: cirrhosis
• Severity: graded according to the West Haven criteria based on clinical features ^[2][5]
  • Covert hepatic encephalopathy: symptoms minor/absent; abnormalities are present on neuropsychological and/or neurophysiological testing
  • Overt hepatic encephalopathy: symptoms present and reproducible; corresponds with West Haven criteria grade II or higher
• Time course
  • Episodic
  • Recurrent
  • Persistent
• Presence of precipitating factors: nonprecipitated or precipitated

General principles ^[2][6]

• Diagnosis of hepatic encephalopathy is largely clinical and based on ruling out alternate explanations for altered mental status.
• It is critical to identify the precipitating factor (e.g., GI bleed).
• The diagnosis of covert hepatic encephalopathy requires psychometric testing, which is usually carried out by a specialist. ^[2][6]

Initial evaluation ^[2][7]

• Physical examination
  • Assessment of mental status (e.g., orientation, Glasgow coma scale)
  • Evaluation for asterixis
• Laboratory studies
  • CBC, BMP: rule out hypoglycemia, hyponatremia, uremia, ketoacidosis, and hypercalcemia
  • CRP, WBC count, blood cultures, urinalysis, and culture: evaluate for underlying infection
  • Blood alcohol: rule out alcohol intoxication
  • Ammonia level: low/normal level may be helpful to rule out hepatic encephalopathy ^[2][5]

Additional evaluation

• Imaging:
  • Chest x-ray to rule out infection
  • Consider an abdominal ultrasound to assess for ascites and PVT
  • Consider CT or MRI head to rule out alternate etiology. ^[8]
• Psychometric tests (e.g., number connection test): usually carried out by specialists to quantify the severity of hepatic encephalopathy

Serum ammonia levels are usually elevated in hepatic encephalopathy. However, elevated levels are not diagnostic and the magnitude of elevation does not correlate with the degree of encephalopathy. ^[7]

General measures ^[2][9]

• Avoid further insult (e.g., hepatotoxic medication, alcohol).
• Treat precipitating factors (e.g., hypovolemia, constipation, GI bleeding, electrolyte disturbances). ^[2]
• Nutritional recommendations ^[9]
  • Routinely assess for malnutrition. See “Clinical evaluation of malnutrition in adults.”
  • Dietary protein restriction is not recommended.
  • Consider branched-chain amino acid supplementation if available.
• Liver transplant is the ultimate treatment.

Identification and treatment of infection and/or bleeding is critical, as these precipitants are associated with high mortality. ^[5]

Pharmacotherapy ^[2]

• Lactulose: a synthetic disaccharide laxative
  • Indications: first-line for ; prevention and treatment of hepatic encephalopathy
  • Routes: lactulose PO or lactulose PR ^[10]
  • Mechanism: Lactulose is converted to lactic acid by intestinal flora → acidification in the gut → conversion of ammonia (NH₃) to ammonium (NH₄⁺) → ammonium is excreted in the feces → decreased blood ammonia concentration → decreased absorption of ammonia in the bowel → improved symptoms of hepatic encephalopathy
• Rifaximin (off-label) ; : a broad-spectrum, nonabsorbable oral antibiotic ^[11]
  • Reduces the number of ammonia-producing intestinal bacteria
  • May be added to lactulose if a second episode occurs to prevent recurrent episodes of hepatic encephalopathy ^[2]

Oral administration of medications may not be safe in patients with overt hepatic encephalopathy at risk of aspiration. Consider alternative administration routes.

Liver transplant ^[5]

• Only definitive treatment option ^[5]
• Consider in all patients with recurrent or persistent HE
• Referral for evaluation by transplant center is recommended for all patients with first episode of overt hepatic encephalopathy

Disposition ^[5]

• Multiple factors play a role in disposition/triage (e.g., GCS level/ability to protect airway, severity of hepatic encephalopathy, prognosis, medical futility)
• ICU management is generally recommended in patients with overt hepatic encephalopathy who are at risk of aspiration ^[5]

Prevention ^[2][5]

• After the initial episode of overt hepatic encephalopathy: lactulose
• For recurrent episodes: combination therapy of lactulose PLUS rifaximin
• Patients with cirrhosis presenting with GI bleeding: consider rapid removal of blood from GI tract via e.g., lactulose by NG tube or enema ^[5]