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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.
- Caused by underlying liver dysfunction (e.g., cirrhosis, acute liver failure)
- Precipitating factors include: 
- Increased absorption or production of ammonia
- Decreased metabolism and clearance of ammonia
- Cirrhosis → ↓ hepatic metabolism and portosystemic shunt → accumulation of neurotoxic metabolites, including ammonia (NH3) → excess glutamine and swelling produced by astrocytes → cerebral edema and ↑ intracranial pressure → neurological deterioration
- Metabolic effects:
- Hypokalemia → shift of K+ ions out of the cells → shift of H+ ions into the cells to maintain electroneutrality → intracellular acidosis → tubular cells produce more ammonia → neurological deterioration
- Metabolic alkalosis → decreased H+ ion availability → decreased conversion of ammonia to ammonium (NH4+) → increased levels of ammonia → diffuses freely through the blood-brain barrier → neurological deterioration
Symptoms are usually reversible and may be nonspecific.
- Fatigue, lethargy, apathy
- Altered , ranging from mild confusion to stupor or coma
- Memory loss
- Impaired sleeping patterns
- Multiple neurological and psychiatric disturbances
- Socially aberrant behavior (e.g., urinating/defecating in public, shouting at strangers)
- Slurred speech
- Muscle rigidity
Classification is generally based on the following four parameters: 
- Underlying disease
Severity: graded according to the West Haven criteria based on clinical features 
- 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
- Presence of precipitating factors: nonprecipitated or precipitated
General principles 
- 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. 
Initial evaluation 
- Physical examination
- 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 
- 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. 
General measures 
- Avoid further insult (e.g., hepatotoxic medication, alcohol).
- Treat precipitating factors (e.g., hypovolemia, constipation, GI bleeding, electrolyte disturbances). 
- Liver transplant is the ultimate treatment.
Identification and treatment of infection and/or bleeding is critical, as these precipitants are associated with high mortality. 
Lactulose: a synthetic disaccharide laxative
- First-line treatment for hepatic encephalopathy
- Improves symptoms of hepatic encephalopathy by decreasing the absorption of ammonia in the bowel
- 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
- Rifaximin : a broad-spectrum, nonabsorbable oral antibiotic (off-label) ;
Liver transplant 
- Only definitive treatment option 
- 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
- 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