Hepatic Encephalopathy

Essentials of Diagnosis

• Stage 1: mild confusion

• Stage 2: drowsiness

• Stage 3: stupor

• Stage 4: coma

• A revised staging system known as SONIC (Spectrum Of Neurocognitive Impairment in Cirrhosis) encompasses absent, covert, and stages 2 to 4 encephalopathy

General Considerations

• A state of disordered central nervous system function resulting from failure of the liver to detoxify noxious agents of gut origin because of hepatocellular dysfunction and portosystemic shunting

• Ammonia is the most readily identified toxin but is not solely responsible for the disturbed mental status

• Precipitants of hepatic encephalopathy

  • Gastrointestinal (GI) bleeding—increases the protein in the bowel and rapidly precipitates hepatic encephalopathy

  • Constipation

  • Alkalosis

  • Potassium deficiency induced by diuretics

  • Opioids, hypnotics, and sedatives

  • Medications containing ammonium or amino compounds

  • Paracentesis with consequent hypovolemia

  • Hepatic or systemic infection

  • Portosystemic shunts (including transjugular intrahepatic portosystemic shunts)

• In one study, risk factors for hepatic encephalopathy in patients with cirrhosis included a higher serum bilirubin level and use of a nonselective β-blocker, whereas a higher serum albumin level and use of a statin were protective

Demographics

• Alcoholic liver disease and chronic hepatitis C are the most common etiologies of cirrhosis

Symptoms and Signs

• Metabolic encephalopathy characterized by

  • Day–night reversal

  • Asterixis, tremor, dysarthria

  • Delirium

  • Drowsiness, stupor, and ultimately coma

• In patients with cirrhosis, may be precipitated by an acute hepatocellular insult or an episode of GI bleeding

• Clinical diagnosis supported by asterixis, elevated serum ammonia with exclusion of other causes of delirium

• Covert hepatic encephalopathy is characterized by mild cognitive and psychomotor deficits

  • EncephalApp

    • A smartphone app that uses the "Stroop test" (asking the patient to name the color of a written word rather than the word itself, even when the word is the name of a different color)

    • Has proved useful for detecting covert hepatic encephalopathy

Differential Diagnosis

• Metabolic encephalopathy, especially hyponatremia, hypoglycemia, or chronic kidney disease

• CNS infection

• Altered mental status from medication effects, particularly if they are hepatically metabolized

Laboratory Tests

• Liver biochemical tests often consistent with advanced chronic liver disease

• Serum (and cerebrospinal fluid) ammonia level is generally elevated

• Role of neuroimaging tests (eg, cerebral positron emission tomography, magnetic resonance spectroscopy) is evolving

Medications

• Purge blood from the GI tract with 120 mL of magnesium citrate by mouth or nasogastric (NG) tube every 3–4 hours until the stool is free of gross blood, or by administration of lactulose

• Lactulose

  • Initial dose is 30 mL three or four times daily orally

  • Titrate so that the patient produces two or three soft stools per day

  • Administer rectally if patient cannot take orally: lactulose 200 g/300 mL in a solution of saline or sorbitol as a retention enema for 30–60 min; it may be repeated every 4–6 hours

• Bowel cleansing with a polyethylene glycol colonoscopy preparation is also effective in patients with acute overt hepatic encephalopathy and may be preferable

• Neomycin sulfate, 0.5–1 g orally every 6 or 12 hours for 7 days

  • Controls the ammonia-producing intestinal flora

  • Side effects include diarrhea, malabsorption, superinfection, ototoxicity, and nephrotoxicity, usually only after prolonged use

• Alternative antibiotics

  • Rifaximin, 550 mg orally twice daily

  • Metronidazole, 250 mg orally three times daily

• Patients who do not respond to lactulose may improve with a 1-week course of an antibiotic in addition to lactulose

• Probiotic agents may have some benefit

• Avoid opioids and sedatives metabolized or excreted by the liver

• If agitation is marked, oxazepam, 10–30 mg (not metabolized by the liver) may be given cautiously orally or by NG tube

• Correct zinc deficiency, if present, with oral zinc sulfate, 600 mg/day in divided doses

• Sodium benzoate, 5 g twice daily, ornithine aspartate, 9 g three times daily, and L-acyl-carnitine, 4 g orally daily, may lower blood ammonia levels, but less is known about these drugs than lactulose

• Flumazenil is effective in about 30% of severe hepatic encephalopathy, but the drug is short-acting and intravenous administration is required

Therapeutic Procedures

• Withhold dietary protein during acute episodes

• When the patient resumes oral intake, protein intake should be restricted to 60–80 g/day as tolerated, and vegetable protein is better tolerated than meat protein

• Use of special dietary supplements enriched with branched-chain amino acids is usually unnecessary except in occasional patients who are intolerant of standard protein supplements

Complications

• Hypernatremia can develop from intensive lactulose use

When to Admit

• Inability to care for self or follow medical instructions