G. Bryan Young, MD
DESCRIPTION
Hepatic encephalopathy is classified into acute and chronic varieties according to its associated liver abnormality. Acute hepatic failure is characterized by an encephalopathy and coagulopathy within 6 months of the onset of liver disease. A subcategory is fulminant hepatic failure that develops within 8 weeks of the onset of the hepatic dysfunction. Chronic liver disease evolves over a longer time and is associated with a fluctuating course of cerebral dysfunction, although some patients accumulate progressive motor and cognitive deficits.
EPIDEMIOLOGY
- Incidence
- Acute hepatic failure affects >2,000 Americans per year. All are encephalopathic, and the mortality is about 80%.
- Conservatively, 1 in 3,000 of the American population is susceptible to chronic hepatic encephalopathy, based on the prevalence of cirrhosis.
- Age
- The age range is wide, but most cases with chronic hepatic encephalopathy are middle-aged adults.
RISK FACTORS
- The risk for chronic hepatic encephalopathy is increased after portal-systemic shunting procedures are used to treat portal hypertension, especially bleeding esophageal varices, including transjugular intrahepatic portal-systemic shunting.
Pregnancy Considerations
- Acute fatty liver of pregnancy occurs late in pregnancy. It is associated with jaundice and a small liver. Often, the fetus is male with a deficiency of long-chain 3-hydroxyacyl-COH dehydrogenase.
ETIOLOGY
- Many cases of acute liver failure are due to acute viral hepatitis or drug-induced liver injury (especially acetaminophen overdose). Less common causes include ischemia of the liver and toxins (e.g., mushroom poisoning or Wilson's disease).
- Chronic liver disease has a more varied association with encephalopathy, and the incidence is not well defined. Most cases are related to alcoholic cirrhosis. GI bleeding is a common precipitant of the encephalopathy in such patients, as this presents an increased load of nitrogen to the hepatic and then systemic circulation. Electrolyte disturbances, drugs (especially sedative drugs), infection, and surgery are other precipitants.
- The specific cause of the brain dysfunction is not known, but exposure of the brain, via the systemic circulation, to nitrogenous substances (including ammonia and increased aromatic amino acids, which can act as false neurotransmitters) is a probable cause. Increased γ-aminobutyric acid, manganese, and opioids in the brain are also proposed to cause brain dysfunction. The cerebral edema that often accompanies acute hepatic encephalopathy is related to osmotic-induced astrocytic swelling (probably related to ammonia), as well as brain hyperemia.
COMMONLY ASSOCIATED CONDITIONS
- Hypoglycemia, hyponatremia, pulmonary infections, and sepsis, coagulopathy (with bleeding complications, including subdural hematoma) are common accompaniments.
- Hepatorenal syndrome occurs in some patients with cirrhosis and patients with acute liver failure, and it consists of worsening azotemia with sodium retention, oliguria, and hypotension. It is probably related to altered renal hemodynamics.
- Hepatopulmonary syndrome comprises hypoxemia-related right-to-left intrapulmonary shunts associated with increased endothelin-1 and pulmonary nitric oxide.
- Acquired (non-Wilsonian) hepatocerebral degeneration associated with cognitive changes, extrapyramidal findings, ataxia, and myelopathy with widespread CNS damage may complicate protracted or repeated bouts of portal-systemic encephalopathy.
- Patients usually have stigmata of liver disease. In acute hepatic failure, jaundice, hyperventilation with respiratory alkalosis, and bruising from the associated coagulopathy are common. Patients with chronic, portal-caval anastomotic liver disease may not be jaundiced when they have exacerbations of liver dysfunction and encephalopathy. However, they usually have other signs, e.g., evidence of portal hypertension (such as ascites and splenomegaly), spider nevi, gynecomastia in adult males, and parotid gland enlargement.
- Acute hepatic failure is characterized by an initial delirium, often with delusions and hyperkinesis. Chronic hepatic encephalopathy shows greater fluctuation, with relapses and remissions over a long time, although acute decompensation is also possible. Even at their best, patients with chronic portal-caval shunting show decreased psychomotor speed and deficits in visual perception, orientation, and constructive ability. Disorders of attention underlie these deficits. Some patients develop extrapyramidal movement disorders, including chorea or athetosis. Asterixis or flapping tremor is a transient loss of tone of muscles, causing the part of the body that is sustained against gravity to slump. This can include the outstretched arms and wrists, the head or the neck, or the whole body while standing upright.
- There are four stages of hepatic encephalopathy (Table 1).
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
- EEG shows typical triphasic waves in adult patients who are moderately encephalopathic, succeeded by diffuse delta (frequencies ≤4 Hz) and suppression in coma.
- No diagnostic liver abnormalities found on commonly available biochemical testing, but elevated serum ammonia is highly suggestive.
- Respiratory alkalosis is characteristic; with advanced hepatic failure, lactic acidosis supervenes.
- Elevated glutamine in the CSF is characteristic, but lumbar puncture is often contraindicated.
Imaging
- CT scanning is helpful in gauging the degree of cerebral edema (cortical sulci less visible, increased visibility of white matter, and basal cisterns obliterated) in acute hepatic encephalopathy. With chronic hepatic encephalopathy, there is an increased T1 signal in the basal ganglia and substantia nigra, probably related to manganese deposition.
Diagnostic Procedures/Other
- In young patients, Wilson's disease is worth excluding. The diagnosis is made by finding any of the following combinations:
- Serum ceruloplasmin <20 mg/dL and Kayser–Fleischer rings.
- Serum ceruloplasmin <20 mg/dL and a copper concentration >250 µg/g dry weight on a liver biopsy sample.
- Compatible clinical picture and urinary excretion <100 µg copper/day in the urine.
DIFFERENTIAL DIAGNOSIS
- Intoxications with alcohol and drugs
- Infections, e.g., sepsis, meningitis
- Subdural hematomas, especially if bilateral, may be associated with fluctuating level of consciousness without strong lateralized features.
- Alcohol withdrawal syndromes
- Other metabolic disorders, including hypoglycemia
MEDICATION
- Induction therapy: Acutely, lactulose syrup 30–60 mL is given every hour until diarrhea occurs. (Although some question the usefulness of lactulose, decreasing the protein in the gut is advisable.) Neomycin 0.5–1.0 g every 6 hours is given orally.
- Maintenance therapy: Chronic encephalopathy, especially in patients with portal-systemic shunting, can be controlled by regular oral administration of lactulose and reducing dietary protein.
- Contraindications
- Avoid sedating drugs, especially benzodiazepines and barbiturates, and any measure that produces a systemic alkalosis, which increases ammonia production from ammonium ion.
- Precautions
- Avoid hypocalcemia, which increases ammonia production. Vigorous paracentesis may produce electrolyte imbalance and precipitate or aggravate encephalopathy. Prevention of constipation is important. Any patient who is to undergo surgery should be monitored closely and the anesthesiologist informed well in advance of the surgery.
- Alternative drugs
ADDITIONAL TREATMENT
General Measures
- Decrease ammonia production in the gut. Evacuate the bowel with laxatives and lactulose (also helps to convert ammonia to ammonium, which is less well absorbed) and enemas. Use neomycin to kill colonic bacteria.
- Give 20% glucose IV to prevent and correct for hypoglycemia.
- Restrict dietary protein and give carbohydrate supplements to exceed 1,600 calories/day.
- Check for and correct coagulopathy.
- Survey for and treat infections.
COMPLEMENTARY AND ALTERNATIVE THERAPIES
- Symptomatic treatment
- Patients with impaired consciousness should be cared for in an intensive care setting with the usual supportive measures.
- Mannitol or hypertonic saline has limited effectiveness in controlling cerebral edema in acute hepatic failure.
- Consider mild hypothermia as a means of preventing brain hyperemia and increased intracranial pressure in acute or hyperacute liver failure. The combination of hyperosmolar therapy and hypothermia may be more effective than either separately.
- Patients with bleeding complications may require transfusions of platelets or fresh frozen plasma.
- Adjunctive treatments
- Branched-chain amino acid infusions, flumazenil (a benzodiazepine receptor blocker), hemoperfusion, and extracorporeal liver-assist techniques are unproven, but the latter two occasionally can “bridge” the patient who is to undergo liver transplantation.
SURGERY/OTHER PROCEDURES
- Liver transplantation is appropriate for certain patients with acute hepatic failure. The King's College criteria are still commonly used (Table 2). Surgery should be done promptly, before the patient develops severe cerebral edema.
IN-PATIENT CONSIDERATIONS
Admission Criteria
- Patients with impaired consciousness require hospital admission, as do patients with acute hepatic failure or disease, in anticipation of encephalopathy. Patients with upper GI bleeding require emergency therapy for the bleeding and careful monitoring for encephalopathy.
- Discharging patients is an individual matter, with due consideration to medical status and support measures being in place.
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Acutely, patients need to be checked at least daily for clinical level of consciousness. Serial or continuous EEG monitoring offers a sensitive and objective assessment. The Mini-Mental State Examination is commonly used to track attention and concentration, but the Confusion Assessment Method and the Delirium Symptom Interview are alternatives. After discharge, follow-up with a family physician helps to ensure compliance with the treatment regimen.
PATIENT EDUCATION
- Regular follow-ups, checks for compliance with diet, prompt recognition and treatment of GI bleeding and infections, and care with medications are important measures.
PROGNOSIS
- Mortality and morbidity are high in patients with all types of hepatic coma. Survivors may be left with neurologic impairment. Severity of encephalopathy, small liver size and epileptiform activity on EEG are unfavorable prognostic features.
