Hepatic Encephalopathy

Hepatic encephalopathyCentral nervous system abnormalities may be seen in patient with chronic liver disease and are especially likely after portocaval shunts. Porta-systemic encephalopathy, ammonia intoxication, hepatic coma, and meat intoxication are terms used to refer to this condition. The manifestations range from lethargy to coma — from minor personality changes to psychosis — from asterixis to paraplegia. Hypothermia and hyperventilation may precede coma.

Pathogenesis

Hepatic encephalopathy is a reversible metabolic neuropathy that results from the action of chemicals absorbed from the gut on the brain. Increased exposure of the brain to these agents is the result of impaired hepatic metabolism due to cirrhosis or shunts of portal venous blood around the liver and increased permeability of the blood-brain barrier. The chemical agents responsible for encephalopathy form from the action of colonic bacteria on protein within the gut. Potential aggravating factors include gastrointestinal hemorrhage, constipation, azotemia, hypokalemic alkalosis, infection, excessive dietary protein, and sedatives. Four main theories concerning mediation of this syndrome currently attract the most attention.

Factors Contributing to Encephalopathy.

Increased systemic toxin levels

  • Extent of portal-systemic venous shunt
  • Depressed liver function
  • Intestinal protein load
  • Intestinal flora
  • Azotemia
  • Constipation

Increased sensitivity of central nervous system

  • Age of patient
  • Hypokalemia
  • Alkalosis
  • Diuretics
  • Sedatives, narcotics, tranquilizers
  • Infection
  • Hypoxia, hypoglycemia, myxedema

Amino Acid Neurotransmitters

Gamma-aminobutyric acid, the principal inhibitory neurotransmitter in the brain, produces a state similar to hepatic encephalopathy when given experimentally. It is normally synthesized in the brain and by bacteria within the colon; GABA in the GI tract is normally degraded by the liver and is found in increased levels in the serum of patient with hepatic encephalopathy. The passage of GABA across the blood-brain barrier is increased in hepatic encephalopathy. Experiments also indicate the presence of increased numbers of GABA receptors in encephalopathy and increased GABA-ergic tone, perhaps due to a benzodiazepine receptor agonist ligand on the receptor complex (GABA/benzodiazepine receptor). This has raised the possibility of treating encephalopathy with benzodiazepine antagonists, and the drug flumazenil has shown promise in preliminary trials.

Ammonia

Ammonia is produced in the colon and is absorbed and transported in portal venous blood to the liver, where it is extracted and converted to glutamine. Ammonia concentrations are elevated in the arterial blood of patients with encephalopathy, and experimental administration of ammonia produces central nervous system symptoms.

False Neurotransmitters

According to this theory, cerebral neurons become depleted of normal neurotransmitters (norepinephrine and dopamine), which are partially replaced by false neurotransmitters (octopamine and phenylethanolamine). The result is inhibition of neural function. Serum levels of branched-chain amino acids are decreased and levels of aromatic amino acids (tryptophan, phenylalanine, tyrosine) are elevated in patients with encephalopathy.

Synergistic Neurotoxins

This theory postulates that ammonia, mercaptans, and fatty acids, none of which accumulate in the brain in amounts capable of producing encephalopathy, have synergistic effects that produce the full-blown syndrome in patient with liver disease.

Prevention of Hepatic encephalopathy

Encephalopathy is a major side effect of portacaval shunt and is to some extent predictable. Elderly patients are considerably more susceptible. Patients with alcoholic liver disease fare better than those with postnecrotic or cryptogenic cirrhosis, apparently owing to the invariable progression of liver dysfunction in the latter. Good liver function partially protects against encephalopathy. If the liver has adapted to complete or nearly complete diversion of portal blood before operation, a surgical shunt is less apt to depress liver function further. For example, patient with thrombosis of the portal vein rarely experience encephalopathy after portal-systemic shunt. Encephalopathy is less common after a distal splenorenal (Warren) shunt than after other kinds of shunts.

Increased intestinal protein, whether of dietary origin or from intestinal bleeding, aggravates encephalopathy by providing more substrate for intestinal bacteria. Constipation allows more time for bacterial action on colonic contents. Azotemia results in higher concentration of blood urea, which diffuses into the intestine, is converted to ammonia, and is then reabsorbed. Hypokalemia and metabolic alkalosis aggravate encephalopathy by shifting ammonia from extracellular to intracellular sites where the toxic action occurs.

Laboratory Findings

Arterial ammonia levels are usually high. The presence of high levels of glutamine in the cerebrospinal fluid may help distinguish hepatic encephalopathy from other causes of coma. Electroencephalography is more sensitive than clinical evaluation in detecting minor involvement. The changes are nonspecific and consist of slower mean frequencies. Studies performed at different times can be compared to assess the effects of therapy.

Treatment of hepatic encephalopathy

Acute encephalopathy is treated by controlling precipitating factors, halting all dietary protein intake, cleansing the bowel with purgatives and enemas, and administering antibiotics (neomycin or ampicillin) or lactulose. Neomycin may be given orally or by gastric tube or rectally as an enema (1% solution one or two times daily). At least 1600 kcal of carbohydrate should be provided daily, along with therapeutic amounts of vitamins. Blood volume must be maintained to avoid prerenal azotemia. After the patient responds to initial therapy, dietary protein may be started at 20 g/d and increased by increments of 10–20 g every 2–5 days as tolerated.

Chronic encephalopathy is treated by restriction of dietary protein, avoidance of constipation, and elimination of sedatives, diuretics, and tranquilizers. To avoid protein depletion, protein intake must not be chronically reduced below 50 g/d. Vegetable protein in the diet is tolerated better than animal protein. Lactulose, a disaccharide unaffected by intestinal enzymes, is the drug of choice for long-term control. When given orally (20–30 g three or four times daily), it reaches the colon, where it stimulates bacterial anabolism (which increases ammonia uptake) and inhibits bacterial enzymes (which decreases the generation of nitrogenous toxins). Its effect is independent of colonic pH. A related compound outside the United States, lactitol (galactoside sorbitol), is also effective and appears to work faster. As a powder, it is easier to use than liquid lactulose. Intermittent courses of oral neomycin or metronidazole may be given if lactulose therapy and preventive measures are inadequate.

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