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Table of Contents

Karin B.
Cesario, MD

Department of
Gastroenterology
and Hepatology

William D.
Carey, MD

Department of
Gastroenterology
and Hepatology

Definition

Prevalence

Pathophysiology

Signs and
Symptoms

Diagnosis

Treatment

Outcomes

References

Hepatic encephalopathy (HE), also known as portosystemic encephalopathy or PSE, is defined as mental or neuromotor dysfunction in a patient with acute or chronic liver disease. Several forms of HE have been described (Table 1).¹ The acute form of HE is often associated with fulminant hepatic failure and may rapidly progress to seizures, coma, decerebrate posturing and death. In patients with cirrhosis, acute encephalopathy is most commonly associated with a precipitating factor such as electrolyte disturbance, medications, gastrointestinal hemorrhage, or infection. Recurrent HE may occur with or without a precipitating factor and is usually easily reversible. Persistent HE is rare, and is defined as the persistence of neuropsychiatric symptoms despite aggressive medical and dietary therapy. The most frequent form of HE is not always clinically apparent: a patient with subclinical HE has only mild cognitive deficits or subtle personality changes. Specific neuropsychological or neurophysiologic testing is required to secure the diagnosis.²

Most ammonia is produced in the intestine by both colonic breakdown of nitrogenous compounds and enterocytic catabolism of amino acids. Other sources of ammonia are the kidneys and skeletal muscle. Normally ammonia is metabolized in the liver (by its conversion to urea) and is excreted through the kidneys or colon. Another means of detoxifying ammonia is through the formation of glutamine from glutamate in the liver and brain. Impaired liver function, the shunting of blood around the liver and increased muscle wasting all lead to increased serum ammonia levels in cirrhotic patients.⁴

Ammonia interferes with brain function at many sites. Ammonia crosses the blood-brain barrier and directly depresses central nervous system functioning by inhibiting postsynaptic potentials.⁵ There is also evidence that hyperammonemia may facilitate the brain's uptake of tryptophan, a substance with neuroactive metabolites such as serotonin.⁶ Excess ammonia may reduce levels of brain adenosine triphosphate resulting in impaired cerebral energy.⁷ Lastly, the metabolism of ammonia to glutamine in the brain increases the intracellular osmolarity of astrocytes, inducing both astrocyte swelling and vasodilation.⁸ Increased astrocyte hydration without overt increased intracranial pressure is currently considered a major factor in the development of HE in patients with chronic liver disease.⁹

Toxins other than ammonia have also been implicated in the pathogenesis of HE. Excesses of neurotoxic short-chain fatty acids and mercaptans have received attention in the past.¹⁰ Patients with cirrhosis have also been shown to have decreased branched-chain amino acid-to-aromatic amino acid ratios. It has been postulated that the increased aromatic amino acid in the cirrhotic patient's brain may competitively inhibit normal neurotransmitters such as dopamine and norepinephrine.^11,12 Cirrhotic patients with HE have greatly increased serum manganese levels. Manganese may deposit directly in the basal ganglia and induce extrapyramidal symptoms.¹³ Manganese may also act synergistically with ammonia to activate peripheral-type benzodiazepine receptors and the GABA-ergic neuroinhibitory system.¹⁴

HE is a diagnosis of exclusion. Similar neuropsychiatric symptoms are seen in a variety of metabolic disorders, toxic ingestions, or intracranial processes (Table 4). In certain patients, brain imaging or electroencephalography may be indicated to exclude an intracranial abnormality. Lumbar puncture with cerebrospinal fluid analysis may also be required in patients with unexplained fever, leukocytosis, or symptoms suggestive of meningeal irritation. Knowledge of the existence of acute or chronic liver disease and/or the history of HE are often helpful in heightening clinical suspicion and/or securing the diagnosis.¹

The most commonly used laboratory test in HE is the venous ammonia level. Because of inconsistent elevation and lack of correlation with the stage of encephalopathy, the ammonia level is not considered a good screening tool.¹⁵ Measurement of serum ammonia can be helpful when, for example, the level is elevated and there is doubt regarding the presence of significant liver disease. The arterial ammonia concentration provides a more accurate assessment of the amount of ammonia at the blood-brain barrier, but is also of limited clinical utility.

Because of implications for diagnosis and treatment, a precipitating factor should be sought in all cirrhotic patients hospitalized for HE (Table 5).⁴ Serum determination of the complete blood cell count, electrolyte levels, and renal function is indicated in almost all cases. Recent use of psychoactive medications, such as narcotics or sedatives, should also be investigated. In a confused patient who cannot give a reliable history, the examination of stool or placement of a nasogastric tube may be of help in detecting gastrointestinal bleeding. Since infection is a common precipitating factor in HE, the culture of body fluids (urine, blood and ascites, if present) should be routinely performed. Lastly, constipation and the consumption of excessive dietary protein can precipitate HE. This is thought to be due to the increased nitrogen load in the gastrointestinal tract. Rare precipitants, such as hepatoma or vascular occlusion, need be investigated only if no other factors are thought to be contributing, or with clinical suspicion.

Standard supportive care is required for all hospitalized patients with HE. Patient safety and frequent monitoring of mental status is crucial. This may require additional personnel. In the case of comatose patients, admission to the intensive care unit and/or endotracheal intubation may be necessary. Patients with HE should also avoid prolonged periods of fasting. Although the restriction of dietary protein at the time of acute HE is often a cornerstone of therapy, protracted nitrogen restriction can lead to malnutrition. Therefore, appropriate enteral nutrition, either by mouth or nasogastric feeding tube, should be administered as soon as feasible.¹

A methodical search to identify and treat any precipitating factors is crucial in reversing the signs and symptoms of HE (see Diagnosis section above).

Because the toxins thought to be responsible for HE arise in the gastrointestinal tract, removal of the nitrogenous load is the mainstay of therapy. Various pharmacologic agents may be used, but the nondigestable disaccharide known as lactulose (Enulose or Kristalose) is currently the first-line therapy.¹ The exact mode of action of lactulose is uncertain, but is thought to involve both bacteriostatic and cathartic effects in the large intestine. After consumption, lactulose passes through the small bowel completely undigested. Once in the colon, lactulose is metabolized by colonic bacteria and the pH is lowered. This acidification of the bowel is thought to underlie the cathartic effect: ammonia can then pass from the bloodstream into the colonic lumen to be excreted. As a result, peripheral ammonia levels are reduced.¹⁶ Because lactulose is completely nonabsorbed, it does not alter serum glucose levels in diabetic patients, a concern of many patients and primary caregivers.

For acute encephalopathy, lactulose can be administered either orally, by mouth or through a nasogastric tube, or via retention enemas (Table 6). The usual oral dose is 45 mL followed by dosing every 1 to 2 hours until evacuation occurs. At that point, dosing is adjusted to attain two or three soft bowel movements daily. This usually requires 15 to 45 mL every 6 to 12 hours. Lactulose by enema is administered as 300 mL in 1 L of water, and should be retained for 1 hour. Due to the difficulty of administration, lactulose by enema is not generally used for chronic therapy. Common side effects include flatulence, bloating, and diarrhea. Lactitol, which is generally easier to tolerate, is used only in Europe and is not currently available in the United States.¹

For patients who do not tolerate lactulose or have continued symptoms, antibiotics are a second-line alternative for therapy.¹ Antibiotics are thought to reverse HE by alteration of colonic bacteria. Metronidazole (Flagyl) and neomycin sulfate (Neo-Fradin) are most commonly used. Metronidazole is generally administered at 250 mg every 8 to 12 hours (500 to 750 mg daily). Dose and duration of metronidazole should be minimized as much as possible to avoid peripheral neuropathy, a side effect associated with its long-term use. Neomycin is as effective as metronidazole and is administered at 1000 mg orally every 4 to 8 hours (3 to 6 grams daily) in acute encephalopathy and 500 to 1000 mg orally every 6 to 12 hours (1 to 2 grams daily) when used chronically. Neomycin use should also be limited, if possible, since long-term use can lead to rare ototoxicity and/or renal failure.⁴ If administered chronically (with or without lactulose) to control HE symptoms, periodic renal and annual auditory monitoring should be performed.¹ If a patient is already receiving antibiotics for prophylaxis of spontaneous bacterial peritonitis-usually norfloxacin (Noroxin) or trimethoprim-sulfamethoxazole (Bactrim or Septra)-the use of additional antibiotics for treatment of HE is discouraged. There are currently no data to suggest that multiple antibiotics provide additional therapeutic benefit, and may contribute to the development of drug-resistant infection.

Several other HE therapies have been investigated but are not routinely used. These include use of ornithine aspartate, flumazenil (Romazicon), and bromocriptine (Parlodel). Early studies using ornithine aspartate are encouraging, but the drug is not currently available in the United States.^17,18 Flumazenil may also be helpful, but is currently indicated only for patients with acute HE and suspected benzodiazepine intake.^1,19 No oral or long-acting preparations are currently available which would make flumazenil very cumbersome to use long-term. Improvement of extrapyramidal symptoms has also been reported when bromocriptine was added to more conventional therapies.²⁰ Bromocriptine at 30 mg orally twice daily can be considered in patients refractory to other therapies.¹

Occasionally, a portosystemic shunt (spontaneous, surgical or from placement of a transhepatic portosystemic shunt), is thought to be the primary cause of recurrent or chronic HE. In these rare cases, the shunt can be occluded. This is generally accomplished by the placing of occlusive coils by an interventional radiologist.²¹ This advanced procedure should be undertaken only at experienced medical centers and after all other measures have failed.¹

Before discharge from the hospital, all cirrhotic patients with HE should be assessed for the need for long-term therapy. Patients should be counseled on avoiding precipitating factors such as constipation and psychoactive medications. Compliance with chronic medications, including lactulose and/or antibiotics, should be emphasized. Prophylaxis for spontaneous bacterial peritonitis and gastroesophageal varices should be implemented when indicated. Lastly, appropriate candidates should be referred to a liver transplantation center after the first episode of overt encephalopathy. The ultimate therapy for cirrhosis and HE is orthotopic liver transplantation.¹

Some forms of HE are reversible, but the development of overt HE carries a poor prognosis. Recovery and recurrence rates vary, but without liver transplantation the 1-year survival is only 40%. Both acute and chronic HE, once advanced to stage 4 (coma), are associated with 80% overall mortality.²²

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