Encephalopathy, Hepatic

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Encephalopathy, Hepatic

Last Updated: March 3, 2005

Synonyms and related keywords: portosystemic encephalopathy, PSE, hepatic coma, cirrhosis of the liver, hepatic cirrhosis, portosystemic collateral vessels, portocaval shunt surgery, portal hypertension, end-stage liver disease, ESLD, coma, dysfunction of hepatic synthetic activity, fulminant hepatic failure, FHF, liver failure, flapping tremor, fetor hepaticus, hyperventilation, elevated blood ammonia level, renal failure, gastrointestinal bleeding, constipation, diuretic therapy, dietary protein overload

Author: C Wolf, MD, FACP, FACG, Medical Director of Liver Transplantation, Associate Professor, Department of Internal Medicine, Division of Gastroenterology and Hepatobiliary Diseases, New York Medical College and Westchester Medical Center

Editor(s): Gunn Lee, MD, Director of Pancreaticobiliary Service, Associate Professor, Department of Internal Medicine, Division of Gastroenterology, University of California at Irvine School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, Pharmacy, eMedicine; BS Anand, MD, Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor University College of Medicine; J Mechaber, MD, FACP, Director of Clinical Skills Program, Assistant Professor, Department of Internal Medicine, Division of General Internal Medicine, University of Miami School of Medicine; and n Katz, MD, Professor, Department of Internal Medicine, Division of Gastroenterology, MCP Hahnemann University

Hepatic encephalopathy is a syndrome observed in patients with cirrhosis of the liver. It is characterized by personality changes, intellectual impairment, and a depressed level of consciousness. An important prerequisite for the syndrome is diversion of portal blood into the systemic circulation through portosystemic collateral vessels. Indeed, hepatic encephalopathy may develop in patients without cirrhosis who have undergone portocaval shunt surgery. The development of hepatic encephalopathy is explained, to some extent, by the effect of neurotoxic substances, which occurs in the setting of cirrhosis and portal hypertension.

Subtle signs of hepatic encephalopathy are observed in nearly 70% of patients with cirrhosis. Symptoms may be debilitating in a significant number of patients and are observed in 24-53% of patients who undergo portosystemic shunt surgery. Approximately 30% of patients dying of end-stage liver disease experience significant encephalopathy, approaching coma. Hepatic encephalopathy accompanied by severe dysfunction of hepatic synthetic activity also is the hallmark of fulminant hepatic failure (FHF). Symptoms of encephalopathy in FHF are graded using the same scale employed to assess encephalopathy symptoms in cirrhosis. However, the pathogenesis of the encephalopathy in FHF differs from that of cirrhosis. In FHF, altered mental function is attributed to increased permeability of the blood-brain barrier and to impaired osmoregulation within the brain. The resulting brain cell swelling and brain edema are potentially fatal. In contrast, brain edema is rarely reported in patients with cirrhosis. The encephalopathy of FHF is not covered in this article but is addressed in Hepatic Failure. For excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center and Hepatitis Center. Also, see eMedicine's patient education article Cirrhosis.

A number of theories have been proposed to explain the development of hepatic encephalopathy in patients with cirrhosis. One theory is that patients develop an alteration of the brain energy metabolism accompanied with increased permeability of the blood-brain barrier. The latter may facilitate the passage of neurotoxins into the brain. Putative neurotoxins include short-chain fatty acids; mercaptans; false neurotransmitters such as tyramine, octopamine, and beta-phenylethanolamines; ammonia; and gamma-aminobutyric acid (GABA).

Ammonia hypothesis Ammonia is produced in the gastrointestinal tract by bacterial degradation of amines, amino acids, purines, and urea. Normally, ammonia is detoxified in the liver by conversion to urea and glutamine by the Krebs-Henseleit cycle. In liver disease or in the presence of portosystemic shunting, portal blood ammonia is not efficiently converted to urea. Increased levels of ammonia may enter the systemic circulation because of portosystemic shunting. Normal skeletal muscle aids in the metabolism of ammonia in the conversion of glutamate to glutamine. The muscle wasting that is observed in patients with advanced cirrhosis may potentiate hyperammonemia. Ammonia has multiple neurotoxic effects, including altering the transit of amino acids, water, and electrolytes across the neuronal membrane. Ammonia can also inhibit the generation of both excitatory and inhibitory postsynaptic potentials. Additional support for the ammonia hypothesis comes with the clinical observation that strategies designed to reduce serum ammonia levels tend to improve hepatic encephalopathy. An argument against the ammonia hypothesis includes the observation that approximately 10% of patients with significant encephalopathy have normal serum ammonia levels. Furthermore, many patients with cirrhosis have elevated ammonia levels without evidence for encephalopathy. Also, ammonia does not induce the classic electroencephalographic (EEG) changes associated with hepatic encephalopathy when it is administered to patients with cirrhosis. GABA hypothesis GABA is a neuroinhibitory substance produced in the gastrointestinal tract. Of all brain nerve endings, 24-45% may be GABAergic. Increased GABAergic tone is observed in patients with cirrhosis, perhaps because of decreased hepatic metabolism of GABA. When GABA crosses the extrapermeable blood-brain barrier of patients with cirrhosis, it interacts with supersensitive postsynaptic GABA receptors. The GABA receptor, in conjunction with receptors for benzodiazepines and barbiturates, regulates a chloride ionophore. Binding of GABA to its receptor permits an influx of chloride ions into the postsynaptic neuron, leading to the generation of an inhibitory postsynaptic potential. Administration of benzodiazepines and barbiturates to patients with cirrhosis increases GABAergic tone and predisposes to depressed consciousness. The GABA hypothesis is supported by the clinical observation that flumazenil, a benzodiazepine antagonist, can transiently reverse hepatic encephalopathy in patients with cirrhosis.

Grading of the symptoms of hepatic encephalopathy is as follows:

Grade 0 - Clinically normal mental status but minimal changes in memory, concentration, intellectual function, and coordination

Grade 1 - Mild confusion, euphoria, or depression; decreased attention; slowing of ability to perform mental tasks; irritability; and disordered sleep pattern, such as inverted sleep cycle

Grade 2 - Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behavior, and intermittent disorientation, usually regarding time

Grade 3 - Somnolent but can be aroused, unable to perform mental tasks, disorientation about time and place, marked confusion, amnesia, occasional fits of rage, present but incomprehensible speech

Grade 4 - Coma with or without response to painful stimuli

Patients with mild and moderate hepatic encephalopathy demonstrate decreased short-term memory and concentration upon mental status testing. They may show signs of asterixis, although the flapping tremor of the extremities is also observed in patients with uremia, pulmonary insufficiency, and barbiturate toxicity. Some patients show evidence of fetor hepaticus, a sweet musty aroma of the breath that is believed to be secondary to the exhalation of mercaptans. Other potential physical examination findings include hyperventilation and decreased body temperature.

An elevated blood ammonia level is the classic laboratory abnormality reported in patients with hepatic encephalopathy. This finding may aid in correctly diagnosing patients with cirrhosis who present with altered mental status. However, serial ammonia measurements are inferior to clinical assessment in gauging improvement or deterioration in a patient under therapy for hepatic encephalopathy. Checking the ammonia level in a patient with cirrhosis who does not have hepatic encephalopathy has no utility. Only arterial or free venous blood specimens must be assayed when checking the ammonia level. Blood drawn from an extremity to which a tourniquet has been applied may provide a falsely elevated ammonia level when analyzed.

Classic EEG changes associated with hepatic encephalopathy are high-amplitude low-frequency waves and triphasic waves. However, these findings are not specific for hepatic encephalopathy. When seizure activity must be ruled out, an EEG may be helpful in the initial workup of a patient with cirrhosis and altered mental status. Visual evoked responses also demonstrate classic patterns associated with hepatic encephalopathy. However, such testing is not performed in common clinical use. Computed tomography and magnetic resonance imaging studies of the brain may be important in ruling out intracranial lesions when the diagnosis of hepatic encephalopathy is in question. MRI has the additional advantage of being able to demonstrate hyperintensity of the globus pallidus on T1-weighted images, a finding that is commonly described in hepatic encephalopathy.

Some patients with a history of hepatic encephalopathy may have normal mental status while under treatment. Others have chronic memory impairment in spite of medical management. Both groups of patients are subject to episodes of worsened encephalopathy. Common precipitating factors are as follows:

Renal failure: Renal failure leads to decreased clearance of urea, ammonia, and other nitrogenous compounds. Gastrointestinal bleeding: The presence of blood in the upper gastrointestinal tract results in increased ammonia and nitrogen absorption from the gut. Bleeding may predispose to kidney hypoperfusion and impaired renal function. Blood transfusions may result in mild hemolysis, with resulting elevated blood ammonia levels. Infection: Infection may predispose to impaired renal function and to increased tissue catabolism, both of which increase blood ammonia levels. Constipation: Constipation increases intestinal production and absorption of ammonia. Medications: Drugs that act upon the central nervous system, such as opiates, benzodiazepines, antidepressants, and antipsychotic agents, may worsen hepatic encephalopathy. Diuretic therapy: Decreased serum potassium levels and alkalosis may facilitate the conversion of NH4+ to NH3. Dietary protein overload: This is an infrequent cause of hepatic encephalopathy.

Distinguishing hepatic encephalopathy from other acute and chronic causes of altered mental status may be difficult in patients with cirrhosis. A decision to perform additional neurologic studies should be based on the severity of the patient's mental dysfunction, the presence of focal neurologic findings (observed infrequently in patients with hepatic encephalopathy), and the patient's responsiveness to an empiric trial with cathartic agents. Even patients with severe hepatic encephalopathy should demonstrate steady improvement in mental dysfunction after an initiation of treatment with lactulose or cathartics derived from polyethylene glycol (PEG).

Differential diagnoses of encephalopathy

Intracranial lesions such as subdural hematoma, intracranial bleeding, stroke, tumor, and abscess

Infections such as meningitis, encephalitis, and intracranial abscess

Metabolic encephalopathy such as hypoglycemia, electrolyte imbalance, anoxia, hypercarbia, and uremia

Hyperammonemia from other causes such as secondary to ureterosigmoidostomy and inherited urea cycle disorders

Toxic encephalopathy from alcohol intake, such as acute intoxication, alcohol withdrawal, and Wernicke encephalopathy

Toxic encephalopathy from drugs such as sedative hypnotics, antidepressants, antipsychotic agents, and salicylates

Organic brain syndrome

Postseizure encephalopathy

Nonhepatic causes of altered mental function must be excluded.

Consider checking the blood ammonia level in the initial assessment of a patient with cirrhosis who has altered mental status. Medications that depress central nervous system function, especially benzodiazepines, should be avoided. To decrease the risk of worsening hepatic encephalopathy, patients with severe agitation may receive haloperidol or short-acting opiates as alternative agents. Treating patients who present with coexisting alcohol withdrawal and hepatic encephalopathy is particularly challenging. These patients may require therapy with benzodiazepines in conjunction with lactulose and other medical therapies for hepatic encephalopathy. Precipitants of hepatic encephalopathy, such as metabolic disturbances, gastrointestinal bleeding, infection, and constipation should be corrected. Lactulose (beta-galactosidofructose) is a nonabsorbable disaccharide. It may inhibit intestinal ammonia production by a number of mechanisms. Lactulose is degraded by colonic bacteria and converted to lactic acid and other acids, with resulting acidification of the gut lumen. This favors conversion of NH4+ to NH3 and the passage of NH3 from tissues into the lumen. Gut acidification inhibits ammoniagenic coliform bacteria, leading to increased levels of nonammoniagenic lactobacilli. Lactulose works as a cathartic, reducing colonic bacterial load. Initial lactulose dosing is 30 mL orally, daily or twice daily. The dose may be increased as tolerated. Patients should be instructed to reduce lactulose dosing in the event of diarrhea, abdominal cramping, or bloating. Patients should take sufficient lactulose as to have 2-4 loose stools per day. Higher doses of lactulose may be administered orally or by nasogastric tube to patients hospitalized with severe hepatic encephalopathy. Lactulose may be administered as an enema to comatose patients who are unable to take the medication by mouth. The recommended dosing is 300 mL lactulose plus 700 mL water administered as a retention enema every 4 hours as needed. The authors have had excellent success using PEG-containing colonic lavage solutions, such as Go-LYTELY, in the acute management of hospitalized patients with severe hepatic encephalopathy. Neomycin and other antibiotics, such as metronidazole, oral vancomycin, paromomycin, and oral quinolones, are administered in an effort to decrease the colonic concentration of ammoniagenic bacteria. Initial neomycin dosing is 250 mg orally 2-4 times a day. Doses as high as 4000 mg/d may be administered. Neomycin is usually reserved as a second-line agent, after initiation of treatment with lactulose. Long-term treatment with this oral aminoglycoside runs the risks of inducing ototoxicity and nephrotoxicity because of some systemic absorption. Ammonia-fixing strategies may be used in management. L-ornithine L-aspartate can stimulate ureagenesis and reduce blood ammonia levels. In a number of European trials, it has been found to be effective in treating hepatic encephalopathy. Sodium benzoate can interact with glycine to form hippurate. The subsequent renal excretion of hippurate results in the loss of ammonia ions. Dosing of sodium benzoate at 5 g orally twice a day can effectively control hepatic encephalopathy. Use of the medication is limited by the risk of salt overload and by its unpleasant taste. Diet may be modified in management. Some patients with hepatic encephalopathy are intolerant of diets high in protein. In the past, low-protein diets were routinely recommended for patients with cirrhosis, in the hope of preventing exacerbations of hepatic encephalopathy. An obvious consequence was the worsening of preexisting protein-calorie malnutrition. Protein restriction may play a role in the management of the patient with an acute flare of hepatic encephalopathy. However, protein restriction is rarely justified in patients with cirrhosis and chronic hepatic encephalopathy because malnutrition is a more serious clinical problem than hepatic encephalopathy for many of these patients. In the author's experience, the vast majority of patients with mild chronic hepatic encephalopathy tolerate more than 60-80 g protein per day. Furthermore, one recent study administered a protein-rich diet (>1.2 g/kg/d) to patients with advanced disease awaiting liver transplantation, without inducing a flare of encephalopathy symptoms. Diets containing vegetable proteins appear to be better tolerated than diets rich in animal protein, especially proteins derived from red meats. This may be because of increased content of dietary fiber, a natural cathartic, and decreased levels of aromatic amino acids. Aromatic amino acids, as precursors for the false neurotransmitters tyramine and octopamine, are thought to inhibit dopaminergic neurotransmission and worsen hepatic encephalopathy. The author recommends that patients consume well-cooked chicken and fish in addition to vegetable protein. Malnourished patients are encouraged to add commercially available liquid nutritional supplements to their diet. Patients do not usually require specialized treatment with oral or enteral supplements rich in branched-chain amino acids. This would be an uncommon occurrence.

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