Hepatic encephalopathy

Metabolic consequence of cirrhosis often is reversible

Souheil Abou-Assi, MD; Z. Reno Vlahcevic, MD*

VOL 109 / NO 2 / FEBRUARY 2001 / POSTGRADUATE MEDICINE

CME learning objectives

• To understand the pathogenesis of hepatic encephalopathy in chronic liver disease
• To recognize the clinical manifestations and diagnostic tools used to detect hepatic encephalopathy
• To be aware of the precipitating factors for hepatic encephalopathy and to try to avoid them in patients with cirrhosis

The authors disclose no financial interests in this article.

Supported by a grant from the National Institutes of Health and a grant from the Department of Veterans Affairs.

*Deceased.

This is the first of three articles on cirrhosis

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Preview: Hepatic encephalopathy is characterized by neuropsychiatric manifestations ranging from a slightly altered mental status to coma, and neuromuscular symptoms may be present. This complication of chronic or acute liver disease is a result of the failure of the liver to detoxify toxins originating in the intestine. The pathogenesis probably is multifactorial, although the predominant causative agent appears to be ammonia. In this article, Drs Abou-Assi and Vlahcevic discuss the timely recognition and correction of factors contributing to this often reversible condition.
Abou-Assi S, Vlahcevic ZR. Hepatic encephalopathy: metabolic consequence of cirrhosis often is reversible. Postgrad Med 2001;109(2):52-70

Those who are made from bile are vociferous, malignant, and will not be quiet.

Hippocrates

Hepatic encephalopathy describes a wide spectrum of often reversible neuropsychiatric abnormalities that occur in patients with acute or chronic liver disease. Clinical manifes-tations range from a slightly altered mental state to coma. Neuromuscular symptoms range from tremor and asterixis to hyperreflexia and decerebrate posture. Often, the term "portal-systemic encephalopathy" is used to emphasize the failure of the liver to detoxify toxins that escape from the intestine. These toxins thus bypass the liver and enter the systemic circulation, causing the primary or secondary changes in brain neurochemistry that produce symptoms of hepatic encephalopathy. This metabolic disorder is characterized by reversibility, which suggests a lack of persistent structural lesions in the brain.

Neuropathologically, hepatic encephalopathy is characterized by astrocytic rather than neuronal changes. Pathologic studies of patients who have died in hepatic coma have revealed Alzheimer type II astrocytosis (ie, enlarged astrocytes with prominent nucleoli, margination of chromatin, and large, pale nuclei). Positron emission tomography (PET), a technique used to examine basic metabolic brain processes, shows significantly decreased glucose utilization in the cerebral cortex and concomitant increased utilization in the thalamus, caudate lobe, and cerebellum (1). These findings suggest that hypometabolism in the brains of patients with chronic liver disease could explain the neuropsychiatric abnormalities characteristic of hepatic encephalopathy.

Variants

Several variants of hepatic encephalopathy have been described, the most common of which are discussed here.

The acute form is associated with fulminant liver failure and is characterized by quick progression to profound coma, seizures, and decerebrate rigidity. This variant, which is accompanied by cerebral edema in the late stages, has a high mortality rate. Deaths of patients with fulminant liver disease are due to cerebral herniation and hypoxia, both of which are caused by increased intracranial pressure and reduced cerebral perfusion pressure.

Another form of hepatic encephalopathy has slower onset, milder symptoms, and shorter duration than the acute form. It usually is triggered by a number of well-defined precipitating factors. Many patients recover completely.

The chronic form is characterized by persistence of neuropsychiatric symptoms despite adequate medical therapy.

Another form of hepatic encephalopathy is characterized by progressive, irreversible neurologic findings that include dementia, extrapyramidal manifestations, cerebellar degeneration, transverse cordal myelopathy, and peripheral neuropathy. It is rather rare and usually is irreversible with standard therapy.

Subclinical hepatic encephalopathy is not associated with overt neuropsychiatric symptoms but rather with subtle changes detected by special psychomotor tests. It typically is reversible with therapy.

Pathogenesis

The various working models of the pathogenesis of hepatic encephalopathy are based on data derived from experimental animal models, brain tissue for in vitro studies, magnetic resonance spectroscopy, and PET. Our understanding of this condition is incomplete because of the difficulties of studying brain function in vivo (eg, poor accessibility, inability to topographically map areas of the brain associated with alertness). In general, all hypotheses center on changes in brain energy levels, metabolic abnormalities in the structure and function of neuronal and synaptic membranes, and alterations in neurotransmitter function.

Understanding of the pathogenesis of hepatic encephalopathy is based on three postulates:

1. The causative metabolic toxins (usually nitrogenous substances) most likely originate in the intestine.

2. Because of portal-systemic shunts, these toxic substances bypass the liver, where they normally are metabolized.

3. After bypassing the liver, these toxic substances cross the blood-brain barrier and exert direct or indirect neurotoxic effects on the central nervous system.

No single agent fulfills all three criteria; therefore the pathogenesis of hepatic encephalopathy is believed to be multifactorial.

Several processes are thought to have a causative role:

• Accumulation of toxins in the brain. Toxins from the intestines cross the blood-brain barrier at the level of endothelial cells that line the capillaries in the brain. The blood-brain barrier in patients with hepatic encephalopathy is disturbed, possibly by the toxic effects of ammonia.
• An alteration in plasma amino acid composition. This leads to accumulation of "false" neurotransmitters in the brain.
• Increases in neuroinhibitory substances, manganese, monoamines, or endogenous opiates. Each of these hypotheses is briefly examined here. Potential effects of different pathogenetic factors on hepatic encephalopathy are shown in figure 1 (not shown).

Accumulation of toxins in the brain
The first experiment implicating a nitrogenous substance as a cause of hepatic encephalopathy was performed by Eck, a turn-of-the-century Russian physiologist who created portal-systemic shunts in healthy dogs and observed that these dogs promptly became comatose after eating meat. This important observation was ignored for more than 50 years until this condition was "rediscovered," and ammonia intoxication became a leading suspect.

The role of ammonia has been postulated on the basis of the following: a reproducible increase in blood ammonia levels of patients with cirrhosis; the development of hepatic coma in patients with advanced liver disease and in experimental animals after ingestion of ammonia; elevated serum ammonia levels in children with genetic abnormalities of urea cycle synthesis, which are associated with neuropsychiatric changes similar to those of patients with hepatic encephalopathy; increased cerebral metabolism of ammonia as detected by PET and the ammonia 13 isotope; increased permeability of the blood-brain barrier to ammonia; and chronic elevations of blood ammonia levels, which lead to characteristic changes in astrocytes. The lack of a strong correlation between blood ammonia levels and stages of hepatic encephalopathy has been used as an argument that ammonia may not be the sole factor in the pathogenesis.

Forty percent of ammonia is generated in the intestine from ingested nitrogenous substances that are broken down by bacterial ureases and amino acid oxidases. The remaining 60% is derived from the metabolism of glutamine and the deamination and transamination of other amino acids. Ammonia liberated in the intestine normally is metabolized in the liver through the cycle of urea synthesis into urea, which is excreted through the kidneys and into the colon. Formation of glutamine from glutamate by glutamine synthetase in the liver and brain is another means of detoxifying ammonia. Additional sources of ammonia are skeletal muscle and the kidneys.

New PET evidence suggests that ammonia readily diffuses into the brain, where it exerts its neurotoxicity. The exposure of the brain to millimolar concentrations of ammonia may impair neuron-astrocyte trafficking and lead to Alzheimer type II astrocytosis. Ammonia inhibits excitatory postsynaptic potentials, thereby depressing overall central nervous system function (2). Excess ammonia ultimately may cause cerebral energy failure due to inhibition of key rate-limiting tricarboxylic-acid-cycle enzymes (3). Finally, ammonia may facilitate brain uptake of tryptophan, a substrate that generates neuroactive metabolites such as serotonin.

However, not all data are consistent with the ammonia toxicity theory. Poor correlation of ammonia with hepatic encephalopathy, the presence of this condition in the absence of elevated ammonia levels, and the neuroexcitatory effects of low ammonia concentrations all cast doubt on the theory.

Other toxins have also been implicated. Patients with chronic liver disease have increased blood levels of short-chain fatty acids (ie, butyrate, valerate), which may cause neuroinhibition. Similarly, there is an increase in serum mercaptans formed from methionine by colonic bacteria. Mercaptans cause fetor hepaticus in patients with cirrhosis. A synergistic effect of these toxic substances has been proposed by Zieve and colleagues (4) as a working hypothesis that emphasizes the action of ammonia.

False neurotransmitters
Patients with cirrhosis have a decreased ratio of branched-chain amino acids (BCAA) to aromatic amino acids (AAA), from 3.5:1 to 1:1. BCAA include valine, leucine, and isoleucine. AAA include phenylalanine, tyrosine, and tryptophan. The decrease in BCAA is caused predominantly by their excessive use by skeletal muscle. It has been postulated that the increase in AAA in the central nervous system may interfere with physiologic neurotransmission by competitively inhibiting "normal" neurotransmitters (ie, dopamine, norepinephrine) and favoring formation of weak, false neurotransmitters (ie, octopamine). This attractive hypothesis raises the possibility that correction of the AAA:BCAA ratio may lead to amelioration of hepatic encephalopathy. However, a multitude of clinical trials have failed to prove that changes in the ratio through intravenous or oral administration of BCAA result in significant improvement of clinical signs or symptoms of this condition.

Accumulation of neuroinhibitory substances
In the 1980s, Basile and Jones (5) at the National Institutes of Health promoted gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, as a cause of hepatic encephalopathy. Under normal circumstances, excitatory glutamatergic tone is balanced by GABA-induced inhibitory tone and modulated through GABA receptors. These receptors represent ligand-gated chloride channels that permit neuroinhibition through depolarization of postsynaptic membranes. Endogenous benzodiazepines also modulate the activity of these receptors. These investigators suggested that elevated ammonia levels enhance GABA-ergic neurotransmission and synergistically augment the action of benzodiazepine receptor agonists.

This unifying hypothesis led to consideration of another synergistic process as an explanation for hepatic encephalopathy (5). Because GABA binds to benzodiazapine receptors, the benzodiazapine receptor agonist flumazenil was tested as a potential treatment for chronic hepatic encephalopathy. Flumazenil caused transient amelioration of the neurologic symptoms in a small subgroup of patients (6). These unimpressive therapeutic results ended the consideration of benzodiazapine receptor agonists as an effective treatment of this disease.

Accumulation of manganese: The potential role of manganese in the pathogenesis of hepatic encephalopathy is based on the observation that more than 80% of patients with cirrhosis in hepatic coma have increased concentrations of manganese. Prolonged exposure to manganese results in extrapyramidal symptoms and abnormal magnetic resonance images (7).

Neurologic examination reveals several signs compatible with basal ganglia dysfunction that often do not disappear with appropriate therapy. Reports demonstrate strong correlation between pallidal signal hyperintensity and extrapyramidal symptoms in patients with cirrhosis. Long-term exposure to manganese also leads to Alzheimer type II astrocytosis. Direct measurements of basal ganglia manganese levels in autopsy samples have shown a twofold to sevenfold increase (8). It has been proposed that ammonia and manganese act synergistically. However, it is unclear how the alteration of intestinal flora could lead to amelioration of symptoms if they were caused solely by manganese deposition. It also is unclear whether manganese accumulation in the brain is an epiphenomenon or whether there is a cause-and-effect relationship (8).

Monoamines: Many of the early neuropsychiatric symptoms of hepatic encephalopathy (eg, altered sleep patterns) have been attributed to modification of the monoamine neurotransmitter serotonin. Serotonin is derived from the amino acid tryptophan, the uptake of which is facilitated by elevated serum ammonia levels (9). Elevated cerebrospinal fluid concentrations of L-tryptophan and serotonin metabolites have been found in the brains of patients with hepatic encephalopathy. Levels of the serotonin-degrading enzyme monoaminooxidase also are increased in the brains of patients with cirrhosis, which suggests serotonin synaptic deficits (10).

Endogenous opiates
Abnormalities of the endogenous opioid system in patients with hepatic encephalopathy are suggested by increased sensitivity to morphine (11), increased plasma levels of the endogenous opioid met-enkephalin (12), and increased concentrations of beta-endorphins in brain extracts of rats with portacaval shunts. Long-acting oral opiate agonists are available, but no clinical trials have been performed to test this interesting hypothesis.

Diagnosis

Diagnosis of hepatic encephalopathy is based on clinical presentation in patients with documented signs and symptoms of chronic liver disease. The major neuropsychiatric signs and symptoms are shown in table 1. With progressive hepatic encephalopathy, there is a gradual decrease in the level of consciousness (from lethargy to somnolence to stupor and, eventually, coma), impairment of intellectual capacity (eg, reasoning, orientation), and progressive neurologic deficits (eg, asterixis). Clinical diagnosis of overt hepatic encephalopathy is not difficult, unlike diagnosis of the subclinical form of the condition. An estimated 50% to 80% of patients with cirrhosis have the subclinical form.

Patients with subclinical hepatic encephalopathy may function normally and have normal findings on neurologic examination. The Number Connection Test and the Symbol Digit Test are the psychometric tests most often used to diagnose subtle neurophysiologic deficits in these patients. Electrophysiologic tests, including visual evoked potentials and brain stem auditory evoked potentials, have been used with variable success (13). Clinical characteristics of various forms of hepatic encephalopathy are listed in table 2.

Table 2. Clinical characteristics of various forms of hepatic encephalopathy
	Acute	Chronic or recurrent	Chronic	Subclinical
Asterixis	-	+	+	-
Precipitating factor	-	++	-	-
Reversibility	+	+	-	+
Clinical course	Short, lethal	Short, transient	Continuous	Insidious
+, associated; -, not associated; +, may or may not be associated.

The most common laboratory test used to diagnose hepatic encephalopathy is the measurement of arterial blood ammonium. Serum ammonium levels are often elevated in patients with cirrhosis. There is only a weak correlation between the degree of neuropsychiatric deficit and blood ammonia levels. This measurement may be more useful if obtained repetitively in a given patient to give some sense of therapy success or failure. The serum ammonium test measures both ionized ammonia (ammonium) and un-ionized ammonia. However, only un-ionized ammonia crosses the membranes and therefore is responsible for hepatic encephalopathy. In patients with normal serum pH, the ammonia represents only a small fraction of total ammonium concentrations; this factor may be in part responsible for the poor predictability of total ammonium measurement as a diagnostic or prognostic test. Measurement of venous ammonia probably has no clinical value because of enrichment of venous blood with ammonia released from muscle.

Nonspecific electroencephalographic abnormalities have been repeatedly reported in patients with hepatic encephalopathy. These abnormalities are characterized by slow waves of large amplitude and by bursts of triphasic wave patterns. They generally are read as "consistent with metabolic encephalopathy" because similar electroencephalographic patterns are observed in uremia, pulmonary or heart failure, and acid-base disorders. The diagnostic value of visual, auditory, and somatosensory evoked potentials is controversial, and these tests are not used routinely.

Differential diagnostic considerations in hepatic encephalopathy are shown in table 3. Computed tomographic scans, which are normal in patients with hepatic encephalopathy, may be diagnostic of intracerebral events that mimic the condition.

Table 3. Differential diagnostic considerations in hepatic encephalopathy

Metabolic encephalopathies Diabetes (hypoglycemia, ketoacidosis) Hypoxia Carbon dioxide narcosis Toxic encephalopathies Alcohol (acute alcohol intoxication, delirium tremens, Wernicke-Korsakoff syndrome) Drugs Intracranial events Intracerebral bleeding or infarction Tumor Infections (abscess, meningitis) Encephalitis

Clinically, the presence of well-defined precipitating factors is extremely important in diagnosis and treatment of hepatic encephalopathy. Precipitating factors in patients with chronic liver disease are shown in order of frequency in table 4. When hepatic encephalopathy is developing in a patient, therapy should be instituted immediately when there is blood in the stool, a history of sedative or opiate use, azotemia, infection, dehydration and electrolyte abnormalities (eg, hypernatremia, hyponatremia, hypokalemic alkalosis), or constipation. For example, subacute bacterial peritonitis often precipitates hepatic encephalopathy; failure to recognize this complication and institute antibiotic therapy often leads to the patient's death.

Table 4. Precipitating factors in hepatic encephalopathy
Factors	Mode of action	Management
Azotemia (29%)	Urea in colon, urease increases ammonia production, excessive diuresis, prerenal azotemia	Lactulose, discontinue diuretics, volume expansion with albumin
Sedatives, tranquilizers, analgesics (24%)	Direct depressant action on brain	Avoid sedatives, lactulose
Gastrointestinal bleeding (18%)	15 to 20 g protein per 100 mL blood, ammonia production, hypovolemia, prerenal azotemia	Lactulose, blood or plasma transfusion, volume expansion
Excess dietary protein (9%)	Excess nitrogenous substances	Lactulose, protein in diet
Metabolic alkalosis (11%)	Diffusion of ammonia across blood-brain barrier	Correct hypokalemia with infusion of potassium
Infection (3%)	Peripheral ammonia production, tissue catabolism leading to ammonia production	Treat infection, administer lactulose
Constipation (3%)	Retention of ammonium in colon, more efficient formation of ammonia by colonic bacteria	Laxatives (eg, lactulose)
, increased; , decreased.

Therapy

The main objective of therapy is to decrease intestinally derived toxins produced by excessive bacterial activity and increased formation of ammonia. An algorithm for the use of available therapies under standard conditions is shown in figure 2 (not shown).

Antibiotics
The first treatment of hepatic encephalopathy was use of the "nonabsorbable" antibiotics neomycin, kanamycin sulfate, and paromomycin. Such antibiotic therapy was very effective, but absorption of a small fraction of these antibiotics caused ototoxic and nephrotoxic side effects; this treatment now is used infrequently. Metronidazole (Flagyl, Protostat) given in a 250-mg dose three or four times a day is as effective as oral neomycin and does not cause ototoxicity or nephrotoxicity. To avoid peripheral neuropathy, metronidazole therapy should not be extended beyond 2 weeks.

Nondigestable disaccharides
Disaccharides such as lactulose pass through the small bowel undigested. In the colon, bacteria degrade lactulose to various organic acids (eg, formic acid, acetic acid) with subsequent lowering of colonic pH. The mode of action is uncertain. It may involve bacteriostatic effects, cathartic effects, or enhancement of conversion of ammonia to ammonium with excess hydrogen ion. Presumably, ammonium is then excreted into the feces and eliminated. Lactulose remains the mainstay therapy, but there is a paucity of clinical trials demonstrating its efficacy. The dose should be adjusted to accomplish three or four soft bowel movements each day. Lactulose can be given orally through a nasogastric tube or through retention enemas. The usual oral dose is 50 to 120 mL each day in divided doses. Stool pH should be below 6.0. Side effects include initial bloating and flatulence and then severe diarrhea with dehydration and acidosis if the dosage is too high (14).

Other therapeutic options are lactose and lactitol (beta-galactosidosorbitol). Neither of these alternatives is available in the United States. Long-term administration of lactulose for prevention of hepatic encephalopathy is appropriate for patients with frequent recurrences and is quite effective in maintaining a normal mental status.

Experimental therapies
Several therapies have been studied but are not routinely used:

Ornithine-aspartate: This compound has been shown in uncontrolled trials to lower serum ammonia levels through stimulation of the urea cycle and urea formation.

Sodium benzoate: This reduces serum ammonia levels by increasing ammonia excretion in urine. It reacts with glycine to form hippurate. For each mole of benzoate, the kidneys excrete 1 mole of nitrogen. The drug is inexpensive compared with lactulose, and its effects in a single clinical trial were comparable to those of lactulose (15). However, this treatment has not been evaluated in the United States.

Levocarnitine: This compound is a protein that shuttles fatty acids across the mitochondrial membranes. Carnitine deficiency is a genetic syndrome manifested by hepatic encephalopathy. Carnitine levels were found to be low in patients with Reye's syndrome. The compound was shown to be beneficial in lowering blood ammonia levels by increasing depleted metabolic energy induced by ammonia (16). However, the results of clinical studies are conflicting.

Intravenous or oral administration of BCAA: These compounds correct the AAA:BCAA ratio in plasma. Several clinical trials have failed to prove the efficacy of oral or intravenous BCAA therapy in patients with hepatic encephalopathy. A meta-analysis of several clinical trials showed a significant trend toward improvement (17). Long-term use of BCAA appears to be superior to isonitrogenous amounts of casein because it establishes protein balance without inducing encephalopathy (18). The oral form of BCAA (Hepatic-Aid II Instant Drink Powder) is available but expensive.

Neuroactive drugs: Flumazenil was shown to be better than placebo in five controlled studies. Other studies, however, showed no effect. Clearly, the results were not encouraging enough to add this compound to the armamentarium of agents to treat hepatic encephalopathy. Critical analysis of a multitude of studies with flumazenil is available (6).

Serotonin receptor agonists are of potential benefit, but no convincing clinical trials have been done. Opiate receptor agonists showed some benefit in ameliorating motor activity of rats with stage III hepatic encephalopathy, but no studies have been done in humans. New treatments have been reviewed extensively (19).

Diet
Limitation of protein in the diet of patients with frequent recurrence of hepatic encephalopathy but no other precipitating factors is reasonable for a short period. Prolonged restriction of dietary protein contributes to malnutrition of patients with cirrhosis. Vegetable proteins may be superior to meat protein, and the fiber content in diet appears to be beneficial (20).

Liver transplantation
The ultimate therapy for hepatic encephalopathy is orthotopic liver transplantation. The frequency and depth of disease are important factors in determining the staging of candidates for liver transplantation.

Summary and conclusion

Hepatic encephalopathy is a well-recognized clinical complication of chronic liver disease. About 30% of patients with cirrhosis die in hepatic coma. Hepatic encephalopathy can occur in patients with fulminant liver disease without evidence of portal-systemic shunting. These patients have increased intracranial pressure and brain edema with a deleterious clinical course and poor prognosis unless liver transplantation is available.

The pathogenesis of portal-systemic hepatic encephalopathy probably is multifactorial, although the predominant causative agent appears to be ammonia. The molecular basis of neurotoxicity of ammonia or other agents implicated in the condition is poorly understood. Therapy includes timely recognition and correction of precipitating factors. Once the condition is manifested, standard therapy is acute administration of lactulose, a disaccharide that is undigested in the small intestine. Its beneficial action is not fully understood. The use of oral antibiotics and BCAAs is of some benefit in patients who do not respond to lactulose. Limitation of protein in the diet may be useful for short periods but is not recommended for long-term use because of potential worsening of already poor nutrition.

Several experimental therapies based on potential pathogenetic mechanisms have not resulted in improved outcomes over standard therapy with lactulose. However, future research will likely focus on the correction of alterations in neurotransmission. It is hoped that newer therapies will provide protection from the putative neurotoxins that cause secondary defects in neurotransmission.

References

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16. Del Olmo JA, Castillo M, Rodrigo JM, et al. Effect of L-carnitine upon ammonia tolerance test in cirrhotic patients. In: Grisolia S, Felipo, V, Mañana M-D, eds. Cirrhosis, hepatic encephalopathy and ammonium toxicity. New York: Plenum, 1990:197-208
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Dr Abou-Assi is a fellow in the division of gastroenterology, McGuire Veterans Affairs Medical Center and Virginia Commonwealth University School of Medicine, Richmond. Dr Vlahcevic, who died in July 2000, was Charles Caravati Professor of Medicine and chair, division of gastroenterology, McGuire Veterans Affairs Medical Center and Virginia Commonwealth University School of Medicine. Correspondence: Souheil Abou-Assi, MD, Division of Gastroenterology, McGuire Veterans Affairs Medical Center (111N), 1201 Broad Rock Rd, Richmond, VA 23249. E-mail: sabouassi@hotmail.com.

Symposium Index

• CIRRHOSIS OF THE LIVER: Introduction to a three-article symposium by Anastasios A. Mihas, MD
• HEPATIC ENCEPHALOPATHY: Metabolic consequence of cirrhosis often is reversible by Souheil Abou-Assi, MD, Z. Reno Vlahcevic, MD
• BLEEDING ESOPHAGEAL VARICES: How to treat this dreaded complication of portal hypertension by Ahmed M. Hegab, MD, Velimir A. Luketic, MD
• MINIMIZING ASCITES: Complication of cirrhosis signals clinical deterioration by Nelson Garcia Jr, MD, Arun J. Sanyal, MBBS, MD

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