Definition

Hepatic encephalopathy (HE) describes a spectrum of potentially reversible neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of unrelated neurologic and/or metabolic abnormalities. The term implies that altered brain function is due to metabolic abnormalities. The full reversibility of symptoms after improvement of liver function is considered to be direct proof of this causal relation.

An important prerequisite for the syndrome is diversion of portal blood into the systemic circulation through portosystemic collateral vessels.¹ Expression of encephalopathy is characterized by personality changes, intellectual impairment, and may advance to a depressed level of consciousness. In patients with cirrhosis, acute encephalopathy is most commonly associated with a precipitating factor, such as electrolyte disturbance, medications, gastrointestinal hemorrhage, or infection.²

Those with fulminant hepatic failure may experience altered mental status, severe cerebral edema and subsequent herniation of brain stem with fatal consequences. Detailed discussion of this entity is beyond the scope of this chapter.

Prevalence

HE may be clinically apparent in as many as one third of cirrhotic patients and, if rigorously tested, up to two thirds have some degree of mild or subclinical HE.

Pathophysiology

While the precise molecular mechanisms that result in these morphological changes in the brain are yet to be identified, many factors have been elucidated, especially the role of ammonia, false neurotransmitters, astrocyte swelling, inflammation, and oxidative stress.

Ammonia

Ammonia, a byproduct of the metabolism of nitrogen-containing compounds, is neurotoxic at elevated concentrations.³ The liver clears almost all of the portal vein ammonia, converting it into glutamine and urea preventing entry into the systemic circulation. However, glutamine is metabolized in mitochondria yielding glutamate and ammonia, and glutamine-derived ammonia may interfere with mitochondrial function leading to astrocytes dysfunction. The increase in blood ammonia in advanced liver disease is a consequence of impaired liver function and of shunting of blood around the liver. Muscle wasting, a common occurrence in these patients, also may contribute since muscle is an important site for extrahepatic ammonia removal.⁴

In addition to direct neurotoxicity, low-grade astrocyte swelling may contribute to brain dysfunction. The enzyme glutamine synthetase (present in the endoplasmic reticulum of astrocytes) is responsible for the conversion of and ammonia to glutamine.⁵ As glutamine acts as osmolyte, water moves inside the astrocyte causing low-grade cerebral edema and a predominantly neuroinhibitory state (that is, slowing of mental processes) is pathognomonic of HE, which is associated with chronic liver disease.^6,7

False Neurotransmitters

The liver plays a central role in amino acid metabolism and protein synthesis and breakdown as well as in several detoxification processes, notably those of end-products of intestinal metabolism, like ammonia. An imbalance in plasma levels of aromatic amino acids (AAA) phenylalanine, tyrosine, and tryptophan and branched chain amino acids (BCAA) leucine, isoleucine and valine and their BCAA/AAA ratio has been suggested to play a causal role in HE by enhanced brain AAA uptake and subsequently disturbed neurotransmission.³

Some 30 years ago, Fischer and colleagues published their unique hypothesis on the pathogenesis of HE, based on the observation that during hepatic failure, plasma levels of BCAA decreased and the AAA increased. These changes in plasma levels were thought to be caused by increased BCAA catabolism in muscle and decreased AAA breakdown in the failing liver. Accumulation of AAA in the circulation in combination with increased breakdown of BCAA, would, according to this hypothesis, give rise to a decrease in the BCAA/AAA ratio, which was called the Fischer-ratio (BCAA/AAA ratio).⁸

The increase in plasma AAA in combination with increased blood-brain barrier permeability for neutral amino acids has been suggested to contribute to an increased influx of AAA in the brain, because they compete for the same transporter (large neutral amino acid transporter). This, in turn, would lead to imbalances in neurotransmitter synthesis and accumulation of false neurotransmitters, such as octopamine in the brain, which may contribute to HE.⁸

Inflammation

Ammonia dysmetabolism cannot solely explain all the neurological changes that are seen in patients with HE. Sepsis is a well known precipitating factor for HE in a previously stable patient with cirrhosis.⁹

The peripheral immune system communicates with the brain in response to infection and inflammation. The systemic inflammatory response syndrome (SIRS) results from the release and circulation of proinflammatory cytokines and mediators. Sepsis-associated encephalopathy is characterized by changes in mental status. In patients with cirrhosis, SIRS may exacerbate the symptoms of HE, both in patients with minimal and overt HE in a process probably mediated with tumor necrosis factor (TNF) and interleukin- 6 (IL6).¹⁰ Both TNF and IL6 enhance fluid–phase permeability of isolated brain endothelial cells in vitro, and TNF also increases the diffusion of ammonia into astrocytes.¹¹

Neurosteroids

In patients with HE, expression of the peripheral type benzodiazepine receptor (18 kDa translocator protein) is thought to be up regulated in microglial cells which are triggered by inflammation. Increased expression of this receptor results in increased mitochondrial synthesis of neuroactive steroids, which are also known as neurosteroids.¹² In the brain, neurosteroids are mainly produced by myelinated glial cells (such as astrocytes). Neurosteroids are positive modulators of the gamma-aminobutyric acid (GABA) receptor; they enhance GABAenergic tone. These effects are responsible for some clinical sequelae in patients with HE.¹³ That would explain why administration of benzodiazepines and similar drugs in cirrhotics may precipitate HE.

Oxidative and Nitrosative Stress

Enhanced production of reactive nitrogen species and reactive oxygen species (ROS) occurs in cultured astrocytes (isolated from rats) that are exposed to ammonia, inflammatory cytokines, hyponatremia or benzodiazepines. It's suggested that glutamine formed in the cytoplasm enters the mitochondrial matrix and is cleaved to release ammonia while still inside the mitochondria.⁵ Evidence indicating a close association and interplay between astrocyte swelling and ROS is now growing.

Manganese

Manganese deposition has been detected by magnetic resonance imaging (MRI) in the basal ganglia of patients with cirrhosis. It is also involved in stimulation of translocator proteins on astrocytes, which further enhances neurosteroid synthesis and GABAenergic tone. Preferential deposition of manganese in the basal ganglia might explain the Parkinsonian symptoms (such as tremors) seen in some patients with HE.¹⁴

History, Signs, and Symptoms

Patients with HE usually have advanced chronic liver disease and thus have many of the physical and laboratory stigmata associated with severe hepatic dysfunction.

Disturbance in the diurnal sleep pattern (insomnia and hypersomnia) is common, and typically precedes overt neurologic signs. More advanced neurologic features include bradykinesia, asterixis (flapping motions of outstretched, dorsiflexed hands). Hyperactive deep tendon reflexes are common; seizures and hallucinations and transient decerebrate posturing may also be seen occasionally.

Laboratory Abnormalities in Hepatic Encephalopathy

Laboratory abnormalities typically include evidence of hepatic biochemical and synthetic dysfunction, and electrolyte disturbances (such as hyponatremia and hypokalemia). In addition, ammonia is the best characterized neurotoxin that precipitates HE. While ammonia elevations are frequently seen, serial ammonia measurements are not advised, as there is frequently a significant temporal disconnect between blood levels and brain function. For clinical practice measuring ammonia concentration remains controversial. It may be useful under certain conditions (e.g., monitoring efficacy of ammonia lowering therapy), but is not required to make the diagnosis of HE or in the long-term follow-up of patients with advanced liver disease, and usually arterial ammonia is more specific than venous one. The longstanding admonition that arterial ammonia levels are required has been supplanted by studies showing venous ammonia levels perform almost as well.¹⁵

Electroencephalography (EEG)

Changes associated with HE are high-amplitude low-frequency waves and triphasic waves. However, these findings are not specific for HE. 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. EEG studies are not required to make a confident diagnosis of HE.

Computed tomography (CT) and MRI

There are no diagnostic features of HE on CT or MRI imaging. These studies are not recommended unless there is consideration of alternative or coincidental intracranial disease.

Diagnosis

The approach to HE comprises exclusion of other causes of encephalopathy, identification of the precipitating cause and a trial of empiric treatment for HE. A rapid response to this empiric treatment confirms a diagnosis of HE, whereas lack of response within 72 hours indicates that further diagnostic options should be considered. Additional testing is usually not required or helpful.

Clinical Scales for Grading HE

A number of scales have been devised for the diagnosis of HE; the first of its kind was proposed by Parsonsmith and colleagues in 1957. For patients with moderate to severe HE, the Glasgow Coma scale can also be employed.

The West-Haven Classification Table (Table 1)

Stage 0. MHE (previously known as subclinical HE). Lack of detectable changes in personality or behavior. Minimal changes in memory, concentration, intellectual function, and coordination. Asterixis is absent.

Stage 1. Trivial lack of awareness. Shortened attention span. Impaired addition or subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria, depression, or irritability. Mild confusion. Slowing of ability to perform mental tasks. Asterixis can be detected.

Stage 2. Lethargy or apathy. Minimal disorientation. Inappropriate behavior. Slurred speech. Obvious asterixis. Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behavior, and intermittent disorientation, usually regarding time.

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

Stage 4. Coma with or without response to painful stimuli. However, the terms that limit each stage of the classification are not clearly defined, and the metric characteristics of the stage are unknown. It is for this reason that other scales such as the Clinical Hepatic Encephalopathy Staging Scale (CHESS) have been proposed.¹⁶ The presence or absence of the nine items on the CHESS score may be helpful in eliminating interobserver variability and in making a distinction between the various grades of encephalopathy. This staging scale, however, requires further validation.

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Minimal or Subclinical Encephalopathy

Patients with minimal hepatic encephalopathy (MHE) have a normal neurological examination; however they may still be symptomatic. Symptoms relate to disturbances in sleep, memory, attention, concentration and other areas of cognition. A classic sign of HE is a sleep disturbance. On a sleep questionnaire, disturbance is seen in 47% of cirrhotics compared with 4.5% of controls.¹⁷ A higher frequency of sleep disturbance in cirrhotic patients with MHE has been confirmed in studies using health-related quality of life questionnaires.^18,19 Sleep disturbance in cirrhosis is not associated with cognitive impairment; thus it may not truly be an MHE symptom. Unsatisfactory sleep is associated with higher scores for depression and anxiety, raising the possibility that the effects of chronic disease may underlie the pathogenesis of sleep disturbance.¹⁹ Disturbances in cirrhotics may also be related to abnormalities of circadian rhythm.

Defective memory may be a sign of MHE. Patients with MHE have impaired short- and long-term memory.¹⁸ This impairment is predominantly related to deficits in attention and visual perception. Memory deficit of MHE seems to comprise short-term but not long-term memory impairment. This can be described as an encoding defect, in which memory recall is intact.

Several cognitive statements and/or complaints, have predictive value for MHE, including impaired psychomotor performance ('I have difficulty doing handwork; I am not working at all'); impaired sleep or rest ('I spend much of the day lying down in order to rest'); decreased attention ('I am confused and start several actions at a time'); and poor memory ('I forget a lot; for example, things that happened recently, where I put things, etc.').¹⁹

Cognitive impairment in MHE mainly affects complex activities involving attention, information processing and psychomotor skills such as driving a car, planning a trip, etc. whereas basic activities of daily life, such as shopping, dressing, personal hygiene, etc. are preserved.^18,20

Patients with MHE had a significant impairment of daily functioning, such as social interaction, alertness, emotional behavior, sleep, work, home management, recreation and pastimes compared with cirrhotic patients who did not have MHE. Treatment with lactulose improved both cognitive functions and health-related quality of life; improvement in the latter was linked to improvement in cognitive function.^18-20

Diagnostic Criteria for MHE

The diagnostic criteria for MHE have not been standardized but rest on careful patient history and physical examination, normal mental status examination, demonstration of abnormalities in cognition and/or neurophysiological function, and exclusion of concomitant neurological disorders.

No consensus on diagnostic criteria or diagnostic tests has been established.

• The presence of a disease that can cause MHE; cirrhotic patients and/or the presence of a transjugular intrahepatic portosystemic shunt (TIPS).
• Without clinical signs of encephalopathy (i.e., normal mental status on clinical examination).
• Disturbed sleep pattern.
• Memory impairment.
• Poor performance in psychometric tests.
• Affects an estimated 60% (50% to 80%) of patients with cirrhosis.
• Cerebral dysfunction has a variable impact on patients' daily living.
• Exclusion of concomitant neurological disorders.

Neuropsychological Test in MHE

Neuropsychological testing is useful methodology for quantifying cognitive impairment due to various forms of encephalopathy, including low-grade or MHE. Neuropsychological tests directly measure cognitive functions that are directly relevant to activities of daily living. They have been applied for the diagnosis of HE for more than 50 years.

The neuropsychological features of MHE point to a disorder of executive functioning, particularly selective attention, visuospatial abilities and fine motor skills. Although these domains are most commonly implicated in MHE, impairments of memory have also been reported.²¹

The attention impairments in MHE are observed on a variety of measures. These include measures of cognitive processing speed involving psychomotor responding, such as the Number Connection tests (NCT), block design test (BDT),the Digit Symbol test (DST), line drawing test, circle-dotting test, serial-dotting test, figure connection test. Impairments on measures of cognitive processing speed and response inhibition that do not require a motor response have also been reported (e.g., with verbal fluency tasks and measures such Stroop test).^22,23 Visuospatial impairments have been primarily reported on block design tasks (which also include a motor/practic component), but also on more pure measures of visuospatial perception, such as line orientation or the Hooper test. Fine motor skill impairments have been noted on measures such as the grooved pegboard task, and on line tracing tasks (the latter also involve visuospatial abilities).²⁴

The NCT is designed from circles that include the numbers from 1 to 13 and the letters from A to L. The subjects are asked to connect numbers and letters in alternating manner, that means go from 1-A-2-B-3-C and so on. Test result is the time needed including error correction time.²⁵

The BDT is a test of visuospatial and motor skills. The task is to take six to nine blocks that have all white sides, all red sides, and red and white sides and arrange them according to a pattern formed by examiner or shown on a card. This test is scored for speed and accuracy.²²

The DST - the subject is given a series of double boxes with a number given in the upper part. The task is to draw a symbol pertinent to this number into the lower part of the boxes. Nine fixed pairs of numbers and symbols are given at the top of the test sheet. Test result is the number of boxes correctly filled within 90 seconds. Pathological test results indicate a deficit in visuo-constructive abilities.²⁵

The line drawing test is a test of motor speed and accuracy. The patients have to follow the route of this labyrinth without crossing or even touching the borderlines. The number of mistakes and the time needed to go through the labyrinth, both, are test results.²³

The circle-dotting test is the simplest test of the battery. It is a test of pure motor speed. The subjects are asked to put a dot in each of the 100 circles given on the sheet, after they have prepared by dotting the 20 circles at the top of the sheet, first. Test result is the time needed.

The smartphone application for Stroop test, which is used to evaluate psychomotor speed and cognitive flexibility, could be used to screen for MHE. The application could be administered and interpreted within 5 minutes by medical assistants and could play an important role in the rapid and objective screening for this condition in the clinic. The Stroop effect is a demonstration of interference in the reaction time of a task. When the name of a color (e.g., "blue," "green," or "red") is printed in a color not denoted by the name (e.g., the word "red" printed in blue ink instead of red ink), naming the color of the word takes longer and is more prone to errors than when the color of the ink matches the name of the color. The effect is named after John Ridley Stroop who first published the effect in English in 1935. The effect has been used to create the psychological test (Stroop Test) that the application is based on and is widely used in clinical practice and investigations.^26,27

Current data suggest that patients with MHE tend to have more frequent episodes of overt HE and poorer survival than in those without MHE, and indicate that patients with MHE have a more advanced liver disease. Child-Turcotte-Pugh score and PHES were associated with a poor prognosis.

Summary

1. HE is a diagnosis of exclusion.
2. Determination of a serum ammonia level can be helpful but is not a good screening or monitoring tool.
3. All cirrhotic patients hospitalized for HE should be evaluated for a precipitating factor.
4. MHE should be kept in mind, while evaluating cirrhotic patients on their outpatient follow up visits, reactions should be taken accordingly.

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Common Precipitants of Hepatic Encephalopathy

Some patients with a history of HE may have normal mental status while under treatment. Others have chronic memory impairment in spite of medical management. HE may wax and wane, when a patient presents with worsening HE, a careful search for correctable cause is warranted.

Factors associated with worsening HE include²⁸:

1. Gastrointestinal bleeding: The presence of blood in the upper gastrointestinal tract results in increased ammonia and nitrogen absorption from the gut.
2. Infection: Infection may activate inflammatory cytokines.
3. Medications: Drugs that act upon the central nervous system, such as opiates, benzodiazepines, antidepressants, and antipsychotic agents, may worsen HE.
4. Constipation: Constipation increases intestinal production and absorption of ammonia.
5. Diuretic therapy: Decreased serum potassium levels and alkalosis may facilitate the conversion of ammonium (NH4) to ammonia (+NH3).
Diuretic-induced hypovolemia is one of the most common reasons for patients with previously well-controlled HE to present to the emergency room with worsening mental function.
6. Dietary protein overload: Although this is an infrequent cause of HE, consumption of the wrong kind of protein (especially red meat protein which is rich in AAA) may exacerbate HE.

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Differential Diagnosis for Hepatic Encephalopathy

Distinguishing HE 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 and the presence of focal neurologic findings (observed infrequently in patients with HE). However seizures, hallucinations and falls are not uncommonly seen with HE. The patient's responsiveness to an empiric trial with cathartic agents can confirm the diagnosis. Even patients with severe HE should demonstrate steady improvement in mental dysfunction after an initiation of treatment.

Differential Diagnoses of Encephalopathy²⁸

• 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
• Post seizure encephalopathy

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Management of Hepatic Encephalopathy

Approach considerations

The approach to the patient with HE depends upon the severity of mental status changes and upon the presence of co-morbidities. As an example, a patient with known cirrhosis and mild complaints of decreased concentration might be served best by an empiric trial of rifaximin or lactulose and a follow-up office visit to check its effect. However, the patient presenting in hepatic coma from gastrointestinal bleeding requires a different approach.

General management recommendations include the following:

1. Exclude non-hepatic causes of altered mental function.
2. Precipitants of HE, such as hypovolemia, metabolic disturbances, gastrointestinal bleeding, infection, and constipation, should be corrected.
3. Avoid medications that depress central nervous system function, especially benzodiazepines and narcotics.
4. Patients with severe agitation and HE may receive haloperidol as a sedative.
5. Treating patients who present with coexisting alcohol withdrawal and HE is particularly challenging. These patients may require therapy with benzodiazepines in conjunction with lactulose and other medical therapies for HE.
6. Patients with grade 3 or 4 HE who are at risk for aspiration should be considered for prophylactic endotracheal intubation. They are optimally managed in the intensive care unit.

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Treatment

The main objectives in the treatment of HE are fourfold:

Provision of Supportive Care

Standard supportive care is required for all hospitalized patients with HE. Patient safety and frequent bedside monitoring of mental status are crucial. This can require additional personnel and, in the case of comatose patients, admission to the intensive care unit, endotracheal intubation, or both. Although temporary restriction of dietary protein may be necessary, patients with HE should avoid prolonged periods of fasting. Although the restriction of dietary protein at the time of acute HE can be part of therapy, protracted nitrogen restriction can lead to malnutrition. Appropriate enteral nutrition, by mouth or nasogastric feeding tube, should be administered as soon as feasible.

Identification and Removal of Precipitating Factors

When there is obvious worsening of HE (development of stage 3 or 4), a vigorous search to identify and eliminate a precipitating factor or factors should be instituted.

In most cases of cirrhosis with acute or chronic HE, a precipitating factor is found, such as the following²⁸:

GI hemorrhage. Exploration requires stool analysis and/or placement of a nasogastric tube.

Infections. This factor requires culture of all appropriate body fluids; blood, urine, ascites, and pleural fluid when present. Spontaneous bacterial peritonitis and pneumonia may present with HE.

Use of psychoactive medication. This factor may require a urine screen for benzodiazepines, narcotics, and other sedatives.

Constipation. Noncompliance with lactulose doses at home.

Renal and electrolyte disturbances. These include renal failure, metabolic alkalosis, hypokalemia, dehydration, and diuretic effects.

Acute deterioration of liver function in cirrhosis. HE in cirrhosis seldom reflects the acute impact of liver failure. Exceptions include the presence of superimposed alcoholic hepatitis, the development of an acute circulatory disturbance (e.g., portal vein thrombosis), and the impairment of liver function seen after surgery in cirrhosis.

TIPS. Precipitating events should also be sought with the development of encephalopathy after placement of TIPS for control of portal hypertension.

Spontaneous encephalopathy (no precipitant factor identified) should raise the suspicion of an abnormal collateral circulation; imaging of the abdomen should be performed looking for spontaneous splenorenal shunt.

Reduction of Nitrogenous Load From the Gut

Cathartics

Lactulose (beta-galactosidofructose) and lactilol (beta-galactosidosorbitol) are nonabsorbable disaccharides in common clinical use since the early 1970s (the latter is not available in the United States). They are degraded by intestinal bacteria to lactic acid and other organic acids.

Lactulose appears to inhibit intestinal ammonia production by a number of mechanisms. Colonic metabolism of lactulose to lactic acid results in acidification of the gut lumen. This favors conversion of ammonium (NH4) to ammonia (NH3) and the passage of ammonia from tissues into the lumen. Gut acidification inhibits ammoniagenic coliform bacteria, leading to increased levels of nonammoniagenic lactobacilli.² Lactulose also works as a cathartic, reducing colonic bacterial load.

Initial lactulose dosing is 30 to 40 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 two to four loose stools per day.

Care must be taken when prescribing lactulose. Overdosage can result in ileus, severe diarrhea, electrolyte disturbances, and hypovolemia. Hypovolemia may be sufficiently severe as to actually induce a flare of encephalopathy symptoms.⁴

High doses of lactulose (e.g., 30 mL q2-4h) may be administered orally or by nasogastric tube to patients hospitalized with severe HE. Lactulose may be administered as an enema to patients who are comatose and 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. Some studies had excellent success using PEG-containing colonic lavage solutions, such as Go-LYTELY administered via nasogastric tube, in the acute management of hospitalized patients with severe HE.²⁸

Antibiotics (Table 2)

Rifaximin a nonabsorbable derivative of rifampin is widely used for treatment of acute exacerbations of HE as well as for maintenance. It has largely supplanted the use of oral neomycin because of its safety and high patient acceptance. Multiple clinical trials have demonstrated that rifaximin at a dose of 400 mg taken orally 3 times a day or 550 mg BID was as effective as lactulose or lactitol at improving HE symptoms.^29,30 Rifaximin is better tolerated than cathartics therapies and some antibiotics.

A recent study showed significant decrease in mortality in cirrhotics with HE after treatment with lactulose plus rifaximin vs. lactulose only. There were significantly more deaths of sepsis in patients received lactulose only compared with the group received lactulose and rifaximin. Interestingly patients received lactulose plus rifaximin group had shorter hospital stay than those treated with lactulose only. Rifaximin addition to lactulose improved overall the physical component of patients' quality of life. It improved capacity to drive as well. Studies have been showing that benefits from using rifaximin are overweighing its expensive monthly cost.³¹

Treatments to Increase Ammonia Clearance

Zinc. Low zinc concentrations are common in patients with cirrhosis of the liver, particularly those with HE. Even in patients who are not zinc deficient. Patients with fulminant hepatic failure and subacute hepatic failure have also been shown to have low serum zinc levels. Zinc deficiency also leads to alteration of neurotransmitters like GABA and norepinephrine. Zinc supplementation has been tried in HE. It may have a role in mild chronic HE, though further trials are necessary.

Unequivocal evidence of benefit of oral zinc therapy for treatment of acute HE is lacking. Zinc sulfate and zinc acetate have been used at a dose of 600 mg orally every day in clinical trials. HE improved in two studies; there was no improvement in mental function in two other studies.³² However, an interesting study from Japan in 2010 showed zinc supplementation significantly improved patients' quality of life, as it improved the physical component scale but not the mental component scale. Zinc supplementation also significantly decreased HE grade and blood ammonia levels and improved Child-Pugh score and neuropsychological tests compared with standard therapy. Interestingly this study showed as well administration of zinc in combination with L-carnosine (combination available for peptic ulcer treatment) showed to enhance intestinal barrier and improve zinc plasma levels.³³

Zinc administration has the potential to improve hyperammonemia by increasing the activity of ornithine transcarbamylase, an enzyme in the urea cycle. The subsequent increase in ureagenesis results in the loss of ammonia ions.³²

Studies have shown importance of zinc for blood-brain barrier integrity as well. It is suggested that zinc deficiency superimposed with oxidative stress predisposes the brain to damage mediated though blood-brain barrier disruption. There is increasing body of evidence to suggest that the endogenous opioid system of the brain is implicated in the mediation of some of the effects of chronic liver disease on central nervous system function. Zinc ions may be important regulators of opioid action in the brain.³⁴

Prebiotics, probiotics, or synbiotics. Prebiotics are nondigestible food ingredients that stimulate growth and activity of microorganisms in the gut. Prebiotics are naturally found in many foods, such as oatmeal and other whole grains, and many fruits and vegetables, including artichokes, asparagus, onions, and bananas. Probiotics are microorganisms that supplement the gut's natural bacteria, helping to "balance" intestinal flora. Synbiotics (probiotics and fermentable fiber) refer to nutritional supplements combining probiotics and prebiotics in a form of synergism, hence synbiotics.

Prebiotics, probiotics, or synbiotics have shown some efficacy in treating patients with MHE,^17,35 and can also be used as long-term therapy. Studies¹⁷ showed that modulation of gut microecology and acidification of gut lumen in patients with liver cirrhosis and MHE by treatment with synbiotics resulted in increased fecal content of nonurease-producing Lactobacillus species, whereas the number of urease-producing pathogenic Escherichia coli and Staphylococcal species decreased. This effect persisted for 14 days after cessation of supplementation and was associated with a reduction in blood ammonia and endotoxin levels and reversal of MHE in nearly 50% of the patients. The severity of liver disease, as assessed according to CTP class, also improved in nearly 50% of the patients. In addition, they help ameliorate the inflammation and oxidative stress in the hepatocytes, leading to increased hepatic clearance of ammonia. These mechanisms may be additive or synergistic in treating MHE. In a randomized control trial, supplementation with probiotic yogurt resulted in a significant reversal of MHE in the group receiving yogurt compared with no treatment.¹⁷

A study from Amsterdam, open-label, prospective, randomized trial enrolled patients 18 to 80 years of age with cirrhosis and no history of overt HE. Study participants were randomly assigned to the probiotic group (n =86) or the control group (n = 74). The researchers used the commercially available VSL#3, which is a mixture of nonurease-producing organisms: Streptococcus thermophilus and various species of Bifidobacterium and Lactobacillus (110 billion colony-forming units, 3 times daily). In the probiotic group, there were significant improvements from baseline to 3 months in arterial ammonia, small intestinal bacterial overgrowth, orocecal transit time, psychometric HE score, and MHE. In the control group, there were no significant differences from baseline in any of these parameters.³⁶

Some examples for probiotics available in USA that contains same species that showed some effect for HE include (all available over the counter, no prescription needed):

• VSL#3 capsules (Streptococcus thermophilus, various species of Bifidobacterium and Lactobacillus; 110 billion colony-forming units, 3 times daily). Monthly cost ~$40.
• Nexabiotic "formerly Benebiotics" (many Lactobacillus species, Bifidobacterium species, and Streptococcus thermophilus). Monthly cost ~$15 to $25.
• Ultimate Flora "Adult Formula" (many Lactobacillus species, Bifidobacterium species). Monthly cost ~$20 to $25.
• Probiotic Pearls (many Lactobacillus species, Bifidobacterium species). Monthly cost ~$12 to $15.

Treatment with a probiotic preparation also improves health-related quality of life. Probiotics may represent a safe, effective, long-term therapy for MHE and may be an alternative to lactulose.^17,35

L -Ornithine L -aspartate (LOLA). LOLA (Hepa-Merz, Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany) is available in Europe, Asia and North Africa in both intravenous formulations and oral formulations. It is not available in the United States. LOLA is a stable salt of the two constituent amino acids. L-ornithine stimulates the urea cycle, with resulting loss of ammonia. Both L-ornithine and L-aspartate are substrates for glutamate transaminase. Their administration results increased glutamate levels. Ammonia is subsequently utilized in the conversion of glutamate to glutamine by glutamine synthetase.

LOLA was found to be effective in treating HE in a number of European trials.^36,37

Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate. Sodium benzoate interacts 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 HE.³⁸

Use of this medication is limited by the risk of salt overload and by its unpleasant taste. The medication, also used as a food preservative, is available through many specialty chemical manufacturers throughout the United States.

Studies have limited its use to patients with severe encephalopathy symptoms. However, studies showed doses of sodium benzoate as low as 2.5 g orally three times per week significantly improved mental function in outpatients who had persistent encephalopathy symptoms despite cotherapy with lactulose and rifaximin.³⁸

Sodium phenylbutyrate is converted to phenylacetate. Phenylacetate, in turn, reacts with glutamine to form phenylacetylglutamine. This chemical is subsequently excreted in the urine, with loss of ammonia ions. Sodium phenylbutyrate (Buphenyl, Ucyclyd Pharma, Scottsdale, AZ) and intravenous sodium phenylacetate in combination with sodium benzoate (Ammonul, Ucyclyd Pharma, Scottsdale, AZ) are approved by the U.S. Food and Drug Administration for the treatment of hyperammonemia associated with urea cycle disorders.³⁹

BCAA. BCAA (leucine, isoleucine, and valine) have been shown to affect gene expression, protein metabolism, apoptosis and regeneration of hepatocytes, and insulin resistance. In patients with advanced chronic liver disease, BCAA concentrations are low, whereas the concentrations of AAA such as phenylalanine and tyrosine are high, conditions that may be closely associated with HE.⁴⁰

In a metanalysis by Als-Nielsen et al, 11 randomized trials (556 patients) assessing BCAA versus carbohydrates, neomycin/lactulose, or isonitrogenous controls were included. The median number of patients in each trial was 55 (range, 22-75). Follow-up after treatment was reported in four trials, median of 17 days (range, 6-30 days). Compared with the control regimens, BCAA significantly increased the number of patients improving from HE at the end of treatment. They found no evidence of an effect of BCAA on survival in eight trials or adverse events in three trials. Sensitivity analyses indicated that methodological quality had significant impact on the results. They found no evidence of an effect of BCAA on improvement of HE in trials with adequate generation of the allocation sequence, adequate allocation concealment or adequate double in three trials.⁴¹

Another study incorporating a more palatable granular formulation of leucine, isoleucine, and valine has been completed in 2006. In what is by far the largest study in this setting, Muto et al, conducted a multicenter, randomized, and nutrient-intake–controlled trial on the comparative effects of BCAA orally administered at 12 g/d for 2 years vs. non-BCAA–supplemented diet therapy. The study was conducted in 646 patients with cirrhosis. The primary end point was a composite of death by any cause, development of liver cancer, rupture of esophageal varices, or progress of hepatic failure (event-free survival). The secondary end points were serum albumin concentration and health-related quality of life. The incidence of events comprising the primary end point decreased in the BCAA group compared with the diet group. Serum albumin concentration increased in the BCAA group compared with the diet group. The general health perception measure was also improved. The study by Muto et al provides important new evidence of a therapeutic benefit to BCAA supplementation in the prevention of complications of cirrhosis and improvement of health-related quality of life.⁴²

To summarize; although the role of BCAA in management of HE is to be determined through wider scale of trials, however there is no evidence of adverse effects, and cirrhotics usually run low levels of those amino acids.

They are available in United States, over the counter with no prescription needed, examples include Optimum Nutrition BCAA and Myology BCAA 5,000 mg powder.

Not to be used alone as primary treatment, could be last resort, if encephalopathy is not well managed by first line of therapy. Given dose should be at least 5 grams per day up to 0.24 per every 1 kg (2.2 lb) of body weight.

L-carnitine. L-carnitine improved HE symptoms in several small studies of patients with cirrhosis.⁴³ Whether the medication works by improving blood ammonia levels or whether it works centrally perhaps by decreasing brain ammonia uptake remains unclear.

Assessment of the Need for Long-Term Therapy

Patients with cirrhosis are at risk of developing new episodes of encephalopathy. Several factors need to be considered:

Diet and Nutrition

Low-protein diets are often erroneously recommended for patients with cirrhosis, in hopes of decreasing intestinal ammonia production and of preventing exacerbations of HE. An obvious consequence was the worsening of preexisting protein-energy malnutrition. Protein restriction may be appropriate in some patients immediately following a severe flare of symptoms (i.e., episodic HE). However, protein restriction is rarely justified in patients with cirrhosis and persistent HE. Indeed, malnutrition is a more serious clinical problem than HE for many of these patients.

It is the infrequent patient who is intolerant of a diet high in protein. Most patients with mild chronic HE tolerate more than 60 to 80 g of protein per day.

Diets containing vegetable proteins appear to be better tolerated than diets rich in animal protein. This may be because of increased content of dietary fiber, a natural cathartic, and decreased levels of AAA. AAA, as precursors for the false neurotransmitters tyramine and octopamine, are thought to inhibit dopaminergic neurotransmission and worsen HE. Ingestion of red meat protein should be discouraged.

Control of Potential Precipitating Factors

These include avoidance of constipation; prophylaxis of bleeding from gastroesophageal varices, when indicated; prophylaxis of spontaneous bacterial peritonitis, when indicated; judicious use of diuretics; and avoidance of psychoactive medication.

Higher Likelihood of Recurrent Encephalopathy

The development of HE in the absence of a precipitating factor or the development of HE in patients with poor liver function (Child B/C) is such a situation. Prevention of a first episode of HE in subjects who have undergone a TIPS procedure is done in some centers, though no controlled data are available.

Patient Education

Patients should be aware of the spectrum of HE that ranges from overt to subclinical, the true prevalence of this condition is not well defined but is estimated to involve up to 60% of patients with cirrhosis. It has been recently reported that even a single episode of HE is associated with a persistent cognitive defect, suggesting that HE is not a truly reversible condition. Whereas overt HE can be demonstrated with a mental status exam, MHE requires complex psychometric testing of specific cognitive functions, including inhibition, attention, and working memory. Such testing is not widely available and certainly not commonly used in routine clinical practice. MHE has been associated with reductions in patient quality of life, and recently with an increased number of motor vehicle violations and auto accidents. Further complicating this association is the apparent poor insight that these patients have into their compromised driving skills.⁴⁴

Assessment of the Need for Liver Transplantation

The development of overt HE carries a poor prognosis,²⁰ with a 1-year survival of 40%. Appropriate candidates should be referred to transplant centers after the first episode of overt encephalopathy of any type. Both acute and chronic HE, once advanced to stage 4 (coma), is associated with an 80% overall mortality rate.

Hepatic Encephalopathy and Fitness to Drive

Many studies on the driving fitness focused on cirrhotic patients with MHE. The most important aspect was to evaluate capacity of cirrhotics for real driving performance. The analysis of both speed and lane-keeping parameters showed in almost all assignments significant differences between normal individuals and cirrhotics with MHE.⁴⁵

Significant performance differences between the cirrhotic subgroups were uncovered during real driving upon introduction of dual-task elements. Patients with MHE showed poorer performance in all measured function areas for real driving (perception and cognitive processing, motor and visual motor control) than normal individuals. This could no longer guarantee a reaction appropriate to the situation.

Cohen and colleagues compiled an evaluation of the legal ramifications for healthcare providers of HE patients who drive. The investigators contacted the Divisions of Motor Vehicles for each of the 50 states in the United States and searched for HE-related lawsuits. Only six states (12%); California, Delaware, New Jersey, Nevada, Oregon and Pennsylvania, had laws for mandatory reporting of these patients. In 25 of the remaining 44 states (57%), legal immunity was provided to healthcare providers who reported these patients although the reporting was not mandatory. Of interest, the definition of "impaired driver" varied considerably and no state specifically mentioned HE or cirrhosis as a reportable condition. None of the database analyses revealed any legal cases against healthcare providers for failure to warn patients with HE against driving. Furthermore, no lawsuits in which HE was identified as a causal condition for a motor vehicle accident were found.⁴⁶

Bajaj and associates suggest that because healthcare providers are not trained in evaluations for driving fitness, nor are they officers of the state agencies charged to enforce these rules, they should follow the applicable local laws. Impaired driving poses a significant risk both to patients and other drivers, so it is important to discuss and evaluate the potential for HE- or MHE-related driving impairment with the patient and family members. One subtle indicator of a driving problem for patients with MHE is an impairment of navigation skills. A focused discussion (with both the patient and family members who may ride with the patient) should query about compromised acuity with respect to navigation skills.⁴⁷

Summary

Acute Encephalopathy in Cirrhosis

General Measures

• Tracheal intubation in patients with stage 3 or 4 HE should be considered.
• A nasogastric tube is placed for patients in deep encephalopathy.
• Avoid sedatives and narcotics.
• Correction of the precipitating factor is the most important measure. Approximately 70% to 80% of patients with HE improve after correction of precipitating factors.

Specific Measures

• Nutrition. In case of deep encephalopathy, oral intake is withheld for 24 to 48 hours and IV glucose is provided until improvement. Enteral nutrition can be started if the patient appears unable to eat after this period. Protein intake begins at a dose of 0.5 g/kg/d, with progressive increase to 1 to 1.5 g/kg/d.
• Lower ammonia levels. Lactulose is administered via enema or nasogastric tube in deep encephalopathy. The oral route is optimized by dosing every hour until stool evacuation appears. Rifaximin can be added to lactulose (400 mg taken orally three times daily or 550 mg taken orally two times a day). A further alternative is sodium benzoate (5 g twice daily). Sodium benzoate is not available as a pharmaceutical in the United States or the European Union.
• Flumazenil may be used in selected cases of suspected benzodiazepine use.

Chronic Encephalopathy in Cirrhosis

• Avoidance and prevention of precipitating factors, including the institution of prophylactic measures.
• Nutrition. Improve protein intake by feeding dairy products and vegetable-based diets. Oral BCAA can be considered for individuals intolerant of all protein.
• Lactulose. Dosing aims at two to three soft bowel movements per day. Antibiotics are reserved for patients who respond poorly to disaccharides or who do not exhibit diarrhea or acidification of the stool.
Lactulose is generally considered first-line therapy for acute and chronic HE. Antibiotics are second-line therapy for HE, but they can have many potential side effects and complications.
• Refer for liver transplantation in appropriate candidates.
• Persistent encephalopathy (nonresponsive to therapy), consider imaging of splanchnic vessels to identify large spontaneous portal-systemic shunts potentially amenable to radiological occlusion. In addition, consider the combination of lactulose and neomycin, addition of oral zinc, and invasive approaches, such as occlusion of TIPS or surgical shunts, if present.

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