HEPATIC ENCEPHALOPATHY

Subtle signs of hepatic encephalopathy are observed in nearly 70% of patients with cirrhosis. Symptoms may be debilitating in a significant number of patients. Overt hepatic encephalopathy occurs in about 30-45% of patients with cirrhosis.⁽¹⁾ It is observed in 24-53% of patients who undergo portosystemic shunt surgery.

The development of hepatic encephalopathy negatively impacts patient survival. The occurrence of encephalopathy severe enough to lead to hospitalization is associated with a survival probability of 42% at 1 year of follow-up and 23% at 3 years.⁽²⁾ Approximately 30% of patients dying of end-stage liver disease experience significant encephalopathy, approaching coma.⁽³⁾

According to one study conducted in Gujranwala, Pakistan, prevalence of HE was noted as more than 60% and main precipitating factor for hepatic encephalopathy was underlying infection. Diabetes mellitus is important co-morbidity factor observed in more than half of the patients. Majority of the patients present in grade 1 have good outcome. Expiry rate is higher in patients presenting with grade 3 and 4 hepatic encephalopathy and with Child-Pugh Score of class C.⁽⁴⁾

Hepatic encephalopathy (HE) or portosystemic encephalopathy (PSE) is a reversible syndrome of impaired brain function occurring in patients with advanced liver failure.

Neurotoxins

Ammonia: Ammonia is the best characterized neurotoxin that precipitates HE. The gastrointestinal tract is the primary source of ammonia, which enters the circulation via the portal vein. Ammonia is produced by enterocytes from glutamine and by colonic bacterial catabolism of nitrogenous sources, such as ingested protein and secreted urea. Another source of ammonia may be urea digested by Helicobacter pylori in the stomach,⁽⁶⁾ although the role of H. pylori in HE is unclear. The intact liver clears almost all of the portal vein ammonia, converting it into glutamine and 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 astrocyte dysfunction.⁽⁷⁾

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. Increasingly, gut microbiota are recognized as a main source of ammonia.⁽⁸⁾

• Impaired blood to brain transport of amino acids: Hyperammonemia may increase the cerebral uptake of neutral amino acids by enhancing the activity of the L-amino acid transporter at the blood-brain barrier. This effect may be the consequence of the brain to blood transport of glutamine, which is formed in excess for ammonia detoxification.⁽⁹⁾
• Increase in intracellular osmolarity in astrocytes: One possible explanation for brain edema is an increase in intracellular osmolarity resulting from the metabolism of ammonia in astrocytes to form glutamine. Inhibition of glutamine synthetase prevents brain swelling in rats infused with ammonia⁽¹⁰⁾ and inhibits cellular swelling in cultures of astrocytes incubated with ammonia.
• Altered neuronal electric activity: Ammonia directly affects neuronal electric activity by inhibiting the generation of both excitatory and inhibitory postsynaptic potentials.^(11-13)

Oxidative stress: Oxidative stress has a major role in cerebral ammonia toxicity and the pathogenesis of hepatic encephalopathy. Ammonia induces rapid RNA oxidation in cultured rat astrocytes, mouse brain slices, and rat brain in vivo.⁽¹⁴⁾ Ammonia-induced RNA oxidation in cultured astrocytes may modulate the N-methyl-D-aspartic acid (NMDA) receptor activation.⁽¹⁵⁾

Since oxidative stress promotes astrocyte swelling, a self-amplifying signaling loop between osmotic and oxidative stress triggers protein tyrosine nitration (PTN), oxidation of RNA, mobilization of zinc, alterations in intra- and intercellular signaling, and multiple effects on gene transcription. PTN can affect the function of a variety of proteins, such as glutamine synthetase. PTN and RNA oxidation are also found in the postmortem human cerebral cortex of patients with cirrhosis with HE but not in those without HE, supporting a role for oxidative stress in the pathophysiology of HE.

Oxindole: Oxindole is a tryptophan metabolite formed by gut bacteria (via indol) that can cause sedation, muscle weakness, hypotension, and coma. It appears to be produced in the intestine and cleared by the liver, which is similar to ammonia.⁽¹⁶⁾

Impairment of neurotransmission:

Hepatic encephalopathy (HE) is characterized by biochemical alterations in functions associated with neural membranes, such as the changes in the uptake of neurotransmitters, in enzyme activities, and the expression of neurotransmitter receptors.

GABA-benzodiazepine neurotransmitter system: A role has been proposed for increased tone of the inhibitory gamma-aminobutyric acid (GABA)A-benzodiazepine neurotransmitter system in the development of HE.

• Neurochemical studies: Multiple studies have examined the GABAA-benzodiazepine neurotransmitter system in liver failure. In contrast to initial reports of an increase in GABA and benzodiazepine receptors on cortical membranes,⁽¹⁷⁾ subsequent studies yielded conflicting results.⁽¹⁸⁾ In most studies, GABA and benzodiazepine receptors and cerebral GABA concentrations are not changed in HE.^(19,20)
• Neurobehavioral studies: Rats with liver failure are more sensitive to the sedative effects of benzodiazepines than normal rats.⁽²¹⁾ Furthermore, administration of antagonists of the GABAA-benzodiazepine receptor complex to animals with fulminant hepatic failure and HE has led to a transient clinical improvement which was associated with a normalization of abnormal visual evoked potentials.^(22,23)
• Electrophysiologic studies: Single cell recordings from Purkinje neurons have revealed increased sensitivity in HE to the inhibitory effects of benzodiazepine agonists, a finding consistent with activation of the GABAA-benzodiazepine neurotransmitter system in HE.⁽²⁴⁾
• Endogenous benzodiazepines: Endogenous benzodiazepines involved in the activation of the GABAA-ergic neurotransmission have been isolated, characterized, and positively identified by gas chromatography-mass spectroscopy as benzodiazepines in brain, sera, and CSF of experimental animals and humans with acute liver failure due to acetaminophen toxicity.^(25,26) The brain concentration of these substances correlated closely with the degree of neurologic impairment in an animal model of HE.⁽²⁷⁾

Neurosteroids: Neurosteroids are metabolites of progesterone and are endogenous neuroactive compounds. Allopregnanolone and tetrahydrodeoxycorticosterone are potent selective positive allosteric modulators of the GABAA receptor complex. Administration of these steroids induces behavioral effects that include sedation, a property consistent with enhancement of the neuronal inhibition characteristic of HE.

Glutamatergic neurotransmission: There is increasing evidence that alterations of glutamatergic function are implicated in the pathogenesis of central nervous system consequences of acute liver failure.

• Neurochemical studies: Total brain glutamate levels are decreased in various models of HE and in patients dying from chronic liver failure.⁽²⁸⁾ NMR-spectroscopy in hyperammonemic rats and in rats with acute liver failure following liver ischemia confirmed the reduced concentration of glutamate in vivo.⁽²⁹⁾ This decrease in glutamate is presumably due to glutamine formation during the process of ammonia detoxification. It is not known whether a similar change occurs in neuronal glutamate.

In contrast, extracellular glutamate concentrations are elevated in HE.^(30,31) This effect may be due to excessive release of glutamate from neurons depolarized by ammonia or to impaired reuptake by neurons or glial cells.^(20,32) Astrocytes may be involved in these derangements since ammonia can impair the ability of these cells to take up glutamate. Reduced capacity of astrocytes to reuptake neuronally-released glutamate and the ensuing compromise in neuron-astrocytic trafficking of glutamate could contribute to the pathogenesis of HE.

• Glutamate receptors: There are three major subtypes of glutamate receptors, defined according to their coupling to ion channels and their affinity to certain ligands:
• N-methyl-D-aspartate (NMDA)
• Non-NMDA – amino-3-hydroxy-5-methyl-4-isoxazol propionic acid (AMPA) and kainite
• Metabotropic glutamate receptor
• Neurobehavioral studies: Memantine is a noncompetitive NMDA-receptor antagonist. In portacaval shunted rats infused with ammonia and rats with acute hepatic failure due to liver ischemia, memantine improved clinical grading, EEG activity, and the increases in CSF glutamate concentrations, intracranial pressure, and brain water content.⁽³³⁾ Memantine had no effect on ammonia concentrations in either model.
• Genetic studies: Certain patients appear to be predisposed to hepatic encephalopathy to a greater degree than others with similarly advanced liver disease. The reasons for these differences in susceptibility are incompletely understood. One study suggested that variation in the glutaminase gene may in part be responsible.⁽³⁴⁾ Patients who had a variant of the promoter region of the glutaminase gene that was associated with increased enzyme activity appeared to have an increased risk of hepatic encephalopathy.

Catecholamines: Altered concentrations of catecholamines in HE have been linked to altered amino acid metabolism. In chronic liver failure, the plasma and brain concentrations of aromatic amino acids (AAAs; phenylalanine, tryptophan, and tyrosine) are increased, while those of the branched-chain amino acids (BCAAs) valine, leucine, and isoleucine are reduced. Since these amino acids share a common carrier at the blood-brain barrier, decreased BCAA concentrations in the blood may result in increased transport of AAA into the brain.⁽³⁵⁾ A low molar ratio of plasma BCAA to AAA is a consistent finding in patients with cirrhosis and HE, but also occurs in patients without HE.^(36,37) This ratio closely correlates with indices of liver function, with a decreased ratio implying poor hepatocellular function.⁽³⁷⁾ Thus, it appears unlikely that changes in the plasma concentrations of neutral amino acids contribute to the development of HE.

Tyrosine-3-hydroxylase is the key enzyme for the synthesis of catecholaminergic neurotransmitters, and high concentrations of phenylalanine in the brain may inhibit the enzyme. In addition, other amines such as tyramine, octopamine, and phenylethanolamine are synthesized from tyrosine by alternative metabolic pathways. These false neurotransmitters may compete with the normal catecholamine neurotransmitters (e.g. dopamine) for the same receptor site.⁽³⁵⁾

However, some of the extrapyramidal symptoms in patients with cirrhosis may be due to altered dopaminergic function, which is closely related to accumulation of manganese in basal ganglia.⁽³⁸⁾

Finally, another fairly consistent finding in animal models of acute or chronic liver failure is a reduced norepinephrine (noradrenaline) concentration in the brain. The decreased brain norepinephrine content is due to overactivity of noradrenergic neurotransmission, possibly induced by hyperammonemia.⁽³⁹⁾

Serotonin: A two to fourfold increase in cerebral concentration of the serotonin metabolite 5-hydroxyindoleacetic acid is the most consistent neurochemical finding in HE.^(40,41) In addition, HE is associated with alterations in the number of 5HT1A and 5HT2 receptors⁽⁴²⁾ and increased activity of both MAOA and MAOB (enzymes catabolizing 5-HT).⁽⁴³⁾ These findings suggest an increased serotonin turnover rate in HE, but do not necessarily imply an overactivity of this neurotransmitter system.

Histamine: The binding properties and the regional densities of histamine H1 receptors in the brains of rats with portacaval anastomosis suggested that this neurotransmitter system is also affected in liver failure. Autopsied brain tissue from cirrhotic patients with HE displayed a higher density and a lower affinity of histamine H1 receptors compared with control human frontal cortex.⁽⁴⁴⁾ A selective increase in H1 receptor density was also observed in parietal and insular cortices of patients with HE. The central histaminergic system is implicated in the control of arousal and circadian rhythmicity. A selective up-regulation of brain H1 could contribute to the neuropsychiatric symptoms characteristic of human HE, and may be amenable to treatment with selective histamine H1 receptor antagonists.

Melatonin: Sleep disturbances are common in patients with subclinical HE⁽⁴⁵⁾ and may be due to a centrally mediated alteration of circadian rhythm.⁽⁴⁶⁾ The 24-hour rhythm of melatonin, which is considered to be the output signal of the biological «clock,» is considerably altered in patients with cirrhosis.⁽⁴⁶⁾ The onset of the rise in plasma levels of melatonin and the melatonin peak during the night are displaced to later hours. Furthermore, plasma melatonin levels are significantly higher during daylight hours, at a time when melatonin is normally very low or absent.

Alteration of the blood-brain barrier:

The brain uptake of various tracer substances is increased in several animal models of acute liver failure.⁽⁴⁷⁾ The reason for this nonspecific increase in blood-brain barrier permeability is unknown. Regardless of the mechanism, this change can lead to exposure of the brain to a variety of neurotoxic substances circulating in the blood and may result in brain edema.

Altered brain energy metabolism:

Undisturbed energy supply and energy metabolism is a prerequisite for normal brain function. Glucose is the most important cerebral energy fuel and hypoglycemia can occur in the terminal stages of liver failure due to impaired hepatic gluconeogenesis. However, the administration of glucose is not sufficient to normalize brain function in HE.

Systemic response to infections and neuroinflammation:

Infection is a well-known precipitant of hepatic encephalopathy, but the mechanisms involved are incompletely understood.^(48,49) Patients with cirrhosis are known to be functionally immunosuppressed and prone to develop infections.⁽⁵¹⁾ Whether infections themselves or the inflammatory response exacerbate HE is unclear.

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 and motor activity, ranging from delirium to coma.⁽⁵¹⁾

During an episode of sepsis, cytokines (15 to 20 kDa) cannot diffuse across the blood-brain barrier and are therefore unable to have a direct effect. Nevertheless, the peripheral immune system can lead to the production of proinflammatory cytokines (both in the periphery and in the brain). These proinflammatory cytokines can signal the brain to elicit a response. Brain signaling may occur through direct transport of the cytokine across the blood-brain barrier.⁽⁵²⁾

Another potential factor inciting an inflammatory response is bacterial translocation of organisms from the gut, which results in chronic endotoxemia.⁽⁵¹⁾ Bacterial translocation may activate proinflammatory cytokines/chemokines and neutrophils through Toll-like and chemokine receptors.⁽⁵⁴⁾

Bacterial overgrowth:

Small bowel bacterial overgrowth has been hypothesized to contribute to minimal hepatic encephalopathy.⁽⁵⁵⁾ However, more studies are needed to clarify the validity and implications of the association.

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:⁽⁵⁶⁾

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. At the author’s institution, diuretic-induced hypovolemia is the most common reason for patients with previously well-controlled hepatic encephalopathy to present to the emergency room with worsening mental function.

Dietary protein overload: This is an infrequent cause of hepatic encephalopathy.

Hepatic encephalopathy is often easy to detect in patients presenting with overt neuropsychiatric symptoms. It may be more difficult to detect in patients with chronic liver diseases who have mild signs of altered brain function, particularly if the underlying cause of the liver disease may be associated with neurologic manifestations (such as alcoholic liver disease or Wilson disease).

Categorization and grading:

Hepatic encephalopathy is categorized based on four factors: the underlying disease, the severity of manifestations, the time course, and whether precipitating factors are present.^(57-59) (figure 1)

• Underlying disease: A classification scheme based on the underlying disease has been proposed:^(57,58)
• Type A: hepatic encephalopathy occurring in the setting of acute liver failure
• Type B: hepatic encephalopathy occurring in the setting of portal-systemic bypass with no intrinsic hepatocellular disease
• Type C: hepatic encephalopathy occurring in the setting of cirrhosis with portal hypertension or systemic shunting
• Severity of manifestations: The severity of hepatic encephalopathy is graded based on the clinical manifestations:⁽⁵⁹⁾
• Minimal: Abnormal results on psychometric or neurophysiological testing without clinical manifestations
• Grade I: Changes in behavior, mild confusion, slurred speech, disordered sleep
• Grade II: Lethargy, moderate confusion
• Grade III: Marked confusion (stupor), incoherent speech, sleeping but arousable
• Grade IV: Coma, unresponsive to pain

Patients with grade I encephalopathy may have mild asterixis, whereas pronounced asterixis is seen in patients with grade II or III encephalopathy.⁽⁶⁰⁾ Asterixis is typically absent in patients with grade IV encephalopathy, who instead may demonstrate decorticate or decerebrate posturing.

Patients with minimal or grade I hepatic encephalopathy are described as having covert hepatic encephalopathy, whereas patients with grade II to IV hepatic encephalopathy are described as having overt hepatic encephalopathy. The separation of minimal hepatic encephalopathy from grade I hepatic encephalopathy is important for clinical studies.

• Time course: The time course for hepatic encephalopathy can be episodic, recurrent (bouts of hepatic encephalopathy that occur within a time interval of six months or less), or persistent (a pattern of behavioral alterations that are always present, interspersed with episodes of overt hepatic encephalopathy).
• Precipitating factors: Episodes of hepatic encephalopathy are described as being either nonprecipitated or precipitated. If precipitated, the precipitating factors should be specified.

Clinical manifestations:

Hepatic encephalopathy is characterized by cognitive deficits and impaired neuromuscular function. Patients with minimal hepatic encephalopathy have subtle cognitive deficits, often appear to be asymptomatic, and may only be detected with psychomotor or electrophysiologic testing. Patients with overt hepatic encephalopathy have signs and symptoms that can be detected clinically, without the use of psychomotor testing (though psychomotor testing may be helpful in evaluating patients with mild encephalopathy).

In addition to the clinical manifestations of hepatic encephalopathy, patients frequently have clinical manifestations of chronic liver disease.

Signs and symptoms: Cognitive findings in patients with hepatic encephalopathy vary from subtle deficits that are not apparent without specialized testing (minimal hepatic encephalopathy), to more overt findings, with impairments in attention, reaction time, and working memory.⁽⁶¹⁾ Patients with severe hepatic encephalopathy may progress to hepatic coma. Neuromuscular impairments include bradykinesia, hyperreflexia, rigidity, myoclonus, and asterixis.

Disturbances in the diurnal sleep pattern (insomnia and hypersomnia) are common initial manifestations of hepatic encephalopathy and typically precede other mental status changes or neuromuscular symptoms. As hepatic encephalopathy progresses, patients may develop mood changes (euphoria or depression), disorientation, inappropriate behavior, somnolence, confusion, and unconsciousness.

Neuromuscular impairment in patients with overt hepatic encephalopathy includes bradykinesia, asterixis (flapping motions of outstretched, dorsiflexed hands), slurred speech, ataxia, hyperactive deep tendon reflexes, and nystagmus. Less commonly, patients develop loss of reflexes, transient decerebrate posturing, and coma.

Patients with hepatic encephalopathy usually have advanced chronic liver disease and thus have many of the physical stigmata associated with severe hepatic dysfunction. Physical findings may include muscle wasting, jaundice, ascites, palmar erythema, edema, spider telangiectasias, and fetor hepaticus. Some of these findings (such as muscle wasting, spider telangiectasias, and palmar erythema) are usually absent in previously healthy patients with acute hepatic failure since their development requires a relatively longer period of hepatic dysfunction.

Laboratory abnormalities: Laboratory abnormalities in patients with hepatic encephalopathy may include elevated arterial and venous ammonia concentrations. In addition, patients typically have abnormal liver biochemical and synthetic function tests due to underlying liver disease. Patients may also have electrolyte disturbances (such as hyponatremia and hypokalemia) related to hepatic dysfunction and/or diuretic use.

The approach to the diagnosis of hepatic encephalopathy includes:

• A history and physical examination to detect the cognitive and neuromuscular impairments that characterize hepatic encephalopathy
• Exclusion of other causes of mental status changes
• Serum laboratory testing to rule out metabolic abnormalities
• A computed tomography (CT) scan of the brain if the clinical findings suggest another cause for the patient’s findings may be present (such as a subdural hematoma from trauma); a CT scan may also demonstrate cerebral edema (found in 80 percent of patients with acute hepatic encephalopathy)
• Evaluation for possible precipitating causes of the hepatic encephalopathy

For patients with mild degrees of hepatic encephalopathy (minimal hepatic encephalopathy or grade I encephalopathy) in whom the diagnosis is unclear, psychometric and electrophysiologic tests may be helpful. In such patients, approach should be to first ask about subtle signs of impaired mental status, and if signs point to the possible presence of minimal hepatic encephalopathy to perform psychometric testing (typically the number connection test). An alternative but less sensitive test is the Mini-Mental State Examination (MMSE).

For patients with more severe hepatic encephalopathy (grades III and IV), the Glasgow Coma Scale may be useful for further stratifying the severity of neurologic impairment.⁽⁶²⁾

History and physical examination:

The evaluation should start by inquiring about mental status changes, keeping in mind that in patients with minimal hepatic encephalopathy the signs may be subtle. Patients should be asked about changes in their sleep patterns and in cognitive capacity (decreased attention span, impaired short term memory) leading to difficulties with normal daily activities. Patients should also be asked about impaired work performance and work- or driving-related accidents. Patients should also be examined for signs of neuromuscular dysfunction.

Laboratory tests:

Ammonia is the best characterized neurotoxin that precipitates hepatic encephalopathy. However, an elevated serum ammonia concentration is not required to make the diagnosis and is not specific for hepatic encephalopathy. In addition, ammonia levels are influenced by factors such as how the blood sample is obtained and handled. Serum ammonia levels should not be used to screen for hepatic encephalopathy in patients who are asymptomatic or who have mental status changes in the absence of liver disease or a portal-systemic shunt.

Other routine laboratory tests should be obtained to exclude other causes of mental status changes (e.g. hypoglycemia, uremia, electrolyte disturbances, and intoxication) and to look for conditions that may have precipitated the hepatic encephalopathy.

Other potential markers: Serum levels of 3-nitrotyrosine may be elevated in patients with minimal hepatic encephalopathy.

Psychometric tests:

Commonly performed bedside tests are insufficiently sensitive to detect subtle changes in mental function. As a result, several psychometric tests have been evaluated that quantify the impairment of mental function in patients with mild stages of hepatic encephalopathy.^(63-67) These tests are more sensitive for the detection of minor deficits of mental function than conventional clinical assessment or an EEG.

The use of psychometric tests is limited because many are cumbersome and time consuming (up to two hours per session), their reliability is decreased by a learning effect when they are applied repeatedly, and there is poor correlation among the tests.^(68,69) Another problem with psychometric tests is that they are nonspecific (i.e. any alteration of brain function will result in abnormal test results). This is a particular problem in patients with alcoholic liver disease or Wilson disease since both are associated with central nervous system abnormalities.

Number connection test (Reitan Test): The most frequently used psychometric test is the number connection test (NCT or Reitan Test), which is easily administered and interpreted. The NCT is a timed connect-the-numbers test. Patients without hepatic encephalopathy should finish the test in a number of seconds less than or equal to their age in years. In other words, if a patient is 50 years old, he should be able to finish the test in ≤50 seconds.

Psychometric Hepatic Encephalopathy Score (PHES): In an attempt to improve the performance of testing for minimal hepatic encephalopathy, a battery of five paper and pencil tests were combined into a new instrument, the Psychometric Hepatic Encephalopathy Score (PHES).⁽⁷⁰⁾ The PHES includes a line tracing test, digit symbol test, serial dotting test, and both parts of the NCT (NCT-A and NCT-B). It examines visual perception, visuospatial orientation, visual construction, motor speed and accuracy, concentration, attention, and memory. The test can be performed in 10 to 20 minutes at the bedside. Possible scores range from -18 to +6 points.

The PHES test has been recommended by a panel of international experts for the neuropsychological assessment of early hepatic encephalopathy, though in practice it is rarely used.⁽⁷¹⁾

Other psychometric tests: More complex tests continue to be used for clinical studies, which often include multiple tests that measure different brain functions (such as memory, motor performance, attention, etc.). The interpretation of the tests often requires a trained psychologist and sophisticated statistical methods.

• The Inhibitory Control Test (ICT) is a computerized test of attention and response inhibition that has been used to characterize attention deficit disorder, schizophrenia, and traumatic brain injury. The subject is instructed only to respond to two alternating letters (X/Y) (called «targets») and not to respond when they are not alternating (called «lures»). Lower lure responses, higher target responses, and shorter lure and target reaction times indicate good psychometric performance.
• Computerized testing that measures neurocognitive functions (e.g. the Cognitive Drug Research [CDR] battery) is an alternative to paper and pencil based testing (such at the PHES).
• The Stroop task is a test of psychomotor speed and cognitive flexibility that evaluates the functioning of the anterior attention system and is sensitive for the detection of cognitive impairment in minimal hepatic encephalopathy.⁽⁷²⁾ The task has two components: «off» and «on» states depending on the discordance or concordance of stimuli. This test is available as an application for smart phones (EncephalApp Stroop) and can be administered in a few minutes.
• The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) measures a wide range of neurocognitive functions relevant to minimal hepatic encephalopathy. The test has been used in multiple clinical trials in the United States for a variety of neurologic disorders and in patients with advanced cirrhosis.⁽⁷³⁾ The RBANS has not yet been compared directly with the PHES, and its responsiveness to hepatic encephalopathy treatment is unknown.
• Another useful test is the measurement of reaction times to auditory and visual stimuli. The equipment is inexpensive, and the time to perform it is reasonably short. It can be applied repeatedly since it is not affected by learning effects.
• Other emerging diagnostic strategies concentrate on computerized tests and batteries such as the Scan test, a three-level-difficulty computerized reaction time test, central nervous system (CNS) vital signs, and Immediate Post-concussion Assessment and Cognitive Testing (ImPACT). A simple test using a smartphone-based application may be a useful tool for repeated assessment of minimal hepatic encephalopathy.

Electrophysiologic tests:

Electrophysiologic tests to detect minimal hepatic encephalopathy include EEG monitoring, evoked potentials, and critical flicker frequency testing. However, none of these tests is widely used.

Electroencephalogram activity: The simplest EEG assessment of hepatic encephalopathy is grading the degree of abnormality of the conventional EEG tracing. A more refined assessment can be accomplished with computer-assisted spectral analysis of the EEG, which permits variables in the EEG (such as the mean dominant EEG frequency and the power of a particular EEG rhythm) to be quantified. Minor changes in the dominant EEG frequency occur in mild hepatic encephalopathy. Spectral EEG analysis may improve the assessment of mild hepatic encephalopathy by decreasing inter-operator variability and providing reliable parameters correlated with mental status.⁽⁷⁴⁾

Evoked potentials: Evoked potentials are externally recorded electrical signals that reflect synchronous volleys of discharges through neuronal networks in response to various afferent stimuli. They are categorized as visual, somatosensory, or acoustic, depending on the type of stimulus.⁽⁷⁵⁾ A more sophisticated form of evoked responses is event-related responses, which require some form of intellectual function. A typical event-related response is the P300 peak after auditory stimuli. The P300 is extremely sensitive for detecting subtle changes of brain function and can be used to diagnose minimal hepatic encephalopathy.⁽⁷⁶⁾

Critical flicker frequency: Advantages of the test are that it is objective and it is not affected by the patient’s age or education/literacy level.^(77-79) In an analysis of patients with cirrhosis and controls, critical flicker frequency differentiated patients with overt hepatic encephalopathy from those without hepatic encephalopathy. PHES testing, critical flicker frequency, and a combination of PHES and critical flicker frequency could not reliably distinguish patients with minimal hepatic encephalopathy from controls or those with overt hepatic encephalopathy.⁽⁸⁰⁾

Radiologic imaging:

Radiologic imaging is primarily used to exclude other causes of mental status changes.

Computed tomography and magnetic resonance imaging of the brain: A noncontrast CT scan is indicated in patients with overt hepatic encephalopathy in whom the diagnosis is uncertain, to exclude other diseases associated with coma or confusion. A CT scan may also reveal generalized or localized cerebral edema, suggesting a diagnosis of hepatic encephalopathy.

Magnetic resonance imaging: Magnetic resonance imaging (MRI) is superior to CT for the diagnosis of brain edema in liver failure, but it is not an established method for diagnosing hepatic encephalopathy.

Magnetic resonance spectroscopy and positron emission tomography: In vivo magnetic resonance spectroscopy (MRS) is a noninvasive method that is being studied but is not yet in routine clinical use. It permits serial measurement of various neurometabolites in the brain using a variety of isotopes, such as (1)H, (32)P, and (12)C. Proton (1H) MRS assesses regional brain concentrations of choline, creatine (Cr), glutamine/glutamate (Glx), myoinositol, and N-acetyl aspartate, depending on the spectral sequence used. (1H) MRS has tremendous potential for the future, particularly for documenting treatment effects.⁽⁸¹⁾

Evaluation for precipitating causes:

There are several conditions that may precipitate an episode of hepatic encephalopathy in patients with liver disease or a portal-systemic shunt. These include:^(82-86)

• Gastrointestinal bleeding
• Infection (including spontaneous bacterial peritonitis and urinary tract infections)
• Hypokalemia and/or metabolic alkalosis
• Renal failure
• Hypovolemia
• Hypoxia
• Sedatives or tranquilizers
• Hypoglycemia
• Constipation
• Rarely, hepatocellular carcinoma and/or vascular occlusion (hepatic vein or portal vein thrombosis)

Patients with hepatic encephalopathy should be evaluated for potential precipitating causes. This evaluation should include:

• A history to determine if the patient has been exposed to any medications or toxins (including alcohol)
• Physical examination to look for signs of gastrointestinal bleeding or hypovolemia
• A search for sources of infection with blood and urine cultures, as well as paracentesis for patients with ascites
• Routine serum chemistries to look for metabolic and electrolyte abnormalities

Serum alpha-fetoprotein

Management of hepatocellular carcinoma (HCC) is best performed in a multidisciplinary setting. Patients should be cooperatively managed by hepatologists, transplant and hepatobiliary surgeons, medical oncologists, interventional radiologists, and palliative care specialists. Specifically, this is crucial to ensure that patients who are candidates for liver transplantation are referred in a timely manner, while their tumors are within the Milan criteria.⁽⁸⁷⁾

Overall, transplantation remains the best option for patients with HCC. Unfortunately, there is a limited supply of good-quality deceased donor organs. Thus, alternative treatments, including resection, radiofrequency ablation (RFA), and, potentially, systemic therapy with sorafenib, should be used to bridge patients to transplant or to delay recurrence if possible. In patients who experience a recurrence following resection or transplantation, aggressive surgical treatment appears to be associated with the best possible outcome.⁽⁸⁸⁾

Acute therapy:

The initial management of acute hepatic encephalopathy in patients with chronic liver disease involves two steps:

• Identification and correction of precipitating causes
• Measures to lower the blood ammonia concentration

Correction of precipitating causes: The first step in the treatment of hepatic encephalopathy is the identification and correction of precipitating causes. Treatment of precipitating causes combined with standard therapy is typically associated with a prompt improvement in the hepatic encephalopathy.

Careful evaluation should be performed to determine if any of the following are present:

• Gastrointestinal bleeding
• Infection (including spontaneous bacterial peritonitis and urinary tract infections)
• Hypokalemia and/or metabolic alkalosis
• Renal failure
• Hypovolemia
• Hypoxia
• Sedative or tranquilizer use
• Hypoglycemia
• Constipation
• Rarely, hepatocellular carcinoma and/or vascular occlusion (hepatic vein or portal vein thrombosis)

When possible, these precipitating causes should be treated.

Lower blood ammonia: The second step in the treatment of hepatic encephalopathy is initiation of measures to lower blood ammonia concentrations (whether or not the values are frankly elevated) with medications such as lactulose, lactitol, or rifaximin. Polyethylene glycol is also being studied for the treatment of acute hepatic encephalopathy and appears to be effective. It is important to note that an elevated serum ammonia level in the absence of clinical signs of hepatic encephalopathy is not an indication for ammonia-lowering therapy.

Correction of hypokalemia is also an essential component of therapy since hypokalemia increases renal ammonia production. However, dietary protein restriction is generally not recommended.

Drug therapy is the mainstay of treatment to lower the blood ammonia concentration. Our approach to drug therapy is as follows:

• It is suggested to initiate drug therapy for acute hepatic encephalopathy with lactulose or lactitol. Lactulose and lactitol act through a variety of mechanisms that lead to decreased absorption of ammonia from the gastrointestinal tract. The dose of lactulose (30 to 45 mL [20 to 30 g] given two to four times per day) should be titrated to achieve two to three soft stools per day. An equivalent dose of lactitol is approximately 67 to 100 grams lactitol powder, diluted in 100 mL of water. Lactulose or lactitol enemas can be given if the patient cannot take lactulose orally.

Ornithine-aspartate, which stimulates the metabolism of ammonia, is an alternative for the treatment of hepatic encephalopathy.

• For patients who have not improved within 48 hours or who cannot take lactulose or lactitol, it is suggested to give treatment with rifaximin. The dose of rifaximin is 400 mg orally three times daily or 550 mg orally two times daily. As a general rule, antibiotics are added to, rather than substituted for, lactulose or lactitol.

Neomycin has been used as a second-line therapy in patients who have not responded to disaccharides, but it has not been shown to be efficacious in randomized trials and is associated with ototoxicity and nephrotoxicity.

Other alternatives for patients who are refractory to conventional therapy include L-ornithine-L aspartate and branched-chain amino acids.

Chronic therapy:

In patients with recurrent encephalopathy, continual administration of lactulose or lactitol is suggested. The dose of lactulose (30 to 45 mL [20 to 30 g] two to four times per day) or lactitol (67 to 100 g of lactitol powder diluted in 100 mL water) should be titrated to achieve two to three soft stools per day. If needed (e.g. if hepatic encephalopathy is not adequately treated or recurs despite lactulose or lactitol), rifaximin can be added to the regimen.

As with the acute treatment of hepatic encephalopathy, patients receiving chronic therapy should generally not have their protein intake restricted.

If the precipitating factors that were responsible for the recurrent hepatic encephalopathy are controlled or if liver function or nutritional status improves, prophylactic therapy may be discontinued.

Minimal hepatic encephalopathy:

Compared with patients who have cirrhosis but do not have minimal hepatic encephalopathy (MHE), patients with MHE appear be at increased risk for developing overt hepatic encephalopathy, requiring hospitalization, requiring liver transplantation, or dying. However, data are limited on the value of treatment in these patients.

Patients with MHE may benefit from treatment with lactulose or lactitol, but the decision to treat should be individualized based on the results of psychometric testing and the degree to which the encephalopathy has an impact on quality of life. Treatment with lactulose or lactitol should be given to patients with minimal hepatic encephalopathy who have impaired quality of life attributable to the minimal hepatic encephalopathy. An elevated serum ammonia level in the absence of clinical signs of hepatic encephalopathy is not an indication for treatment.

Nutritional support: Patients with cirrhosis and minimal hepatic encephalopathy (MHE) are advised to implement oral nutritional therapy.

Specific treatments

Commonly used treatments: Commonly used treatments for hepatic encephalopathy aim to reduce ammonia production and absorption. This is accomplished by correcting hypokalemia, giving synthetic disaccharides (such as lactulose) and/or antibiotics, and favoring colonization with non-urease-producing bacteria.

Correct hypokalemia: Correction of hypokalemia, if present, is an essential component of therapy for hepatic encephalopathy, since hypokalemia increases renal ammonia production. The often concurrent metabolic alkalosis may contribute to hepatic encephalopathy by promoting ammonia entry into the brain by favoring the conversion of ammonium (NH4+), a charged particle that cannot cross the blood-brain barrier, into ammonia (NH3), a neutral particle that can.

Lactulose and lactitol: Lactulose and lactitol are synthetic disaccharides that are a mainstay of therapy of overt hepatic encephalopathy, albeit there is limited evidence from well-designed randomized trials showing their efficacy.

The dose of medication should be titrated to achieve two to three soft stools per day. Typically, lactulose is given as 30 to 45 mL [20 to 30 g] two to four times per day. An equivalent dose of lactitol is approximately 67 to 100 grams lactitol powder diluted in 100 mL of water. Treatment is usually well tolerated, and the principal side effects include abdominal cramping, diarrhea, and flatulence. Lactulose and lactitol may also be given as enemas in patients who are unable to take them orally (1 to 3 L of a 20 percent solution).

Oral antibiotics: Nonabsorbable antibiotics are also effective for treating hepatic encephalopathy. Rifaximin is currently used most often. The dose of rifaximin is 550 mg orally twice daily or 400 mg orally three times daily. As a general rule, antibiotics are added to rather than substituted for lactulose or lactitol. However, antibiotics all cause alterations in gut flora and some are substantially more costly than nonabsorbable disaccharides. As a result, they may be best suited for patients who cannot tolerate or do not respond sufficiently to disaccharides.

Neomycin had been used for many years to treat hepatic encephalopathy, but studies reached variable conclusions regarding its efficacy, and there is concern over its association with ototoxicity and nephrotoxicity if used long-term.

Other antibiotics, such as metronidazole and oral vancomycin, were effective for treating hepatic encephalopathy in limited clinical trials and are not associated with the same toxicities as neomycin. However, metronidazole is associated with neurotoxicity and there are concerns about bacterial resistance in patients receiving vancomycin. As a result, neither is used commonly.

L-ornithine-L-aspartate: Oral L-ornithine-L-aspartate (LOLA) is frequently given to patients with hepatic encephalopathy.

L-ornithine-L-aspartate does not appear to be effective for patients with hepatic encephalopathy in the setting of acute liver failure.

Branched-chain amino acids: It has been suggested that increases in the ratio of plasma aromatic amino acids (AAA) to branched-chain amino acids (BCAA) as a consequence of hepatic insufficiency could contribute to encephalopathy. The altered ratio could then increase brain levels of aromatic amino acid precursors for monoamine neurotransmitters and contribute to altered neuronal excitability. As a result, a number of studies have evaluated the effects of the provision of BCAA, given either intravenously or orally.

Modification of colonic flora (prebiotics and probiotics): Probiotics are formulations of microorganisms that have beneficial properties for the host. Prebiotics are substances that promote the growth of such organisms. Prebiotic and probiotic therapy appear to lower blood ammonia concentrations, possibly by favoring colonization with acid-resistant, non-urease producing bacteria. The most commonly used prebiotic for the treatment of hepatic encephalopathy is lactulose, though it also acts by altering the colonic pH, improving gastrointestinal transit and increasing fecal nitrogen excretion. Fermentable fiber is another prebiotic that may promote the growth of beneficial bacteria.

Most commercial probiotic products have been derived from food sources, especially cultured milk products. The list of such microorganisms continues to grow and includes strains of lactic acid bacilli (e.g. Lactobacillus and Bifidobacterium), a nonpathogenic strain of Escherichia coli (e.g. E. coli Nissle 1917), Clostridium butyricum, Streptococcus salivarius, and Saccharomyces boulardii (a nonpathogenic strain of yeast). The most efficacious species for hepatic encephalopathy appear to be Lactobacilli and Bifidobacteria.

Alteration of gut flora (either with prebiotics or with probiotics) has been associated with improvement in hepatic encephalopathy. Probiotics may prevent recurrent encephalopathy.

Treatments that require more study:

Several additional treatments for hepatic encephalopathy appear to be effective, but additional trials are needed before they can be routinely recommended.

Polyethylene glycol: Polyethylene glycol (PEG) solution is a cathartic that may help treat hepatic encephalopathy by increasing excretion of ammonia in the stool.

Acarbose: Acarbose (an inhibitor of alpha glycosidase that is approved for treatment of diabetes mellitus) inhibits the upper gastrointestinal enzymes (alpha-glucosidases) that convert carbohydrates into monosaccharides. It also promotes the proliferation of intestinal saccharolytic bacterial flora, while reducing proteolytic flora that produce mercaptans, benzodiazepine-like substances, and ammonia. This reduction in proteolytic flora theoretically could improve hepatic encephalopathy.

Sodium benzoate: Sodium benzoate reduces ammonia levels by reacting with glycine to form hippurate, which is renally excreted. For each mole of benzoate used, one mole of waste nitrogen is excreted into the urine.

Flumazenil: While some patients with hepatic encephalopathy have short-term benefit from the benzodiazepine receptor antagonist flumazenil, it cannot be recommended as routine therapy. Flumazenil may be helpful, however, in patients who have received benzodiazepines.

Zinc: Zinc has been suggested as having potential value in some patients with chronic or recurrent hepatic encephalopathy, but little evidence exists to document its effectiveness.

Zinc deficiency is common in patients with cirrhosis and in those with hepatic encephalopathy. Zinc is contained in vesicles in the presynaptic terminals of some classes of neurons, the majority of which are a subclass of the glutamatergic neurons. Stimulated zinc release may modulate ion channel function and neurotransmission. Zinc may also enhance the hepatic conversion of amino acids into urea.

Melatonin: One of the most frequently described symptoms of subclinical forms of hepatic encephalopathy is sleep disturbances or, more generally, alterations in the sleep/wake cycle. Melatonin can influence its own rhythm when administered at defined time points during the day, shifting the curve forward or backward.

Experimental treatments:

A number of experimental approaches are being evaluated in animal models for the treatment of hepatic encephalopathy. Few have received any testing in clinical trials.

• L-Carnitine: Carnitine is a metabolite in the degradation pathway of the essential amino acid lysine and is synthesized by oxidation of E-amino-trimethyl-lysine. It serves as a carrier for short chain fatty acids across the mitochondrial membrane. Data in portacaval-shunted rats suggest that L-carnitine is protective against ammonia neurotoxicity.
• Glutamatergic antagonists: There is good evidence that the glutamatergic neurotransmitter system is involved in the pathogenesis of hepatic encephalopathy. The N-methyl-D-aspartate (NMDA) receptor is one of three known central glutamate receptors. NMDA overactivity has been observed in two different experimental rat models of encephalopathy. The administration of the NMDA receptor antagonist memantine resulted in a significant improvement in clinical grading and less slowing of electroencephalogram activity, smaller increases in cerebral spinal fluid glutamate concentrations, and lower intracranial pressure and brain water content than in untreated control rats.
• Serotonin antagonists: Accumulated neurochemical data in different animal models of fulminant hepatic failure and in humans with hepatic encephalopathy suggest that serotoninergic tone is increased in the brain in hepatic encephalopathy. The nonselective serotonin receptor antagonist methysergide had no effect in control rats, but it increased motor activity in rats with stage II to III hepatic encephalopathy in a dose-dependent manner; by contrast, the 5-HT2 receptor antagonist seganserin had no effect.
• Opioid antagonists: Plasma levels of methionine (Met)-enkephalin and beta-endorphin are elevated in patients and in experimental animals suffering from liver failure. Administration of (+/-)-naltrexone, but not (+)-naloxone, significantly increased the motor activity of rats with stage III hepatic encephalopathy.

Embolization of large spontaneous portosystemic shunts: Large spontaneous portosystemic shunts may contribute to hepatic encephalopathy.

Treatment goals are providing supportive care, identifying and removing precipitating factors, reducing nitrogenous load, and assessing long-term therapy needs.

GUIDELINES

To review, “2014 Practice Guideline by AASLD and EASL on Hepatic Encephalopathy in Chronic Liver Disease”, please click on below link:

https://www.aasld.org/sites/default/files/guideline_documents/hepaticencephenhanced.pdf

PRECAUTIONS

The best way to prevent hepatic encephalopathy is to prevent or manage liver disease. Chances of getting liver disease can be lowered by taking these steps:

• Avoid alcohol or consume it in moderation.
• Avoid high-fat foods.
• Maintain a healthy weight.
• Don’t share contaminated needles.

To avoid getting viral hepatitis:

✔ Wash your hands well after using the bathroom or changing a diaper.

✔ Don’t share contaminated needles.

✔ Avoid close contact with people diagnosed with viral hepatitis.

✔ Get vaccinated against hepatitis A and hepatitis B.

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