AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

Portosystemic encephalopathy (PSE) or hepatic encephalopathy (HE) is a neuropsychiatric syndrome associated with hepatocellular failure or portal-systemic venous shunting. There has been a lack of standardization of terminology used to define HE. The term chronic was used to describe the HE seen in chronic liver failure. Acute HE referred to acute liver failure or acute decompensation in the setting of chronic liver failure.

In 2002, a working committee task force on HE standardized the definition and classified HE into 3 types, as follows:

• Type A: HE associated with acute liver failure
• Type B: HE associated with portal-systemic bypass with no intrinsic hepatocellular disease
• Type C: HE associated with cirrhosis and portal hypertension or portal-systemic shunts. In cases of chronic liver disease, type C encephalopathy can be episodic or persistent. The term subclinical encephalopathy was replaced with minimal encephalopathy.

HE is a reversible metabolic encephalopathy with multifactorial pathogenesis. The widely accepted hypothesis is that encephalopathy is due to a failure of hepatic clearance of gut-derived toxins. Although the exact toxins involved remain controversial, ammonia remains the toxin of interest. This has led to many investigative and therapeutic efforts aimed at identifying and eliminating the putative toxins that originate from the gut lumen. A fluctuating level of consciousness is common, and progression to coma may occur rapidly.

A high index of clinical awareness is critical for anticipating and recognizing complications. A precipitating cause usually is discovered after clinical and laboratory evaluation. Although elevated plasma ammonia levels often are seen and therapy based on this observation generally is effective, poor correlation exists between plasma ammonia levels and the degree of encephalopathy. Multiple mechanisms contribute to the pathogenesis of this disorder. Discrete neuropathological features are described in PSE but may represent epiphenomena. Treatment with lactulose is the mainstay of therapy, but novel developmental approaches show promise.

Pathophysiology

Although the exact pathophysiological mechanisms of HE remain unclear, 2 areas have received more attention: first, the gut-derived neurotoxins (mainly ammonia), and, second, the changes in astrocyte morphology and physiology.

Hyperammonemia and portosystemic shunting led to the hypothesis in 1877 that enteral production of ammonia is central to the pathogenesis of this disorder. Various other putative toxins, which also may be shunted to result in PSE, are described.

Portosystemic shunting is a requisite for the development of PSE. Although disturbances in urea cycle metabolism may result in hyperammonemia, similar encephalopathy does not exist in patients with isolated hyperammonemia in the absence of other evidence of hepatic dysfunction. The pathogenesis of portal hypertension is discussed in Portal Hypertension. This complex condition results in the flow of portal blood containing putative toxins produced in the gut to the systemic circulation and, ultimately, the brain via extrahepatic shunts (collateral flow).

A minority of patients with cirrhosis present with recurrent symptoms of HE often without any precipitating cause. These patients may have minimal or mild hepatocellular dysfunction but have significant neurological impairment. In a recent study, large porto-systemic shunts were detected by CT in most patients. Shunting, in part, appears to be a response to increased hepatic vascular resistance in the setting of cirrhosis; however, shunting may result from other causes, including portal vein thrombosis or compression, congenital hepatic fibrosis, iatrogenic shunt placement, and congenital shunt formation. The latter is an important consideration in younger patients with otherwise unexplained HE (eg, no cirrhosis-induced, iatrogenic-induced, or thrombosis-induced shunt can be demonstrated). These patients may present in middle age and respond to appropriate shunt-reversal surgery.

The intrahepatic shunt (transjugular intrahepatic portosystemic shunt [TIPS]) provides a conduit for portal venous blood flow directly into the hepatic vein while bypassing the hepatic parenchyma. TIPS is associated with the development of PSE in approximately 25% of cases.

Similarly, PSE is a frequent complication of nonselective portocaval shunts. PSE is somewhat less likely to develop following a distal splenorenal surgical shunt procedure.

The proposed gut-derived toxins responsible for PSE include ammonia, phenols, thiols, and short-chain fatty acids. Other possible mediators include cytokines and bacterial endotoxins. The enteral production of gamma-aminobutyric acid (GABA) and endogenous benzodiazepines (BZPs) remains somewhat speculative, although alterations in GABA-receptor–mediated neurotransmission may play a role for other reasons. The GABA complex, when provided with an appropriate ligand, leads to the production of an inhibitory signal. Widespread inhibition of cortical function from excessive GABA-ergic signaling, therefore, has been postulated as a mechanism leading to PSE.

The thiols or mercaptans are small volatile molecules that characteristically are recognized by their pungent odor, which results from the inclusion of a sulfhydryl group. Accordingly, they may lead to the clinical presentation of fetor hepaticus; however, ammonia clearly is the best contender for the most significant gut-derived neurotoxin, and the ammonia hypothesis, therefore, justifies elaboration.

Most successful forms of therapy are based on the concept of ammonia neurotoxicity. Elimination of ammoniagenic luminal bacteria with nonabsorbed antibiotics (eg, neomycin), luminal acidification with nonabsorbed sugars fermented by luminal bacteria (eg, lactulose), avoidance of constipation, and reduction in ammoniagenic substrate intake (eg, protein-restricted diets) support the ammonia hypothesis.

The production of ammonia from the bacterial expression of urease and metabolism of colonic protein accounts for most ammoniagenesis. The bulk of extracolonic ammonia production occurs in the kidneys. Renal failure may promote ammoniagenesis as a consequence of uremia, which increases available substrate for urease. Ammonia is a neurotoxic compound that principally is eliminated from humans by its hepatic conversion to urea. Periportal hepatocytes in the liver primarily metabolize ammonia. Subsequently, urea is excreted in the urine. Residual ammonia in the hepatic sinusoidal circulation is converted to glutamine by perivenous hepatocytes expressing glutamine synthase.

The acute neurotoxicity of ammonia may be the result of activation of N-methyl-D-aspartate (NMDA) type of glutamate receptors. Activation results in a rise in intracellular calcium and subsequent activation of protein kinase C (PKC) along with calcineurin-dependent activation of Na/K adenosine triphosphatase (ATPase). In experimental models, both PKC inhibitors and NMDA receptor antagonists reduce the toxicity of ammonia by interfering with this pathway. Inhibitors of nitric oxide synthase (NOS) and calcineurin also are protective. Acute exposure to ammonia appears to stimulate neuronal L-arginine uptake and an increase in neuronal nitric oxide synthase (nNOS) expression, but the role of nitric oxide (NO) in mediating PSE remains unclear. No clinical work has evaluated the role of nNOS inhibition.

Glutamate leads to a depletion of intracellular adenosine triphosphate (ATP), but a low ATP level is not sufficient for neuronal cell death. However, the excessive activation of the excitatory NMDA receptors or excitotoxicity can result in neuronal cell death, and it is described as a potential mechanism in PSE. Adaptation to this toxicity may occur in vitro and, possibly, in vivo. Cultured neurons exposed to chronic hyperammonemia demonstrate reduced NMDA receptor responsiveness and decreased glutamate toxicity. Carnitine is shown to reduce the neurotoxicity of ammonia and glutamate in mice and cultured neurons, possibly through activation and down-regulation of glutamate receptors or postreceptor mechanisms (eg, PKC). The protective effect of carnitine is blocked by the use of antagonists to metabotropic glutamate receptors and is not due to prevention of ATP depletion. The protective effect of carnitine also is seen with other trimethylamine compounds.

Acute ammonia exposure results in increased neuronal uptake of L-arginine via a specific transport mechanism. This may provide an opportunity for enhanced detoxification through the increased production of glutamine, with arginine serving as the initial substrate; however, this pathway also has potentially toxic consequences due to increases in neural NO generation. Consistent with these observations, increased intracerebral metabolism of ammonia is demonstrated using 13N-based magnetic resonance spectroscopy (MRS). Therefore, several pathways may contribute to ammonia neurotoxicity. In neuropathological studies, Alzheimer type II astrocytosis is typical and likely represents the end result of these mechanisms. Astrocytes demonstrate swollen nuclei, margination of the chromatin, and a prominent nucleolus.

Astrocytes are the only cells in the brain that appear capable of glutamine synthesis (the pathway that represents the major route for cerebral ammonia detoxification). Exposure of newborn rat cerebral astrocytes in primary culture to ammonia or manganese (Mn) resulted in selective reduction in expression of the glutamate transporter GLAST, without resulting in cell death. Ammonia and Mn exposure each additionally led to an increased expression of peripheral-type benzodiazepine receptors (PTBR). This suggests that specific disturbances in astrocyte gene expression documented previously in liver failure may be the direct result of toxicity from these substances.

Because changes in gene expression patterns may be seen in a variety of circumstances that lead to the development of cellular edema, in astrocytes and many other cell types, the mechanisms leading to altered astrocyte gene expression resulting from ammonia exposure may be nonspecific. In vivo proton MRS (1H-MRS) shows that astrocyte swelling without increases in intracerebral pressure may occur early in the pathogenesis of PSE.

Ultimately, the development of advanced PSE may be accompanied by cerebral edema, which may contribute to neurological impairment. While cerebral edema has its most obvious manifestations in the patient with fulminant hepatic failure (FHF), osmotically active substances do accumulate in the brains of patients without overt cerebral edema. An osmotically sensitive pool of myoinositol is released from astrocytes in response to osmotically induced astrocyte swelling. A depletion of myoinositol is shown by 1H-MRS in patients with chronic PSE, and it appears to correlate with an increase in the signal for glutamine and glutamate.

Recently, with the use of magnetic resonance spectroscopy (MRS), low-grade cerebral edema has been demonstrated in patients with cirrhosis and chronic HE.

Despite the demonstration of astrocyte swelling and osmotic phenomena, treatment of HE does not include use of mannitol or hyperventilation unless cerebral edema is suspected, as in FHF. Currently, no established role exists for routine cerebral magnetic resonance imaging or spectroscopy in the evaluation of PSE. The data supporting the ammonia hypothesis in the development of PSE, therefore, are impressive and follow multiple lines of evidence. Indeed, the past decade was remarkable for the recognition of ammonia as a key element in the pathogenesis of PSE. However, other small molecules also may contribute, and these theories are not mutually exclusive. Synergistic toxicity of ammonia and other agents likely is important.

Production of so-called false neurotransmitters may contribute significantly to the pathogenesis of PSE. Putative agents include octopamine and diazepam. Supplementation with branched-chain amino acids (BCAAs) such as isoleucine, leucine, and valine and avoidance of aromatic amino acids, such as phenylalanine, tryptophan, and tyrosine may lead to decreased production of false neurotransmitters; however, the clinical benefit of BCAA supplementation has never been demonstrated convincingly (see Diet).

Increased production of endogenous BZPs has been proposed in patients with PSE. These agents may represent the best-defined false transmitters in PSE; however, their precise role is somewhat unclear. These substances are suggested to depress central nervous system (CNS) function by binding to specific high-affinity BZP sites on GABA-receptor complexes. A second BZP-binding receptor, distinct from the GABA complex, is PTBR. It is increased in the brains of patients with cirrhosis who have HE. The GABA complex, when provided with an appropriate ligand, leads to the production of an inhibitory signal. Therefore, widespread inhibition of cortical function from excessive GABA-ergic signaling has been postulated as a mechanism leading to PSE.

Peptides that bind BZPs are identified and named diazepam-binding inhibitors. These may serve to detoxify natural BZPs that are demonstrated in a variety of organisms and, therefore, might conceivably appear in food. Intraluminal synthesis of these compounds also conceivably may occur in the gut. Attempts to evaluate the role of endogenous BZPs suggest that they may contribute to the pathogenesis, but other factors are likely necessary for clinical manifestations.

In one recent study, plasma diazepam and N-desmethyldiazepam were found in 93% of patients with cirrhosis (n = 113), with concentrations comparable to those of patients using prescribed BZPs. Levels correlated with liver dysfunction. Levels of a diazepam-binding inhibitor peptide also were reduced when compared to control values, suggesting a possible mechanism for the elevated BZP levels; however, a poor correlation existed between the level of endogenous BZPs and the presence of encephalopathy. Therefore, additional factors may be necessary core requisites for manifestations of PSE.

Demonstration of the prevalent use of pharmacologically dosed BZPs in patients with cirrhosis challenges the notion of endogenous BZP production. Administration of exogenous BZPs is suggested as a significant cause for elevated plasma, cerebrospinal fluid (CSF), and BZP concentrations in these patients. Careful review of the clinical records and discussion with family members of patients with severe encephalopathy in one series frequently revealed exposure to BZPs, with sedation for endoscopic procedures providing a noteworthy source.

Endogenous opioid receptor ligands, such as beta-endorphin, recently have been suggested to contribute to the pathogenesis of PSE. However, the role of this neurotransmitter system requires further study before its significance in HE can be established.

Broadly speaking, cytokines are substances produced and released by cells for communication with other cells. Interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-a) are important examples of immunomodulatory cytokines that are increased in the systemic circulation and possibly contribute to the pathogenesis of systemic hemodynamic events in portal hypertension. The rapidly diffusing NO is grouped with these substances for the purposes of this discussion. Although not a cytokine in the strictest sense, NO plays an important, if ill-defined, role in mediating some of the significant communication events resulting from cytokine activation in advanced liver disease.

Endotoxemia, presumably in part from gut mucosal permeability, is demonstrated in cirrhosis with portal hypertension. Associated increased IL-1 and TNF-a concentrations and metabolites of NO in the systemic circulation also are reported. This suggests that shunting of proinflammatory substances from the gut lumen contributes to or perhaps initiates a cascade of events culminating in the hyperdynamic circulation typical of advanced liver disease.

Although a clear mechanism has yet to be established, serum levels of IL-6 are increased in patients with cirrhosis. This correlates with low systemic vascular resistance. Elevated levels of IL-6 also are described in patients with grade 1 PSE, independent of the stage of liver disease. Further significant correlations are identified between IL-6 and Child score, plasma renin activity, serum and urinary sodium, and low mean arterial blood pressure. IL-6 production may be stimulated directly by endotoxin, but it also is increased by TNF-a; however, this may be more relevant physiologically. Because IL-6 has no known ability to induce NO production, it may produce vasodilation through increased prostacyclin synthesis. Whether the increased IL-6 is a direct neurotoxin or simply an epiphenomenon serving as a marker for PSE remains uncertain, but it warrants further investigation.

Conceivably, IL-6 represents a feedback mechanism that is increased in hepatic failure as a result of complications of chronic liver disease. Because IL-6 is important in liver regeneration (as demonstrated in partial hepatectomy models), the use of pharmacologic inhibitors of IL-6 would appear to be an unlikely prospect for the treatment of PSE.

Induction of nNOS activity is seen in association with hyperammonemia and elevated brain ammonia. Arginine transport into neurons and astrocytes increases upon exposure to ammonia in portocaval-shunted animals and appears to result from increased expression of the specific transporter. Subsequent generation of NO may lead to inhibition of NMDA-type glutamatergic receptors; however, NO also may promote release of glutamate from the synapse and inhibit its uptake, thereby increasing available ligand for NMDA receptors.

Cerebral ischemia is another mechanism that contributes to PSE, although it may represent a consequence of ammonia toxicity. A loss of cerebral blood flow autoregulation reflexes may accompany the development of FHF; however, cerebral autoregulation, in general, is preserved in patients with cirrhosis if mean arterial pressure is maintained above 70 mm Hg, even in severe cases of HE. In contrast, patients with advanced HE have reduced cortical blood flow and increased cerebral vascular resistance.

CSF alanine and lactate levels correlate highly with the degree of HE observed in portacaval-shunted rats treated with ammonium acetate, which suggests the induction of glycolysis and, possibly, inhibition of pyruvate oxidation. These features would support ischemia as a contributing factor in the pathogenesis of PSE.

Frequency

United States

True incidence and prevalence figures are not available. This complication is a frequent and possibly inevitable feature of progressive and chronic liver disease.

International

Incidence and prevalence are not clearly established.

Mortality/Morbidity

• The development of PSE indicates decompensated liver disease and, therefore, other features of decompensation, such as impaired coagulation (eg, elevated prothrombin time/International Normalized Ratio), varices, ascites, and portal hypertension, must be sought. Indeed, these manifestations potentially lead to recognition of complications that may account for the development of PSE, such as spontaneous bacterial peritonitis (SBP) or gastrointestinal bleeding. In this setting, PSE often will manifest itself for the first time (acute PSE) or suddenly worsen (acute or chronic PSE). Identification of the factors responsible for precipitating acute HE usually is possible (see Causes).
• Because of the potential for rapid evolution to coma, close clinical monitoring and anticipation of elective endotracheal intubation for airway protection and ventilatory support is essential. Impairment of consciousness poses the greatest threat to the patient with acute PSE and must be evaluated and managed most aggressively. Chronic PSE is a common feature of advanced liver disease and, if left untreated, may evolve into a more severe state without any obvious precipitants, although the course of events may be somewhat slower. The level of consciousness in these patients also may fluctuate significantly in an apparently spontaneous manner.

Race

No specific data apply.

Sex

Presumably, because alcoholic liver disease occurs with greater frequency in men compared to women, a higher proportion of patients appear to be male.

Age

A variety of neurological conditions common in elderly patients (multiple cerebral infarcts, Alzheimer disease, parkinsonism) may exacerbate the manifestations of PSE; however, the condition usually is prominent in patients with advanced liver disease, which may not manifest in very elderly persons because they do not survive. No specific age frequency data are available.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

The patient may present with vague complaints such as fatigue, or they may be brought for evaluation by relatives. Indeed, the family members of patients often are the most useful historians. They may describe restlessness (especially at night), somnolence (typically during the day), and instances reflecting episodic confusion.

• No neurologic features are entirely specific for this disorder.
• Clinical history or physical examination findings suggestive of liver disease, without evidence of another etiology for neurological dysfunction, form the basis for the diagnosis.
• A precipitating factor identified from the clinical history strongly suggests the diagnosis. Therefore, directed questioning in this regard is essential.
• Several predisposing conditions also may contribute to the development of chronic PSE.

Physical

As with many toxic and metabolic encephalopathies, mental status and, in particular, level of consciousness may fluctuate dramatically. In addition to impairment of the level of consciousness, patients with PSE may demonstrate a variety of neurologic signs together or in isolation.

• The grades of PSE are as follows:
• • Subclinical PSE: Early in the course of PSE, patients may appear normal clinically but perform poorly on psychometric testing. This is termed subclinical PSE. This condition may be particularly important to diagnose in patients performing tasks that require rapid reaction times because these are prolonged in patients with subclinical PSE. Judgment also may be erratic or questionable. Recognition of subtle impairment, therefore, may lead to a recommendation to avoid driving an automobile or operating machinery.
  • Grade 1 PSE: With deterioration to grade 1 PSE, the examination reveals difficulty with memory, mild confusion, agitation, and irritability. Patient complaints may include restlessness or sleeping during the day and remaining awake at night. Tremor, a rhythmic or regular oscillation, and incoordination may be seen. Handwriting skills typically are impaired. Constructional apraxia may be easily demonstrated at the bedside by requesting the patient to draw a 5-pointed star.
  • Grade 2 PSE: Progression to grade 2 PSE involves a slowing of mentation and speech, with the appearance of lethargy. The patient's confusion progresses to difficulty with orientation to time, and loss of inhibition ultimately may result in inappropriate behavior. Neurologic signs include asterixis and an irregular flapping tremor that is observed best with the wrists dorsiflexed and fingers spread. Dysarthria, ataxia, and hypoactive deep-tendon reflexes are characteristic.
  • Grade 3 PSE: This grade portends the significant possibility of coma; therefore, plans to perform endotracheal intubation should be made upon recognition of this state. Patients are drowsy but can be woken up; however, they remain markedly confused. They may exhibit frankly aggressive behavior. Asterixis persists, but the deep-tendon reflexes become hyperactive as they are disinhibited, a process that culminates in the development of the decerebration seen in grade 4. Babinski signs may be seen.
  • Grade 4 PSE: This also is known as hepatic coma and represents a medical emergency. Patients are able to protect their airway reliably. Prophylactic endotracheal intubation is mandatory. Patients may remain unresponsive for several days.
• Stigmata of chronic liver disease and portal hypertension may be evident upon examination. These include the presence of gynecomastia and testicular atrophy in males, palmar erythema, spider nevi, splenomegaly, caput medusae, ascites, peripheral edema, and a shrunken liver.
• More specific signs resulting from the underlying liver diseases also may be present, as follows:
• • The Kayser-Fleischer rings of Wilson disease typically are identified only with slit-lamp examination.
  • Bronzed skin and arthropathy are seen in hereditary hemochromatosis.
  • Cholesterol deposition may be seen as xanthelasma in patients with chronic cholestasis of any cause, but it often is most striking in primary biliary cirrhosis.
  • Alcoholic liver disease frequently is accompanied by advanced malnutrition; however, any long-standing liver disease also may lead to temporal, shoulder girdle, and hip girdle muscle wasting.
  • Cutaneous features of hepatitis C virus infection include a characteristic rash due to leukocytoclastic vasculitis resulting from mixed cryoglobulinemia, porphyria cutanea tarda, and lichen planus.

Causes

Precipitating factors that lead to clinical manifestations of PSE may be obvious; however, often a cause is not evident despite concerted efforts to identify one. The importance of trying to determine the precipitating cause cannot be overemphasized. Infection, specifically SBP, is especially important to exclude. Several known causes are categorized below by their proposed mechanisms. In some cases, multiple mechanisms may be responsible.

• Increased ammoniagenesis
• • Increased substrate (protein) for ammoniagenesis
  • Increased protein intake
  • Gastrointestinal bleeding
  • Constipation
  • Dehydration
  • Increased substrate (urea) for ammoniagenesis
  • Renal failure
  • Increased catabolism of protein
  • Infection
  • Hypokalemia
  • Sepsis
• Decreased hepatocellular function
• • Dehydration
  • Hypotension
  • Sepsis
  • Hypoxia
  • Anemia
  • Development of hepatocellular carcinoma
  • Worsened intrinsic liver disease
  • Drug toxicity
  • Superimposed viral hepatitis
• Increased portocaval shunting
• • Portal vein thrombosis
  • Transjugular intrahepatic portosystemic shunt formation
  • Surgical shunt formation
  • Spontaneous shunt formation
• Psychoactive drug use
• • Benzodiazepines
  • Ethanol
  • Antinauseants
  • Antihistamines
  • Others
• Other mechanisms
• • Increased diffusion of ammonia across the blood-brain barrier: Alkalosis may occur, which promotes ammonium ion conversion to less polar and more diffusible ammonia.
  • Blood transfusion: Increased ammoniagenesis from transfusions may not be entirely accurate and possibly is a more theoretical than practical concern. Glutaminase activity and generation of ammonia in stored cellular blood products (especially platelets) may conceivably lead to infusion of ammonia during transfusion.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Structural CNS lesions
Intracranial hemorrhage
Epidural hemorrhage
Subdural hemorrhage
Subarachnoid Hemorrhage
Intraparenchymal hemorrhage
Cerebral infarct
Intracranial infections
Encephalitis (Herpes simplex virus, others)
Meningitis
Intracerebral abscess
Hydrocephalus
Toxic or metabolic etiologies
Drug intoxication
Ethanol
Toxicity, Salicylate
Benzodiazepines
Wernicke Encephalopathy
Hypoglycemia
Ketoacidosis
Electrolyte disturbances
Hypercapnia
Hypoxia
Postictal encephalopathy
Functional psychoses

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• Serum calcium
• Serum ammonia, preferably arterial
• Elevated blood levels are not diagnostic of HE, and normal levels do not rule out HE. Very high levels may suggest an unsuspected urea cycle enzyme deficiency. They are helpful to suggest a diagnosis of HE when the cause is obscure.
• Serum glucose
• Serum albumin
• Serum aspartate aminotransferase: A very high aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) level (eg >1000) may suggest widespread hepatic necrosis as a consequence of acetaminophen toxicity and may help guide appropriate diagnostic evaluations and therapy accordingly (with acetaminophen levels and N-acetylcysteine). However, very high AST and ALT values may be observed in other settings (notably ischemic hepatitis and other causes of submassive or massive hepatic necrosis) and, therefore, are not specific.
• Serum alanine aminotransferase: ALT is more specific for liver origin because AST also may be released from muscle.
• Serum bilirubin
• Complete blood cell count
• Blood and urine screen for drugs
• Blood alcohol level
• Serum electrolytes: Levels may be disturbed for a variety of reasons in patients with advanced liver disease. Hyponatremia resulting from diuretic use, renal failure, water intoxication, or the syndrome of inappropriate secretion of antidiuretic hormone is particularly important to consider as a contributing cause of encephalopathy.
• Serum transaminases: Measuring these is useful as an index of hepatocellular inflammation, although a poor correlation exists with respect to hepatocellular function. Very high transaminase values (eg, >500 U/L) suggest the possibility of acute hepatitis of indeterminate etiology, and, in the context of encephalopathy, consider the possibility of FHF.
• Prothrombin time, albumin, and bilirubin: Measurements are true liver function tests that provide an estimate of the severity of liver damage. They also allow the clinician to anticipate certain potential complications (eg, bleeding) and adjust therapy appropriately.

Imaging Studies

• Computed tomography scan of the head
• • The rationale for CT scan is to exclude structural considerations in the differential diagnosis, including intracranial hemorrhage (epidural, subdural, subarachnoid, intraparenchymal), cerebral infarct, intracranial infections (brain abscess with mass effect, meningoencephalitis), and hydrocephalus.
  • CT scan of the head may not be necessary in patients with well-documented liver disease and a typical history, especially if no focal or localizing signs are evident. However, if the circumstances leave any doubt, then CT scan is critical in helping exclude structural causes for encephalopathy.
  • This test is more widely available than MRI and generally can be performed more rapidly. Therefore, it is the imaging modality of first choice in most instances.
  • Patients may develop PSE and subsequently sustain head trauma. This is particularly common among patients with alcoholism, and the event may not be volunteered upon taking the history or may not be evident upon physical examination. However, in uncomplicated PSE, no characteristic clues or findings are present.
• Magnetic resonance imaging
• • The availability and speed with which CT scans can be performed make them preferable in most instances for helping exclude mass lesions and, especially, intracranial hemorrhage. However, MRI findings may be of particular value in cases in which a diagnosis is not clear-cut based on other clinical and laboratory data.
  • The presence of hyperintense-appearing regions on T1-weighted MRI studies of the brains of patients with cirrhosis is described as a characteristic feature. The increased MRI signal intensity may be the result of Mn deposition in these structures.
  • The globus pallidus, putamen, and caudate nucleus of the basal ganglia and the frontal and occipital cortex of patients with cirrhosis who died with HE are demonstrated to contain increased Mn concentrations when compared to matched control specimens. Pallidal hyperintensity on T1-weighted MRI does not appear to be present in well-compensated patients with cirrhosis who do not have HE. This finding appears to correlate with blood ammonia levels but not the severity of HE itself.
  • The amount of Mn deposition that can be identified at autopsy following hepatic coma appears to be independent of patient age, etiology of cirrhosis, or the presence of chronic HE. In an experimental model using both cirrhotic and portacaval-shunted rats, Mn levels in the basal ganglia were significantly elevated above control values. These levels also were significantly higher in portacaval-shunted rats when compared to those with experimental cirrhosis; therefore, while the precise etiology responsible for Mn deposition is unclear, it is enhanced by portal hypertension.
  • Therefore, signs of extrapyramidal toxicity in HE conceivably may result from Mn deposition. The neurologic and radiologic changes may resolve gradually with time following liver transplantation. Deposition of Mn also may potentiate the effects of BZPs, natural or otherwise, by increasing the number of available peripheral-type BZP binding sites (possibly by promoting receptor expression).
  • These intriguing issues unveiled by the advent of MRI are complemented by metabolic data derived from the application of MRS. This technique has demonstrated findings of altered glutamine metabolism. Its role in clinical evaluation and management of HE currently is unclear. In one series, MRS findings (ie, decreased myoinositol, increased glutamine) correlated poorly with neurological status. These markers were suggested to be more representative of the underlying chronic hepatic dysfunction.
• Positron emission tomography scanning has demonstrated reduced metabolic activity for glucose utilization in the parietal cortex of patients with cirrhosis with mild HE. At present, this technique is best reserved for research applications because no clear clinical guidelines are available for its use and its availability is limited.

Other Tests

• Psychometric testing
• • Psychometric evaluations are of value for establishing the diagnosis and perhaps for monitoring response to therapy in subclinical PSE. The number-connection test and the Trail-Making Test are pragmatic approaches and are used widely at the bedside.
  • More formal testing may not be feasible with many patients, in part due to the length of time taken to administer the tests, and also because of uncooperativeness. However, the results of psychometric testing in subclinical PSE may be of prognostic value independent of the Child-Pugh score of disease severity.
  • Patients with alcohol-induced liver disease exhibit poorer test scores than those with liver disease from other causes, presumably due to cerebral toxicity intrinsic to chronic alcohol use and independent of the hepatic insufficiency.
  • A grading scheme that incorporates the level of consciousness, personality and intellect, neurologic signs, and electroencephalogram (EEG) abnormalities is proposed for HE. The clinical portion of this grading approach has the advantage of being easily administered at the bedside, and it is helpful as a guide to progress.
• Electroencephalography
• • EEG studies of patients in PSE grades 1-3 may demonstrate high voltage and low-frequency triphasic waves of 1-3 Hz. These also may be seen in uremia but are characteristic of HE. With progression to coma, the EEG typically shows delta-wave activity, representing a generalized slowing of the cortex, a nonspecific pattern seen in toxic and metabolic encephalopathies.
  • The EEG is most helpful in excluding the presence of other causes for encephalopathies, such as status epilepticus and akinetic seizures, or the demonstration of postictal slowing with or without focal spike and wave activity that suggests prior seizures.
  • EEG monitoring frequently is useful in assisting with the diagnosis of HE, especially subclinical HE. Computer-assisted or spectral EEG analysis may demonstrate characteristic abnormalities, but the incremental benefit over conventional EEG is unclear.
• Evoked potentials
• • Further electrophysiologic assessment may be performed with evoked-potential studies, but whether this approach is of value remains unclear, except when significant doubt exists with respect to the underlying diagnosis of PSE as the cause for neuropsychiatric dysfunction. This is rarely the case in practice. These studies include visual-evoked potentials, somatosensory-evoked potentials, or brainstem auditory–evoked potentials, and they represent the externally recorded voltage from synchronous firing of neurons in a network response to specific stimuli.
  • The chief value of this approach may be to document abnormal cortical function in subclinical PSE and establish the diagnosis. Brainstem auditory–evoked responses appear particularly sensitive as a marker of perturbed cortical function. Evoked-potential studies in acute HE conceivably may be useful for monitoring clinical response to treatment; however, the use of these electrophysiologic diagnostic modalities currently is not widespread.

Histologic Findings

In neuropathological studies of HE, Alzheimer type II astrocytosis is typical and likely represents the end result of these mechanisms. Astrocytes demonstrate swollen nuclei, margination of the chromatin, and a prominent nucleolus.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

• Nonabsorbable disaccharides
• • Despite the availability of multiple approaches, treatment with nonabsorbed disaccharides remains the mainstay of therapy for HE. These agents act by at least 3 mechanisms, as follows:
  • • First, luminal bacteria metabolize lactulose and lactitol (beta galactoside-sorbitol). The consequent acidification of the gut lumen leads to ammonia being protonated to the ammonium ion (NH4⁺), which is relatively membrane impermeable; therefore, less ammonia is absorbed from the colon.
    • The second benefit to gut luminal acidification is reduction in the number of bacteria present, which reduces the presence of bacterial urease and consequent ammoniagenesis.
    • Lastly, the osmotic effect of nonabsorbed disaccharides enhances gastrointestinal transit.
  • A typical starting dose for the treatment of chronic HE is 20 g lactulose PO bid with the goal of producing 2-3 soft bowel movements daily. Dose increases or reductions may be necessary based on the patient's response. In the acute setting, HE may be treated with 20 g lactulose every few hours until a satisfactory result is achieved, but care must be taken to avoid diarrhea that leads to electrolyte depletion and dehydration. Lactulose enemas may be of benefit when a paralytic ileus precludes oral or nasoenteral tube administration. Because the bacterial metabolism of lactulose results in the production of hydrogen, this agent should not be used as a lavage preparation for colonoscopy because electrocautery under these circumstances may produce explosive results.
  • Clinical evaluations regarding the efficacy of these agents are limited, especially when their widespread use and the potential for adverse reactions are considered. The toxicity of lactulose and lactitol includes gastrointestinal bloating due to bacterial gas production, dehydration, and electrolyte disturbances. The latter may result in a paralytic ileus and, therefore, must be carefully distinguished from the more common bloating. Indeed, these complications of lactulose therapy may paradoxically worsen HE. Gastrointestinal upset infrequently leads to a requirement for dose reduction or ultimately discontinuance. It may be less problematic with lactitol.
• Antibiotics
• • Treatment with nonabsorbable antibiotics also is advocated as a treatment for HE and may be of particular value in a patient intolerant of lactulose. This may be relevant for a patient with intestinal ileus, in whom the administration of lactulose may generate large volumes of hydrogen gas upon bacterial fermentation. Similarly, patients with multiple electrolyte disturbances or dehydration may benefit from this approach rather than from the use of lactulose.
  • Neomycin at 1 g PO tid/qid may be used, but it is not recommended for prolonged use. As much as 3% of an oral dose of neomycin may be absorbed systemically, and nephrotoxicity may result. The efficacy of neomycin was questioned when no clinical benefit could be demonstrated by some, when compared to placebo in treatment of acute HE.
  • Oral metronidazole is used with success, but long-term therapy may result in toxicity, including peripheral neuropathy.
  • Rifaximin is a newer nonabsorbable antibiotic for the treatment of HE. Currently, the efficacy of rifaximin in the treatment of HE has been studied in 20 studies, including 14 randomized controlled studies. In 7 studies, rifaximin was compared to lactulose or lactilol. Results of Cochrane meta-analysis from these studies suggested rifaximin to be significantly more effective than nonabsorbable disaccharides (lactulose or lactilol) in the treatment of HE. Rifaximin is used in a dosage of 400 mg PO tid.
• Altering gut flora
• • The presence of urease-expressing bacterial organisms in the gut microflora forms the basis for efforts to repopulate the gut with nonureolytic organisms, such as Lactobacillus acidophilus and Enterococcus faecium. In theory, this should result in a reduction in colonic ammoniagenesis, but few well-designed studies exist to support the routine clinical application of this approach. Results of small trials with Lactobacillus species are mixed. The use of orally administered Enterococcus species resulted in sustained protection from HE in one study and appeared to be safe. Further evaluation of this approach is justified and needed.
  • The presence of Helicobacter pylori in the gastric mucosa represents another potential source of ammonia because this organism produces urease. Helicobacter ammoniagenesis may be most significant when accompanied by achlorhydria, in part due to increased absorption of nonprotonated ammonia across the gastric mucosa and, possibly, from increased numbers of bacteria. The role of H pylori in the pathogenesis of HE remains contentious; however, some investigators have identified it as an independent risk factor for the development of HE, while others have not.
  • One possible explanation for improvement in HE following eradication therapy for H pylori is that the antibiotics decreased the gut's colonic population of urease-expressing organisms and those of the gastric mucosa. Currently, it appears reasonable to treat patients for H pylori when dictated by routine clinical circumstances (eg, in the treatment of peptic ulcer disease) but not as prophylaxis for HE.
• Increasing ammonia metabolism
• • Another treatment approach is to increase the metabolism of ammonia with the administration of substrates that permit its incorporation.
  • Ornithine is a substrate for urea, and aspartate is a substrate for glutamine. Both enteral and intravenous administration of ornithine aspartate (a mixture of the 2 amino acids) are shown in some controlled trials to lower serum ammonia levels and improve mild HE by increasing the conversion of ammonia to urea. Trials using ornithine alpha-glutarate did not demonstrate a benefit. In part, this may be because it only supplies one substrate for incorporation of ammonia. Relatively large doses of amino acids (18 g/d PO) appear to be necessary for any clinical benefit.
  • The mechanism of action of L-ornithine L-aspartate may extend beyond the urea cycle. Administration of ornithine aspartate to portal hypertensive rats results in high concentrations of glutamate in the plasma and CSF and an associated reduction in plasma ammonia. The elevated glutamate concentrations facilitate synthesis of glutamine by glutamine synthase, which is expressed at high levels in the liver, brain, and skeletal muscle. This mechanism may permit further significant reductions in ammonia levels within both the CNS and the systemic circulation. Indeed, increased glutamine synthase expression is induced in skeletal muscle by portocaval shunting.
  • An increase in plasma concentrations of BCAAs also is an anticipated metabolic consequence of increased glutamate availability. It remains of uncertain significance and does not necessarily contribute to the improvement in HE documented in this experimental model.
  • Sodium benzoate also is shown to be efficacious in reducing serum ammonia. It is conjugated to glycine to form hippuric acid, which is excreted in the urine. Similarly, phenylacetate is conjugated with glutamine to form phenacetylglutamine. Both of these organic acids have been used successfully to treat HE in some clinical trials.
• Zinc supplementation
• • The urea cycle allows conversion of ammonia to urea. Because 2 of the enzymes in this metabolic pathway require zinc as a cofactor and because reduced plasma zinc levels from increased urinary zinc losses are documented in HE, oral zinc supplementation is proposed for the treatment of HE.
  • The measurement of serum zinc levels may not accurately reflect whole-body zinc status, but it would appear reasonable to supplement patients found to have low serum zinc levels with zinc gluconate.
• Flumazenil
• • Treatment efforts with flumazenil, a competitive antagonist of BZPs, are based on the GABA hypothesis; however, results of the small clinical trials performed to date are variable.
  • In 2 well-designed studies, flumazenil was found to be of value in a limited number of patients but clear factors that might permit their identification were not proposed; therefore, because of the difficulty in establishing a more generalized improvement in patient course and the relatively short action of duration of the drug, it is not of convincing benefit.
• Dopamine agonists
• • Parkinsonian or extrapyramidal symptoms may manifest with HE. Treatment with levodopa or bromocriptine is shown to result in improvement in clinical and EEG findings in anecdotal reports and small studies.
  • Although the use of bromocriptine is advocated for cases of refractory HE, well-designed prospective controlled trials have not been conducted.

Surgical Care

• The definitive approach to management of PSE is, of course, orthotopic liver transplantation (OLT). PSE as a complication of end-stage liver disease may warrant discussion of OLT. Indeed, even CNS structural changes evident on MRI may be reversed slowly following OLT; however, a detailed discussion of OLT is beyond the scope of this article (see Liver Transplantation).

Consultations

• Consultation with a neurologist is of value, especially if doubts exist regarding the etiology of the encephalopathy.

Diet

• Nutritional therapy
• • BCAA therapy has been evaluated extensively as a treatment for HE. BCAAs are of suggested benefit in lowering production of false neurotransmitters. Vegetable protein–based diets that exclude meat are relatively high in BCAAs and low in aromatic amino acid content. Clinical trials performed to date with vegetable protein–based diets or BCAAs have not demonstrated any consistent or convincing benefit with respect to clinical manifestations of HE and do not support their widespread use for treatment or prevention of HE.
  • Vegetable protein, however, may have other benefits. In patients with subclinical HE, one study demonstrated computer-analyzed EEG findings improved with vegetable protein–based diets, despite the lack of any change in ammonia levels. Urinary 3-methyl-histidine excretion was increased with the use of an animal-protein diet, and the vegetable diet was associated with a decrease in urinary nitrogen excretion; thus, the nitrogen balance tended to be more positive with the vegetable-protein diet.
  • Patients with advanced liver disease often present with poor nutritional status and may develop a negative nitrogen balance exacerbated by acute or recurrent efforts to restrict dietary protein. Although the practice of strictly limiting dietary protein in these patients was advocated until recently, adverse nutritional consequences now appear to outweigh any potential benefit for the prevention of HE. In general, patients with chronic liver disease should be advised to eat approximately 1 g of dietary protein per kilogram body weight per day. In this context, BCAAs may be a useful dietary supplement to help preserve skeletal muscle mass via protein sparing, with little risk of precipitating HE.
  • With a well-tolerated exogenous source of amino acids, the catabolic metabolism that otherwise results in negative nitrogen balance therefore may be offset. This is of particular importance in patients awaiting OLT, in whom a protracted nutritional decline may occur during the long wait for a suitable donor liver.

Activity

• Consider restricting patients with encephalopathy from driving an automobile or operating potentially dangerous machinery. This may be difficult to justify to patients and their families in the absence of formal psychometric testing. Reaction times and judgment typically are impaired. Similarly, a patient may need to perform different job duties in order to avoid physical or, possibly, financial harm. Clearly, these issues may settle themselves because mental status changes resolve completely with therapy. These difficult issues require review on an individual basis and require periodic reassessment.
• Patients need adequate rest, and their goal should be to sleep at least 8 hours at night. Strenuous activity should be avoided, but regular mild exercise is distinctly advantageous for maintaining bone mass and cardiovascular conditioning in anticipation of the long wait for a donor organ attendant with OLT.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The mainstay of therapy is lactulose, a nonabsorbed disaccharide. The actions of this agent are multiple and culminate in reduced delivery of ammonia to the brain. Lactitol, another disaccharide, may be better tolerated, but this agent is used relatively infrequently. Oral antibiotics are not used as frequently, but they do have a role in patients who are intolerant of lactulose. Flumazenil, bromocriptine, BCAAs, and L-ornithine have been investigated but, currently, cannot be considered first-line therapy.

Drug Category: Nonabsorbed disaccharides

Promote acidification, sterilization, and ammonium ion trapping in colon lumen. Increased stool frequency occurs, and all mechanisms likely reduce ammonia delivery to systemic circulation and the brain. Inexpensive and generally well tolerated.

Drug Category: Nonabsorbed antibiotics

Used for gut sterilization.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Inpatient Care

• Alcohol rehabilitation currently is a requirement for consideration of acceptance for listing for OLT. Regardless of whether the patient is a candidate for OLT, the development of PSE is a potential revelation that permits progress toward achieving and maintaining abstinence. This is a critical step for increasing the probability of survival and often is best approached initially by taking advantage of the inpatient status.

Complications

• Respiratory and ventilatory insufficiency and failure to protect the airway with consequent aspiration are anticipated complications that should be avoided with endotracheal intubation.

Prognosis

• In general, the prognosis for patients with advanced liver disease is poor unless they are able to undergo liver transplantation. The contribution that PSE makes to the decline of these individuals is limited, and rather than acting as a causal factor, it is essentially a marker of decompensated liver disease. As with other complications of chronic liver disease, survival likely correlates better with Child-Pugh score than the outcome of the complication itself.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Failure to diagnose PSE
• Failure to recognize, consider, and treat precipitants of PSE
• Failure to appropriately address potential for loss of airway with progression of the process

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous coauthor, Blake A Jones, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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