eMedicine Specialties > Gastroenterology > Liver

Portal-Systemic Encephalopathy

Author: Gagan K Sood, MD, Associate Professor, Medical Director of Liver Transplantation, Division of Gastroenterology and Hepatology, University of Texas Medical Branch
Contributor Information and Disclosures

Updated: Sep 23, 2008

Introduction

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 hepatic encephalopathy. Acute hepatic encephalopathy referred to acute liver failure or acute decompensation in the setting of chronic liver failure. The term chronic was used to describe the hepatic encephalopathy seen in chronic liver failure.

In 2002, a working committee task force on hepatic encephalopathy standardized the definition and the classification of hepatic encephalopathy. According to the characteristics of neurological manifestations, hepatic encephalopathy is classified as episodic (previously acute), persistent (previously chronic), or minimal (previously subclinical).

Hepatic encephalopathy is classified into 3 types based on the disease state of the liver.

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

Hepatic encephalopathy 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 is usually discovered after clinical and laboratory evaluations. Although elevated plasma ammonia levels are often seen and therapy based on this observation is generally effective, poor correlation exists between the plasma ammonia levels and the degree of encephalopathy. Multiple mechanisms contribute to the pathogenesis of this disorder. Discrete neuropathological features are described in portosystemic encephalopathy 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 hepatic encephalopathy 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 portosystemic encephalopathy, are described.

Portosystemic shunting is a requisite for the development of portosystemic encephalopathy. 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 hepatic encephalopathy often without any precipitating cause. These patients may have minimal or mild hepatocellular dysfunction but have significant neurological impairment. In one study, large portosystemic 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 hepatic encephalopathy (in the absence of cirrhosis or iatrogenic shunts or portosystemic shunts associated with splenic or portal vein thrombosis). 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 portosystemic encephalopathy in approximately 25% of cases.

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

The proposed gut-derived toxins responsible for portosystemic encephalopathy 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 portosystemic encephalopathy.

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.

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 portosystemic encephalopathy.

Ultimately, the development of advanced portosystemic encephalopathy 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 portosystemic encephalopathy, and it appears to correlate with an increase in the signal for glutamine and glutamate.

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

Despite the demonstration of astrocyte swelling and osmotic phenomena, treatment of hepatic encephalopathy does not include use of mannitol or hyperventilation unless cerebral edema is suspected, as in FHF. No established role currently exists for routine cerebral magnetic resonance imaging or spectroscopy in the evaluation of portosystemic encephalopathy. The data supporting the ammonia hypothesis in the development of portosystemic encephalopathy, 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 portosystemic encephalopathy. 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 portosystemic encephalopathy. 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 portosystemic encephalopathy. These agents may represent the best-defined false transmitters in portosystemic encephalopathy; 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 hepatic encephalopathy. 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 portosystemic encephalopathy.

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 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 portosystemic encephalopathy.

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, have been suggested to contribute to the pathogenesis of portosystemic encephalopathy. However, the role of this neurotransmitter system requires further study before its significance in hepatic encephalopathy 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.

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 portosystemic encephalopathy, 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 hepatic encephalopathy. In contrast, patients with advanced hepatic encephalopathy have reduced cortical blood flow and increased cerebral vascular resistance.

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 portosystemic encephalopathy 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 portosystemic encephalopathy, such as spontaneous bacterial peritonitis (SBP) or gastrointestinal bleeding. In this setting, portosystemic encephalopathy often will manifest itself for the first time (acute portosystemic encephalopathy) or suddenly worsen (acute or chronic portosystemic encephalopathy). Identification of the factors responsible for precipitating acute hepatic encephalopathy 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 portosystemic encephalopathy and must be evaluated and managed most aggressively. Chronic portosystemic encephalopathy 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 appears to be male.

Age

A variety of neurological conditions common in elderly patients (eg, multiple cerebral infarcts, Alzheimer disease, parkinsonism) may exacerbate the manifestations of portosystemic encephalopathy; 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

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 portosystemic encephalopathy.

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 portosystemic encephalopathy may demonstrate a variety of neurologic signs together or in isolation.

  • The grades of portosystemic encephalopathy are as follows:
    • Subclinical portosystemic encephalopathy: Early in the course of portosystemic encephalopathy, patients may appear normal clinically but perform poorly on psychometric testing. This is termed subclinical portosystemic encephalopathy. 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 portosystemic encephalopathy. 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 portosystemic encephalopathy: With deterioration to grade 1 portosystemic encephalopathy, 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 portosystemic encephalopathy: Progression to grade 2 portosystemic encephalopathy 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 portosystemic encephalopathy: 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 portosystemic encephalopathy: 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 portosystemic encephalopathy 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.

More on Portal-Systemic Encephalopathy

Overview: Portal-Systemic Encephalopathy
Differential Diagnoses & Workup: Portal-Systemic Encephalopathy
Treatment & Medication: Portal-Systemic Encephalopathy
Follow-up: Portal-Systemic Encephalopathy
References
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Further Reading

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Keywords

portal-systemic encephalopathy, portal systemic encephalopathy, portosystemic encephalopathy, hepatic encephalopathy, liver disease, advanced liver disease, portosystemic shunt, portal-systemic shunt, neurotoxicity, neuropsychosis, hyperammonemia, transjugular intrahepatic portosystemic shunt, TIPS, nonselective portocaval shunts, PSE, HE

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Contributor Information and Disclosures

Author

Gagan K Sood, MD, Associate Professor, Medical Director of Liver Transplantation, Division of Gastroenterology and Hepatology, University of Texas Medical Branch
Gagan K Sood, MD is a member of the following medical societies: American Association for the Study of Liver Diseases and American Gastroenterological Association
Disclosure: Nothing to disclose.

Medical Editor

Ann Ouyang, MBBS, Professor, Department of Internal Medicine, Pennsylvania State University College of Medicine; Attending Physician, Division of Gastroenterology and Hepatology, Milton S Hershey Medical Center
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Noel Williams, MD, Professor Emeritus, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Professor, Department of Internal Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
Noel Williams, MD is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

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