Background
Portosystemic encephalopathy (PSE) or hepatic encephalopathy (HE) is a neuropsychiatric syndrome associated with hepatocellular failure or portosystemic 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 neurologic manifestations, hepatic encephalopathy is classified as episodic (previously, "acute"), persistent (previously, "chronic"), or minimal (previously, "subclinical").
Hepatic encephalopathy is also classified into three types based on the disease state of the liver, as follows:
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Type A: Hepatic encephalopathy associated with acute liver failure
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Type B: Hepatic encephalopathy associated with portosystemic bypass with no intrinsic hepatocellular disease
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Type C: Hepatic encephalopathy associated with cirrhosis and portal hypertension or portosystemic 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 toxin(s) 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. As noted, multiple mechanisms contribute to the pathogenesis of this disorder. Discrete neuropathologic features are described in PSE but these may represent an epiphenomena (a secondary effect occurring with the disease). Treatment with lactulose is the mainstay of therapy, but novel developmental approaches show promise.
Pathophysiology
Although the exact pathophysiologic mechanisms of hepatic encephalopathy remain unclear, two 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 may also be shunted, may result in portosystemic encephalopathy (PSE), are described.
Portosystemic shunting is a requisite for the development of PSE. Although disturbances in urea cycle metabolism may cause 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 neurologic impairment. In one study, large portosystemic shunts were detected by computed tomography scanning in most patients. Shunting, in part, appears to be a response to increased hepatic vascular resistance in the setting of cirrhosis; however, shunting may also 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 an 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 to flow directly into the hepatic vein while bypassing the hepatic parenchyma. TIPS is associated with the development of PSE in approximately 25% of cases.
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 GABAergic 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 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 the available substrate for urease. Ammonia is a neurotoxic compound that principally is eliminated in 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.
Besides causing functional changes such as reduction in cerebral perfusion, ammonia may also be responsible for structural changes in the brains of patients with hepatic encephalopathy. In necropsy studies, brains of cirrhotic patients exhibit Alzheimer type II astrocytosis, characterized by swollen astrocytes with enlarged nuclei and chromatin displaced to the perimeter of the cell. Type II astrocytosis is hypothesized to be caused in part by the detoxification of ammonia. Astrocytes, the only cells in the brain that can metabolize ammonia, contain glutamine.
In vivo proton magnetic resonance spectroscopy (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 neurologic impairment. Although 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.
With the use of 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 the use of mannitol or hyperventilation unless cerebral edema is suspected, as in FHF. No established role currently exists for routine cerebral magnetic resonance imaging (MRI) or MRS in the evaluation of PSE. The data supporting the ammonia hypothesis in PSE development, therefore, are impressive and follow multiple lines of evidence. Indeed, the past decades have been 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 PSE pathogenesis. 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. These agents may represent the best-defined PSE false transmitters; however, their precise role is somewhat unclear. These substances are believed to depress central nervous system (CNS) function by binding to specific high-affinity BZP sites on GABA-receptor complexes. 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 GABAergic signaling has been postulated as a mechanism leading to PSE.
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-α) 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 nitrous oxide (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-α 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.
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 the 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.
Etiology
Precipitating factors that lead to the 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 spontaneous bacterial peritonitis (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
Findings include the following:
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Increased substrate (protein) for ammoniagenesis
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Increased substrate (urea) for ammoniagenesis
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Increased protein intake
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Gastrointestinal bleeding
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Constipation
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Dehydration
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Renal failure
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Increased catabolism of protein
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Infection
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Hypokalemia
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Sepsis
Decreased hepatocellular function
Findings include the following:
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Dehydration
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Hypotension
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Sepsis
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Hypoxia
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Anemia
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Development of hepatocellular carcinoma
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Worsened intrinsic liver disease
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Drug toxicity
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Superimposed viral hepatitis
Increased portocaval shunting
Findings include the following:
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Portal vein thrombosis
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Transjugular intrahepatic portosystemic shunt formation
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Surgical shunt formation
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Spontaneous shunt formation
Psychoactive drug use
The following agents may cause portosystemic encephalopathy:
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Benzodiazepines
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Ethanol
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Antinauseants
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Antihistamines
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Other agents
Other mechanisms
Increased diffusion of ammonia across the blood-brain barrier may occur, potentially resulting in alkalosis, which promotes ammonium ion conversion to less polar and more diffusible ammonia.
Blood transfusion may be a factor. Increased ammoniagenesis from transfusions may not be entirely accurate and is possibly more a theoretical than practical concern. Glutaminase activity and generation of ammonia in stored cellular blood products (especially platelets) may conceivably lead to the infusion of ammonia during transfusion.
Epidemiology
United States and international data
The true incidence and prevalence figures for portosystemic encephalopathy are not available. This complication is a frequent and possibly inevitable feature of progressive and chronic liver disease.
Race-, sex-, and age-related demographics
No specific racial data apply.
Presumably, because alcoholic liver disease occurs with greater frequency in men compared to women, a higher proportion of patients appears to be male.
A variety of neurologic conditions common in elderly patients (eg, multiple cerebral infarcts, Alzheimer disease, parkinsonism) may exacerbate the manifestations of portosystemic encephalopathy; however, this condition usually is prominent in patients with advanced liver disease, which may not manifest in very elderly persons because they may not survive that long. No specific age frequency data are available.
Prognosis
In general, the prognosis of patients with advanced liver disease is poor unless they are able to undergo liver transplantation. The contribution that portosystemic encephalopathy 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 their Child-Pugh score than the outcome of the complication itself.
Morbidity/mortality
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 the 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 will often 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 Etiology).
Because of the potential for rapid evolution to coma, close clinical monitoring and the 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.
Complications
Respiratory and ventilatory insufficiency, and the failure to protect the airway with consequent aspiration are anticipated complications that should be avoided with endotracheal intubation.
