What's new in our understanding of the pathogenesis of hepatic encephalopathy?

Watch a video presentation of this article Watch the interview with the author Astrocyte swelling leading to brain edema is commonly associated with hepatic encephalopathy (HE) in both acute liver failure (ALF) and chronic liver disease (CLD). However, intracranial hypertension is most frequently observed in patients with ALF, causing high mortality from cerebral herniation. Although patients with CLD rarely develop an increase in intracranial pressure, advanced sensitive magnetic resonance techniques have identified an increase in brain water in patients with HE.1 This “low-grade” brain edema is significant because an improvement in HE is associated with its resolution.2 Hypertonicity and subsequent attraction and accumulation of water in the brain are the consequence of an increase in blood-brain barrier (BBB) permeability. Vasogenic (physical breakdown of the BBB) versus cytotoxic (intact BBB but increased traffic of molecules) mechanisms underlying the development of brain edema in CLD are not completely defined. Aside from the physical stress a swollen brain can provoke on neurological function, increase in astrocyte volume (swelling) can lead to altered astrocyte function, dysregulated release, and uptake and metabolism of signaling molecules. Consequently, this leads to alterations in communication between astrocytes and neurons, abnormalities in neurotransmission, and hence neurological deterioration.3 Liver disease results in elevated plasma levels of neuropathogenic factors, including ammonia, inflammation, and oxidative stress, which via the BBB influence the brain, causing various cellular disturbances. Although the pathophysiology of HE is still incompletely understood, hyperammonemia is believed to play a central role. At physiological pH, 2% of ammonia is present as a gas (NH3) and 98% as an ion (NH4+), with NH3 freely diffusing across plasma membranes and NH4+, with similar ionic properties as K+, transported through K+ channels and cotransporters. The primary effects of elevated levels of ammonia involve changes in pH, membrane potential, and cellular metabolism, all of which cause a cascade of pathophysiological and biochemical events that negatively impact cell function. Elevated levels of glutamine and lactate dyshomeostasis in the brain have been demonstrated to play key roles in the development of brain edema in HE, which are believed to occur because of impaired crosstalk between astrocytes and neurons. Astrocytes are the sole cell in the brain that can remove ammonia (through the amidation of glutamate to glutamine catalyzed by the enzyme glutamine synthetase); therefore, increased intracellular glutamine production is believed to render the astrocyte hypertonic and lead to a surge in water influx into the astrocyte. In addition, astrocytes also play an essential role in generating and shuttling lactate as an energy source to neighboring neurons. Reasons for increased brain lactate arising in HE have been speculated to be a result of energy impairment, increased glycolysis, and/or disturbances in the astrocyte-neuron lactate shuttle, causing astrocyte swelling and possibly neuron starvation.4 Hyponatremia is another risk factor that may exacerbate astrocyte swelling by affecting the osmolarity between intracellular and extracellular compartments. Although an overwhelming amount of evidence points at the role of ammonia in the pathogenesis of HE, the correlation between blood ammonia levels and severity of HE is poor in CLD, suggesting that other pathogenic factors are involved. The ailing liver is a fundamental cause of systemic inflammation and oxidative stress, factors that have independently been shown to trigger or exacerbate neurological decline.5 Studies involving animal models of CLD have demonstrated an important synergistic role between systemic inflammation and oxidative stress together with hyperammonemia in the development of brain edema.6, 7 Significant hepatocyte death incites a cytokine storm and inflammatory modulators that modulate the permeability and signaling through the BBB acting via various receptors, transporters, and channels. Neuroinflammation, activation of microglia, and subsequent release of cytokines have been demonstrated in experimental animal models of HE.8 Excess reactive oxygen species (oxidative stress) are highly reactive and can oxidize DNA, RNA, and proteins, causing cell harm and dysfunction. Plasma 3-nitro-tyrosine, a marker of oxidative stress, was found to distinguish cirrhotic patients with and without minimal HE,9 whereas markers of oxidative stress have been primarily found in the brain of patients with overt HE.10 Historically, HE has always been considered to be a reversible metabolic disorder and has therefore been expected to completely resolve after liver transplantation. However, even after the implantation of a new liver, persisting neurological complications remain a problem affecting 8% to 47% of liver transplant recipients.11 Recent retrospective studies documented that cirrhotic patients with a history of existing bouts of overt HE display impaired neurological resolution and an increased risk for mortality and morbidity following liver transplantation.12 Therefore, recurrent episodes of overt HE could possibly lead to progressive structural brain damage, neuronal loss, and irreversibility.13-15 However, the underlying mechanisms leading to permanent neuronal cell injury and death remain unknown and merit being thoroughly investigated. The pathogenesis of HE is multifactorial. Hyperammonemia is believed to render the brain susceptible to further insults, including inflammation and oxidative stress (Fig. 1). Furthermore, the presence of brain edema is significant and may be a predisposing factor in the onset of overt HE. The precise pathophysiological mechanisms underlying the continuum of HE (covert, overt, recurrence, and irreversibility) remain to be meticulously studied.

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