01 February 2011: Review Article
Hepatic encephalopathy: An updated approach from pathogenesis to treatment
Giannakis T. Toris , Christos N. Bikis , Gerasimos S. Tsourouflis , Stamatios E. Theocharis
DOI: 10.12659/MSM.881387
Med Sci Monit 2011; 17(2): RA53-63
Abstract
ABSTRACT: One of the most serious complications of chronic or fulminant liver failure is hepatic encephalopathy (HE), associated most commonly with cirrhosis. In the presence of chronic liver disease, HE is a sign of decompensation, while in fulminant liver failure its development represents a worrying sign and usually indicates that transplantation will be required. Despite the significance of HE in the course of liver disease, the progress in development of new therapeutic options has been unremarkable over the last 20 years. An up-to-date review regarding HE, including both research and review articles. HE is a serious and progressive, but potentially reversible, disorder with a wide spectrum of neuropsychiatric abnormalities and motor disturbances that ranges from mild alteration of cognitive and motor function to coma and death. Although a clear pathogenesis is yet to be determined, elevated ammonia in serum and the central nervous system is the mainstay for pathogenesis and treatment of HE. Management includes early diagnosis and prompt treatment of precipitating factors. Clinical trials and extensive clinical experience have established the efficacy of diverse substances in HE treatment. Novel therapies with clinical promise include: L-ornithine L-aspartate, sodium benzoate, phenylacetate, AST-120, and the molecular adsorbent recirculating system. Eventually, liver transplantation is often the most successful long-term therapy for HE.
Keywords: Hepatic Encephalopathy - therapy
Background
Hepatic encephalopathy (HE) or portosystemic encephalopathy (PSE) is one of the most serious complications of liver failure, either chronic or fulminant. HE refers to a complex and potentially reversible or progressive syndrome of cerebral dysfunction, which consists of neuropsychiatric, cognitive and motor components, characterized by a broad etiological spectrum. It is observed in cirrhotic patients and those with acute liver failure (ALF) in the absence of other known brain disease, as a result of decompensated liver function [1,2]. Five years after the diagnosis of cirrhosis, there is 26% probability for developing at least one episode of HE [3]. HE is also a common problem after insertion of a transjugular intrahepatic portosystemic shunt (TIPS) [4,5]. Despite the impressive advances in our understanding of the several pathophysiological mechanisms which are involved in HE, the treatment options remain an unmet clinical need, accompanied by considerably high mortality rates. After the first clinical manifestation of HE, the patients’ prognosis is very poor; probability of five-year survival is 16% to 22%, compared with that of 55% to 70% in cirrhotic patients without HE [3,6]. The pathophysiology of chronic HE is apparently multifactorial, with several circulating neurotoxins being involved. The systemic accumulation of ammonia neurotoxic concentrations seems to be the most prominent factor [7,8], while the interorgan ammonia and amino acid metabolism is of pivotal importance in the pathogenesis of HE. Since Nencki and Pavlov described meat intoxification in portacaval shunted dogs over 100 years ago [9], ammonia has been considered as a central factor to the pathogenesis of HE [10]. The clinical importance of hyperammonemia’s role in patients with liver failure is no more evident than in the observation that ammonia levels of >150 μmol/L predict brain herniation, coma and death in patients with ALF [11]. Several treatment agents such as lactitol, lactulose, L-ornithine-L-asparate and rifaximin aim to lower blood and cerebral ammonia levels and thereby attenuate its toxic effects.
Ôhe aim of this review is to summarize the current knowledge related to the pathophysiology leading to HE, as well as the subsequent therapeutic options and advances that have primarily arisen out of understanding the progression of HE.
Clinical Hepatic Encephalopathy
MINIMAL HEPATIC ENCEPHALOPATHY:
Coma grade deeper than I is usually defined as overt encephalopathy and grade 0 or less as subclinical or minimal HE (MHE), which is the mildest form of HE spectrum. Patients with MHE have no recognizable clinical symptoms; a mild cognitive and psychomotor deficit are diagnosed under the result of various neuropsychological tests, such as the number correction test (NCT), digit-symbol test, line tracing test, serial-dotting and block design test [21]. Aside from neurophysiologic evaluations, electroencephalogram (EEG) and P3000 auditory evoked potentially are recommended [17]. Although these neurocognitive abnormalities are subtle, they primarily affect attention, speed of information processing, motor abilities and coordination, in a way that is not recognizable on standard neurological examination. These abnormalities are independent of sleep dysfunction or problems with overall intelligence [17,22,23]. The prevalence of MHE is high in patients with liver cirrhosis and varies between 30% and 84%, with higher prevalence in patients presenting poor liver function [24]. The diagnostic criteria for MHE have not been standardized, but are based on careful patient history and physical examination, normal mental status examination, demonstration of abnormalities in cognitive and/or neurophysiological functions and exclusion of concomitant neurological disorders. MHE is associated with impaired health-related quality of life, predicts the development of overt HE, and is associated with poor survival. Hence, screening all patients with cirrhosis for MHE using psychometric tests and treating those with MHE diagnosis has been recommended as a way of improving both quality of life and rate of survival.
ETIOLOGY OF HYPERAMMONEMIA:
Ammonia is created primarily from nitrogenous products in the diet, bacterial metabolism of urea and proteins in the colon, as well as deamination of glutamine in the small intestine by glutaminase (EC 3.5.1.2) [25,26]. Ammonia is also produced by skeletal muscles, although the pattern of these metabolic pathways’ contribution to HE pathogenesis is not yet thoroughly established. From the gut, ammonia enters the portal circulation and is converted to urea by the liver; urea is subsequently excreted by the kidneys [8]. Overall, the main causes of hyperammonemia are presented in Table 3 [27–30].
Vascular anatomic anomalies that result in blood flow bypassing the liver, as well as the existence of slow transit constipation, can both allow increased absorption of ammonia into the mesenteric blood supply, sufficient to overwhelm hepatic excretory pathways and therefore deteriorate into hyperammonemia. Aside from the most common form of decompensated liver disease, where the diagnosis is reasonably straightforward, less frequent causes of hyperammonemia can pose a certain clinical challenge, in the sense that they may present with an identical clinical syndrome. Although rare, some of these less frequent causes may be reversible or even curable with specific therapy, making prompt recognition potentially lifesaving [28].
Pathophysiology
KNOWLEDGE AT THE MOLECULAR LEVEL:
Several studies have been performed in order to elucidate the molecular milestones in the pathogenesis of HE. As already pointed out, the skeletal muscle can detoxify ammonia with the activity of GS. Under normal circumstances the GS-activity is of small importance, but in the case of HE its gene expression and activity are up-regulated [35]. In ALF, genes that code glial glutamate transporter-1 (GLT-1), glucose transporter-1 (GLUT-1), glial fibrillary acidic protein (GFAP), peripheral type benzodiazepine receptor (PTBR) and aquaporin IV alter their expression in astrocytes when the liver fails [44].
The synthesis of neurosteroids, such as pregnenolone, progesterone, allopregnanolone and 3α-5α-tetra-dehydrodeoxy-corticosterone (THDOC), takes place mainly in astrocytes and microglial cells, and it is driven by the up-regulation of PTBR by ammonia and manganese. The PTBR, a heteromeric complex of several subunits [isoquinoline binding protein (IBP), voltage-dependent anion channel (VDAC), adenine nucleotide carrier (ANC)] is localized in the outer and inner mitochondrial membranes, and its activation enhances the uptake of cholesterol, creating a channel, that allows significant cholesterol utilization and conversion to neurosteroids by mitochondrial enzymes. Moreover, de novo synthesis of neurosteroids is driven by PTBR upregulation. Increased expression of peripheral benzodiazepine binding sites (PBBS) has been shown in vivo in HE patients using the [11C](R)-PK11195 ligand and PET. Brain regions such as the pallidum, right putamen and the right dorsolateral prefrontal region, showed increased radioisotope binding [45]. The neurosteroids positively modulate the activity of GABA-A receptor complex through the neurosteroid binding site of the GABA-A receptor, and subsequently the GABA and the benzodiazepine recognition site, which are allosterically coupled. The increased GABA-ergic tone is a result of GABA-A ion channels activation by neuroinhibitory neurosteroids, which allow chloride to enter, hyper-polarize and eventually inhibit nerve cells (Figure 2).
It has also been shown that neurosteroids possess genomic actions that modulate gene expression through transcription in astrocytes [46] by various mechanisms, for example by altering the expression of Ìonoamine Ïxidase A (MAO-A) via the glucocorticoid receptors in humans [47] or Aquaporin IV via progesterone receptors in rats [48].
Several studies have been performed on the implication of NO in pathogenesis of HE. In ALF, vasodilation caused by NO is responsible for high cerebral blood flow, increased delivery of ammonia to the brain and edema. In rats with ALF due to hepatic devascularization, endothelial nitric oxide synthase (eNOS) mRNA exhibits increased expression in cerebral cortex compared to sham operated rats used as controls [49]. In the same study, mild hypothermia sufficient to prevent HE and brain edema in ALF rats normalized eNOS mRNA levels. However, eNOS did not correlate well with HE/edema in the early stages of ALF.
Another pathway impaired in chronic hyperammonemia is glutamate-NO-cGMP. Activation of the N-methyl-D-aspartic acid (NMDA) receptors leads to increased intracellular calcium that, bound in calmodulin, activates NOS, which subsequently produces NO. The synthesis of cGMP is mediated by the soluble guanylate cyclase (EC 4.6.1.2), which is activated by NO. The glutamate-NO-cGMP pathway has a role in learning and memory abilities, which are impaired, among along with other cognitive functions, in HE patients (Figure 3).
As mentioned before, the BBB permeability is altered in HE. An in vitro study on cultured mouse brain capillary endothelial cells revealed that, when exposed to ammonia, mRNA expression of taurine transporter (TAUT) and creatine transporter (CRT), both being BBB transporters, rises, as does their uptake [50,51]. On the other hand, mRNA expression of the tight junction protein claudin-12 was significantly suppressed, suggesting a partial explanation to BBB integrity changes seen in HE. The molecular mediators in HE are summarized in Table 5.
Treatment of hepatic encephalopathy
Dealing with precipitating factors of hyperammonemia and accumulation of toxic metabolites
DEALING WITH PRECIPITATING FACTORS OF HYPERAMMONEMIA AND ACCUMULATION OF TOXIC METABOLITES:
One of the most important aspects of dealing with HE is the ability to potentially reverse its progress by prompt recognition and treatment of its precipitating factors before a decompensated liver function takes place. Fessel et al. demonstrated that HE is caused by reversible factors in over 80% of patients [52]. These common factors that can be reversed include dehydration, constipation, systematic infection, hypokalemia, gastrointestinal hemorrhage, protein over-intake, sedatives and tranquilizers (Table 2). Addressing these factors in time has been proved to be crucial in effectively treating most patients with HE [53].
GASTROINTESTINAL HEMORRHAGE, RENAL FAILURE, DEHYDRATION, CONSTIPATION: Prompt treatment of upper or lower GI bleeding is essential. Acute renal failure as a result of dehydration and diuretics’ effect may precipitate HE through hypokalaemia, hypoglycaemia and metabolic alkalosis. Intravenous thiamine replacement should be promptly initiated in nutritionally depleted and alcoholic patients. The assessment of recent bowel habits is crucial. Adequate defecation is essential and measures to produce it should be taken [54].
INFECTION: Culture from all appropriate body fluids should be received. A diagnostic paracentesis should be performed in all patients with ascites. In patients with hepatic coma, or pending culture results, a short course of empirical antibiotics should be considered [53].
DRUGS: The use of psychoactive medications such as benzodiazepines and narcotics should be evaluated and discontinued if possible. The toxicology of urine may be also necessary. Any condition suggesting the development of encephalopathy should result in total discontinuation of chlordiazepoxide and other sedatives, or in a limitation to minimum possible dosages in drowsy cirrhotic patients who are at risk of delirium tremens [50].
ACUTE BRAIN INJURY AND SEIZURES: The possibility of focal neurological injury must be excluded by a careful history and neurological examination. In case of any doubt, CT brain imaging should be performed. EEG analysis will exclude seizure activity, or may confirm the presence of typical slow, triphasic waveforms in the frontal lobes, which are associated with HE [54].
DIETARY REGULATIONS: It has been demonstrated that dietary protein restriction in cirrhotic patients does not ameliorate or reverse the course of HE [55]. As a result, a daily protein intake of 1–1.5 g/kg of body weight can be safely administrated to a patient with HE, as a positive nitrogen balance is necessary to promote liver regeneration and increase capacity of skeletal muscles to remove ammonia in the form of glutamine [56]. However, it has been proven that the source of the protein intake may be of importance in controlling HE, with vegetable proteins being superior to animal-derived ones [57], although the hypothesis that branched -chain amino acids (BCAAs) can improve HE has failed to be proven. On the other hand, a high fiber intake diet seems to ameliorate HE by increasing the food transit rate through the gastroenteric system and therefore reducing the absorption of ammonia into the mesenteric blood supply [58,59].
REGULATING NEUROTRANSMISSION IN THE BRAIN: Branched-chain amino acids, benzodiazepine antagonists such as flumazenil [82,83], dopamine receptor stimulators such as bromocriptine [84], NMDA receptor antagonists and zinc [85] have been tested as supplementary medication for the treatment of HE-related neurological symptomatology. Their effectiveness however, needs to be more thoroughly proven before they can be systematically introduced into the treatment of HE, given the fact that they can also present considerable side effects in the nervous system.
NOVEL APPROACHES AND STRATEGIES UNDER DEVELOPMENT:
Endocannabinoids have been used in animal studies in order to alleviate the symptoms of cerebral dysfunction, by activating the AMP-activated protein kinase [99]. In addition, continuous intracerebral administration of cGMP, or zaprinast (a cGMP-degrading phospho-diesterase inhibitor that does not cross the BBB), have been proven to enhance the learning ability of hyperammonemic rats [100]. Therefore sildenafil, an inhibitor of cGMP-degrading phospho-diesterase with ability of BBB crossing, has been used in order to improve the cerebral function of patients with HE by increasing the levels of extracellular cGMP [101]. The contribution of glutamatergic transmission in cerebral dysfunction symptoms presenting in HE patients provides the opportunity of a pharmacological approach by means of blocking the metabotropic glutamate receptor 1 [102]. According to current evidence, inflammatory mediators play an important role in inducing the neurophysiological brain alterations observed in patients with HE [103]. Based on this observation, experimental studies have been conducted on animal models, proving the ability of indomethacin [104] and ibuprofen [105] to ameliorate the cerebral symptoms observed in HE patients. L-methinine S-sulfoximine (MSO), an irreversible inhibitor of GS, can prove of therapeutic value for patients with HE, given the fact that it can lower brain glutamine levels and therefore prevent astrocyte swelling and cerebral edema [106]. Oxidative stress, causing mitochondrial permeability transition (mPT), could lead to astrocyte swelling and cerebral edema [107]. Taking this into account, mPT inhibitors, such as pyruvate, minocycline, magnesium and TFP, have been tested as a possible treatment for cerebral manifestations of HE [16]. Moreover, the use of manganese-chelating agents [108], as well as application of moderate hypothermia [109] could aid in alleviating brain symptoms in patients with HE, although their effectiveness remains to be solidly proven.
Conclusions
Hepatic or porto-systemic encephalopathy (HE) is one of the most serious complications of chronic or fulminant liver failure, associated most commonly with cirrhosis, and encompasses a spectrum of neuropsychiatric symptoms and signs. Due to differences in etiology and severity, as well as heterogeneity of manifestations, the diagnosis and management of HE remain a difficult challenge for physicians and medical professionals. Since HE does not clinically differ from encephalopathies of different etiologies, its diagnosis requires the presence of liver disease or a portosystemic shunt. Several factors have been implicated in pathogenesis, with ammonia considered to have a central role, thus prompt recognition of the cause of hyperammonemia can be potentially lifesaving. Identification and correction of precipitating factors remains the cornerstone of treatment, while morbidity and mortality can be decreased by timely intervention. Overall, treatment of HE consists of the following three directions: modifying factors precipitating hyperammonemia and accumulation of toxic metabolites; decreasing blood and cerebral ammonia levels; and addressing the consequences of hyperammonemia and accumulation of toxic metabolites. Screening all patients with cirrhosis for MHE and treating those with MHE diagnosis has been recommended to improve quality of life and rate of survival. Finally, liver transplantation is often the most successful long-term therapy for HE.
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