Hepatic Encephalopathy

Roger F. Butterworth, Ph.D., D.Sc.

Hepatic encephalopathy (HE) is a brain disorder caused by chronic liver failure, particularly in alcoholics with cirrhosis, which results in cognitive, psychiatric, and motor impairments. In these patients, the number of functional liver cells is reduced, and some blood is diverted around the liver before toxins are removed. As a result, toxins such as ammonia and manganese can accumulate in the blood and enter the brain, where they can damage nerve cells and supporting cells called astrocytes. Positron emission tomography analyses have determined that ammonia levels are elevated in the brains of HE patients; ammonia accumulation can alter the expression of various important brain genes. Magnetic resonance images show that manganese is deposited in a brain area called the globus pallidus; manganese deposits may be responsible for structural changes in the astrocytes that are characteristic of HE. Treatment of patients with HE involves measures to lower ammonia levels in the blood, medications to counteract ammonia’s effects on brain cell function, devices to compensate for liver dysfunction, and liver transplantation. KEY WORDS: hepatic encephalopathy; toxic drug effect; neurotoxicity; alcoholic liver cirrhosis; symptom; diagnosis; brain damage; impaired balance and coordination; ammonia; manganese; neuroimaging; positron emission tomography; magnetic resonance imaging; drug therapy; dialysis; liver; organ transplantation

he liver and the brain interact sis), and destruction of the normal liver atic encephalopathy (HE) or portal- in numerous ways to ensure architecture (cirrhosis). When the liver systemic encephalopathy.1 Tnormal brain functioning. For becomes fibrotic and cirrhotic, the num- This article describes the character- example, the liver plays a key role in ber of functional hepatocytes decreases, istics and diagnosis of HE and the supplying nutrients to the brain, which and the liver loses its capacity to remove changes in brain cell structure associ­ cannot produce these compounds itself. toxic substances from the blood. More- ated with this condition. The article The liver also removes toxic substances over, during these disease stages some also reviews imaging techniques that from the blood, including substances of the blood entering the liver through allow researchers to study changes in that have been generated in the brain the portal vein cannot penetrate the brain structure and function occurring and must be eliminated from the body, diseased liver and is diverted directly in patients with HE and describes the as well as compounds produced in other into the general circulation; this phe- contributions of ammonia and man- tissues that are harmful to the brain’s nomenon is known as portal-systemic ganese to the development of HE, as nerve cells (i.e., are neurotoxic). Thus, elucidated by these techniques. Finally, shunting. Blood that bypasses the liver liver dysfunction can cause disturbances the article explores some approaches of brain function and even contribute is not detoxified, and blood levels of currently used or being investigated for to brain damage. toxic substances increase. Researchers have identified several toxins that nor­ Liver dysfunction of varying severity 1 The term “encephalopathy” refers to any abnormal con- is a frequent complication of chronic mally are removed in the liver but are dition in the structure or function of the brain, especially alcohol abuse. The most common found in the circulation of patients with chronic, destructive, or degenerative conditions. and least severe form of alcoholic liver alcoholic cirrhosis, including ammonia, disease—fatty liver (steatosis)—is char- manganese, and chemicals called mer- ROGER F. B UTTERWORTH, PH.D., D.SC., acterized by fat deposits in the primary captans, all of which readily enter the is scientific director of the Neuroscience liver cells (i.e., the hepatocytes). More brain and are neurotoxic. Consequently, Research Unit at the CHUM (Hôpital serious stages of alcoholic liver disease brain function in patients with severe Saint-Luc), and professor of medicine at include inflammation of liver tissue alcoholic liver disease is compromised, the University of Montreal, Montreal, (hepatitis), scar tissue formation (fibro- resulting in a condition known as hep- Canada.

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treating patients with HE resulting from the diagnosis. Patients frequently are Also, small doses of sedatives may trigger alcoholic liver disease. misdiagnosed, particularly in the early overt encephalopathy in these patients. stages of HE, when symptoms occur In addition to patients’ general that are common to a number of medical status or diet, other factors can Characteristics and psychiatric disorders, such as euphoria, trigger or exacerbate HE. For example, Diagnosis of Hepatic anxiety, depression, and sleep disorders. alcoholic cirrhotic patients frequently Encephalopathy The following characteristics have been experience elevated blood pressure in proposed as helpful in diagnosing HE the portal vein transporting blood to HE is a complex neuropsychiatric syn­ in alcoholic cirrhotic patients (Tarter the liver, which may lead to complica­ drome characterized by severe cognitive, et al. 1993): tions such as gastrointestinal bleeding psychiatric, and motor disturbances and accumulation of fluid in the abdomen resulting from chronic liver failure, which •History of liver disease. (a condition known as ascites). To treat in most cases in Western societies is caused these complications, physicians use a by chronic alcohol abuse. As chronic liver •Aslowing (i.e., reduced frequency) nonsurgical procedure known as trans- failure develops and increases in severity, of brain waves measured by electro­ jugular intrahepatic stent shunt (TIPS), patients start to experience sleep distur­ encephalography (EEG). which redirects some of the blood flow bances, changes of mood and personality, around the liver. Following the proce­ and a shortened attention span. These •Impaired performance on neuropsy­ dure, blood bypasses the liver, as do the symptoms are followed by psychiatric chological tests assessing visuospatial toxins contained in the blood (a pro­ conditions such as anxiety and depres­ and perceptual–motor control (e.g., cess similar to the diversion of blood in sion, as well as by motor problems, line-drawing tests and number con­ patients with liver cirrhosis described in including motor incoordination and a nection tests). the introduction). Although TIPS leads type of flapping tremor of the hands to a lower blood pressure in the portal called asterixis. Ultimately, patients no • Asterixis (“flapping tremor”). vein, thereby preventing gastrointesti­ longer respond to external stimuli and nal bleeding and ascites, it also can lead may fall into a coma (i.e., hepatic coma), •Foul-smelling breath associated with to HE because the blood is not detoxi­ which can be fatal. liver disease (i.e., fetor hepaticus). fied. In fact, in up to 50 percent of A fact largely overlooked in the liter­ patients treated with TIPS, the proce­ ature on alcoholic brain disorders is •Enhanced rate of breathing (i.e., dure results in new or worsening that patients suffering from HE often hyperventilation). episodes of HE. have other alcohol-related brain disorders as well, such as Wernicke’s encephalop­ •Elevated concentrations of ammo­ Structural Brain Damage athy and alcoholic cerebellar degenera­ nia in the serum2 after a period of Associated With HE tion (Kril and Butterworth 1997). These fasting. conditions are caused by alcohol-induced HE associated with chronic liver failure deficiencies in the vitamin thiamine •Reduced awareness or consciousness. (regardless of whether the liver disease and/or alcohol’s direct toxic effects on is caused by alcohol or other factors) the brain. It can be difficult to disen­ Although these signs and symptoms does not result in significant loss of tangle the contributions of concurrent are useful tools for diagnosing HE, they nerve cells (i.e., neurons) in the brain alcohol-related brain disorders on the also occur in brain disorders caused by or in other readily observable structural patient’s cognitive functioning; however, metabolic disturbances and therefore damage to the neurons. In contrast, when an alcoholic patient develops are not specific to HE. Furthermore, liver failure causes significant changes significant liver disease, HE becomes a whether—and to what extent—a patient to supporting brain cells called astro­ major factor contributing to the cogni­ displays each symptom may vary depend­ cytes. These large star-shaped cells are tive dysfunction associated with chronic ing on fluctuations in the patient’s essential to the functioning of the cen­ alcoholism. This is clearly illustrated by medical and drug status or diet. For tral nervous system because they help the results of studies involving neuro­ example, sedatives or meals high in maintain the proper composition of psychological tests, which demon­ protein frequently trigger episodes of the fluid surrounding the neurons. strated that alcoholic patients with HE in alcoholic patients with cirrhosis. For example, astrocytes take up brain cirrhosis (who therefore could be expected Thus, an asymptomatic cirrhotic patient chemicals (i.e., neurotransmitters) that to have HE) had significantly lower frequently begins to show signs of HE are released by the neurons and medi­ scores in learning and memory tests ate nerve signal transmission between following ingestion of large amounts of than did alcoholics without cirrhosis cells; astrocytes also take up minerals protein, which is a source of ammonia. (Tarter et al. 1993). (e.g., potassium) generated and HE is difficult to diagnose in alco­ secreted during the brain’s energy 2 The serum is the clear portion of the blood that remains holic patients because no single clinical after blood cells, platelets, and blood-clotting molecules metabolism and remove neurotoxic or laboratory test is sufficient to establish have been removed. substances. Some evidence suggests

Vol. 27, No. 3, 2003 241 that a metabolic “cross-talk” (i.e., the The ligand molecule is labeled by the brain regions in patients with alcohol- release of substances by one cell type to addition of a radioactive atom. Using induced cirrhosis. Studies using 18FDG stimulate another cell type) occurs sophisticated machines to detect the have revealed that alcoholic cirrhotic between astrocytes and neurons which radioactive molecules in various tissues, patients with mild HE show decreases is essential to brain function. investigators can monitor the transport in glucose uptake in the region of the In patients with HE, the astrocytes of ligand molecules and their break­ brain involved in controlling the adopt a characteristic morphologic feature down in the tissues, and thereby can “attention system” responsible for mon­ known as Alzheimer type II astrocyto­ determine the metabolic activities of itoring, for example, visual stimuli as sis, named after the neuropathologist those tissues. For example, researchers well as in selecting appropriate responses who also gave his name to the neuro­ can measure glucose uptake, which to these stimuli (i.e., the anterior cin­ degenerative disease. These abnormal occurs in all cells in the process of gen­ gulate cortex) (Lockwood et al. 2002). astrocytes, which usually are found in erating the energy those cells need, by These findings indicate that this brain pairs or triplets, are characterized by their administering a radioactive form of region is less active in HE patients than enlarged, glassy-looking nuclei (see fig­ glucose called 18F-fluorodeoxyglucose in healthy people. Not surprisingly, the ure 1). This glassy appearance is caused (18FDG). Similarly, investigators can investigators also found that glucose 15 by the fact that the DNA and its use radioactive water ( O-H2O) to utilization in the anterior cingulate cortex, associated proteins are not distributed monitor blood flow, radioactive ammo­ as determined by 18FDG, correlated 13 throughout the nucleus but are confined nia ( N-NH3) to assess ammonia significantly with patients’ performance to its edges. The nuclei of Alzheimer metabolism, and a wide range of radioac­ on neuropsychological tests involving type II astrocytes also contain deposits tive compounds to study various attention-demanding tasks (i.e., patients of a molecule called glycogen, which molecules involved in the activities with reduced glucose utilization exhib­ serves as a storage form of the sugar of neurotransmitters. ited poorer performance). Reduced glucose in cells but typically is not A variety of PET ligands have been glucose utilization in patients with HE found in the nucleus; it is unknown used to assess the functions of various was accompanied by corresponding whether these changes affect astrocyte function, however.

Neuroimaging Helps Elucidate the Mechanisms Leading to HE

Researchers have gained a better under­ standing of the mechanisms and conse­ quences of alcoholic liver disease in the brain by using neuroimaging and spec­ troscopic techniques that allow them to study the metabolism and functions of specific brain regions in living patients. Two neuroimaging techniques used extensively in the study of HE in alco­ holic cirrhotic patients are positron emission tomography (PET) and mag­ netic resonance imaging (MRI). Studies using these techniques have confirmed the contributions of two neurotoxic substances, ammonia and manganese, to the development of HE.

PET Establishes Ammonia’s Role Figure 1 Brain cells called astrocytes from a 51-year-old alcoholic patient with cir­ PET is a technique used to examine rhosis who died in a coma (hepatic encephalopathy [HE]). The image shows both normal astrocytes (N), which have dark nuclei, and Alzheimer the metabolic activity of various body type II astrocytes (Alz), characteristic of HE, which have pale, enlarged regions, including the brain. For these nuclei. analyses, patients are injected with a molecule called a ligand, which nor­ SOURCE: Modified from Butterworth 2002. mally may be metabolized in the body.

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decreases in blood flow in those brain enter the brain and cause damage there. Ammonia normally is removed from structures. Studies have found that in patients with the blood in the liver by a series of Other PET studies have assessed advanced stages of encephalopathy result­ chemical reactions called the urea cycle. the levels of ammonia in the brain. As ing from chronic liver failure, ammonia During these sequential reactions, ammo­ mentioned earlier, ammonia is one of levels in the brain may increase more nia is converted into urea, which is the neurotoxic substances that the liver than twentyfold (Butterworth 2002). excreted in the urine. The brain, how­ normally removes from the blood. PET Ammonia is extremely toxic to the ever, lacks an effective urea cycle and analyses using radioactive ammonia in brain, affecting both neurons and therefore has only a limited capacity to cirrhotic patients with mild HE have astrocytes. For example, ammonia has remove any ammonia that enters the revealed significant increases in ammo­ deleterious effects on nerve signal trans­ tissue from the blood because of the nia uptake and metabolism in the brain mission mediated by numerous neuro­ increased PS. The only way to elimi­ (see figure 2) (Lockwood et al. 1991). transmitter systems (Szerb and Butterworth nate any ammonia that has reached the These investigators found that, in par­ 1992) as well as on the brain’s energy brain cells is through a reaction medi­ ticular, a measure of the extent to which metabolism. In addition, ammonia can ated by an enzyme called glutamine ammonia can enter the brain from the alter the expression4 of various genes synthetase, which combines a molecule general circulation3—a variable called encoding key brain proteins involved of the amino acid glutamate with a the permeability–surface area product in the brain cells’ energy production, molecule of ammonia to form the (PS)—increases as cirrhotic patients start structure, and cell-to-cell interactions. amino acid glutamine. The relevance of to develop HE. When the PS increases, (For more information on the specific this reaction was confirmed in neu­ a greater proportion of the ammonia genes affected by ammonia, see the roimaging analyses measuring glu­ present in the general circulation can sidebar “Altered Gene Expression in tamine levels in the brains of alcoholic enter the brain. Increases in the PS explain the Brain Resulting From Alcoholic patients with HE. These studies found why severe HE can be found in alcoholic Liver Disease.”) These alterations in that the amounts of glutamine formed cirrhotic patients even if the ammonia gene expression may account for some in the brain correlated with the severity levels in the blood are not greatly ele­ of the changes in neurotransmitter of HE, confirming that the brain is vated: In these cases, a higher propor­ activity and astrocyte structure observed exposed to elevated levels of ammonia tion of the ammonia in the blood can in HE patients. (Lockwood et al. 1997). However, glu­ tamine synthetase is present only in astrocytes, not in neurons, and cannot remove all the ammonia that enters the CBF CMRA PS brain. As a result, neurons are virtually defenseless against increased ammonia concentrations and therefore are most likely to exhibit impaired function Normal indicative of ammonia-related damage.

MRI Identifies Signal Hyperintensities That May Result From Manganese Deposits MRI technology is based on the fact that when the body is exposed to radio Patient waves in the presence of a strong mag­ netic field, the nuclei of certain atoms emit signals as they align and realign in the magnetic field. These signals can be

Figure 2 Positron emission tomography (PET) analyses of a healthy person and a 3 The brain is largely separated from the general circula­ 47-year-old alcoholic cirrhotic patient with mild hepatic encephalopathy. tion by the blood–brain barrier, a property of the blood The blood flow through the brain (i.e., cerebral blood flow [CBF]) differs vessels in the brain that prevents the passage of many only minimally between the two subjects. However, the cerebral metabolic molecules from the blood into the brain tissue. As a result, only selected substances can enter the brain from rate for ammonia (CMRA) and the permeability–surface area product (PS)— the blood. This feature protects the brain cells from expo­ a measure of the extent to which ammonia can pass the blood–brai n barrier sure to many toxic substances or disease-causing organ­ and enter the brain—are significantly increased in the alcoholic patient, as isms; however, some molecules (e.g., ammonia) can indicated by the wider distribution and enhanced brightness of the light areas. pass the blood–brain barrier to a certain extent. 4 The term “gene expression” refers to the entire process SOURCE: Modified from Lockwood et al. 1991. of converting the genetic information encoded in a gene into a protein product.

Vol. 27, No. 3, 2003 243 detected by a scanning device and con- form images based on signals emitted the form of water, MRI images differ­ verted into three-dimensional images by hydrogen atoms, the most abundant entiate brain structures based on their of specific structures of the body (e.g., element in biological tissues. Because water content. However, elements brain structures). MRI scanners generally most of the hydrogen in the body is in other than hydrogen, including

Altered Gene Expression in the Brain Resulting From Alcoholic Liver Disease

One of the main causes of brain dysfunction in •Anerve cell–specific form of the enzyme nitric oxide patients with hepatic encephalopathy (HE) is the synthase, which produces nitric oxide, a highly reac­ accumulation of ammonia in the blood, which the tive molecule (i.e., a free radical) that plays a role in patient’s liver, damaged by alcoholic liver disease, various cellular processes, including cell-to-cell com­ cannot remove. Molecular biological techniques have munication and the widening (i.e., dilation) of allowed researchers new insights into how HE develops, blood vessels (Raghavendra Rao et al. 1997). Excess including the specific effects of ammonia. These levels of nitric oxide, however, are toxic to the cells analyses have found that, among other effects, ammonia and can contribute to a cellular state called oxidative alters the expression of certain genes—that is, the rates stress, which is characterized by the presence of at which the genetic information contained in DNA excess free radicals and/or a lack of the compounds is converted into the final protein products encoded that remove these free radicals (i.e., antioxidants). by those genes. Molecular approaches have enabled Oxidative stress can cause cell damage and has been investigators to identify some of the genes affected in implicated in alcoholic liver disease. Increased patients with HE (Butterworth 1998). These genes expression of nitric oxide synthase in the brains of code for key brain proteins that are essential to the patients with chronic liver failure has been linked to cells’ energy production, structure, and interactions excess nitric oxide production, which in turn leads with other cells, including the following proteins: to oxidative stress and cellular dysfunction.

•Aspecific type of monoamine oxidase called MAO-A, •Aprotein called glial fibrillary acidic protein an enzyme responsible for the metabolism of neuro­ (GFAP), which is essential for maintaining the transmitters called monoamines. These compounds structure of astrocytes (Bélanger et al. 2002). include the neurotransmitter serotonin, which is Chronic liver failure or ammonia exposure results involved in the regulation of mood and sleep. in decreased expression of GFAP, which is associated with the presence of Alzheimer type II astrocytes • The mitochondrial (peripheral-type) benzodiazepine that are characteristic of HE. receptor, a receptor protein located on the mem­ branes surrounding small cell structures called mito­ —Roger F. Butterworth chondria, which serve as the cell’s energy factories. This receptor helps facilitate the uptake of choles­ References terol into the mitochondria, which then is converted BÉLANGER, M.; DESJARDINS, P.; CHATAURET, N.; AND BUTTERWORTH, into a family of compounds known as neurosteroids R.F. Loss of expression of glial fibrillary acidic protein in acute hyper­ (Desjardins and Butterworth 2002). Neurosteroids ammonemia. Neurochemistry International 41(2–3):155–160, 2002. can excite or inhibit other neighboring nerve cells, BUTTERWORTH, R.F. Alterations of neurotransmitter-related gene thereby influencing nerve signal transmission. The expression in human and experimental portal-systemic encephal­ brains of patients with alcoholic liver disease show opathy. Metabolic Brain Disease 13:337–349, 1998. increased production of the neurosteroid allopreg­ DESJARDINS, P., AND BUTTERWORTH, R.F. The “peripheral-type” ben­ nanolone, a potent neuroinhibitory compound that zodiazepine (omega 3) receptor in hyperammonemic disorders. could contribute to the development of HE in alco­ Neurochemistry International 41:109–114, 2002. holic liver disease. This increased production proba­ RAGHAVENDRA RAO, V.L.; AUDET, R.M.; AND BUTTERWORTH, R.F. bly results from enhanced cholesterol uptake medi­ Increased neuronal nitric oxide synthase expression in brain following ated by the benzodiazepine receptor. portacaval anastomosis. Brain Research 765:169–172, 1997.

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manganese, also can emit signals that be deposited in the globus pallidus and HE in patients with alcohol-induced are detected by MRI, as discussed below. associated brain structures (i.e., the basal chronic liver failure or for ameliorating When MRI analyses are performed ganglia). Studies using brain tissue from its consequences. These approaches on alcoholics with cirrhosis, more than alcoholic cirrhotic patients who died involve strategies to lower the levels of 80 percent of the patients show regions from HE revealed up to seven times ammonia in the blood, medications to of abnormally high signal intensity (i.e., more manganese in the globus pallidus counteract ammonia’s neurotoxic effects, signal hyperintensities) in both the right compared with normal levels (Butterworth devices to improve liver function, and and left halves of the brain and concen­ et al. 1995). Manganese is known to liver transplantation. trated in an area that is involved in the be neurotoxic, particularly affecting the control of motor function (i.e., the globus actions of certain proteins (i.e., receptors) Ammonia-Lowering Strategies pallidus) (see figure 3) (Lockwood et al. that interact with the neurotransmitter 1997; Spahr et al. 2000). The elevation dopamine. Consistent with this finding, In patients with cirrhosis, HE is fre­ in intensity of these signals correlates researchers found altered dopamine quently triggered by conditions that with the presence of certain signs and receptors in the brains of alcoholic cirrhotic cause an increase in circulating ammo­ symptoms of impaired motor function patients who died in a hepatic coma nia, including gastrointestinal bleeding that are found, for example, in patients (Mousseau et al. 1993). In addition, or a diet that contains high amounts with Parkinson’s disease (e.g., rigidity, manganese induces Alzheimer type II of protein (which generates ammonia abnormally diminished motor activity, changes in astrocytes. Taken together, when broken down). Because levels of and tremors) and also are present in HE these observations suggest that deposits ammonia in the blood and brain are patients (Spahr et al. 2000). However, of manganese in the globus pallidus elevated in these patients, the most pop­ the intensity of the MRI images does not resulting from chronic liver failure ular strategies currently used to manage correlate with the patients’ performance probably cause the motor symptoms and treat HE involve reducing ammo­ on tests assessing global encephalopathy and structural changes of astrocytes that nia production or increasing ammonia and cognitive functioning. are characteristic of HE. metabolism (i.e., the conversion of Increasing evidence suggests that the Amounts of other metals whose chem­ ammonia into harmless molecules) intense MRI signals in the globus pal­ ical properties are similar to those of outside the brain. lidus of cirrhotic alcoholics are caused manganese are not substantially elevated Traditional ammonia-lowering strate­ by deposits of a paramagnetic substance, in the brains of patients with chronic liver gies include the use of certain sugar probably manganese, in that region failure, ruling out those metals as causes molecules that are not absorbed into the (Lockwood et al. 1997). Manganese of HE and its symptoms. body (e.g., lactulose) or certain antibi­ normally is eliminated by the joint actions otics (e.g., neomycin), both of which of the liver, gallbladder, and bile ducts Management of Patients reduce the production of ammonia in (i.e., the hepatobiliary system). In patients With HE the gastrointestinal tract. To increase with chronic liver failure, manganese ammonia metabolism, one can adminis­ concentrations in the blood increase, Researchers and clinicians are exploring ter an agent called L-ornithine L-aspartate and the metal can enter the brain and a variety of approaches for preventing to patients, which enhances the natural process by which ammonia is incorpo­ rated into the amino acid glutamine in the skeletal muscle; this agent also opti­ C P mizes the residual urea synthesis in the patient’s cirrhotic liver. An earlier approach to lowering ammonia levels—that is, seriously limiting the protein intake of patients with alcoholic cirrhosis—is no longer recommended because it can lead to a reduction in the patient’s muscle mass. Maintaining muscle mass is important because, as mentioned above, a chemi­ cal reaction that removes free ammonia from the blood by incorporating it into Figure 3 Magnetic resonance imaging (MRI) of a healthy control subject (C) and glutamine can occur in the skeletal muscle. an alcoholic cirrhotic patient of the same age (P). In the alcoholic patient, abnormally intense signals (arrow) are detected on both sides of the brain in a region called the globus pallidus. This phenomenon has been Neuropharmacological Approaches attributed to deposits of manganese in this brain area. Other possible strategies for managing

SOURCE: Lockwood et al. 1997. HE involve using neuroactive drugs to counteract ammonia’s harmful effects

Vol. 27, No. 3, 2003 245 on neurotransmitter systems in the brain. concentrations as well as in significant References This treatment approach still is in its improvements in cognitive function in ARRIA, A.M.; TARTER, R.E.; STARZL, T.E.; AND VAN infancy, however, because researchers these patients (Arria et al. 1991), clearly THIEL, D.H. Improvement in cognitive functioning have not yet identified the precise nature confirming that HE is a major contrib­ of alcoholics following orthotopic liver transplanta­ of the neurotransmitter systems that tion. Alcoholism: Clinical and Experimental Research utor to the cognitive dysfunction found 15:956–962, 1991. either play a role in the development in alcoholic patients with significant of HE or are affected by the condition. BUTTERWORTH, R.F. Pathophysiology of hepatic liver disease. Liver transplantation also Some studies have reported occasional encephalopathy: A new look at ammonia. Metabolic beneficial effects when the dopamine eliminates the MRI signal hyperintensi­ Brain Disease 17:221–227, 2002. neurotransmitter system was stimulated ties that result from manganese deposits BUTTERWORTH, R.F.; SPAHR, L; FONTAINE, S.; by agents such as L-dopa or bromocrip­ found in the brains of patients with AND POMIER LAYRARGUES, G. Manganese toxicity, HE. However, the MRI signal hyperin­ dopaminergic dysfunction and hepatic encephalopa­ tine, but these approaches have not thy. Metabolic Brain Disease 10(4):259–267, 1995. gained wide acceptance. Likewise, a tensities may take several months to compound called flumazenil that inhibits resolve (Pujol et al. 1993), suggesting KRIL, J.J., AND BUTTERWORTH, R.F. Diencephalic and cerebellar pathology in alcoholic and nonalco­ the actions of sedative agents (i.e., is a that manganese is removed slowly from holic patients with end-stage liver disease. Hepatology benzodiazepine antagonist) initially the brains of these patients. 26:837–841, 1997. was reported to be beneficial, having LOCKWOOD, A.H.; YAP, E.W.H.; AND WONG, an awakening effect on stuporous and W.H. Cerebral ammonia metabolism in patients comatose alcoholic cirrhotic patients Summary with severe liver disease and minimal hepatic (Pomier Layrargues et al. 1994). However, encephalopathy. Journal of Cerebral Blood Flow and Metabolism 11:337–341, 1991. researchers now think that the benefi­ HE is a major neuropsychiatric com­ LOCKWOOD, A.H.; WEISSENBORN, K.; AND cial action of flumazenil resulted from plication of alcoholic liver disease and its activity as an antidote to the benzo­ BUTTERWORTH, R.F. An image of the brain in an important contributor to the cogni­ patients with liver disease. Current Opinion in diazepine medications frequently pre­ Neurology 10:525–533, 1997. scribed to alcoholic cirrhotic patients as tive dysfunction found in chronic alco­ holic patients. HE is caused in part by LOCKWOOD, A.H.; WEISSENBORN, K.; BOKEMEYER, part of an endoscopic evaluation or as a M.; ET AL. Correlations between cerebral glucose sedative. Thus, flumazenil may correct the accumulation in the brain of neuro­ metabolism and neuropsychological test perfor­ benzodiazepine-induced coma in these toxic substances such as ammonia and mance in non-alcoholic cirrhotics. Metabolic Brain patients rather than treat HE per se. manganese, which normally are Disease 17:29–40, 2002. removed by the hepatobiliary system. MITZNER, S.R., AND WILLIAMS, R. Albumin dialy­ sis MARS 2003. Liver International 23 (Suppl. 3): Liver-Assist Devices Increased brain concentrations of ammonia alter the expression of genes 1–72, 2003. A great deal of attention currently is that encode important brain proteins MOUSSEAU, D.D.; PERNEY, P.; POMIER LAYRARGUES, G.; focused on the production of “artificial responsible for regulating neurotransmit­ AND BUTTERWORTH, R.F. Selective loss of pallidal dopamine D2 receptor density in hepatic encephalopathy. livers,” or liver-assist devices. In general, ters; higher levels of ammonia also alter Neuroscience Letters 162:192–196, 1993. these devices are composed of small the structure of brain cells called astro­ columns filled with functional hepato­ POMIER LAYRARGUES, G.; GIGUERE, J.F.; LAVOIE, J.; ET AL. Clinical efficacy of benzodiazepine antagonist cytes, a protein called albumin, or char­ cytes. Manganese deposited in basal gan­ glia structures (particularly the globus RO 15-1788 (flumazenil) in cirrhotic patients with coal, or combinations thereof. The hepatic coma: Results of a randomized double-blind patient’s plasma is circulated through pallidus) in patients with alcoholic cir­ placebo-controlled cross-over trial. Hepatology 19: the columns to remove toxins in a rhosis leads to impaired motor function 32–37, 1994. manner similar to dialysis treatment of and the appearance of distinct, abnor­ PUJOL, A.; PUJOL, J.; GRAUS, F.; ET AL. Hyperintense patients with kidney failure. Initial stud­ mally intense signals, which can be globus pallidus on T1-weighted MRI in cirrhotic patients is associated with severity of liver failure. ies using an albumin system yielded detected by MRI. Prevention and treat­ Neurology 43:65–69, 1993. particularly promising results: Patients ment of HE in alcoholic cirrhotic treated with this approach showed less SPAHR, L.; VINGERHOETS, F.; LAZEYRAS, F.; ET AL. patients continue to rely on strategies Magnetic resonance imaging and proton spectroscopic ammonia circulating in the blood as aimed at lowering blood ammonia con­ alterations correlate with Parkinsonian signs in patients well as amelioration of their HE symp­ centrations. Current research is focused with cirrhosis. Gastroenterology 119: 774–781, 2000. toms (Mitzner and Williams 2003). on identifying neurological and bio­ SZERB, J.C., AND BUTTERWORTH, R.F. Effect of chemical mechanisms underlying HE ammonium ions on synaptic transmission in the mammalian central nervous system. Progress in Liver Transplantation as well as pharmacotherapies that can Neurobiology 29:135–153, 1992. address these mechanisms, and on creat­ Liver transplantation is the ultimate TARTER, R.E.; ARRIA, A.; AND VAN THIEL, D.H. treatment for alcoholic cirrhotic patients ing liver-assist devices aimed at removing Liver-brain interactions in alcoholism. In: Hunt, W.A., with end-stage chronic liver failure. In toxins from the blood. Liver transplanta­ and Nixon, S.J., eds. Alcohol-Induced Brain Damage. NIAAA Research Monograph No. 22. Rockville, general, implantation of a new liver tion is used in chronic alcoholic patients MD: National Institute on Alcohol Abuse and results in normalization of blood ammonia with end-stage liver failure. ■ Alcoholism, 1993. pp 415–429.

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