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Home , Alcoholic liver disease, Complication (medicine), Hepatic encephalopathy

Hepatic — A Serious Complication of Alcoholic

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

lcohol’s harmful effects on liver cells not only depends on fluctuations in the ’s medical status interfere not only with the normal functioning or diet. Diagnosis also is hindered because HE can be A of the liver but also impact distant organs, triggered or exacerbated by a known including the brain. Prolonged liver dysfunction result­ as the transjugular intrahepatic stent shunt (TIPS), ing from excessive consumption can lead to the which commonly is used to treat alcoholic who development of a serious and potentially fatal brain dis­ experience elevated in the portal order known as (HE). Patients that transports blood to the liver. By redirecting blood with HE suffer from sleep disturbances, changes of flow around the liver, the TIPS procedure is intended mood and personality, severe cognitive effects (e.g., a to alleviate this condition and prevent complications shortened attention span), psychiatric conditions such such as gastrointestinal bleeding and accumulation of as anxiety and depression, as well as motor distur­ fluid in the abdomen (i.e., ). bances, including motor incoordination and a type of flapping of the hands called . In the most Relationships Between the Liver and the Brain serious cases, the patients no longer respond to external stimuli and may fall into a (i.e., hepatic coma), Normal brain functioning depends on several aspects which can be fatal. of normal liver functioning. For example, the liver sup­ Analyses of brain tissue of HE patients found char­ plies certain nutrients to the brain that the brain itself acteristic changes in the structure of supporting cells cannot produce. The liver also cleanses the blood of known as rather than obvious destruction of substances that could damage brain cells (i.e., ). nerve cells (i.e., neurons). Astrocytes are large star-shaped Although the brain is protected from many neurotoxic cells, distributed throughout the brain, that help main­ substances by the blood–brain barrier—a property of tain the proper composition of the fluid surrounding blood vessels in the brain that prevents passage of many the neurons. For example, astrocytes take up brain compounds from the blood into the brain tissue— chemicals (i.e., ) that are released by certain neurotoxins can penetrate that barrier. These neurons, and minerals such as , which are substances—which include , , and generated and secreted during the brain’s energy metab­ other chemicals—can enter the brain at least to some olism. In addition, astrocytes eliminate some substances extent unless they are effectively removed from the that are toxic to neurons (i.e., neurotoxic). The proper blood by the liver. functioning of the astrocytes and their interactions with In patients with or (whether caused the neurons are essential to brain function. Patients by excessive alcohol consumption or factors such as with HE frequently have pairs and triplets of abnormal viruses or ), the liver loses its capacity to remove astrocytes with a characteristic structure known as toxic substances from the blood because the number Alzheimer type II astrocytosis, in which the astrocytes’ of functional liver cells (i.e., ) has decreased. nuclei are enlarged and glassy-looking. This glassy Moreover, in these patients some of the blood that nor­ appearance is caused by the fact that the DNA and its mally flows through the portal vein into the liver for associated are confined to the edges of the nuclei, cleansing is diverted directly into the general circulation rather than distributed throughout them. Alzheimer without first passing through the liver, a phenomenon type II astrocytes also exhibit other physiological and known as portal-systemic shunting. As a result, the shunted functional abnormalities. blood is not detoxified and blood levels of toxic sub­ Diagnosing HE in alcoholic patients is difficult because stances rise. Persistently elevated levels dam­ no single clinical or laboratory test can conclusively age brain cells and the patients begin to develop HE. establish the diagnosis. Patients frequently are misdiag­ nosed, particularly in the early stages of HE, when symptoms such as euphoria, anxiety, depression, and ROGER F. B UTTERWORTH , PH.D., D.SC., is scientific sleep disorders occur that are common to a number of director of the Neuroscience Research Unit at CHUM psychiatric conditions. In addition, whether—and to (Hôpital Saint-Luc), and professor of at the what extent—a patient shows each of these symptoms University of Montreal, Montreal, Canada.

Vol. 27, No. 2, 2003 143 In fact, studies involving neuropsychological tests have virtually defenseless against increased ammonia concen­ found that although alcohol’s direct effects on the brain trations and therefore are likely to suffer ammonia-related also cause cognitive deficits and brain damage in alco­ damage. For example, ammonia has deleterious effects holics, HE is a major contributing factor to cognitive on nerve signal transmission that is mediated by numerous dysfunction in alcoholics with severe . In systems (Szerb and Butterworth 1992) these studies, alcoholic patients with cirrhosis had sig­ and impairs the brain’s energy . In addition, nificantly lower scores on learning and memory tests ammonia can alter the expression 1 of various genes that than did alcoholics without cirrhosis, indicating that encode key brain proteins involved in the brain cells’ liver dysfunction is associated with more extensive energy production, structure, and cell-to-cell interac­ brain dysfunction in these patients (Tarter et al. 1993). tions. These alterations in gene expression may account for some of the changes in neurotransmitter activity Mechanisms Leading to HE and structure observed in HE patients. Researchers have gained a better understanding of the The Role of Manganese. Researchers also have used mechanisms leading to HE in patients with alcoholic magnetic resonance imaging (MRI) to analyze changes liver disease by using and spectroscopic in the brains of alcoholics. This technique generates techniques that permit them to study the metabolism images based on differences between tissues in water and functions of specific brain regions in living patients. content as well as in the content of other molecules that These studies have confirmed the contributions of at respond to a magnetic field. MRI analyses have found least two neurotoxic substances, ammonia and man­ that more than 80 percent of alcoholics with cirrhosis ganese, to the development of HE. show regions of abnormally high signal intensity (i.e., signal hyperintensities), primarily in a brain area called The Role of Ammonia. Some of these investigations the globus pallidus, which is involved in control of employed positron emission tomography (PET), a motor function (Lockwood et al. 1997; Spahr et al. technique used to examine the metabolic activity of 2000). The intensity of these signals correlates with the various body regions, including the brain, by monitoring presence of certain of impaired the transport and breakdown of radioactively labeled motor function but not with the patients’ performance molecules using sophisticated detection devices. Some on tests assessing global encephalopathy and cognitive PET studies of alcoholic patients have assessed ammo­ functioning. nia uptake and metabolism in the brain. In cirrhotic Additional analyses have determined that hyperintense patients with mild HE, PET analyses using radioactive MRI signals in the globus pallidus are probably caused ammonia have revealed significant increases in the by manganese deposits in that region (Lockwood et al. amount of ammonia taken up and metabolized in the 1997). Indeed, studies using brain tissue from alcoholic brain (Lockwood et al. 1991). In particular, a variable cirrhotic patients who died from HE have revealed called the permeability–surface area product (PS), a manganese levels in the globus pallidus that were up measure of how much ammonia can enter the brain to seven times higher than manganese levels in subjects from the general circulation, increases as cirrhotic patients without cirrhosis (Butterworth et al. 1995). Manganese start to develop HE. When the PS increases, a greater normally is eliminated by the joint actions of the liver, proportion of the ammonia in the general circulation gallbladder, and bile ducts (i.e., the hepatobiliary system), can enter the brain. but patients with chronic have elevated The brain has only a limited capacity to remove any manganese concentrations in the blood. As a result, ammonia coming in because of the increased PS. The the metal can enter the brain and be deposited in the only way to eliminate any ammonia that has reached globus pallidus and associated brain structures, where the brain cells is through a reaction mediated by an enzyme it particularly affects the actions of certain proteins called synthetase, which is found in the astro­ (i.e., receptors) that interact with the neurotransmitter cytes. This enzyme combines a molecule of the amino dopamine. This effect is demonstrated by the fact that acid glutamate with a molecule of ammonia to form the dopamine receptors are altered in the brains of alcoholic amino acid glutamine. In patients with HE, the amounts cirrhotic patients who died in a hepatic coma (Mousseau et of glutamine formed in the brain are correlated with the al. 1993). In addition, manganese induces Alzheimer type severity of the disease, indicating that the brain is exposed II changes that interfere with the functioning of astro­ to increasing levels of ammonia as the disease progresses cytes. Thus, manganese deposits in the globus pallidus (Lockwood et al. 1997; Butterworth 2002). Ammonia adversely affects both neurons and astro­ 1 The term “gene expression” refers to the entire process of converting the genetic cytes. Because the enzyme that eliminates ammonia information encoded in a gene into a product. in the brain is present only in astrocytes, neurons are

144 Alcohol Research & Hepatic Encephalopathy

may account for both the motor symptoms and the struc­ Summary tural changes in astrocytes that are characteristic of HE. HE is a serious complication of that contributes to cognitive dysfunction in chronic Treatment of Patients With HE alcoholic patients. In patients with HE, the damaged Researchers and clinicians are exploring various liver can no longer remove neurotoxic substances such approaches to preventing HE in patients with alcohol- as ammonia and manganese from the blood. As a induced chronic liver failure or to ameliorating its con­ result, these molecules may enter the brain, where they can exert a variety of harmful effects that interfere with sequences. These approaches include the following: normal neurotransmitter activity, impair motor func­ tions, and cause structural alterations in the astrocytes. • Strategies to lower ammonia levels. One approach— To prevent or treat HE in alcoholic patients with cir­ administering certain sugar molecules (e.g., lactu­ rhosis, physicians currently rely primarily on strategies lose) or (e.g., )—reduces the to lower blood ammonia concentrations as well as on production of ammonia in the gastrointestinal in patients with end-stage liver dis­ tract. Other strategies are intended to increase the ease; new approaches also are also being investigated. ■ conversion of ammonia into harmless molecules outside the brain—for example, by treating the patients with an agent called L-ornithine L-aspartate, References which helps to incorporate ammonia into the amino ARRIA, A.M.; TARTER, R.E.; STARZL, T.E.; AND VAN THIEL, D.H. acid glutamine in the skeletal muscle—and to bol­ Improvement in cognitive functioning of alcoholics following ster the residual ability of the patient’s cirrhotic orthotopic liver transplantation. : Clinical and Experimental liver to eliminate ammonia as . Research 15:956–962, 1991.

BUTTERWORTH, R.F. Pathophysiology of hepatic encephalopathy: A new • Neuropharmacological strategies. These approaches look at ammonia. Metabolic Brain Disease 17:221–227, 2002. involve using neuroactive drugs to counteract ammo- BUTTERWORTH, R.F.; SPAHR, L.; FONTAINE, S.; AND POMIER LAYRARGUES, G. nia’s harmful effects on neurotransmitter systems Manganese , dopaminergic dysfunction and hepatic encephalopa­ in the brain. This type of treatment is in its infancy, thy. Metabolic Brain Disease 10(4):259–267, 1995.

however, because researchers have not yet identified LOCKWOOD, A.H.; YAP, E.W.H.; AND WONG, W.H. Cerebral ammonia the precise nature of the neurotransmitter systems metabolism in patients with severe liver disease and minimal hepatic that contribute to the development of HE or are encephalopathy. Journal of Cerebral Blood Flow and Metabolism 11:337– affected by the condition. 341, 1991. LOCKWOOD, A.H.; WEISSENBORN, K.; AND BUTTERWORTH, R.F. An • Liver-assist devices. These machines, or “artificial ,” image of the brain in patients with liver disease. Current Opinion in are dialysis systems composed of columns that are Neurology 10:525–533, 1997. filled with hepatocytes, a protein called , MITZNER, S.R., AND WILLIAMS, R. Albumin dialysis MARS 2003. Liver charcoal, or combinations thereof. The patient’s International 23 (Suppl. 3):1–72, 2003. blood is circulated through these columns to remove MOUSSEAU, D.D.; PERNEY, P.; POMIER LAYRARGUES, G.; AND the toxins. In initial studies, patients treated with BUTTERWORTH, R.F. Selective loss of pallidal dopamine D2 receptor den­ an albumin-based system showed lower amounts of sity in hepatic encephalopathy. Neuroscience Letters 162:192–196, 1993. ammonia circulating in the blood as well as improve­ PUJOL, A.; PUJOL, J.; GRAUS, F.; ET AL . Hyperintense globus pallidus on ments in the severity of their encephalopathy T1-weighted MRI in cirrhotic patients is associated with severity of liver (Mitzner and Williams 2003). failure. Neurology 43:65–69, 1993. SPAHR, L.; VINGERHOETS, F.; LAZEYRAS, F.; ET AL . Magnetic resonance • Liver transplantation. This approach is widely used imaging and proton spectroscopic alterations correlate with parkinsonian signs in patients with cirrhosis. 119:774–781, 2000. in alcoholic cirrhotic patients with end-stage chronic liver failure. In general, implantation of a new liver SZERB, J.C., AND BUTTERWORTH, R.F. Effect of ammonium ions on results in significant improvements in cognitive func­ synaptic transmission in the mammalian central . Progress in Neurobiology 29:135–153, 1992. tion in these patients (Arria et al. 1991) and corrects the excessive ammonia levels as well as the MRI sig­ TARTER, R.E.; ARRIA, A.; AND VAN THIEL, D.H. Liver-brain interactions in alcoholism. In: Hunt, W.A., and Nixon, S.J., eds. Alcohol-Induced nal hyperintensities that result from manganese Brain Damage. NIAAA Research Monograph No. 22. Rockville, MD: deposits found in patients with HE (Pujol et al. 1993). National Institute on and Alcoholism, 1993. pp. 415–429.

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