Liver-Brain Relations in Alcoholics
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Arria, et al, Liver-brain relations in alcoholics..,
Vol. 14, Alcohol Health & Research World, 01-01-1990, pp 112.
Alcoholics exhibit a number of neurocognitive deficits ranging from impaired memory capacity to limited abstract thinking, some of which result from the direct adverse effect of alcohol on the brain. It appears, however, that some cognitive deficits reflect the pres ence of an underlying liver disease. The neurocogni tive deficiencies that occur with liver disease reveal the link between liver dysfunction and impaired brain function.The central nervous system (CNS) can be adversely affected by a damaged liver. Evidence suggests that impaired liver function, resulting from alcohol abuse as well as other causes, can produce subtle but measurable cognitive deficits (Tarter et al. 1984a). It is well established that chronic alcohol consumption in animals has a direct toxic effect on the brain (Freund 1985). This effect, however, does not appear to explain the spectrum of cognitive deficits that commonly are observed in alcoholics.
The liver is the primary site of alcohol metabolism and can be severely affected by chronic alcohol use. Positioned beneath the diaphragm in the abdominal cavity, this organ acts as a detoxification center by removing toxic substances (i.e., byproducts of metabolism and drugs) from the blood. Although some alcoholics exhibit no evidence of liver damage or dysfunction, alcohol abuse can produce this wide spectrum of liver injury:
- Fatty liver–a benign and reversible condition that causes mild pathological damage, yet no clinical dysfunction.
- Alcoholic hepatitis–a more serious condition that causes increasing destruction of hepatic (liver) tissue and produces varying degrees of liver dysfunction.
- Alcoholic cirrhosis–an advanced form of hepatic degeneration, characterized by diffuse scarring of the liver. If an individual abstains from alcohol consumption, the liver can function normally, without apparent injury. Alcoholic cirrhosis is only one type of cirrhosis. Cirrhosis can develop in nonalcoholic individuals who have liver damage due to a nutritional deficiency or to viral or bacterial infections.
- Alcohol hepatitis plus cirrhosis–a serious condition that can produce severe injury (abnormal pathology) and severe dysfunction (impaired function).
When the liver becomes diseased, its ability to metabolize, digest, and detoxify can become impaired. Impaired liver function contributes to the disruption of proper functioning of other systems that depend, in part, upon normal liver activity, leading to kidney failure, changes in blood chemistry and blood clotting, gastrointestinal bleeding, and brain disorders.
Primary hepatic encephalopathy, a brain dysfunction associated with both alcoholic hepatitis and cirrhosis, is caused by a metabolic liver disorder. The condition is marked by both altered intellectual function and emotion, as well as disturbed psychomotor and behavioral regulation (for a more comprehensive review, see Jones and Gammal 1988). The specific biochemical mechanisms of hepatic encephalopathy are extremely complex. Moreover, our understanding of the link between liver dysfunction and brain function is far from complete.
Results of our studies, as well as findings reported by others, indicate that the neurocognitive deficits (e.g., motor speed, abstraction) observed in alcoholic and nonalcoholic patients with cirrhosis have a similar pattern and severity (Tarter et al. 1988). These findings suggest that cirrhosis, more than alcoholism, per se, may be one of the most important factors underlying neurocognitive deficits commonly observed in alcoholic populations. Some of these cognitive deficits, however, cannot be attributed to hepatic encephalopathy: Alcoholic individuals with cirrhosis do not perform as well as nonalcoholic individuals with cirrhosis on several cognitive tests (e.g., memory) (Arria et al. in submission a). A more comprehensive battery of assessment tests than those administered currently may reveal that, in addition to diminished memory capacity, other higher order brain functions (e.g., abstract thought, learning) also may be impaired.
In alcoholic individuals, there is a correlation between certain biochemical measures of liver injury and function and performance on cognitive tests (Tarter et al. 1986). In addition, a recent study in our laboratory demonstrated that, with the exception of memory capacity, most alcoholics return to normal cognitive and psychomotor functioning following liver transplantation (Arria et al. in submission b). These provocative findings illustrate that hepatic encephalopathy may be a major determinant of the neuropsychological disturbances found in alcoholics.
PORTAL SYSTEMIC ENCEPHALOPATHY
Portal systemic encephalopathy (PSE), the most common form of hepatic encephalopathy, is a cerebral complication of cirrhosis that causes disruption of consciousness, emotional regulation, and mental efficiency and, in its advanced stages, hepatic coma (Zieve 1979). Clinicians observe major biochemical aberrations, which arise from impaired liver function, in tandem with PSE (e.g., elevated levels of ammonia and glutamine, diminished glucose and oxygen consumption). It is important to note that although PSE is associated with these biochemical changes, no single biochemical factor appears to be responsible for the many symptoms related to PSE in humans. In addition, the biochemical disturbances detailed below may not be present in all individuals; their expression depends on the intrahepatic and extrahepatic factors within each person. Researchers believe, however, that PSE is a consequence of the inability of the liver to perform its normal metabolic detoxification function.
In a healthy individual, the liver serves as a detoxification center that breaks down toxins, particularly such nitrogen-containing substances as ammonia, so that they may be excreted into either bile or urine. Ammonia is a toxin that is a normal byproduct of protein digestion; it is carried to the liver, via the portal vein, where the liver selectively can remove the toxin from the circulating blood. In a cirrhotic liver, however, blood flow often is shunted around rather than through the organ. In addition, an intrinsic reduction in liver cell function occurs with cirrhosis. Thus, toxins that can impede proper brain function remain in the plasma.
Individuals with PSE often are found to have increased levels of ammonia and the amino acid glutamine in the blood, brain, spinal fluid, and muscles as a consequence of the impaired liver function. Glutamine is the major transport protein for ammonia. Normally, ammonia is transported via the blood from peripheral tissues to the liver where it is changed to urea. Because ammonia is neurotoxic, it must be converted by the body into a nontoxic compound to be transported through the blood. In many tissues, ammonia is combined enzymatically with glutamate to yield glutamine. Ammonia toxicity may be a significant determinant in the development of PSE. Glutamine transports ammonia from peripheral tissues to the liver, acting as a neutral nontoxic compound that can pass readily through cell membranes.
Decreased brain glucose and oxygen consumption are associated with PSE. Oxygen is vital for sustaining normal brain functions. Glucose, stored in the liver as glycogen, supplies the primary source of energy for work performed by cells. The liver is involved in regulating and maintaining blood glucose concentrations; as energy requirements increase in the body, glycogen is broken down and released as glucose. This process is disrupted in the cirrhotic liver: Decreased glucose metabolism results in a decreased availability of glucose to the brain. Thus, decreased glucose and oxygen consumption by the brain can result in diminished systemic energy. Although clinicians often do not understand fully the correlation between these biochemical abnormalities and PSE, these observed changes may be responsible for the fatigue that often is reported by patients with PSE.
Increased short-chain fatty acid levels have been observed in the blood and may appear in the brain of patients with PSE. These fatty acids result from the incomplete metabolism of fatty substances in the intestine and interfere with the conversion of ammonia to urea in the liver. Researchers have found that short-chain fatty acids potentiate the neurotoxicity of ammonia in animals (Zieve 1979). In addition, they appear to act as an anesthetic in the brain.
Individuals with PSE have altered plasma amino acid ratios resulting from increases in aromatic amino acids and decreases in branched-chain amino acid levels. These amino acids, which differ in structure, are important for brain metabolism. Alcohol and its metabolites may directly affect amino acid metabolism; alcohol-induced liver injury and nutritional imbalances contribute to abnormal plasma amino acid composition. Increased levels of aromatic amino acids and decreased levels of branched-chain amino acids favor the production of “false” neurotransmitters (i.e., octopamine) and are associated with diminished levels of “true” neurotransmitters (i.e., GABA, dopamine) in the brain and the blood of PSE individuals. (A neurotransmitter is a chemical messenger released by a brain cell to excite or inhibit adjacent brain cells.) “False” neurotransmitters displace “true” neurotransmitters at brain receptors, possibly accounting for ineffective neurotransmission.
Increased mercaptan levels have been noted in patients with PSE. Mercaptans are a class of substances that result from the metabolism of the amino acid methionine. Although the link between elevated mercaptan levels and PSE development is unclear, researchers have determined that mercaptans are highly neurotoxic and can induce hepatic coma: Mercaptan levels increase in the brain because the injured liver cannot detoxify these substances. In addition, their toxicity is enhanced in the presence of elevated ammonia levels that occur with cirrhosis.
It also is thought that increased GABA (gamma-aminobutyric acid), the major inhibitory neurotransmitter in the brain, also may play a key role in the expression of hepatic encephalopathy. Jones and Skolnick (1990) have reviewed extensively the neurochemical aberrations that may be involved in the development of hepatic encephalopathy.
CLINICAL MANIFESTATIONS OF PSE
Traditionally, PSE has been graded into four distinct stages based upon clinical characteristics, as summarized in table 1. A grade of zero is given if no overt abnormality is present. Despite the apparent absence of clinical signs or symptoms of encephalopathy, however, subtle cerebral dysfunction that can be detected by neuropsychological tests often is present in individuals (Rikkers et al. 1978). The label of “subclinical” or “latent” hepatic encephalopathy can be assigned to these individuals based on the presence of neurocognitive impairments (e.g., decreased memory capacity, impaired psychomotor function) measured by neuropsychological tests. This group probably comprises the largest percentage of patients with hepatic encephalopathy.
The severity of encephalopathy can progress rapidly through the various stages summarized in table 1. This progression can occur as the result of medical deterioration, gastrointestinal bleeding, dietary overload of animal protein, a confounding infection, or changes in electrolyte balance. (Electrolytes are elements such as sodium or potassium that convey an electrical impulse when in solution.) In addition to its acute manifestations, the encephalopathy can exist in a chronic and a low-grade form. Typically, individuals do not progress to stage 2 (moderate) severity without health care professionals noting the existence of a problem. However, it can be difficult to determine the stage of an individual’s disease. Repeated episodes of acute encephalopathy can superimpose on a chronic low-grade liver disorder. Hence, it is not uncommon for an alcoholic with low-grade encephalopathy to lapse suddenly into an acute hepatic encephalopathy or coma as a result of a change in medical status or external stress (e.g., hypothermia).
Much of our knowledge about the natural history and clinical presentation of hepatic encephalopathy is based upon studies of alcoholics because these individuals comprise the largest population of persons with liver disease. Only recently have researchers attempted to elucidate the type and severity of cerebral dysfunction in alcoholic as well as in nonalcoholic individuals with liver disease. These efforts have been conducted to determine the specific contributions of alcoholism and liver disease to cerebral disturbances that frequently are reported in alcoholics with cirrhosis. Prior investigations of hepatic encephalopathy conducted by hepatologists have focused almost exclusively on alcoholics whose drinking history has confounded the results about the source of the encephalopathy. Conversely, studies of alcoholics conducted by neuroscientists have almost ignored the potential impact of advanced chronic liver disease on CNS integrity. Thus, neuroscientists and medical researchers need to integrate their expertise and knowledge to evaluate the specific contributions of liver disease and alcohol abuse, per se, on brain disturbances observed in alcoholics with cirrhosis.
COGNITIVE DEFICITS ASSOCIATED WITH ALCOHOLISM
The majority of alcoholics in treatment exhibit a variety of cognitive impairments (Parsons et al. 1987). Neuropsychological tests reveal deficits in visuospatial capacity, learning and memory, psychomotor efficiency, and abstracting ability. These processes are critical for everyday functioning.
For example, impaired visuospatial capacity prevents a person from organizing and analyzing elements of his or her visual field, thereby limiting the execution of the appropriate motor responses. In effect, this impairment can affect an individual’s ability to drive a car or operate machinery. A deficiency in the capacity to learn and store information for subsequent recall is disruptive in all aspects of everyday life. Impaired psychomotor efficiency requiring eye-hand coordination and control of fine motor movements can increase chances of accidental injury. Reduced abstracting ability, such as the capacity to form concepts, solve problems, and think flexibly, could compromise psychosocial adjustment severely.
As society becomes technologically more complex, more subtle neurologic disturbances may impede everyday adjustment. With this in mind, it is important to note that almost 75 percent of alcoholic individuals commonly express some form of cognitive impairment, although the prevalence varies from sample to sample of alcoholic individuals (Goldstein and Shelly 1980).
The neurologic deficits found in alcoholics can result from such factors as head trauma or malnutrition. Neuropsychological deficits normally are not evident among alcoholic individuals who are medically intact and have no history of head trauma (Grant et al. 1984). These findings suggest that disease status concomitant to the alcoholism influences the manifestation of cerebral disturbance. Such disease status often is the result of nutritional deficiency and liver disease.
Nutritional Deficiency
Nutritional deficiency–resulting from dietary insufficiency (as an individual substitutes the calories from alcohol for calories from regular meals) or from concomitant liver disease–can compound the effects of alcohol on the brain. Vitamin B deficiencies are common in alcoholic patients. Chronic vitamin B-1 deficiency, for example, can precipitate a Wernicke’s encephalopathy, which typically progresses to the chronic, irreversible Korsakoff’s (amnestic) syndrome, characterized by an inability to remember recent events or to learn new information (see the article by Berman, pp. 120-129). Other vitamin B deficiencies also are common in alcoholics and are associated with neurologic disturbance (e.g., peripheral neuropathies and ocular motor palsies) (Roe 1979).Although deficiencies of the fat-soluble vitamins A and E occur in alcoholics (Leo and Lieber 1982; Bjorneboe et al. 1988), the clinical significance of these vitamin deficiencies has not received much research attention. Vitamin A deficiency is a primary cause of nightblindness, yet there are few data on the prevalence of nightblindness in alcoholics (McClain et al. 1979). Vitamin E deficiency is associated with a neurologic syndrome characterized by lack of muscle coordination known as gait ataxia, neuromuscular weakness, and motor incoordination in individuals with cholestatic liver disease (characterized by diminished bile flow) (Sokol et al. 1983). A recent study has reported an association between vitamin E deficiency and neuropsychological deficits in patients with nonalcoholic cirrhosis (Arria et al. in press). These data suggest that the role of vitamin E deficiency in neuropsychological deficits among alcoholics with and without cirrhosis should be determined.
Liver-Brain Interactions
Chronic liver disease is, perhaps, the most common medical consequence of alcoholism and, in its advanced stage, cirrhosis ranks among the top 10 causes of death. Seventy percent of all liver disease may be associated with alcoholism. Because liver disease often is an irreversible condition that is prevalent in nonabstinent alcoholics, it is important to determine the effects of liver disease on brain integrity. Liver disease is the second major pathological factor that influences neurological status in alcoholics.Several forms of nonalcoholic liver disease can influence neurological status. For example, hepatitis B infection can result in chronic liver injury; 10 percent of the individuals infected with this virus will develop cirrhosis. Similarly, primary biliary cirrhosis (PBC), a possible form of autoimmune liver disease (a condition in which the immune system attacks the body’s tissues) that typically affects postmenopausal women, can be progressive and, at times, fatal. Researchers have compared the neuropsychological test performance of nonalcoholic and alcoholic patients with cirrhosis to determine which deficits are related to the cirrhosis, per se, and which may result solely from alcohol abuse. The studies mentioned below employ these research strategies.
Alcoholics and nonalcoholics with biopsyconfirmed cirrhosis perform similarly on neuropsychological tests (Rehnstrom et al. 1977; Tarter et al. 1988). Specifically, tests reveal that impairments in visuospatial and psychomotor capacity are pronounced in both alcoholic and nonalcoholic individuals with cirrhosis. These two groups also display deficits in nonverbal intelligence, abstracting capacity, learning, and memory (Tarter et al. 1984b). Using a battery of approximately two dozen neuropsychological tests, Tarter and colleagues (1988) recently found that alcoholics and nonalcoholics with biopsy-proven cirrhosis performed comparably. It should be noted, however, that some of the neurocognitive deficiencies (e.g., memory deficits) in alcoholics were not observed in nonalcoholics. These findings suggest that alcoholism has an additional impact on such cognitive processes as memory. Nonetheless, most neuropsychological tests do not discriminate cirrhotic alcoholic individuals from cirrhotic nonalcoholic individuals, suggesting that advanced liver disease and its various sequelae contribute substantially to the neurocognitive disturbances found in chronic alcoholics.
Rikkers and colleagues (1978) administered a battery of neuropsychological tests to a group of nonalcoholic patients with subclinical hepatic encephalopathy. The tests revealed impaired visuospatial ability in the subjects, but did not detect impaired learning and memory capacity. These results suggest that latent hepatic encephalopathy may not produce global intellectual impairments.
In an effort to investigate the mediating role of hepatic disease on memory impairments in alcoholic individuals, we studied the following four groups of subjects: (1) normal healthy controls; (2) alcohol abusers without liver disease; (3) nonalcoholic cirrhotics; and (4) alcoholics with cirrhosis (Arria et al. in submission a). Although differences were observed between normal, healthy controls and each of the disease groups, the performances of the cirrhotic groups were similar. However, alcoholics with cirrhosis performed significantly worse than did the other three groups on a challenging test of short-term memory. In this study, alcoholics without cirrhosis had impaired memory capacity when compared with normal controls. These findings support the hypothesis that alcohol neurotoxicity and liver disease conjointly contribute to the memory deficits observed in alcoholics.
A recent study (Arria et al. in submission b) showed that liver transplantation in alcoholics resulted in a substantial recovery from neurocognitive deficits. This finding lends support to the hypothesis that the cognitive deficits exhibited by abstinent alcoholics may have a metabolic basis linked to a low-grade chronic hepatic encephalopathy. The implantation of a functionally normal liver reversed psychomotor, visuospatial, and perceptual speed deficits; however, memory capacity did not improve. Investigations of nonalcoholics with various types of liver disease before and after their liver transplantation also revealed almost complete neurocognitive recovery (Tarter et al. 1984a; Tarter et al. in press).
Several groups of investigators have documented an association between certain biochemical measures of liver injury and cognitive processes. Gilberstadt and colleagues (1980) observed that the Wechsler Adult Intelligence Scale (WAIS) Performance IQ and tests of psychomotor speed and visuospatial capacity correlated with serum albumin level in alcoholics with cirrhosis. (Serum albumin level is an index of the liver’s capacity of protein synthesis and reflects the extent of disease.) The correlations between the biochemical and cognitive variables ranged between-0.47 and -0.64 for the Trailmaking (which measures attentional and psychomotor speed), Digit Symbol, and Block Design tests (which measure visuospatial capacities) and Performance IQ scores (which measure abstraction and conceptual abilities). The biochemical variables accounted for 22 to 41 percent of the observed variance on the cognitive test performance. The correlation between fasting blood ammonia level (an indicator of the severity of encephalopathy) and cognitive variables was less significant with the WAIS Block Design Test (r = 0.34) and Performance IQ score (r = 0.35).
Other investigators have confirmed the associations between neuropsychological test performance and functional parameters of the liver. Using the Cattell Culture Fair Test (an IQ test), Schomerus and colleagues (1981) found that nonverbal IQ correlated significantly with serum albumin level and inversely with the gamma globulin level, which indicates the severity of the disease. Performance on the Benton Visual Retention Test also correlated significantly with the serum bilirubin and prothrombin time. (These biochemical measures reflect the status of the liver’s excretory and synthetic capacities, respectively). Furthermore, prothrombin time correlated with the WAIS Block Design score, the Trailmaking Test, and Motor Steadiness scores (which measures hand tremors). Hepatic injury variables account for 23 to 56 percent of the cognitive test score variance (Tarter et al 1984b). No systematic association was, however, observed between specific cognitive variables and specific hepatic disease variables; these findings underscore the complexity of the relationship between liver function and brain function.
Moss and colleagues (in submission) recently found that aspects of liver disease may be associated differentially with certain specific types of cognitive impairments in a heterogeneous sample of liver disease patients (e.g., alcoholic and nonalcoholic individuals). Additionally, Irwin and associates (1989) showed that gamma glutamyl transferase (GGT), a measure of the production of liver enzymes, correlated with performance on neuropsychological tests that measure attention, visuospatial sequencing, and visual search. Although the correlations were significant, they accounted for less than 10 percent of the overall variance. Nonetheless, the association between hepatic injury parameters and cognitive performance in alcoholics underscores the important role of liver dysfunction in the cognitive deficits observed in alcoholism.
Although the results that demonstrate an association between biochemical variables and neurocognitive status are intriguing, they should be considered with caution. First, it should be emphasized that no single laboratory index of liver injury or dysfunction is associated consistently with cognitive impairment. Second, no evidence implicates a specific neurotoxin, particularly ammonia or other nitrogenous compounds, as the sole or even major cause of alcoholic encephalopathy. Third, the magnitude of test score variance explained by the correlations indicates that the neurocognitive deficits undoubtedly have a complex multifactorial etiology; although specific laboratory measures of hepatic disturbance may correlate with individual test performance, they may reveal little more than the general severity of liver disease. Other elements, including both factors within and outside the liver, must be considered for a more comprehensive understanding of liver-brain relations. Given these limitations, however, the emerging evidence suggests that liver disease is a major contributing factor to the underlying neurocognitive deficits exhibited by cirrhotic alcoholics.
In summary, it appears that many of the cognitive deficits found in alcoholics reflect an underlying coexistent hepatic encephalopathy. This conclusion is advanced based upon studies comparing cirrhotic alcoholics and nonalcoholics, groups of alcoholics with varying degrees of liver injury, alcoholics before and after liver transplantation, and the association between biochemical measures of liver function and injury to neurocognitive test performance. While the neurocognitive deficits found in alcoholics are not presumed to be entirely caused by underlying liver disease, the importance of cirrhosis as a critical factor increasingly is becoming recognized. The importance of this observation should not be underestimated.
Specifically, the emerging findings suggest that the effective treatment of alcoholic liver disease should improve cognitive functioning. The ramifications for psychosocial rehabilitation of alcoholics are obvious inasmuch as neurocognitive capacity, as mentioned earlier, has a major influence on everyday functioning.
FUTURE RESEARCH
One important goal of future research is to determine the type and severity of the cognitive deficits that are associated with milder forms of liver disease. It is reasonable to speculate that individuals in the early stages of alcoholic liver disease (i.e., fatty liver, alcoholic hepatitis) may well have less severe but nonetheless detectable cognitive impairments as a result of the combined effects of alcohol abuse and liver dysfunction. However, virtually no systematic research has been conducted on this population.
In addition, the multifactorial basis of the encephalopathy in alcoholics needs to be explored further. For instance, we have found recently that a vitamin E deficiency is quite prevalent in alcoholic cirrhotics (Arria et al. in submission c) and is associated with neuropsychological test performance deficits. Hence, hepatic and nutritional variables should be investigated conjointly. Furthermore, it is noteworthy that a vitamin E deficiency also is commonly associated with a vitamin A deficiency; this latter disorder may underlie the presence of nightblindness. Importantly, and as yet not investigated, it may be that nightblindness (as a result of vitamin A deficiency), coupled with deficits in reaction time and attentional capacity, may place an alcoholic individual at greater risk for motor vehicle crashes even while sober, compared to nonalcoholics. The major conclusion from the research conducted to date is that the presence of liver disease not only has significant biomedical consequences and health service delivery implications, but also may have important ramifications for psychosocial adjustment and rehabilitation.
table 1 Progression of Neuropsychiatric Disturbance Associated with Acute Episode of Portal-Systemic Encephalopathy Part I Clinical Features O (Normal) 1 (Mild) Consciousness No detectable No clear impairment change Activation Normal Inversion of sleep pattern and/or insomnia/hypersomnia Behavior Normal Personal ty change: fatigue Affect Normal Irritability; euphoria or depression Cognition Normal Attention deficit. concentration difficulties Neurological Normal Tremor; Response incoordination Part II Severity Grade of Encephalopathy Clinical Features 2 (Moderate) 3 (Severe) 4 (Coma) Consciousness Mild disorientation Confusion/ stupor Activation Inversion of sleep Somnolence pattern and/or insomia/hypersomia Behavior Lethargy: disinhi- Bizarreness, bition, in dispersonalization, appropriateness paronoia Affect Anxiety, anger Range Cognition Impaired time Amnesia sense Neurological Ataxia; asterixis; Dilation of Response slurred speech, pupils; hyperactive hyperactive reflexes reflexes; rigidity; nystagmusREFERENCES
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By AMELIA M. ARRIA, RALPH E. TARTER, PH.D., AND DAVID H. VAN THIEL, M.D. AMELIA M. ARRIA is an NIAAA Predoctoral Fellow in alcohol epidemiology, Graduate School of Public Health, University of Pittsburgh, and is a research associate, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania RALPH E. TARTER, PH.D., is professor of psychiatry and neurology, University of Pittsburgh School of Medicine, and director of the Center for Education and Drug Abuse Research (CEDAR), Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania DAVID H. VAN THIEL, M.D., is professor of medicine, surgery, and psychiatry, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Dr. Van Thiel serves currently as the president of the Research Society on Alcoholism.Alcohol Health & Research World is published by National Inst on Alcohol Abuse and Alcoholism and is not copyrighted.
