Alcohol and Alcoholism Advance Access published online on September 11, 2007
Alcohol and Alcoholism, doi:10.1093/alcalc/agm065
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Brain Atrophy in Alcoholics: Relationship with Alcohol Intake; Liver Disease; Nutritional Status, and Inflammation
Servicios de Medicina Interna, Servicio de Laboratorio. Hospital Universitario, Universidad de La Laguna, Tenerife, Canary Islands Spain
* Author to whom correspondence should be addressed at: Servicio de Medicina Interna, Hospital Universitario.Ofra s/n, Tenerife, Canary Islands Spain. Tel: (34)922 678600; E-mail: egonrey{at}ull.es
Received 2 March 2007; first review notified 3 May 2007; in revised form 7 June 2007; accepted 16 July 2007
 |
ABSTRACT |
|---|
 TOP ABSTRACT IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Objectives: Brain atrophy is a common finding in alcoholics. Several mechanisms may be involved, including ethanol itself, malnutrition, liver failure, and, possibly, ethanol-induced hormone and cytokine changes. The aim of this study was to analyse the relation of brain atrophy—assessed by computerized tomography (CT) scan—and the aforementioned alterations. Methods: Serum insulin-like growth factor 1 (IGF-1), interleukin (IL)-6, IL-8, IL-10, TNF alpha, PTH, estradiol, free testosterone, and corticosterone were measured in 36 alcoholics, ten of them cirrhotics, who also underwent brain CT, which recorded the presence of cortical atrophy or cerebellar atrophy, Evan's, Huckmann's, cella media, bicaudate, cortical atrophy, bifrontal, and ventricular indices, and diameter of the third ventricle; subjective nutritional assessment, midarm anthropometry, and evaluation of liver function. Results: Patients showed marked alterations of all the CT indices compared with 12 controls, but poor relations between these indices and the other parameters analysed (IGF-1, handgrip strength and years of addiction with bifrontal index (P < 0.025 in all cases); PTH and Evan's index (r = 0.36, P = 0.032); mean corpuscular volume with cella index and cortical atrophy (P < 0.05). Cerebellar atrophy was associated with a greater daily ethanol consumption (t = 2.19, P = 0.034). Conclusion: Brain atrophy is frequently observed in alcoholics, but relationships with liver function, cytokines, nutritional status, and hormone levels are poor.
|
Introduction |
|---|
|
TOPABSTRACTIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Among the many brain alterations promoted by chronic ethanol consumption, brain shrinkage due to cortical atrophy is the most striking one. It is related to alcoholic dementia and to atrophy of the corpus callosum (Estruch et al., 1997
), and although clearly dependent on age (Pfefferbaum et al., 1992), brain shrinkage is more intense among heavy drinkers (Kubota et al., 2001). Its pathogenesis is obscure, and probably, multifactorial (Nicolas et al., 2000), but it is at least partially reversible with alcohol abstinence (Gazdzinski et al., 2005a). Although altered blood supply may play a role (Oishi et al., 1999), other studies have found a relation with total ethanol intake (Estruch et al., 1997; Ding et al., 2004), with concurrent cigarette smoking (Gazdzinski et al., 2005b), with sex (Mann et al., 2005), liver disease (Tarter and Alterman, 1984), or nutrition (Cala et al., 1983). On the basis of these facts, in the present study we investigate computerized tomography (CT) assessed brain alterations in alcoholics, its relation with nutritional status, liver function, and with several hormones and cytokines altered in alcoholics. |
Patients and Methods |
|---|
|
TOPABSTRACTIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Patients and controls
We included 36 alcoholic patients consecutively admitted to our hospitalization unit due to withdrawal syndrome. All of them were heavy drinkers of more than 150 g ethanol/day for prolonged (>5 years) time periods. Ten patients were cirrhotics and 26, non-cirrhotics. The diagnosis of liver cirrhosis was established on clinical grounds, including liver ultrasound, scintigraphy, and biopsy when necessary. The mean age of the cirrhotics was 51.6 ± 10.3 years, and that of the non-cirrhotics, 47.2 ± 11.3 years.
The control group was composed of 12 patients who underwent brain CT studies during evaluation of headache and had a normal CT scan, drinkers of less than 10 g ethanol day, aged 41.33 ± 18.99 years (Table 1). Age differences among the three groups were not statistically significant.
|
After informed consent, all the patients and controls (Table 1) underwent a CT scan. Besides routine evaluation by a neuroradiologist, who recorded the presence or not of cortical atrophy and cerebellar atrophy, the following parameters (Amodio et al., 2003
) were determined (Figs. 1–3):
|
|
|
Maximum width of the anterior horns of the lateral ventricles (HLV) in relation to the inner skull width at the same level (Bifrontal index).
Minimum width of the lateral ventricles (MLV) in relation to the inner skull at the same level (Bicaudate index).
Maximum diameter of the third ventricle.
Width of both cellae media in relation to the inner skull at the same level, which corresponds to the maximum inner skull diameter (MISD) (Cella media index).
Evan's index (= HLV/MISD).
Ventricular index (= MLV/HLV).
Huckman's index (= MLV + HLV).
Cortical atrophy (= sum of the width of the four widest sulci at the two highest scanning levels/MISD).
We recorded the presence or absence of ascites, encephalopathy, and body mass index (BMI). In addition, we determined handgrip strength with a dynamometer, triceps skinfold and brachial perimeter, with a lipocaliper and a tap, respectively, and also performed a subjective nutritional evaluation, as reported elsewhere (Santolaria et al., 2000). In addition, we performed a complete laboratory evaluation, including, among other parameters, serum bilirubin, prothrombin activity and serum albumin, and serum ASAT and ALAT, as well as platelet count and mean corpuscular volume (MCV). We also collected blood samples after overnight fasting. Samples were stored at –80° until hormones and cytokines were determined (Table 2). Cytokines and hormones levels of the patients were compared with those of a control group composed of 19 healthy sanitary workers, aged 43.7 ± 9.23 years.
|
We determined TNF-alpha by immunometric chemiluminiscent assay (intra-assay variation coefficient ranging 4–6.5%, interassay variation coefficient ranging 2.6–3.6%, recovery 92–112%, Diagnostic Products Corporation (DPC), Los Angeles, CA, USA); IL-6, by chemiluminiscent assay (interassay variation coefficient ranging 5.3–7.5%, recovery = 85–104%, DPC, Los Angeles, CA, USA); IL-8, by chemiluminiscent assay (interassay variation coefficient ranging 5.3–7.5%, DPC, Los Angeles, CA, USA); IL-10, by enzyme immunometric assay (sensitivity = 3 pg/ml, inter- and intra-assay coefficient of variation ranging from 3.9 to 7.3%; recovery ranging from 86 to 94%; DPC, Los Angeles, CA, USA); serum insulin-like growth factor- 1 (IGF-1) (Chemiluminiscent assay, DPC, Los Angeles, CA, USA); estradiol (competitive immunoassay, DPC, Los Angeles, CA, USA), serum free testosterone (RIA, DPC, Los Angeles, CA, USA), free thyroxine, cortisol, and routine laboratory evaluation.
The study protocol was approved by the local ethical committee of our hospital, and conforms to the ethical guidelines of the 1975 Declaration of Helsinki.
Statistics
The Kolmogorov–Smirnov test was used to test for normal distribution, a condition not fulfilled by TNF-alpha, PTH, IL-6, IL-8, and IL-10. Therefore, non-parametric tests, such as Mann–Whitney's u-test and Kruskall–Wallis were used to analyse differences of these parameters between groups. Student's t-test, variance analysis and Pearson's correlation analysis were used with the remaining parameters, whereas Spearman's rho (instead of Pearson's correlation) was utilized in the case of non-parametric variables. Covariance analyses with age and creatinine were also performed. We also performed a stepwise multivariate analysis between brain atrophy and cytokines, hormones, liver function tests, years of ethanol consumption, daily amount of ethanol consumed, BMI, and age, in order to discern which parameters brain atrophy depends on in alcoholics.
|
Results |
|---|
|
TOPABSTRACTIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
All the indices were significantly different between patients and controls (Table 3), differences which were especially marked regarding cortical atrophy, bicaudate index and cella media index. Also, differences were observed between cirrhotics and non-cirrhotics with respect to cella media index and ventricular index.
|
No relation was observed between brain atrophy parameters and liver function tests or serum hormone levels, except for IGF-1 and bifrontal index (r = –0.43, P = 0.014) and PTH and Evan's index (r = 0.36, P = 0.032). Bifrontal index was inversely related with handgrip strength (r = –0.41, P = 0.017) and years of ethanol consumption (r = 0.39, P = 0.021). MCV was inversely related with cella index (r = –0.29, P = 0.045) and cortical atrophy (r = 0.47, P < 0.001). Platelet count was related with ventricular diameter (r = 0.41, P = 0.018). No relation was observed between cytokines and parameters related to ventricular dilatation and cortical brain atrophy.
Cerebellar atrophy was observed in 12 cases. It was related with the amount of ethanol consumed (236 ± 64 g among those with cerebellar atrophy versus 187 ± 59 g among those without cerebellar atrophy, t = 2.19P = 0.034). Also, no differences were observed between patients with and without cerebellar atrophy, and the different brain atrophy indices.
Cerebral atrophy was informed by the neuroradiologist to be present in 20 cases. No differences were observed between patients with and without cerebral atrophy and any of the parameters analysed. In Table 4, we show the values of the different brain atrophy indices in patients with and without cerebral atrophy. Only the cortical atrophy index was significantly different among patients with and without cerebral atrophy.
|
Stepwise multiple regression analysis with the different indices of ventricular dilatation and brain atrophy revealed that cella media index was related only with bilirubin (r = 0.43, P = 0.012); bifrontal index, with age (P = 0.004) and handgrip strength (P = 0.034), in this order; and Huckmann's index, with age (r = 0.45, P = 0.008). Finally, by logistic regression analysis, daily ethanol consumption was the only parameter that showed an independent, significant relationship with the presence of cerebellar atrophy (P = 0.032).
|
Discussion |
|---|
|
TOPABSTRACTIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
The values obtained for the CT variables of our control population are in agreement with those reported for normal individuals (Gyldenstedt and Kosteljanetz, 1976
; Hahn and Schapiro, 1976; Gyldenstedt, 1977). From our data, it is clear that alcoholics show highly significantly different CT values than the controls. This result is in agreement with others reported in the medical literature. In fact, brain atrophy has been widely described in alcoholics, especially in cirrhotics, both by CT scan (Zeneroli et al., 1987) and MRI studies (Tuluvath et al., 1995; Mukamal et al., 2001). The more intense changes observed in cirrhotics may be due either to the more advanced age of cirrhotics in relation to non-cirrhotics, or to the possibility that cirrhosis is a risk factor for brain atrophy (Bernthal et al., 1987). Undoubtedly, age is a risk factor for brain atrophy in alcoholics (Pfefferbaum et al., 1992), as we have also shown in this study. However, some authors have reported a relationship between liver function and CT brain alterations in non-alcoholic cirrhotics (Tarter et al., 1986). Therefore, liver function impairment seems to play a role on brain atrophy. Although, in our study, the interpretation of the differences observed between cirrhotics and non-cirrhotics may be obscured by the low number of liver biopsies (only 4 cases), the relationships between brain atrophy indices and liver function are poor: only bilirubin shows an independent relationship with an index which estimates ventricular dilatation, as the cella media index; the CT indices were not significantly different in cirrhotics and non-cirrhotics (besides cella media index and ventricular index), and there was no relation between Child–Pugh score and CT indices.
Some indices, such as bifrontal index and cella media index, and cerebellar atrophy, were related with ethanol consumption or with parameters related with chronic ethanol consumption, such as MCV, years of ethanol consumption, and daily amount of ethanol consumed. Indeed, chronic alcoholism is a risk factor for atrophy (Acker et al., 1982; Nicolás et al., 2000), although alterations related to the peculiar life-style of the alcoholic, with vitamin deficiency (Joyce, 1994), trace elements (Maeda et al., 1997) and hormone alterations may also play a role (Menzano and Carlen, 1994). In this study, we have tested the possible relation between altered sexual hormone levels and brain alterations in alcoholics. Controversy exists about the relation of sexual hormones and brain atrophy, some authors pointing to the existence of a positive correlation between testosterone and estradiol levels and volume changes in different areas (Lessov–Schlaggar et al., 2005), whereas others have described a relation between high testosterone and brain atrophy, and high estradiol and lacunar disease (Irie et al., 2006). In our study, neither testosterone nor estradiol showed any relation with ventricular dilatation or cortical brain atrophy. Neuroprotective effects of IGF-1 have been described (Carro and Torres–Alemán, 2004), and a relation between cognitive impairment and serum PTH has been reported (Jorde et al., 2006). Our results, showing an inverse relationship between IGF-1 and bifrontal index, and a direct one between PTH and Evan's index, are in agreement with these findings.
Several lines of evidence support a role of proinflammatory cytokines on brain injury (Lanzrein et al., 1998; Stefanova et al., 2003) and cerebellar atrophy (Journiac et al., 2005). Yamauchi et al. (2001) described an association between polymorphisms of TNF-beta and brain atrophy in alcoholics. Alcoholic liver disease may be considered an inflammatory condition (Sánchez–Pérez et al., 2006), and several proinflammatory cytokines may persist elevated even in abstinent patients, beyond the acute episode which prompted hospital admission (Crews et al., 2006; González–Reimers et al., 2007). However, in our study, no relation was found between any of the cytokines analysed and CT variables.
Malnutrition is frequently observed among alcoholics (World et al., 1985), and may play a role in brain and cerebellar atrophy (Nicolás et al., 2000). However, our results do not support this; we only found a relation between bifrontal index and handgrip strength, a finding, which can be also interpreted as a consequence, rather than a cause, of brain atrophy in relation with motor neurone loss.
Therefore, we conclude that brain atrophy is frequently observed in alcoholics. Although we found some significant relationships between ethanol consumption, some hormones, handgrip strength, and bilirubin with some of the CT indices, overall, the relationships between brain atrophy and liver function, cytokines, nutritional status, and hormone levels are poor, suggesting that perhaps other factors (genetics, vitamins, and micronutrients) may be also involved in its pathogenesis.
|
References |
|---|
|
TOPABSTRACTIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Acker W., Aps E. J., Majumdar S. K., et al. The relationship between brain and liver damage in chronic alcoholic patients. Journal of Neurology Neurosurgery and Psychiatry (1982) 45:984–987.
Amodio P., Pellegrini A., Amistá P., et al. Neuropsychological-neurophysiological alterations and brain atrophy in cirrhotic patients. Metabolic Brain Disease (2003) 28:63–78.
Bernthal P., Hays A., Tarter R. E., et al. Cerebral CT scan abnormalities in cholestatic and hepatocellular disease and their relationship to neuropsychologic test performance. Hepatology (1987) 7:107–114.[CrossRef][Web of Science][Medline]
Cala L. A., Jones B., Burns P., et al. Results of computerized tomography, psychometric testing and dietary studies in social drinkers, with emphasis on reversibility after abstinence. Medical Journal of Australia (1983) 17:264–269.
Carro E., Torres-Alemán I. The role of insulin-like growth factor I in the molecular and cellular mechanisms underlying the pathology of Alzaheimer's disease. European Journal of Pharmacology (2004) 490:127–133.[CrossRef][Web of Science][Medline]
Crews F. T., Bechara R., Brown L. A., et al. Cytokines and alcohol. Alcoholism-Clinical and Experimental Research (2006) 30:720–730.[CrossRef]
Ding J., Eigenbrodt M. L., Mosley T. H., et al. Alcohol intake and cerebral abnormalities on magnetic resonance imaging in a community-based population ogf middle-aged adults. Stroke (2004) 35:16–21.
Estruch R., Nicolas J. M., Salamero M., et al. Atrophy of the corpus callosum in chronic alcoholism. Journal of Neurological Science (1997) 146:145–151.[CrossRef][Web of Science][Medline]
Gazdzinski S., Durazzo T. C., Meyerhoff D. Temporal dynamics and determinants of whole brain tissue volume changes during recovery from alcohol dependence. Drug and Alcohol Dependence (2005a) 78:263–273.[CrossRef][Web of Science][Medline]
Gazdzinski S., Durazzo T. C., Studholme C., et al. Quantitative brain MRI in alcohol dependence: preliminary evidence for effects of concurrent chronic cigarette smoking on regional brain volumes. Alcoholism-Clinical and Experimental Research (2005b) 29:1484–1495.[CrossRef]
González-Reimers E., GarcÍa-Valdecasas-Campelo E., Santolaria-Fernández F., et al. Pro-inflammatory cytokines in stable chronic alcoholics: relatiosnhip with fat and lean mass. Food and Chemical Toxicology (2007) 45:904–909.[CrossRef][Web of Science][Medline]
Gyldenstedt C. Measurement of the normal ventricular system and hemispheric sulci of 100 adults with computed tomography. Neuroradiology (1977) 14:183–192.[CrossRef][Web of Science][Medline]
Gyldenstedt C., Kosteljanetz M. Measurements of the normal ventricular system with computer tomography of the brain. A preliminary study on 44 adults. Neuroradiology (1976) 10:205–213.[CrossRef][Web of Science][Medline]
Hahn F., Schapiro R. The excessively small ventricle on computed axial tomography of the brain. Neuroradiology (1976) 12:137–139.[CrossRef][Web of Science][Medline]
Irie F., Strozyk D., Peila R., et al. Brain lesions on MRI and endogenous sex hormones in elderly men. Neurobiology of Aging (2006) 27:1137–1144.[CrossRef][Web of Science][Medline]
Jorde R., Waterloo K., Saleh F., et al. Neuropsychological function in relation to serum parathyroid hormone and serum 25-hydroxyvitamin D levels: the Tromso study. Journal of Neurology (2006) 253:464–470.[CrossRef][Web of Science][Medline]
Journiac N., Doulazmi M., Pajak F., et al. Quantitative analysis of microglial cells in the degenerating cerebellum of the staggerer (RORA(sg/sg)) mutant mouse. Journal of Neurogenetics (2005) 19:143–154.[CrossRef][Web of Science][Medline]
Joyce E. M. Aetiology of alcoholic brain damage: alcoholic neurotoxicity or thiamine malnutrition? British Medical Bulletin (1994) 50:99–114.
Kubota M., Nakazaki S., Hirai S., et al. Alcohol consumption and frontal lobe shrinkage:study of 1432 non-alcoholic subjects. Journal of Neurology Neurosurgery and Psychiatry (2001) 71:104–106.
Lanzrein A. S., Johnston C. M., Perry V. H., et al. Longitudinal study of inflammatory factors in serum, cerebrospinal fluid, and brain tissue in Alzheimer disease: interleukin-1 beta, interleukin-6, interleukin-1 receptor antagonist, tumor necrosis factor-alpha, the soluble tumor necrosis factor receptors I and II, and alpha-1 antichymotrypsin. Alzheimer Disease & Associated Disorders (1998) 12:215–227.[Web of Science][Medline]
Lessov-Schlaggar C. N., Reed T., Swan G. E., et al. Association of sex steroid hormones with brain morphology and cognition in healthy elderly men. Neurology (2005) 65:1591–1596.
Maeda H., Sato M., Yoshikawa A., et al. Brain MR imaging in patients with hepatic cirrhosis: relationship between high intensity signal in basal ganglia on T1-weighted images and elemental concentrations in brain. Neuroradiology (1997) 39:546–550.[CrossRef][Web of Science][Medline]
Mann K., Ackermann K., Croissant B., et al. Neuroimaging of gender differences in alcohol dependence: are women more vulnerable? Alcoholism-Clinical and Experimental Research (2005) 29:896–901.[CrossRef]
Menzano E., Carlen L. P. Zinc deficiency and corticosteroids in the pathogenesis of alcoholic brain dysfunction—a review. Alcoholism-Clinical and Experimental Research (1994) 18:895–901.[CrossRef]
Mittleman M. A., et al. Alcohol consumption and subclinical findings on magnetic resonance imaging of the brain in older asults: the Cardiovascular Health Study. Stroke (2001) 32:1939–1946.
Nicolas J. M., Fernández-Sola J., Robert J., et al. High etanol intake and malnutrition in alcoholic cerebellar shrinkage. Quarterly Journal of Medicine (2000) 93:449–456.
Oishi M., Mochizukui Y., Shikata E. Corpus callosum atrophy and cerebral blood flow in chronic alcoholics. Journal of Neurological Science (1999) 162:51–55.[CrossRef][Web of Science][Medline]
Pfefferbaum A., Lim K. O., Zipursky R. B., et al. Brain gray and white matter volume loss accelerates with aging in chronic alcoholics: a quantitative MRI study. Alcoholism-Clinical and Experimental Research (1992) 16:1078–1089.[CrossRef]
Sánchez-Pérez M. J., González-Reimers E., Santolaria-Fernández F., et al. Lipid peroxidation and serum cytokines in acute alcoholic hepatitis. Alcohol and Alcoholism (2006) 41:593–597.
Santolaria F., González-Reimers E., Pérez-Manzano J. L., et al. Osteopenia assessed by body composition analysis is related to malnutrition in alcoholic patients. Alcohol (2000) 22:147–157.[CrossRef][Web of Science][Medline]
Stefanova N., Schanda K., Klimaschewski L., et al. Tumor necrosis factor-alpha-induced cell death in U373 cells overexpressing alpha-synuclein. Journal of Neuroscience Research (2003) 73:334–340.[CrossRef][Web of Science][Medline]
Tarter R. E., Alterman A. I. Neuropsychological deficits in alcoholics: etiological considerations. Journal of Studies on Alcohol (1984) 45:1–9.[Web of Science][Medline]
Tarter R. E., Hays A., Sandford S. S., et al. Cerebral morphological abnormalities associated with non-alcoholic cirrhosis. Lancet (1986) II:893–895.
Tuluvath P. J., Edwin D., Yue N. C., et al. Increased signals seen in globus pallidus in T-1 weighted magnetic resonance imaging in cirrhotics are not suggestive of chronic hepatic encephalopathy. Hepatology (1995) 21:440–442.[Web of Science][Medline]
World M. J., Ryle R. R., Thomson A. D. Alcohol, malnutrition and the small intestine. Alcohol and Alcoholism (1985) 20:89–124.
Yamauchi M., Takamatsu M., Maezawa Y., et al. Polymorphism of tumor necrosis factor—beta and alcohol dehydrogenase genes and alcoholic brain atrophy in Japanese patients. Alcoholism-Clinical and Experimental Research (2001) 25:7S–10S.
Zeneroli M. L., Cioni G., Vezzeli C., et al. Prevalence of brain atrophy in liver cirrhosis patients with chronic persistent encephalopathy. Evaluation by computed tomography. Journal of Hepatology (1987) 4:283–292.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||