CC BY
2UDC 616-006.484.03:612.393.1-07-089
ALCOHOL USE DISORDER AND ITS IMPACT ON THE DEVELOPMENT OF
MALIGNANT ASTROCYTOMAS
AISHA TANAS
Karaganda Medical University, Vilnius University Karaganda, Kazakhstan Vilnius, Lithuania
Abstract: Alcohol use disorder (A UD) is a chronic, debilitating condition characterized by an individual's inability to control their alcohol consumption despite its harmful consequences. AUD, classified in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as a substance use disorder, is described by a problematic pattern of alcohol consumption leading to clinically significant impairment or distress. Individuals with AUD may experience cravings, loss of control over drinking, withdrawal symptoms, and tolerance, among other symptoms. AUD has far-reaching effects on mental health, relationships, and overall well-being. This condition poses significant public health concerns globally, with far-reaching impacts on physical and mental health, relationships, and social well-being. Beyond the well-documented health risks associated with alcohol addiction, there is an emerging interest in its potential link to the development of malignant astrocytomas, a group of aggressive brain tumors characterized by marked brain invasion and destruction, and rapid progression. This article discusses the complex relationship between alcohol addiction and malignant astrocytomas, exploring the biological mechanisms and potential risk factors.
Key words: alcohol use disorder, malignant astrocytomas, oxidative stress,
neuroinflammation and neurodegeneration, dose-response relationship.
Alcohol use disorder (AUD) involves patterns of heavy alcohol consumption and an inability to control intake. AUD is widespread mental health issue globally, especially in affluent nations, leading to significant mortality and health burdens, primarily through conditions influencing physical and mental health. These disorders are often undertreated due to the stigma attached and a lack of consistent screening in primary healthcare. Nonetheless, compelling evidence indicates that acetaldehyde, the initial byproduct formed in the process of alcohol breakdown, is accountable for the cancer-causing impact of ethanol. This is attributed to acetaldehyde's numerous mutagenic effects on DNA [1].
Malignant astrocytomas are among the most lethal forms of cancer, with limited treatment options and poor prognoses. Benign and malignant astrocytomas are types of brain tumors which arises from star-shaped astrocytes. Astrocytes are glial cells which provide brain tissue with physical, ion and metabolic support, therefore, they are responsible for neurotransmitter uptake and recycling, synaptic function modulation, neuroprotection, and blood-brain barrier maintenance [2].
According to World Health Organization (WHO), classification of tumors categorizes astrocytomas based on their histopathological characteristics. The WHO grading system for astrocytomas is as follows:
• Grade I (Pilocytic astrocytoma)
• Grade II (Diffuse astrocytoma)
• Grade III (Anaplastic Astrocytoma)
• Grade IV (Glioblastoma Multiforme)
Malignant astrocytoma refers to a high-grade astrocytoma with more aggressive behavior and a higher likelihood of spreading into surrounding brain tissue. The WHO classification system categorizes astrocytomas into different grades, with Grade IV being the most malignant. Glioblastoma multiforme (GBM) is an example of a Grade IV astrocytoma, and it is considered the most aggressive and common type of malignant astrocytoma [3].
While there are well-established risk factors for certain cancers, such as smoking for lung cancer or HPV for cervical cancer, the relationship between alcohol addiction and malignant astrocytomas is less clear. Epidemiological studies examining the association between alcohol consumption and brain cancer have produced mixed results [4]. The challenges in establishing causality in observational research, including difficulties in accurately assessing alcohol consumption and potential confounding factors, contribute to the complexity of this topic.
Alcohol possesses neurotoxic properties, and numerous studies, particularly those involving alcoholics, have documented the short and long-term impacts of excessive alcohol consumption on brain function and pathology. The mechanisms underlying these effects are intricate and still partially unknown. The effects of low or moderate alcohol consumption on the brain are less definitive and more contentious. However, certain studies suggest that even low to moderate alcohol intake may potentially modify brain function and diminish brain health. Additionally, alcohol is a recognized carcinogen, and epidemiological research has demonstrated its association with an increased risk of various cancers, including breast cancer and cancers affecting the upper and lower aero-digestive tract. Despite the evident vulnerability of the brain to the effects of alcohol and its potential carcinogenic consequences, only a limited number of epidemiological studies have investigated the link between alcohol overconsumption and the risk of astrocytoma [5].
The link between alcohol addiction and development of malignant astrocytomas can be characterized by multiple biological mechanisms. To begin with, chronic alcohol consumption can lead to DNA damage and mutations. Ethanol and its metabolites, such as acetaldehyde, can directly interact with DNA, causing genetic mutations that may promote cancer development. The levels of acetaldehyde are dependent on the activity of two enzymes: alcohol-dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH). Some genetic variants in the genes coding for these two enzymes are associated with increased circulating levels of acetaldehyde and with an increased risk of alcohol related cancers. According to the Report on Carcinogens (10th Edition), issued by the U.S. National Toxicology Program, acetaldehyde has been found to possess carcinogenic properties, leading to the occurrence of sister chromatid exchanges and chromosomal aberrations in human cells. Genetic variation in DNA repair genes has the potential to impact an individual's vulnerability to alcohol-related carcinogenesis [6]. The inclusion of DNA repair genotype information would be particularly valuable when coupled with genotyping of polymorphisms in alcohol dehydrogenase and aldehyde dehydrogenase genotypes, which have previously been demonstrated to modify the risk of cancer associated with the consumption of alcoholic beverages [7].
Prolonged alcohol consumption can induce neuroinflammation and neurodegeneration, distinguished by the activation of immune cells in the brain. Chronic neuroinflammation may create a microenvironment conducive to tumor growth and invasion. Research, done by Alfonso-Loeches, has revealed that ethanol stimulates TLR4 signaling in glial cells. This stimulation occurs through the induction of inflammatory mediators and subsequent cell death. These findings suggest that the TLR4 response may play a significant role in the development of neuroinflammation induced by ethanol. Therefore, excessive alcohol intake results in neurodegeneration in the hippocampus and entorhinal cortex that has been linked to a variety of cognitive deficits. Neuroinflammation is estimated to play a role in alcohol-induced neurodegeneration, and the activation of microglia is a significant, albeit not exclusive, element of an inflammatory response. Nonetheless, overconsumption of alcohol triggers an immune response, leading to the activation of microglial cells, which are immune cells in the brain. This immune response can cause inflammation and damage to brain tissue. The present experiments examine the impact of ethanol exposure in a widely accepted model of an AUD on both microglial activation and disruption of the blood-brain barrier, with the objective of comprehending their association with conventional definitions of inflammation and alcohol-induced neurodegeneration [8]. Microglia take on a variety of phenotypes, which can be used to predict the cell's role in brain insult or neurodegenerative disease. The major finding of this work is that both morphological and functional evidence from these experiments support the conclusion that binge
ethanol exposure does not classically activate microglia and is consistent with definitions of partial activation.
In addition, consistent alcohol consumption causes oxidative stress. Therefore, alcohol metabolism generates reactive oxygen species (ROS), which leads to the oxidative stress. As a result, elevated oxidative stress can damage DNA and proteins, potentially contributing to carcinogenesis. Ethanol metabolism is directly involved in the production of ROS and reactive nitrogen species (RNS). These form an environment favourable to oxidative stress. Ethanol treatment results in the depletion of GSH levels and decreases antioxidant activity. It elevates malondialdehyde, hydroxyethyl radical, and hydroxynonenal protein adducts. These cause the modification of all biological structures and consequently result in serious malfunction of cells and tissues [9].
Evidence from the Melbourne Collaborative Cohort Study (2011), Baglietto and colleagues suggest that alcohol consumption increases the risk of glioblastomas consistent with a dose-response relationship. The increase in relative risk for each additional 10 g/day was 16%; people drinking 40 g/day of alcohol or more had up to three-fold higher risk relative to nondrinkers. Hence, it proves that patients suffering from AUD have a higher risk to develop benign or malignant brain tumors, including astrocytomas [10].
In conclusion, alcohol addiction has garnered increasing interest in its potential link to the development of malignant astrocytomas. While the relationship between alcohol addiction and malignant astrocytomas is complex and not yet fully understood, emerging evidence suggests that chronic alcohol use may contribute to tumor development through various biological mechanisms, including DNA damage, neuroinflammation, oxidative stress, and potentially shared genetic factors. Alcohol could exert a carcinogenic effect in the brain directly by altering the expression of genes through methylation and other processes, but the most important mechanisms are probably related to alcohol metabolism. Acetaldehyde is the first product of alcohol metabolism; it is neurotoxic and has long been suspected to cause some of the brain effects of alcohol. Acetaldehyde is highly reactive, forming both short lived and stable protein adducts as well as DNA-DNA crosslinks, and there is convincing evidence that this alcohol metabolite plays a key role in the carcinogenic effect of alcohol. ROS, which is by-product of alcohol metabolism, are toxic cells as they reach with proteins, lipids, and DNA. It is possible that ROS play an important role in brain tumors because the brain is especially vulnerable to ROS-mediated injury. As a result, the evidence implies positive association between alcohol overuse and development of malignant brain tumors, including malignant astrocytomas [11].
However, the limitations of current research highlight the need for further investigation into this critical area. Future studies should focus on elucidating the specific mechanisms linking alcohol addiction to malignant astrocytomas, as well as identifying genetic factors that might render certain individuals more vulnerable to this dual burden. Patients facing the dual burden of AUD and a brain tumor often experience significant psychosocial distress. This may include depression, anxiety, and impaired quality of life. Integrated psychiatric and neurological care is essential to address these complex needs. The coexistence of AUD and brain tumors is a complex and challenging medical scenario. It underscores the importance of holistic, patient-centered care that recognizes the interplay between psychiatric and neurological factors. Early screening, integrated treatment, and psychosocial support are essential components of managing individuals facing these dual diagnoses. Further research is needed to elucidate the relationship between alcohol consumption and brain tumors and to develop tailored interventions to improve patient outcomes in this challenging clinical context.
REFERENCES
1. Ikomi J, & O'Malley S.S. (2019). Alcohol use disorders. Ebert M.H., & Leckman J.F., & Petrakis
I.L.(Eds.), Current Diagnosis & Treatment: Psychiatry, 3e. McGraw
Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2509§ionid=200809076
2. Tawa, E. A., Hall, S. D., & Lohoff, F. W. (2016). Overview of the genetics of alcohol use disorder. Alcohol and alcoholism, 51(5), 507-514.
3. Farmanfarma, K. K., Mohammadian, M., Shahabinia, Z., Hassanipour, S., & Salehiniya, H. (2019). Brain cancer in the world: an epidemiological review. World Cancer Res. J, 6(5), 1-5.
4. Alfonso-Loeches, S., & Guerri, C. (2011). Molecular and behavioral aspects of the actions of alcohol on the adult and developing brain. Critical reviews in clinical laboratory sciences, 48(1), 19-47.
5. Galeone, C., Malerba, S., Rota, M., Bagnardi, V., Negri, E., Scotti, L., ... & Pelucchi, C. (2013). A meta-analysis of alcohol consumption and the risk of brain tumours. Annals of oncology, 24(2), 514-523.
6. Haorah, J., Ramirez, S. H., Floreani, N., Gorantla, S., Morsey, B., & Persidsky, Y. (2008). Mechanism of alcohol-induced oxidative stress and neuronal injury. Free Radical Biology and Medicine, 45(11), 1542-1550.
7. Albano, E. (2006). Alcohol, oxidative stress and free radical damage. Proceedings of the nutrition society, 65(3), 278-290.
8. Ohgaki H. Epidemiology of brain tumors. Methods Mol Biol 2009; 472: 323-42.
9. Hirano, T. (2011). Alcohol consumption and oxidative DNA damage. International Journal of Environmental Research and Public Health, 8(7), 2895-2906.
10. Baglietto, L., Giles, G. G., English, D. R., Karahalios, A., Hopper, J. L., & Severi, G. (2011). Alcohol consumption and risk of glioblastoma; evidence from the Melbourne Collaborative Cohort Study. International journal of cancer, 128(8), 1929-1934.
11. Deshpande, N., Kandi, S., Muddeshwar, M., & Ramana, K. V. (2014). Effect of alcohol consumption and oxidative stress and its role in DNA damage. American Journal of Biomedical Research, 2(1), 7-10.
12. Zahr, N. M., Mayer, D., Rohlfing, T., Sullivan, E. V., & Pfefferbaum, A. (2014). Imaging neuroinflammation? A perspective from MR spectroscopy. Brain pathology, 24(6), 654-664.
13. Lowe, P. P., Morel, C., Ambade, A., Iracheta-Vellve, A., Kwiatkowski, E., Satishchandran, A., ... & Szabo, G. (2020). Chronic alcohol-induced neuroinflammation involves CCR2/5-dependent peripheral macrophage infiltration and microglia alterations. Journal of Neuroinflammation, 17, 1-18.
