Shripad M. Bairagi1, 2*, Prashant Ghule1, 2, Ritu Gilhotra3
- Research Scholar, Gyan Vihar School of Pharmacy, Suresh Gyan Vihar University, Jaipur, Rajasthan, India
- Department of Pharmacology, MES’s College of Pharmacy, Sonai, Ahmednagar, Maharashtra, India
- Dean, School of Pharmacy, Suresh Gyan Vihar University, Jaipur, Rajasthan, India
The alcoholic liver infection has a known etiology however a complex and deficiently known pathogenesis. It is an extremely common disease with huge morbidity and mortality, but the reason why only a few cases of heavy drinkers progress to advanced disease remains cagey. The main aim of the study is to understand the factors responsible for the progression of alcoholic liver disease. We performed an extensive literature review to identify the complex pathogenic pathway and risk factors of alcoholic liver disease. In addition to the cumulative amount of alcohol intake and alcohol consumption patterns, various factors like gender and ethnicity, genetic background, nutritional factors, energy metabolism abnormalities, oxidative stress, immunological mechanisms, and hepatic co-morbid conditions play a key role in the initiation and development of alcoholic liver injury. Understanding the pathological angles and hazards factors of alcoholic liver disease should provide insight into the development of therapeutic strategies.
Keywords: Alcohol, Hazards factors, Liver, Pathophysiology,
Alcohol consumption is well attitude and status symbol in the social area of many adult populations. Due to several factors like legal aspects, easily available and cost-effective. Long-term and excessive alcohol consumption leads to the development of addiction that can cross all barriers like gender, race, age, economic level, and, in many patients it leads to the development of alcoholic liver disease. Heavy drinking habit significantly increases morbidity and mortality as compared to infectious diseases. Excessive drinking over a decade damage nearly every organ in the body.
Alcoholic liver disease highlights a broad spectrum of clinical illness and structural changes from the development of fatty liver to liver inflammation and necrosis (alcoholic hepatitis) to progressive fibrosis (alcoholic cirrhosis). Furthermore, continuous consumption of alcohol supports the progression of other liver diseases, like virus-related chronic hepatitis, also increasing the risk of hepatocellular carcinoma. The liver sustains the greatest degree of tissue injury from excessive drinking because it is the primary site of ethanol metabolism.1
According to the WHO Worldwide, 3 million deaths every year result from harmful use of alcohol, this represents 5.3 % of all deaths. Overall 5.1 % of the global burden of disease and injury is attributable to alcohol, as measured in disability-adjusted life years.
The main aim of this extensive study is that to understand the pathogenesis and risk factors for alcoholic liver diseases. The literature study demonstrated that the duration and the degree of alcohol consumption increase the risk of alcoholic liver disease. However, only a small portion of the population with heavy drinkers have clinical liver disease, suggesting other factors like environmental promote the risk of development of alcoholic liver disease.
The several steps involved in the development of hepatotoxicity. Several primary and secondary factors interact with each other to initiate livery injury. Primary factors like genetic factors, their relationship with alcohol toxicity, and alcohol lead to alteration in metabolic and immunological factors. Secondary factors like the impact of nutrition, these factors potentially contribute for the development of hepatotoxicity.2, 3
EPIDEMIOLOGY OF HEPATOTOXICITY:
Generally, alcohol toxicity is reported in a particular group of people who are consuming an intemperate amount of alcohol. Alcohol dependence is not the single factor responsible for the development of alcoholic liver disease, it is observed that the development of alcoholic liver disease in patients who do not have a history of dependence. Several factors also play important role in the development of alcoholic liver disease along with the higher amount of alcohol consumption, like genetic and environmental factors, malabsorption also reported in the heavy drinker due to negligence of food.4, 5
Although several cases of alcoholic liver disease were reported, no set amount responsible for the induction of disease is not reported. On average 1-2 drinks per day are usually safe and consumption of more than 3 drinks per day is associated with documented adverse effects. Though heavy drinkers have a greater risk of death from non-cardiovascular causes and develop fatty liver, only 10-35% develop hepatitis and 8-20 % will progress to cirrhosis. 6
Low levels of alcohol intake (1-2 drinks per day for women and 2-4 drinks per day for men) are inversely associated with total mortality in both men and women.7 If daily consumption of alcohol increases more than 40-80 g/dad and 20-40 g/day for male and female respectively will lead to the development of alcoholic liver disease. 8 Consuming alcohol with food resulted in a somewhat lower risk than consuming alcohol alone. High consumption of alcohol for a longer time increases the relative risk of alcoholic liver disease. However, wine drinker has a lower risk of liver disease as compared to beer and spirit drinkers. Once the liver disease develops, continuous consumption of alcohol is a major indicator of poor prognosis.
The majority of alcohol liver disease patients are male but the female patients are more susceptible to the toxic effects of alcohol, as females have a greater risk of developing liver cirrhosis for a small dose of alcohol consumption.9,10 Several hypotheses have been postulated for women having higher risk as compared to men, the first one is the sex difference in ethanol pharmacokinetics, following the intake of the same amount of alcohol, and women have higher blood concentration as compared to the men. This can be attributed to several reasons, including a small volume of distribution due to lower total body water content because of a lower weight and higher proportion of fat. 11
In addition to that low gastric ADH level in women also leads to the development of alcoholic liver disease. A fraction of alcohol ingested is metabolized by gastric ADH before systemic circulation. This action directly decreases the systemic concentration of alcohol in the body.12
In some populations the alcohol consumption is high. Among all of them, only a few are susceptible to developing alcoholic liver disease and cirrhosis. Therefore there must be some genetic factors responsible for the development of disease. Some case studies reported that family twins shown genetic determinants play an essential role in the progress of alcohol disorders and dependence. Still, the exact mechanism is not clear as it is complex and difficult to identify. Genetic study reveals that the gene encoding for the enzymes that responsible for the metabolism of alcohol and acetaldehyde influence the predisposition to alcohol dependence, sensitivity to alcohol, and alcoholic liver disease cirrhosis development even the result is still nonconclusive. 13 These genes include those encoding for alcohol-dehydrogenase (ADH), aldehyde-dehydrogenase (ALDH) and C2-promoter allele of the gene coding for cytochrome CYP2E1.
ATP synthesis rate is reduced in the ethanol exposed hepatocytes. Even long-term exposure of ethanol to hepatocytes decreases the mitochondrial functions including a decrease in cytochrome b content, a decrease in the activity of cytochrome oxidase, impaired functioning of proton and electron leads to impaired energy metabolism would to hepatocyte damage. 14
Energy metabolism is also disturbed by low oxygen levels. Chronic alcohol consumption leads to an increase in the oxygen uptake by hepatocytes. 15 Because to metabolize the ethanol liver required more blood supply to the central lobular area, but the oxygen supply and demand are not matched and lead to the development of hypoxia, which can be responsible for tissue injury.
Oxidative stress is a key factor in the development of alcohol-induced liver disease. The three major hepatic systems involved in the oxidation of ethanol to water and carbon dioxide, that are ethanol oxidation by microsomal enzymes present in the smooth endoplasmic reticulum, alcohol dehydrogenase in the cytoplasm, and catalase in the peroxisomal membrane. All these biochemical pathways produce the toxic by-product acetaldehyde.
Ethanol increased hepatic oxidative stress by generating reactive oxygen sepsis (ROS) and adducts. The hepatic biochemical pathway produces acetaldehyde the toxic by-product of alcohol, this acetaldehyde is oxidized to acetate by aldehyde dehydrogenase. Acetaldehyde forms adducts with reactive residues that lead to lipid peroxidation and nucleic acid oxidation. 16 Excessive ethanol consumption leads to induction of CYP2E1alcohol metabolizing enzyme, which contributes alcohol dehydrogenase to development of superoxide radicals via interaction of CYP2E1 with cytochrome reductase, which leads to ROS production. 17
Role of Immunity:
Ethanol impairs immune functions. However, the exact mechanism is still unknown. As excess alcohol consumption increases the tissue permeability to bacterial endotoxins like lipopolysaccharides. They bind the CD 14 cell and sensitize the kupffer cells which leads to transcription of pro-inflammatory cytokines like TNF-a, IL-6 and transforming the growth factors, which contribute the apoptosis and fibrosis leads to a progression of liver disease.18
A higher morbidity rate is observed in the population who are unhealthy by affecting various organs and systems. The pathophysiology of alcohol liver disease is quite complex which involves several factors including genetic, gender, immune, and amount of alcohol consumption.
Alcohol-induced liver damage involved complex mechanisms and it is not completely defined. Generally accepted ethanol induces an altered redox state associated with the generation of free radicals, resulting in lipid peroxidation, cell-membrane damage, and depletion of GSH. The metabolite of ethanol that is aldehyde involved in several toxic effects of alcohol by forming protein adducts which are responsible development of inflammatory response.
However, we are at the beginning, and much more remains to be done to clarify the exact mechanisms of alcohol-induced damage. From the clear-cut understanding of pathophysiology, it will result in a more defined identification of risk factors for the progression of alcoholic liver disease, accredit us to set preventive plans for developing therapeutic approaches.
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