Alcohol and Hepatic System

Excessive alcohol consumption damages nearly every organ in the body. However, the liver suffers the earliest and most severe degrees of tissue injury due to excessive alcohol consumption, as it is the organ responsible for almost all ethanol metabolism (1). In this text, we will explore how the liver is affected by harmful alcohol consumption.

The liver's function

Normal liver function is essential for life. The liver is the largest internal organ in the human body and, in some aspects, the most complex. One of its main functions is to break down toxic substances absorbed from the intestine or produced in other areas of the body, and then excrete them via bile or blood as harmless by-products.

Additionally, the liver secretes bile into the small intestine to aid in the digestion and absorption of fats, stores vitamins, synthesizes proteins and cholesterol, metabolizes and stores sugars. The liver controls blood viscosity and regulates clotting mechanisms (2).

Alcoholic liver disease

One study estimated that 23.6 million people worldwide have alcohol-associated cirrhosis, with approximately 10% of these cases being decompensated disease (3). However, the true burden of alcoholic liver disease is likely underestimated, as it is often undiagnosed.

There is a clear amount-dependent relationship between the amount of alcohol consumed and the risk of severe liver disease. A meta-analysis demonstrated that even very low levels of alcohol consumption increase the risk of cirrhosis-related mortality. This risk is heightened with increased consumption, with men and women who consume more than 60 grams of alcohol per day having a 14 and 22.7 times greater risk, respectively, of cirrhosis-related death compared to non-drinkers (4).

How alcohol affects liver metabolism (5)

When consumed in excess, alcohol interferes with an enzyme called AMPK, which normally helps regulate fat metabolism. AMPK activates another protein, PPARα, which is important for fatty acid burning. Alcohol inhibits AMPK, resulting in reduced fat burning by the liver. Additionally, alcohol damages mitochondria, the cell's "energy factories," which also reduces the liver's ability to burn fats.

Alcohol also increases fatty acid production in the liver. Furthermore, alcohol consumption reduces the production of adiponectin, a hormone that helps control fat levels, and increases the release of fatty acids from body fat deposits.

On the other hand, alcohol inhibits the secretion of fatty acids by the liver, further contributing to fat accumulation in the organ. It also affects various cellular signaling pathways, including those associated with inflammation and regulation of autophagy (cellular cleaning process). These changes contribute to the progression of alcoholic fatty liver disease, a condition characterized by excessive fat accumulation in the liver.

Additionally, alcohol can cause an imbalance in gut bacteria, worsening liver disease. This imbalance increases ethanol metabolism in the intestine and causes intestinal dysfunction. Bacteria and toxins can enter circulation and reach the liver, activating an inflammatory pathway called NFκB. The pro-inflammatory cytokines released in this process contribute to inflammation and fibrosis in the liver. Alcohol also favors necrosis (uncontrolled cell death) over apoptosis (programmed cell death), which can further aggravate the liver condition.

Types of alcohol-induced liver damage

In individuals who abuse alcohol, the most common liver diseases encountered are:

1. Alcoholic steatosis (fatty liver): Fat deposition occurs in almost all individuals who abuse alcohol excessively and frequently. Steatosis corresponds to the first stage of alcoholic liver disease. Steatosis can also occur in diabetic individuals, obese individuals, those with severe protein malnutrition, and users of certain medications  (1).

1. Alcoholic hepatitis: This condition involves inflammation and/or destruction (e.g., necrosis) of liver tissue. Symptoms include loss of appetite, nausea, vomiting, abdominal pain, fever, and in some cases, confusion (2).

1. Alcoholic cirrhosis: It is an advanced form of liver disease resulting from progressive damage to liver cells. A cirrhotic liver is characterized by extensive fibrosis that compromises liver function and can impair the functioning of other organs such as the brain and kidneys (2).

1. Hepatocellular carcinoma (Liver cancer): Chronic and abusive alcohol consumption is also associated with an increased risk of developing hepatocellular carcinoma, a type of liver cancer. This cancer can arise in a liver already presenting cirrhosis or, in some cases, directly due to the carcinogenic effects of alcohol (6).

How alcohol damages the liver?

Alcohol damages the liver through various mechanisms, and not all alcoholics develop liver problems regardless of the amount consumed. Genetic factors may influence the predisposition to cirrhosis, with collagen synthesis in the liver being affected by the activation of specific genes (5). Genetic variations in enzymes that metabolize alcohol, such as the ALDH gene, can also increase susceptibility to liver damage. Alcohol metabolism generates free radicals and acetaldehyde, which cause cellular damage in the liver (7).

Women are more susceptible to cirrhosis with lower accumulated doses of alcohol due to lower gastric ADH activity and differences in fatty acid metabolism (1,5,8). Additionally, nutrition interacts with alcohol toxicity, exacerbating liver damage. Infection with hepatitis C virus also increases the risk and progression of liver injuries in alcoholics (3). In summary, intense and chronic alcohol consumption predisposes individuals to liver diseases, but only a portion of them develop hepatitis or cirrhosis due to the influence of factors such as heredity, gender, diet, and comorbidities. Most alcohol-induced liver injuries result from its metabolism and toxic by-products. Continuous research is essential to better understand these mechanisms and develop effective treatments to improve prevention and management of alcoholic liver diseases.

References:

1. Lieber CS. Alcohol and the liver: metabolism of alcohol and its role in hepatic and extrahepatic diseases. Mt Sinai J Med. 2000 Jan;67(1):84-94. PMID: 10677787.
2. Yamada, T., Alpers, D. H., Kalloo, A. N., Kaplowitz, N., Owyang, C., & Powell, D. W. (2009). Textbook of Gastroenterology, Fifth Edition. Blackwell Publishing Ltd. https://doi.org/10.1002/9781444303254
3. Asrani SK, Mellinger J, Arab JP, Shah VH. Reducing the global burden of alcohol-associated liver disease: a blueprint for action. Hepatology. 2021;73(5):2039–50. 
4. Rehm J, Taylor B, Mohapatra S, Irving H, Baliunas D, Patra J, et al. Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis. Drug Alcohol Rev. 2010;29(4):437–45. 
5. Seitz, H. K., & Stickel, F. (2007). Molecular mechanisms of alcohol-mediated carcinogenesis. Nature Reviews Cancer, 7(8), 599-612.
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7. Edenberg HJ. The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res Health. 2007;30(1):5-13. PMID: 17718394; PMCID: PMC3860432.
8. Parlesak A, Billinger MH, Bode C, Bode JC. Gastric alcohol dehydrogenase activity in man: influence of gender, age, alcohol consumption and smoking in a caucasian population. Alcohol Alcohol. 2002 Jul-Aug;37(4):388-93. doi: 10.1093/alcalc/37.4.388. PMID: 12107043.