What is Alcoholic Liver Disease?
Alcoholic liver disease (ALD) is among the most pressing problems of hepatology. This condition includes fatty liver, alcoholic hepatitis and cirrhosis.
Causes of Alcohol Liver Disease
Of all the foods consumed by man, alcohol most often leads to damage to the liver. Alcohol refers to direct hepatotoxic agents, however, a direct correlation between the degree of liver damage and the amount of alcohol taken is not detected. Most researchers believe that taking 40-80 g of ethanol per day for 10-12 years or more than 80 g for at least 5 years causes the risk of developing alcoholic liver damage.
Prevalence. Alcoholism is a common disease in many countries. In Russia, there are more than 10 million patients with alcoholism. In the United States, every third family has such a patient, and the complications of BPA are more than 10 thousand sick every year. At the same time, our country has one of the highest levels of alcohol consumption in the world, indicating that that the problem of alcoholic hepatopathies is relevant for our country.
Pathogenesis during Alcoholic Liver Disease
The development of ABP does not depend on the type of alcoholic beverages. Constant drinking of alcohol is more dangerous, so the risk of BPO is lower in persons who consume alcohol intermittently at least two days a week. There is a discrepancy between the concepts of “BPO” and “alcoholism”, since the latter is used in narcology to refer to a condition characterized by mental and physical dependence on alcohol. According to A. D. Wodak et al., The majority of patients with ALD have a mild alcohol dependence. However, less than 50% of people who consume alcohol in dangerous doses suffer from severe liver damage (hepatitis and cirrhosis). In the development of alcoholic lesions of the liver, in addition to the direct toxic effect of ethanol, there are other pathogenetic mechanisms and risk factors, in particular, female gender, hereditary factors, overweight, infection with hepatotropic viruses, environmental exposure.
Women are more sensitive to the toxic effect of alcohol, which can be explained by the lower activity of alcohol dehydrogenase, which causes a more active metabolism of ethanol.
A certain role is played by genetic polymorphism of enzymes metabolizing ethanol. Thus, the risk of developing ABP is high in individuals with increased alcohol dehydrogenase activity and low aldehyde dehydrogenase activity.
Systematic use of alcohol increases the risk of infection with the hepatitis C virus, which affects the severity of alcohol-induced liver damage. The effect of alcohol on the body is determined by the level of its basal metabolism in the liver, which allows you to completely oxidize ethanol by dehydrogenase.
Under the condition of chronic alcohol intoxication (HAI), alcohol consumption is perceived in doses exceeding the individual level of its basal metabolism in the liver, and therefore the microsomal and catalase pathways of alcohol utilization are activated, leading to hyperproduction of toxic metabolism -. acetaldehyde, disturbance of the redox potential of hepatocytes, increased lipid peroxidation and, as a result, damage to liver cells and the development of various forms of hepatopathy. Ethanol is a normal metabolite that plays a certain role in metabolism; therefore, the mechanism of the development of inflammatory changes in the liver is not completely clear.
The metabolism of ethanol involves several enzymatic systems that convert alcohol to acetaldehyde: the gastric, hepatic fractions of alcohol dehydrogenase (ADH), the ethanol microsomal oxidation system, localized in the region of cytochrome P-450 2E1. In the future, acetaldehyde aldehyde dehydrogenase (AHD) is metabolized to acetate. In these reactions, nicotinamine dinucleotide (NAD) is involved as a coenzyme, which joins a proton and two electrons, which is reduced to NADH.
10-15% of ethanol is metabolized in the microsomes of the smooth endoplasmic reticulum of the microsomal ethanol-oxidative system (MEOS), which is part of the cytochrome P-450 2E1 system. Increased load MEOS is manifested by self-induction, which causes an increase in tolerance to alcohol.
The main mechanism of liver damage is the toxic effect of acetaldehyde.
Acetaldehyde, which is formed in the liver under the influence of ADH and MEOS, contributes to the appearance of toxic effects in the form of an increase in lipid peroxidation; violations of the electron transport chain in mitochondria; DNA replication suppression; changes in microtubule function; formation of complexes with proteins; stimulation of superoxide production by neutrophils; complement activations; enhance collagen synthesis.
In the gastric mucosa, with the participation of the gastric fraction of ADH (belongs to class IV ADH), the first stage of alcohol metabolism is performed. Genetic information about this enzyme is localized on chromosome 4. There are 3 genes encoding ADH: ADP1, ADG2, ADH3, the products of which are peptide subunits designated a, (these subunits are capable of forming homodimers and heterodimers, which explains the different tolerance of alcohol by different ethnic groups. identified among ADH2 and ADHZ. Subunits (are part of the enzymes that metabolize alcohol rapidly. The body of individuals in these cases produces acetaldehyde much faster than other persons, which explains their lower tolerance to alcohol.An important factor in the development of alcoholic liver damage is a higher acetaldehyde accumulation rate, ethanol elimination gene.When tissue alcohol concentration is above 10 mmol / l (50 mg / dl), MEOS plays a major role in its metabolism It is a component of cytochrome P-450 2E1 (CYP2E1) and has the ability to influence the metabolism of other compounds.
AHD has two isoenzymes: ADP and AldG2. Acetaldehyde is a potentially toxic product of ethanol oxidation. Aldg2 regulates the oxidation of the main amount of acetaldehyde to acetate. With a decrease in the activity of Aldg2, it accumulates in the systemic circulation. In addition, it has been proven that a certain disturbance in the diet, in particular the consumption of refractory fats and the low content of carbohydrates in it, contributes to the damage of the liver.
- Disruption of lipid metabolism.
The oxidation of ethanol causes an increased consumption of coenzyme NAD + and an increase in the ratio of NADH: NAD. And this, in turn, leads to a shift in the reaction to the right: dihydroacetone phosphate + NADH + H + £ “Glycerol-3-phosphate + NAD +.
As a result of increased glycerol-3-phosphate synthesis, esterification of fatty acids and triglyceride-Dov synthesis is intensified, which is the initial stage in the development of hyperlipidemia and fatty liver dystrophy. The increase in the concentration of NADH is accompanied by a decrease in the rate (3-oxidation of fatty acids, which also contributes to their deposition in the liver.
- Hypoxia and fibrosis.
With prolonged systematic use of alcohol are formed
free radicals supporting inflammation and causing liver damage through lipid peroxidation. ethanol consumption increases the ability of endotoxins to penetrate the intestinal wall into the bloodstream. Once in the liver, they activate Kupffer cells that release cytokines to regulate the inflammatory process. Acetaldehyde, cytokines and stellate cells interact with each other in the formation of alcoholic cirrhosis. Under normal conditions, stellate cells accumulate reserves of vitamin A. When activated by cytokines or acetaldehyde, they undergo a number of structural changes and lose their reserves of vitamin A and begin to produce fibrous tissue. The proliferation of connective tissue around the vessels and hepatocytes exacerbates the disruption of oxygen delivery to hepatocytes. High hepatocyte demand for oxygen causes a progressive decrease in the concentration of the latter in the hepatic lobe from zone 1 to zone 3. Hepatocytes localized in zone 3 are most susceptible to fibrosis and necrosis. In BPD, the formation of cirrhosis can occur through the progression of fibrosis in the absence of marked inflammation. In the process of fibrosis, an important place is given to transforming growth factor (TGFbb), under its influence transformation of Ito cells into fibroblasts producing type 3 collagen is observed.
- Mitochondrial dysfunction.
Chronic alcohol consumption reduces the activity of mitochondrial enzymes and dissociates oxidation and phosphorylation in the electron transport chain, which leads to a decrease in ATP synthesis. The development of microvesicular steatosis of the liver is associated with mitochondrial DNA damage by lipid peroxidation products.
- Immune mechanisms.
Cellular and humoral immune response plays a significant role in liver damage in alcohol abuse and explains the progression of liver disease after the cessation of alcohol. At the same time, pronounced immune changes in patients with ALD may be due to other causes, in particular infection with hepatotropic viruses.
Involvement of humoral mechanisms is manifested in increased levels of serum immunoglobulins, mainly due to IgA, and deposition of IgA in the wall of hepatic sinusoids. In addition, serum antibodies to nuclear components and smooth muscle, as well as antibodies to neoantigens (alcoholic hyaline and acetaldehyde) are detected in a low titer protein complexes).
A reflection of cellular mechanisms is the circulation of cytotoxic lymphocytes. CD4 and C08 deficits are found in inflammatory hepatic infiltrates along with increased membrane expression of HLA class I and II molecules. The role of target antigens are the products of the interaction of ethanol metabolites and cellular structures.
With ABP, there is an increase in the concentration of anti-inflammatory cytokines (IL-1, IL-2, IL-6, TNF-a) involved in the interaction of immunocompetent cells. TNF-a and IL-8, through stimulation of the production of reactive oxygen and nitrous oxide, cause damage to the target cells, causing a picture of multiple organ failure in acute alcoholic hepatitis. At the stage of cirrhosis, bacterial endotoxins join as a powerful stimulant.
The main points of the pathogenesis of alcoholic liver damage:
- Disruption of cell membrane lipids leading to adaptive changes in their structure.
- The damaging effect of acetaldehyde.
- Violation of the neutralizing function of the liver in relation to exogenous toxins.
- Impaired immune responses.
- Increased collagenosis, stimulation of carcinogenesis.
At the same time, in the literature there is evidence of the development of liver lesions in alcohol abusers, not in connection with alcohol, but as a result of the action of hepatitis viruses against CAI. Alcohol metabolites, especially acetaldehyde, when accumulated in the liver tissue can disrupt the expression of the viral gene and reduce the cytotoxic effect of T-lymphocytes.
Alcohol Liver Disease Treatment
The basic principle of treatment of ALD is abstention from alcohol. If this requirement is fulfilled at the stage of steatosis and hepatitis, the reverse development of the pathological process is possible. Since it is rather difficult to verify abstinence, a study of the concentration of carbohydrate-poor transferrin will help in this situation. Food for patients with ABP should be complete, its caloric content is 25-35 kcal and 1-1.25 g of protein per 1 kg of ideal body weight per day. For patients with acute encephalopathy, the amount of protein is limited to 20 g per day to improve condition with a gradual increase in its content in the diet at least 0.5 g / kg per day. For patients who are in a coma or continue to drink alcohol before the development of coma, proteins for some time are completely excluded.
Corticosteroids are used only in cases of severe alcoholic hepatitis or in patients with encephalopathy to reduce mortality.
S-adenosylmethionine (Heptral, company “Knoll”, Germany) is a natural substance that is part of the various tissues of the body and plays a key role in the metabolism of the liver. In the body, S-adenosylmethionine is formed from methionine using ATP with the participation of the enzyme S-adenosylmethionine synthase. This compound improves the function of hepatocytes by increasing the membrane fluidity through the transmethylation reaction and increases the production of antioxidants (for example, cysteine and glutathione). As a result of these effects, the elimination of free radicals and other toxic metabolites from hepatocytes is increased. Clinical studies suggest that the use of Heptral in the treatment of ALD increases the level of glutathione in the liver tissue, and also has a positive effect on the survival of these patients (especially in severe forms of the disease). In patients with alcoholic cirrhosis of classes A and B (Child-Pugh classification), the use of Heptral leads to a decrease in mortality from 29 to 12%.
Heptral has an anti-neurotoxic effect, which is very important in the treatment of ALD, as acetaldehyde passes through the blood-brain barrier. Another topical aspect of the use of Heptral is related to the fact that alcohol abuse is combined with emotional problems that can manifest symptoms of general depression and affective disorders. Depression can lead to increased alcohol abuse, forming a vicious cycle. The beneficial effect of Heptral in such patients is due to its antitoxic properties and antidepressant activity.
Heptral initially administered parenterally in 5-10 ml (400-800 mg) intravenously or intramuscularly for 10-14 days, and then 400-800 mg (1-2 tablets) 2 times a day. The duration of treatment is on average 2 months. The drug should not be prescribed for azotemia and in the first 6 months of pregnancy.
Essential phospholipids (Essentiale H) is a purified mixture of polyunsaturated phospholipids (mainly phosphatidylcholine) derived from soybeans. A promising direction for the use of the drug is based on its ability to prevent the transformation of stellate cells into collagen-producing cells and increase the activity of collagenase. In addition, it reduces the degree of oxidative stress and contributes to the destruction of collagen. In the experiment on baboons, the ability of polyunsaturated phospholipids to prevent the development of fibrosis and cirrhosis of the liver is shown. Research in this direction continues.
Liver transplantation is the only effective method of treating the end-stage lesions, including ABP. In the US, among patients undergoing liver transplantation, patients with end-stage ABP are approximately 27%. Their infection with hepatitis C virus does not have a fundamental effect on the survival rate after this operation. A prerequisite for transplantation is a 6-month withdrawal period before it is performed. According to different benign conditions, from 10 to 80% of patients after liver transplantation return to the use of alcohol.
Other directions in the treatment of ABP:
Anabolic steroids – alter the synthesis of nucleic acids and proteins. In exhausted patients, these funds as an adjunct to diet therapy can extend the survival time. However, they are distinguished by potential hepatotoxicity and must be used with great care.
Colchicine – has the ability to reduce the alcohol-induced inflammatory response and the deposition of collagen in the liver. One of the clinical studies showed a significant increase in life expectancy from 3.5 years in patients of the control group to 11 years in patients treated with colchicine with reverse development of fibrous tissue, which was confirmed by repeated biopsies.
Silymarin – the active ingredient of milk thistle (ostropestroy) – has the ability to neutralize free radicals and immunomodulation. Improves functional liver tests and histological picture of liver tissue in patients with BPO. In addition, it prevents lipid peroxidation and lymphocyte proliferation.
Insulin and glucagon – in an experiment on animals contribute to the normalization of liver enzymes. At the same time, the existing danger of hypoglycemia sharply limits activity in the course of further research in this direction.
D-penicillamine – reduces fibrogenesis and prevents the progression of ASD. In patients with alcoholic hepatitis, use of the drug helps to reduce hepatocellular necrosis and collagen deposition. Further research is needed on the effectiveness of this drug.
Propylthiouracil – is able to reduce the need for hepatocytes in oxygen and reduce the degree of hypoxia in the perivenular zone of patients with ABP. Further research is also required.
Naltrexone, an opioid receptor antagonist, is being studied in terms of the effect on the mental status of patients with alcohol dependence.