Alcoholic liver disease

Alcoholic liver damage (alcoholic liver disease) - various disorders of the structure and functional capacity of the liver caused by long-term systematic consumption of alcoholic beverages.

Alcohol causes a range of liver damage that can progress from fatty liver disease to alcoholic hepatitis (often considered an intermediate stage) and cirrhosis.

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Epidemiology

In most Western countries, alcohol consumption is high. In the United States, annual per capita alcohol consumption is estimated at 10 liters of pure ethanol; 15 million people abuse or depend on alcohol. The male-to-female ratio is 11:4.

The share of alcoholic lesions in the overall structure of liver diseases in some countries reaches 30-40%.

Not all people who abuse alcohol develop liver damage; autopsy data show that the prevalence of liver cirrhosis among alcoholics is approximately 10-15%. It is not known what causes the apparent predisposition to alcoholic cirrhosis that exists in some people.

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Causes alcoholic liver disease

The main etiologic factors in the development of alcoholic liver disease are the amount of alcohol consumed, the duration of alcohol abuse (usually more than 8 years), diet, and genetic and metabolic characteristics. Among susceptible individuals, there is a linear correlation between the amount and duration of alcohol consumption and the development of the disease. For example, a small amount of alcohol (20 g for women and 60 g for men) consumed daily for several years can cause severe liver damage.

Consuming more than 60 g per day for 2-4 weeks leads to fatty liver disease even in healthy men; drinking 80 g per day can lead to alcoholic hepatitis, and 160 g per day for 10 years can lead to cirrhosis of the liver. Alcohol content is estimated by multiplying the volume of the drink (in ml) by the percentage of alcohol. For example, 40 ml of an 80-proof drink contains approximately 16 ml of pure alcohol (40% alcoholic drink). Each milliliter of alcohol contains approximately 0.79 g. Although levels can vary, the percentage of alcohol is approximately 2-7% for most beers and 10-15% for most wines.

Only 10-20% of alcohol-dependent patients develop liver cirrhosis. Women are more susceptible than men (even allowing for their smaller body size), probably because women have lower levels of alcohol dehydrogenase in their gastric mucosa, which reduces the amount of alcohol oxidation during the first pass.

Alcoholic liver disease often occurs in families with genetic predisposing factors (eg, deficiency of cytoplasmic enzymes that eliminate alcohol). Malnutrition, especially lack of energy-producing protein, increases susceptibility to the disease. Other risk factors include a diet high in unsaturated fats, deposition of iron in the liver, and co-infection with hepatitis C virus.

The severity of manifestations and frequency of alcoholic liver damage depend on the amount and duration of alcohol consumed. There are different points of view on the quantitative boundaries of safe and risky alcohol consumption zones.

In 1793, Matthew Bailey reported a link between cirrhosis of the liver and alcohol consumption. Over the past 20 years, alcohol consumption has been correlated with the death rate from cirrhosis. In the United States, cirrhosis is the fourth leading cause of death in adult men. The prevalence of alcoholic liver disease is largely dependent on religious and other traditions, as well as the ratio of the cost of alcohol to earnings: the lower the cost of alcohol, the more the lower socioeconomic groups are affected.

Alcohol consumption has increased in almost all countries. However, in France, it has decreased in the last 20 years, which is probably due to the government's anti-alcohol propaganda. In the United States, alcohol consumption, especially strong drinks, has also decreased, probably due to lifestyle changes.

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Risk factors

The average daily alcohol consumption in a large group of men with alcoholic cirrhosis was 160 g/day for 8 years. Alcoholic hepatitis, a precirrhotic lesion, was found in 40% of those who drank less than 160 g/day. For most people, a dangerous dose of alcohol is more than 80 g/day. The duration of alcohol consumption plays an important role. Patients who consumed an average of 160 g/day for less than 5 years did not develop cirrhosis or alcoholic hepatitis, while 50% of 50 patients who consumed large amounts of alcohol for about 21 years developed cirrhosis.

Liver damage does not depend on the type of alcoholic beverage consumed and is associated only with its alcohol content. Non-alcoholic components of the beverage are generally non-hepatotoxic.

Long-term daily alcohol consumption is more dangerous than occasional use, which allows the liver to regenerate. At least 2 days a week should be avoided.

Alcoholic liver disease develops in people with only a low degree of alcohol dependence. Such people usually do not have pronounced withdrawal symptoms; they are able to consume large doses of alcohol for many years and are therefore at increased risk of developing liver damage.

Limits of safe alcohol consumption

Limits of safety Alcohol consumption		Expert group
Men	Women
38-60 g/day	16-38 g/day	National Academy of Medicine of France (1995)
up to 24 g/day	up to 16 g/day	Department of Health and Education (1991) American Council on Science and Health (1995)
20-40 g/day (140-280 r/week)	up to 20 g/day (up to 140 g/week)	WHO (Copenhagen, 1995)

10 g of alcohol is equivalent to 25 ml of vodka, 100 ml of wine, 200 ml of beer.

Toxic and low-toxic doses of alcohol for the liver

Doses	Amount of alcohol/vodka	Time period
Relatively safe doses	210 ml of alcohol (530 ml of vodka) or 30 ml alcohol (76 ml vodka)	Week Day
Dangerous doses	80-160 ml of alcohol (200-400 ml of vodka)	Day
Very dangerous doses	More than 160 ml of alcohol (more than 400 ml of vodka)	Day

Note: The doses are given for men, the doses for women are 2/3 of those given.

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Floor

There is currently an increase in alcoholism among women. This is due to a more tolerant attitude of society towards the use of alcoholic beverages and their greater availability. Women are less likely to be suspected of having alcoholism; they come to the doctor at a later stage of the disease, are more susceptible to liver damage, and they are more likely to relapse after treatment. The higher blood alcohol content after consuming a standard dose in women may be due to a smaller volume of distribution of alcohol. Against the background of alcoholic hepatitis, they more often develop cirrhosis of the liver, even if they stop drinking alcohol.

In addition, women have reduced levels of alcohol dehydrogenase (AlkDG), which is involved in alcohol metabolism, in the gastric mucosa.

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Genetics

Alcohol use patterns are inherited, but no genetic marker has been found to be associated with susceptibility to alcohol-induced liver disease. The rate of alcohol elimination varies by at least threefold between individuals. The incidence of alcoholism is higher in monozygotic than in dizygotic twins, suggesting a hereditary defect.

Modern research does not allow us to draw a clear conclusion about the connection between the genes of the major histocompatibility complex and alcoholic liver disease.

Differences in the degree of alcohol elimination may be due to genetic polymorphism of the enzyme systems. AlkDH is determined by five different genes located on chromosome 4. People with different AlkDH isoenzymes differ in the degree of alcohol elimination. Polymorphism of the most active forms of this enzyme - AlkDH2 and AlkDH3 - may have a protective effect, since rapid accumulation of acetaldehyde leads to lower tolerance to alcohol. However, if such a person drinks alcohol, then more acetaldehyde is formed, which leads to an increased risk of liver disease.

In addition, alcohol is metabolized by microsomal cytochrome P450-II-E1. The gene encoding it has been cloned and sequenced, but the role of different variants of this gene in the development of alcoholic liver disease has not been studied.

Acetaldehyde is converted to acetate by aldehyde dehydrogenase (AldDH). This enzyme is located at four different loci on four different chromosomes. The main mitochondrial enzyme, AldDH2, is responsible for most of the oxidation of the aldehyde. The inactive form of AldDH2 is found in 50% of Chinese and Japanese, which explains why they experience the often disconcerting acetaldehyde "flash" reaction after drinking alcohol. This phenomenon discourages Orientals from drinking alcohol and reduces their risk of developing alcoholic liver disease. However, heterozygotes for the gene encoding AldDH2 have impaired acetaldehyde metabolism and are considered to be at high risk for developing alcoholic liver disease.

Polymorphisms in genes encoding enzymes involved in fibrosis formation may be important in determining individual susceptibility to the stimulatory effect of alcohol on fibrogenesis.

It is likely that susceptibility to alcoholic liver disease is not due to a single genetic defect, but to the combined interaction of many genes. Alcoholism and alcoholic liver disease are polygenic diseases.

Nutrition

In stable patients with alcoholic liver cirrhosis, there is a decrease in protein content associated with the severity of liver disease. The severity of malnutrition in people who abuse alcohol depends on their living conditions: in a difficult socioeconomic situation, a decrease in protein intake and a decrease in energy value often precede liver damage, whereas in a favorable social situation and adequate nutrition, liver damage is apparently not associated with nutrition. At the same time, species-specific differences are revealed in animals. In rats receiving alcohol, liver damage develops only with reduced nutrition, whereas in baboons cirrhosis develops even with normal nutrition. In rhesus macaques, the development of alcoholic liver disease can be prevented by increasing the content of choline and proteins in the diet. It has been shown that in patients with decompensated liver disease who receive a complete diet containing alcohol in an amount covering a third of the daily caloric requirement, the condition gradually improves. At the same time, abstaining from alcohol but with low protein content in the diet does not improve liver function. Malnutrition and hepatotoxicity can act as synergists.

Alcohol may increase the minimum daily requirement for choline, folate, and other nutrients. Nutritional deficiencies, especially protein, lead to decreased levels of amino acids and liver enzymes and may thus contribute to alcohol toxicity.

It is believed that both alcohol and poor nutrition play a role in the development of hepatotoxic effects, with alcohol being the more important. It is likely that with optimal nutrition it is possible to consume a certain amount of alcohol without causing damage to the liver. However, it is also possible that there is a threshold toxic concentration of alcohol, above which dietary changes may not have a protective effect.

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Pathogenesis

Alcohol is readily absorbed from the stomach and small intestine. Alcohol is not deposited; more than 90% is metabolized by oxidation. The first breakdown product, acetaldehyde, is formed as a result of three enzymatic reactions: alcohol dehydrogenase (responsible for approximately 80% of metabolism), cytochrome P-450 2E1 (CYP2E1), and catalase.

Alcohol oxidation in the liver occurs in 2 stages:

• oxidation to acetaldehyde with release of hydrogen;
• oxidation of acetaldehyde to acetic acid, which is then converted to acetyl coenzyme A.

Ethanol metabolism is carried out in hepatocytes by three enzymatic systems.

1. Alcohol dehydrogenase system (ADH). ADH is localized in the cytosol, the liquid part of the cytoplasm of hepatocytes. With the help of this enzyme, ethanol is oxidized to acetaldehyde. This reaction requires the presence of nicotinamide adenine dinucleotide (NAD+). When ethanol is oxidized to acetaldehyde, the hydrogen of ethanol is transferred to NAD+, which is reduced to NADH, thereby changing the oxidation-reduction potential of the hepatocyte.
2. Cytochrome P-450-dependent microsomal system (CDMSS). The enzymes of this system are located in the microsomes of the smooth cytoplasmic reticulum of hepatocytes. CDMSS metabolizes ethanol to acetaldehyde and detoxifies drugs. With alcohol abuse, the smooth cytoplasmic reticulum proliferates.
3. The catalase system of ethanol metabolism is located in the cytoplasmic peroxisomes and mitochondria. With the help of the enzyme NADFH oxidase in the presence of NADF-H and oxygen, hydrogen peroxide is generated, and then with the help of the hydrogen peroxide-H ₂ O ₂ -catalase complex, ethanol is oxidized to acetaldehyde. With alcohol abuse, an increase in the number of peroxisomes in hepatocytes is observed.

All the above systems initially oxidize ethanol to acetaldehyde, which is converted into acetyl coenzyme A by the mitochondrial enzyme acetaldehyde dehydrogenase. Then acetyl coenzyme A enters the Krebs cycle and is oxidized to CO2 _and H2O. At low alcohol concentrations in the blood, its metabolism is carried out primarily by the alcohol dehydrogenase system, and at high concentrations, primarily by the MES and catalase system.

Acetaldehyde is converted to acetate by mitochondrial aldehyde dehydrogenase. Chronic alcohol consumption increases acetate formation. The processes lead to the formation of hydrogen, which converts adenine-nicotinamide dinucleotide (NAD) to its reduced form (NADP), increasing the oxidation-reduction potential in the liver. This replaces fatty acids as an energy source, reduces the oxidation of fatty acids and promotes the accumulation of triglycerides, causing fatty hepatosis and hyperlipidemia. With excess hydrogen, pyruvate is also converted to lactate, which reduces the formation of glucose (as a result of hypoglycemia), causing renal acidosis, decreased excretion of uric acid salts, hyperuricemia and, accordingly, the development of gout.

Alcohol metabolism can also lead to hypermetabolism in the liver, causing hypoxia and damage from free radical release during lipid peroxidation. Alcohol and poor nutrition cause deficiencies in antioxidants such as glutathione and vitamins A and E, predisposing to such damage.

Inflammation and fibrosis in alcoholic hepatitis are largely due to acetaldehyde. It promotes the transformation of stellate cells (Ito) lining the liver's blood channels (sinusoids) into fibroblasts, which produce myocontractile elements and actively synthesize collagen. The sinusoids narrow and become empty, limiting transport and blood flow. Intestinal endotoxins, causing damage, are no longer detoxified by the liver, stimulating the formation of proinflammatory cytokines. By stimulating leukocytes, acetaldehyde and peroxidation products cause even higher production of proinflammatory cytokines. A vicious circle of inflammation occurs, which ends in fibrosis and death of hepatocytes.

Fat is deposited by hepatocytes as a result of impaired deposition in peripheral adipose tissue, increased synthesis of triglycerides, decreased lipid oxidation, and reduced production of lipoproteins, which disrupt fat export from the liver.

Pathogenesis of alcoholic liver disease

1. Hyperfunctioning of the alcohol dehydrogenase system causes:

• increased liver lactate production and hyperlactatemia;
• increased synthesis of fatty acids by the liver and decreased beta-oxidation in the mitochondria of hepatocytes; fatty liver;
• increased production of ketone bodies, ketonemia and ketonuria;
• hypoxia of the liver and an increase in its oxygen demand; the central perivenular zone of the liver lobule is most sensitive to hypoxia;
• inhibition of protein synthesis in the liver.

2. Hyperfunctioning of the MES under the influence of large amounts of alcohol is accompanied by proliferation of the smooth endoplasmic reticulum, an increase in the size of the liver, an increase in the secretion of lipoproteins, hyperlipidemia, and fatty liver.
3. Chronic ethanol consumption leads to a decrease in the ability of mitochondria to oxidize acetaldehyde, and the imbalance between its formation and degradation increases. Acetaldehyde is 30 times more toxic than ethanol itself. The toxic effect of acetaldehyde on the liver is as follows:

• stimulation of lipid peroxidation and the formation of free radicals that damage the hepatocyte and its structures;
• the binding of acetaldehyde to cysteine and glutathione causes a disruption in the formation of reduced glutathione, which in turn contributes to the accumulation of free radicals; reduced glutathione in mitochondria plays an important role in maintaining the integrity of the organelle;
• functional disorders of enzymes associated with hepatocyte membranes and direct damage to the membrane structure;
• inhibition of hepatic secretion and increased intrahepatic cholestasis due to the binding of acetaldehyde to liver tubulin;
• activation of immune mechanisms (acetaldehyde is included in the immune complexes that participate in the formation of alcoholic liver disease).

4. With significant intake of ethanol, an excess of acetyl-CoA occurs, which enters into metabolic reactions with the formation of excess lipids. In addition, ethanol directly increases the esterification of free fatty acids into triglycerides (neutral fat), which contributes to fatty liver and blocks the removal of lipids from the liver in the form of lipoproteins.

Ethanol reduces DNA synthesis in hepatocytes and causes a decrease in the synthesis of albumin and structural proteins in the liver.

Under the influence of ethanol, alcoholic hyaline is formed in the liver, which is perceived by the immune system as foreign. In response to this, autoimmune reactions develop, which are aggravated by acetaldehyde. A major pathogenetic role in the development of autoimmune reactions of proinflammatory cytokines (hyperproduction of tumor necrosis factor by Kupffer cells, as well as IL1, IL6, IL8) has been established. These cytokines enhance the release of proteolytic enzymes from lysosomes and promote the progression of immune reactions. Ethanol stimulates fibrosis processes in the liver, further promoting the development of liver cirrhosis. Ethanol has a necrobiotic effect on the liver through excessive formation of acetaldehyde and pronounced autoimmune reactions induced by the formation of alcoholic hyaline.

Mechanisms of liver damage

Relationship with alcohol and its metabolites

Rodents given alcohol develop only a fatty liver. However, they are not comparable in the amount of alcohol consumed to humans, who can cover 50% of their daily caloric needs with alcohol. This level can be achieved in baboons, which develop cirrhosis of the liver after 2-5 years of alcoholization. Data indicating a direct hepatotoxic effect of alcohol, independent of changes in diet, were obtained in volunteers (healthy people and alcoholics), who, after drinking 10-20 ounces (300-600 ml) of 86% alcohol per day for 8-10 days, developed fatty changes and structural abnormalities of the liver, revealed by electron microscopy of liver biopsies.

Acetaldehyde

Acetaldehyde is formed with the participation of both AlkDG and MEOS. In patients with alcoholism, the level of acetaldehyde in the blood increases, but only a very small part of it leaves the liver.

Acetaldehyde is a toxic substance that causes many of the signs of acute alcoholic hepatitis. Acetaldehyde is extremely toxic and reactive; it binds to phospholipids, amino acid residues, and sulfhydryl groups, damaging plasma membranes by depolymerizing proteins, causing changes in surface antigens. This results in increased lipid peroxidation. Acetaldehyde binds to tubulin and thus damages the microtubules of the cytoskeleton.

Acetaldehyde interacts with serotonin, dopamine and norepinephrine, forming pharmacologically active compounds, and also stimulates the synthesis of type I procollagen and fibronectin by Ito cells.

Putative hepatotoxic effects of acetaldehyde

• Strengthening the POL
• Binding to cell membranes
• Mitochondrial electron transport chain disorder
• Inhibition of nuclear repair
• Microtubule dysfunction
• Formation of complexes with proteins
• Complement activation
• Stimulation of superoxide formation by neutrophils
• Increased collagen synthesis

Changes in intracellular oxidation-reduction potential

In hepatocytes that actively oxidize alcohol breakdown products, there is a significant change in the NADH/NAD ratio, leading to profound metabolic disturbances. For example, the oxidation-reduction ratio between lactate and pyruvate increases significantly, leading to lactic acidosis. Such acidosis, combined with ketosis, disrupts the excretion of urates and leads to the development of gout. Changes in the oxidation-reduction potential also play a role in the pathogenesis of fatty liver, collagen formation, disruption of steroid metabolism, and slowing of gluconeogenesis.

Mitochondria

Swelling of mitochondria and changes in their cristae are detected in hepatocytes, which is probably due to the action of acetaldehyde. Mitochondrial functions are disrupted: oxidation of fatty acids and acetaldehyde is suppressed, the activity of cytochrome oxidase, the respiratory enzyme chain is reduced, and oxidative phosphorylation is inhibited.

Water and protein retention in hepatocytes

In rats, alcohol suppressed the secretion of newly synthesized glycoproteins and albumin by hepatocytes. This may be due to the fact that acetaldehyde binds to tubulin, thereby damaging the microtubules on which protein excretion from the cell depends. In rats given alcohol, the content of fatty acid binding protein in hepatocytes increased, which partly explains the overall increase in cytosolic protein.

Accordingly, the accumulation of protein causes water retention, which leads to swelling of hepatocytes, which is the main cause of hepatomegaly in patients with alcoholism.

Hypermetabolic state

Chronic alcohol consumption increases oxygen consumption, largely due to increased NADH oxidation. Increased liver oxygen demand creates an excessively high oxygen gradient along the sinusoids, resulting in hepatocyte necrosis in zone 3 (centrilobular). Necrosis in this area may be caused by hypoxia. Zone 3 contains the highest concentration of P450-II-E1, and this area also shows the most significant changes in oxidation-reduction potential.

Increased liver fat content

An increase in the amount of fat in the liver may be due to its intake with food, the penetration of free fatty acids from adipose tissue into the liver, or the synthesis of fats in the liver itself. In each case, the cause depends on the dose of alcohol consumed and the fat content of the food. After a single, rapid intake of a large dose of alcohol, fatty acids are found in the liver that come from adipose tissue. In contrast, with chronic alcohol consumption, an increase in the synthesis and a decrease in the breakdown of fatty acids in the liver are observed.

Immune liver disease

Immune mechanisms may explain the rare cases of liver disease progression despite cessation of alcohol consumption. However, excessive alcohol consumption rarely leads to the formation of a histological picture of chronic active hepatitis with immune disorders. Viral markers of hepatitis B and C should be absent.

In alcoholic liver disease, a violation of humoral immunity is detected, manifested by an increase in the level of serum immunoglobulins and the deposition of IgA along the wall of the liver sinusoids.

Liver damage due to impaired cellular immunity has been demonstrated using the antibody response to membrane antigens in alcohol-damaged rabbit hepatocytes. In patients with alcoholic hepatitis, circulating lymphocytes exert a direct cytotoxic effect on various target cells. In the active stage of alcoholic hepatitis, the infiltrate mainly contains neutrophils, which are soon replaced by lymphocytes. The distribution and persistence of lymphocytes expressing CD4 and CD8 antigens in actively progressing alcoholic hepatitis with increased expression of the major histocompatibility complex on hepatocytes, as well as their association with alcoholic hyaline and necrosis, support the assumption that cytotoxic interactions between T lymphocytes and hepatocytes play a role in the formation and consolidation of alcoholic liver damage.

The nature of the antigen stimulator is unknown. Such a role was attributed to Mallory's alcoholic hyaline, but these data were not confirmed. It is unlikely that such an antigen would be alcohol or its metabolites due to the small size of their molecules, but they can act as haptens. Acetaldehyde-collagen complexes were found in liver biopsy samples of patients with alcoholic liver disease. Their quantity correlated with the parameters of disease activity. It is possible that the impairment of cellular immunity is secondary, i.e. it is the body's response to a systemic disease.

Fibrosis

In patients with alcoholism, cirrhosis may develop against the background of fibrosis without an intermediate stage in the form of alcoholic hepatitis. The mechanism of fibrosis formation has not been established. Lactic acid, which enhances fibrogenesis, apparently participates in the pathogenesis of any severe liver damage.

Fibrosis results from the transformation of Ito fat-storing cells into fibroblasts and myofibroblasts. Type III procollagen is found in presinusoidal collagen deposits (Fig. 2 0-5). AlkDG can be detected in rat liver Ito cells.

The main stimulus for collagen formation is cell necrosis, but other causes are possible. Zone 3 hypoxia may be such a stimulus. In addition, an increase in intracellular pressure caused by an increase in hepatocytes may also stimulate collagen formation.

The decay products formed during lipid peroxidation activate Ito cells and stimulate collagen synthesis.

Cytokines

Endotoxins are often found in the peripheral blood and ascitic fluid of severely ill patients with liver cirrhosis. The appearance of these substances, formed in the intestine, is associated with impaired endotoxin detoxification in the reticuloendothelial system and increased intestinal wall permeability. Endotoxins release cytochromes, interleukins (IL) IL-1, IL-2 and tumor necrosis factor (TNF) from non-parenchymatous cells. In patients who constantly abuse alcohol, the concentration of TNF, IL-1 and IL-6 in the blood is increased. In alcoholic hepatitis, the formation of TNF by monocytes increases, the level of IL-8, a neutrophil chemotactic factor, increases in plasma, which may be associated with neutrophilia and liver infiltration by neutrophils. It is also possible that the formation of cytokines is stimulated by hepatocytes activated or damaged by alcohol.

There is a marked parallelism between the biological action of some cytokines and the clinical manifestations of acute alcoholic liver disease. This includes anorexia, muscle weakness, fever, neutrophilia, and decreased albumin synthesis. Cytokines stimulate fibroblast proliferation. Transforming growth factor beta (TGF-beta) stimulates collagen formation by lipocytes. TNF-a can inhibit drug metabolism by cytochrome P450, induce expression of complex HLA antigens on the cell surface, and cause hepatotoxicity. Plasma levels of these substances correlate with the severity of liver damage.

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Pathomorphology of alcoholic liver disease

Fatty liver disease, alcoholic hepatitis, and cirrhosis are often considered separate forms of alcoholic liver disease. However, their characteristic features often combine.

Fatty liver disease (steatosis) is the initial and most common manifestation of excessive alcohol consumption. It is a potentially reversible condition. Fatty liver disease is based on the accumulation of macrovesicular fat in the form of large droplets of triglycerides that displace the hepatocyte nucleus. Less commonly, fat appears in microvesicular form in the form of small droplets that do not displace the cell nucleus. Microvesicular fat contributes to mitochondrial damage. The liver enlarges and its surface becomes yellow.

Alcoholic hepatitis (steatohepatitis) is a combination of fatty liver, diffuse liver inflammation, and liver necrosis (often focal) of varying severity. Liver cirrhosis may also be present. The damaged hepatocyte appears swollen with granular cytoplasm (ballooning) or contains fibrous protein in the cytoplasm (alcoholic or hyaline Mallory bodies). Severely damaged hepatocytes undergo necrosis. Collagen accumulation and fibrosis of the terminal hepatic venules pose a threat to liver perfusion and contribute to the development of portal hypertension. Characteristic histologic features that suggest progression and development of liver cirrhosis include perivenular fibrosis, microvesicular fat accumulation, and giant mitochondria.

Liver cirrhosis is a progressive liver disease characterized by extensive fibrosis that disrupts the normal architecture of the liver. The amount of fat deposits may vary. Alcoholic hepatitis may develop in parallel. Compensatory liver regeneration consists of the appearance of small nodes (micronodular liver cirrhosis). Over time, even with complete abstinence from alcohol, the disease may progress to macronodular liver cirrhosis.

Iron accumulation in the liver occurs in 10% of individuals who abuse alcohol, with a normal liver, with fatty liver disease or cirrhosis. Iron accumulation is not related to iron intake or iron stores in the body.

Symptoms alcoholic liver disease

Symptoms correspond to the stage and severity of the disease. Symptoms usually become evident in patients after 30 years from the onset of the disease.

Fatty liver disease is usually asymptomatic. In one third of patients, the liver is enlarged, smooth, and sometimes painful.

Alcoholic hepatitis can occur in many forms, from a mild, reversible illness to a life-threatening pathology. In moderate severity, patients usually have poor nutrition, complain of fatigue, and may have fever, jaundice, right upper quadrant abdominal pain, hepatomegaly and tenderness, and sometimes a liver bruit. Their condition often worsens over the first few weeks after hospitalization. Severe cases may be accompanied by jaundice, ascites, hypoglycemia, electrolyte disturbances, liver failure with coagulopathy or portosystemic encephalopathy, or other manifestations of cirrhosis. If severe hyperbilirubinemia >20 mg/dL (>360 μmol/L), increased PT or INR (no effect after subcutaneous administration of vitamin K) and encephalopathy are observed, the risk of death is 20-50% and the risk of developing liver cirrhosis is 50%.

Liver cirrhosis may present with minimal signs of alcoholic hepatitis or symptoms of complications of the final stage of the disease. Portal hypertension (often with esophageal varices and gastrointestinal bleeding, ascites, portosystemic encephalopathy), hepatorenal syndrome, or even the development of hepatocellular carcinoma are commonly observed.

Chronic alcoholic liver disease may present with Dupuytren's contracture, spider angiomas, peripheral neuropathy, Wernicke's encephalopathy, Korsakoff's psychosis, and features of hypogonadism and feminization in men (eg, smooth skin, absence of male-pattern baldness, gynecomastia, testicular atrophy). These features are more likely to reflect the effects of alcoholism than liver disease. Malnutrition may cause enlargement of the parotid glands. Hepatitis C virus infection occurs in approximately 25% of alcoholics, a combination that significantly worsens the progression of liver disease.

Alcoholic liver disease has the following forms:

• Alcoholic adaptive hepatopathy
• Alcoholic fatty liver disease
• Alcoholic liver fibrosis
• Acute alcoholic hepatitis
• Chronic alcoholic hepatitis
• Alcoholic cirrhosis of the liver
• Hepatocellular carcinoma

A. F. Bluger and I. N. Novitsky (1984) consider these forms of alcoholic liver damage as successive stages of a single pathological process.

Alcoholic liver disease may be diagnosed during routine testing, such as for life insurance or other medical conditions, when hepatomegaly, elevated serum transaminases, GGT, or macrocytosis are detected.

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Diagnostics alcoholic liver disease

Alcohol is considered a cause of liver disease in any patient who consumes more than 80 g of alcohol per day. If the diagnosis is suspected, liver function tests, a complete blood count, and serologic tests for hepatitis are performed. There are no specific tests to confirm alcoholic liver disease.

Moderate elevation of aminotransferase levels (< 300 IU/L) does not reflect the degree of liver damage. Later, AST levels exceed ALT and their ratio is greater than 2. The cause of the decrease in ALT is deficiency of pyridoxine phosphate (vitamin B ₆ ), which is necessary for enzyme function. Its effect on AST is less pronounced. Serum gamma-glutamyl transpeptidase (GGT) levels increase as a result of ethanol-induced stimulation of the enzyme. Macrocytosis (mean corpuscular volume greater than 100) reflects the direct effect of alcohol on the bone marrow, as well as the development of macrocytic anemia due to folate deficiency, characteristic of malnutrition in alcoholism. The liver disease severity index is determined by the serum bilirubin content (secretory function), PT or INR (synthetic capacity of the liver). Thrombocytopenia may result from the direct toxic effect of alcohol on the bone marrow or from hypersplenism, which is observed in portal hypertension.

Instrumental examination is usually not required for diagnosis. If it is performed for other reasons, abdominal ultrasound or CT may confirm fatty liver or demonstrate splenomegaly, portal hypertension or ascites.

Patients with abnormalities suggestive of alcoholic liver disease should be screened for other liver diseases that require treatment, especially viral hepatitis. Because the features of fatty liver, alcoholic hepatitis, and cirrhosis often coexist, accurate characterization of the findings is more important than ordering a liver biopsy. A liver biopsy is performed to determine the severity of liver disease. If iron deposition is detected, quantitative iron determination and genetic testing can help exclude hereditary hemochromatosis as a cause.

General principles of proof of alcoholic etiology of liver damage

1. Analysis of anamnesis data regarding the quantity, type and duration of alcohol consumption. It should be taken into account that patients often hide this data.
2. Identification of markers (stigmas) of chronic alcoholism during examination:

• characteristic appearance: "crumpled appearance" ("banknote appearance"); puffy purple-blue face with a network of dilated skin capillaries in the area of the wings of the nose ("alcoholic's red nose"), cheeks, auricles; swelling of the eyelids; venous congestion of the eyeballs; pronounced sweating; traces of previous injuries and bone fractures, burns, frostbite;
• tremor of fingers, eyelids, tongue;
• underweight; obesity is common;
• changes in behavior and emotional status (euphoria, licentiousness, familiarity, often mental depression, emotional instability, insomnia);
• Dupuytren's contracture, hypertrophy of the parotid glands;
• muscular atrophy;
• pronounced signs of hypogonadism in men (testicular atrophy, female type of hair growth, low expression of secondary sexual characteristics, gynecomastia).

3. Identification of concomitant diseases of internal organs and the nervous system - companions of chronic alcoholism: acute erosive, chronic erosive and chronic atrophic gastritis, peptic ulcer; chronic pancreatitis (often calcifying); malabsorption syndrome; cardiopathy; polyneuropathy; encephalopathy.
4. Characteristic laboratory data:

• Complete blood count - anemia normo- hypo- or hyperchromic, leukopenia, thrombocytopenia;
• Biochemical blood test: increased activity of aminotransferases (alcoholic liver damage is characterized by a more significant increase in aspartic aminotransferase), gamma-glutamyl transpeptidase (even in the absence of an increase in the level of aminotransferases), alkaline phosphatase; hyperuricemia; hyperlipidemia;
• Immunological blood test: increased immunoglobulin A levels.

Characteristic histological data in the study of liver biopsies:

• detection of alcoholic hyaline (Mallory bodies) in hepatocytes;
• fatty degeneration;
• perivenular hepatocyte damage;
• pericellular fibrosis.

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Early diagnosis

Early diagnosis largely depends on the doctor's alertness. If the doctor suspects that the patient abuses alcohol, the CAGE questionnaire should be used. Each positive answer is worth 1 point. A score of 2 points or more suggests that the patient has alcohol-related problems. The first manifestations of the disease may be nonspecific dyspeptic symptoms: anorexia, morning sickness, and belching.

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CAGE questionnaire

• Have you ever felt the need to get drunk to the point of passing out?
• Do you ever become irritated when someone makes suggestions about alcohol consumption?
• G Do you feel guilty about drinking too much alcohol?
• E Do you drink alcohol in the morning to cure a hangover?
• diarrhea, vague pain and tenderness in the right upper quadrant of the abdomen, or fever.

A patient may seek medical help because of such consequences of alcoholism as social maladjustment, difficulties in performing one's job, accidents, inappropriate behavior, seizures, tremors, or depression.

Alcoholic liver disease may be diagnosed during routine testing, such as for life insurance or other medical conditions, when hepatomegaly, elevated serum transaminases, GGT, or macrocytosis are detected.

Physical signs may not indicate pathology, although an enlarged and painful liver, prominent vascular spiders, and characteristic signs of alcoholism contribute to the correct diagnosis. Clinical data do not reflect histological changes in the liver, and biochemical parameters of liver function may be normal.

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Biochemical indicators

Serum transaminase activity rarely exceeds 300 IU/L. The activity of AST, which is released from alcohol-damaged mitochondria and smooth muscle tissue, is increased to a greater extent than the activity of ALT, which is localized in the liver. In alcoholic liver disease, the AST/ALT ratio usually exceeds 2, which is partly due to the fact that patients develop a deficiency of pyridoxal phosphate, a biologically active form of vitamin B6, which is necessary for the functioning of both enzymes.

Determination of serum GGT activity is widely used as a screening test for alcoholism. Increased GGT activity is primarily due to enzyme induction, but hepatocyte damage and cholestasis may play a role. This test produces many false-positive results due to other factors, such as medications and concomitant diseases. False-positive results are observed in patients whose GGT activity is at the upper limit of normal.

Serum alkaline phosphatase activity may be markedly elevated (more than 4 times above normal), especially in patients with severe cholestasis and alcoholic hepatitis. Serum IgA may be extremely high.

Determination of alcohol content in blood and urine can be used clinically in patients who abuse alcohol but deny it.

In alcoholic excess and chronic alcoholism, nonspecific changes in the blood serum are observed, including increased levels of uric acid, lactate, and triglycerides, and decreased glucose and magnesium. Hypophosphatemia is associated with impaired renal tubular function independent of impaired liver function. Low serum triiodothyronine (T3) levels apparently reflect decreased conversion of T4 to T3 in the liver. T3 levels are inversely proportional to the severity of alcoholic liver disease.

Type III collagen can be assessed by serum procollagen type III peptide levels. Serum type IV collagen and laminin levels allow assessment of basement membrane components. The results of these three tests correlate with disease severity, the degree of alcoholic hepatitis, and alcohol consumption.

Other serum biochemical parameters are more indicative of alcohol abuse than of alcoholic liver disease. They include determination of serum glutamate dehydrogenase activity, the mitochondrial isoenzyme AST. Serum noncarbohydrate transferrin may be a useful indicator of alcohol excess independent of liver disease, but its measurement is not available in all laboratories.

Even sensitive biochemical methods may not detect alcoholic liver disease, so in doubtful cases a liver biopsy should be performed.

[ 43 ], [ 44 ], [ 45 ], [ 46 ], [ 47 ], [ 48 ], [ 49 ], [ 50 ]

Hematological changes

Macrocytosis with a mean corpuscular volume greater than 95 fL (95 μm3 ⁾ is probably due to the direct effect of alcohol on the bone marrow. Deficiency of folate and vitamin B12 is due to malnutrition. In 90% of patients with alcoholism, a combination of increased mean corpuscular volume and increased GGT activity is found.

Liver biopsy

A liver biopsy confirms liver disease and alcohol abuse as the most likely cause. In a conversation with the patient, the danger of liver damage can be emphasized more convincingly.

Liver biopsy has an important prognostic value. Fatty changes themselves do not have such a serious significance as perivenular sclerosis, which is a precursor to cirrhosis. Based on the biopsy, it is also possible to confirm the diagnosis of already developed cirrhosis.

Non-alcoholic steatohepatitis (NASH) can be caused by various reasons. In contrast to alcoholic damage, in NASH the changes are more localized in the periportal zone.

Treatment alcoholic liver disease

Avoidance of alcohol is the mainstay of treatment; it can prevent further liver damage and thus prolong life. Excellent results can be obtained through the efforts of support groups such as Alcoholics Anonymous, provided the patient is positively motivated.

Patients with severe somatic damage refuse alcohol more often than patients with mental disorders. According to data obtained during long-term observation of men admitted to the hepatology clinic, severe disease played a decisive role in the decision to refuse alcohol consumption.

Ongoing medical care is also important. A study of follow-up data on patients with alcoholic liver disease treated at the Royal Free Hospital between 1975 and 1990 found that 50% remained abstinent, 25% drank alcohol but not to excess, and 25% continued to abuse alcohol despite treatment. For less severe cases, a doctor or nurse may limit the treatment to "brief advice". This is effective in 38% of cases, although the results are often temporary. In more severe cases, the patient should be referred to a psychiatrist.

The development of withdrawal syndrome (delirium tremens) can be prevented by prescribing chlormethiazole or chlordiazepoxide.

The improvement in the patient's condition against the background of abstinence from alcohol and bed rest is sometimes so impressive that it actually allows the diagnosis of previous alcoholism.

During the period of alcohol withdrawal or recovery from liver decompensation, patients are prescribed additional nutrients in the form of proteins and vitamins. Initially, the protein content should be 0.5 g / kg, then as quickly as possible it is increased to 1 g per 1 kg of body weight. Encephalopathy can be a reason for limiting protein intake. Such patients usually have insufficient potassium reserves, so, as a rule, potassium chloride with magnesium and zinc are added to the diet. Large doses of vitamins are prescribed, especially groups B, C and K (intravenously if necessary).

Middle-class patients should, of course, be advised to abstain completely from alcohol, especially if liver biopsy has revealed zone 3 fibrosis. If they cannot adhere to a non-alcoholic regimen, they are advised to follow a well-balanced diet with a protein content of 1 g per 1 kg of body weight, with an energy value of at least 2000 kcal. Moderate vitamin supplements are desirable.

Symptomatic treatment involves supportive care. Dietary nutrition and B vitamins are necessary, especially during the first few days of abstinence from alcohol. However, these measures do not affect the outcome even in hospitalized patients with alcoholic hepatitis. Alcohol withdrawal requires the use of benzodiazepines (eg, diazepam). Excessive sedation in patients with established alcoholic liver disease may accelerate the development of hepatic encephalopathy.

There are few specific treatments for alcoholic liver disease. The efficacy of glucocorticoids in alcoholic hepatitis is controversial, but they are reserved for patients with the most severe disease. Drugs that are expected to reduce fibrosis (eg, colchicine, penicillamine) or inflammation (eg, pentoxifylline) have been ineffective. Propylthiouracil may have some benefit in treating the presumed hypermetabolic state of alcoholic liver, but its efficacy has not been confirmed. Antioxidants (eg, S-adenosyl-b-methionine, polyunsaturated phosphatidylcholine) have shown promising improvement in liver injury but require further study. Antioxidants such as silymarin (milk thistle) and vitamins A and E have not been shown to be effective.

Liver transplantation can increase five-year patient survival to more than 80%. Because up to 50% of patients continue to drink alcohol after transplantation, most programs require six months of abstinence from alcohol before a transplant is performed.

Forecast

The prognosis for alcoholic liver disease is determined by the severity of liver fibrosis and inflammation. With the elimination of alcohol, fatty hepatosis and alcoholic hepatitis without fibrosis are reversible; with alcohol abstinence, complete resolution of fatty hepatosis occurs within 6 weeks. With the development of liver cirrhosis and its complications (ascites, bleeding), the five-year survival rate is approximately 50%: the figure may be higher with alcohol abstinence and lower with continued alcohol consumption. Alcoholic liver disease, especially in combination with chronic viral hepatitis C, predisposes to the development of hepatocellular carcinoma.

[ 51 ], [ 52 ], [ 53 ], [ 54 ]