Alcoholic liver disease

Alcoholic liver damage (alcoholic liver disease) - various violations of the structure and functional capacity of the liver, caused by prolonged systematic use of alcoholic beverages.

Alcohol causes a number of liver damage that can progress from fatty hepatosis to alcoholic hepatitis (often this stage is considered intermediate) and liver cirrhosis.

[1], [2], [3], [4], [5], [6]

Epidemiology

In most Western countries, the level of alcohol consumption is high. In the United States, alcohol consumption per year per person is estimated at 10 liters of pure ethanol; 15 million people abuse or depend on alcohol. The ratio of men and women is 11: 4.

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

Not all people who abuse alcohol develop liver damage; Thus, according to autopsy data, the prevalence of cirrhosis among patients with alcoholism is approximately 10-15%. It is not known what is connected with the apparent predisposition of some people to the occurrence of alcoholic cirrhosis.

[7], [8], [9]

Causes of the alcoholic liver disease

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

Consumption of more than 60 g per day for 2-4 weeks leads to fatty hepatosis even in healthy men; the use of 80 grams per day can lead to alcoholic hepatitis, and 160 g per day for 10 years can lead to cirrhosis of the liver. The alcohol content is estimated by multiplying the volume of the drink (in ml) by the percentage of alcohol. For example, 40 ml of 80-degree beverage contains about 16 ml of pure alcohol (40% alcoholic beverage). Each milliliter of alcohol contains approximately 0.79 g. Although the levels can vary, the percentage of alcohol is approximately 2-7% for most types of beer and 10-15% for most wines.

Only 10-20% of patients with alcohol dependence develop cirrhosis of the liver. Women are more susceptible than men (even if we take into account the smaller body volume), probably because women have a lower alcohol-dehydrogenase content in the gastric mucosa, which reduces the amount of alcohol oxidation on the first pass.

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

The severity of manifestations and the frequency of alcoholic liver damage depends on the number and duration of alcohol intake. There are different points of view about the quantitative boundaries of safe and risky drinking areas.

In 1793, Matthew Bailey reported on the relationship of liver cirrhosis with the use of alcohol. Over the past 20 years, alcohol consumption has been correlated with the death rate from liver cirrhosis. In the US, cirrhosis of the liver is the fourth most common cause of death of adult men. Distribution of alcoholic liver disease largely depends on religious and other traditions, as well as on the ratio of the cost of alcohol and earnings: the lower the cost of alcohol, the more affected the lower socio-economic groups of the population.

Alcohol consumption is increasing in almost all countries. However, in the last 20 years, France has seen a decrease in it, which, apparently, is connected with the anti-alcohol propaganda carried out by the government. In the US, the consumption of alcoholic beverages, especially strong, also decreased, probably due to lifestyle changes.

[10], [11], [12],

Risk factors

The amount of alcohol consumed in a large group of men suffering from alcoholic cirrhosis of the liver averaged 160 grams per day for 8 years. Alcoholic hepatitis, pretsirroticheskoe lesion were detected in 40% of those surveyed who drank less than 160 grams per day. For most people, a dangerous dose of alcohol is more than 80 grams per day. An important role is played by the duration of alcohol use. In patients who consumed an average of 160 grams of alcohol per day for less than 5 years, neither cirrhosis nor alcoholic hepatitis was detected, while in 50% of 50 patients who consumed large amounts of alcohol for approximately 21 years, cirrhosis developed.

Damage to the liver does not depend on the type of alcohol used and is associated only with the alcohol content in it. Non-alcoholic beverage components are generally non-hepatotoxic.

The continued daily use of alcohol is more dangerous than the periodic intake, in which the liver has the ability to regenerate. At least 2 days a week should refrain from drinking alcohol.

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

The boundaries of safe use of alcohol

The boundaries of the safe Drinking alcohol		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 of Great Britain (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 are equivalent to 25 ml of vodka, 100 ml of wine, 200 ml of beer.

Toxic and low toxicity in relation to the liver of alcohol dose

Doses	Amount of alcohol / vodka	Time period
Relatively safe doses	210 ml of alcohol (530 ml of vodka) or 30 ml of alcohol (76 ml of vodka)	A 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: doses are indicated for men, doses for women are 2/3 of the above.

[13], [14], [15], [16]

Floor

Currently, there is 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 have alcoholism; they get to the doctor at later stages of the disease, are more sensitive to liver damage, they often develop relapse after treatment. The higher alcohol content in the blood after the use of the standard dose in women may be due to the lower volume of alcohol distribution. Against the background of alcoholic hepatitis, they develop cirrhosis more often, even if they stop using alcohol.

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

[17], [18]

Genetics

Behavioral patterns of alcohol use are inherited, but there is no genetic marker associated with susceptibility to alcoholic liver damage. The degree of elimination of alcohol in different people varies at least 3 times. The frequency of alcoholism is higher in monozygotes than in the dizygotic twins, which confirms the presence of a hereditary defect.

Modern studies do not allow to make an unambiguous conclusion about the connection of the genes of the main histocompatibility complex with alcoholic liver disease.

Differences in the degree of elimination of alcohol can be due to genetic polymorphism of enzyme systems. AlkDG is determined by five different genes located on chromosome 4. People with different isoenzymes of AlkDG differ in the degree of elimination of alcohol. The polymorphism of the most active forms of this enzyme - AlkDG2 and AlkDG3 - can have a protective value, since the rapid accumulation of acetaldehyde leads to a lower tolerance to alcohol. However, if such a person consumes alcohol, then a greater amount of acetaldehyde is formed, which leads to an increased risk of developing liver disease.

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

Acetaldehyde is converted to acetate by aldehyde dehydrogenase (AldDG). This enzyme is determined by four different loci on four different chromosomes. The main mitochondrial enzyme, AldDHH2, is responsible for most of the oxidation of the aldehyde. The inactive form of AldDHH2 is found in 50% of Chinese and Japanese, which explains the occurrence of reaction of acetaldehyde "flare up" after alcohol consumption, which often leads them into confusion. This phenomenon keeps the East from drinking alcohol and reduces the risk of developing alcoholic liver damage. However, in heterozygotes for the gene encoding AldDHH2, the metabolism of acetaldehyde is disrupted and they can be attributed to the group at high risk of developing alcoholic liver disease.

Polymorphism of genes encoding enzymes that participate in the formation of fibrosis can be important in determining individual susceptibility to the stimulating effect of alcohol on fibrogenesis.

Probably, the susceptibility to alcoholic liver damage is not associated with an individual genetic defect, but with the overall interaction of many genes. Alcoholism and alcoholic liver damage are polygenic diseases.

Food

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

Alcohol can increase the minimum daily requirement for choline, folic acid and other nutrients. Deficiency of nutrients, especially proteins, leads to a decrease in the content of amino acids and enzymes in the liver and thus can contribute to the toxic effects of alcohol.

It is suggested that both alcohol and malnutrition play a role in the development of the hepatotoxic effect; while the role of alcohol is more important. Probably, with optimal nutrition, a certain amount of alcohol can be consumed without damaging the liver. However, it is also possible that there is a threshold toxic concentration of alcohol, if exceeded, a change in diet can not have a protective effect.

[19], [20], [21], [22]

Pathogenesis

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

Oxidation of alcohol in the liver is carried out in 2 stages:

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

The metabolism of ethanol is carried out in hepatocytes by three enzyme systems.

1. The system of alcohol dehydrogenase (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, ethanol hydrogen is transferred to NAD +, which is reduced to NADH, and the oxidation-reduction potential of the hepatocyte changes.
2. Cytochrome P-450-dependent microsomal system (MCSE). The enzymes of this system are located in microsomes of the smooth cytoplasmic network of hepatocytes. MCSE carries out the metabolism of ethanol to acetaldehyde, as well as the detoxification of drugs. When alcohol is misused, proliferation of a smooth cytoplasmic network occurs.
3. The catalytic system of ethanol metabolism is in the peroxisomes of the cytoplasm and mitochondria. Using the NADFH oxidase enzyme in the presence of NADF-H and oxygen, hydrogen peroxide is generated, and further, with the hydrogen peroxide-H ₂ O ₂ -catalase complex, ethanol oxidizes to acetaldehyde. With alcohol abuse, there is an increase in the amount of peroxisomes in hepatocytes.

All of the above systems first produce the oxidation of ethanol to acetaldehyde, which is converted to acetylcoenzyme A using the mitochondrial enzyme acetaldehyde dehydrogenase. Further, acetylcoenzyme A is included in the Krebs cycle and oxidized to CO ₂ and H2O. With a low concentration of alcohol in the blood, its metabolism is mainly carried out by the system of alcohol dehydrogenase, and at high concentrations, mainly by the MCSE and the catalase system.

Acetaldehyde is converted to acetate by mitochondrial aldehyde dehydrogenase. Chronic alcohol consumption increases the formation of acetate. The processes lead to the formation of hydrogen, which converts adenine-nicotinamide dinucleotide (NAD) into its reduced form (NADP), increasing the oxidation-reduction potential in the liver. This replaces fatty acids as a source of energy, lowers the oxidation of fatty acids and promotes the accumulation of triglycerides, causing fatty hepatosis and hyperlipidemia. With an excess of hydrogen, pyruvate also turns into 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.

The metabolism of alcohol can also lead to hypermetabolism in the liver, causing hypoxia and damage as a result of the release of free radicals in lipid peroxidation. Alcohol and malnutrition cause a lack of antioxidants such as glutathione and vitamins A and E, which predisposes to such damage.

Inflammation and fibrosis in alcoholic hepatitis is largely due to acetaldehyde. It promotes the transformation of stellate cells (Ito), lining the blood channels of the liver (sinusoids), into fibroblasts, which produce miokontraktilnye elements and actively synthesize collagen. Sinusoids narrow and empty, limiting transport and blood flow. Endotoxins of the intestine, causing damage, are no longer detoxified by the liver, stimulating the formation of pro-inflammatory cytokines. Stimulating leukocytes, acetaldehyde and products of peroxidation cause even higher production of pro-inflammatory cytokines. There is a vicious circle of inflammation, which ends with fibrosis and death of hepatocytes.

Fat is deposited by hepatocytes as a result of disruption of its deposition in peripheral adipose tissue, increasing the synthesis of triglycerides, reducing lipid oxidation and reducing the production of lipoproteins that disrupt the export of fat from the liver.

Pathogenesis of alcoholic liver damage

1. Hyperfunctioning of the alcohol dehydrogenase system causes:

• increase in liver lactate and hyperlactatemia;
• increasing the synthesis of fatty acids by the liver and reducing their beta-oxidation in mitochondria of hepatocytes; obesity of the liver;
• increased production of ketone bodies, ketonemia and ketonuria;
• hypoxia of the liver and increase in its need for oxygen, the central periveneular zone of the hepatic lobe is most sensitive to hypoxia;
• inhibition of protein synthesis in the liver.

2. Hyperfunctioning of MCSE under the influence of large amounts of alcohol is accompanied by proliferation of smooth endoplasmic reticulum, increase in liver size, increased secretion of lipoproteins, hyperlipidemia, and obesity of the liver.
3. Chronic use of ethanol leads to a decrease in the ability of mitochondria to oxidize acetaldehyde, increasing the imbalance between its formation and degradation. 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 structure;
• the binding of acetaldehyde with cysteine and glutathione causes a disruption in the formation of reduced glutathione, which in turn contributes to the accumulation of free radicals; the restored glutathione in mitochondria plays an important role in maintaining the integrity of the organelle;
• functional disorders of enzymes associated with membranes of hepatocytes, and direct damage to the membrane structure;
• inhibition of hepatic secretion and increased intrahepatic cholestasis due to the binding of acetaldehyde with liver tubulin;
• activation of immune mechanisms (acetaldehyde is included in the composition of immune complexes involved in the formation of alcoholic liver disease).

4. With a significant intake of ethanol, there is an excess of acetyl-CoA, 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 obesity of the liver and blocks the removal of lipids from the liver in the form of lipoproteins.

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

Under the influence of ethanol in the liver formed alcoholic hyaline, perceived by the immune system as an alien. In response, autoimmune reactions develop, which are aggravated by acetaldehyde. A large pathogenetic role in the development of autoimmune reactions of pro-inflammatory cytokines (hyperproduction of tumor necrosis factor by Kupffer cells, as well as IL1, IL6, IL8) has been established. These cytokines increase the release of proteolytic enzymes from lysosomes and promote the progression of immune responses. Ethanol stimulates the processes of fibrosogenesis in the liver, contributing to the further development of cirrhosis of the liver. Ethanol exerts a necrobiotic effect on the liver through excessive formation of acetaldehyde and expressed autoimmune reactions induced by the formation of alcoholic hyaline.

Mechanisms of liver damage

Relationship with alcohol and its metabolites

In alcohol-treated rodents, only fatty liver develops. However, they can not be compared by the amount of alcohol consumed with people who can cover 50% of the daily requirement for calories due to alcohol. This level can be reached in baboons, who after 2-5 years of alcoholization develop cirrhosis of the liver. Data showing a direct hepatotoxic effect of alcohol, independent of changes in diet, were obtained on volunteers (healthy people and patients with alcoholism) who, after consuming 10-20 ounces (300-600 ml), 86% of alcohol per day for 8- On 10th day, fat changes and liver structure abnormalities, revealed by electron microscopy of liver biopsy specimens, developed.

Acetaldehyde

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

Acetaldehyde is a toxic substance that causes many signs of acute alcoholic hepatitis. Acetaldehyde is extremely toxic and reactive; it binds to phospholipids, amino acid residues and sulfhydryl groups, affects plasma membranes by depolymerizing proteins, causing changes in surface antigens. This increases the LPO. 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 procollagen I type and fibronectin by Ito cells.

Assumed hepatotoxic effects of acetaldehyde

• Strengthening LPO
• Binding to cell membranes
• Disturbance of the mitochondrial electron transfer chain
• Inhibition of nuclear repair
• Dysfunction of microtubules
• Formation of complexes with proteins
• Activation of complement
• Stimulation of superoxide formation by neutrophils
• Enhancement of Collagen Synthesis

Changes in intracellular redox potential

In hepatocytes, which actively oxidize the products of alcohol breakdown, there is a significant change in the ratio of NADH / NAD leading to profound metabolic disorders. For example, the oxidation-reduction ratio between lactate and pyruvate increases markedly, which leads to lactic acidosis. This acidosis in combination with ketosis violates the excretion of urates and leads to the development of gout. The change in oxidation-reduction potential also plays a role in the pathogenesis of fatty liver, the formation of collagen, a violation of the metabolism of steroids and the slowdown of gluconeogenesis.

Mitochondria

In hepatocytes, mitochondrial swelling and changes in their cristae are detected, which is probably due to the action of acetaldehyde. The functions of mitochondria are disturbed: the oxidation of fatty acids and acetaldehyde is suppressed, the activity of cytochrome oxidase, the chain of respiratory enzymes decreases, and oxidative phosphorylation is inhibited.

The retention of water and proteins in hepatocytes

In experiments on rats, alcohol suppressed the secretion of newly synthesized glycoproteins and albumin by hepatocytes. Perhaps this is due to the fact that acetaldehyde binds to tubulin, thus damaging the microtubules on which the excretion of protein from the cell depends. In rats receiving alcohol, the content of protein that binds fatty acids increased in the hepatocytes, which in part explains the overall increase in the amount of cytosolic protein.

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

Hypermetabolic state

The constant use of alcohol leads to increased consumption of oxygen, which is largely due to increased oxidation of NADH. Increasing the liver's oxygen demand leads to the formation of an excessively high oxygen gradient along the sinusoids, resulting in necrosis of hepatocytes in zone 3 (centrolobular). Necrosis in this area can be caused by hypoxia. Zone 3 shows the highest concentration of P450-II-E1, and the most significant changes in the oxidation-reduction potential are also detected in this region.

Increase in fat in the liver

An increase in the amount of fat in the liver can be due to its intake from food, the penetration of free fatty acids into the liver from adipose tissue 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 in the liver, fatty acids are found, which come from adipose tissue. In contrast, with chronic alcohol consumption, an increase in the synthesis and a decrease in the decomposition of fatty acids in the liver are observed.

Immune liver damage

Immune mechanisms can explain the rare cases of progression of liver disease, despite the cessation of alcohol use. Nevertheless, excessive consumption of alcohol 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.

With alcohol damage of the liver, a violation of humoral immunity is detected, which is manifested by an increase in the level of serum immunoglobulins and the deposition of IgA along the wall of the hepatic sinusoids.

Damage to the liver as a result of the violation of cellular immunity was demonstrated by the example of the reaction of antibodies with membrane antigens of rabbit hepatocytes, damaged by alcohol. 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 contains mainly neutrophils, soon replaced by lymphocytes. The distribution and persistence of lymphocytes expressing CD4 and CD8 antigens with actively progressive alcoholic hepatitis with enhanced expression on hepatocytes of the main histocompatibility complex, as well as their association with alcoholic hyaline and necrosis confirm the hypothesis that cytotoxic agents play a role in the formation and fixation of alcoholic liver damage interactions between T-lymphocytes and hepatocytes.

The nature of the antigenic stimulant is unknown. This role was attributed to the alcoholic hyaline Mallory, but this data was 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. Streets with alcoholic liver damage in liver biopsy have been found acetaldehyde-collagen complexes. Their number correlated with the parameters of disease activity. It is possible that the violation of cellular immunity is secondary, i.e. Is the reaction of the body to a systemic disease.

Fibrosis

In patients with alcoholism, cirrhosis can develop against a background of fibrosis without an intermediate stage in the form of alcoholic hepatitis. The mechanism of formation of fibrosis is not established. Lactic acid, which enhances fibrogenesis, appears to be involved in the pathogenesis of any severe liver damage.

Fibrosis develops as a result of the transformation of fat-storing Ito cells into fibroblasts and myofibroblasts. Procollagen III type is found in the presynusoidal collagen deposits (Figure 2 0-5). In the rat liver Ito cells, AlkDG can be detected.

The main stimulus for the formation of collagen is necrosis of cells, but there are other possible causes. Such an incentive may be the hypoxia of zone 3. In addition, an increase in intracellular pressure caused by an increase in hepatocytes can also stimulate the formation of collagen.

The degradation products formed during LPO activate Ito cells and stimulate the synthesis of collagen.

Cytokines

In the peripheral blood and ascitic fluid of severe patients with cirrhosis of the liver, endotoxins are often found. The appearance of these substances formed in the intestine is associated with a violation of detoxification of endotoxins in the reticuloendothelial system and an increase in the permeability of the intestinal wall. Endotoxins release cytochromes, interleukins (IL) IL-1, IL-2 and tumor necrosis factor (TNF) from nonparenchymal cells. In patients constantly abusing alcohol, the concentration of TNF, IL-1 and IL-6 in the blood is increased. When alcoholic hepatitis increases the formation of TNF monocytes, the level of IL-8, the neutrophil chemotaxis factor, increases in the plasma, with which neutrophilia and neutrophil infiltration of the liver can be associated. It is also possible that the formation of cytokines stimulates hepatocytes, activated or damaged by alcohol.

There is a pronounced parallelism between the biological effect of some cytokines and the clinical manifestations of acute alcoholic liver disease. This refers to anorexia, muscle weakness, fever, neutrophilia and a decrease in albumin synthesis. Cytokines stimulate the proliferation of fibroblasts. The transforming growth factor beta (TGF-beta) stimulates the formation of collagen by lipocytes. TNF-a can suppress the metabolism of drugs with cytochrome P450, induce the expression of complex HLA antigens on the cell surface, and cause a hepatotoxic effect. The level of these substances in plasma correlates with the severity of liver damage.

[23], [24], [25], [26], [27], [28], [29]

Pathomorphology of alcoholic liver disease

Fatty hepatosis, alcoholic hepatitis and cirrhosis of the liver are often considered as separate forms of alcoholic liver disease. However, their characteristic features are often combined.

Fatty hepatosis (steatosis) is the initial and most frequent manifestation of excessive consumption of alcohol. This is a potentially reversible state. The basis of fatty hepatosis is the accumulation of macrovesicular fat in the form of large droplets of triglycerides, which shift the nucleus of the hepatocyte. More rarely, fat appears in the microvesicular form in the form of small droplets, which do not shift the nucleus of the cell. Microvesicular fat contributes to damage to the mitochondria. The liver is enlarged, and its surface becomes yellow.

Alcoholic hepatitis (steatohepatitis) - a combination of fatty hepatosis, diffuse inflammation of the liver and hepatic necrosis (often focal) of varying severity. Cirrhosis can also be present. A damaged hepatocyte looks bloated with a granular cytoplasm (balloon degeneration) or contains a fibrous protein in the cytoplasm (alcoholic, or hyaline, Mallory's bodies). Significantly damaged hepatocytes are necrotic. Accumulation of collagen and fibrosis of terminal hepatic venules entails a threat of impaired perfusion of the liver and contributes to the development of portal hypertension. Characteristic histological signs that suggest the progression and development of liver cirrhosis include periveneular fibrosis, microvesicular fat accumulation and giant mitochondria.

Cirrhosis of the liver is a progressive liver disease characterized by extensive fibrosis, which disrupts the normal liver architectonics. The amount of fat accumulation can be different. In parallel, alcoholic hepatitis can develop. Compensatory regeneration of the liver consists in the appearance of small nodes (micronodular cirrhosis of the liver). Over time, even with complete elimination of alcohol consumption, the disease can progress with the development of macronodular cirrhosis of the liver.

Accumulation of iron in the liver occurs in 10% of people who abuse alcohol, with a normal liver, with fatty hepatosis or cirrhosis. The accumulation of iron is not related to iron intake or the iron reserve in the body.

Symptoms of the alcoholic liver disease

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

Fatty hepatosis usually proceeds asymptomatically. In a third of patients, the liver is enlarged, smooth and sometimes painful.

Alcoholic hepatitis can occur in various forms, from a mild, reversible disease to a life-threatening pathology. At moderate severity, patients usually eat poorly, complain of increased fatigue; they may have fever, jaundice, pain in the upper right quadrant of the abdomen, soreness and hepatomegaly and sometimes hepatic noise. Their condition often worsens in the first few weeks after hospitalization. Severe course can be accompanied by jaundice, ascites, hypoglycemia, electrolyte balance disorders, liver failure with coagulopathy or portosystemic encephalopathy or other manifestations of liver cirrhosis. If severe hyperbilirubinemia> 20 mg / dl (> 360 μmol / L) occurs, an increase in PV or MHO (no effect after subcutaneous administration of vitamin K) and encephalopathy, the risk of death is 20-50%, and the risk of cirrhosis is 50%.

Cirrhosis of the liver can be manifested by minimal signs of alcoholic hepatitis or symptoms of complications of the final stage of the disease. Usually there is portal hypertension (often with esophageal varices and gastrointestinal bleeding, ascites, portosystemic encephalopathy), hepatorenal syndrome or even the development of hepatocellular carcinoma.

In chronic alcoholic liver disease, Dupuytren's contracture, vascular sprouts, peripheral neuropathy, Wernicke's encephalopathy, Korsakovsky psychosis and signs of hypogonadism and feminization in men (for example, smooth skin, absence of male pattern baldness, gynecomastia, testicular atrophy) may be present in chronic alcoholic liver disease. These manifestations, most likely, reflect the influence of alcoholism than liver disease. Malnutrition can lead to an increase in parotid glands. Infection of the hepatitis C virus occurs in about 25% of people with alcoholism - this combination significantly worsens the progression of liver disease.

Alcoholic liver disease has the following forms:

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

AF Bluger and IN Novitsky (1984) consider these forms of alcoholic liver damage as successive stages of a single pathological process.

Alcoholic liver damage can be diagnosed by routine examination conducted, for example, for life insurance or for other diseases, when hepatomegaly is detected, increased activity of serum transaminases, GGTP or macrocytosis.

[30], [31]

Diagnostics of the alcoholic liver disease

Alcohol is considered as the cause of liver disease in any patient consuming more than 80 grams of alcohol per day. If this diagnosis is suspected, hepatic functional tests, a general blood test and serological tests for hepatitis are performed. There are no specific tests to confirm alcoholic liver disease.

A moderate increase in the level of aminotransferases (<300 IU / L) does not reflect the extent of liver damage. Further, the level of ACT exceeds ALT and their ratio is greater than 2. The reason for the decrease in ALT is the deficiency of pyridoxine phosphate (vitamin B ₆ ), which is necessary for the functioning of the enzyme. Its effect on ACT is less pronounced. The level of gamma glutamyltranspeptidase (GGT) of serum is increased as a result of ethanol-induced stimulation of the enzyme. Macrocytosis (mean erythrocyte volume more than 100) reflects the direct effect of alcohol on the bone marrow as well as the development of macrocytic anemia as a result of a deficiency of folic acid, characteristic of malnutrition in alcoholism. The index of severity of liver disease is determined by the serum bilirubin (secretory function), PV or MHO (synthetic ability of the liver). Thrombocytopenia can be the result of a direct toxic effect of alcohol on the bone marrow or hypersplenism that occurs with portal hypertension.

Diagnostics usually does not require an instrumental examination. If it is performed for other reasons, ultrasound of the abdominal cavity or CT scan can confirm fatty hepatosis or prove spleen-nomegaly, portal hypertension or ascites.

Patients with impairments indicating an alcoholic liver disease should be screened for other, requiring treatment for liver disease, especially for viral hepatitis. Since the characteristic signs of fatty hepatosis, alcoholic hepatitis and cirrhosis often combine, an accurate description of the findings is more important than administering a liver biopsy to a patient. A liver biopsy is performed to determine the severity of a liver disease. If iron deposition is established, quantitative determination of iron content and genetic studies will help to exclude hereditary hemochromatosis as a cause.

General principles of evidence of alcohol etiology of liver damage

1. Analysis of the history of the patient in terms of the number, type and duration of consumption of alcoholic beverages. It should be noted that patients often hide this data.
2. Identification of markers (stigma) of chronic alcoholism during examination:

• a characteristic external appearance: "rumpled appearance" ("appearance of the banknote"); a puffy crimson-cyanotic face with a network of dilated skin capillaries in the region of the wings of the nose ("red nose of an alcoholic"), cheeks, ears; swelling of the eyelids; venous plethora of eyeballs; severe sweating; traces of previous injuries and fractures of bones, burns, frostbite;
• tremor of fingers, eyelids, tongue;
• lack of body weight; Often there is obesity;
• changes in behavior and emotional status (euphoria, swagger, familiarity, often mental depression, emotional imbalance, insomnia);
• Dupuytren's contracture, parotid hypertrophy;
• muscular atrophy;
• expressed signs of hypogonadism in men (testicular atrophy, female type of hair, small expression of secondary sexual characteristics, gynecomastia).

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

• The general analysis of a blood - an anemia normo-gipo-or hyperchromic, a leukopenia, a thrombocytopenia;
• Biochemical analysis of blood: an increase in the activity of aminotransferases (for alcoholic liver lesions, a more significant increase in aspartic aminotransferase), gamma-glutamyltranspeptidase (even in the absence of an increase in the level of aminotransferases), alkaline phosphatase; hyperuricemia; hyperlipidemia;
• Immunological analysis of blood: an increase in the content of immunoglobulin A.

Characteristic histological data in the study of liver biopsies:

• detection of alcoholic hyaline in the hepatocytes (Mallory corpuscles);
• fatty degeneration;
• periveneular lesion of hepatocytes;
• pericellular fibrosis.

[32], [33], [34], [35], [36], [37], [38]

Early diagnosis

Early diagnosis is highly dependent on the doctor's alertness. If the doctor assumes that the patient is abusing alcohol, a CAGE questionnaire should be used. Each positive answer is estimated at 1 point. Score of 2 points or higher suggests that the patient has problems with alcohol. The first manifestations of the disease can be nonspecific dyspeptic symptoms: anorexia, nausea in the morning and belching.

[39], [40]

CAGE Questionnaire

• C Have you ever felt the need to get drunk before the trip?
• Do you get irritated in response to hints about alcohol use?
• G Do you feel guilty for excessive drinking?
• E Do you drink alcohol in the morning to fix a hangover?
• diarrhea, undefined pain and soreness in the upper right quadrant of the abdomen or fever.

The patient may seek medical help because of the consequences of alcoholism, such as social disadaptation, difficulties in performing their work, accidents, inadequate behavior, convulsions, tremors or depression.

Alcoholic liver damage can be diagnosed by routine examination conducted, for example, for life insurance or for other diseases, when hepatomegaly is detected, increased activity of serum transaminases, GGTP or macrocytosis.

Physical signs may not indicate a pathology, although the increase and soreness of the liver, pronounced vascular sprouts and characteristic signs of alcoholism contribute to the establishment of a correct diagnosis. Clinical data do not reflect histological changes in the liver, and biochemical indicators of liver function can be normal.

[41], [42]

Biochemical indicators

The activity of serum transaminases in rare cases exceeds 300 IU / l. The activity of ASA, 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 ratio of ASAT / ALAT is usually greater than 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.

The determination of the activity of GGTP in serum is widely used as a screening test for alcoholism. The increase in GGTP activity occurs mainly as a result of induction of the enzyme, however, hepatocyte damage and cholestasis can have a certain value. In this analysis, many false positive results are obtained, related to the effects of other factors, such as medications, and co-morbidities. False positive results are observed in patients in whom GGTP activity is at the upper limit of the norm.

In the blood serum, the activity of alkaline phosphatase (which exceeds the normal value by more than 4 times) can be markedly increased, especially in patients with severe cholestasis and alcoholic hepatitis. An extremely high serum IgA level can be detected.

The determination of blood and urine alcohol content can be used in a clinic in patients who abuse alcohol, but who deny it.

With alcoholic excesses and chronic alcoholism, nonspecific changes in blood serum are observed, including an increase in the level of uric acid, lactate and triglycerides, a decrease in glucose and magnesium. Hypophosphatemia is associated with impaired renal tubular function, regardless of liver function impairment. The low level of serum triiodothyronine (T3) appears to reflect a decrease in the conversion in the liver of T4 to T3. The T3 content is inversely proportional to the severity of alcoholic liver disease.

The content of type III collagen can be estimated from the level of serum peptides of procollagen III type. The serum content of type IV collagen and laminin makes it possible to evaluate the components of the basal membrane. The results of these three analyzes correlate with the severity of the disease, the degree of alcoholic hepatitis and the use of alcohol.

Other biochemical parameters of serum are more likely to indicate alcohol abuse than about alcoholic liver damage. They include the determination of the activity of serum glutamate dehydrogenase, the mitochondrial isoenzyme ASAT. The serum content of carbohydrate transferrin can be a useful indicator of alcoholic excesses, regardless of liver damage, but its determination is not available to all laboratories.

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

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

Hematologic changes

Macrocytosis with an average erythrocyte volume above 95 fl (95 μm ³ ) appears to be due to the direct effect of alcohol on the bone marrow. The lack of folate and vitamin B12 is caused by malnutrition. In 90% of patients suffering from alcoholism, a combination of an increase in the average volume of erythrocytes and an increase in GGTP activity is revealed.

Liver biopsy

A liver biopsy confirms the presence of liver disease and alcohol abuse as the most likely cause of it. In a conversation with a patient, you can more convincingly focus on the dangers of liver damage.

Liver biopsy has important prognostic value. In themselves, fat changes do not have such a serious significance as perivennular sclerosis, which is the precursor of 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 causes. In contrast to alcohol abuse in NASH, the changes are more localized in the periportal zone.

Treatment of the alcoholic liver disease

Alcohol refusal is the basis of treatment; this can prevent further damage to the liver and thus prolong life. Excellent results can be obtained through the efforts of support groups such as anonymous alcoholics, provided that the patient has positive motivation.

Patients with severe somatic lesions refuse alcohol more often than patients with mental disorders. According to the data obtained with prolonged follow-up of men admitted to the hepatology clinic, a serious illness played a decisive role in the decision to abandon the use of alcohol.

Continuous medical care is also important. The study of follow-up data on patients with alcoholic liver disease treated at Royal Free Hospital between 1975 and 1990 showed that 50% of them continued to abstain from drinking alcohol, 25% consumed alcohol, but not in excessive quantities, and 25 % continued to abuse alcohol, despite treatment. For less severe patients, a doctor or nurse can limit themselves to "brief recommendations." This method is effective in 38% of cases, although the result is often temporary. In more severe cases, the patient must be referred to a psychiatrist.

The development of withdrawal syndrome ( alcohol delirium) can be prevented by the appointment of chloromethiazole or chlordiazepoxide.

Improvement of the patient's state against the background of refusal to drink alcohol and bed rest is sometimes so impressive that it actually allows you to diagnose the previous alcoholism.

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

Of course, middle-class patients should be recommended to completely stop using alcohol, especially when liver fibrosis reveals fibrosis of the zone. 3 If they can not comply with the alcohol-free regime, they are recommended a well-balanced diet with a protein content of 1 g per 1 kg of body weight, having an energy value of not less than 2000 kcal. Moderate vitamin supplements are desirable.

Symptomatic treatment implies supportive therapy. Dietary nutrition and B vitamins are needed, especially during the first few days of abstinence from the alcohol. However, these measures do not affect the outcome, even in hospitalized patients with alcoholic hepatitis. Elimination of alcohol requires the appointment of benzodiazepines (eg, diazepam). Excessive sedation in patients with established alcoholic liver disease can accelerate the development of hepatic encephalopathy.

There are several specific methods for treating alcoholic liver disease. The effectiveness of glucocorticoids in alcoholic hepatitis is controversial, but they are used in patients with the most severe stage of the disease. Medicines that would reduce fibrosis (eg, colchicine, penicillamine) or inflammation (eg, pentoxifylline) have proven ineffective. Presumably, propylthiouracil could provide some effect in the treatment of the alleged hypermetabolic state of the alcoholic liver, but its effectiveness has not been confirmed. Antioxidants (eg S-adenosyl-b-methionine, polyunsaturated phosphatidylcholine) have shown encouraging improvement in liver damage, but require further research. The effectiveness of antioxidant drugs, such as silymarin (milk thistle) and vitamins A and E, is not confirmed.

Liver transplantation can improve the five-year survival of patients to a level of more than 80%. Since up to 50% of patients continue to consume alcohol after transplantation, most programs require a six-month abstinence before the transplant is performed.

Forecast

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

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