Alcoholic liver disease: clinical guidelines

List of Abbreviations

MCV – Mean Corpuscular Volume

SAM – S-adenosylmethionine

TLR4 – Toll-like receptor 4

ALD – Alcoholic Liver Disease

ADH – Alcohol dehydrogenase

AH – Alcoholic hepatitis

ALDH – Aldehyde dehydrogenase

ALT – Alanine aminotransferase

AST – Aspartate aminotransferase

AS – Alcoholic steatosis

AC – Alcoholic cirrhosis

EGV – Esophageal varices

GGT – Gamma-glutamyl transferase

GCs – Glucocorticosteroids

GI – Gastrointestinal tract

IL – Interleukin

BMI – Body Mass Index

BRIEF – Brief intervention

CoA – Coenzyme A

LDH – Lactate dehydrogenase

LPS – Lipopolysaccharide

MEOS – Microsomal ethanol-oxidizing system

NADH – Nicotinamide adenine dinucleotide, reduced form

PT – Prothrombin time

LPO – Lipid peroxidation

HE – hepatic encephalopathy

RCT – Randomized controlled trial

TNFα – Tumor necrosis factor alpha

LC – Liver cirrhosis

ALP – Alkaline phosphatase

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Alcoholic liver disease (ALD) is a clinical and morphological concept reflecting liver damage resulting from alcohol abuse. ALD includes the following clinical and morphological forms: alcoholic steatosis (AS), alcoholic hepatitis (AH), and alcoholic cirrhosis (AC).

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiology of alcoholic liver disease is associated with prolonged abuse of alcoholic beverages in hazardous doses, which have a damaging effect on the liver.

According to World Health Organization (WHO) guidelines, there are "hazardous" and "harmful" patterns of alcohol consumption, heavy episodic drinking, and alcohol dependence.

Hazardous alcohol use is a pattern of drinking that brings a risk of physical or mental health harm with continued use [1].

Harmful use is defined as alcohol consumption that causes damage to physical or mental health [1]. At the same time, the patient may not be aware of having the disease (as often happens with ALD due to the lack of pronounced symptoms in the early stages of the disease). Heavy episodic drinking is considered to be more than 60 g of pure alcohol consumed per day.

Alcohol dependence is diagnosed by a narcologist when psychological and physical dependence develops. ALD is diagnosed in almost all patients with alcohol dependence.

In the international community, to provide an objective assessment of an individual's alcohol consumption level regardless of the strength of the alcoholic beverage, experts decided to introduce the term "standard drink". It is customary to calculate the number of standard drinks (SD) consumed by an individual in grams. One SD = 10 g of ethanol (or 12.7 ml of alcohol), which corresponds to 30 ml of spirits (vodka, cognac, etc.), 100 ml of 12% wine, or 250 ml of 5% beer.

You can calculate the amount of ethanol in milliliters (SD) in a beverage using the formula:

Number of alcohol SDs = Volume (ml) × ABV (%) × 8/10000, where ABV (%) = Alcohol by volume (%).

SD = (strength (% vol) × volume (ml) × n (times per week)) / 1275 (for daily dose calculation, n = 1).

Consuming more than one standard drink of alcohol per day increases the likelihood of an unfavorable health prognosis for the patient. Based on research data, according to the guidelines of the Russian Liver Research Society (ROPOL), and the European Association for the Study of the Liver (EASL), a hazardous dose is considered to be the intake of alcoholic beverages in the amount of 30 g of pure ethanol (3 SD) per day for men and 20 g of pure ethanol (2 SD) per day for women [2,3]. For example, 0.5 l of vodka contains 16 SD (160 g of pure ethanol), and 0.5 l of beer (5% _ABV) contains 2 SD. Hazardous and health-threatening doses of alcohol for men are 30 g/day in terms of pure ethanol, which is equivalent to 75 ml of vodka (40% _ABV), 300 ml of dry wine (10% _ABV), 600 ml of beer (5% _ABV). Consuming more than 7 SD for women and more than 14 SD for men per week leads to an increased risk of developing ALD [2].

Among the factors determining the nature of liver damage, the most significant are the following: sex, genetic polymorphism (ethnicity), nutritional status, intake of certain xenobiotics, amount and duration of alcohol consumption, type of alcoholic beverages consumed, and smoking.

Sex. Women are more sensitive to the effects of hazardous doses of alcohol, which can be explained to a certain extent by the lower activity of gastric mucosal alcohol dehydrogenase, leading to a higher concentration of ethanol in blood plasma and more active ethanol metabolism in the liver. Risk factors for ALD may include female-pattern fat distribution, with excess production of proinflammatory cytokines by this tissue. Of interest is the role of estrogens, which promote enhanced expression of the bacterial lipopolysaccharide (LPS) receptor (CD14) on mononuclear phagocytes. This can lead to increased intestinal permeability and more pronounced fibrogenesis [4]. Prolonged exposure to LPS leads to excessive production of proinflammatory cytokines (e.g., TNF-α), which play an important role in the pathogenesis of ALD [5].

Genetic polymorphism of ethanol-metabolizing enzymes. There are 7 ADH isoenzymes. Isoenzymes are grouped into classes based on their amino acid sequence and enzymatic activity. Three main genes encoding ADH (alcohol dehydrogenase) have been identified in humans: ADH1, ADH2, and ADH3. They have different polymorphic variants. Thus, ADH1 has 1 variant, ADH2 has 3 variants, and ADH3 has 2 variants. It is known that the ADH2*1 variant is found with varying frequency in all populations, while ADH2*2 is detected in a higher percentage of cases in Asians and a lower percentage in Europeans. The ADH2*3 variant occurs in 15-20% of cases only in African Americans. Carriers of ADH2*2 often consume less alcohol and also have an increased risk of side effects caused by alcohol intake [6].

The classification of ALDH (aldehyde dehydrogenase) is based on its electrophoretic mobility. Cytosolic ALDH1 and mitochondrial ALDH2 play the primary role in ethanol metabolism. Expression of these enzymes is observed not only in the liver but also in the kidneys, muscles, heart, and pancreas. About 40% of hepatic ALDH activity is accounted for by ALDH2. There is a mutant ALDH isoform designated as ALDH2*2, and the normal variant is ALDH2*1 [6].

ALDH2*2 has low enzymatic activity and is considered an atypical variant. The low activity of this enzyme can manifest clinically as alcohol flush reaction—facial flushing, tachycardia, and sometimes collapse.

Such polymorphism most likely leads to significant differences in ethanol metabolism and determines its tolerance both among individuals and across different populations (races). The risk of toxic effects of alcohol is increased in individuals with high ADH activity and low ALDH activity [6]. Thus, the rate of formation of toxic acetaldehyde increases while its breakdown rate decreases.

Nutrition. Ethanol impairs intestinal absorption and storage of nutrients, and also causes a decrease in appetite due to its high caloric content. As a result, a chronic deficiency of protein, vitamins, and minerals occurs. Nutritional deficiency contributes to the progression of ALD, but adequate nutrition does not prevent alcoholic liver damage [5]. According to the Dionysos study conducted in northern Italy, it was found that drinking alcohol without food and consuming more than 1 type of alcoholic

beverage increases the risk of developing liver cirrhosis (LC) [7].

Obesity is also a risk factor for the progression of liver fibrosis, especially in individuals who abuse alcohol. According to one study, consuming more than 15 SD of alcohol per week by obese individuals leads to an almost 19-fold increase in the risk of death from liver disease (OR = 18.9; 95% CI 6.84–52.4) compared to lean individuals (OR = 3.16; 95% CI 1.28–7.8) [8].

Interesting data have been obtained regarding the risk of developing LC and coffee consumption. According to a meta-analysis, consuming more than 2 cups of coffee a day, all other things being equal, halves the risk of developing alcoholic liver cirrhosis (AC) (RR = 0.62; 95% CI 0.51–0.73) [9].

Hepatotropic virus infection. Infection with hepatitis B and C viruses, which is frequently observed in individuals who abuse alcohol, increases the rate of progression of liver damage. For example, with the combined pathogenic action of alcohol and hepatitis C, the risk of developing hepatocellular carcinoma (HCC) is doubled [5].

Increased toxicity of xenobiotics. Alcohol abuse enhances the hepatotoxic effects of various drugs, including nonsteroidal anti-inflammatory drugs (acetylsalicylic acid, indomethacin, ibuprofen, paracetamol, etc.), antibiotics (e.g., tetracyclines), amiodarone, methotrexate, corticosteroids, estrogens, systemic antifungals, antituberculosis drugs (e.g., isoniazid), as well as laxatives, tamoxifen, anticonvulsants, psychotropics, anesthetics, and antidepressants [10].

Amount and duration of alcohol consumption. The frequency of alcohol consumption also has a significant impact on the risk of ALD progression. In a prospective cohort study by Sandahl T.D. et al., the risk of developing alcoholic cirrhosis was increased in daily alcohol consumers (OR 3.65; 95% CI 2.39-5.55) compared to those who consumed alcohol 2-3 times a week [11].

Several hazardous drinking patterns can be identified:

a) Heavy episodic drinking (consumption of more than 60 g of ethanol per single drinking episode [12].

b) Binge drinking (consumption of more than 4 standard drinks (SDs) for women and more than 5 SDs for men in less than 2 hours).

A study by Askgaard G. et al. showed that daily alcohol consumption is the most powerful inducer of alcoholic cirrhosis formation [13]. At the same time, a study by Aberg F. et al. demonstrated that binge drinking is a leading risk factor for ALD regardless of average alcohol consumption [14]. Binge drinking increases the risk of alcoholic cirrhosis [13].

Type of alcoholic beverages consumed. It has been proven that the risk of developing alcoholic cirrhosis is lower with red wine consumption than with other types of alcohol (RR = 0.3) [15].

Smoking. A twenty-year population-based study showed that smoking more than 1 pack of cigarettes per day led to a 3-fold increase in the risk of ALD progression compared to non-smokers, given an equal amount and pattern of alcohol consumption [16].

The pathogenesis of alcoholic liver disease involves three main components: the direct damaging effect of alcohol and its metabolites, activation of the innate immune system, and alteration of the gut microbiota composition. Let us examine each of them in more detail (Figure 1).

Figure 1. Pathogenesis of alcoholic liver disease

Effects of alcohol and its metabolites. Up to 95% of ethanol is oxidized in the liver. There are three metabolic pathways for this purpose, which can function in parallel or shift in one direction or another depending on the amount and duration of ethanol consumption. These are pathways utilizing: alcohol dehydrogenase (ADH), the microsomal ethanol-oxidizing system, and peroxisomal catalases.

As a result of ethanol oxidation by the aforementioned enzymes, acetaldehyde is formed—a highly toxic compound that exerts the primary damaging effect on liver cells.

With prolonged, chronic alcohol consumption, its metabolism predominantly occurs via cytochrome P450—the microsomal ethanol-oxidizing system (MEOS). Unlike alcohol dehydrogenase, MEOS (CYP2E1 reductase) is an inducible enzyme. In addition, this enzyme system metabolizes xenobiotics, which include a number of medications. It is the induction of CYP2E1 that is associated with the increased sensitivity of heavy drinkers to certain drugs (e.g., nonsteroidal anti-inflammatory drugs, analgesics, particularly paracetamol). This fact must be considered when selecting therapy and drug dosages for patients who abuse alcohol.

The direct toxic effect of accumulated (excess) acetaldehyde promotes lipid peroxidation, disruption of the electron transport chain and mitochondrial dysfunction, suppression of DNA repair (leading to mutation accumulation), depletion of the glutathione peroxidase defense system, and increased collagen synthesis, which activates fibrogenesis. By donating an electron to an oxygen molecule, acetaldehyde initiates the formation of free radicals that damage proteins and membrane phospholipids.

Studies have demonstrated the important role of the innate immune system in the development and progression of ALD, especially alcoholic hepatitis. Damaged hepatocytes release a wide range of cytokines that attract inflammatory cells, predominantly neutrophils, into the liver parenchyma. Activated neutrophils themselves serve as a source of free radicals. Cytokines cause the activation of Ito cells, which begin to intensively synthesize type I collagen, leading to liver fibrosis. Acetaldehyde can directly activate Ito cells. Thus, acetaldehyde is responsible for the destructive, inflammatory, and fibrotic processes in the liver.

It is known that ethanol causes alterations in the composition of the gut microbiota. Systematic ethanol intake leads to bacterial overgrowth in the intestine, predominantly driven by gram-negative flora, and increased intestinal permeability, resulting in a significant amount of lipopolysaccharides (LPS) entering the portal venous system. In the liver, they trigger a complex cascade of reactions leading to the secretion of large amounts of pro-inflammatory cytokines, particularly TNF-α. Together with reactive oxygen species, LPS exert a damaging effect on the cell, triggering mechanisms of necrosis and apoptosis, and stimulating the synthesis of extracellular matrix proteins, thereby promoting liver fibrosis and cirrhosis [17].

One of the main molecules neutralizing free radicals is glutathione. Its synthesis requires cysteine, which is formed with the participation of S-adenosylmethionine (ademetionine, SAM). SAM, in turn, is formed from dietary methionine via the enzyme methionine adenosyltransferase. Methionine is also resynthesized in the body, and its regeneration is closely linked to serine and glycine metabolism and the interconversion of H4-folate derivatives and vitamin B12. SAM not only helps increase glutathione concentration but also reduces the production of tumor necrosis factor-alpha (TNF-α) in response to lipopolysaccharide (LPS) stimulation and increases the production of the anti-inflammatory cytokine interleukin-10 (IL-10) by macrophages [18-21]. Alcohol reduces the production of SAM.

1.3 Epidemiology of the Disease or Condition

Hazardous alcohol consumption leads to 3.3 million deaths per year (5.9% of all-cause deaths), as well as disability and health decline for millions of people worldwide. According to WHO data, harmful and hazardous alcohol consumption accounts to 5.1% of the global burden of disease and injury, which corresponds to about 139 million years of healthy life lost, estimated in DALYs (Disability-Adjusted Life Years) [22]. Alcohol is a leading cause of premature death in young and working-age individuals, accounting for 10%.

Average worldwide alcohol consumption is 6.2 liters of pure ethanol per person per year, and in the European region, it is 10.9 L/year [22]. There are geographical differences in the patterns, styles, and amounts of alcohol consumed, which affect morbidity and mortality rates from this cause. According to Rosstat of the Russian Ministry of Health, the incidence of alcoholism in the Russian population in 2020 was 1,102.8 thousand people. And this is only official statistics for individuals registered at healthcare facilities. The exact figures for the prevalence of ALD, alcoholism, and especially alcohol abuse are virtually impossible to calculate.

An analysis of a population-based study conducted in Moscow in 2012, which included 5,000 participants, showed that 12.5% of the examined individuals abused alcohol, and 5% had dependence according to responses to validated CAGE and AUDIT questionnaires (Appendix G). Consuming alcoholic beverages in a health-damaging dose (> 2 points on the CAGE questionnaire, > 16 points on the AUDIT questionnaire; p=0.04) is an independent risk factor for liver damage [18]. When analyzing the causes of mortality from liver disease, it was found that severe forms of ALD account for 41% [23].

According to a study conducted in 2016, the prevalence of alcohol abuse among gastroenterology patients was 49.8% (AUDIT-C > 12 points), and individuals with suspected alcohol dependence (CAGE > 2 points) accounted for 45.3% [24].

Such an alarming situation prompted the development of both international and state concepts for reducing the harm caused to the population as a result of alcohol abuse. In January 2022, the WHO developed a concept as a priority healthcare project for 2022–2030 for the effective implementation of the global strategy to reduce the harmful use of alcohol. In the Russian Federation, thanks to the measures taken by the government aimed at reducing alcohol consumption by the population, it was possible to achieve a decrease in per capita alcohol consumption figures from 15.8 liters (in terms of pure ethanol) in 2010 to 9.1 liters in 2020 [25]. Although this indicator shows a downward trend, strong alcoholic beverages and beer (39% each) predominate in the structure of consumed alcohol, while wine consumption accounts for only 13% (according to WHO data for 2018).

1.4 Features of Coding the Disease or Condition

K00-K93 Chapter XI. Diseases of the digestive system

K70-K77 Diseases of the liver

K70.0 – Alcoholic fatty liver disease;

K70.1 – Alcoholic hepatitis;

K70.2 – Alcoholic liver fibrosis and sclerosis;

K70.3 – Alcoholic cirrhosis of the liver;

K70.4 – Alcoholic liver failure;

K70.9 – Alcoholic liver disease, unspecified

1.5 Classification of the disease or condition

Based on clinical and morphological criteria, three main forms of alcoholic liver disease are distinguished: steatosis, hepatitis, and cirrhosis.

It is believed that alcoholic steatosis develops in 90% of cases in individuals consuming ethanol in dangerous doses. This is driven by three main metabolic processes in the liver associated with the systematic intake of alcohol:

1) the formation of excess acetyl-CoA in the cytoplasm of hepatocytes, which stimulates fatty acid synthesis; a high concentration of NADH, which reduces dihydroxyacetone phosphate to glycerol-3-phosphate (used together with fatty acids for fat synthesis);

2) a slowdown in the rate of fatty acid β-oxidation due to an excess of NADH and ATP, which shifts the process of utilizing incoming fatty acids toward fat synthesis;

3) impaired synthesis of very low-density lipoproteins (VLDL) and transport of fats from the liver to tissues. As a result, fat accumulates in the liver tissue, which morphologically manifests most often as macrovesicular steatosis, localized mainly in acinar zones 3 and 2. With abstinence, these changes resolve within 4–6 weeks. However, continued alcohol intake in hazardous doses leads in 10–20% of cases to disease progression to the next stage – alcoholic steatohepatitis [26]. At this stage, the disease may manifest as a moderate increase in liver aminotransferases, gamma-glutamyl transpeptidase (GGT), and total bilirubin.

Alcoholic hepatitis is divided into two forms according to the severity of liver damage and life prognosis: steatohepatitis and severe alcoholic hepatitis. The latter manifests with rapid progression of liver failure, the development of jaundice, ascites, blood clotting disorders, and is characterized by high short-term mortality (30–50%).

Thus, determining the severity of alcoholic hepatitis is not a formality, as the prognosis and, accordingly, the patient's treatment tactics are tied to it. In most cases, severe alcoholic hepatitis develops against the background of alcoholic liver cirrhosis, which makes the patient's life prognosis even worse.

Alcoholic liver cirrhosis develops in less than 10% of patients and is classified by the severity of liver cirrhosis from class A to C according to the Child-Pugh scale. The classification of the severity of liver cirrhosis is described in detail in the clinical guidelines for this disease [27].

1.6 Clinical presentation of the disease or condition

Clinical manifestations of ALD depend on the stage of the disease.

Liver steatosis (fatty liver infiltration) is usually asymptomatic; some patients may complain of decreased appetite, dyspeptic disorders, a feeling of discomfort in the upper abdomen after eating, and a dull pain in the right hypochondrium. In biochemical blood tests, deviations from the norm are generally not observed, and liver function is preserved. Liver steatosis is often detected quite accidentally (as a diagnostic finding) during an examination for another reason using abdominal ultrasound.

Alcoholic hepatitis (AH) is a progressive inflammatory-dystrophic liver lesion that can develop at any stage of ALD with prolonged systematic consumption of dangerous doses of ethanol. Since hepatitis usually develops against the background of liver steatosis, the signs of the latter (hepatomegaly, hyperechogenicity of the liver parenchyma) are also present, which is why the term "alcoholic steatohepatitis" is sometimes used. Alcoholic hepatitis manifests with acute-phase reactions, which include fever, general weakness, arthralgia, and myalgia. Inflammatory edema and infiltration of the liver can lead to an increase in its size and stretching of Glisson's capsule, which manifests as pain in the right hypochondrium. At the AH stage, edema and an increase in abdominal volume due to ascites of varying severity are sometimes observed.

With massive liver edema, compression of the hepatic veins and the development of reversible portal hypertension with ascites and splenomegaly may occur. Compression of the smallest bile ducts can lead to the development of intrahepatic cholestasis, characterized by increased activity of alkaline phosphatase (ALP) and GGT; the clinical manifestation is pruritus, which may worsen at night. Patients may complain of yellowing of the skin and sclera.

Alcoholic liver cirrhosis is the terminal stage of ALD. The risk of developing cirrhotic transformation of the liver increases in proportion to the increase in the alcohol dose, starting from an amount of more than 40–60 g of pure ethanol per day. The highest risk of developing ALC is in individuals consuming more than 120 g of ethanol per day. The formation of cirrhosis can occur without a stage of pronounced inflammation. When ALC develops, 60–85% of patients die within 5 years [28], and 90% within 15 years [29]. If complications of cirrhosis have not developed, 10–20% of patients die within the first year; if the patient had esophageal variceal bleeding (EVB) – 20%, ascites – 30%, a combination of ascites and EVB – 50%, hepatic encephalopathy – 60% [28].

In the case of preserved liver function, the well-being of patients may remain relatively satisfactory. Compensated ALC is asymptomatic in 30–40% of cases or presents with some nonspecific complaints: general weakness, decreased or absent appetite, fatigue, reduced working capacity, dyspeptic disorders, weight loss, and loss of muscle mass (sarcopenia). With decompensation of liver function, the above complaints intensify, and clinical signs of liver failure appear. The disease may manifest with the appearance of edematous-ascitic syndrome with an increase in abdominal volume/ascites, lower extremity edema; jaundice, the development of hepatic encephalopathy, bleeding from esophageal and/or gastric, rectal varices, hemorrhagic syndrome (gum bleeding and/or nosebleeds, spontaneous appearance of petechiae and ecchymoses, etc.), sleep inversion (insomnia at night and drowsiness during the day). With tense ascites and/or hydrothorax, exertional dyspnea and cough in the supine position may appear. In women of childbearing age, a manifestation of ALC can be menstrual irregularities up to amenorrhea, and in men – erectile dysfunction and decreased libido [27].

Thus, the clinical picture of LC does not depend on the etiology of the disease, and its detailed description can be found in the 2021 clinical guidelines of the Russian Ministry of Health [27].

An objective physical examination reveals stigmata of prolonged alcohol abuse (section 2.2).

Various manifestations of vitamin deficiency may be observed in patients with ALD. Thus, thiamine deficiency (obtained from food and partially synthesized by the intestinal microflora) due to chronic alcohol consumption serves as one of the factors of brain damage. Thiamine is a precursor of a cofactor (thiamine diphosphate — TDP), which is the active part of TDP-dependent enzymes (pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes, and transketolases) that catalyze metabolic processes associated with energy production. This process is of particular importance in nervous tissue. TDP is involved in carbohydrate metabolism; its deficiency affects numerous cellular functions, in particular, glucose utilization by neurons is reduced. The accumulation of glutamate resulting from a decrease in the activity of the alpha-ketoglutarate dehydrogenase complex against the background of energy deficiency has a neurotoxic effect. As a result, there is a decrease in the number of neurons, demyelination, and gliosis of the periventricular gray matter. Chronic alcohol consumption leads to a decrease in dietary thiamine intake, a decrease in its absorption from the gastrointestinal tract, and a decrease in thiamine-dependent reactions in cells. Moreover, there are differences in individual susceptibility to thiamine deficiency.

In chronic alcohol intoxication accompanied by thiamine deficiency, Wernicke–Korsakoff syndrome develops, which includes Wernicke's encephalopathy (acute phase) and Korsakoff's psychosis (chronic phase).

The classic symptoms of Wernicke's encephalopathy — ophthalmoplegia, nystagmus, altered mental status, and ataxia — are absent in the majority of cases, the disorder remains unrecognized, and patients do not receive the necessary treatment.

The mortality rate in the absence of therapy is 15%, and the probability of transition to Korsakoff's psychosis, which is practically irreversible, reaches 60% [2].

To prevent adverse outcomes of Wernicke's encephalopathy in the absence of its typical manifestations, possible additional symptoms should be taken into account, including nausea, vomiting, arterial hypotension, hypothermia, and coma.

Timely intensive therapeutic intervention (parenteral administration of high doses of thiamine**) makes it possible to prevent death and the development of Korsakoff's psychosis (Section 3).

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of alcoholic liver disease is established with confirmed liver disease resulting from the systematic use of ethanol in hazardous doses. Establishing the fact of long-term alcohol consumption is essential for the effective management and timely treatment of the patient. It is recommended to use questionnaires and screening tests to identify individuals at high risk for ALD. The diagnosis and management of patients with ALD should be carried out by a multidisciplinary team.

The diagnosis of ALD can be suspected based on anamnestic, clinical, laboratory, and instrumental signs. In complex diagnostic cases, morphological verification may be performed according to indications to exclude concomitant pathology.

The diagnosis of alcoholic liver disease can be suspected in the presence of:

1. Anamnestic data (ethanol consumption >20 g/day for women and >30 g/day for men in the presence of clinical and/or laboratory signs of liver damage)

2. Screening tests (AUDIT (Alcohol Use Disorders Identification Test) score > 8 — high risk of alcoholic liver damage)

3. Physical examination (detection of stigmas of alcoholic liver disease (see Section 2.2))

4. Instrumental examination (elevated gamma-glutamyl transpeptidase level, De Ritis ratio > 1 (AST/ALT)).

• The use of questionnaires to identify the alcoholic origin of liver damage is recommended for all patients with a suspected diagnosis of alcoholic liver disease to identify high-risk groups for the development of this disease [2, 23, 30, 34]

ForCLoE 4Level of Evidence C (Level of Likelihood of Evidence – 4).

Comments: It is important to identify patients with ALD in a timely manner and as early as possible before the development of end-stage liver disease. When taking the medical history, it must be taken into account that patients with ALD who consume alcohol in hazardous doses tend to underestimate the amount of alcohol consumed or deny the fact of alcohol consumption altogether. Communication with the patient's relatives plays a significant role in detecting the fact of alcohol abuse.

Taking an alcohol history (screening) must be standardized. Validated questionnaires exist for this purpose; the "gold standard" remains the AUDIT (Alcohol Use Disorders Identification Test) questionnaire developed by WHO in 1982, which demonstrates high sensitivity and specificity in various countries [23, 31]. The AUDIT questionnaire includes 10 questions that can be conditionally divided into sections: questions 1–3 provide information from the patient about the amount of alcohol consumed, questions 4–6 are aimed at detecting dependence, and questions 7–10 provide information about problems associated with alcohol consumption (Appendix G). Each item is evaluated by the patient choosing an answer option, followed by score calculation. Depending on the score obtained, the test is interpreted [32].

Based on the screening results, it is necessary to inform the patient that alcohol abuse is associated with the risk of developing more than 200 diseases, including malignancies.

Comments: For daily use under conditions of time constraints at the initial visit, the abbreviated version of the AUDIT questionnaire — AUDIT-C — can be used, which includes only the first three questions. The maximum score is 12 (Appendix G). The higher the score, the greater the likelihood that the drinking pattern has a negative impact on the human body. If the result of the abbreviated version is positive, it is recommended to use the full version of the AUDIT questionnaire.

Alternatively, screening can be started with question No. 3 from the AUDIT questionnaire: How often do you have 6 or more drinks on one occasion (i.e., ~180 ml of vodka or other strong spirits, or ~600 ml of wine, etc.)? If the answer is "weekly" or "daily or almost daily", it is recommended to complete the entire AUDIT questionnaire.

Comments: The CAGE questionnaire — is one of the well-tested and informative tests in the world (Appendix G). The questionnaire is easy to complete, and the physician can easily and quickly evaluate the patients' answers [34].

Screening for ALD should be carried out in high-risk groups, in all individuals abusing alcohol identified by the attending physician at the initial visit, in patients undergoing treatment in addiction clinics for alcohol dependence, and in alcoholism rehabilitation clinics. It is important to pay attention to stigmas of alcohol consumption (Section 2.2), as well as changes in laboratory test methods (Section 2.3) characteristic of patients with ALD.

• To monitor abstinence, patients with ALD are recommended to have quantitative determination of ethyl glucuronide (EtG) levels in urine or detection of ethyl glucuronide in hair [3]

LeRR CLOE 5Level of Recommendation Readiness C (Level of Evidence – 5)

Comments: There are direct biomarkers of alcohol consumption, which include ethyl glucuronide (EtG), ethyl sulfate (EtS), phosphatidylethanol (PEth), and fatty acid ethyl esters. These are direct products of the non-oxidative metabolism of ethanol, possessing greater specificity compared to indirect biomarkers. Among the listed biomarkers, the determination of ethyl glucuronide in urine should be highlighted. This biomarker is used in many countries to monitor abstinence in individuals on the liver transplantation waiting list. Urine ethyl glucuronide is detected within 80 hours after alcohol consumption. For screening, it is recommended to use an immunoassay method, and in case of a positive result, re-examine using chromatography and spectrometry [3]. An important advantage of this biomarker is the absence of diagnostic errors in patients with cirrhosis. The sensitivity and specificity of this method in patients on the liver transplantation waiting list are 89% and 99%, respectively [3]. However, these diagnostic methods are not used in routine clinical practice.

2.1 Complaints and Anamnesis

There are no ALD-specific complaints. At different stages (from alcoholic steatosis to liver cirrhosis), complaints may vary — see Section 1.6.

Alcohol history – see Section 2. In addition to the alcohol history, it is important to carefully take a medication history in patients with ALD, determining all medications used both on prescription (presence of polypharmacy) and without a prescription. It is necessary to identify drugs that can have a dose-dependent, toxic effect and a direct damaging effect on the liver, as well as to actively interview the patient about the use of dietary supplements, vitamins, and herbal remedies, which patients often prescribe to themselves and do not consider it necessary to tell the doctor about.

It is important to identify the presence of concomitant and comorbid diseases or individual symptoms that may be associated with liver damage and exacerbate the development and course of ALD. Rapid progression of ALD is more commonly observed in individuals with concomitant (diabetes mellitus, obesity and metabolic syndrome, HIV infection, arterial hypertension, hyperlipidemia, etc.) and comorbid (viral hepatitis B and C, iron overload, alpha-1 antitrypsin deficiency, etc.) diseases. Viral hepatitis and alcohol have a synergistic effect on the progression of liver fibrosis.

The presence of autoimmune diseases (e.g., autoimmune thyroiditis, inflammatory bowel disease, Sjögren's syndrome, etc.) should be clarified, as they can be associated with liver damage and enhance the damaging effect of ethanol on liver tissue with the progression of ALD.

It is mandatory to identify other bad habits, including smoking and drug use.

2.2 Physical Examination

Physical examination findings typical of patients with ALD depend on the stage of ALD. They can range from mild asthenia and dyspepsia to symptoms characteristic of acute liver failure.

In hepatic steatosis, as a rule, manifestations are either absent or very scanty. In patients with alcoholic hepatitis with disease progression, body weight loss may be observed, up to emaciation and sarcopenia at the cirrhosis stage. Upon palpation, the liver may be enlarged, with a smooth surface and a rounded edge.

At any stage of ALD, physical examination often reveals stigmata of long-term alcohol abuse: facies alcoholica, bright telangiectasias, gynecomastia, Dupuytren's contracture, palmar erythema, parotid gland enlargement, rhinophyma, vascular dilation of the nose and sclera, muscle atrophy of the shoulder girdle, testicular atrophy, hand tremor, hyperhidrosis of the facial skin and palms, and various degrees of polyneuropathy.

Patients with alcoholic hepatitis may show signs of varying severity of hepatic encephalopathy and hemorrhagic syndrome (bruising, mucosal bleeding, gastrointestinal bleeding) as part of the clinical manifestations of liver failure. General examination at this stage most often reveals undernutrition or even a decreased BMI due to sarcopenia. Abdominal examination may reveal dilation of the anterior abdominal wall veins, edema, ascites, and an enlarged, sometimes tender liver upon palpation. Massive inflammatory edema of the liver may lead to the development of reversible portal hypertension with ascites and splenomegaly. Intrahepatic cholestasis occasionally develops, clinically presenting with pruritus and scratch marks all over the body.

At the alcoholic liver cirrhosis (ALC) stage, signs of liver failure progress, and clinical manifestations become pronounced. Edema of various locations may appear and worsen due to hypoalbuminemia; telangiectasias on the skin of the face, chest, and back, palmar erythema, and gynecomastia due to hyperestrogenemia resulting from impaired inactivation of active estrogen forms in the liver; yellowish skin and sclera due to hyperbilirubinemia resulting from decreased glucuronosyltransferase activity and liver detoxifying function. Signs of portal hypertension: ascites, hepato- and splenomegaly, collateral veins on the anterior abdominal wall (“caput medusae”), and dilated hemorrhoidal veins. Often at the decompensated ALC stage, patients may exhibit resting tachycardia and hypotension (hyperdynamic circulation) [27]. ALC with small intestinal bacterial overgrowth syndrome may manifest as fever (without an obvious source of infection), bloating, abdominal rumbling, abdominal tenderness upon palpation, weakened bowel sounds on auscultation (transient intestinal paresis), and stool disorders, most commonly diarrhea [27].

In the presence of pronounced ascites, percussion over the accumulation of free fluid in the abdominal cavity can reveal a dull sound instead of tympany. In tense ascites, palpation of internal organs is difficult.

ALC may feature multi-organ involvement: alcoholic polyneuropathy, pancreatitis, cardiomyopathy, etc., which requires timely and thorough physical examination and evaluation of such patients by relevant specialists.

Patients with ALC have a high probability of developing hepatic encephalopathy (HE), the main manifestation of which is altered consciousness. HE can range from clinically asymptomatic forms (minimal HE) to a comatose state. Hepatic encephalopathy requires differential diagnosis with other neurological disorders (cerebrovascular accidents, neurological and psychiatric diseases). In any suspicion of HE, it is necessary to assess consciousness, behavior, intelligence, and neurological status (tremor, handwriting changes, psychometric tests).

2.3 Laboratory Diagnostics

Comments: The complete blood count may reveal macrocytosis (an increase in mean corpuscular volume – MCV), an elevated color index (hyperchromemia), as well as a decrease in hemoglobin levels (anemia). Anemia can be of various origins and severities, most commonly due to vitamin deficiencies (folic acid and B12); in addition, occult bleeding, posthemorrhagic anemia, and anemia of chronic disease may contribute.

In patients with ALC, blood tests may reveal tri-lineage cytopenia. Leukopenia and thrombocytopenia may be present, reflecting hypersplenism syndrome. However, in patients with ALC, splenomegaly and hypersplenism may be minimal or completely absent, which does not rule out the cirrhosis stage. In cases of newly diagnosed thrombocytopenia, manual counting of blood cellular elements is mandatory (differential diagnosis with platelet aggregation).

At the same time, in the presence of a pronounced necroinflammatory process in the liver, blood tests may show neutrophilic leukocytosis and an elevated ESR.

Comments: As a result of hepatocyte necrosis, the biochemical blood test shows elevated levels of hepatic ALT, AST (more than twice the upper limit of normal, but rarely exceeding 300 IU/mL), and LDH. As a rule, the AST level is higher than the ALT level (De Ritis ratio – AST/ALT > 1) [2,3,35].

An increase in aminotransferase activity loses clinical significance as chronic liver disease progresses – in decompensated ALC, aminotransferase activity may be normal or only slightly elevated.

Alcohol stimulates GGT gene expression. Serum GGT activity is elevated in approximately 75% of individuals abusing alcohol (sensitivity 60-90%, specificity 50-72%). Screening tests reveal elevated GGT activity in 20% of men and 15% of women consuming about 40 g of alcohol per day, and in 40-50% of men and 30% of women drinking more than 60 g of alcohol per day. The half-life of GGT is 14-26 days, so blood enzyme activity normalizes within 4-5 weeks after alcohol cessation [2,37]. Therefore, GGT activity should be assessed in all patients with suspected ALD. However, it must be remembered that GGT levels can also reflect metabolic disorders (correlating with increased BMI).

Although the above indicators are most often used for early diagnosis of alcoholic liver disease, their sensitivity and specificity are low.

Assessment of albumin levels is mandatory to evaluate the protein-synthetic function of the liver. In the context of liver failure, there is an isolated decrease in albumin levels with normal/borderline total protein levels.

Measuring creatinine concentration helps assess renal function and is also recommended for patients planning to undergo computed tomography (CT) with contrast enhancement. Elevated creatinine levels may indicate an independent hepatorenal system disorder or acute kidney injury in alcoholic liver cirrhosis (ALC). In clinical practice, attention is paid to the dynamics of this parameter over specific time intervals. A rapid increase in creatinine may meet the criteria for acute kidney injury even within the normal range of the parameter.

A decreased creatinine level is an unfavorable prognostic marker and reflects muscle tissue depletion. In addition to human albumin solution transfusions**, such patients are indicated to receive an appropriate high-protein diet and/or enteral nutrition to correct their nutritional status.

Severe liver damage can lead to liver failure, which manifests with the following symptoms: hyperbilirubinemia with a predominance of both the direct bilirubin fraction (impaired transport into bile canaliculi; pronounced edema of the liver parenchyma leading to compression of bile canaliculi) and the indirect fraction (deficiency of glucuronyltransferase activity; impaired uptake of indirect bilirubin at the basolateral membrane of the hepatocyte); hypocoagulation; and hypoalbuminemia. The latter two conditions are associated with decreased protein-synthetic function of the liver.

Comments: in liver failure, there is a decrease in the synthesis of all plasma coagulation factors—both pro- and anticoagulant links of hemostasis. Standard tests predominantly reveal signs of hypocoagulation: an elevated INR, a decreased prothrombin index, and a lowered fibrinogen level. Assessment of prothrombin time is necessary to calculate the Maddrey discriminant function and assess the severity of AH.

Comments: Changes in urinalysis (leukocyturia, hematuria, proteinuria) help rule out hepatorenal syndrome in patients with ALC and indicate the presence of an independent kidney disease or infection. It should be borne in mind that even a latent urinary tract infection can trigger hepatic encephalopathy and acute-on-chronic liver failure (as well as ALC decompensation).

Comments: The involvement of humoral mechanisms in the development of ALD is manifested by an increase in serum immunoglobulins, predominantly IgA. Determination of plasma immunoglobulin M and G concentrations is necessary for differential diagnosis with autoimmune liver diseases.

2.4 Instrumental Diagnostics

Imaging methods, such as ultrasound, magnetic resonance imaging, and computed tomography, allow for the quantitative assessment of the degree of liver steatosis, help exclude other causes of chronic liver disease, and assist in evaluating progressive liver disease and its complications regardless of etiology.

Comments: Abdominal ultrasound is indicated for all patients with ALD for the purpose of screening for portal hypertension, assessing the state of the liver parenchyma, determining its size, location, contours, sound transmission, echogenicity, and functional parameters. During ultrasound examination, special attention is paid to the degree of ultrasound signal attenuation, liver hyperechogenicity, and the size of the portal and splenic veins. Ultrasound reveals a characteristic hyperechogenic liver structure. However, ultrasound has low sensitivity and specificity in diagnosing the degree of liver steatosis (especially at a threshold value below 20-30% steatosis) [3].

On ultrasound, signs of portal hypertension include dilation of the portal vein to 13 mm or more, a decrease in blood flow velocity within it or retrograde blood flow, the appearance of portosystemic collaterals (paraumbilical vein, dilation of the splenic vein, etc.), and splenomegaly [27].

Comments: Esophagogastroduodenoscopy (EGDS) is necessary for patients with suspected portal hypertension to rule out esophageal varices. EGDS is mandatory for patients continuing alcohol consumption who are at high risk of cirrhotic transformation of the liver, or who have a confirmed diagnosis of ALC, to determine the presence and grade of esophageal and gastric varices.

When indicated and there are no contraindications (not for all patients with ALD):

Comments: Since 1988, the International Agency for Research on Cancer (IARC) of the WHO has classified alcohol as a Group 1 carcinogen—substances with the highest capacity to cause cancer in humans. Patients with ALD are at risk of developing hepatocellular carcinoma.

Comments: Approximately 20% of patients with an established diagnosis of ALD are found to have concomitant liver disease. Liver biopsy may be performed to confirm the diagnosis of ALD, assess disease stage, and exclude other causes of liver injury [2,3,5]. Strict indications are required for liver biopsy, along with a preliminary assessment of complete blood count and coagulogram results. Severe complications of liver biopsy, such as intrahepatic hemorrhage, pneumothorax, and others, occur in approximately 2% of patients.

Comments: Absolute contraindications to liver biopsy:

1. Hemostasis disorders; bleeding diathesis with marked prolongation of prothrombin time (thromboplastin time < 70%, aPTT > 1.5 upper limit of normal; thrombin time > 1.5 upper limit of normal, thrombocytopenia < 80 × 10⁹/L)

2. Severe or comatose state of the patient

3. Peritonitis, sepsis

4. Severe portal or biliary hypertension

5. Patient incapacity (stage 3–4 hepatic encephalopathy, mental illness), inability to sign informed consent.

Morphological features of alcoholic liver disease.

The morphological spectrum of ALD manifestations consists of four main groups of changes:

1. steatosis, predominantly macrovesicular, less frequently – micro- or macrovesicular;

2. hepatocyte injury, often described as ballooning degeneration;

3. inflammatory infiltrate with a predominantly lobular localization;

4. fibrosis of varying degrees, up to advanced fibrosis, with disruption of the lobular architecture of the liver tissue and progression to the cirrhosis stage.

A single patient may exhibit a combination of various morphological changes or the presence of only one of them, such as steatosis. The detection rate of individual morphological changes in the liver among individuals who abuse alcohol is unknown. According to individual studies involving liver biopsy, the detection rate of steatosis is 28%, fibrosis (with or without steatosis) – 20%, alcoholic hepatitis – 8.5%, and cirrhosis – 29% [49]. The most frequent and early detected histological sign of ALD – is macrovesicular steatosis, which has traditionally been considered a benign and reversible condition in the event of abstinence. Data have been obtained on the association of steatosis with the risk of rapid progression to fibrosis and the development of cirrhosis within 10.5 years in 10% of patients [49].

Alcoholic hepatitis (steatohepatitis) is characterized by a combination of steatosis, ballooning degeneration, and inflammation represented by a polymorphic cellular neutrophilic infiltrate. The presence of Mallory bodies and megamitochondria is not characteristic of ALD, yet occurs quite frequently and is associated with active alcohol consumption [49]. The development of fibrosis underlies the formation of cirrhosis in ALD, which is observed in 40% of patients with alcoholic hepatitis. Cirrhosis is typically micronodular, and occasionally – mixed macro- and micronodular [2,49].

The prognosis of patients with alcoholic cirrhosis largely depends on the presence of complications. The most serious of these include hepatic encephalopathy, esophageal and/or gastric variceal bleeding, ascites and spontaneous bacterial peritonitis, hepatorenal syndrome, and dilutional hyponatremia. The diagnosis of these conditions must be carried out in strict accordance with established algorithms and clinical guidelines [27].

2.5 Other Procedures

The differential diagnosis should include the following conditions: non-alcoholic steatohepatitis, drug-induced liver injury, acute viral hepatitis, Wilson's disease, iron metabolism disorders, autoimmune liver diseases, and $\alpha_1$-antitrypsin deficiency. To exclude these conditions, a thorough medical history, rational use of laboratory tests and instrumental methods, and in some cases, a liver biopsy are required (Fig. 2).

2.5.1 Non-invasive diagnosis of liver fibrosis.

Serum tests are available to determine the stage of the disease (severity of fibrosis) in ALD. Initially developed for patients with viral hepatitis, they have subsequently been applied to ALD. It should be taken into account that threshold values for differentiating fibrosis stages vary depending on the etiology of liver injury.

Non-invasive diagnostic methods for assessing the stage of liver disease in patients with ALD can be used when routine examination methods fail to yield reliable results, as well as when liver biopsy is impractical or impossible.

Comment: FibroTest is calculated based on blood test results and includes the assessment of the following parameters: $\alpha_2$-macroglobulin, haptoglobin, GGT, apolipoprotein A1 (ApoA1), and bilirubin levels, as well as the patient's sex and age. In a study involving 221 patients with histologically proven ALD, the mean FibroTest value was 0.29 for those without fibrosis and 0.88 for patients with cirrhosis, with an AUROC for patients with cirrhosis of 0.95 [3,44].

In patients with ALD, if FibroTest is unavailable, as well as in complex diagnostic situations to clarify the degree of progressive fibrosis and alcoholic cirrhosis, one or more of the following indices may be additionally calculated:

Comments: FibroMeter is a serum fibrosis marker that includes prothrombin time, $\alpha_2$-macroglobulin and hyaluronic acid levels, and patient age. Its diagnostic accuracy in ALD is comparable to that of FibroTest, with an AUROC of 0.80 for fibrosis and 0.90 for cirrhosis.

Comments: Hepascore is a serum fibrosis marker that includes bilirubin, GGT, hyaluronic acid, and $\alpha_2$-macroglobulin levels, as well as the patient's age and sex. The diagnostic accuracy of FibroTest, FibroMeter, and Hepascore has been evaluated in ALD. The diagnostic performance of FibroMeter and Hepascore did not differ from that of FibroTest in significant fibrosis (AUROC approximately 0.80) and cirrhosis (AUROC approximately 0.90), but was statistically significantly higher than the results of fibrosis assessment using non-patented methods (APRI, Forns – includes platelet count, GGT and cholesterol levels, patient age; FIB-4 – includes platelet count, ALT and AST activity, patient age). The use of any combinations of these tests does not increase diagnostic accuracy and is not recommended for clinical practice [28,45].

Comments: To calculate the PGAA index, the following biomarkers are assessed: prothrombin index, GGT, ApoA1, and $\alpha_2$-macroglobulin.

Comments: The APRI index (AST-to-platelet ratio) was evaluated in 1,308 patients with ALD, demonstrating a sensitivity of 13.2% and a specificity of 77.6%. The diagnostic accuracy of this index in diagnosing fibrosis in ALD has not been studied [28].

Comments: According to a number of studies, liver transient elastography (TE) can be effectively used to determine the stage of fibrosis in patients with alcohol-related liver disease (ARLD) [2,3,35,41,42,43]. Liver stiffness values in patients with alcoholic cirrhosis are significantly higher than those in patients with viral liver cirrhosis [3]. The results of other studies indicate that the presence of active alcoholic hepatitis accompanied by an AST elevation >100 IU/L leads to a significant overestimation of liver stiffness values when using TE [3]. This must be taken into account when performing the study. In addition, inflammation, cholestasis, and hepatic congestion can increase liver stiffness values regardless of the stage of fibrosis. Alcohol consumption can also increase liver stiffness, while alcohol abstinence can decrease this parameter.

A recent systematic review based on five retrospective and nine prospective cohort studies involving a total of 834 patients demonstrated high diagnostic accuracy of liver TE as a method to rule out severe fibrosis or cirrhosis in patients with ARLD using cutoff values of 9.5 and 12.5 kPa, respectively [44]. Severe fibrosis can be ruled out in patients with liver TE values less than 8–10 kPa; severe fibrosis should be suspected in patients with TE values of 12–15 kPa (after excluding causes that can yield a false-positive result) [45].

Nevertheless, liver stiffness cutoff values in patients with ARLD are currently not sufficiently validated, as there is a risk of overestimating liver stiffness values in patients abusing alcohol.

2.5.2 Assessment of alcoholic hepatitis severity

Unlike the ICD-10, in the clinical classification of ARLD, alcoholic hepatitis is divided into steatohepatitis and acute (severe) alcoholic hepatitis. The latter manifests with rapid progression of liver failure, development of jaundice, ascites, blood coagulation disorders, and is characterized by high short-term mortality (30–50%). Therefore, determining the severity of alcoholic hepatitis is not a formality, as the prognosis and, accordingly, the patient's treatment tactics are associated with it.

Comments: To diagnose and treat severe alcoholic hepatitis, evaluation parameters have been developed that allow the identification of patients at high risk of mortality. The most common of these is the Maddrey discriminant function (DF). Appendix G. A result exceeding 32 points indicates severe alcoholic hepatitis and serves as an indication for prescribing prednisolone at a dose of 40 mg/day [2,3]. The advantage of this parameter is its ease of use and long-standing clinical experience. Disadvantages include the use of prothrombin time to calculate the index. This parameter may vary depending on the sensitivity of the thromboplastin reagent used in the laboratory test.

Comments: The MELD score (Appendix G) was developed to assess the severity of liver damage and is used for patient stratification on the liver transplantation waiting list. In severe alcoholic hepatitis, according to the guidelines of the American Association for the Study of Liver Diseases, glucocorticosteroids (GCS) should be prescribed when MELD > 18 points. At the same time, other studies recommend using a MELD threshold ≥ 20 points [3]. The GAHS (Glasgow Alcoholic Hepatitis Score) assesses mortality in alcoholic hepatitis (Appendix G), but the score has not found widespread use in clinical practice. However, its use allows for an alternative assessment of the patient's prognosis.

Comments: The Lille score (Appendix G) was proposed by French hepatologists from the city of Lille and is used to assess the response to GCS therapy 7 days after the start of treatment. If a patient scores more than 0.45 points, corticosteroid use is considered ineffective, and 6-month mortality is 75% [3,47].

Figure 2. Differential diagnosis of alcoholic liver disease

Differential diagnosis of altered mental status represents a particular challenge in the management of patients with ALD. Confusion may occur not only due to hyperammonemia (hepatic encephalopathy), but also as a result of the neurotoxic effects of alcohol, Wernicke's encephalopathy, Korsakoff's psychosis, or withdrawal syndrome. At the stage of cirrhosis, causes of altered consciousness may include extrahepatic conditions that precipitate or exacerbate HE symptoms, the so-called precipitating factors [90]. These include well-known factors: infections (pneumonia, urinary tract infection, spontaneous bacterial peritonitis, sepsis, acute gastroenteritis, and others), gastrointestinal bleeding, constipation, excessive breakdown of glutamine by small intestinal glutaminase, dehydration, hyponatremia, hypokalemia, uncontrolled use of diuretics, benzodiazepine intake, excessive protein intake, and factors whose role in the development of HE has been actively discussed in recent years: skeletal muscle mass loss (sarcopenia) and transjugular intrahepatic portosystemic shunt placement. Measures aimed at eliminating/correcting these factors, combined with ammonia-lowering therapy, are accompanied by clinical improvement in HE.

• In ALD patients with signs of encephalopathy, when the genesis of encephalopathy is in doubt, a trial of ammonia-lower therapy is recommended for differential diagnosis [50].

Leveled for Reliability of Recommendations (LRR) CLevel of Evidence (LoE) 5Level of Reliability of Recommendations C (Level of Evidence 5).

Comments: A normal ammonia level casts doubt on the diagnosis of hepatic encephalopathy. However, its measurement is not a routine laboratory test and is unavailable in most hospitals. For this reason, in the presence of confusion in an ALD patient, the use of ammonia-lowering drugs (Ornithine**) is recommended [51]. The administration algorithm for ornithine** is described in detail in the Russian Ministry of Health clinical guidelines for the management of patients with liver cirrhosis [27]. In case of positive dynamics in the level of consciousness, the diagnosis is considered to be hepatic encephalopathy.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 General measures

Achieving and maintaining abstinence is the only etiotropic treatment option for alcoholic liver disease.

Comments: Abstinence (avoidance of alcohol) is the primary and one of the main therapeutic measures for any form and stage of ALD. Continued alcohol intake significantly worsens the patient's prognosis: there is a risk of liver disease progression, development of severe fibrosis and cirrhosis, complications of portal hypertension, hepatocellular carcinoma, and other cancers (colorectal, upper gastrointestinal tract, pancreas, etc.) [2]. Complete cessation of alcohol intake can lead to normalization of liver tissue histology, a decrease in portal venous pressure, halting the progression of cirrhosis, prevention of complications, and improvement in the patient's prognosis. Long-term prognosis depends primarily on the patient's adherence to abstinence [2]. During this period, the main objectives are: reducing or completely abstaining from alcohol consumption, preventing or reducing the frequency of relapses, and treating alcohol dependence. A meta-analysis by Yan-Di Xie et al. investigating the impact of abstinence on the survival of patients with alcoholic cirrhosis showed that a statistically significant increase in survival appears after 1.5 years of alcohol abstinence (RR: 0.51, [95% CI 0.33–0.81], p=0.004) and persists for 5 years [54].

Comments: If the CAGE score is greater than 1 and/or the AUDIT score is greater than 19 points, a consultation with an addiction psychiatrist (narcologist) is indicated.

Achieving and maintaining abstinence is a complex challenge facing the healthcare system and the state as a whole. Thus, in addition to addiction treatment provided by psychiatrists and addiction specialists, healthcare tasks should include screening for alcohol abuse, providing information on the consequences of alcohol abuse, and conducting brief alcohol intervention (BAI). These measures are not only preventive regarding the development of alcohol-induced diseases, but also the only etiotropic treatment option for many of them.

Thus, the most effective tools in combating the harmful consequences of alcohol abuse are: the activities of the medical community, primarily primary care physicians, who can correct overt or potential alcohol dependence using BAI methodology, as well as motivating patients to seek addiction care services; and state restrictive measures to reduce the harm caused by alcohol (Section 5).

3.2 Nutritional support

The vast majority of individuals who abuse alcohol exhibit nutritional disorders. The most frequently observed are severe protein deficiency, deficiencies in thiamine (vitamin B1), folic acid, pyridoxine (vitamin B6), zinc, and vitamins A and D. The severity of nutritional disorders correlates with the severity of liver disease progression and prognosis [3]. Complete enteral nutrition is indicated for patients with ALD.

Comments: Protein in the diet of an ALD patient should be primarily represented by plant-based proteins and lactalbumin due to their better tolerability. Caloric intake is ensured by an adequate supply of fats and carbohydrates. If it is impossible to obtain the required amount of nutrients from food, specialized enteral nutrition must be used.

Comments: It must be remembered that in the presence of signs of hepatic encephalopathy, dietary protein should be restricted only in individual cases of protein intolerance. To prevent catabolic processes, the incoming protein amount must be at least 60 g/day (in stages 2–3 of HE), mainly from plant and animal protein sources. After the resolution of HE signs, the daily protein amount should be increased to 80–100 g/day (up to 1.5 g/kg). It should be taken into account that every patient with alcoholic cirrhosis has their own threshold of dietary protein tolerance, and in case of protein intolerance, the deficiency must be replenished with parenteral infusions.

Comments: Carbohydrates help reduce plasma concentrations of ammonia and tryptophan; however, it should be remembered that patients with cirrhosis are prone to developing impaired glucose tolerance, which sometimes requires insulin administration.

In addition, carbohydrate metabolism requires an increased consumption of thiamine, which can lead to its acute deficiency and provoke Wernicke's encephalopathy; therefore, any carbohydrate administration requires the preventive administration of thiamine.

The use of fructose, sorbitol, and xylitol is impractical due to the increased risk of lactic acidosis. Given the ability of dietary fibers to stimulate the growth of bifido- and lactobacilli, reduce intestinal wall permeability, and adsorb toxic substances, they can be used to reduce the degree of bacterial translocation in patients with alcoholic cirrhosis complicated by ascites and, accordingly, to prevent spontaneous bacterial peritonitis. The diet of an ALD patient must also contain adequate amounts of vitamins and microelements. If vitamin absorption is impaired, their parenteral administration is indicated.

• Patients with ALD and Wernicke's encephalopathy (or suspected development thereof) are recommended to be prescribed #thiamine** therapy immediately [2,5].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comments: Patients with acute alcoholic Wernicke's encephalopathy undergo therapy according to the following regimen: #thiamine** at a dose of 500 mg 3 times a day intravenously as an infusion for 2–3 days, then 250 mg/day intravenously as an infusion for as long as necessary depending on the dynamics of clinical symptoms in each specific case, followed by 50–100 mg of #thiamine** orally for a prolonged period [2].

#Thiamine**, along with preventing and eliminating the symptoms of Wernicke's encephalopathy, has a therapeutic effect in alcoholic polyneuropathy, the development of which is also associated with a shortage of this vitamin.

• Depending on indications, patients with malnutrition and ALD may be recommended additional therapy with the correction of electrolyte disorders: administration of potassium and magnesium preparations; as well as indicated administration (upon development of vitamin deficiency): pyridoxine** (vitamin B6), cyanocobalamin** (vitamin B12), nicotinic acid (vitamin B3 or PP), ascorbic acid** (vitamin C), and folic acid**. The prescription of multivitamin mixtures orally is possible [2].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

3.3 Pharmacotherapy

• In the absence of active infection, it is recommended that patients with severe alcoholic hepatitis (Maddrey's discriminant function ≥ 32, MELD ≥ 20) start therapy with systemic corticosteroids (prednisolone** 40 mg/day or #methylprednisolone** 32 mg/day) to reduce short-term mortality. However, it should be remembered that corticosteroids do not convincingly affect long-term survival [2,3,55,56].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comments: Prednisolone** is prescribed orally at a dose of 40 mg/day for 28 days, #methylprednisolone** at a dose of 32 mg. Treatment efficacy is evaluated on the 7th day from its start using the Lille model score (Appendix G). If the Lille score is < 0.45, treatment with prednisolone** at the specified dose is continued for 28 days followed by complete withdrawal of the drug. Prednisolone is tapered by 1 tablet every 3 days.

According to the results of a study published in 2015 by M.R. Thursz et al. [23], prednisolone** at the specified dose leads to an insignificant reduction in short-term mortality (within 28 days) and has no effect on disease outcome 90 days or 1 year after its manifestation. According to the same study, severe infections were significantly more frequently identified in the group of patients treated with prednisolone** compared to the placebo group. Before starting prednisolone treatment, patients should be screened for infections and gastrointestinal bleeding. If these complications are detected, it is advisable to resolve them before prescribing prednisolone therapy. The efficacy of #methylprednisolone** 32 mg/slug is comparable to prednisolone 40 mg/day [3].

A recent cohort study involving 3,380 patients determined the appropriate MELD score value for prescribing corticosteroids. The use of corticosteroids significantly increases 30-day survival among patients with a MELD score > 20, with maximum efficacy (survival > 20%) at a MELD score ranging from 25 to 39 [57].

• Patients with severe alcoholic hepatitis who do not respond to corticosteroid treatment on day 7 (Lille score ≥ 0.45) are recommended to discontinue prednisolone** therapy due to its ineffectiveness [2,3].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• In order to increase the efficacy of corticosteroids, as well as to reduce the frequency of hepatorenal syndrome, patients with criteria for severe alcoholic hepatitis are recommended to combine prednisolone** therapy at a dose of 40 mg/day with #ademetionine** (800 mg/day intravenously) [18-21, 58].

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

Comments: In the treatment of 40 patients with severe alcoholic hepatitis, this treatment regimen (prednisolone** + #ademetionine**) demonstrated no differences compared to the efficacy of standard therapy with prednisolone at a dose of 40 mg/day. No significant differences in short-term survival (28 days) were found between the groups (p=0.151). Nevertheless, the response to therapy in patients receiving combination therapy with prednisolone and #ademetionine**, according to the Lille score, was significantly better (p=0.044), and the incidence of hepatorenal syndrome was significantly lower (p=0.035) [58].

Comments: A randomized controlled trial conducted by J. Mato's group [59] demonstrated that the use of ademetionine** in Child-Pugh class A and B alcoholic cirrhosis at a dose of 1200 mg/day orally for 2 years results in a significantly lower mortality rate or need for liver transplantation compared to the placebo group (12% and 29%, respectively). In vitro and in vivo experiments have shown that the depletion of glutathione, the liver's primary antioxidant, leads to hepatocyte damage and necrosis. Therefore, the use of antioxidants, as well as agents that restore glutathione reserves, appears to be a promising therapeutic approach for severe alcoholic hepatitis. Based on the data obtained, it can be hypothesized that the beneficial effect of ademetionine** on the course of alcoholic cirrhosis is due to its membrane-protective and antioxidant properties, as well as the suppression of pro-inflammatory cytokine production (TNFα) [17].

Comments: Ammonia plays a central role in the pathogenesis of HE, and elevated ammonia levels correlate with HE severity. Therefore, it is pathogenetically justified to include agents for correcting hyperammonemia in HE therapy. L-ornithine and L-aspartate, which are components of #Ornithine**, play a major role in converting ammonia into urea. They enter this cycle as substrates and activate the urea synthesis cycle, accelerating ammonia detoxification. The use of #Ornithine** in patients with liver cirrhosis, including those with ALD etiology, is associated with a reduced risk of progression of minimal HE. The efficacy of #Ornithine** in preventing the development of HE has also been noted [60]. According to a meta-analysis, the use of this drug led to lower blood ammonia levels and improved mental status in patients with liver cirrhosis at any stage of HE [61]. A recent study showed that the combination of ornithine** with two other anti-ammonia agents (rifaximin and lactulose**) was accompanied by more significant positive outcomes compared to a two-drug combination. Such triple therapy resulted in a more pronounced decrease in blood ammonia levels, reduced HE severity, and lower mortality in patients, including those with alcoholic cirrhosis [62].

The recommended daily dose of #Ornithine** may vary depending on the severity of ALD. Oral dose: 9 to 18 g/day in the form of granules pre-dissolved in 200 ml of fluid; intravenous dose: 20 to 30 g/day for 3-8 days, pre-diluted in 500 ml of infusion solution, with a maximum infusion rate of 5 g/h [64]. A dosage regimen of 5 g orally 3 times a day for 60 days does not affect cognitive functions, but statistically prevents future episodes of overt hepatic encephalopathy at 6 months (in cirrhosis) [64].

Comments: Individual studies have demonstrated the efficacy of UDCA** in improving clinical and biochemical blood parameters and liver histology, which may be due not only to its anticholestatic effect but also to its influence on the release of pro-inflammatory cytokines.

Comments: The administration of ademetionine to patients with ALD and intrahepatic cholestasis can reduce the levels of biochemical markers of cholestasis (ALP, GGT, bilirubin). Therapy can be oral or combined (intravenous/oral). To calculate the intravenous dose of ademetionine, the following rule can be applied: patients with a body weight < 70 kg should be prescribed 500 mg/day, and those with a weight ≥ 70 kg, 800 mg/day. The recommended dose of the oral form of ademetionine is 10-25 mg/kg of body weight per day.

Patients with an initially high bilirubin level may initially be prescribed intravenous ademetionine for two weeks (500-800 mg daily), followed by a transition to the oral form of ademetionine at a dose of 1500 mg daily for the next six weeks. Patients with initially normal serum bilirubin levels may receive the oral form of ademetionine directly at 1500 mg/day for eight weeks. It is advisable to administer the main dose of the drug in the first half of the day (2 tablets in the morning, 1 tablet in the evening) [67].

Comments: in a controlled comparative randomized trial, the combination drug inosine + meglumine + methionine + nicotinamide + succinic acid at a dose of 400 ml/day demonstrated a more pronounced reduction in cholestatic and cytolytic syndromes (p<0.05) compared to Ademetionine at a dose of 800 mg/day for parenteral administration in patients with ALD. An improvement in the protein-synthesizing function of the liver (increased albumin synthesis by hepatocytes) was established in the Remaxol group (p<0.05). The inclusion of the combination drug inosine + meglumine + methionine + nicotinamide + succinic acid in the comprehensive treatment of patients with ALD at the cirrhotic stage contributed to improved compensatory reserves of the liver and short-term life prognosis: the number of patients with a calculated MELD index > 11 decreased by 2.3 times in the main group, compared to 1.4 times in the comparison group [68].

The prognosis of patients with alcoholic cirrhosis largely depends on the presence of complications. The most serious among these include hepatic encephalopathy, variceal bleeding from the esophagus and/or stomach, ascites and spontaneous bacterial peritonitis, hepatorenal syndrome, and dilutional hyponatremia. The diagnosis and treatment of these conditions must be strictly carried out in accordance with developed algorithms. The treatment of cirrhosis complications does not depend on the etiology of the diseases and must be performed in accordance with current clinical guidelines of the Russian Ministry of Health for 2021 [27].

3.4 Management of alcohol withdrawal syndrome

More than half of patients with alcohol use disorder develop alcohol withdrawal syndrome upon cessation or significant reduction of alcohol intake.

Alcohol withdrawal syndrome can be uncomplicated or complicated.

Complications of alcohol withdrawal include alcohol-related epilepsy (withdrawal seizures) and alcohol withdrawal delirium (delirium tremens).

Alcohol-related epilepsy and alcohol withdrawal delirium most frequently develop on days 2-4 after cessation or a sharp decrease in alcohol intake.

Comments: succinic acid (succinate) is a substrate for the Krebs cycle, which improves energy metabolism and cellular function, including in hepatocytes. Infusions of the combination medicinal product Inosine + Meglumine + Methionine + Nicotinamide + Succinic Acid are widely used in clinical practice.

3.4 Liver Transplantation

Liver transplantation is indicated for patients in the end stage of ALD, as well as for patients with severe alcoholic hepatitis refractory to glucocorticosteroid (GCS) therapy [3]. The primary principle for determining indications for orthotopic liver transplantation is the prediction that the patient's post-transplant survival will exceed their life expectancy without it.

Comments: abstinence for at least 6 months is considered a prerequisite for liver transplantation by most centers, although, according to recent data, there are no significant differences in post-transplant survival between patients who continue and those who have ceased alcohol consumption.

Main contraindications for liver transplantation:

• Extrahepatic malignancies

• Metastatic lesions

• Active HIV infection

• Severe comorbid conditions not correctable by transplantation

• Active alcoholism, substance abuse

• Extrahepatic sepsis

• Severe cardiovascular diseases

• Psychological and social incompetence of the patient

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Medical rehabilitation of patients with liver disease depends on the stage of the disease.

Medical rehabilitation is primarily required for patients with alcoholic cirrhosis of the liver and severe alcoholic hepatitis. At the compensated stage of alcoholic cirrhosis, rehabilitation implies early detection of signs of incipient decompensation of liver cirrhosis, development of new complications, and determination of nutritional deficiency indices.

General nutritional principles for patients with liver disease without insufficiency: a full, balanced diet in terms of proteins, fats, and carbohydrates. Adequate nutrition with a sufficient intake of macro- and micronutrients and vitamins helps prevent weight loss and subsequent sarcopenia, reducing the risk of avitaminosis.

5. Prevention and Dispensary Observation

The main objectives of the national healthcare system are the prevention of alcohol abuse and the treatment of developed alcohol dependence. To achieve these goals, the most effective measures are brief interventions and a combination of cognitive behavioral therapy with pharmacotherapy (in cases of alcohol dependence development).

Comments: Achieving this goal requires measures aimed at reducing alcohol availability, such as increasing its price, including through high taxation, restricting or completely banning the demonstration of alcoholic beverages in the media (including indirect advertising), restricting alcohol sales hours, age restrictions on the purchase of alcohol, as well as educational work among the population on the dangers of alcohol abuse and the active promotion of a healthy lifestyle, especially among youth. A significant contribution can be made by introducing the brief intervention technique into the practice of internists, pharmacotherapy for alcohol dependence, and psychosocial support.

Achieving abstinence is considered the most effective means of preventing the progression of alcoholic liver disease. The onset of alcohol dependence in a patient significantly increases the likelihood of failing to achieve abstinence and the duration of alcohol consumption at health-hazardous doses. Therefore, the follow-up of patients with alcoholic liver disease and alcohol dependence should be carried out jointly by a psychiatrist-narcologist and a psychiatrist.

Comments: Before the onset of dependence and alcohol-associated diseases, there is a period of hazardous alcohol use. The duration of this period is individual and may vary depending on many factors, both modifiable (amount and frequency of alcohol consumed) and non-modifiable (gender differences, genetic polymorphism of proteins, comorbid conditions, etc.). Most often, years or even decades are required for the development of alcohol dependence. Effective intervention in early stages, prior to the development of alcohol dependence, can slow down or prevent the formation of alcoholic liver disease. Screening for hazardous alcohol use should be performed by primary care physicians, general practitioners, and in emergency departments. To achieve this, the physician/healthcare professional must possess appropriate brief intervention skills.

Comments: Gastroenterologists/hepatologists, general practitioners, and other specialists lacking a special certificate for providing narcological/psychiatric care are recommended to use the brief intervention technique in their clinical practice. The essence of brief interventions is to motivate the patient to change alcohol-related behavior, such as reducing the frequency and volume of alcohol consumption, practicing safer behavior, seeking specialized addiction treatment, etc.

The key principle of brief interventions is patient-centered communication. The specialist's task is to help the patient find their own arguments against alcohol consumption and strengthen their self-confidence and the possibility of complete alcohol abstinence.

Brief interventions include three key points:

1) it is a special type of conversation about change (counseling, treatment, method of communication);

2) the conversation is always collaborative and person-centered, implying a partnership rather than an expert-recipient relationship;

3) it encourages recollection, and its goal is to prompt the patient to want to change circumstances, themselves, their life, etc.

Any healthcare worker can master the brief intervention technique; no special specialization is required for this.

The effectiveness of brief interventions in reducing alcohol consumption was proven in a Cochrane meta-analysis (2018) that included 69 studies. The meta-analysis showed that patients who received brief interventions consumed 20 g/week less alcohol at 12 months than patients who did not receive brief interventions or those participants who underwent shorter interventions (fast advice lasting less than 5 minutes) or no intervention at all [74]. A decrease in the frequency and intensity of drinking during the week was noted. At the same time, prolonged psychological counseling (more than 5 meetings with a total duration of more than 60 minutes) did not lead to enhanced effectiveness [74]. Despite the fact that the clinical trials included in this meta-analysis were based on a sample of patients without alcoholic liver disease, the results of the meta-analysis most fully reflect the effect of motivational interviewing at the population level.

According to a systematic review by Khan et al., it was shown that only a combination of motivational and behavioral therapy with supportive therapy for somatic disease for 2 years leads to a statistically significant increase in the frequency of achieving and maintaining abstinence (74% in the combination therapy group vs. 48% in the control group, p=0.02) [75]. Abstinence is a leading factor in improving liver function in patients with alcoholic liver disease in the long term.

In addition to reducing the proportion of patients who abuse alcohol and are alcohol-dependent, an important indicator of the effectiveness of anti-alcohol measures is the reduction in disability-adjusted life years (DALY) caused by alcohol abuse. Brief interventions had the greatest positive impact on this indicator. The introduction of total screening procedures will make it possible to identify a group of frequently hospitalized patients and provide them with qualified medical care.

Comments: The follow-up (dispensary observation) schedule is determined by the attending physician individually, depending on the disease course and presence of complications. Newly diagnosed patients are monitored every 3 months during the first year, every 6 months during the second year, and annually in subsequent years if the condition stabilizes. Follow-up includes laboratory testing (complete blood count, blood chemistry panel, coagulogram - if indicated). The decision regarding abdominal ultrasound and other imaging modalities, as well as EGDS, is made on a case-by-case basis. Dispensary observation does not preclude proactive patient visits in case of clinical deterioration or adverse events during treatment [76].

6. Organization of Medical Care

Patients with alcoholic liver disease (ALD) should be co-managed by a gastroenterologist/hepatologist, psychiatrist, and narcologist.

Indications for hospitalization: jaundice, clinically overt encephalopathy (stage 2 and above), newly onset or medically refractory/tense ascites, edema syndrome, suspected hemorrhage, onset/worsening of asthenic syndrome, oliguria/anuria, suspected infectious complications, onset/worsening of dyspnea. Hospitalization for ALD can be elective or emergency, into a therapeutic or surgical unit depending on the disease stage, and to an intensive care unit (ICU) when indicated.

Indications for discharge: alleviation of clinical symptoms, no further need for surgical treatment or intensive care, stabilization of vital organ functions: cardiovascular system (hemodynamics) and respiratory system, kidneys, CNS.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Vladimir Trofimovich Ivashkin – Doctor of Medical Sciences, Professor, Full Member of the Russian Academy of Sciences, laureate of the Russian Government Prize in Science and Technology (2007) and Education (2013), Honored Doctor of the Russian Federation, Honored Scientist of the Russian Federation, President of the Russian Gastroenterological Association and the Russian Liver Research Society. No conflict of interest.

Leonid B. Lazebnik – MD, PhD, Professor, Vice-President of the Russian Scientific Medical Society of Therapists (RNMOT), President of the Scientific Society of Gastroenterology of Russia (NOGR), Member of the Presidium of the Russian Medical Society, Member of the Presidium of the National Medical Chamber, Professor at the Department of Outpatient Therapy, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health. No conflict of interest.

Elena V. Golovanova – MD, PhD, Professor at the Department of Outpatient Therapy, Faculty of General Medicine, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health. No conflict of interest.

Tatiana A. Deeva – PhD in Medicine, Member of the Russian Society for the Study of the Liver. No conflict of interest.

Oksana M. Drapkina – MD, PhD, Academician of the Russian Academy of Sciences, President of the Russian Society for the Prevention of Non-Communicable Diseases. No conflict of interest.

Elena Yu. Eremina – MD, PhD, Professor, Head of the Department of Propaedeutics of Internal Diseases, National Research Mordovia State University named after N.P. Ogarev, Chief freelance Gastroenterologist of the Ministry of Health of the Republic of Mordovia. No conflict of interest.

Maria S. Zharkova – PhD in Medicine, Laureate of the Government Prize of the Russian Federation in Science and Technology (2017), Member of the Russian Society for the Study of the Liver. No conflict of interest.

Alexander B. Krivosheev – MD, PhD, Professor at the Department of Faculty Therapy, Novosibirsk State Medical University of Roszdrav. No conflict of interest.

Igor V. Maev – MD, PhD, Academician of the Russian Academy of Sciences. No conflict of interest.

Marina V. Maevskaya – MD, PhD, Professor, Laureate of the Government Prize of the Russian Federation in Science and Technology (2017), Vice-President of the Russian Society for the Study of the Liver. No conflict of interest.

Anatoly I. Martynov – MD, PhD, Academician of the Russian Academy of Sciences, President of the All-Russian Public Organization "Russian Scientific Medical Society of Therapists". No conflict of interest.

Tatiana P. Nekrasova – PhD in Medicine, Pathologist, Associate Professor at the Institute of Clinical Morphology and Digital Pathology. No conflict of interest.

Evgeny I. Sas – MD, PhD, Professor at the 2nd Department of Therapy (Advanced Medical Training), S.M. Kirov Military Medical Academy of the Ministry of Defense of the Russian Federation. No conflict of interest.

Yury P. Sivolap – MD, PhD. No conflict of interest.

Larisa V. Tarasova – MD, PhD, Head of the Department of Faculty and Hospital Therapy, I.N. Ulyanov Chuvash State University, Chief freelance Specialist Therapist and Gastroenterologist of the Ministry of Health of the Chuvash Republic, Head of the Republican Gastroenterological Center of the Ministry of Health of the Chuvash Republic, Member of the Presidium of the RNMOT. No conflict of interest.

Petr E. Tkachenko – PhD in Medicine, Member of the Russian Society for the Study of the Liver. No conflict of interest.

Dmitry I. Trukhan – MD, PhD, Professor at the Department of Internal Diseases and Outpatient Therapy, Faculty of General Medicine, Omsk State Medical University. No conflict of interest.

Olga V. Khlynova – MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Vice-Rector for Research, Head of the Department of Hospital Therapy, Academician E.A. Vagner Perm State Medical University of the Russian Ministry of Health. No conflict of interest.

Yulia V. Tsyganova – Senior Lecturer at the Department of Faculty and Hospital Therapy, I.N. Ulyanov Chuvash State University.

Appendix A2. Methodology for Developing Clinical Guidelines

The purpose of these guidelines is to provide practicing physicians with contemporary understanding of the etiology and pathogenesis of alcohol-related liver disease (ALD), and to introduce currently used algorithms for assessing disease severity, prognosis, and treatment.

Target audience of these clinical guidelines:

1. Gastroenterologists

2. General practitioners (family physicians)

3. Internists

4. Narcologists

5. Psychiatrists

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Levels of evidence (LoE) indicating the classification used for levels of evidence

Table 3. Levels of clinical evidence (LCE) indicating the classification system used

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

1. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development and revision of clinical guidelines, their standard form, and requirements for their structure, composition, and scientific validity of the information included in clinical guidelines" (Registered with the Ministry of Justice of Russia on May 8, 2019, No. 54588)

2. Order of the Ministry of Health of the Russian Federation No. 906n dated November 12, 2012, "On approval of the procedure for providing medical care to the population in the field of 'Gastroenterology'" (Registered with the Ministry of Justice of Russia on January 21, 2013, No. 2664)

3. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017, "On approval of criteria for assessing the quality of medical care."

4. Order of the Ministry of Health of the Russian Federation No. 1034n dated December 30, 2015, "On approval of the Procedure for providing medical care in the field of 'psychiatry-narcology' and the Procedure for dispensary observation of individuals with mental disorders and/or behavioral disorders associated with psychoactive substance use" (with amendments and additions).

5. Order of the Russian Ministry of Health No. 933n dated December 18, 2015 (as amended on March 25, 2019) On the procedure for conducting medical examinations for intoxication (alcoholic, narcotic, or other toxic).

6. Order of the Ministry of Health of the Russian Federation No. 1392n dated December 24, 2012, "On approval of the standard of emergency medical care for poisoning by alcohol, organic solvents, and halogenated derivatives of aliphatic and aromatic hydrocarbons."

7. Order of the Ministry of Health of the Russian Federation No. 810n dated December 28, 2022, "On approval of the standard of medical care for adults with liver cirrhosis and fibrosis (diagnosis and treatment)"

Appendix B. Physician Action Algorithms

Management algorithm for patients with alcoholic hepatitis.

Appendix C. Patient Information

Dear patient! Consuming hazardous doses of alcohol can lead to liver damage, which may be asymptomatic in early stages. A hazardous dose is generally considered to be the intake of alcoholic beverages equivalent to 30 g of pure ethanol (3 standard drinks) per day for men and 20 g of pure ethanol (2 standard drinks) per day for women. For example, 0.5 L of vodka contains 16 standard drinks (160 g of pure ethanol), while 0.5 L of beer (5% ABV) contains 2 standard drinks. Health-hazardous and threatening doses of alcohol for men are 30 g/day in terms of pure ethanol, which corresponds to 75 ml of vodka (40% ABV), 300 ml of dry wine (10% ABV), or 600 ml of beer (5% ABV). Consuming more than 7 standard drinks per week for women and more than 14 standard drinks per week for men leads to an increased risk of liver damage.

If alcohol abuse continues, mental disorders may appear, severe hepatitis with jaundice and a high risk of death may develop, and subsequently, liver cirrhosis may occur. Symptoms that may indicate worsening liver condition include: progressive weakness, sleep disturbances, decreased concentration and memory, appearance of subcutaneous hematomas ("bruises") without any physical trauma, hemorrhagic skin rashes, nasal and gingival bleeding, yellowing of the skin, vomiting blood or "coffee grounds", black tarry stools ("melena"), onset or worsening of pain in the upper abdomen, right and/or left hypochondrium. In all these cases, you must consult your attending physician.

Dear patient! The primary and mandatory condition for the prevention and treatment of alcohol-related liver disease is the complete cessation of alcohol consumption!

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. AUDIT Questionnaire

Russian title: Alcohol Use Disorders Identification Test – AUDIT

Original title (if applicable): AUDIT – Alcohol Use Disorders Identification Test

Source (official developer website, validation publication): Babor T.F., Higgins-Biddle J.C., Saunders J.B., Monterio M.G. The Alcohol Use Disorders Identification Test, Guidelines for Use in Primary Care, second edition. // World Health Organization Department of Mental Health and Substance Dependence. 2nd edition. Geneva – 2001.

Type (underline): questionnaire

Purpose: The questionnaire allows for the identification of individuals abusing alcohol with health consequences (a threshold of ≥ 8 points was established, having 92% sensitivity and 94% specificity).

Content (template):

Interpretation of results (key):

Appendix G2. AUDIT-C Questionnaire

Russian title: Alcohol Use Disorders Identification Test, abbreviated version «AUDIT-C»

Original title (if applicable): AUDIT-C – Alcohol Use Disorders Identification Test – C

Source (official developer website, validation publication): https://www.calculators.tech/audit-c-calculator

Type (underline): questionnaire

Purpose: for daily use in time-constrained primary care settings, the abbreviated 3-question AUDIT questionnaire can be used to identify individuals at high risk of hazardous alcohol use.

Content (template):

Interpretation of results (key): the test is considered positive if a man scores 4 points or more, and a woman scores 3 points or more. The maximum possible score on this questionnaire is 12. As a rule, the higher the score, the greater the likelihood that the drinking pattern is having a negative impact on the person's health. If the abbreviated version yields a positive result, it is recommended to use the full AUDIT questionnaire.

Appendix G3. CAGE Questionnaire

Russian title: «CAGE» Questionnaire

Original title (if applicable): The CAGE (Cut, Annoyed, Guilty, Eye-opener) questionnaire

Source (official developer website, validation publication): Dhalla S., Kopec J. A. The CAGE questionnaire for alcohol misuse: a review of reliability and validity studies //Clinical and Investigative Medicine. – 2007. – P. 33-41.

Type (underline): questionnaire

Purpose: Designed to identify patients with alcohol dependence.

Content (template):

Answer "yes" or "no" to each of the following questions.

1. Have you ever felt you should cut down on your drinking?

a) yes b) no

2. Have people annoyed you by criticizing your drinking?

a) yes b) no

3. Have you ever felt bad or guilty about your drinking?

a) yes b) no

4. Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover, or to be able to do something?

a) yes b) no

Interpretation of results (key):

• a positive answer to one of the four questions (even if it is the last, fourth one) does not warrant definitive conclusions; • positive answers to two questions indicate episodic alcohol consumption (binge drinking);

• positive answers to three questions suggest regular alcohol consumption;

• positive answers to all four questions almost certainly indicate regular alcohol consumption approaching or already developed into alcohol dependence. In this case, measures must be taken to correct the situation or, possibly, consult a specialist. The test is considered positive if there are two or more positive answers.

Test sensitivity ‒ 66%, specificity ‒ 91.4% [24].

Appendix G4. Maddrey discriminant function.

Russian title: Discriminant function (Maddrey)

Original title (if applicable): Maddrey score

Source (official developer website, validation publication): Maddrey W.C., Boitnott J.K., Bedine M.S., et al. Corticosteroid therapy of alcoholic hepatitis. // Gastroenterology. – 1978. – Vol.75. – No2. - P. 193–199.

Type: rating scale

Purpose: to assess the severity of alcoholic hepatitis and determine the indication for systemic corticosteroid therapy.

Content (template):

DF = 4.6 × (PT (sec) – Control PT (sec)) + bilirubin (mg/dL)

Result interpretation (key): A Maddrey's discriminant function score ≥ 32 is associated with a 25% – 45% mortality rate within the next 28 days, whereas non-severe hepatitis (Maddrey < 32 points) results in mortality within 3 months in less than 10% of patients. The sensitivity and specificity of the Maddrey score in predicting 1-month mortality are 86% and 48%, respectively.

Appendix G5. MELD Index.

Russian name: Assessment of severity in patients with liver cirrhosis using the MELD score.

Original name (if any): Model for End-Stage Liver Disease.

Source (official developer website, validation publication): https://www.uptodate.com/contents/calculator-model-of-endstage-liver-disease-meld-score-not-for-liver-transplantation-listing-purposes-not-appropriate-for-patients-under-age-12-years?source=see_link

Type: rating scale.

Purpose: This numerical scale is accepted for determining 3-month mortality in patients with alcoholic liver disease (ALD), and is also used to prioritize liver transplantation on the waiting list (due to the limited number of donor organs).

Content (template):

MELD = 9.6Ln (creatinine level) + 3.8Ln (total bilirubin level) + 11.2Ln (INR) + 6.4.

MELD calculator, where Ln is the natural logarithm, and INR is the international normalized ratio.

Result interpretation (key):

Patient 3-month mortality depending on the MELD score is:

40 and above – 71.3%

30–39 – 52.6%

20–29 – 19.6%

10–19 – 6.0%

<9 – 1.9%

The minimum value for any of the three variables is 1 mg/dL, the maximum possible creatinine level is 4 mg/dL, and the maximum possible MELD score is 40. An unfavorable life prognosis is associated with a MELD score > 18. The higher the index value, the more severe the liver disease. The MELD classification has been shown to have high reliability in predicting 3-month mortality in patients with decompensated liver cirrhosis. Thus, with a MELD score > 35 points, mortality is predicted in 80% of cases; with a MELD score of 20 to 34 points, in 10-60%; and with a MELD score < 8 points, the patient is outpatient and requires active monitoring. It is also used to assess the severity of alcoholic hepatitis (> 21 points indicates severe disease).

Appendix G6. Lille Index.

Russian name: Assessment of survival in patients with alcoholic hepatitis using the Lille score.

Original name (if any): Lille model (score) for alcoholic hepatitis

Source (official developer website, validation publication): https://www.mdcalc.com/calc/2024/lille-model-alcoholic-hepatitis.

Type: rating scale.

Purpose: designed to evaluate the efficacy of corticosteroid therapy in severe alcoholic hepatitis and decide on the duration of treatment with these drugs.

Content (template):

R = 3.19 – 0.101 × (age in years) + 0.147 × (albumin on admission in g/L) + 0.0165 × (total bilirubin on day 8 of therapy in µmol/L) + 0.206 × (presence of renal failure – 0 or 1) + 0.0065 × (total bilirubin on admission in µmol/L) + 0.0096 × (prothrombin time in seconds)

Result interpretation: With a score of less than 0.45, it can be predicted that the 6-month survival rate of patients will average 25%.

Appendix G7. Glasgow Alcoholic Hepatitis Score (GAHS)

Russian name: Glasgow Alcoholic Hepatitis Score to determine the severity of alcoholic hepatitis (GAHS)

Original name (if any): the Glasgow Alcoholic Hepatitis Score

Source (official developer website, validation publication): https://www.mdcalc.com/calc/680/glasgow-alcoholic-hepatitis-score

Type (underline): rating scale

Purpose: assessment of short-term survival and severity of alcoholic hepatitis taking into account patient age, blood leukocyte count, INR, serum total bilirubin and urea levels. Compared to previous scales, it is more discrete, which reduces its accuracy but improves formalization; creatinine is replaced by urea, and important factors such as patient age (mortality is higher in the elderly) and the severity of the inflammatory response, assessed by leukocytosis, are added.

Content (template):

Result interpretation: At values greater than 8 points (criteria for severe alcoholic hepatitis), 52% of patients survive by day 28, and 38% by day 84; when such patients are prescribed glucocorticosteroids, survival increases to 78% and 59%, respectively.