Non-alcoholic fatty liver disease NAFLD. Non-alcoholic fatty liver disease: why it occurs and how to treat it. Treatment with folk remedies

Modern concepts of the pathogenesis of non-alcoholic fatty liver disease

Kosobyan E.P., Smirnova O.M.

Federal State University of Endocrinology Research Center, Moscow (director - Academician of the Russian Academy of Sciences and Russian Academy of Medical Sciences I.I. Dedov)

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease characterized by the pathological accumulation of fatty droplets that is not associated with alcohol consumption. NAFLD is often a component of other diseases, such as metabolic syndrome, diabetes mellitus, obesity, and contributes to the prevalence of cardiovascular diseases (CVD) in the population.

The asymptomatic course of the disease, the difficulties of its diagnosis, and the lack of a unified concept for the treatment of NAFLD are pressing problems that require more in-depth study and deserve the close attention of a wide range of specialists.

Key words: non-alcoholic fatty liver disease, cirrhosis, lipids, cytolysis, enzymes

Current concepts of the pathogenesis of non-alcoholic fatty liver disease

Kosobyan E.P., Smirnova O.M.

Endocrinological Research Centre, Moscow

Non-alcoholic fatty liver disease (NAFLD) - common chronic liver disease, characterized by pathological accumulation of fat droplets, not associated with alcohol. NAFLD is often a component of other diseases such as metabolic syndrome, diabetes, obesity, and contributes to the prevalence of CVD among the population.

Asymptomatic disease, the difficulty of diagnosis, the lack of a unified concept of treatment NAFLD - topical issues that require more in-depth study and worthy of attention a wide range of specialists.

Keywords: non-alcoholic fatty liver disease, cirrhosis, lipids, cytolysis, enzymes

Non-alcoholic fatty liver disease (NAFLD) is now recognized worldwide as a common chronic liver disease, which can also be a component of other diseases such as metabolic syndrome (MS), diabetes mellitus (DM), and obesity.

For the first time, Ludwig et al. in 1980 they published data from a study of liver biopsies with a typical morphological picture of alcoholic hepatitis in patients, without indications of alcohol intake in hepatotoxic doses, and formulated the concept of “non-alcoholic steatohepatitis”.

The modern concept of NAFLD covers a spectrum of liver damage, including its three main forms: fatty liver disease (FHL), non-alcoholic (metabolic) steatohepatitis (NASH) and cirrhosis (as an outcome of progressive NASH). Rarely, the outcome of NASH can be hepatocellular carcinoma.

Fatty liver (terms also used in the literature: hepatic steatosis, fatty liver, fatty liver) is a disease or syndrome caused by fatty degeneration of liver cells. It is characterized by pathological - intra- and (or) extracellular - deposition of fat droplets. The morphological criterion of GI is the content of triglycerides in the liver over 5-10% of dry weight.

NASH is a disease characterized by increased activity of liver enzymes in the blood and morphological changes in liver biopsies, similar to changes in alcoholic hepatitis - fatty degeneration (FA) with an inflammatory reaction and fibrosis; however, people with NASH do not drink alcohol in amounts that can cause liver damage.

In recent years, there has been an increase in interest in this problem, which is due, in particular, to the increase in the incidence of morbid obesity among the population of industrialized countries and the subsequent increase in the incidence of NAFLD. Patients suffering from MS have the highest risk of developing NAFLD. A steady increase in incidence has been established.

Due to the fact that mortality from cardiovascular diseases (CVD) ranks 1st in the world, NAFLD becomes even more important, because The studies conducted provide convincing evidence of an increased risk in such patients. Most of them are expected to develop CVD in the long term.

The true prevalence of NAFLD is unknown, but recent studies estimate that the prevalence of NAFLD and NASH in the general population may be as high as 20–24% and 3%, respectively. Studies have shown that in diseases combined with insulin resistance, characteristic changes in the liver are detected in 74% of cases.

The prevalence of NAFLD is high in individuals with insulin resistance due to diseases such as obesity, type 2 diabetes (T2DM), dyslipidemia and MetS. MetS and NAFLD usually coexist, and the presence of MetS often predicts the future development of NAFLD. Thus, ultrasound detects fatty hepatosis in T2DM in 50% and 75% of cases. In one study, ultrasound revealed the presence of gastrointestinal tract in 48% of patients diagnosed with metabolic syndrome. In the same study, GH was diagnosed in 39% of those with a body mass index (BMI) of 25 kg/m2 or more, in 41% of patients with diagnosed diabetes, and in 32% of those with dyslipidemia.

However, the exact mechanisms of liver fibrogenesis have not yet been elucidated. Fibrosis is detected in 20-37% of patients with NAFLD. In 20% of them, cirrhosis develops within 20 years with the development of hepatic cell failure. Population-based studies suggest that 60-80% of cryptogenic liver cirrhoses result from NASH.

It has been established that the combination of T2DM and NASH increases the risk of developing liver cirrhosis and hepatocellular carcinoma by 2-2.5 times (Blinanev E. et al., 2007). In addition, in patients with NAFLD in combination with and without diabetes, a higher prevalence of CVD was found than in patients without NAFLD without diabetes.

depending on obesity and traditional CVD risk factors.

Pathogenesis

The pathogenesis of NASH is not fully understood. The main components of hepatocellular lipids are represented by triglycerides (TG), the substrates for the synthesis of which are fatty acids and glycerophosphate. The accumulation of fatty droplets in the liver may be a consequence of excessive intake of free fatty acids into the liver or their increased synthesis by the liver itself from acetyl coenzyme A, especially when there is an excess of the latter. The sources of glycerophosphate in the hepatocyte are: a) glycerol formed during lipid hydrolysis; b) glucose, which during glycolysis is converted into phosphatidic acid, which triggers TG synthesis reactions. Thus, the production of TG in the hepatocyte is directly dependent on the content of fatty acids, acetyl coenzyme A and glucose. If the formation of TG prevails over the synthesis of lipoproteins and the secretion of the latter from the hepatocyte in the form of very low density lipoproteins (VLDL), fat accumulation occurs in the hepatocyte, which leads to increased processes of free radical oxidation of lipids with the accumulation of lipid peroxidation products (LPO) and development of necrosis of liver cells. In turn, the accumulation of lipid peroxidation products is involved in the metabolism of nitric oxide, namely its excessive consumption, which aggravates endothelial dysfunction, contributes to the progression of arterial hypertension, and the development of cardiovascular complications. Long-term hypertriglyceridemia in conditions of insulin resistance impairs endothelium-dependent vasodilation, causes oxidative stress and is a major risk factor for early atherosclerosis.

A high-calorie diet and sedentary lifestyle in genetically predisposed individuals causes severe postprandial hyperlipidemia, as well as activation of lipolysis and, as a consequence, excessive formation of free fatty acids (FFA), which has a direct lipotoxic effect on pancreatic beta cells; stimulates glycogenolysis in the liver. Excessive concentrations of FFA and post-prandial hyperlipidemia are additional predictors of the formation of insulin resistance, hyperinsulinemia and atherosclerosis.

Insulin is a stimulator of acetyl-CoA carboxylase (ACC) and fatty acid synthetase (FAS), the main enzymes that initiate de novo lipogenesis, which leads to hepatic steatosis. FFAs have direct and LPO-mediated toxicity. Their action leads to inhibition of K/NaATPase, inhibition of glycolysis, uncoupling of oxidative phosphorylation, and activation of the PPAR-a pathway for recycling excess FFA. When the protective properties of the hepatocyte membrane from FFA toxicity decrease, direct or oxidative stress-mediated damage to mitochondria, apoptosis and necrosis of hepatocytes occur. The interaction of oxidative stress and cytokines entails disruption of the functioning of liver stellate cells (HSC), the main producers of extracellular collagen matrix (ECM), leading to an imbalance of fibrogenesis-fibrolysis with activation of fibrogenesis. Oxidative stress products can induce ECM synthesis even in the absence of significant hepatocyte damage and inflammation. Due to repeated injury, the accumulation of fibrillar extracellular matrix reflects the failure of effective remodeling and regeneration. Directly related to the process is also a violation of epithelial-mesenchymal interaction, which is observed in all proliferative processes.

processes associated with damage to cholangiocytes. In this case, the proliferation of cells producing the extracellular matrix and the progression of fibrogenesis occur in concert. From a clinical point of view, these processes can cause the formation of liver cirrhosis.

A common model for the pathogenesis of NAFLD is the “two-hit” theory. The first blow is the development of iron disc disease, the second is steatohepatitis. With obesity, especially visceral obesity, the flow of FFA into the liver increases and hepatic steatosis develops, which is considered as the “first blow”. Under conditions of insulin resistance, lipolysis in adipose tissue increases, and excess FFA enters the liver. As a result, the amount of fatty acids in the cytoplasm of hepatocytes increases sharply, and fatty degeneration of hepatocytes is formed. Oxidative stress develops simultaneously or sequentially - a “second blow” with the formation of an inflammatory reaction and the development of steatohepatitis.

Visceral adipose tissue, in contrast to subcutaneous adipose tissue, is richer in blood supply and innervation. Adipocytes of visceral adipose tissue, having a high sensitivity to the lipolytic action of catecholamines and low sensitivity to the antilipolytic action of insulin, secrete FFA directly into the portal vein. High concentrations of FFA, on the one hand, become a substrate for the formation of atherogenic lipoproteins, on the other hand, they prevent the binding of insulin to the hepatocyte, which leads to hyperinsulinemia and potentiates insulin resistance. Insulin resistance promotes the accumulation of fatty acids in the liver. Thus, NAFLD should be viewed as a dynamic process that occurs at the crossroads between peripheral and metabolic changes in the liver, where hepatic steatosis and insulin resistance potentiate each other's effects.

Insulin takes a leading place in the regulation of lipolysis and the separation of mitochondrial β-oxidation and VLDL cholesterol synthesis in hepatocytes. Insulin resistance plays a fundamental role in the pathogenesis of NAFLD. This served as a prerequisite for studying the relationship between insulin resistance and compensatory hyperinsulinemia and NAFLD.

Various mediators (FFA, tumor necrosis factor-a (TNF-a), adiponectin, etc.) are actively secreted in adipose tissue and regulate the sensitivity of receptors to insulin, and are also involved in atherogenesis, which increases the risk of CVD.

Energy storage in the liver occurs through the deposition of TG with the participation of apoprotein B-100 (Apo-B100), which binds to the protein microsomal triglyceride transporter (MTT) and leads to the formation of a pool containing TG, which passes into VLDL.

Insulin prevents the destruction of Apo-B100 and stimulates the specific adipocyte factor SRBP-1C (adipocyte determination and differentiation factor (ADD-1). With a long-term positive energy balance, insulin increases its expression; due to excess fatty acids, the PPAY-y system is activated. These two systems increase the expression of key enzymes involved in fat storage. Each fat cell increases in size and stores more fat. Activation of these systems also stimulates the differentiation of preadipocytes into new adipocytes. Thus, a long-term positive energy balance can lead to both an increase in the size of adipocytes ( hypertrophy), and to an increase in their number (hyperplasia).

It has been found that obesity has a stimulating effect on the endocannabinoid system, causing hyperactivation of Cb1 receptors, in particular through overexpression of the cannabinoid receptor agonist Anandamide, which activates

virates the Cbl receptor, leading to overexpression of SREBP-lC and consequently increased hepatic de novo lipogenesis and fibrogenesis. The endocannabinoid system induces peripheral lipolysis through activation of lipoprotein lipase and suppression of adiponectin production.

Adiponectin is a hormone of adipose tissue that is an insulin sensitizer and anti-atherogenic factor. It has been found that in obese people its level is reduced. Adiponectin prevents the phenomena of apoptosis and necrosis in hepatocytes by reducing the production of TNF-a and inducing PPAR-a activity.

Adiponectin inactivates AKK and FA, but activates hepatic carnitine-palmitoyl transferase (KPP-I), involved in the synthesis of FA EPP-I, located on the inner surface of the outer membrane of mitochondria, is the rate-limiting enzyme at the stage of FA transport. The activity of this enzyme is also affected malonyl-&A level. When carbohydrates are supplied, the concentration of malonyl-CoA inside the cell increases, and this suppresses the activity of EPP-! and switches metabolism to the synthesis of FA and TG.

The antagonist of adiponectin is leptin, another cytokine in adipose tissue. It is required for 3KO activation and fibrosis development.

SREBP-lC is also activated by the liver receptor LXR-a, which functions as a cholesterol sensor activated in response to increased intracellular cholesterol levels in hepatocytes and other cell types. It induces AKK, JCS and SREBP-lC transcription through the retinoid X-a receptor (RXR-a), as well as transcription of the liver gene SCD-l, responsible for the production of fatty acids.

It has been established that RXR-a mediates the transcriptional activity of PPAR-a, which is acid-sensitive

liver nuclear receptor. Its activation increases the availability of fatty acids for oxidation, which leads to a significant decrease in their content in the liver. The use of exogenous PPAYA-agonists prevents NAFLD in obese mice and promotes its regression in experimental models of NAFLD.

It is known that patients with NAFLD have reduced levels of Ghrelin, a hormone produced in the stomach and duodenum and is a central stimulant of appetite. Ghrelin induces ACC and JSC expression. It has been suggested that ghrelin levels may be regarded as a predictor of GI in patients with nutritional deficiency.

In obese individuals, serum concentrations of TNF-a are increased.

TNF-a activates a protein that stimulates protective inflammatory reactions - inhibitor of kappa kinase beta (1KK|3) in adipocytes and hepatocytes, which leads to disruption of insulin binding to the receptor. The effect of TNF-a on the insulin receptor type 1 (1R8-1) is manifested in its phosphorylation, as a result of which its affinity for insulin decreases, the amount of the special transport protein GLUT4, which ensures the entry of glucose into the cell, decreases, which is expressed in the form of a decrease in the uptake and utilization of glucose cells, an increase in hyperglycemia, which leads to damage to the vascular endothelium and the formation of T2DM. Smooth muscle and endothelial cells of the vessel wall, under the influence of TNF-a, increase the production of monocyte chemotactic protein-1 (MCP-1), which plays a leading role in the pathogenesis of atherosclerosis.

It is noteworthy that cytokines are one of the main stimulators of liver regeneration. It is known that TNF-a is capable of initiating liver necrosis, but in normal

Hypertrophy, hyperplasia and damage to adipose tissue

t Anti-inflammatory cytokines t FFA

t Insulin resistance

t Insulin resistance t Anti-inflammatory cytokines

Fatty degeneration NASH Cirrhosis

inflammation

lipotoxicity

t CRP, MCP-1 t Fibrinogen t PAI-1

t Oxidative stress (LPO, NO) t TG-VLDL, LDL and HDL

t Hyperglycemia

t Postprandial hyperlipidemia t Insulin resistance

Rice. 1. Scheme of the pathogenesis of NAFLD

Table 1

Cardiovascular diseases

Cardiometabolic risks Main symptoms and manifestations

Visceral obesity Insulin resistance Atherogenic dyslipidemia (|TG, |HDL, LDL, TC) Impaired carbohydrate metabolism (IGT, DM) Impaired fibrinolysis (tPAM, fibrinogen) Inflammation (^ CRP) Pro-inflammatory cytokines (|TNF-a, |MCP-1) PCOS (4SHBG, |free testosterone) NAFLD Decreased endothelium-dependent vasodilation of the brachial artery Increased thickness of the intima-media complex of the carotid artery Thrombogenic transformation of the vascular wall Hemostatic impairment Atherosclerosis / coronary artery disease Arterial hypertension Early dysfunction of the left ventricle Dyslipidemia Hyperandrogenism

table 2

Metabolic syndrome

Risk factor Main symptoms and manifestations

Abdominal circumference: Abdominal-visceral obesity

men (>102 cm) Insulin resistance and hyperinsulinemia

women (>88 cm) Dyslipidemia

Triglycerides: Arterial hypertension

>= 1.7 mmol/l Impaired glucose tolerance / T2DM

High-density lipoproteins: Early atherosclerosis / IHD

men (<1,2 ммоль/л) Нарушения гемостаза

women (<1,0 ммоль/л) Гиперурикемия и подагра

Blood pressure: Microalbuminuria

>=130/85 mmHg Hyperandrogenism

Fasting glucose:

>=5.5 mmol/l

In small hepatocytes, necrosis does not occur, because TNF-α-cell genes are usually expressed at minimal levels. Serum TNF-α levels vary between patients with hepatic steatosis and NASH and tend to be higher in patients with NASH, although the difference is not always statistically significant.

Interleukin-6 (IL-6) plays a special role as a “hepatocyte-activating factor.” IL-6 can induce the synthesis of many acute-phase proteins, such as fibrinogen and C-reactive protein (CRP), the increase of which is a well-known risk factor for CVD.

Free radical compounds arising during oxidative stress (O2- and OMOO-) activate the formation of the nuclear transcription factor NF-kB in adipose tissue. The latter, by increasing the expression of cytokines (TNF-a, IL-1|3), mediates mechanisms that promote thrombogenic transformation of the vascular wall. Interestingly, adipocytes, in addition to pro-inflammatory proteins, also express receptors for them; therefore, adipocytes are both the source and target of this inflammatory signal.

Chronic liver inflammation is accompanied by increased production of transforming growth factor beta 1 (TGF-31) by Kupffer and inflammatory cells. TGF-|31 is a multifunctional cytokine and in chronic liver diseases it is a causative factor in its fibrosis through activation of the HSC.

Angiotensin II (AT11) plays a certain role in the progression of NASH. It has been established that, by promoting the proliferation of myofibroblasts, cell migration, the synthesis of collagen and pro-inflammatory cytokines, it activates the processes of fibrogenesis in the liver, aggravates insulin resistance, oxidative stress and iron overload of the liver. One study showed that the expression of type 1 AT11 receptors in NASH was observed not only in smooth-

muscle cells, but also in activated stellate cells and liver parenchymal cells, although their overall expression was reduced. The number of type 1 AT11 receptors correlated with the severity of portal hypertension. In liver cirrhosis, the expression of angiotensin-converting enzyme and chymase increased.

Under conditions of hyperglycemia, hyperinsulinemia and hyper-triglyceridemia, the expression of the plasminogen activator inhibitor-1 (PA1-1) gene increases in cultured human smooth muscle, fat and liver cells. PA1-1 inhibits tissue and urokinase plasminogen activators and plays an important role in predetermining susceptibility to cardiovascular diseases. An increase in the level of PA1-1 in the blood is observed in diabetes, obesity and NAFLD, which are characterized by insulin resistance and hyperinsulinemia, as well as in arterial hypertension (Fig. 1).

It is noteworthy that NAFLD can be associated with insulin resistance without obesity in people without diabetes, and therefore, when developing in people with normal weight, it can be a predictor of early metabolic disorders and diseases.

In patients with NAFLD, a decrease in endothelium-dependent vasodilation of the brachial artery and an increase in the thickness of the intima-media complex (IMT) of the carotid artery, markers of early atherosclerosis, were found. It has been proven that an IMT value of less than 0.86 mm is associated with a low risk of CVD, and more than 1.1 with a high one. In patients with NAFLD, its value averages 1.14 mm. At the same time, a decrease in endothelium-dependent vasodilation of the brachial artery correlates with the degree of morphological changes in the liver, regardless of gender, age, insulin resistance and other components of MS. In addition, patients with NAFLD in the absence of obesity, hypertension, and diabetes have echocardiographic evidence of early left ventricular dysfunction.

Based on a number of studies, it has been established that an increase in the level of liver enzymes in the blood serum is characterized by

ternary for NAFLD, portends an increased risk of CVD, regardless of traditional risk factors and components of MS. Thus, NAFLD itself can be considered an independent risk factor for CVD, in addition to other well-known ones (Table 1).

Almost all components of MS are established risk factors for the development of CVD, and their combination greatly accelerates their development (Table 2).

As mentioned above, NAFLD can exist both as a separate nosological entity and as a component of other diseases associated with insulin resistance (MetS, obesity, T2DM). These diseases have common pathogenetic factors that predetermine their development and progression; therefore, they can combine and potentiate each other’s development (Fig. 2).

Diagnostics

The main feature of NAFLD and NASH is asymptomaticity. Most often, the disease is detected accidentally - on the basis of laboratory or instrumental tests performed on patients with MS.

Symptoms of NASH are nonspecific and reflect the very fact of liver damage, but do not correlate with its severity. Asthenovegetative syndrome is a characteristic feature and is found in more than half of patients with NASH; Unrelated discomfort in the right upper quadrant of the abdomen is less common. The appearance of complaints of skin itching, anorexia, dyspeptic syndrome along with the development of jaundice and the symptom complex of portal hypertension indicates an advanced stage of NASH.

A diagnostic search is carried out in connection with the identification of the following signs in a patient:

Asymptomatic elevation of aminotransferase levels;

Unexplained existence of persistent hepatomegaly;

Hepatomegaly on radiological examination;

Exclusion of all other causes leading to hepatomega-

Often, an increase in aminotransferase activity or constant “asymptomatic” hepatomegaly is detected in patients with T2DM or patients with impaired glucose tolerance (30-50%), with cholelithiasis (10-15%), in people receiving lipid-lowering therapy (5-13%) . Rarely, patients with NASH have signs of chronic liver disease such as telangiectasia and palmar erythema. Signs of NAFLD are found in 10-15% of people without clinical manifestations of MS.

Making this diagnosis is quite difficult due to the need to exclude all other causes causing cytolysis, macrovesicular steatosis and inflammatory-destructive changes in the liver. The secondary nature of liver damage should be excluded (Table 3).

It is also necessary to exclude alcoholic liver damage. The criterion is the amount of alcohol consumed per day.

Daily alcohol intake: up to 30 g for men and up to 20 g for women:

350 ml beer;

120 ml wine;

45 ml of strong drinks.

Upon examination, 30-100% of patients are found to be obese (BMI>30 kg/m2) or overweight, which correlates with the degree of hepatic steatosis. A decrease in muscle mass occurs in 15-30% of patients, but is difficult to diagnose due to obesity.

Biochemical signs of NAFLD include indicators of cytolysis syndromes (increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST))

Insulin resistance

Metabolic syndrome

Rice. 2. Relationship between NAFLD and other diseases

Table 3

Causes of secondary liver damage

Medicinal

drugs

Amiodarone Glucocorticoids Synthetic estrogens Calcium channel blockers (Diltiazem) Cytotoxic / cytostatic drugs (Methotrexate, Ozacitidine, Azauridine, L-asparaginase)

Tamoxifen Cocaine Aspirin Tetracycline Hydralazine Valproic acid Perhexiline maleate Antiviral drugs Antibiotics

(tetracycline, puromycin, bleomycin) Nonsteroidal anti-inflammatory drugs

Nutritional

Total parenteral nutrition Fasting

Rapid weight loss Low protein diet

Surgical

interventions

Gastroplasty Jejunoileal bypass Extensive resection of the jejunum Biliary-pancreatic stoma

Metabolic or genetic

Wolman's disease

Weber-Christian disease

Regional lipodystrophy

Tyrosinemia

Abetolipoproteinemia

Deposition of cholesteryl esters

Acute “fatty liver” during pregnancy

Exogenous

hepatotoxins

Organic solvents Oily solvents Phosphorus Poisonous mushrooms External hepatotoxins

Syndrome of excessive bacterial proliferation in the small intestine Malabsorption syndrome Inflammatory bowel disease Small intestinal diverticulum with infection

and cholestasis (increased levels of alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGTP), direct bilirubin, cholesterol).

There are predictors that suggest a high risk of progression of NAFLD with the development of steatohepatitis and fibrosis, which were established during statistical processing of the results of a large number of observations.

These include:

Age over 45 years;

Female;

BMI more than 28 kg/m2;

Increase in ALT activity twofold or more;

TG level more than 1.7 mmol/l;

Presence of arterial hypertension;

IR index (NOMA-SH) more than 5.

Identification of more than two criteria indicates a high risk of liver fibrosis. The role of hereditary predisposition is being investigated. It is known that genetic factors (β-oxidation defects, changes in the structure of mitochondrial DNA, the presence of certain HLA antigen loci) can also determine the progressive course of NAFLD. According to some data, C282Y heterozygotes are more common among patients with NASH.

In laboratory tests, NAFLD is characterized by the following changes:

Increased activity of ALT and AST aminotransferases by no more than four to five times, AST/ALT index - no more than 1, ALT activity is often increased;

Increased activity of alkaline phosphatase and GGTP; usually no more than 2 norms;

Hypertriglyceridemia, hypercholesterolemia;

Hyperglycemia (IGT or T2DM);

Hypoalbuminemia, increased bilirubin levels, thrombocytopenia, increased prothrombin time in patients with advanced stage NAFLD. Hepatocellular failure develops only

in the formation of liver cirrhosis, however, hypoalbuminemia in NASH occurs in patients with diabetic nephropathy. Before the development of hypersplenism in liver cirrhosis, hematological disorders are not typical for NASH. In 10 - 25% of patients, hypergammaglobulinemia and antinuclear antibodies are detected, the significance of which is unclear.

It should be noted that in patients with NAFLD with histologically verified ID without inflammation and damage to hepatocytes, there are practically no clinical and laboratory signs of liver disease.

The main differential difference between GC and NASH, available in clinical practice, may be the severity of the biochemical syndrome of cytolysis. When analyzing laboratory data obtained in specialized clinics, cytolysis is described in 50 - 90% of NASH patients. More often, ALT activity is higher than AST, but sometimes, especially in patients with transformation into cirrhosis, AST activity predominates. Unlike liver lesions of a different nature, cytolysis in NASH is constant, although fluctuations in ALT levels are possible. The degree of hypertransaminasemia does not correlate with the severity of steatosis and liver fibrosis.

According to some studies, ALT level, along with other metabolic factors, is an indicator of insulin resistance. This suggests the possibility of using this indicator as an additional marker in patients with insulin resistance. At the same time, according to some studies, a low serum ALT level in combination with a high BMI may indicate the probable presence of severe fibrosis in NASH.

Table 4

General characteristics of NAFLD

(according to histological examination)

Moderate alcohol consumption

(up to 30 g for men and up to 20 g for women)

Lack of evidence for secondary liver damage

Population prevalence 20-24%

(mainly as a component of MS)

Histological features of NASH

The most common cause of elevated liver transaminases

Thus, there are a number of signs characteristic of this disease (Table 4).

It should be noted, however, that the absence of changes in laboratory parameters characterizing the functional state of the liver (ALT, AST, ALP, GGTP) does not exclude the presence of an inflammatory-destructive process and fibrosis.

NASH is characterized by apoptosis of hepatocytes, and in late stages of the disease, activated caspases (particularly caspase-3 and caspase-7) cleave the hepatic filament protein cytokeratin-18 (CK-18). According to one study, measuring the number of CK-18 fragments can differentiate NASH from steatosis or normal liver tissue. Thus, a level of CD-18 fragments greater than 395 U/L may indicate the presence of NASH. The specificity and sensitivity of the method are 99.9% and 85.7%, respectively. Determination of increased caspase activity in the blood is a strong and independent predictor of NASH. Moreover, the degree of apoptosis correlates with the severity of steatohepatitis and the stage of fibrosis. Antibodies to caspase-formed CK-18 fragments are an indicator of early cell apoptosis. This non-invasive method of differential diagnosis can help practitioners in selecting patients for liver biopsy, as well as in determining the histological severity of the disease in patients with NAFLD, assessing disease progression and response to treatment.

The “gold standard” for diagnosing and staging NAFLD is still a needle biopsy of the liver.

Since the main liver tests used in clinical practice are not specific and do not always correlate with histological changes (damage, inflammation, fibrosis), liver biopsy, or rather its adequate assessment, occupies a central place in the diagnosis of NASH and determining the effectiveness of therapeutic intervention.

Mandatory indications for biopsy are:

Age over 45 years and chronic cytolysis of unknown etiology;

A combination of chronic cytolysis of unknown etiology with at least two manifestations of MS, regardless of age.

Liver biopsy is not indicated in cases where serum aminotransferase levels are normal.

Morphological examination allows us to determine the degree of NASH activity and the stage of liver fibrosis. The Brunt E. classification (2002) allows one to verify NAFLD most accurately and make a differential diagnosis of NASH with other diffuse liver lesions, including severe alcoholic steatohepatitis (Table 5).

There is a classification by Brunt E. (1999, 2001), which allows one to assess the degree of steatosis, the activity of inflammation and the stage of liver fibrosis based on the severity of certain morphological signs, which is of great importance for making a diagnosis by a practicing physician (Tables 6, 7).

Table 3

Morphological criteria for NAFLD

“Necessary signs” (components of the 1st order) Steatosis (large and small droplets) with a maximum in zone 3 of the acinus Mixed, mild lobular inflammation Scattered infiltration by neutrophils and mononuclear cells Balloon degeneration of hepatocytes, more pronounced in hepatocytes of zone 3 with signs of fatty infiltration

“Usually present, but not obligatory” signs (2nd order components) Perisinusoidal fibrosis in zone 3 of the acinus Glycogenosis of zone 1 nuclei Lipogranulomas in lobules Acidophilic bodies or PAB-positive globules in Kupffer cells Fatty cysts

“May be present, but not required for diagnosis” (3rd order components) Iron deposits in hepatocytes of zone 1 or scattered along the sinuses Megamitochondria in hepatocytes Mallory bodies in hepatocytes with balloon degeneration predominantly in zone 3 of the acinus (in zone 1 of the acinus in T2DM or as a result of taking Amiodarone)

Table b

NASH activity

Degree Steatosis Balloon dystrophy Inflammation

1 (mild NASH) 33-66%; large-droplet minimal, in the 3rd zone of the acinus lobular - scattered or minimal infiltration of polymorphonuclear leukocytes (PMNL) and mononuclear cells portal - absent or minimal

2 (moderate NASH) 33-66%; large- and small-droplet moderate, in the 3rd zone of the acinus lobular - moderate infiltration of PMN and mononuclear cells* portal - absent or soft, moderate

S (severe NASH) >66% (3rd zone or panacinar); large- and small-droplet dominates in the 3rd zone of the acinus, presented panacinar lobular - pronounced scattered infiltration of PMN and mononuclear cells** portal - mild, moderate, no more active than lobular

*may not be associated with balloon degeneration of hepatocytes and/or pericellular fibrosis; **maximally expressed in the 3rd zone of the acinus along with balloon degeneration and perisinusoidal fibrosis.

Table 7

Stages of liver fibrosis in NASH

Stage 1 Perisinusoidal/pericellular fibrosis in the 3rd zone of the acinus, focal or widespread

Stage 2 Stage 1 + focal or widespread periportal fibrosis

Stage 3 Bridging fibrosis, focal or widespread

Stage 4 Cirrhosis of the liver

Based on the existing classification, the NAFLD activity score (NAS) was developed and proposed, representing a comprehensive assessment of morphological changes in scores and combining criteria such as steatosis (0-3), lobular inflammation (0-2) and balloon degeneration of hepatocytes (0-2). A score of less than 3 allows us to exclude NASH, and a score of more than 5 indicates the presence of steatohepatitis in the patient. This scale is also indispensable for assessing the dynamics of NAFLD.

In the absence of clinical symptoms in a patient, abnormalities in liver function tests are detected and histological examination of liver tissue is not possible, ultrasound can serve as an inexpensive and reliable method for recognizing hepatic steatosis, especially if the patient has one or more risk factors for developing NASH, and also allows monitoring dynamics of the disease.

There are four main ultrasound signs of liver steatosis:

Distal echo attenuation;

Diffuse hyperechogenicity of the liver parenchyma (“bright liver”);

Increased echogenicity of the liver compared to the kidneys;

Blurred vascular pattern.

However, sometimes changes on ultrasound can be difficult to distinguish from fibrosis and even cirrhosis of the liver. In some cases, computed tomography and magnetic resonance imaging can detect fatty infiltration of the liver.

The capabilities of computed tomography (CT) and magnetic resonance imaging (MRI) in determining the severity of hepatic steatosis were assessed. The CT results were compared with the results of histological examination of the liver. According to the data obtained, the sensitivity and specificity for CT without contrast in detecting hepatic steatosis were 33 and 100%, respectively, for CT with contrast - 50 and 83%, respectively, for MRI - 88 and 63%, respectively.

It is clear that in the majority of patients NAFLD is characterized by a long, stable asymptomatic course. Therefore, according to modern concepts, special pharmacotherapy is indicated only for patients with a progressive course of this disease or a high risk of its progression. Obesity, T2DM, hyperlipidemia are the main conditions associated with the development of NAFLD.

Table 8

Pharmacotherapy

Lipid-lowering drugs Atorvastatin Clofibrate Bezafibrate Gemfibrozil Lipopharm, Lipostabil Probucol Orlistat

Choleretic Chophytol

Hepatoprotectors Ursodeoxycholic acid Metadoxin Selymarin, Silibinin

Insulin sensitizers Biguanides Glitazones

Enzymes Betaine

Antioxidants N-acetylcysteine ​​α-tocopherol (vitamin E) α-lipoic (thioctic) acid p-carotene Lecithin Selenium S-adenosine methionine

Vasodilators Pentoxifylline

AT11 receptor antagonists Losartran

Antimicrobials Metronidazole Nifuroxazide Rifaximin Polymyxin B

Prebiotics, probiotics, eubiotics Lactulose (Duphalac) Eubicor

Hormones Ghrelin

Therefore, treatment and/or prevention of these conditions should lead to improvement in liver health (Table 8).

Necessary conditions for eliminating the main pathogenetic factor of NAFLD - insulin resistance - are also actions aimed at weight loss: lifestyle changes, low-calorie nutrition, increased physical activity.

For overweight and obese individuals, a realistically achievable goal is to reduce body weight by approximately 7-10% in 6-12 months. Weight loss should be combined with moderate-intensity physical activity for at least 30 minutes a day. Regular muscle activity leads to metabolic changes that reduce insulin resistance. Numerous data on the effect of weight loss on liver health are very contradictory. It has been shown that rapid loss of body weight naturally leads to an increase in the activity of inflammation and the progression of fibrosis. At the same time, its reduction by 11-20 kg/year has a positive effect on the severity of steatosis and inflammation, the degree of liver fibrosis. Weight loss of up to 1600 g per week for adults and up to 500 g per week for children is considered safe, achieved with a daily caloric intake of 25 kcal/kg and active physical exercise or the use of the intestinal lipase inhibitor orlistat. At the same time, against the background of normalization of biochemical parameters of the liver, there is a significant decrease in steatosis, inflammation, damage and fibrosis of the liver.

It should be noted that the activity of transaminases against the background of hunger and rapid weight loss often decreases or even becomes normal, but histologically there is a sharp deterioration (central necrosis, portal inflammation, pericellular fibrosis) in the condition of the liver, with the possible exception of

maybe, degree of railway. The operation of jejunoileal anastomosis, previously used to reduce body weight, which led to a rapid weight loss, is currently not performed due to the high risk of developing NASH. The gastric band operation, which is now quite widely used, allows patients to slowly (2.7-4.5 kg/month) lose body weight, preventing the development of NASH.

Particular attention is paid to the consideration of approaches to the treatment of NAFLD associated with T2DM. It is obvious that the use of drugs that affect insulin resistance can lead to an improvement in the course of NAFLD.

The effects of biguanides are due to a decrease in gluconeogenesis and lipid synthesis in the liver, realized through the activation of cAMP-dependent liver protein kinase, which leads to a decrease in the synthesis of TG from fatty acids and mitochondrial β-oxidation. In addition, biguanides suppress the expression of TNF-α in the liver and the mechanisms induced by this cytokine leading to steatosis, as well as the expression of SREBP-1 in hepatocytes.

The main mechanism of action of metformin to increase fibrinolysis is a decrease in the level of PAI-1, which occurs in patients with T2DM, regardless of its dose. In addition to reducing PAI-1, metformin also reduces the proliferation of smooth muscle cells in the vascular wall in vitro and the rate of atherogenesis in animals.

Studies have been conducted comparing the effectiveness of metformin and diet therapy. The study included 20 patients (without diabetes and obesity). Liver function and insulin levels and insulin resistance were assessed (in euglycemia and hyperinsulinemia during the clamp test). Liver biopsy was performed in 14 patients who received metformin (500 mg x twice a day) and six patients who were on diet therapy for four months. Histological improvement was not assessed. The only significant difference between the two groups was in ALT levels. The patient groups did not differ significantly in terms of weight loss. Although active treatment caused an increase in lactic acid levels (up to 30% of actively treated patients), only one patient had a lactate level outside the normal range of more than 2 mmol/L (2.2 mmol/L).

Uygun et al. conducted a study that included 36 patients with NASH, divided into two groups. One group received metformin (at a dose of 850 mg) along with the diet, the control group was restricted in nutrition (1600-1800 calories per day). Compared with the control group, improvements in the following indicators were detected in the first group: reduction in ALT levels (from 83.5 + 24.6 to 46.4 + 23.3 U/l, respectively, p = 0.0001) and AST (57 .9+17.3 versus 35.8+10.5 U/l, p=0.0001). In the control group: ALT (from 72.8+31.2 to 55.4+16.3 U/l, p=0.001) and AST (from 48.1+26.3 to 41.3+13.5 U/l, p=0.06). No changes were observed in liver biopsies of subjects following treatment.

Other studies evaluating the effectiveness of metformin have shown improvements in the insulin resistance index (as assessed by QUICKI, HOMA or KITT methods). Three studies reported a decrease in liver function tests, and one study showed a slight increase in liver function tests.

In terms of histological improvement, only one report showed statistical differences in inflammation, steatosis, fibrosis, and global NASH scores after treatment.

A study of the effectiveness of metformin (1500 mg/day or 20 mg/kg/day) in the treatment (4-6 months) of patients with NASH showed that against the background of a decrease in body weight (about 1.5 kg/month), transaminases normalize and hypercholesterol levels decrease -

Table 9

Studies on the effectiveness of insulin sensitizers in the treatment of NAFLD

Using metformin Using glitazones

Nair S. et al., 2004 Blaszyk H. et al., 2005 Bugianesi E. et al., 2005 Duseja A. et al., 2006 Azuma T. et al., 2002 Neuschwander-Teri B.A. et al., 200Z Promrat K. et al., 2004

mia, hypertriglyceridemia and hepatomegaly. Positive histological dynamics similar to the experimental data were verified.

Thiazolidinediones (glitazones) selectively improve insulin sensitivity by activating RRLA-γ, stimulating the activity of the cellular glucose transporter GLUT4, which improves the uptake of glucose by peripheral tissues, reducing the concentrations of glucose, insulin, TG, non-esterified fatty acids and TNF-α in the blood.

The effectiveness of the use of thiazolidinediones (pioglitazone, rosiglitazone) was assessed in three studies. The average age of patients in each study was 40-46 years. Two studies used pioglitazone and one used rosiglitazone at different doses (pioglitazone 1530 mg/day and rosiglitazone 4 mg/day). The studies lasted from 12 to 48 weeks. Two studies assessed

insulin resistance according to the HOMA-III index, another compared serum insulin levels. Liver biopsies after treatment were reported in two studies. All studies have proven a decrease in insulin resistance, a significant decrease in the levels of ALT, AST. Biopsies after testing showed statistically significant improvements. Side effects also reported include weight gain, increased serum lactate levels, nightmares, and edema. The rate of withdrawal from the study was high: 11 out of 60 subjects. No cases of liver failure were reported.

Currently, studies are ongoing on the effectiveness of insulin sensitizers in the treatment of NAFLD (Table 9).

In connection with the steady increase in the prevalence of obesity, MS and diabetes among the population, the problem of diagnosing and treating NAFLD will become even more urgent. Poor coverage in the medical literature results in little awareness among physicians about the possible outcomes of this condition and poses a huge problem. The complexity of diagnosis verification, the search for reliable and highly informative markers of the disease and new non-invasive diagnostic methods make further research necessary. This is the goal of multicenter studies that are currently being planned.

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Kosobyan Evgenia Pavlovna postgraduate student, Institute of Diabetes, Federal State Institution Endocrinological Research Center, Moscow

Email: [email protected]

Smirnova Olga Mikhailovna Doctor of Medical Sciences, Professor, Chief Researcher of the Department of Education and Psychosocial Rehabilitation

patients with diabetes mellitus, Federal State Institution Endocrinological Research Center, Moscow

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Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, which leads to decreased quality of life, disability and death. Around the world, about 10–40% of people suffer from NAFLD. The main danger is the transformation of the pathology into non-alcoholic steatohepatitis with the development of liver failure and malignancy of the process.

The term “NAFLD” refers to clinical and morphological changes in the structure of the liver such as steatosis, fibrosis and cirrhosis, which occur in patients who do not drink alcohol in toxic doses. The disease most often affects middle-aged women with metabolic syndrome.

Stages

NAFLD manifests itself in increased fat deposition in the liver, accompanied by a decrease in the sensitivity of peripheral tissues to insulin. The diagnosis is made when steatosis is detected in more than 5% of liver cells on a biopsy. Before making a diagnosis, it is necessary to exclude other causes of liver damage, primarily alcohol consumption in hepatotoxic doses (more than 30 g of ethanol per day for men and 20 g per day for women). Excessive consumption of ethanol-containing drinks indicates alcoholic liver disease.

The development of NAFLD is divided into 4 successive stages:

1. Liver steatosis (accumulation of adipocytes and fat droplets in hepatocytes and liver parenchyma). If NAFLD is suspected, steatosis should be confirmed. This stage can be identified using ultrasound, CT or MRI. Ultrasound is more readily available, but abdominal MRI can reliably diagnose moderate to severe steatosis and provides additional information about the hepatobiliary system.
2. Steatohepatitis (attachment of the inflammatory process to stage 1). Detection of steatohepatitis indicates an increased risk of progression of the disease to subsequent stages and serves as a reason for more careful and frequent monitoring and intensive treatment. Reliable diagnosis of steatohepatitis is possible by performing a liver biopsy.
3. Liver fibrosis (with a long-term, sluggish inflammatory process, hepatocytes begin to be replaced by connective tissue elements, and foci appear in the form of fibrous constrictions). The occurrence of fibrosis is an important factor influencing the prognosis, outcomes and mortality of patients with NAFLD. The presence of severe fibrosis is an indication for hospitalization, a thorough examination of the liver, including a biopsy, and the initiation of intensive drug therapy. Regular monitoring of fibrosis progression is necessary.
4. Liver cirrhosis (an increase in the amount of scar tissue in the liver parenchyma with the development of progressive liver failure). Cirrhosis is a terminal stage of the disease, irreversible damage to the liver parenchyma. The only effective treatment for this condition is liver transplantation.

Symptoms

The disease is asymptomatic and is most often detected by chance during an ultrasound of the abdominal cavity or when increased activity of liver enzymes is detected according to a biochemical blood test.

At the stage of fibrosis and cirrhosis, heaviness and discomfort in the right hypochondrium, weakness, fatigue, itching, yellowness of the skin, mucous membranes and sclera, bitterness and dry mouth may occur. Advanced liver failure manifests itself in the form of ascites, hydrothorax and hydropericardium (accumulation of non-inflammatory fluid in the abdominal cavity, chest and cardiac sac), dilation of the saphenous veins of the anterior abdominal wall, edema of the lower extremities, and enlarged spleen.

Causes of the disease

Poor lifestyle is the main cause of NAFLD. The most common risk factors are a diet consuming excess calories, saturated fats, easily digestible carbohydrates and fructose, and low physical activity.

In some cases (especially among children and adolescents), a hereditary predisposition to NAFLD may be confirmed, resulting from defects in the genetic material (PNPLA3 and TM6SF2 gene).

There is a close connection between NAFLD and impaired glucose utilization by hepatocytes, muscle and adipose tissue cells, as well as metabolic syndrome.

Metabolic syndrome is diagnosed when three of the five criteria associated with insulin resistance are met: type 2 diabetes mellitus or fasting hyperglycemia, an increase in plasma triglyceride levels of more than 1.7 mmol/L, a decrease in HDL cholesterol of less than 1.0 mmol/L in men or less 1.3 mmol/l in women (anti-atherogenic fraction of cholesterol), abdominal obesity (waist circumference more than 94 cm in men and more than 80 cm in women) and arterial hypertension.

If a patient has metabolic syndrome, NAFLD should be suspected. Deposition of triacylglycerols in the liver parenchyma leads to disturbances in energy metabolism and a decrease in insulin function, resulting in hyperglycemia, hypertriglyceridemia and hyperinsulinemia. Progression of liver damage leads to worsening insulin resistance. The HOMA-IR index is used to screen for insulin resistance.

Abdominal obesity (increased waist circumference) indicates the presence of NAFLD. The severity of the disease is also aggravated by diseases associated with obesity: polycystic ovary syndrome, obstructive sleep apnea, hypogonadism, diabetes mellitus.

Patients suffering from diabetes mellitus are characterized by atherogenic dyslipidemia, elevated levels of liver transaminases and accumulation of fatty droplets in the liver. On the other hand, diagnosed NAFLD is associated with a high risk of diabetes mellitus, therefore, such patients are recommended to undergo an oral glucose tolerance test to detect disorders of carbohydrate metabolism.

Possible complications

Main complications of NAFLD:

1. Cardiovascular diseases. Excess weight, diabetes mellitus, and dyslipidemia accompanying NAFLD are risk factors for cardiovascular pathology. Myocardial infarction and stroke are more common causes of death than liver failure in NAFLD.
2. Hepatocellular carcinoma is a malignant tumor into which cirrhosis can transform; the incidence is 7.6% over 5 years.
3. Concomitant diseases of other organs: chronic renal failure, colorectal cancer, osteoporosis, hypovitaminosis D, lipodystrophy.

Diagnostics

If NAFLD is suspected, the following standard diagnostic tests are performed:

In patients without signs of progression of liver failure, monitoring of laboratory and ultrasound parameters should be carried out every 2–3 years. Patients in the stage of fibrosis require annual monitoring, and in case of liver cirrhosis, the dynamics are assessed every 6 months.

The progression of the disease in the first stage is slow, corresponding to one stage every 14 years. Starting from the second stage, the disease progresses by one stage every 7 years, the rate doubles in the presence of arterial hypertension.

Treatment options

The main goal of treatment is to slow the progression of NAFLD to cirrhotic disease. To do this, you need to take the following measures:

1. Changing your diet.
2. Normalization of body weight, possible use of drugs that reduce appetite (orlistat).
3. Quitting bad habits or reducing the intensity of smoking and drinking alcohol.
4. Aerobic exercise and strength training. With active exercise, the supply and utilization of free fatty acids in muscle tissue increases, which leads to a decrease in insulin resistance and weight loss. It is recommended to carry out training 3-5 times a week for at least 30 minutes.
5. Treatment of diabetes mellitus (drug of choice - metformin).
6. Antioxidants (tocopherol - vitamin E 800 mg per day).
7. Cytoprotectors (ursodeoxycholic acid 500–750 mg per day, obeticholic acid, omega-3-polyunsaturated fatty acids 1000 mg per day).
8. Lipid-lowering therapy (statins: Atorvastatin, Rosuvastatin, Simvastatin, bile acid sequestrants, Ezetimibe).
9. Treatment of arterial hypertension with angiotensin-converting enzyme inhibitors: Enalapril, Perindopril, Ramipril; angiotensinogen receptor blockers: Losartan, Valsartan, Telmisartan).
10. Bariatric surgery (surgeries aimed at reducing the mass of adipose tissue are indicated for morbid obesity with a body mass index of more than 50 kg/m2).
11. Liver transplantation is performed in the terminal stages of cirrhotic lesions refractory to drug treatment.

Antihyperglycemic, lipid-lowering and antihypertensive drugs are prescribed for life.

The duration of therapy with cytoprotectors and antioxidants is discussed individually.

Most patients are treated on an outpatient basis. The indication for hospitalization is a liver biopsy to clarify the diagnosis, severe liver failure, complicated liver cirrhosis.

Diet

Meals are fractional, in small portions 4–5 times a day. Principles and recommendations of therapeutic nutrition for NAFLD:

• reducing the consumption of saturated fats to 25–30% of total food;
• replacing quickly digestible carbohydrates (sweets, wheat flour, pasta, white bread) with complex ones (whole grain bread, cereals, porridges);
• polyunsaturated fatty acids (nuts, olives, fatty sea fish and seafood, vegetable oils) should prevail over saturated ones (fatty meat, butter, lard, margarine);
• a diet with reduced cholesterol (refusal to consume animal fats, egg yolks);
• refusal of sweet carbonated drinks, fruit juices;
• Preferred food processing methods: boiling, baking, steaming.

Prognosis and prevention

With the initial stages of the disease and timely treatment, the prognosis is favorable.

Monitoring patients with NAFLD:

• consultation with a gastroenterologist to assess the progression of the disease - every 6 months;
• general blood test, biochemical blood test, lipid spectrum - every 6 months;
• observation by an endocrinologist, study of fasting blood glucose levels, glycated hemoglobin, correction of glucose-lowering therapy - every 6 months;
• Ultrasound of the abdominal organs - every 6 months;
• indirect elastography of the liver for hidden fibrosis - once a year;
• measuring blood pressure, weighing, calculating body mass index - at every medical consultation.

Prevention consists of maintaining a healthy lifestyle, maintaining normal body weight, and treating concomitant diseases.

is a descriptive term used to identify the accumulation of fat droplets in the liver cells and includes a set of specific symptoms that characterize the accumulation of fat and inflammation of the liver tissue.

Most often, this process is diffuse in nature, i.e. covers the entire liver, but there may also be a local detection of the process (lipoma) - during ultrasound examination of the abdominal organs (ultrasound). In the presence of non-alcoholic steatohepatitis a diagnosis can be made - fatty liver degeneration, chronic hepatitis of unspecified etiology, unspecified cirrhosis of the liver. The prevalence ranges from 10 to 40%.

Risk groups for liver steatosis

• Patients with metabolic syndrome (type 2 diabetes mellitus, obesity, increased cholesterol and triglycerides).
• Patients with type 2 diabetes mellitus (in 70-100% of cases).
• Obese patients (in 30-100% of cases).
• Patients with elevated cholesterol and triglyceride levels (20-90%).
• Patients with diabetes mellitus and obesity (steatohepatitis is detected in 50% of cases, liver cirrhosis in 19-20% of cases).

Most often, patients aged 40-60 years are susceptible to the disease, but in children with normal body weight non-alcoholic fat disease detected in 2.6%, in obese children - in 22.5-52.8%.

Depending on gender, the disease predominates in women - 53-85%. First stage – fatty liver disease– 5 times more common in men, and steatohepatitis– 3 times more often in women.

Causes of non-alcoholic steatohepatitis

• Taking certain medications (hormones (glucocorticosteroids), estrogens, nefidipine, methotrexate, aspirin, diltiazem).
• Eating disorders (fasting, rapid weight loss, low protein diet).
• Surgical interventions (stomach and intestinal operations).
• External exposure to toxic substances (organic solvents, phosphorus, poisonous mushrooms).
• Intestinal diseases (inflammatory diseases, malabsorption, excessive growth of bacteria in the intestines).
• Insulin resistance is a decrease in the biological response to one or more effects of insulin.

The development of insulin resistance is facilitated by a hereditary factor - a predisposition to diabetes mellitus, detection of diabetes mellitus in close relatives, as well as excess caloric nutrition and low physical activity. These factors themselves contribute to increased obesity and fat accumulation in liver tissue. In approximately 42% of patients, risk factors for developing the disease cannot be identified.

Symptoms of non-alcoholic fatty liver disease

Most patients have no complaints. There may be discomfort and heaviness in the abdomen, weakness, increased fatigue, heaviness in the right hypochondrium, nausea, belching, and loss of appetite.

Upon examination, an increase in the size of the liver is revealed. Often there is suspicion of non-alcoholic fatty liver disease Diagnosed by performing an ultrasound of the abdominal organs or a biochemical blood test.

Diagnosis of non-alcoholic fatty liver disease

IN biochemical blood test There is an increase in liver enzymes ALT and AST to 4 norms, alkaline phosphatase to 2 norms.

At ultrasound examination (ultrasound) The information content of the method decreases in obese patients.

Computed tomography (CT) – allows you to accurately assess the degree steatosis, the sensitivity and specificity of the method is 93-100%.

Magnetic resonance imaging (MRI) – provides a complete image of the organ in any projection, has a high agreement with the data of histological examination.

Liver elastography – has higher accuracy in advanced stages of liver damage (fibrosis).

Prognosis for non-alcoholic fatty liver disease

With progression non-alcoholic fatty liver disease There is a higher risk of developing cardiovascular diseases, atherosclerosis, metabolic syndrome, and type 2 diabetes.

Overall for non-alcoholic fatty liver disease characterized by a benign course. The development of liver cirrhosis is observed in only 5% of cases. The prognosis of the disease is influenced by such factors as the presence of concomitant pathology, primarily obesity, diabetes mellitus, dyslipidemia, arterial hypertension and adequate correction of metabolic disorders.

Treatment of liver steatosis

• Weight loss, lifestyle changes (diet and exercise).
• Treatment of metabolic syndrome.
• Use of hepatoprotectors.
• Restoration of intestinal microflora.
• Correction of lipid metabolism.

When the doctor and patient work together, treatment liver steatosis goes well. GUTA CLINIC has its own extensive diagnostic base for identifying non-alcoholic fatty liver disease at any stage. We use expert-level equipment from the world's leading manufacturers - leaders in the production of medical devices. Highly qualified doctors of GUTA CLINIC, candidates and doctors of medical sciences, using their rich clinical experience, will prescribe an individual regimen treatment of liver steatosis and help you stay healthy!

Non-alcoholic fatty liver disease poses a serious threat to human health. Doctors at the EXPERT gastro-hepatocenter are experts in the treatment of fatty liver disease: they carefully select therapy, coordinate recommendations with a nutritionist, and develop individual approaches to lifestyle changes and nutritional correction.

What is NAFLD?

Non-alcoholic fatty liver disease (NAFLD) characterized by the accumulation of fat in liver cells. This is one of the most common and complex diseases in hepatology. NAFLD leads to a decrease in the quality of life, an increase in disability and mortality in the working population.

The concept of non-alcoholic fatty liver disease combines a number of structural changes in the organ. This steatosis(excess fat in liver cells), non-alcoholic steatohepatitis(NASH) is a disease accompanied by fat accumulation and inflammatory response of the liver, fibrosis and subsequently cirrhosis.

Reasons for development

Usually, development of NAFLD is a consequence of the syndrome insulin resistance(decreased biological response to one or more effects of insulin).

There are exceptions: cases associated with the following factors:

• taking certain medications that are hepatotoxic (amiodarone, glucocorticoids, synthetic estrogens, diltiazem, nifedipine, methotrexate, tamoxifen, perhexylene maleate, cocaine, aspirin)
• eating disorders(total parenteral (intravenous) nutrition, fasting, rapid weight loss, low protein diet)
• surgical interventions
• metabolic factors
• toxins(organic solvents, phosphorus, poisonous mushrooms)
• intestinal diseases(malabsorption syndrome, inflammatory diseases, intestinal dysbiosis).

At-risk groups

A high risk of developing NAFLD is observed among patients with metabolic syndrome (MS). These are patients with type 2 diabetes mellitus, elevated blood triglyceride levels, and obesity. According to the results of various studies, incidence of NAFLD in patients with type 2 diabetes mellitus and obesity is represented from 70 to 100%. If there is a combination of type 2 diabetes and obesity, the risk of developing NAFLD increases. Thus, among people with type 2 diabetes and obesity, liver steatosis is detected in 100% of patients, steatohepatitis is found in 50%, and even cirrhosis is detected in 19%.

NAFLD is more often detected:

• aged 40 to 60 years
• in women (53-85%).

Risk factors for developing NAFLD

1. Unbalanced diet, consumption of fatty, fried foods, sweets, abuse of caffeine, nicotine, alcohol
2. Chronic stress
3. Obesity, high cholesterol and triglycerides in the blood
4. Genetic factors
5. Concomitant pathology (diabetes mellitus type II, diseases of the cardiovascular system, hormonal and metabolic disorders).

The estimated prevalence of NAFLD in the population is 40%, while the incidence of NASH ranges from 2 to 4%. Studies were conducted in the Russian Federation, according to the results of which the incidence among patients included in the NAFLD study group was 27% in 2007 and 37.3% in 2015.

Symptoms

Usually, NAFLD is characterized by a latent (asymptomatic) course. Often the disease is detected during a random ultrasound examination of the liver or a biochemical blood test.

The most common symptoms of NAFLD are:

• weakness, drowsiness, decreased performance, fatigue
• feeling of heaviness in the right hypochondrium
• spider veins, droplets.

About advanced fatty liver disease, up to cirrhosis, they say:

• the appearance of skin itching
• the appearance of nausea
• stool disorder
• development of jaundice of the skin and mucous membranes
• increase in abdominal volume
• bleeding
• impairment of cognitive abilities.

Very often a person goes to the doctor with complaints of weakness, drowsiness, heaviness in the right hypochondrium, increased pressure up to 130/80 mmHg. and above, but does not always receive a complete response and treatment.

If you are familiar with words like obesity, diabetes, increased liver enzymes, increased bilirubin, increased cholesterol, large and fatty liver, then be sure to consult a liver disease expert.

Diagnostics

It is important to remember that in the diagnosis and treatment of each patient there must be an individual approach and targeted monitoring of the condition. But in the first place is a detailed survey and an objective examination by an expert doctor.

It is necessary to go through a series laboratory and instrumental studies. The most informative study is ultrasound elastography of the liver. In a biochemical blood test, the hepatologist pays attention to liver-specific indicators (liver enzyme levels, metabolic rates and other important markers). Many diseases have similar symptoms, which is why it is important to exclude viral, autoimmune and genetic liver diseases.

If you know or suspect that you have liver disease, do not wait, do not worsen your life prognosis, contact an expert hepatologist. Only in this case will you be able to improve your quality of life, avoid disability, and the occurrence and progression of complications.

For the initial examination, the “Liver is a second heart” program is ideal.

Treatment of non-alcoholic fatty liver disease

The approach to treatment must be comprehensive. First of all, you should pay attention to lifestyle changes and weight loss (properly increase physical activity and adjust nutrition). These measures not only have a positive effect on the course of fatty liver disease, but also reduce the degree of liver steatosis.

Drug therapy is aimed at:

• correction of metabolism (metabolic syndrome) and concomitant pathologies
• treatment of oxidative stress
• prevention and treatment of liver fibrosis
• restoration of intestinal microbiocinosis.

Thanks to the experts’ individual approach to your problem, you will receive treatment results: reduced progression of the disease, reduced risks of liver cirrhosis, diabetes, heart attack, stroke (especially if there is a hereditary factor), reduced liver fat, and most importantly, increased quality and life expectancy.

Forecast

Patients with NAFLD have high risk of death, because Without treatment, liver damage continues to progress. The main causes of death in fatty liver disease are:

1. development of cardiovascular accidents
2. liver failure
3. hepatocellular carcinoma (liver cancer).

As studies show, already during the initial examination of patients with steatohepatitis, fibrosis is detected in 30-40%, and liver cirrhosis in 10-15% of patients. Progression of steatohepatitis with subsequent development of fibrosis and cirrhosis of the liver was noted in more than 50% of patients.

The prognosis in patients with NAFLD is influenced by factors such as the presence concomitant pathology, and first of all - obesity, type 2 diabetes mellitus, increased blood lipids, arterial hypertension and adequate correction of metabolic disorders. Timely treatment aimed at correcting and preventing metabolic disorders significantly improves the prognosis of patients with NAFLD.

It is important to note that, subject to constant monitoring of the condition, NAFLD is characterized by a benign course. Proper nutrition, avoidance of alcohol, correction of metabolic disorders, physical activity, as a rule, reduce the risk of developing NAFLD and lead to an improvement in the condition of those already suffering from this form of the disease.

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NAFLD what is it? Non-alcoholic fatty liver disease (NAFLD) is a modern problem! The current state of the problem is such that the prevalence of non-alcoholic fatty liver disease varies significantly in different countries of the world and amounts to 20-30% of the total world population. The highest prevalence of this disease is observed in regions with an urban lifestyle - the USA, China, Japan, Australia, Latin America, Europe, and the Middle East. In most countries in Asia and Africa, the prevalence of the disease is much lower, around 10%.

What is NAFLD: distribution, symptoms, diagnosis

Non-alcoholic fatty liver disease in children

The pandemic increase in the incidence of NAFLD is closely related to the increase in the prevalence of obesity. Thus, according to a systematic analysis, from 1980 to 2013, the number of children with obesity increased from 8.1 to 12.9% among boys and from 8.4 to 13.4% among girls in lagging countries, and in accordance with 16.9% to 23.8% and from 16.2 to 22.6% in developed countries.

Its prevalence among US adolescents, according to population-based studies, has more than doubled over the past 20 years and amounted to 11% among adolescents in general, reaching 48.1% among obese male adolescents. Given the high level of prevalence of overweight and obesity among schoolchildren, it should be assumed that domestic and global trends are consistent.

Non-alcoholic fatty liver disease symptoms

Non-alcoholic fatty liver disease (NAFLD) has no consistent clinical symptoms and is usually an incidental finding in asymptomatic children. The disease is usually detected before the age of 10 years. The symptomatic picture of the disease in children is dominated by nonspecific signs: general weakness, accelerated fatigue, exhaustion. In 42-59% of patients, more often with progression of steatohepatitis, pain is observed in the right abdominal region. On physical examination, hepatomegaly of varying degrees is found in more than 50% of cases.

Papillary pigmentary dystrophy of the skin, also called acanthosis nigricans, characterized by hyperpigmentation of skin folds on the neck and under the arms, can occur in almost half of patients with NAFLD and is associated with insulin resistance. Measuring waist circumference in children, unlike adults, is a sufficient criterion to confirm the presence of central obesity and a significant predictor of the development of metabolic syndrome. There is a need to develop international and domestic age standards for waist circumference values ​​for use in practice.

Prospects for diagnosis and treatment of NAFLD

The starting step in diagnosing the disease is to identify elevated levels of liver transaminases and/or sonographic symptoms of steatosis during routine ultrasound examination. For timely diagnosis, due to the lack of specific clinical and biochemical markers, there is a need for active screening in risk groups. Screening is recommended for overweight and obese children. The diagnostic search is aimed at identifying steatosis using imaging techniques, clarifying the reasons for the development of steatosis during laboratory examination, and determining the stage of the disease through histological examination.

By the way, you can learn about gallbladder diseases and their treatment from this article.

The development of steatosis is a universal reaction to the influence of various endo- and exogenous factors, therefore, clarification of the etiological factor of its formation takes a leading place in the diagnosis of the disease. A diagnosis of NAFLD is possible in the absence of signs of another nature of liver destruction, mainly autoimmune, drug-induced and viral hepatitis.

Diseases and conditions that require differential diagnosis with NAFLD in children:

General (systemic) pathologies:

• acute systemic diseases;
• protein-energy defect;
• total parenteral nutrition;
• rapid weight loss;
• anorexia nervosa;
• cachexia;
• metabolic syndrome;
• inflammatory bowel diseases;
• celiac disease;
• viral hepatitis;
• thyroid and hypothalamic dysfunction;
• nephrotic syndrome;
• bacterial overgrowth syndrome.

• cystic fibrosis;
• Shwachman syndrome;
• Wilson's disease;
• a1-antitrypsin deficiency;
• hemochromatosis;
• abetalipoproteinemia;
• galactosemia;
• fructosemia;
• tyrosinemia (type I);
• glycogen storage diseases (type I, VI);
• defects in mitochondrial and peroxisomal fatty acid oxidation;
• defects in the synthesis of bile acids;
• homocystinuria;
• familial hyperlipoproteinemia;
• Madelung's lipomatosis.

Rare congenital genetic diseases:

• Ahlstrom's syndrome;
• Bardet-Biedl syndrome;
• Prader-Willi syndrome;
• Cohen's syndrome;
• Cantu syndrome (1p36 deletion);
• Weber-Christian syndrome.

• ethanol;
• estrogens;
• cocaine;
• nifedipine;
• diltiazem;
• tamoxifen;
• valproate;
• zidovudine;
• methotrexate;
• L-asparaginase;
• solvent;
• pesticides.

Risk factors for the formation of the disease

Factors contributing to the onset of disease can be divided into two groups: those that are modifiable and those that cannot be corrected by corrective intervention. Among the factors that are modified are constitutional and dietary ones. Genetic characteristics, gender, ethnic origin are among the factors that cannot be corrected.

The leading constitutional risk factors for the development of the disease that can be modified in children are obesity and insulin resistance. A family history of obesity, NAFLD, or T2DM increases the risk of developing fatty liver disease in children. One study found that 78% of parents and 59% of siblings of children with the disease also had fatty liver disease, and the disease is highly heritable.

Low birth weight is associated with early obesity and is also a predictor of NAFLD. Evidence has been obtained that not only obesity, but also excess weight gain at the age of 1-10 years increases the risk of its occurrence already in adolescence. In addition, rapid weight gain in obese children is also considered a risk factor. Much more often, steatosis is diagnosed in children over 10 years of age, with overweight and obesity. Transient insulin resistance, which occurs during puberty, increases metabolic disorders and leads to the progression of metabolic syndrome.

Factors that can be corrected also include dietary factors. It has been shown that certain dietary features, namely excessive consumption of carbohydrates, fructose, sucrose, and an imbalance between omega 6 and omega 3 polyunsaturated acids in the diet, contribute to the development of this disease.

By the way, just recently, scientists from the USA found that taking just two cans of sweet carbonated drink in one day will greatly increase the likelihood of developing non-alcoholic fatty liver disease.

Constitutional factors that cannot be modified include gender and ethnicity. Thus, male gender is a separate risk factor for the disease: the disease is more common in boys than in girls, in a ratio of 2:1. The prevalence of NAFLD has been shown to be highest among Hispanic Americans.

It is recognized that the onset and progression of the disease is associated with certain individual characteristics of the genome. Nonsynonymous single nucleotide polymorphisms (SNPs) of genes from various clusters may be associated with the development and progression of NAFLD:

1. Genes associated with insulin resistance (adiponectin, resistin, insulin receptor, peroxisome proliferator-activated receptor y).
2. Genes responsible for the hepatic metabolism of free fatty acids (hepatic lipase, leptin, leptin receptor, adiponectin, microsomal triglyceride transporter protein.
3. Cytokine-associated genes (tumor necrosis factor - a, interleukin-10).
4. Genes associated with fibrogenesis in the liver (transforming growth factor b1, connective tissue growth factor, angiotensinogen).
5. Endotoxin receptor genes.
6. Genes involved in the development of oxidative stress (superoxide dismutase-2).

Video essay on NAFLD

And in conclusion of the article, we suggest that you familiarize yourself in more detail with two parts of a video essay on fatty liver disease:

Part 1

Part 2

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