How is non-alcoholic fatty liver disease treated? What is NSAID - symptoms, diagnosis, factors, risk What is the danger of fatty hepatosis
Currently, non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases in hepatology, leading to a deterioration in the quality of life, disability and death. First of all, this is due to the high risk of progression of NAFLD with the development of non-alcoholic steatohepatitis (NASH), liver failure, and hepatocellular carcinoma. The overall prevalence of NAFLD in the population ranges from 10 to 40%, while the incidence of NASH is 2-4%.
Epidemiology and pathogenesis of NAFLD
The concept of NAFLD combines the spectrum of clinical and morphological changes in the liver, represented by steatosis, NASH, fibrosis and cirrhosis, developing in patients who do not consume alcohol in hepatotoxic doses (no more than 40 g of ethanol per day for men and no more than 20 g for women). NAFLD occurs in all age groups, but women aged 40-60 with signs of metabolic syndrome (MS) are at the highest risk of developing it.
The pathogenesis of NAFLD is closely related to insulin resistance syndrome (IR), as a result of which triglycerides (TG) accumulate in the liver and fatty hepatosis (FG) is formed - the first stage or "push" of the disease. Subsequently, free fatty acids (FFA) are released from adipose tissue and synthesized de novo in hepatocytes, contributing to oxidative stress, which is the second "impetus" of the disease and leading to the development of inflammatory and destructive changes in the liver in the form of steatohepatitis.
The maximum risk of developing NAFLD was noted in the group of people with MS - these are patients with type 2 diabetes mellitus (DM), obesity, and hypertriglyceridemia. The incidence of NAFLD in patients with type 2 diabetes and obesity, according to various studies, varies from 70 to 100%. At the same time, type 2 diabetes or impaired glucose tolerance (IGT) is observed in 10-75%, obesity - in 30-100%, hypertriglyceridemia - in 20-92% of patients with NAFLD. At the same time, signs of NAFLD are found in 10-15% of people without clinical manifestations MS, which may be due to other pathogenetic mechanisms of the formation of NAFLD, for example, the syndrome of excessive proliferation of bacteria in the intestine or dysbiosis, as it is customary to formulate in the domestic literature.
The main mechanisms of development of NAFLD in intestinal dysbiosis are associated with impaired synthesis of apo-lipoproteins of classes A and C, which are a transport form for TG in the process of formation of very low density lipoproteins (VLDL), as well as intestinal endotoxicosis, which allows us to consider this condition as an additional source of oxidative stress (fig.).
The relationship between the pathogenesis of NAFLD and IR allows us to consider this disease as one of the independent components of MS, the clinical significance of which lies in the significant progression of atherosclerotic vascular lesions.
A number of studies have shown that NAFLD increases the risk of cardiovascular disease(CVD) regardless of other predictors and manifestations of MS. This is supported by several facts, which include the relationship between NAFLD and plasma adiponectin concentration. It is known that adiponectin has an antiatherogenic effect and, according to the data of many prospective studies, a decrease in its level is an early predictor of CVD and MS. Patients with NAFLD had a lower plasma adiponectin concentration than healthy individuals.
In addition, in this category of patients, compared with the control group, there is a significant increase in the thickness of the intima (TI) of the carotid artery, which is also recognized as a reliable subclinical sign of atherosclerosis. It has been proven that a TI value of less than 0.86 mm is associated with a low risk of CVD, and more than 1.1 - with a high risk. In patients with NAFLD, its value averages 1.14 mm.
Another subclinical sign of atherosclerosis found in patients with NAFLD is the detection of endothelial dysfunction, which is confirmed by a decrease in endothelium-dependent vasodilation of the brachial artery in patients with NAFLD. At the same time, a decrease in this indicator correlates with the degree of morphological changes in the liver, regardless of gender, age, IR and other components of MS.
Thus, the pathogenesis of NAFLD is inextricably linked with MS, and the very fact of the development of this pathology changes the prognosis for these patients, both in the form of progression of liver failure and in the form of a significant increase in the incidence of CVD complications.
Clinic and diagnostics
In general, NAFLD is characterized by an asymptomatic course, therefore, most often in practice, a doctor is faced with a cytolysis syndrome accidentally discovered during a biochemical study. In this case, a patient with NAFLD, as a rule, either does not present complaints, or they are nonspecific in the form of asthenovegetative syndrome (weakness, fatigue) and discomfort in the right hypochondrium. The presence of pruritus, dyspeptic syndrome, along with the development of jaundice and portal hypertension, indicates an advanced stage of NAFLD.
On objective examination of patients with NAFLD, attention is drawn to hepatomegaly, which occurs in 50-75%, and splenomegaly, detected in 25% of patients.
In a laboratory study, NAFLD is characterized by the following changes:
Increase in the activity of alanine (ALT) and aspartic (AST) aminotransferases by no more than 4-5 times, the AST / ALT index is not more than 2, more often the ALT activity is increased;
Increased activity of alkaline phosphatase (ALP) and g-glutamyl transpeptidase (GGTP);
Hypertriglyceridemia, hypercholesterolemia;
Hyperglycemia (NTG or type 2 diabetes);
Hypoalbuminemia, increased bilirubin levels, thrombocytopenia, increased prothrombin time in patients with advanced NAFLD.
The main differential difference between GH and NASH, available in clinical practice, there may be a severity of the biochemical syndrome of cytolysis.
It should be noted, however, that the absence of changes in laboratory parameters characterizing functional state liver (ALT, AST, ALP, GGTP), does not exclude the presence of an inflammatory and destructive process and fibrosis.
As mentioned above, the diagnostic search is carried out in connection with the detection of cytolysis syndrome in the patient, while the presence of type 2 diabetes, abdominal obesity, arterial hypertension and lipid metabolism disorders indicates a high probability of NAFLD. Making this diagnosis is quite difficult due to the need to exclude all other causes of cytolysis, macrovesicular steatosis and inflammatory and destructive changes in the liver. The secondary nature of liver damage should be excluded (Table 1).
To clarify the diagnosis, can be used instrumental methods(ultrasound examination (ultrasound), computed tomography (CT), magnetic resonance imaging (MRI)), which allow verifying hepatomegaly, indirectly assessing the degree of hepatic steatosis and registering the formation of portal hypertension.
Ultrasound is an inexpensive and, according to some authors, a fairly informative instrumental method for diagnosing liver steatosis. There are 4 main ultrasound signs of hepatic steatosis:
Distal echo attenuation;
Diffuse hyperechogenicity of the liver ("bright liver");
Increased echogenicity of the liver compared to the kidneys;
Indistinctness of the vascular pattern.
The advantages of ultrasound also include the ability to register the dynamics of signs of steatosis, including during treatment.
When performing a CT scan of the liver, the main signs indicating the presence of steatosis are:
Decrease in liver X-ray density, which is normally 50-75 units, to 3-5 units (when performing CT without contrast intravenous enhancement, the density of liver tissue with steatosis decreases by about 1.6 units for every milligram of TG contained in one gram of liver tissue) ;
X-ray density of the liver with steatosis is less than the X-ray density of the spleen;
Visualization of intrahepatic vessels, portal and inferior vena cava as more dense structures in comparison with the hepatic tissue;
Crossing normal blood vessels liver in areas of low radiopacity (typical for focal fatty degeneration).
In general, CT is less informative than ultrasound for diffuse liver lesions, but it is the method of choice for focal diseases.
The advantages of modern high-field MRI compared to other imaging methods are: high tissue contrast of the image due to the favorable signal-to-noise ratio, the ability to obtain a complete image of an organ in any projection, as well as large resources software used for differential diagnosis.
However, all imaging diagnostic methods, despite the rather high information content, do not allow assessing the presence of signs of steatohepatitis, the degree of its activity and the stage of fibrotic changes in the liver. Therefore, in order to verify the diagnosis, it is necessary to conduct a puncture biopsy.
The importance of puncture liver biopsy in clinical practice is ambiguous. On the one hand, only a liver biopsy makes it possible to make a differential diagnosis between steatosis and steatohepatitis, to assess the stage of fibrosis and, on the basis of histological data, to predict the further course of the disease, as well as to exclude other causes of liver damage. However, the lack of awareness of doctors about the feasibility, and patients about the safety of the method is hampered by the active introduction of puncture biopsy into practice.
In addition, the morphological criteria of NAFLD are still actively discussed. Until now, in practice, the classification proposed by Brunt E. (1999, 2001) has been widely used, which subdivides NAFLD depending on the degree of steatosis, the activity of inflammation and the stage of liver fibrosis:
I. Degrees of coarse steatosis:
0 degree: no steatosis;
1 degree: steatosis up to 33% of hepatocytes;
2 degree: steatosis 33-66% of hepatocytes;
Grade 3: steatosis more than 66%.
II. Degrees of NASH:
Grade 1 (mild NASH) - steatosis 1-2 degrees, minimal balloon dystrophy in the 3rd acinus zone, lobular inflammation - diffuse or minimal lymphoplasmacytic infiltration, portal inflammation is absent or minimal;
Grade 2 (moderate NASH) - steatosis of any degree (large and small droplets), moderate balloon dystrophy in the 3rd acinus zone, mild or moderate portal and lobular inflammation in the 3rd acinus zone, there may be perisinusoidal fibrosis;
3 degree NASH (severe NASH) - panacinar steatosis (mixed), severe balloon dystrophy, pronounced lobular inflammation, mild or moderate portal inflammation.
III. Fibrosis stages:
Stage 1 - perisinusoidal / pericellular fibrosis in the 3rd acinus zone, focal or widespread;
Stage 2 - perisinusoidal / pericellular fibrosis in the 3rd acinus zone, focal or widespread periportal fibrosis;
Stage 3 - focal or widespread bridging fibrosis;
Stage 4 - liver cirrhosis.
However, according to a number of authors, this classification does not reflect the whole spectrum of morphological signs detected in patients with NAFLD during histological examination. Recently, on the basis of the existing classification, the NAFLD activity score (NAS) was developed and proposed, representing a comprehensive assessment of morphological changes in points and combining such criteria as steatosis (0-3), lobular inflammation (0-2) and balloon dystrophy. hepatocytes (0-2). The sum of points less than 3 allows to exclude NASH, and more than 5 indicates the presence of hepatitis in the patient. This scale is used primarily to assess the effectiveness of NAFLD treatment, since it allows one to determine the reliability of the dynamics of morphological changes during therapy in a relatively short period of time.
In those cases when a puncture biopsy is not possible, the diagnosis of NAFLD is established in accordance with an algorithm that allows to exclude other liver diseases step by step (Table 2).
Due to the fact that all patients with MS are at risk of developing NAFLD, patients with obesity, type 2 diabetes or IGT, impaired lipid metabolism need additional examination, including clinical, laboratory and instrumental methods for diagnosing NAFLD and, in particular, NASH. However, until now, NAFLD and its manifestations are not included either in the criteria for the diagnosis of MS, or in the algorithm for examining patients with suspicion of its presence (Table 3).
Screening of patients at the stage of preclinical manifestations of MS includes:
Anamnesis (heredity, lifestyle, eating habits, physical activity);
Anthropometric measurements (body mass index (BMI), waist (OT) and hips (OB), OT / OB index);
Blood pressure (BP) monitoring, electrocardiographic examination;
Evaluation of lipid profile (TG, total cholesterol, high and low density lipoprotein cholesterol (HDL cholesterol, LDL cholesterol), apo-B plasma);
Determination of fasting glucose, glucose tolerance test according to indications;
Fasting blood insulin.
Taking into account the frequency, role and value of NAFLD, the algorithm for examining patients with MS should include clinical, laboratory and instrumental methods that allow assessing the morphofunctional state of the liver:
Objective examination (assessment of hepatomegaly, splenomegaly, detection of telangiectasias, palmar erythema, etc.);
Clinical blood test (presence of thrombocytopenia, anemia);
Assessment of biochemical parameters reflecting the functional state of the liver (ALT, AST, GGTP, ALP, total bilirubin, prothrombin, proteinogram);
Ultrasound of the liver (degree of steatosis, hepatomegaly, portal hypertension);
Fibrogastroduodenoscopy (screening of varicose veins of the esophagus);
CT, MRI, radioisotope scanning of the liver;
Puncture biopsy of the liver.
Mandatory indications for biopsy are:
Age over 45 years and chronic cytolysis of unknown etiology;
Combination of chronic cytolysis of unknown etiology with at least two manifestations of MS, regardless of age.
It is possible to assess the course of NAFLD based on the data of histological examination of the liver. However, when biopsy is not available, there are predictors that suggest a high risk of progression of NAFLD with the development of hepatitis and fibrosis, which were established by statistical processing of the results of a large number of observations.
These include:
Age over 45;
Female;
BMI over 28 kg / m 2;
Increase in ALT activity by 2 times or more;
TG level is more than 1.7 mmol / l;
The presence of arterial hypertension;
Type 2 diabetes;
IR index (NOMA-IR) more than 5.
Identification of more than 2 criteria indicates a high risk of liver fibrosis.
To formulate a full-fledged clinical diagnosis, it is necessary to take into account the data of clinical laboratory and instrumental examination, the identification of factors of an unfavorable course of the disease and other components of MS. Since the diagnosis of "non-alcoholic fatty liver disease" is still absent in ICD-10 (WHO, 1998), its formulation by practitioners can be made taking into account the rules for diagnosing alcoholic liver disease and viral hepatitis. In the diagnosis, in the first place, it is better to indicate the tunosological unit against which the NAFLD developed, followed by the form of the disease (hepatosis or NASH), the degree of steatosis (according to ultrasound), the activity of hepatitis and the stage of fibrotic changes in the liver in the case of hepatobiopsy. If morphological examination has not been performed, the conclusion is admissible, as in other liver diseases,: unidentified fibrosis. Examples of diagnostic findings:
Obesity II degree. Non-alcoholic fatty liver disease: steatosis II degree (by ultrasound), unidentified fibrosis (biopsy was not performed).
Hypertension stage II. Arterial hypertension of the I degree, the risk is high. Secondary dyslipoproteinemia, combined. Diabetes mellitus, first diagnosed. Obesity I degree. Non-alcoholic fatty liver disease: non-alcoholic steatohepatitis, moderate activity, stage 2 fibrotic changes (periportal fibrosis).
Diabetes mellitus type 2, compensated. Non-alcoholic fatty liver disease: non-alcoholic steatohepatitis, pronounced activity ( heavy course), pronounced (bridging) fibrosis.
Type 2 diabetes mellitus, decompensated. Liver cirrhosis as a result of severe non-alcoholic steatohepatitis, subcompensated, Child class B, severe portal hypertension, ascites, grade II esophageal varicose veins.
Treatment of NAFLD
Due to the high probability of an unfavorable course of NAFLD, especially in combination with other manifestations of MS, all patients, regardless of the severity of the disease, require dynamic monitoring and treatment. However, no standardized therapeutic approaches have yet been developed for the management of patients with NAFLD.
The directions of therapy used in patients with NAFLD are based on the mechanisms of the development of the disease, which primarily include IR syndrome and oxidative stress; therefore, the most important tasks in this category of patients are:
- correction of metabolic disorders:
Weight loss (diet and exercise);
Increasing the sensitivity of cellular receptors to insulin (metformin, thiazolidinediones);
Decrease in TG levels (fibrates, statins);
Decreased concentration of TNFa (pentoxifylline);
Antihypertensive therapy (angiotensin II receptor antagonists);
Antioxidants and hepatoprotectors (vitamin E, silibinin, betaine, N-acetylcysteine, ursodeoxycholic acid (UDC), a-lipoic acid (ALA));
Diet. Taking into account modern ideas about the etiology, pathogenesis and factors of progression of NAFLD, patients are recommended the following dietary principles:
For patients with overweight and obesity - a decrease in the total energy value of the diet. The daily calorie content is selected individually depending on body weight, age, gender, level of physical activity using special formulas. First, the number of calories required for basal metabolism is calculated:
for women:
18-30 years old: (0.06 × weight in kg + 2.037) × 240
31-60 years: (0.034 × weight in kg + 3.54) × 240
over 60: (0.04 × weight in kg + 2.76) × 240
for men:
18-30 years old: (0.06 × weight in kg + 2.9) × 240
31-60 years: (0.05 × weight in kg + 3.65) × 240
over 60 years of age: (0.05 × weight in kg + 2.46) × 240.
The resulting value is multiplied by the coefficient of physical activity (1.1 - low activity, 1.3 - moderate, 1.5 - hard physical work or active sports) and the calorie content of the daily diet is obtained. To reduce body weight, 500-700 kcal are subtracted from the calculated value of daily energy consumption. However, the minimum calorie intake per day should be at least 1200 kcal for women and at least 1500 for men. It has been proven that a 5-10% decrease in body weight is accompanied by a decrease in hepatosplenomegaly, ALT, AST activity and correlates with regression of liver steatosis. It should be noted that rapid weight loss can lead to the development of "acute" NASH with the formation of portal fibrosis, central necrosis against the background of a significant increase in inflammatory activity due to an increase in the supply of FFA to the liver against the background of peripheral lipolysis. For obese patients with NAFLD, it is safe and effective to reduce body weight by 500 g per week for children and 1600 g per week for adults.
Limiting fats to 25-30% of the total energy value of food;
The ratio of polyunsaturated and saturated fatty acids (FA) in food is more than 1 (excluding butter, animal fat, hard margarine, etc., eating foods rich in polyunsaturated fatty acids - vegetable oil, seafood, fish, poultry, olives, nuts, taking into account energy demand);
Reducing the consumption of foods with a high cholesterol content (no more than 300 mg per day) - excluding by-products (liver, kidneys), caviar, egg yolk, raw smoked sausages, fatty meats and dairy products;
Elimination of foods prepared as a result of such food processing as frying, deep frying, etc .;
Fortification of food with vitamins and natural prebiotics (fruits, Jerusalem artichoke, leeks, artichokes);
For patients with IGT and type 2 diabetes, a diet with the exclusion of simple and restriction of complex carbohydrates is relevant, which contributes to the achievement of metabolic control.
Increasing the sensitivity of cell receptors to insulin ... To basic medications In the treatment of IR syndrome in patients with NAFLD, insulin sensitizers - biguanides (metformin) and thiazolidinediones (pioglitazone, rosiglitazone) - drugs that increase the sensitivity of cell receptors to insulin can be attributed. Data application experience medicines indicates a positive effect on the clinical and morphological manifestations of NAFLD in the form of a decrease in the activity of indicators of cytolytic syndrome, the degree of steatosis and inflammation. But in general, the issue of using these drugs in patients with NAFLD requires further research, which is due to the lack of adequate methods of monitoring the effectiveness of treatment (hepatobiopsy) in the performed works.
Lipid-lowering drugs ... Given the pathogenesis of the disease, in patients with NAFLD, the use of lipid-lowering drugs from the fibrate group may be effective. However, the results of a study with the appointment of clofibrate in patients with NAFLD showed its ineffectiveness. One should not forget about the possibility of developing fibrate-induced hepatitis. In relation to statins, there are also a number of contraindications associated with their hepatotoxic effect. In general, the data of the work performed are contradictory and indicate the need for further study of the possibility of using these drugs in patients with NAFLD.
Pentoxifylline. A decrease in the concentration of tumor necrotizing factor-a (TNFa) is important for the progression of NAFLD. Possessing a high biological activity, TNFa enhances IR and leads to the development of oxidative stress. A decrease in its level in blood is associated with regression of clinical and morphological manifestations of NAFLD. A similar effect was found with pentoxifylline. Prescription of this drug in patients with NASH at a daily dose of 1200 mg for 12 months was associated with a decrease in the indicators of cytolytic syndrome and a significant improvement in histological indicators in 67% of patients.
Angiotensin II receptor antagonists. The formation of this approach is due to the role of angiotensin in the progression of NASH. It was found that it, promoting the proliferation of myofibroblasts, cell migration, the synthesis of collagen and pro-inflammatory cytokines, activates the processes of fibrogenesis in the liver. Therefore, the possibility of using angiotensin receptor blockers in patients with NAFLD is currently being investigated. So, taking losartan in patients with NASH and arterial hypertension at a daily dose of 50 mg for 38 weeks led to a significant decrease in ALT and GGTP, which was combined with a decrease in the degree of steatosis and inflammatory activity.
Antioxidants The use of antioxidants in patients with NAFLD is justified by the presence of oxidative stress, which is confirmed by an increase in plasma of patients with NASH of oxidative stress marker - thioredoxin and a decrease in the concentration of antioxidant factors. Currently, the possibility of using vitamin E is actively being studied, the effectiveness of which has been demonstrated in a number of studies. There is also a number of foreign and domestic works devoted to assessing the effect of UDC on the morphofunctional state of the liver. The mechanisms of action of this hydrophilic acid are associated with the fact that, by normalizing the hepatoenteric circulation of bile acids and a number of biologically active substances, displacing toxic bile acids, it helps to eliminate excess cholesterol in hepatocytes by reducing its synthesis and absorption from the intestine. UDC also has a cytoprotective and antiapoptotic effect, preventing the development of oxidative stress, which makes it possible to use it at both stages of NAFLD.
With regard to ALA, it was found that it has a pleiotropic effect on the entire body, exerting a positive effect on energy, lipid (inhibits cholesterol synthesis, suppressing the release of FFA from adipose tissue, which prevents the development of hepatocyte steatosis) and carbohydrate (reduces IR, enhances the uptake and utilization of glucose cell, increases the sensitivity of cellular receptors to insulin) types of metabolism.
In addition, ALA, having a low oxidation-reduction potential, has a powerful antioxidant effect, acting directly on the liver, contributes to an increase in detoxifying substances in hepatocytes (restores glutathione) and improves morphological changes.
Restoration of intestinal microbiocenosis. Unfortunately, most of the works confirming the pathogenetic role of intestinal dysbiosis in the formation of NAFLD and the effectiveness of antibacterial drugs in the treatment of this nosology refers to the 80-90s of the last century.
Therefore, the question of carrying out intestinal sanitation antibacterial drugs remains open. Antibiotics are recommended only if there is a verified sensitive opportunistic flora in the intestine or the formation of a disease after surgical treatment on the abdominal cavity eg "adductor loop syndrome". The advantage of choice in this case belongs to drugs that have the ability to accumulate well in bile with the effect of secondary passage through gastrointestinal tract, which include the first generation fluoroquinolones (ciprofloxacin). Intestinal antiseptics such as metronidazole or nifuroxazide and non-absorbable drugs such as rifaximin may also be used.
In all other cases, when there are no indications for the use of antibiotics, intestinal sanitation in patients with NAFLD should be carried out with prebiotics, and the drug of choice in this case is Eubicor. Its advantage is a balanced composition, which includes dietary fiber and wine yeast ( S. vini). In addition to the powerful prebiotic effect, Eubicor has good sorption properties, which allows not only to restore normal microflora, but also to carry out detoxification. According to the research results, taking Eubicor in this category of patients contributed to an additional decrease in dyslipoproteinemia and an increase in insulin sensitivity.
Treatment of non-alcoholic FG
In general, the requirements for drugs used in the treatment of NAFLD are quite high. First of all, they should be as safe as possible from the point of view of hepatotoxicity; their positive effect on improving clinical, laboratory and morphological changes in the liver is also desirable.
Own experience in the treatment of patients with NAFLD at the stage of hepatosis consists in the use of a combination of ALA with Eubicor. ALA (drug "Berlition", manufacturer - Berlin-Chemie, Germany) was prescribed 600 IU intravenously for 14 days, with the transition to oral administration in the same daily dose, once for 6 months. Eubikor was prescribed 2 sachets 3 times a day with meals. The results of the work showed a positive effect of Berlition and Eubikor not only on the indicators of lipid and carbohydrate metabolism, but also on the degree of fatty degeneration in the liver based on the results of ultrasound and morphological studies. The positive dynamics of these changes is important both for the formation of systemic IR, which is the main reason for the development of MS, and for the course of NAFLD itself and the development of NASH. Therefore, these drugs, along with non-drug therapy, can be considered as a means of basic therapy for the first stage of NAFLD - GI.
NASH treatment
With the development of NASH patients, the therapy of the disease was enhanced by an additional combination of metformin (Siofor, manufacturer - Berlin-Chemie, Germany) at a dose of 1500 mg per day with UDC (Ursosan by PRO.MED.CS Praha as) at a dose of 15 mg per 1 kg of body weight, with a single dose one hour after dinner. The duration of treatment was selected individually, as a rule, it was at least 6 months, sometimes reaching 12 or more months. The duration of the course depended on the severity of clinical manifestations, compliance and dynamics of laboratory and instrumental parameters during treatment. The appointment of these drugs was accompanied by a decrease not only in the clinical and laboratory manifestations of the disease, but also significantly improved the histological picture of the liver. At the same time, combination therapy in this category of patients was the method of choice, since it was in the group that simultaneously received Siofor, Berlition and Ursosan that the dynamics of indicators of cytolysis syndromes, cholestasis, as well as fat and carbohydrate metabolism was more significant. Against the background of treatment, patients with NASH also showed a reverse development of fatty degeneration, the severity of inflammatory changes significantly decreased and there was no progression of the stage of fibrosis in the liver. Thus, combination therapy affects the main etiopathogenetic mechanisms of the formation of metabolic disorders, leads to an improvement in lipid and carbohydrate metabolism in the form of normalization of HDL, TG and IR index in patients with NASH.
UDC (Ursosan) 15 mg / kg / day.
Lipid-lowering diet;
Physical activity - at least 3-4 times a week for 30-40 minutes;
Compensation for diabetes (against the background of a diet in combination with oral antihyperglycemic drugs or insulin);
Eubikor 2 sachets 3 times a day;
Metformin (Siofor) in an individually selected dosage depending on the level of glycemia (do not prescribe to patients with advanced forms of NAFLD, with liver failure due to the risk of lactate acidosis);
ALK (Berlition) 600 units per day;
UDC (Ursosan) 15 mg / kg / day.
Arterial hypertension in patients with NAFLD is one of the risk factors for the progression of fibrosis, therefore, preference in choosing an antihypertensive drug to correct blood pressure (BP) should be given to drugs from the group of angiotensin II receptor antagonists. Recommended algorithm for choosing therapy for patients with NAFLD and arterial hypertension:
In this way, timely diagnosis NAFLD and identification of possible risk factors for an unfavorable course of the disease are important, since taking them into account allows you to choose an adequate method of treatment that prevents further progression of NAFLD. In this regard, all patients with MS who have a high likelihood of having NAFLD and especially NASH should be examined to assess the morphofunctional state of the liver. At the same time, despite the fact that the formation of standards for the diagnosis and treatment of NAFLD remains an unresolved issue, medical specialists, based on the existing need, can use the proposed algorithms in their practice.
For literature questions, please contact the editorial office.
S. N. Mekhtiev
V. B. Grinevich, Doctor of Medical Sciences, Professor
Yu.A. Kravchuk, Candidate of Medical Sciences
A. V. Brashchenkova
VMA them. S. M. Kirov, Saint Petersburg
Modern concepts of the pathogenesis of non-alcoholic fatty liver disease
E.P. Kosobian, O.M. Smirnova
FGU Endocrinological Research Center, Moscow (Director - Academician of RAS and RAMS I.I.Dedov)
Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease characterized by abnormal accumulation of fatty droplets 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 disease (CVD) in the population.
Asymptomatic course of the disease, difficulties in its diagnosis, lack of a unified concept for the treatment of NAFLD - actual problems that require more in-depth study and deserve 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 Center, 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), obesity.
Pioneered by Ludwig et al. in 1980 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 the spectrum of liver damage, which includes its three main forms: fatty hepatosis (FH), non-alcoholic (metabolic) steatohepatitis (NASH) and cirrhosis (as an outcome of progressive NASH). Rarely, hepatocellular carcinoma may result in NASH.
FG (the literature also uses the terms: hepatic steatosis, fatty liver, fatty liver) is a disease or syndrome caused by fatty degeneration of the liver cells. It is characterized by pathological - intra- and (or) extracellular - deposition of fatty droplets. The morphological criterion of GH is the content of triglycerides in the liver over 5-10% of dry weight.
NASH is a disease characterized by an increase in the activity of liver enzymes in the blood and morphological changes in liver biopsies, similar to those in alcoholic hepatitis - fatty degeneration (FD) with an inflammatory reaction and fibrosis; however, people with NASH do not consume alcohol in quantities that can damage the liver.
In recent years, there has been an increase in interest in this problem, which is due, in particular, to an increase in the frequency of morbid obesity among the population of industrialized countries and the subsequent increase in the incidence of NAFLD. Patients with MS are at the highest risk of developing NAFLD. A steady increase in the incidence has been established.
Due to the fact that mortality from cardiovascular diseases (CVD) ranks 1st in the world, NAFLD is becoming even more important because conducted studies provide strong evidence of an increased risk in these patients. Most of them are expected to develop CVD in the long term.
The true prevalence of NAFLD is unknown, however, according to recent studies, the prevalence of NAFLD and NASH in the general population can reach 20-24 and 3%, respectively. Studies have shown that in diseases associated with insulin resistance, characteristic changes in the liver are detected in 74% of cases.
The prevalence of NAFLD is high in people with insulin resistance and diseases such as obesity, type 2 diabetes (T2DM), dyslipidemia, and MS. MS and NAFLD are usually combined, and the presence of MS often predicts the future development of NAFLD. So, with the help of ultrasound, fatty hepatosis is detected in T2DM in 50% and 75% of cases. In one of the studies using ultrasound examination, it was found that FH was present 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% in patients with diagnosed diabetes mellitus, in 32% with dyslipidemia.
However, the exact mechanisms of liver fibrogenesis have not yet been elucidated. Fibrosis occurs in 20-37% of patients with NAFLD. In 20% of them, cirrhosis is formed within 20 years with the development of hepatocellular failure. Population studies suggest that 60-80% of cryptogenic liver cirrhosis is an outcome of 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 (Bilanin E. et al., 2007). In addition, in patients with NAFLD in combination with diabetes and without diabetes, a higher prevalence of CVD was established than in patients without NAFLD outside of the
depending on obesity and traditional CVD risk factors.
Pathogenesis
The pathogenesis of NASH is not fully understood. The main components of hepatocellular lipids are triglycerides (TG), the substrates for the synthesis of which are fatty acids and glycerophosphate. The accumulation of fatty droplets in the liver may be the result of an excessive supply of free fatty acids to the liver or their increased synthesis by the liver itself from acetylcoenzyme A, especially with an excess of the latter. Sources of glycerophosphate in the hepatocyte are: a) glycerol, formed during lipid hydrolysis; b) glucose, which, during glycolysis, turns 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 in it. If the formation of triglycerides 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 accumulates in the hepatocyte, which leads to an increase in the processes of free radical oxidation of lipids with the accumulation of lipid peroxidation products (LPO) and the development of hepatic cell necrosis. In turn, the accumulation of LPO products is involved in the metabolism of nitric oxide, namely, its excessive consumption, which aggravates endothelial dysfunction, promotes the progression of arterial hypertension, and the development of cardiovascular complications. Prolonged hypertriglyceridemia under conditions of insulin resistance disrupts endothelium-dependent vasodilation, causes oxidative stress and is the most important risk factor for early atherosclerosis.
A high-calorie diet, a sedentary lifestyle in genetically predisposed individuals causes severe postprandial hyperlipidemia, as well as activation of lipolysis and, as a result, excessive formation of free fatty acids (FFA), which has a direct lipotoxic effect on pancreatic β-cells; stimulates glycogenolysis in the liver. Excessive FFA concentration and post-prandial hyperlipidemia are additional predictors of insulin resistance, hyperinsulinemia, and atherosclerosis.
Insulin is a stimulant 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 mediated LPO toxicity. Their action leads to inhibition of K / NaATPase, inhibition of glycolysis, uncoupling of oxidative phosphorylation, activation of PPAR-a pathway for utilization of excess FFA. With a decrease in the protective properties of the membrane of hepatocytes from FFA toxicity, there is a direct or mediated oxidative stress damage to mitochondria, apoptosis and necrosis of hepatocytes. The interaction of oxidative stress and cytokines entails a disruption in the functioning of hepatic stellate cells (HSC) - the main producers of extracellular collagen matrix (ECM), leading to an imbalance in fibrogenesis-fibrolysis with activation of fibrogenesis. Oxidative stress products are able to induce ECM synthesis even in the absence of significant damage to hepatocytes and inflammation. Due to repeated damage, the accumulation of fibrillar extracellular matrix reflects the impossibility of effective remodeling and regeneration. Directly related to the process is also a violation of the 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 occurs in concert. From a clinical point of view, these processes can cause the formation of liver cirrhosis.
A common model of the pathogenesis of NAFLD is the "two-hit" theory. The first blow is the development of ID, the second - steatohepatitis. With obesity, especially visceral obesity, the supply of FFA to the liver increases and liver steatosis develops, which is considered the "first blow". Under conditions of insulin resistance, lipolysis in adipose tissue increases, 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. Simultaneously or sequentially, oxidative stress develops - the "second blow" with the formation of an inflammatory reaction and the development of steatohepatitis.
Visceral adipose tissue, in contrast to subcutaneous tissue, is richer in blood supply and innervated. Visceral adipose tissue adipocytes, having a high sensitivity to the lipolytic action of catecholamines and a low sensitivity to the anti-lipolytic action of insulin, secrete FFA directly into the portal vein. High concentrations 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 hepatocytes, 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 actions.
Insulin occupies a leading place in the regulation of lipolysis and separation in hepatocytes of mitochondrial | 3-oxidation and synthesis of VLDL cholesterol. Insulin resistance plays a fundamental role in the pathogenesis of NAFLD. This served as a prerequisite for studying the relationship of insulin resistance with 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.
The storage of energy 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 (MPT) and leads to the formation of a pool containing TGs, passing into VLDL.
Insulin prevents the destruction of Apo-B100 and stimulates the specific adipocyte factor SNEBP-1C (a factor of determination and differentiation of adipocytes (ADD-1). With a long-term positive energy balance, insulin increases its expression; due to excess fatty acids, the PPAYA-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 pre-adipocytes into new adipocytes. Thus, a long-term positive energy balance can lead to both an increase in the size of adipocytes ( hypertrophy) and an increase in their number (hyperplasia).
It was found that obesity has a stimulating effect on the endocanabinoid system, causing hyperactivation of C1 receptors, in particular through overexpression of the cannabinoid receptor agonist Anandamide, which activates
activates the Cbl receptor, which leads to overexpression of SREBP-lC and, consequently, an increase in de novo lipogenesis in the liver and fibrogenesis. The endocanabinoid system induces peripheral lipolysis through the activation of lipoprotein lipase and suppression of adiponectin production.
Adiponectin is an adipose tissue hormone that is an insulin sensitizer and antiatherogenic factor. It has been found that in obese people, its level is reduced. Adiponectin prevents the phenomenon of apoptosis and necrosis in hepatocytes by reducing the production of TNF-a and the induction of PPAR-a-activity.
Adiponectin inactivates AKK and fatty acids, but activates hepatic carnitine palmitoyl transferase (KPP-I), which is involved in the synthesis of FAs EPP-I, located on the inner surface of the outer membrane of mitochondria, is a rate-limiting enzyme at the stage of FA transport. malonyl- & A level. With the intake of carbohydrates, the concentration of malonyl-KoA inside the cell increases, and this suppresses the activity of EPP-! and switches metabolism to the synthesis of fatty acids and triglycerides.
The adiponectin antagonist is leptin, another adipose tissue cytokine. It is required for the activation of 3KO and the development of fibrosis.
SREBP-lC is also activated by the hepatic receptor LXR-a, which functions as a cholesterol sensor activated in response to an increase in intracellular cholesterol levels in hepatocytes and other cell types. It induces AKK, ZhKS and SREBP-lC transcription through retinoid X-a receptor(RXR-a), as well as transcription of the hepatic SCD-l gene, which is responsible for the production of fatty acids.
It was found that RXR-a mediates the transcriptional activity of PPAR-a, which is acid-sensitive
nuclear receptor of the liver. 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 PPAR-a-agonists prevents NAFLD in obese mice and promotes its regression in experimental models of NAFLD.
It is known that in patients with NAFLD, the level of Gellin, a hormone produced in the stomach and duodenum and which is a central stimulant of appetite, is reduced. Ghrelin induces ACC and GST expression. It has been suggested that Ghrelin level may be regarded as a precursor to GI in patients with nutritional deficiencies.
In obese individuals, the serum concentration of TNF-a is increased.
TNF-a activates a protein that stimulates protective inflammatory reactions - an inhibitor of kappa kinase-beta (1KK | 3) in adipocytes and hepatocytes, which leads to a violation of the binding of insulin to the receptor. The effect of TNF-a on the insulin receptor type 1 (IRS-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 provides glucose entry 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 monocytic chemotactic protein-1 (MCP-1), which plays a leading role in the pathogenesis of atherosclerosis.
Remarkable is the fact that cytokines are one of the main stimulators of liver regeneration. It is known that TNF-a is able to initiate liver necrosis, but normally
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. Diagram of the pathogenesis of NAFLD
Table 1
Cardiovascular diseases
Cardiometabolic risks Main symptoms and manifestations
Visceral obesity Insulin resistance Atherogenic dyslipidemia (| TG, | HDL, LDL, OC) Disorders of carbohydrate metabolism (IGT, DM) Violation of fibrinolysis (tPAM, fibrinogen) Inflammation (^ CRP) Proinflammatory cytokines (MSRN-1), | (4HBG, | free testosterone) NAFLD Decrease in endothelium-dependent vasodilation of the brachial artery Increase in the thickness of the intima-media complex of the carotid artery Thrombogenic transformation of the vascular wall Violation of hemostasis Atherosclerosis / IHD Arterial hypertension Early dysfunction of the left ventricle Hyperandidemia
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 mm Hg Hyperandrogenism
Fasting glucose:
> = 5.5 mmol / L
necrosis does not occur in small hepatocytes, because TNF-a-target genes are usually expressed at a minimal level. Serum TNF-a levels are not the same in patients with hepatic steatosis and NASH and are generally higher in patients with NASH, although the difference is not always statistically significant.
Interleukin-6 (IL-6) has 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), an increase in 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 proinflammatory proteins, also express receptors for them; therefore, adipocytes are both a source and a target of this inflammatory signal.
Chronic liver inflammation is accompanied by an increase in the 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 the causative factor of its fibrosis through the activation of HSC.
Angiotensin II (AT11) plays a role in the progression of NASH. It was found that it, promoting the proliferation of myofibroblasts, cell migration, the synthesis of collagen and pro-inflammatory cytokines, activates the processes of fibrogenesis in the liver, aggravates insulin resistance, oxidative stress and liver iron overload. One of the studies showed that the expression of AT11 receptors of the first type 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 AT11 receptors of the first type correlated with the severity of portal hypertension. With cirrhosis, the expression of angiotensin-converting enzyme and chymase increased in the liver.
Under conditions of hyperglycemia, hyperinsulinemia and hyper-triglyceridemia, the expression of the plasminogen activator inhibitor-1 (PA1-1) gene in the culture of human smooth muscle, adipose and hepatic cells increases. PA1-1 inhibits tissue and urokinase plasminogen activators and plays an important role in determining susceptibility to cardiovascular diseases. An increase in the content 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, which means that, when developed in people with normal weight, it can be a predictor of early metabolic disorders and diseases.
In patients with NAFLD, there was a decrease in endothelium-dependent vasodilation of the brachial artery and an increase in the thickness of the intima-media complex (ICIM) of the carotid artery - markers of early atherosclerosis. It has been proven that a TCIM 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 characteristic of
thorny for NAFLD, foreshadows an increased risk of CVD regardless of traditional risk factors and components of MS. Thus, NAFLD itself can be considered an independent CVD risk factor, in addition to other generally known ones (Table 1).
The established risk factors for the development of CVD are practically all components of MS, and their combination accelerates their development many times over (Table 2).
As mentioned above, NAFLD can exist both as a separate nosological unit and as a component of other diseases associated with insulin resistance (MS, obesity, T2DM). These diseases have common pathogenetic factors that predetermine their development and progression, therefore, they can combine and potentiate the development of each other (Fig. 2).
Diagnostics
The main feature of NAFLD and NASH is asymptomatic. Most often, the disease is detected by chance - on the basis of laboratory or instrumental tests performed on patients with MS.
NASH symptoms are nonspecific and reflect the very fact of liver damage, but do not correlate with its severity. Asthenovegetative syndrome is characteristic feature and is found in more than half of patients with NASH; less often there is unrelated discomfort in the right upper quadrant of the abdomen. The appearance of complaints of pruritus, anorexia, dyspeptic syndrome, along with the development of jaundice and a complex of portal hypertension, indicates an advanced stage of NASH.
The diagnostic search is carried out in connection with the identification of the following symptoms in the patient:
Asymptomatic elevation of aminotransferase levels;
Unexplained existence of persistent hepatomegaly;
Radiologic hepatomegaly;
Exclusion of all other causes leading to hepatomeg-
Often, an increase in the activity of aminotransferases or persistent "asymptomatic" hepatomegaly is detected in patients with type 2 diabetes or patients with impaired glucose tolerance (30-50%), in cholelithiasis (10-15%), in persons receiving lipid-lowering therapy (5-13%) ... Rarely, patients with NASH have these symptoms. chronic illness liver like 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 of cytolysis, macrovesicular steatosis and inflammatory and 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 of beer;
120 ml of wine;
45 ml of spirits.
On examination, 30-100% of patients show obesity (BMI> 30 kg / m2) or excess body weight, correlating with the degree of hepatic steatosis. A decrease in muscle mass occurs in 15-30% of patients, but it is difficult to diagnose due to obesity.
Biochemical signs of NAFLD include indicators of cytolysis syndromes (increased levels of alanine amine transferase (ALT), aspartate aminotransferase (AST))
Insulin resistance
Metabolic syndrome
Rice. 2. Relationship of NAFLD with 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
interference
Gastroplasty Jejunoileal bypass surgery Extensive resection of the jejunum Imposition of a biliary-pancreatic stoma
Metabolic or genetic
Wolman's disease
Weber-Christian disease
Regional lipodystrophy
Tyrosinemia
Abetolipoproteinemia
Deposition of cholesterol esters
Acute "fatty liver" during pregnancy
Exogenous
hepatotoxins
Organic solvents Oil solvents Phosphorus Poisonous fungi External hepatotoxins
Syndrome of excessive bacterial proliferation in the small intestine Syndrome of impaired absorption Inflammatory bowel disease Small bowel 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;
Female;
BMI over 28 kg / m2;
An increase in ALT activity by a factor of two or more;
TG level is more than 1.7 mmol / l;
The 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 (defects in β-oxidation, changes in the structure of mitochondrial DNA, the presence of certain loci of antigens of the HLA system) can also predetermine the progressive course of NAFLD. According to some reports, among patients with NASH, heterozygotes for C282Y are more common.
In a laboratory study, NAFLD is characterized by the following changes:
An increase in the activity of ALT and AST aminotransferases is not more than four to five times, the AST / ALT index is not more than 1, more often the activity of ALT is increased;
Increased ALP and GGTP activity; usually no more than 2 norms;
Hypertriglyceridemia, hypercholesterolemia;
Hyperglycemia (NTG or T2DM);
Hypoalbuminemia, increased bilirubin levels, thrombocytopenia, increased prothrombin time in patients with advanced NAFLD. Hepatocellular failure develops only
in the formation of cirrhosis of the liver, however, hypoalbuminemia in NASH occurs in patients with diabetic nephropathy. Prior to the development of hypersplenism in cirrhosis of the liver, hematological abnormalities for NASH are not typical. In 10 - 25% of patients, hypergammaglobulinemia and antinuclear antibodies are detected, the significance of which is unclear.
It should be noted that in NAFLD patients 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 GH 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 patients with NASH. More often, the ALT activity is higher than the AST, but sometimes, especially in patients with transformation into liver cirrhosis, the 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 hepatic steatosis and fibrosis.
According to some studies, the level of ALT, along with other metabolic factors, is an indicator of insulin resistance. Which suggests the possibility of using this indicator as an additional marker in patients with insulin resistance. At the same time, according to some studies, reduced level Serum ALT in combination with a high BMI may indicate the likely presence of severe fibrosis in NASH.
Table 4
general characteristics NAFLD
(according to histological examination data)
Moderate alcohol consumption
(up to 30 g for men and up to 20 g for women)
Lack of data for secondary liver damage
Population prevalence 20-24%
(mainly as a component of MC)
Histological signs of NASH
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 hepatocyte apoptosis, and in the later stages of the disease, activated caspases (in particular caspase-3 and caspase-7) degrade the hepatic filament protein cytokeratin-18 (CK-18). One study found that measuring the number of CK-18 fragments differentiates NASH from steatosis or normal liver tissue. Thus, the level of the number of CK-18 fragments exceeding 395 U / L may indicate the presence of NASH. The specificity and sensitivity of the method is 99.9% and 85.7%, respectively. Determination of increased blood caspase activity 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 ca-spase-formed fragments of CK-18 are an indicator of early cell apoptosis. This non-invasive differential diagnosis can assist practitioners in the selection of patients for liver biopsy, as well as in determining the histological severity of the disease in patients with NAFLD, in assessing the progression of the disease and the response to treatment.
Puncture liver biopsy is still the "gold standard" for diagnosing and determining the stage of development of NAFLD.
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, is central to the diagnosis of NASH and the determination of the effectiveness of therapeutic intervention.
Mandatory indications for biopsy are:
Age over 45 years and chronic cytolysis of unknown etiology;
Combination of chronic cytolysis of unknown etiology, with at least two manifestations of MS, regardless of age.
Liver biopsy is not indicated if serum aminotransferase levels are normal.
Morphological examination allows to determine the degree of NASH activity and the stage of liver fibrosis. The classification of Brunt E. (2002) makes it possible to verify NAFLD most accurately and to carry out 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 makes it possible 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 the diagnosis by a practitioner (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 the 3 zone of acinus Mixed, mild lobular inflammation Dispersed infiltration by neutrophils and mononuclear cells Balloon dystrophy of hepatocytes, more pronounced in hepatocytes 3 zones with signs of fatty infiltration
"Usually present, but not required" signs (components of the 2nd order) Perisinusoidal fibrosis in the 3rd acinus zone Glycogenosis of the nuclei of the 1st zone Lipogranulomas in the lobules Acidophilic bodies or RAB-positive globules in Kupffer cells Fat cysts
“May be present, but not necessary for diagnosis” (3rd order components) Iron deposits in hepatocytes of zone 1 or scattered along the sinuses Megamitochondria in Mallory's Taurus hepatocytes in hepatocytes with balloon dystrophy, mainly in zone 3 of acinus (in zone 1 of acinus in T2DM or as a result of taking Amiodarone)
Table b
NASH activity
Degree Steatosis Balloon dystrophy Inflammation
1 (mild NASH) 33-66%; coarse droplets minimal, in the 3rd acinus zone lobular - diffuse or minimal infiltration with polymorphonuclear leukocytes (PMNL) and mononuclear cells portal - absent or minimal
2 (moderate NASH) 33-66%; large and small droplets moderate, in the 3rd acinus zone lobular - moderate infiltration of PMNL and mononuclear cells * portal - absent or mild, moderate
Z (severe NASH)> 66% (3rd zone or panacinarian); large and small droplets dominates in the 3rd acinus zone, panacinar lobular is presented - pronounced diffuse infiltration of PMNL and mononuclear cells ** portal - mild, moderate, not more active than lobular
* may not be associated with balloon dystrophy of hepatocytes and / or pericellular fibrosis; ** is most pronounced in the 3rd acinus zone along with balloon dystrophy and perisinusoidal fibrosis.
Table 7
Stages of liver fibrosis in NASH
Stage 1 Perisinusoidal / pericellular fibrosis in the 3rd acinus, focal or widespread
Stage 2 Stage 1 + focal or widespread periportal fibrosis
Stage 3 Bridge fibrosis, focal or widespread
4th stage Liver cirrhosis
Based on the existing classification, the NAFLD activity score (NAS) was developed and proposed, representing a comprehensive assessment of morphological changes in points and combining such criteria as steatosis (0-3), lobular inflammation (0-2) and balloon dystrophy of hepatocytes. (0-2). The sum of points less than 3 allows to exclude NASH, and 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 the patient, detection of abnormal liver function tests and if it is impossible to conduct a histological examination of liver tissue, ultrasound can serve as an inexpensive and reliable method for recognizing hepatic steatosis, especially if the patient has one or more risk factors for the development of NASH, and also allows you to monitor 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;
Indistinctness of the 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 liver infiltration.
The possibilities of computed tomography (CT) and magnetic resonance imaging (MRI) in determining the severity of hepatic steatosis were evaluated. The CT results were compared with the results of the 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 quite obvious 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 Bezafibrat Gemfibrozil Lipofarm, Lipostabil Probucol Orlistat
Choleretic Hofitol
Hepatoprotectors Ursodeoxycholic acid Metadoxin Selimarin, Silibinin
Insulin Sensitizers Biguanides Glitazones
Betaine enzymes
Antioxidants N-acetylcysteine a-tocopherol (vitamin E) a-lipoic (thioctic) acid p-carotene Lecithin Selenium S-adenosine methionine
Vasodilators Pentoxifylline
AT11 receptor antagonists Losartran
Antimicrobial drugs Metronidazole Nifuroxazide Rifaximin Polymyxin B
Prebiotics, probiotics, eubiotics Lactulose (Duphalac) Eubikor
Hormones Ghrelin
Therefore, treatment and / or prevention of these conditions should lead to an improvement in liver condition (Table 8).
Necessary conditions for eliminating the main pathogenetic factor of NAFLD - insulin resistance - are also actions aimed at weight loss: lifestyle changes, hypocaloric nutrition, and increased physical activity.
For people with overweight and obesity, a realistically achievable goal is to reduce body weight by about 7-10% in 6-12 months. Weight loss should be combined with moderate-intensity physical activity for at least 30 minutes per day. Regular muscle activity leads to metabolic changes that decrease insulin resistance. Numerous data on the effect of weight loss on the state of the liver are very contradictory. It was shown that the 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 decrease by 11-20 kg / year has a positive effect on the severity of steatosis and inflammation, the degree of liver fibrosis. A 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 an intestinal lipase inhibitor orlistat. At the same time, against the background of the normalization of the 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, a sharp deterioration (central necrosis, portal inflammation, pericellular fibrosis) of the liver condition is noted, with the exception of may
be, the degree of railway. Previously used for weight loss, the operation of jejunoileal anastomosis, which led to its rapid fall, is currently not performed due to the high risk of developing NASH. The operation of gastric banding, which is widely used now, allows patients to slowly (2.7-4.5 kg / month) lose body weight, preventing the development of NASH.
Consideration of approaches to the treatment of NAFLD associated with T2DM deserves special attention. 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-a 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 on increasing 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 (no diabetes and no obesity). Liver function and insulin levels and insulin resistance were assessed (in euglycemia and hyperinsulinemia during the clamp test). Liver biopsies were performed in 14 patients who received metformin (500 mg x 2 r / d) and six patients who received dietary therapy for four months. No histological improvement was assessed. The only significant difference between the two groups was in ALT levels. Patient groups did not differ significantly in terms of weight loss. Although active treatment led to an increase in lactic acid levels (up to 30% of actively treated patients), only one patient had a lactate value outside the normal range of more than 2 mmol / L (2.2 mmol / L).
Uygun et al. conducted studies involving 36 patients with NASH, divided into two groups. One group received metformin (850 mg) along with the diet, the control group was restricted in diet (1600-1800 calories per day). In comparison with the control group, the first group showed improvements in the following indicators: a decrease in the ALT level (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 in liver were observed on biopsies of subjects after treatment.
Other studies evaluating the effectiveness of metformin have shown an improvement in the insulin resistance index (assessed by QUICKI, HOMA or KITT methods). Three studies reported decreases in liver function scores, and one study showed a slight increase in these scores.
In terms of histological improvement, only one report showed statistical differences in inflammation, steatosis, fibrosis, and global posttreatment NASH scores.
The study of the effectiveness of metformin (1500 mg / day or 20 mg / kg / day) in therapy (4-6 months) of patients with NASH showed that, against the background of a decrease in body weight (about 1.5 kg / month), normalization of transaminases occurs, and hypercholesterol decreases. -
Table 9
Research 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
myia, hypertriglyceridemia and hepatomegaly. Positive histological dynamics similar to the experimental data was verified.
Thiazolidinediones (glitazones) selectively improve insulin sensitivity by activating RRLA-y, stimulating the activity of the cellular glucose transporter GLUT4, as a result of which glucose uptake by peripheral tissues improves, the concentrations of glucose, insulin, TG, non-esterified fatty acids and TNF-a in the blood decrease.
The efficacy of thiazolidinediones (pioglitazone, rosiglitazone) was evaluated 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 evaluated
insulin resistance by the HOMA-III index, another compared serum insulin levels. Post-treatment liver biopsies were reported in two studies. In all studies, a decrease in insulin resistance was proved, a significant decrease in ALT levels, AST Biopsies after tests showed statistically significant improvements. It was also reported about side effects: Weight gain, increased serum lactate levels, nightmares, edema. The dropout rate was high: 11 out of 60 subjects. No cases of liver failure have been reported.
Currently, studies are ongoing on the effectiveness of insulin sensitizers in the treatment of NAFLD (Table 9).
In connection with the noted steady increase in the prevalence of obesity, MS and DM among the population, the problem of diagnosis and treatment of NAFLD will become even more urgent. Poor coverage in the medical literature leads to little awareness of doctors about the possible outcomes of this condition and presents 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 it necessary to conduct further research. This is the goal of the multicenter studies that are currently being planned.
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Kosobian Evgeniya Pavlovna Post-graduate student of the 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, FGU Endocrinological Research Center, Moscow
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Non-alcoholic liver steatosis (non-alcoholic fatty liver disease (NAFLD), fatty liver disease, fatty liver, fatty infiltration) - primary disease liver or a syndrome formed by excessive accumulation of fats (mainly triglycerides) in the liver. If we consider this nosology from a quantitative point of view, then "fat" should be at least 5-10% of the liver's weight, or more than 5% of hepatocytes should contain lipids (histologically).
If you do not interfere during the course of the disease, then in 12-14% of cases, NAFLD is transformed into steatohepatitis, in 5-10% of cases - into fibrosis, in 0-5% fibrosis turns into cirrhosis of the liver; in 13% of cases, steatohepatitis is immediately transformed into cirrhosis of the liver.
These data allow us to understand why this problem is of general interest today, if at the same time the etiology and pathogenesis are clear, it will be clear how to most effectively treat this common pathology. It is already clear that in some patients this may turn out to be a disease, and in others it may be a symptom or syndrome.
The recognized risk factors for the development of NAFLD are:
- obesity;
- type 2 diabetes mellitus;
- fasting (dramatic weight loss> 1.5 kg / week);
- parenteral nutrition;
- the presence of an ileocecal anastomosis;
- excessive bacterial growth in the intestine;
- many drugs (corticosteroids, antiarrhythmic drugs, antineoplastic drugs, nonsteroidal anti-inflammatory drugs, synthetic estrogens, some antibiotics, and many others).
The listed risk factors for NAFLD show that a significant part of them are components of metabolic syndrome (MS), which is a complex of interrelated factors (hyperinsulinemia with insulin resistance - type 2 diabetes mellitus (type 2 diabetes), visceral obesity, atherogenic dyslipidemia, arterial hypertension, microalbuminuria, hypercoagulability, hyperuricemia, gout, NAFLD). MS forms the basis of the pathogenesis of many cardiovascular diseases and indicates their close relationship with NAFLD. Thus, the range of diseases that forms NAFLD significantly expands and includes not only steatohepatitis, fibrosis, liver cirrhosis, but also arterial hypertension, ischemic disease heart, myocardial infarction and heart failure. At least, if the direct connections of these conditions require further study of the evidence base, their mutual influence is undoubted.
Epidemiologically distinguish: primary (metabolic) and secondary NAFLD. The primary form includes most of the conditions that develop with various metabolic disorders (they are listed above). The secondary form of NAFLD includes conditions that are formed: alimentary disorders (overeating, starvation, parenteral nutrition, trophological insufficiency - kwashiorkor); drug effects and relationships that are realized at the level of hepatic metabolism; hepatotropic poisons; intestinal bacterial overgrowth syndrome; diseases of the small intestine, accompanied by a syndrome of impaired digestion; resection of the small intestine, small bowel fistula, functional pancreatic insufficiency; liver diseases, including genetically determined ones, acute fatty disease of pregnant women, etc.
If the doctor (researcher) has morphological material (liver biopsy), then three degrees of steatosis are morphologically distinguished:
- 1st degree - fatty infiltration< 33% гепатоцитов в поле зрения;
- 2nd degree - fatty infiltration of 33-66% of hepatocytes in the field of view;
- Grade 3 - fatty infiltration> 66% of hepatocytes in the field of view.
By bringing morphological classification, we must state that these data are conditional, since the process is never uniformly diffuse, and at each specific moment we consider a limited fragment of tissue, and there is no certainty that in another biopsy we will get the same , and, finally, the 3rd degree of fatty liver infiltration should be accompanied by functional liver failure (at least for some components: synthetic function, detoxification function, biliary consistency, etc.), which is practically not characteristic of NAFLD.
The above material shows the factors and states of metabolism that may be involved in the development of NAFLD, and as modern model pathogenesis, the theory of "two blows" is proposed:
the first is the development of fatty degeneration;
the second is steatohepatitis.
With obesity, especially visceral obesity, the supply of free fatty acids (FFA) to the liver increases, while liver steatosis (first stroke) develops. 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 hepatocyte increases sharply, and fatty degeneration of hepatocytes is formed. Simultaneously or sequentially, oxidative stress develops - the "second blow" with the formation of an inflammatory reaction and the development of steatohepatitis. This is largely due to the fact that the functional capacity of mitochondria is depleted, microsomal oxidation of lipids in the cytochrome system is turned on, which leads to the formation of reactive oxygen species and an increase in the production of proinflammatory cytokinins with the formation of inflammation in the liver, death of hepatocytes caused by the cytotoxic effects of TNF-alpha1 - one of the main inducers of apoptosis. The subsequent stages of the development of liver pathology and their intensity (fibrosis, cirrhosis) depend on the persisting factors of the formation of steatosis and the lack of effective pharmacotherapy.
Diagnostics of NAFLD and conditions of its progression (liver steatosis, steatohepatitis, fibrosis, cirrhosis)
Fatty degeneration of the liver is formally a morphological concept, and it would seem that the diagnosis should be reduced to a liver biopsy. However, such a decision has not been made by international gastroenterological associations and the issue is being discussed. This is due to the fact that fatty degeneration is a dynamic concept (it can be activated or undergo a reverse development, it can be both relatively diffuse and focal). A biopsy is always represented by a limited area, and the interpretation of the data is always rather arbitrary. If a biopsy is recognized as a mandatory diagnostic criterion, then it should be performed quite often; the biopsy itself is fraught with complications, and the research method should not be more dangerous than the disease itself. The absence of a biopsy decision is not a negative factor, especially since today hepatic steatosis is a clinical and morphological concept with the presence of many factors involved in pathogenesis.
From the data presented above, it can be seen that diagnostics can start at different stages diseases: steatosis → steatohepatitis → fibrosis → cirrhosis, and the diagnostic algorithm should include methods that determine not only fatty degeneration, but also its stage.
So, at the stage of liver steatosis, the main symptom is hepatomegaly (discovered by chance or during a dispensary examination). The biochemical profile (aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT), cholesterol, bilirubin) establishes the presence or absence of steatohepatitis. With an increase in the level of transaminases, it is necessary to conduct virological studies (which either confirm or reject viral forms of hepatitis), as well as diagnostics of other forms of hepatitis: autoimmune, biliary, primary sclerosing cholangitis. An ultrasound study not only establishes an increase in the size of the liver and spleen, but also signs of portal hypertension (according to the diameter of the splenic vein and the size of the spleen). Less commonly used (and maybe known) is the assessment of fatty liver infiltration, which consists in measuring the "attenuation column", the dynamics of which at different intervals can be used to judge the degree of fatty degeneration (Fig.) (The ultrasound technique is described).
Earlier models of ultrasound devices assessed densitometric parameters (by the dynamics of which it was possible to judge the dynamics and degree of steatosis). Currently, densitometric parameters are obtained using computed tomography of the liver. Considering the pathogenesis of NAFLD, assess the general examination, anthropometric indicators (determination of body weight and waist circumference - OT). Since MS takes a significant place in the formation of steatosis, it is necessary to assess in the diagnosis: abdominal obesity - OT> 102 cm in men,> 88 cm in women; triglycerides> 150 mg / dl; high density lipoproteins (HDL):< 40 мг/дл у мужчин и < 50 мл/дл у женщин; артериальное давление (АД) >130/85 mm Hg. st; body mass index (BMI)> 25 kg / m 2; fasting blood glucose> 110 mg / dl; glycemia 2 hours after glucose load 110-126 mg / dL; Type 2 diabetes, insulin resistance.
The data presented above are recommended by WHO and the American Association of Clinical Endocrinologists. An important diagnostic aspect is also the establishment of fibrosis and its degree. Despite the fact that fibrosis is also a morphological concept, it is determined by various calculated indicators. From our point of view, the Bonacini discriminant counting scale, which determines the fibrosis index (IF), is a convenient method corresponding to the stages of fibrosis. We spent comparative study the calculated IF index with the results of biopsies. These indicators are presented in table. 1 and 2.
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Practical value of IF:
1) IF, assessed on a discriminant counting scale, reliably correlates with the stage of liver fibrosis according to puncture biopsy data;
2) the study of IF allows with high degree the likelihood of assessing the stage of fibrosis and using it for dynamic monitoring of the intensity of fibrosis in patients with chronic hepatitis, NAFLD and other diffuse hepatic diseases, including to assess the effectiveness of therapy.
And finally, if a puncture biopsy of the liver is performed, then it is prescribed, as a rule, in the case of differential diagnosis of tumor formations, including the focal form of steatosis. At the same time, in the liver tissue of these patients, the following are detected:
- fatty degeneration of the liver (large-drop, small-drop, mixed);
- centrilobular (less often portal and periportal) inflammatory infiltration by neutrophils, lymphocytes, histiocytes;
- fibrosis (perihepatocellular, perisinusoidal and perivenular) of varying severity.
The diagnosis of NAFLD (hepatic steatosis) is formulated on the basis of the totality following symptoms and provisions:
- obesity;
- malabsorption syndrome (as a consequence of the imposition of an ileojejunal anastomosis, biliary-pancreatic stoma, extended resection of the small intestine);
- long-term (more than two weeks parenteral nutrition).
Diagnostics also involves the exclusion of the main hepatic nosological forms:
- alcoholic liver damage;
- viral lesion (B, C, D, TTV);
- Wilson-Konovalov's disease (the level of ciruloplasmin in the blood is being investigated);
- diseases of congenital deficiency of alpha1-antitrypsin);
- hemachromatosis;
- autoimmune hepatitis;
- drug hepatitis (drug history and withdrawal possible drug forming intermediate density lipoproteins (IDLs)).
Thus, the diagnosis is formed with the definition of hepatomegaly, the determination of pathogenetic factors contributing to steatosis, and the exclusion of other diffuse forms of liver damage.
Healing principles
Since the main factor of development non-alcoholic steatosis Since the liver is overweight (BW), a decrease in BW is a fundamental condition for the treatment of patients with NAFLD, which is achieved by lifestyle changes, including dietary measures and physical activity, including in cases where there is no need to reduce BW. The diet should be hypocaloric - 25 mg / kg per day with limitation of animal fats (30-90 g / day) and a decrease in carbohydrates (especially quickly absorbed) - 150 mg / day. Fats should be predominantly polyunsaturated, which are found in fish, nuts; it is important to consume at least 15 grams of fiber from fruits and vegetables, as well as foods rich in vitamin A.
In addition to diet, you need at least 30 minutes of daily aerobic physical activity(swimming, walking, gym). Physical activity by itself reduces insulin resistance and improves quality of life.
The second important component of therapy is the impact on metabolic syndrome and insulin resistance in particular. Of the drugs aimed at correcting it, the most studied is metformin. At the same time, it was shown that treatment with metformin leads to an improvement in laboratory and morphological parameters of inflammatory activity in the liver. Insulin sensitizers are used in type 2 diabetes, and a meta-analysis has not shown any benefit in their effect on insulin resistance.
The third component of therapy is the elimination of the use of hepatotoxic drugs and drugs that cause liver damage (the main morphological substrate of this damage is liver steatosis and steatohepatitis). In this regard, it is important to collect a medical history and refuse the drug (s) that damage the liver.
Since bacterial overgrowth syndrome (SIBO) plays an important role in the formation of hepatic steatosis, it must be diagnosed and corrected (drugs with antibacterial action - preferably not absorbed; probiotics; motor regulators, liver protectors), and the choice of therapy depends on the initial pathology forming SIBR.
The question of the use of liver protectors is not entirely correct today. There are works that show their low efficiency, there are works that show them high efficiency... It seems that their use does not take into account the stage of NAFLD. If there are signs of steatohepatitis, fibrosis, liver cirrhosis, then their use seems reasonable. I would like to present analytical data, on the basis of which and depending on the number of factors involved in the pathogenesis of NAFLD, you can choose a hepatoprotector (Table 3).
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From the presented table it can be seen (the most used protectors have been introduced, if desired, it can be expanded by introducing other protectors) that ursodeoxycholic acid preparations (Ursosan) act on the maximum number of pathogenetic links of liver damage.
We would like to present the results of treatment with Ursosan in patients with NAFLD. 30 patients were studied (15 of them were based on obesity, 15 - MS; women were 20, men - 10; age from 30 to 65 years (mean age 45 ± 6.0 years).
The selection criteria were: an increase in the level of AST - 2-4 times; ALT - 2-3 times; BMI> 31.1 kg / m2 in men and BMI> 32.3 kg / m2 in women. Patients received Ursosan at a dose of 13-15 mg / kg body weight per day; 15 patients for 2 months, 15 patients continued taking the drug for up to 6 months. The results of the treatment are presented in table. 4-6.
The exclusion criteria were: viral nature of the disease; concomitant pathology in the stage of decompensation; taking drugs potentially capable of forming (maintaining) fatty degeneration of the liver.
Group 2 continued to receive Ursosan at the same dose for 6 months (with normal biochemical parameters). At the same time, appetite stabilized, and body weight gradually (1 kg / month) decreased. According to the ultrasound data, the structure and size of the liver did not change significantly, the dynamics of the “attenuation column” continued (Table 6).
Thus, according to our data, the use of liver protectors in patients with NAFLD at the stage of steatohepatitis is effective, which is reflected in the normalization of biochemical parameters and a decrease in fatty liver infiltration (according to ultrasound data, a decrease in the “attenuation column” of the signal), which in general is an important rationale for their use.
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O. N. Minushkin, Doctor of Medical Sciences, Professor
FSBI UNMC of the Administrative Department of the President of the Russian Federation, Moscow
Fatty hepatosis, non-alcoholic fatty liver disease (NAFLD)- symptoms and treatment
What is fatty liver disease, non-alcoholic fatty liver disease (NAFLD)? We will analyze the causes of occurrence, diagnosis and treatment methods in the article by Dr. Vasiliev R.V., a general practitioner with 13 years of experience.
Definition of disease. Causes of the disease
Non-alcoholic fatty liver disease / NAFLD (hepatic steatosis or fatty hepatosis, non-alcoholic steatohepatitis) is a non-infectious structural liver disease characterized by changes in the tissue of the liver parenchyma due to the filling of liver cells (hepatocytes) with fat (liver steatosis), which develops due to a violation of the structure of the membranes of hepatocytes , slowing down and disturbance of metabolic and oxidative processes inside the liver cell.
All of these changes are steadily leading to:
- destruction of liver cells (non-alcoholic steatohepatitis);
- the accumulation of adipose and the formation of fibrous tissue, which causes already irreversible, structural (morphological) changes in the liver parenchyma;
- change biochemical composition blood;
- the development of metabolic syndrome (diabetes mellitus);
- eventually cirrhosis.
Metabolic syndrome is a widespread condition characterized by a decrease in the biological effect of insulin (insulin resistance), impaired carbohydrate metabolism (), central obesity with an imbalance of fat fractions (plasma lipoproteins and triglycerides) and arterial hypertension.
In most cases, NAFLD develops after age 30.
Risk factors of this disease are:
- sedentary lifestyle (physical inactivity);
- improper diet, overeating;
- long-term use of medications;
- overweight and visceral obesity;
- bad habits.
The main reasons for development NAFLD are:
- hormonal disorders;
- violation fat metabolism(plasma lipoprotein imbalance);
- violation of carbohydrate metabolism (diabetes mellitus);
- arterial hypertension;
- nocturnal hypoxemia ().
In the presence of hypertension, obesity, diabetes mellitus, regular medication, or in the presence of two of the above conditions, the probability of having NAFLD reaches 90%.
Obesity is defined by the formula for calculating body mass index (BMI): BMI = weight (kg): (height (m)) 2. If a person, for example, weighs 90 kg, and his height is 167 cm, then his BMI = 90: (1.67 x 1.67) = 32.3. This result speaks of grade I obesity.
- 16 or less - pronounced mass deficit;
- 16-17.9 - underweight;
- 18-24.9 - normal weight;
- 25-29.9 - overweight (pre-obesity);
- 30-34.9 - degree I obesity;
- 35-39.9 - degree II obesity;
- 40 and more - obesity III degree ().
If you find similar symptoms, consult your doctor. Do not self-medicate - it is dangerous for your health!
Symptoms of fatty liver disease, non-alcoholic fatty liver disease (NAFLD)
In most patients, this disease is early stages is asymptomatic - this is the great danger.
In 50-75% of patients, symptoms of general (chronic) fatigue, decreased performance, malaise, weakness, heaviness in the right hypochondrium, weight gain, prolonged increase in body temperature for no reason, red dots on the skin in the chest and abdomen area may appear. The liver is often enlarged. Digestive disorders occur, increased gassing, pruritus, rarely - jaundice, "hepatic signs".
Often NAFLD is accompanied by diseases of the gallbladder: chronic cholecystitis, cholelithiasis. Less often, in advanced cases, there are signs of portal hypertension: enlargement of the spleen, varicose veins of the esophagus and ascites (accumulation of fluid in the abdominal cavity). As a rule, these symptoms are observed at the stage of liver cirrhosis.
Pathogenesis of fatty hepatosis, non-alcoholic fatty liver disease (NAFLD)
The accumulation of cholesterol, namely lipids (fat-like organic compounds) in the liver, is primarily caused by the following factors:
In obese patients, the liver tissue has an increased content of free fatty acids, which can be the cause of liver dysfunction, since fatty acids are chemically active and can damage the biological membranes of hepatocytes, forming a gate in them for the entry of endogenous fat into the cell, in particular lipids (mainly low and very low density), and the transport is an ester - triglyceride.
Thus, hepatocytes are filled with fat, and the cell becomes functionally inactive, swells and increases in size. When more than a million cells are damaged, the liver grows macroscopically in size, in the areas of fatty infiltration, the liver tissue becomes denser, and these areas of the liver do not perform their functions or perform them with significant defects.
Lipid peroxidation in the liver leads to the synthesis of toxic intermediates that can trigger the process of apoptosis (programmed death) of the cell, which can cause inflammation in the liver and form fibrosis.
Induction of cytochrome P-450 2E1 (CYP2E1), which can be induced both by ketones and a diet high in fat and low in carbohydrates, is also of important pathogenetic significance in the formation of NAFLD. CYP2E1 generates toxic free radicals leading to liver damage and subsequent fibrosis.
In addition, endotoxin-mediated damage has a pathogenetic significance in the formation of NAFLD, which, in turn, enhances the production of pro-inflammatory cytokines (TNF-α, IL-6 and IL-8), leading to disruption of the integrity of hepatocyte membranes and even to their necrosis. as well as the development of inflammatory cell infiltration both in the portal tracts and in the lobules of the liver, which leads to steatohepatitis.
Products of lipid peroxidation, hepatocyte necrosis, TNF and IL-6 activate stellate (Ito) cells, causing damage to hepatocytes and the formation of fibrotic changes.
Classification and stages of development of fatty hepatosis, non-alcoholic fatty liver disease (NAFLD)
At the moment, there is no generally accepted classification of NAFLD, however, a number of authors distinguish the stages of the course of the disease and the degree of non-alcoholic steatohepatitis (NASH).
Evaluation of liver steatosis and histological activity of NAFLD according to the E.M. Brunt:
- I degree (mild NASH) - large droplet steatosis, no more than 33-66% of affected hepacites;
- II degree (moderate NASH) - large and small droplets, from 33% to 66% of affected hepacites;
- III degree (severe NASH) - large and small droplets, more than 60% of affected hepacites.
You can also conditionally divide the degrees of steatosis, fibrosis and necrosis according to the result of the FibroMax test - the severity of fatty infiltration:
- S1 (up to 33% fatty infiltration);
- S2 (33-60% fatty infiltration)
- S3 (more than 60% fatty infiltration)
- F1, F2, F3, cirrhosis.
Complications of fatty hepatosis, non-alcoholic fatty liver disease (NAFLD)
The most common complications of NAFLD are hepatitis, replacement of the normal parenchymal tissue of the liver with fibrous tissue, which is functionally inoperative, with the eventual formation of cirrhosis of the liver.
A more rare complication, but still occurring, is liver cancer - hepatocellular carcinoma. Most often it occurs at the stage of liver cirrhosis and, as a rule, is associated with viral hepatitis.
Diagnosis of fatty hepatosis, non-alcoholic fatty liver disease (NAFLD)
In the diagnosis of NAFLD, laboratory and instrumental research methods are used.
First of all, the state of the liver is assessed for inflammatory changes, infectious, autoimmune and genetic diseases (including storage diseases) using general clinical, biochemical and special tests.
Further, the functions performed by the liver (metabolic / metabolic, digestive, detoxification) are assessed according to the ability to produce certain proteins, the characteristics of fats and carbohydrates. The detoxification function of the liver is assessed mainly using the C13-metacetin test and some biochemical tests.
When the first two stages are completed, the structural state of the liver is investigated using ultrasound, MSCT, MRI and elastometry ( FibroScan), if necessary, the morphological state is examined - liver biopsy.
Elastometry examines the elasticity of soft tissues. Malignant tumors differ from benign tumors in increased density, inelasticity, they are difficult to compress. On the monitor FibroScan denser tissues are colored blue and blue, adipose tissue is yellow-red, and connective tissue is green. The high specificity of the method avoids unnecessary biopsies.
After the diagnosis, the final diagnosis is established and the appropriate treatment is carried out.
Treatment of fatty hepatosis, non-alcoholic fatty liver disease (NAFLD)
Taking into account the mechanism of the development of the disease, schemes have been developed for the course treatment of NAFLD, aimed at restoring the structure of cell membranes, metabolic and oxidative processes inside liver cells at the molecular level, cleaning the liver from intracellular and visceral fat which makes it difficult for her to work.
In the course of treatment, the following is performed:
- correction of carbohydrate, fat (lipid) metabolism;
- normalization of oxidation processes in the cell;
- influence on the main risk factors;
- weight loss;
- improvement of the structure of the liver in reversible stages.
After treatment, there is a noticeable improvement in the detoxification (protective), digestive and metabolic (synthetic) functions of the liver, patients lose weight, overall well-being improves, and mental and physical performance increases.
Course treatment programs take from three to six months and are selected depending on the severity of metabolic disorders. These include:
- Light program;
- the program "Medium";
- the "Premium" program;
- an individual treatment program - is developed based on concomitant diseases, the current condition of the patient and the required intensity of treatment.
Programs include screening, diagnosis and drug treatment, which consists of two stages:
- infusion therapy with prolongation of taking medications inside, selection of diet and physical activity;
- delivery of control analyzes and evaluation of results.
Forecast. Prophylaxis
In the early stages of the disease, the prognosis is favorable.
Prevention of NAFLD involves proper nutrition, an active lifestyle, and regular medical check-ups.
TO proper nutrition include the inclusion in your diet of omega-3 polyunsaturated fatty acids, short carbohydrates, limiting the consumption of spices, very fatty and fried foods. Diet variety is also key to a nutritious diet. Shown is the consumption of foods rich in plant fiber.
For an active lifestyle, it is enough to walk 8,000 to 15,000 steps a day and devote three hours a week to physical exercise.
With regard to the calendar clinical examination, an ultrasound of the abdominal organs should be performed annually and the level of your liver enzymes (ALT, AST, total bilirubin) should be assessed, especially when taking any medications on an ongoing basis.
