UA133075U - METHOD OF COMPLEX TREATMENT OF PATIENTS WITH NON-ALCOHOLIC LIVER DISEASE - Google Patents

Abstract

Method for complex treatment of patients with non-alcoholic fatty liver disease by prescribing basic therapy. In addition, prescribe L-carnitine at a dose of 2 g (10 ml) once daily, jet, for 14 days.

Description

A useful model belongs to the field of medicine, namely hepatology, and can be used in the treatment of patients with non-alcoholic fatty liver disease (NAFLD).

Nonalcoholic fatty liver disease is the most common nosology among liver diseases (Skrypnyk I.M. et al., 2013; Stepanov Yu.M. et al., 2016; Gootba K., Sope?-

Ripo N., 2015), which occurs in 20-30 96 of the adult population in the countries of Western Europe and

of North America and 5-18 95 in Asian countries (Zauipeg M. Yei aI., 2016). It is predicted that NAFLD will become the main reason for liver transplantation in the next 20 years (SaiI2adia

V.S. ei ai.,, 2016). This is related to the increase in the number of people with obesity, dyslipidemia, the increase in the incidence of type 2 diabetes and metabolic syndrome (Abrahamovych 0.0. et al., 2014; Fadeyenko G.D. et al., 2016; Kharchenko N.V. ., 2016; I opagao A. ei ai., 2016).

NAFLD often occurs against the background of obesity, metabolic syndrome, type 2 diabetes (Abrahamovych 0.0. et al., 2008; Sklyarov SYA. et al., 2015;

Kharchenko N.V. et al., 2011; I a?o M. ei ai., 2015). According to the latest data, non-alcoholic steatosis of the liver occurs in 80-90 95 people with excess weight or obesity (OligK 72.A. ei ai., 2014).

The occurrence of NAFLD in obesity is caused not only by the increased intake of fatty acids with food and their formation from glucose, but also by the fact that along with the increase in fat content in the body, the functions of fat cells change (Kharchenko N.V. et al., 2011). In obesity, enlarged adipocytes synthesize adipokines, which regulate the sensitivity of cells to insulin and can form the syndrome of insulin resistance. The most important among them are leptin and adiponectin. Adiponectin reduces the synthesis of tumor necrosis factor-o (TME-o), stimulates the production of anti-inflammatory cytokines: interleukin-10 and the antagonist of the interleukin 1 receptor, increases the consumption of glucose by tissues and increases the expression of genes of receptors for activators of peroxisome proliferation, which play an important role in lipid metabolism (Andreeva

O.O. et al., 2009). At the same time, hyperleptinemia indirectly participates in the accumulation of triacylglycerols by the liver against the background of insulin resistance and affects the degree of liver steatosis (mMaishepa 5. ei ai., 2005).

The level of serum adiponectin decreases in patients with steatohepatitis compared to patients with steatosis and practically healthy individuals (Gii N. ei aiYi., 2014; Motspov5i 7.M. ei aiI., 2008) and is negatively correlated with the severity of nonalcoholic steatohepatitis and histological changes in the liver such patients (Gi 0. ei ai.,, 2012). A decrease in the production of adiponectin, combined with obesity, can contribute to the progression of nonalcoholic steatohepatitis (Voparase 5. ei ai., 2012). In addition to a decrease in the level of adiponectin in the blood plasma, patients with NAFLD also have a decrease in the hepatic expression of its receptor and a violation of the intracellular ways of realizing the functions of adiponectin (Khuoi M. ei ai., 2009).

An urgent issue of modern internal medicine is the search for new methods of complex treatment of patients with NAFLD, which would not only effectively reduce the clinical and laboratory manifestations of the disease, but also pathogenetically affect the mechanisms of its occurrence and course, in particular cytokine and adipokine imbalance.

There is a well-known method of treating non-alcoholic fatty liver disease in patients with type 2 diabetes (Patent of Ukraine Mo80978, МПК АбЭ1В 8/00, АбИК 35/00. Bodnar P.M., Yankovskyi

D.S., Myhalchyshyn G.P., Berehova T.V., Falaleeva T.M., Dyment G.S., Kobylyak N.M.; The applicant

National Medical University named after O.O. Bogomolets - statement. Mo. 2013301169 dated 31.01.2013 publ. 10.06.2013, Bull. Mo 11), in which the multiprobiotic symbiter acidophilic concentrated is prescribed.

The disadvantages of the analogue method are that it does not specify the possibility of correcting pro-inflammatory and steatogenic cytokines and adipokines, which play an important role in the course

NAFLD and imbalance of which is registered in patients with this nosology.

The closest analogue is the method of treatment of patients with non-alcoholic steatohepatitis combined with obesity (Patent of Ukraine Me48702, IPC AbI1R 3/00, AE1R 1/00. Prudnykova I.V.,

Frolov V.M., Androsov E.D.; Applicant Prudnykova I.V., Frolov V.M., Androsov E.D. - statement Mo. 200911219 dated 05.1.1.2009 publ. 25.03.2010, Bull. Mo 6), in which hepalin is prescribed in addition to basic therapy.

The disadvantages are that the complex treatment of patients with non-alcoholic steatohepatitis does not take into account the need to correct the adipokine balance, which is damaged in such patients.

The basis of the useful model is the task of improving the method of complex treatment of patients with NAFLD by prescribing the drug I-carnitine in addition to the basic therapy.

Common features of a useful model and the closest analogue are the appointment of basic therapy of NAFLD.

Distinctive features of a useful model from the nearest analogue are that, in addition to the basic therapy, the drug I-carnitine is prescribed in a dose of 2 g (10 ml) once a day, intravenously, for 14 days.

Definition of terms used when describing a useful model: non-alcoholic fatty liver disease, I-carnitine, adiponectin, leptin.

Theoretical prerequisites for the implementation of the claimed method.

Carnitine (3-hydroxy-4-M-(trimethyl-ammonium) butyric acid) is an amino acid that plays an important role in the transport of activated fatty acids with a long chain from the cytoplasm to sites of p-oxidation in mitochondria (Rii.. ei ai., 2013; Kerka A. ei ai., 2011; 5papo K. ei ai!., 2014;

Midoi N. ei ai., 2014). The total pool of carnitine in the body consists of free I-carnitine and its complex esters and is maintained by its intake with food, endogenous biosynthesis from two essential amino acids (lysine and methionine) in the liver and kidneys, and reabsorption in the renal tubules (98-99 95 from its content in the glomerular filtrate). The synthesis of carnitine also requires vitamins C, Bz, Bje, Bj2, iron ions and folic acid. It is worth noting that the bioavailability with oral intake of I -carnitine is low and ranges from 5 to 18 95 (RIpadap 4... ei ai., 2010), which is associated with binding by gastrointestinal microbiota (Koeip

E.A. et al., 2013). Carnitine plays an important role in the energy balance of tissues, which receive most of their energy as a result of the oxidation of fatty acids, in particular, cardiac and skeletal muscles (Zgipima5 5.K. ei ai., 2007). In addition, carnitine takes part in the removal of products of oxidative breakdown of fats and xenobiotics from mitochondria (Kharchenko N.V. et al., 2011).

The obtained data on the use of I-carnitine for the correction of NAFLD (Kapa .-.5. ейі ай!., 2011;

Kop K. ei ai., 2017; Rappai 5.K. et al., 2015). In particular, in the experimental studies of K. Kopei a. showed that I-carnitine prevents the formation of steatohepatitis in mice fed a high-calorie diet for a long time by activating β-oxidation in mitochondria, increasing insulin sensitivity and decreasing the activity of lipogenesis in the liver (Kop K. ei ai., 2017).

N. IbPpikazsha ey ai. in the experiment, it was found that II-carnitine prevents the progression of non-alcoholic steatohepatitis by regulating p-oxidation and redox systems in

From mitochondria (Izpikama N. ei ai., 2014). An experiment on mice showed the properties of carnitine to selectively increase the content of high-density lipoproteins, while not affecting the level of low-density lipoproteins and triacylglycerols in the blood plasma, which was associated with a decrease in the size of the liver and the amount of adipose tissue in it (Kapd 9.5. ей айЙ., 2011 ). In a multicenter clinical study, it was demonstrated that the use of carnitine orotate is determined by a decrease in the activity of alanine aminotransferase (ALT) in the blood and an improvement in the attenuation index of the liver parenchyma according to the data of computer tomography (Vai

U.b. Yei and I., 2015). Similar conclusions were reached by M. Maiadzagpega et al., who proved that the administration of carnitine in patients with non-alcoholic steatohepatitis helps to reduce the activity of ALT, aspartate aminotransferase (AST), y-glutamyl transpeptidase (GHTP), levels of total cholesterol, cholesterol of high-density lipoproteins and low-density lipoproteins , triacylglycerols, C-reactive protein and TME-o; in the blood (Maiadtsagpega M. ei ai., 2010).

Such pharmacological properties of I-carnitine allowed its use in complex treatment of patients with NAFLD.

Approbation of the proposed method was carried out at the department of propaedeutics of internal diseases

of the higher state educational institution of Ukraine "Bukyvinsky State Medical University" and on the basis of the gastroenterology departments of the regional clinical hospital and the city clinical hospital MeZ in Chernivtsi.

To study the influence of the effectiveness of a complex treatment program with the inclusion of I - carnitine on the clinical course of NAFLD, the activity of markers of cytolytic, cholestatic and intoxication syndromes, cytokine and adipokine blood profiles in patients with

NAFLD, in addition to the main treatment, I-carnitine was prescribed in a dose of 2 g (10 ml) once a day for 14 days (main group). The comparison group was 30 patients with NAFLD who received basic treatment, in accordance with the Order of the Ministry of Health of Ukraine No. 826 of 06.11.2014 and the adapted evidence-based clinical guideline "Non-alcoholic fatty liver disease" (2014) and EABI-EABO-EABO Siipisa! Rgasiise Sicydeiipev Tog She tapadetepi oi pop-aIsonoiis Ttayu

Imeg Disease (2016). The control group consisted of 45 practically healthy individuals, representative of the patients of the studied groups in terms of age and gender.

Improvement of the therapeutic effect from the additional course prescription of I-carnitine was observed in all patients of the main group. These patients noted an improvement in well-being, a decrease in the intensity of heaviness in the right hypochondrium, nausea, and an improvement in working capacity one to three days earlier.

The dynamics of the activity of biochemical agents, which are markers of the processes of cytolysis, cholestasis and the intensity of the intoxication syndrome, are criteria for the effectiveness of treatment of patients with chronic diffuse liver diseases, including NAFLD.

In the patients of the main group, a significant decrease in the activity of AsAT by 51.5 95 (р « 0.05) and AlAT by 50.995 (р « 0.05) was noted after treatment (Table 1). In the patients of the comparison group, only a tendency to decrease the activity of cytolytic syndrome markers was registered. In addition to a significant decrease in the activity of cytolytic processes, in patients who were additionally prescribed | - carnitine, a significant decrease in the activity of total lactate dehydrogenase was noted by 16.2 95 (p « 0.05) (Table 1), which indicates a decrease in the intensity of redox processes in them.

The activity of GHTP - an integral enzyme of the metabolic-intoxication state of the body during treatment significantly decreased in patients of both groups, but more significantly in patients of the main group - by 55.8 95 (p«0.05), while in patients of the comparison group - by 27.7 905 (ry « 0.05) (Table 1).

Table 1

Biochemical indicators of blood in patients with non-alcoholic fatty liver disease in the dynamics of treatment (Met, p, p)

Comparison group n-30 Main group n-30 pzo -

Indexes . After: . p-45 Before treatment and Before treatment |/|After treatment treatment

Total bilirubin, z1izote | 199Ж1.32 | 13.7x1.20 13.521.50 13.621.24 r "0.001 r: - 0.03 μmol/l

Direct bilirubin, 3120.31 4.950.72 34 3.750.55 3.930 44 μmol/l p--0.02

Albumin, g/l 45.0--0.41 43.8--1.10 45.1-0.88 44.6:1.45 44,941.28

Total protein, 73.8:2-1.47 72.A4-1.79 5.20.30 5.5-0.41 5.620.55 5.320.56

Creatinine, 82,631.80 | 90.0Ж3.59 8574369 89.534.29 87.854.95 μmol/l r:--0.04 32.8Ж3.36 29.5Ж2.33 30.622.82 20.252.14 lsAt, OD/l 2265137 ri-0.001 01-0.006 re-0.03 34.7-4.15 31.8:53.32 34.155.42 22.6x3.97

AlAT, units/l 18,521.46 | ru-00001. | ri«0.001 rg-0.046 465.7zh27.70 | 442.9421.09 489.9228.32 421.5226.14

LF, Units/l 80,353.20 89.6-6.69 88,534.49 86,854.58 83,854.29 41,523.86 29.2x3.30

GP, Units/l 21,831.62 mon ri « 0.001 tvo to ri-0.008 ri t, re-0.03 ri re-0.04

Notes: 1. PZO - practically healthy persons; 2. ri - reliability of differences compared to indicators in a group of practically healthy people;

Z. re - reliability of differences between indicators before and after treatment.

The results of the study of cytokine and adipokine profiles of blood in patients with NAFLD in the dynamics of treatment are shown in Table 2. In patients who additionally received I-carnitine, a significant decrease in the content of TME-o was noted; in the blood by 39.8 95 (p « 0.05) after treatment.

The study of the adipokine profile in the examined patients of both groups showed a higher level of leptin and a lower content of adiponectin in the blood compared to those in practically healthy individuals, which indicates the formation of an adipokine imbalance in the examined patients, which is typical for patients with NAFLD. For the patients of the main group, a significant decrease in the content of leptin in the blood by 44.1 95 (p « 0.05) in combination with an increase in the concentration of adiponectin - by 2.03 times (p « 0.05) was characteristic, which was not observed in patients of the comparison group (Table 2).

Table 2

Indicators of cytokine and adipokine profiles in the blood of patients with NAFLD in the dynamics of treatment (Met, p, p) pzo - - treatment treatment

Necrosis factor from 0.6 to 8.4 24,843.94 33.0x2.53 | 236y1.86 15.3--0.95 ri «0.001, tumor-so, pg/ml ri-0.02 ri «0.001 ri « 0.001 ro-0.04 14,132.20 12.0--1.43 13 ,4-1,19 9,322,33 5,941,24 3,0-0,60 3,1-0,42 2,90,82 vych rg-0,03

Notes: 1. PZO - practically healthy persons; 2. ri - reliability of differences compared to indicators in a group of practically healthy people; 3. rg - reliability of differences between indicators before and after treatment.

The method is carried out as follows.

In addition to basic therapy, patients with NAFLD are prescribed the drug I-carnitine in a dose of 2 g (10 ml) once a day intravenously for 14 days.

Examples of practical use of a useful model.

Example. Patient R., 49 years old, diagnosis: Non-alcoholic fatty liver disease. Excess body weight. He has been sick for 5 years, in the anamnesis - a violation of the regime and quality of food, a tendency to overeating in the evening. He came in with complaints: pain in the right hypochondrium of a pressing nature of moderate intensity, bitterness in the oral cavity, rapid fatigue. Objective examination: body mass index - 29.7, the skin is pale pink, xanthomas and xanthelasma are present on the eyelids, the abdomen is enlarged due to subcutaneous fat, slightly painful when palpated in the right hypochondrium, the lower edge of the liver protrudes 2 cm below the edge of the right costal arch, spleen - under the left costal arch, heart rate - 7bpm, blood pressure - 130/75 mmHg, heart sounds are rhythmic, sonorous. Vesicular breathing is heard above the lungs. During the ultrasound examination of the liver, it was found: the size along the mid-clavicular line is 162 mm, the size along the middle line is 83 mm, the contours are even, the capsule is differentiated, the parenchyma is fine-grained, the structure is heterogeneous, the echogenicity is increased, the course of the vessels is normal, the vascular pattern is not clear, dorsal attenuation of the ultrasound signal is noted. Acoustic beam pulse elastography of the liver was performed to clarify the nature of pathological changes in the liver. According to the obtained data, the condition of the liver parenchyma was determined in the patient, which corresponded to stage E1, which made it possible to rule out the presence of steatogenic liver cirrhosis. The electrocardiogram revealed moderate changes in the myocardium.

Biochemical studies were carried out: the content of total bilirubin in the blood was revealed - 19.0 μmol/l, albumin - 54.4 g/l, a slight increase in the activity of ALT - 68 U/l, AST - 42 U/l,

GHTP - 67 units/l, alkaline phosphatase activity - 91 units/l. The study of the pro- and anti-inflammatory link of the cytokine profile and the concentration of adipokines established that the concentration of interleukin 10 in the blood was 4.5 pg/ml, TME-o - 31.8 pg/ml, leptin - 14.3 ng/ml, adiponectin - 3 .0 μg/ml.

The treatment program is prescribed in accordance with the Order of the Ministry of Health of Ukraine No. 826 of 06.11.2014 and the adapted clinical guideline based on the evidence "Non-alcoholic fatty liver disease" (2014) and EABI-EABO-EABO Siipisa! Rgasiise SpcideYipev og She tapadetepi oi popaisopoiis Tatsu Imeg disease (2016) with the additional inclusion of the drug I -carnitine in a dose of 2 g (10 ml) once a day doveno, jet for 14 days.

The patient noted an improvement in well-being, as well as a decrease in general weakness and a feeling of heaviness in the right hypochondrium, objectively increased tolerance to physical exertion. Laboratory tests showed a decrease in total bilirubin - 12.4 μmol/l, activity of AlAT - 29 Units/l, ASAT - 17 Units/l, GHTP - 33 Units/l, alkaline phosphatase - 79 Units/l. The level of interleukin 10 was 4.1 pg/ml, TME-o; - 22.3 pg/ml, leptin - 9.7 ng/ml, adiponectin - 5.7 μg/ml.

Technical result. The proposed method allows effective comprehensive treatment of patients with non-alcoholic fatty liver disease, while reducing the manifestations of cytolytic syndrome and normalizing cytokine and adipokine imbalance.

Claims (1)

USEFUL MODEL FORMULA The method of comprehensive treatment of patients with non-alcoholic fatty liver disease by prescribing basic therapy, which is distinguished by the fact that the drug I - carnitine is additionally prescribed in a dose of 2 g (10 ml) once a day intravenously, in a jet for 14 days.