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8III size, painless) was revealed. Pathology among respiratory and cardiovascular systems is not revealed.
Examination is conducted. Data of a clinical and biochemical blood analysis throughout treatment within age norm. MBT in a sputum were not found. A Mantoux test with 2 TE - 12 mm, the diaskintest - 10 mm.
The child is advised by the ophthalmologist, the dermatovenerologist.
On MSCT from 27.09.2016 a picture of focal tuberculosis of the lower lobe left lung in a phase of not clear activity, involving of a pleura (pleural effusion) at the left and inlagement of intrathoracic lymph nodes were revealed.
The clinical diagnosis is established: generalized tuberculosis, focal tuberculosis of left lung phase of infiltration, intrathoracic lymph nodes tuberculosis active phase. Tuberculosis cutis. MBT (-). IA (-).
The course of antituberculosis therapy third regime in an intensive phase (HZRK) is appointed.
Against the background of the carried-out therapy the health of the girl improved: temperature was normalized. Gradually formations of a shin were condensed and decreased in sizes and by 11.08.2016 were not palpated at all.
For a response time in a hospital episodes of nausea, vomiting and pain in epigastriums which, perhaps were symptoms of the accompanying pathology were repeatedly noted. Flamin, the Yessentuki 4 mineral water, Fosfogliv, Metoclopramidum, Regidron's solution were appointed.
Ultrasonography of an abdominal cavity of 31.05.2016 was done and it allowed to reveal calcinations of spleen.
Now she is getting third regime of chemotherapy intensive phase.
Conclusion. This case shows late identification of a severe form of tuberculosis at the child. Feature of
this case consists in volume, incorrect tactics of inspection and treatment latent proceeding of focal tuberculosis led to development of an empyema of pleura and generalization of process. So, in 2011 conversion (virage) of tuberculin test was revealed, however addresses to the phthisiatrician did not follow. Repeated hyperergic reaction in 2013 was taken for manifestation of the current atopic dermatitis, and Bazen's erythema - for a furunculosis. Important diagnostic criteria of tuberculosis in this case was identification of tubercular granulomas at a skin biopsy. However this research was executed only at repeated hospitali-zation. For successful diagnostics and treatment achievement and maintenance of a interactions both with parents, and with the patient is important.
Literature.
1. Krasnov V. A. The factors interfering improvement of a situation on tuberculosis in subjects of Siberian Federal District / V.A. Krasnov, V. M. Cher-nyshev. Moscow 2013.
2. Mordyk A.V. The modern international and national concepts of fight against tuberculosis / A.V. Mordyk, L. V. Puzyreva, L. P. Aksyutina//Far East magazine of infectious pathology. — 2013. — No. 22(22). — Page 92 — 97.
3. Kulchavenya, E.V. The current trends of an epidemic situation on extra thoracic tuberculosis / E.V. Kulchavenya, V. A. Krasnov, S. N. Skornyakov [etc.]//Tuberculosis and pulmonary diseases. — 2013.
— T. 90, No. 12. — Page 34 — 39.
4. Nechayeva, O. B. An epidemic situation on extra pulmonary tuberculosis in the Russian Federation / O. B. Nechayeva, V. V. Skachkov // Tuberculosis and pulmonary diseases. — 2013. — T. 90, No. 8.
— Page 3 — 9.
5. YuE R. Indurative ERYTHEMA of BAZEN//Russian magazine of skin and venereal diseases. - 2012. - No. 1.
Kostitska I. O.
candidate of medical sciences, associate professor of the department of endocrinology Ivano-Frankivsk National Medical University
FEATURES OF AUTONOMIC REGULATION OF THE MOTOR-EVACUATION FUNCTION OF THE STOMACH IN PATIENTS WITH DIABETES MELLITUS
Summary: The study is devoted to the assessment of the motor-evacuation function of the stomach alongside with the determination of the indicators of autonomic balance and the state of nerve ending demyelination in patients with diabetes mellitus depending on duration of the disease. The relationships between the abnormalities in autonomic mechanisms as well as regulation of the stomach function and duration of the disease, the state of carbohydrate metabolism compensation, labile course of diabetes mellitus, the incidence of hypoglycemic states and the degree of damage to the nerve endings were assessed as well. The obtained results indicated that for early diagnosis of diabetic gastroparesis all patients with diabetes mellitus regardless of its duration have to undergo the assessment of the motor-evacuation function of the stomach.
Key words: diabetic gastroparesis, motor-evacuation function of the stomach, Kerdo autonomic index, peripheral myelin protein 22.
Nowadays, the application of new classes of tablets lowering blood sugar levels as well as insulin therapy contributes to the normalization of the indicators of carbohydrate metabolism and the improvement
of life quality in patients with diabetes mellitus (DM). Unfortunately, despite the positive results of therapy, its prevalence significantly exceeds the experts' forecasts, since every 6 seconds, somewhere around the
world a lethal case due to complications of DM and two new cases of DM are diagnosed [5,11]. In the 7th edition of the IDF Diabetes Atlas, chronic cardiovascular and neurological complications associated with diabetes which determine severe irreversible consequences of the disease and lead to significant financial costs as well as long-term disability alongside with in-capacitation are the most common ones.
Despite significant scientific achievements in di-abetology, pathogenetic mechanisms of the development and progression of labile course of DM are insufficiently studied. Clinical symptoms of cardiac autonomic neuropathy are considered by clinicians and patients as those which may invoke potentially life-threatening outcomes; however, no attention is paid to other forms of diabetic autonomic neuropathy as they appear under a mask of other disease. The sympathetic nervous system, its hyperactivity in particular, is of great importance in the genesis of slowing down the motor-evacuation function (MEF) of the stomach in patients with DM, which should be considered as the initial manifestation of diabetic gastroparesis (DG) [1, 9, 10, 11]. However, the diagnosis is made too late, i.e. when the patient experiences weight loss, persistent nausea, vomiting with no relief, frequent episodes of hypoglycemia secondary to decompensated DM. The problem of diagnostic algorithm for autonomic failure in patients with DM which is controlled by the parasympathetic and sympathetic subdivisions of the autonomic nervous system remains open. Scientists constantly search for new pathogenetically justified mechanisms and diagnostic methods of the evaluation and analysis of the state of neurohumoral regulation in the preclinical and clinical stages of developing chronic complications of DM. A number of researchers [6, 13, 15] study new criteria for the detection and prevention of diabetic polyneuropathy: early changes include not only axonal degeneration but also nerve trunk demyelination; when the duration of DM increases myelin is involved in the pathological process as well. Peripheral myelin protein 22 (PMP22) is the main component of the myelin sheath being produced primarily by Schwann cells; the indicator of its serum level can be considered as the marker of myelin damage. Thus, the determination of PMP22 in patients with DM is an early diagnostic criterion for the progression of diabetic polyneuropathy symptoms [16, 17, 20].
Therefore, the objective of the research was to study the state of the autonomic nervous system as well as the activity of the MEF of the stomach in patients with DM.
Materials and methods
44 patients with DM (20 males, 24 females), treated at the endocrinology dispensary and the endocrinology department of the Ivano-Frankivsk Regional Clinical Hospital, were randomly selected to undergo complete physical examination after signing the informed consent form to participate in a clinical trial. Group I included 22 (10 males, 12 females; the average age was 34.3±1.3 years) patients with type 1 DM and Group II included 22 (10 males, 12 females; the average age was 58.9±1.1 years) patients with type 2
DM. Depending on DM duration, all the patients were divided into 3 subgroups: in patients of subgroup I (n=14, 4 males/4 females with type 1 DM and 3 males/3 females with type 2 DM) DM was diagnosed within the first 5 years after onset of the disease; in patients of subgroup II (n=17, 3 males/5 females with type 1 DM and 4 males/5 females with type 2 DM) DM was diagnosed within 6 to 10 years after disease onset; in patients of subgroup III (n=13, 3 males/3 females with type 1 DM and 3 males/4 females with type 2 DM), the duration of DM was more than 11 years.
To diagnose type 1 DM and type 2 DM as well as to evaluate the degree of carbohydrate metabolism compensation, national standards were used (the Order of the MOH of Ukraine of 29.12 2014 No 1,021; the Order of the MOH of Ukraine of 05.08.2009 No 574; the Order of the MOH of Ukraine of 21.12.2012 No 1,118) [7, 8].
Patients of Group I received insulin therapy according to individually adjusted schemes. Patients of Group II underwent combination therapy: 36.4% (8 persons) of patients received insulin therapy in combination with different classes of oral antidiabetic drugs (OADs); 40.9% (9 persons) of patients received OADs only; 22.7% (5 persons) of patients underwent insulin therapy.
To determine gastrointestinal pathology, anam-nestic data, medical reports as well as the survey results - the Diagnostic Adaptive Behavior Scale (DABS) and the Gastroparesis Cardinal Symptom Index (GCSI) - were taken into account. The degree of DG severity was determined applying a three-minute patients' survey - the GCSI which allows the patients to evaluate the severity of symptoms by themselves [19, 21]. The symptoms were rated on a 5-point scale (0-absent, 1-very mild, 2-mild, 3-moderate, 4-severe, 5-extremely severe). The total sum within 1 to 11 points indicates mild degree of severity, while the total sum within 12 to 22 points indicates moderate degree of severity; total sum within 23-33 points indicates severe degree, while the total sum of more than 34 points indicates extremely severe degree. The incidence and severity of hypoglycemia episodes were determined based on the results of the DABS.
The state of autonomic tone was assessed using the Kerdo autonomic index (KAI): the KAI = the state of eutonia; the KAI<0 is typical for hyperparasym-pathicotonia; the KAI>0 is typical for hypersympath-icotonia [2, 3].
The MEF of the stomach was determined using the 13C-octanoate breath test (OBT); normal value for the time by which half of the gastric content is evacuated (T/) to the duodenum is 40-75 minutes; motility acceleration - T/<40 minutes; mild degree of motility acceleration - 79-95 minutes; moderate degree of motility deceleration - 96-115 minutes; severe degree of motility deceleration - more than 115 minutes.
Blood glucose levels were measured by glucose oxidase method using an automatic glucose analyzer AGKM-01K (Kvertimed, Ukraine). Glycated hemoglobin (HbA1C) levels were measured using ion exchange liquid chromatography method.
The identification of PMP22 level was made using the enzyme-linked immunosorbent assay (ELISA, USA).
Exclusion criteria for participation in the study included taking medications of symptomatic treatment affecting gastric motility, liver dysfunction, organic diseases of the gastrointestinal tract, cholelithiasis, viral hepatitis, demyelinating diseases of the central nervous system, thyroid disorders, and renal impairment.
For statistical processing of the material at all stages of the research several Microsoft Excel-based computer programs were developed (calculation of relative values, their deviations, t-test). The mean values were calculated by the statistical software package of Microsoft Excel, descriptive statistics in particular; the interval scale indicators were presented in the form of the mean values and standard deviations. Quality indicators were displayed in the form of absolute frequencies and proportions as percentage. The correlation coefficient was determined using a statistical analysis program Statistica 7.0 based on the Pearson Square method, a value of p<0.05 was considered significant.
The patients' health and well-being, human rights and dignity were protected in accordance with the moral and ethical principles of the WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects, the Council of Europe's Convention on Human Rights and Biomedicine and relevant laws of Ukraine
Results and their discussion
Purposeful complete physical examination of patients with DM proved a high prevalence of gastric dysmotility. According to the results of the GCSI, only in 36.4% (16 persons) of patients with type 1 DM and 31.8% (14 persons) of patients with type 2 DM there were no gastrointestinal disorders; however, after examination, clinical picture has changed indicating an asymptomatic course of the initial stages of slowing down of the MEF of the stomach which is the main manifestation of DG being described in several research papers [4, 18]. The additional methods of examination revealed a direct correlation between the average GCSI score and the results of the 13C-OBT (r=0.61). Bradygastria contributed to the development of asymptomatic postprandial hyperglycemia which, in turn, exacerbated primary disease.
Clinical and metabolic compensation of DM was evaluated calculating individual targets for glycated hemoglobin (HbA:C); only in 4 (9.1%) patients the compensation of the diseases was achieved (HbA1C<7.0%), while in the remaining patients (90.9%) with DM, this indicator exceeded 7.0%. Episodes of hypoglycemia were recorded in 22.7% (10 patients) of cases (the DABS) indicating brittle DM.
Thus, for early diagnosis of DG, all patients with DM lasting for more than 5 years should be interviewed and their MEF of the stomach should be determined using modern instrumental examinations -the 13C-OBT.
The main clinical and laboratory as well as instrumental indicators which were used to perform the initial examination are presented in Table 1.
Table 1
Characteristics of studied patients
Indicators Group I (n=22) Group II (n=22)
Gender (male/female) 10/12 10/12
Age, years 34.3±1.3 58.9±1.1
DM duration, years 13.8±1.2 15.4±4.6
Body mass index, kg/m2 24.1±1.1 31.3±3.2
SBP, mm HG 113.5±24.5 134.4±25.1
DBP, mm Hg 68.6±3.4 74.7±5.3
HR, beats per minute 90.3±13.2 91.9±12.3
KAI, c.u. -0.3±0.5 -0.3±0.4
Results of questionnaire survey
GCSI total score 11.2±10.0 9.1±6.1
Degree of DG severity
mild, n [%] 6 [27.3] 6 [27.3]
moderate, n [%] 7 [31.8] 3 [13.6]
severe, n [%] 3 [13.6] 1 [4.5]
Incidence of hypoglycemia episodes according to the DABS results, n [%] 6 [27.3] 4 [18.2]
Carbohydrate metabolism
Glycated hemoglobin, HbA:C, % 8.9±1.4 10.2±0.9
Prandial hyperglycemia, mmol/L 9.2±0.7 9.9±0.3
Postprandial hyperglycemia, mmol/L 10.4±0.6 11.6±0.7
Degree of DM compensation
Compensation, n [%] 3 [13.6] 1 [4.5]
Subcompensation, n [%] 13 [59.1] 14 [63.7]
Decompensation without ketosis, n [%] 6 [27.3] 7 [31.8]
Criterion for nerve fiber demyelination
PMP22, ng/ml 12.6±1.3 9.9±1.6
Instrumental evaluation of the MEF of the stomach
13C-OBT, T/ , min 80.5±3.6 96.2±5.2
Degree of gastric motility deceleration
mild, n [%] 2 [9.1] 6 [27.3]
moderate, n [%] 4 [18.2] 4 [18.2]
severe, n [%] 2 [9.1] 4 [18.2]
Syntropic complications of DM
Peripheral polyneuropathy, n [%] 20 [90.9] 21 [95.5]
Retinopathy, n [%] 10 [45.4] 18 [81.8]
Nephropathy, n [%] 7 [31.8] 11 [50.0]
The progression of the processes of nerve fiber demyelination is recognized as one of the main patho-genetic factors of severe manifestations of peripheral and autonomic neuropathy [5, 12, 16]. In order to study the effect of nerve ending demyelination on early symptoms of gastrointestinal autonomic neuropathy, a correlation analysis was made to quantify the association between one of the markers of PMP22 level and velocity of the MEF of the stomach according to the results of the 13C-OBT which revealed a moderate direct correlation in patients of both Group I (r=0.42) and Group II (r=0.41). Consequently, we can state that the increase in the concentration of PMP22, which negatively affects the motor function of the stomach in patients with DM, is a specific marker of the progression of nerve ending demyelination. There was a strong direct correlation (r=0.71) between the state of carbohydrate metabolism compensation (HbA1C, %) and the degree of gastric motility deceleration according to the parameters of the 13C-OBT as well. However, the results of questionnaire survey (the GCSI, the DABS) did not reveal any correlation between the symptoms of DG and the incidence of hypoglycemic states. In all groups, there was a correlation (r=0.38) between the degree of slowing down the MEF of the stomach according to the results of the 13C-OBT and the manifestations of autonomic dysfunction according to the KAI indicators. The slowing down of the MEF of the stomach may influence the state of carbohydrate metabolism compensation and depends on DM duration and the state of the autonom-ic nervous system.
According to a number of scientists, the progression of autonomic dysfunction worsens the manifesta-
tions of gastrointestinal autonomic neuropathy [1, 2]. Histological examination of biopsy specimens from gastric mucosa of patients with DM and signs of gastrointestinal autonomic neuropathy revealed that the vagus nerve-mediated regulation of gastric secretion was impaired and there were observed changes typical for vagus nerve disorders, namely the disappearance of myelinated fibers and the decrease in the number of unmyelinated nerve fibers [14]. The axonal damage to the nerve trunks belongs to early signs of neuropathy, whereas with the progression of the symptoms myelin is involved in the pathological process. Under physiological conditions, PMP22 affects the process of nerve ending demyelination as well as the stabilization of intercellular junctions. In patients with DM, the deceleration in nerve conduction velocity was observed. Due to the destruction of the myelin sheath of the nerve endings, the concentration of PMP22 increased significantly in patients of both Group I (12.6±1.3 ng/ml) and Group II (9.9±1.6 ng/ml) while its normal level is 0.05±0.27 ng/ml. Thus, the progression of the processes of neuron demyelination was more pronounced in patients with type 1 DM.
7 (16.1%) patients with DM (11.5% of patients with type 1 DM and 4.6% of patients with type 2 DM) were diagnosed with eutonia. In 17 (39.1%) patients, there was observed the predominance of parasympa-thetic tone (KAI<0), the development of which is associated with increasing duration of type 2 DM; the largest proportion (13.8%) of such patients was found in subgroup III. The signs of hypersympathicotonia were detected in 20 (46.0%) patients with DM. More detailed information on the assessment of autonomic balance is presented in Table 2.
Table 2
Distribution of patients according to the assessment of autonomic balance
Groups/subgroups KAI=0 KAI<0 KAI>0
I (n=22, male/female - 10/12)
I (n=8, male/female - 4/4) 4 (9.2%) 2 (4.6%) 2 (4.6%)
II (n=8, male/female - 3/5) 1 (2.3%) 2 (4.6%) 5 (11.5%)
III (n=6, male/female - 3/3) 0 3 (6.9%) 3 (6.9%)
Total 5 (11.5%) 7 (16.1%) 10 (23.0%)
II (n=22, male/female - 10/12)
I (n=6, male/female - 3/3) 2 (4.6%) 2 (4.6%) 2 (4.6%)
II (n=9, male/female - 4/5) 0 2 (4.6%) 7 (16.1%)
III (n=7, male/female - 3/4) 0 6 (13.8%) 1 (2.3%)
Total 2 (4.6%) 10 (23.0 %) 10 (23.0%)
The assessment of autonomic balance using the KAI indicated that impaired autonomic balance with the predominance of hyperparasympathicotonia as well as hypersympathicotonia were observed in the first subgroups of patients with DM already at the time of making diagnosis. In patients of both Group I and Group II with DM duration of 6-10 years, the increased incidence of the alterations in sympatho-vagal balance towards the weakening of vagal tone and the predominance of sympathetic tone was observed which was confirmed by the value of the KAI as well. In patients with type 2 DM lasting for more than 10 years, the predominance of parasympathetic tone was seen, while in patients with type 1 DM lasting for more than 10 years, the distribution was uniform.
The results of the 13C-OBT showed that only in 13 (29.9%) patients of Group I, the disorders of the MEF of the stomach were detected (T/ - 50.4±6.5 min); in 2.3% of cases, accelerated bowel evacuation
was observed (T/ - 31.9±3.7 min); mild degree of motility deceleration (T/ - 92.5±2.3 min) was diagnosed in 2 (4.6%) patients; moderate degree of motility deceleration (T/ - 99.3±2.6 min) was found in 9.2% (4 patients) of cases; 2 (4.6%) patients were diagnosed with severe degree of motility deceleration (T/ - 128.4±3.1 min). Among patients of Group II, the functional activity of the stomach was not impaired in 18.4% of cases (T/ - 56.6±9.6 min); in 13.8% of cases, mild degree of motility deceleration was observed (T/ - 93.8±2.3 min); moderate degree of motility deceleration (T/ - 101.1±4.4 min) was detected in 9.2% of cases; severe degree of motility deceleration (T/ -133.3±4.5 min) was diagnosed in 9.2% of patients as well. Absolute and percentage distribution of patients according to the results of the 13C-OBT depending on the degree of gastric dysmotility is presented in Table 3.
Table 3
Distribution of patients according to the results of the 13C- octanoic breath test
Type of the MEF of the stomach Subgroup I, number (abs/%) Subgroup II, number Subgroup III, number
according to the results of the 13C-OBT (T/), min (abs/%) (abs/%)
Group I (n=22, 10 males/12 females)
Norm 6 (13.8%) 5 (11.5%) 2 (4.6%)
Acceleration 1 (2.3%) 0 0
Mild « <D 1 (2.3%) 1 (2.3%) 0
Deceleration Moderate sa ад 0 2 (4.6%) 2 (4.6%)
Severe <D T3 0 0 2 (4.6%)
Group II (n=22, 10 males/12 females)
Norm 5 (11.5%) 3 (6.9%) 0
Acceleration 0 0 0
Mild СЛ <D 1 (2.3%) 4 (9.2%) 1 (2.3%)
Deceleration Moderate га ад 0 1 (2.3%) 3 (6.9%)
Severe <D ТЗ 0 1 (2.3%) 3 (6.9%)
The results of the 13C-OBT showed that in most patients regardless of DM duration, the slowing down of the MEF of the stomach according to the indicators of T/ was detected which was associated with a severe and prolonged impairment in the mechanism of regulation. The development and progression of the stages of slowing down the MEF of the stomach in patients with DM are caused by a simultaneous impairment of autonomic balance with the signs of both hy-perparasympathicotonia and hypersympathicotonia as
well. The symptoms of bradygastria in patients with DM exacerbate primary disease as well as contribute to the occurrence of frequent episodes of postprandial hyperglycemia and the deterioration of carbohydrate metabolism compensation which, in turn, affect the development of DG.
Conclusions
The obtained results indicated intercorrelations between DM duration, lability of its course and slowing down of the MEF of the stomach due to the pro-
gression of the manifestations of gastrointestinal autonomic neuropathy.
The increase in serum levels of PMP22 in patients with DM indicates the progression of the manifestations of diabetic polyneuropathy as well as DG.
With the increase in DM duration, the tendency to the deceleration of gastric motility alongside with a simultaneous impairment of autonomic balance and the signs of hyperparasympathicotonia as well as hypersympathicotonia is observed.
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