Download Endocrine system

MINISTRY OF HEALTH PROTECTION OF UKRAINE
Vynnitsa national medical university named after M.I.Pyrogov
«CONFIRM»
on methodical meeting of
endocrinology department
A chief of endocrinology
department, prof. Vlasenko M.V.
_________________
“_31_”_august___ 2012 y
METHODOLOGICAL RECOMМENDATIONS
FOR INDEPENDENT WORK OF STUDENTS
BY PREPARATION FOR PRACTICAL CLASSES
Scientific discipline
Мodule № 1
substantial module №1
Topic
Course
Faculty
Internal medicine
Basis of Internal medicine
“Diagnostic, treatment and prophylactic basis of
main endocrinology diseases”
Topic №11: Thyrotoxicosis syndrome. Diffuse toxic goiter.
Classification. Clinics. Laboratory and instrumental
diagnostics. Differential diagnosis.
4
Medical № 1
Vynnitsa – 2012
METHODOLOGICAL RECOMМENDATIONS
for the students of 4-th course of medical faculty for preparation to the practical
classes from endocrinology
1.Тopic №11: Thyrotoxicosis syndrome. Diffuse toxic goiter. Classification. Clinics. Laboratory
and instrumental diagnostics. Differential diagnosis.
2. Relevance of topic: Hyperthyroidism is the condition resulting from the effect of excessive
amounts of thyroid hormones on body tissues. Thyrotoxicosis is a main syndrome. Sometimes the
term hyperthyroidism can be used in a narrower sense to denote this state when the thyroid gland is
producing too much thyroid hormones in contrast with excessive ingestion of thyroid hormone
medication. At one time or another, approximately 0,5 % of the population suffers from
hyperthyroidism. Graves disease is the most common cause of hyperthyroidism and is fairly
common in the population. It is responsible for over 80 % of hyperthyroid cases. It occurs most
often in young women, but it may occur in men and at any age.
Thyrotoxicosis is a syndrome of clinical and biochemical displays of excessive amounts of thyroid
hormones in blood, regardless of reason of increase of their level. In most cases thyrotoxicosis
develops as a result of excessive thyroid hormones producting by thyroid gland (hyperthyroidism).
Among all forms of thyrotoxicosis 90 % a diffuse toxic goiter and thyro-toxic adenoma make.
The variety of clinical symptoms of thyrotoxicosis stipulates the origin of certain diffculties at
diagnostics of disease. According to this it is especially important to be able to fnd out the
symptoms of thyrotoxicosis in time, conduct differential diagnostics of its basic symptoms, estimate
the features of course of disease, to appoint in time the proper treatment of diffuse toxic goiter, that
helps to prevent a lot of heavy complications of the illness, such as a myocardiopathy (thyrotoxic
heart), hypertension, thyrotoxic encephalopathy, rapid progress of ophtalmopathy, liver function
disorders, osteoporosis.
Similar clinical symptoms cause the necessity of differential diagnostics of diffuse toxic goiter
with autoimmune thyroiditis, thyroid gland cancer which run across with thyrotoxicosis, so far as
correct surgical treatment often keeps patient life.
3. Aim of lesson:
4. References
4.1. Main literature
1. Endocrinology. Textbook/Study Guide for the Practical Classes. Ed. By Petro M. Bodnar: Vinnytsya: Nova Knyha Publishers, 2008.-496 p.
2. Basіc & Clіnіcal Endocrіnology. Seventh edіtіon. Edіted by Francіs S. Greenspan, Davіd G.
Gardner. – Mc Grew – Hіll Companіes, USA, 2004. – 976p.
3. Harrison‘s Endocrinology. Edited J.Larry Jameson. Mc Grew – Hill, USA,2006. – 563p.
4. Endocrinology. 6th edition by Mac Hadley, Jon E. Levine Benjamin Cummings.2006. –
608p.
5. Oxford Handbook of Endocrinology and Diabetes. Edited by Helen E. Turner, John A. H.
Wass. Oxford, University press,2006. – 1005p.
4.2. Additional literature
6. Endocrinology (A Logical Approach for Clinicians (Second Edition)). William Jubiz.-New
York: WC Graw-Hill Book, 1985. - P. 232-236. Pediatric Endocrinology. 5th edition. –
2006. – 536p.
7. Thyroid Disordes (Aclevelend Clinic Guide) by Mario Skugor, Jesse Bryant Wilder
Clevelend Press,2006. – 224p.
Basic Level.
1. Localization of thyroid gland.
2. Normal sizes and weight of thyroid gland.
3. Biological effects of thyroid hormones’ action.
4. Regulation of thyroid gland function.
Students’ Independent Study Program.
You should prepare for the practical class using the existing text books and lectures. Special
attention should be paid to the following:
1. The terms “hyperthyroidism” and “thyrotoxicosis”
2. Predisposing factors of hyperthyroidism.
3. Pathogenesis of hyperthyroidism.
4. Degrees of the thyroid gland enlargement.
5. Stages of thyrotoxicosis severity.
6. Changes of the cardiovascular system in patients with hyperthyroidism.
7. Changes of the nervous system in patients with hyperthyroidism.
8. Changes of the gastrointestinal tract in patients with hyperthyroidism.
9. Changes of the other endocrine organs in patients with hyperthyroidism.
10. Ophthalmologic signs and symptoms of hyperthyroidism.
11. Endocrine encephaloophthalmopathy.
12. Pretibial mixedema.
13. Differential diagnosis of hyperthyroidism.
14. Particularities of hyperthyroidism in young, adult and pregnant patients.
15. Nodular hyperthyroidism: etiology, pathogenesis, diagnostic criteria, differential diagnosis.
16. Complications of hyperthyroidism.
17. The main methods of treatment patients with hyperthyroidism.
18. Antithyroid preparations: mechanism of action, side effects.
19. Usage of β-blockers, glucocorticoids, thyroid hormones.
20. Surgical treatment.
21. Iodine therapy.
22. Treatment of endocrine encephalopathy.
23. Thyroid storm: diagnostic criteria, treatment.
Short content of the theme.
The thyroid is a firm vascular organ lying in the neck, caudal to cricoid cartilage. It is composed
of two nearly equal lobes connected by a thin isthmus and weights approximately 20 gr. Rests of
thyroid tissue are occasionally presents in sublingual or retrosternal areas.
Thyroid secrets: T3, T4,thyrocalcitonin. The thyroid hormones, thyroxine (T4) and
triiodothyronine (T3) are secreted under the stimulatory influence of pituitary thyrotropin (thyroidstimulating hormone or TSH). TSH secretion is primary regulated by a dual mechanism:
- thyrotropin-releasing hormone (TRH);
- thyroid hormone.
Thyroid hormone exits in circulation in both free and bound forma. The thyroid gland is the sole
source of T4 and only 20% of T3 is secreted in the thyroid. Approximately 80% of T3 in blood is
derived from peripheral tissue (mainly hepatic or renal) deiodinatoin of T4 to T3.
(Thyroid hormones.
Iodide, ingested in food or water, is actively concentrated by the thyroid gland, converted
organic iodine by peroxidase, and incorporated (by the thyroid gland) into tyrosine in intrafollicular
thyroglobulin. The thyrosines are iodinated at eihter one (monoiodotyrosine, MIT) or two
(diodotyrosine,DIT) sites and then coupled to form the active hormones (diiodotyrosine +
diiodotyrosine → tetraiodothyronine (thyroxine, T4); diiodotyrosine + monoiodotyrosine →
triiodotyronine (T3).
Thyroglobuline, a glycoprotein, containing T3 and T4 within its matrix, is taken up from the
follicle as colloid droplets by the thyroid cells. Lysosomes containing proteases cleave T3 and T4
from thyroglobulin, resulting in release of free T3 and T4. The iodotyrosines (MIT and DIT) are also
released from thyroglobulin but do not normally reach the bloodstream. They are deiodinated by
intracellular deiodinases, and their iodine is neutralized by the thyroid gland.
Although some of free T3 and T4 is deiodinated in the thyroid gland with the iodine
reentering the thyroid iodine pool, most diffuses into the bloodstream where it is bound to certain
serum proteins for transport. The major thyroid transport protein is thyroxine binding globulin
(TBG), which normally accounts for about 80% of the bound thyroid hormones. Other thyroid
binding proteins, including thyroxine-binding prealbumin (TBPA) and albumin, account for the
remainder of the bound serum thyroid hormone (20 %). About 0,05 % of the total serum T4 and 0,5
% of the total serum T3 remain free but in equilibrium with the bound hormone.
About 15 - 20 % of the circulating T3 is produced by the thyroid. The remainder is produced
by monodeiodination of the auter ring of T4, mainly in the liver. Monodeiodination of the inner
ring of T4 also occurs in hepatic and extrahepatic sites, including kidney, to yield 3,3/, 5/-T3 (reverse
T3 or rT3). This compound has minimal metabolic activity but is present in normal human serum or
globulin.
Observations pertaining to rT3 metabolism in fetal life are of great importance. Total amniotic T4
and T3 are low, in contrast to levels in maternal serum. Fetal rT3 levels in amniotic fluid are much
higher than the corresponding values in maternal serum throughout pregnancy (15 to 42 wk). These
data imply that rT3 derives primarily from the fetus and that it may be possible to diagnose fetal
hypothyroidism as early as 15 wk of pregnancy, utilizing radioimmunoassay for rT3. These levels
appear to decrease after 30 wk gestation and may be serve as a useful index of pregnancies of < 30
wk duration.
Physiologic effects of thyroid hormones
Thyroid hormones have a major physiologic effects:
1) they increase protein synthesis in virtually every body tissue
2) they increase O2 consumption by increasing the activity of Na+ H+ ATPase (Na pump),
primarily in tissues responsible for basal O2 consumption (i.e., liver, kidney, heart and
skeletal muscle).)
Hyperthyroidism (thyrotoxicosis) Toxic diffuse goiter. Grave’s diseaseis the condition resulting from the effect of excessive amounts of thyroid hormones on body tissues.
Etiology:
Autoimmune disorders, which can be provoked by:
- insolation;
- acute infections;
- hormone disbalance (pregnancy and others).
Pathogenesis.
Insufficiency of T suppressors  excessive level of T helpers  increasing function of B
lymphocyte  secretion of thyroid – stimulating immunoglobulin (TSI)  blood  the thyroid.
TSI works as an antibody to the thyrotropin receptor on the thyroid follicular all resulting in
stimulation of this receptor  secretion of T4, T3.
Clinical manifestations
The clinical presentation may be dramatic or subtle.
Cardiovascular system
Dysfunction of the cardiovascular system is common, and in some instances, the only manifestation
of hyperthyroidism. Heart rate and cardiac output are increased, and peripheral resistance is
decreased. These changes result in:
- constant palpitation;
-sinus tachycardia or atrial fibrillation;
-heart failure.
Examination reveals:
- tachycardia;
- widened pulse pressure;
- a prominent apical impulse;
- bounding arterial pulsation;
- accentuated heart sounds;
- systolic ejection murmurs;
- occasionally cardiac enlargement..
Other than arrhythmia, electrocardiographic changes are limited to nonspecific ST and T wave
abnormalities.
Psychological symptoms:
- nervousness;
- physical hyperactivity;
- emotional lability;
- anxiety;
- distractibility;
- insomnia.
These changes occur commonly and often result in impairment of work or school performance and
disturbances in home and family life.
Neuromuscular symptoms:
- a fine tremor is often evident in the hands and fingers;
- performance of skills requiring fine coordination becomes difficult;
- deep tendon reflexes are hyperactive;
- some evidence of myopathy is common;
- weakness lit usually develops gradually, is progressive, and may be accompanied by muscle
wasting.
Skin.
The skin is warm, fine, moist and its texture is smooth or velvety erythema and pruritus may be
present. Increased sweating is common complaint . Hair may become thin and fine, and alopecia
occurs. Infiltrative dermopathy, also known as pretibial mixedema (a confusing term, since
mixedeme suggests hypothyroidism), is characterized by nonpitting infiltration of proteinaceous
ground substance, usually in the pretibial area. The lesion is very pruritic and erythematous in its
early stages and subsequently becomes browny it may appear years before or after the
hyperthyroidism. TSIS are invariably present. The dermopathy usually remits spontaneously after
months or years.
Eyes. Eye sings include:
- stare (Schtelvag’s symptom);
- lid lag;
- lid retraction (symptoms of Dalrympl; Greffe; Koher),
which results in “apparent” proptosis, but not eye and is often accompanied by symptoms of:
- conjunctival irritation.
These eye signs are largely due to excessive adrenergic stimulation and zemit promptly after
upon successful treatment of thyrotoxicosis
- infiltrative ophthalmopathy is present in 20 to 40% of patients with Graves’ disease. It is
characterized by increased retro-orbital tissue, producing exophthalmos and by lymphocyte
infiltration of the extraocular muscles, producing a spectrum of ocular muscle weakness
frequently leading to blurred and double vision. The pathogenesis of infiltrative ophthalmopatny
is poorly understood.
It may occur before the onset of hyperthyroidism or as 15 to 20 years afterward and frequently
worseness or improves independent of the clinical course of hyperthyroidism. Infiltrative
ophthalmopathy results from immunoglobulins directed to the extraocular muscles and specific
antibodies that cause retro – orbital inflammation and subsequent edema (it is not because of TSH
or LATS). The antibodies are distinct from those initiating Graves’ type hyperthyroidism.
The symptoms include:
- pain in the eyes;
- lacrimation;
- photophobia;
- diplopia;
- blurring or loss of vision.
The major signs are:
- proptosis (exophthalmos);
- periorbital and conjunctival congestion and edema (chemosis);
- limitation of ocular mobility.
Thyroid gland
Enlargement of thyroid gland is very common. Both thyroid lobes are usually moderately
symmetrically enlarged, but thyroid enlargement may be absent.
Degrees of thyroid gland enlargement.
0- we can’t see or palpate thyroid gland;
IA- we can’t palpate but can’t see;
IB- thyroid gland can be seen when patient put head back;
II –thyroid gland can be seen in normal position of the head.
III – thyroid gland can be seen from the distance of 5 meters or more
Respiratory function
Abnormalities of respiration include:
- decreased vital capacity;
- decreased pulmonary compliance.
They result in dyspnea and hyperventilation during exercise and sometimes rest.
Gastrointestinal system
Increased caloric utilization is almost always present. It results in increased appetite and
food intake, but compensation is usually inadequate, and modest loss occurs.
Increased gastrointestinal motility may result in increased frequency of bowel movements
and even frank diarrhea.
Minor abnormalities in hepatic function are often found.
Hematopoetic system
Some patients have a modest anemia, caused by mild deficiency in one or more
hematopoetic nutrients or increased plasma volume. Mild granulocytopenia and thrombocytopenia
may be present.
Energy and intermediary metabolism because of increased energy expenditure, energy
production must be augmented, this is accompanied by increased oxygen consumption and heat
production. In patients with diabetes mellitus, requirement for exogenous insulin catabolism.
Endocrine system
In women, hypomenorrhea or amenorrhea may occur, although no changes are noted.
In men, there may be loss of libido and impotence hypercalcemia is found occasionally; it is
caused by increased bone resorption, but clinical osteopenia is rare.
In patients mild adrenal insufficiency may occur. It is present by low diastolic blood
pressure and darkness of upper lid (Elynecks symptom).
Degrees of severity of thyrotoxicosis
I. mild degree: work capacity is normal;
heart beat – is under 100/min;
weight loss is less than 10 %.
II. moderate degree: work capacity is decreased;
heart beat – is 100 to 120/min;
weight loss is 10 to 20 %.
III. severe degree: patients cant work;
heart beat – is over 120/min and arrhythmia is present;
weight loss is more than 20%.
Criteria
Clinical signs
Mild
Moderately
expressed
Neurological
symtoms
Expressed insignifcantly
Decline of
working
capacity
Insignifcant
Decline of body
mass
To 10 % of initial
Moderate
More expressed
Severe
Considerably expressed
Considerable changes,
Considerable emotional and
muscular weakness,
vegetative violations, muscular
atrophy
of proxymal
weakness, atrophy of proxymal muscle departments
of
muscle departments of extrem- extremities, hypotho-nia
ities, hypothonia of skeletal
of skeletal muscles are
muscles
more expressed
Considerable
Complete loss of capacity
To 20 % of initial
More than 20 % of
initial
More than 120 min,
arrhythmia
Pulse
To 100 min
To 120 min
Pulse pressure
Rises insigni-fcantly
Rises considerably
Rises considerably
Signs of
insuffciency of
blood circulation
Absent
Insuffciency of blood
circulation of 1 degree
Insuffciency of blood
circulation of 2–3 degrees
Ophtalmopathy
Thyreotoxic
ophtalmopathy
Endocrine ophtalmo-pathy of 1
degree
Endocrine ophtalmopathy of 2–3 degrees
Levels of T3, T4 in Increased to 15 %
of the high normal
blood
level
Increased to 60 % of the high
normal level
Increased more than on
60 % of the high
normal level
Diagnosis of toxic diffuse goiter
I.
Clinical manifestations (were discussed).
II.
Laboratory findings.
(The diagnosis of hyperthyroidism is usually
straightforward and depends on careful clinical history and physical examination, a high index of
suspection, and routine thyroid hormone determination).
1. In most patients serum total T3 and T4 concentrations, are increased (however, these changes,
also can be caused by increased thyroxine – binding globulin production, e.g. as a result of
estrogen therapy).
2. Elevation of T3 - resin uptake.
(T3 - resin uptake is not a measurement of circulating T3. In normal patients, 25 to 35% of TBG
binding sites are occupied by thyroid hormone. When 131I-T3 is added to the patients serum, in
vitro, a portion binds to unoccupied TBG sites. After equilibration, a resin is added that binds
the remaining unbound 125/-T3).
Thus in hyperthyroidism, characterized by increased levels of circulating thyroid hormone,
there are more occupied and less unoccupied TBG binding sites. Less 131I-T3 is bound to TBG,
resulting in more uptake of 131I-T3 by the resin.
3. TSN (serum thyroid stimulating hormone) may be decreased, but it is not very sensitive assay in
the assessment of thyroid hyperfunction.
4. If the diagnosis of hyperthyroidism remains unclear after these initial tests, more expensive,
sophisticated and time – consuming tests may be required, e.g. A TRH test (thyrotropin releasing hormone).
Serum TSN is determined before and after an i/v injection of 500 mkg of synthetic TRH. Normally,
there is a rapid rise in TSH of 5 to25 mkU/ml, reaching a peak in 30 min and returning to normal by
120 min.
In patients with hyperthyroidism TSH release remains suppressed, even in response to
injected TRH, because of the inhibitory effects of the elevated free T4 and T3 on the pituitary
thyrotroph cells.
The diagnosis of infiltrative ophthalmopathy when hyperthyroidism is or recently was
present is not difficult. The diagnosis is less certain if the patient is not or never was hyperthyroid
orbital ultrasonography or computed tomography is the best procedure to confirm the diagnosis of
ophtalmopathy such as orbital pseudotumor and orbital tumors.
Differential diagnostics of diffuse toxic goiter (Graves’ disease) and functional
autonomy of thyroid gland
Sign
Diffuse toxic goiter
Functional autonomy
Character of illness Autoimmune disease
Iodine-defcit disease
Palpation of thyro- More frequent diffuse en- More frequent multinodular id gland
largement of thyroid gland; goiter in a 10 % goiter absent
Age of patient
Anamnesis
Young age (20 – 40 years)
Short
More senior 45 – 50 years
Protracted motion of euthyroid goiter
Clinic of
thyrotox-icosis
More frequent manifesting
Ophtalmopathy
Clinically obvious endocrine
ophtalmopathy in 50 % cases
Often olygosymptomic or
monosymptomic course
There is not endocrine ophtal-mopathy
(not to mix up thyrot-oxicosis with eye
symptoms!)
Pretibial
It is in 3–4 % patients
myxed-ema
Antibodies to
In most cases, appear (most specifc
the thyroid
antibodies –rTSH)
gland
Contents of
Maintenance in blood of T4 and T3
thyroid
is increased
hormones in
blood
Radioisotope
The diffuse strengthening of
scanning of
fascination of Tc-99m at scintigraphy
thyroid gland
Ultrasonography
Diffuse enlargement
of the thyroid
gland
Proof remision after the protracted
Treatment
thyreostatic therapy in the group of
patients correctly selected for this treatment in 30 – 40 % cases
Tests and Assignments for Self-assessment.
Multiple Choice.
Choose the correct answer/statement:
1. The normal weight (gr.) of the thyroid gland is:
Absent
Usually absent
Maintenance in blood mainly T3 (T3thyrotoxicosis), rarer T4 is increased
Hot nodules or alternation of areas of
increased and decreased accumulation
of Tc-99m
A nodule is determined
Thyreostatic therapy liquidates
thyrotoxicosis only on the time of
getting preparations and generally have
no perspectives
A. 7 – 10;
B. 1 – 3;
C. 20 – 30;
D. 45 – 55;
E. 50 – 60.
2. Clinical sign of hyperthyroidism which is very rare in old patients:
A. large goiter;
B. parkinsonic’ trembling of the fingers;
C. nodular forms of goiter;
D. prominent heart failure;
E. atrial fibrillation.
3. In a woman of 50 years old atrial fbrillation is found out. In anamnesis there are colds, acute
tonsillitis. Objectively: temperature of 37,1 °C, heart rate – 128/min., pulse – 128/min., blood pressure
is 145/60 mmHg. The thyroid gland enlargement of 3 grade. Left border of heart on 2 cm outside
from a left media-clavicular line. Tones of heart are intensives, systolic murmur above an apex,
accent of II sound in second rib on the left near a breastbone. A skin is moist. Manifestation of what
disease may be arrhythmia most probably?
A. Diffuse toxic goiter
B. Climacteric cardiomyopathy
C. Rheumatic vice
D. Dilatational cardiomyopathy
E. Miocardiatic cardiosclerosis
4. A woman of 47 years old complains of weakness, hyperhid-rosis, shaking in a body, loss of
weight, palpitation, increasing the sizes of neck, lacrimation, photophobia. Objectively: a thyroid
gland is diffusely enlarged, elastic, mobile, painless. Heart rate - 128/min, atrial fbrillation. What
symptom in all will allow to estimate the degree of thyrotoxicosis severity more reliable?
A. Presence of arrhythmia
B. Size of thyroid gland
C. State of eyeballs
D. Hight and weight
E. Numbers of arterial pressure
5. A woman of 25 years old has a diffuse toxic goiter during 5 years. Emotionally instable, at
examination there is tremor of fngers of hands, skin moist, heat feeling, an apex shove is increased,
the heart bounds are displaced to the left, atrial fbrillation, systolic murmur on an apex. Pulse 96/min, blood pressure is 170/70 mmHg. A thyroid gland is enlarged to the 3 grade. What
pathogenetic mechanisms lies in basis of violation of cardio-vascular system function of patient?
A. Damage action of thyroid hormones on the myocardium
B. Increasing sensitiveness of receptors to katecholamines
C. Increasing of albuminous substrats catabolism
D. Infuencing of thyreostimulated antibodies
E. Change of vegetative nervous system tone
6. The patient of 32 years complains of permanent irritability, palpitation, pain in eyes, lacrimation,
tremor of extremities and all body, hy-perhydrosis, weight loss of 10 kg for 4 months. Objectively:
skin is warm, moist, mild exophthalmos, there are symptoms of Grefe, Kokher, Mebius. A thyroid
gland is diffusely enlarged, that is seen at swallowing, painless. Pulse - 108/min, blood pressure is
140/66 mmHg. Shallow tremor of fngers of hands. Your diagnosis?
A. Diffuse toxic goiter
B. Fibrous thyroiditis
C. Diffuse nontoxic goiter
D. Nervous exhaustion
E. Subacute thyroiditis
Answer: 1 – B. 2 – A. 3 – A. 4 – A. 5 – A. 6 – A.
Real-life situations to be solved:
Patient F, 38 years old, complaints on general weakness, increased sweating, palpitation.
Physical examination shows: skin is moist, hot; trembling of the fingers, thyroid gland is enlarged,
positive eye’s symptoms, pulse rate 116/minute, systolic murmur on the region of the heart and
thyroid. Put previous diagnosis and make the plan of the examination.
Answer: Hyperthyroidism, moderate stage of thyrotoxicosis. Ultrasonic examination of the thyroid
gland, the levels of TSH, T3,T4.
Students Practical Activities.
Work 1 : Students’ group is divided into 2 sub-groups, that work near the patients’ bed: ask the
patients on organs and systems, take anamnesis of the disease , anamnesis of life, make objective
exam. With the teacher’s presence. In the class-room they discuss the patients, learn data of
laboratory and instrumental exam. of these patients.
1.To group the symptoms into the syndromes.
2.To find out the leading syndrome and make differential diagnosis.
3.To formulate the diagnosis.
4.To make a plan of treatment.
Methodological recommendation prepared assistant, c.m.s. Chernobrova O.I.
It is discussed and confirm on endocrinology department meeting
" 31 " august 2012 y. Protocol № 1.