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DOI: http://dx.doi.org/10.20534/ESR-16-9.10-89-93
Inoyatova Flora Ilyasovna, MD, Professor, Head of Hepatology Department of Republican Specialized Scientific Practical Medical Center of Pediatrics, Tashkent, Uzbekistan Ikramova Nodira Anvarovna, Junior Researcher of Hepatology Department of Republican Specialized Scientific Practical Medical Center of Pediatrics, Tashkent, Uzbekistan Inogamova Gulnoza Zaxidjanovna, PhD, Senior Researcher of Hepatology Department of Republican Specialized Scientific Practical Medical Center of Pediatrics, Tashkent, Uzbekistan. E-mail: [email protected]
Pathogenesis and clinical features of anemia of inflammation in children, during chronic hbv infection
Abstract: Examination of 125 children with chronic hepatitis B (CHB) and concomitant anemia has ascertained the frequency of refractory variants of anemia (52.5%). The disease progressed seriously on the background of anemia, that was indicated the prevalence of CHB with severe activity forms (71.4%). The pathognomonic symptoms of anemic processes were revealed. Two pathogenetic variants of the anemia inflammation genesis at children with CHB are being considered: the first is defined by veritable iron deficiency with ferrokinetic markers of iron-deficiency anemia; the second — by re-distributive iron deficit typical for hemosiderosis and refractoriness development.
Keywords: chronic hepatitis B, anemia, children, ferrokinetic markers.
The range of anemia prevalence in population, especially among children (up to 46-65% according to WHO, 2005) and high morbidity rate of chronic viral hepatitis preserved for the last decades (the third place after cardiac-vascular and oncologic pathologies, according to WHO, 2008) formed a global problem, which causes a great economical and social damage to the society and the state [5; 17; 20]. It becomes evident, that the contingent of children with chronic hepatitis B (CHB), has the prevalence ofanemia ofinflammation that reaches up to 94.6% cases, deserves a special attention; and it serves the basis for considering that nosology as one of unfavorable factors of chronic viral hepatic pathology is progressing [6; 8]. In hepatic pathology practice that problem can be often deteriorated by development of anemia forms refractory to ferrum therapy (up to 40%), which require a certain solution. Causative factors consider the close interrelation of pathogenetic aspects of the studied nosologies, particularly pathologic processes in liver, such as decrease of iron absorption in intestine as a result of viral persistence in enterocytes, liver participation in the synthesis ofproteins transporting and deposing iron, development of occult hemolysis of erythrocytes, disorder of iron re-utilization and erythropoesis [12]. On the other hand; anemic processes, such as hem and tissue hypoxia, disorder of lipids peroxide oxidation, antioxidant system and internal cellular metabolism, formation of membrane pathologies, syndrome of regeneration-plastic disfunction, initiator of which is also viral replication [18]. Finally, that promotes suppression of the total resistance of macro organism and reality of all ways of progression of CHB. If we take into account - hepcidin - as one of the main regulators of iron hemostasis synthesized by hepatocytes [9; 14; 15], we can confirm not only significant role of liver in the genesis of anemia, but also get a new point of view on pathogenesis of anemia of inflammation in the conditions of chronic viral persistence. As hepcidin controls the level of extra cellular iron by means of regulation of intestinal absorbtion, placental transport and release of iron from deposits, and, being a philogenetic ancient factor, it has
a direct bactericidal effect and ability to increase resistance of the organism [1; 7; 11].
Thus, high possibility of development of anemia of inflammation in children with CHB, especially refractory to ferrotherapy variants, made us consider the problem of combined pathology more attentively. Complexity of that problem was conditioned by few modern scientific researches in that field; absence of the revealed ferrokinetic schemes of anemia in CHB in children; high range of its clinical manifestations, and the motives of making some decision about the therapy of refractory variants of anemia.
The objective of the study was the assessment of the characteristics of clinical progress and ferrokinetic of refractory variant of anemia of inflammation in children with CHB.
Material and methods of the research
125 children with CHB in the age from 3 to 18 years old with concomitant anemia were examined, 62.4% of which were boys. Marked activity of CHB diagnosed in 33.6% patients, moderate in 44.8% and minimal in 21.6% cases. The term of the diseases was 6.2±0.4 years. Diagnosis of CHB was set on the basis of anamnesis, clinical data, some serological, biochemical, and instrumental tests in compliance with the diagnostic criteria of the activity degree of the pathological process in liver in children [17]. The fact of anemia was determined according to WHO criteria [20]. 97 patients (I group) out of the total number of the patients had refractory to the iron therapy anemia (RA). The rest 28 children with non- refractory anemia (nRA) composed the II group. The control group involved 19 healthy children.
Biochemical analysis of blood included definition of: ALAT and ASAT activity, protein content and its fractions, total and direct bilirubin, Gamma Glutamyl Transpeptidase, alkali Phosphatase, tymolic test, C-Reactive protein, fibrinogen, and prothrombin by means of unified methods on biochemical analyzer FP-901 using "HUMEN" set (Germany). Middle molecular peptides (MMP)
were studied with the help of spectral-photometer method (Ga-brielyan N.I., 1982). Viral verification (HBV, HCV, HDV) was performed by means of ELISA and PCR methods using the sets of "DNA-technology" and "Vector-Brest" test-systems (Russia).
ELISA method was used for definition of ferrokinetic, markers such as hepcidin, transferrin (Tf), soluble transferrin receptors (sTfR), serum iron, ferritin (Ft), interleukin (IL-1), interleukin (IL-6) with the help of«Biochemmack» set, Moscow (2012) and «Bachem Group», USA (2011). Ratio of soluble transferrin receptors to log. ferritin (sTfR/log Ft index) was calculated [16]. The obtained results had been mathematically processed by means of variation statistics using Student t-criterion with special Excel-2000 software.
Results and discussion
Examination of children with CHB and concomitant anemia provided definition of the prevalence of refractory variant of anemia in 77.6% cases. Analysis of clinical progress of chronic hepatitis showed that with RA the pathology proceeded more severe, with prolongation of the period of exacerbation average to 3.7±0.1 days, and it was also proven by prevailing of more severe forms of the disease (71.4%).
The most complaints of patients with RARA combined with CHB (table 1) were dizziness and dimness, intensified when change to orthostatic state (92.8% versus 53.5% of the children with nRA, p<0.001).
Table 1. - Symptoms, characteristic for anemic process in children with CHB
CVH with RA CVH with nRA
Symptoms (I) n=97 (II) n=28 Р
abs. % abs. %
Dizziness 89 92.8±2.8 15 53.5±9.4 <0.001
Tinnitus 56 57.7±5.6 9 32.1±8.8 <0.001
Palpitation 67 69.0±4.6 9 32.1±8.8 <0.05
Brittleness of nails 82 85.5±3.6 16 57.1±9.3 <0.01
Acro cyanosis of nails 85 87.6±3.3 10 35.7±9.0 <0.001
Deformation of nails 30 30.9±4.6 2 7.1±4.8 <0.001
Hair fall 60 61.9±4.9 11 39.3±9.2 <0.05
Xerosis in skin 41 42.3±5.0 3 10.7±5.8 <0.001
Angular cheilitis 27 27.8±4.5 6 21.4±7.7 >0.05
Dysgeusia 41 42.3±5.0 6 21.4±7.7 <0.05
Pagophagia 33 34.0±4.8 2 7.1±4.8 <0.001
Osmesis inversion 45 46.9±5.0 7 25.0±8.1 <0.05
Stomatitis 45 46.9±5.0 7 25.0±8.1 <0.05
Glossitis 27 27.8±4.5 7 25.0±8.1 >0.05
P - reliability of the differences between the studied groups.
The study of the symptoms, characteristic for anemic process identified complaints such as tinnitus and palpitation, which were claimed by the children with RA (57.7% and 69% versus 32.1%, p<0.05). During the examination we paid attention to manifestations such as brittleness and acro cyanosis of nails (85.5% and 87.6% versus 57.1% and 35.7%), deformation of nail plates (30.9% versus 7.1%), dryness and excessive hair fall (61.9% versus 39.3%), chaps on finger "pillows" (42.3% versus 10.7% respectively with the groups with RA and nRA, p<0.001-0.05). In the I group of children there was more often characteristic abnormal taste alteration (pica chlo-rotica) such as dysgeusia - eating of soil, chalk, raw pastry (2 folds), pagophagia - eating frozen products and ice (4.7 folds), pathoos-mia - predilection to unpleasant smells, such lacquer, acetone, and others (1.8 fold) and inclination for development of stomatitis (1.8
fold, p<0.05). At the same time development of glossitis was met almost with the same frequency in both groups.
Among the clinical syndromes of CHB was reliably (p<0.05-0.001) more frequently met symptoms of asthenia complaints of weakness, fatigue, insomnia, and headache (94.8%), hemorrhagic syndrome in the form of nasal bleedings and ecchymoses (90.7%) and marked hepatosplenomegaly (63.9%) with the accent of fast progressing of the disease (fig.1). Besides that, we paid attention to the prevailing (to 32.2%) weight loss among the children with RARA (69.0% versus 32.1%, p<0.05). Moreover the expression of certain extra hepatic symptoms such as palmar erythema, arteriolovenular bridge, spider veins, and venous collateral was manifested in the majority of the patients independently of the character of anemia progressing (92.8% - 100%).
Figure 1. Prevalence of clinical syndromes of CHB in children dependently on the variant of anemia progression, %
AVS — asthenic-vegetative syndrome, DP-dyspeptic, CS — cholestatic, HS — hemorrhagic, HM- hepatomegaly, SM — spenomegaly; * — reliability of differences in the comparison group p<0.05-0.001.
The obtained data of the biochemical analysis testified more severe disorders of the functional state of liver in children with CHB with refractory progressing anemia. The leading biochemical manifestations of liver damage were as: cytolysis with development of characteristic long-term hyperenzymemia (77.3%), mesenchymal inflammation (83.5%) and endotoxemia (92.8%). Thus, average values of ALAT reached 2.87±0.10 mkmol/ls, and it was 1.4 fold exceeding analogical value of the children with CHB and nRA (1.99±0.12 mkmol/ls, p<0.001) and more than 4.2 folds the control values (0.68±0.02 mkmol/ls, p<0.001). Similar situation we observed in relation to the second indicator of cytolysis — ASAT, which was 2.00±0.10 mkmol/ls, 1.00±0.09 mkmol/ls and 0.38±0.02 mkmol/ls respectively in children of the I, II and control groups (p<0.001). It should be noted that, in most cases (76.2%) of refractory progressing anemia there was characteristic revealed hyperenzymemia, preserved for several months and not responsive to basic therapy. The manifestation of mesenchymal inflammation disTable 2. - Ferrokinetic markers in children with
orders in CHB with superimposed RA in children was rise of tymolic test and gamma globulin level in comparison with the control values average 4.0 and 2.0 folds respectively (p<0.001). Level of tymolic test reached 14.7±0.62 units and gamma globulin up to 32.8±0.68%. In the group of children with nRA. these parameters were reliably lower in comparison with the children with RA., but still above the control parameters (10.2±0.46 units and 26.6±0.88% versus 3.6±0.20 units and 15.7±0.47% respectively, p<0.05). The values of middle molecular peptides were significantly higher than analogical values of the control group (more than 10.3 folds, p<0.001), the amount of which varied from 0.66 to 3.45 mg/ml. And the greatest increase was registered in children with RA., and in average it was 2.88±0.12 mg/ml, relatively lower in patients with nRA. — average 2.49±0.10 mg/ml, while in the control — 0.24±0.02 mg/ml (p<0.01 between the examined groups).
Comparative analysis of ferrokinetic markers revealed diversity of the parameters, which mostly depended on the variant of anemia progressing in children, with CHB (table 2).
CHB dependently on the progress of anemia
Value CVH with RA n=97 CVH with nRA n=28 Control P 1-2
Hepcidin, ng/ml 28.680±0,63 * 56.367±1,6 * 39.4 ± 6.5 <0.05
Serum iron, mkmol/l 8.76 ± 1.22* 4.67 ± 0.86* 15.4 ± 0.86 <0.01
Ferritin, ng/ml 124.3 ± 2.42* 31.8 ± 1.82* 62.2 ± 1.21 <0.001
Transferrin, mg/dl 166.9 ± 4.23* 365.5 ± 7.6* 275.6 ± 4.4 <0.001
sTfR, mkg/ml 1.37 ± 0.47 2.66 ± 0.40* 1.38 ± 0.02 <0.05
sTfR/log Ft index 0.867 ± 0.19 2.256 ± 0.16* 0.769 ± 0.10 <0.001
P — reliability of the differences between the examined groups; * — to control
(p<0.05-0.00l).
With the general deficit of iron, the lowest Serum iron values were noted among the children with nRA. (4.67±0.86 mkmol/l). Patients with RA. had Ft amount more than 3.9 folds higher than the similar value of other examined children (p<0.001). In contrast the amount of Tf in that group of the children was decreased to 166.9±4.23 mg/dl, while in the group of children with nRA. it was increased to 365.5±7.6 mg/dl (and in the control 275.6±4.4 mg/dl, p<0.001).The similar tendency was noted in the alterations of sTfR and sTfR/log Ft index. While the parameters of the category of children with RA were closer to the control values and statistically did not differ, in the group of the children with non-refractory anemia these parameters were significantly increased (sTfR — up to 2.66±0.40 mkg/ml and sTfR/log Ft index — up to 2.256 ±0.16). The assessment of sTfR/log Ft index testified that children with CHB and nRA had "true" iron deficit, while the patients with RA were sub-divided differently. Generally, if the average level of sTfR/log Ft index was equal to 0.867±0.19, in the individual analysis in 61.9% cases sTfR/log Ft index was < 1 (absence of the deficit of iron), in 16.7% cases — in the range 1-2 (latent deficit), and in 21.4% cases > 2 (true iron deficit). Taking into account the current situation, we can
conclude the necessity of sTfR/log Ft index determination in children with RA for the definition ofiron deficit degree and, respectively, prescription of differential approach to the therapy of patients with CHB.
When we considered the parameters of hepcidin, its level was ambiguous, namely it was decreased to 28,680±0,63 in group of children with RA and was increased to 56,367±1,6 in group of children with nRA (and in the control 39,401±6,5 p<0.001). If we take into account that hepcidin is a protein consisting of 25 amino acids, synthesized in hepatocytes under the influence of metriptase enzyme [2; 3; 4], and the majority of the patients with RA had expressed activity of CHB, we can explain its low amount in blood.
Among the other laboratory values the most informative for the patients with CHB and RA were ones of common blood analysis such as anisocytosis (80.9%), poykilocytosis (73.8%), and decrease of the percentage of erythrocytes Hb saturation below 0.7 (57.1%, p<0.05).
Testing the systemic inflammatory markers in that category of children revealed high values of the parameters in refractory progressing of anemia (fig.2).
Figure 2. Markers of systemic inflammation in children with CHB and concomitant anemia a — reliability of the differences to the control; b — between the checked groups (p<0.05-0.01]
The average level of interleukin-1 was raised in both groups with higher levels in children with RA (9,81±0,63 pg/ml, against of the children with nRA 8,22±0.43 pg/ml, p<0.05 and the control 6.45±0.34 pg/ml, p<0.001). The same trend was the level of inter-leukin-6 corresponded to 12.85±0.50 pg/ml, with the total range of bordering values from 9.2 pg/ml to 16.5 pg/ml, and it was reliably (p<0.05) high er than the values of the children with nRA (9.20±0.43 pg/ml), and the control (7.75±0.75 pg/ml). Statistic difference between the latter was not determined (p>0.05). Similar tendency was registered in the values of C-reactive protein. Thus, with the general ranging from 0.45 to 1.86 mg/l, in children with RA the average amount was in the limits 1.33±0.19 mg/l, and it was significantly higher in comparison with children with nRA (0.71±0.14 mg/l, p<0.001), and the control (0.37±0.10 mg/l, p <0.001).
Conclusion
By summerisng obtained results, it could be stated that the contingent of the children with CHB, where the prevalence of anemia inflammation could reach 94.6%, deserves a special attention. According to our data, in the half of cases (52.5%) there is development of refractory anemia, and it provides the basis for considering that nosology is progressing in children as one of the main factors of chronic viral liver pathology. So with superimposed RA the pathology proceeded more severe, and it was testified by prevailing of more marked forms of the disease (71.4%) with stable prevailing of asthenic-vegetative (95.2%), hemorrhagic (91.6%) syndromes and explicit hepatomegaly (59.5%). Among the symptoms, characteristic for the anemic process the accented ones were dizziness, acro cyanosis, and deformation of nails, chaps on fingers, and pagophagia.
The leading biochemical values of liver damage were the syndromes such as cytolysis with characteristic long-term hyperenzy-memia, mesenchymal-inflammatory, and endotoxemia.
In the genesis of anemia development in CHB in children there are two pathogenetic variants ofprogressing. The first one was characterized by true iron deficit (sTfR/log Ft index >2) with layout of ferrokinetic markers, peculiar for iron deficiency anemia — rise of transferrin spectrum with decreased values of serum iron and ferritin; the second one — re-distributive of iron deficiency (sTfR/log Ft index <1), typical for hemosiderosis — rise of ferritin and decrease of transferrin value. The development of the second variant
characteristic for refractory progressing of anemia, evidently, should be considered as prolonged negative-stress-factor, leading to progressing severe CHB in children.
RA. is characterized by high inflammatory index. Taking into account the toxic effect of the majority of pro-inflammatory cytokines on the synthesis of erythropoietin with further inadequate production of erythrocytes by bone marrow (increased destruction, shortening of life term, etc.), and in the conditions of hepatic pathology insufficient inducing its effect on the synthesis of hepcidin in hepatocytes, we can partially explain compatibility of severe forms of hepatitis with refractory progressing anemia. in our opinion, together with the increase of the pathologic activity as a result of a whole cascade of metabolic shifts with viral genesis, such as replication of viruses in cells of reticuloendothelial system, suppression of bone marrow blood production, hypersplenism, bleedings from various veins, hemolysis of erythrocytes, etc. [4; 10], finally there is exhaustion of compensatory-adaptation capabilities of an organism with transformation at the certain stage of the first mentioned mechanism of iron metabolism disorder in the second, and development of refractory progressing of anemia. For the detection of "true" iron deficiency, or redistributing genesis, additional ferrokinetic monitoring is required with application of diagnostic markers such as ferritin, transferrin, sTfR, and calculation of sTfR/log Ft index.
Thus, in pathogenetical field these alterations reflected virus-induced pathological stress-reactions, in the progress of which, as a result of various metabolic shifts, there was formation of damaging mechanisms; and, in the conditions of associate progressing, it promoted development of two parallel mutually deteriorating processes, which conditioned progressing of CHB. Taking into account the aforesaid, therapy of refractory forms of anemia in CHB in children is a complex problem demanding its solution. Unjustified prescription of the agents of iron in the RARA therapy in children with CHB is not only ineffective, but also can cause harm to the patient such as decrease of antioxidant protection, immune suppression, generalization of bacterial processes, etc. [13; 19]. For the definition of optimal therapeutic routines of RA therapy during CHB in children we need prospective controllable studies with the account of the revealed pathogenetic schemes of anemia of inflammation development.
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Correlation of thyroidectomy difficulty scale with the time of an operation and its complications
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DOI: http://dx.doi.org/10.20534/ESR-16-9.10-93-98
Ismailov Said Ibragimovich, Doctor of medical sciences, Professor, Director of the Republic specialized scientific research center of endocrinology (Tashkent, Uzbekistan),
E-mail: [email protected] Alimdzhanov Nusratzhon Amildzhonovich, Candidate of medical sciences, Head of the Department of endocrine surgery of the Republic specialized scientific research center of endocrinology
(Tashkent, Uzbekistan), E-mail: [email protected] Rashitov Murad Mukhammedzhanovich, Candidate of medical sciences, senior research associate at the Department of endocrine surgery of the Republic specialized scientific research center
of endocrinology (Tashkent, Uzbekistan), E-mail: [email protected] Uzbekov Kamil Kashafovich, Candidate of medical sciences, senior research associate at the Department of endocrine surgery of the Republic specialized scientific research center
of endocrinology (Tashkent, Uzbekistan), E-mail: [email protected]. Omilzhonov Murodzhon Nusratdzhonovich, Junior research associate at the Department of endocrine surgery of the Republic specialized scientific research center of endocrinology (Tashkent, Uzbekistan),
E-mail: [email protected] Elov Azizkul Alikulovich,
Junior research associate at the Department of endocrine surgery of the Republic specialized scientific research center of endocrinology (Tashkent, Uzbekistan),
E-mail: [email protected]
Correlation of thyroidectomy difficulty scale with the time of an operation and its complications
Abstract: The aim of the research was to evaluate the use of thyroidectomy difficulty scale (TDS) for its concordance, correspondence with operative time and correlation with complications. TDS can serve as a tool of forecast of operation difficulty. Keywords: thyroid gland, thyroidectomy, difficulty of an operation.
Introduction
Last century, thyroidectomywas associated with high mortality and frequent development of post-operative complications. Many medical specialists ofthat time started considering thyroid gland surgery as murderous, which led to the ban on its conduct because ofhigh mortality.
With the improvement of notions of physiology and anatomy of thyroid gland, thyroid surgery has become much safer. Theodor Kocher
reduced mortality below 1% and received a Noble prize in 1909 for the promotion of thyroid surgery. Today, thyroidectomy is associated with almost zero mortality and extremely low incidence of disease, when it is performed by experienced surgeons [1]. Nevertheless, the complications of thyroidectomy can affect the quality of life. They include the damages ofrecurrent laryngeal nerve causing hoarseness and dysphagia, damages of parathyroid glands as a result of which, hypocalcemia and
