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UDC 616.441-002:616.36-002.2
AUTOIMMUNE THYROIDITIS IN PATIENTS WITH CHRONIC HEPATITIS C
1 Altai State Medical University, Barnaul
2 City Hospital No.3, Barnaul
3 I.M. Sechenov First Moscow State Medical University, Moscow
M.A. Nikonorova1, N.S. Lubskaya2, E.V. Volchkova3, O.I. Matros1
Chronic viral hepatitis - is one of the most pressing health problems. In the meantime, autoimmune thyroiditis (AIT) is one of the most common diseases in endocrine practice. According to different researchers, in patients with HCV, antithyroid antibodies detection frequency ranges from 2,5 to 42,3%. The purpose of this study is a comparative evaluation of thyroid functional status in patients with chronic viral hepatitis C in combination with autoimmune thyroiditis. There was held a prospective, dynamic, clinical, laboratory and instrumental examination of 76 patients in three clinical groups: group I with autoimmune thyroiditis, group II with autoimmune thyroiditis in combination with chronic viral hepatitis C, group III with chronic viral hepatitis C. There was defined the structure of thyroid gland pathologies, evaluated the clinical course of autoimmune tyreopathies on the background of hepatitis C, investigated the performance of the functional condition of the thyroid system in this group of patients. It was found that hepatitis C virus affects thyroid status system that proves the role of HCV as a causative factor in the development of autoimmune thyroiditis. Key words: chronic viral hepatitis, thyroid gland, autoimmune thyroiditis.
Chronic viral hepatitis (CVH) is one of the most pressing health problems. The prevalence of chronic hepatitis C (CHC) ranks third among all infectious diseases [1, 2]. In the pathogenesis of organ damage during HCV infection, the direct cytopathic effect of the virus and the immunological reactions caused by it leading to liver damage are discussed, as well as viral replication outside the liver - in tissues of lymphoid and non-lymphoid origin [3, 4, 5, 6, 7, 8]. Viral hepatitis is not limited to liver damage and is a systemic disease that occurs with the regular development of extrahepatic manifestations [5, 6, 9, 10, 11]. Extrahepatic lesions can occur both clinically latently and in the form of expressed clinical syndromes or independent diseases characterized by a high frequency and originality of their spectrum. Despite the contradictory data in the literature concerning the relationship between HCV infection and autoimmune thyroiditis, the prevailing view is that HCV may play the role of one of the etiological factors of this disease, and that by chronic hepatitis C, its latent forms are often manifested under the influence of IFN-a. The incidence of symptoms of autoimmune thyroiditis (AIT) varies in different studies from 2.5% to 42% [5]. Chronic viral liver diseases often lead to the development of thyroid dysfunction (thyroid gland), in particular, an increase in the level of thyroxin-binding globulin (TBG) and thyroxin (T4) serum; a decrease in the level of triiodothyronine (T3) due to a decrease in its secretion, deiodination and assimilation by the T4 hepatocytes; increase in the level of reverse T3. The level of thyroxin can also decrease due to defective production of TBG or by reducing T4 binding at the periphery [12].
Thyroid dysfunction in patients with chronic hepatitis C is manifested in most cases of hypothy-
roidism and occurs in 3.5-7% of cases, according to a number of authors [13]. A much larger part of the surveyed (31-42.5%) revealed diagnostic significant levels of anti-thyroid antibodies (anti-mic-rosomal, anti-peroxidase, antibodies to thyroglobu-lin) [14, 15]. The mechanisms for the development of the above complications in hepatitis C are not clear enough. There are various assumptions. According to some data, the hepatitis C virus directly affects such organs as the salivary glands, pancreas and thyroid gland [16], and according to other sources, the virus triggers autoimmune processes of tissue and organ damage [17]. The hepatitis C virus, localized in thyroid tissue, is likely to directly cause its damage [18, 19, 20]. On the other hand, it is possible that autoimmune reactions are caused by such a peculiarity of the virus as the ability to mimicry some components of thyroid tissue [19, 21]. In general, all authors indicate the presence of elevated titers of antithyroid antibodies, including antibodies to thyroglobulin, peroxidase, thyrotropin receptors and antimicrosomal antibodies [22, 23, 24]. A single prognostic parameter of the thyroid gland is not developed. This question requires further study, since this criterion is very important.
The research objective is to compare the functional state of the thyroid gland in patients with chronic viral hepatitis C in combination with and without autoimmune thyroiditis.
Materials and methods
The study included 76 patients divided into three clinical groups: group I with autoimmune thyroiditis (21), of which 9 men and 12 women, the average age was 49.0 ± 6.0 years; group II - 28 people (12 men and 16 women) with AIT in combi-
nation with CHC, average age - 36.70 ± 2.35 years; group III - 27 patients (12 men and 15 women) with chronic hepatitis C, average age - 37.10 ± 7.91 years.
All patients underwent a thorough medical examination (collection of complaints, anamnesis, physical examination, standard laboratory research methods). All patients were tested to determine the level of serum hormones - TSH, T3, T4, as well as antibodies to thyroperoxidase (AtTPO) and liver and thyroid gland ultrasound. All patients were examined by an endocrinologist. The level of hormones was determined on an automated bio-immunoassay analyzer "Bio-Rad", model 680 Reader (USA) using Alkibio Tiroid IFA reagent kits. Diagnosis of CHC was confirmed: by PCR with determination of HCV RNA (quantitative, genotype), ELISA (presence of antibodies to core, NS 3-5), blood biochemical parameters, fibrosis level according to Metavir scale (elastography and/or puncture biopsy of the liver.
Before the disease of viral hepatitis, thyroid pathology in patients had not been registered. Patients did not receive specific therapy for viral hepatitis. Statistical processing of research results was performed using parametric methods on a PC using Microsoft Excel, Statistica 6.0 for Windows. The data are presented as arithmetic means and errors of the mean (M ± m). To assess the significance of differences of compared means (relative values) there was used the Student's criterion (p <0.05).
In patients of group I, levels of T3 (2.29 ± 1.30 nmol/l), T4 (112.7 ± 6.60 nmol/l), TSH (l.98 ± 1.04 mU/l) were within normal values, and the level of AtTPO (13.82 ± 2.76 IU/ml) slightly exceeded the reference values (Table 2). In patients of group II, T3 levels (2.28 ± 1.57 nmol/l), T4 (110.67 ± 3.09 nmol/l) and TSH (1.84 ± 1.43 mU/l) were also within normal values. Elevated values of AtTPO were detected in 18 (64.2%) patients of group II and averaged 16.03 ± 1.66 mU/ml, which was significantly (p = 0.006) higher than the values of patients of group I. Studies have shown an increase
Results and discussion
Clinical symptoms in patients of group I (AIT) were manifested as asthenovegetative - 38.0% (weakness, decreased performance), dyspeptic - 14.2% (nausea, heartburn, bitter mouth, decreased appetite), cardiac - 24.0% (rapid heartbeat), dermatological - 19.0% (dry skin, excessive sweating) and hyperthermic - 4.7% of syndromes. In patients of group II (AIT with chronic hepatitis C), in addition to asthenovegetative (53.5%), dyspeptic (28.5%), dermatological (10.7%) syndromes, the arthralgic syndrome occurred (7.1%). Patients of group III (CHC) showed the presence of the as-thenovegetative (48.1%) syndrome, in combination with dyspeptic (33.3%) and arthralgic (14.8%) syndromes, and in 3.7% of patients, subfebrile body temperature was registered.
According to biochemical blood tests, patients showed moderate signs of cytolytic and dyspro-teinemic syndromes. In particular, an increase in the activity of AlAT by two times (129.16 ± 58.48 U/l) and AsAT by two time (97.6 ± 40.16 U/l), a relative decrease in albumin in 42.8% of patients and an increase of y-globulin in 46.4% (34.2 ± 4.2 g/l). An increase in the activity of AlAT and AsAT was observed in 98.3% of patients, GGT - in 53.3%, ALP - in 15.0%, thymol sample - in 9.1%. In patients of group I, no changes in the biochemical analysis of blood were detected (Table 1).
in the level of AtTPO in 17 (62.9%) patients of group III, on average it was 15.90 ± 2.43 IU/ml (p = 0.03), which is also significantly higher than in patients of group I. AtTPO increase in patients with mixed pathology with normal T3 values (2.34 ± 1.51 nmo-l/l), T4 (100.66 ± 4.91 nmol/l) and TSH (2.31 ± 1.84 mU/l), is possibly determined by an autoimmune process in the thyroid gland, the etiological factor of which may be HCV infection.
In 7 (33.3%) patients of group I, there was a slight increase in TSH and a decrease in T3 total. In group II, 11 (39.2%) patients had an increase
Results of biochemical analysis of blood in the study groups Table 1
Parameter (MU) group I n=21 group II n=28 group III n=27 Norm
Total bilirubin (^mol/l) 15,05±3,18 18,54±4,35 16,11±4,28 8,55-20,52
Direct bilirubin (^mol/l) 4,2±1,26 4,97±1,64 4,21±1,29 1-5,1
Indirect bilirubin (^mol/l) 11,24±2,46 11,47±3,66 12,94±2,43 15,4
ALAT (Un/l) 30,12±5,18 129,16±58,48 102,4±16,1 0-40
ASAT (Un/l) 30,5±4,12 97,6±40,16 81,8±41,04 0-40
GTP (Un/l) 40,10±5,12 63,29±15,06 59,5±25,9 11-63
ALP (Un/l) 130,11±26,17 191,37±64,22 152±48,12 0-350
PTI (%) 96,78±5,12 96,8±5,14 96,24±5,30 80-100
Albumin (g/l) 38,09±6,13 30,75±0,5 38,07±7,33 30-55
Globulins (g/l) 24,14±6,14 35,78±6,23 31,2±2,21 17-35
in TSH, a decrease in T3 total, in 5 patients - T4 free and for 8 (29.6%) patients with chronic hepatitis C, increased TSH, a decrease of T3 total and in 2 patients - T „„„•
According to the results of the study, it is seen that in patients of group II, a significant decrease in the level of triiodothyronine is observed (Table 3).
Table 2
Thyroid hormone and AtTPO levels
Parameter (MU) group I group II group III Norm
n=21 n=28 n=27
TSH ( |jU/ml) 1,98±1,04 1,84±1,43 2,31±1,84 0,2-3,2
T3 total (nmol/l) 2,29±1,30 2,28±1,57 2,34±1,51 1,1-3,0
T4 total (nmol/l) 112,69±6,60 110,67±3,09 100,66±4,91 53-158
T4 free (nmol/l) 14,07±5,39 15,68±5,93 14,27±5,66 10-25
AtTPO (U/ml) 13,82±2,76 16,03±1,66 p=0,006** 15,90±2,43 p=0,03** 4o 15
Note: *p<0,05; **p<0,02
Thyroid hormone levels by autoimmune thyroiditis (AIT) in Table 3 combination with chronic viral hepatitis C
Parameter (MU) AIT n=7 AIT and CHC n=11 CHC n=8 Norm
TSH (|jMU / ml) 3,91±0,46 5,00±1,26*** 4,45±0,44*** 0,2-3,2
T3 total (nmol/l) 1,09±1,01 0,93±0,04* 0,96±0,50 1,1-3,0
T4 total (nmol/l) 105,22±7,75 117,38±9,72 110,07±4,71 53-158
T4 free (nmol/l) 14,06±0,23 9,04±0,43* 10,25±0,76 10-25
Note: *p<0,05; **p<0,02; ***p<0,01
The functional activity of the thyroid gland mainly depends on the level of thyroid-stimulating (TSH) hormone of the pituitary gland in the blood. Secretion of TSH is regulated by the principle of "long chain" feedback and is determined primarily by the level of thyroid hormones. Triiodothyronine (T3) is the main regulator of TSH secretion at the pituitary level. When examining the values of thyroid-stimulating hormone, the parameters in patients of groups II and III were most elevated and were significantly higher (p <0.01) than in group I patients, which indicates the activation of the thyroid-stimulating function of the pituitary against the background of CHC. Disruption of hepatotropic function by hepatitis led in parallel to a decrease in thyroid function (T3 tot, T4 free).
Thyroxin (T4) is the main hormone, a kind of source or prohormone of triiodothyronine secreted by the thyroid gland, its significant decrease was noted only in the second group of patients (p <0.05). The level of T3 is also reduced in patients of group II (p <0.05).
Thus, in patients with chronic hepatitis C, which occurs on the background of AIT, hypofunc-tion of the thyroid gland and an increase in the level of thyroid stimulating hormone were revealed, which indicates the activation of the thyrotropic function of the pituitary gland. The concomitant reduction in thyroid hormone levels allows the diagnosis of subclinical hypothyroidism in the stud-
ied group of patients. By subclinical hypothyroidism, the presence of AtTPO may affect the decision to initiate replacement therapy, since the carrier status of AtTPO is a risk factor for the progression of subclinical hypothyroidism to obvious.
According to the results of thyroid ultrasound in all patients of group I, heterogeneous echogenicity was revealed, of which 16 (76.1%) patients had foci of fibrosis, 5 (23.8%) had foci of fibro-sis and nodal inclusions. In patients of group II, on the background of inhomogeneous echogenicity, 12 (42.8%) had foci of fibrosis, 11 (39.2%) had foci of fibrosis and nodal inclusions. In group III, diffusely heterogeneous changes were observed in 9 (33.3%), nodal inclusions, cysts in 8 (29.6%) patients.
Conclusions
1. A significant increase in AtTPO level in patients with AIT in combination with CHC may be determined by the presence of an autoimmune inflammatory process in the thyroid gland, occurring against the background of moderate hepatitis activity, the etiological factor of which is HCV infection.
2. The combined course of CHC aggravates the course of AIT.
3. Autoimmune thyroiditis on the background of viral hepatitis significantly more often occurs with subclinical hypothyroidism.
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Contacts
Corresponding author: Nikonorova Marina Ana-
tolyevna, Doctor of Medical Sciences, Professor
of the Department of Infectious Diseases and Phthi-
siology of ASMU, Barnaul.
656038, Barnaul, Lenina Prospekt, 40.
Tel.: (3852) 268342.
E-mail: ma.nikulina@mail.ru
Author information
Lubskaya Nina Sergeyevna, Infectious Disease Physician of the City Polyclinic №3, Barnaul. 656031, Barnaul, ul. Molodezhnaya, 35. Tel.: (3852) 624579. E-mail: gp3@barnaul.zdravalt.ru
Volchkova Elena Vasilyevna, Doctor of Medical Sciences, Professor, Head of the Department of Infectious Diseases of the I.M. Sechenov First Moscow State Medical University, Moscow. 119435, Moscow, ul. Bolshaya Pirogovskaya, 2 - 4. Tel.: (499) 2480553. E-mail: rektorat@mma.ru
Matros Olga Ivanovna, Candidate of Medical Sciences, Associate Professor of the Department of Infectious Diseases and Phthisiology of ASMU, Barnaul.
656038, Barnaul, Lenina Prospekt, 40.
Tel.: (3852) 268342.
E-mail: olga-matros@yandex.ru
