THYROID FUNCTION AND SERUM PROLACTIN LEVELS IN JUVENILES WITH SYSTEMIC LUPUS ERYTHEMATOSUS
Marcos V. Ronchezel, Claudio A. Len, Angela Spinola-Castro, Silvana Sacchetti, Valéria M. Lourenzi, Sergio Ajzen, Sérgio Tufik and Maria Odete E. Hilário - Division of Allergy, Clinical Immunolgy and Rheumatology, Department of Pediatrics, Sao Paulo Federal University - Escola Paulista de Medicina, São Paulo, Brazil
Marcos V. Ronchezel, M.D.: Pediatric Rheumatologist, Division of Allergy, Clinical Immunolgy and Rheumatology, Department of Pediatrics, Sao Paulo Federal University - Escola Paulista de Medicina, and Professor, Pediatric Rheumatoloy Unit, Department of Pediatrics, Santa Casa de São Paulo, São Paulo, Brazil.
Claudio A. Len, M.D.: Pediatric Rheumatologist, Division of Allergy, Clinical Immunolgy and Rheumatology, Department of Pediatrics, Sao Paulo Federal University - Escola Paulista de Medicina.
Angela Spinola-Castro, M.D.: Professor of Pediatrics and Head, Endocrinology Unit, Department of Pediatrics, Sao Paulo Federal University - Escola Paulista de Medicina.
Silvana Sacchetti, M.D.: Professor, Pediatric Rheumatoloy Unit, Department of Pediatrics, Santa Casa de São Paulo, São Paulo, Brazil.
Valéria M. Lourenzi, M.D.: Depatment of Psychobiology, Department of Medicine, Sao Paulo Federal University - Escola Paulista de Medicina.
Sergio Ajzen, M.D.: Professor, Department of Diagnostic Imaging, Sao Paulo Federal University - Escola Paulista de Medicina.
Sergio Tufik, M.D.: Professor and Head, Department of Psychobiology, Department of Medicine, Sao Paulo Federal University - Escola Paulista de Medicina.
Maria Odete E. Hilário, M.D.: Professor of Pediatrics and Head, Division of Allergy, Clinical Immunolgy and Rheumatology, Department of Pediatrics, São Paulo Federal University - Escola Paulista de Medicina.
Correspondence address:
Maria Odete E. Hilário, M.D.
Alameda dos Anapurús, 1370 Ap. 144
CEP 04087-004 São Paulo, SP, Brazil
Tel.: (5511) 576 4426 Fax.: (5511) 570 1590
Running head: Thyroid Function and Prolactinemia in Juvenile Systemic Lupus Erythematosus
ABSTRACT; INTRODUCTION; PATIENTS AND METHODS; RESULTS; DISCUSSION; REFERENCES
Objective. To evaluate both thyroid function and serum prolactin levels in patients with juvenile systemic lupus erythematosus (JSLE) and to detect possible correlation with disease activity.
Methods. Forty two JSLE patients (3 - 15 years old at disease onset), twenty-two were pubertal. All patients were evaluated according their clinical manifestations and disease activity. We determined serum prolactin, thyroid-stimulating hormone (TSH), T4, free T4, T3, thyroid peroxidasis and thyreoglobulin antibodies in all patients and controls. Thyroid ultrasonography was performed in the patients.
Results. We did not observe difference in thyroid hormone and prolactin levels between patients and controls. One JSLE patient presented hyperthyroidism and six presented thyroid antibodies. We observed ultrasonography abnormalities in four patients (9.3%), specially heterogeneity of the gland echotexture. We did not find correlation between prolactin levels, clinical manifestations and disease activity.
Conclusions. Evaluation of thyroid function should not be a routine among JSLE patients. Thyroid hormones and prolactin should be measured only in patients with clinical manifestations of hypo or hyperthyroidism.
Keywords. Juvenile systemic lupus erythematosus, thyroid function, prolactin.
Reports in the literature show evidence of a relation between thyroid alterations and diffuse diseases of connective tissue, such as rheumatoid arthritis (RA) (1), Sjögren’s syndrome (2) and progressive systemic sclerosis (3).
The association between thyroid autoimmune disease and SLE has been suggested by some authors (4-6) although there are disagreements as to the predominance of hypo or hyperthyroidism (7,8). A higher frequency of thyroglobulin and thyroid peroxidasis antibodies, as well as a correlation between TSH and the presence of these antibodies have been observed in some patients with lupus (9). Biochemical abnormalities of the thyroid function in SLE patients without clinical evident endocrine disease have also been described (9).
Although the studies including children and adolescents with juvenile systemic lupus erithematosus (JSLE) are uncommom, their results also point to a greater frequency of thyroid antibodies and abnormalities in thyroid function (10,11).
Prolactin (PRL) is a simple chain polypeptidic hormone, comprising 199 aminoacids, similar to growth hormone and placentary lactogen (12). Fertile age women have higher levels than men and children (13). During the infancy the levels remain low, increasing in girls during puberty. Significant rise in PRL synthesis may occur in physiological situations such as pregnancy (increase of 10 to 30 times), lactation and the lutean phase of the menstrual cycle, probably as a result of increases in estrogenic levels (13). Normal PRL concentrations in adults may vary from 5 to 20ng/ml (13).
The most common cause of abnormal PRL secretion is the hypophysaric tumour (13). Alterations in thyroid function and the use of certain medications such as methoclopramide, anti-histamines, chlorpromazine, reserpine, alphametildope and diphenilhydantoin (14) should also be taken in account as possible causes of hyperprolactinemia.
A relationship between hyperprolactinemia and the positive antinuclear antibodies (ANA) in girls with JRA, and levels of interleukin 6 and ANA in children with chronic juvenile arthritis have been described in different studies (15,16). As for JSLE, a correlation was observed between hyperprolactinemia and central nervous system involvement as well as with the disease activity (17).
A possible association between hyperprolactinemia and clinical activity of collagen diseases such as SLE (14, 18, 19) and juvenile rheumatoid arthritis (JRA) (15) has been reported in different studies.
The aim of our study was to evaluate both thyroid function and serum prolactin levels in patients with JSLE and possible associations with the disease activity.
Patients
Forty two consecutive female patients were evaluated, with age at disease onset of less than 18 years old, which fulfilled the American College of Rheumatology (1982) classification criteria for SLE (20). The mean age at disease onset was 9.5 years (3-15 years) and the mean duration of the disease 4.2 years (1 month - 13 years). Twenty one patients were pre-pubertal (Tanner stages l ) and 21 pubertal (Tanner stages II, lll and lV) (21). The patients were evaluated by the main clinical manifestation and the disease activity was evaluated by the Systemic Lupus Erythematosus Disease Activity Index - SLEDAI (22), according the following score: 1) without activity, SLEDAI= 0 (18 patients); 2) mild activity , SLEDAI = 1 to 9 (16 patients), and 3) moderate/intense activity, SLEDAI ³ 10 (8 patients).
Twenty three children and adolescents, matched for gender and age, comprised the control group, 11 pre-pubertal and 12 pubertal.
The consent from parents or those responsible was obtained for each child or adolescent to participate in the study. The research was approved by the local Ethical Medical Commission.
METHODS
Hormonal Measurement
Blood samples were collected from all patients and controls between 8 and 10 am . The serum was separated and frozen at -20° C until hormonal measurement. The serum PRL, thyroid-stimulating hormone (TSH), T4, free T4 and T3 determinations were carried out by the immunoenzymometric method (Tosoh Medics Inc., Foster City, CA, USA) and the measurement of thyroid antibody (thyroid peroxidasis and thyreoglobulin) by hemaglutination. The normality range for each hormone in our laboratory was : PRL = 2.1 to 47.6 ng/mL; TSH = 0.5 to 6.0 m Ul/mL; T4 = 4.0 to 11.0 m g/dL; free T4 = 0.75 to 1.54 ng/dL and T3 = 70 to 170 ng/dL.
Thyroid Ultrasonography
A thyroid ultrasonography was performed in all patients, always by the same radiologist to observe the presence of goiter or other thyroid alterations.
STATISTICS
Mann Whitney test was used for the comparison of laboratory findings between patients and controls. Kruskal Wallis test was used to analyse the prolactin levels and the SLEDAI score. Fisher exact test evaluated the relationship between PRL and thyroid antibodies. In all tests the nullity rejection hypothesis was fixed at 0.05 or 5%, significant values being marked with an asterisk.
We did not observe significant difference in thyroid hormone levels between patients and controls. However, we detected alterations in one 13 years old female patient. The thyroid ultrasonography showed an increase in the dimensions of the gland and a diffuse heterogeneous echotexture. The patient also presented positive thyroglobulin and thyroid peroxidasis antibodies, low TSH levels (0.1 m UI/mL) and high T3 and T4 levels (200 ng/dL and 15 ng/dL, respectively). The antiphospholipid antibodies were negative. The treatment was initiated with prednisone, propiltiuracil, propanolol and heparinization, with a good response.
Thyroid antibodies were found in 6 patients (14%) with JSLE and in 1 control (4.4%). The antibody for thyroid peroxidasis was detected in the 6 patients, with titers ranging from 1/400 to 1/25600 whereas the thyroglobulin antibody was present in 5 cases, with titers ranging from 1/400 to 1/102000. One of the patients (the 13 years old girl above mentioned) with positive antibodies presented alterations in thyroid hormone levels (T3 = 200 ng/dL, T4 = 15 ng/dL) and in TSH level (0.1 m UI/mL). The control that presented positive thyroid antibodies was euthyroid. The comparison of the antibody frequency among the patients and the controls did not show a statistically significant difference.
The thyroid ultrasonography showed abnormalities in 4 patients (9.3%). In 3 of them the gland echotexture was diffusely heterogenous, suggestive of thyroiditis (confirmed by the positivity of the anthyroid antibodies). The fourth patient who presented a diffuse increase of the thyroid without antithyroid antibodies, was submitted to an aspirative punction and a coloid goiter was diagnosed.
The serum PRL levels in our study ranged from 3.0 to 81.1 ng/mL . The mean of the patients and controls with late pubertal stages were 16.8 ng/mL and 13 ng/mL respectively, and for the patients and controls with early pubertal stages 11.8 ng/mL and 9.4 ng/mL, respectively. We did not observe statistical differences between patients and controls.
A 16 year old patient presented a persistently high PRL level without apparent cause. She presented transitory amenorrhea 2 years before without galactorrhea. The first PRL measurement, 1 year after the SLE diagnosis was of 81.1 ng/mL with a SLEDAI score = 6. After 8 months a new PRL measurement showed values higher than 200 ng/mL (SLEDAI = 8). This patient was submitted to a magnetic resonance which showed microadenoma of the hypophysis. Treatment with bromocriptine was started and there was a good response, with normalization of the PRL levels, without interfering in the SLE activity.
The comparison among the PRL levels for the 3 classified groups according to the SLEDAI score showed no statistically significant difference among them.
The mean PRL levels of the patients who presented thyroid antibodies (n=6) was of 13.4 ng/mL, which did not differ statistically from those patients without these antibodies (mean = 14.5 ng/mL). The only patient with hyperprolactinemia had positive thyroid antibodies.
The incidence of thyroid alterations in patients with SLE range from 7.5 to 8.9% (7,8,10). In children with SLE the prevalence of Hashimoto’s thyroiditis is 1.2% (10). Two studies showed thyroid abnormalities in patients with JSLE. Eberhard et al. (10) evaluated the thyroid hormones and antibodies of 35 children and adolescents with JSLE, mean age of 15. Six patients (17.1%) developed biochemical evidence of thyroid abnormality, 4 with hyperthyroidism, requiring treatment with hormone replacement with good results. The other 2 presented high T4 levels and normal TSH. Feitosa et al. (11) evaluated 22 patients with JSLE and did not find alterations in T3 and T4 levels, but the TSH level was high in 3/16 patients (18%). We observed alteration in thyroid function in one of our JSLE patients (2.5%); although this is a lower frequency than that found in the two previous studies it is compatible with the rate of ocurrence of thyroid function alterations in adults with SLE (7,8).
The frequency of positive thyroid antibodies in our study was of 14%, higher than that found in the controls (4.4%). Our patient with abnormal thyroid function presented these antibodies and ultrasonographic alterations, both suggestive of auto-immune thyroiditis. Our findings are similar to those observed in studies with adults with SLE concerning the frequency of the positivity of thyroid antibodies (8,9,23). The only study with pediatric patients is that of Eberhard et al. (10) who evaluated 35 patients through hemaglutination and found a 34% positivity for thyroid antibodies. The overall prevalence of autoimmune hypothyroidism in the general population is around 0.4% (24).
Kausman and Isenberg (23) studied SLE patients and observed fluctuation in the thyroid serology in some individuals who presented thyroid antibodies at least in one occasion. The authors also observed that these patients were more likely to develop either clinical or subclinical thyroid disease (23).
Thus, our results suggest that there is not a greater frequency of hyperprolactinemia in patients with JSLE. Furthermore, our evaluation did not show any significant correlation between the PRL levels and disease activity (SLEDAI), as observed in studies of PRL levels in adult patients with SLE (25-29).
One of our patients presented persistently high levels of PRL, with no apparent cause such as thyroid dysfunction or drug abuse, which led us to further investigations and to the diagnosis of hypophysary microadenoma with secondary hyperprolactinemia. Treatment with bromocriptine was started, with normalization of PRL levels, menstrual cycle and headche, without clinical changes in the SLE activity. McMurray at al (28) described 3 patients in whom hyperprolactinemia was associated with the onset of SLE, suggesting a possible relationship between these two pathological processes. Our patient already presented JSLE for one year before the detection of the secondary hyperprolactinemia. McMurray et al. (28) described a fourth patient who presented increased PRL levels after SLE diagnosis and bromocriptine treatment was initiated, with an improvement in the lupus activity.
The hyperprolactinemic states are associated with a high incidence of autoimmune diseases such as thyroiditis and thyroid antibodies, which could be the consequence of non-specific stimulation of the B lymphocyte by PRL (30,31). We did not observe this correlation in our study.
We conclude that the evaluation of thyroid function (hormonal levels and thyroid antibodies) should not be carried out routinely in patients with JSLE. Thyroid hormones should be measured only in patients with clinical manifestations of hypo or hyperthyroidism
We did not observe higher serum PRL levels in JSLE patients nor any correlation with clinical activity of the disease. As well as thyroid hormons, PRL measurement should become a part of the investigation only in selected patients.