Thyroid Dysfunction and Thyroid Autoimmunity in EgyptianPediatric Vitiligo Patients

Abstract

Objectives: Thyroiditis with hypothyroidism seems to be the most common associated disease in vitiligo patients. Few data have been reported about the incidence of thyroiditis in paediatric patients with vitiligo.

Aim of the work: This study aimed to assess the prevalence of thyroid dysfunction and thyroid autoimmunity in Egyptian pediatric vitiligo patients.

Methods: This study was conducted on 36 pediatric vitiligo patients (22 females and 14 males). 20 healthy age and sex matched children were included as a control group. They were recruited from the outpatient clinic of Dermatology and Venereology, Benha Teaching Hospital. Patients underwent thorough history taking, complete physical, endocrinological and dermatological examinations. Patients were grouped into segmental and non segmental according to the distribution of vitiligo lesions. Assessment of serum levels of free tri-iodothyronine (FT₃), Free thyroxine (FT₄), thyroid stimulating hormone (TSH), thyroid peroxidase antibodies (TPO Ab) and thyroglobuline antibodies (Tg Ab). The principle of the assay was competitive enzyme immunoassay.

Results: Vitiligo patients had significantly higher serum levels of TPO Ab and TSH and significantly lower T₃ and T₄ serum levels compared with controls. TSH serum levels were significantly higher in female vitiligo patients compared with male vitiligo patients. All studied parameters showed insignificant differences in segmental and non segmental vitiligo patients.

Conclusion: Pediatric vitiligo was more prevalent in females. The non-segmental type was the most prevalent type among our patients. Our patients were hypothyroid which was more evident in female patients. The proof of autoimmunity was more evident in male patients. No significant differences of all studied parameters were present between segmental and non segmental vitiligo.

Recommendation: It will be useful to screen thyroid autoantibodies and thyroid parameters in all pediatric patients with vitiligo.

Introduction

Vitiligo is an acquired depigmentary disorder affecting around 1% of the world's population. It is characterized by selective destruction of melanocytes of basal layer of the epidermis and / or occasionally hair follicles⁽¹⁾.

Various theories have been proposed for the aetiology of vitiligo, including genetic, neural and autoimmune theories⁽²⁾. It is frequently associated with various organ specific autoimmune diseases, e.g. Hashimoto's thyroiditis(the most common association in children⁽¹⁾).

Addison's disease, diabetes mellitus type 1, and pernicious anemia⁽²⁾.

Thyroid functional disorders and autoimmune thyroid diseases have been reported in association with vitiligo and it seems that the incidence of clinical and subclinical thyroid involvement is more common in vitiligo patients than healthy subjects⁽³⁾. Vitiligo frequently precedes the thyroid involvement, thus screening vitiligo patients for thyroid functions and thyroid antibody seems plausible⁽⁴⁾. 

Aim of the work

Our aim was to assess the prevalence of thyroid dysfunction and thyroid autoimmunity in pediatric vitiligo patients in order to establish whether a routine screening of these patients was of importance.

Material & Methods

This study was conducted on 36 pediatric vitiligo patients (group A) [22 females (group B) and 14 males (group C)]. 20 healthy age and sex matched children were included as a control group (group D). They were recruited from the outpatient clinic of Dermatology and Venereology, Benha Teaching Hospital. A written informed concent was taken from parents of each child.

Exclusion criteria for patients and controls:

·      Individuals on immunosuppressants, anticonvulsants, salicylates, iodides and isoniazide.

·      Patients having diabetes mellitus, pernicious / haemolytic anemia, Addison's disease, collagenoses, kidney, liver, heart conditions, malnutrition or other skin conditions.

·      Patients with known thyroid disease, history of thyroid surgery and those receiving thyroid medications.

All patients underwent:

1.   Thorough history taking.

2.   Complete physical and dermatological examinations. Vitiligo was defined clinically using wood's light. Patients were grouped into segmental (G) and non segmental (H) vitiligo on the basis of the distribution pattern of lesions.

3.   Examination of thyroid gland by endocrinologist, including gland palpation, heart rate, blood pressure and observation of fine tremors.

4.   5 ml venous blood samples were collected from patients and controls in the morning (eight – hour fasting). Sera were separated and stored at - 70°C till the time of the analysis.

5.   Analysis included assessement of serum levels of free tri-iodothyronine (FT₃), free thyroxine (FT₄), thyroid stimulating hormone (TSH), thyroid peroxidase antibodies (TPO Ab) and thyroglobulin antibodies (Tg Ab) by quantitative evaluation.

Free T₃ and free T₄were measured in the collected samples by the use of Dima kits provided by Dima Gesellschaft fur Diagnostika. The Principle of the assay was competitive enzyme immunoassay⁽⁵⁾. It was a solid phase enzyme immunoassay in which mixing immobilized antibody, enzyme – antigen conjugate and a serum containing the native free antigen results in a competition reaction between the native free antigen and the enzyme – antigen conjugate for a limited number of binding sites. Then the antibody – bound fraction was separated from unbound antigen by aspiration. The enzyme activity in the antibody – bound fraction was inversely proportional to the native free antigen concentration which was measured from the curve done by the use of different serum references.

Thyroid Stimulating Hormone (TSH) was measured by the use of DRG kit provided by DRG International, Inc., USA the principle of the assay depends on ELISA Technique using an immobilized antigen, circulating antibody and enzyme – linked specific antibody⁽⁶⁾. In this procedure, the immobilization took place during the assay at the surface of the micro plate well through the interaction of 8 strap taviden coated on the well and exogenously added biotinylated antigen.

Thyroid peroxidase antibodies (TPO Ab) was measured by the use of Zeus Scientific Kit provided from Zeus Sentific, Inc., USA. The principle of the assay depended on (TPO) ELISA test system which was designed to detect IgG class antibodies to TPO in human serum wells of plastic microwell strips were sensitized by passive absorption with RPO antigen⁽⁷⁾.

Thyroglobulin antibodies (Tg Ab): The Quantitative Determination of Thyroglobulin (Tg) autoantibodies in human serum or plasma by microphlate Enzyme immunoassay⁽⁸⁾ by using Kits from MONBIND, INC. (USA). 

Results

This study was conducted on 36 pediatric vitiligo patients [22(61%) females and 14(39%) males]. Their ages ranged from 1.25 to 11 years. Duration of the disease ranged from 2 to 102 months. 20 healthy age and sex matched volunteers [12(60%) females and 8(40%) males] were included as a control group. Patients were divided according to clinical presentation of vitiligo into segmental and non segmental types. Thyroid peroxidase antibodies were within normal reference range (up to 25 Iu/ml) (Table 1).

Vitiligo patients had significantly lower serum levels of free T₃ and free T₄ and significantly higher serum levels of TSH and TPO Ab compared with controls. Tg Ab showed insignificant difference. TSH serum levels were significantly higher in female vitiligo patients compared with male patients, otherwise all parameters showed insignificant difference. Free T₃ and free T₄ serum levels were significantly lower in male and female patients compared with their corresponding controls. TSH serum levels were significantly higher in female patients compared with female controls. TPO Ab serum levels were significantly higher in male patients versus male controls (Table 2).

All studied parameters showed insignificant difference in segmental vitiligo patients compared with non segmental group. Serum levels of free T₃ and free T₄ were significantly lower in segmental and non segmental vitiligo patients compared with controls. TSH serum levels were significantly higher in segmental vitiligo patients compared with controls (Table 3).

Vitiligo patients with low free T₄ serum levels showed significantly lower free T₃ serum levels and significantly higher TSH and TPO Ab serum levels versus controls (Table 3).

TSH showed positive significant correlation with TPO Ab in non-segmental vitiligo patients. TSH showed positive significant correlation with TgAb antibodies in total vitiligo patients and male vitiligo patients (Table 4).

Table 1.    Demographic and clinical data of pediatric vitiligo patients and controls.

Table 2.    Studied clinical and laboratory parameters in pediatric vitiligo patients and controls.

N = Number, NS = Non-significant, * = P < 0.05, ** = P < 0.01, *** = P < 0.001

Discussion

Vitiligo is a common pigmentary disorder⁽⁹⁾. Its aetiology is unknown, but several hypothesis have been proposed including autoimmunity⁽¹⁰⁾. 

Vitiligo in children represents an important entity since in 50% of patients the onset is before the age of 20⁽¹¹⁾ and in 25% before the age of 10⁽¹²⁾.

Thyroiditis with hypothyroidism seems to be the most common associated disease in vitiligo patients, with a prevalence among adults of 30%⁽¹⁰⁾, while the frequency in the general population is around 10%⁽¹³⁾. On the other hand, few data have been reported about the incidence of thyroiditis in pediatric patients with vitiligo⁽¹⁴⁾. The early diagnosis of thyroid dysfunction is particularly important in children to prevent any significant impact on their growth as thyroid hormones influence normal childhood development and play a crucial role as regulators of growth and puberty, of dental and skeletal development, of metabolism and organ functions⁽¹⁵⁾.

Our study was conducted on 36 pediatric vitiligo patients and 20 healthy age and sex matched volunteers served as control group.

Our study revealed that the disease was more prevalent in females constituting 61% of patients and that non segmental type comprising 56% of patients. Serum levels of thyroid peroxidase antibodies were within normal reference range with mean ± SD was 14.03 ± 3.9 Iu/ml but significantly higher compared with controls. 11% of patients showed high serum levels of thyroglobulin antibodies. But total patients showed insignificant difference of Tg Ab serum levels compared with controls. 89% of patients had decreased T₃ serum levels. Total patients showed significantly lower T₃ serum levels compared with controls. 67% of patients had decreased T₄ serum levels. Total patients showed significantly lower T₄ serum levels versus controls. We also revealed that TSH serum levels was significantly higher compared with controls, but within the normal range (11% had slightly increased TSH serum levels).

So our pediatric patients were hypothyroid with significantly higher serum levels of TPO Ab in spite of being within normal reference range. This could be due to low ages of our patients. Children normally have lower antibody than that of adults⁽¹⁶⁾. However thyroid antibodies does not always appear in the serum of patients with autoimmune thyroid diseases⁽¹⁷⁾. Follow-up of our patients with estimation of TPO Ab and Tg Ab may help for early detection of thyroid autoimmunity among our patients. Vitiligo usually appears before the development thyroid disease^(9,18). TPO Ab are sensitive tools for the detection of early subclinical autoimmune thyroid diseases⁽¹⁹⁾. Tg antibodies play a minor role in the pathogenesis of autoimmune thyroiditis⁽²⁰⁾.

Hashimoto’s thyroiditis is the most common autoimmune disease associated with vitiligo in children. Hashimoto's thyroiditis was found to be 2.5 times and hypothyroidism 10 times more frequent in Greek children and adolescents with known vitiligo than in healthy age and sex matched population. Hashimoto’s thyroiditis followed the onset of vitiligo. So it was proposed that children and adolescents with vitiligo should be screened annually for thyroid dysfunction particularly autoimmune thyroiditis⁽²¹⁾.

Fernandes and Campos⁽²²⁾ stated that the results of their study did not show a higher risk for thyroid disease and antithyroid antibodies. They concluded that no changes regarding vitiligo were observed even if a gland dysfunction was detected.

Imam et al.⁽²³⁾ stated that adolescence and early adulthood age groups with vitiligo had elevated anti-TPO compared to children.

Our study revealed that female vitiligo patients had significantly higher TSH serum levels versus male vitiligo patients (inspite of being within the normal range). Female vitiligo patients had significantly lower free T₃ and free T₄ serum levels and significantly higher TSH serum levels versus female controls. Male patients had significantly lower serum levels of free T₃ and free T₄ and significantly higher TPO Ab versus male controls (in spite of being within normal range). So the evidence of hypothyroidism was more powerful in female vitiligo patients and the proof of autoimmunity was more evident in male vitiligo patients.

We also found that TSH serum levels showed positive significant correlation with Tg antibodies in total patients and male patients. This was another evidence for the presence of autoimmunity among our vitiligo patients especially males.

Lacovelli et al.⁽⁹⁾recorded that alterations of thyroid parameters were more frequent in female patients than in males. This findings agreed with other studies that showed a higher frequency of autoimmune thyroiditis in female children with vitiligo than in males^{(14, 24-27)}. They revealed that all patients with autoimmune thyroiditis had anti –TPO. Several studies reported a strong correlation between TPO antibodies and thyroid dysfunction⁽²⁷⁾. 

Our study revealed that all studied parameters were insignificantly different in segmental and non segmental vitiligo patients. Both groups showed significantly lower serum levels of free T₃ and free T₄ serum levels compared with controls. But segmental vitiligo patients showed significantly higher TSH serum levels versus controls. So the proof of hypothyroidism was more evident in segmental vitiligo patients as the duration of the disease was significantly higher in segmental vitiligo patients versus non-segmental vitiligo patients.

Our study showed that TSH serum levels showed positive significant correlation with TPO antibodies in non segmental vitiligo patients. This proved the presence of hypothyroidism associated with autoimmune thyroid dysfunction in non segmental vitiligo patients.

Yang et al.⁽¹⁸⁾ found a significant incidence of thyroid dysfunction in pediatric patients with non segmental vitiligo. Pagovich et al.⁽³⁰⁾ revealed the presence of high percentage of active thyroid disease in children with non segmental vitiligo.

Lacovelli et al.⁽⁹⁾ concluded that in pediatric patients with non segmental vitiligo, a significant incidence of thyroid dysfunction was found. Their data showed that thyroid dysfunction seemed to correlate with the type of vitiligo, but not with its extension and localization.

Hann and Lee⁽²⁵⁾,found a very low incidence of autoimmune pathologies in a study included segmental vitiligo patients. Several preceding reports described an even lower association between segmental vitiligo and autoimmune thyroid disease^(14,26).

Several studies included adult non-segmental vitiligo patients revealed increased prevalence of thyroid dysfunction particularly hypothyroidism and thyroid antibodies compared to general population^(16,31,32). 

We also found that vitiligo patients with low free T₄ serum levels had significantly lower free T₃ serum levels and significantly higher TSH and TPO Ab serum levels compared with controls. This will give us a clue to the presence of hypothyroidism and the susceptibility to thyroid autoimmunity.

In conclusion: Our study revealed that pediatric vitiligo was more prevalent in females and non segmental vitiligo was the most prevalent type among our patients. Serum levels of TPO Ab was significantly higher in patients versus controls in spite of being within the normal reference range. Our patients were hypothyroid as TSH serum levels were significantly higher and each one of free T₃ and freeT₄ serum levels were significantly lower compared with controls. The evidence of hypothyroidism was more powerful in female vitiligo patients and the proof of autoimmunity was more evident in male vitiligo patients. All studied parameters showed insignificant difference in segmental and non-segmental vitiligo patients.

Recommendations

More thorough studies on a wide scale of patients are needed to get more details on the relation of thyroid disorders and autoimmunity in pediatric vitiligo patients. Follow up of our patients with periodical estimation of TPO Ab and Tg Ab may confirm the presence of thyroid autoimmunity among these patients. We recommend measurement of serum levels of TSH and TPO antibodies in all pediatric patients with vitiligo. Early diagnosis of thyroid dysfunction in pediatric population is important to prevent any significant impact on growth, metabolism and organ functions.

References

1.       Kakourou T (2009): Vitiligo in children. World J Pediatr, 5 (4): 265-268.

2.       Nyoo MD and Westerhof W (2001): Vitiligo. Pathogenesis and treatment. Am J Clin Dermatol, 2: 167 – 181.

3.       Hegedus L, Heidenheim M, Gervil M et al.(1994): High frequency of thyroid dysfunction in patients with vitiligo. Acta Derm Venereol; 74: 120 -3.

4.       Shong YK and Kim JA (1991): Vitiligo in autoimmune thyroid disease. Thyroidology; 3: 89 – 91.

5.       Young DS, Pestaner LC and Gilbeman U (1975): Effect of Drugs on clinical laboratory tests, Clinical Chemistry, 21, 3660.

6.       Engall E (1980): Methods in Enzymology. In: Vanvunakis H and Langene JJ (Eds), 70: 419 – 492. Academic Press, New York.

7.       Tung KS, Ramos CV and Deodhar SD (1974): Am J Clin Pathol, 61: 549.

8.       Volep R (1994): Clin Chem, 40: 2132.

9.       Lacovelli P, Sinagra JLM, Vidolin AP et al. (2005): Prevalence of thyroiditis and of other autoimmune diseases in children with vitiligo. Dermatology, 210: 26 – 30. 

10.     Kemp EH, Waterman EA and Weetman AP (2001): Autoimmune aspects of vitiligo. Autoimmunity, 34: 65 – 77.

11.     Majumder PP, Nardlund JJ and Nath SK (1993): Pattern of familial aggregation of vitiligo. Arch Dermatol, 29: 994 – 998.

12.     Janniger CK (1993): Childhood vitiligo. Cutis, 51: 25 – 28.

13.     Hegedus L, Heidenheim M, Gervil M et al. (1994): High frequency of thyroid dysfunction in patients with vitiligo. Acta Derm Venereol, 74: 120-123.

14.     Halder R M (1997):  Childhood vitiligo. Clin Dermatol, 15: 899 – 906.

15.     Bettendorl M (2002): Thyroid disorders in children from birth to adolescence. Eur J Nucl Med, 29 (2): S439 – S446.

16.     Moradi S and Ghafarpoor G (2008): Thyroid dysfunction and thyroid antibodies in Iranian patients with vitiligo. Indian J of Dermatology, 53 (1): 9 – 11.

17.     Sostre S and Reyes MM (1991): Sonographic diagnosis and grading of Hashimoto’s thyroiditis. J Endocrinol Invest, 14: 115 – 121.

18.     Yang Y, Lin X, Fu W et al.(2009): An approach to the correlation between vitiligo and autoimmune thyroiditis in Chinese children. Clinical and Experimental Dermatology.

19.     Kemp EH (2004): Autoantibodies as diagnostic and predictive markers of vitiligo. Autoimmunity; 37: 287 – 90.

20.     Tozzoli R, Villalta D, Bizzaro N et al.(2001): Laboratory diagnosis of autoimmune thyroid disease (in Italian). Recenti Prog Med., 92: 609 – 617.

21.     Kakourou T, Kanaka – Gantenbein C, Papadopoulo A et al. (2005): Increased prevalence of chronic autoimmune (Hashimoto's) thyroiditis in children and adolescents with vitiligo. J Am Acad Dermatol, 53: 220 – 223.

22.     Fernandes NC and Campos MMC (2009): Childhood vitiligo and thyroid disease. An Bras Dermatol, 84 (2): 200 – 2.

23.     Imam AA, Abdallah M, Emam HM et al. (2007): Estimation of antithyroid microsomal antibodies in Egyptian vitiligo patients of different age group JASMR, 2 (2): 135 – 142.

24.     Hann SK and Lee HJ (1996): Segmental vitiligo: Clinical findings in 208 patients. J Am Acad Dermatol, 35: 671 – 674.

25.     Jaisaankar TJ, Baruah MC and Garg BR (1992): Vitiligo in children. Int J Dermatol, 31: 612 – 623.

26.     Roth C, Scortea M, Stubbe P et al. (1997): Autoimmune thyroiditis in childhood – Epidemiology, Clinical and laboratory findings in 61 patients. Exp Clin Endocrinol Diabetes, 105 (4): 66 – 69.

27.     Bjoro T, Holmen J, Kruger O et al. (2000): Prevalence of thyroid disease, thyroid dysfunction and thyroid peroxidase antibodies in a large, unselected population: the health study of Nord Trondelag (HUNT). Eur J Endocrinol, 143: 639 – 647.

28.     Koch CA and Sarlis NJ (2001): The spectrum of thyroid disease in childhood and its evolution during transition to adulthood: Natural history, diagnosis, differential diagnosis and management. J Endocrinol Invest, 24: 659 – 675.

29.     Sarvanan P and Dayan CM (2001): Thyroid autoantibodies. Endocrinol Metab Clin North Am, 30: 315 – 337.

30.     Pagovich OE, Silverberg JI, Freilich E et al. (2008): Thyroid abnormalities in pediatric patients with vitiligo in New York City. Cutis, 81 (6): 463 – 6.

31.     Nasser AH, Alsalamony AM and Abdulhalim A (2009): Thyroid autoimmunity in vitiligo patients without and with alopecia areata. Panarab J, 20 (2): 9 – 16.

32.     Daneshapazhooh M, Mostofizadeh M, Behjati J et al. (2006): Antithyroid peroxidase antibody and vitiligo: a controlled study. BMC Dermatology; 6: 3.