Thyroid Autoimmunity in Vitiligo Patients Without and With Alopecia Areata

The causes of vitiligo and alopecia areata have been remaining controversial over decades. Today, autoimmune mechanisms such as thyroid autoimmunity are generally accepted. The presence of autoantibodies such as thyroid autoantibodies was used to prove this theory. The aim of the study was to investigate the possible relation of thyroid autoimmunity and dysfunction to the development of vitiligo without/with alopecia areata. It was conducted on 46 patients (female:male ratio=2.3:1); 36 of them had vitiligo only (Group I) and the remaining 10 patients had concurrent association of vitiligo and alopecia areata (Group II). They were subjected to history taking, physical examination, and investigations which included antibodies to thyroid peroxidase (anti-Tpo) and thyroglobulin (anti-Tg), thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4)] and thyroid ultrasonography. Anti-Tpo antibody was positive in 34.8% patients (19.5% of Group I and 90% of Group II) and its mean levels showed a highly statistically significant difference between both groups of patients (P=0.004). Anti-Tg antibody was positive in 17.4% patients (8.3% of Group I and 50% of Group II) and its mean levels showed a statistically significant difference between both groups of patients (P=0.017). TSH level was elevated in 28.3% patients (8.3% of Group I and 90% of Group II) and its mean levels showed a statistically significant difference between both groups of patients (P=0.03). There was no significant correlation between either anti-Tpo antibody or anti-Tg antibody and TSH level in Group I patients (r=0.28, P=0.09 and r=0.12, P=0.24; respectively). There was a significant positive correlation between anti-Tpo antibody and TSH level in Group II patients (r=0.8, P=0.01) and a weak positive correlation between anti-Tg antibody and TSH level in Group II patients (r=0.33, P=0.06). The incidence of autoimmune thyroiditis is high in patients with concurrent association of vitiligo and alopecia areata. Patients with either vitiligo or alopecia areata have to be inquired about the history of the other disease and investigated for the possible presence of thyroid autoimmunity with/without thyroid dysfunction or other autoimmune diseases.

Introduction

Vitiligo is a relatively common condition affecting about 1 % of the population(1). Although alopecia areata accounts for around 2% of new dermatological outpatient attendances in Britain and the United States(2), severe alopecia is less common(1).

Various theories were suggested for the etiology of vitiligo and alopecia areata. In both skin diseases, an autoimmune hypothesis is suggested by its clinical association with a number of disorders considered to be autoimmune such as Hashimoto’s thyroiditis, diabetes mellitus, Addison’s disease, pernicious anemia and systemic lupus erythematosus(3,4,5,6,7). In addition, the presence of a localized lymphocytic infiltrate at the progressing edge of a lesion of vitiligo and peribulbar lymphocytic infiltrate in biopsy specimens of a lesion of alopecia areata and the response to oral steroids have been cited as evidences to the autoimmune pathogenesis(8).

This led to an intense search for immune derangements(4). The presence of auto- antibodies was used to prove this theory(9). Reviewing the literature by MEDLINE revealed independent sporadic case reports(8,9) and researches dealing with association of vitiligo(6,10) or alopecia areata(11,12) with autoimmune thyroiditis and only one study about the concurrent association of alopecia areata, vitiligo and chronic thyroiditis in three patients(13).

Autoimmune diseases affect a substantial percentage of the population, providing a strong impetus for research into ways whereby such diseases can be detected, prevented and even cured(14,15).The association of thyroid disorders with skin manifestations is complex(16). In this study, the possible relation of thyroid autoimmunity and dysfunction to the development of vitiligo without/with alopecia areata was investigated.

Patients and methods

This study was carried out prospectively between July 2007 and June 2008. It involved all the new patients with vitiligo. They were 46 patients (14 males and 32 females). 10 of them (6 males and 4 females) were concurrently having alopecia areata. They were attending the outpatient department of Dermatology, Andrology, and Sexually Transmitted Diseases. Consultations were performed to the Diabetes and Endocrinology Department for further evaluation and management. Both departments are affiliated to Alnoor Specialist Hospital, the tertiary level hospital of the Holy Makkah, Saudi Arabia.

All the patients were subjected to thorough history taking with stressing on the medical history including thyroid disease, diabetes mellitus, Addison’s disease, alopecia areata or other medical conditions as well as a family history of vitiligo. No patient was diagnosed before this study as having any type of thyroid dysfunction. Physical examination included skin examination with stressing on the clinical types of both vitiligo and alopecia. The patients were categorized into 2 groups:

·         Group I which involved only vitiligo patients, and

·         Group II which involved patients having both vitiligo and alopecia areata.

Thyroid gland examination was performed. Laboratory investigations included thyroid autoantibodies; antibodies to thyroid peroxidase (anti-Tpo) and thyroglobulin (anti-Tg), thyroid stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4). They were measured using Electrochemiluminescence immunoassay "ECLIA". (Roche Diagnostics GmbH, Mannheim, USA). The laboratory reference ranges were 0-34 IU/mL for anti-Tpo and 0-10 IU/mL for anti-Tg, 0.27-4.2 µIU/mL for TSH, 0.18-.64 ng/dL for FT3 and 0.93-1.7 ng/dL for FT4. Thyroid ultrasound was performed in all patients using equipment with a 10-MHz linear-array transducer (Acuson X300, Siemens, Germany).

The diagnosis of autoimmune thyroiditis based on positive serum anti-Tpo and/or anti-Tg and the demonstration of diffuse or irregular hypoechogenicity of the thyroid gland characteristic of autoimmune thyroiditis on ultrasound.

Statistical analysis

Data were shown as mean±SD (standard deviation). They were analyzed using SPSS software version 12. Paired t-test was used to assess the statistical significanceof any differences in all the analyses.

Results

Forty six patients were enrolled in this study. 32 patients were females and 14 patients were males (female:male ratio=2.3:1). The age range for the whole group of patients was 4 to 72 years. The mean age, gender, and mean duration of vitiligo and alopecia areata in both groups of patients are shown in Table 1. With the exception of only one patient (female), alopecia areata started long time before vitiligo in Group II patients. There was a statistically significant difference between the mean duration of alopecia areata (8.4±5.6 years) and that of vitiligo (3.4±3.6 years) (P=0.003) in that group.

Table 1.    The mean age, gender, and mean duration of vitiligo and alopecia areata in both groups of patients

Clinical findings

Group I (n=36)

Group II (n=10)

Age (year)

20.7±14.3

29.1±12.5

Gender

    Male

    Female

 

8 (22.2%)

28 (77.8%)

 

6 (60%)

4 (40%)

Duration of vitiligo (year)

4.62±4.61

3.4±3.6

Duration of alopecia areata (year)

-

8.4±5.6

All patients had vitiligo of different types. Table (2) shows the distribution of clinical types of vitiligo among the whole group of patients. 3 patients had halo nevi. Group I patients showed all the clinical types of vitiligo while Group II patients had only generalized (8/10, 80%) and focal (2/10, 20%) vitiligo. Family history was positive in the first degree relatives of 6 patients of Group I. 3 patients from Group I were from one family (1 brother and 2 sisters) with the brother and one sister having atopic dermatitis also.

Table 2.    Distribution of clinical types of vitiligo among the whole group of patients

Types of vitiligo

Number of patients (n=46)

%

Generalized

21

45.7

Focal

14

30.4

Acral with/without facial

 9

19.6

Segmental

 2

4.3

 

Table (3) shows the distribtution of patients with vitiligo without/with alopecia areata between the two groups and Table 4 shows the distribution of clinical types of alopecia areata among Group II patients.

Table 3.    Distribution of patients among the two groups.

Group

Number (%) of patients

Group I (Vitiligo)

36 (78.3%)

Group II (Vitiligo and alopecia areata)

10 (21.7%)

Table 4.    Distribution of clinical types of alopecia areata among Group II patients.

Types of alopecia areata

Number of patients (n=10)

%

Localized

3

30

Totalis

3

30

Universalis

4

40

Table (5) shows the incidence of family history of thyroid disease and the associated manifestations in the both groups of patients. Clinical hypothyroidism was noticed in Group II patients (90%). Hyperthyroidism was not reported in any patient. Diabetes mellitus was reported in 7 (19.4%) patients (5 had type I and 2 had type II) from Group I and 3 (30%) patients (all had type I) from Group II patients. 8 (17.4%) patients (3 from Group I and 5 from Group II) had the typical hypoechoiec pattern of autoimmune thyroiditis on thyroid ultrasound.

Table 5.    The incidence of family history of thyroid disease and associated manifestations in both groups of patients

Associated
manifestations

Number (%) of patients

 

Group I (n=36)

Group II (n=10)

Family history of thyroid disease

1 (2.7%)

3 (30%)

Thyroid dysfunction

   Hypothyroidism

       Clinical (overt)

       Subclinical

   Hyperthyroidism

 

 

0 (0.0%)

3 (8.3%)

0 (0.0%)

 

 

                9 (90%)

                1 (10%)

0 (0.0%)

Goiter

3 (8.3%)

5 (50%)

Diabetes mellitus

7 (19.4%)

3 (30%)

Microcytic hypo-chromic anemia

8 (22.2%)

3 (30%)

Atopic dermatitis

4(11%)

1(10%)

Table (6) shows thyroid-related laboratory findings in both groups of patients. Anti-Tpo antibodies were positive in 16/46 (34.8%) patients (7/36, 19.5% of Group I and 9/10, 90% of Group II). Its level showed a statistically significant difference between both groups of patients (P=0.004). Anti-Tg antibodies were positive in 8/46 (17.4%) patients (3/36, 8.3% of Group I and 5/10, 50% of Group II). Its level showed a statistically significant difference between both groups of patients (P=0.017). TSH level was elevated in 13/46 (28.3%) patients (3/36, 8.3% of Group I and 10/10, 90% of Group II), and its mean level showed a statistically significant difference between both groups of patients (P=0.03).

There was no significant correlation between anti-Tpo antibody and TSH level in Group I patients (r=0.28, P=0.09), while there was a significant positive correlation in Group II patients (r=0.8, P=0.01). A weak positive correlation was detected between anti-Tg antibody and TSH level in Group II patients (r=0.33, P=0.06) but no correlation was found in Group I patients (r=0.12, P=0.24).

Both FT3 and FT4 levels were within the normal reference range in all (36/36, 100%) Group I patients, while in Group II, FT3 and FT4 levels were low in 9/10 (90%) patients. There was a statistically significant difference in FT3 (P=0.002) and FT4 (P=0.001) levels between both groups (Table 6).

Table 6.    Laboratory findings in the both groups of patients

Variable

Group I

Group II

P  value

Anti-Tpo antibodies (IU/ml)

33.6±21.4

141.6±11.88

0.004

Anti-Tg antibodies (IU/ml)

35.2±13.5

128.8±32.7

0.017

TSH level (µIU/ml)

2.3±1.4

7.04±2.08

0.03

FT3 (ng/dl)

0.33±0.54

0.14±0.31

0.002

FT4 (ng/dl)

1.33±0.17

0.46±0.18

0.001

Statistically significant: P<0.0

Discussion

The hypothesis that immune derangements are possible causes of various diseases is largely based on the clinical observation of the co-existence of various supposedly ‘autoimmune’ diseases with in vitro and in vivo experimental data showing autoantibodies(8).

The etiopathogenesis of both vitiligo and alopecia areata is still controversial. Currently, autoimmunity and endocrine dysfunction appear to be the most plausible as suggested by the frequent findings of other concomitant autoimmune diseases or antibodies in patients with these skin diseases(5-13). In vitiligo, melanocytes are destroyed secondary to autoantibodies(17-20).Although the effects of hypothyroidism on hair have long been known, the mechanism has not been elucidated(21).

In this study, vitiligo was present independently in 78.3% of patients and in association with alopecia areata in 21.7% of patients. In Group II patients, alopecia areata started as localized alopecia areata in the scalp then over long durations (~ years), it remained in some patients as localized alopecia areata and extended in others to involve the whole scalp without/with extension to other hairy parts of the head and body with subsequent development of alopecia totalis or alopecia universalis; respectively. Alopecia areata started long time before vitiligo in Group II of patients as indicated by its earlier start and the statistically significant difference between the length of duration of both diseases (P=0.003). This might be explained by the earlier reactivity of the pilar units than that of melanocytes to the effect of thyroid autoantibodies. On reviewing the literature, no article discussing the chronological order of vitiligo and alopecia areata in patients with thyroid disease could be found.

The current study reported thyroid autoimmunity in patients with generalized and focal vitiligo but not in those with acral with/without facial and segmental. Other studies, like our study, reported a significant frequency of thyroid autoimmunity in patients with non-segmental vitiligo(22,23,24).

Thyroid autoimmunity is defined by the lymphocytic infiltration of the thyroid gland accompanied by the detection of autoantibodies to thyroid antigens in the serum (anti-Tpo, anti-Tg and anti-TSH-receptor antibodies)(25).

In this study, anti-Tpo and anti-Tg antibodies were positive in 34.8% and 17.4% of patients; respectively. Several independent studies on vitiligo(6,10,20,24-28) (Table 7) and alopecia areata(11,29) (Table 8) revealed the positivity percentages of thyroid autoantibodies in these diseases. In vitiligo, the rate of positivity of thyroid autoantibodies varied from 2.2%30 to 50%(26). To the best of our knowledge, only one study about the concurrent presence of alopecia areata, vitiligo, and chronic thyroiditis was performed on 3 patients. In that study, Ueki et al.(13) reported that anti-Tpo antibody was at a high titer in 2 patients with all patients were confirmed as having chronic thyroiditis by thyroid aspiration biopsy(13).

Table 7.    Percentages of vitiligo patients with positive antithyroid antibodies in some studies

Studies

Number of
patients

Anti-Tpo antibody (%)

Anti-Tg antibody (%)

Sedighe and Gholamhossein (6)

109

36.7

32.1

Daneshpazhooh et al.(10)

94

18.1

-*

Zettinig et al.(20)

106

21

18

Imam et al.(24)

60

27

-*

Mandry et al.(26)

20

50

40

Dave et al.(27)

35

31.4

31.4

Kakourou et al.(28)

54

27.8

27.8

*Anti-Tg antibody level was not measured.

 

Table 8.    Percentages of alopecia areata patients with positive antithyroid antibodies in 2 studies

Studies

Number of patients

Anti-Tpo antibody (%)

Anti-Tg antibody (%)

Kurtev and Iliev(11)

46

33.3

39.5

Erdem et al.(30)

40

7.5

Ŧ Anti-Tg antibody level was negative.

 

Anti-Tpo antibodies level correlated positively with TSH level in Group II (r=0.8, P=0.01) but not in Group I (r=0.28, P=09) patients, while anti-Tg antibodies shows a weak positive correlation with TSH level in Group II patients (r=0.33, P=0.06), and there was no correlation in Group I patients (r=0.12, P=0.24). FT3 and FT4 showed a statistically significant decrease in Group II than in Group I. This suggests that the anti-Tpo tend to have more correlation with thyroid dysfunction and possibly to the development of vitiligo and/or alopecia areata, than do the anti-Tg. In 1993, Nordyke et al., reported that anti-Tpo antibody tends to have more correlation with thyroid dysfunction than does the anti-Tg antibody(31). Daneshpazhooh et al.(10) and Imam et al.(24) measured only the serum level of anti-Tpo antibody and reported significantly high levels in vitiligo patients compared to healthy controls (18.1% versus 7.3%) and (27% versus 7.5%); respectively.

In this study, 55.5% (5/9) of patients having positive anti-Tpo antibodies had positive anti-Tg antibodies while all patients (5/5, 100%) having positive anti-Tg antibodies had also positive anti-Tpo (100%, 5/5). Weetman et al.(32) reported that patients with anti-Tg antibodies also demonstrate anti-Tpo antibodies 99% of the time and that as many as 65% of patients who are seropositive for anti-Tpo antibodies are seronegative for anti-Tg antibodies(32). This corroborates the findings of the current study. Kemp(33) stated that various thyroid autoantibodies including thyroid stimulating antibody, anti-Tg antibody and anti-Tpo antibody are detectable in autoimmune thyroid diseases with the latter being the most sensitive. Hence, it is the preferred test for the diagnosis and follow-up of this group of diseases(33).

One patient of Group II had generalized vitiligo in association with only a large patch of alopecia areata in the scalp together with subclinical hypothyroidism, but antithyroid autoantibodies were negative. The patient will be followed up for the possible detection of antibodies as autoimmune thyroiditis, according to former studies, may present either simultaneously or after the onset of vitiligo but not before it(20,28).  

In this study, the thyroid dysfunction reported in some of the patients who suffered from vitiligo without/with alopecia areata was hypothyroidism either clinical or subclinical but no patient had hyperthyroidism. The association of vitiligo or alopecia areata with autoimmune thyroid disorders, both hypothyroidism and hyperthyroidism, was seen with greater tendency towards the hypothyroid state(6,7,22,34,35).

Vitiligo seems to occur about four times as often in patients with alopecia areata as in the general population(4) and both diseases may colocalize(36).The occurrence of depigmentation in vitiligo and hair loss in alopecia areata is certain but the etiopathogenesis remains an enigma. Vitiligo without/with alopecia areata may occur together in a patient having autoimmune thyroid disease. It is possible that the occurrence of these diseases in the same patient is the result of a basic autoimmune disturbance involving the melanocytes, the pilar units, and the thyroid glands in a patient who is genetically predisposed to these diseases. Therefore, all patients with a single autoimmune disease must be considered at risk for other autoimmune diseases(37).

Conclusions and recommendations

Vitiligo, without/with alopecia areata, is associated with other autoimmune diseases particulary autoimmune thyroiditis in some patients. The incidence of autoimmune thyroiditis is high in patients having both skin diseases together. Both dermatologists and endocrinologists have to inquire their patients about the family history of autoimmune diseases and to look for associated autoimmune diseases each from his/her own specialty point of view. Patients with either vitiligo or alopecia areata have to be inquired about the history of the other disease and investigated for the possible presence of thyroid autoimmunity with/without thyroid dysfunction. Finally, more thorough studies in this direction on a wide scale of patients are needed to settle these results.

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