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www.lndebioiene.om Dermto-Endorinology 255

REsEaRch papER REsEaRch papER

Dermto-Endorinology 3:4, 255-258; Otober/November/ 2011; © 2011 Lnde Bioiene

*Correspondence to: Vincenzo Nuzzo; [email protected]

Submitted: 10/01/11; Accepted: 10/29/11

DOI: http://dx.doi.org/10.4161/derm.3.3.16838

Introduction

Urticaria is dened as a widespread, ugacious, itchy cutaneous

swelling; it is one o the most requent dermatosis, being its prev-alence in general population estimated about 20%.1 Urticaria isregarded as idiopathic in approximately 75% o aected patients.1 Chronic orm is dened as at least 6-week history o the disorderand chronic urticaria (CU) was observed in about 25% o thecases.

An increase prevalence o autoimmune diseases was observedin subjects with CU.2-8 Thyroid autoimmune thyroiditis andHashimoto’s thyroiditis were described among patients withCU, and increased serum levels o antithyroid antibodies werereported with requency ranging between 12–29% in dierentstudies.2-5, 7-8

Although number o authors reported on the association

between CU and thyroid autoimmunity, there are not yet avail-able data regarding this association in areas with mild-to-moder-ate iodine deciency.2-9 The present study attempts to address thisissue. This prospective case-control study is aimed at determin-ing the prevalence o thyroid autoimmune disorders in a cohorto patients with CU, all living within the province o Naples,Southern Italy.

Urtiri i one o te mot requent dermtoi, being it revlene in generl oultion etimted bout 20%. Tiroetive e-ontrol tudy w imed t determining te revlene o tyroid utoimmune diorder in oort o tient wit roni urtiri (cU), ll living witin n re wit mild-to-moderte iodine deieny. Fity our oneutivetient eted by cU were reruited nd omred to 108 elty ontrol. aement o te tyroid untioninluded meurement o erum onentrtion o Tsh, FT3, FT4, nti-tyreoglobulin (nti-TG) nd nti-eroxide (nti-

TpO) ntibodie. Ultround n o te tyroid glnd w erormed in ll ubjet uing 7.5 Mhz liner trnduer. allubjet were ollowed u or 6 mont. Te revlene o tyroid ntibodie w ignintly iger in our oort o tient wit cU tn in ontrol (22% v. 6.5 %). himoto’ tyroiditi w lo more requent in tient tn ontrol(18.5% v. 1.8%). Tee requenie do not dier rom toe reviouly reorted by ome oter utor nd onrm teoition between cU nd tyroid utoimmunity lo in te re o iodine deieny. however, reene o ntibodieor tyroiditi doe not eem to infuene linil oure o cU. Tee reult ugget tt reening or tyroid untionmy be ueul in ll te tient wit cU.

Idiopathic chronic urticariaand thyroid autoimmunity

Experience of a single center

Vinenzo Nuzzo,1 Libue Tumnov,2 pol colnti,3 alono Zuoli¹ nd annmri colo²

1Internl Mediine Unit; 2Dermtology Unit; “s. Gennro” hoitl; Nle, Itly; 3Dertment o Moleulr nd clinil Endorinology nd Onology;

“Federio II” Univerity o Nle; Nle, Itly

Keywords: urticaria, Hashimoto’s thyroiditis, iodine deiciency

Results

Thyroid autoantibodies were detected in 12 o the 54 patients,

all emales (Table 1); their mean age was 31.5 years (median: 27yrs, range: 21–47 years). As shown in Table 1, 6 out o these 12patients had increased levels o anti-TPO antibodies and 6 othershad increased both anti-TPO and anti-TG antibodies.

Ten o the 12 patients (18.5%) with positive thyroid autoan-tibodies were also ound as being aected by hypothyroidism.Diagnosis o chronic thyroiditis was conrmed by thyroid ultra-sound by a picture o non-homogeneous hypoechoic pattern with-out nodules.11 Two o aected patients were sisters. Hypothyroidpatients were given replacement therapy with L-thyroxine (100+/- 12.50 mcg daily).

We did not observed any dierence in the clinica l eatureso CU between patients with and without thyroid autoantibod-

ies, when considering the requency o the crises, association o urticaria with angioedema and resistance to antihistaminic treat-ments (Table 2).

Only 7 controls had detectable anti-thyroid antibodies (Table3); 2 had increased anti-TPO antibodies, other 2 had anti-TGantibodies and 3 other subjects had both anti-TPO and anti-TGantibodies. One o them was hypothyroid.

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Comparing patients to controls, thyroid autoantibodies were more requently ound in patients (22.2% , p = 0.0074).Moreover, patients with CU developed hypothyroidism morerequently than controls (18.5%, p = 0.0001).

Signicantly increased ANA levels were observed in 4 out o

10 patients aected by Hashimoto’s thyroiditis (Table 1). Oneo them developed lupus erythematous discoid (LED) during the 6-month period o observation. No other abnormality in thebiochemical tests was revealed among our patients with autoim-mune thyroid disorders.

In 10 patients without thyroid autoimmunity, an increasein total IgE and/or specic IgE was revealed. In particular, 6patients had an increase in total IgE; one patient had IgE anti-bodies directed against some inhalant and/or ood allergens and3 patients had an increase in both total IgE and some specic IgEantibodies.

Iodine urinary excretion was similar in patients and healthy controls; they were both in the lower third o the normal range.Median urinary iodine excretion was below 55 mcg/l that wasound by Aghini-Lombardi et al. in an iodine-decient area o Southern Italy.12

Discussion and Conclusions

In this prospective, case-control study we evaluated the associa-tion between CU and thyroid autoimmunity in an area withmild-to-moderate iodine deciency. The prevalence o thyroidantibodies was signicantly higher in our cohort o patients withCU than in controls (22% vs. 6.5 %). Hashimoto’s thyroiditis wasalso more requent in patients than controls (18.5% vs. 1.8%).These requencies do not dier rom those previously reported by some other authors and conrm the association between CU and

Table 1. Tyroid ntibodie nd tyroid untion, c3, c4, immunoglobulin, Reumtet, aNa, ENa in tient wit roni urtiri

Patients Sex Age FT3 FT4 TSH Ab-TG Ab-TPO C3 C4 RF ANA ENA Diagnosis

2 F 24 2.65 11.8 0.4 463 >8000 N N N neg neghimoto’tyroiditi,yotyroidim

3 F 30 3.13 9.5 7.54 neg 345 N N N neg neg

himoto’

tyroiditi,yotyroidim

5 F 47 2.01 13.1 5.41 neg 465 N N N neg neghimoto’tyroiditi,yotyroidim

8 F 45 6.1 12.5 1.46 375 461 N N N 1/160 Neghimoto’tyroiditi,yotyroidim

17 F 21 5.65 10.8 5.21 494 392 N N N 1/160ssBo

himoto’ ty-roiditi, ublinilyotyroidim

27 F 22 5.36 12.9 1.59 neg 229 N N N neg negIolted oitivity o utontibodie

32 F 22 4.15 11.0 6.01 421 420 N N N 1/160 neg himoto’ ty-roiditi, ublinilyotyroidim

36 F 44 2.11 12.3 5.75 441 542 N N N 1/160 neghimoto’tyroiditi,yotyroidim

42 F 23 4.94 12.8 2.34 neg 357 N N N Neg negIolted oitivity o utontibodie

49 F 29 2.16 11.2 7.63 neg 327 N N N neg neghimoto’tyroiditi,yotyroidim

52 F 25 2.58 10.2 5.38 585 894 N N N Neg Neghimoto’tyroiditi,yoyroidim

54 F 46 1.97 9.2 5.38 neg 489 N N N Neg Neghimoto’tyroiditi,yotyroidim

normlrnge

3.7–6.8g/ml

9.3–17g/ml

0.3–4.2mUI/ml

<300IU/ml

<110IU/ml

70–150mg/dl

14–40mg/ml

<20IUml

<1/80 Neg

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thyroid autoimmunity also in the area o iodinedeciency.2-5, 7-8 However, presence o antibod-ies or thyroiditis does not seem to infuence clinica lcourse o CU, as suggested by similar requenciesand eatures o the crises among patients with or without thyroid autoimmune disorders.

According to other reports, both CU and thy-

roiditis occurred more requently in women thanmen; thereore, also the association o these twodisorders was more requent in women. However, we can not exclude a gender-related bias.3,7

Thyroid autoimmune disorders in patients withCU may appear with variable eatures, ranging rom a simple positivity o thyroid autoantibodiesto a lymphocytic thyroiditis or Hashimoto’s thy-roiditis with or without hypothyroidism.2-9 Suchan association was rst described by Lezno et al.in 1983 who observed that 12% o patients withCU were also aected by autoimmune thyroiditis.8 Since then, the prevalence o positive thyroid auto-

antibodies ranged rom 12 to 29% in patients withCU in dierent studies.2-5, 7-8 Interestingly, no caseo Graves disease was described among patients with urticaria.

The role o geographical area has never beeninvestigated regarding this issue, in particular, thereare no literature data regarding the requency o the association in areas o mild-to-moderate iodinedeciency, such as Southern Italy.13 In these areas,a higher prevalence o antithyroid antibodies occurs in generalpopulation.14 This may be related to a prolonged TSH-stimulatedrelease o thyreoglobulin with increased immunogenicity in the

bloodstream. Indeed, a variable degree o thyreoglobulin iodin-ation may account or dierent immunological properties withthe generation o new epitopes that provide greater immunoge-nicity to the molecule.15 The only data regarding the associationo thyroid autoimmunity and CU in the province o Naples wereprovided by Aversano et al.9 However, these authors evaluated theeects o L-thyroxine on the CU outcome in patients aected by autoimmune thyroiditis, and their study was not aimed at evalu-ating the prevalence o thyroid disorders among patients with CU.

The eects o replacement treatment or hypothyroidism onclinical symptoms o urticaria are still controversial. Lezno etal. reported that the L-thyroxin therapy improved clinical symp-toms o CU.7 Some studies conrmed this observation, while

other authors ailed to nd any infuence o L-thyroxine on thecourse o urticaria.9,16,17 In our patients with thyroiditis, the treat-ment with L-thyroxine had no infuence on the clinical course o urticaria.

Mechanisms that link thyroid autoimmunity and CU are stillunknown and are object o controversies.18 It was shown thatthyroid autoantibodies do not induce urticaria and are only anepiphenomenon. CU may have autoimmune basis, since as many as 5–69% o the patients have autoantibodies to the high an-ity receptor or IgE (anti FcεRI) on mast cells and basophils,these antibodies may be pathogenetic in the onset o CU.18-20 No

other etiology o CU except or the autoimmune one was revealedamong our patients.

Other biochemical tests that were carried out in our patients

were aimed at evaluating o association with other autoim-mune disorders, in particular, diseases o the connective tissue.Positivity o ANA (>1:160) that was ound in 4/10 patients withHashimoto’s thyroiditis and development o lupus erythematousdiscoid in one o them urther conrms the autoimmune patho-genesis o CU.

In conclusion, results rom the present study conrms thehigh prevalence o thyroid autoimmune disorders in patients with CU and extends the nding on the population with mild-to-moderate iodine deciency. Indeed, in the province o Naples,an area with iodine deciency, the prevalence o antithyroid auto-antibodies and Hashimoto’s thyroiditis in patients with CU were22% and 18.5%, respectively. These results suggest that screen-

ing or thyroid unction may be useul in all the patients withCU. Non symptomatic positivity o antithyroid antibodies is a serological markers or chronic thyroiditis that represents a risk actor or development o hypothyroidism. Predictive value o this association remains to be elucidated.

Patients and Methods

Patients. This is a prospective case-control study that enrolledpatients and controls during 6 months, rom December to July 2007, and ollowed all o them or urther 6 months.

Table 2. clinil eture o te urtiri in tient ording to te reeneo nti-tyroid utontibodie

Patients without

antibodies (n=42)

Patients with

antibodies (n=12)P value

N. patients with crises less

than once a day more than 3

times a week

28 8 0.99

N. patients with less thancrises 3 times a week 14 4 0.99

Association with angio-

edema18 4 0.74

Resistance to antihistamines 34 7 0.13

Table 3. clinil eture o te urtiri in tient ording to te reeneo nti-tyroid utontibodie

Patients with chronic

urticaria(n= 54)Controls (n=108) P value

Positivity of thyroid

antibodies12 (22.2 %) 7 (6.5 %) 0.99

N. patients with less thancrises 3 times a week

10 (18.5 %) 2 (1.8 %) 0.0005

Association with

angioedema10 (18.5%) 1 (0.9%) 0.0001

Resistance to

antihistamines8 (15%) 0 (0%) 0.0002

Subclinical

hypothyroidism2 (3.7%) 1 (0.9%) 0.53

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Ultrasound scan o the thyroid gland was perormed in allsubjects using a 7.5 MHz linear transducer.

The patients were ollowed up or 6 months ater the study entry to observe the course o urticaria and eventual appearance o other autoimmune diseases.

All controls underwent the same evaluation at the study entry;their medical history, physical examination and biochemical

tests excluded any previous or current urticaria. They were alsoollowed or 6 months ater their initial evaluation, in order toexclude any new onset o urticaria or other disorder.

Assays. Determinations o thyroid hormones, TSH and anti-bodies were perormed with the same commercial kits or the whole study period. Serum TSH was measured using an immuno-radiometric assay (Dela, Wallac, Inc. Finland) and ree thyroidhormones were determined by radioimmunoassay Lisophase kits(Technogenetics, Milan, Italia). Anti-TG antibodies were mea-sured with an Ares Serono kit (Milan, Italy) and anti-TPO anti-bodies by a DiaSorin kit (Saluggia, Italy). Iodine urinary excretion was measured in extemporaneous morning samples using the col-orimetric ceric ion arsenious acid wet ash method based on the

Sandell-Koltho reaction (10) and spectrophotometer equipped with an automatic sipper. The intra-assay variation coecient was<3.6% and the inter-assay one <7.8% or all the measurements.

Blood chemistry prole, blood count, and liver and kidney unction were analyzed using a standard autoanalyzer.

Statistical analysis. All statistical procedures were perormedusing a Statistical Package or Windows (Sigma-Stat). The di-erences between patients and controls were compared by using the Pearson’s chi-square test or categorical variables. All resultsare given as percentage, media, median, standard deviation andrange. Statistical signicance was set at 5%.

Disclosure o Potential Conficts o Interest

No potential conficts o interest were disclosed.

Fity-our consecutive patients aected by CU were recruitedat the outpatient clinic o Allergological Dermatology; there were 42 emales and 12 males, with a median age o 36 years(range, 15–58 years), all were living in the province o Naples.

For each patient enrolled, two control subjects matched orage and gender were selected among the population o usualblood donors and included in the data analysis. Indeed, the

control group consisted o 108 healthy individuals (84 emalesand 24 males, median age 35 years (range, 18-59 years); with-out history o urticaria. All control subjects lived within thesame geographic area.

None o the 162 subjects were taking any drugs or had his-tory o other autoimmune diseases.

The study was perormed according to the procedures indi-cated by the Helsinki II Declaration. All enrolled subjects gavetheir inormed consent to participate in the study.

Methods. All the patients underwent a complete medicaland pharmacological anamnesis, a complete physical examina-tion, a dermatological objective examination to reveal eventualpresence o other skin disorders.

Biochemical evaluation included a routine laboratory screening with complete blood count, erythrocyte sedimenta-tion rate (ESR), C-reactive protein (CRP), Antistreptolysin Otitre, glucose levels, liver and kidney unction tests, electro-phoresis o serum proteins), Rheumatoid actor (RF), C3 andC4 components o the complement system, immunoglobulin,cryoglobulin, HBsAg, HCV-Ab, VDRL, antinuclear antibodies(ANA), anti-extractable nuclear antigens (ENA), total IgE, IgEantibodies directed towards mixed ood and inhalant allergensand parasitological evaluation o the stool (on 3 samples col-lected in 3 days). Assessment o the thyroid unction includedmeasurement o serum concentrations o TSH, FT3, FT4,

anti-thyreoglobulin (anti-TG) and anti-peroxidase (anti-TPO)antibodies.

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