**14. Follow-up**

Although a percentage of patients acquire hypothyroidism gradually within months or years, most children who are euthyroid at presentation remain euthyroid. Over several years, about half of children with subclinical hypothyroidism revert to euthyroidism, while the other half develops overt hypothyroidism. In a multicentre study Radetti et al. investigated the outcome of euthyroid children with HT and showed that 64.8% of them remained euthyroid, 9.5% progressed to subclinical hypothyroidism and 25.7% to overt hypothyroidism after 5 years (78).

Few studies have examined the spontaneous evolution of the disease (80,81). A recent Italian retrospective study described the outcome of 160 children affected with HT followed for up to 32.6 years in 20 pediatric endocrine clinics (78). In compatible with other reports (80,81), TSH concentrations have showed large uctuations overtime. The presence of associated diseases has not worsened the prognosis, because at the end of the follow-up no difference has been found in the frequency of abnormally elevated TSH between the groups with or

adjustment of the LT4 dosage. Very high TSH levels at diagnosis can be associated with thyrotroph hypertrophy and gradual suppression over the rst year of treatment (74,75). Once biochemical euthyroidism has been achieved, TSH can be monitored every 4-6 months in the growing child and yearly up to the attainment of nal height. If poor compliance is

Levothyroxine should be administered at least 20 min, before eating or ingestion of any medication known to impair its absorption, such as calcium and iron supplements, sucralfate, potassium-binding resins, antacids containing aluminium, and bile-acids binding resins. All other medications should be checked for interactions, particularly with

Growth and sexual development should be followed systematically as in any pediatric patient. Parents of children with HT should be advised that the hypothyroidism is likely to be permanent and monitoring of thyroid function for all patients should be life long. The prognosis for recovering lost linear growth depends on the duration of the hypothyroidism as well as the age at which treatment is started. If hypothyroidism is long-standing, thyroid replacement will not recover all lost stature. Similarly, if the diagnosis is made around puberty, there may be limited time for recovering the growth spurt before attaining nal height. If the onset of childhood hypothyroidism occurs after age 3 years, no permanent

Surgical therapy for HT most commonly is recommended in case of malignancy or for relief of compressive symptoms in patients who develop a nodular or diffuse goiter. Patients may have an associated rm nodule in the thyroid gland and the thyroid gland may be adherent to adjacent structures with associated enlarged lymph nodes, mimicking thyroid cancer. Large goiter with HT can cause local compressive symptoms such as dysphagia, coughing or choking spells, dyspnea, and hoarseness that may require surgery for relief of compression (76). Thirty-two (15%) of 216 patients with HT were referred with thyroid enlargement and compressive symptoms; 25 (78%) had an associated nodule and 12 (38%) had retrosternal extension. Symptom resolution occurred in 30 (94%) and improvement occurred in 2 (6%) patients after total thyroidectomy in 21 (66%) and thyroid lobectomy in 11 (34%) patients. The only complication was transient hypocalcemia in 12 (38%) patients.

Although a percentage of patients acquire hypothyroidism gradually within months or years, most children who are euthyroid at presentation remain euthyroid. Over several years, about half of children with subclinical hypothyroidism revert to euthyroidism, while the other half develops overt hypothyroidism. In a multicentre study Radetti et al. investigated the outcome of euthyroid children with HT and showed that 64.8% of them remained euthyroid, 9.5% progressed to subclinical hypothyroidism and 25.7% to overt

Few studies have examined the spontaneous evolution of the disease (80,81). A recent Italian retrospective study described the outcome of 160 children affected with HT followed for up to 32.6 years in 20 pediatric endocrine clinics (78). In compatible with other reports (80,81), TSH concentrations have showed large uctuations overtime. The presence of associated diseases has not worsened the prognosis, because at the end of the follow-up no difference has been found in the frequency of abnormally elevated TSH between the groups with or

suspected as the cause of treatment failure, fT4 should be measured.

antidepressants and seizure medications.

intellectual damage or neurologic decit is probable.

One patient had an incidental thyroid lymphoma (77).

**14. Follow-up** 

hypothyroidism after 5 years (78).

without associated diseases. In agreement with previous ndings in children (82,83) and in contrast with adults (84), the TSH level at baseline was not a useful marker to predict disease evolution. Both thyroid antibodies were signicantly higher at the last visit in the group with deteriorating thyroid function; however, whereas anti-Tg antibodies were

already higher at baseline, anti-TPO antibodies increased progressively with time. This nding suggests that anti-TPO antibodies might represent a marker of deteriorating thyroid function, in agreement with a previous report showing a good correlation between anti-TPO antibodies levels and lymphocytic inltration of the gland (85). The evaluation of patients, according to their nal outcome, revealed that subjects with deteriorating thyroid function had signicantly higher anti-Tg antibodies, TSH concentrations, and greater thyroid volume at presentation. Nonetheless, these ndings were not helpful in individual patients. On the other hand, it should be remarked that at 5 years of followup, more than 50% of the patients remained or became euthyroid. Ikemoto investigated 199 adult patients with HT and reported a recovery rate from hypothyroidism of 40% within 10.5 years of follow-up. In the same study elevated titres for thyroid autoantibody, age above 50 years and the presence of a stony-hard goitre were the best predictive factors for permanent hypothyroidism (86). In children the presense of predictive factors for permanent hypothyroidism are controversial. In the current study, initial TSH levels and thyroid volume at presentation, duration of levothyroxine therapy and anti-TPO Ab titre were not predictive for permanent hypothyroidism (79). Previously it was shown that iodine supplementation is associated with increased incidence of HT (87,88). In addition, it has been suggested that patients with HT are prone to develop hypothyroidism following iodine administration. Daily iodine supplementation over 1 mg has been shown to potentially contribute to underlying thyroid pathology in those with HT or Graves' disease. Exacerbation of nodularities in euthyroid individuals may occur if daily intake exceeds 20 mg iodine or iodide (89,90).

It is usually offered a trial of LT4 therapy to adolescents, after the completion of growth and puberty. Thyroid function is retested 6–8 weeks after the stop of medication, to determine if hypothyroidism is permanent and potentially restart therapy.

#### **15. References**


Hashimoto's Thyroiditis in Children and Adolescents 37

[28] Andrade LJ, Atta AM, D'Almeida Junior A, Paraná R Thyroid dysfunction in hepatitis

[29] Boas M, Main KM, Feldt-Rasmussen U. Environmental chemicals and thyroid function:

[30] Bahn AK, Mills JL, Snyder PJ, Gann PH, Houten L, Bialik O, Hollmann L, Utiger RD.

[31] Ban Y, Greenberg DA, Concepcion E, Skrabanek L, Villanueva R, Tomer Y. Amino acid

[32] Ban Y, Davies TF, Greenberg DA, Kissin A, Marder B, Murphy B, Concepcion ES,

[34] Weetman AP: Thyroid disease. In: the Autoimmune Disease. Rose NR, Mackay IR

[35] Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Evans JG, Young

[36] Staii A, Mirocha S, Todorova-Koteva K, Glinberg S, Jaume JC. Hashimoto thyroiditis is

[37] Kliegman RM: Disorder of thyroid gland. In: Kliegman RM, Behrman RH, Jenson HB, Stanton BMD (eds). Nelson Textbook of Pediatrics. 18th ed, Sounders, 2007. [38] Demirbilek H, Kandemir N, Gonc E.N, Ozon A, Alikasifoglu A, and Yordam N.

[39] Ferracci F, Bertiato G, Moretto G. Hashimoto's encephalopathy: epidemiologic data

[40] Gayatri NA, Whitehouse WP. Pilot survey of Hashimoto's encephalopathy in children.

[41] Mocellin R, Walterfang M, Velakoulis D. Hashimoto's Encephalopathy Epidemiology,

[42] Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA,

[43] Kothbauer-Margreiter I, Sturzenegger M, Komor J, Baumgartner R, Hess CW.

[44] Brodtmann A. Hashimoto encephalopathy and Down syndrome. Arch Neurol 2009;

Braverman LE. Serum TSH T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey

Encephalopathy associated with Hashimoto thyroiditis. J Neurol 1996: 243: 585-593.

an update. Curr Opin Endocrinol Diab Obes 2009; 16: 385-391.

[33] Hay ID. Thyroiditis: A clinical update. Mayo Clin Proc 1985; 60: 836-843.

Whickham survey. Clin Endocrinol (Oxf) 1977; 7: 481-493.

Pediatric Endocrinology & Metabolism 2007; 20:1199-1205.

and pathogenetic considerations. J Neurol Sci 2004; 217: 165-168.

Pathogenesis and Management. CNS Drugs 2007; 21: 799-811.

(NHANES III). J Clin Endocrinol Metab 2002; 87: 489-499.

clinical state. Thyroid Research 2010, 3: 11.

Dev Med Child Neurol 2005; 47: 556-558.

Dis 2008; 12:144-148.

1980; 302: 31-33.

2003; 4: 586-593.

66: 663-666.

(eds). 2006; 467-482.

15124.

C individuals treated with interferon-alpha and ribavirin—a review. Braz J Infect

Hypothyroidism in workers exposed to polybrominated biphenyls. N Engl J Med

substitutions in the thyroglobulin gene is associated with susceptibility to human and murine autoimmune thyroid disease. Proc Natl Acad Sci USA 2003; 100: 15119-

Villanueva RB, Barbesino G, Ling V, Tomer Y. Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease. Genes Immun

E, Bird T, Smith PA. The spectrum of thyroid disease in a community: The

more frequent than expected when diagnosed by cytology which uncovers a pre-

Hashimoto's Thyroiditis in Children and Adolescent: A Retrospective Study on Clinical Epidemiological and Laboratory Properties of the Disease. Journal of


[8] Hall R, Stanbury JB. Familial studies of autoimmune thyroiditis. Clin Exp Immunol 1967;

[9] Segni M, Wood J, Pucarelli, Toscano V, Toscano R, Pasquino AM. Clustering of

[10] Dittmar M, Libich C, Brenzel T, Kahaly GJ. Increased Familial Clustering of

[12] Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting

[13] Yeşilkaya E, Koç A, Bideci A, Camurdan O, Boyraz M, Erkal O, Ergun MA, Cinaz P.

[14] Deirdre CE, Alia H, Yaron T, Cutting E. The Etiology of Autoimmune Thyroid

[15] Brent GA. Environmental exposures and autoimmune thyroid disease. Thyroid 2010;

[16] Papanastasiou L, Vatalas L, Koutras DA, Mastorakos G. Thyroid autoimmunity in the

[17] Teng W, Shan Z, Teng X, Guan H, Li Y, Teng D, Jin Y, Yu X, Fan C, Chong W, Yang F,

[18] Doufas AG, Mastorakos G, Chatziioannou S, Tseleni-Balafouta S, Piperingos G, Boukis

[19] Beckett GJ, Arthur JR. Selenium and endocrine systems. J Endocrinol 2005; 184: 455-

[20] Duntas LH. The role of selenium in thyroid autoimmunity and cancer. Thyroid 2006;

[21] Caturegli P, Kimura H, Rocchi R, Rose NR. Autoimmune thyroid diseases. Curr Opin

[22] Klecha AJ, Barreiro Arcos ML, Frick L, Genaro AM, Cremaschi G. Immune-Endocrine

[23] Tanda ML, Piantanida E, Lai A, Lombardi V, Dalle Mule I, Liparulo L, Pariani N,

[24] Menconi F, Hasham A, Tomer Y. Environmental triggers of thyroiditis: Hepatitis C and

[25] Mori K, Yoshida K. Viral infection in induction of Hashimoto's thyroiditis: a key player or just a bystander? Curr Opin Endocrinol Diabetes Obes 2010; 17: 418-424. [26] Tomer Y, Davies TF. Infections and autoimmune endocrine disease. Bailli eres Clin

[27] Desailloud R, Hober D. Viruses and thyroiditis: an update. Virol J 2009; 12: 6: 5.

Interactions in Autoimmune Thyroid Diseases. Neuroimmunomodulation 2008; 15:

Bartalena LThyroid autoimmunity and environment. Horm Metab Res 2009; 41:

Dai H, Yu Y, Li J, Chen Y, Zhao D, Shi X, Hu F, Mao J, Gu X, Yang R, Tong Y, Wang W, Gao T, Li C. Effect of iodine intake on thyroid diseases in China. N Engl J Med

MA, Mantzos E, Caraiskos CS, Mantzos J, Alevizaki M, Koutras DA. The predominant form of non-toxic goiter in Greece is now autoimmune thyroiditis.

CTLA-4 gene polymorphisms in children and adolescents with autoimmune

Autoimmune Thyroid Diseases. Horm Metab Res 2011; 43: 200-204. [11] Yaron T, Amanda H. The etiology of autoimmune thyroid disease: A story of genes

and environment. Journal of Autoimmunity 2009; 32: 231-239.

Diseases. Curr Opin Endocrinol Diabetes Obes 2010; 17: 437-439.

and reporting linkage results. Nat Genet 1995; 11: 241-247.

current iodine environment. Thyroid 2007; 17: 729-739.

Ped Endocrinol Metab 2001; 14: 1271-1297.

thyroid diseases. Genet Test 2008; 12: 461-464.

autoimmune thyroid diseases in children and adolescents: a study of 66 families. J

2: 719-725.

20; 755-761.

465.

68-75.

436-442.

16: 455-460.

2006; 354: 2783-2793.

Eur J Endocrinol 1999; 140: 505-511.

interferon-α J Endocrinol Invest 2011; 34: 78-84.

Endocrinol Metab 1995; 9: 47-70.

Rheumatol 2007; 19: 44-48.


Hashimoto's Thyroiditis in Children and Adolescents 39

[61] Hegedu's L, Hansen JM, Feldt-Rasmussen U, Hansen BM, Hoier-Madsen M.

[63] Pedersen OM, Aardal NP, Larssen TB, Varhaug JE, Myking O, Vik-Mo H. The

[64] Schiemann U, Avenhaus W, Konturek J, Gellner R, Hengst K, Gross M. Relation

[65] Raber W, Gessl A, Nowotny P, Vierhapper H. Thyroid ultrasound versus antithyroid

[66] Loy M, Cianchietti ME, Cardia F, Melis A, Boi F, Mariotti S. Correlation of

[67] Vlachopapadopoulou E, Thomas D, Karachaliou F, Chatzimarkou F, Memalai L,

[68] Alos N, Huot C, Lambert R, Van Vliet G. Thyroid scintigraphy in children and

[69] Hancock SL, McDougall IR, Constine LS. Thyroid abnormalities after therapeutic external radiation. Int J Radiat Oncol Biol Phys. 1995; 31: 1165-1170.

[70] Bessho K, Etani Y, Ichimori H, Miyoshi Y, Namba N, Yoneda A, Ooue T, Chihara T,

[71] Mandel SJ, Brent GA, Larsen PR. Levothyroxine therapy in patients with thyroid

[72] Van Dop C, Conte FA, Koch TK, Clark SJ, Wilson-Davis SL, Grumbach MM.

[75] Ahmed M, Banna M, Sakati N, Woodhouse N. Pituitary gland enlargement in primary

[73] Lafranchi S. Thyroiditis and acquired hypothyroidism. Pediatr Ann 1992; 21: 32-39. [74] Kuroiwa T, Okabe Y, Hasuo K, Yasumori K, Mizushima A, Masuda K. MR imaging of

adolescents with Hashimoto disease. J Pediatr 1995; 127: 951-953.

consumptive hypothyroidism. Eur J Pediatr. 2010; 169: 215-221.

juvenile hypothyroidism. N Engl J Med 1983; 308: 1076-1080.

antibodies in Hashimoto's thyroiditis. Clin Endocrinol 1991; 35: 235-238. [62] Schmidt M, Voell M, Rahlff I, Dietlein M, Kobe C, Faust M, Schicha H. Long-term

Thyroid 2008; 18: 755-760.

thyroiditis. Med Sei Monit 2003; 9: 49-53.

Endocrinology & Metabolism 2009; 22: 339-344.

disease. Ann Intern Med 1993; 119: 492-502.

Clinical Imaging 1991; 15: 202–205.

32: 188-192.

subjects. Thyroid 2002; 12: 725-731.

10: 251-259.

2004; 32: 136-140.

Inuence of thyroxine treatment on thyroid size and anti-thyroid peroxidase

follow-up of antithyroid peroxidase antibodies in patients with chronic autoimmune thyroiditis (Hashimoto's thyroiditis) treated with levothyroxine.

value of ultrasonography in predicting autoimmune thyroid disease. Thyroid 2000;

of clinical features and laboratory parameters to thyroid echogenicity measured by standardized grey scale ultrasonography in patients with Hashimoto's

peroxidase antibody determination: a cohort study of four hundred fifty-one

computerized gray-scale sonographic findings with thyroid function and thyroid autoimmune activity in patients with Hashimoto's thyroiditis. J Clin Ultrasound

Vakaki M, Kaldrymides P, Michalacos S. Evolution of Sonographic Appearance of the Thyroid Gland in Children with Hashimoto's Thyroiditis. Journal of Pediatric

Morii E, Aoki T, Murakami M, Mushiake S, Ozono K. Increased type 3 iodothyronine deiodinase activity in a regrown hepatic hemangioma with

Pseudotumor cerebri associated with initiation of levothyroxine therapy for

pituitary hypertrophy due to juvenile primary hypothyroidism: a case report.

hypothyroidism: a report of 5 cases with follow-up data. Hormone Research 1989;


[45] Chong JY, Rowland LP. What's in a NAIM? Hashimoto encephalopathy, steroid-

[47] Körner A, Tóth-Heyn P, Dezsofi A, Veres G, Madácsy L, Arató A. Incidence of thyroid

[48] Schroner Z, Lazurova I, Petrovicova J. Autoimmune thyroid disease in patients with

[49] Shari F, Ghasemi L, Mousavinasab N. Thyroid function and antithyroid antibodies

[50] Araujo J, Brandão LA, Guimarães RL, Santos S, Falcão EA, Milanese M, Segat L, Souza

[51] Payami H, Joe S, Thomas G. Autoimmune thyroid disease type 1 diabetic families.

[52] Villano MJ, Huber AK, Greenberg DA, Golden BK, Concepcion E, Tomer Y.

[53] Ai J, Leonhardt JM, Heymann WR. Autoimmune thyroid diseases: Etiology,

[54] Tamimi DM. The association between chronic lymphocytic thyroiditis and thyroid

[55] Schäffler A, Palitzsch KD, Seiffarth C, Höhne HM, Riedhammer FJ, Hofstädter F,

[56] Okayasu I, Fujiwara M, Hara Y, Tanaka Y, Rose NR. Association of chronic

[57] Holm LE, Blomgren H, Lowhagen T. Cancer risks in patients with chronic lymphocytic

[58] Saravanan P, Dayan CM. Thyroid autoantibodies. Endocrinology and Metabolism

[59] Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA,

[60] Aksoy DY, Kerimoglu U, Okur H, Canpinar H, Karaagaoglu E, Yetgin S, Kansu E,

stage in thyroid carcinoma. Eur J Clin Invest 1998; 28: 838-844.

(NHANES III). J Clin Endocrinol Metab 2002; 87: 489-499.

Hashimoto's thyroiditis. Endocr J 2005; 52: 337-343.

Thyroid Research 2010; 2011:675-703.

J Allergy Asthma Immunol 2008; 31: 6-10.

tumors. Int J Surg Pathol 2002; 10: 141-146.

thyroiditis. N Engl J Med 1985; 312: 601-604.

Clinics of North America 2001; 30: 315-337.

Diabetes 2008; 9: 272-276.

Genet Epidemiol 1989; 6: 137-143.

diabetes mellitus. Bratisl Lek List 2008; 109: 125-129.

4012-4406.

1466.

659.

2318.

responsive encephalopathy associated with autoimmune thyroiditis, or nonvasculitic autoimmune meningoencephalitis? Arch Neurol 2006; 63: 175-176. [46] Cappa M, Bizzarri C, Crea F. Autoimmune Thyroid Diseases in Children. Journal of

autoimmunity in children with type 1 diabetes mellitus. Orv Hetil 2008; 149:

in Iranian patients with type 1 diabetes mellitus: inuence of age and sex. Iran

PR, de Lima-Filho JL, Crovella S. Prevalence of autoimmune thyroid disease and thyroid dysfunction in young Brazilian patients with type 1 diabetes. Pediatr

Autoimmune thyroiditis and diabetes: dissecting the joint genetic susceptibility in a large cohort of multiplex families. J Clin Endocrinol Metab 2009; 94: 1458-

pathogenesis, and dermatologic manifestations. J Am Acad Dermatol 2003; 48: 641-

Schölmerich J, Rüschoff J. Coexistent thyroiditis is associated with lower tumour

lymphocytic thyroiditis and thyroid papillary carcinoma. A study of surgical cases among Japanese, and white and African Americans. Cancer 1995; 76: 2312-

Braverman LE. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey

Gedik O. Effects of prophylactic thyroid hormone replacement in euthyroid


[76] Shih ML, Lee JA, Hsieh CB, Yu JC, Liu HD, Kebebew E, Clark OH, Duh QY. Thyroidectomy for Hashimoto's thyroiditis: complications and associated cancers. Thyroid 2008; 18: 729-734.

**3** 

*Belgium* 

**Primary Sjögren's Syndrome: Current** 

Christine Delporte1, Jason Perret1 and Muhammad S. Soyfoo1,2

*1Laboratory of Biological Chemistry and Nutrition, Université Libre de Bruxelles, Brussels,* 

Sjogren's syndrome (SS) is a chronic autoimmune disease characterized by the lymphocytic infiltration of exocrine glands, mainly the salivary and lachrymal glands entailing the classical sicca syndrome of xerostomia (Sjögren, 1933) and xeropthalmia. Lymphocytic infiltration of other organs results in systemic manifestations. SS is classified as either primary (pSS), when occurring alone, or secondary (sSS), when occurring in addition to other autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus or myositis. As one of the most frequent autoimmune disease, affecting approximately 0.5% of the world population, SS is often associated with other diseases such as Hashimoto thyroiditis, coeliac disease, Biermer's disease or systemic sclerosis. SS evolves as a slow, insidious disease affecting predominantly middle-aged women (female to male ratio of 9:1), SS lies at the cross roads of autoimmune diseases characterized by both cellular and humoral abnormalities. The disease typically affects middle-aged women around their fourth and fifth decades with extremes ranging from to 2 to 83 years. The morbidity of patients suffering from SS is incapacitating ranging from severe fatigue to evolving arthralgia. Even if the patients suffering from SS have a mortality rate comparable to the general population, they present an increased risk of developing lymphoma. The diagnosis of SS is based upon defined criteria according to the American-European consensus encompassing subjective and objective clinical signs and symptoms as well as immunological alterations. The pathogenesis of SS is complex and involves many components taking part in the autoimmune destruction of exocrine glands: proinflammatory cytokines secretion, apoptosis, matrix metalloproteases upregulation, autoantibody formation, as well as T and B cell proliferation. In SS, the classical histological findings in exocrine glands comprise focal inflammatory infiltrates, cell destruction and fibrosis in later stages of the disease. So far, SS treatment has been mainly symptomatic, consisting in relieving the clinical signs. However, recent pathophysiological findings have

The diagnosis of SS is currently essentially based on the American-European criteria. These criteria, 6 in total, include 2 subjective and 4 objective criteria. The subjective criteria are

**1. Introduction** 

led to the development of new treatments.

**2. Diagnostic criteria** 

**Pathophysiological, Diagnostic and** 

*2Division of Rheumatology, Erasme University Hospital Brussels,* 

**Therapeutic Advances** 

