**12. Diagnosis**

32 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

type II/III, ovarian failure, Down syndrome, Klinefelter's syndrome, Turner's syndrome), infectious (Hepatitis C infection), neurologic (Miller Fisher syndrome, Guillain-Barre´ syndrome, multiple sclerosis, myasthenia gravis) and renal diseases (minimal change

The coexistence of papillary thyroid carcinoma and HT is not known exactly, but it is reported to range from 10% to 58% in various studies (54,55). The prevalence of HT in patients with papillary thyroid carcinoma has been reported to be signicantly higher than with benign thyroid tumours (56). Patients with HT are suggested to be at higher risk for

Although the level of TSH may be slightly or even moderately raised in some individual's thyroid function tests are often normal, termed subclinical hypothyroidisms (37). In a study from iodine-replete area, twenty-four patients (21%) were euthyroid, 48 (42%) had compensated hypothyroidism, and 42 (37%) had hypothyroidism (including two patients with transient hyperthyroidism reversed to hypothyroidism within weeks). There was no difference in clinical symptoms of hypothyroidism by thyroid status, except for a higher rate of constipation in the hypothyroid group (38). The fact that many children with lymphocytic thyroiditis do not have elevated levels of TSH indicates that the goiter may be caused by the

In normal individuals, positive anti-TPO were detected in 13.0 ± 0.4%, and positive Anti-Tg was detected in 11.5 ± 0.5%. The prevalence of positive antibodies was lower in the diseasefree population: Anti-TPO, 11.3 ± 0.4% and Anti-Tg, 10.4 ± 0.5%. The prevalence of positive Anti-TPO and positive Anti-Tg in the total and disease-free population was higher in females than males (P< 0.001) and increased with age, especially among females. Approximately 18% of the disease-free population had detectable Anti-Tg or Anti-TPO of those with positive Anti-Tg, 69.9% also had positive Anti-TPO; and of those with positive Anti-TPO, 54.5% also had positive Anti-Tg. Anti-TPO was positive alone in 4.4%, and Anti-Tg was positive alone in 3.4%. Anti-TPO and Anti-Tg were detected together in 6.9% (59). Almost all young children with HT have serum antibody titres to TPO, but the anti-Tg test for thyroid antibodies is positive in fewer than 50%. Antibodies to TPO and Tg are found equally in adolescents with HT. When both tests are used, approximately 95% of patients with thyroid autoimmunity are detected. Levels in children and adolescents are lower than those in adults with HT, and repeated measurements are indicated in questionable instances because titres may increase later in the course of the disease (37). Results about decreasing Anti-TPO under LT4 treatment have been found variable with 10% and 90% after a followup of 6 to 24 months (60,61). Decreasing Anti-TPO under LT4 treatment appears to depend

papillary thyroid carcinoma compared with patients without HT (57)

lymphocytic infiltrations or by thyroid growth-stimulating immunoglobulins.

on time, a 45 % decrease after 1 year and a 70% decrease after 5 years (62).

Thyroid ultrasonography is a useful tool to support the diagnosis, and classical sonographic findings are present in 20-95% of affected individuals (63). Furthermore, their presence is related to subclinical hypothyroidism and levels of thyroid autoantibodies (64,65), and ultrasonography has been used for the follow-up of patients (66). Thyroid ultrasonography is usually heterogeneous because of fibrosis and hypoechogenic areas, it is not necessary for

glomerular disease) (53).

**10. Laboratory findings** 

**11. Imaging** 

Hashimoto's thyroiditis is diagnosed based on findings of seropositivity for Tg autoantibodies and/or TPO autoantibodies, accompanied by at least one of the following: abnormal thyroid function; enlarged thyroid gland; morphological changes on thyroid ultrasound. If anti-TPO antibodies are absent, less common etiologies of primary hypothyroidism should be considered for example transient hypothyroidism due to postsubacute thyroiditis, hypothyroidism related to external irradiation (69) and consumptive hypothyroidism due to the inactivation of thyroid hormone by the paraneoplastic expression of type III iodothyronine deiodinase, mostly in vascular tumors (70).

The typical patient with hypothyroidism secondary to HT has an elevated TSH, a low fT4, and positive anti-TPO antibodies. In early stages of the disease, TSH may be normal and anti-TPO antibodies may be positive with or without goiter. Later, TSH elevation becomes modest (5-10 IU/mL) with a normal fT4 (biochemical or subclinical hypothyroidism). Up to 90% of patients with hypothyroidism secondary to HT have positive anti-TPO antibody (46). If HT is suggested and thyroid autoantibodies are negative, they should be controlled later. It is possible to raise in follow-up.

### **13. Treatment**

Most of these patients are asymptomatic, but studies in the adult population suggest that individuals with the combined risk factors of TSH level above the normal limit and positive thyroid antibodies (anti-Tg or anti-TPO) are at high risk for progression to overt hypothyroidism. For this reason, thyroid hormone replacement is recommended in all patients with TSH values >10 IU/mL or with TSH values >5 IU/mL in combination with goiter or thyroid autoantibodies (71). Levothyroxine is the replacement therapy of choice. There are almost no adverse reactions; its good intestinal absorption and its long half life of 5-7 days allow oral administration once a day. Although very rare, the development of pseudotumor cerebri associated with the initiation of LT4 has been described in a few school-age children (72). Alternatively, a starting dose can be estimated based upon the patient's age and ideal body weight (73). The medication's long half-life insures a gradual equilibration over the course of 5 – 6 weeks, and dosing should be individualized based on biochemical monitoring (73). TSH normalization (0.5-2 micro IU/mL) is the goal of replacement. This will usually be associated with an fT4 in the upper half of the normal range. Thyroid function tests should be obtained about 6-8 weeks after the beginning or next

Hashimoto's Thyroiditis in Children and Adolescents 35

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).

hypothyroidism is permanent and potentially restart therapy.

lymphomatosa). Arch Klin Chir 1912; 97: 219-248.

**15. References** 

682.

107: 63-66.

2007; 83: 209-216.

Medicine 1996; 335: 99-107.

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

[1] Hashimoto H. Zur kenntniss der lymphomatosen veranderung der schilddruse (struma

[2] Setian NS. Hypothyroidism in children: diagnosis and treatment. Jornal de Pediatria

[3] Rallison ML, Dobyns BM, Keating FR, Rall JE, Tyler FH. Occurrence and natural history

[4] Brown RS: Thyroid disease in infancy, childhood and adolescence. In: Braverman LE (ed). Contemporary Endocrinology. Totowa, Humana Press, 1997, 81-102. [5] Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. New England Journal of

[6] Weetman AP. Autoimmunity and endocrinology. Exp Clin Endocrinol Diabetes 1999;

[7] Villanueva R, Greenberg DA, Davies TF, Tomer Y. Sibling recurrence risk in

autoimmune thyroid disease. Thyroid 2003; 13: 761-764.

of chronic lymphocytic thyroiditis inchildhood. Journal of Pediatrics 1975; 86: 675-

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

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 antidepressants and seizure medications.

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 intellectual damage or neurologic decit is probable.

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. One patient had an incidental thyroid lymphoma (77).
