**6. Diagnostic studies to determine an underlying etiology**

Since additional investigations for etiology do not alter the treatment plan they can be delayed. Treatment of CH should never be deferred after confirmation pending the determination of etiology.

### **6.1. Thyroid radionuclide uptake and scan**

Thyroid radionuclide uptake and scanning is the most accurate imaging modality to determine the size and location of thyroid tissue. Iodine123 (I123) or sodium pertechnetate 99 m (Tc99m) are tracers of choice as I131 delivers a higher dose of radioactivity. Radionuclide uptake and scan is used to identify thyroid aplasia (absent uptake), hypoplasia (decreased uptake, small gland in a eutopic location) or an ectopic gland. Other conditions not showing any uptake include; TSHβ gene mutations, TSH receptor inactivating mutations, iodide trapping defects and in those with maternal thyrotropin receptor blocking antibodies (TRBAb). Dyshormonogenesis beyond trapping of iodide results in a large gland in a eutopic location with increased uptake on the scan. A perchlorate discharge test can be performed to confirm the diagnosis of dyshormonogenic CH.

#### **6.2. Thyroid ultrasound**

infants that might have "delayed TSH elevation" whereas measuring TSH first and then T4 also detects mild or subclinical forms of hypothyroidism. Broadly speaking, if the screening T4 value is less than 10th percentile of cut off and/or the TSH is greater than 40 mU/L, the infant should be called again for confirmatory serum testing. In cases having "intermediate results," TSH 20–40 mU/L, recommendation is to repeat TSH screening in early second week

Diagnosis must not be completely and solely reliant on the screening tests only they must be confirmed by serum testing, venipuncture blood should be drawn and serum should be sent for TSH and free T4, or total T4 and T3 resin uptake as some measure of binding proteins. These serum based results must be compared with age normalized values as during the first week of life TSH and T4 are fluctuant [32]. Most confirmatory serum tests could be obtained in first 2 weeks of life, as during this upper TSH range has fallen to an around 10 mU/L.Although all hormones are higher during first week of age they come down to infancy range within 2–4 weeks.

A low total serum T4 or free T4 level along with an elevated serum TSH level confirms the diagnosis of primary hypothyroidism and levothyroxine (LT4) must be started immediately after the confirmatory tests are done even before the results are available. Before age of 2 weeks, venous TSH >20 mIU/L and after 2 weeks, TSH > 10 mIU/L, suggests primary CH [33]. Serum T4 < 10 μg/dL (<128 nmol/L) or FT4 < 1.17 ng/dL (<15 pmol/L) is considered

A transient or permanent thyroid dysfunction or delayed maturation of the hypothalamic–pituitary axis is indicated by normal levels of total T4 or free T4 along with elevated TSH. Initiating levothyroxine in such cases is still controversial. Since TSH concentration is the most sensitive indicator of hypothalamic-pituitary-thyroid axis therefore when confirmatory serum TSH level is between 6 and 20 mIU/L with normal FT4 levels, it is reasonable to watch serum thyroid function tests closely (every 1–2 weeks) and not start LT4 and if TSH is increases or if FT4 decreases to below normal level, treatment should be initiated. After 2 weeks of age a TSH > 10 mU/L is

Hypothalamic immaturity particularly in preterm infants, in infants during illness, in central hypothyroidism or in primary hypothyroidism and delayed TSH elevation low T4 with normal TSH may be seen. No guidelines exists for the followup of these patients, but they

considered abnormal [34, 35]. And if TSH elevation persists, the infant must be treated.

of life. A TSH value <20 mIU/L is considered as normal.

**4.2. Confirmatory serum thyroid testing**

**5.1. Low T4 and elevated TSH values**

**5.2. Normal T4 and elevated TSH values**

**5.3. Low T4 and normal TSH values**

**5. Test results**

8 Thyroid Disorders

low in infancy.

When it comes to etiology determination thyroid ultrasound is usually the first modality performed. It confirms thyroid aplasia when radionuclide scan show absent uptake. TSHβ gene mutations, TSH receptor inactivating, iodide trapping defect and maternal TRBAb shows the absence of radionuclide uptake in the presence of thyroid gland in the normal position. Dyshormonogenesis is associated with absent uptake in radionuclide scan and large thyroid in ultrasound. Color Doppler flow may be able to detect up to 90% of cases of ectopic thyroid [37].

#### **6.3. Serum thyroglobulin (Tg) measurement**

Serum thyroglobulin is reflective of the thyroid mass and is usually raised in increased activity of the thyroid gland. In a recent study, Beltrão et al., suggested that color Doppler ultrasound combined with serum thyroglobulin measurement may become very valuable tools for the diagnosis of the cause of CH and will also help minimize more harmful tests, like radionuclide scan [38]. Increased thyroglobulin levels and absent uptake on radionuclide scan suggests presence of thyroid gland along with a TSH receptor inactivating mutation, a trapping defect, or maternal TRBAb, rather than aplasia.

### **6.4. Thyroid receptor antibody**

Transient CH in children can also be caused by maternal thyroid receptor blocking antibodies TRBAb. Absent radionuclide uptake with small or normal sized eutopic gland suggests transient congenital hypothyroidism as a result of transplacental passage of the antibody from the mother to the child. For confirmation the measurement of serum TRB-Ab in mother and/or infant may be done by a thyrotropinbinding inhibitor immunoglobulin (TBII) assay.

**7.3. Dosages**

those started on lower initial doses of 37.5 μgm [45].

overtreatment with levothyroxine in CH children [52].

• At 2 and 4 weeks after the initiation of lthyroxine treatment.

• Every 1–2 m during the first 6 m of life.

• Every 3–4 m between 6 m and 3 years of age

• Every 6–12 m thereafter until growth is complete

**7.4. Target concentrations**

**8. Follow-up**

For the optimal neurodevelopmental outcome, the treatment goal is to normalize T4 and TSH within 2 and 4 weeks respectively [33, 43, 44]. In a study infants had significant lower cognitive, attention and achievement scores who took more than 2 weeks to normalize thyroid function compared to infants who attained normal thyroid function at 1 or 2 weeks of treatment [45]. Adequacy and the timing of treatment determines optimal neurodevelopmental outcome and thus American academy of pediatrics and European society of pediatric endocrinology recommend 10–15 μgm/kg/day as initial dose [46]. Studies show that this dose normalizes serum T4 within 3 days and TSH within 2–4 weeks. To achieve these goals, it is important to start higher initial dose of the recommended range in case of severe CH. In a study infants who were started on higher initial doses of 50 μgm had fullscale IQ scores 11 points higher than

Congenital Hypothyroidism

11

http://dx.doi.org/10.5772/intechopen.81129

The target T4 concentrations lies in the upper half of reference range according to the Guidelines issued by the American academy of pediatrics and European society for pediatric endocrinology [30, 47–49]. Target values for T4 being 10–16 μgm/dl; FT4 1.4–2.3 ng/dl and TSH <5 μU/dl (optimally 0.5–2.0 μU/dl) for initial 3 years of life following this T4 should be kept in the upper half of normal range. Low IQ in infants with T4 concentration below 10 μgm/dl and TSH above 15 μU/dl was seen during the first year of life compared to those had serum T4 more than 10 μgm/dl [50]. Better intellectual outcome in children with CH was seen with higher doses of levothyroxine (lthyroxine) [51]. Contrary to this other studies have shown behavior problems like increased anxiety, social withdrawal and poor concentration with higher doses in children at age of 8 years. Thus demonstrating potential dangers of

Congenital anomalies are also more frequent in CH than in general population (10% in CH compared to 3% in general population) most common of these anomalies is cardiac malformation particularly pulmonary stenosis, atrial septal defect and ventricular septal defect. Adequate monitoring is required to maintain the thyroid functions within the recommended levels. The

American Academy of Pediatrics recommends the following monitoring schedule [53].

## **6.5. Urinary iodine estimation**

24 h urinary iodine excretion approximates the iodine ingestion. For neonates the normal range is approximately 50–100 mg/24 h. Urinary iodine measurement may provide confirmation regarding iodine deficiency or excess.
