ACQUIRED HYPOTHYROIDISM

1.      What is the most common causes of Acquired Hypothyroidism in children?
Autoimmune hypothyroidism i.e chronic lymphocytic hypothyroidism (Hashimotos thyroiditis )
 
2.      What are conditions associated with autoimmune thyroiditis?
·         Trisomy 21
·         Turners syndrome
·         Klinefelter Syndrome
·         Typ1 DM
·         APS 2 (Autoimmune polyglandular syndrome 2)
About 20% of Type 1 DM children develop hypothyroidism and 5% become hypothyroid.
 
Etiological Classification



1.      How often children with trisomy 21 develop hypothyroidism?
Approx 30% develop antibodies and 15-20% develops subclinical or overt hypothyroidism.
 
2.      How often in Turner’s syndrome?
Approx 40% develop Abs and 15-30% develops subclinical hypothyroidism.
 
3.      What is IPEX syndrome?
Immune dysregulation-Polyendocrinopathy-enteropathy and X-linked syndrome. It is often associated with autoimmune hypothyroidism.
 
4.      Williams Syndrome is associated with hypothyroidism but it is not autoimmune in origin.
 
5.      Amiadarone which is a class 3 antiarrhythmic drug contain 37% iodine by weight and can cause hypothyroididm in 20% of children treated with it.
 
6.      Anti epileptic drugs – phenytoin, phenobarbitone and valproate can cause hypothyroidism which may be due to activation of cytochrome p450 in liver which increases metabolism and clearance of T4.
 
7.      Oxcarbazepine which is an anticonvulsant can cause secondary hypothyroidism.
 
8.      Irradiation therapy used for malignancy and Bone marrow transplant can damage thyroid gland.
 
9.      Anti thyroid drugs, thyroidectomy and radioactive thyroid ablation for graves disease or thyroid cancer can also cause hypothyroidism.
 
10.  Cranial irradiation, Craniophharyngioma or tumour infiltration like langerhan cell histiocytosis can damage pituitary thyrotropes causing central hypothyroidism.
 
11.  Nephropathic cystinosis is a condition characterized by intralysosomal storage of cystine in body tissues.
·         They can acquire hypothyroidism and by 13 yrs 66% require thyroid hormone replacement.
 
12.  LCH i.e. Langerhan cell histiocytosis can also infiltrate thyroid and cause hypothyroidism.
 
13.  What are the symptomatic presentations of juvenile hypothyroidism?
The symptomatic presentations of juvenile hypothyroidism include
·         Short stature,
·         Delayed puberty,
·         Poor scholastic performance,
·         Precocious puberty (Van Wyk–Grumbach syndrome),
·         Myopathy (Kocher–Debre–Semelaigne syndrome)
·         Limping gait (stippled epiphysis and slipped femoral epiphysis),
·         Headache and visual field defects (thyro-lactotrope hyperplasia),
·         Diffuse goiter and
·         rarely, acute abdomen (huge multicystic ovaries and acute cholecystitis)
·         Pericardial effusion.








14.     How is the school performance in juvenile hypothyroidism?
Performance often declines, but it improves in some children, perhaps because they are less active and, therefore, less easily distracted and better able to concentrate. One reason for delay in diagnosis is that parents see the latter changes as positive.
 
15.      Why is short stature a common manifestation of juvenile hypothyroidism ?
·         Short stature with retarded bone age is a common manifestation of juvenile
·         hypothyroidism.
·         This is because thyroid hormone is required for GH secretion and GH-mediated IGF1 generation. In addition, thyroid hormone has a direct effect on growth plate and promotes differentiation of chondrocytes to hypertrophic chondrocytes and enhances angiogenesis.
 
16.      What are the unique features of precocious puberty associated with primary
hypothyroidism ?
·         The characteristic features of precocious puberty associated with primary
hypothyroidism are decreased growth velocity and retarded bone age, whereas
other causes of precocious puberty are associated with increased growth velocity
and advanced bone age.
·         Girls with precocity due to primary hypothyroidism usually present with vaginal bleed and/or thelarche, whereas boys present with isolated testicular enlargement.
·         Pubic/axillary hair is characteristically absent in both sexes despite precocity.
·         This is because precocious puberty associated with hypothyroidism is predominantly mediated through FSH, and lack of LH drive results in decreased androgen production.
·         In addition, thyroid hormone plays an important role in the growth and development of pilosebaceous unit.
 
17.      Why do patients with juvenile hypothyroidism develop precocious puberty?
·         Precocious puberty associated with primary hypothyroidism is gonadotropinin dependent.
 
·         Basal FSH is elevated; however, basal LH is low, and LH response to GnRH is prepubertal.
 
·         Precocious puberty in patients with primary hypothyroidism is due to the action of TRH and TSH on GnRH and FSH receptors, respectively (“specificity-spillover”).
 
·         The loss of feedback inhibition of T4 on hypothalamus results in elevated levels of TRH, which acts on GnRH receptors and preferentially stimulates FSH secretion.
 
·         As both TSH and FSH are glycoprotein hormones, elevated levels of TSH in patients with primary hypothyroidism act on FSH receptors in ovary and testes, to induce ovarian follicular growth and testicular enlargement, respectively.
 
 
18.      Why is FSH secretion high and LH is low in hypothyroidism?
·         LH secretion is suppressed as a result of hyperprolactinemia, which is a consequence of elevated TRH, whereas FSH secretion is driven by elevated TRH, even in presence of hyperprolactinemia.
 
19.      Why epiphseal stippling occurs in Hypothyroidism?
·         Thyroid hormone is essential for the development of growth plate; therefore, thyroid hormone deficiency/resistance results in fragmentation of ossification centers leading to
stippled epiphysis.
 
20.      How do we investigate a case of acquired hypothyroidism?
·         TFT
·         Anti-TPO Abs – Hashimotos thyroidoitis
·         Radionuclide study
·         Bone age determination by X ray
 
21.      A 6 - year - old girl presented with goiter. Thyroid function test revealed T 4 3 μ g / dl and TSH 32 μ IU / ml. What is the further process of evaluation?
·         The index child has primary hypothyroidism.
 
·         The common causes of primary hypothyroidism in children include Hashimoto’s disease and delayed- onset dyshormonogenesis.
 
·         Therefore, further evaluation includes estimation of antithyroid peroxidase antibody and perchlorate discharge test.
 
·         In addition, X-rays for bone age estimation should also be performed.
 
·         In children without goiter, 99m Tc pertechnetate scan should be performed to assess the presence/absence of ectopic thyroid tissue.
 
 
 
22.      A 11 - year - old girl presented with headache and visual impairment.MRI of brain was suggestive of a sellar – suprasellar mass and the child was referred toa neurosurgeon. Preoperative evaluation revealed T 4 2.4 μg / dl and TSH150 μ IU / ml ; prolactin 104 ng / ml ; cortisol 400 nmol / L with prepubertal LH ,FSH , and testosterone ; and low IGF1. Is surgery warranted?
 
·         In all patients with sellar–suprasellar mass, anterior pituitary function tests including T 4 , TSH, 0800h cortisol, prolactin, LH/FSH, testosterone/estradiol,and IGF1 should be done.
 
·         In the index child, hormonal profile was suggestive of primary hypothyroidism with hyperprolactinemia.
 
·         Low IGF1 in the index patient may be due to low T 4 or mass effect.
 
·         In a patient with primary hypothyroidism, presence of a sellar–suprasellar mass should raise a
suspicion of thyro-lactotrope hyperplasia.
 
·         In this scenario, optimal replacement with L-thyroxine not only reverses features of hypothyroidism but also results in visual improvement in 1–4 months followed by regression of thyrolactotrope hyperplasia.
 
Hence, surgery should be avoided in these patients.
 
23.  What are the height prospects in children with juvenile hypothyroidism?
·         Early diagnosis and optimal replacement therapy result in attainment of normal final adult height in children with juvenile hypothyroidism.
·         Children with long-standing hypothyroidism will experience catch-up growth after initiation of L-thyroxine; however, catch-up growth is often incomplete in these patients due to diminished chondrocyte reserve.
·         Children in the peripubertal age and those who are overzealously treated with L-thyroxine may
experience rapid skeletal maturation and, hence, compromised final adult height.
 
24.  What are the causes of lack of “catch - up growth ” in a child with juvenile hypothyroidism
who is on optimal L - thyroxine replacement ?
Failure to have a catch-up growth despite optimal L-thyroxine replacement in children with juvenile hypothyroidism should raise a suspicion of coexisting disorders like celiac disease, Turner syndrome, or growth hormone deficiency.
 
25.  How to treat and monitor juvenile hypothyroidism ?
·         Levothyroxine is the treatment of juvenile hypothyroidism.
·         The recommended daily dose of L-thyroxine in children aged 1–3 years is 4-6 μg/Kg, 3-5 μg/Kg in those between 3 and 1o years of age, and 2-4 μg/Kg in those aged 10-16 years, who have not completed the puberty.
·         However, in postpubertal children L-thyroxine should be administered at dose of 1.6–1.8 μg/Kg/day.
 
26.  How do we monitor therapy?
o   Both T 4 and TSH should be monitored till 3–4 years of age;
 
o   TSH should be maintained in the lower half of normal reference range (0.5–2.5 μIU/ml) and T 4 in the upper half of normal reference range.
 
o   TSH alone can be monitored every 4–6 monthly and 4-6 weekly whenever dosing are changed.
 
27.  What are the adverse effects of Levothyroxine therapy?
·         Poor school performance, restlessness, short attention span and behavioral problems may develop at the start of therapy which is transient and easily managed.
 
·         Persistent headaches, visual problems indicate pseudotumor cerebri which is a rare complication.
 
28.  What is the outcome of complications related to long - standing juvenile hypothyroidism ?
·         Long-standing severe juvenile hypothyroidism is associated with short stature,delayed puberty, thyro-lactotrope hyperplasia, multicystic ovaries, precocious puberty, pseudo-myohypertrophy, epiphyseal dysgenesis, and slipped capital femoral epiphysis.
 
·         Most of these manifestations usually reverse within 3–6 months of optimal L-thyroxine replacement. Although height improves after L-thyroxine therapy, final adult height is often subnormal in those with long-standing juvenile hypothyroidism.
 
·         Stippled epiphysis normalizes with L-thyroxine therapy but slipped capital femoral epiphysis need surgical intervention.
 
 
29.  Why are clinical manifestations less severe in children with secondaryhypothyroidism as compared to those with primary hypothyroidism?
 
o   This is because T 4 deficiency is usually mild in secondary hypothyroidism due to ongoing TSH-independent T 4 synthesis, which contributes to 10–15 % of circulating T4.
 
o   In addition, presence of concurrent multiple pituitary hormone deficiencies may mask the features of hypothyroidism.
 
o   However, in primary hypothyroidism T 4 deficiency is usually severe, and markedly elevated TSH contributes to myxedematous manifestations.
 
30.  How to treat a child with secondary hypothyroidism ?
·         Oral L-thyroxine is the therapy of choice in secondary hypothyroidism.
·         In  children with secondary hypothyroidism and coexisting glucocorticoid deficiency, glucocorticoid replacement should be initiated prior to L-thyroxine therapy, to prevent the risk of adrenal crisis.
·         L-Thyroxine requirement is usually lower in secondary hypothyroidism, as TSH-independent thyroid hormone biosynthesis continues in these patients.
 
31.  A 7 - year - old boy was evaluated for poor scholastic performance and thyroid function test showed T 4 4 μ g / dl and TSH 2.3 μ IU / ml. Patient was clinically euthyroid and serum - free T 4 was done which was normal. What is the likely diagnosis?
·         Low T 4 but normal FT 4 and TSH suggest the diagnosis of thyroxine-binding globulin (TBG) deficiency. TBG is a glycoprotein which binds approximately 70 % of circulating T 4 and 80 % of circulating T 3.
·         TBG deficiency is inherited as X-linked recessive disorder, with a prevalence of 1 in 5000 newborns.
·         The acquired causes of TBG defi ciency include nephrotic syndrome, hepatic failure,
and drugs like glucocorticoids and androgens.
·         However, these patients do not require L-thyroxine therapy as FT 4 is normal.