Hyperthyrotropinaemia in Children and Adolescents diagnosis treatment and

everything in between

Marie Noufi Barhoum March 2013 Kibbutz lavi

• A 12 years old healthy girl • Referred to endocrinologist with suspected

hypothyroidism • Her grandmother suffer from hypothyroidism • Physical examination : height 75 percentile, weight 90

percentile, BMI 85 percentile, no goiter • Laboratory tests: TSH:8.18, 4.67 mu/L (0.4-4.2 mu/L ) FT4:14.2, 16 pmol/L (10.7-18.7pmol/L) Negative anti-TPO, anti-TG • Normal thyroid gland at ultrasound

What is the diagnosis? How to follow up and treat?

Subclinical hypothyroidism hyperthyrotropinaemia

Subclinical hypothyroidism (SH) or :hyperthyrotropinaemia

is defined as a raised serum thyroid stimulating hormone (TSH) associated with normal total or free thyroxine (T4) and triiodothyronine(T3) Arch Dis Child 2011

MJ O’GRADY

In most laboratories the normal upper limit is

4.5-5 mU/L

Arq Bras Endocrinol Metab Oct.2010

The normal TSH range is defined as range in which 95% of values in healthy

people fall

The prevalence in the adult population in most community-based studies is 1-10% The prevalence in the pediatric population seems to be slightly lower than 2%

JCEM July 2009

Rapa et al

The diagnosis of SH is determined mainly by laboratory evaluations because it has been observed that most patients exhibit few or no signs or symptoms of thyroid dysfunction The abnormalities most frequently associated in the pediatric population are: weight gain, increased cholesterol levels, impaired growth velocity, anemia, sleepiness, weakness, and impaired psychomotor and cognitive development

Differential Diagnosis:

Maternal blocking Ab’s

*Maternal anti thyroid drug (PTU, metimazole) Endemic iodine deficiency Maternal iodine exposure Environmental newborn iodine exposure

*Abnormalities of the embryological process

unilateral hypoplasia hemiagenesis

*Abnormalities in hormone synthesis

Development of thyroid gland

Migration, bifurcation, proliferation, differentiation

The thyroid is the first endocrine gland to develop and begins on the 24th day of gestation as a midline proliferation of endoderm on the floor

of the pharynx

At 10 weeks gestation the thyroid gland can uptake iodine

and produce thyroxine

Iodide transport defect ( NIS) Organification defects (TPO) Pendered syndrome (Pendrin) Thyroglobulin defect Iodotyrosine deiodinase defect TSH-R defect

Subclinical or transient hypothyroidism Family history of thyroid disease Maternal thyroid disease Passage of TSH blocking IgG from mother

to fetus (by placenta)

Placental permeability for various thyroid related substances

Thyroidal causes Hashimoto’s thyroiditis* TSH-R gene variations* Overtreatment of Graves’ disease Iodine deficiency Subacute thyroiditis Nonthyroidal causes Overweight/Obese subjects* Anti thyroid drugs* Soya-based milk formulae* Radiotherapy for head and neck malignancies Untreated adrenal insufficiency Hetrophilic antibodies Williams syndrome B-Thalassemia major Cystic fibrosis Chronic renal failure

• The most common cause of hypothyroidism or

goiter above 6 years old

• Family history of thyroid disease in 30-40%

• More common in girls than in boys (7-folds)

• Prevalence : 3-8:1000

• Diffuse goiter -80-90%

• Positive antibodies- anti TPO, anti TG

• Subclinical hypothyroidism 30-40%

• Spontaneous remission in 30%

• Cyclic nature-hypothyroidism,euthyroid,hyperthyroidism

Chromosomal disorders: Down syndrome Turner syndrome Klinefelter syndrome

Autoimmune disorders: Type 1 diabetes mellitus Celiac disease

Hypoparathyroidism, Addison’s disease, chronic -1Type mucocutanaeous candidiasis.10-15%- Thyroiditis autoimmune. (Autoimmune Polyendocrinopathy –candidiasis-ectodermal dystrophy (APECED- AIRE gene)

, Addison 1DM typeAutoimmune thyroiditis (major component), -2Type

disease. Premature ovarian failure, lymphocytic hypophysitis, vitiligo, alopecia areata, celiac disease, pernicious anemia, myasthenia gravis. Rheumatic disorders: RA, SLE, Sjogren’s disease, temporal arteritis Others: Chronic active hepatitis, Billiary cirrhosis, dermatitis herpetiformis, autoimmune thrombocytopenia.

Polyglandular syndrome

Loss of function mutations Hypothyroidism Gain of function mutations Hyperthyroidism Somatic mutation in the TSH-R Autoimmune toxic adenoma

• TSH-R is located on the plasma membrane

• It activate G-protein , adenyl -cyclase cyclic- AMP pathway

• Located on chromosome 14

• 10 axons (9 for the extracellular portion and axon 10 for the intracellular portion)

)OMIM#275200( TRH CRH

GnRH Somatostatin

TSH LH

HCG ACTH PTH

•First described in 1995

•Autosomal recessive inheritance

•Known about 49 mutation

•Overt hypothyroidism or hyperthyrotropinaemia without goiter

•The frequency of heterozygous mutation in some population is 1:172

Most of the loss of function mutation are located in the

extracellular domain

highest prevalence (29%) of TSHR gene mutations in children and adolescents with non-autoimmune subclinical hypothyroidism not selected by neonatal screening

Nicoletti et al. JCEM 2009

•increased leptin-mediated production of pro-TRH •impaired feedback due to a lowered number of T3 receptors in the hypothalamus •variations in peripheral deiodinase activity abnormalities in thyroid function and TSH mostly normalize

after weight loss, independent of whether the loss is obtained with diet or bariatric surgery

high TSH levels

A consequence Not a cause

Radetti et al JCEM 2008

Antiepileptic drugs (AEDs): • Carbamazepine • Sodium valproate • Gabapentin interferon therapy in children with chronic

hepatitis B Soya-based milk formulae- isoflavones

Subclinical Hypothyroidism in Children and Adolescents

Children and adolescents (1-18 yr):(88 patients) 1. A slight to moderate elevation of circulating

TSH 2. Normal free thyroid hormone levels 3. Negative thyroid auto antibodies * TSH (μIU/ml) Range 4.6 - 20.3 (0.35-4.5) clinical characteristics, biochemical

parameters, and TSH-R gene variations were evaluated

Rapa et al JCEM 2009

TSH levels according to the presence of overweight/obesity, positive family history of thyroid diseases, and hypoechogenicity at thyroid US. Data are represented as median (point),

interquartile range (box), and 10th-90th percentiles (whiskers).

Rapa A et al. JCEM 2009;94:2414-2420

©2009 by Endocrine Society

Molecular analysis of TSH-R gene They identified in the TSH-R gene a total of 19 known

variations (all of them are in the heterozygous state) The prevalence of positive family history of thyroid

diseases was 1.9-fold higher in patients with a nonsynonymous mutation in the TSH-R gene than in patients without any detected mutation

Rapa et al JCEM 2009

Idiopathic subclinical hypothyroidism= Idiopathic

hyperthyrotropinaemia Is it always a predictor of thyroid dysfunction ? What is the natural history of initial abnormal TSH ? Who is at greater risk for developing a thyroid dysfunction?

Natural History of Thyroid Function Tests over 5 Years in a Large Pediatric Cohort

CHMO ensured the health care of 1.043 million children and adolescents aged from 0.5 to 16 yr. These were found to include 145,270 patients who had undergone TSH determination in 2002

Excluded: 1. thyroid dysfunction 2. documentation of previous radioactive iodine treatment 3. treatment with medications that may interfere with

thyroid functions 4. Pregnancy 5. subjects lost to follow-up

Lazar L et al. JCEM 2009

Natural History of Thyroid Function Tests over 5 Years in a Large Pediatric Cohort

Remaining 121,052 patients(11.6%)

9.1% of the boys and 14.1% of the girls

TSH testing increased with age(24% of 12–16 year old children)

Being determined more frequently among the girls

the cause for TSH measurement was not specified

Lazar L et al. JCEM 2009

Natural History of Thyroid Function Tests over 5 Years in a Large Pediatric Cohort

1. TSH levels within the normal range (0.35–5.5 mIU/liter)96.5%

2. low TSH levels (<0.35 mIU/liter)0.2% 3. elevated TSH levels (>5.5 to ≤10 mIU/liter)2.9% 4. highly elevated TSH levels (>10 mIU/liter) 0.4% subclinical hypothyroidism was diagnosed in approximately

3% Overt thyroid dysfunction was detected in < 1%

Positive antithyroid antibodies: 60.4% when TSH > (>10 mIU/liter 23.6% when TSH >5.5 to ≤10 mIU/liter 15.9% when TSH 0.35–5.5 mIU/liter

Lazar L et al. JCEM 2009

Distribution of TSH results in the second test according to the category of the first TSH measurements in untreated patients (tests were performed between 2002 and 2006).

Lazar L et al. JCEM 2009;94:1678-1682

©2009 by Endocrine Society

Throughout the 5 yr of follow-up, hypothyroidism requiring medical

intervention was diagnosed in 0.4% of the cohort. This population constitutes 51.2% of patients with initial highly elevated TSH levels (>10 mIU/liter) and 8.5% of patients

with initial elevated TSH levels (5.5–10 mIU/liter).

A second highly elevated TSH concentration was significantly higher in patients with initial

TSH levels >7.5 mIU/liter and in female gender

Natural History of Thyroid Function Tests over 5 Years in a Large Pediatric Cohort

Lazar L et al. JCEM 2009

2-year follow-up the spontaneous changes in TSH and FT4 values in a healthy pediatric population

• Ninety-two selected patients with ‘idiopathic’ SH • incidental finding of elevated TSH concentrations in their

usual annual checkup • Thyroid ultrasonography (US) was normal and thyroid

autoimmunity was negative

M.Wasniewska et al Eur J.Endo 2009

• 41.3% out of 92 patients normalized their TSH values during follow-up • 46.7% maintained their TSH within the initial values • 12% underwent a deterioration of thyroid function, as demonstrated by

an increase in TSH values • this results was more evident in the pubertal patients than in the

prepubertal ones, it was not significantly affected by either sex, or FT4 levels or familial antecedents of thyroid diseases

• TSH changes were not associated with any changes in either FT4 values or clinical status or auxological parameters

M.Wasniewska et al Eur J.Endo 2009

• TSH levels in healthy individuals tend to fluctuate during the day

• Recovery from “Non-Thyroidal Illness” • Mild AIT Which recovers or improves

Controversy exists on whether infants and children with SH require thyroxine supplementation:

• Growth and puberty • Peak bone mass • Impair cognitive development • Increased cardiovascular risk (low HDL)

In children < 3 years old: •Follow cognitive development and growth parameters •Measure TSH,FT4 every 3-6 month

If TSH,FT4 are stable during two years, follow up every 3-5 years

• An increasing number of children undergo thyroid testing • SCH is a very common finding in children • Several etiologies have been identified • The majority of elevated TSH levels either revert to

normal or remain mildly elevated • Progression to overt hypothyroidism is rare • Monitoring rather than immediate treatment may be the

preferred strategy • high prevalence of TSHR gene mutations in children and

adolescents with non-autoimmune subclinical hypothyroidism