Thyroid Disease is the Most Common Endocrinopathy Observed in Children

Incidences, Presentations, and Clinical Consequences Differ Markedly than in adults

Failure to Diagnose and Treat Promptly may Lead to Irreversible Neurologic Damage

INTRODUCTION

Derived from pharyngeal endoderm at 4/40

Migrate from base of the tongue to cover the 2&3 tracheal rings.

Blood supply from ext. carotid & subclavian and blood flow is twice as renal blood flow/g tissue.

Starts producing thyroxin at 14/40.

THYROID GLAND

Orignates from thyroid diverticulum and ultimobranchial bodies

Ontogeny influenced by several transcription factors (TTF, PAX8, HOX3)

Largely complete by 10-12 weeks

Gradual Maturation in Hypothalamic-Pituitary-Thyroid Axis

Thyroid Development

• TSH detectable by 12 wks

• Feedback mechanisms established by 20 wks

• T3 levels remain low

• Reverse T3 levels high

Fetal Thyroid Maturation:

Maternal and fetal glands are independent

Little T4 transplacental transfer

TSH does not cross the placenta although it is

permeable to TRH, IgG, and thionamides

Fetal brain converts T4 to T3 efficiently

Effect of maternal hypothyroidism is most important in

first trimester

Placental and Fetal ThyroidMetabolism

Cord Blood Thyroid Levels are Influenced by gestational age

with Progressive increase with approach to term.

TSH surge at birth followed by T4 and T3 rise to approximates

maternal level but increases rapidly during the first week of life.

Lower rise in preterm Infants

High TSH in the first 5 days of life can give false positive

neonatal screening

Thyroid Changes at Birth

Iodine & tyrosine form both T3 & T4 under TSH stimulation.

10% of T4 production is autonomous and is present in patients with central hypothyroidism.

Less than 1% of T4 & T3 is free in plasma.

T4 is deiodinated in the tissues to either T3 (active) or reverse T3 (inactive).

When released into circulation T4 binds to:Globulin TBG 75%Prealbumin TBPA 20%Albumin TBA 5%

THYROID HORMONES

Is a Glico-protein with Molecular Wt of 28000

Secreted by the anterior pituitary under influence of TRH

It stimulates iodine trapping,oxidation,organification, coupling and proteolysis of T4 & T3

It also has trophic effect on thyroid gland

TSH

T4 & T3 are feed-back regulators of TSH

TSH is stimulated by a-adrenergic agonists

TSH secretion is inhibited by:

DopamineBromocreptineSomatostatinCorticosteroids

Conversion of T4 to T3 is decreased by:Acute & chronic illnessesb-adrenergic receptor blockersStarvation & severe PEMCorticosteroidsPropylthiouracilHigh iodine intake (Wolff-Chaikoff effect

THYROXINE (T4)

Total T4 level is decreased in:Premature infantsHypopituitarismNephrotic syndromeLiver cirrhosisPEMProtein losing entropathy

Total T4 is decreased with the following drugs :

SteroidsPhenytoinSalicylatesSulfonamidesTestosteroneMaternal TBII

Total T4 is increased with:Acute thyroiditisAcute hepatitisEstrogen therapyClofibrateiodidesPregnancyMaternal TSI

Thyroid hormones are essential for:

Linear growth & pubertal development

Normal brain development & function

Energy production

Calcium mobilization from bone

Increasing sensitivity of b-adrenergic receptors

to catecholeamines

•Congenital• Acquired

– Primary

Surgery

Radiation

Autoimmune

Iodine Deficiency

– Secondary

Surgery

Radiation

Infiltrative

Tumor

– Primary Thryoid Agenesis, Hypoplasia & mal-

descent

Dyshormonogenesis

Iodine Deficiency

– Secondary

Hypopituitarism Intake of goitrogens during

pregnancy

Idiopathic

Hypothyroidism

CONGENITAL HYPOTHYROIDISM

Incidence 1:4000

– Slightly higher in female infants

– Higher in Asian babies

– Lower in Black babies

Overt symptoms may not be present at birth

Profound effects on brain development, thus it is The most

common cause of preventable mental retardation in children

Reliable testing available (T4 and/or TSH)

No sequelae if treatment initiated by 4 wks– 10-15 mcg/kg/d

Epidemiology:

Relatively High Prevalence

Deleterious Consequence of Delayed

Diagnosis

Difficult ClinicalRecognition

Reliable Method of Screening

(sensitive & specific)

Safe, Effective Treatment available

Principles of NewbornScreening

Extensive testing for precise

etiology is generally not necessary (will not change immediate care plans)

May allow assessment of risk in future pregnancies

May allow early determination of transient vs permanent disease

Etiology of Congenital Hypothryoidism:

Defined as abnormal newborn screen with

abnormal confirmatory labs

75-80% of abnormal screens due to false +

Incidence estimated to be ~10% of cases

Most common in premature infants

Causes:

– Iodine deficiency or excess

– Maternal antithyroid medication

– Maternal TSH receptor blocking antibodies

Transient Congenital Hypothyroidism:

Incidence estimated at 1:180,000

Often history of treated Graves in mom

Mothers may have unrecognized hypothryoidism

Infant will not have goiter

Difficult to distinguish from thyroid dysgenesis May

have permanent neurocognitive deficit if present in utero

Resolves in 2-3 months as antibody clears

Maternal TSH receptor blocking antibodies:

A condition of severely stunted physical

and mental growth due to untreated

congenital deficiency of thyroid hormones (

congenital hypothyroidism)

Cretinism is :

Gestational age > 42 weeks

Birth weight > 4 kg

Open posterior fontanel

Nasal stuffiness & discharge

Macroglossia

Constipation & abdominal distension

Feeding problems & vomiting

Symptoms and Signs:

Non pitting edema of lower limbs & feet

Coarse features

Umbilical hernia

Hoarseness of voice

Anemia

Decreased physical activity

Prolonged (>2/52) neonatal jaundice

Dry, pale & mottled skin

Low hair line & dry, scanty hair

Hypothermia & peripheral cyanosis

Hypercarotenemia

Growth failure

Retarded bone age

Stumpy fingers & broad hands

Infantile proportions

Hip & knee flexion

Exaggerated lumbar lordosis

Delayed teeth eruption

Under developed mandible

Delayed closure of anterior fontanel

Skeletal abnormalities:

Hypotonia & later spasticity

Lethargy

Ataxia

Deafness + Mutism

Mental retardation

Slow relaxation of deep tendon jerks

Neurological manifestations

• Decreased bone turnover

• Decreased VIII, IX & platelets adhesion

• Decreased GFR & hyponatremia

• Hypertension• Increased levels of

CK, LDH & AST • Abnormal EEG &

high CSF protein• Psychiatric

manifestations

• Overt obesity

• Myopathy & rheumatic pains

• Speech disorder

• Impaired night vision

• Sleep apnea (central & obstructive)

• Anasarca

• Achlorhydria & low intrinsic factor

OCCASIONAL FEATURES

Autoimmune diseases (Diabetes Mellitus)

Cardiomyopathy & CHD

Galactorrhoea

Muscular dystrophy + pseudohypertrophy

(Kocher-Debre-Semelaigne)

ASSOCIATIONS

• Most common cause of aquired hypothyroidism

• Female: male ratio 3:1

• Most children presents with asymptomatic

goiter or non specific Symptoms

• Most frequent in Down and turner syndromes

Hashimoto thyroiditis

Early detection by neonatal screening

High index of suspicion in all infants with

increased risk

Overt clinical presentation

Confirm diagnosis by appropriate lab and

radiological tests

DIAGNOSIS

Low (T4, RI uptake & T3 resin uptake)

High TSH in primary hypothyroidism

High serum cholesterol & carotene levels

Anaemia (normo, micro or macrocytic)

High urinary creatinine/hydroxyproline ratio

CXR: cardiomegaly

ECG: low voltage & bradycardia

LABROTARY FINDINGS

X-ray films can show:Delayed bone age or epiphyseal dysgenesis

Anterior peaking of vertebraeCoxavara & coxa plana

Thyroid radio-isotope scan

Thyroid ultrasound

CT or MRI

IMAGING TESTS

Confirm all abnormal newborn screens with laboratory TSH and free T4

Borderline results may require repeat testing in 2-4 Wks

If repeat labs abnormal, begin thryoxine (25-37.5 mcg/day)

Goal is to start treatment within first month of life

Recheck q 2-3 months and adjust dose if Necessary

If no need to increase dose by 2 ½ -3 yrs, give 4 wk trial off of thyroxine

Treatment Guidelines

Life-long replacement therapy

5 types of preparations are available:

•L-thyroxin (T4)

•Triiodothyronine (T3)

• Synthetic mixture T4/T3 in 4:1 ratio

•Desiccated thyroid (38mg T4 & 9mg T3/grain)

•Thyroglobulin (36mg T4 & 12mg T3/grain)

TREATMENT

L-Thyroxin is the drug of choice. Start with small dose

to avoid cardiac strain.

Dose is 10 mg/kg/day in infancy. In older children start

with 25 mg/day and increase by 25 mg every 2 weeks till

required dose.

Monitor clinical progress & hormones level

Is good for linear growth & physical features

even if treatment is delayed

for mental and intellectual development early

treatment is crucial.

Sometimes early treatment may fail to

prevent mental subnormality due to severe

intra-uterine deficiency of thyroid hormones

PROGNOSIS

• Acquired

– Inflammation

– Colloid

– Iodine Deficiency

– Goiterogen

– Infiltrative disease

– Toxic goiter

– Thyroglossal duct

cyst

– Adenoma

– Carcinoma

• Congenital

– Dyshormonogenesis

– Maternal Antibodies

• Blocking

• Stimulating

– Maternal Antithyroid drug

PTU, methimazole

– TSH receptor Activating

Mutation

– McCune Albright Syndrome

– Thyroid Tumor

Goiter: Differential Diagnosis

• Usually euthryoid

• Diffuse gland enlargement

• Rare in US (iodized salt provides adequate iodine

source)

• Rule out autoimmune thyroiditis

• Treament Doses in Children (6-12 months)

– Infants 100 mcg/d

– Children 200 mcg/day

– Adolescents 200-300 mcg/d

Endemic Goiter:

• Graves Disease (>95% of Cases)

– Relatively rare in children

– Incidence increases with puberty

– Female:Male (3-5:1)

• Neonatal Graves; Transplacental Antibodies

• Hashitoxicosis

• TSH receptor mutations (gain of function); McCune Albright syndrome

• Subacute Thyroiditis

• Exogenous thyroxine Exposure

Hyperthyroidism:

• Almost always transient

• Usually associated with maternal Graves:

– Transplacental passage of TSI

– Blocking and stimulating Abs may coexist

• Incidence ~1:50,000 infants

– 1-2% of moms with Graves disease

• Often presents in first week of life

– Emerges with clearance of maternal thionamide

Neonatal Hyperthyroidism

– PTU or Methimazole

– SSKI (If severe symptoms)

– Propranolol (If significant sympathetic

symptoms (HR>160)

• Treatment:

• Change in School Performance

• Insomnia

• Restlessness and Irritability

• Nocturia

• Bone age advancement

• Infants: Premature birth, Craniosynostosis, Poor

feeding, Failure to Thrive

Signs of Hyperthyroidism in Children

• Other classic signs:

– Weight Loss, Polyphagia, Tachycardia, Increased

Pulse

Pressure, Heat Intolerance, Diarrhea, Tremor

• Suppressed TSH

• Elevated T4, Free T4, T3 levels

• Positive Thyroid Stimulating Antibodies:

(May be helpful if exophthalmos absent)

– Thyroid Peroxidase

– Thyroglobulin

– Thyroid Stimulating Immunoglobulin

Grave’s Disease: Diagnosis

• Radioactive Iodine

– Preferred treatment in older children and adolescents

– Theoretical risk of radiation not established

– Possible increased risk of thryoid cancer (<5yrs)

• Thionamides (methimazole, PTU)

– Agranulocytosis, hepatitis, rash

– Poor long term remission rates

– Difficult to titrate dose, frequent monitoring

– Poor compliance in adolescents

• Surgical Thyroidectomy; Rarely indicated

Treatment of Graves’ Disease

• Diffuse enlargement of thryoid gland evident

usually during pubertal years

• Normal thyroid function tests

• Often family history

• May represent mild autoimmune thryoiditis; TPO Ab titer may be helpful to distinguish

• May be associated with nodular goiter as adults

• Therapy usually not necessary; May respond to thryoid suppression (controversial)

Colloid (Nontoxic) Goiter

• Low Prevalence in Children (0.2% <16 yrs)

• Higher Incidence of Malignancy (18-22%)

• Evaluation:

– Ultrasound can assist in detection but not helpful to distinguish benign from malignant nodules

– Uptake scan generally not helpful (Hot nodules can be malignant)

– Fine needle aspiration (90% accuracy)

– Excisional biopsy

• Majority are due to colloid cysts or follicular adenomas

Thryoid Nodules

Carcinoma is rare (1.5% in kids <15 yrs)

– Papillary Carcinoma ~85-90%

– Medullary Carcinoma ~5%

– Follicular and Anaplastic Carcinoma

• Risk Factors:

– Ionizing Radiation (esp if < 5 yrs)

– Iodine Deficiency

– Autoimmune thyroiditis

– Prolonged TSH elevation

– Family history (MEN)

Thyroid Cancer