Transcript Maternal TSH receptor blocking antibodies

INTRODUCTION
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
THYROID GLAND
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 Development
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
Fetal Thyroid Maturation:
• TSH detectable by 12 wks
• Feedback mechanisms established by 20 wks
• T3 levels remain low
• Reverse T3 levels high
Placental and Fetal Thyroid
Metabolism
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
Thyroid Changes at Birth
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 HORMONES
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%
TSH
 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
 T4 & T3 are feed-back regulators of TSH
 TSH is stimulated by a-adrenergic agonists
 TSH secretion is inhibited by:
Dopamine
Bromocreptine
Somatostatin
Corticosteroids
THYROXINE (T4)
Conversion of T4 to T3 is decreased by:
Acute & chronic illnesses
b-adrenergic receptor blockers
Starvation & severe PEM
Corticosteroids
Propylthiouracil
High iodine intake (Wolff-Chaikoff effect
Total T4 level is decreased in:
Premature infants
Hypopituitarism
Nephrotic syndrome
Liver cirrhosis
PEM
Protein losing entropathy
 Total T4 is decreased with the following drugs :
Steroids
Phenytoin
Salicylates
Sulfonamides
Testosterone
Maternal TBII
 Total T4 is increased with:
Acute thyroiditis
Acute hepatitis
Estrogen therapy
Clofibrate
iodides
Pregnancy
Maternal 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
Hypothyroidism
• Acquired
•Congenital
– Primary
– Primary

Thryoid Agenesis, Hypoplasia
descent
 Dyshormonogenesis
Surgery
& mal-
 Radiation
 Autoimmune
Iodine Deficiency
 Iodine Deficiency
– Secondary
– Secondary
Surgery
 Hypopituitarism

Intake of goitrogens during
pregnancy
Idiopathic
Radiation
Infiltrative
Tumor
Epidemiology:
 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
Principles of Newborn
Screening
Relatively High Prevalence
Deleterious Consequence of Delayed
Diagnosis
Difficult ClinicalRecognition
Reliable Method of Screening
(sensitive & specific)
Safe, Effective Treatment available
Etiology of Congenital Hypothryoidism:
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
Transient Congenital Hypothyroidism:
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
Maternal TSH receptor blocking
antibodies:
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
Cretinism is :
A condition of severely stunted physical
and mental growth due to untreated
congenital deficiency of thyroid hormones
(congenital hypothyroidism)
Symptoms and Signs:
Gestational age > 42 weeks
Birth weight > 4 kg
Open posterior fontanel
Nasal stuffiness & discharge
Macroglossia
Constipation & abdominal distension
Feeding problems & vomiting
 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
Skeletal abnormalities:
Infantile proportions
Hip & knee flexion
Exaggerated lumbar lordosis
Delayed teeth eruption
Under developed mandible
Delayed closure of anterior fontanel
Neurological manifestations
Hypotonia & later spasticity
Lethargy
Ataxia
Deafness + Mutism
Mental retardation
Slow relaxation of deep tendon jerks
OCCASIONAL FEATURES
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Overt obesity
Myopathy &
rheumatic pains
Speech disorder
Impaired night vision
Sleep apnea (central
& obstructive)
Anasarca
Achlorhydria & low
intrinsic factor
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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
ASSOCIATIONS
 Autoimmune diseases (Diabetes Mellitus)
 Cardiomyopathy & CHD
 Galactorrhoea
 Muscular dystrophy + pseudohypertrophy
(Kocher-Debre-Semelaigne)
Hashimoto thyroiditis
• 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
DIAGNOSIS
 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
LABROTARY FINDINGS
 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
IMAGING TESTS
 X-ray films can show:
Delayed bone age or epiphyseal dysgenesis
Anterior peaking of vertebrae
Coxavara & coxa plana
 Thyroid radio-isotope scan
 Thyroid ultrasound
 CT or MRI
Treatment Guidelines
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
TREATMENT
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)
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
PROGNOSIS
 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
Goiter: Differential Diagnosis
• Congenital
• Acquired
– Dyshormonogenesis
– Inflammation
– Maternal Antibodies
– Colloid
• Blocking
– Iodine Deficiency
• Stimulating
– Goiterogen
– Maternal Antithyroid drug
– Infiltrative disease
PTU, methimazole
– Toxic goiter
– TSH receptor Activating
– Thyroglossal duct
Mutation
cyst
– McCune Albright Syndrome
– Adenoma
– Thyroid Tumor
– Carcinoma
Endemic Goiter:
• 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
Hyperthyroidism:
 • 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
Neonatal 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
• Treatment:
– PTU or Methimazole
– SSKI (If severe symptoms)
– Propranolol (If significant sympathetic
symptoms (HR>160)
Signs of Hyperthyroidism in Children
 • Change in School Performance
 • Insomnia
 • Restlessness and Irritability
 • Nocturia
 • Bone age advancement
 • Infants: Premature birth, Craniosynostosis, Poor
feeding, Failure to Thrive
• Other
classic signs:
– Weight Loss, Polyphagia, Tachycardia, Increased
Pulse
Pressure, Heat Intolerance, Diarrhea, Tremor
Grave’s Disease: Diagnosis
• Suppressed TSH
• Elevated T4, Free T4, T3 levels
• Positive Thyroid Stimulating Antibodies:
(May be helpful if exophthalmos absent)
– Thyroid Peroxidase
– Thyroglobulin
– Thyroid Stimulating Immunoglobulin
Treatment of Graves’ Disease
 • 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
Colloid (Nontoxic) Goiter
 • 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 )
Thryoid Nodules
 • 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
Thyroid Cancer
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)