THE THYROID
The Thyroid Gland
• The thyroid is a small (25 grams) butterfly-shaped gland located at the base of the throat. The largest of the endocrine glands, it consists of two lobes joined by the isthmus. The thyroid hugs the trachea on either side at the second and third tracheal ring, opposite of the 5th, 6th and 7th cervical vertebrae. It is composed of many functional units called follicles, which are separated by connective tissue.
• Thyroid follicles are spherical and vary in size. Each follicle is lined with epithelial cells which encircle the inner colloid space (colloid lumen). Cell surfaces facing the lumen are made up of microvilli and surfaces distal to the lumen lie in close proximity to capillaries.
The Thyroid Gland• Formation of the thyroid gland occurs during weeks 7-9 of gestation as an
epithelial proliferation of the floor of the pharinx at the site of foramen cecum linque. The gland riches its final position by week 9 descending along the thyro-glosal duct.
• Weeks 7-9 : thyroid formation begins• Week 10 : TSH and T4 are detectable• Week 17 : structural maturity of the thryoid gland• Week 20 : type 2 and type 3 deiodinase are present• Weeks 18 – 40 :
– TRH present– TSH is present and controls thyroid hormone production– Fetal thyroid response to TSH - thyroid hormone to TRH and TSH hormone
feed established
Thyroid anatomy
Microscopic appearance of thyroid follicles
Thyroid hormones in the body
Thyroid hormones synthesisThe thyroid is stimulated by the pituitary hormone TSH to produce two
hormones, Thyroxine (T4) and triiodothyronine (T3) in the presence of iodide. Hormone production proceeds by six steps:
1. Dietary iodine is transported from the capillary through the epithelial cell into the lumen NIS and Pendrin.
2. Iodine is oxidized to iodide by the thyroid peroxidase enzyme (TPO) and is bound to tyrosine residues on the thyroglobulin molecule to yield monoiodotyrosine (MIT) and diiodotyrosine (DIT).
3. TPO further catalyzes the coupling of MIT and DIT moieties to form T4 and/or T3.
4. The thyroglobulin molecules carrying the hormones are taken into the epithelial cells via endocytosis in the form of colloid drops.
5. Proteolysis of the iodinated hormones from thyroglobulin takes place via protease/peptidase action in lysosomes and the hormones are released to the capillaries.
6. Any remaining uncoupled MIT or DIT is deiodinated to regenerate iodide and tyrosine residues.
Iodine metabolism in normal thyroid cellsTSH signaling via the TSH receptor (which is shown at the bottom of the thyrocyte on the left) controls thyroid hormone synthesis, and it can increase expression of NIS in the basolateral membrane of thyrocytes. As shown in the thyrocyte on the right, NIS takes up iodide from the blood. The proteins involved in efflux of iodide at the apical membrane are not known, and the roles of AIT and pendrin are unclear. As shown in the left-hand thyrocyte, iodide is organified in the tyrosyl residues of Tg in a reaction catalyzed by TPO, in the presence of H2O2, which is produced by DUOX. Tg contains MIT, DIT, T3, and T4 and is stored in colloid until T3 and T4 need to be released into the blood.
ION TRANSPORT BY THETHYROID FOLLICULAR CELL
I- I- organification
Propylthiouracil (PTU) blocks iodination of thyroglobulin
COLLOID
BLOOD
NaI symporter (NIS) and pendrine
Thyroid peroxidase (TPO)
ClO4-, SCN-
TSHTSH receptor
Iodination ofTyr residues of Tg
COLLOID
TPO
THYROGLOBULIN SYNTHESIS IN THETHYROID FOLLICULAR CELL
THYROID HORMONE SECRETION BY THETHYROID FOLLICULAR CELL
COLLOID
TSHTSH receptor
DITMIT I-
T4T3
O OH
I
I
II
OH
O
NH2
Thyroxine (T4)
O OH
I
I
IOH
O
NH2
3,5,3’-Triiodothyronine (T3)
THYROID HORMONES
Thyroid hormone transport
• bound to thyroxine-binding globulin (TBG): 70%
• bound to transthyretin or "thyroxine-binding prealbumin" (TTR or TBPA):10-15%
• Paralbumin: 15-20%
• unbound T4 (fT4): 0.03%
• unbound T3 (fT3): 0.3%
FEEDBACK REGULATIONTHE HYPOTHALAMIC-PITUITARY-THYROID AXIS
Hormones derived from the pituitary that regulate the synthesis and/or secretion of other hormones are known as trophic hormones.
Key players for the thyroid include:
TRH - Thyrophin Releasing Hormone
TSH - Thyroid Stimulating Hormone
T4/T3 - Thyroid hormones
Control of thyroid function
TRHThyrotropin releasing hormone is produced by the
hypothalamus and functions to stimulate the anterior pituitary to release TSH. TRH is a small tripeptide that acts in conjunction with somatostatin and dopamine to regulate the synthesis and release of TSH in a dose dependent manner. Dysfunction at this stage in the stimulatory cascade results in decreased TSH production and hence hypothyroidism, termed a tertiary thyroid disorder. While thyroid hormones T4 and T3 down-regulate TSH in a classic feedback inhibition scheme, TRH production is also inhibited the these thyroid hormones, albeit to a lesser degree, in the hypothalamus.
Control of thyroid functionTSH
Thyroid stimulating hormone (TSH) or thyrotropin is a glycoprotein with a molecular weight of approximately 28,000 daltons, synthesized by the basophilic cells (thyrotropes) of the anterior piyuitary TSH is composed of two noncovalently linked subunits designated alpha and beta. Although the alpha subunit of TSH is common to luteinizing hormone (LH), follicle stimulating hormone (FSH) and human chorionic gonadotropin (hCG), the beta subunits of these glycoproteins are hormone specific and confer biological as well as immunological specificity. Both alpha and beta subunits are required for biological activity. TSH stimulates the production and secretion of the metabolically active thyroid hormones, thyroxine (T4) and triiodothyronine (T3), by interacting with a specific receptor on the thyroid cell surface. T3 and T4 are responsible for regulating diverse biochemical processes throughout the body which are essential for normal development and metabolic and neural activity.
THYROID HORMONES ACTIONS
OO
H
NH 2
II
I
IO
H
O
T4
I
I
OH
OR
3,3’-T2
II
I
OH
O
R
T3
“Step up”
I
I
IO
H
O
R
rT3
“Step down”
THYROID HORMONE METABOLISM
OO
H
NH 2
R =
THYROID HORMONE DEIODINASES
• Three deiodinases (D1, D2 & D3) catalyze the generation and/disposal of bioactive thyroid hormone.
• D1 & D2 “bioactivate” thyroid hormone by removing a single “outer-ring” iodine atom.
• D3 “inactivates” thyroid hormone by removing a single “inner-ring”iodine atom.
• All family members contain the novel amino acid selenocysteine (SeC) in their catalytic center.
extracellular domain
A
C
B E
D
intracellular domain
NH2
COOH
BASIC ORGANIZATION OF THE SELENODEIODINASES
EXISTS AS ADIMER
BASICS OF THYROID HORMONE ACTION IN THE CELL
SPECIFIC ACTIONS OF THYROID HORMONE: METABOLIC
• Regulates of Basal Metabolic Rate (BMR).
• Increases oxygen consumption in most target tissues.
• Permissive actions: TH increases sensitivity of target tissues to catecholamines, thereby elevating lipolysis, glycogenolysis, and gluconeogenesis.
• TH is critical for normal development of the skeletal system and musculature.
• TH is also essential for normal brain development and regulates synaptogenesis, neuronal integration, myelination and cell migration.
• CRETINISM is the term for the constellation of defects resulting from untreated neonatal hypothyroidism.
SPECIFIC ACTIONS OF THYROID HORMONE: DEVELOPMENT
THYROID HORMONES MECHANISM OF ACTIONS
• Passive diffusion or active transport?• Deiodination of T4 to T3• T3 binds to specific nuclear receptor• Nuclear receptor activation increases RNA and protein
synthesis • Increased Na/K aATP-ase and ATP turn-over• Increased oxigen consumption in mitochondrias• Calorigenic effects
THYROID HORMONES ACTIONS
• Increase basal metabolic rate• Increase heat production through stimulation of Na/K ATP-ase• Stimulate protein synthesis• Regulate long bone growth synergistic with GH• Stimulate neuronal maturation• Increase number of cathecolamine receptors• TH are essential for normal development and differentiation of
all cells of the human body• Increase lipid catabolism / lypolisis• Increase glucose uptake and metabolism
• Growth, development, body temperature, energy metabolism regulation
Thyroid hormones are responsible for neuronal mielinization
EXAMPLES OF THYROID DISEASES
Hypothyroidism Hyperthyroidism
EXAMPLES OF THYROID DISEASES
Congenital HypothyroidismJuvenile Hypothyroidism
Physiological system Hyperthyroidism (thyrotoxicosis)
Hypothyroidism
skin --appendages
warm, moist skin; sweating; fine, thin hair; Plumber's nails; pretibial dermopathy (Graves' disease)
pale, cool, puffy skin; brittle hair and nails
Eyes, face Upper lid retraction (wide stare); periorbital edema; exophthalmos, diplopia (Graves' disease)
Eyelid drooping; periorbital edema; puffy, nonpitting facies; large tongue
Physiological system Hyperthyroidism (thyrotoxicosis)
Hypothyroidism
Cardiovascular decreased peripheral resistance, increased cardiac output, stroke volume, heart rate, pulse pressure; congestive heart failure (high-output); increased contractility,. arrhythmogenic; angina
increased peripheral resistance, decreased cardiac output, stroke volume, heart rate, pulse pressure; congestive heart failure (low output); bradycardia (low voltage ECG with prolonged PR interval, flat T wave); pericardial effusion
Respiratory dyspnea; reduced vital capacity
hypoventilation (CO2 retention) pleural effusions
Physiological system Hyperthyroidism (thyrotoxicosis)
Hypothyroidism
CNS Nervousness, hyperkinesia, variable emotional states
lethargy, neuropathy
Gastrointestinal increased appetite; increased bowel movement frequency; hypoproteinemia
decreased appetite, decreased bowel movement frequency; ascites
Physiological system Hyperthyroidism (thyrotoxicosis)
Hypothyroidism
Musculoskeletal Weakness; fatigue; hypercalcemia, osteoporosis, increased deep tendon reflex
muscle fatigue, reduced deep tendon reflex, increased alkaline phosphatase, LDH, AST
Renal Increased renal blood flow; increased GFR; mild polyuria
Decreased renal blood flow; decreased GFR; reduced water excretion
Physiological system Hyperthyroidism (thyrotoxicosis)
Hypothyroidism
Hematopoietic anemia (increased RBC turnover); increased erythropoiesis
anemia (decrease production rate, decreased iron absorption, decreased folate acid absorption, autoimmune pernicious anemia),decreased erythropoiesis
Reproductive decreased fertility; menstrual irregularity; enhanced gonadal steroid metabolism
infertility;hypermenorrhea decreased libido; impotence, decreased gonadal steroid metabolism
Physiological system Hyperthyroidism (thyrotoxicosis)
Hypothyroidism
Metabolic increased basal rate; negative nitrogen balance, hyperglycemia; increased free fatty acids, decreased cholesterol and triglycerides; increased hormone degradation; increased requirement for fat-and water-soluble vitamins; enhanced drug detoxification
decreased basal rate; delayed insulin degradation, with increased sensitivity; enhanced cholesterol and triglyceride levels; decreased hormone degradation; decreased requirements for fat-and water-soluble vitamins; decreased drug detoxification.
Normal ultrasound appearence of the thyroid gland
Calculation of thyroid volume
Formula of a rotationg elipsoid a = AP diameter APb = Transverse diameterc = longitudinal diameter
I a x b x c x / 6II a x b x c x 0.479III a x b x c x 0.53IV a x b x c x 0.5
Malignant thyroid nodule
Thyroid scintigraph
Thyroid scintigraph with 123IThe nodule on the right lobe appears to be hypofunctioning (cold nodule).
Magnetic resonance imaging:
large goiter and anaplastic carcinoma of the thyroid
Thyroid computed tomography multiple malignant nodules
Thyroid computed tomography – large multinodular goiter
TSH, T4 and T4 assessment and their values in thyroid diseases
Thyroid function tests – decisional algorithm
ENDEMIC GOITERIodine Deficiency Disorders
Role of iodine and sources
• Fetal body and brain development• Hearing system development• Normal prenatal body function
• Animal products: meet, milk• Water• Factors that interfere with iodine metabolism:
goitrogens: cassava, cabage, tiocyanates, fluoride, selenium deficiency
Iodine Deficiency
• Goiter in children and adults / increased volume of thyroid gland
• Severe mental retardation• Growth failure• Speech and hearing defects• Low intelectual capacity even in mild iodine
deficiency• Cretinism: neurologic or mixedematous ( when
iodine deficiency and selenium coexist)
IDDs
• Prenatal: mental retardation, low birth weight, increased prenatal death
• Newborn: goiter, transient hypothyroidism, definitive hypothyroidism, increased frequency of congenital mixedema
• Childhood and adolescence: goiter, growth and mental retardation, hypothyroidism: clinical or subclinical
• Adulthood : – goiter and complications, including thyroid nodules and
aggressive follicular cancer– Endemic mental retardation– Hypothyroidism– Reduces fertility
IDDs – normal iodine supply
• 50 μg for infants less than 12 month• 90 μg for children ( 2-6 years of age)• 120 μg for scholl children (7-12 years of age)• 150 μg for adult beyond 12 years of age• 200-250 μg for lactating women
IDDs – a worldwide health problem
1. 1.6 billion people at risk
2. 50 millions of children at risk
3. 100,000 cretins are borned each year• Africa
– Population at risk: 220 million– Fetal death: 15,000– Cretins: 30,000– Brain- demaged children: 1 million
• China– Endemic goiter prevalence: 8.4-85 %– Endemic cretinism: 0.63-11.4 %
IDDs – evalution
1. Clinically: O – normal, I – palpable, II – visible in normal position of the neck
2. Calculation of thyroid volume• Normal for adult men: up to 25 mL• Normal for adult women: up to 18 mL
3. Biochemical :• urinary iodine :10 μg / dL• Serum TSH slightly increased > 5 mIU/L• Serum thyroglobuline: less than 10 ng/mL in adults• Maternal milk: 9 μg / dL
IDDs severity of iodine deficiency
Assessed variable Normal Mild Moderate Severe
Goiter adults %
Thyroid volume over normal %
Urinary iodine μg/dl
Serum thyroglobuline ng/mL
<5
<5
>10
>10
5 - 19.9
5 - 19.9
5 - 9.9
10 - 19.9
20 - 29.9
20- 29.9
2 - 4.9
20 – 39.9
> 30
> 30
<2
>40
Newborns
TSH in serum > 5 mIU/L
Urinary iodine ng/mL
< 3
> 10
3 – 19.9
3.5 – 9.9
20 – 39.9
1.5 – 3.4
> 40
< 1.5
“historical” huge endemic goiter
Histology in endemci goiter: Inequal follicles
Large intrathoracic goiter
Endemic cretinism with goiter mixedematous:
short stature, hipothyroidism, mental retardation
Endemic cretins – neurologic
Spastic paresis, severe mental retardation, deafness
Most effected areas by IDDs
• Himalaya
• Central Africa
• South America – Andine areas
Urinary iodine excretion per liter after
Universal Salt Iodization program implementation
Goiter prevalence varies inversely with iodine excretion which is the witness of iodine intake
Endemic goiter prevalence before and after iodine replacement
Goiter prevalence in South America
In spite of iodine replacement programs goiter prevalence still increases due to increase population at risk and discontinous survey
of results
IDDs profilaxis
• Iodine given as:– Iodisyzed salt– Iodizyzed oil, injectable – Universal Salt Iodization Program: advocacy,
implementation, continuous survey
Goiter was practically eradicated in Europe but small areas with borderline deficiency still exist
First country in which goiter was eradicated was Switzerland
In our country still exist areas with mild endemic goiter
HYPOTHYROIDISM
HYPOTHYROIDISMClinical and biochemical syndrome that results from thyroid
hormone defiency and slow metabolic rateIn chiledrean and adolescents hypothyroidism results in slow
growth rate and mental retardation
In all cases hypothyroidism results:• in reduced basal metabolic rate • Reduced oxigen consumption• Deposition of glycosamino glicans in the extracell space
especially in muscles and skin with water infiltration that may be severe in untreated hypothyroidism and classic aspect of MIXOEDEMA
Signs and symptoms of hypothyroidism are all reversible under treatment except for untreated congenital hypothyroidism
ADULT HYPOTHYROIDISM INCLUDING CHILDHOOD AND ADOLESCENCEND CAUSESPRIMARY HYPOTHYROIDISM:1. Hashimoto’s thyroiditis
a. with goiterb. without goiter late stage of autoimmune thyroiditis with thyroid fybrosis
2. Radioactive iodine treatment for Graves’ disease3. Thyroidectomy for Graves’ disease, nodular goiter or thyroid cancer 4. Excessive iodine ingestion, including contrast media (effect Wolf – Chaikoff 5. Subacute thyroiditis transient6. Severe iodine deficiency7. Drugs: litium, interpheron alpha, amiodarone
SECONDARY HYPOTHYROIDISM • MULTIPLE PITUITARY HORMONE DEFICIENCY OR ISOLATED
TERTIARY hypothyroidism – hypothalamic dysfunction
SYNDROME OF GENERALISED THYROID HORMONE RESISTANCE
HYPOTHYROIDISM: pathogeny
• Reduction of basal metabolic rate• Reduced oxigen consumption• Deposition of glycosamino glicans in the
extracell space especially in muscles and skin with water infiltration that may be severe in untreated hypothyroidism and classic aspect of MIXOEDEMA
• Slow function of neurons
HYPOTHYROIDIS IN ADULTSIGNS AND SYMPTOMS
COMMON FEATURES FOR SEVERE AND MODERATE HYPOTHYROIDISM:
• Fatigability• Cold intolerance• Moderate increase in weight • Constipation• Menstrual abnormalities, heavy menstrual bleeding• Muscle crampsPhysical examination:• Cold, dry skin• Undepresible edema of hands and feet• Voce răguşită• Reflexe lente• Carotenodermie
HYPOTHYROIDIS IN ADULTSIGNS AND SYMPTOMS
Cardio vascular system: • Bradicardia• Abnormal contractility of ventricular walls (Ultrasound) • Pericardial effusion (ultrasound) • Incresed vascular resistance
ECG:• Hypovoltage of QRS waves• Increased cholesterol, LDL-cholesteron, lypprotein A and
Homocisteine which act as atherogenic factors
• Low basal meabolic rate in hypothyroid old patients may be protective for angina
HYPOTHYROIDIS IN ADULTSIGNS AND SYMPTOMS
Lung function: • Slow respiratory rate• Abnormal response to hypoxia and hypercapnia wich
may be involved with onset of mixoedema coma • Digestive system:• Chronic constipation Marcat redusă cu constipaţie
cronică şi eventual ileus Kidney function
• Reduces glomerular rate filtration• Inability to excrete free water with secondary water
intoxication and severe hyponatremia
HYPOTHYROIDIS IN ADULTSIGNS AND SYMPTOMS
Anemia: • Iron deficency• Anability to have normal folate absorbtion • Vitamin B12 and megaloblastic anemia• Association with autoimmune anemia in patients with
Hashimoto’s thyroiditisNervous and muscular system:• Severe muscle cramps• Paresthesias• Muscle weakness
HYPOTHYROIDIS IN ADULTSIGNS AND SYMPTOMS
Reproductive system:• Anovulaţion şi infertility • Heavy menstrual bleeding
Central nervous system: • Chronic weakness• Letargy• Inability ot concentrate• Slow speech• Loss of memory• Depression • Extreme agitation (“mixoedema meadness)
HYPOTHYROIDISM IN ADULTSRARE FEATURES
• Neurastenia• Paresthesias• Persistent weakness• Infertility • Precocious or delayed puberty• Idiopatic edema or pericardial efusion• Chronic rhinitis and hoarse voice due to
infiltration of vocal cards • Severe depression or emotional instability
HIPOTIROIDISMUL LA ADULTSEMNE ŞI SIMPTOME
Anemia: • Deficit de fier şi sinteza anormală a hemoglobine• Deficit de folat datorită tulburărilor de absorbţie • Deficit de vitamina B12 şi anemie megaloblastică• Tiroidita hashimoto ca maladie autoimună se poate asocia cu
anemia megaloblastică, altă afecţiune autoimună
Neuromuscular system:• Crampe musculare severe• Paresezii• Astenie musculară
HYPOTIROIDISM - DIAGNOSIS
Patients does not take thyroid hormones
TSH and fT4
fT4 low
TSH increased
PRIMARY HYPOTHYROIDISM
Ft4 low
TSH normal or decreased
SECONDARY HYPOTHYROIDISM
Patient takes thyroid hormonesi
Stop medication for 6 weeks
fT4 normal
TSH normal
EUTIROIDISM
US, antiTPO, anti Tg antibodies
Assess pituitary
Subclinical hypothyroidism
TSH
Increased TSH Low T4 and T3 Low TSH Low T4 and T3
Primary hypothyroidism Secondary hypothyroidism
Low urinary iodine, Increased I uptake
Iodine deficiency
Increased
Antithyroid antibodies
Autoimmune thyroiditis
History of thyroid surgery, antithyroid drugs
Radioiodine
for hyperthyroidism
Increased iodine excretion: iodine excess
TRH test
Negative
Pituitary failure
Positive
Hypothalamic disease
Subclinical hypothyroidism: increased TSH, low or normal fT4
• Risk factor for atherosclerosis• Adverse effect on hearth function• Abnormal lipid profile• Adverse effects on fetal development if subclinical
hypothyroidism is ignored during pregnancy • Increased prevalence of depression • Abnormal coagulability
Prevalence of suclinical hypothyroidism increases with age
HYPOTYROIDISM COMPLCATIONS
• ATEROSCLEROSIS: major risk factor for atherosclerosis
• Reduced vascular compliance and flux-endothelial mediated vascular dilataiton
• Hearth function abnormalities (ultrasound)– Increased vascular resistance– Decreased left ventricular ejction fraction– Decreased vascular compliance
HYPOTYROIDISM COMPLCATIONS
Mixoedema coma is a very rare complication which occurs in untreated hypothyroidism in
certain favoring conditions: winter time, untreated hearth or lung disease, stroke, sedatives given to untreated patients
Clinical features:• Pregressive weakness• hypotermia• hypoventilation• hypoglicaemia• hyponatremia• Shock • Death in more than 50 % (to 80% of cases)
Mixoedema coma clinical characteristicsHistory: hypothyroidism known by relatives, radioiodine treatment for
Graves disease, post thyroidectomy scar The development of coma is slow and progressive to gradual
development of letargy and coma
Clinical examination:• Frequently the patient is an old woman with hypotermia, pale and
yeloww skin, hoarse voice• Large tonque, edema of the face and extremities, ileus• Slow reflexes• Signs of other diseases: stroke, myocardial infarction, digestive
hemorrhage, hypocalcemia, seizures • other:• pleural effusion, peritoneal or pericardic effusion
Mixoedema coma – pathophysiology
CO2 retention• Hypoxia este determed by reduced sensitivity of respiratory
centers to oxigen deficiency and hyper CO2, reduced respiratory muscles efficiency, obesity. It need assisted ventilation
• Reduced kidney perfusion with water retention, hyponatremia and cerebral edema.
• Hypotermia due to TH deficiency central body temperature may drop to 340C
Treatment • High doses of glucocorticoides : hydrocortisone acetate100mg. i.v.
followed by 50 mg. every 6 h• T4 in high dose: 300-400μg i.v. followed by 80 % of substitution
dosage every day • These high doses may worsen angina or precicpitate arrhitmias
Mortalitaty may be up to 80 %
HYPOTHYROIDIS - TREATMENT
LEVOTIROXINE – T4• Has a half life of 7 days and this allows to be taken once a day • Has a good absorbtion which allows to maintain a stable concentration
during the day • All dose must be taken in the morning on an empty stomach• Monitoring treatment: serum TSH and fT4 every 3 month• Serum T4 may be increased 4 h after T4 is taken but without clinical
problems• The dose for complete subsittution in an adult is 2.2 μg/kg.bw/d• The full dose must be done from the beginning of treatment in patients
under 45 (50) years• In older patients treatment begin with low dose of 25 μg day for 7 -14
daysdays with increase in dosage with 25 μg every 7-14 days till full replacement dose is reached
• The dosage is adhusted every 4-6 week in order to maintain THS in the normal limits:0.4-4 mIU/L
CONGENITAL HYPOTHYROIDISM - CAUSES
1. PRIMARY HYPOTHYROIDISM IN THE NEWBORN:a. WITH GOITER: • Imborn erors in thyroid hormone synthesis • Severe iodine deficiency (mixedematous endemic cretinism)• Transient hypothyroidism in arias with severe iodine deficiency
b. Without goiter• Thyroid agenesis or hypogenesis• Due to trans placental passage of thyroid bloking antibodies from
mother with autoimmune thyroiditis (transient)
2. SECONDARY HYPOTHYRIIDISM IN THE NEWBORN Congenital TSH deficiency usually associated with other pituitary
hormone deficiency
Classification and etiology of congenital hypothyroidism Primary hypothyroidismThyroid dysgenesis: hypothyroidism due to a developmental anomaly(Thyroid ectopia, athyreosis, hypoplasia, hemiagenesis)Associated mutations: (these account for only 2% of thyroid dysgenesis cases; 98% unknown)TTF-2,NKX2.1,NKX2.5PAX-9Thyroid dyshormonogenesis: hypothyroidism due to impaired hormone productionAssociated mutations:Sodium-iodide symporter defectThyroid peroxidase defectsHydrogen peroxide generation defects (DUOX2, DUOXA2 gene mutations)Pendrin defect (Pendred syndrome)Thyroglobulin defectIodotyrosine deiododinase defect (DEHAL1, SECISBP2 gene mutations)Resistance to TSH binding or signalingAssociated mutations:TSH receptor defectG-protein mutation: pseudohypoparathyroidism type 1a
Syndromic hypothyroidism
Pendred syndrome - (hypothyroidism- deafness - goiter) Pendrin mutationBamforth-Lazarus syndrome - (hypothyroidism - cleft palate - spiky hair) TTF-2 mutationEctodermal dysplasia - (hypohidrotic - hypothyroidism - ciliary dyskinesia)Hypothyroidism - (dysmorphism - postaxial polydactyly - intellectual deficit)Kocher - Deber - Semilange syndrome - (muscular pseudohypertrophy- hypothyroidism)Benign chorea - hypothyroidismChoreoathetosis - (hypothyroidism - neonatal respiratory distress) NKX2.1 /TTF-1 mutationObesity - colitis - (hypothyroidism - cardiac hypertrophy - developmental delay)
Transient congenital hypothyroidism
Maternal intake of antithyroid drugs
Transplacental passage of maternal TSH receptor blocking antibodies
Maternal and neonatal iodine deficiency or excess
Heterozygous mutations of THOX2 or DUOXA2
Congenital hepatic hemangioma/hemangioendothelioma
Central hypothyroidism (syn: Secondary hypothyroidism)
Isolated TSH deficiency (TSH b subunit gene mutation)Thyrotropin-releasing hormone deficiencyIsolated, pituitary stalk interruption syndrome (PSIS), hypothalamic lesion, e.g. hamartomaThyrotropin-releasing hormone resistanceTRH receptor gene mutationHypothyroidism due to deficient transcription factors involved in pituitary development or functionHESX1, LHX3, LHX4, PIT1, PROP1 gene mutations
Peripheral hypothyroidism
Resistance to thyroid hormoneThyroid receptor b mutationAbnormalities of thyroid hormone transportAllan-Herndon-Dudley syndrome (monocarboxylase transporter 8 [MCT8] gene mutation)
Transcription factor gene mutations resulting inthyroid dysgenesis and associated clinical findingsMutated Gene Associated clinical findings
Thyroid transcription factor 2 (TTF2):thyroid dysgenesis, choanal atresia, cleft palate, and spiky hair
NKX2.1 congenital hypothyroidism, respiratory distress, ataxia and benign chorea
NKX2.5 Congenital hypothyroidism and cardiac malformations
PAX-8 Thyroid dysgenesis, kidney and ureteral malformations
Rastogi and LaFranchi Orphanet Journal of Rare Diseases 2010, 5:17http://www.ojrd.com/content/5/1/17
Etiology of congenital hypothyroidism in 148 patients diagnosed in the Quebec Newborn Screening, program from 1990-2004. (modified from: Eugene et al.J Clin Endocrinol Metab 90:2696-2700, 2005 [111])
Female Male Total PercentageAthyreosis 14 10 24 16Ectopic 78 24 102 68Orthotopic/dyshormonogenesis 9 13 22 15Totals 101 47 148 100
Incidence of congenital hypothyroidism: Selecteddemographics from New York State (2000-2003)(modified from: Harris & Pass, Molec Genet Metab91:268-277, 2007 [5])Demographic IncidenceOverall 1:1681GenderMale 1:1763Female 1:1601EthnicityWhite 1:1815Black 1:1902Asian 1:1016Hispanic 1:1559Birth weightClassic :1/4000-1/5000
Birth weight< 1500 g 1:13961500 - 2500 g 1:851> 2500 g 1:1843Single vs. multiple birthsSingle 1:1765Twin 1:876Multiple 1:575Mother’s age< 20 years 1:170320-29 years 1:160830-39 years 1:1677> 39 years 1:1328Rastogi and LaFranchi Orphanet Journal of Rare Diseases 2010, 5:17http://www.ojrd.com/content/5/1/17Page 2 of 22
Prevalence of individual symptoms ofhypothyroidism at the time of diagnosis. (modified from:Alm et al. Brit Med J 289:1171-175, 1984
Prolonged Jaundice 59 vs 33**Feeding Difficulty 35 vs 16**Lethargy 34 vs 14**Umbilical Hernia 32 vs18*Macroglossia 25 vs12*Constipation 18 vs10Cold or mottled skin 18 vs 10Hypothermia 3 vs 3No symptoms 16 vs 33**Other clinical featuresreported:Abnormal cry 7 vs 6Edema 5 vs 3Hypothyroid appearance 6 vs 2Hypotonia 3 vs 3
• TSHb mutations• TSH receptor inactivating mutations• Thyroid dysgenesis◦ TTF-2 mutations◦ NKX2.1 mutations◦ PAX-8 mutations• Thyroid dyshormonegenesis◦ Sodium-iodide symporter mutations◦ Hydrogen peroxide mutations▪ DUOX2 mutations▪ DUOX2A mutations◦ Thyroid peroxidase mutations▪ Pendred syndrome (PDS): pendrin genemutations◦ Thyroglobulin mutations◦ Deiodinase mutations• Defects in thyroid hormone transport◦ MCT8 mutation
Infant with congenital hypothyroidism. A - 3 month old infant with untreated CH; picture demonstrates hypotonic posture,myxedematous facies, macroglossia, and umbilical hernia. B - Same infant, close up of face, showing myxedematous facies, macroglossia, andskin mottling. C - Same infant, close up showing abdominal distension and umbilical hernia.
Radiograph of the left lower extremity of two infants, showing absence of the distal femoral epiphysis on left. Radiograph of the left lower extremity of two infants. The infant on the left with congenital hypothyroidism demonstrates absence of the distal femoral and proximal tibial epiphyses, while in the normal infant on the right the distal femoral epiphysis is present.
Defect Radionuclide image Ultrasonography Serum
thyroglobulin Maternal TRab
Aplasia
Hypoplasia
Ectopia
TSHb mutations
TSH receptor inactivating mutation
TSH receptor inactivating mutation
Trapping error
Beyond trapping errorMaternal TRB-Ab
No uptake gland
↓ uptake
↓ uptake,
No uptake
↓ uptake
↓ uptake
↓ or no uptake
↑ uptake
↓ or no uptake
Absent glandSmall, eutopic
Ectopic gland (hypoplastic)
Eutopic gland (hypoplastic)
Eutopic gland
Eutopic gland
Eutopic gland
Eutopic, large gland
Eutopic gland
Low NegativeIntermediate Negative
Intermediate Negative
Intermediate Negative
Intermediate-high Negative
Intermediate-high Negative
Low-intermediate Negative
High Exception: Tg gene mutations Negative
Low-intermediate Positive
Technetium 99 m scan findings in congenital hypothyroidism. A-Technetium 99 m scan, showing a large gland (approximatelytwice normal size) in eutopic location, consistent with dyshormonogenesis. B-Technetium 99 m scan, showing uptake in ectopic location, i.e.ectopic gland. C-Minimal uptake, consistent with aplasia or severe hypoplasia.
Treatment of CHTerm as well as preterm infants with low T4 and elevated TSH should bestarted on L-thyroxine as soon as the diagnosis is made.
The initial doseof L-thyroxine should be 10-15μg/ kg/ day with the aim to normalize the T4 level at the earliest.
Those infants with severe hypothyroidism (very low T4, very high TSH and absence of distal femoral and proximal tibial epiphyses on radiograph of knee) should be started with the highestdose of 15μg/ kg/ day.
Age Dose of T4 in μg/kg/day
0 – 6 mo
7 – 11 mo
1 – 5 yr
6 – 10 yr
11 – 20 yr
Adults
10 – 15
6 – 8
5 - 6
4 - 5
1 – 3
1 – 2
Tratamentul hipotiroidismului congenital
Age Dose of T4 in μg/kg/day
0 – 6 mo
7 – 11 mo
1 – 5 yr
6 – 10 yr
11 – 20 yr
Adults
10 – 15
6 – 8
5 - 6
4 - 5
1 – 3
1 – 2
Monitoring of therapy:T4 should be kept in the upper half of normal range (10-16 μg/dL) or freeT4 in the 1.4 - 2.3 ng/dl range with the TSH suppressed in the normalrange.
T4 and TSH levels should be checked according to the followingschedule:
0-6 months: every 6 weeks
6 months-3 years: every 3 months
> 3 years: 6 monthly
T4 and TSH should also be checked 6-8 weeks after any dosage change.
It is equally important to avoid over treatment. Adverse effects of overtreatment include premature fusion of cranial sutures, acceleration ofskeletal maturation and problems with temperament and behavior.