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


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


Hypothyroidism

CNS Nervousness, hyperkinesia, variable emotional states

lethargy, neuropathy

Gastrointestinal increased appetite; increased bowel movement frequency; hypoproteinemia

decreased appetite, decreased bowel movement frequency; ascites


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


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


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


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


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


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


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.

THE THYROID

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