THE THYROID The Thyroid Gland The thyroid is

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THE THYROID

THE THYROID

The Thyroid Gland • The thyroid is a small (25 grams) butterfly-shaped gland located

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 5 th, 6 th and 7 th 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

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 T 4 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

Thyroid anatomy

Microscopic appearance of thyroid follicles

Microscopic appearance of thyroid follicles

Thyroid hormones in the body

Thyroid hormones in the body

Thyroid hormones synthesis The thyroid is stimulated by the pituitary hormone TSH to produce

Thyroid hormones synthesis The thyroid is stimulated by the pituitary hormone TSH to produce two hormones, Thyroxine (T 4) and triiodothyronine (T 3) 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 T 4 and/or T 3. 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 cells TSH signaling via the TSH receptor (which is

Iodine metabolism in normal thyroid cells TSH 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 H 2 O 2, which is produced by DUOX. Tg contains MIT, DIT, T 3, and T 4 and is stored in colloid until T 3 and T 4 need to be released into the blood.

ION TRANSPORT BY THE THYROID FOLLICULAR CELL Cl. O 4 -, SCNBLOOD I- I-

ION TRANSPORT BY THE THYROID FOLLICULAR CELL Cl. O 4 -, SCNBLOOD I- I- organification Na. I symporter (NIS) and pendrine Thyroid peroxidase (TPO) COLLOID Propylthiouracil (PTU) blocks iodination of thyroglobulin

THYROGLOBULIN SYNTHESIS IN THE THYROID FOLLICULAR CELL Iodination of Tyr residues of Tg COLLOID

THYROGLOBULIN SYNTHESIS IN THE THYROID FOLLICULAR CELL Iodination of Tyr residues of Tg COLLOID TSH receptor TPO

THYROID HORMONE SECRETION BY THE THYROID FOLLICULAR CELL T 4 T 3 COLLOID DIT

THYROID HORMONE SECRETION BY THE THYROID FOLLICULAR CELL T 4 T 3 COLLOID DIT MIT TSH receptor I-

THYROID HORMONES OH OH I I I O O NH 2 I O OH

THYROID HORMONES OH OH I I I O O NH 2 I O OH Thyroxine (T 4) NH 2 I O OH 3, 5, 3’-Triiodothyronine (T 3)

Thyroid hormone transport • bound to thyroxine-binding globulin (TBG): 70% • bound to transthyretin

Thyroid hormone transport • bound to thyroxine-binding globulin (TBG): 70% • bound to transthyretin or "thyroxinebinding prealbumin" (TTR or TBPA): 1015% • Paralbumin: 15 -20% • unbound T 4 (f. T 4): 0. 03% • unbound T 3 (f. T 3): 0. 3%

FEEDBACK REGULATION THE HYPOTHALAMIC-PITUITARY-THYROID AXIS Hormones derived from the pituitary that regulate the synthesis

FEEDBACK REGULATION THE 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 T 4/T 3 - Thyroid hormones

Control of thyroid function TRH Thyrotropin releasing hormone is produced by the hypothalamus and

Control of thyroid function TRH Thyrotropin 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 T 4 and T 3 downregulate TSH in a classic feedback inhibition scheme, TRH production is also inhibited these thyroid hormones, albeit to a lesser degree, in the hypothalamus.

Control of thyroid function TSH Thyroid stimulating hormone (TSH) or thyrotropin is a glycoprotein

Control of thyroid function TSH 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 (h. CG), 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 (T 4) and triiodothyronine (T 3), by interacting with a specific receptor on the thyroid cell surface. T 3 and T 4 are responsible for regulating diverse biochemical processes throughout the body which are essential for normal development and metabolic and neural activity.

THYROID HORMONES ACTIONS

THYROID HORMONES ACTIONS

OH “Step down” I O O I “Step up” I OH I NH 2

OH “Step down” I O O I “Step up” I OH I NH 2 THYROID HORMONE METABOLISM I I OH R O I I R O r. T 3 R O I I 2 3, 3’-T 2 OH NH R= O OH T 3 I OH I T 4

THYROID HORMONE DEIODINASES • Three deiodinases (D 1, D 2 & D 3) catalyze

THYROID HORMONE DEIODINASES • Three deiodinases (D 1, D 2 & D 3) catalyze the generation and/disposal of bioactive thyroid hormone. • D 1 & D 2 “bioactivate” thyroid hormone by removing a single “outer-ring” iodine atom. • D 3 “inactivates” thyroid hormone by removing a single “inner-ring”iodine atom. • All family members contain the novel amino acid selenocysteine (Se. C) in their catalytic center.

BASIC ORGANIZATION OF THE SELENODEIODINASES NH 2 extracellular domain A intracellular domain B E

BASIC ORGANIZATION OF THE SELENODEIODINASES NH 2 extracellular domain A intracellular domain B E C EXISTS AS A DIMER D COOH

BASICS OF THYROID HORMONE ACTION IN THE CELL

BASICS OF THYROID HORMONE ACTION IN THE CELL

SPECIFIC ACTIONS OF THYROID HORMONE: METABOLIC • Regulates of Basal Metabolic Rate (BMR). •

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.

SPECIFIC ACTIONS OF THYROID HORMONE: DEVELOPMENT • TH is critical for normal development of

SPECIFIC ACTIONS OF THYROID HORMONE: DEVELOPMENT • 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.

THYROID HORMONES MECHANISM OF ACTIONS • • Passive diffusion or active transport? Deiodination of

THYROID HORMONES MECHANISM OF ACTIONS • • Passive diffusion or active transport? Deiodination of T 4 to T 3 binds to specific nuclear receptor Nuclear receptor activation increases RNA and protein synthesis • Increased Na/K a. ATP-ase and ATP turn-over • Increased oxigen consumption in mitochondrias • Calorigenic effects

THYROID HORMONES ACTIONS • • Increase basal metabolic rate Increase heat production through stimulation

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

Thyroid hormones are responsible for neuronal mielinization

EXAMPLES OF THYROID DISEASES Hypothyroidism Hyperthyroidism

EXAMPLES OF THYROID DISEASES Hypothyroidism Hyperthyroidism

EXAMPLES OF THYROID DISEASES Juvenile Hypothyroidism Congenital Hypothyroidism

EXAMPLES OF THYROID DISEASES Juvenile Hypothyroidism Congenital Hypothyroidism

Physiological system Hyperthyroidism (thyrotoxicosis) Hypothyroidism skin -appendages warm, moist skin; sweating; fine, thin hair;

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,

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 (CO 2 retention) pleural effusions

Physiological system Hyperthyroidism (thyrotoxicosis) Hypothyroidism CNS Nervousness, hyperkinesia, variable emotional states lethargy, neuropathy Gastrointestinal

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

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

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

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

Normal ultrasound appearence of the thyroid gland

Calculation of thyroid volume Formula of a rotationg elipsoid a = AP diameter AP

Calculation of thyroid volume Formula of a rotationg elipsoid a = AP diameter AP b = Transverse diameter c = longitudinal diameter I axbxcx /6 II a x b x c x 0. 479 III a x b x c x 0. 53 IV a x b x c x 0. 5

Malignant thyroid nodule

Malignant thyroid nodule

Thyroid scintigraph

Thyroid scintigraph

Thyroid scintigraph with 123 I The nodule on the right lobe appears to be

Thyroid scintigraph with 123 I The nodule on the right lobe appears to be hypofunctioning (cold nodule).

Magnetic resonance imaging: large goiter and anaplastic carcinoma of the thyroid

Magnetic resonance imaging: large goiter and anaplastic carcinoma of the thyroid

Thyroid computed tomography multiple malignant nodules

Thyroid computed tomography multiple malignant nodules

Thyroid computed tomography – large multinodular goiter

Thyroid computed tomography – large multinodular goiter

TSH, T 4 and T 4 assessment and their values in thyroid diseases

TSH, T 4 and T 4 assessment and their values in thyroid diseases

Thyroid function tests – decisional algorithm

Thyroid function tests – decisional algorithm

ENDEMIC GOITER Iodine Deficiency Disorders

ENDEMIC GOITER Iodine Deficiency Disorders

Role of iodine and sources • Fetal body and brain development • Hearing system

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

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,

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

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. 2. 3. • 1. 6 billion people

IDDs – a worldwide health problem 1. 2. 3. • 1. 6 billion people at risk 50 millions of children at risk 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

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 m. L Normal for adult women: up to 18 m. L 3. Biochemical : • • urinary iodine : 10 μg / d. L Serum TSH slightly increased > 5 m. IU/L Serum thyroglobuline: less than 10 ng/m. L in adults Maternal milk: 9 μg / d. L

IDDs severity of iodine deficiency Assessed variable Normal Mild Moderate Severe Goiter adults %

IDDs severity of iodine deficiency Assessed variable Normal Mild Moderate Severe Goiter adults % Thyroid volume over normal % Urinary iodine μg/dl Serum thyroglobuline ng/m. L <5 <5 >10 5 - 19. 9 5 - 9. 9 10 - 19. 9 20 - 29. 9 20 - 29. 9 2 - 4. 9 20 – 39. 9 > 30 <2 >40 Newborns TSH in serum > 5 m. IU/L Urinary iodine ng/m. L <3 > 10 3 – 19. 9 3. 5 – 9. 9 20 – 39. 9 1. 5 – 3. 4 > 40 < 1. 5

“historical” huge endemic goiter

“historical” huge endemic goiter

Histology in endemci goiter: Inequal follicles

Histology in endemci goiter: Inequal follicles

Large intrathoracic goiter

Large intrathoracic goiter

Endemic cretinism with goiter mixedematous: short stature, hipothyroidism, mental retardation

Endemic cretinism with goiter mixedematous: short stature, hipothyroidism, mental retardation

Endemic cretins – neurologic Spastic paresis, severe mental retardation, deafness

Endemic cretins – neurologic Spastic paresis, severe mental retardation, deafness

Most effected areas by IDDs • Himalaya • Central Africa • South America –

Most effected areas by IDDs • Himalaya • Central Africa • South America – Andine areas

Urinary iodine excretion per liter after Universal Salt Iodization program implementation

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

Goiter prevalence varies inversely with iodine excretion which is the witness of iodine intake

Endemic goiter prevalence before and after iodine replacement

Endemic goiter prevalence before and after iodine replacement

Goiter prevalence in South America

Goiter prevalence in South America

In spite of iodine replacement programs goiter prevalence still increases due to increase population

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 –

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

HYPOTHYROIDISM

HYPOTHYROIDISM Clinical and biochemical syndrome that results from thyroid hormone defiency and slow metabolic

HYPOTHYROIDISM Clinical and biochemical syndrome that results from thyroid hormone defiency and slow metabolic rate In 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 CAUSES PRIMARY HYPOTHYROIDISM: 1. Hashimoto’s thyroiditis a. with

ADULT HYPOTHYROIDISM INCLUDING CHILDHOOD AND ADOLESCENCEND CAUSES PRIMARY HYPOTHYROIDISM: 1. Hashimoto’s thyroiditis a. with goiter b. without goiter late stage of autoimmune thyroiditis with thyroid fybrosis 2. Radioactive iodine treatment for Graves’ disease 3. Thyroidectomy for Graves’ disease, nodular goiter or thyroid cancer 4. Excessive iodine ingestion, including contrast media (effect Wolf – Chaikoff 5. Subacute thyroiditis transient 6. Severe iodine deficiency 7. 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

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 ADULT SIGNS AND SYMPTOMS COMMON FEATURES FOR SEVERE AND MODERATE HYPOTHYROIDISM: •

HYPOTHYROIDIS IN ADULT SIGNS AND SYMPTOMS COMMON FEATURES FOR SEVERE AND MODERATE HYPOTHYROIDISM: • Fatigability • Cold intolerance • Moderate increase in weight • Constipation • Menstrual abnormalities, heavy menstrual bleeding • Muscle cramps Physical examination: • Cold, dry skin • Undepresible edema of hands and feet • Voce răguşită • Reflexe lente • Carotenodermie

HYPOTHYROIDIS IN ADULT SIGNS AND SYMPTOMS Cardio vascular system: • • Bradicardia Abnormal contractility

HYPOTHYROIDIS IN ADULT SIGNS 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 ADULT SIGNS AND SYMPTOMS • • • Lung function: Slow respiratory rate

HYPOTHYROIDIS IN ADULT SIGNS 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 ADULT SIGNS AND SYMPTOMS Anemia: • Iron deficency • Anability to have

HYPOTHYROIDIS IN ADULT SIGNS AND SYMPTOMS Anemia: • Iron deficency • Anability to have normal folate absorbtion • Vitamin B 12 and megaloblastic anemia • Association with autoimmune anemia in patients with Hashimoto’s thyroiditis Nervous and muscular system: • Severe muscle cramps • Paresthesias • Muscle weakness

HYPOTHYROIDIS IN ADULT SIGNS AND SYMPTOMS Reproductive system: • Anovulaţion şi infertility • Heavy

HYPOTHYROIDIS IN ADULT SIGNS 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 ADULTS RARE FEATURES • • Neurastenia Paresthesias Persistent weakness Infertility Precocious or

HYPOTHYROIDISM IN ADULTS RARE 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 ADULT SEMNE ŞI SIMPTOME Anemia: • Deficit de fier şi sinteza anormală

HIPOTIROIDISMUL LA ADULT SEMNE ŞI SIMPTOME Anemia: • Deficit de fier şi sinteza anormală a hemoglobine • Deficit de folat datorită tulburărilor de absorbţie • Deficit de vitamina B 12 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 Patient takes thyroid hormonesi Patients does not take thyroid hormones Stop

HYPOTIROIDISM - DIAGNOSIS Patient takes thyroid hormonesi Patients does not take thyroid hormones Stop medication for 6 weeks TSH and f. T 4 normal TSH normal EUTIROIDISM f. T 4 low Ft 4 low TSH increased TSH normal or decreased PRIMARY HYPOTHYROIDISM SECONDARY HYPOTHYROIDISM US, anti. TPO, anti Tg antibodies Assess pituitary

Subclinical hypothyroidism

Subclinical hypothyroidism

TSH Increased TSH Low T 4 and T 3 Primary hypothyroidism Low TSH Low

TSH Increased TSH Low T 4 and T 3 Primary hypothyroidism Low TSH Low T 4 and T 3 Secondary hypothyroidism Increased Antithyroid antibodies Low urinary iodine, Increased I uptake TRH test History of thyroid surgery, antithyroid drugs Negative Positive Pituitary failure Hypothalamic disease Radioiodine for hyperthyroidism Iodine deficiency Autoimmune thyroiditis Increased iodine excretion: iodine excess

Subclinical hypothyroidism: increased TSH, low or normal f. T 4 • • Risk factor

Subclinical hypothyroidism: increased TSH, low or normal f. T 4 • • 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

Prevalence of suclinical hypothyroidism increases with age

HYPOTYROIDISM COMPLCATIONS • ATEROSCLEROSIS: major risk factor for atherosclerosis • Reduced vascular compliance and

HYPOTYROIDISM COMPLCATIONS • ATEROSCLEROSIS: major risk factor for atherosclerosis • Reduced vascular compliance and fluxendothelial 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

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 characteristics History: hypothyroidism known by relatives, radioiodine treatment for Graves disease,

Mixoedema coma clinical characteristics History: 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 CO 2 retention • Hypoxia este determed by reduced sensitivity

Mixoedema coma – pathophysiology CO 2 retention • Hypoxia este determed by reduced sensitivity of respiratory centers to oxigen deficiency and hyper CO 2, 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 340 C Treatment • • • High doses of glucocorticoides : hydrocortisone acetate 100 mg. i. v. followed by 50 mg. every 6 h T 4 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 – T 4 • Has a half life of 7

HYPOTHYROIDIS - TREATMENT LEVOTIROXINE – T 4 • 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 f. T 4 every 3 month • Serum T 4 may be increased 4 h after T 4 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 days 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 m. IU/L

CONGENITAL HYPOTHYROIDISM - CAUSES 1. PRIMARY HYPOTHYROIDISM IN THE NEWBORN: a. WITH GOITER: •

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 hypothyroidism Thyroid dysgenesis: hypothyroidism due to a

Classification and etiology of congenital hypothyroidism Primary hypothyroidism Thyroid 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, NKX 2. 1, NKX 2. 5 PAX-9 Thyroid dyshormonogenesis: hypothyroidism due to impaired hormone production Associated mutations: Sodium-iodide symporter defect Thyroid peroxidase defects Hydrogen peroxide generation defects (DUOX 2, DUOXA 2 gene mutations) Pendrin defect (Pendred syndrome) Thyroglobulin defect Iodotyrosine deiododinase defect (DEHAL 1, SECISBP 2 gene mutations) Resistance to TSH binding or signaling Associated mutations: TSH receptor defect G-protein mutation: pseudohypoparathyroidism type 1 a

Syndromic hypothyroidism Pendred syndrome - (hypothyroidism- deafness - goiter) Pendrin mutation Bamforth-Lazarus syndrome -

Syndromic hypothyroidism Pendred syndrome - (hypothyroidism- deafness - goiter) Pendrin mutation Bamforth-Lazarus syndrome - (hypothyroidism - cleft palate - spiky hair) TTF-2 mutation Ectodermal dysplasia - (hypohidrotic - hypothyroidism - ciliary dyskinesia) Hypothyroidism - (dysmorphism - postaxial polydactyly - intellectual deficit) Kocher - Deber - Semilange syndrome - (muscular pseudohypertrophyhypothyroidism) Benign chorea - hypothyroidism Choreoathetosis - (hypothyroidism - neonatal respiratory distress) NKX 2. 1 /TTF-1 mutation Obesity - colitis - (hypothyroidism - cardiac hypertrophy - developmental delay)

Transient congenital hypothyroidism Maternal intake of antithyroid drugs Transplacental passage of maternal TSH receptor

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 THOX 2 or DUOXA 2 Congenital hepatic hemangioma/hemangioendothelioma

Central hypothyroidism (syn: Secondary hypothyroidism) Isolated TSH deficiency (TSH b subunit gene mutation) Thyrotropin-releasing

Central hypothyroidism (syn: Secondary hypothyroidism) Isolated TSH deficiency (TSH b subunit gene mutation) Thyrotropin-releasing hormone deficiency Isolated, pituitary stalk interruption syndrome (PSIS), hypothalamic lesion, e. g. hamartoma Thyrotropin-releasing hormone resistance TRH receptor gene mutation Hypothyroidism due to deficient transcription factors involved in pituitary development or function HESX 1, LHX 3, LHX 4, PIT 1, PROP 1 gene mutations

Peripheral hypothyroidism Resistance to thyroid hormone Thyroid receptor b mutation Abnormalities of thyroid hormone

Peripheral hypothyroidism Resistance to thyroid hormone Thyroid receptor b mutation Abnormalities of thyroid hormone transport Allan-Herndon-Dudley syndrome (monocarboxylase transporter 8 [MCT 8] gene mutation)

Transcription factor gene mutations resulting in thyroid dysgenesis and associated clinical findings Mutated Gene

Transcription factor gene mutations resulting in thyroid dysgenesis and associated clinical findings Mutated Gene Associated clinical findings Thyroid transcription factor 2 (TTF 2): thyroid dysgenesis, choanal atresia, cleft palate, and spiky hair NKX 2. 1 congenital hypothyroidism, respiratory distress, ataxia and benign chorea NKX 2. 5 Congenital hypothyroidism and cardiac malformations PAX-8 Thyroid dysgenesis, kidney and ureteral malformations Rastogi and La. Franchi Orphanet Journal of Rare Diseases 2010, 5: 17 http: //www. ojrd. com/content/5/1/17

Etiology of congenital hypothyroidism in 148 patients diagnosed in the Quebec Newborn Screening, program

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 Athyreosis 14 10 24 Ectopic 78 24 102 Orthotopic/dyshormonogenesis 9 13 22 Totals 101 47 148 Total Percentage 16 68 15 100

Incidence of congenital hypothyroidism: Selected demographics from New York State (2000 -2003) (modified from:

Incidence of congenital hypothyroidism: Selected demographics from New York State (2000 -2003) (modified from: Harris & Pass, Molec Genet Metab 91: 268 -277, 2007 [5]) Demographic Incidence Overall 1: 1681 Gender Male 1: 1763 Female 1: 1601 Ethnicity White 1: 1815 Black 1: 1902 Asian 1: 1016 Hispanic 1: 1559 Birth weight Classic : 1/4000 -1/5000 Birth weight < 1500 g 1: 1396 1500 - 2500 g 1: 851 > 2500 g 1: 1843 Single vs. multiple births Single 1: 1765 Twin 1: 876 Multiple 1: 575 Mother’s age < 20 years 1: 1703 20 -29 years 1: 1608 30 -39 years 1: 1677 > 39 years 1: 1328 Rastogi and La. Franchi Orphanet Journal of Rare Diseases 2010, 5: 17 http: //www. ojrd. com/content/5/1/17 Page 2 of 22

Prevalence of individual symptoms of hypothyroidism at the time of diagnosis. (modified from: Alm

Prevalence of individual symptoms of hypothyroidism 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 vs 18* Macroglossia 25 vs 12* Constipation 18 vs 10 Cold or mottled skin 18 vs 10 Hypothermia 3 vs 3 No symptoms 16 vs 33** Other clinical features reported: Abnormal cry 7 vs 6 Edema 5 vs 3 Hypothyroid appearance 6 vs 2 Hypotonia 3 vs 3

 • TSHb mutations • TSH receptor inactivating mutations • Thyroid dysgenesis ◦ TTF-2

• TSHb mutations • TSH receptor inactivating mutations • Thyroid dysgenesis ◦ TTF-2 mutations ◦ NKX 2. 1 mutations ◦ PAX-8 mutations • Thyroid dyshormonegenesis ◦ Sodium-iodide symporter mutations ◦ Hydrogen peroxide mutations ▪ DUOX 2 A mutations ◦ Thyroid peroxidase mutations ▪ Pendred syndrome (PDS): pendrin gene mutations ◦ Thyroglobulin mutations ◦ Deiodinase mutations • Defects in thyroid hormone transport ◦ MCT 8 mutation

Infant with congenital hypothyroidism. A - 3 month old infant with untreated CH; picture

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, and skin 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

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 No

Defect Radionuclide image Ultrasonography Serum thyroglobulin Maternal TRab Aplasia Hypoplasia Ectopia TSHb mutations No uptake gland ↓ uptake, No uptake Absent gland Low Intermediate Negative TSH receptor inactivating mutation ↓ uptake Small, eutopic Ectopic gland (hypoplastic) Eutopic gland Negative TSH receptor inactivating mutation Trapping error Beyond trapping error Maternal TRB-Ab ↓ uptake Eutopic gland Intermediate-high Negative ↓ or no uptake Eutopic gland ↑ uptake Eutopic, large gland Low-intermediate Negative High Exception: Tg gene mutations Negative ↓ or no uptake Eutopic gland Low-intermediate Positive Intermediate-high Negative

Technetium 99 m scan findings in congenital hypothyroidism. A-Technetium 99 m scan, showing a

Technetium 99 m scan findings in congenital hypothyroidism. A-Technetium 99 m scan, showing a large gland (approximately twice 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 CH Term as well as preterm infants with low T 4 and

Treatment of CH Term as well as preterm infants with low T 4 and elevated TSH should be started on L-thyroxine as soon as the diagnosis is made. Age 0 – 6 mo 7 – 11 mo 1 – 5 yr 6 – 10 yr 11 – 20 yr Adults Dose of T 4 in μg/kg/day 10 – 15 6– 8 5 - 6 4 - 5 1– 3 1– 2 The initial doseof L-thyroxine should be 10 -15μg/ kg/ day with the aim to normalize the T 4 level at the earliest. Those infants with severe hypothyroidism (very low T 4, very high TSH and absence of distal femoral and proximal tibial epiphyses on radiograph of knee) should be started with the highest dose of 15μg/ kg/ day.

Tratamentul hipotiroidismului congenital Age 0 – 6 mo 7 – 11 mo 1 –

Tratamentul hipotiroidismului congenital Age 0 – 6 mo 7 – 11 mo 1 – 5 yr 6 – 10 yr 11 – 20 yr Adults Dose of T 4 in μg/kg/day 10 – 15 6– 8 5 - 6 4 - 5 1– 3 1– 2

Monitoring of therapy: T 4 should be kept in the upper half of normal

Monitoring of therapy: T 4 should be kept in the upper half of normal range (10 -16 μg/d. L) or free T 4 in the 1. 4 - 2. 3 ng/dl range with the TSH suppressed in the normal range. T 4 and TSH levels should be checked according to the following schedule: 0 -6 months: every 6 weeks 6 months-3 years: every 3 months > 3 years: 6 monthly T 4 and TSH should also be checked 6 -8 weeks after any dosage change. It is equally important to avoid over treatment. Adverse effects of over treatment include premature fusion of cranial sutures, acceleration of skeletal maturation and problems with temperament and behavior.