THE THYROID• 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.

• 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

THE THYROID ANATOMY

Microscopic appearance of the thyroid

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. In the colloid there is formed first a large glycosylated protein called thyroglobulin which contains the aminoacid –thyrozine that will be iodinated to result finally thyroid hormones.

Hormone production has six steps:1. Dietary iodine is transported from the capillary through the epithelial cell into the

lumen with a carrier called Natrium/iodine Symporter -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 the iodide pool which will serve for as a reserve for thyroid hormones synthesis 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.

Thyroid hormone transport in blood• 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 hypothalamus and pituitary that regulate the synthesis and/or secretion of other hormones are known as trophic hormones

Key hormones for the thyroid control include:TRH - Thyrophin Releasing HormoneTSH - Thyroid Stimulating HormoneT4/T3 - Thyroid hormones

TRHThyrotropin Releasing Hormone is produced by the hypothalamus and functions

to stimulate the anterior pituitary to release TSH. TRH is a small peptide formed of 3 amino acids 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.

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 (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 control by hypothalamic-pituitary system and feed-back mechanism

OOH

NH 2

II

I

IOH

O

T4

I

I

OH

O

R

3,3’-T2

II

I

OH

O

R

T3

“Step up”

I

I

IOH

O

R

rT3

“Step down”

THYROID HORMONE METABOLISM

OOH

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.BASICS OF THYROID HORMONE

ACTION IN THE CELL

Mechanism of action of thyroid hormones • Passive diffusion or active transport?• Deiodination of T4 to T3• T3 binds to speicific 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 enter into the target cells, are deiodinated T4 to T3 by deiodinases and than T3 inter into the nucleus, binds to thyroid hormones responsive element on nuclear DNA and stimulates transcriptional events which lead to synthesis of proteins and enzymes that represent the genetically programmed response of target cells to thyroid hormone action

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• Thyroid hormones are critical for normal development of the skeleton 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 neurological and psychological

(mental retardation) defects resulting from untreated neonatal hypothyroidism.

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

Results of thyroid hormones deficiency and excess

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; exophtalmos, diplopia (Graves' disease)

Eyelid drooping; periorbital edema; puffy, non pitting edema of the face; 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,. arhythmias; angina

increased peripheral resistance, decreased cardiac output, stroke volume, heart rate, pulse pressure; congestive heart failure (low output); bradicardia (low voltage ECG with prolonged PR interval, flat T wave); pericardial effusion

Respiratory dyspnea; reduced vital capacity

hypoventilation (CO2 retention) pleural effusions

CNS Nervousness, hyperkinesia, variable emotional states

lethargy, neuropathy

Gastrointestinal increased appetite; increased bowel movement frequency; hypoproteinemia

decreased appetite, decreased bowel movement frequency; ascites

Musculoskeletal Weakness; fatigue; hypercalcemia, osteoporosis, increased deep tendon reflex time

muscle fatigue, reduced deep tendon reflex, increased alkaline phosphatase, LDH, AST

Kidney Increased renal blood flow; increased GFR; mild polyuria

Decreased renal blood flow; decreased GFR; reduced water excretion

Hematopoiesis anemia (increased RBC turnover); increased erythropoiesis

anemia (decrease production rate, decreased iron absorption, decreased folate acid absorption, autoimmune pernicious anemia),decreased erythropoiesis

Reproduction decreased fertility; menstrual irregularity; enhanced gonadal steroid metabolism

infertility;hypermenorrhea decreased libido; impotence, decreased gonadal steroid metabolism

Metabolic increased basal rate; negative nitrogen balance, hyperglycemia;

decreased basal rate; delayed insulin degradation, with increased sensitivity; enhanced cholesterol

increased free fatty acids, decreased cholesterol and triglycerides; increased hormone degradation; increased requirement for fat-and water-soluble vitamins; enhanced drug detoxification

and triglyceride levels; decreased hormone degradation; decreased requirements for fat-and water-soluble vitamins; decreased drug detoxification.

Thyroid examination , thyroid imagery and hormone assessment

Thyroid examination must be made in the aria between upper part of the sternum, laryngeal cartilage and sternocleidomastiodian muscles. Examination of lymph notes situated upper of the istmus, around sternocleidomastoidian muscles.

The most accessible imagery for the thyroid gland is ultrasound examination. It allows to determine the thyroid volume by assessing the longest diameter of each lobe, its width and depth and than calculate the volume after a rotation ellipsoid formula. A volume larger than 18 ml in women and 25 ml in men means a goiter.

Normal ultrasound appearance of the thyroid gland

Calculation of thryoid volume

Formula of a totationg elipsoida = 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

Goiter is diagnosed in female patients if thyroid volume is over 18 ml, and in male patients if goiter volume is over 25 ml.

Thyroid has in M mode of examination (gray scale) a salt and pepper aspect. Autoimmune thyroid disease are associated with a hypoechoic pattern generalized or inhomogenous. Thyroid nodules may be hyper echoic , usually benign, or hypo echoic , that may be benign or malign nodules. Benign nodules have an hypoechoic hallo and malign nodules have irregular margins and microcalcifications. In color Doppler examination benign nodules are surrounded by a ring of vessels and have only a few or no vessels inside. Malign nodules have a high intra nodular vascularity.

Ultrasound appearance of a malignant thyroid noduleThyroid scintigraphy consist in administration of a radioactive element which is

normally trapped by the thyroid gland (radioactive iodine – 131 I, 125 I, 123125 I, I, Tc 99m or other) usually in direct relationship with the function of a certain area of the gland. Non functioning thyroid nodules do not appear on the scintigram - “cold nodules”. Those nodules that are functioning appear as area of intensive trapping (hyperfunctioning thyroid adenoma).

Normal scintigram of the thyroid glandThyroid Computed Tomography (CT) and MRI ( magnetic resonance imaging)

are not routine examination for thyroid gland exception for thyroid cancers already suspected in order to establish the report of the malignant tumors with other structures of the neck to avoid complication and planning surgical strategy.

“Hot” hyperfunctioning thyroid adenoma

The nodule on the right lobe appears to be hypofunctioning (cold nodule).

MRI imaging of a thyroid carcinoma

Thyroid computed tomography multiple malignant nodules

TSH, T4 and T4 assessment and their values in thyroid diseasesThere are different techniques to asses thyroid hormones in plasma, radioimuno-assays, enzymo-assays (ELISA, IRMA).

Calcitonin determination is mandatory in suspected medullary thyroid carcinoma (MTC), in MEN involving MTC and in the follow-up of patients treated for MTC.

Antibodies directed against different elements of the thyroid cells like, thyroperoxidase, thyroglobulin, TSH receptor (blocking or stimulating antibodies) must be also detected in suspect autoimmune thyroid diseases.

Dynamic assessment for thyroid hormones: Werner’s test: high doses of T3 inhibits iodine uptake in dyshomongenetic goiters

and not in Graves disease

TRH-stimulation test differentiate primary (TSH is higly stimulated) from secondary hypothyroidism (TSH is not stimulated). In thyrotoxicosis TSH in inhibited by increased thyroid hormones and not stimulated by TRH.

Other investigation:- bone age: highly decreased is compared with chronological age in

congenital or infantile hypothyroidism- Other bone abnormalities in congenital hypothyroidism: epiphyseal

dysgenesis, increased surface of sella turcica.

Fine needle biopsy is the corner stone assessment for thyroid nodules .It is mandatory to be made in all thyroid nodules with more than 1 cm (0.8 cm in other recommendations) , the largest diameter on ultrasound control .

Thyroid function tests – decisional algorithm

ENDEMIC GOITERIodine Deficiency Disorders (IDDs)

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

– Sources of iodine intake

• Animal products: meet, milk• Water• Factors that interfere with iodine metabolism: goitrogens: cassava, cabbage,

tiocyanates, fluoride, selenium deficiency

Iodine Deficiency produces• 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 hypothyroidism

• Adulthood : – goiter and complications, including thyroid nodules and aggressive

follicular cancer– Endemic mental retardation– Hypothyroidism– Reduced 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 μg for lactating women

IDDs – a worldwide health problem1. 1.6 billion people at risk2. 50 millions of children at risk3. 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 – evalution1. Clinically: O – normal, I – palpable, II – visible in normal position of the neck2. 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 SevereGoiter adults %Thyroid volume over normal %Urinary iodine μg/dlSerum thyroglobuline ng/mL

<5<5>10>10

5 - 19.95 - 19.95 - 9.9

10 - 19.9

20 - 29.920- 29.92 - 4.9

20 – 39.9

> 30> 30<2>40

NewbornsTSH in serum > 5 mIU/LUrinary iodine ng/mL

< 3> 10

3 – 19.93.5 – 9.9

20 – 39.91.5 – 3.4

> 40< 1.5

“Historical” huge endemic goiter

Endemic Cretinism Severe iodine deficiency may be associated with impaired brain development

leading to endemic cretinism. There are two forms of endemic cretinism:

- Neurologic endemic cretinism with severe mental retardation, goiter, deafness, muscle spasticity and normal height. Is seen Himalaya and New Guinea

- Mixedematous cretinism: thyroid aplasia, short stature, severe mental retardation. Selenium deficiency seems to be involved along with iodine deficiency. Is seen in Central Africa.

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

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

IDDs profilaxis

_ Iodine given as:– Iodisyzed salt– Iodizyzed oil , injectable – Universal Salt Iodization Programs: 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 SwitzerlandIn our country still exist areas with mild endemic goiter