SCHOOL OF PHARMACEUTICAL SCIENCES

DEPARTMENT OF PHARMACY PRACTICE & PHARM D

ASSIGNMENT – 01

TOPIC: THYROID FUNCTION TEST

SUBJECT : CLINCAL PHARMACY (THEORY)

COURSE : PHARM D - IV YEAR

BATCH : 2010 - 2016

SUBMITTED ON : July’ 2013

SUBMITTED TO : Dr. Aswathy Rajan

SUBMITTED BY : Mohammed. Sulaiman Sait. J

HOD : Dr. J. ANBU

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INDEX :-

S.NO

TOPIC PAGE NUMBER

1. INTRODUCTION- THE THYROID GLAND,THYROID SYTEM, ITS FUNCTIONS AND REGULATIONS

2

2. DISORDERS OF THE THYROID SYSTEM 4

3. DIAGNOSTIC TESTS AND THEIR SIGNIFICANCE 5

4. THYROID STIMULATING HORMONE (TSH) TEST 5

5. TOTAL THYROXINE 6

6. FREE THYROXINE 6

7. TOTAL TRIIODOTHYRONINE 7

8. FREE TRIIODOTHYRONINE 8

9. THYROID HORMONE UPTAKE 8

10. SECRETORY CAPACITY (GT) 9

11. REFERENCES 10

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INTRODUCTION- THE THYROID GLAND, THYROID SYSTEM, ITS FUNCTIONS AND REGULATIONS

The thyroid gland or simply, the thyroid Gland is one of the largest endocrine glands.

The thyroid gland is found in the neck, below the thyroid cartilage (which forms the laryngeal prominence, or "Adam's apple"). The thyroid gland controls how quickly the body uses energy, makes proteins, and controls how sensitive the body is to other hormones. It participates in these processes by producing thyroid hormones, the principal ones being triiodothyronine (T3) and thyroxine which can sometimes be referred to as tetraiodothyronine (T4). These hormones regulate the growth and rate of function of many other systems in the body. T3 and T4 are synthesized from iodine and tyrosine. The thyroid also produces calcitonin, which plays a role in calcium homeostasis.

Hormonal output from the thyroid is regulated by thyroid-stimulating hormone (TSH) produced by the anterior pituitary, which itself is regulated by thyrotropin-releasing hormone (TRH) produced by the hypothalamus.

T3 and T4 production and action

Thyroxine (T4) is synthesised by the follicular cells from free tyrosine and on the tyrosine residues of the protein called thyroglobulin (Tg).Iodine is captured with the "iodine trap" by the hydrogen peroxide generated by the enzyme thyroid peroxidase (TPO) and linked to the 3' and 5' sites of the benzene ring of the tyrosine residues on Tg, and on free tyrosine. Upon stimulation by the thyroid-stimulating hormone (TSH), the follicular cells reabsorb Tg and cleave the iodinated tyrosines from Tg in lysosomes, forming T4 and T3 (in T3, one iodine atom is

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absent compared to T4), and releasing them into the blood. Deiodinase enzymes convert T4 to T3. Thyroid hormone secreted from the gland is about 80-90% T4 and about 10-20% T3.

Cells of the developing brain are a major target for the thyroid hormones T3 and T4. Thyroid hormones play a particularly crucial role in brain maturation during fetal development. A transport protein that seems to be important for T4 transport across the blood–brain barrier(OATP1C1) has been identified. A second transport protein (MCT8) is important for T3 transport across brain cell membranes.

Non-genomic actions of T4 are those that are not initiated by liganding of the hormone to intranuclear thyroid receptor. These may begin at the plasma membrane or within cytoplasm. Plasma membrane-initiated actions begin at a receptor on the integrin alphaV beta3 that activates ERK1/2. This binding culminates in local membrane actions on ion transport systems such as the Na(+)/H(+) exchanger or complex cellular events including cell proliferation. These integrins are concentrated on cells of the vasculature and on some types of tumor cells, which in part explains the proangiogenic effects of iodothyronines and proliferative actions of thyroid hormone on some cancers including gliomas. T4 also acts on the mitochondrial genome via imported isoforms of nuclear thyroid receptors to affect several mitochondrial transcription factors. Regulation of actin polymerization by T4 is critical to cell migration in neurons and glial cells and is important to brain development.

T3 and T4 regulation

The production of thyroxine and triiodothyronine is regulated by thyroid-stimulating hormone (TSH), released by theanterior pituitary. The thyroid and thyrotropes form a negative feedback loop: TSH production is suppressed when the T4levels are high.[19] The TSH production itself is modulated by thyrotropin-releasing hormone (TRH), which is produced by the hypothalamus and secreted at an increased rate in situations such as cold exposure (to stimulate thermogenesis). TSH production is blunted by somatostatin (SRIH), rising levels of glucocorticoids and sex hormones (estrogen andtestosterone), and excessively high blood iodide concentration.

An additional hormone produced by the thyroid contributes to the regulation of blood calcium levels. Parafollicular cellsproduce calcitonin in response to hypercalcemia. Calcitonin stimulates movement of calcium into bone, in opposition to the effects of parathyroid hormone (PTH). However, calcitonin seems far less essential than PTH, as calcium metabolism remains clinically normal after removal of the thyroid (thyroidectomy), but not the parathyroids.

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DISORDERS OF THE THYROID SYSTEMThyroid disorders include

HYPERTHYROIDISM (abnormally increased activity of the thyroid gland),

HYPOTHYROIDISM (abnormally decreased activity of the thyroid gland) and

THYROID NODULES, which are generally benign THYROID NEOPLASMS, but may be thyroid cancers

(i) HYPERTHYROIDISM Hyperthyroidism, or overactive thyroid, is the overproduction of the thyroid hormones T3 and T4, and is most commonly caused by the development of Graves' disease,[citation needed] an autoimmune disease in which antibodies are produced which stimulate the thyroid to secrete excessive quantities of thyroid hormones. The disease can result in the formation of a toxic goiter as a result of thyroid growth in response to a lack ofnegative feedback mechanisms. It presents with symptoms such as a thyroid goiter, protruding eyes (exopthalmos), palpitations, excess sweating, diarrhea, weight loss, muscle weakness and unusual sensitivity to heat. The appetite is often increased.

(ii) HYPOTHYROIDISM Hypothyroidism is the underproduction of the thyroid hormones T3 and T4. Hypothyroid disorders may occur as a result of :

- Congenital thyroid abnormalities (Thyroid deficiency at birth. See congenital hypothyroidism),

- Autoimmune disorders such as Hashimoto's thyroiditis,- Iodine deficiency (more likely in poorer countries) or- The removal of the thyroid following surgery to treat severe hyperthyroidism

and/or thyroid cancer.

Typical symptoms are abnormal weight gain, tiredness, baldness, cold intolerance, and bradycardia. Hypothyroidism is treated with hormone replacement therapy, such as levothyroxine, which is typically required for the rest of the patient's life. Thyroid hormone treatment is given under the care of a physician and may take a few weeks to become effective

(iii) THYROID NODULES In most cases, thyroid cancer presents as a painless mass in the neck. It is very unusual for thyroid cancers to present with symptoms, unless they have been neglected. One may be able to feel a hard nodule in the neck. Diagnosis is made using a needle biopsy and various radiological studies

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DIAGNOSTIC TESTS AND THEIR SIGNIFICANCE

Thyroid function tests (TFTs) is a collective term for blood tests used to check the function of the thyroid.

TFTs may be requested if a patient is thought to suffer from hyperthyroidism (overactive thyroid) or hypothyroidism (underactive thyroid), or to monitor the effectiveness of either thyroid-suppression or hormone replacement therapy.

(i) THYROID STIMULATING HORMONE

Thyroid-stimulating hormone (also known as TSH or thyrotropin) is a hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid gland.

Diagnosis

TSH concentrations are measured as part of a thyroid function test in patients suspected of having an excess (hyperthyroidism) or deficiency (hypothyroidism) of thyroid hormones. Interpretation of the results depends on both the TSH and T4 concentrations. In some situations measurement of T3 may also be useful.

TSH test is based on the way TSH and thyroid hormones work together. Normally, the pituitary boosts TSH production when thyroid hormone levels in the blood are low. The thyroid responds by making more hormone. Then, when the body has enough thyroid hormone circulating in the blood, TSH output drops. The cycle repeats con tinuously to maintain a healthy level of thyroid hormone in the body. The TSH test measures the amount of TSH being secreted by the pituitary.

In adults, a standard reference range is between 0.4 and 3.0 µ IU /mL (equivalent to mIU/L), but values vary slightly among labs. In the UK, guidelines issued by the Association for Clinical Biochemistry suggest a reference range of 0.4-4.5 mIU/L. It expected the normal range for adults to be reduced to 0.4–2.5 µIU/mL, because research had shown that adults with an initially measured TSH level of over 2.0 µIU/mL had "an increased odds ratio of developing hypothyroidism over the [following] 20 years, especially if thyroid antibodies were elevated".

TSH concentrations in children are normally higher than in adults.

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(II) TOTAL THYROXINE

Total thyroxine (Total T4) is generally elevated in hyperthyroidism and decreased in hypothyroidism. It is usually slightly elevated in pregnancy secondary to increased levels of thyroid binding globulin (TBG).

Reference ranges:

Lower limit Upper limit Unit

4 (M) , 5.5(FM)

11(M) , 12.3(FM) μg/dL

60 140(M) , 160 (FM)

nmol/L

(III) FREE THYROXINE

Free thyroxine (Free T4) is generally elevated in hyperthyroidism and decreased in hypothyroidism.[2]

Patient type Lower limitUpper limit

Unit

Normal adult0.7, 0.8 1.4, 1.5 ng/dL

9, 10, 18, 23 pmol/L

Infant 0–3 d2.0 5.0 ng/dL

26 65 pmol/L

Infant 3–30 d0.9 2.2 ng/dL

12 30 pmol/L

Child/Adolescent 0.8 2.0 ng/dL

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31 d – 18 y 10 26 pmol/L

Pregnant0.5 1.0 ng/dL

6.5 13 pmol/L

(IV) TOTAL TRIIODOTHYROXINE

Total triiodothyronine (Total T3) also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate.

Production of T3 and its prohormone thyroxine (T4) is activated by thyroid-stimulating hormone (TSH), which is released from the pituitary gland. This pathway is regulated via a closed-loop feedback process: Elevated concentrations of T3, and T4 in the blood plasma inhibit the production of TSH in the pituitary gland. As concentrations of these hormones decrease, the pituitary gland increases production of TSH, and by these processes, afeedback control system is set up to regulate the amount of thyroid hormones that are in the bloodstream

DIAGNOSIS AND MEASUREMENT

Triiodothyronine can be measured as free triiodothyronine, which is an indicator of triiodothyronine activity in the body. It can also be measured as total triiodothyronine, which also depends on the triiodothyronine that is bound to thyroxine-binding globulin.

Only about 20 percent of the T3 circulating in the blood comes from the thyroid gland, while all of the circulating T4 comes from the thyroid. The remaining 80 percent of circu lating T3 comes from various cells all over the body where T4 is converted to T3. T3 is far more active than T4 and, like T4, exists in both bound and free states. In some cases of hyperthyroidism, FT4 is normal but free T3 (FT3) is elevated, so measuring both forms is useful if hyperthyroidism is suspected. The normal FT3 range is about 0.2 to 0.5 ng/dL. The T3 test is not useful in diagnosing hypo thyroidism because levels are not reduced until the hypothyroidism is severe

Total triiodothyronine (Total T3) is generally elevated in hyperthyroidism and decreased in hypothyroidism.[2]

Reference ranges:

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Test Lower limit Upper limit Unit

Total triiodothyronine

60(M) , 75(FM) 175(M), 181(FM)

ng/dL

0.9(M), 1.1(FM)

2.5(M) , 2.7(FM) nmol/L

(V) FREE TRIIODOTHYROXINE

Free triiodothyronine (Free T3) is generally elevated in hyperthyroidism and decreased in hypothyroidism.

Reference ranges:

Patient type Lower limit Upper limit Unit

Normal adult3.0 7.0 pg/mL

3.1 7.7 pmol/L

Children 2–16 y

3.0 7.0 pg/mL

1.5 9.2 pmol/L

(VI) Thyroid hormone uptake

Thyroid hormone uptake (Tuptake or T3 uptake) is a measure of the unbound thyroxine binding globulins in the blood, that is, the TBG that is unsaturated with thyroid hormone. Unsaturated TBG increases with decreased levels of thyroid hormones. It is not directly related to triiodothyronine, despite the name T3 uptake.

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Reference ranges:

Patient type Lower limit Upper limit Unit

Females 25 35 %

In pregnancy 15 25 %

Males 25 35  %

(VII) SECRETORY CAPACITY (GT)

Thyroid's secretory capacity (GT, also referred to as SPINA-GT) is the maximum stimulated amount of thyroxine the thyroid can produce in one second. GT is elevated in hyperthyroidism and reduced in hypothyroidism.

GT is calculated with

or

: Dilution factor for T4 (reciprocal of apparent volume of distribution, 0.1 l−1)

: Clearance exponent for T4 (1.1e-6 sec−1)K41: Dissociation constant T4-TBG (2e10 l/mol)K42: Dissociation constant T4-TBPA (2e8 l/mol)DT: EC50 for TSH (2.75 mU/l)[20]

Lower limit Upper limit Unit

1.41 8.67 pmol/s

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REFERENCES

1. The thyroid gland in Endocrinology: An Integrated Approach by Stephen Nussey and Saffron Whitehead (2001)

2. Boron WF, Boulpaep E (2003). "Chapter 48: "synthesis of thyroid hormones"". Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders

3. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR (2002). "Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine

4. Johannes W. Dietrich (2002). Der Hypophysen-Schilddrüsen-Regelkreis. Berlin, Germany: Logos-Verlag Berlin.

5. Thyroid Problems eMedicine Health. Retrieved on 2010-02-076. ^ Thyroid Disorders Information MedicineNet. Retrieved on 2010-02-077. Thyroid Function Tests In turn citing: Operational Medicine 2001, Health Care in Military

Settings, NAVMED P-5139, May 1, 2001, Bureau of Medicine and Surgery, Department of the Navy, 2300 E Street NW, Washington, D.C., 20372-5300

8. Blood Test Results - Normal Ranges Bloodbook.Com9. Demers, Laurence M.; Carole A. Spencer (2002). "LMPG: Laboratory Support for the Diagnosis

and Monitoring of Thyroid Disease". National Academy of Clinical Biochemistry(USA). Retrieved 2007-04-13

10. ^ Dietrich, J. W., K. Brisseau und B. O. Boehm (2008). "Resorption, Transport und Bioverfügbarkeit von Schilddrüsenhormonen" [Absorption, transport and bio-availability of iodothyronines]. Deutsche Medizinische Wochenschrift 133 (31/21):

11. "Hypothyroidism Causes, Symptoms, Diagnosis, Treatment Information Produced by Medical Doctors", Retrieved on 2009-3-27

12. Dietrich, J. W., K. Brisseau und B. O. Boehm (2008). "Resorption, Transport und Bioverfügbarkeit von Schilddrüsenhormonen" [Absorption, transport and bio-availability of iodothyronines]. Deutsche Medizinische Wochenschrift 133 (31/21): 1644-8. DOI 10.1055/s-0028-1082780