Thyroid function tests

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Notes on Renal function tests. . By Dr. Ashish Jawarkar Contact: [email protected] Website: pathologybasics.wix.com/notes

THYROID FUNCTION TESTS

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OVERVIEW

1. Biosynthesis of thyroid hormones 2. Regulation thyroid hormone production 3. What happens to thyroid hormones after release 4. Concept of FT3 and FT4 5. Hypothyroidism

a. Causes b. Clinical features c. Laboratory features

6. Hyperthyroidism a. causes b. Clinical features c. Laboratory features

7. Thyroid function tests in detail a. TSH b. Total T4 and Free T4 c. Total T3 and Free T3 d. TRH Stimulation test e. Anti thyroid antibodies f. RAIU test g. Thyroid scintigraphy

8. Summary and result interpretation 9. Neonatal hypothyroidism screening

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*Biosynthesis of thyroid hormones:-

Steps: 1. Iodide (I-) enters the thryroid cell via sodium iodide symporter 2. It enters the colloid through pendrin receptor 3. It is oxidized into Iodine (I0) by peroxidase enzyme 4. Then it is organified into MIT and DIT (mono and di iodo thyronine) 5. Then after coupling it forms T3 (Tri iodo thyronine) and T4 (Thyroxine) 6. T3 and T4 conjugate with TBG (thyroid binding globulin) 7. conjugated TBG is stored in colloid till required 8. While releasing into blood stream, it is first endocytosed into thyroid cell and then de -

coupled to form, T3 and T4 with MIT and DIT 9. MIT and DIT can be reutilized for coupling 10. T3 and T4 are released into the blood stream

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*Regulation of thyroid hormone production

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*What happens to thyroid hormones after release

Action of thyroid hormone on the body:

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*Concept of FT3 and FT4

1. Out of the total T3 and T4 in circulation, most of it remains bound to thyroid binding

globulin *, thyroid binding prealbumina nd Thyroid binding albumin. (*note – this is not thyroglobulin)

2. Only about 0.05% of each T3 and T4 remains free in circulation. This is FT3 and FT4. 3. These are better indicators for thyroid function than total T3 and Total T4.

(total=bound+free) 4. For example in pregnancy, level of thyroid binding globulin rises; hence though total T3

and total T4 remains same, level of FT3 and FT4 decreases.

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*Hypothyroidism Causes:

Primary Hypothyroidism High TSH

In response to low T3 and T4

thyroid problem

Secondary hypothyroidism Low TSH with normal TSH-RH

i.e. pituitary problem

Tertiary hypothyroidism LOW TSH, Low TSH-RH

i.e. hypothalamic problem

1. Iodine deficiency 2. Goitrogens 3. Hashimoto’s

(antimicrosomal antibodies)

4. Iatrogenic – surgery, antithyroid drugs, radiation

1. diseases of pituitary

1. diseases of the hypothalamus

Exaggerated response to TSH-RH stimulation

No response to TSH-RH stimulation

Rise and Delayed response to TSH-RH stimulation

Clinical Features:

1. Lethargy 2. Weight gain 3. Cold intolerance 4. Menstrual disturbances 5. Dry skin 6. myopathy 7. myxedema coma

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Laboratory features:

Clinical Features of hypothyroidism

Measure TSH and FT4

High TSH High TSH Low TSH Low FT4 Normal FT4 Primary hypothyroidism Subclinical hypothyroidism Sec or Tertiary Hypothroidism Check for antimicrosomal a/w Antibody 1. Bad obstetric outcome 2. hypercholesterolemia risk TRH Stimulatn 3. Poor cognitive development test 4. Risk of progression to overt Check TSH Hypothroidism FT4 Increased Normal Little or no response Delayed but Present TSH response Hashimoto’s iodine def Secondary Tertiary Congenital T4 synth def hypothyroidism hypothyroidism

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*Hyperthyroidism Causes:

Primary hyperthyroidism Low TSH, High T4

Secondary Hyperthyroidism High TSH, High T4

Pituitary/Paraneoplastic syndrome

Factitious Hyperthyroidism

1. Grave’s disease 2. Toxicity in

multinodular goiter 3. toxicity in adenoma 4. subacute thyroiditis

1. TSH secreting pituitary adenoma

2. Trophoblastic tumors that secrete TSH (choriocarcinoma, H. mole)

Clinical Features:

1. anxiety 2. insomnia 3. fine tremors 4. weight loss 5. heat intolerance 6. amenorrhoea and infertility 7. palpitations and tachycardia 8. cardiac arrythmias 9. muscle weakness 10. proximal myopathy 11. osteoporosis Triad of Grave’s Ophthalmopathy 1. Hyperthyroidism 2. Ophthalmopathy

a. exophthalmos b. lid retraction c. lid lag d. corneal ulceration e. impaired eye muscle function

3. Pretibial myxedema (dermopathy)

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Laboratory Features: Clinical features of hyperthyroidism

Measure TSH and FT4

High FT4, Low TSH Normal FT4, Low TSH High FT4, High TSH Primary Hyperthyroidism Secondary Hyperthyr Isotope thyroid scan Measure FT3 TRH test Diffuse Nodular Irregular Normal High Uptake Uptake uptake Grave’s Toxic Toxic Subclinical T3 Thyrotoxicosis Adenoma multinodular Hyperthyroid Goiter a/w

1. atrail fibrillation 2. osteoporosis 3. progression to overt hyperthyroidism Increased response No response i.e i.e. TRH – inc TSH – inc FT4 self controlled

Resistance to thyroid hormone Pituitary Adenoma/ Paraneoplastic

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*Thyroid function tests in detail Rider: Thyroid levels can be affected by various non thyroidal diseases mentioned below. Hence thyroid function tests should not be carried out during active diseases. 1. infections 2. liver diseases 3. malignancies 4. trauma 5. surgery 6. renal failure 7. cardiac failure

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(a) Thyroid stimulating hormone (TSH) Method: (Radioimmunoassay)(RIA) The technique was introduced in 1960 by Berson and Yalow as an assay for the concentration of insulin in plasma. It represented the first time that hormone levels in the blood could be detected by an in vitro assay. (known concentration of I125/I131 labelled TSH) (anti TSH antibody) (Known concentration of unlabelled TSH)

A mixture is prepared of o radioactive antigen

Because of the ease with which iodine atoms can be introduced into tyrosine residues in a protein (TSH here), the radioactive isotopes 125I or 131I are often used.

o antibodies ("First" antibody) against that antigen. Known amounts of unlabeled ("cold") antigen (known unlabelled TSH) are added to

samples of the mixture. These compete for the binding sites of the antibodies.

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At increasing concentrations of unlabeled antigen, an increasing amount of radioactive antigen is displaced from the antibody molecules.

The antibody-bound antigen (assay sample TSH) is separated from the free antigen (radioactive TSH) in the supernatant fluid, and

the radioactivity of each is measured. From these data, a standard binding curve, like this one shown in red, can be drawn.

The samples to be assayed (the unknowns) are run in parallel. After determining the ratio of bound to free antigen ("cpm Bound/cpm Free") in each

unknown, the antigen concentrations can be read directly from the standard curve (as shown above).

This method is used for assaying all thyroid function tests. Normal levels:

Adults Normal 0.5 to 5 mU/L Borderline 5 to 10 mU/L High >10 mU/L Low <0.1 mU/L

Abnormal values:

Low TSH High TSH 1. primary hyperthyroidism 2. T3 thyrotoxicosis 3. Secondary and tertiary hypothyroidism

1. Primary hypothyroidism 2. Secondary hyperthyroidism (pituitary adenoma/paraneoplastic syndromes)

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(b) Total T4 and Free T4 TSH combined with FT4 gives best assessment of thyroid function Method: Competititve immunoassay Principle same as for TSH Free T4: 1. Free T4 constitutes around 0.05% of total T4 2. Levels co relate better with metabolic state than total, because free levels are not affected

by TBG levels – TBG levels are affected in

a. pregnancy b. OCP use c. Nephrotic syndrome

Normals: Total T4 5-12 µg/dL Free T4 0.7-1.9 ng/dL

Abnormals:

Causes of increased T4 (Total) Causes of decreased T4 (total) 1. Primary hyperthyroidism 2. Increased thyroid binding globulin Decreased FT4

Increased TSH Increased T4 Normal FT4, Elevated total T4

3. Factitious hyperthyroidism 4. Secondary hyperthyroidism (pituitary

adenoma/paraneoplastic syndromes)

1. Primary hypothyroidism 2. Secondary and tertiary hypothyroidism 3. Anti thyroid Drugs, estrogen, danazol 4. Decreased thyroid binding globulin Increased FT4 Decreased TSH Decreased T4 Normal FT4, decreased total T4

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(c) Total T3 and Free T3 For routine assessment, TSH and T4 are enough, T3 levels are very low compared to T4 hence may not be used. Method: Same as for TSH Free T3: 1. Free T3 constitutes around 0.5% of total T3 2. Levels co relate better with metabolic state than total, because free levels are not affected by TBG levels – TBG levels are affected in

a. pregnancy b. OCP use c. Nephrotic syndrome

Normals:

T3 80-180 ng/dL Free T3 0.5% of T3 ie 2.3 to 4.2 pg/ml

Uses:

1. For early diagnosis of hyperthyroidism – in early stages T4 is normal but T3 is elevated 2. For measurement of T3 thyrotoxicosis

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(d) TRH Stimulation test Method:

Baseline sample collected for estimation of basal serum TSH levels

Inject TRH (200 to 500 mU/L)

Measure TSH at 20 & 60 mins Uses: 1. Confirmation of secondary (pituitary/hypothalamic) hypothyroidism 2. suspected hyperthyroidism Interpretation: Baseline TSH 20 min TSH 60 min TSH interpretation

Normal Rise of >2mU/L

Small decline normal

Elevated Further rise Small decline Primary hypothyroidism Low No rise - Secondary

hypothyroidism (pituitary)

Hypothyroidism

Low rise Further rise (delayed)

Hypothalamic hypothyroidism

elevated rise - Thyroid hormone resistance

Hyperthyroidism

elevated No rise - Pituitary adenoma/paraneoplastic

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(v) Antithyroid antibodies Antibodies used:

Anti microsomal antibody Anti thyroid peroxidase antibody (anti TPO)

Hashimoto

Anti TSH receptor antibody Grave’s Uses: For diagnosis and monitoring of autoimmune thyroid disorders

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(vi) Radioactive Iodine Uptake (RAIU) Principle: Radioactive iodine uptake co relates with functional activity of thyroid gland Method:

Patient is administered tracer dose of I123 or I131 orally

The I123 or I131 is taken up through Iodine symporters in follicular cells

Radioactivity over thyroid gland is measured at 2 to 6 hours and again at 24 hours Normals:

RAIU @ 24 hrs 10-30% Causes: RAIU separates causes of hyperthyroidism into-

Increased uptake Decreased uptake 1. Grave’s disease 2. Toxic multinodular goiter 3. Toxic adenoma 4. TSH secreting tumor

1. Cryptogenic hyperthyroidism (exogenous hormone administration)

2. Subacute thyroiditis

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(vii) Thyroid Scintigraphy Method:

99m Tc pertechnate is administered

A gamma counter is used to assess its distribution within the thyroid gland

Interpretation and uses: 1. EVALUATION OF CAUSES OF THYROTOXICOSIS WITH INCREASED RAIU

Uniform/diffuse uptake multiple discrete areas uptake single area of uptake Grave’s Toxic multinodular goiter Adenoma 2. EVALUATION OF A SOLITARY THYROID NODULE Hot nodule Cold nodule Hyperfunctioning Non functioning (20% malignant)

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*summary and result interpretation

Sr. No. TSH FT4 RESULT 1 Normal Normal Euthyroid 2. Low Low Secondary hypothyroidism 3 High Normal Subclinical hypothyroidism 4 High Low Primary hypothyroidism 5 Low Normal with

normal ft3 Subclinical hyperthyroidism

6 Low Normal with raised ft3

T3 thyrotoxicosis

7 Low High Primary hyperthyroidism

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*Neonatal Hypothyroidism Screening Rationale: 1. Thyroid hormone deficiency can cause cretinism that can be prevented by early detection and treatment Method:

Take dry blood spots on filter paper (3rd to 5th day of life) OR Cord serum

Test for TSH

If elevated, diagnostic of hypothyroidism

To confirm do I123 RAIU

Increased uptake No uptake Dyshormonogenesis thyroid agenesis Normals:

Neonatal TSH <20 mU/L

Thyroid function tests

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