Thyroid Function Tests

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THYROID FUNCTION TESTS

Notes on Renal function tests. . By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
OVERVIEW 1. 2. 3. 4. 5. Biosynthesis of thyroid hormones Regulation thyroid hormone production What happens to thyroid hormones after release Concept of FT3 and FT4 Hypothyroidism a. Causes b. Clinical features c. Laboratory features Hyperthyroidism a. causes b. Clinical features c. Laboratory features 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 Summary and result interpretation Neonatal hypothyroidism screening
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*Biosynthesis of thyroid hormones:-
Steps: Iodide (I-) enters the thryroid cell via sodium iodide symporter It enters the colloid through pendrin receptor It is oxidized into Iodine (I0) by peroxidase enzyme Then it is organified into MIT and DIT (mono and di iodo thyronine) Then after coupling it forms T3 (Tri iodo thyronine) and T4 (Thyroxine) T3 and T4 conjugate with TBG (thyroid binding globulin) conjugated TBG is stored in colloid till required 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 1. 2. 3. 4. 5. 6. 7. 8.
*Regulation of thyroid hormone production
*What happens to thyroid hormones after release
Action of thyroid hormone on the body:
*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.
*Hypothyroidism Causes: Primary Hypothyroidism High TSH In response to low T3 and T4 thyroid problem 1. Iodine deficiency 2. Goitrogens 3. Hashimotos (antimicrosomal antibodies) 4. Iatrogenic surgery, antithyroid drugs, radiation Exaggerated response to TSHRH stimulation Secondary hypothyroidism Low TSH with normal TSH-RH i.e. pituitary problem 1. diseases of pituitary Tertiary hypothyroidism LOW TSH, Low TSH-RH i.e. hypothalamic problem 1. diseases of the hypothalamus
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
Laboratory features: Clinical Features of hypothyroidism
Measure TSH and FT4
High TSH Low FT4
High TSH Normal FT4
Low TSH
Primary hypothyroidism
Subclinical hypothyroidism
Sec or Tertiary Hypothroidism
Check for antimicrosomal Antibody
a/w 1. Bad obstetric outcome 2. hypercholesterolemia risk 3. Poor cognitive development 4. Risk of progression to overt Hypothroidism
TRH Stimulatn test Check TSH FT4
Increased
Normal
Little or no response
Delayed but Present TSH response
Hashimotos
iodine def Congenital T4 synth def
Secondary hypothyroidism
Tertiary hypothyroidism
*Hyperthyroidism Causes: Primary hyperthyroidism Low TSH, High T4 Secondary Hyperthyroidism High TSH, High T4 Pituitary/Paraneoplastic syndrome 1. TSH secreting pituitary adenoma 2. Trophoblastic tumors that secrete TSH (choriocarcinoma, H. mole) Factitious Hyperthyroidism
1. Graves disease 2. Toxicity in multinodular goiter 3. toxicity in adenoma 4. subacute thyroiditis
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 Graves 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 Primary Hyperthyroidism
Normal FT4, Low TSH
High FT4, High TSH Secondary Hyperthyr
Isotope thyroid scan
Measure FT3
TRH test
Diffuse Uptake
Nodular Uptake
Irregular uptake
Normal
High
Graves
Toxic Toxic Adenoma multinodular Goiter
Subclinical T3 Thyrotoxicosis Hyperthyroid
a/w 1. atrail fibrillation 2. osteoporosis 3. progression to overt hyperthyroidism
Increased response i.e. TRH inc TSH inc FT4
No response i.e 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 I /I131 labelled TSH)

125
(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 131 I 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 Borderline High Low
0.5 to 5 mU/L 5 to 10 mU/L >10 mU/L <0.1 mU/L
Abnormal values: Low TSH 1. primary hyperthyroidism 2. T3 thyrotoxicosis 3. Secondary and tertiary hypothyroidism High TSH 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 Free T4 Abnormals: Causes of increased T4 (Total) 1. Primary hyperthyroidism 2. Increased thyroid binding globulin Decreased FT4 Increased TSH Increased FT4 Increased T4 Decreased TSH Normal FT4, Elevated total T4 Decreased T4 3. Factitious hyperthyroidism 4. Secondary hyperthyroidism (pituitary adenoma/paraneoplastic syndromes) Normal FT4, decreased total T4 1. 2. 3. 4. Causes of decreased T4 (total) Primary hypothyroidism Secondary and tertiary hypothyroidism Anti thyroid Drugs, estrogen, danazol Decreased thyroid binding globulin
5-12 g/dL 0.7-1.9 ng/dL
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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 Free T3
80-180 ng/dL 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 Normal Elevated Low 20 min TSH Rise of >2mU/L Further rise No rise 60 min TSH Small decline Small decline interpretation normal Primary hypothyroidism Secondary hypothyroidism (pituitary) Hypothalamic hypothyroidism Thyroid hormone resistance Pituitary adenoma/paraneoplastic
Hypothyroidism
Low
Hyperthyroidism
rise rise No rise
elevated elevated
Further rise (delayed) -
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(v) Antithyroid antibodies

Antibodies used: Anti microsomal antibody Anti thyroid peroxidase antibody (anti TPO) Anti TSH receptor antibody Uses: For diagnosis and monitoring of autoimmune thyroid disorders Hashimoto Graves
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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 intoIncreased uptake Graves disease Toxic multinodular goiter Toxic adenoma TSH secreting tumor Decreased uptake 1. Cryptogenic hyperthyroidism (exogenous hormone administration) 2. Subacute thyroiditis
1. 2. 3. 4.
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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
Graves
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. 1 2. 3 4 5 6 7 TSH Normal Low High High Low Low Low FT4 Normal Low Normal Low Normal with normal ft3 Normal with raised ft3 High RESULT Euthyroid Secondary hypothyroidism Subclinical hypothyroidism Primary hypothyroidism Subclinical hyperthyroidism T3 thyrotoxicosis 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 Normals: Neonatal TSH
thyroid agenesis
<20 mU/L

Thyroid Function Tests

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1

THYROID FUNCTION TESTS

*Biosynthesis of thyroid hormones:-

*Regulation of thyroid hormone production

*What happens to thyroid hormones after release

Action of thyroid hormone on the body:

No response to TSH-RH stimulation

Rise and Delayed response to TSH-RH stimulation

Laboratory features: Clinical Features of hypothyroidism

Measure TSH and FT4

High TSH Low FT4

High TSH Normal FT4

Sec or Tertiary Hypothroidism

Check for antimicrosomal Antibody

TRH Stimulatn test Check TSH FT4

Delayed but Present TSH response

iodine def Congenital T4 synth def

1. Graves disease 2. Toxicity in multinodular goiter 3. toxicity in adenoma 4. subacute thyroiditis

Laboratory Features: Clinical features of hyperthyroidism

Measure TSH and FT4

High FT4, Low TSH Primary Hyperthyroidism

Normal FT4, Low TSH

High FT4, High TSH Secondary Hyperthyr

Isotope thyroid scan

Toxic Toxic Adenoma multinodular Goiter

Subclinical T3 Thyrotoxicosis Hyperthyroid

a/w 1. atrail fibrillation 2. osteoporosis 3. progression to overt hyperthyroidism

Increased response i.e. TRH inc TSH inc FT4

No response i.e self controlled

Resistance to thyroid hormone

Pituitary Adenoma/ Paraneoplastic

(a) Thyroid stimulating hormone (TSH)

(known concentration of I /I131 labelled TSH)

(anti TSH antibody)

(Known concentration of unlabelled TSH)

Normal Borderline High Low

0.5 to 5 mU/L 5 to 10 mU/L >10 mU/L <0.1 mU/L

(b) Total T4 and Free T4

5-12 g/dL 0.7-1.9 ng/dL

(c) Total T3 and Free T3

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

(d) TRH Stimulation test

Inject TRH (200 to 500 mU/L)

rise rise No rise

Further rise (delayed) -

(v) Antithyroid antibodies

(vi) Radioactive Iodine Uptake (RAIU)

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

Normals: RAIU @ 24 hrs 10-30%

(vii) Thyroid Scintigraphy

multiple discrete areas uptake

single area of uptake

Toxic multinodular goiter

2. EVALUATION OF A SOLITARY THYROID NODULE

Non functioning (20% malignant)

Test for TSH

If elevated, diagnostic of hypothyroidism To confirm do I123 RAIU

Dyshormonogenesis Normals: Neonatal TSH

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