Thyroid Function Notes

Physiology

• Thyroglobulin:

  • Synthesized by thyroid follicular cells.

  • Contains tyrosine residues that are iodinated by thyroperoxidase to form thyroid hormones (T4/T3).

  • Precursor of thyroid hormones.

• Thyroid Hormone Synthesis:

  1. Iodide uptake by thyroid follicular cells (controlled by TSH).

  2. Iodide converted to iodine.

  3. Iodine binds with tyrosyl residues on thyroglobulin via thyroid peroxidase (TPO).

  4. Production of:

     • Monoiodotyrosine (MIT)

     • Diiodotyrosine (DIT)

     • Thyroxine (T4): MIT + DIT

     • Triiodothyronine (T3)

  5. TSH signals follicular cells to ingest colloid via endocytosis.

  6. Lysosomes digest colloid into T4 & T3.

• T4 & T3 bind to thyroxine-binding globulin (TBG), prealbumin, and albumin.

  • Only free, unbound thyroid hormones are physiologically active.

  • Free hormones regulate TSH secretion.

  • Total hormone levels depend on thyroid function and binding protein concentrations.

• Hormone Synthesis:

  • Thyroid hormones are synthesized by iodination and coupling of tyrosine.

  • Iodine from fish & iodized salt. 1/3 is taken up by the thyroid.

Peripheral Conversion

• T4 to T3:

  • T4 is deiodinated to T3 (and reverse T3) in peripheral tissues (liver & kidneys).

  • T3 has higher binding affinity, T4 is more potent.

  • Conversion reduced by:

    • Systemic illness

    • Prolonged fasting

    • Drugs (e.g., beta-blockers).

  • Conversion increased by:

    • Drugs (e.g., phenytoin).

  • T3 is a poor indicator due to non-thyroidal factors.

Euthyroid Sick Syndrome

• Occurs in critical illness, calorie deprivation, major surgeries, trauma, and stress.

• Characteristics:

  • Altered TSH secretion (decreases then normalizes).

  • Peripheral conversion of T3 to rT3.

  • FT4 levels are low/normal.

Control of TSH Secretion

• Controlled by:

  1. Free thyroid hormones (FT3 > FT4):

     • Bind to nuclear receptors in the anterior pituitary.

     • Anterior pituitary more sensitive to Free T4 than T3.

     • In early hypothyroidism, T3 levels may be normal.

  2. TRH:

     • Stimulates TSH secretion.

     • Effect overridden by Free T4 concentrations.

     • Exogenous TRH has little effect in hyperthyroidism (TRH test).

Testing Thyroid Hormones

• Testing done to:

  • Confirm biochemical response

  • Monitor treatment.

• Measurements:

  • Free and total hormones, TSH.

• Factors:

  • Time of blood collection (before medication).

  • Patient details (pregnant, medications).

  • Specimen type: plasma or serum.

  • Limitations & interferences.

  • Reference ranges vary.

Plasma Total T4 & TBG

• Measure Free T4 & Plasma TBG.

• TBG binding sites:

  • Euthyroid: 1/3 occupied by T4.

  • Hyperthyroidism: ↑ Total & Free T4, fewer unoccupied sites.

  • Hypothyroidism: ↓ Total & FT4, more unoccupied sites.

• Increased TBG:

  • ↑Estrogen (pregnancy, newborns, oral contraceptives).

  • Inherited TBG excess (rare).

• Decreased TBG:

  • Severe illness.

  • Loss of low molecular weight proteins (nephrotic syndrome).

  • Androgens & Danazol.

  • Inherited TBG deficiency (rare).

Free T4

• Biologically active portion (≈0.05% of total T4).

• Specimen: plasma or serum (separate within 48 hours).

• Interferences:

  • Hemolyzed or lipemic samples.

  • Herbal remedies.

  • Anti-T4 abs.

  • Biotin, anti-strepavidin abs.

  • Heterophile antibodies.

  • Altered binding globulins (unless compensated).

TSH (Thyrotropin)

• Reference: 0.3 - 5.0 mU/ml.

• Measure with Free T4 (and FT3 when necessary).

• Raised levels = Hypothyroidism.

• Suppressed levels = Hyperthyroidism.

• Values:

  • > 20 mU/mL = primary thyroid failure.

  • 5 -15mU/mL = borderline, requires evaluation.

• Interpretation:

  • TSH >15mU/mL = primary hypothyroidism.

  • TSH <5mU/mL = secondary hypothyroidism.

  • Low Free T4 with very low TSH suggests pituitary/hypothalamic cause.

• Levels:

  • Decreased in Grave's Disease.

  • Increased in TSH-secreting pituitary adenomas.

  • Elevated in primary hypothyroidism.

• Test Interferences:

  1. Macro-TSH.

  2. Biotin: sandwich assay = low TSH.

  3. Anti-streptavidin antibody: sandwich & competitive assays = low TSH.

  4. Heterophilic antibody interference, HAAM.

Free T3

• Active (≈0.5%).

• x4-5 higher levels than T4.

• Increases before T4.

• Use of investigation:

  • Diagnosis of hyperthyroidism (FT4 borderline).

  • Confirms T3 thyrotoxicosis (suppressed TSH & normal FT4).

TRH Test

• Assess Anterior pituitary function.

• TRH → ↑ TSH → ↑Thyroid hormones → ↓TSH.

• Interpretation:

  1. HIGH plasma TSH: Hypothyroidism (1°)= low FT4 levels are stimulating a high TSH level; levels of TSH are further increased after the TRH test

  2. LOW plasma TSH: Hypopituitarism (2°): pituitary does NOT respond to TRH; thus levels of TSH remain low. N.B. FT4 levels also tend to be low
     Hyperthyroidism (1°): A very high FT4 concentration which overrides the stimulatory effect of the TRH test. Thus, TSH levels remain low.. Rely on TSH assay

• Benefits:

  • Diagnosis of confusing TFTs.

  • Hyperthyroidism: TSH is low & FT4 is high; TRH induces little or no change in TSH level.

  • Hypothyroidism (end organ failure): TRH induces prompt increase in TSH.

Thyroglobulin (TG) Test

• Only produced by thyroid tissue→ ELEVATIONS = thyroid carcinoma (papillary/follicular).

• Uses:

  • Tumor marker (monitor residual tumor, metastasis, recurrence).

  • Evaluate treatment effectiveness.

  • Serial monitoring post-thyroidectomy/iodine treatment.

  • Detect recurrence of follicular thyroid carcinoma.

Thyroid Auto-antibodies

• Related to autoimmune processes.

• Types:

  • Anti-thyroglobulin antibodies (ATA).

  • Anti-thyroid peroxidase antibody (Anti-TPO ab).

  • TSH-Receptor Abs (TRAbs).

    • TSH-Receptor Stimulatory antibodies (Tsab).

    • TSH-Receptor inhibitory immunoglobulins (TBII).

  • Thyroid hormone autoantibodies (THAab) – Anti-T4 & Anti-T3.

Anti-TPO Abs

• Mediate antibody-dependent thyroid cell destruction.

• Present in Hashimoto (>90%) and Graves (≈75-80%).

• Uses:

  • Resolving diagnostic dilemma when TSH elevated and FT4 normal.

  • Evidence for early autoimmune disease.

  • Monitor response to immunotherapy.

  • Identify at-risk individuals.

  • Predict postpartum thyroiditis.

  • Predisposition to autoimmune disease.

Thyroglobulin Abs (ATA)

• Uses:

  • Diagnose & monitor autoimmune thyroid disease.

  • Distinguish autoimmune from other thyroid diseases.

  • Guide treatment decisions.

  • Limitations: presence of anti-thyroglobulin antibodies (ATAs) causes inaccurate measurements.

Disorders of the Thyroid Gland

• Hyperthyroidism: EXCESSIVE thyroid hormone secretion.

• Hypothyroidism: DEFICIENT thyroid hormone secretion.

• Goitre: diffuse OR due to nodule(s).

Goitre

• Abnormal enlargement of the thyroid gland.

• Can occur with:

  • Hyperthyroidism

  • Hypothyroidism

  • Euthyroidism

• Indicates a condition causing thyroid growth.

Hyperthyroidism

• Increased metabolic rate.

• Symptoms: weight loss, diarrhea (elderly).

• Thyrotoxicosis: excessive thyroid hormone levels.

• Causes:

  • Grave’s Disease: antibodies attach to TSH receptor sites→ increased hormone production; test for TPO, anti-Tg.

Toxic Nodules

• Single or multiple.

• Older people with cardiovascular symptoms.

• Secrete hormones autonomously→ TSH suppressed.

• Detected by radioactive iodine uptake.

Investigation of Hyperthyroidism

1. Measure FT4 & TSH (↑Free T4 & ↓TSH: measure Autoabs).

2. FT4 normal & ↓TSH: Measure FT3.

3. ↑FT4 & TSH normal: Measure plasma TBG & TT4.

4. Measure Anti-TPO & TSab (Graves’).

5. Thyroglobulin assay.

6. Check Calcium levels.

Hypothyroidism

• Investigation:

  1. Patient history & status.

  2. Plasma TSH & FT4 (↓FT4 & ↑ TSH: 1° hypothyroidism→ Measure Anti-TPO & Anti-thyroglobulin abs. Measure Anti-Thyroid binding inhibitory immunoglobulin (TBII) abs).

  3. Normal TSH & Low FT4 (Drug competition for TBG binding sites or TBG…→ Measure Plasma TBG & TT4, Thyroid Hormone Binding Ratio, Patient DRUG history).

  4. TSH is low( perform TRH stimulation test→ 2° (hypothalamus/pituitary)): Basal plasma TSH, 200 ug of TRH injected IV, Bloods for TSH.TSH should increase & exceed upper limit at 20 mins & decrease.

Interferences: Thyroid function

• Macro-TSH.

• TSabs & TBII.

• Biotin sandwich assay = low TSH; FT4 & FT3 = high levels

• Anti-streptavidin antibody.

• Anti-Thyroglobulin abs (interfere with measurement of TG).

• Anti-T4 & anti-T3 abs interfere in the measurement of T4 & T3.

• Heterophilic antibody interference, Human anti-mouse abs and human anti-animal abs

• Variants in the albumin gene &TBG leading to altered levels of albumin & hence total T4&T3

• Factors that affect levels of binding globulins (e.g. drugs, paraproteins, etc)

Here's a table summarizing thyroid function tests, the analytes measured, result interpretations, and associated diseases:

Important Notes:

• Reference ranges can vary between laboratories.

• Clinical context is crucial for accurate interpretation.

• TBG = Thyroxine-Binding Globulin; levels can be affected by various factors (e.g., pregnancy, medications).

• This table simplifies complex scenarios; consult endocrinology guidelines for detailed interpretations.

Here's a table summarizing lab values indicative of hypothyroidism and hyperthyroidism: