Thyroid Functions
- 1. Approach to Thyroid Function Tests Indications for TFT • Clinical suspicion of thyroid disease. • Newborn: heel prick test for TSH for early detection of neonatal hypothyroidism. • Woman: o Pregnant. o Planning to be pregnant. o Post-partum: 4 – 8 weeks. • Elderly. • Drug exposure: Amiodarone, Lithium. • History of neck irradiation. • Autoimmune diseases as T1DM.
- 2. Hypothalamic Pituitary Thyroid (HPT) Axis Primary Disorder (Hypo or Hyperthyroidism) Secondary Disorder (Pituitary) Tertiary Disorder (Hypothalamic) Central
- 3. T4 T3 Plasma Concentration • Total • Free 70 times more 7 times more Free Fraction 0.03 % 0.3 % Relative Potency Mainly a prohormone Nearly 10 times more potent T ½ 6 – 7 days 1 – 2 days Source 100 % thyroid 20% thyroid 80% peripheral deiodination of T4 (largely in the liver)
- 5. Binding Proteins • TBG (Thyroxine Binding Globulin). • TBPA (Thyroxine Binding Prealbumin) (Transthyretin). • Albumin (non- specific binder). ↑ Bininding Proteins (mainly TBG) → ↑ TTH, but usually fTH adjusts • Hyperestrogenaemia: o Pregnancy o Oestrogens o Contraceptive pills o Gonadotrophins, eg, for IVF o Clomiphine (↑ gonadotrophins) o SERM (selective estrogen receptor modulators) as Raloxifene • Other drugs: Opiates, Fibrates, Nicotinic Acid • Congenital hyperthyroglobulinaemia (euthyroid hyperthyroxinaemia)
- 6. ↓ Bininding Proteins (mainly TBG) → ↓ TTH, but usually fTH adjusts • Acute, chronic illness (-ve acute phase reactants) • Fasting, starvation • Liver disease • Kidney disease (nephrotic syndrome) • Drugs: o Androgens o Corticosteroids o Anticonvulsants as phenytoin, primidone • Congenital hypothyroglobulinaemia (euthyroid hypothyroxinaemia) Familial Dysalbuminaemic Hyperthyroxinaemia Albumin has increased affinity for TH binding ↑ TTH but usually fTH adjusts
- 7. Displacement of Thyroid Hormones from Plasma Protein Binding Sites • Hereditary disorders producing lower affinity binding proteins • Drugs competing for the binding sites o Heparin (unfractionated or low molecular wt.) → Stim of lipoprotein lipase → liberation of FFA which compete with TH for plasma protein binding sites → artefactual hyperthyroxinaemia if fTH are assed in patients on heparin therapy, eg, HD patients (Sample should be taken 10 hh after last heparin injection) o Frusemide o Salicylates o NSAIDs o Phenytoin ↓ TTH but usually fTH adjusts
- 8. TSH • TSH remains the most commonly used endocrine test in clinical practice. • TSH stimulates cellular growth and vascularity of thyroid gland. • It stimulates several follicular cell functions: • Iodide trapping • Iodide organification • Thyroid hormone release • The negative feedback control of TSH by TH generates a log linear relationship between TSH and TH so that small changes in TH lead to much amplified counter-regulatory TSH changes. So, TSH is usually the 1st TFT to fall out of the reference interval (though it is relatively wide). So, TSH is regarded as the best initial screening test for thyroid disorders in most circumstances.
- 9. • TSH is the most sensitive and specific test for investigation and management of 1ry thyroid dysfunction (but may be misleading alone in the rare central thyroid dysfunction). •A TSH value within the reference range excludes most cases of 1ry overt thyroid disease. • TSH shows a diurnal variation of up to + 50% with peak after midnight and nadir in afternoon. • This variation has minimal effect on serum T4, bec hourly T4 secretion rate (3 – 5 ug) represents a very small fraction of the extrathyroidal T4 pool (500 – 600 ug). • In pregnancy, TSH ↓ during 1st trimester then gradually returns to pre-pregnancy value • TH (conversely) ↑ during 1st trimester then gradually return to pre- pregnancy value (or even ↓ below the reference range in 3rd trimester) • Some labs report trimester specific reference ranges.
- 11. 0.3 - 5 > 105 - 10< 0.03 0.03 – 0.3 Normal (0.4 – 4.5) Requires treatment Requires treatment Requires follow up for confirmation and assessment of other indicators for treatment Requires follow up for confirmation and assessment of other indicators for treatment 0.1 was the boundary between these 2 categories in older references when TSH values below 0.1 were difficult to measure Interpretation of TSH values if TH values are normal: Subclinical Hyperthyroidism Subclinical Hypothyroidism
- 12. • The distribution of TSH values within the refernce range is not normal, with the median values (also depending on population iodine intake) usually between 1 – 1.5 mU/L • This signifies that values in the range of 2.5 – 4.5 mU/L may (particularly in younger persons) indicate subtle hypothyroidisn (though these values do not justify for the definition of subclinical hypothyroidism).
- 13. Thyroid Hormones • T4 utilization rate ↓ progressively with age after birth from 10 ug/kg/day in 1st few days of life to 1- 2 ug/kg/day in adult life. This last figure is used to guide thyroxine replacement therapy (Eltroxine or Euthyrox tablets, 50, 100 ug) • Total and free T3, T4 ↓ more modestly with age. • rT3 ↑ with age • There is little or no change due to puberty, gender or racial variation. • Specific normal reference ranges are advocated for age groups, pregnancy trimesters and puerperium.
- 14. 1ry Thyroid Disorders • Defined by either ↓ (hypo) or ↑ (hyper) TH with reciprocal (and actually earlier and more evident) changes in TSH. • Considered subclinical if TSH abnormal while TH still within normal. • Subclinical thyroid disorders are relatively common: o Subclinical hypothyroidism: 4 – 8% (up to 20% in women > 60Y) o Subclinical hyperthyroidism: 2%
- 15. Etiology of 1ry Thyroid Disorders 1ry Hypothyroidism 1ry Hyperthyroidism • Congenital • Iodine deficiency (endemic goitre) • Iodine induced (Wolff Chaikoff effect)_transient • Autoimmunity • Post thyroiditis – Subacute: transient – Chronic: persistent • Post thyroid ablation: – Thyroidectomy – Radio-Iodine • Graves` disease • Toxic multinodular goitre The 2 commonest causes • Toxic nodule • Iodine induced (Jod Basedow effect)_transient • Early thyroiditis (subacute or chronic) (transient) • Ectopic TH, eg, struma ovarii • Excess thyroxine (factitious thyrotoxicosis)
- 16. Subclinical Hypothyroidism Subclinical Hyperthyroidism • Progression to frank hypothyroidism. • Menstrual irregularities, subfertility. • Adverse pregnancy outcome (abortion, neonatal hypothyroidism). • Dyslipidaemia. • Atherosclerotic CVD (CAD, MI, PAD). • ↑ All cause, cardiovascular mortality. • Progression to frank hyperthyroidism. • Menstrual irregularities, subfertility. • Adverse pregnancy outcome (abortion, neonatal hyperthyroidism). • Atrial fibrillation • Osteoporosis • Cardiac dysfunction • ↑ All cause, cardiovascular mortality. Health Risks of Subclinical 1ry Thyroid Disorders
- 17. Indicators for Need for Treatment in Subclinical 1ry Thyroid Disorders Subclinical Hypothyroidism Subclinical Hyperthyroidism • TSH > 10 mU/L • Follow up TSH (after 3 months) progressively increasing. • Clinical features possibly attributed to hypothyroidism. • Therapeutic trial → favourable clinical and/or TSH response. • History of prior thyroid dysfunction. • Other autoimmune disorders, eg T1DM. • Woman with family history of thyroid disease. • Woman who is pregnant or planning to be pregnant. • +ve Anti TPO Ab / Dyslipidaemia •TSH < 0.1 (0.03) mU/L • Follow up TSH (after 3 months) progressively decreasing. • Clinical features possibly attributed to hyperthyroidism. • Therapeutic trial → favourable clinical and/or TSH response. • History of prior thyroid dysfunction. • Other autoimmune disorders, eg T1DM. • Woman with family history of thyroid disease. • Elderly.
- 18. Non-Thyroidal Illness (NTI) (Syndrome) Euthyroid Sick Syndrome Low T3 Syndrome • The most common biochemical abnormality of endocrine function among medical inpatients. • Abnormal TFT (mainly low TT3) are present in > 70% of ICU patients, with 50% having low TT4. • Non- Thyroidal Illness: the most widely adopted name nowadays. It implies an illness that manifests as abnormal TFT in absence of intrinsic thyroid disease. • Euthyroid sick syndrome: was based on the observation that, despite TFT abnormalities, there is no clinical features of thyroid dysfunction and no conclusive benefit from treatment. • Low T3 syndrome: describes the earliest and most common and characteristic abnormality, present even in the mildest forms.
- 19. Mechanisms of NTI Central Hypothyroidism • Malnutrition → ↓ leptin → ↓ TRH • Inhibition of TRH, TSH secretion by increased local T3 dt stim of dopamine (D2) receptors by o Sepsis, inflammation o Dopamine, dopaminergic drugs ↓ Plasma Protein Binding Capacity for Thyroid Hormones (↓TH) These proteins are –ve acute phase reactants. They ↓ dt: • ↓ Synthesis • ↑ Breakdown • Movement out of plasma space • ↓ Binding affinity ↑Thyroid Hormone Degradation and/or Excretion This may be the most important factor responsible for acute drop in T3
- 20. Changes in Deiodinase Activity These changes are triggered by: • Hormonal changes: ↑ glucocorticoids, glucagon • ↑ Proinflammatory cytokines as IL-1, IL-6, TNF-α • ↑ Free radicals, heavy metals • ↓ Vit B12, zinc Although change in deiodinase activity is a plausible mechanism, it does not play a major role in the acute drop of T3 and it may be a consecuence rather than a cause for this. Contrary to other deiodinases, D2 is retained in the endoplasmic reticulum, so it is particularly adept at supplying T3 for local use in hypothalamus, pituitary, brown adipose tissues and muscles. Tissues w express D1 as liver, kidney export much of the T3 produced to plasma
- 21. Patterns of NTI • Changes involve mainly the total hormone levels; changes in free fractions are only modest. • T3 ↓, and T4 ↓ to a lesser extent → ↓ BMR, ↓ protein and fat catabolism. • Whether these changes are adaptive or maladaptive remains controversial. • Different patterns were described: Low T3 Syndrome (70%) • Commonest and present to some degree in other patterns • T3 falls rapidly and progressively within ½ - 24hh of onset of causative illness • rT3 is increased Low T3, T4 Syndrome (30%) • Observed in severely ill patients admitted to ICU • T4 falls over a period of 1 – 2 days High T4 Syndrome (1%) • Acute psychiatric illness • Hepatitis (↑ binding protein production) • Iodine exposure
- 23. Other Abnormalities ↓ Nocturnal TSH surge, unrelated to ambient circulating T4, T3 levels, but probably related to hypothalamic dysregulation Changes during Recovery A transient rise in TSH consistently precedes restoration of T3, T4 levels. Neither the fall of TH during NTI nor the rise in TSH during recovery justify thyroid hormone treatment. Importance of NTI • Diagnosis to be able to differentiate between TFT abnormalities indicative of NTI and those indicative of intrinsic thyroid disease. • Prognosis Thyroid function disturbances correlate with disease severity. Low TH predict poor prognosis. • Treatment In order not to give unnecessary or even harmful treatment
- 24. Patterns of Abnormal TFT TSH TH • 1ry hyperthyroidism • NTI (esp acute psychiatric illness) • THR • Early thyroiditis • NTI (esp acute psychiatric illness) • Central hyperthyroidism • THR • NTI (esp acute psychiatric illness) • Recovery from NTI •Subclinical hyperthyroidism • 1ry hyperthyroidism early on treatment • Thyroxine overdose • NTI • Normal • Properly treated hypo or hyperthyroidism • Subclinical hypothyroidism • 1ry hypothyroidism early on treatment • AntiThyroid overdose • NTI (recovery) • Central hypothyroidism • NTI • NTI (main presentation) • Late thyroiditis 1ry hypothyroidism N↓ ↑ N ↓ ↑
- 25. Auto Antibodies in Thyroid Disease • Most thyroid disorders are autoimmune in nature. • Look for thyroid disorders in patients with autoimmune diseases and look for autoimmune diseases in patients with thyroid disorders. • 3 AutoAntibodies are the most important: TPOAb (Thyroid Peroxidase Ab) • Previously called antimicrosomal Ab (AMA) • Associated with 1ry hypothyroidism TRAb (Thyrotropin Receptor Ab) • Previously called LATS (long acting thyroid stimulator) or TSI (thyroid stimulating Ig). • Associated with Graves` disease • Correlates with activity and severity of thyroid associated ophthalmopathy Anti TBG * Associated with Hashimoto thyroiditis
- 26. Thyroglobulin Level • Differentiates between Graves` disease (elevated) and factitious thyrotoxicosis (decreased). • Useful for detection of recurrence of differentiated thyroid cancer
- 27. Approach for Discordant TFT • Re-evaluate the clinical history. • Age: neonatal period / elderly • Pregnancy. • NTI. • Underlying iodine deficiency → Wolff Chaikoff effect / Jod Basedow effect • Thyroxine therapy. • Medications. • Exclude TH, TSH assay interference. • Investigate for rare disorders of HPT function.
Editor's Notes
- #5: Defending plasma T3 is a biologic priority Serum T3 is the main target around which serum T4 and TSH are adjusted Individual tissues could be said to have specific thyroid status, relatively independent of serum thyroid hormone level. This tissue specificity depends on variations in: TH receptor expression. TH transporters. TH metabolism. Idothyronine deiodinase activity. Deiodinases are selenoenzymes: contain the trace metal selenium. Selenium deficiency was suggested to link illness with deiodinase activity changes in NTI; this was later on disproved. There are 3 separate deiodinases, encoded from 3 different genes D1 is present in liver, kidney, thyroid D2 is present in brain, pituitary, thyroid, brown adipose tissue, skeletal muscle, heart (Presence of D in BAT facilitates adaptive themogenesis) D2 ACTIVATES T4 to T3. It causes local thyrotoxicosis D3 INACTIVATES T4 and T3. it causes local hypothyroidism D1 catalyzes the 4 deiodination reactions, but it has much less affinity for T4 than D2, so it may act mainly as a scavenger enzyme, to clear from the circulation rT3 and other inactive sulfated and iodothyronines which are not degraded efficiently by D2 or D3. The released iodine can be reclaimed for thyroid hormone synthesis in case of iodine deficiency.
- #6: TTH: total thyroid hormone fTH: free thyroid hormone
- #16: During pregnancy, hCG and it has TSH like activity. This may produce hyperthyroidism early in pregnancy, esp in complicated pregnancy: Hyperemesis gravidarum Molar pregnancy (vesicular mole, choriocarcinoma)
- #25: THR: Thyroid hormone resistance
- #28: HPT: hypothalamo-pituitary-thyroid