Endocrinology: Physiology - Thyroid gland Flashcards by Hannah Meiklejohn

Two thyroid gland functions

Secretion of thyroid hormones
Secretion of calcitonin

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Describe the anatomy of the thyroid gland

Two lobes separated by isthmus +/- pyramidal lobe arising from isthmus

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Describe the difference in structure and appearance of the follicular thyroid when active vs inactive

Inactive: large follicles, abundant colloid, flat epithelial lining
Active: small follicles, “reabsorption lacunae” present where colloid draining from follicle, cuboidal or columnar epithelial lining

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Which thyroid hormone is more abundant? Which has greater biologic activity?

T3 (triiodothyronine) produced in lesser amounts than T4 (thyroxine) but is more biologically active

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What is the minimum daily intake of iodine required for normal thyroid function in adults?

150ug/day

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What is the average daily iodine intake in adults in developed countries? How is this achieved?

500ug/day
Due to supplementation of table salt

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Describe iodine metabolism (including specific values)

500ug ingested
120ug to thyroid -> 40ug to ECF, 80ug as T3 and T4
80ug as T3 and T4 received by liver and other tissues -> 60ug to ECF, 20ug to faeces as bile
480ug filtered and excreted by kidneys

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How is iodine taken up by thyrocytes?

Taken up across basolateral membrane via Na+/I- symporter (NIS): this is a form of secondary active transport where energy is generated by Na+/K+ ATPase which pumps Na+ out to generate electrochemical gradient for inward movement

Then transported across apical membrane via Cl-/I- exchanger called pendrin

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What is the effect of TSH on NIS expression?

Increases expression and retention in basolateral membrane

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Describe the synthesis of thyroid hormones in thyrocytes

Iodine transported into colloid, then undergoes oxidation and incorporation into thyroglobulin via thyroid peroxidase
Produces monoiodotyrosine (MIT) and diiodotyrosine (DIT)
DIT + DIT -> T4
MIT + DIT -> T3
DIT + MIT -> RT3
Thyroid peroxidase also involved in the catalyse of these coupling reactions

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What is the fate of MIT and DIT if not as thyroid hormones?

Deiodinated via iodotyrosine deiodinase
Iodine reutilised

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What are the four functions of thyrocytes?

Collect and transport iodine
Synthesise and secrete (into colloid) thyroglobulin
Generate thyroid hormones
Remove thyroid hormones from thyroglobulin and secrete into circulation

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Normal T4 level. How much of this is protein-bound?

8ug/dL (103nmol/L)
99.98% protein-bound, predominantly TBG

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Normal T3 level. How much of this is protein-bound?

0.15ug/dL (2.3nmol/L)
99.8% protein-bound, predominantly TBG and some albumin

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Which is more highly protein-bound: T3 or T4?

T4 (99.98% vs 99.8% for T3)

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What feeds back to suppress TSH release?

Free thyroid hormones (not protein-bound)

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What are the three plasma proteins that bind thyroid hormones? What are their respective half-lives?

Albumin: t1/2 = 13 days
Transthyretin (a prealbumin): t1/2 = 2 days
Thyroxine-binding globulin (TBG): t1/2 = 5 days

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Which of the plasma proteins has the highest capacity for binding thyroid hormone? Which has the highest affinity (and therefore carries the most)?

Highest capacity: albumin
Highest affinity: thyroid-binding globulin

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List six factors which increase the concentration of thyroid-binding globulin

Pregnancy
Exogenous oestrogens
Methadone
Heroin
Antipsychotics
Clofibrate

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List four factors which decrease the concentration of thyroid-binding globulin

Glucocorticoids
Androgens
Danazol
Asparaginase

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List three drugs which inhibit T4 binding to TBG

Phenytoin
Salicylates
5-fluorouracil

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What pattern of TBG concentration, total plasma thyroid hormone concentration, free thyroid hormone concentration, plasma TSH levels, and clinical state, is seen with:
a) hyperthyroidism
b) hypothyroidism
c) increased thyroid hormone binding proteins
d) decreased thyroid hormone binding proteins

a) normal, increased, increased, decreased, hyperthyroid
b) normal, decreased, decreased, increased, hypothyroid
c) increased, increased, normal, normal, euthyroid
d) decreased, decreased normal, normal, euthyroid

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Why are patients with derangements in the concentration of thyroid hormone binding proteins usually euthyroid?

Levels of free thyroid hormones control TSH release: increased binding and therefore decreased free thyroid hormone leads to increased TSH release, which restores levels of free and thus active hormone (even if total concentration increased)

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Describe the metabolism of thyroid hormones

T3 and T4 are deiodinated in the kidney, liver and other tissues by deiodinases (D1, D2 and D3)
Catabolises hormones but also increases local concentration of T3 which is the primary physiologic mediator

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Which of the deiodinases is the primary deiodinase responsible for conversion of T4 to T3 in the periphery?

What % of circulating T4 is converted to T3 in the periphery? What % is converted to RT3?

1/3 to T3 45% to RT3

What % of circulating T3 is secreted by the thyroid and what % is formed by deiodination in the periphery?

13% secreted from thyroid 87% from T4 in periphery

What tissues have high T3/T4 ratios?

Pituitary Cerebral cortex

What is the difference in composition of circulating thyroid hormones during fetal life compared with adulthood? When does this change?

Relatively more RT3 and less T3 Ratio shifts ~6/52 post birth

List 8 states which suppress deiodinases (thereby decreasing T3 +/- increasing RT3)

1. Selenium deficiency 2. Burns, trauma 3. Advanced cancer 4. Cirrhosis 5. CKD 6. MI 7. Fever 8. Starvation

Describe the structure of TSH. What does it resemble and what is the clinical significance of this?

Alpha and beta subunits Alpha subunit identical to that of LH, FSH and hCG hCG-secreting placental tumours can cause mild hyperthyroidism

What is the half-life of TSH?

60mins

Describe the pulsatile secretion pattern of TSH

Peaks at midnight Declines throughout the day

What is the effect of longterm TSH on thyrocytes and thyroid overall?

Induces hypertrophy of thyrocytes May result in goitre

List five factors which decrease TSH secretion

1. Free T3, T4 2. Stress 3. Glucocorticoids 4. Somatostatin 5. Dopamine

Describe the regulation of thyroid hormone secretion in brief

Thyrotropin-releasing hormone stimulates release of thyroid stimulating hormone TSH increases thyroid hormone production and release Free thyroid hormones provide negative feedback to the pituitary to decrease TSH secretion

How do thyroid hormones exert their effects on a cellular level?

Enter cell and bind to thyroid receptor in nucleus (T3 binds more avidly than T4) Hormone-receptor complex then binds to DNA via zinc fingers and induces expression of specific genes

How many more times potent than T4 is T3?

3-5x

Describe the physiologic effects of thyroid hormones on the heart and how these are mediated

Positive chronotropy and inotropy via three mechanisms: 1. Increased expression of B-adrenergic receptors 2. Increased response to circulating catecholamines 3. Increased a-myosin heavy chain (higher ATPase activity)

Describe the physiologic effects of thyroid hormones on adipose tissue

Increased lipolysis

Describe the physiologic effects of thyroid hormones on muscle

Increased protein breakdown -> thyrotoxic myopathy Also results in increased K+ in urine

Describe the physiologic effects of thyroid hormones on bone

Promotes normal growth and skeletal development

Describe the physiologic effects of thyroid hormones on the nervous system

Promotes normal brain development

Describe the physiologic effects of thyroid hormones on the gut

Increased carbohydrate absorption

Describe the physiologic effects of thyroid hormones on lipoprotein

Increased expression of LDL receptors in liver -> decreased circulating cholesterol

Describe the physiologic effects of thyroid hormones on metabolism generally

Increased BMR Increased O2 consumption by most metabolically active tissues Increased Na+/K+ ATPase activity in many tissues May precipitate vitamin deficiencies due to increased requirement

Which metabolically active tissues do not increase O2 consumption in response to thyroid hormones?

Testes Uterus Lymph nodes Spleen Anterior pituitary (may slightly decrease consumption due to negative feedback on TSH production/release)

What is the syndrome of congenital hypothyroidism also called and what are the two main features?

Cretinism Results in dwarfism and mental retardation

List five causes of congenital hypothyroidism

1. Maternal iodine deficiency 2. Fetal thyroid dysgenesis 3. Inborn errors of thyroid hormone synthesis 4. Maternal antithyroid antibodies 5. Fetal hypopituitary hypothyroidism

What are the two broad classifications (and sub-classifications) of hypothyroidism causes in adults? Which of these are responsive to TSH?

1. Primary thyroid disease 2. Secondary hypothyroidism: - Pituitary hypothyroidism* - Hypothalamic hypothyroidism* * responsive to TSH

What level of iodine intake will produce hypothyroidism?

<50ug/day

What causes goitre: hypothyroidism or hyperthyroidism?

Both can cause E.g. iodine deficiency goitre or goitre with other primary hypothyroidism (increased circulating TSH), Graves disease hyperthyroidism

What is the most common cause of hyperthyroidism and what % of cases does this represent?

Graves' disease 60-80% of cases

Is Graves' disease more common in men or women?

Women

What is the underlying pathophysiology of Graves' disease?

Due to presence of anti-TSH-R antibodies which cause activation of the receptor thereby increasing free T3 and T4 (and decreasing TSH levels due to negative feedback)

What is the hallmark clinical feature of Graves' disease: in what % of cases does it occur?

Exophthalmus, which can precede other features of hyperthyroidism Seen in 50% of patients with Graves' disease

What Abs may be seen in Graves' disease?

Anti-TSH-R (primarily) Anti-thyroglobulin Anti-thyroid peroxidase (anti-TPO)

Does Hashimoto's thyroiditis cause hyperthyroidism or hypothyroidism?

Causes initial transient hyperthyroidism due to inflammation of gland Later causes hypothyroidism due to destruction of gland by antibodies (classically anti-TPO) and cytotoxic T cells

How might hyperthyroidism be treated?

1. Drugs: thioureylenes (e.g. prophylthiouracil, methimazole) 2. Radioactive iodine 3. Surgery

How does propylthiouracil work?

Competitively inhibits MIT iodination and blocks coupling reaction D2 deiodinase inhibitor

Nine clinical features of hypothyroidism

1. Myxoedema (non-pitting oedema of skin) 2. Decreased BMR (40%) 3. Coarse, sparse hair 4. Dry skin 5. Carotenaemia 6. Muscle weakness 7. Cold intolerance 8. Slow mentation, poor memory 9. Increased cholesterol

What % of normal BMR may be seen in hypothyroidism vs hyperthyroidism?

Hypothyroidism: 40% Hyperthyroidism: +10% to +100%

Nine clinical features of hyperthyroidism

1. Weight loss 2. Polyphagia 3. Increased BMR (110-200%) 4. Fine tremor 5. Warm, soft skin 6. Muscle weakness 7. Heat intolerance 8. Nervousness 9. Increased pulse pressure

Describe the Wolff-Chaikoff effect

Large doses of iodine act directly on thyroid to cause, mild transient inhibition of organic iodine binding and therefore thyroid hormone synthesis

List six causes of hyperthyroidism due to thyroid overactivity, and two extrathyroidal causes

Thyroid overactivity: 1. Graves' disease 2. Solitary toxic adenoma 3. Toxic multinodular goitre 4. Early Hashimoto's 5. TSH-secreting pituitary tumour 6. Mutations causing constitutive activation of TSH-R Extrathyroidal: 1. T3/T4 administration 2. Ectopic thyroid tissue