Endocrinology Medic Flashcards
Thyroid basics
Anatomy
The thyroid gland has its embryological origin at the back of the tongue. It migrates downwards to the midline, and sits anteriorly to the thyroid cartilage in the neck. This may lead to remnant tissue, which can present as a lingual thyroid or thyroglossal cyst. The thyroid gland has a left and right lobe joined by a central isthmus. The thyroid can be distinguished from other neck lumps by its movement on swallowing. The recurrent laryngeal nerve lies laterally on each side and the parathyroid glands lie posteriorly – both may be damaged during thyroid surgery. The thyroid gland has a rich vascular supply from the inferior and superior thyroid arteries. Thyroid tissue is made up of a substance called colloid, which contains iodinated thyroglobulin. Thyroglobulin is synthesised by the surrounding follicular cells and is the large molecule from which thyroxine is made and stored in colloid. The thyroid is also made up of neuroendocrine cells (C-cells) which secrete calcitonin. Calcitonin levels are elevated in medullary thyroid cancer which is a rare form of thyroid cancer which often has a genetic basis.
Physiology
Thyroid hormones are made up of iodinated tyrosine molecules to form thyroxine (T4) and triiodothyronine (T3). T4 is the main circulating hormone, which is converted peripherally to the more potent and shorter-acting T3. The number indicates how many iodine atoms are in the molecule. Thyroid hormones are bound thyroxine binding globulin [TBG], transthyretin and albumin. The free hormone acts on intracellular thyroid receptors. There are two main types of thyroid receptor (TRα and TRβ).
Actions of thyroid hormones
Thyroid hormones increase the basal metabolic rate and affect growth in children, as well as having many other effects in adults. They act on the cardiovascular system to increase the heart rate, as well as having effects on the CNS and reproductive system. Because of the widespread role of thyroid hormones in metabolism, disorders of thyroid function can present with many different symptoms and to many different specialists.
Thyroid function tests
Thyroid function tests are commonly requested in clinical practice. The pituitary-thyroid axis is based on a negative feedback system. TRH stimulates pituitary TSH secretion, which drives T3 and T4 secretion. Thyroid hormones are stable, therefore basal levels are sufficient for interpretation.
Primary versus secondary hypothyroidism
Primary hypothyroidism is due to a problem with thyroid gland itself, most commonly auto- immune in origin. It is characterised by reduced circulating T4 and a high TSH. Secondary hypothyroidism is due to TSH deficiency and is usually a result of pituitary disease. Secondary hypothyroidism is characterised by low T4 levels and a non-elevated TSH.
Hyperthyroidism
Primary hyperthyroidism is characterised by increased T3 / T4 levels with a suppressed TSH. If TSH is not suppressed in the context of high T4/ T3, this is unusual and suggests a TSHoma, thyroid hormone resistance or assay interference.
Factors affecting thyroid results
Thyroid function tests may be affected by non-thyroidal illness. Thyroid function tests are therefore best interpreted when patients are relatively well, rather than during acute illness. Medication, such as lithium and amiodarone, as well as pregnancy may also affect thyroid function results.
Hyperthyroidism also known as?
Thyrotoxicosis
Most commonly affected by hyptherthyroidism?
Young women but can also develop in men and present at any age.
Causes of hyperthyroidism?
Auto-immune (Graves’ disease) is the commonest cause of hyperthyroidism, and is due to the presence of TSH receptor stimulating antibodies. It typically affects young women and usually follows a relapsing-remitting course.
Nodular thyroid disease typically presents at an older age than auto-immune. Nodular hyperthyroidism is caused by autonomous secretion of T3 / T4 either from a solitary toxic nodule, or numerous nodules situated within a toxic multi- nodular goitre
Thyroiditis is inflammation of the thyroid gland causing a release of thyroxine. It may be caused by viral infection, medication (e.g amiodarone) or following childbirth (post- partum thyroiditis). A hypothyroid phase often follows the initial toxic phase.
Clinical features of hyperthyroidism
Hyperthyroidism presents with a range of symptoms caused by increased sympathetic action. Classical features include weight loss with increased appetite, insomnia, irritability, anxiety, heat intolerance, palpitations and tremor. Other symptoms include pruritus, increased bowel frequency and loose motions, menstrual disturbance and reduced fertility. Elderly patients may present atypically with reduced energy levels (termed ‘apathetic thyrotoxicosis’). Hyperthyroidism is less common in children than adults, and may present with classical symptoms, or with accelerated growth and behavioural disturbance. General signs of hyperthyroidism include a resting tachycardia (sinus rhythm or atrial fibrillation), warm peripheries, resting tremor, hyper-reflexia and lid lag. Lid-lag maybe seen in any cause of hyperthyroidism, due to increased sympathetic tone of the upper eyelid. Lid retraction and proptosis are only seen in Graves’ disease. Patients may have hypertension and a flow murmur. Patients often appear agitated and hyperkinetic. Specific clinical signs of Graves’ disease include thyroid eye disease, and skin changes (dermopathy) characterised by pre- tibial myxoedema as well as nail changes similar to clubbing (‘thyroid acropachy’). These are a result of cross-reactivity with TSH receptors in the back of the orbit and skin.
Investigations of hyperthyroidism
The hallmark of hyperthyroidism is an elevated free fT4 and free fT3 with undetectable TSH. An elevated fT3 alone with normal fT4 and suppressed TSH is termed T3-toxicosis. Patients with a normal FT4 / FT3 and suppressed TSH have ‘subclinical hyperthyroidism’, suggesting autonomous thyroid activity. The presence of elevated fT4 and fT3 with non-suppressed TSH is unusual and requires further investigation. Thyroid peroxidase antibodies (TPO) are non-specific markers of auto-immune thyroid disease. TSH-receptor stimulating antibodies (TSHrAb) are more specific and may be helpful in particular clinical situations such as pregnancy. Thyroid ultrasound may help to confirm nodular thyroid disease but does not assess gland activity. Nuclear imaging (technetium or iodine uptake isotope scan) may help determine functionality and therefore the cause of hyperthyroidism. In Graves’ disease there is uniform increase uptake, whereas in nodular disease there is increased uptake only in the autonomous nodule(s). In thyroiditis there is absent uptake on isotope scan.
Hyperthyroidism treatment
Management options for hyperthyroidism include medication, surgery and radioactive iodine. Medical treatment is usually the first line approach, with definitive options later on. Thionamides (carbimazole and propylthiouracil) reduce the synthesis of T3 and T4. It usually takes 4-6 weeks to normalise results after initiation of anti-thyroid drugs. Beta-blockers may be used to control symptoms until thyroid function returns to normal
Definitive treatment of hyperthyroidism
These include radioactive iodine and thyroidectomy. Both treatments have advantages and disadvantages and are usually driven by patient choice. Radioactive iodine involves the administration of a single dose of 131I. It is contra-indicated in pregnancy and may lead to a flare up of eye disease in patients with pre-existing ophthalmopathy. It commonly causes hypothyroidism, which requires lifelong thyroxine replacement. Patients emit a small amount of radiation after administration of 131I and are advised to avoid close contact with young children and pregnant women for a few weeks after treatment. Thyroid surgery is an effective definitive treatment, particularly in situations where patients cannot easily comply with radiation restriction guidance (e.g. mothers with young children).Thyroid function should be controlled pre-operatively to avoid anaesthetic problems. Beta-blockade may be used during anaesthetic induction if thyroid function is not optimal, to prevent peri-operative atrial fibrillation. Complications of thyroid surgery include bleeding, infection, damage to the recurrent laryngeal nerve and temporary or permanent hypocalcaemia (due to hypoparathyroidism), but these risks are low if the surgery is undertaken by an experienced surgeon.
Hypothyroidism causes
This is most commonly due to autoimmune disease. Enlargement of the gland with hypothyroidism is sometimes termed ‘Hashimoto’s thyroiditis
Pregnancy may lead to transient or permanent hypothyroidism after delivery, and can be misdiagnosed as post-natal depression (post-partum thyroiditis).
In developing countries, iodine deficiency is a preventable cause of neonatal hypothyroidism, which causes severe mental retardation (‘cretinism’
A rare genetic defect in thyroid hormone synthesis may cause hypothyroidism in infancy (familial thyroid dyshormonogenesis).
Secondary hypothyroidism (TSH deficiency)
This is much less common than primary hypothyroidism and is caused by TSH deficiency due to hypothalamic-pituitary disease. Secondary hypothyroidism is characterised by low fT4 with non-elevated TSH, and should prompt full investigation of the pituitary gland.
Hypothyroidism clinical features
The classical features of hypothyroidism include weight gain, cold intolerance, fatigue, constipation, bradycardia, with thickening of the skin and puffiness around the eyes (‘myxoedema’). More commonly hypothyroidism presents with subtle symptoms and is often diagnosed incidentally during routine blood tests. Symptoms of hypothyroidism may be similar to depression or chronic fatigue, which is experienced by up to 40% of the normal population, so slightly abnormal thyroid results may not always be the cause of the patients’ symptoms.
Hypothyroidism investigations
The hallmark of primary hypothyroidism is a low fT4 with elevated TSH. Most laboratories in the UK use TSH alone to diagnose hypothyroidism. This is sufficient to diagnose primary hypothyroidism, but fT4 must be measured as well as TSH when secondary hypothyroidism (TSH deficiency) is suspected. Auto-immune hypothyroidism is confirmed by measuring thyroid antibodies. Thyroid peroxidase (TPO) antibodies are usually strongly positive in Hashimoto’s thyroiditis.
Hypothyroidism treatment
This consists of thyroxine replacement, given at a dose sufficient to improve symptoms and normalise thyroid function. A typical starting dose is 50-100ug / day. Elderly patients or those with ischaemic heart disease may be started on a lower dose (25ug / day). A persistently elevated TSH suggests under-replacement, poor compliance or malabsorption (e.g. from coeliac disease or concurrent medication such as iron, calcium or proton pump inhibitors). A suppressed or undetectable TSH suggests over-replacement, leading to increased risk of atrial fibrillation and osteoporosis. The use of T3 (liothyronine) and dessicated thyroid extract (‘armour thyroid’) as alternatives to thyroxine is not recommended routinely. Patients who remain symptomatic despite normalisation of thyroid function should be investigated for non- thyroid pathology. In patients with secondary hypothyroidism, fT4 should be replaced to the upper part of the normal range since TSH cannot be relied upon as a measure of optimal replacement. Doses should not be mistakenly reduced on the basis of a suppressed TSH level.
Sub clinical hypothyroidism
Subclinical hypothyroidism refers to a normal fT4 with elevated TSH. If patients are asymptomatic, treatment may not be needed. Thyroid function spontaneously reverts to normal during repeat testing in 10-15% of patients in this situation. Guidelines recommend starting thyroxine if TSH is > 10 miU/L even if patients are asymptomatic due to the high likelihood of progression to frank hypothyroidism. Treatment should also be considered at lower levels of TSH elevation (TSH of 5 to 10 miU/L) in women planning pregnancy, on a trial basis in symptomatic patients, and in patients with significant dyslipidaemia. Patients with positive thyroid antibodies should have an annual thyroid function test to ensure they do not progress to overt hypothyroidism.
Adrenal cortex
Glucocorticoids - Cortisol is the major glucocorticoid and plays a key role in metabolism. Its synthesis is regulated by ACTH. Cortisol exerts negative feedback on the hypothalamus, to reduce CRH (and vasopressin), and on the anterior pituitary to reduce ACTH. Cortisol is highest at 0800 and lowest at midnight. Most cortisol is bound to cortisol binding globulin (CBG; 80-90%) and albumin (5-10%), with only a small proportion existing in the free biologically active state. Current cortisol immunoassays measure total (bound and free) cortisol, hence conditions which stimulate CBG levels (e.g. oestrogen therapy) may increase measured cortisol levels without affecting biologically active free levels.
Adrenal androgens - Adrenal androgens are mainly controlled by ACTH. They have a more important role in adult women, and in both sexes pre-pubertally, as adult men rely mainly on testicular production of androgens. DHEA and DHEA-S, and androstenedione are converted to the more potent testosterone and dihydrotestosterone in peripheral tissues. Androgens exert their effects on sebaceous glands, hair follicles, the prostate gland and external genitalia.
Mineralocorticoids - Aldosterone is the major mineralocorticoid. It is regulated by the renin- angiotensin system. In response to low circulating blood volume, hyponatraemia or hyperkalaemia, renin is activated to catalyse the conversion of angiotensinogen to angiotensin I, which is converted by angiotensin-converting enzyme (ACE) to angiotensin II. Angiotensin II stimulates aldosterone release upon binding to the angiotensin receptor. Aldosterone acts mainly at the renal distal convoluted tubule on its receptor to cause sodium retention and potassium loss.
Adrenal medulla
This has a completely different embryological origin from the cortex and consists of tissue made up of the sympathetic nervous system, which secretes adrenaline, noradrenaline, dopamine and their metabolites (metanephrines, nor-metanephrines and 3- methoxytyramine).
Addison’s disease?
This arises as a result of destruction of the adrenal gland, or genetic defects in steroid synthesis. All three zones of the adrenal cortex are usually affected.
Clinical features of Addison’s disease
Symptoms may be non-specific and gradual in onset so it is important to maintain a high index of suspicion in order to make the diagnosis. Patients usually describe fatigue, weakness, anorexia, weight loss, nausea and abdominal pain. Dizziness and postural hypotension occur as a result of mineralocorticoid deficiency. Glucocorticoid loss leads to hypoglycaemia, and increased pigmentation due to ACTH excess from reduced cortisol negative feedback. Androgen deficiency in women may lead to reduced libido and loss of axillary and pubic hair.
There are several causes of primary adrenal failure but autoimmunity is by far the commonest cause in the UK, and is supported by detection of positive adrenal autoantibodies. Other causes such as infection or infiltrative processes are rare but should be considered when antibody testing is
negative.
