Only a very small fraction of the thyroid hormones circulating in the blood are free. The majority is bound to transport proteins. Only the free thyroid hormones are biologically active, and measurement of total thyroid hormone levels can be misleading. The relative percentages of bound and unbound thyroid hormones are:Bound to thyroid-binding globulin -70%Bound to albumin -15-20%Bound to transthyretin -10-15%Free T3 -0.3%Free T4 -0.03%

PTH is synthesised and released from the chief cells of the four parathyroid glands located behind the thyroid gland.It is a polypeptide containing 84 amino acids and it controls free calcium in the body.The following stimuli causes release of PTH:Increased plasma phosphate concentrationDecreased plasma calcium concentrationPTH release is inhibited by:Normal or increased plasma calcium concentrationHypomagnesaemiaThe main actions of PTH are:Increases plasma calcium concentrationDecreases plasma phosphate concentrationIncreases osteoclastic activity (increasing calcium and phosphate resorption from bone)Increases renal tubular reabsorption of calciumDecreases renal phosphate reabsorptionIncreases renal conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (via stimulation of 1-alpha hydroxylase)Increases calcium and phosphate absorption in the small intestine (indirectly via increased 1,25-dihydroxycholecalciferol)

Glucagon binds to class B G-protein coupled receptors and activates adenylate cyclase, increasing cAMP intracellularly. This activates protein kinase A. Protein kinase A phosphorylates and activates important enzymes in target cells.

Parathyroid hormone (PTH) is a polypeptide containing 84 amino acids. It is the principal controller of free calcium in the body.PTH is synthesised by and released from the chief cells of the four parathyroid glands that are located immediately behind the thyroid gland.PTH is released in response to the following stimuli:Decreased plasma calcium concentrationIncreased plasma phosphate concentration (indirectly by binding to plasma calcium and reducing the calcium concentration)PTH release is inhibited by the following factors:Normal/increased plasma calcium concentrationHypomagnesaemiaThe main actions of PTH are:Increases plasma calcium concentrationDecreases plasma phosphate concentrationIncreases osteoclastic activity (increasing calcium and phosphate resorption from bone)Increases renal tubular reabsorption of calciumDecreases renal phosphate reabsorptionIncreases renal conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (via stimulation of 1-alpha hydroxylase)Increases calcium and phosphate absorption in the small intestine (indirectly via increased 1,25-dihydroxycholecalciferol)

The hormone-active metabolite of vitamin D is 1,25-dihydroxycholecalciferol (commonly known as calcitriol). Its activities raise calcium and phosphate levels in the bloodstream.In the presence of UVB light, 7-dehydrocholesterol is converted to cholecalciferol in the epidermal layer of the skin, resulting in 1,25-dihydroxycholecalciferol.Cholecalciferol is then converted to 25-hydroxycholecalciferol in the endoplasmic reticulum of liver hepatocytes by 25-hydroxylase (calcifediol).Finally, 1-alpha-hydroxylase converts 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol in the kidney. The key regulatory point in the formation of 1,25-dihydroxycholecalciferol is 1-alpha-hydroxylase, which is induced by parathyroid hormone or hypophosphatemia.The following are the primary effects of 1,25-dihydroxycholecalciferol:Calcium and phosphate absorption in the small intestine is increased.Calcium reabsorption in the kidneys is increased.Increases phosphate reabsorption in the kidneys.Increases the action of osteoclastic bacteria (increasing calcium and phosphate resorption from bone)Inhibits the action of 1-alpha-hydroxylase in the kidneys (negative feedback)

Calcium is stored in bones for nearly all of the body’s calcium, but it is also found in some cells (most notably muscle cells) and the blood. The average adult diet comprises roughly 25 mmol of calcium per day, of which the body absorbs only about 5 mmol.

A phaeochromocytoma is a rare functional tumour that develops in the adrenal medulla from chromaffin cells. Extra-adrenal paragangliomas (extra-adrenal pheochromocytomas) are tumours that arise in the sympathetic nervous system’s ganglia and are closely connected to extra-adrenal paragangliomas (extra-adrenal pheochromocytomas). Catecholamines are secreted by these tumours, which generate a variety of symptoms and indications associated with sympathetic nervous system hyperactivity.Hypertension is the most prevalent presenting symptom, which can be continuous or intermittent.Symptoms are usually intermittent, occurring anywhere from many times a day to occasionally. The symptoms of the condition tend to grow more severe and frequent as the disease progresses.The ultimate therapy of choice is surgical resection, and if full resection is done without metastases, hypertension is typically cured.Preoperative medical treatment is critical because it lowers the risk of hypertensive crises during surgery. This is commonly accomplished by combining non-competitive alpha-blockers (such as phenoxybenzamine) with beta-blockers. To allow for blood volume expansion, alpha-blockade should be started at least 7-10 days before surgery. Beta-blockade, which helps to regulate tachycardia and some arrhythmias, can be started after this is accomplished. Hypertensive crises can be triggered if beta-blockade is started too soon.There should also be genetic counselling, as well as a search for and management of any linked illnesses.

Cushing’s syndrome is a collection of symptoms and signs caused by prolonged exposure to elevated levels of either endogenous or exogenous glucocorticoids.The most common cause of Cushing’s syndrome is the iatrogenic administration of corticosteroids. The second most common cause of Cushing’s syndrome is Cushing’s disease.Cushing’s disease should be distinguished from Cushing’s syndrome and refers to one specific cause of the syndrome, an adenoma of the pituitary gland that secretes large amounts of ACTH and, in turn, elevates cortisol levels. This patient has a diagnosis of Cushing’s disease, and this is, therefore, the underlying cause in this case.The endogenous causes of Cushing’s syndrome include:Pituitary adenoma (Cushing’s disease)Ectopic corticotropin syndrome, e.g. small cell carcinoma of the lungAdrenal hyperplasiaAdrenal adenomaAdrenal carcinoma

The hormone-active metabolite of vitamin D is 1,25-dihydroxycholecalciferol (commonly known as calcitriol). Its activities raise calcium and phosphate levels in the bloodstream.The following are the primary effects of 1,25-dihydroxycholecalciferol:Calcium and phosphate absorption in the small intestine is increased.Calcium reabsorption in the kidneys is increased.Increases phosphate reabsorption in the kidneys.Increases the action of osteoclastic bacteria (increasing calcium and phosphate resorption from bone)Inhibits the action of 1-alpha-hydroxylase in the kidneys (negative feedback)Thyroid hormone (parathyroid hormone) Calcium reabsorption in the tubules of the kidneys is increased, but renal phosphate reabsorption is decreased.

Insulin, a peptide hormone, is produced in the pancreas by the beta-cells of the islets of Langerhans.The beta-cells first synthesise an inactive precursor called preproinsulin which is converted to proinsulin by signal peptidases, which remove a signal peptide from the N-terminus. Proinsulin is converted to insulin by the removal of the C-peptide.Insulin has a short half-life in the circulation of about 5-10 minutes.Glucagon and parasympathetic stimulation stimulates insulin release.

Hypocalcaemia occurs when there is abnormally low level of serum calcium ( >2.2 mmol/l) after correction for the serum albumin concentration.Rhabdomyolysis causes hyperphosphatemia, and this leads to a reduction in ionised calcium levels.Patients with rhabdomyolysis are commonly cared for in a high dependency care setting. Addison’s disease, hyperthyroidism, thiazide diuretics and lithium all cause hypercalcaemia.

Cortisol levels fluctuate throughout the day, with the greatest levels occurring around 0900 hours and the lowest occurring at 2400 hrs during sleep.The diurnal swing of cortisol levels is lost in Cushing’s syndrome, and levels are greater throughout the 24-hour period. In the morning, levels may be normal, but they may be high at night-time, when they are generally repressed.

Hyperthyroidism results from an excess of circulating thyroid hormones. It is commoner in women, and incidence increases with age.Hyperthyroidism can be subclassified into:Primary hyperthyroidism – the thyroid gland itself is affectedSecondary hyperthyroidism – the thyroid gland is stimulated by excessive circulating thyroid-stimulating hormone (TSH).Graves’ disease is the most common cause of hyperthyroidism (estimates are that it causes between 50 and 80% of all cases).Although toxic multinodular goitre, thyroiditis,TSH-secreting pituitary adenoma and drug-induced hyperthyroidism also causes hyperthyroidism, the commonest cause is Graves’ disease.

Corticotropin-releasing hormone (CRH) is a neurotransmitter and peptide hormone. It is generated by cells in the hypothalamic paraventricular nucleus (PVN) and released into the hypothalamo-hypophyseal portal system at the median eminence through neurosecretory terminals of these neurons. Stress causes the release of CRH.The CRH is carried to the anterior pituitary through the hypothalamo-hypophyseal portal system, where it activates corticotrophs to release adrenocorticotropic hormone (ACTH). Cortisol, glucocorticoids, mineralocorticoids, and DHEA are all produced in response to ACTH.Excessive CRH production causes the size and quantity of corticotrophs in the anterior pituitary to expand, which can lead to the creation of a corticotrope tumour that generates too much ACTH.

The only mechanism by which insulin facilitates uptake of glucose into cells is by facilitated diffusion through a family of hexose transporters.The major transporter used for glucose uptake is GLUT4. GLUT4 is made available in the plasma membrane by the action of insulin.When insulin concentrations are low, GLUT4 transporters are present in cytoplasmic vesicles, where they are cannot be used for transporting glucose.

Glucagon, a peptide hormone, is produced and secreted by alpha cells of the islets of Langerhans, located in the endocrine portion of the pancreas. Its main physiological role is stimulation of hepatic glucose output leading to increase in blood glucose. It is the major counter-regulatory hormone to insulin in maintaining glucose homeostasis.The principal stimulus for the secretion of glucagon is hypoglycaemia. Hypoglycaemia then stimulates:GlycogenolysisGluconeogenesisLipolysis in adipose tissue leading to increased glycaemia.Secretion of glucagon is also stimulated by arginine, alanine, adrenaline, acetylcholine and cholecystokininSecretion of glucagon is inhibited by:InsulinSomatostatinIncreased free fatty acidsIncreased urea production

Although Addisonian crisis is a rare illness, it can be fatal if it is misdiagnosed. Hypoglycaemia and shock are the most common symptoms of an Addisonian crisis (tachycardia, peripheral vasoconstriction, hypotension, altered conscious level, and coma).Other clinical characteristics that may be present are:FeverPsychosisLeg and abdominal painDehydration and vomitingConvulsions 

Cushing’s syndrome is a group of symptoms and signs brought on by long-term exposure to high amounts of endogenous or exogenous glucocorticoids. Cushing’s syndrome affects about 10-15 persons per million, and it is more common in those who have had a history of obesity, hypertension, or diabetes.A typical biochemical profile can help establish a diagnosis of Cushing’s syndrome. The following are the primary characteristics:HypokalaemiaAlkalosis metabolique

When there are excessive levels of aldosterone independent of the renin-angiotensin aldosterone axis, primary hyperaldosteronism occurs. Secondary hyperaldosteronism occurs due to high renin levels.Causes of primary hyperaldosteronism include:Conn’s syndromeAdrenal hyperplasiaAdrenal cancerFamilial aldosteronismCauses of secondary hyperaldosteronism include:Renal vasoconstrictionOedematous disordersDrugs – diureticsObstructive renal artery diseaseAlthough patients are usually asymptomatic, when clinical features are present, classically hyperaldosteronism presents with:HypokalaemiaSodium levels can be normal or slightly raisedHypertensionMetabolic alkalosisLess common, clinical features are:LethargyHeadachesIntermittent paraesthesiaPolyuria and polydipsiaMuscle weakness (from persistent hypokalaemia)Tetany and paralysis (rare)

Hypothyroidism is diagnosed using the results of thyroid function tests (TFTs). In the early stages of the disease, the earliest biochemical change noticed is a rise in thyroid-stimulating hormone (TSH) levels. Free triiodothyronine (T3) and thyroxine (T4) levels are usually normal.In primary hypothyroidism, the serum TSH level is usually greater than 10 mU/L, and free T4 levels are below the reference range.Subclinical hypothyroidism is diagnosed when the serum TSH level is above the reference range, and the free T4 levels are within the reference range. The test should, however, be repeated after 3-6 months to exclude transient causes of raised TSH.In summary, how to interpret TFTs in cases of suspected hypothyroidism is shown below:Subclinical hypothyroidismTSH is raisedFree T4 is normalFree T3 is normalPrimary hypothyroidismTSH is raisedFree T4 is loweredFree T3 is lowered or normalSecondary hypothyroidismTSH is lowered or normalFree T4 is loweredFree T3 is lowered or normal

A thyroid function test is used in the diagnosis of hyperthyroidism.Serum TSH should be the first-line investigation for patients with suspected hyperthyroidism as it has the highest sensitivity and specificity for hyperthyroidism. A normal TSH level almost always excludes the diagnosis, though there are rare exceptions to this.Antithyroglobulin antibodies are commonly present in Graves’ disease, but the test has a sensitivity of 98% and specificity of 99, and is not widely available.Radioactive iodine uptake scan using iodine-123 – shows low uptake in thyroiditis but high in Graves’ disease and toxic multinodular goitre. It is however, not first-line investigation in this caseThyroid ultrasound scan – is a cost-effective and safe alternative to the radioactive iodine uptake scan.

​Primary hyperparathyroidism the commonest cause of hypercalcaemia. It is commonest in women aged 50 to 60.The commonest cause of primary hyperparathyroidism is a solitary adenoma of the parathyroid gland (approximately 85% of cases). Primary hyperparathyroidism may present with features of hypercalcaemia such as polyuria, polydipsia, renal stones, bone and joint pain, constipation, and psychiatric disorders.In primary Hyperparathyroidism:PTH is elevatedCalcium is elevatedPhosphate is loweredIn secondary Hyperparathyroidism:PTH is elevatedCalcium is low or low-normalPhosphate is raised in CRFIn tertiary Hyperparathyroidism:PTH is elevatedCalcium is elevatedPhosphate is lowered in CRF

Cushing’s syndrome is a group of symptoms and signs brought on by long-term exposure to high amounts of endogenous or exogenous glucocorticoids.Iatrogenic corticosteroid injection is the most prevalent cause of Cushing’s syndrome. Cushing’s illness is the second most prevalent cause of Cushing’s syndrome. Cushing’s disease is distinct from Cushing’s syndrome in that it refers to a single cause of the illness, a pituitary adenoma that secretes high quantities of ACTH, which raises cortisol levels.Because cortisol enhances the vasoconstrictive impact of endogenous adrenaline, patients with Cushing’s syndrome are usually hypertensive.Hyperglycaemia (due to insulin resistance) rather than hypoglycaemia is a common symptom.Cortisol levels fluctuate throughout the day, with the greatest levels occurring around 0900 hours and the lowest occurring at 2400 hrs during sleep. The diurnal swing of cortisol levels is lost in Cushing’s syndrome, and levels are greater throughout the 24-hour period. In the morning, levels may be normal, but they may be high at night-time, when they are generally repressed.A dexamethasone suppression test or a 24-hour urine free cortisol collection can both be used to establish the existence of Cushing’s syndrome.

When there are excessive circulating levels of aldosterone, hyperaldosteronism occurs. There are two main types of hyperaldosteronism:Primary hyperaldosteronism (,95% of cases)Secondary hyperaldosteronism (,5% of cases)Primary causes of hyperaldosteronism include:Adrenal adenoma (Conn’s syndrome) Adrenal hyperplasiaAdrenal cancerFamilial aldosteronismSecondary causes of hyperaldosteronism include:DrugsObstructive renal artery disease Renal vasoconstrictionOedematous disorders syndrome Adrenal adenoma is the commonest cause of hyperaldosteronism (seen in ,80% of all cases).

Parathyroid hormone (PTH) is a polypeptide containing 84 amino acids. It is the principal controller of free calcium in the body.The main actions of parathyroid hormone are:Increases plasma calcium concentrationDecreases plasma phosphate concentrationIncreases osteoclastic activity (increasing calcium and phosphate resorption from bone)Increases renal tubular reabsorption of calciumDecreases renal phosphate reabsorptionIncreases renal conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (via stimulation of 1-alpha hydroxylase)Increases calcium and phosphate absorption in the small intestine (indirectly via increased 1,25-dihydroxycholecalciferol)

Hypothyroidism occurs when there is a deficiency of circulating thyroid hormones. It is commoner in women and is most frequently seen in the age over 60.Iodine deficiency is the commonest cause of hypothyroidism worldwide.In the UK and other developed countries, iodine deficiency is not a problem and autoimmune thyroiditis is the commonest cause.

Osteoclasts are bone cell that break down bone tissue. Parathyroid hormone increases osteoclastic activity.1,25-dihydroxycholecalciferol increases osteoclastic activityCalcitonin inhibits osteoclastic activityBisphosphonates are osteoclast inhibitors.

Cushing’s syndrome is a group of symptoms and signs brought on by long-term exposure to high amounts of endogenous or exogenous glucocorticoids. Cushing’s syndrome affects about 10-15 persons per million, and it is more common in those who have had a history of obesity, hypertension, or diabetes.Cushing’s syndrome has a wide range of clinical manifestations that are dependent on the degree of cortisol overproduction. The appearance might be vague and the diagnosis difficult to detect when cortisol levels are just somewhat elevated. On the other hand, in long-term cases of severely increased cortisol levels, the presentation might be colourful and the diagnosis simple.Cushing’s syndrome has the following clinical features:Obesity and weight growth in the true senseSupraclavicular fat pads are fat pads that are located above the clavicle.Buffalo humpFullness and plethora of the face (‘moon facies’)Muscle atrophy and weakening at the proximal levelDiabetes mellitus, also known as impaired glucose toleranceHypertensionSkin thinning and bruisingDepressionHirsutismAcneOsteoporosisAmenorrhoea or oligomenorrhoeaCortisol levels fluctuate throughout the day, with the greatest levels occurring around 0900 hours and the lowest occurring at 2400 hrs during sleep. The diurnal swing of cortisol levels is lost in Cushing’s syndrome, and levels are greater during the whole 24-hour period. In the morning, levels may be normal, but they may be high at night-time, when they are generally repressed. As a result, random cortisol testing is not an effective screening technique and is not advised.The following are the two most common first-line screening tests:Cortisol levels in the urine are measured every 24 hours.A diagnosis of Cushing’s syndrome can be made if more than two collections measure cortisol excretion more than three times the upper limit of normal.Physical stress (e.g., excessive exercise, trauma), mental stress (e.g., sadness), alcohol or drug misuse, complex diabetes, and pregnancy can all cause false positives.Renal dysfunction, inadequate collection, and cyclical Cushing’s disease can all cause false negatives.The overnight low-dose dexamethasone suppression test (LDDST) involves giving 1 mg of dexamethasone at 11 p.m. and measuring blood cortisol levels at 8 a.m. the next day.Cushing’s syndrome is diagnosed when cortisol is not suppressed to less than 50 nmol/L.It might be difficult to tell the difference between mild Cushing’s disease and normal cortisol production.False positives can occur as a result of depression, severe systemic sickness, renal failure, prolonged alcohol misuse, old age, and the use of hepatic enzyme-inducing medicines, among other things.False negatives are extremely uncommon in Cushing’s disease patients.A characteristic biochemical picture might also be helpful in confirming the diagnosis of Cushing’s syndrome. The following are the primary characteristics:HypokalaemiaAlkalosis metabolique

The earliest biochemical change seen in hypothyroidism is an increase in thyroid-stimulating hormone (TSH) levels.Triiodothyronine (T3) and thyroxine (T4) levels are normal in the early stages.TBG levels are generally unchanged in primary hypothyroidism.

The commonest cause of hypercalcaemia in the UK is primary hyperparathyroidism, which accounts for around 70-80% of cases. It is commoner in younger patients and in community setting.