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 concentration
Increased 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 concentration
Hypomagnesaemia
The main actions of PTH are:
Increases plasma calcium concentration
Decreases plasma phosphate concentration
Increases osteoclastic activity (increasing calcium and phosphate resorption from bone)
Increases renal tubular reabsorption of calcium
Decreases renal phosphate reabsorption
Increases 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)

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 case

Thyroid ultrasound scan – is a cost-effective and safe alternative to the radioactive iodine uptake scan.

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:
Glycogenolysis
Gluconeogenesis
Lipolysis in adipose tissue leading to increased glycaemia.

Secretion of glucagon is also stimulated by arginine, alanine, adrenaline, acetylcholine and cholecystokinin

Secretion of glucagon is inhibited by:
Insulin
Somatostatin
Increased free fatty acids
Increased urea production

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 hyperplasia
Adrenal cancer
Familial aldosteronism
Secondary causes of hyperaldosteronism include:
Drugs
Obstructive renal artery disease
Renal vasoconstriction
Oedematous disorders syndrome

Adrenal adenoma is the commonest cause of hyperaldosteronism (seen in ,80% of all cases).

A negative feedback mechanism involving the hypothalamic-pituitary-thyroid axis controls the release of T3 and T4 into the bloodstream.

When metabolic rate is low or serum T3 and/or T4 levels are decrease, this triggers the secretion of thyrotropin-releasing hormone (TRH) from the hypothalamus.

TRH goes to the anterior pituitary gland and stimulates secretion of thyroid-stimulating hormone (TSH).

An increased serum level of T3 and T4 inhibits the release of TRH.

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.

Osteoclasts are bone cell that break down bone tissue.

Parathyroid hormone increases osteoclastic activity.

1,25-dihydroxycholecalciferol increases osteoclastic activity

Calcitonin inhibits osteoclastic activity

Bisphosphonates are osteoclast inhibitors.

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 receptor (IR), in addition to being activated by insulin, is also activated by IGF-I and IGF-II.

The IR is a dimer with two identical subunits spanning the cell membrane and are connected by a single disulphide bond. The two sub-units include: The alpha chain situated on the exterior of the cell membrane and the beta chain spanning the cell membrane in a single segment.

When insulin is detected, the alpha chains move together folding around the insulin making the beta chains move together, converting them into an active tyrosine kinase. This initiates a phosphorylation cascade increasing the expression of GLUT4 and allowing uptake of glucose by cells.

Glucagon is a peptide hormone that is produced and secreted by alpha cells of the islets of Langerhans, which are located in the endocrine portion of the pancreas. The main physiological role of glucagon is to stimulate hepatic glucose output, thereby leading to increases in glycaemia. It provides the major counter-regulatory mechanism to insulin in maintaining glucose homeostasis.
Hypoglycaemia is the principal stimulus for the secretion of glucagon but may also be used as an antidote in beta-blocker overdose and in anaphylaxis in patients on beta-blockers that fail to respond to adrenaline.
Glucagon then causes:
Glycogenolysis
Gluconeogenesis
Lipolysis in adipose tissue
The secretion of glucagon is also stimulated by:
Adrenaline
Cholecystokinin
Arginine
Alanine
Acetylcholine
The secretion of glucagon is inhibited by:
Insulin
Somatostatin
Increased free fatty acids
Increased urea production

Glycolysis is the metabolic pathway that converts glucose into pyruvate. The free energy released by this process is used to form ATP and NADH. Glycolysis is inhibited by glucagon, and glycolysis and gluconeogenesis are reciprocally regulated so that when one cell pathway is activated, the other is inactive and vice versa.

Glucagon has a minor effect of enhancing lipolysis in adipose tissue. Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into glycerol and free fatty acids. It makes fatty acids available for oxidation.

Osteoclasts are a type of bone cell that breaks down bone tissue. This is a critical function in the maintenance, repair and remodelling of bones. The osteoclast disassembles and digests the composite of hydrated protein and minerals at a molecular level by secreting acid and collagenase. This process is known as bone resorption and also helps to regulate the plasma calcium concentration.
Osteoclastic activity is controlled by a number of hormones:
1,25-dihydroxycholecalciferol increases osteoclastic activity
Parathyroid hormone increases osteoclastic activity
Calcitonin inhibits osteoclastic activity
Bisphosphonates are a class of drug that slow down and prevent bone damage. They are osteoclast inhibitors.

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.

A history of recent weight loss is very suggestive of an absolute deficiency of insulin seen in type I diabetes mellitus.

An age of onset of less than 20 years makes a diagnosis of type I diabetes mellitus more likely. However, an increasing number of obese children and young people are being diagnosed with type II diabetes.

Microalbuminuria, peripheral neuropathy, and retinopathy all occur in both type I and type II diabetes mellitus. They are not more suggestive of type I DM.

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.

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.

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 lung
Adrenal hyperplasia
Adrenal adenoma
Adrenal carcinoma

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 syndrome
Adrenal hyperplasia
Adrenal cancer
Familial aldosteronism

Causes of secondary hyperaldosteronism include:
Renal vasoconstriction
Oedematous disorders
Drugs – diuretics
Obstructive renal artery disease

Although patients are usually asymptomatic, when clinical features are present, classically hyperaldosteronism presents with:
Hypokalaemia
Sodium levels can be normal or slightly raised
Hypertension
Metabolic alkalosis
Less common, clinical features are:
Lethargy
Headaches
Intermittent paraesthesia
Polyuria and polydipsia
Muscle weakness (from persistent hypokalaemia)
Tetany and paralysis (rare)

The anterior pituitary gland produces and secretes a peptide hormone called adrenocorticotropic hormone (ACTH) (adenohypophysis). It is secreted in response to the hypothalamus’s secretion of the hormone corticotropin-releasing hormone (CRH).

ACTH promotes cortisol secretion via binding to cell surface ACTH receptors in the zona fasciculata of the adrenal cortex.

ACTH also promotes the production of beta-endorphin, which is a precursor to melanocyte-releasing hormone (MRH).

The adrenal glands produce too little steroid hormones, which causes Addison’s disease. The production of glucocorticoids, mineralocorticoids, and sex steroids are all altered. The most prevalent cause is autoimmune adrenalitis, which accounts for 70-80 percent of cases.

It affects more women than males and occurs most frequently between the ages of 30 and 50.

The following are some of the clinical signs and symptoms of Addison’s disease:

Weakness and sluggishness
Hypotension is a condition in which the blood pressure (notably orthostatic hypotension)
Vomiting and nausea
Loss of weight
Axillary and pubic hair loss
Depression
Hyperpigmentation is a condition in which a person’s (palmar creases, buccal mucosa and exposed areas more commonly affected)
The following are the classic biochemical hallmarks of Addison’s disease:
Hyponatraemia
Hyperkalaemia
Hypercalcaemia
Hypoglycaemia
Acidosis metabolica
When ACTH levels are combined with cortisol levels, it is possible to distinguish between primary and secondary adrenal insufficiency:
In primary insufficiency, levels rise.
In secondary insufficiency, levels are low or low normal.

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 hypothyroidism
TSH is raised
Free T4 is normal
Free T3 is normal

Primary hypothyroidism
TSH is raised
Free T4 is lowered
Free T3 is lowered or normal

Secondary hypothyroidism
TSH is lowered or normal
Free T4 is lowered
Free T3 is lowered or normal

When there are excessive levels of aldosterone outside of the renin-angiotensin axis, primary hyperaldosteronism occurs. High renin levels will lead to secondary hyperaldosteronism.

The classical presentation of hyperaldosteronism when symptoms are present include:
Hypokalaemia
Metabolic alkalosis
Hypertension
Normal or slightly raised sodium levels

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.

Glucagon, secreted from the pancreatic islet alpha cells, is considered to be the main catabolic hormone of the body. It raises the concentration of glucose and fat in the bloodstream

There are five different pancreatic islet cells:
Alpha cells (20%) – produce glucagon
Beta cells (70%) – produce insulin and amylin
Delta cells (<10%) – produce somatostatin
Gamma cells (<5%) – produce pancreatic polypeptide
Epsilon cells (<1%) – produce ghrelin

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 concentration
Decreases plasma phosphate concentration
Increases osteoclastic activity (increasing calcium and phosphate resorption from bone)
Increases renal tubular reabsorption of calcium
Decreases renal phosphate reabsorption
Increases 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)

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:
Hypokalaemia
Alkalosis metabolique

Primary hyperaldosteronism occurs when there are excessive levels of aldosterone independent of the renin-angiotensin axis. Secondary hyperaldosteronism occurs due to high renin levels.
The causes of primary hyperaldosteronism include:
Adrenal adenoma (Conn’s syndrome) – the most common cause of hyperaldosteronism (,80% of all cases). These are usually unilateral and solitary and are more common in women.
Adrenal hyperplasia – this accounts for ,15% of all cases. Usually, bilateral adrenal hyperplasia (BAH) but can be unilateral rarely. More common in men than women.
Adrenal cancer – a rare diagnosis but essential not to miss
Familial aldosteronism – a rare group of inherited conditions affecting the adrenal glands
The causes of secondary hyperaldosteronism include:
Drugs – diuretics
Obstructive renal artery disease – renal artery stenosis and atheroma
Renal vasoconstriction – occurs in accelerated hypertension
Oedematous disorders – heart failure, cirrhosis and nephrotic syndrome
Patients are often asymptomatic. When clinical features are present, the classically described presentation of hyperaldosteronism is with:
Hypertension
Hypokalaemia
Metabolic alkalosis
Sodium levels can be normal or slightly raised
Other, less common, clinical features include:
Lethargy
Headaches
Muscle weakness (from persistent hypokalaemia)
Polyuria and polydipsia
Intermittent paraesthesia
Tetany and paralysis (rare)
Often the earliest sign of hyperaldosteronism is from aberrant urea and electrolytes showing hypokalaemia and mild hypernatraemia. If the patient is taking diuretics, and the diagnosis is suspected, these should be repeated after the patient has taken off diuretics.
If the diagnosis is suspected, plasma renin and aldosterone levels should be checked. Low renin and high aldosterone levels (with a raised aldosterone: renin ratio) is suggestive of primary aldosteronism.
If the renin: aldosterone ratio is high, then the effect of posture on renin, aldosterone and cortisol can be investigated to provide further information about the underlying cause of primary hyperaldosteronism. Levels should be measured lying at 9 am and standing at noon:
If aldosterone and cortisol levels fall on standing, this is suggestive of an ACTH dependent cause, e.g. adrenal adenoma (Conn’s syndrome)
If aldosterone levels rise and cortisol levels fall on standing, this is suggestive of an angiotensin-II dependent cause, e.g. BAH
Other investigations that can help to distinguish between an adrenal adenoma and adrenal hyperplasia include:
CT scan
MRI scan
Selective adrenal venous sampling

Glucagon is a peptide hormone that is produced and secreted by alpha cells of the islets of Langerhans, which are located in the endocrine portion of the pancreas. The main physiological role of glucagon is to stimulate hepatic glucose output, thereby leading to increases in glycaemia. It provides the major counter-regulatory mechanism to insulin in maintaining glucose homeostasis.
Hypoglycaemia is the principal stimulus for the secretion of glucagon but may also be used as an antidote in beta-blocker overdose and in anaphylaxis in patients on beta-blockers that fail to respond to adrenaline.
Glucagon then causes:
Glycogenolysis
Gluconeogenesis
Lipolysis in adipose tissue
The secretion of glucagon is also stimulated by:
Adrenaline
Cholecystokinin
Arginine
Alanine
Acetylcholine
The secretion of glucagon is inhibited by:
Insulin
Somatostatin
Increased free fatty acids
Increased urea production

Glycolysis is the metabolic pathway that converts glucose into pyruvate. The free energy released by this process is used to form ATP and NADH. Glycolysis is inhibited by glucagon, and glycolysis and gluconeogenesis are reciprocally regulated so that when one cell pathway is activated, the other is inactive and vice versa.

Glucagon has a minor effect of enhancing lipolysis in adipose tissue. Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into glycerol and free fatty acids. It makes fatty acids available for oxidation.

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.

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.
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.

Insulin resistance causes hyperglycaemia, which is a frequent symptom. Insulin resistance can produce acanthosis nigricans in the axilla and around the neck, as well as other skin abnormalities.

In contrast to menorrhagia, elevated testosterone levels are more likely to produce amenorrhoea or oligomenorrhoea. Infertility in women of reproductive age can also be caused by high androgen levels.

A dexamethasone suppression test or a 24-hour urine free cortisol collection can both be used to establish the existence of Cushing’s syndrome.

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.