Endocrine Flashcards
Describe the thyroid axis
The Thyroid Axis
The hypothalamus releases thyrotropin-releasing hormone (TRH). TRH stimulates the anterior pituitary to release thyroid-stimulating hormone (TSH). TSH stimulates the thyroid gland to release triiodothyronine (T3) and thyroxine (T4).
The hypothalamus and anterior pituitary respond to T3 and T4 by suppressing the release of TRH and TSH, resulting in lower amounts of T3 and T4. The lower T3 and T4 offer less suppression of TRH and TSH, causing more of these hormones to be released, resulting in a rise of T3 and T4. This way, the thyroid hormone level is closely regulated to keep it within normal limits.
When the end hormone (e.g., T3 and T4) suppresses the release of the controlling hormones (e.g., TRH and TSH), this is called negative feedback.
Describe the adrenal axis
Describe the growth hormone axis
Cortisol is secreted by the two adrenal glands, which sit above each kidney. The hypothalamus controls the release of cortisol. Cortisol is released in pulses throughout the day and in response to a stressful stimulus. It is a “stress hormone”. It has diurnal variation, meaning it is high and low at different times of the day. Typically cortisol peaks in the early morning, triggering us to wake up and get going, and is at its lowest late in the evening, prompting us to relax and fall asleep.
The hypothalamus releases corticotropin-releasing hormone (CRH). CRH stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH). ACTH stimulates the adrenal glands to release cortisol.
The adrenal axis is also controlled by negative feedback. Cortisol is sensed by the hypothalamus and anterior pituitary, suppressing the release of CRH and ACTH. This results in lower amounts of cortisol. This way, cortisol is closely regulated to keep it within normal limits.
The hypothalamus produces growth hormone-releasing hormone (GHRH). GHRH stimulates the anterior pituitary to release growth hormone (GH). Growth hormone stimulates the release of insulin-like growth factor 1 (IGF-1) from the liver.
Through this mechanism, growth hormone works directly and indirectly on almost all cells and has many functions. Most importantly, growth hormone:
Stimulates muscle growth
Increases bone density and strength
Stimulates cell regeneration and reproduction
Stimulates growth of internal organs
Describe the parathyroid axis
Describe the The Renin-Angiotensin-Aldosterone System
The Parathyroid Axis
Parathyroid hormone (PTH) is released from the four parathyroid glands (situated at the four corners of the thyroid gland) in response to a low calcium level in the blood. The role of PTH is to increase serum calcium concentration.
PTH increases the activity and number of osteoclasts in bone, causing reabsorption of calcium from the bone into the blood, increasing serum calcium concentration.
PTH also stimulates calcium reabsorption in the kidneys, meaning less calcium is excreted in the urine.
PTH also stimulates the kidneys to convert vitamin D3 into calcitriol, the active form of vitamin D. Vitamin D is a hormone that promotes calcium absorption from food in the intestine.
These three effects of PTH (increased calcium absorption from bone, the kidneys and the intestine) all help to increase the serum calcium. When the serum calcium level is high, it suppresses the release of PTH (via negative feedback), helping to reduce the serum calcium level.
The Renin-Angiotensin-Aldosterone System
Renin is an enzyme secreted by the juxtaglomerular cells in the afferent (and some in the efferent) arterioles in the kidney. They sense the blood pressure in these vessels. They secrete more renin in response to low blood pressure and less renin in response to high blood pressure. Renin acts to convert angiotensinogen (released by the liver) into angiotensin I. Angiotensin I converts to angiotensin II in the lungs with the help of an enzyme called angiotensin-converting enzyme (ACE).
Angiotensin II acts on blood vessels, causing vasoconstriction. Vasoconstriction increases blood pressure. Angiotensin II also stimulates the release of aldosterone from the adrenal glands, and contributes to cardiac remodelling by promoting hypertrophy of heart muscle cells (myocytes).
Aldosterone is a mineralocorticoid steroid hormone. It acts on the nephrons in the kidneys to:
Increase sodium reabsorption from the distal tubule
Increase potassium secretion from the distal tubule
Increase hydrogen secretion from the collecting ducts
When sodium is reabsorbed in the kidneys, water follows it by osmosis. This leads to increased intravascular volume and, subsequently, blood pressure.
TOM TIP: Understanding the renin-angiotensin-aldosterone system is essential to understanding the mechanism of action of ACE inhibitors and angiotensin II receptor blockers. By blocking the action of angiotensin-converting enzyme or angiotensin II receptors, they reduce the activity of angiotensin II, reducing vasoconstriction, cardiac remodelling and the secretion of aldosterone. Reduced aldosterone leads to reduced sodium reabsorption in the kidneys and less water retention. However, the reduced potassium secretion means these medications can cause hyperkalaemia (raised potassium).
What is hyperthyroidism and what causes it?
What are the features of Graves disease?
What is the management?
Hyperthyroidism is where there is over-production of the thyroid hormones, triiodothyronine (T3) and thyroxine (T4), by the thyroid gland.
The causes of hyperthyroidism can be remembered with the “GIST” mnemonic:
G – Graves’ disease
I – Inflammation (thyroiditis)
S – Solitary toxic thyroid nodule
T – Toxic multinodular goitre
Graves’ disease has specific features relating to the presence of TSH receptor antibodies:
- Diffuse goitre (without nodules)
- Graves’ eye disease, including exophthalmos
- Pretibial myxoedema
- Thyroid acropachy (hand swelling and finger clubbing)
Management:
A specialist endocrinologist guides the treatment of hyperthyroidism.
Carbimazole is the first-line anti-thyroid drug, usually taken for 12 to 18 months. Once the patient has normal thyroid hormone levels (usually within 4-8 weeks), they continue on maintenance carbimazole and either:
The carbimazole dose is titrated to maintain normal levels (known as titration-block)
A higher dose blocks all production, and levothyroxine is added and titrated to effect (known as block and replace)
TOM TIP: The MHRA issued a warning in 2019 about the risk of acute pancreatitis in patients taking carbimazole. In your exams, look out for a patient on carbimazole presenting with symptoms of pancreatitis (e.g., severe epigastric pain radiating to the back).
Propylthiouracil is the second-line anti-thyroid drug. It is used in a similar way to carbimazole. There is a small risk of severe liver reactions, including death, which is why carbimazole is preferred.
TOM TIP: Both carbimazole and propylthiouracil can cause agranulocytosis, with a dangerously low white blood cell counts. Agranulocytosis makes patients vulnerable to severe infections. A sore throat is a key presenting feature of agranulocytosis. In your exams, if you see a patient with a sore throat on carbimazole or propylthiouracil, the cause is likely agranulocytosis. They need an urgent full blood count and aggressive treatment of any infections.
What causes primary and secondary hypothyroidism?
What is the management?
Causes of Primary Hypothyroidism
Hashimoto’s thyroiditis is the most common cause of hypothyroidism in the developed world. It is an autoimmune condition causing inflammation of the thyroid gland. It is associated with anti-thyroid peroxidase (anti-TPO) antibodies and anti-thyroglobulin (anti-Tg) antibodies.
Iodine deficiency is the most common cause of hypothyroidism in the developing world. In the UK, iodine is particularly found in dairy products and may be added to non-dairy milk alternatives (e.g., soya milk).
Treatments for hyperthyroidism have the potential to cause hypothyroidism:
- Carbimazole
- Propylthiouracil
- Radioactive iodine
- Thyroid surgery
Lithium inhibits the production of thyroid hormones in the thyroid gland and can cause a goitre and hypothyroidism.
Amiodarone interferes with thyroid hormone production and metabolism, usually causing hypothyroidism but can also cause thyrotoxicosis.
Causes of Secondary Hypothyroidism
Secondary hypothyroidism is often associated with a lack of other pituitary hormones, such as ACTH, referred to as hypopituitarism. This is rarer than primary hypothyroidism, and may be caused by:
- Tumours (e.g., pituitary adenomas)
- Surgery to the pituitary
- Radiotherapy
- Sheehan’s syndrome (where major post-partum haemorrhage causes avascular necrosis of the pituitary gland)
- Trauma
Management
Oral levothyroxine is the mainstay of treatment of hypothyroidism. Levothyroxine is a synthetic version of T4 and metabolises to T3 in the body.
The dose is titrated based on the TSH level, initially every 4 weeks.
What is cushing sydrome?
What are the causes?
What are the features?
Cushing’s syndrome refers to the features of prolonged high levels of glucocorticoids in the body.
There are two groups of corticosteroid hormones:
Glucocorticoids (e.g., cortisol)
Mineralocorticoids (e.g., aldosterone)
Cortisol is the primary natural glucocorticoid hormone produced by the adrenal glands.
Cushing’s disease refers to a pituitary adenoma secreting excessive adrenocorticotropic hormone (ACTH), stimulating excessive cortisol release from the adrenal glands. This is not the only cause of Cushing’s syndrome.
The prolonged use of exogenous corticosteroids, such as prednisolone or dexamethasone, often causes Cushing’s syndrome. Exogenous refers to when it originates (-genous) is outside (exo-) the body.
Features
Features on inspection (round in the middle with thin limbs):
- Round face (known as a “moon face”)
- Central obesity
- Abdominal striae (stretch marks)
- Enlarged fat pad on the upper back (known as a “buffalo hump”)
- Proximal limb muscle wasting (with difficulty standing from a sitting position without using their arms)
- Male pattern facial hair in women (hirsutism)
- Easy bruising and poor skin healing
- Hyperpigmentation of the skin in patients with Cushing’s disease (due to high ACTH levels)
**Metabolic effects:
**
* Hypertension
* Cardiac hypertrophy
* Type 2 diabetes
* Dyslipidaemia (raised cholesterol and triglycerides)
* Osteoporosis
Causes of Cushing’s Syndrome
You can remember the causes of Cushing’s syndrome with the “CAPE” mnemonic:
C – Cushing’s disease (a pituitary adenoma releasing excessive ACTH)
A – Adrenal adenoma (an adrenal tumour secreting excess cortisol)
P – Paraneoplastic syndrome
E – Exogenous steroids (patients taking long-term corticosteroids)
Paraneoplastic Cushing’s syndrome occurs when ACTH is released from a tumour somewhere other than the pituitary gland. ACTH from somewhere other than the pituitary gland is called ectopic ACTH. Small cell lung cancer is the most common. Ectopic ACTH stimulates excessive cortisol release from the adrenal glands.
TOM TIP: A high level of ACTH causes skin pigmentation by stimulating melanocytes in the skin to produce melanin, similar to melanocyte-stimulating hormone. This is an important sign of Cushing’s disease (where excess ACTH comes from a pituitary adenoma) and also primary adrenal insufficiency (where there is inadequate cortisol from the adrenals with a lack of negative feedback to the pituitary). In a patient with Cushing’s syndrome, the pigmentation allows you to determine the cause as excess ACTH, either from Cushing’s disease or ectopic ACTH. This sign is absent in an adrenal adenoma or exogenous steroids.
How do you diagnose cushing syndrome?
What are the treatments?
Dexamethasone Suppression Tests
The dexamethasone suppression tests are used to diagnose Cushing’s syndrome caused by a problem inside the body. There is no point in using them to diagnose Cushing’s syndrome caused by exogenous steroids.
A normal response to dexamethasone is suppressed cortisol due to negative feedback. Dexamethasone causes negative feedback on the hypothalamus, reducing the corticotropin-releasing hormone (CRH) output. It causes negative feedback on the pituitary, reducing the ACTH output. The lower CRH and ACTH levels result in a low cortisol output by the adrenal glands. A lack of cortisol suppression in response to dexamethasone suggests Cushing’s syndrome.
There are three types of dexamethasone suppression test:
Low-dose overnight test (used as a screening test to exclude Cushing’s syndrome)
Low-dose 48-hour test (used in suspected Cushing’s syndrome)
High-dose 48-hour test (used to determine the cause in patients with confirmed Cushing’s syndrome)
For the low-dose overnight test, dexamethasone (1mg) is given at night (usually 10 or 11 pm), and the cortisol is checked at 9 am the following morning. A normal result is that the cortisol level is suppressed. Failure of the dexamethasone to suppress the morning cortisol could indicate Cushing’s syndrome, and further assessment is required.
For the low-dose 48-hour test, dexamethasone (0.5mg) is taken every 6 hours for 8 doses, starting at 9 am on the first day. Cortisol is checked at 9 am on day 1 (before the first dose) and 9 am on day 3 (after the last dose). A normal result is that the cortisol level on day 3 is suppressed. Failure of the dexamethasone to suppress the day 3 cortisol could indicate Cushing’s syndrome, and further assessment is required.
The high-dose 48-hour test is carried out the same way as the low-dose test, other than using 2mg per dose (rather than 0.5mg). This higher dose is enough to suppress the cortisol in Cushing’s syndrome caused by a pituitary adenoma (Cushing’s disease), but not when it is caused by an adrenal adenoma or ectopic ACTH.
Adrenocorticotropic hormone (ACTH) can be measured directly. ACTH is suppressed due to negative feedback on the pituitary when excess cortisol comes from an adrenal tumour (or endogenous steroids). It is high when produced by a pituitary tumour or ectopic ACTH (e.g., small cell lung cancer).
Treatment
The primary treatment is to remove the underlying cause:
- Trans-sphenoidal (through the nose) removal of pituitary adenoma
- Surgical removal of adrenal tumour
- Surgical removal of the tumour producing ectopic ACTH (e.g., small cell lung cancer), if possible
Where surgical removal of the cause is not possible, another option is to surgically remove both adrenal glands (adrenalectomy) and give the patient life-long steroid replacement therapy.
Nelson’s syndrome involves the development of an ACTH-producing pituitary tumour after the surgical removal of both adrenal glands due to a lack of cortisol and negative feedback. It causes skin pigmentation (high ACTH), bitemporal hemianopia and a lack of other pituitary hormones.
Metyrapone reduces the production of cortisol in the adrenals and is occasionally used in treating of Cushing’s.
What is Primary and secondary Hyperaldosteronism?
What are the causes?
-
Primary Hyperaldosteronism
Primary hyperaldosteronism is when the adrenal glands are directly responsible for producing too much aldosterone. Serum renin will be low as the high blood pressure suppresses it.
The adrenals may produce too much aldosterone for several possible reasons:
- Bilateral adrenal hyperplasia (most common)
- An adrenal adenoma secreting aldosterone (known as Conn’s syndrome)
- Familial hyperaldosteronism (rare)
Secondary Hyperaldosteronism
Secondary hyperaldosteronism is caused by excessive renin stimulating the release of excessive aldosterone.
Excessive renin is released due to disproportionately lower blood pressure in the kidneys, usually due to:
- Renal artery stenosis
- Heart failure
- Liver cirrhosis and ascites
What investigations would you do if suspected hyperaldosteronism?
What is the management?
Investigations
The aldosterone-to-renin ratio (ARR) is used as a screening test:
High aldosterone and low renin indicate primary hyperaldosteronism
High aldosterone and high renin indicate secondary hyperaldosteronism
Other investigations that relate to the effects of aldosterone include:
Raised blood pressure (hypertension)
Low potassium (hypokalaemia)
Blood gas analysis (alkalosis)
Investigations for the underlying cause include:
CT or MRI to look for an adrenal tumour or adrenal hyperplasia
Renal artery imaging for renal artery stenosis (Doppler, CT angiogram or MR angiography)
Adrenal vein sampling of blood from both adrenal veins to locate which gland is producing more aldosterone
Management
Medical management is with aldosterone antagonists:
Eplerenone
Spironolactone
Treating the underlying cause involves:
Surgical removal of the adrenal adenoma
Percutaneous renal artery angioplasty via the femoral artery to treat renal artery stenosis
What is primary, secondary and tertieary adrenal insufficiency and give examples of their causes
What are the clinical signs of adrenal insufficiency?
Addison’s disease refers specifically to when the adrenal glands have been damaged, resulting in reduced cortisol and aldosterone secretion. This is called primary adrenal insufficiency. The most common cause is autoimmune.
Secondary adrenal insufficiency results from inadequate adrenocorticotropic hormone (ACTH) and a lack of stimulation of the adrenal glands, leading to low cortisol. This is the result of loss or damage to the pituitary gland. Secondary adrenal insufficiency can be due to:
Tumours (e.g., pituitary adenomas)
Surgery to the pituitary
Radiotherapy
Sheehan’s syndrome (where major post-partum haemorrhage causes avascular necrosis of the pituitary gland)
Trauma
Tertiary adrenal insufficiency results from inadequate corticotropin-releasing hormone (CRH) release by the hypothalamus. This is usually the result of patients taking long-term oral steroids (for more than 3 weeks), causing suppression of the hypothalamus (via negative feedback). When the exogenous steroids (originating outside the body) are suddenly withdrawn, the hypothalamus does not “wake up” fast enough, and endogenous steroids (originating inside the body) are not adequately produced. Therefore, long-term steroids must be tapered slowly to allow the adrenal axis to regain normal function.
The signs of adrenal insufficiency are:
Bronze hyperpigmentation of the skin, particularly in creases (ACTH stimulates melanocytes to produce melanin)
Hypotension (particularly postural hypotension – with a drop of more than 20 mmHg on standing)
What are the investigations if suspecting adrenal insufficiency?
What is the management?
Investigations
Hyponatraemia (low sodium) is a key biochemical finding. This may be the only presenting feature.
The short Synacthen test is also known as the ACTH stimulation test. It is the test of choice for diagnosing adrenal insufficiency. It is ideally performed in the morning.
The test involves giving a dose of Synacthen, which is synthetic ACTH. The blood cortisol is checked before and 30 and 60 minutes after the dose. The synthetic ACTH will stimulate healthy adrenal glands to produce cortisol. The cortisol level should at least double. A failure of cortisol to double indicates either:
Primary adrenal insufficiency (Addison’s disease)
Very significant adrenal atrophy after a prolonged absence of ACTH in secondary adrenal insufficiency
Management
Treatment of adrenal insufficiency is with replacement steroids titrated to signs, symptoms and electrolytes. Hydrocortisone (a glucocorticoid) is used to replace cortisol. Fludrocortisone (a mineralocorticoid) is used to replace aldosterone, if aldosterone is also insufficient.
Patients are given a steroid card, ID tag and emergency letter to alert emergency services that they depend on steroids for life. Doses should not be missed, as they are essential to life. Doses are doubled during an acute illness to match the normal steroid response to illness.
Patients and close contacts are taught to give intramuscular hydrocortisone in an emergency.
What is type 1 diabetes?
What are the long term complications?
Type 1 diabetes is a condition where the pancreas stops being able to produce adequate insulin. Without insulin, the cells of the body cannot absorb glucose from the blood and use it as fuel. Therefore, the cells think there is no glucose available. Meanwhile, the glucose level in the blood keeps rising, causing hyperglycaemia.
The underlying cause of type 1 diabetes is unclear. There may be a genetic component, but it is not inherited in any clear pattern. Certain viruses, such as the Coxsackie B and enterovirus, may trigger it.
Type 1 diabetes may present with the classic triad of symptoms of hyperglycaemia:
Polyuria (excessive urine)
Polydipsia (excessive thirst)
Weight loss (mainly through dehydration)
Long Term Complications
Chronic high blood glucose levels cause damage to the endothelial cells of blood vessels. This leads to leaky, malfunctioning vessels that are unable to regenerate. High glucose levels also cause immune system dysfunction and create an optimal environment for infectious organisms to thrive.
Macrovascular complications include:
- Coronary artery disease is a significant cause of death in diabetics
- Peripheral ischaemia causes poor skin healing and diabetic foot ulcers
- Stroke
- Hypertension
Microvascular complications include:
- Peripheral neuropathy
- Retinopathy
- Kidney disease, particularly glomerulosclerosis
Infection-related complications include:
- Urinary tract infections
- Pneumonia
- Skin and soft tissue infections, particularly in the feet
- Fungal infections, particularly oral and vaginal candidiasis
What is diabetic ketoacidosis and how does it present?
What is the treatement of diabetic ketoacidosis?
Ketoacidosis
Without insulin, the body’s cells cannot recognise glucose, even when there is plenty in the blood, so the liver starts producing ketones to use as fuel. Over time, there are higher and higher glucose and ketones levels. Initially, the kidneys produce bicarbonate to counteract the ketone acids in the blood and maintain a normal pH. Over time, the ketone acids use up the bicarbonate, and the blood becomes acidic. This is called ketoacidosis.
Treatment of Diabetic Ketoacidosis
The most dangerous aspects of DKA are dehydration, potassium imbalance and acidosis. These are what will kill the patient. Therefore, the priority is fluid resuscitation to correct dehydration, electrolyte disturbance and acidosis. This is followed by an insulin infusion to get the cells to start taking up and using glucose and stop producing ketones.
Diabetic ketoacidosis is a life-threatening medical emergency. Get experienced senior support and follow local protocols when treating patients. Local policies will dictate precisely what fluids and insulin to prescribe.
The principles of management can be remembered with the “FIG-PICK” mnemonic:
F – Fluids – IV fluid resuscitation with normal saline (e.g., 1 litre in the first hour, followed by 1 litre every 2 hours)
I – Insulin – fixed rate insulin infusion (e.g., Actrapid at 0.1 units/kg/hour)
G – Glucose – closely monitor blood glucose and add a glucose infusion when it is less than 14 mmol/L
P – Potassium – add potassium to IV fluids and monitor closely (e.g., every hour initially)
I – Infection – treat underlying triggers such as infection
C – Chart fluid balance
K – Ketones – monitor blood ketones, pH and bicarbonate
What is type 2 diabetes?
What are the risk factors?
What is the diagnosis for type 2 diabetes?
Repeated exposure to glucose and insulin makes the cells in the body resistant to the effects of insulin. More and more insulin is required to stimulate the cells to take up and use glucose. Over time, the pancreas becomes fatigued and damaged by producing so much insulin, and the insulin output is reduced.
A high carbohydrate diet combined with insulin resistance and reduced pancreatic function leads to chronic high blood glucose levels (hyperglycaemia). Chronic hyperglycaemia leads to microvascular, macrovascular and infectious complications, as described in the type 1 diabetes section.
Risk Factors
Non-modifiable risk factors:
- Older age
- Ethnicity (Black African or Caribbean and South Asian)
- Family history
Modifiable risk factors:
- Obesity
- Sedentary lifestyle
- High carbohydrate (particularly sugar) diet
Diagnosis
An HbA1c of 48 mmol/mol or above indicates type 2 diabetes.
The sample is typically repeated after 1 month to confirm the diagnosis (unless there are symptoms or signs of complications).
What is the medical management for type 2 diabetes?
Medical Management
First-line is metformin.
Once settled on metformin, add an SGLT-2 inhibitor (e.g., dapagliflozin) if the patient has existing cardiovascular disease or heart failure. NICE suggest considering an SGLT-2 inhibitor in patients with a QRISK score above 10%.
Second-line is to add a sulfonylurea, pioglitazone, DPP-4 inhibitor or SGLT-2 inhibitor.
Third-line options are:
Triple therapy with metformin and two of the second-line drugs
Insulin therapy (initiated by the specialist diabetic nurses)
Where triple therapy fails, and the patient’s BMI is above 35 kg/m2, there is the option of switching one of the drugs to a GLP-1 mimetic (e.g., liraglutide).
TOM TIP: SGLT-2 inhibitors are increasingly being recommended. Older patients often have a QRISK score above 10%, making them fall into the “high risk” category for cardiovascular disease. NICE suggests considering SGLT-2 inhibitors alongside metformin as part of the first-line treatment in type 2 diabetics at high risk of cardiovascular disease. SGLT-2 inhibitors are recommended second-line as part of dual therapy in these patients. The significant potential side effect to remember is diabetic ketoacidosis.
