Endocrine Flashcards
The anterior pituitary gland releases:
- Thyroid Stimulating Hormone (TSH)
- Adrenocorticotropic Hormone (ACTH)
- Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH)
- Growth Hormone (GH)
- Prolactin
The posterior pituitary releases:
Oxytocin
Antidiuretic Hormone (ADH)
Explain the hormone cycle in the thyroid
The hypothalamus releases thyrotropin-releasing hormone (TRH). This stimulates the anterior pituitary to release thyroid stimulating hormone (TSH). This in turn stimulates the thyroid gland to release triiodothyronine (T3) and thyroxine (T4).
T3 and T4 are sensed by the hypothalamus and anterior pituitary, and they suppress the release of TRH and TSH. This results in lower amounts of T3 and T4. In this way, the level of thyroid hormone is closely regulated to keep it within normal limits. This is called negative feedback.
Explain the hormonal cycle of the adrenal gland
Cortisol is secreted by the two adrenal glands, which sit above each kidney. The release of cortisol is controlled by the hypothalamus. Cortisol is released in pulses and in response to a stressful stimulus (it is a “stress hormone“). It has diurnal variation, which basically means that 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 it’s lowest late in the evening, prompting us to relax and fall asleep.
The hypothalamus releases corticotrophin release hormone (CRH). This stimulates the anterior pituitary to release adrenocorticotrophic hormone (ACTH). This in turn stimulates the adrenal gland to release cortisol.
The adrenal axis is also controlled by negative feedback. Cortisol is sensed by the hypothalamus and anterior pituitary, and it suppresses the release of CRH and ACTH. This results in lower amounts of cortisol. In this way, cortisol is closely regulated to keep it within normal limits.
Cortisol has several actions within the body
WHat are these actions:
- Inhibits the immune system
- Inhibits bone formation
- Raises blood glucose
- Increases metabolism
- Increases alertness
What is the phsyiology of GH
Growth hormone releasing hormone (GHRH) is released from the hypothalamus. This stimulates growth hormone (GH) release from the anterior pituitary. 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 of the body 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
Explain the physiology of PTH
Parathyroid Hormone (PTH) is released from the four parathyroid glands (situated in four corners of the thyroid gland) in response to low serum calcium. It is also released in response to low magnesium and high serum phosphate. It’s role is to increase the serum calcium concentration.
PTH increases the activity and number of osteoclasts in bone, causing reabsorption of calcium from the bone into the blood thereby increasing serum calcium concentration.
PTH also stimulates an increase in calcium reabsorption in the kidneys meaning that less calcium is excreted in the urine.
Additionally, it stimulates the kidneys to convert vitamin D3 into calcitriol, which is the active form of vitamin D that promotes calcium absorption from food in the small intestine.
These three effects of PTH (increased calcium absorption from bone, the kidneys and the small intestine) all help to raise the level of serum calcium. When serum calcium is high this suppresses the release of PTH (via negative feedback) helping to reduce the serum calcium level.
Angiotensin II acts on blood vessels to cause ___________ This results in an increase in blood pressure.
Angiotensin II also stimulates the release of ___________ from the adrenal glands.
Angiotensin II acts on blood vessels to cause vasoconstriction. This results in an increase in blood pressure.
Angiotensin II also stimulates the release of aldosterone from the adrenal glands.
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 an increase in _________ ________ and subsequently blood pressure.
When sodium is reabsorbed in the kidneys water follows it by osmosis. This leads to an increase in intravascular volume and subsequently blood pressure.
The body ideally wants to keep blood glucose concentration is between?
4.4. and 6.1 mmol/l.
What type of hormone is glucagon
catabolic
Explain Ketogenesis
Ketogenesis occurs when there is insufficient glucose supply and glycogens stores are exhausted, such as in prolonged fasting.
The liver takes fatty acids and converts them to ketones. Ketones are water soluble fatty acids that can be used as fuel. They can cross the blood brain barrier and be used by the brain as fuel. Producing ketones is normal and not harmful in healthy patients when under fasting conditions or on very low carbohydrate, high fat diets. Ketones levels can be measured in the urine by “dip-stick” and in the blood using a ketone meter. People in ketosis have a characteristic acetone smell to their breath.
Ketone acids (ketones) are buffered in normal patients so the blood does not become acidotic. When underlying pathology (i.e. type 1 diabetes) causes extreme hyperglycaemic ketosis this results in a metabolic acidosis that is life threatening. This is called diabetic ketoacidosis.
What i sType 1 Diabetes
What is triggered by?
Type 1 diabetes mellitus (T1DM) is a disease where the pancreas stops being able to produce insulin. What causes the pancreas to stop producing insulin is unclear. There may be a genetic component. When there is no insulin being produced, the cells of the body cannot take glucose from the blood and use it for fuel. Therefore the cells think the body is being fasted and has no glucose supply. Meanwhile the level of glucose in the blood keeps rising, causing hyperglycaemia.
It may be triggered by certain viruses, such as the Coxsackie B virus and enterovirus
When does DKA occur
Diabetic ketoacidosis occurs in type 1 diabetes where the person is not producing adequate insulin themselves and is not injecting adequate insulin to compensate for this. It occurs when they body does not have enough insulin to use and process glucose. The main problems are ketoacidosis, dehydration and potassium imbalance.
What is Ketoacidosis
As the cells in the body have no fuel and think they are starving they initiate the process of ketogenesis so that they have a usable fuel. Over time the patient gets 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 starts to become acidic. This is called ketoacidosis.
How are people dehydrated in DKA
Hyperglycaemia overwhelms the kidneys and glucose starts being filtered into the urine. The glucose in the urine draws water out with it in a process called osmotic diuresis. This causes the patient to urinate a lot (polyuria). This results in severe dehydration. The dehydration stimulates the thirst centre to tell the patient to drink lots of water. This excessive thirst is called polydipsia.
Explain the potassium imblance in people with DKA
Insulin normally drives potassium into cells. Without insulin potassium is not added to and stored in cells. Serum potassium can be high or normal as the kidneys continue to balance blood potassium with the potassium excreted in the urine, however total body potassium is low because no potassium is stored in the cells. When treatment with insulin starts patients can develop severe hypokalaemia (low serum potassium) very quickly and this can lead to fatal arrhythmias.
Presentation of DKA
This is a life threatening medical emergency. The pathophysiology described above leads to:
- Hyperglycaemia
- Dehydration
- Ketosis
- Metabolic acidosis (with a low bicarbonate)
- Potassium imbalance
The patient will therefore present with symptoms of these abnormalities:
- Polyuria
- Polydipsia
- Nausea and vomiting
- Acetone smell to their breath
- Dehydration and subsequent hypotension
- Altered Consciousness
- They may have symptoms of an underlying trigger (i.e. sepsis)
The most dangerous aspects of DKA are ________ ________ ________ and _______. These are what will kill the patient. Therefore the priority is _____ __________ to correct the 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.
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 the 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.
Diagnosing DKA
Check the local DKA diagnostic criteria for your hospital. To diagnose DKA you require:
- Hyperglycaemia (i.e. blood glucose > 11 mmol/l)
- Ketosis (i.e. blood ketones > 3 mmol/l)
- Acidosis (i.e. pH < 7.3)
Treating DKA (FIG-PICK)
- F – Fluids – IV fluid resuscitation with normal saline (e.g. 1 litre stat, then 4 litres with added potassium over the next 12 hours)
- I – Insulin – Add an insulin infusion (e.g. Actrapid at 0.1 Unit/kg/hour)
- G – Glucose – Closely monitor blood glucose and add a dextrose infusion if below a certain level (e.g. 14 mmol/l)
- P – Potassium – Closely monitor serum potassium (e.g. 4 hourly) and correct as required
- I – Infection – Treat underlying triggers such as infection
- C – Chart fluid balance
- K – Ketones – Monitor blood ketones (or bicarbonate if ketone monitoring is unavailable)
DKA
Remember as a general rule potassium should not be infused at a rate of more than __ mmol per hour.
Remember as a general rule potassium should not be infused at a rate of more than 10 mmol per hour.
What are the long term management of TYpe 1 Diabetes
Patient education is essential. Monitoring and treatment is relatively complex. The condition is life-long and requires the patient to fully understand and engage with their condition. It involves the following components:
- Subcutaneous insulin regimes
- Monitoring dietary carbohydrate intake
- Monitoring blood sugar levels on waking, at each meal and before bed
- Monitoring for and managing complications, both short and long term
Insulin is usually prescribed as a combination of a background, long acting insulin given once a day and a short acting insulin injected 30 minutes before intake of carbohydrate (i.e. at meals). Insulin regimes are initiated by a diabetic specialist.
Injecting into the same spot can cause a condition called “lipodystrophy”, where the subcutaneous fat hardens and patients do not absorb insulin properly from further injections into this spot. For this reason patients should cycle their injection sites.
Short term complications relate to immediate insulin and blood glucose management
Type 1 DM.
Hypoglycaemia
Hyperglycaemia (and DKA)
How can a type 1 diabteic patient become hypoglycaemic
Hypoglycaemia is a low blood sugar level. Most patients are aware of when they are hypoglycaemic by their symptoms, however some patients can be unaware until severely hypoglycaemic. Typical symptoms are tremor, sweating, irritability, dizziness and pallor. More severe hypoglycaemia will lead to reduced consciousness, coma and death unless treated.
Hypoglycaemia needs to be treated with a combination of rapid acting glucose such as lucozade and slower acting carbohydrates such as biscuits and toast for when the rapid acting glucose is used up. Options for treating severe hypoglycaemia are IV dextrose and intramuscular glucagon.
How can a type 1 diabteic patient become hyperglycaemic
If the patient is hyperglycaemic but not in DKA then they may require their insulin dose to be increased. Patients will get to know their own individual response to insulin and be able to administer a dose to correct the hyperglycaemia. For example, they may learn that 1 unit of novorapid reduces their sugar level by around 4 mmol. Be conscious that it can take several hours to take effect and repeated doses could lead to hypoglycaemia.
If they meet the criteria for DKA then they need admission for treatment of DKA.
Macrovascular Complications of DM
Coronary artery disease is a major cause of death in diabetics
Peripheral ischaemia causes poor healing, ulcers and “diabetic foot”
Stroke
Hypertension
Microvascular Complications of DM
Peripheral neuropathy
Retinopathy
Kidney disease, particularly glomerulosclerosis
Infection Related Complications of DM
Urinary Tract Infections
Pneumonia
Skin and soft tissue infections, particularly in the feet
Fungal infections, particularly oral and vaginal candidiasis
What do we monitor in patients with DM
HbA1c
When we check HbA1c we are counting glycated haemoglobin, which is how much glucose is attached to the haemoglobin molecule. This is considered to reflect the average glucose level over the last 3 months because red blood cells have a lifespan of around 3-4 months. We measure it every 3 – 6 months to track progression of the patient’s diabetes and how effective the interventions are. It requires a blood sample sent to the lab, usually red top EDTA bottle.
Capillary Blood Glucose
This is measured using a little machine called a glucose meter that gives an immediate result. Patients with type 1 and type 2 diabetes rely on these machines for self-monitoring their sugar levels.
Flash Glucose Monitoring (e.g. FreeStyle Libre)
This uses a sensor on the skin that measures the glucose level of interstitial fluid. There is a lag of 5 minutes behind blood glucose. This sensor records the glucose readings at short intervals so you get a really good impression of what the glucose levels are doing over time. The user needs to use a “reader” to swipe over the sensor and it is the reader that shows the blood sugar readings. Sensors need replacing every 2 weeks for the FreeStyle Libre system. It is quite expensive and NHS funding is only available in certain areas at the time of writing. The 5 minute delay also means it is necessary to do capillary blood glucose checks if hypoglycaemia is suspected.
Describe some Non modifiable and modifiable RF of Type 2 DM
Non-Modifiable
- Older age
- Ethnicity (Black, Chinese, South Asian)
- Family history
Modifiable
- Obesity
- Sedentary lifestyles
- High carbohydrate (particularly refined carbohydrate) diet
Presentation
Consider type 2 diabetes
- Consider RF
- Fatigue
- Polydipsia and polyuria (thirsty and urinating a lot)
- Unintentional weight loss
- Opportunistic infections
- Slow healing
- Glucose in urine (on dipstick)
What is Oral Glucose Tolerance Test (OGTT)
An oral glucose tolerance test (OGTT) is performed in the morning prior to having breakfast. It involves taking a baseline fasting plasma glucose result, giving a 75g glucose drink and then measuring plasma glucose 2 hours later. It tests the ability of the body to cope with a carbohydrate meal.
What is Pre diabetes
Pre-diabetes is an indication that the patient is heading towards diabetes. They do not fit the full diabetic diagnostic criteria but should be educated regarding diabetes and implement lifestyle changes to reduce their risk of progressing to diabetes. They are not currently recommended to start medical treatment at this point.
Pre-diabetes Diagnosis
Pre-diabetes can be diagnosed with a HbA1c or by “impaired fasting glucose” or “impaired glucose tolerance”. Impaired fasting glucose means that their body struggles to get their blood glucose levels in to normal range, even after a prolonged period without eating carbohydrates. Impaired glucose tolerance means their body struggles to cope with processing a carbohydrate meal.
- HbA1c – 42-47 mmol/mol
- Impaired fasting glucose – fasting glucose 6.1 – 6.9 mmol/l
- Impaired glucose tolerance – plasma glucose at 2 hours 7.8 – 11.1 mmol/l on an OGTT
Diabetes Diagnosis
Diabetes can be diagnosed if the patient fits the criteria on plasma glucose, an oral glucose tolerance test or HbA1c.
- HbA1c > 48 mmol/mol
- Random Glucose > 11 mmol/l
- Fasting Glucose > 7 mmol/l
- OGTT 2 hour result > 11 mmol/l
Name some dietary modification in type 2 DM
Vegetables and oily fish
Typical advice is low glycaemic, high fibre diet
A low carbohydrate may in fact be more effective in treating and preventing diabetes but is not yet mainstream advice
Lifestyle modifications for Type 2 DM
- Exercise and weight loss
- Stop smoking
- Optimise treatment for other illnesses, for example hypertension, hyperlipidaemia and cardiovascular disease
Monitoring for Complications
- Diabetic retinopathy
- Kidney disease
- Diabetic foot
SIGN Guidelines 2017 and NICE Guideline 2015 recommend the following HbA1c treatment targets:
- 48 mmol/mol for new type 2 diabetics
- 53 mmol/mol for diabetics that have moved beyond metformin alone
Explain the medical management for type 2 DM
- First line: metformin titrated from initially 500mg once daily as tolerated.
- Second line add: sulfonylurea, pioglitazone, DPP-4 inhibitor or SGLT-2 inhibitor. The decision should be based on individual factors and drug tolerance.
- Third line: Triple therapy with metformin and two of the second line drugs combined, or;
- Metformin plus insulin
SIGN Guidelines 2017 suggest the use of SGLT-2 inhibitors and GLP-1 mimetics (e.g. liraglutide) preferentially in patients with cardiovascular disease.
Metformin
Class:
Mechanism:
S/E:
Class: biguanide
Mechanism: increases insulin sensitivity and decreases liver production of glucose.
S/E:
- Diarrhoea and abdominal pain. This is dose dependent and reducing the dose often resolves the symptoms
- Lactic acidosis
- Does NOT typically cause hypoglycaemia
Does Metformin cause weight loss
No
It is considered to be “weight neutral” and does not increase or decrease body weight.
Pioglitazone
Class:
Mechanism:
S/E:
Class:thiazolidinedione
Mechanism: It increases insulin sensitivity and decreases liver production of glucose.
S/E:
- Weight gain
- Fluid retention
- Anaemia
- Heart failure
- Extended use may increase the risk of bladder cancer
- Does NOT typically cause hypoglycaemia
Sulfonylurea
Common drug:
Mechanism:
S/E:
Common drug:gliclazide
Mechanism: Sulfonylureas stimulate insulin release from the pancreas.
S/E:
- Weight gain
- Hypoglycaemia
- Increased risk of cardiovascular disease and myocardial infarction when used as monotherapy
Incretins (relevant for DPP-4 inhibitors and GLP-1 mimetics)
Mechanism
Incretins are hormones produced by the GI tract. They are secreted in response to large meals and act to reduce blood sugar. They:
- Increase insulin secretions
- Inhibit glucagon production
- Slow absorption by the GI tract
The main incretin is______ _____ ______ Incretins are inhibited by an enzyme called “_____ _____ ______” (DPP-4).
The main incretin is “glucagon-like peptide-1” (GLP-1). Incretins are inhibited by an enzyme called “dipeptidyl peptidase-4” (DPP-4).
DPP-4 inhibitor
Common Drug
Mechanism
S/E
Common Drug: sitagliptin
Mechanism: It inhibits the DPP-4 enzyme and therefore increases GLP-1 activity.
S/E:
- GI tract upset
- Symptoms of upper respiratory tract infection
- Pancreatitis
GLP-1 mimetics
Examples
S/E
These medications mimic the action of GLP-1. A common GLP-1 mimetic is “exenatide”. Exenatide is given as a subcutaneous injection either twice daily by the patient or once weekly in a modifiable-release form. Another GLP-1 mimetic is liraglutide, which is given daily as a subcutaneous injection. They are sometimes used in combination with metformin and a sulfonylurea in overweight patients.
Notable Side Effects:
- GI tract upset
- Weight loss
- Dizziness
- Low risk of hypoglycaemia
SGLT-2 Inhibitors
Examples:
Mechamism:
S/E:
Examples: SGLT-2 inhibitors end with the suffix “-gliflozin”, such as empagliflozin, canagliflozin and dapagliflozin
Mechamism: The SGLT-2 protein is responsible for reabsorbing glucose from the urine in to the blood in the proximal tubules of the kidneys. SGLT-2 inhibitors block the action of this protein and cause glucose to be excreted in the urine.
S/E:
- Glucoseuria (glucose in the urine)
- Increased rate of urinary tract infections
- Weight loss
- Diabetic ketoacidosis, notably with only moderately raised glucose. This is a rare complication
- Lower limb amputation appears to be more common in patients on canagliflozin. It is not clear if this applies to other SGLT-2 inhibitors
Example of Rapid-acting Insulins
These start working after around 10 minutes and last around 4 hours
Novorapid
Humalog
Apidra
Example of Short-acting Insulins
These start working in around 30 minutes and last around 8 hours
Actrapid
Humulin S
Insuman Rapid
Example of Intermediate-acting Insulins
These start working in around 1 hour and last around 16 hours:
Insulatard
Humulin I
Insuman Basal
Example of Long-acting Insulins
These starts working in around 1 hour and lasts around 24 hours:
Lantus
Levemir
Degludec (lasts over 40 hours)
Investigations of hypothyroidism
Summar of hyperparathyroidism
cause
pth
calcium
Water Deprivation Test Results
