Module 3D Endocrine - Conditions Flashcards
Give a summary of type 1 diabetes
- what is it + little bit of pathophysiology
- presentation
- long term complications
- management overview
- Type 1 diabetes is a chronic autoimmune disease —> it causes immune-mediated destruction of insulin-producing pancreatic beta cells, which results in an absolute insulin deficiency and subsequent hyperglycaemia
- Patients commonly present in childhood/adolescence with the classic triad of symptoms of hyperglycaemia: polyuria, polydipsia, and weight loss (or critically unwell with DKA)
- Long-term hyperglycaemia in T1DM can lead to many complications including macrovascular damage (eg. cardiovascular, cerebrovascular, or peripheral vascular disease) and microvascular damage (eg. nephropathy, retinopathy, and neuropathy)
- The long-term management of T1DM requires an MDT approach and treatment is with exogenous insulin administration, diet, and exercise education with an aim to achieve tight glycaemic control to minimise acute risk of DKA and chronic complications
Type 1 diabetes mellitus (T1DM) aetiology
- need to cut these questions down, only way to do this is by doing them to know what to change them to
- results from an immune-mediated destruction of insulin-producing pancreatic beta-cells –> the triggers for the autoimmune attack are not fully known but thought to be influenced by both genetic and environmental factors
.
Genetic: - thought to be linked to HLA genotypes –> HLA-DR and HLA-DQ alleles
- HLA-DQ2 genotype is sometimes seen in T1DM associated with coeliac disease
.
Environmental (thought to be): - Viral infections
- Cow’s milk ingestion
- Vitamin D deficiency
- Early introduction of cereals
Type 1 diabetes mellitus (T1DM) pathophysiology + action of insulin
- results from autoimmune destruction of the insulin-producing beta cells in the islets of Langerhans of the pancreas
.
Normal action of insulin: - Insulin is needed for cells to take in glucose from the blood –> insulin activates insulin-receptors on the membranes of insulin-responsive tisues (eg. peripheral muscle and adipose tissue), stimulating the migration of glucose transporters to the cell membrane to facilitate uptake of circulating glucose into these tissues
- In addition, insulin also stimulates glycogen synthesis, and inhibits gluconeogenesis, glycogenolysis, and lipolysis
In the absence of insulin (as in T1DM), glucose cannot be taken up by insulin-responsive tissues –> causing hyperglycaemia
.
Pathophysiological process in T1DM: - most commonly a type IV hypersensitivity autoimmune reaction
- progressive beta cell destruction also leads to dysfunction of neighbouring alpha cells which produce the counter-regulatory hormone, glucagon –> this leads to overstimulation of glucagon causing further hyperglycaemia
In T1DM, long-term hyperglycaemia causes chronic macrovascular and microvascular damage –> what is the pathophysiology behind this?
(Need to redo this card - why does this happen + can use other resources (eg. Osmosis/lectures)
- thought to be related to oxidative stress, free radical damage, sorbitol production, and glycosylation of tissues
Clinical features of T1DM
Classic triad of hyperglycaemia:
- Polyuria (excessive urination)
- Polydipsia (excessive thirst)
- Weight loss (due to dehydration)
(often accompanied by fatigue and sometimes blurred vision)
Why does T1DM present with the classic triad of symptoms?
- Polyuria and polydipsia –> due to hyperglycaemia causing osmotic diuresis in the renal tubules, leading to dehydration which stimulates thirst
- Unexplained weight loss –> due to depletion of glycogen stores and breakdown of adipose tissue as the body attempts to compensate for cellular glucose deficiency by increasing energy production from proteins and fats
- Fatigue –> results from impaired glucose utilisation within cells leading to low energy levels
T1DM investigations
First-line:
- Blood glucose testing –> fasting plasma glucose test (>7 mmol/L) OR a random plasma glucose test (>11mmol/L) on more than one occasion
- Glycated haemoglobin (HbA1c) –> provides an overview of blood sugar levels over the past 2-3 months (>48 mmol/mol or higher on two separate tests confirms diagnosis)
- Urine testing (urine dipstick) –> glucosuria and ketonuria are common findings in T1DM
.
Further investigations:
- Autoantibody testing –> can confirm T1DM, glutamic acid decarboxylase (GAD) antibodies, Islet cell cytoplasmic autoantibodies (ICA), Insulinoma-associated-2 antibodies (IA-2A), and insulin autoantibodies (IAA)
- C-peptide measurement –> C-peptide is co-released with insulin from beta cells in pancreas –> low lvls along with hyperglycaemia suggests T1DM due to beta-cell destruction
.
- Can perform routine bloods (FBC, renal function, and lipid profile) to screen for associated complications
What is the criteria for diagnosing diabetes mellitus in general? (as per WHO)
- Random plasma glucose level >11.1 mmol/L in the presence of symptoms of hyperglycaemia
OR - Fasting plasma glucose >7mmol/L
OR - Plasma glucose level >11mmol/L 2 hours after a 75g oral glucose load
OR - HbA1c >48mmol/mol (can be unreliable if pt has concurrent condition affecting RBC survival)
(If pt is asymptomatic then further tests should be done to confirm diagnosis)
Diabetes mellitus can be broadly classified into T1DM, T2DM, and gestational diabetes –> how would you go about identifying T1DM as the diagnosis
- Age –> often childhood/adolescence
- Clinical presentation –> classic triad or DKA
- Ketosis –> often present (may develop DKA which is life-threatening)
- Family hx –> 10% have relatives with T1DM/autoimmune conditions
- Autoantibodies –> presence of autoantibodies to islet cells, insulin, islet antigens (IA2 and IA2-beta), GAD, or the zinc transporter ZnT8 indicate autoimmune beta-cell destruction and are suggestive of T1DM (absence doesn’t rule out T1DM however)
- C-peptide –> low or undetectable (reflects endogenous insulin production)
Differentials for T1DM + temporary hyperglycaemia
- T2DM –> strong association with obesity, CVD risk factors, and family hx of T2DM + slower onset and older age + negative for autoantibodies
- Gestational diabetes –> onset during pregnancy, generally resolves after birth
- Maturity onset diabetes of the young (MODY) –> monogenic diabetes caused by mutations in an autosominal dominant gene + strong family hx + often absence of autoantibodies
- Latent autoimmune diabetes in adults (LADA) –> form of T1DM, positive for autoantibodies, low C-peptide, BUT presents in adults + slower onset
- Drug-induced diabetes –> hx of prolonged courses of drugs (eg. corticosteroids, tacrolismus, L-asparaginase, or antipsychotics)
.
Causes of temporary hyperglycaemia: - Critical illness (eg. sepsis)
- Drugs
- Neonatal hyperglycaemia
T1DM management
T1DM involves an MDT approach:
- HbA1c –> monitored every 3-6 months (target of <48 mmol/mol)
- Self-monitoring of blood glucose –> test at least 4 times a day (including before each meal and before bed)
- Blood glucose targets –> 5-7mmol/L on waking AND 4-7 mmol/L before meals at other times of the day
- Insulin administration (basal-bolus regimen) –> twice-daily insulin detemir or once daily insulin glargine AND rapid-acting insulin analogues injected before meals
(NICE recommend adding metformin if BMI > 25 kg/m²)
T1DM complications –> acute and chronic
Acute:
- Diabetic ketoacidosis (DKA) –> life-threatening, characterised by hyperglycaemia, ketosis, and metabolic acidosis (symptoms include polyuria, polydipsia, nausea, vomiting, abdo pain, and altered mental state)
- Hypoglycaemia –> can occur due to imbalance of insulin administration (too much insulin +/- carb intake and physical activity) –> presents with sweating, tremors, tachycardia, confusion, and maybe loc
.
Chronic:
- Nephropathy –> diabetes is leading cause of end-stage renal disease, usually develops after 10-20yrs, early detection via microalbuminuria screening is vital
- Retinopathy –> non-proliferative retinopathy may progress to proliferative retinopathy characterised by neovascularisation leading to vitreous haemorrhage or retinal detachment
- Neuropathy (peripheral neuropathy) –> tingling, numbness, or burning sensation –> autonomic neuropathy affects cardiovascular, gastrointestinal and genitourinary systems causing postural hypotension, gastroparesis or erectile dysfunction respectively
- CVD –> T1DM increases the risk of coronary artery disease, peripheral arterial disease and stroke. (cardiovascular complications are a major cause of morbidity and mortality in these patients)
(The management of these complications involves optimal glycaemic control, regular screening and early intervention to prevent progression and minimise impact on patient’s quality of life)
Summary of type 2 diabetes (T2DM)
- T2DM is a chronic metabolic disorder characterised by insulin resistance and impaired insulin secretion, leading to hyperglycemia
- The aetiology of T2DM is multifactorial (genetic and environmental) –> obesity, sedentary lifestyle, and poor diet + age, ethnicity, and smoking
- T2DM is associated with microvascular and macrovascular complications, along with diabetic foot, infections, and hyperglycemia emergencies
- Management involves blood glucose control, risk factor modification, and prevention of complications through regular screening and appropriate interventions
Aetiology of T2DM
Genetic factors:
- There is a strong genetic predisposition to T2DM –> exact details are not known
.
Environmental factors:
- Obesity (particularly visceral adiposity) –> excess adipose tissue leads to increased release of pro-inflammatory cytokines and free fatty acids, which contribute to insulin resistance
- Physical inactivity –> promotes obesity, impairs glucose uptake in skeletal muscle, and reduces insulin sensitivity
- Diet –> high caloric intake, particularly from refined carbs and saturated fats
- Age and ethnicity –> > 45yrs + black/hispanic/asians
- Other factors –> smoking, sleep disorders, and a hx of gestational diabetes or PCOS
What diet should be recommended to pts with T2DM?
Diets rich in fibre, whole grains, and unsaturated fats have been shown to reduce the risk of T2DM by improving insulin sensitivity and glucose metabolism
T2DM pathophysiology
- characterised by insulin resistance and β-cell dysfunction
1. Initial phase (insulin resistance) - diminished ability of cells in the liver, muscle tissue, and adipose tissue to respond to the action of insulin –> this leads to an increased demand for insulin production by pancreatic β-cells
2. In response to this increased demand, β-cells proliferate and increase insulin output –> this compensatory phase is marked by hyperinsulinemia but normoglycaemia as blood glucose levels are maintained within normal limits
3. However, over time and with persistent exposure to high levels of glucose and lipids (glucolipotoxicity), β-cell function deteriorates
4. The deterioration in β-cell function coupled with continued insulin resistance leads to a relative deficiency in the amount of functional insulin that can be produced –> this results in a failure to maintain normoglycaemia, leading to the onset of hyperglycaemia and the clinical manifestation of T2DM
(once hyperglycaemia is established, it further exacerbates insulin resistance and β-cell dysfunction through glucotoxicity - vicous cycle)
How is T2DM usually diagnosed?
T2DM is a silent disease and tends to be diagnosed on screening or routine investigations (asymptomatic)
- Some patients will present with symptoms (polyuria, polydipsia) and 25% of pts will already have microvascular complications at time of diagnosis (nephropathy, neuropathy, retinopathy)
Diagnosis criteria for T2DM + criteria for impaired fasting glucose (IFG)/impaired glucose tolerance (IGT)
- Random glucose OR oral glucose tolerance test (2hrs post 75g glucose load) –> >11.1 mmol/L
- In asymptomatic pts –> need to repeat test to confirm diagnosis
- Note: HbA1c may not be accurate if pt has increased red cell turnover condition
. - Impaired fasting glucose (IFG) –> fasting plasma glucose of 6.1-7 mmol/l
- Diabetes UK say people with IFG should then be offered a OGTT to rule out a diagnosis of diabetes –> OGTT value of 7.8-11.1 mmol/l + fasting plasma glucose < 7 mmol/l is defined as impaired glucose tolerance (IGT)
Maturity-Onset Diabetes of the Young (MODY) is a key differential for T2DM –> what is MODY
- MODY = a monogenic form of diabetes that is often misdiagnosed as T2DM
- MODY is characterised by an autosomal dominant inheritance pattern and typically presents before 25yrs of age –> it results from mutations in one of several genes that play a role in beta-cell function
What are the most common genes involved in MODY?
HNF1A, HNF4A, and GCK
What clinical features differentiate a diagnosis of MODY over T2DM?
- Age of onset –> before 25yrs of age
- Family hx –> strong family hx spanning 3 generations
- Phenotype –> pts often lack typical T2DM features (such as obesity and metabolic syndrome)
- C-peptide levels –> normal or elevated (indicating preserved beta-cell function)
- Antibody testing –> absence of diabetes-related autoantibodies (eg. GAD, IA2, and ZnT8)
(Note: if still suspicious of MODY then perform genetic testing –> HNF1A, HNF4A, and GCK)
Conservative management for T2DM (lifestyle)
- Diet –> encourage high fibre, low glycaemic index sources of carbohydrates + low-fat dairy products and oily fish + control intake of saturated fats and trans fatty acids
- Weight loss –> aim for 5-10% initial weight loss
HbA1c targets for T2DM patients –> how often should they be checked
- HbA1c should be checked every 3-6 months until stable, then 6 monthly
First-line management of type 2 diabetes mellitus (T2DM)
- metformin should be titrated up slowly to avoid risk of GI upset
- basically if pt has any CVD condition then give an SGLT-2 inhibitor in addition to metformin (eg. dapagliflozin)
- DPP-4 inhibitor –> eg. sitagliptin
T2DM scenario –> first-line management (eg. metformin +/- SGLT-2-inhibitor) has not worked to control HbA1c levels (HbA1c is now > 58 mmol/l), what is the further management?
- GLP-1 mimetics mimic the action of the GLP-1 hormone to treat type 2 diabetes and obesity –> give if BMI > 35 g/m2
- insulin-based treatment –> human NPH insulin (isophane, intermediate-acting) taken at bed-time or twice daily according to need
T2DM pt management example –> you review an established type 2 diabetic on maximum dose metformin. Her HbA1c is 55 mmol/mol (7.2%)
Do you add another drug?
You do not add another drug as she has not reached the threshold of 58 mmol/mol (7.5%)
T2DM patients –> what is the management of risk factor modification?
- Hypertension –> ACE-inhibitors (eg. ramipril) (or ARB (eg. losartan) if black African) are first-line
(Note: BP targets are same as normal –> see image) - Antiplatelets –> only offer if pt has existing CVD
- Lipids –> offer a statin if Q-risk > 10% (atorvastatin 20mg)
T2DM complications –> Microvascular complications
- Diabetic retinopathy –> characterised by damage to the retinal vasculature, leading to microaneurysms, hemorrhages, and neovascularization
- Diabetic nephropathy –> common cause of chronic kidney disease and end-stage renal disease, it is characterised by albuminuria, declining glomerular filtration rate (GFR), and eventually renal failure
- Diabetic neuropathy –> peripheral neuropathy is most common form (pain/numbness/tingling in extremities –> increasing risk of foot ulcers and amputations), autonomic neuropathy affects autonomic NS leading to GI, cardiovascular, and genitourinary dysfunction
T2DM complications –> macrovascular complications
- Coronary artery disease (CAD) / MI / heart failure
- Cerebrovascular disease (stroke / TIAs)
- Peripheral arterial disease (PAD)
T2DM complications –> apart from microvascular and macrovascular complications, what other complications can occur?
- Diabetic foot –> arise from a combination of neuropathy, PAD, and impaired wound healing –> can result in foot ulcers, infections, and ultimately amputations
- Infections –> T2DM pts are more susceptible to infections due to immune dysfunction, impaired wound healing, and increased colonisation of pathogens –> common infections include UTIs, skin and soft tissue infections, and respiratory infections
- Hyperglycaemic emergencies –> HHS is more common than DKA in T2DM pts
Summary of diabetic ketoacidosis (DKA)
- DKA is a serious and potentially life-threatening complication of diabetes mellitus, characterised by hyperglycaemia, ketosis, and metabolic acidosis
- It is more common in pts with T1DM
- DKA results from an absolute or relative deficiency of insulin, leading to increased hepatic glucose production, decreased peripheral glucose utilisation, and enhanced lipolysis with subsequent ketone body formation
- Prompt recognition, diagnosis, and treatment are crucial to prevent complications and improve patient outcomes
Aetiology of diabetic ketoacidosis (DKA)
Risk factors:
- Insulin deficiency –> inadequate insulin therapy or poor compliance with insulin treatment is the most common precipitating factor for DKA –> this may be due to financial constraints (socially deprived), fear of hypoglycaemia, or psychological issues (eg. depression, eating disorders)
- Infection –> acute infections can increase insulin requirements by inducing a state of physiological stress –> common infections include pneumonia (Strep. pneumoniae) and UTIs (E.coli)
- New-onset diabetes –> DKA may be the first presentation of T1DM
- Certain medications –> eg. glucocorticoids, thiazide diuretics, atypical antipsychotics, and SGLT2 inhibitors can increase the risk of DKA by raising blood glucose levels or decreasing insulin sensitivity
DKA is a severe metabolic disorder resulting from insulin deficiency, typically in the context of T1DM, the pathogenesis of DKA is complex and multifactorial, involving several interrelated processes.
Name some of these processes
- Insulin deficiency and hyperglycaemia
- Gluconeogenesis and Glycogenolysis
- Osmotic diuresis
- Lipolysis and Ketoacidosis
- Ketonuria
- Respiratory compensation
- Electrolyte imbalances
Explain the pathophysiology behind the hyperglycaemia that occurs in DKA
- Insulin deficiency and hyperglycaemia –> DKA begins with a severe deficiency of insulin, leading to decreased glucose uptake by peripheral tissues –> this results in hyperglycaemia as glucose remains in the bloodstream instead of being transported into cells for energy use
- Gluconeogenesis and Glycogenolysis –> the lack of insulin triggers hepatic gluconeogenesis and glycogenolysis, further contributing to the elevated blood glucose levels (simultaneously, reduced inhibition of glucagon release leads to enhanced gluconeogenesis and glycogen breakdown)
Explain the pathophysiology behind the metabolic acidosis (low blood pH) or ‘ketoacidosis’ that occurs in DKA
- Lipolysis and Ketoacidosis –> in response to cellular starvation caused by a lack of glucose utilisation, lipolysis occurs in adipose tissue releasing free fatty acids (FFAs) –> these FFAs are converted into ketone bodies (acetoacetate, beta-hydroxybutyrate, and acetone) in the liver through a process called ketogenesis –> in high concentrations, these ketone bodies decrease the blood pH leading to metabolic acidosis (hence the name ‘ketoacidosis’)
- Ketonuria –> ketone bodies are also excreted in the urine (ketonuria), which can further exacerbate dehydration and electrolyte imbalances –> the presence of ketones in urine is a key diagnostic feature of DKA
Why is there a risk blood volume depletion, hypotension, and renal impairment in a pt with DKA? (pathophysiology)
- Osmotic diuresis –> the resultant hyperglycemia causes osmotic diuresis as glucose is excreted in the urine along with water and electrolytes such as sodium and potassium –> this can lead to volume depletion, hypotension, and renal impairment if not promptly managed
What is Kussmaul breathing?
- Kussmaul breathing = rapid, deep respirations characteristic of severe DKA
- Respiratory compensation can occur in DKA –> in response to the metabolic acidosis, hyperventilation occurs as part of the body’s compensatory mechanism to decrease CO2 lvls and increase blood pH –> leading to Kussmaul breathing
Why might cardiac arrhythmias occur in a pt with DKA?
Due to electrolyte imbalances –> due to combination of osmotic diuresis and acid-base disturbance leads to significant electrolyte imbalances –> particularly hyponatraemia and hypokalemia (can cause cardiac arrhythmias)
What is the typical triad seen in DKA and what are the main clinical features of DKA?
- Hyperglycaemia, ketosis, and metabolic acidosis
. - Polyuria, polydipsia, and profound weakness, with notable signs including Kussmaul breathing, dehydration, and a distinct acetone odour on the breath
A blood pH of less than what value with a bicarbonate level below what value typically indicates metabolic acidosis?
- A blood pH of less than 7.3 with a bicarbonate level below 15 mmol/L typically indicates metabolic acidosis
–> patients exhibit deep, rapid (Kussmaul) breathing as a compensatory mechanism to expel excess carbon dioxide
What causes the characteristic acetone odour on the breath in a pt with DKA?
- Due to insulin deficiency, there is increased lipolysis, leading to the production of ketone bodies, which are acidic
- Ketosis presents with a characteristic sweet, fruity, or acetone odour on the breath
First-line investigations for suspected DKA
- Blood-glucose (point of care finger prick sample) –> >11.1 mmol/L is a key diagnostic criterion for DKA
- Ketones –> presence of ketones in blood (> 3 mmol/L) or urine (+2 or more on dipstick) confirms diagnosis
(note: blood ketone testing is preferred over urine due to its greater sensitivity and specificity) - Venous blood gas (VBG) –> this will reveal metabolic acidosis (expect to find a low bicarbonate and low pH (< 7.3)
- U&Es –> to assess renal function and identify any electrolyte imbalances that may need correction (particularly potassium levels)
DKA diagnostic criteria
- Blood glucose > 11 mmol/L or known diabetes mellitus
- pH < 7.3
- Bicarbonate < 15 mmol/L
- Ketones > 3 mmol/l or urine ketones ++ on dipstick
Give 3 differentials for DKA
- HHS –> typically presents in pts with T2DM + usually more severe hyperglycaemia (> 33.3) + no ketonaemia or metabolic acidosis + pts will often have neuro signs
- Alcoholic ketoacidosis (AKA) –> usually a hx of heavy drinking followed by poor oral intake + blood glucose lvls will be normal + often a concomitant metabolic alkalosis due to vomiting
- Lactic acidosis –> can occur in diabetes patients due to biguanide use (eg. metformin), but also from critical illness or sepsis + both have high anion gap metabolic acidosis but lactic acidosis has no ketonaemia or glycosuria + elevated lactate lvls
Diabetic ketoacidosis (DKA) management
- Fluid replacement –> IV fluids (isotonic saline)
- IV insulin infusion
- Correction of electrolyte disturbance –> serum potassium often high on admission, this often falls following insulin treatment resulting in hypokalemia –> potassium may need to be added to fluids (potentially need cardiac monitoring)
- Long-acting insulin should be continued, short-acting insulin should be stopped
(note: slower infusion indicated in young adults (18-25 yrs) due to risk of cerebral oedema)
When should a pt in DKA be discharged?
DKA resolution:
- pH > 7.3
- blood ketones < 0.6 mmol/L
- bicarbonate > 15.0 mmol/L
.
- Both the ketonaemia and acidosis should have been resolved within 24 hrs –> if not then need senior endocrinologist
- If pt is eating and drinking –> switch them back to subcutaneous insulin
- The patient should be reviewed by specialist nurse prior to discharge
What is HHS (hyperosmolar hyperglycaemic state)?
- HHS is a severe complication of diabetes mellitus, predominantly T2DM, characterised by extreme hyperglycaemia and hyperosmolarity without significant ketosis
Pathophysiology of HHS
- Insulin deficiency and increased counter-regulatory hormones, leading to excessive hepatic glucose production and impaired renal excretion –> this results in elevated serum osmolality and triggers a shift of water from intracellular to extracellular space, causing cellular dehydration
- Hyperglycaemia results in osmotic diuresis with associated loss of sodium and potassium
- Severe volume depletion results in a significant raised serum osmolarity –> resulting in hyperviscosity of blood
Clinical features of HHS
- It typically presents with polyuria, polydipsia and profound dehydration due to osmotic diuresis
- Neurological symptoms may also be present, ranging from lethargy to seizures or coma
3 things needed for diagnosis of HHS
A precise definition of HHS does not exist so use this as a guide to help differentiate from DKA:
1. Hypovolaemia
2. Marked Hyperglycaemia (>30 mmol/L) without significant ketonaemia or acidosis
3. Significantly raised serum osmolarity (> 320 mosmol/kg)
How does HHS differ from DKA in terms of onset
- DKA presents within hrs of onset, HHS comes on over many days –> consequently the dehydration and metabolic disturbances are more extreme
HHS management
- Management includes aggressive fluid replacement, correction of electrolyte imbalances particularly potassium, and cautious insulin therapy
- Concurrent illnesses often precipitate HHS –> hence identification and treatment of underlying conditions are integral parts of management.
- HHS carries a high mortality rate; therefore vigilant monitoring for complications such as thromboembolic events, AKI or cerebral oedema is essential during treatment
Aetiology of hypoglycaemia
- Excess levels of insulin causes hypoglycaemia –> most commonly this is from exogenous, injectable insulin used in the management of T1DM/T2DM –> ie. pt has injected too much insulin OR has used the same amount of insulin whilst not eating enough/skipping a meal
- Sulfonylureas (eg. gliclazide) act by increasing the secretion of insulin from β-cells –> hypoglycaemia is a common adverse effect (esp. when starting this medication)
- Hypoglycaemia more likely to occur in diabetics who have a viral illness, have drunk alcohol, or exercised more than usual
. - Non-diabetic causes –> alcohol consumption is the most common non-iatrogenic cause of hypoglycaemia –> due to its inhibitory effects on gluconeogenesis and glycogenolysis
- Rare cause –> insulinoma (neuroendocrine tumour of pancreas) which causes unregulated secretion of insulin
Which part of the body is most sensitive to low glucose lvls (hypoglycaemia)?
The brain is particularly sensitive to low glucose levels as it relies heavily on glucose for energy
Hypoglycaemia triggers a cascade of hormonal responses –> what are these/how does the body respond to low blood glucose lvls? (pathophysiology)
The initial response to declining blood glucose involves the autonomic nervous system and counter-regulatory hormones.
- As glucose levels drop, the pancreas reduces insulin secretion
- Concurrently, there is an increase in glucagon release from pancreatic alpha cells –> glucagon promotes glycogenolysis and gluconeogenesis in the liver, elevating plasma glucose concentrations
.
- Adrenaline (epinephrine) is also released from the adrenal medulla, stimulating hepatic glycogenolysis and inhibiting insulin release further
- This hormone additionally activates lipolysis in adipose tissue, providing free fatty acids as an alternative energy source for peripheral tissues, thereby sparing glucose for cerebral use
.
- Cortisol and growth hormone are secreted in response to prolonged hypoglycaemia –> cortisol enhances gluconeogenesis and decreases peripheral utilisation of glucose by antagonising insulin action at target tissues
- Growth hormone similarly supports gluconeogenesis while promoting lipolysis
Clinical features of hypoglycaemia (triad of symptoms)
- Autonomic symptoms –> sweating (due to increased sympathetic stimulation), tachycardia (due to adrenaline release), pallor (due to vasoconstriction caused by sympathetic activation), tremors, and hunger (polyphagia)
- Neuroglycopenic symptoms –> cognitive impairment (due to reduced cerebral glucose supply), dizziness and weakness (due to lack of glucose within nervous system), vision changes (impaired function of neurons in retina and optic nerve), mood changes, and seizures (due to brain’s increased excitability from lack of glucose)
- Non-specific symptoms –> fatigue, nausea, paresthesias
(note: presentation can vary widely)
Diagnosis of hypoglycaemia –> Whipple’s triad
- Symptoms or signs of hypoglycaemia
- Low blood glucose
- Resolution of symptoms with the correction of blood glucose
Hypoglycaemia differentials
- Stroke/TIA
- MI
- Sepsis –> altered mental status may be the only presenting feature of sepsis
- Epilepsy
Hypoglycaemia management –> community + hospital-setting
Management in community:
- oral glucose (10-20g) should be given –> eg. sweets or liquid form (not chocolate!)
- OR a quick-acting carbohydrate may be given –> GlucoGel or Dextrogel
- OR a ‘HypoKit’ may be prescribed –> contains syringe and vial of glucagon for IM or SC injection at home
.
Management in hospital setting:
- If pt alert –> quick-acting carbohydrate can be given in the form of a glucose gel on the buccal mucosa
- If pt unconscious or unable to swallow –> subcut or IM injection of glucagon may be given
- OR IV 20% glucose solution given IV
Note: once blood glucose back to normal –> pt should consume slower-acting carbohydrates (eg. toast or biscuits) to prevent lvls from dropping again
What is a long-term consequence of recurrent episodes of hypoglycaemia?
- Recurrent episodes of hypoglycaemia lead to ‘hypoglycaemic unawareness’ where patients do not develop autonomic symptoms of low blood glucose –> this is more frequent in type II diabetes and increases the chance of neuroglycopenic complications of hypoglycaemia
What is gestational diabetes?
- refers to diabetes triggered by pregnancy –> it is caused by reduced insulin sensitivity during pregnancy, and resolves after birth
- after birth, women are at a higher risk fo developing T2DM
The most significant immediate complication of gestational diabetes is a large for dates fetus and macrosomia, what does this pose a risk for during birth?
Shoulder dystocia
When should any woman with risk factors for diabetes be screened?
- Anyone with risk factors should be screened with an oral glucose tolerance test at 24 – 28 weeks gestation
- Women with previous gestational diabetes also have an OGTT soon after the booking clinic
Risk factors for gestational diabetes
- Previous gestational diabetes
- Previous macrosomic baby (≥ 4.5kg)
- BMI > 30
- Ethnic origin (black Caribbean, Middle Eastern and South Asian)
- Family hx of diabetes (first-degree relative)
Normal results for oral glucose tolerance test (OGTT) –> gestational diabetes
- Fasting –> < 5.6 mmol/l
- At 2 hrs –> < 7.8 mmol/l
(results higher than these are used to diagnose gestational diabetes)
Management of gestational diabetes
- 4 weekly USS scans to monitor the fetal growth and amniotic fluid volume form 28 to 36 weeks gestation
.
Initial management: - Fasting glucose < 7 mmol/l –> trial of diet and exercise for 1-2 weeks, followed by metformin, then insulin
- Fasting glucose > 7 mmol/l –> start insulin +/- metformin
- Fasting glucose > 6 mmol/l + macrosomia (or other complications) –> start insulin +/- metformin
(Glibenclamide (a sulfonylurea) is suggested as an option for women who decline insulin or cannot tolerate metformin)
Gestational diabetes –> NICE guidelines for target blood sugar levels
- Fasting
- 1 hr post-meal
- 2 hrs post-meal
- in general
- Fasting –> 5.3 mmol/l
- 1 hr post-meal –> 7.8 mmol/l
- 2 hrs post-meal –> 6.4 mmol/l
- in general –> avoiding levels of 4 mmol/l or below
What medication should a pregnant woman with pre-existing diabetes take from preconception until 12 weeks gestation?
Folic acid 5mg –> to reduce risk of neural tube defects and other developmental complications
How are women with T2DM managed during pregnancy (ie. what changes about their management?)
- managed using metformin and insulin only –> other diabetic medications should be stopped
What screening should be done for women with pre-existing diabetes (performed shortly after booking + at 28 weeks gestation)?
Retinopathy screening
Gestational diabetes will resolve after birth –> when should a fasting glucose be measured?
after at least 6 weeks
What is the main risk for babies of mothers with diabetes?
- Neonatal hypoglycaemia –> baby becomes accustomed to a large supply of glucose during pregnancy, and after birth they struggle to maintain the supply they are used to with oral feeding alone
- needs close monitoring (aim to keep blood glucose > 2 mmol/l) –> if falls then give IV dextrose by nasogastric feeding
Give a summary of hypothyroidism
- Hypothyroidism is a common endocrine disorder characterized by decreased thyroid hormone production
- It affects approximately 5% of the population, with women being more commonly affected than men
- The most common cause of hypothyroidism is autoimmune thyroiditis, also known as Hashimoto’s thyroiditis –> other causes include iodine deficiency, thyroid surgery, and radiation therapy
- Symptoms of hypothyroidism can be subtle and nonspecific, including fatigue, weight gain, constipation, and cold intolerance
- Diagnosis is made through measurement of thyroid-stimulating hormone (TSH) and free thyroxine (T4) levels
- Treatment involves replacement of thyroid hormone with levothyroxine, with regular monitoring of TSH levels to ensure adequate dosing
Aetiology of hypothyroidism –> primary / secondary / tertiary
Primary hypothyroidism:
- Hashimoto’s thyroiditis (autoimmune thyroiditis) –> most common cause of hypothyroidism –> body produces antibodies that attack the thyroid gland, resulting in inflammation and impaired thryoid hormone production
- Iodine deficiency (more common in developing world) –> iodine is essential for the synthesis of thyroid hormones
- Surgical removal OR Radioactive iodine treatment –> these treatments for hyperthyroidism or thyroid cancer often result in hypothyroidism due to reduction or removal of functional thyroid tissue
.
Secondary hypothyroidism:
- Pituitary disorders such as pituitary adenomas or hypopituitarism can lead to reduced production of thyrotropin-releasing hormone (TRH) –> leading to decreased stimulation of the thyroid gland and subsequent hypothyroidism
.
Tertiary hypothyroidism:
- Hypothalamic disease can result in diminished secretion of TRH, leading to reduced stimulation of the pituitary gland and subsequently lowered release of thyroid-stimulating hormone (TSH)
Risk factors for developing hypothyroidism
- Female sex
- Age –> > 60yrs
- Family hx
- Certain medications –> lithium and amiodarone
- Radiation exposure –> head or neck
Describe thyroid hormone synthesis and secretion (pathophysiology)
- The synthesis and secretion of thyroid hormones are primarily regulated by the hypothalamic-pituitary-thyroid (HPT) axis
- In response to low circulating levels of thyroid hormones, thyrotropin-releasing hormone (TRH) is secreted from the hypothalamus –> this stimulates the anterior pituitary gland to release thyroid-stimulating hormone (TSH)
- TSH then binds to receptors on the surface of thyroid follicular cells, stimulating endocytosis of thyroglobulin from the colloid, proteolysis and subsequent release of triiodothyronine (T3) and thyroxine (T4).
Describe the role of iodine in thyroid hormone synthesis (T3 and T4)
Iodide uptake into the follicular cells from plasma is an essential step for thyroid hormone synthesis. The sodium-iodide symporter (NIS), located on the basolateral membrane, mediates this process.
Once inside the cell, iodide is transported to the apical membrane where it undergoes oxidation to iodine via thyroid peroxidase enzyme. Iodination of tyrosyl residues within thyroglobulin forms monoiodotyrosine (MIT) and diiodotyrosine (DIT). Coupling reactions between MIT and DIT yield T3 and T4.
What is the stereotypical presentation of hypothyroidism?
- Middle-aged woman who presents with fatigue, weight gain, cold intolerance, and constipation
- Other symptoms –> MSK, neuro (eg. cognitive impairment), skin (dry skin, hair loss), CVD (bradycardia is common finding), reproductive (menstrual irregularities and infertility, decreased libido and erectile dysfunction)
(note: there are many ways that hypothyroidism can present as it affects multiple systems)
First-line investigations for hypothyroidism
- Serum Thyroid-Stimulating Hormone (TSH) Test –> an elevated TSH level typically indicates primary hypothyroidism, due to decreased thyroid hormone production resulting in increased pituitary TSH secretion
- Serum Free Thyroxine (FT4) Test –> if TSH levels are abnormal, this test should be performed next –> a low FT4 level alongside high TSH confirms primary hypothyroidism
–> Normal FT4 with high TSH indicates subclinical hypothyroidism
What further investigations can be done to confirm a diagnosis of hypothyroidism with an autoimmune cause (Hashimoto’s thyroiditis)?
- Serum Thyroglobulin (Tg) and Anti-Thyroglobulin Antibody (TgAb) Tests –> elevated lvls suggest Hashimoto’s thyroiditis
Differentials for hypothyroidism –> 3 conditions that might present similarly
- Pituitary adenoma (eg. prolactinoma) –> similar symptoms, but often presents with galactorrhoea (milk production) and menstrual irregularities in females or reduced libido and infertility in males + may cause secondary hypothyroidism (serum TSH lvls low/normal despite low free thyroxine (T4) lvls)
- Cushing’s syndrome –> similar symptoms, but will often presents with moon face, supraclavicular fat pads, and striae + lab findings will differ (eg. high cortisol)
- Myxedema coma –> life-threatening form of hypothyroidism characterised by altered mental status (confusion/coma) and hypothermia, but other symptoms are similar + lab findings will show profound hypothyroidism with very low T4 lvls and significantly elevated TSH lvls
Management of hypothyroidism (include alteration of dose for pregnant women)
- Levothyroxine –> titrate up as necessary
- thryoid function tests should be checked every 8-12 weeks
- TSH lvl targets –> between 0.5-2.5 mU/l
- women with established hypothyroidism who become pregnant should have their dose increased by at least 25-50 micrograms due to increased demands of pregannay
Side effects of thyroxine therapy (levothyroxine)
- hyperthyroidism –> due to over-treatment
- reduced bone mineral density
- worsening of angina
- atrial fibrillation
Interactions of levothyroxine –> what mineral reduces absorption of levothyroxine
iron –> absorption of levothyroxine reduced, give at least 2 hours apart
The complications of hypothyroidism can be severe and varied, often manifesting in cardiovascular, neuropsychiatric, gastrointestinal, musculoskeletal and reproductive systems. Please give details of complications for each system.
- cardiovascular –> can lead to increased LDL cholesterol, causing atherosclerosis and subsequent CAD
- neuropsychiatric –> depression is common due to increased metabolic activity in the brain + cognitive impairment (eg. memory loss or decreased concentration) + myxedema coma (life-threatening condition causing slowing of function in multiple organs)
- gastrointestinal –> can slow down gut motility leading to constipation
- musculoskeletal –> adhesive capsulitis, carpal tunnel syndrome, and myopathy, presenting as muscle weakness and cramps
- reproductive systems –> menstrual irregularities (menorrhagia) + infertility + pregnancy problems (miscarriage, pre-eclampsia, placental abruption, and postpartum haemorrhage)
What is PCOS (polycystic ovarian syndrome)?
- PCOS is a complex condition of ovarian dysfunction thought to affect between 5-20% of women of reporductive age
- The aetiology is not fully understood
- Both hyperinsulinemia and high levels of LH are seen in PCOS
Clinical features of PCOS
- subfertility and infertility
- menstrual disturbances –> oligomenorrhea and amenorrhoea
- hirsutism + acne –> due to hyperandrogenism
- obesity
- acanthosis nigricans –> due to insulin resistance (see image)
PCOS investigations
- pelvic ultrasound –> multiple cysts on the ovaries
- FSH, LH, prolactin, TSH, and testosterone are useful investigations –> raised LH:FSH ratio is a ‘classical’ feature but is no longer thought to be useful in diagnosis. Prolactin may be normal or mildly elevated. Testosterone may be normal or mildly elevated - however, if markedly raised consider other causes
- check for impaired glucose tolerance
PCOS diagnosis –> Rotterdam criteria
Two out of three of the following criteria are required to make the diagnosis:
- Oligo- and/or anovulation –> ie. oligo- or amenorrhoea
- Clinical and/or biochemical signs of hyperandrogenism –> e.g. hirsutism, acne, or elevated levels of total or free testosterone
- Polycystic ovaries (by ultrasound) –> defined as the presence of 12 or more follicles (measuring 2-9 mm in diameter) in one or both ovaries and/or increased ovarian volume (greater than 10 cm3)
PCOS management
General:
- weight reduction if appropriate
- if a woman requires contraception then combined oral contraceptive (COC) pill may help regulate her cycle and induce a monthly bleed
.
Hirsutism:
- COC pill (3rd gen) OR co-cyprindiol (anti-androgen action)
- if no response to COC –> try topical eflornithine
- spironolactone, flutamide, and finasteride may be used under specialist supervision
.
Acne:
- COC pill (co-cyprindiol has the best anti-androgen effects) –> however, there is a risk of VTE
- Other standard treatments for acne –> topical adapalene (retinoid), topical antibx (eg. clindamycin 1% with benzoyl peroxide 5%), topical azelaic acid 20%, and oral tetracycline antibx (eg. lymecycline)
.
Infertility:
- weight loss is first step
- specialist –> clomifene, laparoscopic ovarian drilling, IVF
- metformin and letrozole may also help restore ovulation
Why do thyroglossal cysts rise during tongue protrusion?
Because the tongue is attached to the thyroglossal duct
Causes of hyperthyroidism
G - Grave’s disease (most common cause)
I - Inflammation (thyroiditis)
S - Solitary toxic thyroid nodule
T - Toxic mulitnodular goitre
.
Others:
- postnatal thyroiditis –> transient in nature, usually followed by a transient hypothyroid period
Hyperthyroidism VS Thyrotoxicosis
- Hyperthyroidism –> high lvls of thyroid hormones (overproduction of T3 and T4 by the thyroid gland)
- Thyrotoxicosis –> refers to the clinical syndrome of hyperthyroidism
Ie. A pt can present with thyrotoxicosis but not have hyperthyroidism
Primary hyperthyroidism VS Secondary hyperthyroidism VS Subclinical hyperthyroidism
- Primary hyperthyroidism –> due to thyroid pathology (thyroid is producing excessive thyroid hormone)
- Secondary hyperthyroidism –> due to pathology of hypothalamus or pituitary (pituitary gland produces too much TSH, stimulating the thyroid gland to produce excessive thyroid hormones
- Subclinical hyperthyroidism –> T3 and T4 are normal, TSH is suppressed (low) - there may be mild or absent symptoms
Grave’s disease - Summary
- Grave’s disease is an autoimmune condition resulting in the overproduction of thyroid hormones (T3 and T4)
- This is due to the formation of antibodies to TSH, it is the most common cause of hyperthyroidism in developed countries
- About 30% of pts with Grave’s disease will display extrathyroidal manifestations –> orbitopathy, acropachy, and pretibial myxoedema (these only occur with Grave’s and not other forms of hyperthyroidism)
Grave’s disease is associated with other autoimmune diseases, name some
- T1DM
- Addison’s disease
- Pernicious anaemia
Grave’s disease –> pathophysiology
- autoimmune thyroid disease in which the body produces IgG antibodies to the thyroid-stimulating hormone (TSH) receptor
- These antibodies bind to TSH receptors found on thyroid follicular cells within the thyroid gland, causing chronic stimulation –> hence, this is a type II hypersensitivity reaction
.
The follicular cells are responsible for the production of thyroid hormone –> therefore, this hyperstimulation results in: - Excessive production of thyroid hormone (T3 and T4)
- Hypertrophy of the thyroid gland
- Hyperplasia of thyroid follicular cells
- Subsequent signs and symptoms of hyperthyroidism and the presence of a goitre
General signs and symptoms of hyperthyroidism + specific symptoms associated with Grave’s disease
General hyperthyroidism signs and symptoms:
Metabolic:
- Heat intolerance: due to increased metabolism leading to higher body temperature.
- Weight loss: caused by higher metabolic rate and accelerated metabolism.
- Increased appetite: in 90% this is in the absence of weight gain.
- Excessive sweating: must be differentiated from ‘hot flushes’ due to oestrogen deficiency in post-menopausal women.
Cardiac:
- Palpitations: this includes atrial fibrillation (20%) or other supraventricular tachycardias, especially in older patients.
- Tachycardia
- Atrial fibrillation: a cause of palpitations, especially in older patients.
- Hypertension
- Heart failure: thyrotoxic cardiomyopathy, especially in the elderly.
Excessive nervous stimulation:
- Anxiety: a feeling of nervousness and trembling.
- Tremor: usually fine.
Other:
- Palpable thyroid: smooth, diffusely and uniformly enlarged thyrotoxic (excess production of thyroid hormone) goitre.
- Oligomenorrhoea
.
Extrathyroidal manifestations specific to Graves’ disease:
- Eye disease (30%): upper eyelid retraction, exophthalmos, ophthalmoplegia, eye pain, tearing, diplopia, photophobia, blurred vision.
- Pretibial myxoedema (3%): waxy, discoloured induration of the skin on the anterior aspect of the lower legs.
- Thyroid acropachy (1%): clubbing of fingers and toes with soft tissue swelling due to sub-periosteal formation of new bone.
Initial investigations for suspected hyperthyroidism
NICE say to test for thyroid dysfunction as step 1, then step 2 is to do further testing for Grave’s disease
.
Step 1 - TFTs
- TSH –> low
- Free thyroxine (fT4) –> high
- Free triiodothyronine (fT3) –> high
Step 2 - specific tests for Grave’s disease
- TSH receptor antibodies (TRAbs) –> present in Grave’s disease (very sensitive and specific test)
- Technetium scan of thyroid gland –> considered if TRAvs are -ve
Scenario: Hyperthyroidism is confirmed in a pt, you palpate a discrete thyroid nodule, what investigations would you do?
Imaging:
- USS –> assess size, vascularity, and presence of nodules
- Radioactive iodine scan –> uneven uptake indicates the presence of a nodule, diffuse and high uptake suggests Grave’s, low uptake suggests thyroiditis
Investigations for thyroid eye disease
- Examine visual fields, acuity, and movements
- MRI or CT scans –> can confirm diagnosis (esp. if subclinical)
Management of Grave’s disease
- First-line definitive treatment –> radioactive iodine
- Beta-blockers (eg. propanolol) –> for rapid control of symptoms (note: symptom control not treatment)
- Anti-thyroid drugs (eg. carbimazole, propylthiouracil) –> 12 to 18 month course –> can do maintenance dose or “block and replace” (high dose which blocks all production and levothyroxine is used to replace)
- Surgery –> total thyroidectomy (if concerns about compression or malignancy, or other treatments are not suitable) - pts become hypothyroid so replacement therapy required (levothyroxine)
Carbimazole side effect you need to look out for + condition which carbimazole and propylthiouracil (anti-thyroid medications) can cause
- Carbimazole –> Acute pancreatitis
- carbimazole and propylthiouracil –> agranulocytosis (dangerously low WBC count –. at risk of infections)
Which nerve is at risk of being damaged in thyroidectomy surgery?
Recurrent laryngeal nerve
What is the emergency hyperthyroidism condition?
Thyroid storm (aka. thyrotoxic crisis)
- sudden and significant rise in thyroid hormone lvls
- results in fever, tachycardia, and delirium
- requires admission –> supportive care (IV fluids, anti-arrhythmic medication, and beta-blockers) + normal thyrotoxicosis treatment
What is subacute (De Quervain’s) thyroiditis + what are the 3 phases?
- a transient episode thought to occur following viral infection (temporary inflammation of the thyroid gland) and typically presents with hyperthyroidism
.
1. Thyrotoxicosis
2. Hypothyroidism
3. Return to normal
In subacute (De Quervain’s) thyroditis, is the thyroid swelling painful and tender or non-tender?
- Very tender –> differs from other thyroid swellings
(if thyroid is tender then likely to be subacute (De Quervain’s) thyroiditis
Subacute (De Quervain’s) thyroiditis –> symptoms/signs of the initial thyrotoxic phase?
- Excessive thyroid hormones
- Thyroid swelling and tenderness
- Flu-like illness (fever, aches and fatigue)
- Raised inflammatory markers (CRP and ESR)
Management of subacute (De Quervain’s) thyroiditis
It is a self-limiting condition, symptomatic relief and inflammation control can be provided:
- Analgesia –> NSAIDs (for pain + inflammation)
- Corticosteroids (eg. prednisolone) –> in more severe cases (or NSAIDs are contraindicated)
- Beta-blockers (eg. propranolol) –> for hyperthyroidism symptoms (palpitations, tremors, anxiety)
- Levothyroxine –> for hypothyroidism symptoms
Toxic multinodular goitre (Plummer’s disease) –> Summary
- a condition where multiple autonomously functioning nodules develop on the thyroid gland, these are unregulated by the thyroid axis and continuously produce excessive thyroid hormones –> resulting in hyperthyroidism
- These nodules are often benign (however, non-functioning thyroid nodules can be malignant)
- Iodine deficiency, head + neck irradiation and age > 50 yrs are risk factors
Clinical features of toxic multinodular goitre (Plummer’s disease)
Pts may present with subclinical hyperthyroidism, accompanied by swelling of the thyroid gland
- Pts can present with hyperthyrodiism symptoms –> hyperphagia, weight loss, heat intolerance, palpitations, anxiety, oligomenorrhoea, or hyperdefecation
- The nodular nature of the goitre helps differentiate it from Grave’s disease which is more diffuse
Excess thyroid hormone results in increased contraction of which muscle of the eyelid, causing lid lag?
levator palpebrae muscle
Management of toxic multinodular goitre (Plummer’s disease)?
- Radioactive iodine (RI) –> 1st-line in non-pregnant adults
- Surgery (thyroidectomy) –> swelling of thyroid gland may obstruct breathing or swallowing which is an indication for surgery (or RI not worked)
. - Beta-blockers (propranolol) –> for symptomatic relief
. - Pregnant women –> MDT approach, commence anti-thyroid medication (carbimazole)
What is a toxic thyroid nodule (adenoma)?
- aka. autonomously functioning thyroid nodules –> solitary hyperfunctioning nodules within the thyroid gland that autonomously produce thyroid hormones, leading to thyrotoxicosis
- The nodules are usually benign adenomas
What is the main risk factor for the development of a toxic thyroid adenoma?
Dietary iodine deficiency
Toxic thyroid adenomas ad Grave’s disease both present with hyperthyroidism symptoms, what is the key differentiating symptom?
Toxic thyroid adenomas don’t present with exopthalmos (extraocular muscle involvement)
- (occurs in 25-30% of Graves’ disease, but not in thyroid adenoma)
Investigations for suspected toxic thyroid nodule (adenoma)
Blood tests:
- TFTs –> TSH will be suppressed (if TSH normal then can rule out adenoma), fT3 and fT4 are elevated
- TSH receptor and TPO antibodies –> to exclude Graves’ disease (will be -ve in adenoma)
- ESR –> to rule out thyroiditis
Imaging:
- Thyroid ultrasound –> 1st-line imaging of any thyroid nodule
- Radioisotope scanning (99mtechnetium or 131iodine) –> shows a’ hot’ nodule which indicates autonomous activity
Why would you do an ECG in a patient with hyperthyroidism?
Hyperthyroidism is associated with atrial fibrillation –> so it is important to identify and anti-coagulate
Differentials for toxic thyroid nodule (adenoma) –> essentially differentials for hyperthyroidism
- Graves’ disease –> diffuse goitre rather than solitary nodule, expothalmos/eyelid retraction/extraocular muscle involvement, autoimmune mediated (+ve for antibodies)
- Toxic multinodular goitre –> large, irregular goitre, usually older pts, radioisotope scan will show hot and cold areas
- Thyroiditis –> usually transient and self-limiting, raised ESR, key risk factor is postnatal women, radioisotope scan shows little/no uptake
- Thyroid cancer –> usually associated cervical lymphadenopathy, ultrasound shows suspicious features (eg. irregular hyperechoic mass)
Management of a toxic thyroid nodule (adenoma)
- Radioactive iodine or surgery for definitive treatment
- Symptomatic relief –> beta-blockers +/- anticoagulation (if pt has AF)
Radioactive iodine –> absolute contraindications and relative contraindications
- Absolute contraindications –> Pregnant or lactating women
- Relative contraindications –> children and adolescent pts
What is the most common type of thyroid cancer?
Papillary carcinoma
How are most thyroid cancers detected?
Most are asymptomatic and are detected incidentally on imaging studies or during physical examination
- most common presenting symptom is a painless thyroid nodule/mass
- associated cervical lymphadenopathy is often present
What is Addison’s disease (aka. primary adrenal insufficiency)
- characterised by inadequate production of cortisol and aldosterone by the adrenal cortex
- autoimmune destruction is the most common cause (80%)
- pts may present with an adrenal crisis which is a life-threatening condition
Primary VS Secondary VS Tertiary adrenal insufficiency
- Primary adrenal insufficiency (Addison’s disease) –> refers to when the adrenal glands have been damaged, resulting in reduced cortisol and aldosterone secretion
- Secondary adrenal insufficiency –> results from inadequate adrenocorticotropic hormone (ACTH) and a lack of stimulation of the adrenal glands (this is the results of loss or damage to the pituitary gland)
- Tertiary adrenal insufficiency –> results from inadequate corticotropin-releasing hormone (CRH) release by the hypothalamus (usually the results of sudden withdrawal of long-term oral steroids and the hypothalamus hasn’t “woke up” fast enough (hypothalamus has been suppressed)
What is the main cause of Addison’s disease (primary adrenal insufficiency)?
Autoimmune adrenalitis –> involves autoimmune destruction of the adrenal cortex
- Other causes –> infections (eg. TB), genetic disorders (CYP21A2 - congenital adrenal hyperplasia), metastatic infiltration
- Adrenal haemorrhage –> can result in acute adrenal insufficiency (trauma, anticoagulation, and sepsis)
- Medications –> eg. prolonged use of glucocorticoids (eg. ketoconazole) can suppress the HPA axis, leading to adrenal atrophy and insufficiency
Addison’s disease (primary adrenal insufficiency) involves the deficiency of what hormones?
Primarily cortisol and aldosterone, but also adrenal androgens:
- Cortisol is crucial for marinating glucose homeostasis, immune function, and stress response –> insufficient cortisol production results in hypoglycaemia, increased susceptibility to infections, and an inadequate response to stressors
- Aldosterone is responsible for regulating sodium and potassium balance –> insufficient aldosterone production leads to hyponatremia, hyperkalemia, and volume depletion (causing orthostatic hypotension and impaired renal function)
- Adrenal androgens are involved in secondary sexual characteristics and libido –> deficiency may result in reduced body hair and reduced libido
Addison’s disease (primary adrenal insufficiency) –> symptoms + 2 main signs
- Symptoms –> fatigue, muscle weakness, muscle cramps, dizziness, thirst and ‘salt-craving’, weight loss
.
Signs: - Bronze hyperpigmentation of the skin –> elevated ACTH lvls result in melanocyte-stimulating hormone (MSH) production
- Hypotension –> particularly postural hypotension - with a drop of more than 20 mmHg on standing
Investigations for a pt with suspected Addison’s disease ?
- ACTH stimulation test (short Synacthen test)
- Biochemistry –> hyponatremia is a key finding (can also get hypoglycaemia, hyperkalemia)
- Autoantibodies –> adrenal cortex antibodies, 21-hydroxylase antibodies
- ACTH can be measured directly –> ACTH lvl high in primary adrenal insufficiency (as pituitary producing lots of ACTH without -ve feedback in absence of cortisol), ACTH lvl low in secondary adrenal failure
- Early morning cortisol (9am) –> has a role but often falsely normal
- Imaging (eg. CT or MRI) –> can be done but not routinely used
- MRI of pituitary –> gives further info on pituitary pathology
Describe the process of the ACTH stimulation test (short Synacthen test).
Test of choice for diagnosis adrenal insufficiency:
- a dose of Synacthen (synthetic ACTH) is given
- blood cortisol is checked before and 30 and 60 mins after the dose
- the synthetic ACTH will stimulate healthy adrenal glands to produce cortisol (cortisol lvl should at least double)
–> a failure to double indicates either primary adrenal insufficiency (Addison’s disease) or very significant adrenal atrophy (after a prolonged absence of ACTH in secondary adrenal insufficiency)
Management of Addison’s disease
- Hydrocortisone (glucocorticoid) –> used to replace cortisol
- Fludrocortisone (mineralocorticoid) –> used to replace aldosterone
. - Pts are given a steroid card, ID tag, and emergency letter to alert emergency services that they depend on steroids for life
- Pt education is important –> sick day rules + importance of not missing glucocorticoid doses
- Pts and close contacts are taught to give IM hydrocortisone in an emergency (Adrenal crisis)
Sick day rules for pts with Addison’s disease (and therefore taking steroids long-term)
Glucocorticoid doses (hydrocortisone) are doubled during an acute illness to match the normal steroid response to illness
- note: fludrocortisone dose stays the same
What is an Adrenal crisis (aka. Addisonian crisis) and what is the management?
- an acute life-threatening condition characterised by severe hypotension, hypoglycaemia, altered mental status, and electrolyte imbalances (hyponatraemia and hyperkalemia)
- may be initial presentation of adrenal insufficiency or triggered by an infection
.
Management: - ABCDE approach
- IV hydrocortisone (100mg followed by infusion)
- IV fluids
- correct hypoglycaemia –> IV dextrose
- correct electrolyte imbalances + monitor
Name two longer-term complications of Addison’s disease (primary adrenal insufficiency)
- Osteoporosis –> long-term glucorticoid therapy increeases risk (give bisphosphonates and Adcal D3 as preventative measures)
- Infections –> increased susceptibility to infections due to impaired immune function
What is Sheehan’s syndrome?
where post-partum haemorrhage causes avascular necrosis of the pituitary gland –> a cause of secondary adrenal insufficiency
Cushing’s syndrome VS Cushing’s disease
- Cushing’s syndrome –> refers to features of prolonged high lvls of glucocorticoids in the body
- Cushing’s disease –> refers to a pituitary adenoma secreting excessive ACTH, which stimulates excessive cortisol release from the adrenal glands
What are the 2 types of corticosteroid hormones?
- Glucocorticoids (eg. cortisol) –> the primary natural glucocorticoid hormone produced by the adrenal glands
- Mineralocorticoids (eg. aldosterone)
What is the most common (70%) cause of endogenous Cushing’s syndrome?
Cushing’s disease –> adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma
What anatomical part is the primary site of cortisol production?
Zona fasciculata
Describe how Cushing’s disease affects the HPA axis
- In a normally functioning HPA axis, rising cortisol lvls would suppress the release of CRH from the hypothalamus and ACTH from the pituitary –> thereby forming a negative feedback loop
- However, the pituitary adenoma in Cushing’s disease is often insensitive to this feedback inhibition –> resulting in a persistent state of ACTH hypersecretion
Cushing’s disease –> clinical features
- Central obesity
- Redistribution of adipose tissue –> moon facies, supraclavicular region, dorsocervical area (“buffalo hump”)
- Abdominal striae
- Proximal myopathy –> leading to difficulty rising from a seated position
- Osteopenia + osteoporosis
- Thin skin with easy bruising and poor wound healing
- Hirsutism (due to increased adrenal androgens)
- Anxiety, depression, and insomnia
- Hypertension –> due to cortisol-mediated sodium retention + potentiation of catecholamine action on blood vessels
- T2DM –> due to cortisol-induced insulin resistance
- Dyslipidaemia
Apart from Cushing’s disease, what are some other causes of Cushing’s syndrome (ie. high lvls of corticosteroids/glucocorticoids)?
- Exogenous steroids –> eg. pt taking long-term corticosteroids
- Adrenal adenoma –> adrenal tumour secreting excess cortisol
- Paraneoplastic syndrome –> when ACTH is released from a tumour somewhere other than the pituitary gland - ectopic ACTH - stimulating excessive cortisol release (small cell lung cancer is the most common)
Investigations for suspected Cushing’s syndrome (endogenous cause)
- Low-dose overnight dexamethasone suppression test –> most sensitive test and used first-line to exclude Cushing’s syndrome
- 24hr urinary free cortisol –> two measurements required
- Bedtime salivary cortisol –> two measurements required
. - High-dose dexamethasone suppression test –> used to localise the issue
Dexamethasone suppression tests –> describe how they work
Dexamethasone suppression tests are used to diagnose Cushing’s syndrome caused by a problem inside the body (no point if exogenous cause)
- A normal response to dexamethasone is suppressed cortisol due to negative feedback –> dexamethasone causes -ve feedback on the hypothalamus (reducing the CRH output) –> causing -ve feedback on pituitary (reducing the ACTH output) –> the lower CRH and ACTH lvls result in a low cortisol output by the adrenal glands
- A lack of cortisol suppression in response to dexamethasone suggests Cushing’s syndrome
.
Low-dose overnight test:
- dexamethasone (1mg) is given at night (usually 11pm), and the cortisol is checked at 9am the following morning
- a normal result is that the cortisol lvl is suppressed –> failure of the dexamethasone to suppress the morning cortisol could indicate Cushing’s syndrome and further assessment is required to localise the issue
.
Low-dose 48hr test:
- 0.5mg taken every 6hrs for 8 doses (starting at 9am on first day)
- cortisol is checked at 9am on day 1 and 9am on day 3 –> a normal result is that cortisol on day 3 is suppressed (failure of this suggests Cushing’s syndrome)
.
High-dose 48hr test:
- carried out same way as low-dose, but using 2mg instead of 0.5mg
- this higher dose is enough to suppress the cortisol in Cushing’s disease (pituitary adenoma), but not when it is caused by an adrenal adenoma or ectopic ACTH
Cortisol is a hormone produced by the adrenal glands, it is secreted in a diurnal pattern –> what is meant by this?
- high in the morning, low at night
Explain how direct measurement of ACTH lvls should be interpreted when investigating suspected Cushing’s syndrome
- 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)
Cushing’s investigations table –> low-dose test (cortisol) + high-dose test (cortisol) + direct ACTH lvls
Management of Cushing’s syndrome
- Trans-sphenoidal removal of pituitary adenoma (Cushing’s disease)
- Surgical removal of adrenal tumour
- Surgical removal of tumour-producing ectopic ACTH (eg. small cell lung cancer), if possible
. - Where removal of the cause is not possible –> bilateral adrenalectomy (removal of adrenal glands) is an option –> pt has to be placed on life-long steroid replacement therapy
A complication of bilateral adrenalectomy is Nelson’s syndrome, what is this?
- low/no endogenous cortisol following this procedure causes a massive increase in ACTH production by the pituitary gland (via negative feedback)
–> this causes rapid pituitary enlargement –> this causes skin pigmentation (high ACTH)
What is myxoedema coma?
- a severe, life-threatening form of hypothyroidism characterised by mental status changes and hypothermia –> often triggered by something (eg. infection)
- While it shares many symptoms with typical hypothyroidism, the distinguishing feature is the altered mental status ranging from confusion to coma
- Requires immediate treatment –> IV levothyroxine (T4) + supportive care (warm pt, fluids for hypotension) + treat underlying precipitating factors (eg. antibx for infection)
What is a thyroid storm (aka. thyrotoxic crisis)?
- a rare, but life-threatening condition characterised by a sudden and significant increase in thyroid hormone lvls
- presents with fever, tachycardia, and delirium
- Treatment is supportive –> fluids, anti-arrhythmic medication, and beta-blockers
What is Primary hyperaldosteronism + what is Conn’s syndrome?
- Primary hyperaldosteronism = an endocrine disorder caused by excessive secretion of aldosterone from the adrenal glands
- Conn’s syndrome = refers to an adrenal adenoma producing too much aldosterone
Primary hyperaldosteronism VS Secondary hyperaldosteronism
- Primary –> where the adrenal glands are directly responsible for producing too much aldosterone (serum renin will be low as the high blood pressure suppresses it)
- Secondary –> caused by excessive renin stimulating the release of excessive aldosterone
Causes of primary hyperaldosteronism and causes of secondary hyperaldosteronism
Primary:
- Bilateral adrenal hyperplasia
- Adrenal adenoma secreting aldosterone (Conn’s syndrome)
.
Secondary (excessive renin is released to disproportionately lower blood pressure in the kidneys), usually due to:
- Renal artery stenosis
- Heart failure
- Liver cirrhosis and ascites
The two most common causes of primary hyperaldosteronism are bilateral adrenal hyperplasia and an aldosterone-producing adrenal adenoma (Conn’s syndrome) –> where does the pathology occur in both of these conditions
Zona glomerulosa
- Aldosterone-producing adenoma –> benign tumour that originates from the outer layer of the adrenal gland - zona glomerulosa
- Bilateral adrenal hyperplasia –> characterised by an enlargement of both adrenal glands due to an increased number of cells in the zona glomerulosa
Clinical features of primary hyperalodsteronism
- Refractory hypertension –> stubborn hypertension due to excess aldosterone causing Na+ retention and K+ excretion, leading to an increase in blood volume and consequently blood pressure
- Hypokalaemia –> due to excess K+ excretion (symptoms include muscle weakness, cramps, palpitations)
- Metabolic alkalosis –> due to increased H+ secretion stimulated by aldosterone
.
(Note: a significant proportion of pts with primary hyperaldosteronism will be asymptomatic –> often identified when looking into refractory hypertension)
Investigations in a pt with suspected primary hyperaldosteronism (eg. pt has refractory hypertension with hypokalemia)
- Plasma aldosterone/renin ratio is first-line –> primary hyperaldosteronism should show high aldosterone lvls with low renin lvls (-ve feedback due to sodium retention from aldosterone)
- High-resolution CT abdomen –> look for adrenal tumour/hyperplasia
- Renal artery imaging (doppler, CT angiogram) –> to look for renal artery stenosis
- adrenal vein sampling –> can distinguish between unilateral adenoma and bilateral hyperplasia (uses aldosterone lvls in blood to tell you which gland is producing more aldosterone)
Management of secondary hyperaldosteronism
- Percutaneous renal artery angioplasty –> via femoral artery to treat renal artery stenosis
Management of primary hyperaldosteronism
- Surgery –> laparoscopic adrenalectomy (removal of the adenoma) is treatment of choice
- Medical (if surgery contraindicated or bilateral disease) –> aldosterone antagonists (eg. eplerenone, spironolactone)
What is the most common cause of secondary hypertension?
Hyperaldosteronism –> worth investigating if pt with hypertension isn’t improving with hypertension medications and/or have a low potassium
What is a phaeochromocytoma?
- a tumour of the adrenal glands that secretes unregulated and excessive amounts of catecholamines (adrenaline)
- to be more specific, it is a tumour of the chromaffin cells
Where is adrenaline produced + what is the function of adrenaline (in simple terms)?
- by chromaffin cell sin the adrenal medulla of the adrenal glands
- adrenaline is a catecholamine hormone that stimulates the sympathetic nervous system and is responsible for the “fight or flight” response
Phaeochromocytomas are more common in certain genetic disorders, name the 3
About 30-40% of pts have a genetic cause:
- multiple endocrine neoplasia type II (MEN 2)
- neurofibromatosis type 1
- von Hippel-Lindau disease
Phaeochromocytomas –> what is the 10% rule to describe the pattern of tumours?
- 10% bilateral
- 10% cancerous
- 10% outside the adrenal gland –> most common site is organ of Zuckerkandl, adjacent to the bifurcation of the aorta
Clinical features of a pt with a phaeochromocytoma
Features are typically episodic - relating to periods when the tumour is secreting adreanlaine:
- Hypertension (in 90% of cases)
- Diaphoresis (sweating)
- Tachycardia
Investigations for a suspected phaeochromocytoma
- Plasma free metanephrines
- 24hr urinary collection of metanephrines
(measuring the serum catecholamine or adrenaline level is unreliable as the levels fluctuate and have a very short half-life of only a minute or so –> metanephrines (a breakdown product of adrenaline) have a longer half-life with more stable levels) - CT or MRI –> can be used to localise tumour
- Genetic testing of pt +/- relatives
Management of a pt with a phaeochromocytoma
- Surgery –> definitive management
- Medical –> alpha-blocker (eg. phenoxybenzamine) given before a beta-blocker (eg. propranolol)
(Note: patients have their symptoms controlled medically before surgery to reduce the anaesthesia and surgery risks)
(alpha-blockers given before beta-blockers to reduce vasoconstriction and normalise blood pressure, beta-blockers are then added to control tachycardia or arrhythmias)
Primary hyperparathyroidism VS Secondary hyperparathyroidism
- Primary –> caused by excess secretion of PTH by a tumour of the parathyroid glands resulting in hypercalcaemia
- Secondary –> where there is insufficient vitamin D or CKD reduces calcium absorption from the intestines, kidneys, and bones –> this results in hypocalcemia –> this causes parathyroid glands to increase PTH production –> so calcium lvls are low/normal and PTH lvls are high
What is the most common cause of hypercalcemia in outpatients?
Primary hyperparathyroidism
Clinical features of hyperparathyroidism
Pts with primary hyperparathyroidism are most commonly asymptomatic (raised calcium lvls picked up incidentally)
- Stones –> increased risk of kidney stones
- Bones –> bone pain + osteoporosis
- Abdominal groans –> constipation, nausea, vomiting
- Psychiatric moans –> fatigue, depression, psychosis
Investigations for suspected hyperparathyroidism
- Serum calcium –> hypercalcaemia (primary)
- PTH lvls –> elevated or normal PTH with hypercalcemia supports diagnosis of primary hyperparathyroidism
- Kidney function tests (eGFR) –> CKD can lead to secondary/tertiary hyperparathyroidism
- Vitamin D lvls (25-hydroxyvitamin D) –> low vit D lvls can stimulate PTH secretion (leading to secondary hyperparathyroidism)
Why is 25-hydroxyvitamin D used to measure vitamin D lvls rather than 1,25-hydroxyvitamin D (active form)?
- 25-hydroxyvitamin D is more stable and reliable indicator of vitamin D within the body
- 25-hydroxyvitamin D acts as the primary store of vitamin D
Differential diagnosis of primary hyperparathyroidism
- Familial Hypocalciuric Hypercalcaemia (FHH) –> autosomal dominant disorder characterised by lifelong stable mild hypercalcaemia + reduced urinary calcium excretion (usually increased in primary hyperparathyroidism)
- Malignancy-associated Hypercalcaemia –> PTH lvls usually suppressed + likely to be other symptoms
- Secondary hyperparathyroidism –> calcium lvls will be low/normal +/- reduced eGFR +/- low vit D
Management of primary hyperparathyroidism
- Parathyroidectomy for most pts –> high cure rates (98%)
.
Medical (when surgery not acceptable): - Calcitonin –> inhibits bone and kidney resorption of calcium
- Cinacalcet –> acts to reduce serum Ca2+ conc. while not affecting bone density or urinary calcium conc.
- Denosumab –> impairs Ca2+ resorption
- Bisphosphonates
What are some complciations of untreated hypercalcaemia?
- Osteoporosis and fragility fractures
- Kidney stones and kidney injury
- Hypertension and heart disease
- GI problems –> peptic ulcers, pancreatitis, gall stones
Name 2 parathyroidectomy-specific complications
- Damage to recurrent or superior laryngeal nerves
- Post-operative hypocalcemia (if removal of too much parathyroid tissue)
What is the most common aetiology of hyperparathyroidism?
- Post-surgical –> inadvertent damage or removal of parathyroid glands during neck surgery (esp. thyroidectomy)
In hypoparathyroidism, there are low calcium lvls and high phosphate lvls, why is this?
Low calcium lvls
- PTH stimulates osteoclast activity leading to bone resorption and the release of calcium into the bloodstream –> low PTH means less Ca2+ being released into the bloodstream
- PTH also acts on the kidneys to promote Ca2+ reabsoprtion from the glomerular filtrate –> low PTH leads to more calcium being excreted in the urine (exacerbating the hypocalcemia)
.
High phosphate lvls:
- PTH reduces renal tubular phosphate reabsorption, leading to increased phosphate excretion –> reduced PTH action causes phosphate retention
Clinical features of hypoparathyroidism
The hallmark of hypoparathyroidism is hypocalcaemia, which presents with neuromuscular irritability:
- Symptoms –> mild numbness or tingling of extremities and around mouth + muscle cramps + fatigue
- Signs –> Chvostek’s sign (twitching of facial muscles in response to tapping over facial nerve) + Trousseau’s sign (carpopedal spasm induced by occluding the brachial artery with a blood pressure cuff
Investigations for hypoparathyroidism
Diagnosis is made based off hypocalcaemia (+low PTH lvls) + hyperphosphataemia
- ECG may show prolonged QT interval due to hypocalcemia
- magnesium lvls should also be checked –> risk of magnesium deficiency
Management of hypoparathyroidism
We want to maintain a slighlty low/low-normal serum calcium to avoid hypercalciuria and renal complications:
- Oral calcium supplements (eg. calcium carbonate) + active vitamin D analogues (calcitriol or alfacalcidiol)
- Monitor for hypocalcemia symptoms + phosphate and magnesium lvls + renal function and urinary calcium excretion
What is acromegaly?
- an endocrine disorder caused by excessive secretion of growth hormone (GH)
Where is growth hormone produced?
produced by the anterior pituitary gland
Aetiology of acromegaly (excessive GH)
- Pituitary adenoma (95% of cases) –> this can be microscopic or large enough to cause compression of local structures
- Paraneoplastic syndrome (rare) –> acromegaly can be secondary to cancer –> the tumour secretes ectopic growth hormone-releasing hormone (GHRH) or growth hormone (GH)
What is Gigantism and how does it differ from acromegaly?
- Gigantism results from excessive GH seceretion before epihyseal closure during childhood, leading to increased linear growth (height)
- acromegaly occurs post-puberty resulting in enlargement of extremities rather than height
Clinical features of acromegaly
- Coarse facial appearance (frontal bossing), spade-like hands, increase in shoe size, increase in ring size (good measure of severity)
- Large tongue (macroglossia), large protruding jaw (prognathism), interdental spaces
- Excessive sweating and oily skin –> caused by sweat gland hypertrophy
- Features of pituitary tumour –> hypopituitarism, headaches, bitemporal hemianopia
- Raised prolactin in 1/3 cases (galactorrhoea)
What type of visual field loss occurs as a result of a pituitary tumour?
Bitemporal hemianopia
- the optic chiasm sits just above the pituitary gland
- the optic chiasm is where the optic nerves from the eyes cross over to the opposite side of the head before traveling to the visual cortex in the occipital lobe
- a pituitary tumour of significant size can press on the optic chiasm
A patient has bilateral carpal tunnel syndrome and features of acromegaly –>
Need to think of acromegaly –> comes up in exams apparently?
Investigations for suspected acromegaly
- Inuslin-like growth factor-1 (IGF-1) –> first-line + used to monitor
- Growth hormone suppression test (or OGTT) –> used to confirm diagnosis if IGF-1 raised –> the glucose should suppress GH (failure to do so indicates acromegaly)
- MRI of pituitary –> may localise a pituitary tumour
(note: testing GH directly is unreliable as it fluctuates throughout the day)
Management of acromegaly caused by a pituitary tumour
- Trans-sphenoidal surgery –> first-line + definitive
.
Medical:
1. Somatostatin analogues (eg. octreotide) –> blocks GH release
2. Dopamine agonists (eg. bromocriptine) –> block GH release
3. Pegvisomant (GH receptor antagonist) –> given OD by subcut injection - Radiotherapy sometimes has a role in treatment
.
(if ectopic cause –> surgical removal of that tumour ideally)
What is somatostatin and why are somatostatin analogues (eg. octreotide) given in the treatment of acromegaly?
- Somatostatin is also known as growth hormone-inhibiting hormone
- it is normally secreted by the brain, gastro-intestinal tract and pancreas in response to complex triggers
- one of the functions of somatostatin is to block growth hormone release from the pituitary gland
What is a prolactinoma?
a type of pituitary adenoma that results in the overproduction of prolactin hormone –> it is the most common type of pituitary tumour
Microprolactinomas VS Macroprolactinomas
- Microprolactinomas –> smaller than 10mm
- Macroprolactinomas –> larger than 10mm
Clinical features of prolactinomas (in women + in men)
Excess prolactin in women:
- amenorrhoea (absence of menstruation)
- infertility
- galactorrhoea (excess milk production)
- osteoporosis
.
Excess prolactin in men:
- impotence
- loss of libido +/- erectile dysfunction
- galactorrhoea
What are the 3 main features of macroadenomas (large pituitary adenomas - > 10mm)?
- Headaches
- Bitemporal hemianopia
- hypopituitarism signs and symptoms
Investigation + management of prolactinomas
- prolactin lvls + imaging studies - eg. MRI to view pituitary tumour
. - Dopamine agonists - cabergoline OR bromocriptine
Pituitary apoplexy –> what is it + presentation + investigation (include anatomical location of where oedema/haemorrhage is located) + management
- a rare, but life-threatening clinical syndrome characterised by acute haemorrhagic infarction of the pituitary gland (typically within an existing pituitary adenoma)
- Presentation –> abrupt onset of severe headache, visual disturbances, ophthalmoplegia due to cranial nerve palsies, altered mental status, and endocrine dysfunction (adrenal insufficiency or hypopituitarism)
- Investigation –> MRI (identifies hemorrhagic transformation and oedema within the sella turcica) + lab investigations (to assess anterior pituitary hormonal function)
- Management –> high-dose glucocorticoid therapy + surgical decompression via transspehnoidal approach +/- fluids
Name 2 viruses that may trigger T1DM
- Coxsackie B
- Enterovirus
What are the 3 most common scenarios for DKA to occur?
- The initial presentation of type 1 diabetes
- An existing type 1 diabetic who is unwell for another reason, often with an infection
- An existing type 1 diabetic who is not adhering to their insulin regime
When would autoantibodies and serum C-peptide be measured?
- Only used if there is doubt between T1DM and T2DM
- (Autoantibodies in T1DM –> anti-islet cell antibodies, anti-GAD antibodies, anti-insulin antibodies)
- Serum C-peptide measures levels of endogenous insulin –> tells us about whether insulin production is high or low
What type of injection is insulin given as?
Subcutaneous injection –> injection sites should be rotated regularly to avoid lipodystrophy
What is the basal-bolus regime used in the management of T1DM?
A basal-bolus regime of insulin involves a combination of:
- Background, long-acting insulin injected once a day
- Short-acting insulin injected 30 minutes before consuming carbohydrates (e.g. at meals)
Name some injection sites used to inject insulin + why is it important to regularly rotate the injection site?
- Injecting into the same spot can cause lipodystrophy, where the subcutaneous fat hardens
- Areas of lipodystrophy do not absorb insulin properly from further injections
- For this reason, patients should cycle their injection sites
- If a patient is not responding to insulin as expected, ask where they inject and check for lipodystrophy
When would a pancreas transplant be considered, and what are the disadvantages of having a pancreas transplant?
- A pancreas transplant involves implanting a donor pancreas to produce insulin
- The original pancreas is left in place to continue producing digestive enzymes
- The procedure carries significant risks, and life-long immunosuppression is required to prevent rejection
- Therefore, it is reserved for patients with severe hypoglycaemic episodes and those also having kidney transplants
. - Islet transplantation involves inserting donor islet cells into the patient’s liver
- These islet cells produce insulin and help in managing diabetes
- However, patients often still need insulin therapy after islet transplantation
What is SIADH (syndrome of inappropriate anti-diuretic hormone)?
- SIADH refers to the increased release of antidiuretic hormone (ADH) from the posterior pituitary
- This increases water reabsorption from the urine, diluting the blood and leading to hyponatraemia (low sodium)
Where is ADH produced and secreted + action of ADH
- Antidiuretic hormone (ADH) is produced in the hypothalamus and secreted by the posterior pituitary gland –> it is also known as vasopressin
- ADH stimulates water reabsorption from the collecting ducts in the kidneys
What are the two potential sources of too much ADH?
- Increased secretion by the posterior pituitary
- Ectopic ADH, most commonly by small cell lung cancer
What happens when there is too much ADH (excessive ADH)?
- Excessive ADH results in increased water reabsorption in the collecting ducts, diluting the blood
- This excess water reduces the sodium concentration (hyponatraemia)
- The extra water is not usually significant enough to cause fluid overload. SIADH results in euvolaemic hyponatraemia
- Euvolaemic means normal (eu-) volume (-vol-) of blood (-aemic)
. - The urine becomes more concentrated as the kidneys excrete less water –> therefore patients with SIADH have high urine osmolality and high urine sodium
How does SIADH present?
- The symptoms of SIADH relate to low sodium (hyponatraemia)
.
Depending on the sodium level and how rapidly it occurs, they may be asymptomatic or present with non-specific symptoms: - Headache
- Fatigue
- Muscle aches and cramps
- Confusion
. - Severe hyponatraemia can cause seizures and reduced consciousness
What are the 3 main causes of SIADH?
- Post-operative after major surgery
- Medications (e.g., SSRIs and carbamazepine)
- Malignancy, particularly small cell lung cancer
Management of SIADH (syndrome of inappropriate ADH)
- Admission if symptomatic or severe
- Treat underlying cause (eg. stop causative medication or treat infection)
- Fluid restriction (to correct the hyponatraemia)
- Vasopressin receptor antagonist (eg. tolvaptan)
How do vasopressin receptor antagonists (eg. tolvaptan) work?
Block ADH receptor - cause a rapid rise in sodium
What condition can occur if sodium is corrected too quickly in a pt with hyponatraemia (eg. pt with SIADH)?
Osmotic demyelination - can lead to encephalopathy and if persists then demyelination of the neurons (particularly in pons)
- note: prevention of osmotic demyelination is important as once it occurs, treatment is only supportive and pt will be left with neuro deficit
What is diabetes inspidus + why does it occur?
- Diabetes insipidus is a condition characterized by large amounts of dilute urine and increased thirst
.
Diabetes insipidus occurs due to: - A lack of antidiuretic hormone (cranial diabetes insipidus)
- A lack of response to antidiuretic hormone (nephrogenic diabetes insipidus)
What are the two main symptoms of diabetes insipidus?
- Polyuria (excessive amounts of urine)
- Polydipsia (excessive thirst)
(Primary polydipsia is when the patient has a normally functioning ADH system but drinks excessive amounts of water, leading to excessive urine production (polyuria). This is not diabetes insipidus)
What is nephrogenic diabetes inspidus?
Nephrogenic diabetes insipidus is when the collecting ducts of the kidneys do not respond to ADH
What is cranial diabetes inspidus?
Cranial diabetes insipidus is when the hypothalamus does not produce ADH for the pituitary gland to secrete
What are the presenting features of diabetes inspidus?
- Polyuria (producing more than 3 litres of urine per day)
- Polydipsia (excessive thirst)
- Dehydration
- Postural hypotension
(Primary polydipsia is when the patient has a normally functioning ADH system but drinks excessive amounts of water, leading to excessive urine production (polyuria). This is not diabetes insipidus)
What investigations would you do for suspected diabetes insipidus?
Investigations show:
- Low urine osmolality (lots of water diluting the urine)
- High/normal serum osmolality (water loss may be balanced by increased intake)
- More than 3 litres on a 24-hour urine collection
.
- The water deprivation test is the test of choice for diagnosing diabetes insipidus.
Explain how the water deprivatoin test works
- The water deprivation test is also known as the desmopressin stimulation test
.
1. The patient avoids all fluids for up to 8 hours before the test (water deprivation)
2. After water deprivation, urine osmolality is measured –> if the urine osmolality is low, synthetic ADH (desmopressin) is given
3. Urine osmolality is measured over the 2-4 hours following desmopressin
. - In primary polydipsia, water deprivation will cause urine osmolality to be high
- Desmopressin does not need to be given
- A high urine osmolality after water deprivation rules out diabetes insipidus.
. - In cranial diabetes insipidus, the patient lacks ADH
- The kidneys are still capable of responding to ADH. Initially, the urine osmolality remains low as it continues to be diluted by the excessive water lost in the urine
- After desmopressin is given, the kidneys respond by reabsorbing water and concentrating the urine
- The urine osmolality will be high
. - In nephrogenic diabetes insipidus, the patient is unable to respond to ADH
- The urine osmolality will be low both before and after the desmopressin is given
What is the management of diabetes insipidus?
- The underlying cause should be treated (e.g., stopping lithium)
- Mild cases may be managed conservatively
. - Desmopressin (synthetic ADH) can be used in cranial diabetes insipidus to replace the absent antidiuretic hormone
- The serum sodium needs to be monitored, as there is a risk of hyponatraemia (low sodium) with desmopressin
.
Nephrogenic diabetes insipidus is less straightforward to treat. Management options include: - Ensuring access to plenty of water
- High-dose desmopressin
- Thiazide diuretics
- NSAIDs
What type of hypersensitivity reaction is T1DM?
most commonly a type IV hypersensitivity reaction
