PBL ILO’s Flashcards
1
Q
Glucose metabolism
A
Glucose metabolism involves multiple processes, including glycolysis, gluconeogenesis, and glycogenolysis, and glycogenesis.
2
Q
Glycolysis
A
Glycolysis is a series of reactions that extract energy from glucose by splitting it into two three-carbon molecules called pyruvates.
Each reaction in glycolysis is catalyzed by its own enzyme. The most important enzyme for regulation of glycolysis is phosphofructokinase, which catalyzes formation of the unstable, two-phosphate sugar molecule, fructose-1,6-bisphosphate44start superscript, 4, end superscript. Phosphofructokinase speeds up or slows down glycolysis in response to the energy needs of the cell.
3
Q
Gluconeogenesis
A
Gluconeogenesis is the synthesis of glucose from nonsugar precursors, such as lactate, pyruvate, and the carbon skeleton of glucogenic amino acids.
4
Q
Glycogenolysis
A
Glycogenolysis is the biochemical pathway in which glycogen breaks down into glucose-1-phosphate and glucose. The reaction takes place in the hepatocytes and the myocytes. The process is under the regulation of two key enzymes: phosphorylase kinase and glycogen phosphorylase.
5
Q
Glycogenesis
A
Glycogenesis is the process of storing excess glucose for use by the body at a later time.
6
Q
Micro vascular complications of diabetes
A
Microvascular complications:
• Long-term complications that affect small blood vessels.
• These typically include retinopathy, nephropathy and neuropathy.
7
Q
Non proliferation retinopathy - diabetic complication
A
- Retinopathy
Nonproliferative retinopathy: development of microaneurysms, venous loops, retinal hemorrhages, exudates (fluid that leaks out of blood vessels into nearby tissues).
Pathophysiology
• Microaneurysms may form due to the release of vasoproliferative factors, weakness in the capillary wall or increased intra-luminal pressures.
• Microaneurysms can cause vascular permeability in the macula which can lead to macular oedema that threatens central vision.
• As capillary closure becomes extensive, intraretinal haemorrhages develop
8
Q
Proliferative retinopathy- diabetic complication
A
Proliferative retinopathy: presence of new blood vessels, with or without vitreous hemorrhage. It is a progression of nonproliferative retinopathy.
Pathophysiology
• Develops due to retinal ischemia and release of vasoactive substances which stimulate new blood vessel formation.
• These may erupt through the surface of the retina and grow on the posterior surface of the vitreous humor -> vitrous hamorrhages which can contract and lead to retinal detachment.
• Can cause blindness.
9
Q
Nephropathy- diabetic complication
A
- Nephropathy
Progressive deterioration in renal function resulting in end-stage renal disease, particularly glomerular sclerosis
Pathophysiology
• Increased glomerular capillary flow with urine containing high glucose levels results in increased extracellular matrix production and endothelial damage
• The vascular damage to the glomerulus causes increased permeability to macromolecules, results in proteinuria (excessive protein loss in the urine)
• Causes mesangial expansion and interstitial sclerosis which can cause glomerular sclerosis.
• Also nonaluminium renal impairment due to unresolved episodes of acute kidney injury
Tests
• ARC (albumin to creatine ratio)
• EGFR (glomerular filtration rate)
10
Q
Neuropathy - diabetic complication
A
- Neuropathy
Heterogeneous condition associated with nerve pathology.
The condition is classified according to the nerves affected and includes focal, diffuse, sensory, motor, and autonomic neuropathy.
Pathophysiology
• Diabetes is associated with dyslipidemia, hyperglycemia, and low insulin and growth factor abnormalities.
• These abnormalities are associated with glycation of blood vessels and nerves which causes structural nerve damage including: segmental demyelination, axonal atrophy and loss, and progressive demyelination.
• These effects causes a decrease in nerve sensitisation and also affect ANS function -> neuropathy.
• In addition, autoimmunity may affect nerve structure.
• Poor blood supply and nerve damage can also lead to the formation of ulcers seen often on diabetic’s feet.
11
Q
Macro vascular complications of diabetes
A
Macrovascular complications
• Primarily diseases of the coronary arteries, peripheral arteries and cerebrovascular.
• Early macrovascular disease is associated with atherosclerotic plaque in the vasculature supplying blood to the heart, brain, limbs and other organs.
• Late stages of macrovascular disease involve complete obstruction of these vessels, which can increase the risk of MI, stroke, claudication and gangrene.
• Peripheral ischaemia causes poor skin healing and diabetic foot ulcers
Pathophysiology
Result from hyperglycemia, excess free fatty acid and insulin resistance -> increases oxidative stress, protein kinase activation and activation of glycine end products which act on the endothelium to cause:
• Increased vasoconstriction which causes hypertension and vascular smooth muscle cell growth
• Increased inflammation
• Thrombosis, hypercoagulation and platelet activation and decreased fibrinolysis
These pathways ultimately lead to atherosclerosis and the cause of macro-vascular complications of diabetes
12
Q
T1 diabetes
A
T1DM is a condition where the pancreas stops being able to produce adequate insulin
Without insulin, the cells of the body cannot absorb glucose from the blood as use it as fuel.
The glucose levels in the blood keep rising, causing hyperglycaemia
13
Q
Genetic susceptibility to Type 1 diabetes
A
Genetic susceptibility
• One trigger → cold weather
○ Develops more often in winter than summer and is more common in places with cold climates.
• Another trigger → viruses
○ Possible that a virus that has only mild effects on most people triggers T1DM in others
○ Enterovirus infections have been shown to be associated with T1DM
○ Coxsackie B may also trigger it
• Early diet may also play a role
○ T1DM is less common in people who were breastfed and in those who first ate solid foods at later ages
• Researchers are learning how to predict a person’s odds of getting diabetes
○ e.g. most white people with T1DM have genes called HLA-DR3 or HLA-DR4 which are linked to an autoimmune disease
14
Q
Aetiology and risk factors of Type 1 diabetes
A
Aetiology and risk factors
• T1DM develops when the immune system mistakenly attacks and destroys cells in the pancreas that makes insulin
• This results in a deficiency of insulin → causing excess blood glucose levels
T1DM is caused by an immune reaction. Risk factors aren’t clear, but known risk factors include:
• Family history → having a parent, brother or sister with T1DM
• Age → you can get T1DM at any age, but it usually develops in children, teens or young adults
15
Q
Presenting symptoms of Type 1 diabetes
A
Presenting symptoms
• T1DM may present with the classic triad of symptoms of hyperglycaemia:
○ Polyuria (excessive urine)
○ Polydipsia (excessive thirst)
○ Weight loss (mainly through dehydration
○ May also present with diabetic ketoacidosis
16
Q
Diabetic ketoacidosis
A
Diabetic ketoacidosis
• Occurs as a consequence of inadequate insulin
• Three key features are:
○ Ketoacidosis
○ Dehydration
○ Potassium imbalance
Ketoacidosis
• Liver produces ketones to use as fuel as body cannot recognise glucose
• Over time, there are high glucose and ketone levels
• Initially the kidneys produce bicarbonate to counteract the ketone acids in the blood and maintain normal Ph
• Overtime, ketone acids use up the bicarbonate and blood becomes acidic → ketoacidosis
Dehydration
• High blood glucose (hyperglycaemia) overwhelm the kidneys, glucose leaks into urine
• Glucose in urine draws out water by osmotic diuresis
• Causes increased urine production (polyuria) → severe dehydration
• Dehydration = excessive thirst (polydipsia)
Potassium imbalance
• Insulin normally drives potassium into cells
• Without insulin, potassium is not added to and stored in cells
• Serum potassium can be high/normal
• However, total body potassium is low because no potassium is stored in cells
• When treatment with insulin starts, patients can develop severe hypokalaemia (low serum potassium) very quickly, leading to fatal arrhythmias
17
Q
Diagnosing DKA
A
Diagnosing DKA
• Diagnosis requires all three of:
○ Hyperglycaemia (e.g. blood glucose above 11 mmol/L)
○ Ketosis (e.g. blood glucose above 3 mmol/L)
○ Acidosis (e.g. pH below 7.3)
18
Q
Treatment of DKA
A
Treatment of DKA
• Fluids - IV fluid resuscitation with normal saline (1 litre in first hour, followed by 1 litre every 2 hours)
• Insulin - fixed rate insulin infusion (e.g. Actrapid at 0.1 units/kg/hour)
• Glucose - closely monitor blood glucose and add a glucose infusion when it is less than 14 mmol/L
• Potassium - add potassium to IV fluids and monitor closely (e.g. every hour initially)
• Infection - treat underlying triggers
• Chart - chart fluid balance
• Ketones - monitor blood ketones, pH and bicarbonate
19
Q
Short term complications of T1DM
A
Short-term complications of T1DM
• Hypoglycaemia:
○ Low blood sugar level
○ May be caused by too much insulin, not consuming enough carbohydrates or not processing carbohydrates correctly
○ Needs to be treated with rapid-acting glucose
• Hyperglycaemia:
○ High blood sugar level
○ May indicate that insulin dose needs to be increased
○ Insulin injections can take several hours to take effect and repeated doses could lead to hypoglycaemia
20
Q
Long term complications of T1DM
A
Long term complications of T1DM
• Chronic high blood glucose levels cause damage to endothelial cells of blood vessels
• Leads to leaky, malfunctioning vessels that are unable to regenerate
• High glucose also cause immune system dysfunction and creat an optimal environment for infectious organisms to thrive
Macrovascular complications:
• Coronary artery disease
• Peripheral ischaemia
• Stroke
• Hypertension
Microvascular complications:
• Peripheral neuropathy
• Retinopathy
• Kidney disease, particularly glomerulosclerosis
Infection-related complications:
• Urinary tract infections
• Pneumonia
• Skin and soft tissue infections
• Fungal infections, particularly oral and vaginal candidiasis
21
Q
Genetic susceptibility of type 2 diabetes
A
Type 2 diabetes has a stronger link to family history and lineage than type 1, and studies of twins have shown that genetics play a very strong role in the development of type 2 diabetes.
1) A genetic inability of the tissues to respond normally to insulin (insulin resitance) 2) A genetic inability of the insulin producing cells to secrete enough insulin to overcome the insulin resistance
Pro-diabetes factors
Obesity
Sedentary life style
Pro-diabetes medications
High carbohydrate diet
Smoking
Alcohol
Aging
Ethnicity (black African or Caribbean and South Asian)
Family history
Anti-diabetes factors
Balanced diet
Active lifestyle
Weight loss
22
Q
Age of onset of type 2 diabetes
A
Age of onset
You can develop type 2 diabetes at any age, even during childhood.
You are more likely to develop type 2 diabetes if you are age 45 or older, have a family history of diabetes, or are overweight or have obesity.
23
Q
Presenting features of type 2 diabetes
A
Presenting features of diabetes include:
• Tiredness • Polyuria and polydipsia (frequent urination and excessive thirst) • Unintentional weight loss • Opportunistic infections (e.g. oral thrush) • Slow wound healing • Glucose in urine (on a dipstick)
24
Q
Complications of type 2 diabetes
A
• Infections (e.g., periodontitis, thrush and infected ulcers)
• Diabetic retinopathy
• Peripheral neuropathy
• Autonomic neuropathy
• Chronic kidney disease
• Diabetic foot
• Gastroparesis (slow emptying of the stomach)
• Hyperosmolar hyperglycaemic state
• Cardiovascular risk factors
25
Insulin resistance
Insulin resistance
Repeated exposure to glucose and insulin makes peripheral tissue resistant to the effects of insulin. More and more insulin is required to stimulate the cells to take up and use glucose (blood sugar).
Over time, the pancreas becomes fatigued and damaged by producing so much insulin, and the insulin output is reduced.
26
Chronic hyperglycaemia
Chronic hyperglycaemia
A high carbohydrate diet combined with insulin resistance and reduced pancreatic function leads to chronic high blood glucose levels (hyperglycaemia).
Chronic hyperglycaemia damages microvascular and macrovascular blood vessels which can lead to heart attack, stroke, and problems with the kidneys, eyes, gums, feet and nerves. There are also infectious complications.
27
Treatment of hypoglycaemia
Hypoglycaemia
• Plasma glucose of <3.0mmol/L
• If patient is conscious:
○ Administer glucose gel by mouth (e.g. GlucoGel)
○ Repeat capillary blood glucose after 10-15 minutes and if the patient is still hypoglycaemic, repeat administration of glucose gel a further 2-3 times
○ When the patient is fully alert, provide a longer-acting carbohydrate for the patient to eat (e.g. toast)
• If patient is unconscious:
○ Administer intravenous glucose (e.g. 150-160 ml of 10% glucose)
○ If the patient then regains consciousness, switch to using oral glucose as above
○ If IV access is not able to be established rapidly, administer glucagon 1mg via the intramuscular or subcutaneous route. Glucagon stimulates the conversion of stored glycogen within the liver into glucose. As a result, glucagon is ineffective in patients with depleted glycogen stores (e.g. elderly patients with poor oral intake and patients with eating disorders)
28
Treatment of DKA (FIGPICK)
Treatment of DKA - FIGPICK
• Fluids - IV fluid resuscitation with normal saline (1 litre in first hour, followed by 1 litre every 2 hours)
• Insulin - fixed rate insulin infusion (e.g. Actrapid at 0.1 units/kg/hour)
• Glucose - closely monitor blood glucose and add a glucose infusion when it is less than 14 mmol/L
• Potassium - add potassium to IV fluids and monitor closely (e.g. every hour initially)
• Infection - treat underlying triggers
• Chart - chart fluid balance
• Ketones - monitor blood ketones, pH and bicarbonate
29
Treatment of hypovolaemic shock
Treatment of hypovolaemic shock
• Fluid resuscitation
○ 500ml bolus of Hartmann's solution or 0.9% sodium chloride (warmed if available) over 15 mins
○ Administer 250ml boluses in pts at increased risk of fluid overload (e.g. heart failure)
○ After each fluid bolus, reassess for fluid overload (JVP, auscultation of lungs)
○ Repeat administration of fluid boluses up to 4 times reassessing each time
○ Senior response if patient has negative response - increased chest crackled or pt not responding adequately to repeated boluses i.e. persistent hypotension
30
Hyperglycaemic hyperosmolar non-ketotic HONK coma
Hyperglycaemic hyperosmolar non-ketotic (HONK) coma
• Characterised by hyperosmolality (water loss leads to very concentrated blood), high sugar levels (hyperglycaemia) and the absence of ketones, distinguishing it from ketoacidosis
• It presents with polyuria, polydipsia, weight loss, dehydration, tachycardia, hypotension and confusion
• Medical emergency with high mortality. Involve experienced seniors early. Treatment is with IV fluids and careful monitoring
31
Hyperglycaemic hyperosmolar non-ketotic (HONK) coma treatment
Normalise osmolarity (glucose and sodium)
Replace fluids (1 litre of sodium chloride 0.9%)
Monitor and replace electrolytes (replace potassium if below 5.5mmol/L
Normalise blood glucose
Minimise risk (minimise risk of further complications such as prophylactic dose of a low molecular weight heparin to prevent venous thromboembolism
32
HbA1c non fasting diabetic test
Non fasting blood tests:
HbA1c:
An HbA1c test is the main blood test used to diagnose diabetes. It tests your average blood sugar levels for the last two to three months
Diabetes = HbA1c level is 48mmol/mol or above (6.5% or above)
Pre-diabetes (T2)= HbA1c level is between 42 and 48mmol/mol (5.7 to 6.4%)
33
Random blood glucose test for diabetic diagnosis
Random blood glucose test:
If you have severe symptoms of diabetes, you may have a random blood test at any time of the day. This is a quick test, through a finger prick or a vein in your arm.
Diabetes = blood glucose of 11.1mmol/l or more (200mg/dL or above) - regardless of how quickly you ate
34
Fasting blood test for diabetes diagnosis
Fasting blood tests:
Fasting blood sugar test (fasting plasma glucose FPG)
Fasting required for at least 8 hours
Diabetes = 7mmol/l or more (126mg/dL or above)
Pre-diabetes = 100 to 125 mg/dL
35
Oral glucose tolerance test for diabetes diagnosis
Oral Glucose Tolerance Test (OGTT):
This test is routinely done when diagnosing gestational diabetes.
The test is in two parts - a fasting glucose blood sample is taken and then a sugary drink is given. Two hours later another blood sample is taken.
If you are pregnant you have gestational diabetes if:
Fasting glucose is 5.6mmol/l or more
2 hour glucose is 7.8mmol/l or more
36
How to distinguish between type 1 and type 2 diabetes
Type 1 or Type 2:
If you're diagnosed with diabetes, your provider may also run blood tests. These will check for autoantibodies that are common in type 1 diabetes. The tests help your provider decide between type 1 and type 2 diabetes when the diagnosis isn't certain. The presence of ketones — byproducts from the breakdown of fat — in your urine also suggests type 1 diabetes, rather than type 2.
37
Dealing with a hypo as a diabetic patient
Dealing with Hypos
Px should be able to recognize a hypo from the following symptoms:
• Headache
• Anxiety
• Hunger
• Shaking
• Weakness or feeling faint
• Dizziness
• Sweating
• Dry mouth
Patients need to be aware to carry fast-acting sugar at all times in case they become hypoglycemic.
• Jelly Babies
• Dextrose tablets (Lucozade tablets)
• Sugar gel
If your sugar is low you may need to:
1. Take 3-6 dextrose tablets or Jelly Babies.
2. The effect of the fast-acting glucose will not last long, so take more substantial food within
½ an hour of having the dextrose tablets or Jelly Babies, such as a sandwich or toast and a
glass of milk.
3. Test your blood sugar regularly until normal.
4. You may not be able to help yourself so tell your family and friends when and how
they can help you.
38
Blood glucose targets for type 1 and type 2 children and adult diabetics
If you’re a child with type 1 diabetes
• when you wake up and before meals: 4 to 7mmol/l
• after meals: 5 to 9mmol/l
If you’re an adult with type 1 diabetes
• when you wake up and before meals: 5 to 7mmol/l
• before meals at other times of the day: 4 to 7mmol/l
If you have type 2 diabetes
• before meals: 4 to 7mmol/l
• two hours after meals: less than 8.5mmol/l
If you have gestational diabetes
• Fasting: below 5.3mmol/l
• One hour after meals: below 7.8mmol/l
39
Insulin regimens
Once Daily
• Suitable for those Type 2 diabetics taking insulin.
• Usually ultra long acting insulin with no peak of activity - mimicking the background levels in a healthy person.
Twice Daily
• Biphasic insulin taken
• In type 1 diabetes, a twice daily regimen is suitable in people who have a consistent day to day routine.
Basal Bolus/ multiple daily injection
• A basal-bolus regimen, also known as multiple daily injection therapy, involves taking a long acting or intermediate acting dose and separate injections of short or rapid acting insulin at each meal.
Insulin Pump
• Continuous subcutaneous insulin infusion (CSII), also known as insulin pump therapy, involves having an insulin pump connected to your body.
• The pump is not much larger than a mobile phone and delivers a constant feed of insulin into the body via a cannula which stays inserted into the fat under your skin.
• At meal times, an increased burst (bolus) of insulin can be delivered to keep blood glucose levels under control.
Fixed dose vs flexible
These will depend on the type of insulin taken and the patient. Some patients will take a varied amount of insulin depending on the meal they have eaten. Some patients will not take a variable amount post prandial, and instead are on a fixed dose. These will be incorporated into the above regime.
40
Metformin:
Clinical indication
Route dose frequency
Names
Metformin
Clinical indication
Gold standard for type 2 diabetes
• No weight gain.
• Has cardiovascular-protective effects= reduces risk of MI and death
• Does not usually cause hypoglycaemia.
• Cost-effective & long-term evidence
Route dose, frequency
Needs to be taken with meals
• Starting dose is 500mg daily & needs to be titrated up gradually over a period of weeks
41
Metformin basic pharmacology
Basic pharmacology
Has no direct effect on the pancreas and works by:
• reducing hepatic glucose production
• inhibiting intestinal absorption of glucose
• increasing glucose utilisation by enhancing the action of insulin at peripheral receptors
• increasing glucose uptake by muscles
42
Metformin:
Cautions
Contraindications
Side effects
Cautions
Risk factors for lactic acidosis
• Caution in chronic stable heart failure (monitor cardiac function)
• concomitant use of drugs that can acutely impair renal function.
• avoid in conditions that can acutely worsen renal function, or cause tissue hypoxia.
• Care if eGFR < 45, avoid if < 30 ml/min/1.72m
Contra-indications
Acute metabolic acidosis including lactic acidosis + diabetic ketoacidosis
Side effects
• Commonly - GI upset- abdominal pain; including nausea, vomiting, taste disturbance, anorexia and diarrhoea.
• Lactic acidosis – rare but metformin may be a contributory factor among patients who develop an intercurrent illness that causes metformin accumulation (e.g. renal impairment), increased lactate production (e.g. sepsis, hypoxia) or reduced lactate metabolism (e.g. liver failure).
43
Metformin monitoring
Monitoring
• Monitor renal function- once a year in normal people, twice a year in people with risk factors for renal function deteriorations.
• Assess blood glucose control by measuring HbA1c
• In treating type 2 diabetes with a single agent, the target HbA1c is usually <48 mmol/mol. Treatment is intensified by adding a second agent if the HbA1c is >58 mmol/mol, and a new target of <53 mmol/mol is then set (balancing the risks of hyperglycaemia against the risks of treatment, particularly hypoglycaemia).
44
Counselling points about Metformin
Counselling
• 3 meals a day recommended – to minimise fluctuations in blood glucose levels- extreme hyper and hypoglycaemia = shown to lead to poorer long-term outcomes.
• SICK day rules
45
Sulfonylureas:
Names
Clinical indications
Route, dosage & frequency
Names
Sulfonylureas
• Short acting: gliclazide
• Long acting: glimepiride, glibenclamide.
Clinical indication
• First line for patients who are not overweight or in whom metformin is contra-indicated or where a rapid response to therapy is required because of hyperglycaemic symptoms
• Steroid induced hyperglycaemia
In Type 2 diabetes:
• In combination with metformin (and/or other hypoglycaemic agents) where blood glucose is not adequately controlled on a single agent.
• As a single agent to control blood glucose and reduce complications where metformin is contraindicated or not tolerated.
✓Cost effective & long-term data
✓Better than metformin at bringing blood sugars down initially especially of the patient is symptomatic.
Route, dosage, frequency
• Gliclazide: easiest to use, particularly in elderly pts with impaired renal function
• Usually started at: 40-80mg od
• Dose gradually increased will blood glucose= controlled
• Mr form available
• To be taken with meals
46
Sulfonylureas basic pharmacology
Basic pharmacology
Work by:
• stimulating insulin secretion by acting directly on pancreatic beta cells
• increasing tissue sensitivity to insulin
• requires residual beta cell function
47
Cautions, contra indications and side effects of sulfonylureas
Cautions
Can encourage weight gain; elderly; G6PD deficiency, Elderly
Contra-indications
Severe renal/hepatic impairment
Side effects
• Weight gain
• Generally well tolerated, however can cause GI disturbances.
• Liver function impairment
• Increased risk of hypoglycaemia
48
Monitoring of Sulfonylureas
Monitoring
• HbA1c
• Measure renal and hepatic function before treatment: determine the need for caution/contraindications
49
Counselling for Sulfonylureas
Counselling
Driving considerations so only have to tell the DVLA if you’re on insulin or your on oral agents and have had 2 episodes of severe hypos in 12 months were you have required someone else to treat you, or you have had a disabling hypo whilst driving, or are unable to recognise a hypo when it starts.
50
Examination of a thyroid gland
General inspection:
Weight- gain or loss
Behaviour- anxiety, agitation, depression
Clothing- intolerance to heat or cold
Hoarse voice- compression of larynx due to thyroid enlargement
Mobility aids- indicating muscle weakness
Prescription/ charts
Hands
• Thyroid Acropachy - similar to clubbing but caused by phalangeal bone overgrowth as result of Graves disease.
• Onycholysis - Painless detachment of nail from nailbed
• Palmar erythema - redness of the palms
• Peripheral Tremor - indicative of overactive sympathetic nervous system
• Radial rate and rhythm - Tachycardic vs Bradycardic
Face
• Dry skin
• Excessive sweating
• Eyebrow loss - loss of the outer third of the eyebrows is a rare sign
Eyes
Lid retraction
Exophthalmos (bulging of the eye)
Eye inflammation
Pain or restriction during eye movement
Lid lag
Thyroid inspection
Scars, masses or changes
Thyroid should not be visible
Further Inspection of Mass
Swallow - ask the patient to swallow some water and observe the movement of the mass.
• Thyroid gland masses will move upward with swallowing.
• Lymph nodes will not move much during swallow
• Invasive thyroid malignancy may not move with swallow
Tongue protrusion
Thyroid palpation:
Size
Symmetry
Consistency
Masses
Palpable thrill
Palpation of the lymph nodes
Tracheal deviation
Percussion of the sternum
Auscultation of the thyroid gland
Reflexes:
Knee jerk reflex
Bicep reflex
Assess for promixal myopathy
51
The hypothalamic pituitary adrenal axis role in cortisol release
• Cortisol is secreted by the two adrenal glands, which sit above each kidney.
• The hypothalamus controls the release of cortisol. Cortisol is released in pulses throughout the day and in response to a stressful stimulus. It is a “stress hormone”.
• It has diurnal variation, meaning it is high and low at different times of the day. Typically cortisol peaks in the early morning, triggering us to wake up and get going, and is at its lowest late in the evening, prompting us to relax and fall asleep.
• The hypothalamus releases corticotropin-releasing hormone (CRH). CRH stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH). ACTH stimulates the adrenal glands to release cortisol.
• The adrenal axis is also controlled by negative feedback. Cortisol is sensed by the hypothalamus and anterior pituitary, suppressing the release of CRH and ACTH. This results in lower amounts of cortisol. This way, cortisol is closely regulated to keep it within normal limits.
52
Actions of cortisol within the body
○ Increases alertness
○ Inhibits the immune system – inhibits the production of several inflammatory cytokines
○ Inhibits bone formation – chronically elevated cortisol can lead to osteoporosis)
○ Raises blood glucose – stimulating gluconeogenesis (synthesis of glucose from non-carbohydrate sources)
○ Increases metabolism – promoting breakdown of proteins which can result in muscle wasting in chronic states of cortisol elevation
○ An initial surge in cortisol levels triggers lipolysis, however, chronically elevated cortisol promotes lipogenesis.
53
What is cushing’s syndrome
Cushing’s syndrome refers to the features of prolonged high levels of glucocorticoids in the body.
There are two groups of corticosteroid hormones:
• Glucocorticoids (e.g., cortisol)
• Mineralocorticoids (e.g., aldosterone)
Cortisol is the primary natural glucocorticoid hormone produced by the adrenal glands.
54
Symptoms of Cushing’s syndrome
Symptoms:
• Weakness (proximal myopathy)
• Facial fullness
• Weight gain
• Low mood
• Decreased libido
• polydipsia
• polyuria
• Increased frequency of infection
55
Features on inspection of Cushing’s syndrome:
Features on inspection (round in the middle with thin limbs):
• Round face (known as a “moon face”)
• Central (truncal) obesity
• Abdominal striae (stretch marks)
• Enlarged fat pad on the upper back (known as a “buffalo hump”)
• Proximal limb muscle wasting (with difficulty standing from a sitting position without using their arms)
• Male pattern facial hair in women (hirsutism)
• Easy bruising and poor skin healing
• Hyperpigmentation of the skin in patients with Cushing’s disease (due to high ACTH levels)
○ ACTH is stimulating melanocytes to produce melanin
○ This is absent if the cause is an adrenal adenoma or exogenous steroids
• Hypertension
• Signs of tumour in Cushing's disease e.g. headaches, visual field defects
56
Metabolic effects of Cushing disease
• Hypertension
• Cardiac hypertrophy
• Type 2 diabetes
• Dyslipidaemia (raised cholesterol and triglycerides)
• Osteoporosis
57
Mental health effects of Cushing’s disease
Anxiety
Depression
Insomnia
Rarely psychosis
58
Causes of Cushing’s disease
Endogenous
• Cushing’s disease = pituitary adenoma secreting excessive adrenocorticotropic hormone (ACTH), stimulating excessive cortisol release from the adrenal glands.
○ Around 80% of endogenous cases
• Cushing's syndrome can also be caused by adrenal adenomas and adrenal carcinomas, these are corticotropin-independent
Exogenous
• The prolonged use of exogenous corticosteroids, such as prednisolone or dexamethasone, often causes Cushing’s syndrome.
• Exogenous refers to when it originates (-genous) is outside (exo-) the body.
You can remember the causes of Cushing’s syndrome with the “CAPE” mnemonic:
• C – Cushing’s disease (a pituitary adenoma releasing excessive ACTH)
• A – Adrenal adenoma (an adrenal tumour secreting excess cortisol)
• P – Paraneoplastic syndrome – ACTH is released from a tumour somewhere other than the pituitary gland (ectopic ACTH) stimulating excessive cortisol release from the adrenal gland e.g. small cell lung cancer
• E – Exogenous steroids (patients taking long-term corticosteroids)
59
Dexamethasone suppression test
Dexamethasone suppression tests
Only used in diagnosing Cushing's syndromes that have an endogenous cause (not exogenous cause e.g. steroids)
• Normal response to dexamethasone = suppressed cortisol due to negative feedback.
○ Dexamethasone causes negative feedback on the hypothalamus, reducing the corticotropin-releasing hormone (CRH) output.
○ It causes negative feedback on the pituitary, reducing the ACTH output.
○ The lower CRH and ACTH levels result in a low cortisol output by the adrenal glands.
A lack of cortisol suppression in response to dexamethasone suggests Cushing’s syndrome.
There are three types of dexamethasone suppression test:
• Low-dose overnight test (used as a screening test to exclude Cushing’s syndrome)
• Low-dose 48-hour test (used in suspected Cushing’s syndrome)
• High-dose 48-hour test (used to determine the cause in patients with confirmed Cushing’s syndrome)
60
Cushing’s syndrome investigations:
Dexamethasone suppression test
Adrenocorticotrophic hormone (ACTH) can be measured
24 hour urinary free cortisol
Lat enlighten silvery cortisol measurement
Inferior petrosal sinus sampling
Others investigations:
• Full blood count may show a high white blood cell count
• U&Es may show low potassium if an adrenal adenoma is also secreting aldosterone
• MRI brain for a pituitary adenoma
• CT chest for small cell lung cancer
• CT abdomen for adrenal tumours
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Treatment for Cushing’s syndrome
Treatment
The primary treatment is to remove the underlying cause:
Cause Treatment
(C) Pituitary adenoma Trans-sphenoidal (through the nose) removal of the tumour
May also require adjunct radiotherapy
(A) Adrenal tumour Surgical removal – laparoscopic excision
(P) Ectopic ACTH Surgical removal of the tumour (e.g. small cell lung cancer) if possible
(E) Exogenous steroids Review patients current glucocorticoid treatments and reduce doses if possible
• Where surgical removal of the cause is not possible, another option is to surgically remove both adrenal glands (adrenalectomy) and give the patient life-long steroid replacement therapy.
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What is Nelson syndrome?
• Nelson’s syndrome = development of an ACTH-producing pituitary tumour after the surgical removal of both adrenal glands due to a lack of cortisol and negative feedback. It causes skin pigmentation (high ACTH), bitemporal hemianopia and a lack of other pituitary hormones.
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Complications of Cushing’s syndrome
Complications
• hypertension
• diabetes
• obesity
• Metabolic syndrome
• Osteoporosis
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What is Addison’s disease?
Adrenal insufficiency is where the adrenal glands do not produce enough steroid hormones, particularly cortisol and aldosterone. Steroids are essential for life. Therefore, the condition is life-threatening unless the hormones are replaced.
• Primary adrenal insufficiency (Addison's disease) = when adrenal glands are damaged -> reduced cortisol and aldosterone secretion, most common cause is autoimmune.
• Secondary adrenal insufficiency = inadequate adrenocorticotropic hormone (ACTH) and a lack of stimulation of the adrenal glands, leading to low cortisol.
○ This is the result of loss or damage to the pituitary gland.
○ Secondary adrenal insufficiency can be due to:
▪ Tumours (e.g., pituitary adenomas)
▪ Surgery to the pituitary
▪ Radiotherapy
▪ Sheehan’s syndrome = where major post-partum haemorrhage causes avascular necrosis of the pituitary gland
▪ Trauma
• Tertiary adrenal insufficiency = inadequate corticotropin-releasing hormone (CRH) release by the hypothalamus.
○ Usually the result of patients taking long-term oral steroids (for more than 3 weeks), causing suppression of the hypothalamus (via negative feedback)
○ When the exogenous steroids (originating outside the body) are suddenly withdrawn, the hypothalamus does not “wake up” fast enough, and endogenous steroids (originating inside the body) are not adequately produced
○ Long-term steroids must be tapered slowly to allow the adrenal axis to regain normal function.
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Causes of Addison’s disease
Autoimmune adrenalitis (mot common in western world)
Infective adrenalitis (TB, HIV, fungal, syhillis)
Other- haemorrhage (meningitis), malignant invasion
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Symptoms of Addison’s disease
Symptoms
• Fatigue
• Muscle weakness
• Muscle cramps
• Dizziness and fainting
• Thirst and craving salt
• Weight loss
• Abdominal pain
• Depression
• Reduced libido (mainly in women)
• Loss of hair in axillary/pubic regions (mainly in women)
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Clinical signs of Addison’s disease
Clinical Signs
• Bronze hyperpigmentation of the skin (particularly in creases, scars, lips and buccal mucosa) = excessive ACTH stimulates melanocytes to produce melanin
• Hypotension (particularly postural hypotension – with a drop of more than 20 mmHg on standing)
TOM TIP: If you see a patient in an OSCE exam who may have adrenal insufficiency, check for a medical alert bracelet worn to alert medical services that they are steroid-dependent if they become unconscious.
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What would blood tests show in Addisons disease?
Blood tests
• Hyponatraemia (low sodium) is a key biochemical finding. This may be the only presenting feature.
Other potential biochemical findings may occur. Normal results do not exclude the diagnosis:
○ Hyperkalaemia (high potassium)
○ Hypoglycaemia (low glucose)
○ Raised creatinine and urea due to dehydration
○ Hypercalcaemia (high calcium)
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Short Synacthen Test
Short Synacthen Test – Main test for Addison’s disease
• Also known as the ACTH stimulation test. It is the test of choice for diagnosing adrenal insufficiency.
• It is ideally performed in the morning.
• The test involves giving a dose of Synacthen (synthetic ACTH)/ IV administration of 250mcg of tetracosactide (synthetic ACTH). The blood cortisol is checked before and 30 and 60 minutes after the dose.
○ Normal = cortisol level should at least doubel,synacthen will stimulate healthy adrenal glands to produce cortisol.
○ Failure of cortisol to double indicates either:
▪ Primary adrenal insufficiency (Addison’s disease)
▪ Very significant adrenal atrophy after a prolonged absence of ACTH in secondary adrenal insufficiency
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Management of Addison’s disease
Management
Treatment of adrenal insufficiency is with replacement steroids titrated to signs, symptoms and electrolytes.
• Hydrocortisone 15-30mg/day divided into doses(a glucocorticoid) is used to replace cortisol.
• Fludrocortisone 50-300mcg/day (a mineralocorticoid) is used to replace aldosterone, if aldosterone is also insufficient.
Patients are given a steroid card, ID tag and emergency letter to alert emergency services that they depend on steroids for life. Doses should not be missed, as they are essential to life.
Doses are doubled during an acute illness to match the normal steroid response to illness.
Patients and close contacts are taught to give intramuscular hydrocortisone in an emergency.
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Adrenal crisis
Adrenal crisis, also known as Addisonian crisis, describes an acute presentation of severe adrenal insufficiency, where the absence of steroid hormones leads to a life-threatening emergency. They may present with:
• Reduced consciousness
• Hypotension
• Hypoglycaemia
• Hyponatraemia and hyperkalaemia
It may be the initial presentation of adrenal insufficiency or triggered by infection, trauma or other acute illness in established adrenal insufficiency.
Do not wait to perform investigations and establish a definitive diagnosis before starting treatment in suspected adrenal crisis.
Management involves:
• ABCDE approach to initial assessment and arrange transfer to hospital
• Intramuscular or intravenous hydrocortisone (the initial dose is 100mg, followed by an infusion or 6 hourly doses)
• Intravenous fluids
• Correct hypoglycaemia (e.g., IV dextrose)
• Careful monitoring of electrolytes and fluid balance
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Physiology of the pituitary gland:
The pituitary gland, the "master gland" of the body, is composed of endocrine cells, which secrete hormones essential for homeostasis. The gland consists of the adenohypophysis (anterior pituitary) and the neurohypophysis (posterior pituitary), two unique structures that differ anatomically and functionally.
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Which hormones does the anterior lobe of he pituitary gland make?
Adrenocorticotrophic hormone (ACTH) -
Plays a role in how you’re body responds to stress.
It stimulates your adrenal glands to produce cortisol, which has many functions such as controlling BP, metabolism, blood glucose and inflammation.
Follicle stimulating hormone (FSH) -
FSH stimulates sperm production in males. FSH stimulates the ovaries to produce oestrogen and plays a role in egg development in females. This is known as a gonadotrophic hormone.
Growth hormone (GH)-
In children, growth hormone stimulates growth. In other words, it helps children grow taller. In adults, growth hormone helps maintain healthy muscles and bones and impacts fat distribution. GH also impacts your metabolism.
Luteinising hormone (LH)-
LH stimulates ovulation in females and testosterone in males. LH is also known as a gonadotrophic hormone because of the role it plays in controlling the function of the ovaries and testes, known as the gonads.
Prolactin-
Prolactin stimulates breast milk production (lactation) after giving birth. It can also affect fertility and sexual functions in adults.
Thyroid stimulating hormone (TSH)-
TSH stimulates your thyroid to produce thyroid hormones that manage your metabolism, energy levels and your nervous system.
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Which hormones are made in the posterior pituitary lobe?
Antidiuretic hormone (ADH/vasopressin)-
This hormone regulates the water balance and sodium levels in your body.
Oxytocin-
Your hypothalamus makes oxytocin, and your pituitary gland stores and releases it. In females, oxytocin helps labor to progress during childbirth by sending signals to their uterus to contract. It also causes breast milk to flow and influences the bonding between parent and baby. In males, oxytocin plays a role in moving sperm.
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Hypopituitarsm
Hypopituitarism happens when the pituitary gland is not active enough. It does not make enough hormones. Hypopituitarism can directly affect the pituitary gland. Or it can indirectly affect the gland through changes in the hypothalamus. Symptoms depend on which hormones the pituitary gland is not making enough of ie:
GH deficient
LH/FSH deficient
TSH deficient
ACTH deficient
ADH deficient
Prolactin deficient
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Signs and symptoms of GH deficiency (hypopituitarism)
Growth hormone (GH) deficiency
In children, GH deficiency may cause growth problems and short stature. Most adults who have GH deficiency don't have any symptoms, but for some adults it can cause:
• Fatigue
• Muscle weakness
• Changes in body fat composition
• Lack of ambition
• Social isolation
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Signs and symptoms of LH/FSH deficiency (hypopituitarism)
Luteinising hormone (LH) and follicle-stimulating hormone (FSH) deficiency
Deficiency of these hormones, called gonadotropins, affect the reproductive system. In women, the deficiency decreases egg and estrogen production from the ovaries. In men, the deficiency decreases sperm and testosterone production from the testicles. Women and men may experience a lower sex drive, infertility or fatigue. In children and adolescents, delayed puberty is usually the only symptom.
Women may also have symptoms such as:
○ Hot flashes
○ Irregular or no periods
○ Loss of pubic hair
○ An inability to produce milk for breast-feeding
Men may also have symptoms such as:
§ Erectile dysfunction
§ Decreased facial or body hair
§ Mood changes
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Signs and symptoms of TSH deficiency (hypopituitarism)
Thyroid-stimulating hormone (TSH) deficiency
This hormone controls the thyroid gland. A TSH deficiency leads to low levels of thyroid hormones (hypothyroidism). This causes symptoms such as:
□ Fatigue
□ Weight gain
□ Dry skin
□ Constipation
□ Sensitivity to cold or difficulty staying warm
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Signs and symptoms of ACTH deficiency (hypopituitarism)
Adrenocorticotropic hormone (ACTH) deficiency
This hormone helps your adrenal glands work properly, and helps your body react to stress. Symptoms of ACTH deficiency include:
® Severe fatigue
® Low blood pressure, which may lead to fainting
® Frequent and prolonged infections
® Nausea, vomiting or abdominal pain
® Confusion
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Signs and symptoms of ADH deficiency (hypopituitarism)
Anti-diuretic hormone (ADH) deficiency
This hormone, which is also called vasopressin, helps your body balance its fluid levels. An ADH deficiency can cause a disorder called diabetes insipidus, which can cause:
◊ Excessive urination
◊ Extreme thirst
◊ Electrolyte imbalances
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Signs and symptoms of prolactin deficiency (hypopituitarism)
Prolactin deficiency
Prolactin is the hormone that tells the body when to start making breast milk. Low levels of prolactin can cause women to have problems making milk for breast-feeding.
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Causes of hypopitiutarism
Main cause = tumour of the pituitary gland
• Head injuries
• Brain surgery
• Radiation treatment to the head or neck
• Lack of blood flow to the brain or pituitary gland (stroke) or bleeding (hemorrhage) into the brain or pituitary gland
• Certain medications, such as narcotics, high-dose corticosteroids or certain cancer drugs called checkpoint inhibitors
• Inflammation of the pituitary gland caused by an abnormal immune system response (hypophysitis)
• Infections of the brain, such as meningitis, or infections that can spread to the brain, such as tuberculosis or syphilis
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Diagnosing hypopituitarism
Blood tests:
Thyroid
Adrenal
Sex hormones
Brain imaging
MRI/CT to detect a tumour
Vision tests:
Determine if growth of tumour has affected sight
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Treatment of hypopituitarism
Hormone replacement medications may include:
• Corticosteroids. These drugs, such as hydrocortisone (Cortef) or prednisone (Rayos), replace the adrenal hormones that aren't being produced because of an adrenocorticotropic hormone (ACTH) deficiency. You take them by mouth.
• Levothyroxine (Levoxyl, Synthroid, others). This medication treats the low thyroid hormone levels (hypothyroidism) that a thyroid-stimulating hormone (TSH) deficiency can cause.
• Sex hormones. These include testosterone in men and estrogen or a combination of estrogen and progesterone in women. Testosterone is administered either by injection or through the skin with a patch or a gel. Female hormone replacement can be administered with pills, gels or patches.
• Growth hormone. Also called somatropin (Genotropin, Humatrope, others), growth hormone is administered through an injection beneath your skin. It promotes growth, which helps produce a more normal height in children. Adults with symptoms of growth hormone deficiency also may benefit from growth hormone replacement, but they won't grow taller.
• Fertility hormones. If you've become infertile, gonadotropins can be administered by injection to stimulate ovulation in women and sperm production in men.
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Prolactinoma
A prolactinoma occurs when some of the cells in the pituitary gland (the ones producing prolactin) multiply more than usual to form a small growth (tumour) in the pituitary gland. The prolactinoma makes too much prolactin and this can cause symptoms.
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Signs and symptoms of prolactinoma
Women
Irregular or no periods (as prolactin decreases FSH/LH)
Reduced fertility
Reduced sex drive
Galactorrhea
Increased hair growth on face and body
Men
Reduced fertility
Erectile dysfunction
Reduced sex drive
Breast enlargement
Galactorrhea
Children
Reduced growth
Delayed puberty
Everyone- also may press on the brain if the prolactinoma grows large causing symptoms such as:
Head ache
Eye symptoms (bitemporal heminopia)
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Diagnosis of prolactinoma
1) The first test for women is a pregnancy test - prolactin goes up in pregnancy, and occasionally an undiagnosed pregnancy can be mistaken for a prolactinoma. A blood sample can check the level of prolactin in the blood. A very high prolactin level usually means that a prolactinoma is present. However, there are other causes of raised prolactin levels. For example, some medicines may cause high prolactin levels. These include:
• Anti sickness medication
• Anti depressants (SSRI) type
• Some medicines used to treat schizophrenia or bipolar disorder
2) thyroid and kidney function tests
3) eye test
4) scans - MRI/CT + bone density scan
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Treatment of prolactinoma
Treatment usually works well to stop the symptoms of prolactinoma and to improve fertility. There are various options to treat prolactinomas but the usual treatment is medication. Some treatment options depend on the size of the growth.
Not treating may be an option
For a small prolactinoma (a microprolactinoma), if symptoms are not too troublesome then one option is just to monitor the situation. This means having regular blood tests and possibly scans. If symptoms get worse or the prolactinoma seems to be growing, treatment can be started whenever necessary.
If you are choosing the no-treatment option, you may be advised to take oestrogen hormones (for women) or testosterone hormones (for men). This can help to prevent 'thinning' of the bones (osteoporosis).
Medication
Dopamine agonists - bromocriptine, cabergoline, quinagolide
These act on the pituitary gland to reduce the amount of prolactin it makes, as well as also shrinking the tumour
Medication during pregnancy
If you are planning pregnancy, it is best to discuss treatment options with your doctor beforehand. Treating the prolactinoma usually improves fertility, so can help you become pregnant. Bromocriptine is thought to be the safest of the dopamine agonists for pregnancy, because it is the most tried and tested one. Many women have had babies after taking bromocriptine.
Surgery
Surgery may be an option if medication does not work, is not wanted, or for larger prolactinomas. The operation is called trans-sphenoidal surgery, because the surgeon gets to the pituitary gland through the sphenoid bone, via a small cut above the upper front teeth or from inside a nostril. It is done under general anaesthetic.
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Thyroid gland
Thyroid gland
• Consists of 2 lateral lobes → cover the anterolateral surfaces of the trachea, cricoid cartilage and lower part of thyroid cartilage
• Isthmus → connects lateral lobes. Crosses anterior surfaces of 2nd and 3rd tracheal cartilages
• Is in the visceral compartment of the neck → lying deep to the sternohyoid, sternothyroid and omohyoid muscles
• Arterial supply:
○ Superior thyroid artery
○ Inferior thyroid artery
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Parathyroid glands
Parathyroid glands
• Two pairs of small, ovoid, yellowish structures on deep surface of the lateral lobes of thyroid gland
• Designated as superior and inferior parathyroid glands
• Arterial supply:
○ Inferior thyroid arteries
○ Superior thyroid arteries may contribute to supply of superior parathyroid glands
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Thyroid hormone release
Thyroid hormone release
• Released as part of the hypothalamic-pituitary-thyroid axis.
• Hypothalamus detects low plasma concentration of thyroid hormone and releases thyrotropin-releasing hormone into the hypophyseal portal system
• TRH binds to receptors on thyrotrophic cells of the anterior pituitary gland, causing them to release thyroid stimulating hormone into the systemic circulation
• TSH binds to TSH receptors on basolateral membrane of thyroid follicular cells and induces synthesis and release of thyroid hormone
Thyroid hormone:
• Represents a combination of two main hormones that the thyroid gland releases:
○ Thyroxine (T4)
○ Triiodothyronine (T3)
• Often collectively referred to as 'thyroid hormone' because T4 is largely inactive (doesn't impact cells) and T3 is active
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The pathway of T3 and T4 and how this is regulated through negative feedback
The hypothalamus releases thyrotropin-releasing hormone (TRH).
• TRH stimulates the anterior pituitary to release thyroid-stimulating hormone (TSH).
• TSH stimulates the thyroid gland to release triiodothyronine (T3) and thyroxine (T4).
The hypothalamus and anterior pituitary respond to T3 and T4 by suppressing the release of TRH and TSH, resulting in lower amounts of T3 and T4.
The lower T3 and T4 offer less suppression of TRH and TSH, causing more of these hormones to be released, resulting in a rise of T3 and T4.
This way, the thyroid hormone level is closely regulated to keep it within normal limits.
When the end hormone (e.g., T3 and T4) suppresses the release of the controlling hormones (e.g., TRH and TSH), this is called negative feedback.
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Primary vs secondary hyperthyroidism
Hyperthyroidism is where there is over-production of the thyroid hormones, triiodothyronine (T3) and thyroxine (T4), by the thyroid gland.
• Thyrotoxicosis refers to the effects of an abnormal and excessive quantity of thyroid hormones in the body.
Primary hyperthyroidism is due to thyroid pathology. The thyroid is behaving abnormally and producing excessive thyroid hormone.
Secondary hyperthyroidism is due to pathology in the hypothalamus or pituitary. The pituitary gland produces too much thyroid-stimulating hormone, stimulating the thyroid gland to produce excessive thyroid hormones.
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Graves’ disease
Graves’ disease is an autoimmune condition where TSH receptor antibodies cause primary hyperthyroidism. These TSH receptor antibodies, produced by the immune system, stimulate TSH receptors on the thyroid. This is the most common cause of hyperthyroidism.
• Exophthalmos (also known as proptosis) describes the bulging of the eyes caused by Graves’ disease. Inflammation, swelling and hypertrophy of the tissue behind the eyeballs force them forward, causing them to bulge out of the sockets.
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Toxic multinodular goitre
Toxic multinodular goitre (also known as Plummer’s disease) is a condition where nodules develop on the thyroid gland, which are unregulated by the thyroid axis and continuously produce excessive thyroid hormones. It is most common in patients over 50 years.
• Goitre refers to the neck lump caused by swelling of the thyroid gland.
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Primary vs secondary hypothyroidism
Hypothyroidism refers to insufficient thyroid hormones, triiodothyronine (T3) and thyroxine (T4).
Primary hypothyroidism is where the thyroid behaves abnormally and produces inadequate thyroid hormones. Negative feedback is absent, resulting in increased production of TSH. TSH is raised, and T3 and T4 are low.
Secondary hypothyroidism, also called central hypothyroidism, is where the pituitary behaves abnormally and produces inadequate TSH, resulting in under-stimulation of the thyroid gland and insufficient thyroid hormones. TSH, T3 and T4 will all be low.
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What tests are used to diagnose thyroid disease?
Hormone tests
· Thyroid stimulating hormone (TSH) are used as a screening test for thyroid disease. Triiodothyronine (T3) and thyroxine (T4) can be measured
○ Primary hyperthyroidism (thyroid behaves abnormally): High T3 & T4, Low TSH
○ Secondary hyperthyroidism (pituitary behaves abnormally): High T3, T4, TSH
○ Primary hypothyroidism: Low T3, T4, High TSH
○ Secondary hypothyroidism: Low T3, T4, TSH
TSH T3 and T4
Primary hyperthyroidism Low High
Secondary hyperthyroidism High High
Primary hypothyroidism High Low
Secondary hypothyroidism Low Low
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Imaging in the diagnosis of thyroid disease
Imaging
· Ultrasound of thyroid gland – diagnose thyroid nodules and distinguish between cystic and solid nodules
· Radioisotope scans – investigate hyperthyroidism and thyroid cancers
○ Radioactive iodine is given orally or IV and travels to thyroid, where it’s taken up by thyroid cells. Iodine needed to produce thyroid hormones.
○ Gamma camera detects gamma rays emitted from radioactive iodine, the greater the rays emitted, the more radioactive iodine has been taken up:
→ Diffuse high uptake found in Grave’s disease
→ Focal high uptake found in toxic multinodular goitre and adenomas
→ ‘Cold’ area (abnormally low uptake) can indicate thyroid cancer
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Antibody testing for thyroid disease diagnosis
Antibodies
· Anti-TPO antibodies are antibodies against thyroid gland – most relevant thyroid autoantibody in autoimmune thyroid disease. Present in Grave’s disease and Hashimoto’s thyroiditis
· Anti-Tg antibodies are antibodies against thyroglobulin – protein produced and present in thyroid gland. Raised in Grave’s, Hashimoto’s and thyroid cancer. Can be present in healthy individuals too.
· TSH receptor antibodies – autoantibodies that mimic TSH. Bind to TSH receptor and stimulate thyroid hormone release. Cause Grave’s disease
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Additional investigations used in thyroid disease diagnosis
Other investigations that could be conducted
· FBC – to rule out anaemia (Hb, haematocrit) / infection (white blood cells)
· B12 and Folate
· Serum lipids
· HbA1c
· Coeliac serology
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Carbimazole indication and dose
Indication:
Hyperthyroidism
Dose:
15-40 mg daily until the patient becomes euthyroid, usually after 4-8 weeks. Higher does should be prescribed under specialist supervision only.
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Carbimazole side effects
Rare or very rare: Bone marrow disorders, haemolytic anaemia, severe cutaneous adverse reactions, thrombocytopenia
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Mod of action of Carbimazole
When you have an overactive thyroid, also known as hyperthyroidism or thyrotoxicosis, your thyroid gland produces too much of the thyroid hormones. When these hormone levels are too high, you can have mood swings and weight loss.
Your thyroid gland uses a chemical called iodine to produce these hormones. Carbimazole blocks the way your body processes iodine and reduces the amount of thyroid hormones produced. This can then help your symptoms.
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Indication an dose of propanolol
Indication:
Thyrotoxicosis, hypertension, prophylaxis of variceal bleeding in portal hypertension, angina, hypertrophic cardiomyopathy anxiety tachycardia, anxiety with symptoms such as palpitation, sweating and tremor, arrhythmias (plus a few more)
Dose:
Hypertension: initially 80 mg twice daily, dose should be increased at weekly intervals as required; maintenance 160-230 mg daily
Modified released preparations can be used for once daily administration.
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Contra indications of propanolol
Asthma, cardiogenic shock, hypotension, bradycardia, metabolic acidosis
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Side effects of propanolol
Abdominal discomfort, bradycardia, confusion, depression, diarrhoea, dizziness, dry eye, dyspnoea, rash, syncope, vomiting, heart failure (many more)
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Radioactive sodium (131) iodine indications, dose and safety information
Indications:
Hyperthyroidism, some types of thyroid cancer
Dose and safety information:
The dose of radiation used during radioactive iodine treatment is very low, but there are some precautions you'll need to take after treatment:
• avoid prolonged close contact with children and pregnant women for about 3 weeks
• women should avoid getting pregnant for at least 6 months
• men should not father a child for at least 4 months
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Mode of action of radioactive iodine
Radioactive iodine is a targeted treatment. The radioactive iodine circulates throughout your body in your bloodstream. It is mainly taken up by thyroid cells, having little effect on other cells. Thyroid cancer cells in your body pick up the iodine. The radiation in the iodine then kills the cancer cells.
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Levothyroxine indication and dose
Primary hypothyroidism
Initially 1.6 micrograms/kg once daily, adjusted according to response, round dose to nearest 25 micrograms. Dose to be taken preferably 30-60 minutes before breakfast, caffeine-containing liquids or other medication.
See BNF for dose in elderly.
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Levothyroxine side effects
Angina pectoris, anxiety, arrhythmias, arthralgia, diarrhoea, dyspnoea, fever, flushing, headache (many more)
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Levothyroxine mode of action
Levothyroxine is a synthetic version of thyroxine. You take levothyroxine tablets to replace the thyroxine that your thyroid gland cannot produce and prevent the symptoms of hypothyroidism.
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Hyperthyroidism drug management
Hyperthyroidism Management
A specialist endocrinologist guides the treatment of hyperthyroidism.
Carbimazole is the first-line anti-thyroid drug, usually taken for 12 to 18 months. Once the patient has normal thyroid hormone levels (usually within 4-8 weeks), they continue on maintenance carbimazole and either:
• The carbimazole dose is titrated to maintain normal levels (known as titration-block)
• A higher dose blocks all production, and levothyroxine is added and titrated to effect (known as block and replace)
TOM TIP: The MHRA issued a warning in 2019 about the risk of acute pancreatitis in patients taking carbimazole. In your exams, look out for a patient on carbimazole presenting with symptoms of pancreatitis (e.g., severe epigastric pain radiating to the back).
Propylthiouracil is the second-line anti-thyroid drug. It is used in a similar way to carbimazole. There is a small risk of severe liver reactions, including death, which is why carbimazole is preferred.
TOM TIP: Both carbimazole and propylthiouracil can cause agranulocytosis, with a dangerously low white blood cell counts. Agranulocytosis makes patients vulnerable to severe infections. A sore throat is a key presenting feature of agranulocytosis. In your exams, if you see a patient with a sore throat on carbimazole or propylthiouracil, the cause is likely agranulocytosis. They need an urgent full blood count and aggressive treatment of any infections.
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Parathyroid anatomy and role
Parathyroid Anatomy
· The parathyroid glands sit in the neck, on the posterior surface of the lateral lobes of the thyroid.
· Most adults have four, which are commonly described in two pairs (the superior and inferior parathyroid glands), although their positions in the neck can be highly variable.
Role
Normal Physiology
· Normally the role of the parathyroid glands is to regulate serum calcium and phosphate levels via the secretion of parathyroid hormone (PTH) from chief cells.
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Hyperparathyroidism
Hyperparathyroidism
• Hyperparathyroidism occurs when there is an excess of PTH being secreted from the parathyroid glands in the neck due to the disturbance of the calcium homeostasis mechanism.
• It is the most common cause of hypercalcaemia, therefore is seen quite common in both primary and secondary care.
There are three sub-types of hyperparathyroidism
1. Primary hyperparathyroidism (over secretion of PTH, despite normal serum calcium which leads to hypercalcaemia
2. Secondary hyperparathyroidism (due to a disorder in calcium phosphate bone metabolism)
3. Tertiary hyperparathyroidism (Following a prolonged period of hyperparathyroidism. Glands become hyperplastic and secrete PTH autonomously)
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Hyperparathyroidism history and blood test results;
Primary, secondary and tertiary
Type History Blood test results
Primary hyperparathyroidism Often asymptomatic, may have a family history ↑PTH ↑ Ca2+
if associated with a genetic condition like MEN
Secondary hyperparathyroidism Conditions affecting calcium metabolism such as ↑PTH ↓Ca2+
vitamin D deficiency, CKD or nutritional calcium deficiency
Tertiary hyperparathyroidism As for secondary, often with evidence of recent
treatment of the condition such as vitamin D
replacement in deficiency
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Clinical presentation of parahyperthyroidism;
History
Symptoms
History:
Primary hyperparathyroidism is commonly asymptomatic and picked up incidentally on blood test
But as serum calcium increases, so does the probability of having symptoms. When present symptoms are often mild and non-specific, the same as hypercalcaemia regardless of the underlying cause.
Symptoms
· Fatigue
· Polyuria and polydipsia
· Constipation
· Abdominal pain
· Vomiting
· Confusion
· Depression
· Bone pain
· Renal stones
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What laboratory investigations should be done for suspected parahyperthyroidism
Laboratory Investigations
· Corrected calcium: in patients with suspected primary hyperparathyroidism.
· Serum PTH: measure with a paired corrected calcium - helpful to suggest the cause for hypercalcaemia.
· Vitamin D: if low, offer supplements
· Urea & electrolytes: chronic kidney disease is a common cause
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Imaging of Hyperparathyroidism
Imaging
• DEXA scan: to assess for reduce bone mineral density - osteoporosis
• Ultrasound of renal tract: looking for renal stones
• Ultrasound of the neck: pre-operative planning and to identify adenomas (first-line)
• Nuclear imaging (eg sestamibi scan): for pre-operative planning and to identify adenomas (first-line)
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Management of parahyperthyroidism
Management
Mild primary hyperparathyroidism:
• May only require monitoring symptoms and complications
• Annual tests for corrected calcium and creatinine or eGFR
• Also cardiovascular and fracture risk
Medical Management
Acute, severe hypercalcaemia
Urgent management in secondary care
1. IV fluids
2. Bisphosphates: preserve bone density and reduce fracture risk
3. Cinacalcet (a calcium-sensing receptor agonist): reduces PTH secretion and thus serum calcium. Used in primary hyperparathyroidism when surgery isn't appropriate, declined or unsuccessful
Secondary hyperparathyroidism
• Treat the underlying cause
• Cinacalcet if this fails or if patient is on dialysis
• Phosphate binders and calcium/vit D supplements for those who have chronic kidney disease
Tertiary hyperparathyroidism
• Surgical intervention (partial parathyroidectomy)
• Residual parathyroid tissue is reimplanted elsewhere in the body - more accessible if future problems arise
Surgery
• Curative therapies: parathyroidectomy
• NICE recommend surgical management if the patient has:
1. Symptoms of hypercalcaemia such as thirst, polyuria and constipation
2. End-organ disease (renal stones, fragility fractures or osteoporosis)
3. Corrected calcium level of 2.85mmol/litre or greater
COMPLICATIONS of Surgery
- Hypocalcaemia
- Hoarseness and cough due to damage to the recurrent laryngeal nerve, bleeding, infection or failure of surgery
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What is acromegaly and what are its symptoms
Acromegaly
Acromegaly is the hypersecretion of pituitary growth hormone, usually as a result of a pituitary tumour, which leads to an abnormal increase in size of the skeletal extremities.
· Rare – approx 3-4 people in every million
· Most often caused by a benign pituitary tumour, but can in rare cases be caused by a non-endocrine tumour secreting GH
· Further divided into micro and macroadenomas (macros most common) = Acro – extremities, mega – large
· Some genetic link
Symptoms:
· Onset often slow and insiduous, most often diagnosed in middle age. Men and women are equally affected.
· Growth of hands and feet
· Change in facial features – widening bridge of nose, thick lips, protruding jaw and brow, macroglossia, teeth seperation
· Headaches and visual disturbance due to tumour
· Deeper voice
· Skin tags, excessive sweating. Mild hirsuitism in women.
· Joint pain and carpal tunnel syndrome.
· Hypertension and diabetes
· Organomegaly (liver/spleen/goitre)
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Acromegaly investigations
Investigations
· Routine bloods – glucose, lipids, bone profile (may all be raised)
· IGF-1 excludes acromegaly if normal
· OGTT to confirm raised IGF-1
· Check thryoid, prolactin, gonadal and adrenal hormones
· MRI scan to assess for tumour
· CT if non-endocrine tumour suspected
· Cardiac work up: ECG and echo
· Thyroid ultrasound (inc risk of Ca)
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Acromegaly treatment
Treatment
· Nothing is 100% so normally a combination
· Endoscopic trans-sphnoidal surgery first line
· Radiotherapy as adjuvant
· Somatostatin analogues first line drug treatment (ie octreotide)
· Dopamine agonists such as bromocriptine sometimes used
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What is diabetes insipidus?
Diabetes insipidus
Diabetes Insipidus (DI) is a disorder caused by hyposecretion or insensitivity to ADH which leads to polydipsia, polyuria and large amounts of dilute urine.
1. Cranial DI – caused by any condition which impairs the production, transportation or release of ADH which in turn reduces the process involved in the concentration of urine leading to polyuria and polydipsia.
2. Nephrogenic DI – decreased inability to concentrate urine due to conditions within the renal collecting duct causing a resistance to ADH. There are also two minor forms of DI
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Causes and symptoms of diabetes insipidus:
Causes:
· Idiopathic
· Tumour of the brain- craniopharyngioma, germinoma, lymphoma
· Intracranial surgery
· Head injury
· Infection- encephalitis, meningitis
· Vascular disorder- aneurysms, sickle cell disease
· Radiotherapy
Symptoms
Polyuria
Large dilute vol of urine
Polydispsia
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Investigations of diabetes insipidus
Investigation
Record 24 hr urine = looking for >3L within 24hrs
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Management of diabetes insipidus
Management: varies based on form of DI = nephrogenic DI:
· Oral fluids encouraged
· Metabolic abnormalities are corrected if present
· Medication review for possible causes/worsening drugs
· If symptoms are mild (<4L urine per day) intervention is not usually advised
· Moderate cases – treated with Desmopressin.
· Can consider combination treatment involving thiazide diuretic and NSAID
· In severe cases may require intermittent catheterization
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Androgen secreting tumours
• These tumors make too much testosterone and can cause a virilizing (i.e. masculinizing) syndrome.
• Women with tumors that make androgens (male hormones) may notice excessive facial and body hair growth, a receding hairline, acne, irregular menstrual periods, deepening of their voice (hirsutism) and ambiguous genitalia.
• Diagnosis: high blood testosterone + DHEA-s levels + urine 17 ketosteroids
• Localization: imaging- MRI/CAT scan to find the location of the tumour or venous sampling: surgeon/radiologist draws blood out directly from the veins draining both adrenal glands and ovaries = determine which organ is making too much hormone
• Treatment: remove tumour- open adrenalectomy with lymph node dissection ( these tumours have a high risk of spreading to lymph nodes.
• Drugs that destroy adrenal tissue: mitotane or ketoconazole
• Young patients with complete removal of the tumour have a better prognosis than older patients with larger tumours.
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Pheochromocytoma (fee-o-kroe-moe-sy-TOE-muh)
A pheochromocytoma (fee-o-kroe-moe-sy-TOE-muh) is a rare, usually benign tumor that develops in an adrenal gland. However, 1 in 10 pheochromocytomas are malignant.
Pheochromocytomas are catecholamine producing tumours (usually from sympathetic paraganglion cells in adrenal medulla).
• The adrenal glands are part of the body's hormone-producing (endocrine) system. The endocrine system also includes the pituitary gland, thyroid gland, parathyroid glands, pancreas, ovaries (in females) and testicles (in males).
Usually, a pheochromocytoma develops in only one adrenal gland.
The adrenal glands make the hormones adrenaline and noradrenaline, which are released into the bloodstream when needed. These hormones control heart rate, blood pressure and metabolism.
• If you have a pheochromocytoma, the tumor releases hormones that may cause high blood pressure, headache, sweating and symptoms of a panic attack. If a pheochromocytoma isn't treated, severe or life-threatening damage to other body systems can result.
Surgery to remove a pheochromocytoma usually returns blood pressure to normal.
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Symtoms of pheochromocytomas
Signs and symptoms of pheochromocytomas often include:
• High blood pressure
• Headache
• Heavy sweating
• Rapid heartbeat
• Tremors
• Pallor
• Shortness of breath
• Panic attack-type symptoms
Less common signs or symptoms may include:
• Anxiety or sense of doom
• Blurry vision
• Constipation
• Weight loss
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Complications of Pheochromocytoma
Complications
High blood pressure can damage organs, particularly tissues of the heart and blood vessel (cardiovascular) system, brain and kidneys. This damage can cause several critical conditions, including:
• Heart disease
• Stroke
• Kidney failure
• Problems with the nerves of the eye
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Differentials of Pheochromocytoma
The typical primary symptom is hypertension, which may be either episodic or continual. A diagnosis of pheochromocytoma should be suspected when the patient simultaneously presents with hypertension and the classic triad of heart palpitations, headaches, and profuse sweating.
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Investigations and management of Pheochromocytoma
Investigations:
• Plasma + 3x24hr urinary metadrenaline and normetadrenaline
• Abdominal CT or MRI (to detect adrenal tumours)
Management:
• Alpha blockade and beta blockade
• Surgery, if malignant then chemotherapy and radiotherapy may be helpful
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Psychiatric manifestations of hypothyroidism
Cognitive changes
Impaired memory
Reduced attention spam
Vegetative symptoms
Hypersomnia
Sleep apnoea
Fatigue
Apathy
Low libido
Mood
Depression
Mood instability
Mania
Anxiety
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Affect of hyperthyroidism on mood and cognitive function
Hyperthyroidism
1. Depression and anxiety (mainly nervousness)
2. Irritability
3. Memory impairment
4. Palpitations
