Week 4 Flashcards
In what context is a low sodium serious?
If it is under 120 mmol/L
If it has rapidly fallen from normal to almost serious levels - this too can be severe
NB - this also applies to hypernatraemia
Sodium is confined to the (intracellular/extracellular) fluid
extracellular
What other ion mirrors sodium? What pump is used by these two to interact?
Potassium
The Na+/K+-ATPase pump
Too much mineralocortiocoid (i.e. aldosterone) activity means (loss/retention) of sodium
Too little mineralocortiocoid (i.e. aldosterone) activity means (loss/retention) of sodium
Too much aldosterone = sodium retention
Too little aldosterone = sodium loss
Increased ADH = (lowered/raised) urine concentration
Decreased ADH = (lowered/raised) urine concentration
Increased ADH = raised concentration of urine
Decreased ADH = dilute urine
Patient presents with DKA and has been vomiting a lot, therefore has lost a lot of fluid
How does this affect Sodium?
Raised plasma sodium (water loss exceeds sodium loss) i.e. hypernatraemia
How does Addison’s disease result in hyponatraemia and hyperkalaemia?
Damage to adrenal gland = cannot make mineralocorticoids (mainly aldosterone)
Lack of aldosterone = inability to retain sodium, lost in the urine.
Low sodium also means Na+/K+-ATPase pump cannot function, so potassium is retained.
Where are the anterior and posterior pituitary derived from, embryologically?
Anterior - derived from Rathke’s pouch
Posterior - extension of neural tissue consisting of modified glial cells and axonal processes
What type of cells secrete the following hormones in the anterior pituitary
- GH
- PRL
- LH/FSH
- TSH
- ACTH
GH - somatotrophs
PRL - mammotrophs
LH/FSH - gonadotrophs
TSH - thyrotrophs
ACTH - corticotrophs
What genetic defect are Pituitary Adenomas associated with?
MEN1
Name some posterior pituitary syndromes
SIADH
Diabetes insipidus
How much do the adrenal glands weigh?
4-5g each
What is Waterhouse-Friderichsen Syndrome?
Acute adrenocortical hypofunction
Caused by bleeding into the adrenal glands, commonly due to severe bacterial infection (typically Neisseria meningitides)
What cell type are phaeochromocytomas derived from?
What do they secrete?
Derived from Chromaffin cells in the adrenal medulla
Secrete catecholamines (adrenaline, noradrenaline
Phaeochromocytoma - presentation
Hypertension (90%) - paroxysmal episodes are common, brought about by stress, exercise, postural changes, palpation of tumour
Complications - cardiac failure, infarctions, arrhythmias
Phaeochromocytoma - investigation
Detection of urinary excretion of catecholamines and metabolites
Why are phaeochromocytomas known as the “10% tumour”?
10% are extra-renal
10% are bilateral
10% are biologically malignant
10% are NOT associated with hypertension
(25% are familial)
What special feature do phaeochromocytomas exhibit histologically?
Tumour cells cluster together and form nests - zellballen
What genetic defect are phaeochromocytomas associated with?
MEN2A
MEN2B
What does each layer of the adrenal cortex secrete?
Zona Glomerulosa - secretes mineralocorticoids (e.g. aldosterone)
Zona Fasciculata - secretes glucocorticoids (e.g. cortisol)
Zona Reticularis - sex steroids and glucocorticoids
Why should a fluid bolus not be given to a child with DKA (unless you suspect they are in shock)?
How is this risk moderated?
Because of the risk of cerebral oedema
In order to minimise the risk of cerebral oedema, start giving IV fluids 1 hour before giving insulin
If a child presents to you in clinic and you suspect DKA, at what point would you arrange immediate hospitalisation?
Child presents with elevated blood glucose, no ketones in urine and clinically well - urgent referral to paediatric team and arrange review in 24 hours
Child presents with elevated blood glucose, ketones present in urine and clinically well - urgent referral to paediatric team and same day review
Child presents with elevated blood glucose, ketones in urine and symptoms of DKA - immediate emergency referral via ambulance
What is the first clinical sign that will be seen in diabetic nephropathy?
What other microvascular complications might develop?
Microalbuminuria is the first sign to appear
Sensory nerve damage
Diabetic retinopathy
Skin vascular changes
Diabetic cheiroarthrpathy (thickened skin and swelling of the joints)
16 year old patient with type 1 DM needs to work out how much insulin to take prior to a meal.
Current bloog glucose = 10 mmol
Having lasagne = 70g carbohydrate
Carb ratio is 1:10 i.e. 1 unit of insulin = 10g carbs
Insulin sensitivity is 1:2 i.e. 1 unit of insulin = drop of 2 mmol glucose
Target blood glucose is 6 mmol
Currently at 10, target is 6, therefore 2 units to bring to desired blood glucose
70g carbohydrates will require 7 units to cover
7 + 2 = 9 units of insulin total
Congenital thyroid disease in the young - presentation
Jaundice is the most common symptom
Poor feeding but “normal” weight gain
Hypotonia (“floppy baby syndrome”)
Skin and hair changes
How is congenital thyroid disease screened for?
When is this done? Why?
By performing the Guthrie Test - pin prick blood test taken from the heel of the baby that screens for a variety of diseases, including measuring TSH levels
Performed at day 5, as babies have a naturally high TSH when first born
What does continued absence of thyroxine in a baby result in?
Absence of thyroxine after 3 months of life leads to global developmental delay - cretinism
What is the most common cause of acquired thyroid disease in the young?
What are some of the other causes?
Most common cause - autoimmune
Other causes - post-infectious, delayed congenital, iodine deficiency
How do hypo and hyperthyroidism present in the young?
Hypothyroidism
- slow progress
- failure to grow, delayed puberty
- poor general health
- educational difficulties
Hyperthyroidism
- general symptoms - behaviour problems, anxiety, restlessness, sleep disturbances
- Goitre - more likely than in hypo
- precocious puberty
How would virilisation as a result of Congenital Adrenal Hyperplasia (and therefore excess testosterone) present in a) boys and b) girls
Boys - precocious puberty
Girls - ambiguous genitalia
Congenital Adrenal Hyperplasia can cause a deficiency in Aldosterone and Cortisol, which could precipitate an Addisonian Crisis.
What are the 3 main features of an Addisonian Crisis?
Hyponatraemia
Hyperkalaemia
Hypotension
During development, what are the names of the male and female ducts?
What causes the regression of each?
How is this affected by CAH?
Male duct - Wollfian ducts, regression is caused by a lack of testosterone (due to the presence of ovaries)
Female duct - Mullerian ducts - regression is caused by anti-Mullerian Hormone produced by Sertoli cells
In CAH, there is excess testosterone produced and so the Wollfian ducts will not regress, hence the appearance of ambiguous genitalia
How are a) monogenic disorders and b) polygenic disorders best evaluated?
Monogenic - historically done through study of families (linkage studies). Now done with Next Gen Sequencing
Polygenic - evaluated by looking at large populations (GWAS - genome-wide association studies)
MEN1 and MEN2 defects are classic examples of (monogenic/polygenic) disorders
Can you name some more?
Monogenic
McCune-Albright
Carney Complex
Von-Hippel Lindau disease
Neurofibromatosis type I
Defects in which genes cause the following conditions?
- MEN1
- MEN2
- McCune-Albright
- Carney complex
- Von-Hippel Lindau
- Neurofibromatosis type I
MEN1 - MEN1 gene
MEN2 - RET gene
McCune-Albright - GNAS1 gene
Carney Complex - PRKAR1A gene
Von-Hippel Lindau - VHL gene
Neurofibromatosis I - NF1
How do MEN1 and MEN2 disorders differ in terms of requirements for pathology to occur?
MEN1 - “two hits”, requires inactivation and tissue activation. MEN1 is a classic tumour suppressor gene
MEN2 - “one hit”, just needs activation as MEN2 is a proto-oncogene
What conditions are the different MEN disorders assocaited with?
MEN1 (3 P’s) - pituitary adenoma, parathyroid hyperplasia, pancreatic cancer
MEN2A - parathyroid hyperplasia, medullary thyroid carcinoma, phaeochromocytoma
MEN2B - mucosal neuromas, Marfanoid body habitus, medullary thyroid carcinomas, phaeochromocytomas
How might someone with McCune-Albright syndrome present clinically?
Cafe-au-lait macules (Coast of Maine appearance)
Polyostotic fibrous displasia (affecting bones)
Precocious puberty (mainly females)
Thyroid nodules
GH excess
Cushing’s syndrome
The mutation seen in Von-Hippel Lindau is (autosomal dominant/autosomal recessive)
Autosomal dominant
What regulates each layer of the adrenal cortex?
Zona Glomerulosa - regulated by Angiotensin II and K+
Zona Fasciculata - regulated by ACTH
Zona Reticularis - regulated by ACTH and “unknown factors”
Everything made by each layer of the adrenal cortex requires what initial component?
Cholesterol
Aldosterone release is regulated by…..
Renin-Angiotensin-Aldosterone system and plasma K+
Angiotensin II has both direct (vasoconstriction) and indirect (activation of aldosterone) effects on BP
List some of the actions of Cortisol
Reduces serum calcium
Reduces wound healing and collagen formation
Reduces the immune/inflammatory response
Increases lipolysis and proteolysis
Causes an increase in blood glucose
Increases Cardiac output, BP and renal blood flow
How does aldosterone affect the sodium/potassium balance?
Causes retention of Na+ and a loss of K+ (and also H+)
What condition is Addison’s commonly misdiagnosed as?
Anorexia
What is the most common cause of adrenal insufficiency in a) developed and b) developing countries?
Developed - Addison’s
Developing - adrenal TB, also HIV/AIDS
Addison’s - treatment
Hormone replacement
Mineralocorticoids - Fludrocortisone
Glucocorticoids - Hydrocortisone
How do you clinically tell the difference between someone with Addison’s and someone with secondary adrenal failure?
What is the most common cause of secondary adrenal failure?
Skin will be pale (as there is no raised ACTH)
Aldosterone production will also be intact
Most common cause of secondary adrenal failure is exogenous steroid use
What is the most common cause of iatrogenic Cushing’s Syndrome?
Prolonged high-dose steroid therapy (e.g. asthma, RA, IBD, transplants)
Chronic suppression of ACTH results in adrenal atrophy
What might be the diagnosis in a patient presenting with hypertension and hypokalaemia?
In what group of people would you specifically want to investigate high BP?
Conn’s Syndrome - primary hyperaldosteronism
90% of hypertension cases are ‘essential’ i.e. no apparent underlying cause. Investigate if the hypertension is persistent despite medications and the patient is young
How is Conn’s Syndrome tested for?
Measure plasma aldosterone and renin levels and express as a ratio
If ratio is raised, investigate further with a saline suppression test - failure to suppress by more than 50% = hyperaldosteronism
Once confirmed, investigate subtype by performing adrenal CT
What is the most common deficiency seen in Congenital Adrenal Hyperplasia?
How is it inherited?
21-Alpha-Hydroxylase (95% of cases)
Autosomal recessive
What classical signs will someone with CAH present with?
Classically present with hirsutism in 20s and 30s
Also salt wasting, acne, oligomenorrhoea, infertility/sub-fertility
Males
- adrenal insufficiency
- poor weight gain
- precocious puberty
Females
- genital ambiguity
In someone with CAH, what will lab studies show?
Hypoglycaemia (due to hypocortisolism)
Hyponatraemia (due to hypocortisolism)
Hyperkalaemia (due to hypoaldosteronism)
Elevated 17alpha-hydroxyprogesterone
What is the classic triad of symptoms associated with a phaeochromocytoma?
Hypertension
Headaches
Sweating
What % of patients with a hip fracture die within a year of the incident?
20%
What is the most widely used measure of assessing bone density?
DEXA bone scans
How are the following classed…
- Osteopenia
- Osteoporosis
- Severe Osteoporosis
Osteopenia - bone mass density is between -1 and -2.5 of the standard deviation
Osteoporosis - bone mass density is equal to or less than -2.5 of the standard deviation
Severe osteoporosis - same as osteoporosis but with fragility fractures
Was is the recommended amount of dietary calcium per day?
How does this change for post-menopausal women?
700mg a day
Post-menopausal women - 1000mg a day
What drugs are available to help prevent fractures?
Bisphosphonates - most commonly used - slows down the breakdown of bone by inhibiting osteoclast activity (e.g. Alendronate, Risedronate)
Calcium and Vit D supplements
HRT
Denosumab
Teriparatide (recombinant form of PTH)
What are some of the long-term concerns associated with bisphosphonate use?
Osteonecrosis of the jaw
Oesophageal cancer
Atypical fractures
How does Teriparatide work?
Recombinant PTH - works to stimulate bone growth, rather than inhibit osteoclast activity
Glucocorticoids have what effect on calcium?
Cause hypocalcaemia
Decreased Ca2+ absorption and increased Ca2+ excretion in the gut
Also affect the kidneys, pituitary and bone (reduces matrix synthesis resorption)
Hence why steroids cause osteoporosis
What is Paget’s Disease of Bone?
How does it present clinically?
Abnormal osteoclastic activity followed by increased osteoblastic activity, resulting in reduced bone strength and increased risk of fracture.
Presents with bone pain, deformity, deafness or compression neuropathies
What biochemical marker can be used to give an indication of osteoclast activity?
Alk Phos
What genes are involved in Osteogenesis Imperfecta?
What is the classical clinical seen in a child?
Mutations of Type I collagen genes (COL1A1, COL1A2)
Child may present with blue-tinted sclera
How is Relative Risk (also known as a risk ratio) calculated?
RR (exposed) = Incidence in exposed/Incidence in not exposed
Which sinuses are closely related to the pituitary gland?
The sphenoid sinus
The Left Recurrent Laryngeal Nerve hooks under ____
The Right Recurrent Laryngeal Nerve hooks under ____
Left - arch of the aorta
Right - Right subclavian artery
How will diffuse causes of goitre (e.g. Grave’s, Thyroiditis) compare to focal causes (e.g. dominant nodule) on scintigraphy?
Scintigraphy assesses pattern and quantity of tracer uptake
Diffuse causes will show a generalised increase in uptake, while focal causes will show a “hot spot”
NB - in the case of TMN goitre, there may be general increased uptake with a dominant nodule causing a hotspot
Describe briefly the physiology of PTH and its relationship to calcium
PTH is released from parathyroid glands…
Acts on the gut to increase absorption
Acts on the bones to increase resorption (increases activity and osteoclasts and decreases the activity of osteoblasts)
Acts on the kidneys to increase resorption
This results in an increase in serum Ca2+
Calcium-Sensing Receptors on the parathyroid gland then pick up this increase in serum calcium and switch off PTH release
What is the active form of Vitamin D? Where is it produced?
Vitamin D is (mostly) taken in via the sun, converted to Cholecalciferol in the skin, then converted to 25 (OH) Vitamin D in the Liver, and then finally converted to it’s active form of 1,25 (OH) Vitamin D in the Kidneys (a.k.a. calcirtiol)
Hypercalcaemia - symptoms
“stones, groans, bones and psychic moans”
Acute - thirst, dehydration, polyuria, confusion
Chronic - myopathy, osteopaenia, fractures, depression, hypertension, renal stones, pancreatitis
Hypercalcaemia - causes
Hyperparathyroidism - main cause
Malignancy
Drugs - Vitamin D, thiazides
Granulomatous diseases - sarcoidosis, TB etc.
Famiilia Hypocalciuric Hypercalcaemia
How is primary hyperparathyroidism diagnosed?
- Raised PTH (or inappropriately normal - should be low to negatively feed back)
- Raised Calcium
- Increased urinary calcium secretion
How is hypercalcaemia treated?
Fluids
Consider diuretics once stable. NB - avoid thiazides
Bisphosphonates to lower Ca2+ (decreases osteoclast activity)
Steroids occasionally used
What are the indications for surgery to treat primary hyperparathyroidism?
It’s either surgery or nothing!
- End organ damage e.g. bone diseases, renal stones, gastric ulcers etc.
- Very high serum Ca2+
- under 50 years old
- GFR <60 ml/min
What are the causes of secondary and tertiary hyperparathyroidism? How do they differ to primary?
Secondary - caused by physiological response to low Calcium e.g. Vitamin D deficiency, renal disease, osteomalacia etc.
Secondary = low Ca2+, high PTH
Tertiary - occurs after many years of secondary, PTH becomes autonomous
Tertiary = high Ca2+, high PTH
How can you differentiate between primary hyperparathyroidism and familial hypocalciuric hypercalcaemia clinically?
(clue is sort of in the name…)
How is FHH inherited?
Both will present with hypercalcaemia and raised PTH
However, FHH will present with LOWERED calcium in the urine, while primary hyperparathyroidism will raised calcium in the urine
FHH is autosomal dominant
What are Trosseau sign and Chovstek sign? What do they indicate?
Trosseau - carpopedal spasm causing flexion at the MCPs, PIPs and DIPs
Chovstek - tapping over the facial nerve elicits a facial twitch
Both are signs of possible hypocalcaemia
What are some of the causes of hypocalcaemia?
Chronic renal failure - most common cause
Vitamin D deficiency (osteomalacia, Rickets)
Hypoparathyroidism
How is acute hypocalcaemia managed?
Medical emergency - treat with 10-10-10
IV calcium gluconate, 10 mls, 10% over 10 mins (in 50ml saline or dextrose)
Which electrolyte is required to make PTH and, if low, may result in hypoparathyroidism?
Mg2+ is required to make PTH, and hypomagnesaemia may result in hypoparathyroidism
Magnesium is also required to release Ca2+ from cells, and so if magnesium is deficient this will result in high intracellular calcium = inhibition of PTH release
What drugs might cause hypomagnesaemia?
(Alcohol)
Thiazide diuretics
PPIs
Pseudohypoparathyroidism - cause and biochemical presentation
Genetic defect = GNAS1 (same as McCune-Albright)
Low Ca2+ but elevated PTH due to PTH resistance
Pseudohypoparathyroidism - presentation
Bone abnormalities
Obesity
Subcutaneous calcification
Learning difficulties
Brachdactyly (4th metacarpal)
What is pseudo-pseudohypoparathyroidism?
Same as pseudohypoparathyroidism, but with normal Ca2+
Osteomalacia - clinical presentation
(NB - rickets = osteomalacia but in children)
Low Ca2+
Muscle wasting due to proximal myopathy
Dental defects
Tenderness, fractures, rib and limb deformities
Hypoparathyroidism - causes
Congenital absence (DiGeorge’s syndrome)
Destruction (surgery, radiotherapy)
Autoimmune
Hypomangesaemia
Idiopathic
Why does hypoparathyroidism result in a lack of Calcium?
No PTH = no resorption of Ca2+ from kidneys, gut and bone = low serum Ca2+
