Endocrinology Flashcards
What are endocrine hormones?
blood borne, acting at distant sites
What are exocrine hormones?
glands that pour secretions through a duct to the site of action
What are paracrine hormones?
hormones acting on adjacent cells
What are autocrine hormones?
Feedback on the same cells that secretes the hormone
Water soluble hormones
how is it transported, interacts with cell, half life, clearance, ex?
unbound, binds to surface receptor, short HL, fast clearance, peptides / monoamines
Fat soluble hormones
how is it transported, interacts with cell, half life, clearance, ex?
Protein bound, diffuses into the cell, long HL, slow, thyroid hormones, steroids
Name the 4 hormone classes?
peptides, amines, iodothyronine, steroids
Nature of peptides as hormones & ex?
linear / ring / vary in length
ex insulin
- stored in secretory granules
- released in pulses or bursts
- cleared by tissue or circulating enzymes
Nature of amines as hormones & ex?
ex adrenaline & noradrenaline
- water soluble
- binds to alpha & beta adrenoreceptors
- stored in secretory granules
- released in pulses or bursts
- rapid clearace
Nature of iodothyronine as hormones & ex?
thyrosine, iodine
- basis of thyroid hormone synthesis
- not water soluble, 99% protein bound
- usually measure T3 & T4 not this
How might iodothyronine be synthesised into thyroid hormones?
- thyroglobulin released into colloid - acts as base for thyroid hormone synthesis
- iodine + tyrosine → iodothyrosine
- conjugation of iodothyrosines give rise to T3 & T4 & stored in colloid bound to thyroglobulin
Subtypes of steroids & cholesterol derivatives?
vitamin D, adrenocortical & gonadal steroids, steroid
Nature of vitamin D?
it is a hormone!!
- fat soluble
- enters cell directly to nucleus to stimulate mRNA production
- Transported by vitamin D binding protein
Nature of adrenocortical & gonadal steroids?
- protein bound - fat soluble
- usually bind to cytoplasmic receptor, pass to nucleus and induce a response
- altered to active metabolites
- inactivated in liver by reduction and oxidation or conjugation to glucoronide & sulphate groups
Nature of pure steroids?
- diffuse through plasma membrane (lipid soluble!), binds to receptor
- binding occurs in cytoplasm, move to nucleus
- mimic transcription to form mRNA → exert steroid function
- (protein synthesis?)
Where are hormone receptors found and what type of hormones bind to them respectively?
- Cell Membrane (peptide)
- Cytoplasm (steroids)
- Nucleus (thyroid, estrogen, vitamin D)
think about fat solubility!
Types of hormone secretion patterns?
continuous or pulsatile
superadded rhythms - day/night cycles
Define type 1 diabetes mellitus?
autoimmune condition where beta cells are damaged with genetic component
profound insulin deficiency
Define type 2 diabetes mellitus?
chronic hyperglycaemia due to relative insulin deficiency, resistance or both
Diagnostic criteria for DM!
- HbA1c ≥ 48 mmol / mol (6.5%)
- Fasting VBG ≥ 7 mmol/L
- Random VBG ≥ 11.1 mmol/L
- OG Tolerance T>11 mmol/L
If someone is prediabetic, they would have
Impaired glucose tolerance
Where is insulin produced?
pancreas
Beta cells in the pancreatic islet of Langerhans
INHIBITED by beta blockers
How does insulin work?
acts on the liver to reduce its glucose output, inhibiting glycogenolysis and gluconeogenesis
promotion of glucose uptake in peripheral tissues
Decreases serum potassium through stimulation of Na/K ATPase pump
Risk factors for type 1
- Northern European / Scandinavian
- Family History (less but is)
-
Other autoimmune disease as comorbidity
- Addison’s, coeliac, autoimmune thyroid
Risk factos for type 2
- sedentary lifestyle, diet high in calories, obseogenic environment
- overweight
- fam hx - gestational diabetes, hypertension / vascular disease
Pathophysio of type 1?
autoimmune
pancreas stops producing insulin. glucose is not taken up
level of glucose in blood keeps rising → hyperglycaemia
Pathophysio type 2?
- repeated exposure to glucose & insulin makes cells in the body resistant to insulin
- beta cells in pancreas fatigued & damaged therefore producing less
- or due to lipid depo in pancreatic islets, normal secretion cannot be
Differentiate type 1 / type 2 DM?
ketones
1 - increasing level // 2 - almost never excess
insulin
1 - deficiency // 2 - always detectable
both lead to profound skeletal muscle breakdown & unrestrained lipolysis
Presentations - T1DM?
4T’s: toilet, thin, tired, thirsty
- Short history, rapid onset
- Weight loss, fatigue → check if intentional
- lipid & muscle loss due to unrestrained gluconeogenesis
- Repeated infections? Blurred vision?
- Moderate or large urinary ketones
- immediate tx with insulin!
Additional testing for type 1?
for other autoimmune diseases
and for antibodies related to T1DM
Antibodies associated with T1DM?
- Anti GAD
- Pancreatic islet cell antibodies
- Islet antigen-2 antibodies
- ZnT8
common in children, the more the better
Presentations - T2DM?
- Usually in people over 30’s
- More obese children
- and obese now?
- Onset is very gradual
- Stronger positive family history
- (less in type 1!!)
- identical twins, almost 100% concordance
Further typical presentations, T2DM
(like if you misdiagnosed and seeing patient again…)
ketone breath
free fatty acid from impaired glucose uptake - lipolysis instead so produces ketone bodies
Differentiate T1 & T2 at presentation?
type 2 in younger, including childhood
but t1 can be obese, uncontrolled t2 can present with weight loss & ketonuria → check hx, weight loss intentional?
if in doubt treat with insulin
Goal of treatment - DM
if not on insulin = normal HbA1c 50 mmol/mol
if on insulin = fasting BG between 4-7mmol/L
Types of insulin & how they should be used?
basal Insulin - covers time between meals and especially during the night, given once or twice daily
prandial or bolus (meal time) insulin (rapid acting analogues) → adjusted according to glucose & carbohydrate content of meals
Typical insulin regime for type 1?
intensive basal-bolus (both types) used = best treatment
separate basal from bolus to mimic physiology
Typical insulin regime for type 2?
insulin usually given later on in disease course, or those with poor glycemic controls
usually start with just basal → lowers nocturnal, may add bolus later (and is often required)
Ways insulin can be given (dosage)?
- analogue insulin - less risk of hypoglycemia
-
premix insulin - (mixed quick acting & long acting) - better for people who don’t want to take 5 injections a day
- but risks of hyper / hypo as day goes by and higher target needed
GUIDELINE order for oral therapy T2DM
[2022]
- metformin / metformin MR (Gi into)
if CVD with SGLT2 inhibitors - DPP4 inhibitor / pioglitazone / sulfonylurea
- insulin and/or GLP-1
Mechanism of metformin?
- decrease hepatic glucose output (gluconeogenesis) & increase peripheral glucose uptake (+ insulin sensitivity!)
- AMP kinase activation - helps with weight loss
Metformin CI?
CA renal and hepatic impairment, reduce dose or avoid
acute alcohol intox & chronic alcohol abuse
withheld 48 hours after injecting IV contrast media (+ renal imapirment)
Metformin SE?
biggest is lactic acidosis & GI upset
anorexia / diarr / nausea / abdo pain
Mechanism of SGLT-2 inhibitors
(‘flozin’s)
- block the reabsorption of glucose in the kidney, increase glucose excretion & lower blood glucose levels
- also helps with weight loss
- Specific benefit in reducing CV mortality!
Examples of SGLT-2 inhibitors?
‘flozin’s
Empaglifozin, Dapaglifozin, Canaglifozin, Ertugliflozin
CI SGLT-2 inhibitors?
CI ketoacidosis
CA in renal impairment, diuretics, low systolic BP & elderly
SE SGLT-2 inhibitors?
genital thrush
increased risk of euglycaemic ketoacidosis in T2
Incretins - what are they?
GLP-1 & GIP - glucose dependent, released by intestines to food, inactivated by DPP-4!
promote insulin secretion & suppress glucagon release
Mechanism of DPP-4 inhibitors
(‘gliptin’s)
lowers blood glucose by competitively inhibiting the action of DPP-4 (enzyme) which destroys incretins
low risk of hypo, no effect on weight
Examples of DPP-4 inhibitors?
vidagliptin, sitagliptin
‘gliptin’s
CI DPP-4 inhibitors?
type 1, ketoacidosis
preg, breastfeed, elderly >80, pancreatitis
moederate to severe renal impairment
SE DPP-4 inhibitors?
low risk, but still present, of hypoglycaemia
acute pancreatitis
Which type of medications may mask symptoms of hypoglycaemia?
beta blockers
Mechanism of pioglitazone?
improve insulin sensitivity, binds to peroxisome proliferator activated receptor
activate genes concerned with glucose uptake, utilisation & metabolism
→ need insulin for a therapeutic effect, so relatively rarely used
CI pioglitazone?
heart failure, macular haem or oedema, high risk of fractures
avoid in hepatic impairment
Mechanism of sulfonylureas?
- stimulate pancreatic insulin release by binding to beta cell receptors
- improve glycemic control, but at the expense of weight fain
- can cause hypo
→ only in patients with residual pancreatic function
CI & SE sulphonylureas?
renal & hepatic impairment
GI upset, hypoglycaemia
Complications for diabetes?
Retinopathy, nephorpathy, neuropathy
cardiovascular disease
acidosis
hypoglycaemia
Feature of diabetic ketoacidosis?
Must have all 3!!
- Hyperglycaemia: plasma gluc > 50 mmol / l
- Raised plasma / urinary ketones: 3mmol/L or > 2+ dipstick
- Metabolic acidosis plasma bicarbonate bicarbonate < 15.0 mmol/L and/or venous pH < 7.3
Which type of DM is more prone to DKA?
type 1 (lots of ketones)
but type 2 incidences increasingly recognised - as low insulin levels are sufficient to suppress catabolism & prevent ketogenesis, but may occur when hormone rise to high lvl, e.g MI
How can ketones cause acidosis?
Lack of insulin = unable to utilise glucose
Lipolysis instead: products = ketones (acetone, beta-hydroxybutyrate and acetoacetate) → acidic
accumulates in blood = acidosis
Present - ketoacidosis
Hyperventilation - getting rid of Co2 & carbonic acid in blood
dehydration - might pres with vomit / diarr, hypotention, tachycardia, coma
Treatment of ketoacidosis?
1st line - rehydration, 3l first 3 hours
20ml /kg 0.9% NaCl over 15 mins
replace slowly or risk of cerebral oedema
insulin - reverse ketone production & fat breakdown
replace electrolytes, esp K+ (drive in to cell)
Complications DKA?
Cerebral oedema = swelling of brain parenchyma
What are the counterregulatory hormones for insulin?
glucagon, adrenaline, cortisol, growth hormone
When might someone be at risk for hypoglycaemia?
- Low HbA1c, High pre-treatment HbA1c in type 2
- long duration of diabetes
- daily insulin dosage > 0.85 U / kg / day
- history of previous hypo, recent episodes of severe hypo
-
impaired awareness → checks if ability to secrete adrenaline is still intact
- → ask when do they get hypo symptoms! if below 3.0 mmol / l = adrenaline no longer exists, if above = adrenaline still there
- physically active
- impaired renal and or liver function
Hypoglycaemia - symptoms?
Autonomic: trembling, palpitations, sweating, anxiety, hunger
Neuroglycopenic: difficulty concentrating, confusion, weakness, drowsy / dizziness, vision changes & difficulty speaking
Non-specific: nausea & headache
** may be symptomless if adrenaline secretion is gone too (beta blocker!)
Diagnostic criteria for hypoglycaemia?
If no known DM then Whipple’s triad
- blood glucose concentration < 4.0 mmol/L
- symptoms of hypoglycaemia
- Reversal of symptoms when BG normal
Which other conditions can cause hypoglycaemia?
- Beta cell secretagogue ingestion (e.g. ingestion of a medication that stimulates insulin release from beta cells)
- Islet beta-cell tumour (e.g. insulinoma)
- Functional beta cell disorder (e.g. high insulin secretion not due to an insulinoma)
- Insulin autoimmune hypoglycaemia (antibodies develop against insulin or its receptor)
Treatment for hypoglycaemia?
- glucose load - oral if alert, IV if coma
- retest and give more if needed
- if coma does not respond - consider glucagon but diff if poor glycogen stores; then IV glucose infusion if needed
How might one prevent hypoglycaemia?
- correct choice of therapy - sulfonylureas and insulin
- adjust targets, specialist support?
- discuss with patient - alcohol, exercise, consider sleep & age
What is diabetic neuropathy?
a collection of conditions that result from glucose-related damage to neurones of the somatic and autonomic nervous systems
Signs and symptoms, diabetic neuropathy?
glove and stocking sensory loss
Pain - burning, nocturnal exacerbation
like electrical shocks, walking on glass
Extreme spectrum sensitivity - hyper & paraesthesia, insensitivity
Consequences of diabetic neuropathy?
Diabetic foot ulceration, Charcot’s joint
Peripheral neuropathy & peripheral vascular disease - nerves and circulation affected and damaged
Treatment for general diabetic neuropathy?
good glycaemic control
opioids, antidepressants etc,
Transcutaneous nerve stimulation / acupuncture / spinal cord stimulators / Psychological interventions
Screening tests for diabetic foot ulceration?
- Test sensation
- 10 gm monofilament
- neurotips
- Vibration perception
- tuning fork
- biothesiometer
- Ankle reflexes
Treatment for diabetic foot ulceration?
lower limb amputation
What is diabetic retinopathy?
Persistent damage to retina leads to ischaemia and angiogenic factors which promotes new formation of weak and friable vessels → microaneurysms, haemorrhage, fibrosis retinal detachment
Risk factors for diabetic retinopathy?
- long duration diabetes
- poor glycemic control
- hypertensive
- on insulin treatment
- pregnancy
How might one prevent diabetic retinopathy?
National Eye screening programme
Treatment for diabetic retinopathy?
-
Laser therapy
- proven treatment for DR
- aim is to stabilise changes
- but treatment does not improve sight!!
What is diabetic nephropathy & pathophysiology?
Diabetic kidney disease
High BG → damage to blood vessel clusters in kidney & kidney itself → pressure increased on filtering system in the kidneys → glomerular changes/injury → filtration rate endangered → DN
Present diabetic nephropathy?
hallmark = proteinuria (albuminuria)
reduced calculated creatinine clearance, decreased glomerular filtration rate
How might one screen for diabetic nephropathy?
at least two urine samples, collected with 3-6 months
test for urine albumin, albumin:creatine ratio, eGFR
→ can use CKD classify system
Consequences / complications - diabetic nephropathy?
major risk for CVD, kidney failure
this is more common in T2 and less in T1
What is peripheral vascular disease?
decreased perfusion to an area due to macrovascular disease
symptoms more likely to occur at more dital sites
= 15-40x more likely for amputation
Signs and symptoms of peripheral vascular disease?
most common at more distal sites
intermittent claudication + rest pain = key
- Diminished or absent pedal pulses
- Coolness of feet and toes
- Poor skin & nails
- Absence of hair on feet & legs
How might one diagnose peripheral vascular disease?
Doppler Pressure studies & Ankle Brachial Index!
Duplex arterial imaging / MRA
Treatment for peripheral vascular disease?
- quit smoking
- Pressure relieving footwear, podiatry, revascularisation, antibiotics
- surgical intervention
Preventive measures for peripheral vascular disease (& diabetic foot)?
- Screening
- Education, providing orthotic shoes
- MDT Foot clinic - treat the ulcer !!!!
- Pressure relieving footwear, podiatry, revascularisation, antibiotics
Which hormones are released by the anterior pituitary?
- Thyroid stimulating hormone (TSH) → Thyroid
- Adrenocorticotropic hormone (ACTH) → Adrenal cortex
- Follicle stimulating hormone (FSH) & Luteinising hormone (LH)
- Growth hormone (GH) → entire body & liver
- Prolactin → Mammary gland
Which hormones are released by the posterior pituitary?
Oxytocin, Antidiuretic Hormone (ADH)
Outline the thyroid axis?
= Hypothalamus stimulating (via anterior pituitary) thyroid, releases T3 & T4
- Hypothalamus: Thyrotropin-releasing hormone (TRH)
- Anterior Pituitary: Thyroid stimulating hormone (TSH)
- Thyroid: triiodothyronine (T3) & Thyroxine (T4)
= Negative feedback cycle to control hormones
- Hypo & AP: senses T3 & T4: Suppress TRH & TSH
- Lower amount of T3 & T4 released
Function of thyroid hormones?
- accelerates and enhances food metabolism
- increase ventilation, heart rate & cardiac output
- growth rate accelerated & brain dev postnatal
How is thyroid hormone consumed by the body?
Thyroid gland produces thyroxine (T4) which is converted to triiodothyroxine (T3) in target tissues!
What is primary hyperthyroidism?
thyroid pathology → excessive Thyroid hormone
pathology = thyroid
Causes for primary hyperthyroidism?
- graves’ disease (75-80%)
- toxic multinodular goitre
- toxic adenoma
- drug induced - AMIODARONE (high iodine)
What is secondary hyperthyroidism?
thyroid overstimulated by thyroid stimulating hormone → excessive TH
pathology = hypothalamus or pituitary
What is Grave’s disease?
TSH receptor antibodies (abnormal) produced by immune system mimics TSH, overstimulate TSH receptors on thyroid → excessive TH
pathology = autoimmune
→ associated with anti-TSH antibodies and anti-thyroglobulin (anti-tg)
→ may cross placenta! ophthalmopathy strongly associated
What is a goitre?
palpable & visible thyroid enlargement
- variety of causes
- commonly sporadic or autoimmune
- endemic in iodine deficient areas
3 mechanisms for increased levels of thyroid hormones (T3 or T4)?
- overproduction of thyroid hormones
- leakage of preformed hormone from (inflamed) thyroid
- ingestion of excess thyroid hormone (from overtreatment or overingestion of pharm)
General symptoms of hyperthyroidism?
Goitre - may develop into facial swelling
- tachycardia
- lid-lag + stare → suspect autoimmune
- anxiety, irritability, sweating, heat intolerance
- Unintentional weight loss but with increased appetite, diarrhoea
- frequent loose stools
- Sexual dysfunction, sub-fertility, menstrual disturbance (infrequent & light)
- dry, brittle hair or thinning hair on your scalp and body - underactive thyroid
- AF lol
Grave’s specific symptoms of hyperthyroidism?
-
Diffused goitre - symmetrical
- entire, smooth
- Pretibial myxoedema - waxy oedematous on tibia - specific to Grave’s
- Thyroid eye disease - 50% - eyes & eyelids are swollen and red
- Exophthalmos - bulging of the eyeball out of the socket (stare-y eyes) (from swelling, inflam & hypertrophy of tissues behind eyes)
- Acropachy - finger clubbing
Differentiate between a diffused goitre vs a nodular goitre?
Diffused - entire thyroid gland swells and feels smooth to the touch
Nodular - lumpy to touch due to solid or fluid filled lumps
Biggest risk factor for autoimmune hyperthyroidism?
(single biggest) being female → very common postpartum
- during pregnancy: autoimmune activity goes down
- postpartum: rise in immunity
- autoimmune thyroiditis
- grave’s thyroiditis
Diseases associated with thyroid autoimmunity?
- T1DM
- Pernicious anaemia
- Vitiligo (skin discolouration
- Coeliac disease (1 in 3 with autoimmune hyperthyroidism have coeliac)
Testing for thyroid diseases?
- *Thyroid function tests: free TSH & fT4/T3**
- *primary** = suppressed TSH
- *secondary** = inapp high TSH
Thyroid antibodies & isotope uptake scan
urinary iodine secretion
Doppler ultrasound of thyroid for nodules etc
Pharmacological tx for hyperthyroidism?
Antithyroid drugs - for symptom control
= act as a preferred substrate for iodination by thyroid peroxidase (key enzyme in thyroid hormone production)
In order - Carbimazole, PTU, beta blockers
Carbimazole - mechanism
prevents thyroid peroxidase enzyme (TPO) from coupling and iodinating thyroglobulin (which degrades into T3 and T4) hence reducing production of TPO
Carbimazole indications & regime?
1st line, Successful even for Grave’s
Normal thyroid function in 4-8 weeks, may serve as maintenance
Give as either
- Titration-block: dose is carefully titrated to maintain normal levels
- Block and replace: dose is sufficient and block all production → patient takes levothroxine titrated to effect
Propylthiouracil PTU mechanism and indications?
if carbi not tolerated, prepreg / 1st trimester, specialist for thyroid crisis
inhibits conversion of T4 → T3
small risk of liver injury so not 1st line
How might beta blockers be useful in hyperthyroidism?
blocks adrenaline related syndromes of hyperthyroidism = controls symptoms whilst the definitive treatment takes time to work
= propanolol = good choice, as non selective
= very useful in thyroid storm
SE antithyroid drugs?
common = rash
less common = arthralgia, hepatitis, neuritis, thrombocytopenia, vasculitis etc
but resolvable if stop drug
agranulocytosis → most serious!!
Signs of agranulocytosis
& how to prevent?
- sore throat, fever, mouth ulcers
- MUST warn patient before starting ATD
- STOP if patients develop symptoms & check FBC
Other tx options for hyperthyroidism?
radioactive iodine treatment
thyroid surgery
Mechanism for radioactive iodine treatment & indications?
1st line definitive for Grave’s & toxic multi-nodular goitre
Uses iodine isotope (as iodine needed for TSH production) to induces DNA damage → death of thyroid cells, causing a decrease in thyroid function and / or reduction in thyroid size
Care & CI, radioactive iodine treatment for hyperthyroidism?
radioprotection after treatment - children & preggers
CI Grave’s with active orbitopathy, pregnant / conceiving / breastfeeding women
Thyroid surgery - indications?
total or hemi or for single thyroid nodule
for intolerant to drug, recurrence, coexisting potential malignant, compression symp’s
What is Sporadic Non-toxic Goitre
- commonest endocrine disorder
- 8.6% prevalence thyroid enlargement
- Euthyroid → thyroid function is normal
- Goitre - diffuse, multinodular, solitary nodule, dominant nodule
- differentiate benign from malignant
What is toxic multi-nodular goitre?
= Plummer’s disease
nodules develop on the thyroid gland that acts independently of the normal feedback system
continuous production of excessive TSH
Features of toxic multi-nodular goitre?
- goitre with firm nodules
- Most patient’s aged over 50
- second most common cause of thyrotoxicosis (hyperthyroidism)
What is De Quervain’s thyroiditis?
= Subacute thyroiditis
self limiting condition from viral infection
Features of Subacute thyroiditis?
Viral infection with fever, neck pain, dysphagia (swallowing problems)
Features of hyperthyroidism
Phases: viral infect - hyperthyroid - hypothyroid - euthyroid (normal!)
Treatment for De Quervain’s thyroiditis?
self limiting
but can treat with NSAIDs for pain & inflam.
beta blockers for symptomatic relief of hyperthyroidism
What is a thyroid storm?
emergency, thyrotoxic crisis
rare presentation of hyperthyroidism
Features of a thyroid storm?
hyperthermia, tachycardia, arrhythmias, nausea, vomiting, seizures and cognitive decline.
Treatment for thyroid storm?
Admission, support with fluid
Pharm
Beta blockers, thionamides (PTU), steroids, Lugol’s iodine
Hypothyroidism - define & types?
inadequately low output of thyroid hormones by the thyroid gland
Primary (thyroid pathology) or Secondary (pituitary pathology)
tingling of carpal tunnels
Features of primary hypothyroidism?
= 99% hypothyroidism
caused by thyroid gland insufficiency
T3 & T4 will be low
TSH will be high
(pit producing TSH to stimulate thyroid)
Features of secondary hypothyroidism?
caused by pituitary (or hypothalamic pathology)
TSH will be low → no production
How might you investigate hypothyroidism?
TSH = most sensitive marker
free T4 to confirm
antibodies - anti-TPO, anti-Tg, TSHR-Ab
What is Hashimoto’s thyroiditis?
- autoimmune inflammation of the thyroid gland
- associated with antithyroid peroxidase (anti-TPO - specific) & antithyroglobulin (anti-tg) antibodies (also in Graves)
- Goitre → atrophy (shrinkage) of the thyroid gland
Causes of primary hypothyroidism?
Hashimoto’s thyroiditis
iodine deficiency
tx for hyperthyroidism
medications - lithium & amiodarone
limits production of TSH, interfere with thyroid metabolism
Causes of secondary hypothyroidism?
hypopituitarism
may be caused by tumours, infection, vascular, radiation
Signs and symptoms, hypothyroidism?
- weight gain, fatigue
- dry skin
- coarse hair and hair loss
- fluid retention (oedema, pleural effusions, ascites)
- heavy or irregular periods
- constipation
- muscle - delayed reflexes, cramps
Tx for hypothyroidism?
Thyroid hormone replacement
oral levothyroxine = T4,
leothyroxine = T3 = shorter half life so for emergency
CI thyroid hormone replacements?
coronary heart disease, hypopituitarism
Interactions for thyroid hormone replacements?
increase dose if taking CYP450 inducers e.g. carbamazepine
can increase effects of insulin & warfarin
What is the adrenal axis?
Hypothalamus stimulating (via anterior pituitary) the adrenal glands (above each kidney), releasing cortisol
Effect of cortisol?
major metabolic & stress hormone
diurnal variation
- inhibits immune system & bone formation
- raises blood glucose
- increases alertness & metabolism
Briefly outline the adrenal axis?
- Hypothalamus: corticotrophin release hormone (CRH)
- Anterior pituitary: adrenocorticotrophic hormone (ACTH)
- Adrenal gland: cortisol
= Negative feedback cycle to control hormones
Hypo & AP senses cortisol: suppress release of CRH & ACTH
What is Cushing’s - differentiate between syndrome & disease?
Syndrome = symptoms that develop after prolonged abnormal elevation of cortisol
Disease = specific condition with excess glucocorticoids resulting from inappropriate ACTH secretion from a pituitary adenoma
→ Disease causes syndrome, but syndrome is not always caused by disease
Where is cortisol released from and by?
zona glomerulosa of the adrenal cortex above the kidneys
3 mechanisms which will give you excess cortisol?
either result from excess ACTH (antpit) or from neoplasms in adrenals stimulating z.reticu to release more
also from ingesting excess glucocorticoids, e.g. prednisolone
Symptoms, cushing’s
= round in the middle (trunk, abdomen and neck) with thin limbs!
- round ‘moon’ face
- central obesity
- abdominal striae
- buffalo hump = neck
- osteoporosis
- easy bruising and poor skin healing
- failure for children to grow tall despite excess weight
Signs of cushing’s
High level of stress hormone
- hypertension
- cardiac hypertrophy
- hyperglycaemia (DM2)
- depression, mood change - irritability
- proximal weakness
- gonadal dysfunction
Causes of Cushing’s
- pituitary adenoma releasing excess ACTH (can be benign), peak 30-50 yrs
- adrenal adenoma = 80%
- ectopic ACTH = small cell lung cancer / carcinoid tumours
- exogenous steroids - long term high dose
- alcohol pseudo-Cushing’s, obese, preg
Differentials - Cushing’s
- alcohol pseudo-Cushing’s = caused by alcohol excess, resolve 1-3 wks after abstinence
- asthma patients on ACTH
- obesity, pregnancy
How might you investigate Cushing’s
Dexamethasone suppression test, 24hr & 48 hr, if positive then
plasma ACTH, if positive then
High dose dexameth supp / corticotropin releasing hormone (CRH) test
Outline Dexamethasone Suppression Test?
should in a healthy patient, send neg feedback to pit&hypo → decreased ACTH & cortisol
low dose given to patient at midnight & cotisol & ACTH measured in the morning
if cortisol suppression < 50nmol, then Cushing’s can be excluded
high / normal cortisol = further invest for type
How might high dose dexamethasone suppression test differentiate between diff types of abnormalities
High dose = 8mg = further invest
Cushing’s = cortisol suppressed
Adrenal adenoma = cortisol unsuppressed, ACTH suppressed
Ectopic ACTH = neither cortisol nor ACTH suppressed
How might a 48h dexamethasone confirm the diagnosis?
Oral dex x4/day for 2 days, measure cortisol at 0 & 48hr
in Cushing’s there will be no suppression of cortisol
If dex suppression tests are positive, how might you further confirm diagnosis of Cushing’s?
Plasma ACTH
if ACTH detectable then distinguish pituitary cause from ectopic ACTH production → high dose dexa or CRH test
if ACTH undetectable then adrenal tumour. Image to confirm; if no mass then adrenal vein sampling
What is a Corticotropin releasing hormone (CRH) test?
- Human IV CRH given - activates and release ACTH
- Measure cortisol at 120 mins
- Cortisol will rise with pituitary disease but NOT with ectopic ACTH production
- if positive cortisol response to CRH → cushing’s disease, pit MRI to confirm
- if negative cortisol response to CR → hunt for ectopic source of ACTH
Alternative to dexamethasone test?
24 hour urinary free cortisol
but cumbersome to carry out and does not indicate underlying cause
Take > 2 measurements (cortisol is bound to albumin, when capacity is reached then will spill out to urine)
Tx for Cushing’s?
Surgical & pharma to inhibit cortisone synthesis
Surgical options for Cushing’s?
remove pituitary adenoma
go with trans sphenoidal
if impossible or adrenal adenoma
bilateral adrenalectomy & replacement hormones for life
if adrenal carcinoma = radiotherapy & adsrenolytic drugs - e.g. mitotane
If source unlocatable or recurrence post op - syndrome?
present?
Nelson’s syndrome
present as increased skin pigmentation from enlarged pit tumour
will respond to pit radiotherapy
Pharma options for Cushing’s
Drugs to inhibit cortisol synthesi
esp ectopic ACTH, post op or awaiting radiation
= METYRAPONE, KETOCONAZOLE and FLUCONAZOLE
What is acromegaly
multi-system disorder characterised by excessive growth hormone
mean age of diag = 44!
Cause of acromegaly?
benign pituitary GH producing adenoma
in almost all cases
expansion of the tumour in the pituitary can result in compression of surrounding structures resulting in headaches & visual field loss
hyperplasia e.g. ectopic GH releasing hormone from a carcinoid tumour
in rare cases
Action of growth hormone?
- indirectly through induction of insulin-like growth factor (IGF-I) which is synthesised in the liver & other tissues
- directly onto tissues such as the liver, muscle bone, or fat to induce metabolic changes
GH secretion monitoring?
inhibited by? stimulated by?
inhibited by somatostatin & high glucose!
stimulated by ghrelin - synthesised in stomach, also stimulates GH secretion
Classification of acromegaly?
- gigantism = excessive GH production in children before fusion of the epiphytes of the long bones
- acromegaly = excess GH in adults
Presentation - acromegaly?
- large hands = ‘acral enlargement’ - tight rings, carpal tunnel in 50%
-
maxillofacial changes
- coarsening of facial features
- wide nose, skin darkening
- mandibular prognathism (地包天 or 天包地)
- arthralgia (joint stiff), bony and soft tissue overgrowth = sleep apnoea
- headache, hypogonadal, microglossia (- size tongue)
Complications for acromegaly?
-
cardiomegaly & hypertension
- a very big risk factor!
- increased risk of cerebrovascular events and headaches
- MSK - bony / soft tissue overgrowth / arthritis
- insulin resistant diabetes or exacerbation of type 2
- sleep apnea
Key investigations for acromegaly?
IGF-1 test
Glucose tolerance test
Mechanism & diagnostic of growth hormone test for acromegaly
In normal patients, GH falls as glucose wears off, in acromegaly = opposite = GH peaks as glucose wears off
diagnostic if there is no suppression of glucose, since normally glucose should inhibit GH release
Relevance of IGF-1 in acromegaly testing?
secreted by liver in response to growth hormones
almost always raised in acromegaly & fluctuate less than GH
this is diagnostic if high (if not → OGTT)
How might you further assess / confirm acromegaly?
Glucose tolerance test (GTT)
Imaging - ECG / ECHO for cardio disease
check for pituitary adenoma
How would you check for a pituitary adenoma?
- visual field exam - can be bilateral temporal hemianopia due to pituitary adenoma
- MRI scan of pituitary fossa
- serum lactin will be raised if pituitary adenoma
1st line treatment for acromegaly?
- *pituitary surgery** - transsphenoidal
- *remove tumour**, correct & prevent tumour compression of surrounding struc
difficult if large size & invasive, most needs lifelong monitoring
if surgery fails, pharmacological therapy options for acromegaly?
dopamine agonists - cabergoline
fair amt wont respond
somatostatin analogues - IM octerotide or lanreotide
bound & inhibit multitude of hormones
SE GI cramps, flatulence, loose stools
growth hormone receptor antagonist - SC Pegvisomant
blocks IGF-I action, GH analogue
Option besides surgery and pharma?
radiotherapy - lots of options
What is prolactinoma?
excessive prolactin secretion by the lactotroph cell tumour of the pituitary
What is prolactin?
secreted by? inhibited by?
secreted - anterior pit
tonic inhibited - dopamine
= if dopa stops, prolac will rise
function (and a rise leads to)
lactation
reduced sex hormones
Hyperprolactin - besides prolactinoma,
can be caused by?
pituitary stalk damage
drugs - metoclopramid or ectasy
physiological - preggers, breastfeed, stress
Presentation for prolactinoma?
menstrual dysfunction (often initial!), infertility, galactorrhoea, low libido, erectile dysfunc / low testosterone, reduced facial hair
tumour - headache, bitem hemia, CSF leak from skull base erosion
Galactorrhoea can also be caused by
liver disease!! - associated with impaired oestrogen metabolism, which can cause breast tissue growth
Antipsychotics, antidepressants (SSRIs), Cimetidine, beta-blockers
Investigation for hyperprolactimea?
blood test
for basal prolactin levels
Differentials for hyperprolactimea
non functioning pituitary tumour - compression will interfere, but even then prolactin will be low
antidopaminergic drugs
macro / micro (<1cm) prolactinoma
Management of prolactinoma?
Pharma only - use dopamine agonists
e.g. carbergoline, bromocriptine, quinagolide
usually remarkable shrinkage in a day/two
- *macro** - usually sight change will improve!
- *micro** - respond to carbergoline once / twice / week
What is vasopressin?
= AVP = ADH Anti diuretic hormone
Function of vasopressin?
act on collecting ducts by inserting aquaporin 2 channels therefore
allow kidney to reabsorp water → concentrates urine: increase H2O permeability in kidney, due to concentration gradient in the glomerular nephron
also causes vasoconstriction on vasculature = restore arterial BP
Vasopressin - controls?
secreted by? controlled by?
made in paraventriculae nuclei in hypothalamus
secreted by posterior pituitary
(other one is oxytocin)
release controlled by
- *osmoreceptors** in hypothalamus = d2d
- *baroreceptors** in brainstem & great vessels = emergency
What is diabetes insipidus?
passage of large volume (>3 L / day) of dilute urine due to impaired water reabsorption in the kidney either due to
lack of vasopressin secretion or vaso resistence
plasma osmolality will be high, urine osmolality will be low
Differentiate cranial DI from nephrogenic DI?
Cranial = lack of vasopressin secretion, congenital defect in ADH gene
Nephrogenic = resistance to action of vasopressin by kidneys, acquired or congenital
Causes of cranial DI?
tumour - never anterior pituitary though
severe head injury → damage to hypothalamus or pit gland
complications from neuro or pit surg
Causes of Nephrogenic DI?
Congenital - AVPR2 or AQP2 mutations
Acquired - lithium (BPD), +Ca, -K, kidney infect
Presentation DI?
- *polyuria** = excessive urine, 15L in 24 hours
- *hypernatraemia** = water loss > Na loss
polydipsia = excessive thirst
can dehydration
NO glycosuria
How might you diagnose DI?
urine volume measure to confirm polyuria
Water deprivation then vasopressin test
(must be > 3L / day)
Briefly outline the water deprivation test?
morning = osmolality measure, stop patient from drinking.
see if osmolality increases, if so is it matched in urinary osmolality?
- normal individuals = urine concentration gets darker (higher) as no water
- DI = osmolality not matched in urine, does not get concentrated
How can the vasopressin test be used to differentiate between cranial and nephrogenic DI?
Give IM Synthetic vasopressin (= desmopressin) & water at 4pm
[vasopressin concentrates urine]
cranial = give both = plasma osmolality falls, urine osmolality increases (will be more concentrated)
nephrogenic = urine stays the same as resistant to vasopressin
What is hypertonic saline infusion and measurement of vasopressin used for?
measures copeptin, a part of the same protein that vasopressin is made
able to distinguish primary polydipsia from two DI’s
Management for cranial DI?
TUC
desmopressin - works at V2 receptor, maintain sodium and symptomatic relief
Management for nephrogenic ID?
TUC, avoid precipitation drugs
free access to water, very high dose desmopressin
can try thiazide diuretics → encourage kidney Na+ uptake or NSAID - inhibit prostaglandin which locally inhibit action of ADH
What is SIADH?
Syndrome of anti-diuretic hormone secretion
= continuous & excess secretion of vasopressin despite plasma being very dilute → hyponatraemia
= opposite of DI
urine osmolality will be high, plasma osmolality will be low
Cause of SIADH?
Proton Pump Inhibitor!!!!!
Tumours - pituitary tumour, carcinoma of lung, other
Respiratory causes
Signs and symptoms - SIADH
reduction in GCS and confusion with drowsiness, fits and coma - occurs later
water retention - lose salt in urine, can’t switch on urino angiotensin, no aldesterone
but clinically no oedema
increased GRF, less Na reabsorption in PCT
normal thyroid and adrenal func
How might you distinguish SIADH from salt & water depletion?
test with 1-2l of 0.9% saline
SIADH will not respond, sodium depletion will respond!
Treatment options for SIADH?
TUC, fluid restriction, U&E replacement
If giving U&E, must be careful of?
Reperfusion injury - osmolality demyelination syndrome
can demyelinate the brain and irreversible (if chronic) - may take up to 2 weeks to manifest
LIMIT is <8 mmol / l whereas normal < 10-12 mmol/l in any 24 hour period
Pharmacological options for SIADH?
Selective V2 receptor oral antagonist = tolvaptan
- competitive antagonist to vasopressin
- cause a profound ‘aquaresis’
- collecting duct impervious to water, water is able to pass out
Salt and loop diuretic = furosemide to prevent circulatory overload
Presentation thyroid cancer
- Thyroid nodule/mass
- Hoarseness/change in voice
- difficulty swallowing & breathing
- Cervical lymphadenopathy
- Stridor (a harsh, high pitched sound, normally heard on inspiration, indicative of upper airway obstruction)
Types of thyroid cancer and specific features
Thyroid follicular epithelial-derived cancer
FEMALE ELDERLY risk
Papillary - (commonest) younger, lymph node mets (separate from gland)
Follicullar- womenn
Anaplastic - 65 female high aggressive poor prog
Medullary = neuroendocrine, secretes calcitonin!
MEN II, RET gene
Primary thyroid lymphoma = with Hashimoto’s
Free card for break
Parathyroid hormone
released from?
by chief cells in four parathyroid glands in each corner of thyroid gland
Parathyroid hormone
released in response to? controlled by?
low serum calcium
low magnesium and & high serum phosphate
controlled through negative feedback by serum sodium! (increase Ca = suppress)
Where is does PTH act on and what is its function?
increase serum calcium to 1.1 mmol/l by
increasing activity of osteoclast
= reabsorption of Ca from bone
increasing calcium reabsorp in kidneys
in distal convoluted tubule
and in the GI tract
stimulate kidney to convert vitamin D3 to calcitrol = active form = promotes Ca absorption form food in small intestine
Function of vitamin D in Ca physiology
converted by PTH to active form
act on all three of processes
therefore acts along PTH to increase Ca reabsorption
Epidemiology of hyperparathyroidism?
- esp in elderly women
- primary hyperparathyroidism & malignancies = most common causes of hypercalcaemia
- but hypercalcaemia is rarely the first presenting symptom of malignancy
Types of hyperparathyroidism?
Primary
Secondary
Tertiary - as extension of secondary
Outline pathophysio of primary hyperparathyroidism?
uncontrolled PTH production by tumour of parathyroid gland
80% due to single benign adenoma (out of 4 parathyroid), 15-20 due to gland hyperplasia, < 0.5% malignant
mostly asymptomatic. surgical removal
Outline pathophysio of secondary parathyroidism?
insufficient vitamin D or chronic kidney disease = low Ca → compensatory PTH → hyperplasia / hypertrophy of gland
Outline pathophysio of tertiary hyperthyroidism?
secondary continues for years
hyperplasia of gland after secondary, baseline PTH increases dramatically but long term ⇒ autonomous gland even after tx
surgical removal partial
Disease pictures of the three types of hyperthyroidism?
Primary - high PTH, high Ca
normal phos / alk phos
**Secondary** - high PTH, low Ca high phos (renal disease) / alk phos
Tertiary - high PTH, high/norm Ca
What is malignancy hyperparathyroidism?
fake PTH secreted by carcinomas → mimic
= parathyroid related protein
squamous cell lung, breast, renal
so high Ca, normal PTH
calcium mobilisation, secondary mets in bone
Signs and symptoms of hyperparathyroidism?
Bones, stones, groans and moans
-
Bones - from excessive bone resorption
- pain & fractures
- osteoporosis / osteopenia / osteomalacia
- osteitis fibrosa cystica
- Kidney stones - from excessive calcium = renal colic or biliary stone
- Psychic moans
- confusion, depression, anxiety, insomnia
- Abdominal groans
- abdo pain
- constipation
- acute pancreatitis
- polyuria & nocturia - if ca2+ deposit in renal tubules
- high ca2+ also dehydration, confusion and risk of cardiac arrest
How would you investigate the parathyroid in hyperparathyroidism?
- PTH measure
-
renal function measure - if low then secondary or tertiary?
- Albumin-adjusted serum calcium
-
24 hour urinary calcium
- high in hypercalcaemia
- where excess reabsorp despite hypercalcaemia, urinary will be low
What imaging would you use for hyperparathyroidism
- doppler ultrasound / CT / MRI - malignancy // radioisotope scanning will be 90% sensitive for adenomas
- DXA bone scan - bone effects
How would you treat hyperparathyroidism
primary & tertiary - surgery
secondary - TUC replace vit D or renal transplant in those with renal failure
Pharmacological tx for hyperparathyroidism post surgery!
- hypocalcaemia after surgery
- if surgery CI = calcimimetic - increase sensitivity of parathyroid cells to ca2+ thereby causing less PTH secretion - e.g. oral cinacalcet
- avoid thiazide diuretics and high ca2+ and vitamin D intake
What is an acute severe hyperglycaemia & tx?
= emergency!
- rehydrate IV 0.9% saline fluids to prevent stones
- bisphosphonates after rehydration IV pamidronate to prevent bone resorption
- measure serum UE and serum ca2+ 48hrs post tx
- glucocorticoid steroids ORAL prednisolone in myeloma, sarcoidosis and vit D excess
How might hypercalcaemia present?
rarely first sign of hyperparathyroidism! but
- renal stones
- ECG: short QT
- thirst: polyuria (diluted)
- nausea, constipation, confuse, coma
Causes of hypercalcaemia?
malignancy - mets, PTH related peptides
primary hyperparathyroidism
When looking at high / low Ca results, always question if ‘true’ or ‘pseudo’ - think these
tourniquet damage
sample is old and haemolysis
if low - hypoalbuminaemia?
How would you correct calcium from albumin
(40 - serum albumin ) *0.02 + total serum calcium
for every gram that serum albumin is below 40, + 0.02
Epidemiology of hypoparathyroidism?
- all ages and both sexes
- extremely common in hospitalised patients and correlates with severity of illness - in 88% of intensive care patients
Causes of hypoparathyroidism?
secondary to increased serum phosphate
chronic kidney disease - most common cause
severe vitamin D deficiency
malabsorption, crohn’s, anti-epileptic drugs
reduced PTH function
Define primary hypoparathyroidism?
= gland failure
PTH low, Ca+ is low, Phosphate high
autoimmune causes - DiGeorge or idiopathic
Define secondary hypoparathyroidism
post- surgical or radiation
Define secondary hypoparathyroidism
post- surgical or radiation
Define functional hypoparathyroidism?
caused by Magnesium deficiency
- present with low PTH & low Ca
- need magnesium to excrete PTH! (carry vesicle to cell surface)
- caused by alcoholic, drugs etc
Presentation of hypocalcaemia?
SPASMODIC
Spasms - Trousseu’s sign (how much)
Periodical paraesthesia
Anxious, irritable, irrational
Seizures
Muscle tone +
wheeze + longer QT
Orientation impaired & confusion
Dermatitis
Impetigo herpetiformis - reduced Ca and pustules in preggers
Chvostek’s sign, Cataract, Cardiomyopathy
What is the Trusseau’s sign?
sign of muscle spasm in the hands
inflate BP cuff to 20 mmhg above systolic for five minutes
positive if hand elicit ‘how much’ sign
What is the Chvostek’s sign?
sign of muscle spasm
tap over facial nerve and twitch of facial muscles
sign of hypocalcaemia
Define pseudohypoparathyroidism?
organs resistant to PTH
mutation in GNAS1 receptor
low Ca, high PTH
inherited from father
Presentation pseudohypoparathyroidism
- short stature, obesity, round facies, mild learning difficulties
- subcutaneous calcification
- !! short fourth metacarpals
- make a fist & fourth metacarpal won’t be there → just a dimple
- 4th and 5th may be same length
- other hormone resistance
Diagnostics for hypoparathyroidism?
- usually history is enough
- bloods
-
low serum calcium - used to confirm history
- remember to correct for albumin abnormality
- urea:creatinine for eGFR for renal disease
-
serum PTH
- absent / low in hypo
- high in other causes of hypocalcaemia
- parathyroid antibodies - for idiopathic
- serum 25-hydroxyvitamin D - low in vit D deficiency
- Mg2+ level - severe hypomagnesaemia - functional hypoparathyroidism
-
low serum calcium - used to confirm history
How would you treat hypoparathyroidism / hypocalcaemia generally?
-
calcitonin
- decreases plasma Ca2+ and phosphate
- bisphosphonates - reduce osteoclast activity therefore stop ca2+ declining
- calcium supplements + calcitrol (active vit D)
How would you treat an acute episode of hypocalcemia?
-
tetany
- IV calcium gluconate over 30 min with ECG monitoring
-
vitamin D deficiency
- oral colecalciferol (D3) or oral Adcal (calcium + D3) (calcitrol?)
- ineffective for those with hypoparathyroidism as PTH is needed to convert D3 to 1, 25 dihydroxyvitaminD
Aldosterone is secreted by?
Zona glomerulosa of the adrenal gland
Aldosterone is a part of which system?
Renin-angiotensin-aldosterone
increases BP
Briefly outline the renin-angiotensin-aldosterone system?
renin (kidney) on angiotensinogen (liver) → angio I → ACE → angio II → stimulates release of aldosterone
raises BP by both angiotensin II & aldosterone
What cells monitors the BP in kidneys
& where is it located?
juxtaglomerular cells
monitors kidney BP
in the afferent arteriole
Aldosterone acts on which part of the body and what effects does it have?
on the distal tubules
- *sodium reabsorption**
- *potassium secretion**
on the collecting ducts
hydrogren secretion
Nature of aldosterone?
Minerocorticoid steroid hormone
Overall effects of aldosterone?
increase sodium reabsorption into blood
= water also reabsorped (retain H2O)
blood volume is increased, systemic vascular resistance changed,
blood pressure is increased
Biggest linked condition with hyperaldosteronism?
most common cause of secondary hypertension
consider hyperaldosteronism if patient not responding to hypertension treatments!
→ screen with renin aldosterone ratio blood test, clue can be low potassium in blood
Presentation for hyperaldosteronism?
hypertension &
hypokalaemia (often absent)
but may present as:
- muscle weakness, paraesthesia, mood disturbance
- polyuria / nocturia as potential diuresis
What is Primary hyperaldosteronism
= Conn’s syndrome
= when adrenal glands secretes too much aldosterone
= serum renin is low (renin is only secreted when BP is high!) → suppressed by high BP entering kidneys
Causes of primary hyperaldosteronism?
adrenal adenoma = 30-40%
bilateral adrenal hyperplasia = 60-70%
familial hyperaldosteronism
adrenal carcinoma (rare)
What is secondary hyperaldosteronism?
= when excessive renin is stimulating the adrenal gland to produce more aldosterone
= serum renin will be high → cause!
Causes of secondary hyperaldosteronism?
principle = juxtaglomerular cells, which senses kidney BP, keep sensing low → lots of renin → adrenal stimulated but kidney will not feel high BP
renal artery stenosis
= narrowing of artery supplying the kidney
= atherosclerosis (plaque)
renal artery obstruction
How would you confirm hyperaldosteronism & differentiate?
renin : aldosterone ratio in blood
low / normal renin = primary
high renin = secondary
How would you investigate for causes of hyperaldosteronism?
Imaging
CT / MRI
for adrenal tumour
Renal doppler ultrasound, CT angiogram or MRA
for renal artery stenosis or obstruction
3 classic investigative findings for hyperaldosteronism?
BP - hypertension
Serum electrolytes - hypokalaemia
Blood gas - alkalosis
What is hyperaldosteronism typically associated with?
Heart failure
How would you pharmacologically manage hyperaldosteronism?
aldosterone receptor antagonists
- eplerenone - no gynaecomastia
- spironolactone - gynaecomastia
- if not tolerated - ENaC inhibitor = amiloride
antihypertensives if needed
Which aldosterone receptor antagonist could potentially cause gynaecomastia?
spinocolactone
How would you surgically treat hyperaldosteronism?
surgically remove adrenal adenoma
percutaneous angioplasty for renal artery stenosis
What is adrenal insufficiency?
= adrenal glands do not produce enough steroid hormones, particularly cortisol & aldosterone.
primary = Addison’s
Briefly outline the adrenal axis?
Hypothalamus = CRH
Corticotrophin releasing hormone
Anterior pituitary = ACTH
adrenocorticotrophic hormone
Adrenal gland = cortisol
Cortisol inhibits CRH & ACTH throgh negative feedback
Function of cortisol?
= major metabolic & stress hormone
- inhibits immune system & bone formation
- raises blood glucose
- increases alertness & metabolism
Key signs of adrenal insufficiency!
= bronze hyperpigmentation to skin
particularly in skin creases like hands
- *= hypotension,** particularly
- *postural hypotension**
= low Na, high potassium
hyponatraemia, hyperkalaemia
Symptoms of adrenal insufficiency?
HYPOTENSION, low Na high K
- dehydration
- reduced libido, hair loss in axilla / pubic region !! esp in women
- weight loss, muscle wasting
- mood disturbance
- cramps, abdo pain, fatigue, nausea, vomit
What is primary adrenal insufficiency?
= Addison’s disease
= damage of the adrenal glands, resulting in a reduction of cortisol & aldosterone secretion
= high ACTH, trying to stimulate but no response or neg feedback (no cortisol production)
What are the causes of primary adrenal insufficiency?
- most common = autoimmune → esp in women
-
infective
- tuberculosis (most common worldwide)
- HIV, fungal, syphilis
- other
- haemorrhage
- malignancy
What is secondary adrenal insufficiency?
= inadequate (low) ACTH stimulating the adrenal glands
Causes of secondary adrenal insufficiency?
-
loss or damage to the pituitary gland
- injury, surgery, radiotherapy
- infection
- loss of blood flow
- pituitary gland necrosis from massive blood loss during childbirth - Sheehan’s syndrome
What is tertiary adrenal insufficiency?
= inadequate CRH release by hypothalamus
Causes of adrenal insufficiency?
= steroids not being tapered off properly
long term exogenous steroid being suddenly withdrawn, hypothalamus doesn’t wake up fast enough & no replacement
= taper slowly for adrenal axis to regain normal function
How might you investigate adrenal insufficiency?
Short Synacthen = test of choice!
Plasma ACTH = primary / secondary
adrenal autoantibodies
= adrenal cortex antibodies & 21 hydroxylase antibodies
Imaging if suspecting tumour, haemorr or other structural pathology
How might plasma ACTH differentiate between primary & secondary adrenal insufficiency?
primary = high ACTH
trying to get adrenal to work
secondary = low ACTH
loss of injury to pit
What are the autoantibodies associated with Addison’s?
adrenal cortex antibodies & 21 hydroxylase antibodies
Outline the short synacthen test?
give synacthen = synthetic ACTH
(IV 250 mcg of tetracosactide)
in the morning
measure blood cortisol at baseline, 30 & 60 minutes after administration
How might you interpret the results of the short synacthen test?
if blood cortisol
double of baseline = pituitary issue
(secondary) as adrenals responsive
less than double of baseline = adrenal issue
(primary) = Addison’s as not responsive
How might you treat someone with adrenal crisis?
= replacement steroids titrated to signs, symptoms and electrolytes
hydrocortisone for cortisol
fludrocortisone for aldosterone
steroid card and tag, double dose in acute illness
What is an Addisonian crisis?
= adrenal crisis, acute Addison’s
emergency
can be first presentation of Addisons
or triggered by infection, trauma, or other acute illness in someone with est. Addie’s or steroid withdrawal!
Presentation of an acute adrenal crisis?
HYPOtension
low glucose, low Na, high K
reduced consciousness, patient very unwell
How might you treat an acute adrenal crisis?
parenteral steroids - IV hydrocortisone 100mg stat then 100mg every 6 hours
- IV fluid resus
- correct hypoglycaemia
- careful monitoring of electrolytes and fluid balance
What is serotonin syndrome?
due to increased serotonergic activity in CNS which can be induced by a range of medications that increase serotonergic transmission by altering neurotransmitter serotonin
Risk factors of serotonin syndrome?
within several hours of taking a new drug
increasing the dose of a drug you’re already taking
Overdose
in all ages, esp young adults
Function of serotonin?
= monoamine neurotransmitter derived from tryptophan
CNS = theromoregulation, behavior, attention
PNS - vasoconstriction, bronchoconstriction, GI motility, uterine contraction
Promotes platelet aggregation = risk
haemorrhagic + if used with antiplatelet
Drugs implicated in serotonin syndrome?
serotonin inhibitors, receptor agonists,
impaired serotonin reuptakes, increased
SSRI’s, SNRI’s. TCA, MAOI
MDMA (ectasy), cocaine, lithium!
Outline pathophysiology of SS?
serotonin reuptake is inhibited from synaptic cleft into presynaptic neuron
Presentation of serotonin syndrome?
-
altered mental status
- anxiety, restless, disorientation, or agitation
-
autonomic hyperactivity = HYPER tension, thermia, TACHYCARDIA
- flushed skin, diaphoresis (sweating lol)
-
neuromuscular abnormalities
- dilated pupils
- clonus (repeat rhythmic), myoclonus (sudden)
- positive babinski! bilateral upgoing plantars
How might you investigate serotonin syndrome?
Hunter criteria
patient is taking a serotonergic agent and presents with ONE of the following
spontaneous clonus
Inducible/ocular clonus and agitation or diaphoresis
tremor / hyperreflexia
hyperthermia, hypertonia, ocular / inducible clonus
differentials for serotonin syndrome?
MDMA / cocaine use
neuroleptic malignant syndrome
broad as it is with confusion - encephalitis, drug intox, phaechromocytoma
What is the general tx for serotonin syndrome?
observation, supportive care if needed
cardiac monitoring, electrolyte, acute kidney, rhabdomyolysis
iv fluids, antipyretics
specific antihypertensive for profound hypertension
Specific antihypertensive for serotonin syndrome?
cyproheptadine, and propofol
Mechanism of cyproheptadine
histamine receptor antagonist with action against serotonin receptors
Complications of serotonin syndrome?
- Cardiac arrest
- Cardiac arrhythmias
- Acute kidney injury
- Rhabdomyolysis
- Disseminated intravascular coagulation
- Seizures
- Respiratory failure
- Venous thromboembolism
What is rhabdomyolysis?
clinical syndrome characterised by skeletal muscle necrosis due to release of toxic intracellular contents including myoglobin and electrolytes
Aetiology of rhadomyolysis?
(3)
Muscle compression from crush injury
compartment syndrome, surgical operation, electrical injury, prolonged immbo
Non traumatic, exertional
Non traumatic, non exertional
statins & colchicine, cocaine, opioids, benzodiazepines, amphetamine, toxins
What leaks out of the muscles during rhabdomyolysis?
creatinine kinase and myoglobin
High risk of which disease is linked to rhabdomyolysis?
AKI as creatinine kinase inceases
Pathophysio of rhabdomyolysis
myocyte injury
= as a cause or as a step in process
depletes ATP = everything foes
releases creatinine kinase & myoglobin
myocyte damages kidney - renal rubular obstruct, intrarenal vasoconstrict
creatinine also increase risk of AKI
Rhabdomylysis presentation & trigger?
suspect when unexplained AKI = following immobile, crush, muscle tender or meh U&E
myalgia, muscle weakness, dark urine (coca cola)
aches, calves & lower, from myoglobin
others - soft tissue swelling, altered mental status // skin changes, limb deformity
investigations for serum creatine kinase?
serum creatine kinase - KEY
= marker of skeletal breakdown
= rhabdo if CK > 5x upper limit of normal
will rise within 12 hrs of injure & peak 24-72
Myoglobin in urine
= 50% patients as excreted quickly
= will show on dipstick as ‘blood’
Renal function - stat!
= 15-50% will have AKI
= risk increases with higher CK
ECG = risk of UE abnormality
Management for rhabdo?
fluid resus aggressive and early
dialysis if needed
loop diuretics, IV bicarb
What is carcinoid syndrome
syndrome which arise when a neuroendocrine tumour (aka carcinoid syndrome) begins secreting hormones
What is a carcinoid tumour?
Tumour of the neuroendocrine cells
releases hormones into blood
e.g. serotonin, histamine, bradykinin (vdilate), prostaglandins (vdilate)
When do symptoms usually arise?
when tumour has spread to the liver** and releasing hormones e.g. **serotonin into bloodstream
Symptoms of carcinoid syndrome?
abdo - RUQ, diarr, const, poo blood
cough - blood, wheeze, short breath, pain
general cancer stuff
flushing of the skin! particularly the face bluish red - caused by bradykinin
fast heart rate, breathlessness, wheezing, carcinoid heart disease - heart valve thicken and stop working properly
What is a carcinoid crisis?
when tumour outgrows its blood supply or is handled too much during surgery - mediators flow out
vasodilate, bronchoconstrict = bradykinin
tachycardia = serotonin
hypotension = ACTH
hyperglycaemia = glucagon and ACTH
exacerbated by alcohol and stress!!
How might you diagnose a carcinoid tumour?
urinalysis = will show
increased 5 hydroxyindoleacetic acid
imaging = ct, mri scan
otreoscan / gallium 68 pet scan
blood test = niacin deficiency!
How might you treat carcinoid syndrome?
surgical removal of tumor
pharmacology
lifestyle - avoid ALCOHOL & stress
as symptoms exacerbated
Surgical options to remove carcinoid tumor?
removal, radiotherapy,
block blood supply to the tumour esp if in liver = hepatic artery embolisation
pharmacological options to treat carcinoid tumor?
somatostatin analogues
= octreotide and lanreotide - slows growth of the tumour, receptor antagonist
Lifestyle advice for carcinoid syndrome?
avoid alcohol and stress
avoid food with tyramine = in aged cheese, salted or pickled meats,
avoid spicy food
What is a pheochromocytoma?
tumour of the chromaffin cells in adrenal glands which secretes unregulated and excessive amounts of adrenaline
What is phaeochromocytoma linked to?
Linked to multiple endocrine neoplasia type 2 (MEN2)!!, Von Hippel Lindae syndrome
Adrenaline is secreted by?
Chromaffin cells in adrenal medulla of adrenal glands
Effects of the tumour?
- alpha-adrenergic - + BP, increased cardiac contract, increased glycogenolysis / gluconeogenesis (glucose utilise)
- beta-adrenergic - increased heart rate and contractility
Where might you find a phaeochromocytoma?
abdomen >95%
Symptoms of a phaeochromocytoma?
PAROXYSMAL
episodic headache
sweating
tachycardia, palpitations, paroxysmal atrial fibrillation
→ resembles panic attack
What is a phaeochromocytoma crisis?
= hypertensive crisis, if severe could lead to circulatory collapse
= hypertension, hyperthermia, confusion
end organ dysfunction - cardiomyopathy, pulmonary oedema
How might you diagnose phaeochromocytoma?
24 hour urine catecholamines
plasma free metanephrines
= breakdown product of adrenaline
CT / MRI cross section
alt MIBG scintigraphy - MIBG substance taken up by adrenergic tissue
How might you manage a phaeochromocytoma?
BP control
= phenoxybenzamine, alpha blocker
irreversible, long acting
alt CCB, and beta blocker once established on alpha blockers
Metyrosine - inhibit catecholamine synthesis
High sodium diet to replace with excessive catecholamines
adrenalectomy = removes the tumour = GOLD