Block 6: Addison's, Acromegaly, Cushing's Flashcards
Hyperaldosteronism
Primary: Bilateral adrenal hyperplasia (most common)
Adrenal adenoma: Conns
Primary hyperaldosteronism features
- Hypertension
- Hypernatraemia, polydipsia, polyuria
- Hypokalaemia i.e. muscle weakness
- Dizziness
- Headache, visual changes
Investigating primary hyperaldosteronism
Bedside: ECG
Bloods:
- Repeat U&Es (to monitor)
- plasma aldosterone:renin ratio (high aldosterone and low renin = suggestive of primary hyperaldosteronism (not driven by hyperreninism).
- Blood gas may show alkalosis due to aldosterone causing H+ loss
Imaging: MRI/CT for adrenal tumour
Management of primary hyperaldosteronism
Conservative:
- Risk assessment – driving, job, children. Review other medications (COCP).
- Put in touch with support group/specialist nurses.
Medical: Aldosterone antagonists: Eplenerone/Spironolactone (K+ and hypertension).
Surgical: Following imaging for cause: if adenoma then surgical removal.
- Don’t usually need surgery for bilateral adrenal hyperplasia
Addison’s disease
Primary adrenal insufficiency caused by the destruction of the adrenal cortex. Causes lack of glucocorticoids (cortisol) and mineralocorticoids (aldosterone). Increased CRH and ACTH, decreased adrenal steroids
Different part of the adrenal gland
- Medulla: Catecholamines
- Cortex- Zona glomerulosa: Mineralocorticoids
- Cortex- Zona fasciculata: Glucocorticoids
- Cortex- Zona reticularis: androgens
Addisons- causes
- Autoimmune –most common cause in developed world. Can be part of autoimmune polyglandular syndromes (APS) type 1 or 2.
- Tuberculosis-most common cause worldwide
- Adrenal metastasis
- Adrenal haemorrhage
- Infections: histoplasmosis, cryptococcosis, CMV, HIV
- Amyloidosis and haemochromatosis
- Congenital adrenal hyperplasia
- Bilateral adrenalectomy
- Congenital or neonatal primary adrenal insufficiency
- Other genetic causes: Mutations in genes like CYP21A2 (congenital adrenal hyperplasia) and AIRE (APS-1)
Addison’s disease: pathophysiology
- Cortisol deficiency:needed for maintaining glucose homeostasis, immune function, and stress response. Reduced cortisol production results in hypoglycemia, increased susceptibility to infection.
- Aldosterone deficiency:Aldosterone is responsible for regulating sodium and potassium balance. Insufficient aldosterone production leads to hyponatremia, hyperkalemia, and volume depletion, causing orthostatichypotensionand impaired renal function.
- Adrenal androgens deficiency:adrenal androgens (dehydroepiandrosterone [DHEA] and androstenedione) are involved in secondary sexual characteristics and libido. A deficiency may result in reduced body hair and decreased libido.
Addison’s disease: Epidemiology
- Rare
- Common between 30-50 year olds
- More prevalent in women than men
- Fatal if not treated, must be treated lifelong. Even with treatment increased risk of premature death
Addison’s clinical features
- Weight loss, malaise, weakness
- Low libido, amenorrhea
- N+V, diarrhoea, confusion
- Abdominal pain, constipation
- Myalgia, joint or back pain
- Pigmentation especially of new scars and palmar creases
- Postural hypotension: dehydration, salt craving
- Buccal pigmentation, hyperpigmentation, loss of body hair
Addison’s disease: diagnosis
- Morning cortisol (8-9am): if <100 nmol/l it 100-400 nmol/L do a ACTH stimulation (synathen) test
- Short Synacthen test (SST)- ACTH stimulation test: Cortisol at 0 minutes, administer ACTH (250mcg IV or IM). Measure cortisol at 30 and 60 mins. If doubles from baseline probably normal. If cortisol < 500 nmol/l at 30 or 60 mins indicate AI. Perform 18-24h after last steroid dose
- ACTH: elevated
- Na: normal or low
- Hyperkalaemia, hypoglycaemia, metabolic acidosis
- Adrenal antibodies (positive 80%)
- CT abdomen
Addison’s disease: treatment
- Glucocorticoid replacement: Hydrocortisone 15-30 mg daily in divided doses. Following circadian rhythm (breakfast, lunch, dinner: 10-5-5). Prednisone and dexamethasone can also be used. Sick rules: double the dose while unwell or IM hydrocortisone if diarrhoea or vomiting
- Mineralocorticoid replacement: Fludrocortisone 50-300 mcg daily
- Androgen replacement: (not licensed in UK): Dehydroepiandrosterone (DHEA)
- MedicAlert bracelet and steroid cards
- Emphasise importance of not missing doses
Adrenal crisis
A life threatening endocrine emergency, requires urgent treatment. When steroid requirements is higher then steroids being administered
Adrenal crisis: clinical features
- Fatigue, lack of energy, weight loss
- Low blood pressure, postural hypotension dizziness, collapse, in severe cases hypovolaemic shock
- Abdominal pain, tenderness and guarding, nausea, vomiting
- Fever
- Confusion, somnolence, in severe cases delirium or coma
- Back and leg cramps/spasms
- Low blood pressure and abdominal pain think adrenal crisis
Adrenal crisis: lab findings
- Hyponatraemia
- Hyperkalaemia
- Pre-renal failure (increased serum creatinine due to hypovolaemia)
- Hypoglycaemia
Adrenal crisis investigations
- Adrenal insufficiency should be ruled out in any acutely ill patient
- Assess blood pressure and fluid balance status; measure blood pressure from supine to standing to check for postural drop
- Take drug history (glucocorticoids?)
- Bloods: FBC, U&E, TFT, cortisol and ACTH
- Diagnostic measures should never delay treatment. No adverse effects for initiating hydrocortisone
Adrenal crisis treatment
- Hydrocortisone: (immediate bolus injection of 100mg hydrocortisone i.v. or i.m) followed by continuous intravenous infusion of 200mg hydrocortisone per 24h (alternatively 50mg hydrocortisone per i.v. or i.m. Injection every 6h)
- Rehydration: with rapid intravenous infusion of 1000mL of isotonic saline infusion within the first hour, followed by further intravenous rehydration as required (usually 4–6L in 24h)
- Contact an endocrinologist for urgent review
Complications of Addison’s disease
- Adrenal crisis: severe hypotension, hypoglycaemia and altered mental state
- Chronic complications: inadequate hormone replacement can cause persistent fatigue, weight loss and electrolyte imbalance
- Osteoporosis: due to long term glucocorticoid therapy
- Infections: increased susceptibility
Acromegaly definition
Long term endocrine condition due to hyper-secretion of growth hormone, normally due to a pituitary adenoma. Causes enlargement of extremities (fingers, toes). A minority of cases are caused by ectopic GHRH or GH production by tumours e.g. pancreatic.
Acromegaly initial presentation
- Diagnosed in 5th to 7th decade
- Present with Type 2 Diabetes, Blood pressure
- Change in glove size, shoe size, spade like hands
- Large fingers, toes
- Visual field defect: bitemporal hemianopia
Acromegaly: clinical presentation
- Coarse facial features: jaw protruding, large lips and tongue
- Increase in inter-dental spacing: teeth separated
- Growth in soft tissue, cartilages, membranous bones
- Sweating, headache
- Carpal tunnel syndrome
- Obstructive sleep apnoea
- Cardiovascular disease, Osteoporosis
- Long term association with cancer
- Can have galactorrhoea and 6% have MEN-1
Acromegaly Diagnosis
- High IGF-1: if moderate to oral glucose tolerance
- Oral Glucose Tolerance Test: Failure of suppression of GH to <2 mu/L
- Pituitary MRI
Acromegaly monitoringand screening
- Screening for cancer: Colonoscopy
- Monitor for end organ problems: Echo, DEXA Scan
- Monitor IGF-1 Level for recurrence
Cushing’s syndrome: definition
Due to chronic exposure to excess glucocorticoids. Important endocrine cause of obesity
Steroid biosynthesis
- All made from cholesterol.
- Mineralocorticoid pathway results in Aldosterone.
- Glucocorticoid pathway results in cortisol. Made in Zona fascicular of adrenal cortex
- Androgenic pathway results in Testosterone and oestrogen
Cushing’s syndrome: pathophysiology
- Anti-inflammatory and immunosuppressive
- Increases hepatic gluconeogenesis decreases peripheral glucose uptake: elevated blood glucose
- Bone metabolism: osteoporosis
- Protein catabolism: muscle wasting
Cushing’s syndrome: signs and symptoms
- Decreased libido, menstrual changes
- Red cheeks, extensive striae, skin bruising
- Central Obesity, round face (moon face), thin arms and legs, large stomach, nuchal fat pads
- Thin skin, Hirsuitism
- Hypertension
- Ecchymoses: red marks
- Lethargy, depression
- Abnormal glucose tolerance
Cushing’s investigations: confirm cortisol use
- Elevated 24-hour urinary free cortisol (UFC) excretion= calculate cortisol:creatinine ratio. Two measurements are required
- Bedtime salivary cortisol: two measurements are required
- Overnight 1 mgDexamethasone suppression test (DST): Give at 11 PM. Cortisol checked at 9 AM. Cushing’s syndrome suspected if no suppression and >/= to 50 nmol/L
Cushings: Tumour location
- Pituitary tumours are ACTH dependent: 70%
- Ectopic ACTH secretion secondary to malignancy is also ACTH dependent
- Adrenal adenoma are cortisol dependent
Cushings: general findings
- Hypokalaemic metabolic alkalosis
- Impaired glucose tolerance
- Ectopic ACTH secretion: very low potassium
Cushings investigations: localise the site (pituitary or adrenal)
- Undetectable ACTH suggests adrenal pathology: Proceed to adrenal imaging (CT scan)
- Detectable ACTH (suspect pituitary) – proceed to 48 hr High dose Dexamethasone suppression test= 2 mg ofdexamethasoneorally every six hours at 8 AM, 2 PM, 8 PM, and 2 AM. If 48 hour 9 AM cortisol is <50% of the basal value after 48 hours of last dose then suppressed.
- Suppression with high dose dexamethasone is seen in pituitary Cushing’s disease but not ectopic ACTH production or adrenal tumours → Proceed to Pituitary MRI
Cushings: interpreting high dose dexamethasone suppression test
- Adrenal adenoma: Cortisol not suppressed, ACTH suppressed
- Pituitary adenoma: Cortisol suppressed, ACTH suppressed
- Ectopic ACTH syndrome: Cortisol not suppressed, ACTH not suppressed
Cushing’s: other tests
- CRH stimulation: if pituitary source then cortisol rises. If ectopic/adrenal then no change in cortisol
- Petrosal sinus sampling of ACTH may be needed to differentiate between pituitary and ectopic ACTH secretion.
- An insulin stress test is used to differentiate between true Cushing’s and pseudo-Cushing’s.
Cushing’s medical management
- Metyrapone, Ketocanazole
- Use pre-operatively or conservatively if not fit for surgery
Cushing’s surgical management- pituitary tumours
- Trans-sphenoidal surgery: Pituitary radiotherapy as adjunctive treatment if surgical cure not achieved
- Laparoscopic or open adrenalectomy for adrenal tumours
- Surgery is definitive treatment
Cushings complications
Venous thromboembolism, stroke and myocardial infarction. Good survival patients live >40 years post cure
Hypernatraemia
- > 145mmol
- Two variables: can have hypernatremia due to high sodium or low water. Normally due to too little water
- Risk factors: hospital admission, inability to drink water/access water, infancy, old age, Nursing home residents
- Dehydration: the elderly, terminal illness, water loss>water intake
- Excess Na+ in IV therapy: saline
Clinical features of DI
- Urinary frequency, nocturia
- Pale urine
- Hypernatremia, normal glucose, high plasma osmolarity
- Dehydration: fatigue, dizziness, weakness
- Space occupying lesion causing DI: headache, visual changes, seizure
ADH
- Osmoreceptors detect increased osmotic pressure
- Baroreceptors (carotid sinus, aortic arch) detect decreased blood pressure
- Posterior pituitary releases ADH
- Causes blood vessel vasoconstriction and increased reabsorption of water in the kidneys
- Leads to increased blood volume and pressure
Diagnosis of diabetes insipidus
- Water deprivation test: deprive patient of fluids to allow serum osmolality to rise and assess whether urine concentrates (i.e. urine osmolality increases)
- Patient usually fasted overnight though is allowed to have fluids
- Weight, Serum and urine osmolality measured regularly
- Test stopped early if >3% body weight lost
- Diabetes Insipidus: Continued production of dilute urine despite fluid deprivation, when the kidneys should usually conserve water. High plasma sodium and increased plasma osmolality with inappropriately low urine osmolality
Water deprivation test: results
- Cranial DI: urine osmolality <300, Urine osmolality after vasopressin administration: >800
- Nephrogenic DI: urine osmolality <300, Urine osmolality after vasopressin administration <300
- Primary polydipsia (patient drinking too much water): urine osmolality >800, urine osmolality after vasopressin administration >800
- Vasopressin is given after water deprivation test
- Cranial DI: issues with ADH release from posterior pituitary
- Nephrogenic DI: issues with ADH site of action in CD
Causes of DI
- Cranial Acquired: Trauma, surgery (pituitary), tumours (germ cell) (craniopharyngiomas), sarcoid, TB, infections (meningitis), idiopathic. Commonly due to destruction of magnocellular cells
- Cranial familial: DIDMOAD ( syndrome with following conditions= D.I, diabetes mellitus, optic atrophy, deafness- Wolfram syndrome)
- Nephrogenic Acquired: Drugs (lithium), chronic renal disease, post obstructive uropathy, metabolic (hypercalcaemia, hypokalaemia)
- Nephrogenic familial: (X linked recessive (mutations in vasopressin-2-receptor) and autosomal recessive(mutations in aquaporin 2 gene)).
- Gestational DI
- Dipsogenic DI: impairement of thirst mechanism- chronic meningitis, MS
DI investigations
- 24 hour urine volume measurement (> 3 litres/day)
- Exclude diabetes mellitus, renal failure i.e. OGGT, U&E, calcium
- Check electrolytes (calcium and potassium)
- Urine and serum osmolality to calculate the urine to plasma (U:P) osmolality ratio= If U:P ratio is <2:1 DI likely
- Water deprivation test
- MRI brain: tumours
- Serum ACE: sarcoidosis
- Serum copeptin: precursor of ADH, high in nephrogenic DI
DI treatment
- Desmopressin: ADH analogue with longer half life. Oral and nasal administration. Monitoring of serum sodium and osmolality. Acts on kidneys, little effect on blood vessels. For cranial DI
- Due to treatment cranial DI has fewer symptoms then nephrogenic
Nephrogenic DI treatment
- Correction of the underlying cause
- High doses of desmopressin can be trialled
- High fluid intake
- Thiazides diuretics and some NSAID’s can be helpful: inhibit local prostaglandins
Types of hormones
- Endocrine – enters circulation and has an effect on a target cell/organ
- Paracrine – has an effect on a local cell but does not enter circulation
- Autocrine – affects cell type that secreted it
- Intracrine – acts intracellularly
- All secreted internally
Three main classes of hormones
- Protein (peptides e.g insulin) or amino acid (usually tyrosine e.g.thyroxine) derivatives
- Steroids
- Eicosanoids e.g.prostaglandins: tend to be paracrine or autocrine
Anatomy of hormone signalling
- Three tiers: Tertiary (hypothalamus), Secondary (Pituitary), Primary (secretory gland)
- Vascular signalling- anterior pituitary. Blood flows from the hypothalamus into the anterior pituitary and the rest of the body, its a porto-venous system
- Neural signalling- posterior pituitary
Hormones released from anterior pituitary
- TSH → Thyroid gland
- ACTH → Adrenal cortex
- FSH → testes/ovaries
- LH → testes/ovary
- Prolactin → breast
- Growth hormone → Liver (affects bone and muscle growth)
Pituitary tumours
Affects the internal carotid artery, cranial nerves and the optic chiasm
Addisons bloods
- Hyperkalaemia
- Hypoglycaemia
- Raised creatinine and urea
- Hypercalcaemia