Adrenal Disorders Flashcards
What is Cushing’s disease?
Increased free circulating glucocorticoid
What is the aetiology of Cushing’s disease?
- The most common cause of excess cortisol is the therapeutic administration of synthetic steroids
- Cushing’s disease is when the increased cortisol levels are caused by a functioning pituitary adenoma, all other causes are referred to as Cushing’s syndrome
ACTH dependent
- pituitary adenoma (68%) → Cushing’s disease
- Ectopic ACTH (12%) - carcinoid/carcinoma e.g., lung, pancreas
- Ectopic CRH (<1%)
ACTH independent
- exogenous steroids
- adrenal adenoma (10%) or carcinoma (8%)
- adrenal cortical nodular hyperplasia (1%)
- false positive (psuedo) - severe depression, severe alcoholism
What is the pathophysiology of ACTH independent Cushing’s disease?
- Autonomous over-production of cortisol by the adrenal gland due to neoplasia/nodular hyperplasia
- Adrenal enlargement in ACTH-independent disease is usually nodular
What is the pathophysiology of ACTH dependent Cushing’s disease?
- Adrenal enlargement in ACTH-dependent disease is usually diffusePituitary adenomas (Cushing’s disease)
- Pituitary secretes increased ACTH → increased cortisol production by adrenal gland
- Carcinoma e.g. small cell lung cancer secretes ACTH → increased cortisol production by adrenal gland
- Carcinoma e.g. medullary thyroid carcinoma secretes CRH → increased ACTH by pituitary → increased cortisol by adrenal gland
What are the consequences of increased cortisol levels?
- Protein loss
- Altered carbohydrate and lipid metabolism
- Excess mineralocorticoid
- Excess androgen
What is the presentation of Cushing’s Disease?
- Plethora (redness of the face)
- Moon face
- Hypertension
- Central obesity
- Depression/psychosis
- Glycosuria/diabetes mellitus
- Oedema
- ‘Buffalo hump’
- Oligo/amenorrhoea
- Virilism
- Bruising
- Striae (purple or red)
- Pigmentation (only occurs with ACTH-dependent causes)
- Thin skin
- Hirsutism
- Acne
- Proximal myopathy, wasting
- Osteoporosis, fractures
What is characteristic of Cushing’s disease and not obesity?
- Thin skin
- Proximal myopathy
- Frontal balding in women
- Conjunctival oedema (chemosis)
- Osteoporosis
What are the investigations for Cushing’s disease?
- Overnight 1mg dexamethasone suppression test (oral) - first line
- Normal: cortisol <50 nmol/l next morning
- Abnormal: cortisol >130 nmol/l
- 24hr urine free cortisol (24hr urine collection)
- Total <250 is normal
- Cortisol/creatinine ratio of<25 is normal
- Diurnal cortisol variation (midnight/8am)
- Loss of diurnal variation suspicious of Cushings
- Serum/saliva/spot urine collection
How is Cushing’s disease diagnosed?
- Low dose dexamethasone suppression test
- 2 day 2mg/day dexamethasone
- Normal: cortisol <50 nmol/l 6 hours after last dose
- Cushing’s: cortisol >130 nmol/l
- Repeat to confirm
What are the differentials for Cushing’s disease?
- If serum ACTH levels are low, this suggests non-ACTH-dependent disease and adrenal imaging should be planned (CT or MRI)
- If serum ACTH levels are high, this suggests ACTH-dependent disease and pituitary MRI should be planned as well as biochemical tests to distinguish between pituitary and ectopic ACTH (high-dose dexamethasone suppression test or exogenous CRH)
What is the management of Cushing’s disease?
Pituitary
- Hypophysectomy (transsphenoidal route)
- External radiotherapy if recurs
- Last line: bilateral adrenalectomy
Adrenal Adenoma
- Adrenalectomy
Ectopic
- Remove source
- OR bilateral adrenalectomy
Drug Management
- Metyrapone given when other treatments fail or while waiting for radiotherapy to work
- Side effects e.g. N+V common
- Other options include ketoconazole (hepatotoxic) and pasireotide LAR (somatostatin analogue)
What is primary adrenal insufficiency?
Decreased production of adrenocortical hormones (glucocorticoids, mineralocorticoids, and adrenal androgens)
What is the aetiology of primary adrenal insufficiency?
- Involves destruction of the entire adrenal cortex
- Autoimmune adrenalitis is the most common cause, accounting for ~80-90% of all cases of primary adrenal insufficiency
- May be part of wider autoimmune syndromes e.g. autoimmune polyglandular syndrome (APS)
- Associated with other autoimmune diseases - T1DM, autoimmune thyroid disease, pernicious anaemia
- Infectious adrenalitis - TB, CMV disease, HIV
- Metastatic malignancy - lung, breast
- Adrenal haemorrhage
- Septicaemic infection - Waterhouse-Friderichsen syndrome
- Disseminated intravascular coagulation (DIC)
- Anticoagulation treatment
What is the pathophysiology of primary adrenal insufficiency?
- Decreased mineralocorticoids
- K+ retention, Na+ loss
- Hyperkalaemia, hyponatraemia, volume depletion and hypertension
- Decreased glucocorticoids → hypoglycaemia
- Excess pigmentation reflects excess ACTH from pituitary
- ACTH molecule contains sequence for MSH within it
- ACTH is degraded by proteases eventually exposing MSH
What is the presentation of primary adrenal insufficiency?
- Signs and symptoms occur once >90% of the gland has been destroyed
- Vague symptoms - weakness, fatigue, anorexia, N+V, weight loss, diarrhoea, dizziness and low BP, abdominal pain
- Skin pigmentation (raised POMC) - not seen in hypopituitarism
- Look ‘tanned’, as well as black spots in buccal mucosa, dark palmar creases and dark finger spaces
What are the investigations for primary adrenal insufficiency?
- Adrenal autoantibodies positive in 70%
- Biochemistry - ↓ Na+, ↑ K+, may be hypoglycaemia (especially in paediatrics)
- Short synacthen test
- Measure plasma control before and 30 mins after IV/IM ACTH injection
- Normal: baseline >250 nmol/L, post ACTH >550 nmol/L
- ACTH levels very high (results in skin pigmentation)
- Renin/aldosterone levels - ↑↑ renin, ↓ decreased aldosterone
What is the management of primary adrenal insufficiency?
Pharmacological Management
- Hydrocortisone as cortisol replacement
- If unwell IV first
- Usually 15-30mg PO daily in divided doses
- Try and mimic diurnal rhythm (higher dose in morning)
- Fludrocortisone as aldosterone replacement
- Careful monitoring of BP and K+
Education
- ‘Sick day rules’ - increase steroid replacement when unwell or undergoing other stress e.g. preoperative
- Cannot stop suddenly or risk adrenal crisis
- Need to carry identification - emergency steroid card, alert to long term steroid treatment bracelet
- There are rules for medical professionals regarding steroid management for interventions/surgery (usually require increased dose)
What is secondary adrenal insufficiency?
lack of production of ACTH by the pituitary gland
What is tertiary adrenal insufficiency?
lack of CRH secretion by the hypothalamus
What is the aetiology of secondary/tertiary adrenal insufficiency?
- Iatrogenic (excess exogenous steroid) - inhibit CRH production and ACTH production, adrenal gland becomes atrophied and is unable to produce cortisol even acutely when ACTH is given endogenously
- Pituitary/hypothalamic disorders - tumours, surgery and radiotherapy
What is the presentation of secondary/tertiary adrenal insufficiency?
Similar to Addison’s except:
- Skin pale (no ↑ ACTH)
- Aldosterone production intact (regulated by RAAS)
- No hypertension
What is the investigation for secondary/tertiary adrenal insufficiency?
- Insulin tolerance test
- CRH stimulation test
- MRI
What is the management of secondary/tertiary adrenal insufficiency?
Treat with hydrocortisone replacement (fludrocortisone unnecessary)
What is adrenal adenoma?
Benign neoplasm emerging from the cells of the adrenal cortex
What is the aetiology of adrenal adenoma?
found in almost all age groups but increase in frequency with age
What is the pathophysiology of adrenal adenoma?
- majority (~95%) are non-functioning and asymptomatic
- well circumscribed, encapsulated lesions
- solitary, small (2 to 3cm), bright yellow (Lipid) and buried within the gland - do not cause a mass lesion
What are the histological features of adrenal adenoma?
- composed of cells resembling adrenocortical cells
- well-differentiated, small nuclei
What is the presentation of adrenal adenoma?
- often incidental finding during abdominal imaging
- patients with hyperfunctioning adrenal gland adenomas present with manifestations of excess hormone secretion e.g., Cushing’s, Conn Syndrome
What are the investigations for adrenal adenoma?
- imaging (CT, MRI)
- Hormonal testing
What is the management of adrenal adenoma?
- a small adrenal lesion with typical features of an adenoma and without biochemical abnormality can be safely left in situ
- Surgical excision required if:
- functioning lesion
- large lesion (>3-5cm) as considered potentially malignant
What is primary hyperaldosteronism?
Autonomous production of aldosterone independent of its regulators (angiotensin II/potassium)
What is the aetiology of primary hyperaldosteronism?
Adrenal Adenoma (Conn’s syndrome):
- ~30% cases
- Do not suppress ACTH - adjacent and contralateral adrenal tissue is not atrophic
Bilateral adrenal hyperplasia:
- Idiopathic
- Accounts for ~60% cases
Rare Causes:
- Genetic mutations - several familial forms of hyperaldosteronism recognised as well as recurrent somatic mutations observed in sporadic cases
- Unilateral hyperplasia
What are the genetic factors related to adrenal adenoma and primary hyperaldosteronism?
- KCNJ5 channel is a rectifying selective channel which maintains membrane hyperpolarisation
- Mutations lead to loss of ion selectivity; Na+ entry and depolarisation and therefore increased aldosterone production
What is the pathophysiology of primary hypoaldosteronism?
- Commonest secondary cause of hypertension
Cardiac actions of aldosterone:
- Increased cardiac collagen
- Cytokines and ROS synthesis
- Increased sodium retention
- Abnormal endothelial function
- Increased sympathetic outflow
- All contribute to increased BP, LVH and atheroma
What is the presentation of hyperaldosteronism?
- Significant hypertension
- Hypokalaemia (~30%)
- Alkalosis
What are the investigations for primary hyperaldosteronism?
Confirm aldosterone excess
- Measure plasma aldosterone: renin ratio
- If ratio raised investigate further with saline suppression test
- Failure of plasma aldosterone to suppress by > 50% with 2 litres of normal saline confirms PA
Confirm subtype
- Adrenal CT to demonstrate adenoma
- Sometimes adrenal vein sampling to confirm adenoma is true source of aldosterone excess
What is the management of primary hyperaldosteronism?
Adrenal adenoma
- Unilateral laparoscopic adrenalectomy
- Cures hypokalaemia
- Cures hypertension in 30-70% of cases
Bilateral adrenal hyperplasia
- Mineralocorticoid receptor antagonists - spironolactone or eplerenone
What is secondary hyperaldosteronism?
Increased adrenal production of aldosterone in response to nonpituitary, extra-adrenal stimuli such as renal hypoperfusion
What is the aetiology of secondary hyperaldosteronism?
- Reduced renal blood flow leads to excess renin (and hence angiotensin II)
- Causes of reduced renal blood flow include:
- Obstructive renal artery disease (e.g., atheroma, stenosis)
- Renal vasoconstriction (as occurs in accelerated hypertension)
- Oedematous disorders (e.g., heart failure, cirrhosis with ascites)
What is the presentation of secondary hyperaldosteronism?
Hypertension
What are the investigations of secondary hyperaldosteronism?
- Renin/aldosterone ratio - high aldosterone and high renin indicates secondary hyperaldosteronism
- Doppler ultrasound, CT angiogram or magnetic resonance angiography (MRA) to look for renal artery stenosis or obstruction
What is the management of secondary hyperaldosteronism?
- Aldosterone antagonists e.g., spironolactone
- Treat underlying cause e.g., percutaneous renal artery angioplasty via the femoral artery to treat in renal artery stenosis
What is phaeochromocytoma?
Catecholamine-secreting tumour that typically derived from chromaffin cells of the adrenal medulla
What is the aetiology of phaeochromocytoma?
- 10% (up to 30%) are extra-adrenal → paragangliomas
- Occur elsewhere in the sympathetic chain - typically occur in the head and neck but are also found in the thorax, pelvis and bladder
- More closely associated with genetic associations than phaeochromocytoma
- 10% are bilateral (up to 50% in familial cases)
- 10% are biologically malignant (metastasis)
- More common (20-40%) in paragangliomas
- 10% are NOT associated with hypertension
- 25% are familial
What are the familial risk factors for phaeochromocytoma?
- Germline mutations in one of several known pre-disposing genes including neurofibroma type 1, RET (MEN2), VHL, succinate dehydrogenase enzymes and tuberous sclerosis
- Younger presentation, more often bilateral
- More often malignant if associated with germline mutation of B unit of succinade dehydroxinate
What is the pathophysiology of phaeochromocytoma?
- Secrete catecholamines
- Rare cause of secondary hypertension
Spread
- Propensity for skeletal metastasis
- Other sites include regional lymph nodes, liver and lung
What is the presentation of phaeochromocytoma?
- Insidious onset in most patients
- 10% have no symptoms of adrenal disease
Symptoms
- Classical triad (up to 90% of cases) - hypertension, headache, sweating
- Paroxysmal sweating, headache, anxiety
- Episodes triggered by stress, exercise, posture, palpation of the tumour
- Paraganglioma of the bladder associated with micturition during episodes
- Weight loss
Signs
- Hypertension (50% paroxysmal, 50% persistent)
- Postural hypotension in 50% of cases
- Pallor
- Tachycardia, paradoxical bradycardia
- Pyrexia
What are the investigations for phaeochromocytoma?
Lab Tests
- 2 x 24 hr catecholamines or metanephrines
- 7% of phaeochromocytomas had normal 24 hr urinary catecholamines - secretion is episodic so take samples when patient symptomatic
- Plasma metanephrines, ideally at time of symptoms
Other biochemical abnormalities
- Hyperglycaemia
- May be low K+
- High haemocrit (raised Hb concentration)
- Mild hypercalcaemia
- Lactic acidosis - in absence of shock
Imaging
- MRI - abdomen or whole body
- MIBG scan
- PET scan
What is the management of phaeochromocytoma?
Pre-operative Management
- Full ⍺-blockade (phenoxybenzamine), when stable full β-blockade (propranolol, atenolol or metoprolol)
- Fluid and/or blood replacement
- Anaesthetic assessment
Definitive treatment
- Laparoscopic surgery
- Total excision where possible
- Tumour de-bulking if unlikely to be cured by surgery - reduces excess hormone production
- Chemotherapy if malignant, consider radio labelled MIBG
After surgery
- Long-term follow-up
- Genetic testing and family tracing and investigation
- Patients with known Phaeo predisposition genes should undergo periodical clinical, biochemical and radiological evaluation to facilitate the early detection of tumours
What are the complications of phaeochromocytoma?
- Cardiac failure, infarction, arrhythmias
- CVA
What is congenital adrenal hyperplasia?
Inherited group of disorders characterised by a deficiency in one of the enzymes necessary for cortisol synthesis
What is the aetiology of congenital adrenal hyperplasia?
90% due to an autosomal recessive 21⍺-hydroxylase deficiency
What is the pathophysiology of congenital adrenal hyperplasia?
- 21⍺-hydroxylase deficiency prevents the production of aldosterone and cortisol
- Increased volume of precursors will be diverted into the androgen pathway → increased testosterone and dihydrotesterone
- Reduced cortisol stimulates ACTH release and cortical hyperplasia
- Other enzyme deficiencies will result in varied clinical features depending on the pathway affected (e.g. adrenal insufficiency with no signs of reduced aldosterone or vice versa)
What is the presentation of congenital adrenal hyperplasia?
Classic CAH
- Presents at birth or shortly after
- Genital ambiguity (virilisation) in females
- Adrenal failure - collapse, hypotension, hypoglycaemia, poor weight gain
- Biochemical patten of Addison’s disease
Non-Classic CAH
- Partial 21⍺-hydroxylase deficiency
- Presents later (adolescence/adulthood)
- Precocious puberty
- Hirsutism
- Acne
- Oligomenorrhoea, infertility or sub-fertility
What are the investigations of congenital adrenal hyperplasia?
- Basal (or stimulated) 17-OH progesterone
- Genetic analysis
What is the management of congenital adrenal hyperplasia?
Paediatrics
- Glucocorticoid replacement
- Mineralocorticoid replacement in some
- Surgical correction
- Achieve maximal growth
Adults
- Glucocorticoid replacement, avoiding steroid over-replacement
- Control androgen excess
- Restore fertility
