Disease Profiles: Adrenal Disorders Flashcards
Define secondary hyperaldosteronism
Reduced renal blood flow leads to excess renin (and hence angiotensin II)
Name a side effect of ketoconazole
Hepatotoxic
Which further investigations would you perform in a patient with confirmed Cushing’s who’s serum ACTH is high?
Suggests ACTH-dependent disease and pituitary MRI should be planned as well as biochemical tests to distinguish between pituitary and ectopic ACTH
Describe the classical body habitus of a patient with Cushing’s
Central obesity, oedema, virilism, ‘buffalo hump’
Describe the histology of an adrenal adenoma
Composed of cells resembling adrenocortical cells
Well-differentiated, small nuclei
Name two causes of secondary adrenal insufficiency
Iatrogenic (excess exogenous steroid) - inhibits ACTH production
Pituitary disorder - tumours, surgery, radiotherapy
Name an endocrine feature associated with Cushing’s
Glycosuria/diabetes mellitus
What is a paraganglioma?
Catecholamine-secreting tumour that arises along the sympathetic chain
Describe the clinical features of a familial phaeochromocytoma
Younger presentation, more often bilateral
Describe the investigations of an adrenal adenoma
Imaging (CT, MRI)
Hormonal testing
How would you manage Cushing’s caused by ectopic hormone secretion?
Remove source
OR bilateral adrenalectomy
Decreased ________ as a result of primary adrenal insufficiency causes hypoglycaemia
Glucocorticoids
What is Cushing’s disease?
Increased free circulating cortisol caused by a functioning pituitary adenoma
Name three causes of secondary hyperaldosteronism
Obstructive renal artery disease (eg, atheroma, stenosis)
Renal vasoconstriction (as occurs in accelerated hypertension)
Oedematous disorders (e.g. heart failure, cirrhosis with ascites)
How would you manage an adrenocortical carcinoma?
Resection with adjuvant therapy (if not metastatic)
Name the diagnostic test for Cushing’s
Low dose dexamethasone suppression test (repeat to confirm)
Describe the management of a large and/or functioning adrenal adenoma
Surgical excision
Name 3 ACTH dependent causes of Cushing’s
Pituitary adenoma, ectopic ATCH (e.g. SCLC), ectopic CRH
Describe the classical skin features associated with Cushing’s
Bruising
Striae (purple or red)
Pigmentation (only occurs with ACTH-dependent causes)
Thin skin
Hirsutism
Acne
Where do paragangliomas usually occur?
In the sympathetic chain - typically occur in the head and neck but are also found in the thorax, pelvis and bladder
How does excess ACTH in primary adrenal insufficiency cause excess pigmentation?
ACTH molecule contains sequence for MSH within it
ACTH is degraded by proteases eventually exposing MSH
Define an adrenal crisis
Acute, severe glucocorticoid deficiency caused by either stress in a patient with underlying adrenal insufficiency or sudden discontinuation of glucocorticoids after prolonged glucocorticoid therapy
Which patient group is most likely to develop an adrenocortical carcinoma?
Mainly occurs in adults, equal sex incidence
How would you manage an adult patient with congenital adrenal hyperplasia?
Glucocorticoid replacement, avoiding steroid over-replacement
Control androgen excess
Restore fertility
Define tertiary adrenal insufficiency
Lack of CRH secretion by the hypothalamus
How would you investigate primary hyperaldosteronism?
Confirm aldosterone excess - plasma aldosterone: renin ratio, if raised saline suppression test
Confirm subtype e.g. adrenal CT +/- adrenal vein sampling
Name three options for drug treatment given to patients with Cushing’s when other treatments fail or while waiting for radiotherapy to work
Metyrapone, ketoconazole, pasireotide LAR
Describe the management of primary adrenal insufficiency
Hydrocortisone as cortisol replacement, fludrocortisone as aldosterone replacement, education
Germline mutations in neurofibroma type 1, RET (MEN2), VHL, succinate dehydrogenase enzymes and tuberous sclerosis have all been associated with the formation of ___________
Phaeochromocytomas
Where do 40% of neuroblastomas arise?
Adrenal medulla
When do signs and symptoms of primary adrenal insufficiency appear?
Once >90% of the gland has been destroyed
Describe the classical musculoskeletal features associated with Cushing’s
Proximal myopathy, wasting
Osteoporosis, fractures
Describe the usual metastatic spread of adrenocortical carcinoma
Usually haemogenous (liver, lung and bone)
Describe the classical reproductive features associated with Cushing’s
Oligo/amenorrhoea
Describe the clinical presentation of an adrenal adenoma
95% non-functioning - asymptomatic, incidental finding
If hyperfunctioning will present with excess hormone secretion - Cushing’s, Conn syndrome
Why are phaeochromocytomas sometimes referred to as the ‘10% tumour’?
10% extra-adrenal (paragangliomas)
10% bilateral
10% malignant (metastasis)
10% not associated with hypertension
10% familial
Describe the gross appearance of an adrenal adenoma
Well circumscribed, encapsulated lesions
Solitary, small (2 to 3 cm), bright yellow (lipid) and buried within the gland
What causes the varied clinical features seen in congenital adrenal hyperplasia?
Clinical features depend on the enzyme/pathway affected e.g. may have adrenal insufficiency with no signs of reduced aldosterone
Name the most common cause of primary adrenal insufficiency (Addison Disease)
Autoimmune adrenalitis
Describe the clinical presentation of an adrenocortical carcinoma
Hormonal effects
Abdominal mass effects
Carcinomas with necrosis can cause fever
Name three infectious diseases linked to the development of primary adrenal insufficiency (Addison Disease)
TB, CMV disease, HIV
Define primary hyperaldosteronism
Autonomous production of aldosterone independent of its regulators (angiotensin II/potassium)
Describe the histology of an adrenocortical carcinoma
Haemorrhage and necrosis
Frequent mitosis, atypical mitoses
Lack of clear cells
Capsular or vascular invasion
Name an mood disorder associated with Cushing’s
Depression/psychosis
Increased cortisol (Cushing’s) causes altered ______ and _____ metabolism
Carbohydrate and lipid metabolism
Describe the histology of a neuroblastoma
Composed of primative appearing cells but can show maturation and differentiation towards gangliod cells
Describe the pathophysiology of Cushing’s disease (pituitary adenoma)
Pituitary secretes increased ACTH → increased cortisol production by adrenal gland
How would you manage primary hyperaldosteronism caused by an adrenal adenoma?
Unilateral laproscopic adrenalectomy
What is a phaeochromocytoma?
Catecholamine-secreting tumour typically derived from chromaffin cells of the adrenal medulla
Name 3 ACTH independent causes of Cushing’s
Adrenal adenoma/carcinoma, adrenal cortical nodular hyperplasia, pseudo-Cushings (severe depression, severe alcoholism)
How would you manage a patient with a phaeochromocytoma/ paraganglioma post-surgery?
Long-term followup
Genetic testing and family tracing and investigation
Adrenal enlargement in ACTH-dependent disease is usually _______
Diffuse
Adrenal _______ e.g. from septicaemic infection can cause primary adrenal insufficiency (Addison Disease)
Haemorrhage
Define secondary adrenal insufficiency
Lack of production of ACTH by the pituitary gland
Describe the definitive management of a phaeochromocytoma/ paraganglioma
Lap. surgery - total excision, de-bulking if not possible
Chemotherapy if malignant, consider radio-labelled MIBG
Describe the ‘sick day rules’ for a patient with primary adrenal insufficiency
Increase steroid replacement when unwell or undergoing other stress e.g. preoperative
How would you manage Cushing’s caused by an adrenal adenoma?
Adrenalectomy
Describe the pathophysiology of ACTH-independent Cushing’s
Autonomous over-production of cortisol by the adrenal gland due to neoplasia/nodular hyperplasia
What is the ‘classical triad’ with reference to phaeochromocytomas?
Accounts for up to 90% of cases - hypertension, headache, sweating
Name two causes of tertiary adrenal insufficiency
Iatrogenic (excess exogenous steroid) - inhibits CRH production
Hypothalamic disorder - tumours, surgery, radiotherapy
Long term steroid treatment suppresses ACTH production which leads to atrophy of the adrenal cortex. This means patients need extra doses of steroid in response to ______ (e.g. illness/surgery)
Stress
Amplification of N-myc and expression of telomerase predict a ___ outcome in neuroblastoma
Poor
How do KCNJ5 channel mutations increase aldosterone production by an adrenal adenoma?
Mutations lead to loss of ion selectivity → Na+ entry and depolarisation and therefore increased aldosterone production
Describe the signs of a phaeochromocytoma/ paraganglioma
Hypertension, postural hypotension
Pallor
Tachycardia, paradoxical bradycardia
Pyrexia
Describe the pathophysiology of Cushing’s syndrome caused by ectopic ACTH
Carcinoma e.g. small cell lung cancer secretes ACTH → increased cortisol production by adrenal gland
Define Conn syndrome
Primary hyperaldosteronism caused by an adrenal adenoma
How would you investigate congenital adrenal hyperplasia?
Basal (or stimulated) 17-OH progesterone
Genetic analysis
Define primary adrenal insufficiency (Addison Disease)
Decreased production of adrenocortical hormones due to destruction of the entire adrenal cortex, most commonly by autoimmune adrenalitis
Describe the clinical presentation of an adrenal crisis
Vomiting
Abdominal pain
Hypotension
Shock
Describe the management of a small, non-functioning adrenal adenoma
Leave in situ
What is the most common cause of Cushing’s syndrome?
Therapeutic administration of synthetic steroids (iatrogenic)
Adrenal enlargement in ACTH-independent disease is usually _______
Nodular
Define adrenocortical carcinoma
Very rare malignancy of the adrenal cortex
Somatic mutations of the potassium channel KCNJ5 in the region of the selectivity filter have been found in a significant number of aldosterone-producing _______ _______
Adrenal adenomas
Describe the symptoms of a phaeochromocytoma/ paraganglioma
Paroxysmal sweating, headache, pallor, tachycardia, anxiety
Weight loss
Paraganglioma of the bladder associated with micturition during episodes
Describe the clinical presentation of non-classic congenital adrenal hyperplasia (partial 21⍺-hydroxylase deficiency)
Presents later (adolescence/adulthood)
Precocious puberty
Hirsutism
Acne
Oligomenorrhoea, infertility or sub-fertility
Describe the pre-operative management of a phaeochromocytoma/ paraganglioma
Full ⍺-blockade (phenoxybenzamine), when stable full β-blockade (propranolol, atenolol or metoprolol)
Fluid and/or blood replacement
Anaethetic assessment
How would you manage a paediatric patient with congenital adrenal hyperplasia?
Glucocorticoid replacement
Mineralocorticoid replacement in some
Surgical correction
Aim to achieve maximal growth
Describe the pathophysiology of Cushing’s syndrome caused by ectopic CRH
Carcinoma e.g. medullary thyroid carcinoma secretes CRH → increased ACTH buy pituitary → increased cortisol by adrenal gland
How would you investigate a patient with suspected Cushing’s?
- Establish cortisol excess
- Low dose dexamethasone suppression test (diagnostic)
- Establish cause
Familial phaeochromocytomas are more commonly malignant if they are associated with germline mutation of B unit of ________ ________
Succinade dehydroxinate
What is the only definite criterion for adrenocortical carcinoma (vs benign lesion)?
Metastasis
Decreased ________ as a result of primary adrenal insufficiency causes hyperkalaemia, hyponatraemia, volume depletion and hypertension due to K+ retention and Na+ loss
Mineralocorticoids
Define adrenal adenoma
Benign neoplasm emerging from the cells of the adrenal cortex
Describe some complications of phaeochromocytoma/ paraganglioma
Cardiac failure, infarction, arrhythmias
CVA
Paralytic ileus of bowel
Describe the classic facial features of a patient with Cushing’s
Plethora (redness of the face)
Moon face
Describe the clinical presentation of primary hyperaldosteronism
Significant hypertension
Hypokalaemia (~30%)
Alkalosis
Name a side effect of metyrapone
Nausea and vomiting
Describe the management of secondary/tertiary adrenal insufficiency
Treat with hydrocortisone replacement (fludrocortisone unnecessary)
Describe the clinical presentation of classic congenital adrenal hyperplasia
Presents at birth or shortly after
Genital ambiguity (virilisation) in females
Adrenal failure - collapse, hypotension, hypoglycaemia, poor weight gain (biochemical pattern of Addison’s disease)
What is Cushing’s syndrome?
Increased free circulating glucocorticoid
Name 4 causes of primary hyperaldosteronism
Adrenal adenoma (Conn’s syndrome)
Bilateral adrenal hyperplasia (idiopathic)
Genetic mutations
Unilateral hyperplasia
Describe the gross appearance of a phaeochromocytoma
Range from small to large necrotic tumour masses, average 100g
May see adrenal remnants on the surface
Yellow, red/brown to haemorrhagic and necrotic
Describe the clinical presentation of secondary/tertiary adrenal insufficiency
Similar to Addison’s: weakness, fatigue, anorexia, N+V, weight loss, diarrhoea, dizziness and low BP, abdominal pain
Differences:
- Skin pale (no ↑ ACTH)
- Aldosterone production intact (hypertension)
How would you investigate a patient with suspected primary adrenal insufficiency?
Adrenal autoantibodies
↓ Na+, ↑ K+, may be hypoglycaemia
Short synacthen test
↑ ACTH
↑↑ renin, ↓ decreased aldosterone
Malignant phaeochromocytomas have a propensity for which type of metastatic spread?
Propensity for skeletal metastasis
Which patient group is most likely to develop an adrenal adenoma?
Found in almost all age groups but increase in frequency with age
Which further investigations would you perform in a patient with confirmed Cushing’s who’s serum ACTH is low?
Suggests non-ACTH-dependent disease - adrenal imaging should be planned (CT or MRI)
Why will K2Cr2O7 turn a phaeochromocytoma dark brown?
Oxidation of catecholamines in tumour cells
Name the commonest secondary cause of hypertension
Primary hyperaldosteronism
Adrenocortical carcinoma in younger patients can be associated with __-_______ _______
Li-Fraumeni syndrome
What is zellballen?
Describes the nest-like cellular arrangement of the tumour cell in phaeochromocytomas/ paragangliomas
Autoimmune adrenalitis is associated with other ______ _______ e.g. T1DM
Autoimmune diseases
Which skin feature of Cushing’s only occurs with ACTH-dependent causes?
Pigmentation
Describe the pathophysiology of congenital adrenal hyperplasia
21⍺-hydroxylase deficiency prevents the production of aldosterone and cortisol
There will be increased precursors diverted into androgen pathway → increased testosterone and dihydrotestosterone
Reduced cortisol stimulates ACTH release and cortical hyperplasia
Name the mutation responsible for 90% of cases of congenital adrenal hyperplasia
Autosomal recessive 21⍺-hydroxylase deficiency
Name the most common drug treatment given to patients with Cushing’s when other treatments fail or while waiting for radiotherapy to work
Metyrapone
Hyper______ and mild hyper______ is often seen in patients with a phaeochromocytoma/ paraganglioma
Hyperglycaemia, mild hypercalcaemia
Name three methods of establishing cortisol excess in suspected Cushing’s
Overnight 1mg dexamethasone suppression test (oral)
24hr urine free cortisol (24hr urine collection)
Diurnal cortisol variation (midnight/8am)
List some features of Cushing’s that help to differentiate between Cushing’s and obesity
Thin skin
Proximal myopathy
Frontal balding in women
Conjunctival oedema (chemosis)
Osteoporosis
Define congenital adrenal hyperplasia
Inherited group of disorders characterised by a deficiency in one of the enzymes necessary for cortisol synthesis
Define neuroblastoma
Malignant neuroendocrine tumour of the sympathetic nervous system that originates from neural crest cells
How would you manage Cushing’s caused by a pituitary adenoma?
Hypophysectomy (transsphenoidal route)
External radiotherapy if recurs
Last line: bilateral adrenalectomy
Where do 60% of neuroblastomas arise?
Sympathetic chain
How would you manage primary hyperaldosteronism caused by bilateral adrenal hyperplasia?
Mineralocorticoid receptor antagonists - spironolactone or eplerenone
When are neuroblastomas usually diagnosed?
18 months, 40% diagnosed in infancy
Describe the management of an adrenal crisis
Rehydration with NaCL, hydrocortisone, manage underlying cause/precipitant
How would you investigate a patient with suspected adrenocortical carcinoma?
Imaging - CT, MRI
Biopsy
Describe the clinical presentation of primary adrenal insufficiency (Addison’s disease)
Weakness, fatigue, anorexia, N+V, weight loss, diarrhoea, dizziness and low BP, abdominal pain
Skin pigmentation - look ‘tanned’, as well as black spots in buccal mucosa, dark palmar creases and dark finger spaces
How would you investigate a phaeochromocytoma/ paraganglioma?
2 x 24 hr catecholamines or metanephrines
Plasma metanephrines, ideally at time of symptoms
Imaging - MRI, MIBG, PET scan
If you identify cranial diabetes insipidus in a patient through a water deprivation test, what should your next investigation be?
CT scan or MRI of the head should be conducted to rule out brain tumours (especially craniopharyngioma)
