Adrenal Disease and Cortisol Excess

Question 1

Features of Cushings syndrome/disease

Answer 1

• Cushing’s Syndrome is used to refer to the signs and symptoms that develop after prolonged abnormal elevation of cortisol. Cushing’s Disease is used to refer to the specific condition where a pituitary adenoma (tumour) secretes excessive ACTH.
• Round in the middle with thin limbs
  
  • Round ‘moon face’
  • Central obesity
  • Abdominal striae
  • Buffalo hump (fat pad on upper back)
  • Proximal limb muscle wasting
• High levels of stress hormone
  
  • HTN
  • Benign intracranial HTN
  • Cardiac hypertrophy
  • Depression
  • Insomnia
• Other
  
  • Osteoporosis
  • Euphoria
  • Cataracts
  • Avascular necorsis of the femoral head
  • Easy bruising
  • Poor wound healing
  • Thinning of skin

Question 2

Causes of Cushings syndrome/disease

Answer 2

• Exogenous steroids (in patients on long term high dose steroid medications)
• Cushing’s Disease (a pituitary adenoma releasing excessive ACTH)
• Adrenal Adenoma (a hormone secreting adrenal tumour)
• Paraneoplastic Cushing’s (excess ACTH released form a cancer - SCLC is the most common cause)

Question 3

Diagnosis of Cushings syndrome/disease

Answer 3

• Urinary free cortisol (x3 cortisol:creatinine ratio or 24hr urine collection for cortisol)
• Late night salivary cortisol (should be undetectable or very low in normal)
• Dexamethasone suppression test (patient takes a dose of dexamethasone at night and their cortisol and ACTH is measured in the morning to find out whether the dexamethasone suppresses their normal morning spike of cortisol)
  
  • Low dose - Normal response supresses release of cortisol by negative feedback on the hypothalamus and pituitary. Reduced CRH output from hypothalamus and reduced ACTH output from the pituitary, resulting in a low cortisol level. If cortisol level is not suppressed, this is the abnormal result seen in Cushing’s Syndrome.
  • The high dose dexamethasone suppression test is performed after an abnormal result on the low dose test. In Cushing’s Disease (pituitary adenoma) the pituitary still shows some response to negative feedback and 8mg of dexamethasone is enough to suppress cortisol. Where there is an adrenal adenoma, cortisol production is independent from the pituitary. Therefore, cortisone is not suppressed however ACTH is suppressed due to negative feedback on the hypothalamus and pituitary gland. Where there is ectopic ACTH (i.e. SCLC), neither cortisol or ACTH will be suppressed because the ACTH production is independent of the hypothalamus or pituitary gland.

Question 4

How is Cushings syndrome/disease treated

Answer 4

• The main treatment is to remove the underlying cause (surgically remove the tumour)
  
  • Trans-sphenoidal (through the nose) removal of pituitary adenoma
  • Surgical removal of adrenal tumour
  • Surgical removal of tumour producing ectopic ACTH
• If surgical removal of the cause is not possible another option is to remove both adrenal glands and give the patient replacement steroid hormones for life.

Question 5

Features of hypoadrenalism/Addison’s

Answer 5

• Adrenal glands do not produce enough steroid hormones (i.e. cortisol, aldosterone)
• Addison’s disease refers to specific condition where adrenal glands are damaged - autoimmune disease
• Secondary adrenal insufficiency is a result of inadequate ACTH stimulating the adrenal glands (i.e. Sheehan’s syndrome where massive blood loss during childbirth leads to pituitary gland necrosis)
• Tertiary adrenal insufficiency is the result of inadequate CRH release by the hypothalamus (usually as a result of long term oral steroids)
• Signs and symptoms
  
  • Fatigue
  • Nausea
  • Cramps
  • Abdominal pain
  • Reduced libido
  • Bronze hyperpigmentation to skin (ACTH stimulates melanocytes to produce melanin)
  • Hypotension (particularly postural hypotension)

Question 6

Diangosis of hypoadrenalism/Addison’s

Answer 6

• ↓Na,
• ↑K
• Hypoglycaemia
• Early mormning cortisol (although often falsley normal)
• Short synACTHen test (measure plasma cortisol before and 30 minutes after IV ACTH injection, normal >250nmol/L, post ACTH >480nmol/L)
• ACTH levels (should be ↑↑ in primary adrenal failure - causes skin pigmentation, ↓ in secondary adrenal failure)
• Renin/aldosterone levels (↑↑renin, ↓aldosterone)
• Adrenal autoantibodies (adrenal cortex antibodies, 21-hydroxylase antibodies)
• CT/MRI if suspected adrenal tumour
• MRI pituitary if pituitary pathology

Question 7

Management of hypoadrenalism/Addison’s

Answer 7

• Hydrocortisone as cortisol replacement
• Fludrocortisone as aldosterone replacement (monitor BP and K)

Question 8

Addisonian crisis

Answer 8

• Acute presentation of severe Addisons, where the absence of steroid hormones leads to a life threatening presentation. They present with:
  
  • Reduced consciousness
  • Hypotension
  • Hypoglycaemia, hyponatraemia, hyperkaemia
• It can be the first presentation o or triggered by infection, trauma or other acute illness and in someone on long term steroids suddenly withdrawing.
• Need immediate treatment with:
  
  • Intensive monitoring if unwell
  • Parenteral steroids
  • IV fluid resuscitation
  • Correct hypoglycaemia
  • Careful monitoring of electrolytes and fluid balance

Question 9

Features of CAH

Answer 9

• AR disorder
• 21-hydroylase responsible for converting progesterone into aldosterone and cortisol (progesterone is also used to create testosterone)
• Defect in 21-hydroxylase means they can’t convert hormones to next stage
• Female patients with CAH usually presents at birth with virilised genitalia, known as “ambiguous genitalia” and an enlarged clitoris due to the high testosterone levels.
• In mild cases patients present tall for their age, deep voice, early puberty and facial hair/absent periods in females and large penis/small testicles in males.
• Patients with more severe CAH present shortly after birth with hyponatraemia, hyperkalaemia and hypoglycaemia.
• Treatment with cortisol and aldosterone replacement - females with virilised genitals may require corrective surgery

Question 10

Features of phaeochromocytoma

Answer 10

• Adrenaline is produced by chromaffin cells in adrenal glands - phaeochromocytoma is a tumour of the chromaffin cells that secretes unregulated and excessive amounts of adrenaline
• 25% associated with MEN2
• 10% rule:
  
  • 10% bilateral
  • 10% cancerous
  • 10% outside the adrenal gland
• Signs and symptoms include HTN, headache, palpitations, sweating, tremor, anxiety, nausea, vomiting, tachycardia, paroxysmal AF, chest and abdominal pain
• Diagnosis
  
  • 24 hour urine catecholamines
  • Plasma free metanephries (breakdown product of adrenaline which has a longer half-life)
  • Imaging using CT and MIBH scan (chromaffin seeking analogue)
• Management (should manage medically to reduce risk of anaesthesia in surgery)
  
  • Alpha blockers (i.e. phenoxybenzamine)
  • Beta blockers once established on alpha blockers
  • Adrenalectomy to remove tumour is the definitive management

Question 11

Features of primary hyperaldosteronism/Conn’s syndrome

Answer 11

• Most common cause of secondary HTN
• Afferent arteriole in kidney there are juxtaglomerular cells that sense BP - when BP is low they secrete renin which activates the RAAS ending in release of aldosterone form the adrenal glands. Aldosterone then increases Na reabsorption and K secretion in the DCT and hydrgen secretion in the CD.
• Primary (Conn’s syndrome) - adrenal glands directly responsible (i.e. adrenal adenoma, bilateral adrenal hyperplasia, familial, adrenal carcinoma)
• Secondary - excessive renin (i.e. renal artery stenosis, renal artery obstruction, HF)
• Diagnosis
  
  • Aldosterone-renin-ratio (ARR)
    
    • High aldosterone and low renin = primary
    • High aldosterone and high renin = secondary
  • HTN, hyperkalaemia and alkalosis
  • CT to look for adrenal cause
  • Renal dopples US, CT angiogram of MRA for renal cause
• Management
  
  • Aldosterone antagonists (i.e. eplerenone, spironolactone)
  • Treat underlying cause (i.e. adenoma removel, renal artery angioplasty)