Cushing's syndrome

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Cushing's syndrome
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• Definition
• Cushing's syndrome is the term used to describe
  the clinical state of increased free circulating
  glucocorticoid.
• It occurs most often following the therapeutic
  administration of synthetic steroids or ACTH .
• All the spontaneous forms of the syndrome are
  rare.

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Causes of Cushing's Syndrome

• Adrenal hyperplasia
• -Secondary to pituitary ACTH overproduction
• -Pituitary-hypothalamic
  dysfunction
• -Pituitary ACTH-producing
  micro- or macroadenomas
• -Secondary to ACTH or CRH-producing non endocrine
  tumors (bronchogenic carcinoma, carcinoid of the
  thymus, pancreatic carcinoma, bronchial adenoma)
• Adrenal macronodular hyperplasia
• Adrenal micronodular dysplasia
• -Sporadic
• -Familial

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• Adrenal neoplasia
• -Adenoma
• -Carcinoma
• Exogenous, iatrogenic causes
• -Prolonged use of glucocorticoids
• -Prolonged use of ACTH

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Causes of Cushing's syndrome are usually
subdivided into two groups

• increased circulating ACTH from the pituitary
  (65 of cases), known as Cushing's disease, or
  from an 'ectopic', non-pituitary, ACTH-producing
  tumour else where in the body (10) with
  consequential glucocorticoid excess.
• A primary excess of endogenous cortisol secretion
  (25 of spontaneous cases) by an adrenal tumour
  or nodular hyperplasia, with subsequent
  (physiological) suppression of ACTH.

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• Rare cases are due to aberrant expression of
  receptors for other hormones (e.g.
  glucose-dependant insulinotrophic peptide GIP,
  LH or catecholamines) in adrenal cortical cells.
• A cushingoid appearance can be caused by excess
  alcohol consumption (pseudo-Cushing's syndrome) -
  the pathophysiology is poorly understood.

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Clinical features

• The predominant clinical features of Cushing's
  syndrome are those of glucocorticoid excess .
• Pigmentation occurs only with ACTH-dependent
  causes.
• Impaired glucose tolerance or frank diabetes are
  common, especially in the ectopic ACTH syndrome.
• Hypokalaemia due to the mineralocorticoid
  activity of cortisol is common with ectopic ACTH
  secretion.

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Frequency of Signs and Symptoms in Cushing's
Syndrome

Sign or Symptom Percent of Patients
Typical habitus (centripetal obesity)   97
Increased body weight 94
Fatigability and weakness 87
Hypertension (blood pressure gt 150/90) 82
Hirsutism  80
Amenorrhea 77
Broad violaceous cutaneous striae  67
Personality changes 66
Ecchymoses  65
Proximal myopathy  62
Edema 62
Polyuria, polydipsia 23
Hypertrophy of clitoris 19
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Moon face and plethora
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Cushing's syndrome with truncal obesity and striae
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Hirsutism with facial plethora
Buffalo hump appearance
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Diagnosis

• There are two phases of the investigation
• 1. confirmation of the presence or absence of
  Cushing's syndrome .
• 2. differential diagnosis of its cause (e.g.
  pituitary, adrenal or ectopic).

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Confirmation

• Most obese, hirsute, hypertensive patients do not
  have Cushing's syndrome, and some cases of mild
  Cushing's have relatively subtle clinical signs.
• Confirmation rests on demonstrating inappropriate
  cortisol secretion, not suppressed by exogenous
  glucocorticoids difficulties occur with obesity
  and depression where cortisol dynamics are often
  abnormal.
• Random cortisol measurements are of no value.

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Investigations to confirm the diagnosis include

• 48-hour low-dose dexamethasone test
• Normal individuals suppress plasma cortisol to lt
  50 nmol/L. Patients with Cushing's syndrome fail
  to show complete suppression of plasma cortisol
  levels. This test is highly sensitive (gt 97).
• 24-hour urinary free cortisol measurements.
• This is simple, but less reliable - repeatedly
  normal values (corrected for body mass) render
  the diagnosis most unlikely, but some patients
  with Cushing's have normal values on some
  collections (approximately 10).

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• Circadian rhythm.
• -After 48 hours in hospital, cortisol samples are
  taken at 0900 h and 2400 h (without warning the
  patient).
• -Normal subjects show a pronounced circadian
  variation those with Cushing's syndrome have
  high midnight cortisol levels (gt 100 nmol/L),
  though the 0900 h value may be normal.
• Other tests.
• -There are frequent exceptions to the classic
  responses to diagnostic tests in Cushing's
  syndrome. If any clinical suspicion of Cushing's
  remains after preliminary tests then specialist
  investigations are still indicated, these may
  include insulin stress test, desmopressin
  stimulation test and CRH tests.

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Test and protocol Measure Normal test result or positive suppression Use and explanation
Dexamethasone (for Cushing's) Dexamethasone (for Cushing's) Dexamethasone (for Cushing's) Dexamethasone (for Cushing's)
Overnight Overnight Overnight Overnight
Take 1 mg on going to bed at 2300 h Plasma cortisol at 0900 h next morning Plasma cortisol lt 100 nmol/L Outpatient screening test Some 'false positives'
'Low-dose' 'Low-dose' 'Low-dose' 'Low-dose'
0.5 mg 6-hourlyEight doses from 0900 h on day 0 Plasma cortisol at 0900 h on days 0 and 2 Plasma cortisol lt 50 nmol/L on second sample For diagnosis of Cushing's syndrome
'High-dose' used in differential diagnosis 'High-dose' used in differential diagnosis 'High-dose' used in differential diagnosis 'High-dose' used in differential diagnosis
2 mg 6-hourlyEight doses from 0900 h on day 0 Plasma cortisol at 0900 h on days 0 and 2 Plasma cortisol on day 2 less than 50 of that on day 0 suggests pituitary-dependent disease Differential diagnosis of Cushing's syndromePituitary-dependent disease suppresses in about 90 of cases

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Differential diagnosis of the cause

• This can be extremely difficult since all causes
  can result in clinically identical Cushing's
  syndrome.
• The classical ectopic ACTH syndrome is
  distinguished by a short history, pigmentation
  and weight loss, hypokalaemia, clinical or
  chemical diabetes and plasma ACTH levels above
  200 ng/L, but many ectopic tumours are benign and
  mimic pituitary disease closely both clinically
  and biochemically.
• Severe hirsutism/virilization suggests an adrenal
  tumour.

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Biochemical and radiological procedures for
diagnosis include

• Adrenal CT or MRI scan.
• -Adrenal adenomas and carcinomas causing
  Cushing's syndrome are relatively large and
  always detectable by CT scan.
• -Carcinomas are distinguished by large size,
  irregular outline and signs of infiltration or
  metastases.
• -Bilateral adrenal hyperplasia may be seen
  in ACTH-dependent causes or in ACTH-independent
  nodular hyperplasia.
• Pituitary MRI.
• -A pituitary adenoma may be seen but the
  adenoma is often small and not visible in a
  significant proportion of cases.

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• Plasma potassium levels.
• - Hypokalaemia is common with ectopic ACTH
  secretion.
• High-dose dexamethasone test.
• -Failure of significant plasma cortisol
  suppression suggests an ectopic source of ACTH or
  an adrenal tumour.

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• Plasma ACTH levels.
• -Low or undetectable ACTH levels (lt 10 ng/L) on
  two or more occasions are a reliable indicator of
  non-ACTH-dependent disease.
• CRH test.
• -An exaggerated ACTH and cortisol response to
  exogenous CRH suggests pituitary-dependent
  Cushing's disease, as ectopic sources rarely
  respond.
• Chest X-ray
• Is mandatory to look for a carcinoma of the
  bronchus or a bronchial carcinoid. Carcinoid
  lesions may be very small if ectopic ACTH is
  suspected, whole-lung and mediastinal CT scanning
  should be performed.

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• Others
• Bronchoscopy, cytology and regional arteriograms
  are occasionally necessary.
• Radiolabelled octreotide (111In octreotide) is
  occasionally helpful in locating ectopic ACTH
  sites.

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• prognosis
• -Untreated Cushing's syndrome has a very bad
  prognosis.
• Causes of death
• -hypertension, myocardial infarction,
  infection and heart failure.

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Treatment

• Whatever the underlying cause, cortisol
  hypersecretion should be controlled prior to
  surgery or radiotherapy.
• Choice of further treatment depends upon the
  cause.
• Cushing's disease (pituitary-dependent
  hyperadrenalism)
• -Trans-sphenoidal removal of the tumour is the
  treatment of choice.
• -Selective adenomectomy nearly always leaves the
  patient ACTH-deficient immediately
  postoperatively, and this is a good prognostic
  sign.
• - Overall, pituitary surgery results in remission
  in 75-80 of cases - but results vary
  considerably and an experienced surgeon is
  essential.

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• -External pituitary irradiation alone is slow
  acting, only effective in 50-60 even after
  prolonged follow-up and mainly used after failed
  pituitary surgery. Children, however, respond
  much better to radiotherapy, 80 being cured.
• -Medical therapy to reduce ACTH (e.g.
  bromocriptine) is rarely effective.
• -Bilateral adrenalectomy is an effective last
  resort if other measures fail to control the
  disease.

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• Adrenal carcinomas are highly aggressive and the
  prognosis is poor.
• In general, if there are no widespread
  metastases, tumour bulk should be reduced
  surgically.
• The adrenolytic drug op'DDD (Mitotane) may
  inhibit growth of the tumour and prolong
  survival. Some would also give radiotherapy to
  the tumour bed after surgery.

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• Tumours secreting ACTH ectopically should be
  removed if possible.
• Otherwise chemotherapy/radiotherapy may be used,
  depending on the tumour.
• Control of the Cushing's syndrome with
  metyrapone or ketoconazole is beneficial for
  symptoms, and bilateral adrenalectomy may be
  appropriate to give complete control of the
  Cushing's syndrome if prognosis from the tumour
  itself is reasonable.

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Nelson's syndrome

• Nelson's syndrome is increased pigmentation
  (because of high levels of ACTH) associated with
  an enlarging pituitary tumour, which occurs in
  about 20 of cases after bilateral adrenalectomy
  for Cushing's disease.
• The syndrome is rare now that adrenalectomy is an
  uncommon primary treatment, and its incidence may
  be reduced by pituitary radiotherapy soon after
  adrenalectomy.
• The Nelson's adenoma may be treated by pituitary
  surgery and/or radiotherapy .

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Congenital adrenal hyperplasia (CAH)

• Pathophysiology
• This condition results from an autosomal
  recessive deficiency of an enzyme in the cortisol
  synthetic pathways.
• There are six major types, but most common is
  21-hydroxylase deficiency which occurs in about 1
  in 15 000 births and which has been shown
  to be due to defects on chromosome 6 .
• As a result, cortisol secretion is reduced and
  feedback leads to increased ACTH secretion to
  maintain adequate cortisol - leading to adrenal
  hyperplasia.

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• Diversion of the steroid precursors into the
  androgenic steroid pathways occurs. Thus,
  17-hydroxyprogesterone, androstenedione and
  testosterone levels are increased, leading to
  virilization. Aldosterone synthesis may be
  impaired with resultant salt wasting.

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Clinical features

• If severe, this presents at birth with sexual
  ambiguity or adrenal failure (collapse,
  hypotension, hypoglycaemia), sometimes with a
  salt-losing state (hypotension, hyponatraemia).
• In the female, clitoral hypertrophy, urogenital
  abnormalities and labioscrotal fusion are common,
  but the syndrome may be unrecognized in the male.
• Precocious puberty with hirsutism is a later
  presentation.
• Rare, milder cases only present in adult life,
  usually accompanied by primary amenorrhoea.
• Hirsutism developing before puberty is
  suggestive of CAH.

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• Investigations
• 17-Hydroxyprogesterone levels are increased.
• Urinary pregnanetriol excretion is increased.
• Basal ACTH levels are raised.
• Treatment
• Replacement of glucocorticoid activity, and
  mineralocorticoid activity if deficient, is as
  for primary hypoadrenalism .Correct dosage is
  often difficult to establish in the child but
  should ensure normal 17-hydroxyprogesterone
  levels while allowing normal growth excessive
  replacement leads to stunting of growth.

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Uses and problems of therapeutic steroid therapy

• Apart from their use as therapeutic replacement
  for endocrine deficiency states, synthetic
  glucocorticoids are widely used for many
  non-endocrine conditions .
• Short-term use (e.g. for acute asthma) carries
  only small risks of significant side-effects
  except for the simultaneous suppression of immune
  responses.
• The danger lies in their long-term use. In
  general, therapy for 3 weeks or less, or a dose
  of prednisolone less than 10 mg per day, will not
  result in significant long-term suppression of
  the normal adrenal axis.

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• Long-term therapy with synthetic or natural
  steroids will, in most respects, mimic endogenous
  Cushing's syndrome. Exceptions are the relative
  absence of hirsutism, acne, hypertension and
  severe sodium retention, as the common synthetic
  steroids have low androgenic and
  mineralocorticoid activity.
• Local and inhaled steroids rarely cause Cushing's
  syndrome, although they commonly cause adrenal
  suppression.

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• All patients receiving steroids should carry a
  'Steroid Card'. They should be made aware of the
  following points
• Long-term steroid therapy must never be stopped
  suddenly.
• Doses should be reduced very gradually, with most
  being given in the morning at the time of
  withdrawal - this minimizes adrenal suppression.
• Doses need to be increased in times of serious
  inter-current illness (defined as presence of a
  fever), accident and stress. Double doses should
  be taken during these times.

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• Other physicians, anesthetists and dentists must
  be told about steroid therapy.
• Patients should also be informed of potential
  side-effects and all this information should be
  documented in the clinical record.
• Regular supervision including, e.g. DXA scan.