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Cushing's syndrome

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Title: Cushing's syndrome


1
Cushing's syndrome
2
  • 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.

3
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

4
  • Adrenal neoplasia
  • -Adenoma
  • -Carcinoma
  • Exogenous, iatrogenic causes
  • -Prolonged use of glucocorticoids
  • -Prolonged use of ACTH

5
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.

6
  • 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.

7
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.

8
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
9
Moon face and plethora
10
Cushing's syndrome with truncal obesity and striae
11
Hirsutism with facial plethora
Buffalo hump appearance
12
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).

13
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.

14
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).

15
  • 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.

16

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

17
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.

18
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.

19
  • 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.

20
  • 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.

21
  • Others
  • Bronchoscopy, cytology and regional arteriograms
    are occasionally necessary.
  • Radiolabelled octreotide (111In octreotide) is
    occasionally helpful in locating ectopic ACTH
    sites.

22
  • prognosis
  • -Untreated Cushing's syndrome has a very bad
    prognosis.
  • Causes of death
  • -hypertension, myocardial infarction,
    infection and heart failure.

23
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.

24
  • -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.

25
  • 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.

26
  • 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.

27
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 .

28
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.

29
  • 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.

30
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.

31
  • 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.

32
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.

33
  • 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.

34
  • 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.

35
  • 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.
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