Title: Cushing's syndrome
1Cushing'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.
3Causes 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
5Causes 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.
7Clinical 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.
8Frequency 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
9Moon face and plethora
10Cushing's syndrome with truncal obesity and striae
11Hirsutism with facial plethora
Buffalo hump appearance
12Diagnosis
- 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).
13Confirmation
- 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.
14Investigations 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.
16Test 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
17Differential 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.
18Biochemical 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.
23Treatment
- 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.
27Nelson'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 .
28Congenital 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.
30Clinical 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.
32Uses 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.