hypercortisolism , cushing, cushing's disease

1. Cushing's syndrome
BY
HAZEM SAMY HUSSEIN
ASSISTANT LECTURER OF INTERNAL MEDICINE

2. Definition
 an illness resulting from excess cortisol secretion, which has a high
mortality if left untreated.

3. Epidemiology of Cushing’s disease
 Rare; annual incidence approximately 2/million.
 Commoner in ♀ (♀:♂, 3–15:1).
 Age—most commonly, 20–40 years.

4. Causes of Cushing’s syndrome
 Pseudo-Cushing’s syndrome:
• Alcoholism <1%.
• Severe depression 1%.
 ACTH-dependent:
• Pituitary adenoma 68% (Cushing’s disease).
• Ectopic ACTH syndrome 12%.
• Ectopic CRH secretion <1%.
 ACTH-independent:
• Adrenal adenoma 10%.
• Adrenal carcinoma 8%.
• Nodular (macro- or micro-) hyperplasia 1%.
 Exogenous steroids, including skin creams, e.g. clobetasol.

5. Clinical features
 progressive and may be present for several years prior to diagnosis.
 A particular difficulty may occur in a patient with cyclical Cushing’s where
the features and biochemical manifestations appear and disappear with a
variable periodicity.
 Features may not always be florid, and clinical suspicion should be high.

6. Clinical features
• Most patients don’t have all these
signs/symptoms
• Many doctors may have only seen 1
case of Cushing’s and textbooks may
show only severe cases.

7. Clinical features
 Facial appearance—round plethoric complexion, acne and hirsutism, thinning of scalp
hair.
 Weight gain—truncal obesity, buffalo hump, supraclavicular fat pads.
 Skin—thin and fragile due to loss of SC tissue, purple striae on abdomen, breasts,
thighs, axillae, easy bruising, tinea versicolor, occasionally pigmentation due to ACTH.
 Proximal muscle weakness.
 Mood disturbance—labile, depression, insomnia, psychosis.
 Menstrual disturbance.
 Low libido and impotence.
 There is a high incidence of venous thromboembolism (careful during surgery).
 Overall mortality greater than of general population (by a factor of 6).
 Growth arrest in children.

8. Striae rubra

9. Associated features
 Hypertension (>50%) due to mineralocorticoid effects of cortisol (cortisol
overwhelms the renal 11B-hydroxysteroid dehydrogenase enzyme
protecting the mineralocorticoid receptor from cortisol). Cortisol may
also increase angiotensinogen levels.
 Impaired glucose tolerance/diabetes mellitus (30%).
 Osteopenia and osteoporosis (leading to fractures of spine and ribs).
 Vascular disease due to metabolic syndrome.
 Susceptibility to infections.

10. Investigations
 Does the patient have Cushing’s syndrome?
 What is the underlying cause?

11. Does the patient have Cushing’s
syndrome?
 Outpatient tests:
1. 24h urinary free cortisol:
 2–3x
 false –ve rate of 5–10% means that it should not be used alone (reduced
GFR <30mL/min) .
 false +ves(Fenofibrate, carbamazepine, and digoxin) depending on assay.
 Mild elevation occurs in pseudo-Cushing’s and normal pregnancy.

12. Does the patient have Cushing’s
syndrome?
2. Overnight dexamethasone suppression test
 Administration of 1mg dexamethasone at midnight is followed by a serum
cortisol measurement at 9 a.m.
 Cortisol <50nmol/L(1.8 mcg/dl.) makes Cushing’s unlikely.
 False +ves with poor dexamethasone absorption or hepatic enzyme
induction.
 The false –ve value is 2% of normal individuals but rises to <20% in obese
or hospitalized patients.

13. Does the patient have Cushing’s
syndrome?
 If both the above tests are normal, Cushing’s syndrome is unlikely.

14. Does the patient have Cushing’s
syndrome?
 Inpatient tests:
1. Midnight cortisol:
 Loss of circadian rhythm of cortisol secretion is seen in Cushing’s
syndrome, and this is demonstrated by measuring a serum cortisol at
midnight (patient must be asleep for this test to be valid and ideally after
48h as an inpatient).
 In normal subjects, the cortisol at this time is at a nadir (<50nmol/L), but
in patients with Cushing’s syndrome, it is elevated.

15. Does the patient have Cushing’s
syndrome?
2. Low-dose dexamethasone suppression test:
 Administration of 0.5mg dexamethasone 6-hourly (30
micrograms/kg/day) for 48h at 9 a.m., 3 p.m., 9 p.m., and 3 a.m. should
lead to complete suppression of cortisol to <50nmol/L in normal subjects
(30 micrograms/kg/day).
 Serum cortisol is measured at time 0 and 48h (day 2).

16. Does the patient have Cushing’s
syndrome?
3. Diurnal Salivary Cortisol Test:
• Salivary cortisol levels reflect plasma cortisol levels.
• Midnight plasma cortisol measurement requires
blood-drawing and may be difficult to obtain in an
outpatient setting.
• uses a "Salivette" in which the patient chews on a
cotton tube for 2-3 minutes. The samples are
stable for a week at room temperature and salivary
cortisol is independent of the rate of saliva
production.

17. Does the patient have Cushing’s
syndrome?

18. Pseudo-Cushing’s
 Patients with pseudo-Cushing’s syndrome will also show loss of diurnal
rhythm and lack of low-dose suppressibility.
 However, alcoholics return to normal cortisol secretory dynamics after a
few days’ abstinence in hospital. Severe depression can be more difficult
to differentiate, particularly since this may be a feature of Cushing’s
syndrome itself.
 Typically, patients with pseudo-Cushing’s show a normal cortisol rise with
hypoglycaemia (tested using ITT) whereas patients with true Cushing’s
syndrome show a blunted rise. However, this is not 100% reliable, as up to
20% of patients with Cushing’s syndrome (especially those with cyclical
disease) show a normal cortisol rise with hypoglycaemia.

19. Pseudo-Cushing’s
 The combined dexamethasone suppression test–CRH test (0.5mg
dexamethasone 6-hourly for 48h, starting at 12 p.m., followed by ovine
CRH 1 microgram/kg IV at 8 a.m.) (2h after last dose of dexamethasone)
may be helpful, as patients with pseudo-Cushing’s are thought to be
under chronic CRH stimulation, thus showing a blunted response to CRH
after dexamethasone suppression (cortisol 15min after CRH >38nmol/L in
Cushing’s and <38nmol/L in pseudo-Cushing’s).
 No screening tests are fully capable of distinguishing all cases of
Cushing’s syndrome from normal individuals/pseudo-Cushing’s

20. Cyclical Cushing’s
 A small group of patients with Cushing’s syndrome have alternating
normal and abnormal cortisol levels on an irregular basis.
 All causes of Cushing’s syndrome may be associated with cyclical
secretion of cortisol.
 Clearly, the results of dynamic testing can only be interpreted when the
disease is shown to be active (elevated urinary cortisol secretion and loss
of normal circadian rhythm and suppressibility on dexamethasone).

21. What is the underlying cause?
 ACTH
 Serum potassium.
 High-dose dexamethasone suppression test.
 Corticotrophin-releasing hormone test.
 Inferior petrosal sinus sampling

22. What is the underlying cause?
1. ACTH:
 serum basal ACTH should be measured to differentiate between ACTH-dependent and
ACTH-independent aetiologies .
 ACTH may not be fully suppressed in some adrenal causes of Cushing’s; however,
ACTH >4pmol/L is suggestive of an ACTH-dependent aetiology.
 The basal ACTH is of very little value in differentiating between pituitary-dependent
Cushing’s syndrome and ectopic Cushing’s syndrome, as there is considerable overlap
between the two groups, although patients with ectopic disease tend to have higher
ACTH levels

23. What is the underlying cause?
2. Serum potassium:
 useful discriminatory test, as hypokalaemia <3.2mmol/L is found in
almost 100% of patients with ectopic secretion of ACTH but in <10% of
patients with pituitary-dependent disease.

24. What is the underlying cause?
3. High-dose dexamethasone suppression test:
 performed in an identical way to the low-dose test but with 2mg doses of
dexamethasone (120 micrograms/kg/day).
 In Cushing’s disease, the cortisol falls by >50% of the basal value. In
ectopic disease, there is no suppression.
 However, approximately 10% of cases of ectopic disease, particularly
those due to carcinoid tumours, show >50% suppression, and 10% of
patients with Cushing’s disease do not suppress.

25. What is the underlying cause?
4. Corticotrophin-releasing hormone test:
 administration of 100 micrograms of CRH IV leads to an exaggerated rise
in cortisol (14–20%) and ACTH (35–50%) in 95% of patients with pituitary-
dependent Cushing’s syndrome.
 There are occasional reports of patients with ectopic disease who show a
similar response.
 Side effects: transient flushing; very rarely, apoplexy reported.

26. What is the underlying cause?
5. Inferior petrosal sinus sampling:
 Bilateral simultaneous inferior petrosal sinus sampling with measurement of ACTH
centrally and in the periphery in the basal state and following stimulation with IV CRH
(100 micrograms) allows differentiation between pituitary-dependent and ectopic
disease.
 A central to peripheral ratio of >2 prior to CRH is very suggestive of pituitary-
dependent disease, and >3 following CRH gives a diagnostic accuracy approaching
90–95% for pituitary-dependent disease.


27. What is the underlying cause?
5. Inferior petrosal sinus sampling (cont.):
 The test should be performed when cortisol levels are elevated.
 The accurate lateralization of a tumour using the results from inferior
petrosal sinus sampling (IPSS) is difficult, as differences in blood flow and
catheter placement, etc. will affect the results.
 Brainstem vascular events and deep vein thrombosis are rare
complications.

28. What is the underlying cause?

29. What is the underlying cause?

30. Investigation of ACTH-dependent
Cushing’s syndrome

31. Pituitary imaging
 MRI, following gadolinium enhancement which significantly increases
the pickup rate, localizes corticotroph adenomas in up to 80% of cases.
 However, it should be remembered that at least 10% of the normal
population harbour microadenomas and, therefore, the biochemical
investigation of these patients is essential, as a patient with an ectopic
source toCushing’s syndrome may have a pituitary ‘incidentaloma’.

32. Adrenal Imaging
• Patients with severe pituitary Cushing’s can have
adrenal enlargement.
• not helpful for the diagnosis of hypercortisolism
• Helpful for determining the type of Cushing’s
syndrome .

33. FIG. 1. Algorithm for testing patients suspected of having Cushing's
syndrome (CS)
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34. Treatment of Cushing’s disease

35. 1. Transsphenoidal surgery:
 First-line option in most cases.
 Selective adenomectomy gives the greatest chance of cure, with a
reported remission rate of up to 90%.
 However, strict criteria of a post-operative cortisol of <50nmol/L lead to
lower cure rates but much lower recurrence rates (<10% compared with
up to 50% in those with detectable post-operative cortisol).
 Delayed normalization (1–2 months) of cortisol after surgery can occur.
 Risk of relapse lasts for at least 10 years and is higher in Cushing’s disease
than for other secreting adenomas (13% at 5 years).

36. 2. Pituitary radiotherapy
 usually as second-line treatment, following unsuccessful transsphenoidal
surgery.
 As control of cortisol levels may take months to years, medical treatment
to control cortisol levels, while waiting for cortisol levels to fall, is essential.
 A more rapid response to radiotherapy is seen in childhood.

37. 3. Adrenalectomy
 This used to be the favoured form of treatment. It successfully controls cortisol
hypersecretion in the majority of patients.
 Occasionally, a remnant is left and leads to recurrent hypercortisolaemia.
 Bilateral adrenalectomy may still be indicated when pituitary surgery,
radiotherapy, and medical treatment have failed to control the disease.
 It is also helpful in Cushing’s syndrome due to ectopic disease when
the ectopic source remains elusive or inoperable.
 Laparoscopic surgery minimalizes morbidity and complications.

38. 4. Medical treatment
 indicated during the preoperative preparation of patients or while
awaiting radiotherapy to be effective or if surgery or radiotherapy are
contraindicated.
 Inhibitors of steroidogenesis:
1. metyrapone : usually used first-line.
2.Ketoconazole:
 used as first-line in children, as it is unassociated with increased adrenal
metabolites.
 There is also a suggestion that ketoconazole may have a direct action on
the corticotroph as well as lowering cortisol secretion.

39. 4. Medical treatment (cont.)
 Disadvantage of these agents inhibiting steroidogenesis is the need to
increase the dose to maintain control, as ACTH secretion will increase as
cortisol concentrations decrease.
 Steroidogenesis inhibitors may be used with glucocorticoid replacement
regimen to completely inhibit cortisol or with an aim for partial inhibition
of cortisol production.
 aiming for a mean cortisol of 150–300nmol/L, as this approximates the
normal production rate.

40. Follow-up of Cushing’s disease
 Successful treatment for Cushing’s disease leads to a cortisol that is
undetectable (<50nmol/L) following surgery. (This is due to the total
suppression of cortisol production from the normal corticotrophs in
Cushing’s disease.)
 An undetectable post-operative cortisol leads to a significantly higher
chance of long-term cure compared to the patients who have post-
operative cortisol between 50–300nmol/L.
 • The aim of follow-up is:
To detect recurrent Cushing’s.

41.  When cortisol is detectable following surgery,
recurrent disease must be excluded (low-dose
dexamethasone suppression). If recurrence is
excluded, it is then important to document the
adequacy of the stress response once weaned off
glucocorticoid replacement (ITT).

42. Thank you