cushung's syndrome

1. DR. IGBITI O.J.
REGISTRAR, INTERNAL MEDICINE DEPARTMENT
CUSHING’S
SYNDROME

2. Outline
o Introduction
o Epidemiology
o Relevant anatomy and physiology
o Aetiology
o Clinical features
o Diagnostic approach
o Treatment
o Summary/key points
o Conclusion
o References

3. Introduction
Cushings syndrome is a constellation of clinical
features resulting from prolonged exposure to excess
glucocorticoids of any aetiology.

4. Epidemiology
o The exact incidence of Cushing syndrome is challenging.
o The true incidence might be underestimated.
o Globally, it is considered a rare disease with an incidence of 1-2 per
100,000 population per year.
o In a European population based study, the annual incidence of
endogenous cushing’s syndrome was reported to be 1.2-1.7 per
million per year.
o LUTH: It has an incidence of 2-5 new cases /million people/year
and 10% of these new cases occur in children

5. Epidemiology
o The female-to-male incidence ratio is approximately 5:1
for Cushing syndrome due to an adrenal or pituitary tumor.
o Ectopic ACTH production is more frequent in men than in
women.
o The peak incidence of Cushing syndrome due to either an
adrenal or pituitary adenoma is in persons aged 25-40
years.

6. Functional anatomy
o 2 adrenal glands sit on top of the
kidneys
o The Cortex forms about 90% of
the adrenal mass
o Medulla 10%
o Synthesizes and secretes steroid
hormones from cholesterol
o Blood supply from the branches
of the aorta, phrenic and renal
arteries

7. Steroid synthesis

8. Steroid synthesis

9. Regulation of cortisol synthesis

10. Regulation of cortisol synthesis

11. Etiology
o ACTH-dependent
o (Pseudo Cushing’s Syndrome)
o Pituitary (Cushing’s Disease) (70%)
oMicroadenomas (95%)
oMacroadenomas (5%)
o Ectopic ACTH or CRH (10%)
oSmall cell lung carcinoma
oCarcinoids: lung, pancreas, thymus

12. Etiology
o ACTH-independent
o (Factitious)
o Unilateral
oAdrenal adenoma (10%)
oAdrenal carcinoma (5%)
o Bilateral
oMacronodular Hyperplasia (AIMAH) (<2%)
oPrimary Pigmented Micronodular Adrenal disease - PPMA (<2%)
oMcCune Albright Syndrome (<2%)

13. Clinical features
o General
o Truncal obesity
o Proximal muscle
weakness
o Hypertension
o Headaches

14. Clinical features
o Dermatologic
o Wide purple striae
o Spontaneous ecchymoses
o Facial plethora
o Hyperpigmentation
o Acne, hirsutism
o Fungal skin infections

15. Clinical features

16. Clinical features
o Endocrine/Metabolic
o Hypokalemic alkalosis
o Hypokalemia
o Osteopenia
o Hypogonadism
o Glucose intolerance
o Hyperlipidemia
o Hyperhomocysteinemia
o Kidney stones
o Polyuria
o Hypercoagulability

17. Clinical features
o Neuropsychiatric
o Insomnia
o Depression, frank psychosis
o Impaired cognition and short-term memory

18. Making a diagnosis
1. Establishing the diagnosis of Cushing’s Syndrome
2. Establishing the cause of Cushing’s Syndrome
a. ACTH-dependent vs independent
b. Identifying the source in the ACTH-dependent forms
3. Imaging

19. Physiological principles
o Cortisol hypersecretion in most patients with Cushing’s
Syndrome is cyclical
o There is loss of circadian rhythm in pts with CS
o Pituitary tumors are partly autonomous—they retain feedback
inhibition, but at a higher set point.
o Adrenal and ectopic tumors have autonomous hormone secretion
and do NOT (usually) exhibit feedback inhibition

20. Establishing the diagnosis
o 24-hour urinary free cortisol
o Low-dose dexamethasone suppression tests
o Midnight plasma cortisol or late-night salivary
cortisol

21. Establishing the diagnosis
o 24-hr urinary free cortisol (UFC)
o Direct assessment of circulating free (biologically active)
cortisol
o Up to 3 collections if high suspicion
o UFC >4x normal value is diagnostic (normal 3.5 to
45mcg/24 hours)

22. Establishing the diagnosis
o False negatives <6%
oAssess whether collection is complete
oIf GFR<30mls/min, UFC may be falsely low
o FP rate <4%
oRecently shown with fluid intake >5L/day

23. Establishing the diagnosis
o Low-dose Dexamethasone Suppression Test (Overnight vs 48-hr)
o AM cortisol >50nmol/L
o Excellent sensitivity but borderline specificity—false positives
oPseudo-Cushing’s
oPatient’s error in taking medication
oDrugs accelerating dexamethasone metabolism
oElevated cortisol binding globulin

24. Establishing the diagnosis
o Midnight plasma cortisol
o Level <50nmol virtually rules out the disease
o Level >130 nmol/L is diagnostic
o Late-night salivary free cortisol
o Patients collect saliva by chewing on cotton
o However, a modified cortisol assay is required so not
validated by all labs
o Excellent sensitivity and specificity—but exact cutoffs not
established

25. Establishing the diagnosis
o Differentiating between pseudo-Cushing’s and
Cushing’s syndrome
o Very difficult with co-existent depression,
alcoholism, obesity
o The dexamethasone stimulation test-Cortocotropin
releasing hormone stimulation test has shown
100% specificity and diagnostic accuracy in
differentiating.
o Spot midnight cortisol level
o Midnight/morning cortisol levels >0.67

26. Establishing the cause
o Clinical features may provide a clue
o First step is to measure plasma ACTH to differentiate ACTH-
dependent from ACTH-independent cushing’s
o If ACTH <1 pmol/L, it is an adrenal cushing’s syndrome
o If ACTH >3.3 pmol/L, it is ACTH-dependent
o If ACTH 1-3CRH stimulation is necessary

27. Establishing the cause
o ACTH-dependent
o Distinguishing pituitary from non-pituitary sources is difficult
o Carcinoids can be clinically undistinguishable from cushings
disease and are difficult to identify by imaging
o Biochemical assessment rather than imaging is used to
differentiate between pituitary and non-pituitary causes

28. Establishing the cause
o Two biochemical tests in ACTH-dependent CS
o High dose Dexamethasone Stimulation Test
o CRH stimulation test

29. o High-dose Dexamethasone Stimulation Test (DST)
oPrinciple that pituitary tumors are only partially
autonomous.
oIn contrast, adrenal and ectopic tumors are usually
autonomous.
o High dose DST x 48hrs, with baseline and final cortisol value.
Suppression >50 % suggestive of CD.
Establishing the cause

31. Establishing the cause
o Corticotropin Releasing Hormone (CRH) stimulation test
o Principle that pituitary tumors are responsive to an
exogenous dose of CRH whereas ectopic and adrenal
tumors are not
o Ovine CRH administered as an IV bolus and ACTH and
cortisol drawn at 0, 30, 60, 90, and 120 minutes.
o >50% rise in ACTH, >20% rise in cortisol
o In ectopic CS, levels are usually not altered.

32. Establishing the cause
o Adrenal CT
o In cases of ACTH-independent cushing’s syndrome
o CXR and chest CT
o In cases suggesting ectopic source
o If negative, CT abdomen, +/-pelvic, +/-neck
o Head MRI
o In cases suggesting pituitary source
o >40% of cushing’s disease have normal MRI (average size
5mm)
o 3-27% have pituitary incidentalomas

33. Cushing’s Syndrome Imaging

34. Establishing the cause
o Bilateral inferior petrosal sinus sampling is the most reliable
test to differentiate the source of ACTH and should be done in
MOST patients
o Can be avoided:
oIf a patient has ACTH dependent Cushing’s syndrome with
concordant dexamethasone stimulation test and CRH
stimulation test suggestive of cushing’s disease and an MRI
lesion >6mm

35. Inferior Petrosal Sinus Sampling (IPPS)
o The most direct way of knowing if the pituitary is making
excess ACTH is to measure it
o The inferior petrosal sinuses receive the drainage of the pituitary
gland without admixture of blood from other sources
o Each half of the pituitary drains in the ipsilateral petrosal sinus

37. Inferior Petrosal Sinus Sampling (IPSS)
o Interpretation
o Localization
oIf pituitary/periphery ratio >2 (>3 with CRH), the patient
has Cushing’s Disease
oIf pituitary/periphery ratio <1.5 (<2 with CRH), the patient
has ectopic Cushing’s Syndrome
o Lateralization
oIf the higher side/lower side >1.4/1, the tumor is on the
side with higher ACTH levels

38. Inferior Petrosal Sinus Sampling (IPPS)
o Failure to localize
o Inability to catheterize
o Incorrect catheter
placement
o Anomalous venous
drainage
o Periodic hormonogenesis
o Ectopic tumor secreting
CRH
o Failure to lateralize
o Incorrect catheter placement
o Sample withdrawal too rapid
o Midline microadenoma
o Prior transphenoidal surgery
o Ectopic tumor secreting CRH

41. Cushing’s Syndrome, Surgical Treatment
o Transphenoidal adenomectomy
o Remission rate of 80-90%, Most common surgical failures
occur with macroadenomas
o Cure is confirmed by demonstrating profound
hypoadrenalism post-op (am cortisol <50 nmol/L)
o Morbidity extremely low
o There is a period of adrenal insufficiency requiring
glucocorticoids for 6 – 8 months

42. Surgical Treatment
o Adrenal Surgery
o Laparoscopic surgery is the treatment of choice for unilateral
adrenal adenomas
o Bilateral adrenalectomy is 2nd line treatment for patients with
cushing’s disease who have not been cured by pituitary surgery
+/-radiotherapy
oPermanent need for glucocorticoids and mineralocorticoids
o15-25% risk of Nelson’s syndrome
o10% risk of recurrence due to remnant or ectopic

43. Pituitary Irradiation
o Conventional irradiation induces remission in only 20-83% of adults
o Onset of remission: 6months -5 years
o Disadvantages:
o Delayed effectiveness
o Significant risk of hypopituitarism
o Risk of neurologic and cognitive damage
o The role of newer stereotactic radiosurgery remains to be determined

44. Medical Therapy
o Uses of medical therapy
o Selected cases of Cushing’s disease prior to surgery
o In cases of cushing’s disease awaiting the effect of
radiotherapy
o Ectopic cushing’s syndrome due to an unresectable
tumor
o Adrenal carcinoma

45. Medical Therapy
o Cortisol synthesis inhibitors
o Ketoconazole
o Metyrapone
o Aminoglutethimide
o Mitotane
o Etomidate

46. Medical Therapy
o Drugs acting at the hypothalamic-pituitary level
o PPARγ agonists
o Dopamine agonists
o Somatostatin analogs
o Retinoic acid

47. Summary
o Cushing syndrome results from endogenous or exogenous
exposure to glucocorticoids; it is associated with poor
suppressibility of endogenous cortisol production with oral
dexamethasone.
o The most common cause of Cushing syndrome is the
administration of exogenous glucocorticoid therapy for another
medical condition.
o Initial tests for Cushing syndrome include the overnight low-dose
dexamethasone suppression test, 24-hour urine free cortisol, and
late-night salivary cortisol.

48. Conclusion
o Diagnosis and management of cushing’s syndrome is a challenge
o An algorithm should be closely followed to avoid misdiagnosis
o Tumour-specific surgery is the primary treatment followed by
radiotherapy and/or medical treatment
o However, treatment of cushing’s disease remains disappointing
and further developments are needed in this area

49. Sources
o Iatrogenic cushing’s syndrome in children following nasal steroid
Isaac Oludare Oluwayemi, Abiola Olufunmilayo Oduwole, Elizabeth Oyenusi,
Alphonsus Ndidi Onyiriuka, Muhammad Abdullahi, Olubunmi Benedicta Fakeye-
Udeogu, Chidozie Jude Achonwa, Moustapha Kouyate
The Pan African Medical
Journal. 2014;17:237. doi:10.11604/pamj.2014.17.237.3332
o Disorders of the adrenal cortex, Wiebke Arlt, Harrisson’s principles of internal
medicine, 19th edition, 2015, p.2940-2949
o Adrenal cortex and cushing’s syndrome, Ian B. Wilkinson, Tim Raine, Kate
Wiles, Anna Goodhart, Catriona Hall, Harriet O’Neill, P.224-225
o Endogenous Cushing Syndrome, Ha Cam Thuy Nguyen, Romesh Khardori, MD,
PhD, FACP, Catherine Anastasopoulou, MD, PhD, FACE. www.Medscape.com

50.  Late night salivary cortisol as a screening test for cushing’s syndrome.
Hershel Raff, Jonathan L. Raff, James W. Findling. Journal of clinical
endocrinology and metabolism volume 83.