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Introduction Cushings syndrome ( hypercortisolism ) is a hormonal - PowerPoint PPT Presentation

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Introduction Cushings syndrome ( hypercortisolism ) is a hormonal disorder caused by prolonged exposure to high levels of steroid hormones called glucocorticoids. Exogenous Cushings syndrome: caused by taking excessive amounts of

  2. Introduction  Cushing’s syndrome ( hypercortisolism ) is a hormonal disorder caused by prolonged exposure to high levels of steroid hormones called glucocorticoids.  Exogenous Cushing’s syndrome: caused by taking excessive amounts of medications e.g. prednisone, dexamethasone  for chronic asthma, rheumatoid arthritis, lupus, to suppress immune system after transplant to prevent rejection, other inflammatory diseases.  Endogenous Cushing’s syndrome : excess cortisol produced by the adrenal glands. This is far rarer, but if left undiagnosed & untreated it can result in a shorter lifespan.

  3. CRH ( +) ( -) ACTH ( +) ( -) Cortisol

  5. Facial Plethora & Centripetal Obesity

  6. Wide (>1cm) Purple Striae

  7. Spontaneous Ecchymoses

  8. Neuropsychological changes Emotional lability •Agitated depression •Irritability •Anxiety •Panic attacks •Mild paranoia

  9. Causes of Cushing’s Syndrome  ACTH-dependent  Pituitary ACTH- dependent Cushing’s syndrome (Cushing’s disease)  Ectopic ACTH syndrome  Ectopic CRH syndrome  ACTH-independent  Adrenal Adenoma or Carcinoma  Adrenal hyperplasia (Micro- and macro-)  Glucocorticoids administration

  10. Causes cont…  The most common cause of hypercortisolism is ingestion of STEROIDS usually for Non-Endocrine disease.  Oral  Injected  Topical (intra-articular, epidural, nasal, & dermal)  Inhaled glucocorticoids

  11. Ectopic ACTH  SCLC >50%  Thymic carcinoid 15%  Islet cell tumors 10%  Bronchial carcinoid 10%  Other carcinoids 5%  Pheochromocytomas 2%

  12. Differential Diagnosis  Alcoholism  Anorexia nervosa (high urine free cortisol)  Familial cortisol resistance

  13. Cushing’s Syndrome Diagnostic approach 1. Establishing the diagnosis of CS 2. Establishing the cause of CS a. ACTH-dependent vs independent b. Identifying the source in ACTH-dependent 3. Imaging

  14. Cushing’s Syndrome Establishing the diagnosis Source: Newell-Price et al. Lancet

  16. Coronal T1-weighted Coronal T1-weighted Dynamic MRI (Contrasted) Static MRI (Contrasted)

  17. Treatment Cushing’s Disease : Transphenoidal resection of pituitary adenoma   Adrenal neoplasms: resection  Ectopic ACTH: resection if possible  Bilateral adrenal hyperplasia: may need adrenalectomies (lifelong glucocorticoid and mineralcorticoid replacement

  18. Cushing’s Syndrome Surgical Treatment  Transphenoidal adenomectomy  Done by neurosurgeons who perform pituitary surgery frequently  Remission rate of 80-90%-- Most common surgical failures with macroadenomas  Cure is confirmed by demonstrating profound hypoadrenalism post-op (8am cortisol <50 nmol/L)

  19. Cushing’s Syndrome Surgical Treatment cont…  Adrenal Surgery  Laparoscopic surgery is the treatment of choice for unilateral adrenal adenomas.  Pitfalls  Permanent need for GC and MC  10% risk of recurrent CS

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

  21. Medical Therapy for Cushing's Disease  No effective drug lowers ACTH production and shrinks the pituitary tumor.  There are medications that inhibit the adrenal glands production of cortisol.  There are 4 main indications of medical treatment: in case of contra-indication or refusal of surgery, in the lack of adenoma image on pituitary MRI, waiting for radiation techniques to be effective, as multimodality approach in the rare cases of pituitary carcinomas

  22. Steroidogenesis inhibitors  Mitotane inhibits side chain cleavage of cholesterol and also other cytochrome P450 enzymes (11-alpha and 18-hydroxylase)  Ketoconazole is an antifungal agent which causes inhibition of cytochrome P450 enzymes. It was reported to normalize cortisol levels in Cushing’s disease in about 50% of cases. Metyrapone is a pyridine derivative that blocks cortisol synthesis by mainly  inhibition of 11 beta hydroxylase..  In a small series of 13 patients with CD, Jeffcoate et al demonstrated a rapid clinical improvement in combination with a fall in plasma cortisol level after treatment with metyrapone in all patients..  Etomidate is an intravenous anaesthetic agent. It inhibits cortisol synthesis by inhibiting CYP11B1 with 11-beta hydroxylase activity, and cytochrome P450 at high concentrations.  Glucocorticoid receptor antagonist Mifepristone is currently the only available glucocorticoid receptor antagonist. Only rare cases have been reported to date.

  23. Novel therapies  Pasireotide is a novel somatostatin agonist with a particular binding affinity for somatostatin receptor (sstr) isoforms 1, 2, 3 and 5.. Potential novel adrenal-blocking drugs  LCI699 is a potent inhibitor of 11_-hydroxylase and 18-hydroxylase . The drug is currently under investigation for its efficacy in patients with CD.  Finally, the serotonin antagonist cyproheptadine , as an inhibitor of hypothalamic CRH and vasopressin secretion, as well as the amino butyric acid uptake inhibitor.  sodium valproate have been tested with limited success in CD to lower ACTH and cortisol levels.

  24. STUDIES  63y.o M admitted with muscle weakness and a T6 sensory level  Diagnosis?

  25. Cushings syndrome presenting as epidural lipomatosis

  26. Case presentation  41 y.o woman referred by her family doctor with fatigue and weight gain  History significant for DM (1year), hypercholesterolemia, and HTN resistant to 2 medications

  27. Case presentation….  Physical examination wt gain over 1 year   Severe insomnia, depression and difficulty concentrating  Round, plethoric face proximal muscle weakness   Abdominal striae and hyperpigmentation

  28. Cushing’s Syndrome Diagnostic approach 1. Establishing the diagnosis of CS 2. Establishing the cause of CS a. ACTH-dependent vs independent b. Identifying the source in ACTH-dependent 3. Imaging

  29. Case presentation ACTH dependent cushing syndrome MRI pit; bulge on right lobe of pitutary gland CXR, CT chest: normal

  30. Case presentation Patient underwent a transphenoidal surgery to resect the right lobe of the pituitary  Pathology: 2 mm corticotroph adenoma

  32. Conclusion  Diagnosis and management of CS remains a considerable challenge.  Diagnostic algorithm (biochemical confirmation followed by localisation) should be closely followed to avoid major pitfalls and misdiagnosis.  Tumour-specific surgery is the mainstay of treatment followed by radiotherapy and/or medical treatment.

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