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Cushings DD
- 1. Diagnosis and Differential Diagnosis of Cushing's Syndrome A review article By Dr. Sunil Thomas George Prof Dr C Ramakrishnan's Unit M4
- 2. Introduction More Than 100 years ago HARVEY CUSHING coined the term “PLURIGLANDULAR SYNDROME” to be described as a disorder having 1. Central Obesity 2. Arterial Hypertension 3. Proximal muscle weakness 4. Diabetes mellitus 5. Oligomenorrhea 6. Hirsutism 7. Thin skin and Eccymoses
- 3. Introduction He goes on towards the recognition of the consequences of hypercortisolism With time it becomes clear that some of these cases were caused by small basophilic adenomas of the pituitary gland – Cushing's disease The pluriglandular syndrome became known as Cushing's syndrome
- 4. Introduction The incidence of Cushing's syndrome varies between 0.7 – 2.4 per million population/year This review article focuses on the problems faced with diagnosis and differential diagnosis of Cushing's syndrome in the era of obesity epidemic and ways to alter traditional approach in diagnosis REFERENCE 1. Lindholm J, Juul S, Jørgensen JO, Astrup J, Bjerre P, Feldt-Rasmussen U, et al. Incidence and late prognosis of cushing's syndrome: A population-based study. J Clin Endocrinol Metab. 2001;86:117–23. [PubMed] 2. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing's syndrome. Lancet. 2006;367:1605–17. [PubMed] 3. Etxabe J, Vazquez JA. Morbidity and mortality in Cushing's disease: An epidemiological approach. Clin Endocrinol (Oxf) 1994;40:479–84.
- 5. Cushing's syndrome vs Metabolic syndrome The metabolic syndrome caused by glucocorticoid excess can be differentiated from the obesity related metabolic syndrome with presence of osteopenia, osteoporosis, thin skin, and ecchymoses These are present in Cushing's syndrome but not in patients with simple obesity.
- 6. Urinary Free Cortisol The diagnosis of every endocrine diseases requires a clinical presentation compatible with the disease and identification of the pathophysiological cause. The assessment of excess glucocorticoid effects can be made by measuring the 24-hour urine free cortisol level – This is a direct reflection of the free, bioactive cortisol level in plasma
- 7. Urinary Free cortisol Hence in a patient presenting with obesity, hypertension, Type 2 diabetes, and hirsutism having thin skin, osteopenia, ecchymoses and an increased urinary free cortisol level The probability of Cushing's syndrome is 100 % For such cases, the clinician must move directly to a differential diagnostic evaluation
- 8. Dexamethasone-Suppression Test This test was developed as a differential diagnostic test to distinguish corticotrophin-dependent from corticotropin-independent Cushing's syndrome. This is now done by measuring the serum corticotropin levels. Unfortunately, dexamethasone suppression test has continued to be used as a screening test in Cushing's syndrome The positive predictive value of this test is only 0.4 %
- 9. Outliers In patients with definite evidence of Cushing's syndrome the differential diagnostic process should be initiated However, a small fraction of patients will not meet these criteria Some patients may have a strongly indicative physical examination but low or nil urinary free cortisol levels.
- 10. Outliers The corticotropin levels are suppressed in such patients They may be receiving exogenous steroids which must be identified, tapered and discontinued
- 11. Outliers Some patients have few or no clinical signs of cushings syndrome BUT have elevated urinary free cortisol excretion Plasma corticotropin is measured in such patients All these patients must undergo inferior petrosal sinus sampling to identify the source of corticotropin secretion Ectopic sources of secretion are nearly always neoplastic and are usually found in the chest. REFERENCE 1. Isidori AM, Lenzi A. Ectopic ACTH syndrome. Arq Bras Endocrinol Metabol 2007;51:1217-1225
- 12. Outliers Patients having eutopic secretion of corticotropin usually have a syndrome of generalized glucocorticoid resistance REFERENCE Chrousos GP, Vingerhoeds A, Brandon D, et al. Primary cortisol resistance in man: a glucocorticoid receptor-mediated disease. J Clin Invest 1982;69:1261-1269
- 13. Outliers Finally, some patients have convincing evidence on physical examination coupled with a normal urinary free cortisol level In such scenarios, the clinician should make sure that the urinary free cortisol is being measured with 1. High-performance liquid chromatography and mass spectrometry, 2. That the renal function is normal, and the 3. Collections are complete
- 14. Outliers “Periodic” Cushing's syndrome should be ruled out by measurement of urinary free cortisol frequently over the course of a month and followed up for a year. REFERENCE 1.Meinardi JR, Wolffenbuttel BH, Dullaart RP. Cyclic Cushing’s syndrome: a clinical challenge. Eur J Endocrinol 2007;157:245-254
- 15. Differential Diagnosis If the plasma corticotropin is measurable this means the disease process is corticotropin-dependent If corticotropin is not measurable, it means the process is corticotropin-independent.
- 16. Measure plasma corticotropin Corticotropin-dependent Corticotropin-independent Measurable? Not measurable ?
- 17. Corticotropin-dependent Determine ratio of central-plasma to peripheral-plasma corticotropic Ratio ≥3 Ratio ≤3 Eutopic Ectopic
- 18. Perform CT or MRI of pituitay and hypothalamus Perform CT or MRI of Chest Pituitary microadenectomy Bilateral adrenalectomy Curable? Unlikely? Positive for Cushing's syndrome Negative for Cushing's syndrome Surgery
- 19. Positive for Cushing's syndrome Negative for Cushing's syndrome Surgery Cortisol synthesis blockade Perform CT or MRI of abdomen and pelvis
- 20. Corticotropin-Independent Perform CT or MRI of adrenal glands Unilateral disease Bilateral disease Bilateral adrenalectomy Contrast-enhanced washout study
- 21. Contrast-enhanced washout study ≤60% at 15 min ≥60% at 15 min Open surgery Laparoscopic surgery
- 22. Summary Obesity epidemic has led to necessary alterations in the evaluation and treatment of patients with crushing's syndrome Dexamethasone-suppression test, although still popular, no longer has a role in the evaluation and treatment of patients with crushing's syndrome Only three biochemical tests are ever needed: 1. Urinary free cortisol (confirmatory) 2. Plasma corticotropin (Ectopic vs Eutopic) 3. Plasma costisol
- 23. Summary Inferior petrosal sinus sampling is done for corticotropin-dependent crushing's Plasma cortisol is done for determining the success or failure of surgery/treatment
- 24. Thank you
Editor's Notes
- Today, a z score of −2 at the lumbar spine supports this criterion. kinfold thickness is conveniently measured with an electrocardiographic caliper. The skin over the proximal phalanx of the middle finger of the nondominant hand is commonly used for this measurement A thickness of less than 2 mm is considered to be thin skin. patients who have three or more ecchymoses that are larger than 1 cm in diameter and not associated with trauma such as venipuncture are more likely to have Cushing’s syndrome
- on physical examination and an elevated 24-hour urinary free cortisol level
- They are usually identified during an evaluation for arterial hypertension.
- The most dramatic change is the emphasis on the antianabolic alterations in Cushing’s syndrome, which can provide a strong basis for separating patients with Cushing’s syndrome from the more numerous patients with obesity and the metabolic syndrome.
- transsphenoidal microadenomectomy or adrenalectomy. If the plasma cortisol level is not measurable on the morning after the operation (<5 μg per deciliter [138 μmol per liter]), the procedure was a success; if it is measurable, the operation failed. The surgeon must not administer intraoperative or postoperative synthetic glucocorticoids until the plasma cortisol level has been measured.