Cushing’s syndrome Primary hyperparathyroidism Phaeochromocytoma Dr Tng Eng Loon Associate Consultant Endocrinologist Disclosure • Nil Scope 1. Cushing’s syndrome a) Clinical features b) Biochemical testing 2. Primary hyperparathyroidism c) Imaging 3. Phaeochromocytoma d) Treatment The Endocrine Diagnostic Algorithm • Recognize clinical features Suspect • Labs Confirm • Labs &/or imaging Localize • Medical &/or surgical modalities Treat Cushing’s syndrome Features of Cushing’s syndrome • Non-specific • Span across a spectrum i.e. highly variable • Depend on: – Duration of exposure – Degree of excess – Associated features from aetiology Features of Cushing’s syndrome • Features that are more specific: – Easy bruising – Facial plethora – Broad violaceous striae – Proximal myopathy – Unexplained osteoporosis – Growth retardation in children J Clin Endocrinol Metab. 2008 May;93(5):1526-40. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. Non-specific features of Cushing’s syndrome Symptoms Signs Overlapping conditions Depression Facial fullness T2DM Fatigue Dorsocervical fat Hypertension Wt ↑ Supraclavicular fat PCOS Back pain Obesity Osteoporosis Changes in appetite Thin skin Unusual infections Concentration ↓ Poor wound healing Hypokalaemia Memory ↓ Acne Renal stones Insomnia Hirsutism Irritability Androgenic alopaecia Libido ↓ Peripheral oedema Menstrual irregularities J Clin Endocrinol Metab. 2008 May;93(5):1526-40. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. Central fat distribution Tissue fragility Time will tell… • Suspect Cushing’s syndrome when: – Accumulation of features (particularly over time) – Severe features (particularly the specific ones) Diagnostic algorithm Exclude Clinical suspicion for Biochemical exogenous Cushing’s syndrome screening tests cortisol exposure An extra step in the algorithm Screening for Cushing’s syndrome 1. 24-hours urine free cortisol 2. Late-night salivary cortisol 3. Overnight dexamethasone suppression test 4. 2-day low dose dexamethasone suppression test J Clin Endocrinol Metab. 2008 May;93(5):1526-40. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. Screening tests • Designed to be highly sensitive (i.e. specificity will be poorer) – SNNOUT – SPPIN • Each test has its advantages & disadvantages → tailor the test to the patient Screening tests • The exact cut-off for each test is debatable • Numbers must be interpreted in clinical context Screening test Negative Positive No disease Pseudo-Cushing’s False-positive Drug interaction Cushing’s True-positive syndrome Cushing’s syndrome ACTH-dependent ACTH-independent Measure the serum ACTH level J Clin Endocrinol Metab. 2008 May;93(5):1526-40. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. ACTH measurement • ACTH is suppressed → ACTH-independent Cushing’s syndrome • ACTH is detectable → ACTH-dependent Cushing’s syndrome Beware: false-negative from pulsatility Aetiology of Cushing’s syndrome ACTH-independent ACTH-dependent Adrenal adenoma Cushing’s disease* Ectopic ACTH syndrome Adrenal carcinoma Ectopic CRH Micronodular syndrome hyperplasia Macronodular hyperplasia CT adrenal glands MRI pituitary gland CT thorax/abdomen/pelvis IPSS HDDST CRH test Treatment of ACTH-independent Cushing’s syndrome Condition Treatment Adrenal adenoma Unilateral adrenalectomy Adrenal carcinoma Adrenalectomy + mitotane + chemotherapy Adrenal hyperplasia Bilateral adrenalectomy Pre-op optimization – CV risk & metabolic insult Hydrocortisone pre- & post-op Expert Opin Pharmacother. 2015 Aug;16(12):1829-44. Cushing's syndrome: an update on current pharmacotherapy and future directions. Lancet. 2015 May 21. pii: S0140-6736(14)61375-1. Cushing's syndrome. Treatment of ACTH-dependent Cushing’s syndrome Cushing’s disease Trans-sphenoidal adenectomy DXT Bilateral adrenalectomy Pharmacologic (enzyme inhibitors, somatostatin analogues, & mifepristone) Ectopic ACTH syndrome Resect primary tumour Pharmacologic Ectopic CRH syndrome Resect primary tumour Pharmacologic Expert Opin Pharmacother. 2015 Aug;16(12):1829-44. Cushing's syndrome: an update on current pharmacotherapy and future directions. Lancet. 2015 May 21. pii: S0140-6736(14)61375-1. Cushing's syndrome. Primary hyperparathyroidism Features of PHPT • Asymptomatic (health screening) • Hypercalcaemia – Bones – fragility fractures, OFC – Stones (renal) – Psychic moans – neuropsychiatric symptoms – Abdominal groans – constipation J Clin Endocrinol Metab. 2014 Oct;99(10):3570-9. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. Confirming the diagnosis • Serum calcium – total vs. corrected vs. ionized • PTH J Clin Endocrinol Metab. 2014 Oct;99(10):3570-9. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. Other lab tests • Phosphate • ALP • Urea & creatinine • 25-hydroxyvitamin D • 24-hours urine calcium & creatinine J Clin Endocrinol Metab. 2014 Oct;99(10):3570-9. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. Serum total calcium 10% Ionized 50% Protein-bound Complexed to anions 40% Corrected calcium + + • 2 = 0.02 40 + 2 − g/dL mmol/L PTH • Must be suppressed in the context of hypercalcaemia • “Normal” levels ≠ normal in the setting of PHPT 25OHD • Common reason for ↑ PTH • Optimal levels are debated: 20ng/ml vs. 30ng/ml • Vitamin D deficiency defined as 25OHD ≤ 20ng/ml http://iom.nationalacademies.org/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx J Clin Endocrinol Metab. July 2011, 96(7): 1911–1930. Evaluation, Treatment, and Prevention of vitamin D deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2014 Nov;99(11):4265-72. Differences in overlapping meta-analyses of vitamin D supplements and falls. 24-hours urine tests • Measure the following: – Calcium – Creatinine Creatinine excretion Any renal impairment? Calcium : creatinine ratio Is this FHH? J Clin Endocrinol Metab. 2014 Oct;99(10):3570-9. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. Imaging tests • Screen for renal stones: – X-ray – US – CT J Clin Endocrinol Metab. 2014 Oct;99(10):3570-9. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. Management algorithm ↑ Ca2+ & non- Treatment: Excluded FHH suppressed surgery vs. & ↓ vit D PTH conservative Surgery or not? Indications for parathyroidectomy All symptomatic cases Asymptomatic cases Serum Ca2+ exceeds ULN ≥ 0.25mmol/L Peri-/postmenopausal women T-score ≤ -2.5 Premenopausal women Z-score ≤ -2.5 Men older than 50 yr old T-score ≤ -2.5 Men younger than 50 yr old Z-score ≤ -2.5 Creatinine clearance < 60ml/min 24-hours urine Ca2+ ≥ 400mg/day Renal stones Age < 50 yr old J Clin Endocrinol Metab. 2014 Oct;99(10):3607-18. Medical management of primary hyperparathyroidism: proceedings of the fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism. J Clin Endocrinol Metab. 2014 Oct;99(10):3595-606. The surgical management of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. Surgery • Parathyroidectomy – bilateral exploration vs. minimally invasive Pre-op localization • Not designed to be diagnostic studies • Facilitates minimally invasive surgery • Investigations: – 99mTc-sestamibi scan ± SPECT – 4D-CT – US neck J Clin Endocrinol Metab. 2014 Oct;99(10):3595-606. The surgical management of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. Intra-op localization • Intra-op PTH – Fall > 50% – Fall into normal range – Fall within 10 – 15 minutes • Nothing beats an experienced surgeon J Clin Endocrinol Metab. 2014 Oct;99(10):3595-606. The surgical management of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. Post-op care • Monitor for complications: – Haematoma – Recurrent laryngeal nerve palsy – Hypocalcaemia • Calcium & calcitriol supplements Post-op hypocalcaemia • Transient – parathyroid gland suppression • Permanent – parathyroid gland injury • Post-op hypoparathyroidism vs. hungry bone syndrome – clue: phosphate Surgical failure • Hyperplasia • Ectopic gland(s) • Supra-numerary gland(s) Super-numerary & ectopic glands Ann Surg. 1977 Aug;186(2):140-5. Parathyroid re-exploration. A clinical and pathological study of 112 cases. Conservative treatment • Majority of conservatively patients do not develop complications/progress in severity • Caveat: follow-up studies up to 15 years • Indications: – Does not meet criteria for surgery – Poor surgical candidate – Refusal for surgery J Clin Endocrinol Metab. 2014 Oct;99(10):3607-18. Medical management of primary hyperparathyroidism: proceedings of the fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism. Conservative treatment • Monitoring: – Annually surveillance of Ca2+ & PTH – DXA scan every 1 – 2 years • Supplements: – Vit D – keep 25OHD ≥ 20ng/dL – Ca2+ – do not restrict (but watch out for hypercalcaemia) J Clin Endocrinol Metab. 2014 Oct;99(10):3607-18. Medical management of primary hyperparathyroidism: proceedings of the fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism. Conservative treatment • Pharmacologic agents: – PO bisphosphonates