Cushing's Syndrome Hyperparathyroidism Phaeochromocytoma

Home , Hypercalcaemia

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

𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝐶𝐶𝐶𝐶 𝑥𝑥 − 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝐶𝐶𝐶𝐶

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

• 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)

• Pharmacologic agents: – PO bisphosphonates –↑ BMD but does not ↓ Ca2+ – Cinacalcet –↓ Ca2+ but does not ↑ BMD

Ann Endocrinol (Paris). 2015 May;76(2):163-4. Benefits and place of calcimimetics in the management of primary hyperparathyroidism. Conservative treatment

• Offer surgery to these patients if condition progresses: – Ca2+ exceeds ULN ≥ 0.25mmol/L – T-score < -2.5 (or T-score < -2 with ↓ trend from baseline) – Fragility fracture – Renal stone – Creatinine clearance < 60ml/min

• Classic triad: headache, sweating, & tachycardia • Hypertension – paroxysmal vs. persistent • Palpitations • Tremors • Pallor • Panic attacks • DM • Cardiomyopathy Features

• Non-specific! Suspicious situations

• Hyperadrenergic spells • Resistant hypertension • Young hypertension • Familial syndromes • Pressor response during surgery/anaesthesia

N Engl J Med. 2007 Feb 8;356(6):601-10. Clinical practice. The incidentally discovered adrenal mass. Rule of 10%

• ~10% are extra-adrenal • ~10% are bilateral • ~10% are malignant • ~10% are found in children • ~10% are familial • ~10% are not associated with hypertension • ~10% contain calcification Confirming the diagnosis

• 24-hours urine fractionated catecholamines & metanephrines • Plasma fractionated metanephrines

• No consensus on which is the “best test” • Plasma test is more sensitive, but less specific • Beware of false-positives!

Nat Clin Pract Endocrinol Metab. 2007 Feb;3(2):92-102. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005.

J Clin Endocrinol Metab. 2014 Jun;99(6):1915-42. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. Catecholamine metabolism Localizing the disease

• CT or MRI of the abdomen and pelvis • MIBG

J Clin Endocrinol Metab. 2014 Jun;99(6):1915-42. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. CT

• Usually large (> 3cm) • Heterogeneous (necrosis & haemorrhage) • Enhances with contrast • Slow washout

N Engl J Med. 2007 Feb 8;356(6):601-10. Clinical practice. The incidentally discovered adrenal mass. MRI

• Large • Heterogeneous • Hyperintense compared to the liver on T2- weighted image

N Engl J Med. 2007 Feb 8;356(6):601-10. Clinical practice. The incidentally discovered adrenal mass. Basic MRI reading

http://www.slideshare.net/keshrad/basics-of-mri MIBG Management of phaeochromocytoma

• Pre-operative preparation • Intra-operative care • Post-operative follow-up Pre-operative care

• Focus: – Avoidance of hypertensive crisis – BP control – Volume restoration Avoiding a crisis

• Avoid the following: 1. ↑ intra-abdominal pressure 2. Physical & emotional stress 3. Foods rich in catecholamine substrates (bananas, caffeine, blue cheese … etc.) 4. Certain drugs Drugs to avoid

• Corticosteroids • Metoclopramide • Phenothiazines • TCAs • Sympathomimetic agents • Decongestants • ß-blockers

Indian J Endocrinol Metab. 2011 Oct;15 Suppl 4:S329-36. Medical management of pheochromocytoma: Role of the endocrinologist. BP control

• α-blockers → ß-blockers – ß-blockers induce vasoconstriction – ß-blockers are negatively inotropic • CCBs • Metyrosine Metyrosine: mechanism X Volume restoration

• Liberal salt & fluid • Caution in those with cardiomyopathy • Aim: prevent post-operative hypotension Intra-operative care

• Certain anaesthetic agents should be avoided • Avoid excessive tumour manipulation • Avoid tumour spillage → tumour seeding • Be prepared – BP can swing either way

N Engl J Med. 2007 Feb 8;356(6):601-10. Clinical practice. The incidentally discovered adrenal mass. Anaesthetic agents that trigger crises Agent Mechanism Alternative Atracurium Histamine release Vecuronium Pancuronium Indirect sympathetic stimulation Rocuronium Morphine Histamine release Fentanyl Post-op follow-up

• Recurrence and/or metastases are known to occur > 20 years later • Long-term follow-up is needed • Annual biochemical testing: – 24-hours fractionated urine catecholamines & metanephrines – Plasma fractionated metanephrines

J Clin Endocrinol Metab. 2014 Jun;99(6):1915-42. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. End