HYPERCALCAEMIA 101 FOR THE INTERNIST

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1 HYPERCALCAEMIA 101 FOR THE INTERNIST Dr Chionh Siok Bee Dept of Medicine, National University Hospital Medicine Review Course 18/09/2011

2 Outline of Talk Definition of hypercalcaemia Aetiology of hypercalcaemia Clinical manifestations of hypercalcaemia Diagnostic approach to hypercalcaemia Treatment of hypercalcaemia Case study to illustrate the approach to the investigation of hypercalcaemia No conflicts of interest to declare

3 Definition of Hypercalcaemia Corrected total serum Calcium above the normal range (NUH: mmol/l) Ionised Calcium above mmol/l Calcium is 45% bound to protein Correct for albumin level 10% bound to anions 45% free (ionised) Affected by ph

4 Aetiology of Hypercalcaemia Endocrine Disorders causing Hypercalcaemia With excess PTH - Hyperparathyroidism (HPT) Without excess PTH Malignancy-Associated Hypercalcaemia (MAH) With excess PTH-related peptide (PTHrP) With other systemic factors PHPT and MAH account for 90% of hypercalcaemia

5 Aetiology of Hypercalcaemia Inflammatory Disorders Chronic Granulomatous Disorders: activation of extra-renal 1-α hydroxylase 1,25(OH) 2 D = Calcitriol Non-infectious: Sarcoidosis, Wegener s, Berylliosis, Eosinophilic granulomatosis, silicone-induced and paraffin-induced granulomatosis, infantile fat necrosis Infectious: TB, histoplasmosis, candidiasis, leprosy, coccidiomycosis, cat-scratch disease AIDS HIV, CMV, HTLV-III

6 Aetiology of Hypercalcaemia Drug-related Thiazides Renal reabsorption of Ca Ur Ca Lithium Theophylline toxicity Teriparatide (rhpth1-34) Vitamin D and Vitamin D analogues e.g. Calcitriol Excessive Vitamin A and analogues: cis- or transretinoic acid Oestrogens and Antioestrogens Aluminium Intoxication Milk-Alkali Syndrome (> 3 G elemental Calcium/day) alkalosis, Ur Ca, nephrocalcinosis, renal failure Parenteral nutrition

7 Aetiology of Hypercalcaemia Hypercalcaemia of Unknown Aetiology Williams Syndrome elfin facies cardiac abnormalities, esp AS Idiopathic Infantile Hypercalcaemia Miscellaneous Causes Rhabdomyolysis ARF diuretic phase Immobilisation in Paget s Disease

8 Endocrine Causes of Hypercalcaemia Endocrine Disorders causing Hypercalcaemia With Excess PTH: Sporadic Primary Hyperparathyroidism % of PHPT is due to a single adenoma 10-15% due to polyglandular hyperplasia 1% due to parathyroid carcinoma Very rare: Autoimmune Hypocalciuric Hypercalcaemia due to Ab against the CaSR Familial Primary Hyperparathyroidism Tertiary Hyperparathyroidism

9 Endocrine Causes of Hypercalcaemia: Familial HPT CaSR gene MEN 1 gene HRPT2 gene RET Protooncogene From Endotext.com

10 Endocrine Causes of Hypercalcaemia Endocrine Disorders causing Hypercalcaemia Without Excess PTH Primary hyperthyroidism up to 20% of thyrotoxic patients bone turnover and resorption Adrenal insufficiency Phaeochromocytoma? PTH-rP Acromegaly Jansen's Metaphyseal Chondrodysplasia activating mutation of PTHR short-limbed dwarf

11 Malignancy-Associated Hypercalcaemia (MAH) Hypercalcaemia occurs in up to 10% of cancers MAH with Excess Circulating PTHrP Absent or few skeletal mets Ca, PO4, Ur Ca not pure osteolysis 50-90% of solid tumours with hypercalcaemia Squamous cell ca, esp lung; renal cell, bladder and Ovarian ca 20-60% of haematological malignancies with hypercalcaemia NHL, CML, CLL, ATL, Myeloma

12 Malignancy-Associated Hypercalcaemia (MAH) MAH without Excess Circulating PTHrP Other Systemic Factors Calcitriol e.g. in NHL Cytokines such as IL-6, RANKL Ectopic PTH e.g. ovarian, lung, thyroid, thymic carcinoma Osteolytic mets Local PTH-rP Myeloma also produce cytokines, RANKL, DKK-1 hypercalcaemia exacerbated by renal failure

13 Clinical Manifestations of Hypercalcaemic Disorders Symptoms and signs of underlying disorder Symptoms and Signs of Hypercalcamia More symptoms if acute onset or severe with Total Ca > 3.0 mmol/l, as is seen with MAH Fewer symptoms if chronic and mild, as in most cases of PHPT T Ca usually < 2.75

14 Clinical Manifestations of Hypercalcaemia Gastrointestinal Renal Neuro-muscular Cardiac Acute Anorexia, nausea, vomiting Polyuria, polydipsia, ARF Depression, fatigue, confusion, stupor, coma Short QT, Bradycardia, first degree atrioventricular block Chronic Dyspepsia, constipation, pancreatitis, peptic ulcer Nephrolithiasis, nephrocalcinosis, Distal RTA, Nephrogenic DI, CRF Muscle weakness, bone pain, Osteoporosis/Osteopaenia Hypertension, digitalis sensitivity Adapted from Endotext.com

15 If severe: Repeat with PTH immediately -PTH must be paired with Ca and Sx, FHx, DHx, PE PTH if non-urgent: Fasting sample, in plain tube on ice FBC, ESR U/E/Cr PO4, ALP PTH<2 pmol/l $500 each not necessary if malignancy clinically obvious 25 (OH)D, TSH, Myeloma screen (UCa/ SCa) (Ucr x 100 / SCr) Adapted from UpToDate

16 US and Sestamibi scan

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18 Treatment of Severe Hypercalcaemia (Total Ca > 3.5 mmol/l) Hydration IV N/S 3-4 L over hours ( ml/h then adjust for urinary output of ml/h) Inhibition of Bone Resorption SC/IM Calcitonin 4-8 units/kg 6-12 hrly Reduces T Ca by 0.5 mm; tachyphylaxis occurs after 48 h IV Bisphosphonate: caution if S Cr > 400 umol/l Zoledronic acid 4 mg over minutes Pamidronate mg over 4 hrs IV Plicamycin mg/kg over 4-6 hrs Toxic to kidney, liver and bone marrow

19 Treatment of Severe Hypercalcaemia Calciuresis when re-hydrated - with loop diuretic Frusemide mg especially if PTHrP if oedema occurs Glucocorticoid eg IV Hydrocortisone 100 mg 8 hourly for 3-5 days Haematological malignancies e.g. lymphoma and myeloma Vitamin D toxicity and granulomatous disease

20 Treatment of Severe Hypercalcaemia Gallium nitrate 200 mg/m 2 x 5/7 Dialysis if refractory hypercalcaemia or in renal or heart failure Haemodialysis or Peritoneal dialysis Mobilisation

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22 Treatment of Mild Hypercalcaemia (Total Ca < 3 mmol/l, No Acute Sx) Avoid factors that aggravate hypercalcaemia e.g. drugs like thiazide diuretics, dehydration, high-calcium diet (elemental Ca >1000 mg/day), prolonged bed rest Adequate hydration with 8 glasses of H 2 O/ day

23 Treatment of Hypercalcaemia Treatment of underlying disorder Primary hyperparathyroidism parathyroidectomy unless very mild and asymptomatic Calcimimetic e.g. Cinacalcet for unresectable parathyroid carcinoma

24 Treatment of Mild Primary Hyperparathyroidism Guidelines for parathyroid surgery in asymptomatic primary hyperparathyroidism from the NIH Workshop of Measurement Surgery Recommended 2 T Ca >1.0 mg/dl (0.25 mmol/l) above normal CCT (calculated) Below 60ml/min /1.73 m2) T score < -2.5 SD at spine, hip (total or femoral BMD neck) or radius (distal 1/3 site) or presence of fragility fracture Age Age < 50 years 1 Surgery is also indicated in patients for whom medical surveillance is neither desired nor possible. 2 If any one of these criteria are met, the patient is considered to be a candidate for parathyroid surgery.

25 Summary Hypercalcaemia can be acute or chronic and can be mild, moderate or severe Diagnostic approach is primarily based on clinical features and presence or absence of excess PTH 90% of hypercalcaemia is due to Sporadic Primary Hyperparathyroidism or Malignancy Treatment of symptomatic hypercalcaemia of > 3.5 mmol/l is urgent