StR Teaching in GIM 19th September 2017 Hypercalcaemia: Diagnosis, acute management and cases Afroze Abbas BSc PhD FRCP Consultant Endocrinologist [email protected] 2017 1 What should a GIM StR know about calcium disorders? HYPERCALCAEMIA • Diagnostic approach • Symptoms and signs • Causes • Mechanisms • Acute management • Cases • Questions! [email protected] 2017 2 Case 1: Presentation • 23 year old woman • Readmitted 2 days later • Presents to A&E with extremely dehydrated nausea, vomiting and and unwell. abdominal pain • Adjusted calcium: • Pregnancy test negative 4.20mmol/L (2.20- 2.60mmol/L) • Venous gas: normal pH, HCO3- slightly low, • U&E consistent with calcium 2.3mmol/L dehydration • Diagnosed with gastroenteritis and discharged. [email protected] 2017 3 Hypercalcaemia • Common • 90% cases: • Malignancy • Primary Hyperparathyroidism • Entry of calcium into blood > urinary calcium excretion + calcium bone deposition • Mechanisms: • Accelerated bone resorption • Excessive GI absorption • Decreased renal calcium excretion [email protected] 2017 4 Calcium Homeostasis • Tightly regulated • Muscle function • Intracellular signalling • Neuronal function • Coagulation • 45% bound to proteins (albumin) • 15% bound to anions (phosphate and citrate) • 40% free/ionised calcium – metabolically active [email protected] 2017 5 Calcium Homeostasis • Calcium range 2.20-2.60mmol/L (variable) • ↓ Alb 1g/dL = ↓Calcium 0.2mmol/L • Volume overload, illness, nephrotic syndrome, malnutrition • Adjusted-calcium better measure in hypo/ hyperalbuminaemia • pH – alkalosis enhances protein binding and vice versa • Ionised calcium 1.16-1.31mmol/L (stable) • Hormonal regulation [email protected] 2017 6 Hypercalcaemia: Clinical features Mild Severe • Polyuria, polydipsia • Abdo pain • Mood disturbance • Vomiting • Coma • Anorexia • Pancreatitis • Nausea • Peptic ulceration • Fatigue • Hypertension • Constipation • Cardiomyopathy • Renal impairment • Dehydration • Cardiac arrhythmias and short QT • Renal stones • Muscle weakness [email protected] 2017 7 Case 1: Questions • 23 year old woman A. What further • Presents to A&E with information would nausea, vomiting and you want from the abdominal pain history? • Adjusted calcium: B. What other blood 4.20mmol/L (2.20- tests/ investigations 2.60mmol/L) would you want as soon as possible? • U&E consistent with dehydration [email protected] 2017 8 Investigations History Examination • Symptoms and duration • Cognitive impairment? • Systemic symptoms • Weight loss, night sweats • Fluid status? etc. • Systems exam for • PMH underlying cause • Renal calculi, osteoporosis, previous • Breast, LN, resp etc cancers • ECG – shortened QT • Family History • Bloods- adj. Ca, PO4, • Drugs including OTC U&E, Vit D • PTH [email protected] 2017 9 Parathyroid hormone (PTH) • Secreted by chief cells of parathyroid gland • Polypeptide containing 84 amino acids [email protected] 2017 10 [email protected] 2017 11 • Fast • Binding to osteoblasts and osteocytes leading to deposition of calcium ions from bone fluid into the extracellular fluid • Slow • Indirect stimulation of osteoclasts via effects on osteoblast signalling – leading to enhanced bone resorption (over days) [email protected] 2017 12 • Activation of vitamin D • Conversion of 25 hydroxy vitamin to 1,25 hydroxy vitamin D3 (calcitriol) by activating the enzyme 1- hydroxylase in the proximal tubules of the kidney • The primary action of calcitriol is to promote gut absorption of calcium by stimulating formation of calcium-binding protein within the intestinal epithelial cells (days) • Enhanced resorption of calcium and magnesium from the distal tubule and thick ascending limb (minutes) • Decreased resorption of phosphate, thus increasing the calcium:phosphate ratio. [email protected] 2017 13 Actions of 1,25-dihydroxyvitamin D3: • GUT: Increased calcium and phosphate absorption via small intestine • KIDNEY: Increased renal tubular absorption of calcium • BONE: Activation of osteoclasts and bone resorption by stimulating RANKL from osteoblasts • PARATHYROID: Inhibition of PTH production (negative feedback) [email protected] 2017 14 CaSR Vit D Mg 2+ CaSR= Calcium Sensing Receptor Mg 2+ = serum magnesium Vit D = 1,25 dihydroxyvitamin D3 [email protected] 2017 15 PTH and Calcium • CaSR senses ionised calcium • Increased PTH secreted instantly in response to even small reductions in ionised calcium 1. Directly increases calcium reabsorption in distal tubule = decreased urinary calcium excretion 2. Increased intestinal calcium absorption, via calcitriol production 3. Increased bone resorption • Negative feedback leads to PTH suppression as calcium rises • Hypercalcaemia either HIGH PTH or LOW PTH [email protected] 2017 16 True or False? The following are recognized causes of hypercalcaemia: 1. Cushing’s syndrome 2. Indapamide 3. Hyperthyroidism 4. Sarcoidosis 5. Multiple endocrine neoplasia 1 6. Lithium 7. Pancreatitis 8. Phaeochromocytoma [email protected] 2017 17 General principle • High calcium + high PTH = Primary or tertiary hyperparathyroidism • High calcium + suppressed PTH = malignancy or other rarer causes • Some cases of high calcium with normal PTH levels which may not be straightforward. [email protected] 2017 18 Causes of hypercalcaemia • Non-PTH mediated • PTH-mediated • Malignancy • Sporadic primary • Vitamin D intoxication • Chronic granulomatous disorders hyperparathyroidism • e.g. sarcoidosis • Medications • Familial: • Thiazide diuretics, Lithium, Teriparatide, Theophylline • MEN1 and 2A toxicity • Familial • Immobilisation hypocalciuric • Rhabdomyolysis • Milk-alkali syndrome hypercalcaemia • Other endocrine conditions • Familial isolated • Hyperthyroidism, acromegaly, hyperparathyroidis phaeochromocytoma, adrenal insufficiency m [email protected] 2017 19 Hypercalcaemia of malignancy • 20-30% of all cancer • Solid tumours and leukaemias • Commonest • Breast, lung, multiple myeloma • PTH suppressed • Calcium levels >3.25mmol/L more likely to be malignancy [email protected] 2017 20 Hypercalcaemia of malignancy - mechanisms 1. Tumour secretion of parathyroid hormone-related peptide (PTHrP) 2. Osteolytic metastases with local release of cytokines (including osteoclast activating factors) 3. Tumour production of 1,2- dihydroxyvitamin D (calcitriol) 4. Ectopic PTH production from tumour (rare) [email protected] 2017 21 Parathyroid Hormone Related Peptide (PTHrP) • Widely expressed in a variety of tissues • Homology with PTH and can bind PTH-1 receptor • PTH-like effects on bone and kidney • Less likely than PTH to activate Vitamin D • PTHrP secretion suppresses PTH production [email protected] 2017 22 PTHrP humoural hypercalcaemia of malignancy • Common cause of hypercalcaemia in non- metastatic solid tumours and non-Hodgkin’s lymphoma • Mostly squamous cell carcinomas, renal, bladder, breast or ovarian • Also CML, non-Hodgkin lymphoma, adult T-cell leukaemia [email protected] 2017 23 Osteolytic metastases • 20% of cases of Findings with osteolytic hypercalcaemia of metastases: malignancy • Low PTH • Local osteolysis by • Low or low-normal 1,25- tumour cells dihydroxyvitamin D • Especially breast cancer • Low or low-normal serum and multiple myeloma PTHrP • Osteoclastic activation • Extensive skeletal by factors produced by metastases or marrow tumour infiltration [email protected] 2017 24 Calcitriol and hypercalcaemia of malignancy • Increased 1,25 dihydroxyvitamin D (calcitriol) is cause of hypercalcaemia in: • Hodgkin lymphoma (almost all cases) • Non-Hodgkin lymphoma (one-third cases) • Granulomatous diseases (Sarcoidosis, TB) • Hypercalcaemia inhibits PTH and therefore should inhibit renal PTH activation of vitamin D [email protected] 2017 25 Calcitriol and hypercalcaemia of malignancy • Extra-renal production (PTH independent) of 1,25 dihydroxy vitamin D can occur in malignant lymphocytes and macrophages • Results in increased calcium absorption and bone resorption • Biochemistry: • Elevated 1,25 dihydroxyvitamin D • Low PTH • Low or normal 25 hydroxyvitamin D levels • Usually responds well to glucocorticoid therapy [email protected] 2017 26 Humoral Hypercalcaemia (PTHrP) Squamous cell Ca Renal Ca Bladder Ca Breast Ca Ovarian Ca NHL CML Leukaemia Lymphoma Osteolytic metastases Ectopic PTH Breast Ca Ovarian Ca Multiple myeloma Lung Ca Lymphoma Thyroid papillary Ca Leukaemia Rhamdomyosarcoma Pancreatic Ca 1,25-dihydroxyvitamin D Lymphoma Ovarian dysgerminomas [email protected] 2017 27 Other non-PTH mediated • Thyrotoxicosis • 15-20% have mild hypercalcaemia • Secondary to increased bone resorption • Immobilisation • especially in Paget disease of the bone • Hypervitaminosis A and D • Secondary to increased bone resorption • Calcium absorption • Rarely due to excess calcium ingestion unless reduced urinary calcium excretion (CKD, milk-alkali syndrome) [email protected] 2017 28 Case 1: Further history • 23 year old woman • No significant past • Usually fit and well. medical history • Taking OCP. No other • Brother: Wilms tumour medication or over the of kidney and problems counter remedies with high calcium • Had been unwell for • No symptoms about 1 month with consistent with other nausea, poor appetite endocrinopathy and constipation. [email protected] 2017 29 Case 1: Further investigations • PTH 186.1 pmol/L (1.6-7.6pmol/L) • Repeat calcium 4.25mmol/L (2.2-2.6mmol/L) • Vitamin D 17 nmol/L (50-100nmol/L) • Alk phos 824 iU/L(150-300) • Phosphate 0.43 mmol/L (0.8-1.3)