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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 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 , and and unwell. • 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: • • Primary

• 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 ( 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 • , • Abdo pain • Mood disturbance • Vomiting • • • • Nausea • Peptic ulceration • • Hypertension • • Cardiomyopathy • Renal impairment • Dehydration • Cardiac and short QT • Renal stones • Muscle

[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 • ECG – shortened QT • Family History • Bloods- adj. Ca, PO4, • Drugs including OTC U&E, Vit D • PTH

[email protected] 2017 9 (PTH)

• Secreted by chief cells of • 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

• Slow • Indirect stimulation of via effects on osteoblast signalling – leading to enhanced bone resorption (over days)

[email protected] 2017 12 • Activation of • Conversion of 25 hydroxy vitamin to 1,25 hydroxy vitamin D3 () 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. 4. 5. Multiple endocrine neoplasia 1 6. 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 • • Familial: • , Lithium, Teriparatide, Theophylline • MEN1 and 2A toxicity • Familial • Immobilisation hypocalciuric • • Milk-alkali syndrome hypercalcaemia • Other endocrine conditions • Familial isolated • Hyperthyroidism, , hyperparathyroidis phaeochromocytoma, m

[email protected] 2017 19 Hypercalcaemia of malignancy • 20-30% of all • Solid tumours and leukaemias • Commonest • Breast, lung, • 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 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 • Mostly squamous cell carcinomas, renal, bladder, breast or ovarian • Also CML, non-, 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 • 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 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 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 • 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 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) • Magnesium: 0.87 mmol/L (0.7-1.00mmol/L) • eGFR 33 (>90) • TFT: Normal • Amylase : Normal • 9am cortisol: 550 nmol/L • ECG: Sinus tachycardia. No change in QT interval • Diagnosis?

[email protected] 2017 30 Hyperparathyroidism (HPT) Primary Secondary Tertiary

Calcium: Normal or Calcium: Usually high Calcium: Usually high low

PTH: Inappropriately PTH: Appropriately PTH: Inappropriately high high high

Phosphate high if due Low phosphate and Phosphate can be high to chronic kidney high alk phos common or low disease Causes: After Causes: Sporadic or Causes: Mainly CKD or prolonged secondary familial HPT, usually in CKD

[email protected] 2017 31 Primary Hyperparathyroidism (PHPT) • Now presentation is much earlier in disease course and is usually asymptomatic • Used to present with severe hypercalcaemia, and/or symptomatic renal and skeletal disease • Majority of cases present at >45 years of age • Women twice as likely to be affected compared to men • Inappropriately elevated PTH in the presence of high calcium suggests PHPT

[email protected] 2017 32 PHPT: Adenomas

• Adenomas (benign) • Single adenoma account for 85% of cases of primary HPT • Additional 5% have double parathyroid adenomas • Most adenomas encapsulated and consist of parathyroid chief cells • (malignant) • 1-2% of all cases of hyperparathyroidism • Features of invasion on histology • Usually aggressive disease, with significant hypercalcaemia and possibility of distant metastases

[email protected] 2017 33 PHPT: Hyperplasia

• Glandular hyperplasia • Approx. 6-10% of cases of primary HPT • All 4 glands enlarged • Lower glands usually larger than upper ones • Usually composed of Chief cells • Can occur sporadically or part of genetic syndromes (MEN1, MEN2A or familial hyperparathyroidism) • Medical or surgical therapy • If surgery: 3.5 glands often removed • Ectopic adenomas • Rarely ectopic adenomas in mediastinum • Some parathyroid adenomas found in thymus gland • Parathyroid cells which migrated during embryogenesis

[email protected] 2017 34 PHPT: • Similar to hypercalcaemia. • 90% of all cases of hypercalcaemia are malignancy or primary HPT • PTH usually low or undetectable with malignancy but elevated or high-normal in primary HPT • Consider Familial Hypocalciuric Hypercalcaemia (FHH) • Consider drugs (especially thiazide diuretics and lithium) • Secondary hyperparathyroidism • Other familial syndromes, especially MEN1

[email protected] 2017 35 Familial hypocalciuric hypercalcaemia (FHH)

• Inactivating mutation in calcium-sensing receptor (CaSR) in parathyroid/ kidney • FH of hypercalcaemia without symptoms is often present in history • 15-20% of patients with FHH may have elevated PTH levels. • Important to distinguish from primary HPT as FHH usually follows benign course. • FHH usually has low urine calcium excretion (check urine calcium/creatinine clearance ratio), whereas primary HPT has normal or elevated urine calcium excretion

[email protected] 2017 36 Drug-related hyperparathyroidism • Thiazide diuretics • e.g. bendroflumethiazide • Reduce urinary calcium excretion and thereby cause mild hypercalcaemia (up to 2.9mmol/L) • May unmask underlying primary HPT • In all hypercalcaemic patients withdraw thiazide and reassess calcium and PTH 2-3 months later

[email protected] 2017 37 Drug-related hyperparathyroidism • Lithium • Decreases parathyroid gland sensitivity to calcium • 10-20% of patients on lithium may develop hypercalcaemia and hypocalciuria, with high PTH concentrations. • If lithium can be stopped safely – hypercalcaemia may resolve • Less likely to resolve if long duration of lithium treatment • Patients on lithium may also have concurrent primary hyperparathyroidism so need to investigate fully • Effects of lithium on bone density inconclusive

[email protected] 2017 38 Familial PHPT

• Suspect familial cause: • Age <40 years • Positive family history • Multifocal or recurrent tumours or neoplasia • 2 or more organ systems affected

• FHH • MEN 1 (3 Ps) • MEN 2A (MTC/Phaeo/HPT) • CDC-73 related hyperparathyroidism

[email protected] 2017 39 Clinical Manifestations of PHPT

• Classical • Symptoms related to hypercalcaemia(as described) • Renal disease (nephrolithiasis, chronic kidney disease) • Bone disease (osteoporosis, ) • Proximal muscle wasting

[email protected] 2017 40 Clinical manifestations of PHPT

• Non-classical • Neuropsychiatric • Lethargy, , decreased cognitive function, • Neuromuscular • Weakness and fatigue • Cardiovascular • Hypertension, left ventricular hypertrophy, diastolic dysfunction more common in PHPT patients • Impaired glucose tolerance and T2DM • Increased frequency in PHPT patients • Mortality • There may be excess mortality even with mild PHPT, although data is not conclusive • ? Related to vascular damage • Helped by parathyroidectomy but persists even 15 years after surgery

[email protected] 2017 41 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) • Magnesium: 0.87 mmol/L (0.7-1.00mmol/L) • eGFR 33 (>90) • TFT: Normal • Amylase : Normal • 9am cortisol: 550 nmol/L • ECG: Sinus tachycardia. No change in QT interval • What is your immediate management?

[email protected] 2017 42 True or False?

The following are recognised treatments for hypercalcaemia: 1. 2. 3. IV 4. 5. 6. SC Teriparatide 7. SC Denosumab 8. Cinacalcet

[email protected] 2017 43 Emergency management of hypercalcaemia

Rate of rise and degree of hypercalcaemia contribute to severity of symptoms

<3.0mmol/L 3.0-3.5mmol/L >3.5mmol/L Often asymptomatic and May be well tolerated if it Requires urgent correction does not usually require has risen slowly, due to the risk of urgent correction May be symptomatic and dysrhythmia and coma prompt treatment usually indicated

• Society for : Acute Hypercalcaemia Guideline 2015

[email protected] 2017 44 Immediate therapy

• Isotonic saline Chronic hypercalcaemia • Corrects volume and renal problems: depletion • Nephrogenic diabetes • Restore euvolemia insipidus • Individualise rate to • Nephrolithiasis patient • Renal tubular acidosis • Caution in heart failure, (distal) etc • Renal insufficiency • Need to ensure patient has good urine output • Loop diuretics not routinely advised • Hypercalcaemia can • Consider dialysis if severe impair salt excretion renal failure • caution advised

[email protected] 2017 45 After rehydration: • IV Zoledronic acid 4mg over 15 mins • OR Pamidronate 30mg to 90mg (depending on severity) at 20mg/hr • Zoledronic acid more potent than pamidronate and given in shorter time • Remember: • All bisphosphonates are either contraindicated or require dose reduction in renal impairment • Serum calcium may take 2-4 days to fully respond • Can provoke hypocalcaemia in vit D deficiency or if PTH suppressed

[email protected] 2017 46 Bisphosphonates: Mechanism of action • Mimic pyrophosphate structure • Adsorb to hydroxyapatite • Ingested by osteoclasts

Coxon, et al. Prostate Cancer and prostatic [email protected] 2017 diseases, 2004 47 Second line treatments

• • Calcimimetics • inhibit 1,25 OHD • Primary HPT, parathyroid production cancer or renal failure • Effective in lymphoma, granulomatous disorders or Vit D toxicity • Parathyroidectomy • Prednisolone 40mg od • In acute severe primary • Effective in 2 to 4 days HPT that is not responding • Calcitonin to other measures • Rarely used • Dialysis • Denosumab • Hypercalcaemia refractory • Specialist endocrine use to other treatments

[email protected] 2017 48 Calcitonin

• Increases renal calcium excretion • Inhibits osteoclast bone resorption • Salmon calcitonin IM/ SC 12 hourly (not nasal) • Works rapidly (4-6) hours • Efficacy limited to first 48 hours • Tachyphylaxis • Use combined with rehydration and bisphosphonates

[email protected] 2017 49 Denosumab, a RANK Ligand Inhibitor, Inhibits Osteoclast Formation, Function, and Survival

Osteoclast precursor Prolia® prevents RANK Ligand RANK ligand from 2 Prolia® inhibits RANK binding to RANK 3 osteoclast formation OPG Prolia®

Prolia® inhibits 4 osteoclast function and survival Differentiated ® Prolia binds osteoclast 1 to and inhibits RANK ligand

Osteoblasts Activated osteoclast

DMB-UKIRE-AMG-089-2013-NP ® Prolia (denosumab) prescribing information, Amgen. 2013 UK/DNB/0037/13 ©2013 Amgen Inc. All rights reserved. Amgen confidential. Do not copy or distribute. Preparation date: April 2013 Refractory hypocalcaemia with features of 'hungry bone' after high dose Denosumab

Alkaline phosphatase (miu/L) Denosumab 120mg SC Adjusted calcium (mmol/L)

5 Continuous IV calcium infusion 4000 Alkaline phosphatase (miu/L)

4 3000

(mmol/L) 3 2000

2+

CALCIUM

2 1000

Adj. Ca Adj.

UPPER LIMIT OF NORMAL ALK PHOS 1 0 0 20 40 60 80 100 120 Days since admission

[email protected] 2017 51 Case 1: Immediate management

• Life-threatening hypercalcaemia and dehydration • IV fluids • 0.9% saline. Restore circulatory volume and rehydrate • Also helps to reduce calcium levels • Correction of magnesium and phosphate • Anti-emetics • IV (zoledronic acid) given once fully hydrated • Aim: Calcium <3mmol/L and symptom free before discharge

[email protected] 2017 52 Case 1 Progress

• Calcium 2.57mmol/L after 4 days of treatment. • Patient discharged and seen in outpatients. • Concerning features: • Aggressive hypercalcaemia and very high PTH levels • Young age at presentation • Family history of hypercalcaemia • Parathyroid imaging requested • USS renal tract requested • DXA scan requested • Genetic tests for MEN1, MEN 2A and CDC73

[email protected] 2017 53 Case 1: Progress

• Readmitted only 2 weeks later with recurrent hypercalcaemia. Very symptomatic. Calcium 3.36mmol/L • Treated with IV fluids and bisphosphonates again • Started on cinacalcet • Decision for urgent parathyroidectomy • Vitamin D levels low. Replaced at 20000 units per week. • Small renal calculi in right kidney • Mild osteopenia on DXA • Pituitary profile and fasting gut hormone profile normal

[email protected] 2017 54 Case 1: Imaging

• USS Neck • 3 echopoor masses • Largest 18mm • 2 on left side • Inferior lesion extending below clavicle

• Planar and CT SPECT neck and upper chest: • Bilateral parathyroid adenomas right superior and left inferior positions

[email protected] 2017 55 Case 1: Imaging

[email protected] 2017 56 Case 1 : Surgery and postoperative course • Operated on within 4 weeks of first presentation • Operation: Partial right lobe thyroidectomy. Removal of left superior and right inferior parathyroid • Severe hypocalcaemia postoperatively • Histology: • Left inferior parathyroid (6.8g) 35mmx15mmx10mm – CONSISTENT WITH • Right lobe of thyroid with parathyroid adenoma (4.2g) 20mmx15mmx10mm – CONSISTENT WITH PARATHYROID ADENOMA • Right inferior parathyroid (0.1g) 8mmx5mm – NORMAL PARATHYROID • Left node (0.04g) 5mmx5mm – NORMAL PARATHYROID • No features of malignancy

[email protected] 2017 57 Hungry Bone Syndrome

• Rapid, profound and prolonged hypocalcaemia post parathyroidectomy in patients with severe hyperparathyroidism • Associated high alk phos, low phosphate and low magnesium • Sudden influx of calcium into bone as PTH stimulus for bone resorption removed • Risk factors: • High bone turnover preoperatively • Aggressive hypercalcaemia or large parathyroid mass • Vitamin D deficiency • Older age • Bone disease preoperatively • Role of pre-op bisphosphonates controversial

[email protected] 2017 58 Case 1: Resolution

• Spent 4 weeks in hospital requiring continuous IV calcium infusions and high dose calcitriol supplements • Genetics came back postoperatively: novel CDC-73 germline Leu63Pro missense mutation (HPT-Jaw tumour syndrome) • Undetectable PTH post operatively • Now 5 years postop. PTH still undetectable • Maintained on calcium, vitamin D and calcitriol supplements • Annual surveillance for HPT-JT related tumours (kidney, uterus, jaw) and complications from calcitriol therapy

[email protected] 2017 59 Case 2: Presentation

• Father of index case • CT C/A/P- normal 2014 • HPT-JT syndrome confirmed. Same mutation. • No features of • Presented with primary malignancy hyperparathyroidism, elevated calcium, and cerebellar symptoms. • Parathyroidectomy – • Bilateral cerebellar lesions on normalised PTH and MRI of uncertain aetiology calcium levels • Positive voltage-gated channel(VGKC) • Annual surveillance for antibodies HPT-JT tumours • Neurologists felt uncertain significance. Monitor only.

[email protected] 2017 60 Case 2: Questions • 2 weeks later – very • 2017, on routine clinic review: unwell. Vomiting and Fatigue. Non-specifically unwell. confused. Losing weight. • What’s going on? • Calcium 3.42mmol/L, • Calcium 2.43mmol/L PTH 0.6 pmol/L, Vit D • PTH 3.7 pmol/L (1.6-7.6pmol/L) 54 nmol/L, U&E – mild • Vit D 32nmol/L dehydration. • U&E normal, TFT normal, FBC normal. • Treatment? • Resolving appearances MRI cerebellum • Diagnosis? • Reassured re: recurrence. Planning CT C/A/P. • What investigations • Given VitD3 replacement (40,000 would you do next? units per week for 8 weeks)

[email protected] 2017 61 Case 2: Resolution • PTHrP – <1.0 (0.7-1.8) • Treatment: • Lymph node biopsy – • Calcium still 3mmol/L following IV fluids and IV consistent with zoledronic acid sarcoidosis • Treated with • CT C/A/P – extensive prednisolone. Calcium lymphadenopathy, levels normalised rapidly splenomegaly and lung • Likely diagnosis- changes • Hypercalcaemic crisis • Serum ACE 88.8 ug/L secondary to vitamin D intoxication in the context (elevated) of undiagnosed • 1,25 dihydroxyvitamin D3 sarcoidosis on a – grossly elevated background of treated familial primary HPT

[email protected] 2017 62 Sarcoidosis and hypercalcaemia

• 30-50% have • Activated macrophages in lung and lymph nodes • Produce extra-renal • 10-20% have calcitriol independent of hypercalcaemia PTH control • Aggravated by sunlight • Don’t respond to usual exposure feedback mechanisms • Hypercalcaemia secondary • Glucocorticoid treatment to increased calcitriol • Inhibits calcitriol synthesis production • Prednisolone 20- • -> increased intestinal 40mg/daily will reduce calcium absorption serum calcium • -> increased bone concentrations within 2-5 resorption days (max effect 7-10 days)

[email protected] 2017 63 Case 3: Presentation • 88 year old female • In hospital: admitted to hospital with • Vitamin D replacement weight loss, fatigue. • CT scan – small renal cell cancer. Calcium 2.79mmol/L (2.20- • Referred to urology 2.60) urgently PTH 9.1pmol/L (1.6-7.6) • Discharged with calcium of 2.83mmol/L Vit D 28nmol/L (75-120) • Patient continuing to decline eGFR 48 • Urology seen within 2 weeks Alk phos 62 iu/L (30-130) of discharge - felt decline and hypercalcaemia unlikely • No offending secondary to renal cell cancer medications • Referred to Calcium Clinic: ? • What would you do? Primary hyperparathyroidism • What is the diagnosis?

[email protected] 2017 64 Case 3: Presentation Calcium 2.93mmol/L (2.2-2.6) • What would you do? PTH 11.2 pmol/L (1.6-7.6) • What is the diagnosis? Alk phos 52 iu/L (30-130) Phosphate 4.32 mmol/L (0.8- 1.3) • High phosphate and Vit D 73 nmol/L (75-120) severity of symptoms eGFR 45 not in keeping with Hb 105 g/L (low) primary • Severe nausea, decreased hyperparathyroidism appetite, weight loss 2 stone in 4 months, lethargy • Renal cell cancer - ? Bone metastases or • Seen with family members. Very concerned. PTHrP production

[email protected] 2017 65 Case 3:Resolution • Anaemia + renal Normal 1,25 dihydroxyvitD impairment + levels hypercalcaemia = ?multiple Normal 24 hour urine myeloma phosphate levels • Phosphate levels sometimes very high/ Low PTH-related peptide sometimes normal in last 3 NM-bone scan – no months metastases. T12 lucent lesion • Serum electrophoresis –IgG Normal/High PTH in context kappa paraprotein and of myeloma? urine BJP • Concurrent presentation of • Spurious primary hyperphosphataemia seen hyperparathyroidism with in IgG myeloma (cross multiple myeloma and reactivity with assay)

[email protected] 2017 66 Myeloma and hypercalcaemia

MULTIPLE MYELOMA • Tumour cells release osteoclast activating factors (paracrine) • Osteoclast-induced bone resorption (lytic lesions) at focal points through the skeleton • Inhibition of osteoblast formation (and new bone formation) • IL-6, RANKL, osteoprotegerin, IL- 3 and macrophage inflammatory protein contribute to this process

[email protected] 2017 67 Hypercalcaemia of malignancy vs PHPT

• Higher incidence of cancer in patients with primary HPT and vice versa • In cancer patients with hypercalcaemia: 1. If PTHrP and PTH are both high, suggestive that primary HPT is also present. 2. If PTH is elevated and PTHrP is suppressed in a patient without bone mets, then primary HPT likely sole cause of hypercalcaemia • Ectopic PTH secretion very rare • Hyperalcaemia of malignancy tends to be more severe and more acute than primary HPT

[email protected] 2017 68 Key points

• A careful clinical assessment will point to aetiology in most cases of hypercalcaemia • PTH should be checked in all cases of hypercalcaemia • along with Vit D, phosphate, alk phos • Hypercalcaemia of malignancy may occur through different mechanisms • Rehydration and IV bisphosphonate therapy are the mainstay of urgent treatment Questions? • Specific scenarios may respond better to second-line therapies [email protected]