Case of the week

Case of The WeekChor Kuan and JudyPatient detailsMrs LG 52 year old femaleICU nurse 2HOPCHypercalcaemiaCa 3.13AsymptomaticStones, bones, abdominal groans, psychological moansPresented with asymptomatic hypercalcaemia, Ca 3.13 on background of primary hyperparathyroidism secondary to parathyroid adenoma. Measured by GP. Recently diagnosed with metastatic SCC with unknown primary, of the left parotid, submandibular and axillary lymph nodes awaiting surgical management will discuss in next slide.

Q: What are the symptoms of hypercalcamia?Stones, bones, groans, psychiatric moansStones (renal)Bones (bone pain, osteopenia, pseudogout)Abdominal groans (constipation, peptic ulcers, pancreatitis)Psychological moans (confusion)Ca blocks sodium channels and inhibits depolarization of nerve and muscle fibres, hence increased calcium raises the threshold for depolarization. Hypercalcaemia can increase gastrin production peptic ulcers Negative chronotropic (HR) and positive ionotropic (contractibility) arrhythmias

Had good fluid intake 2-3L/day 3Past medical historyMetastatic SCC - unknown primary (2015)PET scan: metastasis left parotid, submandibular, left axillary lymph node1o hyperparathyroidism 2o to parathyroid adenoma Ca 3.22 (2.20 - 2.60)PTH 47.5(1.5 - 7.0)Sestamibi: 2cm x 1.8cm x 2cm mass inferior pole left thyroidLeft lower lobe thyroid nodule US neck: 2cm x 1.9cm x 1.6cm hypervascular nodule FNA: no malignancy

# Poorly differentiated metastatic SCC with unknown primary Diagnosed in early February 201510 year history of left buccal mass previously diagnosed as lipomaIncreased size over 2/52US guided biopsy consistent with poorly differentiated SCCPET scan consistent with metastatic SCC in left parotid, submandibular, upper cervical and left axillary node

#Primary hyperparathyroidismIncidental finding as part of workup for left buccal massCa noted to be 3.22 (2.20-2.60), PTH 47.5 (1.5-7.0)AsymptomaticSestamibi scan: 2 x 1.8 x 2cm mass intimately related to inferior pole of left thyroid consistent with parathyroid adenoma

Q. What is a sestamibi scan?NM scanSestamibi (labelled with technetium) absorbed faster by hyperfunctioning parathyroid gland than normal gland Additionally, normal parathyroid glands are inactive when there is high calcium, and therefore should not take up the radioactive particles

# Left lower lobe thyroid noduleUS neck demonstrated multiple thyroid nodules, one on lower left lobe with internal vascularity FNA: benign colloid nodule, nil suspicious for malignancy

On D/C:Left total parotidectomy under ENTCa 2.7, PTH 97 after IV pamidronate and IV fluid therapy. ParathyroidectomyResection of thyroid nodule

Q: What is pamidronate? Why is it being used?BisphosphonateInhibit osteoclastic bone resorption/breakdown reduce CaWill be covered later (hopefully!)

Between admission in Feb, and current admission, has had two other admissions for hypercalcaemia.Similar presentations: asymptomatic, present after hypercalcaemia detected on blood tests performed by GP.On both occasions, managed with IV pamidronate and IV fluid therapy, lowered Ca to normal range, but PTH remained elevated from 74-88.2. 4Past medical historyHTNHypercholesterolaemia Piriformis syndrome

No significant family history 5MedicationsRosuvastatin 5mg DPregabalin 150mgMagmin BDPhosphate BD

AllergiesTramadolEndoneAllergies nausea and vomiting 6Social historyLives at home with husbandNon-smokerNon-drinkerICU nurse

7ExaminationHR 80 regular, RR 16, O2 sats 99%RA, BP 130/70, afebrileHead and neck: submandibular mass, multiple thyroid nodulesChest: unremarkable Abdomen: unremarkableNo bony tenderness along spineAlert and oriented to time, place. Sitting upright in bed, appeared comfortable. Vital signs normalHead and neck: submandibular mass non-tender, multiple thyroid nodules bilaterally (non-tender, non-mobile, firm)

8InvestigationsFBE: 98*/3.2*/186UEC: 135/5.3*/111/18* Ur 8.7* Cr 92* eGFR 62*Alb 44CMP: 3.31*/0.64*/0.68*Corr Ca: 3.23PTH: 123.5*TSH 1.16 FBE: normocytic anaemia for over one month, UEC: potassium high, bicarb low, urea and creatinine high normalised the next day, eGFR lowCMP: calcium high, magnesium and phosphate low Q: How do we calculate corrected Ca?Corrected Ca = 3.31 + 0.02 (40-44) = 3.23PTH: very high TSH normal (0.03-5.0)9IssuesHypercalcaemia 20 parathyroid adenoma Metastatic SCC, hyperparathyroidism, thyroid nodule for surgical management in 4 days

Plan to optimize calcium levels prior to surgery 10ManagementIV fluid therapyIV pamidronate 60mgENT R/VLeft total parotidectomyNeck dissectionRemoval of parathyroid adenomaRemoval of thyroid nodule

11CurrentlyDay 3 post-opCa 2.12Alb 33Corr Ca 2.26Endo: continue to monitor calcium levels 12DiscussionOverview of HypercalcemiaContentHypercalcemiaSymptomsCauses of HypercalcemiaInvestigationsManagementHypercalcemia>90% of cases of hypercalcemia due to hyperparathyroidism or malignancyPrimary hyperparathyroidism is common especially in women aged 40-60 yearsUsually due to adenoma of 1 of 4 parathyroid glandsPTH-rP is responsible for up to 80% of hypercalcemia in malignancy (eg: Squamous Cell Carcinoma, Breast and Kidney)PTH-rP act on same receptors as PTH and shares the first 13 amino acids with PTHSymptoms of HypercalcemiaStones, Bones, Abdominal Groans and Psychic moansRenal or biliary stonesBone PainAbdominal Pain, Nausea and VomitingConfusion, depression16Control of PTHPlasma Ca2+PTHOsteoclasticResorptionBoneKidneyPO43- excretionRelease of Ca2+ and PO43-Ca2+ ReabsorptionVitamin D 1-HydroxylationIntestinalCa2+ and PO43-AbsorptionCauses of HypercalcemiaIncreased calcium absorptionIncreased Ca2+ Increased Vit DIncreased Bone ReabsorptionPrimary and Tertiary HyperparathyroidismMalignancyHyperthyroidism

Decreased Renal excretion of calciumDrugs (eg: diuretics and lithium)InvestigationsWhat is the best first investigation to determine the cause of hyper Ca2+?Hyper Ca2+ normally supresses PTHPTH best first test to identify cause of hypercalcemiaIf detectable (in or above normal range) the patient must have hyperparathyroidism

InvestigationsWhat other investigations would you order?BloodsSerum CalciumPTHrP (elevated in malignancy)Serum ACE (elevated in Granulomatous disease; eg: Sarcoidosis)Tests for multiple myeloma25-OH Vitamin DChest X-Ray (to survey for malignancy)Whole body bone scan (for skeletal metastasis)CT Scan/MRIManagementAcute hypercalcemia (serum calcium > 3mmol/L)Adequate rehydration 3-4L saline/dayLoop Diuretics to promote calcium excretion(Note not Thiazide which increase reabsorption)IV bisphosphanates (eg: pamidronate disodium)Identification of the cause and its subsequent specific treatment (eg: corticosteroids for sarcoid if indicated)Evidence Based MedicineRandomized trials have demonstrated the efficacy of IV pamidronate for the treatment of hypercalcemia due to excessive bone resorption from malignancy, acute primary hyperparathyroidism, immobilization, hypervitaminosis D, and sarcoidosisTrials show pamidronate is more effective in managing hypercalcemia of malignancy than IV etidronate or clodronate (70% versus 40%)

Stewart, A. F. (2005). Hypercalcemia associated with cancer. New England Journal of Medicine, 352(4), 373-379.Gucalp, R., et al. (1992). Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. Journal of clinical oncology, 10(1), 134-142.Ralston, S. et al. (1989). Comparison of three intravenous bisphosphonates in cancer-associated hypercalcaemia. The Lancet, 334(8673)Evidence Based MedicineZoledronic acidis considered to be the drug of choice for malignancy-associated hypercalcemia because it is more potent and effective than pamidronateCan be administered over shorter period of time 15 minutes vs 2 hourspooled analysis of two phase III trials involving 275 patients with tumor-induced hypercalcemia, single dose of ZA (either 4 mg or 8 mg) normalized the corrected serum calcium concentration in 88% of patients, compared with only 70% of those receiving pamidronate (90 mg)

Rosen, L. S. et al (2004). Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer, 100(1), 36-43.ReferencesWalker, B. R., Colledge, N. R., Ralston, S. H., & Penman, I. (2013). Davidson's principles and practice of medicine. Elsevier Health Sciences.Kalra, P. A. (4th Ed.). (2014). Essential revision notes for MRCP. PasTest.Stewart, A. F. (2005). Hypercalcemia associated with cancer. New England Journal of Medicine, 352(4), 373-379.Gucalp, R., et al. (1992). Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. Journal of clinical oncology, 10(1), 134-142.Ralston, S. et al. (1989). Comparison of three intravenous bisphosphonates in cancer-associated hypercalcaemia. The Lancet, 334(8673)Rosen, L. S. et al (2004). Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer, 100(1), 36-43.