This document discusses calcium homeostasis and hypercalcemia. It explains that blood calcium levels are tightly regulated by the parathyroid hormone (PTH), vitamin D, gut, bone and kidneys. The main causes of hypercalcemia are primary hyperparathyroidism, malignancy-related hypercalcemia from bone metastases, and hypervitaminosis D from excessive vitamin D intake or production. The document provides details on the pathophysiology, clinical evaluation and management of hypercalcemia.

1. Hypercalcemia; Approach to the diagnosis Wisit Cheungpasitporn, M.D. Phang-Nga Hospital, Thailand

2. CALCIUM PHYSIOLOGY: BLOOD CALCIUM BLOOD CALCIUM IS TIGHTLY REGULATED PRINCIPLE ORGAN SYSTEMS GUT, BONE, KIDNEYS HORMONES PARATHYROID HORMONE (PTH),Calcitonin,VITAMIN D INTEGRATED PHYSIOLOGY OF ORGAN SYSTEMS AND HORMONES MAINTAIN BLOOD CALCIUM

3. CALCIUM PHYSIOLOGY: BLOOD CALCIUM CALCIUM FLUX INTO AND OUT OF BLOOD “ IN” FACTORS: INTESTINAL ABSORPTION, BONE RESORPTION “ OUT” FACTORS: RENAL EXCRETION, BONE FORMATION (Ca INCORPATION INTO BONE) BALANCE BETWEEN “IN” AND “OUT” FACTORS ORGAN PHYSIOLOGY OF GUT, BONE, AND KIDNEY HORMONE FUNCTION OF PTH AND VITMAMIN D

4. CALCIUM HOMEOSTASIS DIETARY CALCIUM INTESTINAL ABSORPTION ORGAN PHYSIOLOGY ENDOCRINE PHYSIOLOGY DIETARY HABITS, SUPPLEMENTS BLOOD CALCIUM BONE KIDNEYS URINE THE ONLY “IN” THE PRINCIPLE “OUT” ORGAN PHYS. ENDOCRINE PHYS. ORGAN, ENDOCRINE

5. CALCIUM HOMEOSTASIS

6. FUNCTION OF VITAMIN D TISSUE SPECIFICITY GUT STIMULATE TRANSEPITHELIAL TRANSPORT OF CALCIUM AND PHOSPHATE IN THE SMALL INTESTINE (PRINCIPALLY DUODENUM) BONE STIMULATE TERMINAL DIFFERENTIATION OF OSTEOCLASTS STIMULATE OSTEOBLASTS TO STIMULATE OSTEOCLASTS TO MOBILIZE CALCIUM PARATHYROID INHIBIT TRANSCRIPTION OF THE PTH GENE (FEEDBACK REGULATION)

7. VITAMIN D SYNTHESIS SKIN LIVER KIDNEY 7- DEHYDROCHOLESTEROL VITAMIN D 3 VITAMIN D 3 25(OH)VITAMIN D h  25-HYDROXYLASE 25(OH)VITAMIN D 1,25(OH) 2 VITAMIN D ( ACTIVE METABOLITE ) 1  -HYDROXYLASE TISSUE-SPECIFIC VITAMIN D RESPONSES

9. PTH and C alcitonin PTH and calcitonin  regulate blood calcium levels . Calcitonin, secreted by the thyroid gland inhibits osteoclasts and stimulates osteoblasts , thus decreasing blood calcium levels . Parathyroid hormone is secreted by the parathyroid glands ; increase blood calcium levels .

10. PARATHYROID HORMONE (PTH) PHYSIOLOGY PTH FUNCTIONS TO PRESERVE NORMAL BLOOD CALCIUM (AND PHOSPHATE) PTH inhibits osteoblasts, stimulates osteoclasts  STIMULATES BONE RESORPTION AND, THUS, INCREASES BLOOD CALCIUM PTH STIMULATES RENAL TUBULAR REABSORPTION OF CALCIUM, AND THUS, INCREASES BLOOD CALCIUM PTH STIMULATES RENAL 1a-HYDROXYLATION OF 25(OH)VITAMIN D, THUS INDIRECTLY STIMULATING INTESTINAL ABSORPTION OF CALCIUM

12. CALCIUM, PTH, AND VITAMIN D FEEDBACK LOOPS NORMAL BLOOD Ca RISING BLOOD Ca FALLING BLOOD Ca SUPPRESS PTH STIMULATE PTH BONE RESORPTION URINARY LOSS 1,25(OH) 2 D PRODUCTION BONE RESORPTION URINARY LOSS 1,25(OH) 2 D PRODUCTION

14. Ionized Ca> 5.6 Total Ca>10.5 Corrected Ca = (4 – alb) x 0.8 + Ca lab Asymptomatic hypercalcemia ควร repeat lab ไม่รัดแขน ถ้า > 12 ให้นึกถึง tumor Hypercalcemia

15. Mild <12mg/dl Mod 12-14 mg/dl Severe >14 mg/dl Severity

16. Increased absorption eg. VitD intox ( exogenous or endogenous ) Increased bone resorption by PTH, PTHrP, Cytokines ( IL-1,IL-6,TNF ) Decreased renal clearance from dehydration, PTH/PTHrP =>  reabsorption of Ca from distal tubule. Pathophysiology

17. PTH-dependent PTH-independent CAUSES

18. PTH-dependent 1ry HyperPTH 3ry HyperPTH FHH ( Familial Hypocalciuric ) Ectopic PTH secreting tumor CAUSES

19. PTH-independent Neoplasm PTH-rP ; SQCA ( lung,eso,head&neck,Cx,skin ), RCC, ovary,bladder,pheochromocytoma,Lma Ectopic VitD : NHL,HD Lytic Bone Metastasis : Breast MM ; OAF CAUSES

21. PTH-independent Granulomatous Dz ( Vit D ) TB, Fungus, Leprosy, Sarcoid, WG, EG Endocrine disorder Thyrotox ( osteoclast, can Rx by B-blocker ) Pheochromocytoma Adrenal insyff CAUSES

22. PTH-independent RF Immobilization Drug ; Vit A, Vit D, Milk-alkali, HCTZ, Li, Alu, Estrogen&Antiest Infection ; HIV, PCP CAUSES

23. CAUSES T Thiazide, other drugs - Lithium R Rabdomyolysis A AIDS P Paget’s disease, Parental nutrition, Pheochromocytoma, Parathyroid disease Approx. 80% of all cases are caused by Malignancy or Primary Hyperpathyroidism V Vitamins I Immobilization T Thyrotoxicosis A Addison’s disease M Milk-alkali syndrome I Inflammatory disorders N Neoplastic related disease S Sarcoidosis

24. Primary hyperPTH Solitary adenoma 85% Multiple adenoma/hyperplasia 15% MENI : para,pancreas ( ZE synd,gastrinoma,insulinoma, VIPOMA ) ,ant pituitary MENIIa: parathyriod, Medullary,Pheochromocytoma CA 1% Age 60-70 Bone change ( resorption pharygeal tuft,subperiosteal resortion ) FECa>2%

25. 1 o HPT is characterized by hypercalcemia PTH above the normal range hypercalciuria increased risk of fractures increased risk of kidney stones seldom causes extreme hypercalcemia unless confounded by renal failure, dehydration, etc. Primary hyperPTH

26. Cancer local resorption of bone induced by metastases (mediated by local release of cytokines such as tumor necrosis factor and interleukin-1) the production of humoral osteoclast activators, particularly PTH-related protein HyperCa can be caused by tumoral production in patients with Hodgkin's disease or non-Hodgkin's lymphoma.

27. HYPERVITAMINOSIS D EXCESSIVE INTAKE OF VITAMIN D RELATIVELY HARD TO DO IF ALL RELEVANT ORGAN SYSTEMS ARE FUNCTIONING PROPERLY; GENERALLY REQUIRES PRESCRIPTION STRENGTH VITAMIN D, PARTICULARLY 1,25(OH) 2 D (CALCITRIOL) EXCESSIVE PRODUCTION OF 1,25(OH) 2 D EXTRA-RENAL 1-HYDROXYLATION OF 25(OH)VITAMIN D BY AN ENZYME WITH 1-HYDROXYLASE ACTIVITY, BUT WHICH IS DISTINCT FROM THE RENAL ENZYME USUALLY ASSOCIATED WITH GRANULOMAS (MACROPHAGES) OR ABNORMAL LYMPHOID TISSUE (B CELL LYMPHOMA) NOT REGULATED BY PTH OR CALCIUM

28. HYPERVITAMINOSIS D: CLINICAL CHARACTERISTICS HYPERCALCEMIA SUPPRESSED PTH INCREASED 1,25(OH) 2 D SOURCE DIET? GRANULOMA? SARCOIDOSIS,TB, OTHERS LYMPHOMA?

29. NON-HORMONAL HYPERCALCEMIA MILK-ALKALI SYNDROME: INTAKE OF HIGH DOSES OF CALCIUM AND ABSORBABLE ANTACID (SUCH AS NaCO 3 ) RARE CAUSE OF HYPERCALCEMIA NOW MORE COMMONLY DESCRIBED IN EARLIER PART OF 20 TH CENTURY (NO H2 BLOCKERS OR PPI’S!!) MECHANISM NOT ABSOLUTELY CLEAR: INCREASED INTESTINAL ABSORPTION DECREASED RENAL CLEARANCE PTH SUPPRESSED, PTHrP NORMAL, 1,25(OH) 2 D NORMAL

30. RENAL FAILURE-ASSOCIATED HYPERCALCEMIA RENAL FAILURE MAY CAUSE EITHER HYPERCALCEMIA OR HYPOCALCEMIA HYPERCALCEMIA USUALLY RESULTS FROM A COMBINATION OF FACTORS INCLUDING DECREASED CALCIUM CLEARANCE AND INCREASED BONE RESORPTION, +/- GI UPTAKE PTH ELEVATION LOW ENDOGENOUS 1,25(OH) 2 D EXOGENOUS 1,25(OH) 2 D MAY CONTRIBUTE TO HYPERCALCEMIA CALCIUM AND PHOSPHATE RENAL CLEARANCE IS ABOLISHED, AND DIALYSIS DOES A RELATIVELY POOR JOB AT CLEARANCE

31. DRUG-INDUCED HYPERCALCEMIA THIAZIDE DIURETIC-INDUCED HYPERCALCEMIA: STIMULATE RENAL TUBULAR CALCIUM REABSORPTION DECREASE URINARY LOSS OF CALCIUM UNCOMMON CAUSE OF HYPERCALCEMIA AT DOSES USED TO TREAT HYPERTENSION MORE LIKELY IN COMBINATION WITH RENAL DISEASE, 1 o HPT, ETC.

32. DRUG-INDUCED HYPERCALCEMIA LITHIUM-INDUCED HYPERCALCEMIA: LITHIUM MAY BE ASSOCIATED WITH HYPERCALCEMIA AT DOSES ROUTINELY USED TO TREAT BIPOLAR AFFECTIVE DISORDER (DURATION OF THERAPY IS A FACTOR) SHIFTS “SET POINT” FOR CALCIUM REGULATION OF PTH SECRETION PATHOPHYSIOLOGIC CORRELATE: CALCIUM-SENSING RECEPTOR, ABOVE AUGMENTS PTH EFFECT AT TARGET TISSUES (BONE AND KIDNEY)

33. DRUG-INDUCED HYPERCALCEMIA HIGH DOSES OF VITAMIN A, OR RETINOIC ACID-INDUCED HYPERCALCEMIA: VARIOUS RETINOIDS ARE USED IN TREATMENT OF ACNE, AND CERTAIN HEMATOLOGIC MALIGNANCIES APPEAR TO DIRECTLY ACTIVATE OSTEOCLASTS AND MEDIATE BONE RESORPTION HYPERCALCEMIA IS ASSOCIATED WITH SUPPRESSED PTH, NORMAL PTHrP, NORMAL 1,25(OH) 2 D

34. Clinical ( >12 ) Renal ; NDI , stone, nephrocalcinosis GI ; N/V, Constipation, PU, Pancratitis Neuro ; Weakness, Drowsiness, Apnea Cardio ; Short QT ( <0.3 ) ,Broad T, Heart Block, Vent arrhythmia,Asystole, Sense to digoxin Musculo ; Cramp, Bone pain, Pathologic Fx Others ; Band Keratopathy

35. Signs and Symptoms Bones, stones, abdominal groans, and psychic moans. Malaise, fatigue, headaches, diffuse aches and pains, constipation. Patients are often dehydrated Lethargy and psychosis when hypercalcemia is severe. Calcifications in skin, cornea, conjunctiva, and kidneys.

38. Approach STEP 1: ASSESS CLINICAL DATA AND DRAW PTH LEVEL Family Hx of hyperPTH evidence of MEN Hx of childhood radiation of the head or neck an asymptomatic patient with prolonged hypercalcemia.

39. Approach Measurement of the serum phosphate concentration and urinary calcium excretion  Ca,  PO4 ; 1ry HyperPTH, PTHrP ( SCC )  Ca,  PO4 ; 3ry HyperPTH, Granulomatous dz, lymphoma, VitD overdose

40. Approach Measurement of the serum phosphate concentration and urinary calcium excretion Urinary calcium excretion is usually raised or high-normal in hyperparathyroidism and hypercalcemia of malignancy.

41. Approach 3 disorders in which an increase in renal calcium reabsorption leads to relative hypocalciuria (less than 100 mg/day [2.5 mmol/day]): The milk-alkali syndrome Thiazide diuretics Familial hypocalciuric hypercalcemia

42. Approach STEP 2: ANALYZE PTH LEVEL STEP 3: ANALYZE PTH-RELATED PROTEIN LEVEL STEP 4 : ANALYZE VITAMIN D METABOLITE LEVELS

43. Approach

45. STEP 5: LOOK FOR OTHER CAUSES OF HYPERCALCEMIA Multiple myeloma Thyrotoxicosis Immobilization Paget's disease Vitamin A toxicity Milk - alkali syndrome Approach

46. Approach Acute or Unknown duration PTH high; 1ry hyperPTH,MEN PTH low ; CA, เจาะ PTHrp Chronic duration ( month ) PTH low ; granulomatous dz, FHH, Milk alkali, Li,HCTZ,Immobilization,VitA/D,ACI,Thyrotox PTH high ; 1,3 ry hyper PTH, MEN

48. Management >14 >12 with symptomatic

50. Management 1. General Hydration ( 2-4L/day ) Keep urine output > 1-2 ml/kg/hr onset 12-24 hr ( NSS100ml/hr ลด Ca ได้ ~1-3mg/dl ) Lasix 10-20 mg iv. q 6-12 hr * only after adequate hydration * Mobilization Dialysis

51. Management 2. Specific Calcitonin Bishosphonates Gallium nitrite Plicamycin, Mithramycin Hydrocortisone

52. Calcitonin ยับยั้ง Bone resorption เพื่มขับ Ca ทางไต 4-8 u/kg/dose q 6-12 hour sc im (iv not intranasal) 200-300 u sc q 8 hr Action เร็วสุด ลดใน 2-6 hr, ลด Max ที่ 12-24 hr กลับสู่ระดับเดิมใน 24-48 hr ( Tachyphylaxis ) ถ้าให้คู่กับ steriod จะออกฤทธิ์นานขึ้น ลด ~ 2 mg% ลด Bone pain ได้ S/E : N/V, Flushing, Tachyphylaxis

53. Bisphosphonates ( Alendronate ไม่ลด ) Ethidronate, Pamidronate, Ibandronate, Zoledronate Zoledronate มี efficacy ดีสุด ยับยั้ง Osteoclast Pamidronate 90 mg + 5%D/W or NSS iv in 4 hour Zoledronate 4 mg iv in 15 minute Onset 48 hours, peak several days, duration 3-4 weeks S/E ; fever with chill, myalgia, leukopenia,HypoCa&PO4, granulocytosis

54. Glucocorticoid in Hematologic malignancy or granulomatous disease แต่ใช้ไม่ได้กับ PTH, non hemato CA ต้าน VitD Hydrocortisone 100-300 mg/day, prednisolone 10-25 mg q 6 hr(4x3), Dexa 2-4 mg q 6 hr Onset 3-5 days Mech :  calciuresis,  absorption via Vit D,  α - 1OHlase,  osteoblastic activity.

55. Phosphate Oral ไม่ช่วย only in chronic IV ; onset; hr-24-48 h ?? Only in severe cardiac & renal decompensate SE ; ectopic calcify, renal damage, fatal hypocal

56. PARATHYROIDECTOMY Symptomatic hypercalcemia Ca 1 mg/dL above upper normal limit BMD T score any side <- 2 .5 Reduction CrCl < 3 0 % Urine Ca > 4 00 mg/day Age < 5 0 years