1

Hypercalcemia; Hypercalcemia; Approach to the Approach to the

diagnosisdiagnosisWisit

Cheungpasitporn, M.D.

Phang-Nga Hospital, Thailand

2

CALCIUM PHYSIOLOGY: CALCIUM PHYSIOLOGY: BLOOD CALCIUMBLOOD 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:CALCIUM PHYSIOLOGY:BLOOD CALCIUMBLOOD 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 HOMEOSTASISCALCIUM HOMEOSTASIS

DIETARY CALCIUM

INTESTINAL ABSORPTIONORGAN PHYSIOLOGY

ENDOCRINE PHYSIOLOGY

DIETARY HABITS,

SUPPLEMENTSBLOOD CALCIUM

BONE

KIDNEYS

URINE

THE ONLY “IN”

THE PRINCIPLE “OUT”

ORGAN PHYS.

ENDOCRINE PHYS.

ORGAN, ENDOCRINE

5

CALCIUM HOMEOSTASISCALCIUM HOMEOSTASIS

6

FUNCTION OF VITAMIN DFUNCTION 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 SYNTHESISVITAMIN D SYNTHESIS

SKIN LIVER KIDNEY

7-DEHYDROCHOLESTEROL

VITAMIN D3

VITAMIN D3

25(OH)VITAMIN D

h25-HYDROXYLASE

25(OH)VITAMIN D

1,25(OH)2 VITAMIN D

(ACTIVE METABOLITE)

1-HYDROXYLASE

TISSUE-SPECIFIC VITAMIN D RESPONSES

8

9

PTH and CPTH and Calcitoninalcitonin•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 .

10PARATHYROIDPARATHYROID HORMONE (PTH) HORMONE (PTH) PHYSIOLOGYPHYSIOLOGY

• 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

11

12CALCIUM, PTH, AND VITAMIN D CALCIUM, PTH, AND VITAMIN D FEEDBACK LOOPSFEEDBACK 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

13

14

•Ionized Ca> 5.6•Total Ca>10.5•Corrected Ca = (4 – alb) x 0.8 + Ca lab

•Asymptomatic hypercalcemia ควร repeat lab ไม่�ร�ดแขน

•ถ้�า > 12 ให้�น�กถ้�ง tumor

HypercalcemiaHypercalcemia

15

•Mild <12mg/dl•Mod 12-14 mg/dl•Severe >14 mg/dl

SeveritySeverity

16

1. Increased absorption eg. VitD intox(exogenous or endogenous)

2. Increased bone resorption by PTH, PTHrP, Cytokines(IL-1,IL-6,TNF)

3. Decreased renal clearance from dehydration, PTH/PTHrP => reabsorption of Ca from distal tubule.

PathophysiologyPathophysiology

17

•PTH-dependent

•PTH-independent

CAUSESCAUSES

18

•PTH-dependent–1ry HyperPTH–3ry HyperPTH–FHH(Familial Hypocalciuric)

–Ectopic PTH secreting tumor

CAUSESCAUSES

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

CAUSESCAUSES

20

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

CAUSESCAUSES

22

•PTH-independent–RF–Immobilization–Drug ; Vit A, Vit D, Milk-alkali, HCTZ, Li, Alu, Estrogen&Antiest

–Infection ; HIV, PCP

CAUSESCAUSES

23

CAUSESCAUSES

• 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 hyperPTHPrimary 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

• 1o 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 hyperPTHPrimary hyperPTH

26

CancerCancer•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 DHYPERVITAMINOSIS 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)2D (CALCITRIOL)

• EXCESSIVE PRODUCTION OF 1,25(OH)2D

– 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

28HYPERVITAMINOSIS D: CLINICAL HYPERVITAMINOSIS D: CLINICAL CHARACTERISTICSCHARACTERISTICS

•HYPERCALCEMIA•SUPPRESSED PTH

•INCREASED 1,25(OH)2D

•SOURCE–DIET?–GRANULOMA?

• SARCOIDOSIS,TB, OTHERS

–LYMPHOMA?

29

NON-HORMONAL HYPERCALCEMIANON-HORMONAL HYPERCALCEMIA

• MILK-ALKALI SYNDROME:– INTAKE OF HIGH DOSES OF CALCIUM AND

ABSORBABLE ANTACID (SUCH AS NaCO3)

– RARE CAUSE OF HYPERCALCEMIA NOW•MORE COMMONLY DESCRIBED IN EARLIER

PART OF 20TH CENTURY (NO H2 BLOCKERS OR PPI’S!!)

– MECHANISM NOT ABSOLUTELY CLEAR:•INCREASED INTESTINAL ABSORPTION•DECREASED RENAL CLEARANCE

– PTH SUPPRESSED, PTHrP NORMAL, 1,25(OH)2D NORMAL

30RENAL FAILURE-ASSOCIATED RENAL FAILURE-ASSOCIATED HYPERCALCEMIAHYPERCALCEMIA

• 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)2D• EXOGENOUS 1,25(OH)2D MAY CONTRIBUTE TO HYPERCALCEMIA

– CALCIUM AND PHOSPHATE RENAL CLEARANCE IS ABOLISHED, AND DIALYSIS DOES A RELATIVELY POOR JOB AT CLEARANCE

31

DRUG-INDUCED HYPERCALCEMIADRUG-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, 1o HPT, ETC.

32

DRUG-INDUCED HYPERCALCEMIADRUG-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 HYPERCALCEMIADRUG-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)2D

34

Clinical Clinical ((>12>12))1. Renal ; NDI , stone, nephrocalcinosis2. GI ; N/V, Constipation, PU, Pancratitis3. Neuro ; Weakness, Drowsiness,

Apnea4. Cardio ; Short QT(<0.3),Broad T,

Heart Block, Vent arrhythmia,Asystole, Sense to digoxin

5. Musculo ; Cramp, Bone pain, Pathologic Fx

6. Others ; Band Keratopathy

35

Signs and SymptomsSigns 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.

36

37

38

ApproachApproach

•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

ApproachApproach

•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

ApproachApproach

•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

ApproachApproach

•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

ApproachApproach

•STEP 2: ANALYZE PTH LEVEL

•STEP 3: ANALYZE PTH-RELATED PROTEIN LEVEL

•STEP 4 : ANALYZE VITAMIN D METABOLITE LEVELS

43

ApproachApproach

PTH PTHrP 1,25D Ca

1ry HyperPTH -

2nd HyperPTH - -

3ry HyperPTH - -

CA High -

Granuloma High

44

45

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

ApproachApproach

46

ApproachApproach

•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

47

Pseudohypercalcemia Sporadic---adenoma/hyperplasia >5.2 Prim HPT MEN 1 / MEN 2

Heriditary fami hypocaU hypercalcem Isolated adult HPT Ectopic Li HYPERCALCEMIA----- N or low Miscellaneous Recovery from ARF malabsorption Secondary HPT renal failure Tertiary HPT >81pmol/l vit D intoxication Hyperthyroidism >55pg/ml tumor production of vit D Adrenal insufficieny sarcoidosis Pheochromocytoma Pancreatic cholera N or low PTH Endocrine Immobilization Increased bone release Malignency Check Vit D 10-55ng/ml-N Hypervitaminosis A Thiazide diuretics Dialysis osteomalacia Milk-alkali syndrome

Check s.albumin

Check PTH

48

ManagementManagement

•>14•>12 with symptomatic

49

50

ManagementManagement•1. General

–Hydration (2-4L/day ) Keep urine output > 1-2 ml/kg/hr onset 12-24 hr (NSS100ml/hr ลด Ca ได�~1-3mg/dl)

–Lasix 10-20 mg iv. q 6-12 hr * only after adequate hydration *

–Mobilization–Dialysis

51

ManagementManagement

•2. Specific–Calcitonin –Bishosphonates–Gallium nitrite–Plicamycin, Mithramycin–Hydrocortisone

52

CalcitoninCalcitonin• ยั�บยั��ง Bone resorption• เพื่��ม่ข�บ Ca ทางไต•4-8 u/kg/dose q 6-12 hour sc im (iv

not intranasal)200-300 u sc q 8 hr

•Action เร!วสุ#ด ลดใน 2-6 hr, ลด Max ท$� 12-24 hr

• กล�บสุ%�ระด�บเด&ม่ใน 24-48 hr(Tachyphylaxis) ถ้�าให้�ค%�ก�บ steriod จะออกฤทธิ์&*นานข��น

• ลด ~ 2 mg%• ลด Bone pain ได�•S/E : N/V, Flushing, Tachyphylaxis

53BisphosphonatesBisphosphonates((Alendronate Alendronate ไม่�ลดไม่�ลด))

• Ethidronate, Pamidronate, Ibandronate, Zoledronate

• Zoledronate ม่$ efficacy ด$สุ#ด• ยั�บยั��ง 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

GlucocorticoidGlucocorticoid

– in Hematologic malignancy or granulomatous disease

–แต�ใช้�ไม่�ได�ก�บ PTH, non hemato CA–ต�าน 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

PhosphatePhosphate

–Oral ไม่�ช้�วยั only in chronic– IV ; onset; hr-24-48 h ?? Only in severe cardiac & renal decompensate

–SE ; ectopic calcify, renal damage, fatal hypocal

56

PARATHYROIDECTOMYPARATHYROIDECTOMY

•Symptomatic hypercalcemia•Ca 1 mg/dL above upper normal limit

•BMD T score any side <-2.5•Reduction CrCl < 30 %•Urine Ca > 400 mg/day•Age < 50 years