1

Commonly encountered in Practice Diagnosis often is made incidentally The most common causes are primary hyperparathyroidism and malignancy Diagnostic work-up includes measurement of serum calcium, intact parathyroid hormone (I-PTH), h/o any medications Hypercalcemic crisis is a life-threatening emergency 2

Most often asymptomatic – Incidental Dx Mild Hypercalcemia is asymptomatic Most important cause is hyper parathyroid DD is needed to decide the treatment Optimal step by step evaluation is a must. 3

98% of the body calcium is in the skeleton Only 2% is circulation and only half of this is free calcium (ionized Ca ++ ) This only is physiologically active The reminder 1% is bound to proteins Direct measurement of free Calcium ?? 4

5 Parathyroid Hormone1,25 DHC or Vitamin D3Calcitonin

6  Bone Resorption  Intestinal Absorption  Renal Excretion

(1,000 mg/day) 7

HormoneEffectBoneGutKidney PTH  Ca  Po4 Increases Osteoclasts Indirect via Vit. D Ca reab Po4 exr. Vitamin D3  Ca  Po4 No direct action  Ca  Po4 absorption No direct effect Calcitonin  Ca  Po4 Inhibits Osteoclasts No direct effect Ca & Po4 excretion 8

Corrected total calcium (mg%) = [(Measured total calcium mg%) + {(4.4 - measured albumin g%) x 0.8}] Example: [ {(4.4 – 2.4) x 0.8}] = [ (2 x 0.8)] = = 13.6 mg% 9

Calcitriol (Active) Supplements Vitamin D 2 10

Second hydroxylation in the Kidney at first position 1,25 dihydroxy CholecalciferolActive Vitamin D (Calcitriol) Successive hydroxylations of Cholecalciferol 25 hydroxylation in the Liver25 hydroxy Cholecalciferol Vitamin D is a steroid hormone From dietary sourcesAction of Sunlight on skin 11

PTH 4 PT glands 84 AA hormone Low Ca stimulates it Calcitriol (D) Active bone formation Main effect is on the Gut PTH  Vit. D Calcitonin Para follicular C of Thyroid 34 AA hormone On Kidney 12

13 Critical - > 14 mg % Moderate - 12 to 14 mg % Mild – 10.4 to 11.9 mg % Normal – 8.5 to 10.3 mg %

14  Ca ++ PTH PTHrPCalcitriol  Ca at GIT

 Ca ++ PTH Vitamin D MalignancyMedicinesEndocrineGenetic 15

More than 90 percent of hypercalcemia cases are Primary hyperparathyroidism and malignancy These conditions must be differentiated early to provide optimal treatment & accurate prognosis Humoral hypercalcemia of malignancy implies a very limited life expectancy — only a matter of weeks Primary hyperparathyroidism has a benign course. 16

Primary hyperparathyroidism Sporadic, familial, associated with Multiple Endocrine Neoplasia (MEN I or II) Tertiary hyperparathyroidism Associated with chronic renal failure PTH  due to Vitamin D deficiency 17

Vitamin D intoxication Iatrogenic Vitamin D injections Usually 25-hydroxyvitamin D2 in over-the-counter supplements Granulomatous disease – Sarcoidosis, Berylliosis, Tuberculosis Hodgkin’s lymphoma 18

Humoral hypercalcemia of malignancy (mediated by PTHrP) – common cause Solid tumors, especially lung, head and neck squamous cancers Renal Cell Carcinoma (RCC) Local osteolysis (mediated by cytokines) Multiple Myeloma Breast cancer 19

Thiazide diuretics (usually mild) - common Lithium for depressive illnesses Milk-alkali syndrome (calcium + antacids) Vitamin A intoxication (including analogs used to treat acne) 20

Hyperthyroidism Adrenal insufficiency Acromegaly Pheochromocytoma 21

Familial hypocalciuric hypercalcemia (FHH) mutated calcium-sensing receptor gene Immobilization, with high bone turnover (e.g., Paget’s disease, bedridden child) Recovery phase of Rhabdomyolysis 22

CNSGIT SKELETON KIDNEY STONESBONES GROANS MOANS 23

Renal “stones” Nephrolithiasis Nephrogenic Diabetes Insipidus Dehydration Nephrocalcinosis 24

Skeleton “bones” Bone pains Arthritis Osteoporosis Osteitis fibrosa cystica in HPTH 25

Abdominal “Moans” Nausea, vomiting Severe anorexia, weight loss Constipation (not relieved by Rx.) Abdominal pain (vague and diffuse) Pancreatitis Peptic ulcer disease 26

Psychological “Groans” Impaired concentration Impaired memory, Depression Confusion, stupor, coma Lethargy and severe fatigue Extreme muscle weakness Corneal calcification (band keratopathy) 27

Cardiovascular Hypertension, Increased risk of CHD ECG changes of shortened QT interval, PR prolonged, QRS widened, ST , Bradycardia Cardiac arrhythmias; Vascular calcification Others Itching (Generalized Pruritus) Keratitis, conjunctivitis 28

29 ? Suspect  Calcium Serum Calcium 8.5 to 10.3> 10.3 mg %< 8.0 mg % Hypocalcemia Normal calcium

Medications> 10.3 mg%I-PTHHigh/NormalPri  PTHSuppressedVit D ToxicityMilk Alkali Cancers/ Lymphoma SuppressedPTHrP 30

PTHrP Low or Normal 1, 25 Vit. D If Low Cancer If High Lymphoma High 24 hr. urine calcium Low – FHH N or  Sestamibi 31 Endocrine

32

33 Increased screening for serum Ca ++ and Wider availability of I-PTH assay 80% of cases single parathyroid adenoma Usually benign adenoma or hyperplasia Rarely parathyroid cancer High PTH in the setting of hypercalcemia Slowly progressive – Sestamibi N-scan 25% require surgery – RLN paralysis

34 64 yrs male - “hyper parathyroid storm” with a serum calcium level of 16.4 mg%

Serum calcium level > 12 mg % at any time Episodes of hyper parathyroid crisis Marked hypercalciuria (urinary Ca ++ > 400 mg /day) Nephrolithiasis; Impaired renal function Osteitis fibrosa cystica – Thinning of cortical bone Reduced bone density by DEXA scan (Z score < 2) Classic neuromuscular symptoms, Proximal muscle weakness and atrophy, Hyper reflexia and ataxia Age younger than 50 years 35

36 25 OH - Vitamin D 2 is the supplemental Vit D Level of 25 OH – Vitamin D 3 is to be measured Macrophages in the granulomas, lymphomas cause extra renal conversion of 25 OH form to the1,25 hydroxy derivative –the active Calcitriol PTH levels are suppressed; Calcitriol levels  Stop the offending use of Vitamin D Glucocorticoids – for over one month or more Manage hypercalcemia vigorously

37 Most commonly mediated by systemic PTHrP Humoral Hypercalcemia of malignancy PTHrP mimics the bone & renal effects of PTH Normal Calcitriol and suppressed PTH levels Excessive bone lysis due to primary or bone secondaries can cause hypercalcemia MM and metastatic Br Ca present in this way. In Osteolytic hypercalcemia, SAP is markedly  Hodgkin’s lymphoma –  production of Calcitriol

Thiazide diuretics increase renal calcium resorption and cause mild hypercalcemia Resolves after discontinuing the drug Thiazide unmasks hyperparathyroidism Milk–alkali syndrome – Ca + Antacids Lithium –  the set point for PTH  Excess Vitamin A -  bone resorption and causes hypercalcemia. 38

FHH – Familial Hypocalciuric Hypercalcemia AD – 100% penetrance – Ca-R gene mutation Moderate hypercalcemia with normal/  PTH 24 hour urinary calcium is very low No benefit from parathyroidectomy High bone turnover in Paget’s disease or prolonged immobilization Recovery phase of Rhabdomyolysis 39

Ca 10.3 mg% – no appreciable clinical benefit – they need evaluation Any patient with Serum Ca > 12 mg% should be aggressively treated Ca > 14 mg% is Hypercalcemic crisis Always correct the Ca value for Sr Albumin 40

I.V. Saline Hydration & Diuresis Gluco- Corticoids Bisphos- phonates Calcitonin I.M/S.C. 41

Vigorous I.V. Nacl Diuresis – N Saline Adequate hydration – urine out put must be maintained 200 ml/hour = 5 L /day The safest and most effective treatment of Hypercalcemic crisis is saline rehydration Once the urine out put is maintained – give I.V. Furosemide – a loop diuretic in low doses of 10 to 20 mg ERT - might be beneficial in PMW – new RCT 42

In severe hypercalcemia refractory to saline diuresis Calcitonin (Zycalcit, Miacalcin) 6 -8 U/kg IM/SC (400 i.u) given every six hours. This treatment has a rapid onset but short duration of effect Patients develop tolerance to the calcium- lowering effect of Calcitonin. 43

Zoledronic acid (Zometa) - 4 mg IV diluted in 100 ml of N Saline - over at least 15’ once a M Pamindronate (Pamidria) - 60 mg IV infusion over 4 h initial – repeated after a month Etidronate (Didronel) mg/kg IV over 4 h daily for 3-7 d; dilute in at least 250 ml of sterile N Saline They inhibit bone resorption, inhibit the Osteoclastic activity. 44

Dialysis for refractory Hypercalcemic crisis Parathyroidectomy for adenomas Rx. of the underlying cause – Eliminate drugs Plicamycin (Mithracin) 25 mcg/kg/d IV for 4 d Gallium nitrate (Ganite) 100 mg/m 2 /d IV for 5 days in 1 L of NS or 5% Dextrose Cinacalcet (Sensipar) - 30 mg PO od – (i ncreases sensitivity of calcium sensing receptor) 45

Hypercalcemia is often asymptomatic Screen all suspected by doing Sr Calcium If elevated, do I-PTH and follow algorithm 90% Hyperparathyroidism and malignancy Vitamin D toxicity is an important cause Thiazide diuretics common cause, Vitamin A Adequate hydration - N Saline + Furosemide Calcitonin + Zoledronic acid main stay of Rx. 46