1. Calcium Regulation & Related Disorders Dr. Wael H.Mansy, MD Assistant Professor College of Pharmacy King Saud University 2009

2. Calcium Metabolism: 99 % of calcium resides within skeleton. Major mineral in bone is hydroxyapatite [Ca 10 (PO 4 ) 6 (OH) 2 ] 1% in extracellular fluid

3. Extracellular Calcium: Calcium circulates in plasma in 3 forms: - ionized (50%) - protein-bound{ albumin, globulin} (40%) -complexed to bicarbonate, phosphate, citrate (10%) Ionized (free): physiologically active

4. Extracellular Calcium: Albumin concentration affects total concentration correct for low albumin (0.8mg /dl, 0.2 mmol/l) for every 1 g/dl decrease in albumin Acidosis decreases binding to albumin (e.g. CRF) Alkalosis increases binding (e.g. hyperventilation syndrome)

5. Calcium Balance: Normal plasma level: 8.5-10.5 mg/dl, 2.2-2.6 mmol/l Normal ionized level: 4 - 4.6 mg/dl, 1.0-1.15 mmol/l

6. Calcium Metabolism/ Hormones Involved: Vitamin D PTH Calcitonin

7. Net Effect CalciumPhosphorus PTHHighLow CalcitriolHigh CalcitoninLow

8. Overview of Calcium-Phosphate Regulation

9. Causes of Hypercalcemia: > 90% of patients have either primary Hyperparathyroidism or malignancy Primary Hyperparathyroidism predominates in the outpatient population, while malignancy-induced hypercalcemia in hospitalized patients

10. Primary Hyperparathyroidism Females > Males. Mostly sporadic -85% solitary adenoma -15% multiple hyperplasia -<5% carcinoma Could be familial (familial hyperparathyroidism). These typically multiple hyperplasia.

11. Symptoms: NON-SPECIFIC “Renal stones, painful bones, groin pain, psychic moans and fatigue”

12. Signs: Uncommon, non-specific Hypertension (predominant CVS sign), bradycardia Short QT interval on EKG Band keratopathy (rare)

14. Laboratory diagnosis of HPT: HYPERCALCEMIA HYPOPHOSPHATEMIA ELEVATED PTH

15. Radiology role in HPT: Osteopenia Sub-periosteal bone resorption

17. Radiology role in HPT: Technetium-Sestamibi scan for localization of gland; >90% sensitive & specific.

18. Management of HPT Conservative Surgical

19. Treatment of hypercalcemia Increase urinary calcium excretion Inhibition of bone resorption Decrease intestinal absorption Dialysis Treat underlying cause if possible

20. Diagnostic Approach to Hypocalcemia Confirm diagnosis Determine cause

21. Confirm Diagnosis Particularly important in patients with hypoalbuminemia Measure ionized calcium

22. Identify Cause: Hypomagnesemia (S-Mg). Renal Failure (S-creatinine, PUN). Pancreatitis (amylase). PTH or Vitamin D disorders (decreased production or action)

23. Ideopathic Hypoparathyroidism Rare Alone or as part of polyglandular autoimmune disease type I (candidiasis, hypoparathyroidism, Addison’s). Antibodies common in both types.

24. Vitamin D Vitamin D ensures normal milieu (environment) for mineralization (Calcium & phosphate)

25. Vitamin D Deficiency < 25 nmol/l Deficiency of Calcium & phosphate needed for mineralization

26. Vitamin D deficiency: Low level or low action of D leads to abnormal mineralization of newly formed matrix: -mature bone: osteomalacia -growing bone: rickets

28. Rickets and Osteomalacia What causes Rickets and Osteomalacia? Inadequate supply of vitamin D from poor diet or lack of sun exposure The metabolism of vitamin D is abnormal. Kidney problems: Diseases of the small intestines with mal-absorption Disorders of the liver or pancreas disease Cancer And Certain drugs, such as: Anticonvulsants: phenytoin and barbiturates. Cadmium Fluoride Lead Aluminum

29. Symptoms of Osteomalacia: Diffuse skeletal (bone) pain (aggravated by physical activity or palpation) Muscle weakness Fractures from minor trauma If hypocalcemia present (paresthesias of hands & around mouth, muscle cramps, seizers)

30. Rickets Affect growing children. Delayed eruption of teeth. Delayed closure of fontanells. Bow legs. Rosary beads. Pigeon’s Chest.

32. Treatment When osteomalacia is caused from a dietary or sunlight deficiency, replenishing the low levels of vitamin D in the body usually cures the condition. Most people with osteomalacia take vitamin D supplements by mouth for several weeks or months. If the blood levels of calcium and phosphorous are low the patient may also take supplements of these minerals. After a patient begins treatment, they may undergo periodic blood tests to assure blood levels of vitamin D and certain minerals are within normal limits. X-rays are also taken to determine the improvement of the bones. Symptoms may lessen within a few weeks of treatment. BeforeAfter

33. Prevention Osteomalacia caused by inadequate sun exposure and a diet low in vitamin D can be prevented. Spend a few minutes in the sun Direct exposure in the sun to the arms and legs for five to ten minutes daily is sufficient for adequate vitamin D production. If a person lives in cold climate and don’t get enough sun exposure during the winter, they can build enough vitamin D stores in the skin during warmer months. Although regular use of sunscreen helps prevent skin cancer and premature aging of the skin, there is concern that the frequent use of strong sunscreen can increase the risk of developing ostemalacia. Eat food high in vitamin D Eat foods that are naturally rich in vitamin D such as oily fishes (salmon, mackerel, and sardines) and egg yolks. Other foods that are fortified with vitamin D include cereal, bread, milk, and yogurt. Take supplements If a person doesn’t get enough vitamins and minerals in their diet or if they have a medical condition affecting the ability of their digestive system to absorbing nutrients, they are recommended to ask a doctor about taking vitamin D and calcium supplements. Exercise Exercise such as walking helps strengthen bones, but if a patient has slight fractures due to osteomalacia, they should avoid strenuous activity until their bones heal.

34. Clinical Manifestations of Hypocalcemia: Tetany is hallmark of acute hypocalcemia, indicates neuromuscular irritability (ranges from parasthesias to muscle cramps, laryngospasm & seizures),

35. Laboratory Diagnosis in Hypocalcemia Calcium, PO, PTH in same sample Low PO4, High PTH: vitamin D deficiency/secondary hyperparathyroisism (check: 25(OH)D) High PO: Hypoparathyroidism (normal-low PTH). Pseudohypoparathyroidsm (high PTH)

36. Treatment of Hypocalcemia: Varies with severity, chronicity, etiology Chronic and/ or asymptomatic: 1-2 gm calcium orally+ vitamin D or metabolite Acute, symptomatic: IV calcium gluconate (10 ml) over several minutes. Then 0.5-1.5 mg/kg/hr, until effective oral calcium received orally