calcium and phosphate balance

1. calcium and phosphate balance DR. MALIK ALQUB MD. PHD.

2. INTRODUCTION • The maintenance of calcium and phosphate homeostasis involves changes in intestinal, bone, and renal function. Regulation of intestinal function is important because, in contrast to the complete absorption of dietary NaCl and KCl, the absorption of Ca2+ and phosphate is incomplete. This limitation is due both to the requirement for vitamin D and to the formation of insoluble salts in the intestinal lumen, such as calcium phosphate, calcium oxalate, and magnesium phosphate.

3. INTRODUCTION • Most of the body Ca2+ and much of the phosphate exist as hydroxyapatite, Ca10(PO4)6(OH)2, the main mineral component of bone. Phosphate also is present in high concentration in the cells. Within the plasma, both Ca2+ and phosphate circulate in different forms. Of the plasma Ca2+, roughly 40 percent is bound to albumin, 10 percent is complexed with citrate, sulfate, or phosphate, and 50 percent exists as the physiologically important ionized (or free) Ca2+.

4. Three Forms of Circulating Ca2+

5. Calcium Balance • Intake = output • Negative calcium balance: Output > intake • Neg Ca2+ balance leads to osteoporosis • Positive calcium balance: Intake > output • Occurs during growth • Calcium is essential, we can’t synthesize it

6. PARATHYROID HORMONE  • Parathyroid hormone (PTH) is a polypeptide secreted from the parathyroid glands in response to a decrease in the plasma concentration of ionized Ca2+ . This change is sensed by a specific Ca2+-sensing protein in the cell membrane of the parathyroid cells. The receptor permits variations in the plasma Ca2+ concentration to be sensed by the parathyroid gland, leading to the desired changes in PTH secretion.

7. Regulation of PTH Secretion and Biosynthesis • Extracellular Ca 2+ regulates secretion of PTH • Low Ca 2+ increases • High Ca 2+ decreases • Ca2+ also regulates transcription • High levels of 1,25 dihydroxyvitamin D3 inhibit transcription

8. PARATHYROID glands

9. PARATHYROID HORMONE  PTH acts to increase the plasma Ca2+ concentration in three ways: • In the presence of permissive amounts of vitamin D, it stimulates bone resorption, resulting in the release of calcium phosphate. • It enhances intestinal Ca2+ and phosphate absorption by promoting the formation within the kidney of calcitriol (1,25 dihydroxycholecalciferol), the major active metabolite of vitamin D. • It augments active renal Ca2+ reabsorption.

10. PARATHYROID HORMONE  PTH also influences phosphate balance, although its actions. • It tends to increase phosphate entry into the extracellular fluid by its effects on bone and intestinal absorption. • PTH also reduces proximal tubular phosphate reabsorption, resulting in enhanced excretion.

12. VITAMIN D  • is a fat-soluble steroid, which is present in the diet and also can be synthesized in the skin from 7-dehydrocholesterol in the presence of ultraviolet light. The hepatic enzyme 25–hydroxylase places a hydroxyl group in the 25 position of the vitamin D molecule, resulting in the formation of 25-hydroxyvitamin D or calcidiol.

13. VITAMIN D • Calcidiol produced by the liver enters the circulation and travels to the kidney, bound to vitamin D binding protein. In the kidney, tubular cells contain two enzymes (1-alpha-hydroxylase and 24-alpha-hydroxylase) that can further hydroxylatecalcidiol, producing 1,25 dihydroxyvitamin D (calcitriol), the most active form of vitamin D.

14. VITAMIN D • The main action of calcitriol is to enhance the availability of calcium and phosphate both for new bone formation and for the prevention of symptomatic hypocalcemia and hypophosphatemia. This is primarily achieved by increases in bone resorption, intestinal absorption, and renal tubular Ca2+ reabsorption;

16. REGULATION OF PLASMA CALCIUM AND PHOSPHATE CONCENTRATIONS  • for example, hypocalcemia does occur, there is a direct stimulus to PTH secretion and the subsequent formation of calcitriol. PTH increases calcium phosphate release from bone and urinary phosphate excretion, whereas calcitriol augments intestinal calcium phosphate absorption. Both hormones also reduce urinary Ca2+ excretion. The net effect is an increase in the plasma Ca2+ concentration with little change in the plasma phosphate concentration. This sequence is reversed with hypercalcemia or a high Ca2+ diet as both PTH secretion and calcitriol production are diminished.

18. calcitriol is the primary hormone that responds to changes in phosphate balance. Phosphate depletion tends to raise and phosphate loading to lower renal calcitriolproduction.

20. Calcitonin • Product of parafollicular C cells of the thyroid • 32 aa • Inhibits osteoclast mediated bone resorption • This decreases serum Ca2+ • Promotes renal excretion of Ca2+

21. Calcitonin • Probably not essential for human survival • Potential treatment for hypercalcemia

23. Measuring the total plasma Ca2+ • Measuring the total plasma Ca2+ concentration is sufficient, since changes in this parameter usually are associated with parallel changes in the ionized concentration.

24. Three Forms of Circulating Ca2+

25. Different Forms of Calcium At any one time, most of the calcium in the body exists as the mineral hydroxyapatite, Ca10(PO4)6(OH)2. Calcium in the plasma: 45% in ionized form (the physiologically active form) 45% bound to proteins (predominantly albumin) 10% complexed with anions (citrate, sulfate, phosphate) To estimate the physiologic levels of ionized calcium in states of hypoalbuminemia: [Ca+2]Corrected = [Ca+2]Measured + [ 0.8 (4 – Albumin) ]

26. Etiologies of Hypercalcemia Increased GI Absorption Milk-alkali syndrome Elevated calcitriol Increased Loss From Bone Increased net bone resorption Elevated PTH Hyperparathyroidism Malignancy Osteolytic metastases PTHrP secreting tumor Increased bone turnover Paget’s disease of bone Hyperthyroidism Decreased Bone Mineralization Elevated PTH Aluminum toxicity Decreased Urinary Excretion Thiazide diuretics Elevated calcitriol Elevated PTH

27. Etiologies of Hypocalcemia Increased Urinary Excretion Low PTH Decreased GI Absorption Poor dietary intake of calcium Impaired absorption of calcium Vitamin D deficiency Decreased conversion of vit. D to calcitriol Liver failure Renal failure Low PTH Hyperphosphatemia Decreased Bone Resorption/Increased Mineralization Low PTH (hypoparathyroidism) Vitamin D deficiency / low calcitriol

28. Etiologies of Hyperphosphatemia Increased GI Intake Phospho-Soda Decreased Urinary Excretion Renal Failure Low PTH (hypoparathyroidism) Cell Lysis Rhabdomyolysis Tumor lysis syndrome

29. Etiologies of Hypophosphatemia Decreased GI Absorption Phosphate binders (calcium acetate) Decreased Bone Resorption / Increased Bone Mineralization Vitamin D deficiency / low calcitriol Increased Urinary Excretion Elevated PTH (as in primary hyperparathyroidism) Vitamin D deficiency / low calcitriol

30. Hyperparathyroidism • The disorder is characterized by hypercalcemia, hypercalcuria, hypophosphatemia, and hyperphosphaturia • Parathyroid hormone causes phosphaturia and a decrease in serum phosphate • Calcium rises and it is also secreted in the urine • Most common complication are renal stones made of calcium phosphate • Most serious complication is the deposition of calcium in the kidney tubules resulting in impaired renal function

31. Primary Hyperparathyroidism • Calcium excretion > calcium intake • Large regions of bone are replaced by connective tissue

32. Hyperparathyroidism Clinical Sx • Kidney stones, painful bones, abdominal groans, psychic moans, and fatigue overtones • Kidney stones calcium phosphate and oxalate • Osteopenia, osteoporosis. • Peptic ulcer disease, pancreatitis • Psychiatric manifestations such as psychosis, coma, depression, anxiety, fatigue

33. Diagnosis • Doctors Visit • Medical History & Symptoms • Physical Exam • Blood Tests • Other Tests • Electrocardiograms • Urine Test • Bone Density Test

34. Diagnosis • Hypercalcemia • Elevated PTH

35. Pathophysiology • Primary • Adenoma • Hyperplasia • Carcinoma • Secondary • Hyperplasia • chronic renal failure, malabsorbtion

36. Case 1 Mr. G is a 40 year old man with a history of alcoholism. He had not seen a doctor for 15 years before police brought him to the ER after finding him confused and disheveled behind a local convenience store. In the ER, he was thought to be confused simply due to intoxication, but was admitted for mild alcoholic hepatitis and marked malnutrition. His mental status cleared up about 8 hours after admission. During morning rounds on hospital day #2, he complained of feeling fatigued and weak. Later that day, the nurses find him seizing. The seizures stop with low dose IV diazepam. Stat labs are sent: Sodium – 136 meq/L Potassium – 3.2 meq/L Calcium (total) – 6.8 mg/dL (normal ~ 8.5-10.2 mg/dL) Phosphate – 0.7 mg/dL (normal ~ 2.0-4.3 mg/dL) Albumin – 1.8 g/dL (normal ~ 3.5-5.0 g/dL) Creatinine – 1.3 mg/dL CK – 3500 U/L

37. Case 2 Mr. H is a 74 year old man with a past history significant for hypertension and COPD from smoking 2 packs per day for the last 40 years. He presented to an urgent pulmonary clinic appointment with 2 months of increased cough and 5 days of “mild” hemoptysis. Upon further obtaining further history, he reports feeling fatigued, nauseous, and chronically thirsty for several weeks. His exam is significant for bilateral rhonchi (no change from baseline lung exam) and absent reflexes. Stat labs are ordered from clinic: Sodium – 138 meq/L CBC, PT/PTT – WNL Potassium – 3.7 meq/L PTH - Pending Magnesium – 1.8 mg/dL Albumin – 2.2 g/dL Calcium (total) – 13.1 mg/dL Phosphate – 1.3 mg/dL Creatinine – 2.8 mg/dL (baseline creatinine = 1.1)

38. Case 3 Miss L is a 16 year old woman with no significant past medical history, who is brought to the ER by her mother after she noted her to be acting bizarrely for the past several weeks. Thought to be actively psychotic, a psychiatry consult is asked to see the patient, who recommends checking routine labs: Sodium – 142 meq/L Urine tox. screen – Negative Potassium – 4.1 meq/L Urine pregnancy - Negative Magnesium – 2.3 mg/dL Calcium (total) – 6.9 mg/dL Phosphate – 4.4 mg/dL Albumin – 4.2 g/dL Creatinine – 0.8 mg/dL