CALCIUM AND PHOSPHATE BALANCE

DR. MALIK ALQUB MD. PHD.

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.

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+.

Three Forms of Circulating Ca2+

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

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.

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

PARATHYROID glands

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.

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.

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.

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 hydroxylate calcidiol, producing 1,25 dihydroxyvitamin D (calcitriol), the most active form of vitamin D.

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;

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.

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

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+

Calcitonin

Probably not essential for human survival

Potential treatment for hypercalcemia

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.

Three Forms of Circulating Ca2+

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) ]

Etiologies of Hypercalcemia

Increased GI AbsorptionMilk-alkali syndromeElevated calcitriol

Increased Loss From BoneIncreased net bone resorption

Elevated PTH

HyperparathyroidismMalignancy

Osteolytic metastases

PTHrP secreting tumor

Increased bone turnoverPaget’s disease of boneHyperthyroidism

Decreased Bone Mineralization

Elevated PTH

Aluminum toxicity

Decreased Urinary Excretion

Thiazide diuretics

Elevated calcitriol

Elevated PTH

Etiologies of Hypocalcemia

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

Increased Urinary Excretion

Low PTH

Etiologies of HyperphosphatemiaIncreased GI Intake

Phospho-Soda

Decreased Urinary Excretion

Renal Failure

Low PTH (hypoparathyroidism)

Cell Lysis

Rhabdomyolysis

Tumor lysis syndrome

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

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

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

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

Diagnosis

Doctors Visit Medical History & Symptoms

Physical Exam Blood Tests Other Tests

Electrocardiograms Urine Test Bone Density Test

Diagnosis

Hypercalcemia Elevated PTH

Pathophysiology

Primary Adenoma Hyperplasia Carcinoma

Secondary Hyperplasia

chronic renal failure, malabsorbtion

Case 1Mr. 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/LPotassium – 3.2 meq/LCalcium (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/dLCK – 3500 U/L

Case 2Mr. 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 - PendingMagnesium – 1.8 mg/dL Albumin – 2.2 g/dL Calcium (total) – 13.1 mg/dL Phosphate – 1.3 mg/dLCreatinine – 2.8 mg/dL (baseline creatinine = 1.1)

Case 3Miss 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 – NegativePotassium – 4.1 meq/L Urine pregnancy - NegativeMagnesium – 2.3 mg/dLCalcium (total) – 6.9 mg/dLPhosphate – 4.4 mg/dLAlbumin – 4.2 g/dLCreatinine – 0.8 mg/dL