Calcium and Phosphate Regulation Functions of Calcium: Structural: bone and teeth. Neuromuscular: control of excitability, release of neurotransmitters and initiation of muscle contraction. Enzymatic: coenzyme in coagulation factors. Signaling: intracellular second messenger. Calcium is the most abundant mineral in the human body, 99% is bound in the skeleton. Bone is not metabolically inert most of the calcium in bone is stable but some of it moves between bone and the ECF to support calcium homoeostasis

Plasma Calcium In the plasma, calcium is present in these forms: Only the ionized form is the physiologically active and it is the concentration of ionized calcium which is maintained by homeostastatic mechanisms.

Adjusted calcium (mmol/L)= Total measured calcium + 0.02 (47-albumin) Serum Calcium A healthy person has a total serum calcium of around 2.4 mmol/L About half is bound to protein, mostly albumin (non-diffusible) Binding is pH dependent and is decreased in acidosis, because the amino acids side chains on albumin become more positively charged. The unbound calcium (diffusible) is the biologically active fraction The unbound calcium concentration is recognized by PTH Changes in serum albumin concentration in patients cause changes in total calcium concentration. So: Adjusted calcium (mmol/L)= Total measured calcium + 0.02 (47-albumin) The measured calcium is ‘adjusted’ by 0.1 mmol/L for every 5 g/L that the albumin is less than 47

Calcium-regulating Hormones Calcium concentration in the ECF is normally maintained within narrow limits by a control system involving two hormones: Parathyroid hormone (PTH) and calcitirol (1,25-dihydroxycholccalciferol). These hormones control calcium and the inorganic phosphate concentration in the ECF Calcitonin has only a minor role in Ca homeostasis Parathyroid hormone (PTH) This hormone is a polypeptide, comprising 84 amino acids PTH is secreted from the parathyroid glands in response to a low unbound plasma calcium. Higher normal ECF calcium levels inhibit PTH secretion

Actions of parathyroid hormone (PTH): Bone: rapid release of calcium, increase osteoclastic resorption which leads to increase in plasma calcium concentration. Kidney: increase calcium reabsorption, decrease phosphate reabsorption and decrease bicarbonate reabsorption (leads to acidosis). Activation of vitamin D which increases the calcium and phosphate absorption from the GIT.

Calcitirol (1,25-dihydroxycholccalciferol) This hormone is derived from vitamin D by successive hydroxylation in the liver (25-hydroxylation) and kidney (1 α-hydroxylarion). Hydroxylation in the liver is not subject to feedback control, but that in the kidney is closely regulated. In the gut it stimulates absorption of dietary calcium and phosphate In the bone it stimulates the resorption of the bone and increase the release of phosphate and Ca It increases gastrointestinal calcium absorption, facilitates the effect parathyroid hormone (PTH) on bone resorption, and increases (to little extent) renal tubular absorption of calcium. Production of calcitriol by the cells of the proximal tubule of the nephron in the kidney is stimulated by hypocalcemia and hypophosphatemia as well as parathyroid hormone

Calcitirol (1,25-dihydroxycholecalciferol)

Calcium and phosphate homoeostasis Hypocalcaemia stimulates the secretion of PTH and this activates the production of calcitirol  increase ECF of Ca and Pi (increase gut uptake and bone release) PTH has phosphaturic effect excess Pi will be excreted by the kidney In hypophosphataemia, calcitriol secretion is increased but PTH is not, the increase of the plasma calcium concentration inhibit PTH secretion. Calcium and phosphate absorption from the gut are stimulated. Calcitriol has a much smaller effect on renal calcium reabsorption than PTH with the result that, in the absence of PTH, the excess calcium absorbed from the gut is excreted in the urine. The net outcome is the re-establishment of the phosphate concentration towards normal, independently of that of calcium.

- PTH and calcitriol are essential for the maintenance of the plasma Ca2+ concentration, since their absence is associated with progressive hypocalcemia due to decreases in bone resorption and intestinal absorption and an increase in urinary Ca2+ excretion . In addition to their individual effects, both hormones are able to interact so that Ca2+ and phosphate balance can be independently regulated.

Hypocalcemia Causes: Hypoparathyroidism: Congenital or Acquired Magnesium deficiency: Mg is required for PTH secretion and its action on target tissues Vitamin D deficiency: may be due to malabsorption, or an inadequate diet with little exposure to sunlight decrease absorption of Ca and phosphate from the gut. It causes osteomalacia in adults and rickets in children. Renal disease: the diseased kidneys fail to synthesize 1,25 DHCC. Increased PTH secretion in response to the hypocalcaemia may lead to bone disease if untreated. Pseudohypoparathyroidism: PTH is secreted but there is failure of target tissue receptors to respond to the hormone.

Clinical features Neurological features: tingling, tetany and mental changes Cardiovascular signs: abnormal ECG Cataracts High levels of ALP (alkaline phosphatase) Treatment Treatment of the cause Oral calcium supplements are commonly prescribed in mild disorders. Intravenous Ca gluconate can be given 1,25DHCC, or the synthetic vitamin D can be given

Trousseau’s sign is the most reliable indication of latent tetany Trousseau sign is a medical sign observed in patients with low calcium. This sign may become positive before other gross manifestations of hypocalcemia To elicit the sign, a blood pressure cuff is placed around the arm and inflated to a pressure greater than the systolic blood pressure and held in place for 3 minutes. This will occlude the brachial artery. In the absence of blood flow, the patient's hypocalcemia and subsequent neuromuscular irritability will induce spasm of the muscles of the hand and forearm.

A diagnostic decision chart Low Ca, Low Pi  low vit D Low Ca, High Pi  low PTH

PTH Corrected serum calcium Phosphate Hypoparathyroidism Low Elevated Activating mutation calcium sensing receptor Normal or low low Hypomagnesemia Normal PTH resistance (pseudohypoparathyroidism) Vitamin D deficiency Low or normal Chronic kidney disease

Hypercalcemia Two causes of hypercalcaemia account for up to 90% of cases: Primary hyperparathyroidism: adenoma Hypercalcemia associated with malignancy: this is a very common cause of hypercalcaemia. There may or may not be obvious metastases in bone. Non-metastatic hypercalcaemia is due to the secretion by the tumor of PTH-related peptides (PTHrP). This is a peptide having some N-terminal amino acid sequence homology with PTH.

Rarer causes of hypercalcaemia include Large doses of f vitamin D or its metabolites e.g. in the treatment of hypoparathyroidism or renal disease or due to self-medication. Certain tumors (such as lymphomas) because of the increase in synthesis of 1,25 dihydroxycholecalciferol. Thyrotoxicosis very occasionally leads to increased bone turnover and hypercalcaemia. Diuretic (thiazide) therapy: it decrease Ca excretion but the hypercalcaemia is usually mild. Renal disease: Long-standing secondary hyperparathyoidism may lead to PTH secretion becoming independent of calcium feedback.. Calcium therapy: Patients are routinely given calcium containing solutions during cardiac surgery, and may have transient hypercalcaemia afterwards. Milk alkali syndrome: the combination of an increased calcium intake together with bicarbonate, as in a patient self medicating with proprietary antacid, may cause severe hypercalcaemia, but the condition is very rare

Clinical features Hypercalcaemia is usually discovered during the investigation of an illness hypercalcaemia is often clinically silent and is discovered in accidentally. Neurological and psychiatric features: lethargy, confusion, irritability and depression GIT problems: anorexia, abdominal pain, nausea and vomiting and constipation Renal features: thirst and polyuria and renal calculi Cardiac arrhythmias

Treatment Treatment is urgent if the adjusted calcium is greater than 3.5 mmol/L and the priority is to reduce it to a safe level. Intravenous saline is administered first to restore the glomerular filtration rate and promote a diuresis. Drugs that lower Ca level can be used like bisphosphonates, steroids, calcitonin and intravenous phosphate. Bisphosphonates such as pamidronate have become the treatment of choice in patients with hypercalcaemia, it acts by inhibiting bone resorption. The cause of the hypercalcaemia should be treated if possible. Surgical removal of a parathyroid adenoma usually provides a complete cure for a patient with primary hyperparathyoidism. Immediately after successful surgery, transient hypocalcaemia may have to be treated with vitamin D metabolites, until the remaining parathyroids begin to operate normally.

A diagnostic decision chart

Phosphate Phosphate is abundant in the body and is an important intracellular and extracellular anion Much of the phosphate inside cells is covalently attached to lipids and proteins, phosphorylation of proteins. Most of the body’s phosphate is in bone Phosphate changes accompany calcium deposition or resorption of bone Control of ECF phosphate concentration is achieved by the kidney, where tubular reabsorption is reduced by PTH. The phosphate which is not reabsorbed in the renal tubule acts as an important urinary buffer

Plasma inorganic phosphate At physiological hydrogen ion concentrations, phosphate exists in the ECF both as monohydrogen phosphate and as dihydrogen phosphate. Both forms are together termed 'phosphate‘, and the total is normally maintained within the limits of 0.8-1.40 mmol/L Approximately 20% of plasma phosphate is attached to protein In plasma, calcium and phosphate often have a reciprocal relationship. In particular, if phosphate rises, calcium falls

Hyperphosphatemia Persistent hyperphosphataemia may result in calcium phosphate deposition in soft tissues Causes of a high serum phosphate concentration include: Renal failure. Phosphate excretion is impaired. This is the commonest cause of hyperphosphataemia. Hypoparathyroidism. The effect of a low circulating PTH decreases phosphate excretion by the kidneys Hemolysis. This may occur intravascularly in the patient, or may be a consequence of an improper sampling procedure Psuedohypoparathyroidism. There is tissue resistance to PTH 5. Neonatal causes. Increased intake of phosphate in milk (cow’s milk)

Signs and symptoms: Signs of hyperphosphatemia include an elevated blood phosphate level. Other electrolyte values are likely to be affected, depending on the disease. There are no symptoms of hyperphosphatemia. Patient may not know that his blood phosphate levels are elevated. The symptoms that he have are due to the underlying disease. Diagnosis: - The diagnosis of hyperphosphatemia is most often made only by the laboratory finding of serum phosphate > 1.6 mmol/L. - The specific cause of hyperphosphatemia can usually be determined from the clinical history, but serum creatinine and electrolytes should be obtained. - In patient who have hyperphosphatemia from administration of phosphate salts, metabolic acidosis with large anion gap can be found.

Treatment: - High phosphate levels can be avoided with phosphate binders and dietary restriction of phosphate. - Phosphate binders: are a group of medications used to reduce the absorption of phosphate and taken with meals and snacks. They are typically used in patients with chronic renal failure (CRF) as they cannot get rid of the phosphate that gets into their blood. - Common phosphate binders: Aluminium hydroxide, Calcium carbonate, Calcium acetate.

Hypophosphatemia - Is an electrolyte disturbance in which there is an abnormally low level of phosphate in the blood. An increase in phosphate in the urine is called phosphaturia. Severe hypophosphataemia (<0.3 mmol/L) is rare and causes muscle weakness which may lead to respiratory impairment. The symptomatic disorder requires immediate intravenous infusion of phosphate Modest hypophosphataemia is much more common Causes: Refeeding syndrome: is a syndrome consisting of metabolic disturbances that occur as a result of reinstitution of nutrition to patients who are starved or severely malnourished . Refeeding syndrome usually occurs within four days of starting to feed. Most effects result from a sudden shift from fat to carbohydrate metabolism and a sudden increase in insulin levels after refeeding which leads to increased cellular uptake of phosphate.

2. Alkalosis: Hypophosphatemia secondary to phosphorus redistribution is commonly caused by alkalosis and refeeding of malnourished patients. Acute respiratory alkalosis and metabolic alkalosis decrease serum phosphorus concentration 3. Alcohol abuse: Alcohol impairs phosphate absorption. Alcoholics are usually also malnourished with regard to minerals. Patients (specially chronic alcoholics) are given large amounts of carbohydrates, which creates a high phosphorus demand by cells, removing phosphate from the blood and the stress of alcohol withdrawal may create respiratory alkalosis, which exacerbates hypophosphatemia. 4. Malabsorption: This includes GI damage, and also failure to absorb phosphate due to lack of vitamin D, or chronic use of phosphate binders such as sucralfate, aluminum-containing antacids, and (more rarely) calcium- containing antacids.

Hypophosphatemia Other causes of a low serum phosphate include: Hyperparathyroidism. The effect of a high PTH is to increase phosphate excretion by the kidneys and this contributes to a low serum concentration Congenital defects of tubular phosphate reabsorption. In these conditions phosphate is lost from the body Ingestion of non-absorbable antacids, such as aluminum hydroxide. These prevent phosphate absorption Treatment of diabetic ketoacidosis. The effect of insulin in causing the shift of glucose into cells may cause similar shifts of phosphate Severe dietary deficiency. Oncogenic hypophosphatemia. This is a rare cause of severe hypophosphataemia, and the causative factor produced by the tumor remains to be identified

Sings and symptoms: Except for the effects on mineral metabolism, the symptoms of hypophosphatemia are due to two consequences of intracellular phosphate depletion which impact virtually all organ systems : Red cell 2,3-DPG (diphosphoglycerate) levels fall, thereby increasing the affinity of hemoglobin for oxygen and reducing oxygen release at the tissue level. Intracellular ATP levels fall with severe hypophosphatemia and those cell functions dependent upon energy-rich phosphate compounds begin to fail. Weak muscles Muscle dysfunction Respiratory depression Low cardiac output Respiratory muscle weakness

Management Parenteral phosphate supplementation is generally reserved for patients who have life-threatening hypophosphatemia or nonfunctional gastrointestinal syndromes. Vitamin D supplementation is appropriate for patients with vitamin D deficiency. The management of patients with hypophosphatemia can be divided into various subgroups based on the severity of the hypophosphatemia and the need for ventilation: Severe hypophosphatemia (< 0.3 mmol/L) in critically ill, should be managed with intravenous replacement therapy (0.08–0.16 mmol/kg) over 2-6 hours. Moderate hypophosphatemia (0.3–0.8 mmol/L) in patients on a ventilator should be managed with intravenous replacement therapy (0.08–0.16 mmol/L) over 2-6 hours. Moderate hypophosphatemia (0.3–0.8 mmol/L) in non-ventilated patients should be managed with oral replacement therapy (1000 mg/d). Mild hypophosphatemia should be managed with oral replacement therapy (1000 mg/dl)

Magnesium - Magnesium is an essential element in biological systems, occurs typically as the Mg2+ ion. Magnesium is the fourth most abundant mineral in the body and is the second-most abundant intracellular cation, it is essential to good health. Approximately 50% of total body magnesium is found in bone. The other half is found predominantly inside cells of body tissues and organs. Only 1% of magnesium is found in blood, but the body works very hard to keep blood levels of magnesium constant. Green vegetables such as spinach are good sources of magnesium , Some legumes (beans and peas), nuts and seeds, and whole, unrefined grains are also good sources of magnesium and Tap water ” hard water “ can be a source of magnesium.

Magnesium Magnesium ions are the second most abundant intracellular cations Some 300 enzyme systems are magnesium activated. Most aspects of intracellular biochemistry are magnesium dependent, including glycolysis, oxidative metabolism and transmembrane transport of potassium and calcium. The electrical properties of cell membranes are affected by any reduction in the intracellular magnesium concentration.

Functions It is an essential mineral nutrient for life and is present in every cell type in every organism. For example, ATP must be bound to a magnesium ion in order to be biologically active. ATP is often actually Mg-ATP. - Similarly, magnesium plays a role in the stability of all polyphosphate compounds in the cells, including those associated with DNA and RNA synthesis. It helps maintain normal muscle and nerve function, keeps heart rhythm steady, supports a healthy immune system, and keeps bones strong. Magnesium also helps regulate blood sugar levels, promotes normal blood pressure, and is known to be involved in energy metabolism and protein synthesis. Magnesium influences the secretion of PTH by the parathyroid glands and severe hypomagnesaemia may cause hypoparathyroidism.

Magnesium homeostasis Magnesium influences the secretion of PTH by the parathyroid glands and severe hypomagnesaemia may cause hypoparathyroidism. Magnesium homeostasis Since magnesium is an integral part of chlorophyll green vegetables are an important dietary source, as are cereals and animal meats. An average dietary intake is around 15mmol per day which generally meets the recommended dietary intake. Children and pregnant or lactating women have higher equirements. About 30% of the dietary magnesium is absorbed from the small intestine and widely distributed to all metabolically active tissue. Hypermagnesaemia is uncommon but is occasionally seen in renal failure. The symptoms of hypomagnesaemia are very similar to those of hypocalcacmia: impaired neuromuscular function such as tetany, hyperirritability, tremor, convulsions and muscle weakness.

Magnesium Deficiency Since magnesium is present in most common foodstuffs, low dietary intakes of magnesium is associated with general nutritional insufficiency. Magnesium deficiency can be expected as a result of: dietary insufficiency accompanied by intestinal malabsorption, severe vomiting, diarrhnea or other causes of intestinal loss. osmotic diuresis such as occurs in diabetes mellitus. prolonged use of diuretic therapy especially when dietary intake has been marginal prolonged. nasogastric suction. cytotoxic drug therapy such as cisplatinum which impairs renal tubular reabsorption of magnesium treatment with the immunosuppressant drug; cyclosporin.

Laboratory diagnosis Magnesium concentration of less than 0.7 mmo1/L in a serum specimen is evidence of marked intracellular depletion. However, intracellular magnesium depletion may exist where the serum magnesium concentration is within the reference range. Management Oral, IM and IV regimens have been proposed. Administration of magnesium salts, by whatever route is contraindicated when there is a significant degree of renal impairment. In these circumstances any supplementation must be monitored carefully to avoid toxic effects associated with hypermagnesaemia.

Bone metabolism: Bone is constantly being broken down and reformed in the process of bone remodeling Osteoblasts or osteocytes: bone forming cells Osteoclasts: resorption

Biochemical markers Biochemical markers of bone resorption and bone formation can be useful in assessing the extent of disease, as well as monitoring treatment: Hydroxyproline, from the breakdown of collagen Deoxypyridinoline, collagen degradation product Alkaline phosphatase, the osteoblasts (bone forming cells) have high activity of this enzyme Osteocalcin, noncollagenous constituent of bone Common bone disorders Osteoporosis Osteomalacia and rickets Paget’s disease: increased osteoclastic activity which leads to increased bone resorption. Increased osteoblastic activity repairs resorbed bone, but the new bone is laid down in a disorganized way Osteoporosis

Osteomalacia Osteomalacia term for the softening of the bones due to defective bone mineralization. Osteomalacia in children is known as rickets, and because of this, use of the term osteomalacia is often restricted to the milder, adult form of the disease. It may show signs as diffuse body pains, muscle weakness, and fragility of the bones. A common cause of the disease is a deficiency in vitamin D, which is normally obtained from the diet and/or sunlight exposure

Osteoporosis The underlying mechanism in all cases of osteoporosis is an imbalance between bone resorption and bone formation. In normal bone, there is constant matrix remodeling of bone; Bone is resorbed by osteoclast cells (which derive from the bone marrow), after which new bone is deposited by osteoblast cells. Osteoporosis is most common in women after menopause, when it is called postmenopausal osteoporosis, It may also develop in men, and may occur in anyone in the presence of particular hormonal disorders It may also develop in chronic diseases or as a result of medications, specifically glucocorticoids, when the disease is called steroid- or glucocorticoid-induced osteoporosis. Given its influence in the risk of fragility fracture, osteoporosis may significantly affect life expectancy and quality of life.

Paget’s disease In this disease there will be an increased osteoclastic activity which leads to increased bone resorption. Increased osteoblastic activity repairs resorbed bone, but the new bone is laid down in a disorganized way It is a chronic disorder that typically results in enlarged and deformed bones This causes bone to weaken, resulting in bone pain, arthritis, deformities, and fractures. Men are more commonly affected than women Causes Paget disease may be caused by a slow virus infection (i.e., paramyxoviruses) present for many years before symptoms appear There is also a hereditary factor

Paget’s disease