Serum calcium is important for muscle contractility, cardiac function, blood clotting and neural transmission. The total calcium in the blood can be measured to determine parathyroid function and calcium metabolism. The normal levels of serum calcium is between 2.25-2.75 mmol/l. George’s serum calcium is 3.24 mmol/l which is higher than the normal range. Increased levels of serum calcium (hypercalcemia) could be due to hyperparathyroidism. Another cause of hypercalcemia is malignancy, tumour metatasis (myeloma, lung and renal cell) to the bone which causes resorption and pushes the calcium into the blood. Cancer (lung and renal cell ) can produce similar substance to parathyroid hormone (PTH) and can cause an increase in serum calcium. (Pagana, Pagana T, p153-155 , 2006).
Too much indigestion of vitamin D can also elevate serum calcium by increasing renal and GI absorption. Sarcoidosis and tuberculosis which are granulomatous infections can also be linked to hypercalcemia (Pagana, Pagana T p153-155, 2006). Phosphate Measuring phosphate levels can help determine abnormalities of calcium and parathyroid. In the body majority of the phosphate is a part of organic compounds and only a tiny part is inorganic phosphate. It is the inorganic phosphate which is involved in electrical and acid-base homeostasis. (Pagana, Pagana T, p399, 2006). The normal level of phosphate is between 0.97-1.45 mmol/l and George’s phosphate level is 1.20 mmol/l which falls in the normal range. However the is an inverse relationship between calcium and phosphate if one decreases the other increases.
Alkaline phosphatise Alkaline phosphatise determines bone or liver disorders. Alkaline phosphatise is found in the liver, biliary tract epithelium, bone, placenta and intestinal mucosa. It is also found in the majority of the tissues (Pagana, Pagana T p49-50, 2006). The normal levels of Alkaline phosphatise is between 30-120 iu/l. George’s alkaline phospatise level which is 90 iu/l falls within the normal range.
Urea Liver converts ammonia to urea as ammonia is very toxic. Urea is excreted in the urine. Renal glomerulus filters urea from the blood and tubular reabsorption occurs (Walker and Whittlesea p70, 2007). Normal range for urea is 3.6-7.1mmol/l. George’s urea level is 10 mmol/l which higher than the normal range. Urea levels which is more than 10 mmol/l shows an indication of renal disease or low renal blood flow after shock or dehydration. Urea levels start to increase when glomerular filtrate rate falls by 50% or more.
Diet including a high protein intake or a haemorrhage in the gut can increase urea levels up to 10 mmol/l (Walker and Whittlesea p70, 2007). Creatinine Creatinine is used in skeletal muscle contraction. The amount of creatinine produced everyday depends on the muscle mass. Kidneys excrete creatinine therefore creatinine is directly proportional to renal excretory function. Impaired renal function can be determined by serum creatinine test. Glomerulonephritis (inflammation of the renal glomeruli), pyelonephritis (inflammation of the kidneys), acute tubular necrosis (reversible damage to renal tubules) and urinary obstruction are renal disorders which can cause an increase in creatinine (Pagana, Pagana T p207-208, 2006).
Other causes of increased serum creatinine can be diet which contains a large amount of meat. Drugs such as Gentamicin (aminoglycoside), Cimetidine and nephrotoxic drugs like cephalosporins can also increase creatinine. PTH Parathyroid hormone (PTH) was not detected probably due to parathyroids being suppressed by hypercalaemia. Low levels of PTH are seen in patients with metastatic bone tumours or patients with sarcoidosis or vitamin D intoxication. (Pagana, Pagana T, p 385, 2007).
Acute symptomatic hypercalcemia Calcium homeostasis involves a complex interplay between multiple organ systems and regulatory hormones. The three predominant sources of calcium and targets for regulation are the bones, renal filtration and reabsorption, and intestinal absorption. The major regulators of calcium levels are parathyroid hormone (PTH) and vitamin D, which target the bones, intestine, and kidney to increase serum calcium. Calcitonin, less influential in regulation, decreases serum calcium by its effects on bone and kidney. Cyclically, high levels of calcium suppress PTH and thereby decrease levels of the active form of vitamin D by decreasing the activity of renal 1 a -hydroxylase. (Griffin J E, Ojeda S R, p350, 2004).
Hypercalcaemia and hypercalciuria are usually asymptomatic but the toxic effects of calcium on renal tubules may produce symptoms of polyuria, volume depletion, and polydipsia. The clinical signs and symptoms of hypercalcemia vary according to serum levels and rate of development. George’s serum calcium was found to be 3.24mmol/l and therefore is classified under symptomatic moderate hypercalcemia, (3mmol/l-3.5mmol/l). In patients presenting with mild symptomatic hypercalcemia, the likely diagnosis is primary hyperparathyroidism. This condition is also associated with hypophosphatemia by the actions of excess PTH in the renal system, acting to decrease renal tubular phosphate reabsorption. (Felig P, Frohman LA, p1111, 2001). However, the normal serum phosphate does not support this diagnosis.
Symptomatic hypercalcaemia presenting with dehydration, polyuria and an altered conscious state is a rare but recognized complication of sarcoidosis. (Griffith C, Hoellein A R, p316, 2007). Symptoms are related to the effects of calcium on neuromuscular excitability and cell membrane permeability. This sedative action results in fatigue, muscular weakness and depressed deep tendon reflexes. (Hankins J et al, p119, 2001). George experienced some joint pain.
Treatment of acute hypercalcaemia The first-line therapy would be saline diuresis; George was given an intravenous saline which replaces the electrolytes that have been caused by dehydration. An intravenous saline could be administered together with a loop diuretic, such as furosemide, which increases calcium excretion. Normally 4 to 6 L of 0.9% saline on the first day and 3 to 4 L for several days. Central venous pressure should be monitored to control the hydration rate.
Intravenous bisphosphonates can also be used for hypercalcaemia of malignancy or undiagnosed cause. Loop diuretics such as Furosemide can also be used to increase the elimination of Calcium, but it requires the use of high volumes of intravenous saline at the same time; it is advised that there is intensive monitoring of fluid balance. Loop diuretics act on the thick ascending limb of the Loop of Henle, it reversibly and competitively inhibits the Na+-K+-2Cl- cotransporter on the luminal surface. This causes reduced reabsorption of Ca+ and prevents the generation of a counter current multiplier.
Hyperparathyroidism
Hyperparathyroidism is the over activity of the parathyroid glands leading to the excess production of parathyroid hormone. Parathyroid hormone increases the release of calcium and phosphate from bone, increases calcium reabsorption by the kidney and increases renal production of calcitriol (PatientUK). This has the effect of increasing intestinal absorption of calcium. Therefore an increase in the activity of the parathyroid glands has the effect of increasing calcium levels and decreasing phosphate levels in the blood. Hyperparathyroidism can be either, primary, secondary or tertiary. Primary hyperparathyroidism occurs where the parathyroid glands over function.
Secondary hyperparathyroidism occurs when hypocalcaemia is responded to by the parathyroid glands. Tertiary hyperparathyroidism is due to hyperplasia of the parathyroid glands Hypercalcemia caused by disorders such as sarcoidosis, myeloma, immobilisation and milk-alkali syndrome not infrequently cause acute renal failure.
The acute renal effects of hypercalcemia, polyuria, and polydipsia result from renal compensatory mechanisms that increase urinary calcium absorption. Polyuria is caused by a defect in renal tubular function that leads to an inability to conserve water resulting in dehydration, causing polydipsia. Such a defect may relate to excessive calcium levels that alter the kidneys’ ability to concentrate urine due to a defect in vasopressin-induced water reabsorption, resulting in polyuria and fluid volume depletion. (Matarese LE, Gottschlich MM, p126, 2003). George displayed polyuria and slight dehydration. While volume depletion and dehydration describe two distinct entities, they can, and often do, occur together.
The dehydration caused by polyuria due to the excessive calcium levels accentuates the hypercalcemia because the body attempts to compromise renal function. (Johnson B L, Gross J, p694, 1998). The body strives to preserve water by decreasing the glomerular filtration rate (GFR) and increasing sodium reabsorption as a response to the dehydration. However, a decrease in the GFR results in a reduction in calcium excretion while increased sodium reabsorption promotes increased calcium reabsorption. Both mechanisms mean the patient is unable to excrete calcium.
Acute hypercalcaemia may result in renal tubule necrosis from intracellular calcium overload and tubule obstruction by calcium precipitates. Renal impairment in sarcoidosis is often nephrocalcinosis – a generalised increase in the calcium content of the kidneys resulting from prolonged hypercalcemia. Other renal complications of sarcoidosis due to abnormal calcium metabolism include nephrolithiasis which refers to the presence of calculi in the kidneys and more rarely tubular disorders such as nephrogenic diabetes insipidus. Nephrolithiasis may impair renal function by obstructing the urinary tract resulting in hydronephrosis. (Baughman RP, p652, 2006).
Possible causes of polyuria in sarcoidosis, include hypercalcemia caused by increased calcitrol made by the granulomas, which results in nephrogenic DI (NDI). (McPhee SJ, p771, 2008). Hypercalcemia and hypercalciuria can occur as a result of the sarcoidosis itself and they also can cause polyuria. This is related to effects on the kidney. Treatment The mainstay of treatment for sarcoidosis renal disease is steroid therapy.
The steroids work on the granulomatous legions, reducing calcitriol synthesis thereby reducing hypercalcemia. Although many have poor renal function on presentation, patients may respond dramatically to steroid therapy. The steroids are taken for 1-2 months at a high dose, which is then reduced for the remainder of the course, which should be no shorter than one year. In patients presenting with inadequate renal function, hemodialysis has also been found to be very effective in lowering plasma calcium. (Bongard FS et al, p56, 2008). However, equally important measures include restriction of calcium intake, avoidance of Vitamin D – containing dietary supplements, preventing exposure to sunlight and increasing fluid intake
Sarcoidosis
Sarcoidosis is a multi system disorder which has as its main feature, small inflammatory nodules. The disease commonly manifests itself in the lungs first. The disease causes hypercalcaemia . It is an inflammatory disease of the connective tissue and it affects every organ in the body. The incidence of sarcoidosis is most common among young men and women (Baughman RP). The disease is characterised by small inflammatory nodules and these nodules most commonly appear in the lungs.