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
Symptoms
The symptoms of hyperparathyroidism are described using the phrase, “moans, groans, stones and bones. These symptoms include
- Weakness and tiredness
- Nausea
- Constipation and abdominal pain
- Bone pain
- Thirst
- Polyuria
- Mood disturbances
Relevance of results to present case
Hyperparathyroidism is characterised by high serum calcium levels and these raised levels are present in George’s results. Decreased serum phosphate levels are indicative of hyperparathyroidism, however, in Georges case these levels are normal. Alkaline phosphatise levels may increase in secondary hyperparathyroidism but not in primary hyperparathyroidism and in Georges case these levels are normal which may possibly lend towards a diagnosis of hyperparathyroidism. Georges levels of phosphate are normal however there is an inverse relationship between calcium and phosphate.
Causes
When the parathyroid glands secrete too much hormone the balance is disrupted and hypercalcaemia follows.
In most people with primary hyperparathyroidism, a benign tumor called an adenoma has formed on one of the parathyroid glands, causing it to become overactive.
Treatment
• Parathyroidectomy for patients with symptomatic hyperparathyroidism, kidney stones, or bone disease
• Bisphosphonates (eg, pamidronate) for acute treatment of severe hypercalcemia while preparing for surgery
• For asymptomatic patients: maintain adequate fluid intake and avoid immobilization, thiazide diuretics, and calcium-containing antacids
• Estrogen replacement for postmenopausal women
Slight renal impairment
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.
Symptoms
Symptoms of Sarcoidosis include,
- Fatigue
- Weight loss
- Aches and pains
- Shortness of breath
- Lack of energy
- Eye complications
- Thirst. However the thirst is seen as a symptom of the hypercalcaemia rather than directly of the disease itself
Relevance of results to present case
Sarcoidosis is characterised by hypercalcaemia and there are raised levels of calcium in George’s blood. An increase in the blood levels of alkaline phosphatise is also associated with sarcoidosis. In George’s case, however, his serum levels of alkaline phosphate are normal.
In George’s case a chest radiography has been carried out. In Georges case there is some increased hilar shadowing and this is associated with sarcoidosis
Causes
The exact cause of Sarcoidosis is unknown. Individuals can have an initial sudden onset of the disease or it can manifest itself gradually over time (Medicinenet). Although little is known about the disease it is not regarded as completely debilitating, with most patients carrying out a normal lifestyle
Treatment of Sarcoidosis
Corticosteroids are required to treat Sarcoidosis. If the disease is not improving after 6 months of diagonosis then Prednisolone 30mg for 6 weeks should be used. This should be reduced to 15mg alternate day treatment for 6-12 months. Systemic Prednisolone should be given to patients who have persistent hypercalcaemia. If erythema nodosum, (painful rash on the legs) of sarcoidosis, is persistent or severe then a 2 week course of Prednisolone will be effective, (Kumar, Clark 2005, a).
Vitamin D Intoxication
There are two forms of vitamin D which are important for nutrition these include:
-
Vitamin D2 (ergocalciferol): which is used in very high dose supplements.
-
Vitamin D3 (cholecalciferol): which is the most active form of vitamin D and is formed in the skin when the skin is exposed to direct sunlight. Foods which include vitamin D3 are mainly cereals and dairy products. Vitamin D3 is also present in fish liver oils and fatty fish.
Vitamin D is stored in the liver. Vitamin D2 and D3 are not active in the body they are metabolized by the liver and kidneys into an active form which is called calcitriol. The active form allows absorption of calcium and phosphorus from the intestine. Calcium and phosphorus are included into bones to make them strong and dense. Therefore vitamin D is important for the formation, growth, and repair of bones. Vitamin D also increases immune function and improves muscle strength. As people age requirements for vitamin D increases
High doses of Vitamin D can cause toxicity and a high calcium level in the blood. Early symptoms include symptoms of hypercalcaemia such excessive thirst and polyuria which are the symptoms presented by George. Other symptoms which can be present in a person with high levels of vitamin D include loss of appetite, nausea vomiting, weakness, nervousness, and high blood pressure. Due to calcium levels being high, calcium can be deposited throughout the body, especially in the kidneys, blood vessels, lungs, and heart. The kidneys can be damaged and malfunction, which can result in kidney failure.
Excess Vitamin D is diagnosed when blood tests detect a high calcium level in a person who takes high doses of vitamin D. The diagnosis is confirmed by measuring the level of vitamin D in the blood. George’s symptoms of thirst and polyuria are probably due to too much exposure to sunlight as vitamin D3 is formed when the skin is exposed to direct sunlight. However George’s diet needs to be taken into consideration which would help to determine whether it includes high intake of vitamin D3 food supplements such as dairy products.
Treatments would include:
- Stopping vitamin D supplements (if being taken)
- Following a low-calcium diet for a while to decrease the effects of a high calcium level in the body
- Taking drugs (such as corticosteroids or bisphosphonates) to suppress the release of calcium from the bones
Discussion
Having reviewed George’s symptoms, his blood tests and the five potential diseases, it is evident that George is suffering from either Hyperparathyroidism or Sarcoidosis. As is often the case, there is no clear cut diagnosis and there is evidence pointing in the direction of both diseases.
Sarcoidosis is characterised by hypercalcaemia and there are raised levels of calcium in George’s blood. However this is also true of Hyperparathyroidism. An increase in the blood levels of alkaline phosphatise is also associated with sarcoidosis, however, these levels are normal in Georges case. George has undergone a chest radiograph and this has revealed increased hilar shadowing. This finding is consistent with a diagnosis of Sarcoidosis. The presence of granulomas is also associated with Sarcoidosis. These granular abnormalities usually appear first in the lungs but there is no evidence of their presence in George’s chest radiograph.
Hyperparathyroidism is characterised by high serum calcium levels and these raised levels are present in George’s results. Decreased serum phosphate levels are indicative of hyperparathyroidism, however, in Georges case these levels are normal. Alkaline phosphatise levels may increase in secondary hyperparathyroidism but not in primary hyperparathyroidism and in Georges case these levels are normal which may possibly lend towards a diagnosis of hyperparathyroidism. George’s levels of phosphate are normal however there is an inverse relationship between calcium and phosphate.
Hydrocortisone (glucocorticoid) tablets were given which reduced the serum calcium to 2.80 mmol/l. Glucocorticoids lower calcium levels if there is an increase in vitamin D or there are high levels of calcium which is present in sarcoidosis. Glucocorticoids are usually given to suppress the immune response or suppress inflammation and are of a great value when used to treat conditions that cause hypersensitivity. Cortisol also known as Hydrocortisone is a natural glucocorticoid. When administered orally they are more active comparing to when given by any other route. Receptors for cortisol are found in many tissues; Glucocorticoids inhibit the transcription of the genes for synthesis of cyclooxygenase (COX-2) This then inhibits cytokine release which leads to a decrease in action of TNFa and interleukins IL-1, IL-2 and IL-5. Glucocorticoids also block the synthesis of arachidonic acid which then inhibits the action of phospholipase A2 therefore reduces the synthesis of prostaglandins. B lymphocyte maturation and T helper lymphocyte profilatation is reduced. Glucocorticoids also decrease histamine release form basophils, decrease IgG production and decrease generation of induced nitric oxide, (Walker, Renwick, Hillier 2001, a).
These results show evidence for the proposition that George may be suffering from either Sarcoidosis or Hyperparathyroidism. It is necessary, therefore, to carry out further tests. These tests will serve to either confirm one of the diseases or possibly eliminate the other. In the case of sarcoidosis an increase in the levels of serum angiotensin converting enzyme is indicative of the disease. If this test was carried out it would give a better indication as to the possible diagnosis of Sarcoidosis. To exclude hyperthyroidism serum TSH can to be done.
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