Causes and Symptoms of Hypercalcemia - Assignment Example

Hypercalcemia [The name of the writer appears here] [The name of institution appears here] Hypercalcemia Q.1 Common cause of Hypercalcemia: Hypercalcemia is said to exist when the serum calcium is 10.5 mg/dL or greater. This figure may vary slightly depending on the normal values of the method as established by the individual laboratory. With automation of laboratory procedures, biochemical screenings or profiles are often done routinely, both in the physician’s office and in the hospital. The serum calcium is generally included in these screenings and elevations are often seen in asymptomatic patients. Elevation of the serum calcium level is found in about 1 % of routine biochemical screens. Hypercalcemia might be associated with hyperthyroidism alone or may occur as a manifestation of associated primary hyperparathyroidism, although neither disorder has been hitherto adequately understood. In the former scenario, an accelerated bone turnover state is speculated to increase bone resorption sufficiently to cause hypercalcemia. Hypercalcemia is usually discovered accidentally by blood multipanel screening. Most patients are asymptomatic. Parathyroid adenomas are usually so small deeply located in the neck that they are almost never palpable; when a mass is palpated, it usually turns out to be an incidental thyroid nodule. Symptomatic patients are said to have problems with bones, stones, abdominal groans, psychic moans with fatigue over tones. Classic history for primary hyperparathyroidism is stones, bones, moans and groans from renal calculi, osteitis fibrosa, constipation and neuropsychiatric problems respectively. Renal calculi and osteitis fibrosa are seldom associated with hypercalcemia of malignancy because both result from long lasting hypercalcemia. Hypercalcemia causes a variety of non specific symptoms including polyuria, plydypsia, constipation, nausea, vomiting, anorexia, and mental status changes which can range from confusion to coma. There may also be associated bone pains. Multiple cause of hypercalcemia has been elucidated. Hyperparathyroidism and malignancy account for 90% of cases. The various known common causes of hypercalcemia include the following conditions: 1. Malignancy—probably the most common in hospitalized patients. a. Metastaic carcinoma to bone. Breast, lung and renal cell carcinoma. b. Hematologic malignancies. Direct bone involvement with multiple myeloma, Leukemia and Lymphoma. c. Non endocrine, parathyroid hormone-secreting carcinoma (lung, kidney, ovary, colon, cervix, pancreas), ectopic hyperparathyroidism. 2. Primary Hyperparathyroidism. a. Tumor of the parathyroid gland. b. Primary Hyperplasia of the parathyroid gland. c. Carcinoma of the Parathyroid gland. 3. Drug induced hypercalcemia, including thiazides and spironolactone- increasingly common. . It increases renal tubular absorption of calcium. Exogenous calcium carbonate intake such as in certain antacids. 4. Vitamin D intoxication. A fat soluble vitamin that increases intestinal absorption, increases mobilization from bones and increases renal reabsorption of calcium. 5. Milk alkali syndrome. From increased intake of calcium and alkali results in hypercalcemia, hypocalciurea, hyperphosphatemia, renal failure and metastatic calcification. 6. Multiple endocrine neoplasia, I and II; Zollinger-Ellison Syndrome. 7. Benign Familial hypercalcemia (familial hypocalciuric hypercalcemia). 8. Other causes include hypothyroidism and hyperthyroidism, adrenal insufficiency, sarcoidosis and other granulomatous disease and immobilization particularly in the elderly. Prolonged bed rest increase bone reabsorption resulting in hypercalcemia and osteoporosis.1, 2 Q. 2 The first step in the laboratory assessment is to exclude factitious hypercalcemia, which may result from an increase in circulating concentrations of plasma proteins. About 50% to 60% of circulating calcium is bound to these proteins, so elevation in their concentrations (as occurs in HIV infection, chronic viral hepatitis, and multiple myeloma) will produce a proportionate rise in the total calcium concentration. The ionized calcium concentration, however, remains normal. To adjust for elevations in plasma protein, the serum calcium level should be lowered by 0.8 mg/dl for every 1 g/dl of albumin (or protein) above the normal range. When performed correctly, ionized calcium measurement is more accurate than adjusted total calcium. Because acute renal failure may occasionally lead to hypercalcemia, renal function should also be assessed. 3 Once hypercalcemia is confirmed, the next step is measurement of the serum PTH concentration. This is the most important test for determining the cause of hypercalcemia.3 Several PTH assays are commercially available. The most commonly utilized is the two-site immunochemiluminometric assay (ICMA, or so-called bio-intact PTH). Earlier assays could not distinguish between full-length PTH and inactive molecular fragments that circulate in significant concentrations. The ICMA measures only the intact PTH molecule and is therefore the preferred test in most instances, especially in patients whose serum creatinine level is elevated. 3 Other helpful tests include measurement of serum creatinine and alkaline phosphatase, as well as inorganic phosphorus assays and an electrolyte panel. Assessment of 24-hour urinary calcium excretion is usually performed. Serum creatinine may be elevated in patients with nephrocalcinosis secondary to prolonged hypercalcemia. The alkaline phosphatase level may be elevated in patients with hypercalcemic states involving increased bone turnover. Patients with hypercalcemia caused by malignancy may demonstrate biochemical or hematologic findings consistent with the site of neoplasia and the degree of its dissemination. Most causes of hypercalcemia are also accompanied by hypercalciuria (24-hour urinary calcium excretion > 4 mg/kg/day), which may lead to nephrocalcinosis or renal stone formation. A serum calcium × phosphate product greater than 70 suggests the patient is at risk for calciphylaxis, and efforts to lower the serum phosphate level (e.g., with phosphate binders) should accompany the interventions to lower serum calcium. 3 Other diagnostic studies may be dictated by clinical circumstances. Electrocardiographic abnormalities of severe hypercalcemia include shortening of the QTc interval and, rarely, atrioventricular blocks. In addition, many hypercalcemic conditions cause a decrease in BMD, which may be noted on plain x-rays but is best quantified by measurement of bone density (see below). Abdominal x-rays may identify renal stones or nephrocalcinosis. Specific bone radiographic findings are few, and in primary hyperaparathyroidism, specific bony abnormalities are now rare, thanks to early detection of hypercalcemia. Due to the relationship between PTH and calcium, calcium levels should be tested at the same time as PTH. Most laboratories have established reference values to indicate what PTH level is normal for a particular calcium level. In addition, the effects of PTH on kidney function and bone strength indicate that serum calcium, phosphorus, and creatinine levels should be measured together with PTH. The creatinine test measures kidneys function and aids in the diagnosis of parathyroid dysfunction. 4 First of all it is wise to re-confirm elevated calcium and the severity of the hypercalcemia before establishing diagnosis. Remember, a high normal total calcium may also signify hypercalcemia in the presence of marked hypoalbumenimia. So a repeat calcium along with an albumin or an ionized calcium is required. A calcium value must be corrected in the presence of hypoalbumenimia. Normally, the total calcium decreases by 0.2 mmol/L or 0.4 mEq/L for every 1.0 g/dL decrease in the serum albumin without changing the ionized calcium level. Symptoms usually develop at 6.5 mEq/L or 3.25 mmol/L. The ionized fraction of serum calcium is the biologically active form, making it the preferred form of serum calcium to measure; a greater number of PHP patients have increased serum ionized calcium concentrations than serum total calcium. 5, 6 However measurement of urinary calcium excretion is crucial as its low value con If we are suspecting HRTP2 or HRTPI then presence of mutant gene that encodes parafibromin can be detected on genetic testing include with FHH presence. 1 Q. 3 PTH is broken down in the body into three different molecular forms: the intact PTH molecule and several smaller fragments which include an amino acid or N- terminal, a midregion or midmolecule, and a carboxyl or C-terminal. Two tests are currently used to measure intact PTH and its terminal fragments. While both tests are used to diagnose hyper-or hypoparathyroidism, each test also has specific applications as well. The C-terminal PTH assay is used to diagnose the ongoing disturbances in PTH metabolism that occur with secondary and tertiary hyperparathyroidism. The assay for intact PTH and the N-terminal fragment, which are both measured at the same time, is more accurate in detecting sudden changes in the PTH level. For this reason, the N-terminal PTH assay is used to monitor a patient's response to therapy. Parathyroid hormone (PTH) is an 84 amino acid polypeptide produced by the parathyroid glands that influences calcium and phosphate homeostasis by its action on target organs, bone and kidney. In bone, it mobilizes calcium and phosphate thus raising serum calcium concentration. In the kidney, calcium is conserved by increasing renal tubular reabsorption, and excretion of phosphate in the urine is increased by inhibition of tubular reabsorption. PTH also stimulates renal hydroxylation of 25-(OH) vitamin D to 1,25 (OH)2 vitamin D which, in turn, enhances intestinal calcium absorption. PTH secretion is regulated by free calcium concentrations in the blood through a negative feedback mechanism. A fall in serum calcium concentration stimulates PTH secretion, whereas a rise in serum calcium produces an opposite effect. The measurement of serum PTH levels is crucial in the assessment of calcium metabolism disorders. Human blood contains both intact PTH (1-84) and several PTH fragments. Intact PTH has a half-life in the blood of only 3-4 minutes. It is rapidly degraded either within the parathyroid glands or in the peripheral tissues (liver and kidney) to yield N- and C- terminal PTH fragments. The small N-terminal fragment (1-34) is a full PTH agonist, which is rapidly cleared from the circulation and is usually undetectable. The large C-terminal fragment, also known as N-terminal truncated fragment, has a relatively long half-life of a few hours and is removed from the circulation primarily by glomerular filtration. Therefore, intact PTH (1-84) and N-terminal truncated fragments are the principal circulating forms of PTH. N-terminal truncated fragments have been traditionally thought to lack biological activity. Recent evidence shows that they may act as PTH antagonists. The major biological effects of PTH are through the activation of the PTH receptor, and activation requires the N-terminal portion of PTH (1-84) and PTH (1-34). This effect is eliminated when the N-terminal serine residue is truncated (7-84). The ratio of fragments to intact PTH is very variable and largely depends on renal function. N-terminal truncated fragments represent approximately 1-20% of circulating PTH in healthy individuals and in primary hyperparathyroidism. This ratio may increase to 35% or more in end-stage renal failure due to decreased clearance of PTH fragments. Blood calcium concentrations also influence the proportion of PTH fragments. When blood calcium concentrations rise, relatively greater amounts of N-terminal truncated fragments and lesser amounts of intact PTH are detected in the plasma. In contrast, more intact PTH and less C-terminal fragments are found when blood calcium concentrations are reduced. Initially, PTH was measured using radioimmunoassay (RIA) with a single antibody directed against the more immunogenic C-terminal region of PTH. The heterogeneous nature of circulating PTH made these assays nonspecific and unreliable especially in kidney disease where clearance may be compromised. The specificity has been improved with the introduction of two-site immunoradiometric assays (IRMA) for intact PTH. The principle of these assays is to detect intact PTH using two distinct antibodies, one is a solid phase capture antibody directed against the C-terminal region of PTH, and one is a radiolabeled detection antibody directed against the N-terminal region of the PTH peptide. A major drawback of these assays is that they not only detect intact PTH (1-84), but also cross react with large N-terminal truncated PTH fragments (7-84). As N-terminal truncated PTH fragments may inhibit PTH activity, simultaneous measurement of intact PTH and its potential inhibitor not only overestimates PTH levels, but also makes it difficult to interpret PTH measurements. This is particularly true in chronic renal failure where these large fragments may accumulate in the blood and have implications in the management of secondary hyperparathyroidism in these patients. The Bio-Intact PTH assay, a two-site immunochemiluminometric assay recently developed for measurement of “true” intact PTH (1-84) was introduced in our laboratory and is provided by the HRLMP. The major advantage of this assay over the first-generation IRMA test is to specifically measure intact PTH (1-84) in human serum or plasma, and not PTH fragments (7-84). The specificity of this assay is achieved by using a detection antibody directed toward the first six amino acids at the N-terminal end. PTH fragments lacking one or several amino acid residues at N-terminal region will not be detected. Recently, we have completed the method validation of this new Bio-Intact PTH assay and our results support clinical application of this assay for detection of PTH. It has been proved by several studies that intact PTH proved most reliable in detecting changes in parathyroid hormone secretion in response to variations in ionized calcium induced by haemodialysis. In patients with extensive intestinal resection, both assays showed increased levels of PTH. It is concluded that measurement of intact PTH is a more reliable index of parathyroid function than measurement of midregion/C-terminal PTH. Thus such an approach should be the one of choice for clinical evaluation of calcium homeostasis. The reference value for this assay is 6 - 40 pg/mL. 7. 8. 9 Reference ranges for PTH tests vary somewhat depending on the laboratory, and must be interpreted in association with calcium results. The following ranges are typical: Intact PTH: 10-65 pg/mL PTH N-terminal (includes intact PTH): 8-24 pg/mL PTH C-terminal (includes C-terminal, intact PTH, and midmolecule): 50-330 pg/mL. 10, 11, 12 Q.4. Clues given in this clinical vignette like past history of renal stones and family history of hyperparathyroidism heralds that this patient might be having familial disorders with hypercalcemia including Multiple endocrine neoplasia (MEN I and MEN II) that are inherited in an autosomal dominant pattern or familial isolated hyperparathyroidism (HRTP1 and HRTP2) or familial hypocalciuric hypercalcemia (FHH).Hereditary hyperparathyroidism can occur without other endocrine abnormalities but is usually part of a multiple endocrine neoplasia syndrome. MEN I ( Wermer’s Syndrome ) consist of hyperparathyroidism and the tumors of the pituitary and pancreas, often associated with gastric hypersecretion and peptic ulcer disease (Zolliger Ellison Syndrome). MEN IIa is characterized by pheochromocytomaa and medullary carcinoma of the thyroid as well as hyperparathyroiudism; MEN IIb has additional features such as multiple neuromas but usually lacks hyperparathyroidism. Each of these MEN syndromes is transmitted in an apparent autosomal dominant manner, although the genetic basis does not always involve a dominant allele. Since this patient is not having any other sign or symptoms which steer towards the criteria for MEN I and MEN II chances are least likely that he will be suffering from these syndromes. So in my opinion he is most probably suffering from primary hyperparathyroidism. The diagnosis is supported by the symptoms of joint pain, renal stones history, lethargy and the lab findings. This diagnosis is confirmed by raised serum calcium and alkaline phosphatase, low phosphate, and markedly raised intact PTH and C-terminal PTH despite normal serum creatinine level. 13, 14 Q. 5. The most common cause of hyperparathyroidism is parathyroid adenomas of the which accounts for approx. 80% of the cause. They occur in either sex, most often during middle age. Generally solitary, may be multiple. They may arise in ectopic sites (e.g. intrathyroidal, intra thymic, retro esophageal, pericardial) reflecting aberrant migration of developing glands. Adenomas are most often located in the inferior parathyroid glands. They are usually 0.5 to 5.0g in size but may be as large as 10-20 g (normal gland wt. is 25 mg). 15, 16 Morphologically they are well demarcated, soft yellow-to- red mass often less than 2 cm in diameter. Microscopically may be composed of a single cell type (usually chief ce4lls) or mixtures of chief cells, oxyphil cells, and /or cells with optically clear cytoplasm termed water–clear cells. Stromal fat is absent. Follicular structures containing proteinaceous material are present in some lesions and may be difficult to distinguish from thyroid parenchyma. Significant nuclear atypia may be present; mitoses are rare. The presence of a rim of compressed, atrophic parathyroid parenchyma at the periphery of lesion is helpful in distinguishing adenoma from hyperplasia. Fat stains of frozen section material demonstrate absence of intracellular lipid within the adenoma, in contrast to adjacent non-neoplastic gland. Q.6 Hypercalcemia completely abated after treatment of thyrotoxicosis. Notwithstanding that hypercalcemia is an unusual manifestation of hyperthyroidism, asymptomatic elevation of serum calcium concentration had been documented in up to one-fourth of patients with proved hyperthyroidism. The current case is unusual in that the patient demonstrated a significant degree of hypercalcemia secondary to hyperthyroidism alone, with a serum calcium level as high as 3.14 mmol/L. 17 Also other less common causes of hyperparathyroidism is primary hyperplasia and parathyroid carcinoma of the parathyroid gland. Primary hyperplasia Accounts for 15% of cases of primary hyperparathyroidism. Typically involves all glands; may be asymmetric in some cases and difficult to distinguish from adenomas. Histologic pattern is dominated by either chief cells or clear cells Chief cell hyperplasia produces mild-to-moderate enlargement or combinations of chief and oxyphil cells, with significantly less Stromal fat than normal gland. Proliferation may be diffuse or nodular, creating possible confusion with adenoma in biopsy material. Clear cell hyperplasia is associated with more striking enlargement of glands. Involved glands are diffusely enlarged by uniformly distributed cells with pale, vacuolated cytoplasm; adipose tissue and oxyphil cells are in inconspicuous.18 Parathyroid carcinoma accounts for 2-3 % of cases of primary hyperparathyroidism. Associated hyperparathyroidism may be more severe than that associate with adenoma. Distinction from adenoma may be difficult. Features supporting diagnosis of carcinoma include metastases to regional nodes or distant sites, capsular and /or blood vessels invasion, mitotic activity, extensive fibrosis and trabecular growth pattern. Local recurrence may indicate malignancy, but can occur with adenomas. Death is more often due to the effects of hyperparathyroidism than the effects f local invasion or metastatic spread. 19, 20 Reference: 1. Intarnal Medicine on call, Steven A. Haist, John B. Robinsons and Leonard G.Gomella, 2003, pp 340 2. Problem oriented medical diagnosis, H. Harold Friedman, 2002, pp 210-222 3. Elizabeth H. Holt, MD, PHD, Silvio E. Inzucchi, MD. Diseases of Calcium Metabolism and Metabolic Bone Disease: Hypercalcemia (Reference); ACP Medicine Online, Oct 2002, pp 77 4. www.ahealthyadvantage.com 5. Lawrence M. Tirney, Jr., MD, Stephen J. Mcphee, MD, Maxine A. Papadakis, MD. Current Medical Diagnosis and Treatment; ange medical book; 2003, pp 90 6. Golkowski F, Jabrocka-Hybel A, Trofimiuk M, Huszno B. [Diagnostic problems with recognition of primary hyperthyroidism] Przegl Lek. 2005; 62(7):685-9. Polish. 7. Inaba M, Nakatsuka K, Imanishi Y, Watanabe M, Mamiya Y, Ishimura E and Nishizawa Y. Technical and clinical characterization of the Bio-PTH (1-84) immunochemiluminometric assay and comparison with a second-generation assay for parathyroid hormone. Clin Chem 2004; 50:385-390. 8. Goodman WG, Juppner H, Salusky IB, Sherrard, DJ.Parathyroid hormone (PTH), PTH-derived peptides, and new PTH assays in renal osteodystrophy. Kidney Int. 2003 Jan; 63:1-11. 9. A New Assay for "True" Bio-Intact Parathyroid Hormone; Issue No. 75 QUARTERLY NEWSLETTER June 2004, pp 145 10. Jacobs, David S., et al. Laboratory Test Handbook. 4th ed. New York: Lexi-Comp Inc., 1996., pp 305-314 11. Pagana, Kathleen Deska. Mosby's Manual of Diagnostic and Laboratory Tests. St. Louis: Mosby, Inc., 1998, pp 67-77 12. Cahill, Mathew. Handbook of Diagnostic Tests. Springhouse, PA: Springhouse Corporation, 1995, 199-202 13. Harrison’s Principles of Internal Medicine, Dennis L Kasper, Anthony S. Fauci, Dan L. Longo, 2005, pp 444 14. Silver Berg SJ et al; Primary hyperparathyroidism: 10 – year course with or without parathyroid surgery N Engl J Med 332:1249, 1999 15. Carlos Ponce, MD; Jaspal S. Gujral, MBBS, FACP, MRCP (UK). Renal Failure and Hypercalcemia as Initial Manifestations of Extrapulmonary Sarcoidosis. Sarcoidosis is a multisystem disorder characterized by an increased cellular immune response to an unknown antigen and the formation of noncaseating granulomas in affected tissues; Southern Medical Journal, Jun 2004, pp 102 16. Bilezikian JP, Potts JT Jr. Asympotomatic primary hyperparathyroidism; New issues and new questions bridging the past with the future. J Bone Min Res 17 (Suppl 2) N57, 2002 17. Kai Ming Chow, MD; Cheuk Chun Szeto, MD. An Unusual Cause of Hypercalcemia; Southern Medical Journal, Jun 2004; South Med J. 2004 Jun;97(6):588-9. 18. Colognesi A, de Tullio D, Messina F, Ferrocci G, Stano R, Azzena G. Primary hyperparathyroidism related to a parathyroid adenoma: the dramatic clinical evolution of a misdiagnosed patient and its surgical solution. Minerva Chir. 2006 Feb; 61(1):51-6. 19. Robbins pathologic basis of disease, Stanley L. Robbins, Ramzi S. Coran and Vinay Kuma, 2004, pp 270 20. Thaker RV; Molecular genetics of parathyroid disease. Curren6t Opin endocrinl diab 3;521, 1996 Read More