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What is the best workup for hypocalcemia?
Unexplained hypocalcemia can usually be diagnosed by a limited number of serum tests when the cause isn’t obvious from the history (recent neck surgery or renal failure):
- calcium (corrected for serum albumin)
- creatinine
- phosphorus
- magnesium
- parathyroid hormone (PTH).
The most common causes, categorized according to the results of these tests, are (strength of recommendation: C, expert opinion, case series, and physiologic principles):
- high PTH, high phosphorus, and high creatinine: renal failure
- high PTH, low or normal phosphorus, and normal creatinine: vitamin D deficiency or pancreatitis
- low PTH, high phosphorus, and normal creatinine: inadequate parathyroid gland function or hypomagnesemia.
Important supporting tests—serum albumin, phosphorus, magnesium
Grant Hoekzema, MD
Mercy Family Medicine Residency, St. Louis, Mo
Serious abnormal laboratory results often are encountered in outpatient testing using multitest panels such as basic and comprehensive metabolic profiles. Hypocalcemia found on a basic metabolic panel is a good example of such a result.
Given the broad differential diagnosis outlined by the authors of this Clinical Inquiry, we must interpret abnormal results with the proper supporting tests. In this case, the most important is serum albumin, which can be a critical indicator of whether the patient truly has hypocalcemia. That is why I tend to order a comprehensive metabolic panel when disorders of calcium metabolism are part of the differential.
This Clinical Inquiry also highlights the important role of phosphorus and magnesium in calcium metabolism. It’s important to note that these tests are no longer a regular component of many multitest blood panels and must be ordered when hypocalcemia is found.
Evidence summary
Normal values for total or corrected serum calcium are 8.5-10.2 mg/dL and for ionized calcium, 4.4-5.4 mg/dL. Because total serum calcium is approximately 50% free (ionized) and 50% bound, primarily to albumin, the serum level must be “corrected” if hypoalbuminemia exists. Because serum calcium comprises less than 1% of body stores, severe total body deficiency of calcium can exist without hypocalcemia.1,2
Ionized calcium is under tight physiologic control, monitored by calcium-sensing proteins in the parathyroid gland; low ionized calcium augments PTH secretion, which in turn has 3 primary actions:
- decreased calcium excretion by the kidneys
- increased activity of osteoclasts, leading to calcium release from bone
- increased activity of renal 25-OH vitamin D hydroxylase, resulting in elevated serum levels of calcitriol, the active form of vitamin D; elevated calcitriol in turn augments gastrointestinal absorption of calcium.
An adequate supply of 25-OH vitamin D to the kidneys requires adequate gastrointestinal absorption or sun-induced skin production of vitamin D and sufficient liver function to carry out the first of the 2 hydroxylation steps.1,3
Common causes of hypocalcemia
We found no studies that established the frequency of various causes of hypocalcemia in the general population, but reviewers concurred that the most common specific causes, in order of frequency, are (TABLE):2,3
- renal failure
- vitamin D deficiency
- hypomagnesemia
- pancreatitis
- hypoparathyroidism.
It is not surprising that renal failure is a common cause of hypocalcemia, given the high prevalence of chronic kidney disease in adults—11.2% of the total United States population older than 20 years has at least a mildly reduced glomerular filtration rate (stage 2, chronic kidney disease, with glomerular filtration rate <90 cc/min).4 Despite elevated PTH, serum calcium may be slightly reduced (and osteomalacia present) even in mild chronic kidney disease.5,6 Only severe or end-stage chronic kidney disease (glomerular filtration rate <30 cc/min, 5.8% of population) is often associated with actual hypocalcemia.5,6 Likewise, the prevalence of vitamin D deficiency (<15 ng/mL of 25-OH vitamin D) is 35% to 55% in the general population,7,8 and 95% in institutionalized elderly patients.9
Chronic kidney disease (66%) and vitamin D deficiency (24%) were the most common causes of hypocalcemia in a study of 594 elderly general medicine inpatients.10 In a study of 62 hypocalcemic patients in a medical intensive care unit, the cause of the hypocalcemia could be determined in only 28 (45%); most of the cases were caused by hypomagnesemia (28%), renal insufficiency (8%), and pancreatitis (3%).11
TABLE
Causes of hypocalcemia by key test results
| TEST RESULTS | COMMON CAUSES | LESS COMMON CAUSES |
|---|---|---|
| High PTH, high phosphorus | Renal failure |
|
| High PTH, low phosphorus | Vitamin D deficiency (with low bone calcium) caused by:
|
|
| Low PTH, high phosphorus | Hypoparathyroidism and hypomagnesemia |
|
| PTH, parathyroid hormone. | ||
Serious causes of hypocalcemia
The usual cause of critically low serum calcium (<7 mg/dL “corrected” or <3.2 mg/dL ionized) is parathyroidectomy or acute renal failure. Hypocalcemia resulting from partial parathyroidectomy or thyroidectomy (with inadvertent parathyroidectomy) occurs in approximately 5% of these surgeries; 99.5% of cases resolve completely within a year.12
Recommendations
Several reviewers recommend a similar workup and differential diagnosis for hypocalcemia. Unfortunately, none cites quantitative data on the prevalence of hypocalcemia and its causes.2,13
Some authors recommend measuring 25-OH vitamin D in all hypocalcemia patients with elevated PTH without hyperphosphatemia to confirm vitamin D deficiency.1,2 Others emphasize the importance of measuring ionized calcium to detect hypocalcemia, especially in critically ill patients, in whom many acute variables can decrease ionized calcium (alkalosis can increase protein binding, for example).1,3,14
Although several reviewers present an algorithmic approach to determining the cause of hypocalcemia,3 we could find no data on the derivation or validation of the diagnostic effectiveness of these algorithms.
1. Fukugawa M, Kurokawa K. Calcium homeostasis and imbalance. Nephron. 2002;92(suppl 1):41-45.
2. Ruppe M. Hypocalcemia. In: American College of Physicians (ACP) Physician’s Information and Education Resource (PIER) database. Available at: http://pier.acponline.org/index.html. Accessed October 30, 2007.
3. Carlstedt F, Lind L. Hypocalcemic syndromes. Crit Care Clin. 2001;17:139, 53, vii-viii.
4. Centers for Disease Control and Prevention (CDC). Prevalence of chronic kidney disease and associated risk factors—United States, 1999-2004. MMWR Morb Mortal Wkly Rep. 2007;56:161-165.
5. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.
6. Rix M, Andreassen H, Eskildsen P, Langdahl B, Olgaard K. Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure. Kidney Int. 1999;56:1084-1093.
7. Thomas MK, Lloyd-Jones DM, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med. 1998;338:777-783.
8. Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D insufficiency among free-living healthy young adults. Am J Med. 2002;112:659-662.
9. Fardellone P, Sebert JL, Garabedian M, et al. Prevalence and biological consequences of vitamin D deficiency in elderly institutionalized subjects. Rev Rhum Engl Ed. 1995;62:576-581.
10. Hodkinson HM. Serum calcium in a geriatric inpatient population. Age Ageing. 1973;2:157-162.
11. Desai TK, Carlson RW, Geheb MA. Prevalence and clinical implications of hypocalcemia in acutely ill patients in a medical intensive care setting. Am J Med. 1988;84:209-214.
12. Pattou F, Combemale F, Fabre S, et al. Hypocalcemia following thyroid surgery: incidence and prediction of outcome. World J Surg. 1998;22:718-724.
13. Guise TA, Mundy GR. Clinical review 69: evaluation of hypocalcemia in children and adults. J Clin Endocrinol Metab. 1995;80:1473-1478.
14. Hastbacka J, Pettila V. Prevalence and predictive value of ionized hypocalcemia among critically ill patients. Acta Anaesthesiol Scand. 2003;47:1264-1269.
Unexplained hypocalcemia can usually be diagnosed by a limited number of serum tests when the cause isn’t obvious from the history (recent neck surgery or renal failure):
- calcium (corrected for serum albumin)
- creatinine
- phosphorus
- magnesium
- parathyroid hormone (PTH).
The most common causes, categorized according to the results of these tests, are (strength of recommendation: C, expert opinion, case series, and physiologic principles):
- high PTH, high phosphorus, and high creatinine: renal failure
- high PTH, low or normal phosphorus, and normal creatinine: vitamin D deficiency or pancreatitis
- low PTH, high phosphorus, and normal creatinine: inadequate parathyroid gland function or hypomagnesemia.
Important supporting tests—serum albumin, phosphorus, magnesium
Grant Hoekzema, MD
Mercy Family Medicine Residency, St. Louis, Mo
Serious abnormal laboratory results often are encountered in outpatient testing using multitest panels such as basic and comprehensive metabolic profiles. Hypocalcemia found on a basic metabolic panel is a good example of such a result.
Given the broad differential diagnosis outlined by the authors of this Clinical Inquiry, we must interpret abnormal results with the proper supporting tests. In this case, the most important is serum albumin, which can be a critical indicator of whether the patient truly has hypocalcemia. That is why I tend to order a comprehensive metabolic panel when disorders of calcium metabolism are part of the differential.
This Clinical Inquiry also highlights the important role of phosphorus and magnesium in calcium metabolism. It’s important to note that these tests are no longer a regular component of many multitest blood panels and must be ordered when hypocalcemia is found.
Evidence summary
Normal values for total or corrected serum calcium are 8.5-10.2 mg/dL and for ionized calcium, 4.4-5.4 mg/dL. Because total serum calcium is approximately 50% free (ionized) and 50% bound, primarily to albumin, the serum level must be “corrected” if hypoalbuminemia exists. Because serum calcium comprises less than 1% of body stores, severe total body deficiency of calcium can exist without hypocalcemia.1,2
Ionized calcium is under tight physiologic control, monitored by calcium-sensing proteins in the parathyroid gland; low ionized calcium augments PTH secretion, which in turn has 3 primary actions:
- decreased calcium excretion by the kidneys
- increased activity of osteoclasts, leading to calcium release from bone
- increased activity of renal 25-OH vitamin D hydroxylase, resulting in elevated serum levels of calcitriol, the active form of vitamin D; elevated calcitriol in turn augments gastrointestinal absorption of calcium.
An adequate supply of 25-OH vitamin D to the kidneys requires adequate gastrointestinal absorption or sun-induced skin production of vitamin D and sufficient liver function to carry out the first of the 2 hydroxylation steps.1,3
Common causes of hypocalcemia
We found no studies that established the frequency of various causes of hypocalcemia in the general population, but reviewers concurred that the most common specific causes, in order of frequency, are (TABLE):2,3
- renal failure
- vitamin D deficiency
- hypomagnesemia
- pancreatitis
- hypoparathyroidism.
It is not surprising that renal failure is a common cause of hypocalcemia, given the high prevalence of chronic kidney disease in adults—11.2% of the total United States population older than 20 years has at least a mildly reduced glomerular filtration rate (stage 2, chronic kidney disease, with glomerular filtration rate <90 cc/min).4 Despite elevated PTH, serum calcium may be slightly reduced (and osteomalacia present) even in mild chronic kidney disease.5,6 Only severe or end-stage chronic kidney disease (glomerular filtration rate <30 cc/min, 5.8% of population) is often associated with actual hypocalcemia.5,6 Likewise, the prevalence of vitamin D deficiency (<15 ng/mL of 25-OH vitamin D) is 35% to 55% in the general population,7,8 and 95% in institutionalized elderly patients.9
Chronic kidney disease (66%) and vitamin D deficiency (24%) were the most common causes of hypocalcemia in a study of 594 elderly general medicine inpatients.10 In a study of 62 hypocalcemic patients in a medical intensive care unit, the cause of the hypocalcemia could be determined in only 28 (45%); most of the cases were caused by hypomagnesemia (28%), renal insufficiency (8%), and pancreatitis (3%).11
TABLE
Causes of hypocalcemia by key test results
| TEST RESULTS | COMMON CAUSES | LESS COMMON CAUSES |
|---|---|---|
| High PTH, high phosphorus | Renal failure |
|
| High PTH, low phosphorus | Vitamin D deficiency (with low bone calcium) caused by:
|
|
| Low PTH, high phosphorus | Hypoparathyroidism and hypomagnesemia |
|
| PTH, parathyroid hormone. | ||
Serious causes of hypocalcemia
The usual cause of critically low serum calcium (<7 mg/dL “corrected” or <3.2 mg/dL ionized) is parathyroidectomy or acute renal failure. Hypocalcemia resulting from partial parathyroidectomy or thyroidectomy (with inadvertent parathyroidectomy) occurs in approximately 5% of these surgeries; 99.5% of cases resolve completely within a year.12
Recommendations
Several reviewers recommend a similar workup and differential diagnosis for hypocalcemia. Unfortunately, none cites quantitative data on the prevalence of hypocalcemia and its causes.2,13
Some authors recommend measuring 25-OH vitamin D in all hypocalcemia patients with elevated PTH without hyperphosphatemia to confirm vitamin D deficiency.1,2 Others emphasize the importance of measuring ionized calcium to detect hypocalcemia, especially in critically ill patients, in whom many acute variables can decrease ionized calcium (alkalosis can increase protein binding, for example).1,3,14
Although several reviewers present an algorithmic approach to determining the cause of hypocalcemia,3 we could find no data on the derivation or validation of the diagnostic effectiveness of these algorithms.
Unexplained hypocalcemia can usually be diagnosed by a limited number of serum tests when the cause isn’t obvious from the history (recent neck surgery or renal failure):
- calcium (corrected for serum albumin)
- creatinine
- phosphorus
- magnesium
- parathyroid hormone (PTH).
The most common causes, categorized according to the results of these tests, are (strength of recommendation: C, expert opinion, case series, and physiologic principles):
- high PTH, high phosphorus, and high creatinine: renal failure
- high PTH, low or normal phosphorus, and normal creatinine: vitamin D deficiency or pancreatitis
- low PTH, high phosphorus, and normal creatinine: inadequate parathyroid gland function or hypomagnesemia.
Important supporting tests—serum albumin, phosphorus, magnesium
Grant Hoekzema, MD
Mercy Family Medicine Residency, St. Louis, Mo
Serious abnormal laboratory results often are encountered in outpatient testing using multitest panels such as basic and comprehensive metabolic profiles. Hypocalcemia found on a basic metabolic panel is a good example of such a result.
Given the broad differential diagnosis outlined by the authors of this Clinical Inquiry, we must interpret abnormal results with the proper supporting tests. In this case, the most important is serum albumin, which can be a critical indicator of whether the patient truly has hypocalcemia. That is why I tend to order a comprehensive metabolic panel when disorders of calcium metabolism are part of the differential.
This Clinical Inquiry also highlights the important role of phosphorus and magnesium in calcium metabolism. It’s important to note that these tests are no longer a regular component of many multitest blood panels and must be ordered when hypocalcemia is found.
Evidence summary
Normal values for total or corrected serum calcium are 8.5-10.2 mg/dL and for ionized calcium, 4.4-5.4 mg/dL. Because total serum calcium is approximately 50% free (ionized) and 50% bound, primarily to albumin, the serum level must be “corrected” if hypoalbuminemia exists. Because serum calcium comprises less than 1% of body stores, severe total body deficiency of calcium can exist without hypocalcemia.1,2
Ionized calcium is under tight physiologic control, monitored by calcium-sensing proteins in the parathyroid gland; low ionized calcium augments PTH secretion, which in turn has 3 primary actions:
- decreased calcium excretion by the kidneys
- increased activity of osteoclasts, leading to calcium release from bone
- increased activity of renal 25-OH vitamin D hydroxylase, resulting in elevated serum levels of calcitriol, the active form of vitamin D; elevated calcitriol in turn augments gastrointestinal absorption of calcium.
An adequate supply of 25-OH vitamin D to the kidneys requires adequate gastrointestinal absorption or sun-induced skin production of vitamin D and sufficient liver function to carry out the first of the 2 hydroxylation steps.1,3
Common causes of hypocalcemia
We found no studies that established the frequency of various causes of hypocalcemia in the general population, but reviewers concurred that the most common specific causes, in order of frequency, are (TABLE):2,3
- renal failure
- vitamin D deficiency
- hypomagnesemia
- pancreatitis
- hypoparathyroidism.
It is not surprising that renal failure is a common cause of hypocalcemia, given the high prevalence of chronic kidney disease in adults—11.2% of the total United States population older than 20 years has at least a mildly reduced glomerular filtration rate (stage 2, chronic kidney disease, with glomerular filtration rate <90 cc/min).4 Despite elevated PTH, serum calcium may be slightly reduced (and osteomalacia present) even in mild chronic kidney disease.5,6 Only severe or end-stage chronic kidney disease (glomerular filtration rate <30 cc/min, 5.8% of population) is often associated with actual hypocalcemia.5,6 Likewise, the prevalence of vitamin D deficiency (<15 ng/mL of 25-OH vitamin D) is 35% to 55% in the general population,7,8 and 95% in institutionalized elderly patients.9
Chronic kidney disease (66%) and vitamin D deficiency (24%) were the most common causes of hypocalcemia in a study of 594 elderly general medicine inpatients.10 In a study of 62 hypocalcemic patients in a medical intensive care unit, the cause of the hypocalcemia could be determined in only 28 (45%); most of the cases were caused by hypomagnesemia (28%), renal insufficiency (8%), and pancreatitis (3%).11
TABLE
Causes of hypocalcemia by key test results
| TEST RESULTS | COMMON CAUSES | LESS COMMON CAUSES |
|---|---|---|
| High PTH, high phosphorus | Renal failure |
|
| High PTH, low phosphorus | Vitamin D deficiency (with low bone calcium) caused by:
|
|
| Low PTH, high phosphorus | Hypoparathyroidism and hypomagnesemia |
|
| PTH, parathyroid hormone. | ||
Serious causes of hypocalcemia
The usual cause of critically low serum calcium (<7 mg/dL “corrected” or <3.2 mg/dL ionized) is parathyroidectomy or acute renal failure. Hypocalcemia resulting from partial parathyroidectomy or thyroidectomy (with inadvertent parathyroidectomy) occurs in approximately 5% of these surgeries; 99.5% of cases resolve completely within a year.12
Recommendations
Several reviewers recommend a similar workup and differential diagnosis for hypocalcemia. Unfortunately, none cites quantitative data on the prevalence of hypocalcemia and its causes.2,13
Some authors recommend measuring 25-OH vitamin D in all hypocalcemia patients with elevated PTH without hyperphosphatemia to confirm vitamin D deficiency.1,2 Others emphasize the importance of measuring ionized calcium to detect hypocalcemia, especially in critically ill patients, in whom many acute variables can decrease ionized calcium (alkalosis can increase protein binding, for example).1,3,14
Although several reviewers present an algorithmic approach to determining the cause of hypocalcemia,3 we could find no data on the derivation or validation of the diagnostic effectiveness of these algorithms.
1. Fukugawa M, Kurokawa K. Calcium homeostasis and imbalance. Nephron. 2002;92(suppl 1):41-45.
2. Ruppe M. Hypocalcemia. In: American College of Physicians (ACP) Physician’s Information and Education Resource (PIER) database. Available at: http://pier.acponline.org/index.html. Accessed October 30, 2007.
3. Carlstedt F, Lind L. Hypocalcemic syndromes. Crit Care Clin. 2001;17:139, 53, vii-viii.
4. Centers for Disease Control and Prevention (CDC). Prevalence of chronic kidney disease and associated risk factors—United States, 1999-2004. MMWR Morb Mortal Wkly Rep. 2007;56:161-165.
5. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.
6. Rix M, Andreassen H, Eskildsen P, Langdahl B, Olgaard K. Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure. Kidney Int. 1999;56:1084-1093.
7. Thomas MK, Lloyd-Jones DM, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med. 1998;338:777-783.
8. Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D insufficiency among free-living healthy young adults. Am J Med. 2002;112:659-662.
9. Fardellone P, Sebert JL, Garabedian M, et al. Prevalence and biological consequences of vitamin D deficiency in elderly institutionalized subjects. Rev Rhum Engl Ed. 1995;62:576-581.
10. Hodkinson HM. Serum calcium in a geriatric inpatient population. Age Ageing. 1973;2:157-162.
11. Desai TK, Carlson RW, Geheb MA. Prevalence and clinical implications of hypocalcemia in acutely ill patients in a medical intensive care setting. Am J Med. 1988;84:209-214.
12. Pattou F, Combemale F, Fabre S, et al. Hypocalcemia following thyroid surgery: incidence and prediction of outcome. World J Surg. 1998;22:718-724.
13. Guise TA, Mundy GR. Clinical review 69: evaluation of hypocalcemia in children and adults. J Clin Endocrinol Metab. 1995;80:1473-1478.
14. Hastbacka J, Pettila V. Prevalence and predictive value of ionized hypocalcemia among critically ill patients. Acta Anaesthesiol Scand. 2003;47:1264-1269.
1. Fukugawa M, Kurokawa K. Calcium homeostasis and imbalance. Nephron. 2002;92(suppl 1):41-45.
2. Ruppe M. Hypocalcemia. In: American College of Physicians (ACP) Physician’s Information and Education Resource (PIER) database. Available at: http://pier.acponline.org/index.html. Accessed October 30, 2007.
3. Carlstedt F, Lind L. Hypocalcemic syndromes. Crit Care Clin. 2001;17:139, 53, vii-viii.
4. Centers for Disease Control and Prevention (CDC). Prevalence of chronic kidney disease and associated risk factors—United States, 1999-2004. MMWR Morb Mortal Wkly Rep. 2007;56:161-165.
5. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.
6. Rix M, Andreassen H, Eskildsen P, Langdahl B, Olgaard K. Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure. Kidney Int. 1999;56:1084-1093.
7. Thomas MK, Lloyd-Jones DM, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med. 1998;338:777-783.
8. Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D insufficiency among free-living healthy young adults. Am J Med. 2002;112:659-662.
9. Fardellone P, Sebert JL, Garabedian M, et al. Prevalence and biological consequences of vitamin D deficiency in elderly institutionalized subjects. Rev Rhum Engl Ed. 1995;62:576-581.
10. Hodkinson HM. Serum calcium in a geriatric inpatient population. Age Ageing. 1973;2:157-162.
11. Desai TK, Carlson RW, Geheb MA. Prevalence and clinical implications of hypocalcemia in acutely ill patients in a medical intensive care setting. Am J Med. 1988;84:209-214.
12. Pattou F, Combemale F, Fabre S, et al. Hypocalcemia following thyroid surgery: incidence and prediction of outcome. World J Surg. 1998;22:718-724.
13. Guise TA, Mundy GR. Clinical review 69: evaluation of hypocalcemia in children and adults. J Clin Endocrinol Metab. 1995;80:1473-1478.
14. Hastbacka J, Pettila V. Prevalence and predictive value of ionized hypocalcemia among critically ill patients. Acta Anaesthesiol Scand. 2003;47:1264-1269.
Evidence-based answers from the Family Physicians Inquiries Network