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What is the best workup for hypocalcemua?

Evidence-based answer

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.

Clinical commentary

Important supporting tests--serum albumin, phosphorus, magnesium

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 multi-test blood panels and must be ordered when hypocalcemia is found.

Grant Hoekzema, MD

Mercy Family Medicine Residency, St. Louis, Mo

* 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.l.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)

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.

FAST TRACK

The most important supporting test is serum albumin, which can show whether the patient truly has hypocalcemia

Because serum calcium comprises less than 1% of body stores, severe total body calcium deficiency can exist without hypocalcemia

The most common causes of hypocalcemia:

* renal failure

* vitamin D deficiency

* hypomagnesemia

* pancreatitis

* hypoparathyroidism

References

(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 ME 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;22:718724.

(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.

Michele Bosworth, MD, and David Mouw, MD

Mountain Area Health Education

Center, Asheville, NC

Deborah C. Skolnik, MLS

Mountain Area Health Education

Center, Asheville, NC
TABLE
Causes of hypocalcemia by key test results

High PTH,    Renal failure               * Pseudohypoparathyroidism
high                                     (unresponsiveness to PTH)

phosphorus                               * Other hyperphosphatemic
                                         states (eg, rhabdomyolysis
                                         or massive tumor lysis)

High PTH,    Vitamin D deficiency        * Blood transfusions (citrate)
low          (with low bone
phosphorus   calcium) caused by:         * Bisphosphonates

             * inadequate diet           * End organ unresponsiveness
             or lack of sunlight         to vitamin D

             * gastrointestinal          * Congenital absence
               malabsorption,            of renal vitamin D
               including drug-induced    hydroxylase
               malabsorption
               (cholestyramine)

             * hepatobiliary disease
               and hepatic drug
               metabolism

             * pancreatitis

Low PTH,     Hypoparathyroidism          * Thyroid and parathyroid
high         and hypomagnesemia          surgery
phosphorus
                                         * Autoimmune disorder
                                         (polyglandular syndrome)

                                         * Hypothyroidism

                                         * Damage to parathyroid gland
                                         from invasion or infiltration
                                         (eg, tumor) or radiation

                                         * Inherited hypoparathyroidism

PTH, parathyroid hormone.
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Title Annotation:CLINICAL INQUIRIES: Evidence Based Answers from the Family Physicians Inquiries Network
Author:Bosworth, Michele; Skolnik, Deborah C.
Publication:Journal of Family Practice
Geographic Code:1USA
Date:Oct 1, 2008
Words:1375
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