Significance of measurement of corrected calcium in patients with normoalbuminemia.
The total calcium (TC) of serum or plasma is distributed as free calcium, calcium bound to proteins, and calcium bound to inorganic anion. About half of the calcium in serum is bound to serum proteins, particularly albumin. Changes in albumin concentration cause changes in TC without affecting the physiologically and clinically important ionized calcium fraction. [1,2] Correction of calcium is done using different formulas when albumin is below the reference range. While correction of TC in patients with low serum albumin is frequently practiced, there are no data available as to effect of physiological variation in albumin on serum calcium. The current study compares serum calcium and corrected calcium (CC) in patients with normal serum albumin.
About 80% of protein-bound calcium is associated with albumin, with the remaining 20% associated with globulins. Low total serum calcium (hypocalcemia) may be due to a reduction in albumin-bound calcium, the free fraction of calcium, or both. Hypoalbuminemia is the most common cause of apparent hypocalcemia on a standard biochemical profile, particularly in hospitalized patients, because 1 g/dl of albumin binds approximately 0.8 mg/dl of calcium. [1,3,4]
Adjusted or Corrected TC
Wide variation in the concentrations of compounds that bind calcium in blood will affect the measured TC concentration without changing the free calcium fraction. Several types of calculation have been suggested to "adjust" the measured calcium concentration. The goal is to produce a corrected result that would have been found if the concentrations of all compounds that bind calcium had been within their respective reference intervals. In practice, only adjustments based on albumin are used.
The following two equations are used for results expressed as mg/dl and mmol/L, respectively: 
CC mg/dl = TC mg/dl + 0.8 [4 - measured albumin g/dl]
CC mmol/L = TC mmol/L + 0.02 [40 - measured albumin g/L]
Apart from above equation various other formula are also used. [2,3]
CC (mg/dl) = Calcium (mg/dl) - albumin (g/dl) + 4
CC (mg/dl) = Calcium - (0.676 x total protein (g/dl)) + 4.87
CC = Calcium (mmol/L) - (0.25 x albumin (g/l)) + 1.0
MATERIALS AND METHODS
The study is performed at New Civil Hospital, Surat Laboratory Services, an NABL accredited laboratory. Eight hundred consecutive serum specimens received in the laboratory with a request for calcium estimation were analyzed for calcium and albumin in Erba XL 640 AutoAnalyzer by Arsenazo III method for calcium and bromocresol green in succinic acid buffer at pH 4.2 for albumin.
Specimens included in this study were from different wards and outpatient departments. No account was taken of age, sex, or provisional diagnosis. Quality was satisfactory during the study period and assured by the use of multirule quality control procedures at two levels.  From this eight hundred samples, samples with normal range of albumin (3.2-5.2 mg/dl) were selected for measurement of CC. CC concentrations were calculated by the following formula:
CC = 0.8(4 - serum albumin g/dl)+Total serum calcium mg/dl.
Sample containing albumin level <3.2 g/dl and >5.2 g/dl are not included in the study. Calcium reference range of 8.510.5 mg/dl is used.
For each sample, TC and CC were compared to find out which of the following condition is satisfied.
* TC and CC within reference range (concordance).
* TC and CC outside reference range (concordance).
* TC outside and CC inside reference range (discordance).
* TC inside and CC outside reference range (discordance).
Frequency and percentage of discordance were calculated for each calcium value between 8.5 and 10.5 (at 0.1 mg/dl interval).
Figure 1 shows % of discordance with relation to serum calcium.
There are two distinct peaks of discordance between 7.9 and 9.2 (n = 353) mg/dl and 10.3 and 10.7 (n = 7) mg/dl. The discordance is concentrated around lower and upper limit of reference ranged (i.e., 8.5 and 10.5). Overall there is 20% discordance rate between 7.9-9.2 mg/dl and 40% discordance at 10.3-10.7 mg/dl. However, number of samples analyzed at 10.3-10.7 mg/dl range is very low, compared to 7.9-9.2 mg/dl range.
The study shows that if TC of a patient is within reference range but CC is not (and vice versa), clinicians need to make clinical decision based on TC or CC. Such situation may arise when TC and serum albumin are at both ends of their referenced range.
For example, in one patient in the study with serum calcium 8.0 mg/dl and serum albumin level 3.3 g/dl, CC was 8.56 mg/dl. Thus, in this patient, clinician looking at TC will consider the serum calcium abnormal, but actually, the lower result is due to albumin near lower limit of reference. In this patient, CC is within reference range; indicating that the patient's calcium homeostasis is normal.
Similarly, in another patient with serum calcium level 8.8 mg/dl and serum albumin level 4.4 g/dl, CC was 8.35 mg/dl. In this patient, serum albumin at upper range of reference, lower calcium is masked by higher value of albumin-bound calcium.
Both examples show that discordance in calcium and CC level with normal albumin level in patient may be clinically significant to make management decision.
Payne et al.  studied CC in 189 patients. The study included both normal and abnormal albumin. Seventy-five patients had normal calcium, which became abnormal on adjustment of albumin.
Payne et al.  concluded that it is impossible to interpret a patient's serum calcium concentration without some measurement of protein concentration.
However, parent X  concluded that the clinically justified adjustment due to hypoalbuminemia should not be extended to other situations, particularly, when albumin is increased.
The high rate of discordance at 7.9-9.2 mg/dl and 10.3-10.7 mg/dl between TC and CC indicates that clinical interpretation of laboratory data by clinician will differ if only TC is reported versus both TC and CC are reported. The study also shows that discordance becomes more obvious on borderline of the reference range. The laboratory may choose to report CC even when patient albumin is with in reference range, thereby giving a clearer idea to clinician about how to interpret serum calcium reports in patients.
CC was done only by using single formula. The other equations based on different parameters (e.g. total protein) needs to be evaluated similarly. This is of importance because calcium in serum also binds other serum proteins. It is an ionized form of calcium, which gives truly idea about the status of calcium homeostasis. Measurement of ionized calcium can improve conclusions of the study.
There is discordance between total and CC even when patient albumin is within normal range. Such discordance may be of clinical significance and routine use of CC at all ranges of albumin is advised.
Access this article online
[1.] Carl AB, Edward RA, David EB. Bone and mineral metabolism. In: Risteli J, Kleerekoper M, Risteli L, editors. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 5th ed. New Delhi: Elsevier, A Division of Reed Elsevier India Private Limited; 2012. p. 1735-55.
[2.] Payne RB, Carver ME, Morgan DB. Interpretation of serum total calcium: Effects of adjustment for albumin concentration on frequency of abnormal values and on detection of change in the individual. J Clin Pathol. 1979; 32(1):56-60.
[3.] Payne RB, Little AJ, Williams RB, Milner JR. Interpretation of serum calcium in patients with abnormal serum proteins. Br Med J. 1973; 4(5893):643-6.
[4.] James MT, Zhang J, Lyon AW, Hemmelgarn BR. Derivation and internal validation of an equation for albumin-adjusted calcium. BMC Clin Pathol. 2008; 8:12.
[5.] Westgard JO, Barry PL, Hunt MR, Groth T. A multi-rule Shewhart chart for quality control in clinical chemistry. Clin Chem. 1981; 27(3):493-501.
[6.] Parent X, Spielmann C, Hanser AM. Corrected calcium: Calcium status underestimation in non-hypoalbuminemic patients and in hypercalcemic patients. Ann Biol Clin (Paris). 2009; 67(4):411-8.
Source of Support: Nil, Conflict of Interest: None declared.
Dipti S Karbhari, Nilam S Karbhari, Shailesh Patel
Department of Biochemistry, Government Medical College, Surat, Gujarat, India Correspondence to: Dipti S Karbhari, E-mail: email@example.com
Received: January 11, 2017; Accepted: February 15, 2017
Caption: Figure 1: Relation of total serum calcium versus percentage of discordance
|Printer friendly Cite/link Email Feedback|
|Title Annotation:||Research Article|
|Author:||Karbhari, Dipti S.; Karbhari, Nilam S.; Patel, Shailesh|
|Publication:||International Journal of Medical Science and Public Health|
|Date:||Jun 1, 2017|
|Previous Article:||A comparative study of cytomorphological subtypes of Schneiderian papilloma.|
|Next Article:||Tobacco and alcohol use in elderly population of rural India.|