Qual cálcio é correto pedir? Cálcio Total ou Cálcio iônico??

Mais de uma vez ouvi a discussão: Qual Cálcio pedir? Iônico ou total? Lembrei de um texto muito bom do UpToDate sobre essa relação que vou reproduzir abaixo.

Além da necessidade de corrigir o cálcio total pela albumina, há várias outras particularidades. Qualquer um dos dois pode variar sem mudar o outro. Na verdade, em algumas situações, é interessante pedir os dois. Não existe um correto e o outro errado, mas uma relação entre eles. Mas vale lembrar: o que exerce os efeitos biológicos é o iônico!

Particularmente nos renais crônicos, o cálcio iônico é preferido, conforme texto abaixo.

Segue o texto. Quem quiser o texto abaixo em PDF, clique aqui.

INTRODUCTION — The plasma (or serum) calcium concentration measured in the laboratory is usually reported in units of mg/dL in the United States, in mmol/L in many other countries, and in meq/L in some laboratories. The relationship between these units is defined by the following equations:

mmol/L = [mg/dL x 10] ÷ mol wt

meq/L = mmol/L x valence

Since the molecular weight of calcium is 40 and the valence is +2, 1 mg/dL is equivalent to 0.25 mmol/L and to 0.5 meq/L. Thus, the normal range of total serum calcium concentration of 8.8 to 10.3 mg/dL is equivalent to 2.2 to 2.6 mmol/L and 4.4 to 5.2 meq/L.

DETERMINANTS OF THE SERUM CALCIUM CONCENTRATION — The total serum calcium concentration consists of three fractions [1,2]:

• Approximately 15 percent is bound to multiple organic and inorganic anions such as sulfate, phosphate, lactate, and citrate.
• Approximately 40 percent is bound to albumin in a ratio of 0.8 mg/dL (0.2 mmol/L or 0.4 meq/L) of calcium per 1.0 g/dL (10 g/L) of albumin.
• The remaining 45 percent circulates as physiologically active ionized (or free) calcium. The ionized serum calcium concentration is tightly regulated by parathyroid hormone and vitamin D, and can be modified by a variety of factors. (See 'Change in ionized fraction but not total calcium' below.)

The wide range in the normal total serum calcium concentration is probably due to variations in the serum concentration of albumin among normal healthy individuals and occasionally to variations in the state of hydration that can alter the serum albumin concentration.

Thus, measurement of the total serum calcium concentration alone is sometimes misleading, since this parameter can change without affecting the concentration of ionized calcium [3]. In addition, the ionized fraction can change without an alteration in the total serum calcium concentration.

Change in total but not ionized calcium — An abnormal total serum calcium concentration in the absence of an abnormal ionized calcium concentration can occur in patients with hypoalbuminemia, hyperalbuminemia, and multiple myeloma. If the total serum calcium is low but the ionized calcium is normal, it is called pseudohypocalcemia. If the total serum calcium is high in the setting of a normal ionized calcium, it is called pseudohypercalcemia.

Hypoalbuminemia — The total serum calcium concentration will change in parallel to the albumin concentration. Thus, hypoalbuminemia due to hepatic or renal disease is associated with hypocalcemia. In comparison, globulins only minimally bind calcium and changes in the globulin level are usually not associated with changes in the calcium concentration with the occasional exception of marked hyperglobulinemia in multiple myeloma.

In general, the serum calcium concentration falls by 0.8 mg/dL (0.2 mmol/L) for every 1.0 g/dL (10 g/L) fall in the serum albumin concentration. Thus, the measured serum calcium concentration can be corrected for the presence of hypoalbuminemia from the following equation:

Corrected [Ca] = Measured total [Ca] + (0.8 x (4.5 - [alb]))

where the serum calcium and albumin concentrations are measured in units of mg/dL and g/dL, respectively. As an example, if the measured values for total serum calcium and albumin are 7.6 mg/dL and 2.5 g/dL, respectively, then:

Corrected [Ca] = 7.6 + (0.8 x 2) = 9.2 mg/dL

Hyperalbuminemia — An elevation in serum albumin, leading to a rise in serum calcium, can be induced by extracellular volume depletion or by fluid movement out of the vascular space due, for example, to a tight tourniquet [4]. Hyperalbuminemia has also been reported in athletes who consume very high protein diets (more than 2 g of protein per kg of body weight per day) [5]. 

Multiple myeloma — Myeloma can induce pseudohypercalcemia by a mechanism other than hyperalbuminemia. Rarely, a monoclonal myeloma protein binds calcium with high affinity, potentially leading to a marked elevation in the total serum calcium concentration [6-8]. The absence of hypercalcemic symptoms is the major clue suggesting that the ionized fraction is normal in this setting and that therapy aimed at correcting the hypercalcemia is not indicated.

The hyperproteinemia in myeloma can also cause a spurious elevation in the serum phosphate concentration [9]. The mechanism is uncertain but may involve interference with the normal assay used to measure to serum phosphate concentration.

Change in ionized fraction but not total calcium — Physiologically important changes in the ionized calcium concentration may occur without an alteration in the total serum calcium concentration.

Acid-base disorders — Acid-base disorders can lead to changes in the ionized calcium concentration. An elevation in extracellular pH (alkalemia) increases the binding of calcium to albumin, thereby lowering the serum ionized calcium concentration [10]. The fall in ionized calcium with acute respiratory alkalosis is approximately 0.16 mg/dL (0.04 mmol/L or 0.08 meq/L) for each 0.1 unit increase in pH [10]. Thus, acute respiratory alkalosis, as in the hyperventilation syndrome, can induce symptoms of hypocalcemia, including cramps, paresthesias, tetany, and seizures although the alkalosis is likely to be of primary importance. The same relationship is true in vitro when the pH is changed in specimens of whole blood or serum [11].

There is also a significant fall in the ionized calcium concentration in chronic respiratory alkalosis. However, the fall in ionized calcium in this setting is not due to increased calcium binding, since the renal adaptation lowers the serum bicarbonate concentration and minimizes the rise in extracellular pH. The hypocalcemia in this setting is due both to relative hypoparathyroidism and to renal resistance to PTH, with resultant hypercalciuria [12]. Why these changes occur is not well understood. (See "Simple and mixed acid-base disorders”.)

In chronic metabolic acidosis, the increase in ionized calcium due to less albumin binding may not be recognized by measurement of total calcium concentrations [13,14]. In one study, for example, the total serum calcium underestimated the diagnosis of hypercalcemia in incident renal transplant recipients [14]. This was explained primarily by the high prevalence of metabolic acidosis in these patients.

The binding of calcium to albumin that is induced by an elevation in extracellular pH may be important in patients with severe chronic kidney disease who often have both hypocalcemia and metabolic acidosis, which will tend to raise the ionized calcium concentration. Treatment of the metabolic acidosis with bicarbonate therapy or dialysis can lower the ionized calcium concentration [15,16], which may exacerbate preexisting hypocalcemia and precipitate symptoms such as tetany [16].

Parathyroid hormone — Parathyroid hormone (PTH) may decrease the binding of calcium to albumin and therefore increase ionized calcium at the expense of the protein-bound fraction, resulting in an increased ratio of ionized to total calcium in patients with elevated levels of PTH [17]. On the other hand, the sensitivities of ionized and total calcium concentrations in the diagnosis of primary hyperparathyroidism were identical in a large cohort of patients [18], suggesting that this effect of PTH on protein binding of calcium does not have diagnostic implications. (See "Diagnosis and differential diagnosis of primary hyperparathyroidism", section on 'Normocalcemic primary hyperparathyroidism'.)

Hyperphosphatemia — Acute hyperphosphatemia (as with phosphate release from cells due to a marked increase in cell breakdown) can reduce the ionized serum calcium concentration by binding to circulating calcium. The total serum calcium concentration will also fall in a short period of time as the calcium-phosphate precipitates and is deposited in soft tissues. (See "Etiology of hypocalcemia in adults".)

MEASURING THE SERUM CALCIUM IN PATIENTS WITH CKD — In patients with a reduced glomerular filtration rate (GFR less than 60 mL/min per 1.73m2), the total serum calcium concentration does not reliably predict the ionized calcium concentration, even if the total serum calcium is corrected for a low serum albumin [13,14]. This was best shown in 691 consecutive patients with CKD who had simultaneous measurement of total serum calcium, ionized calcium, and serum albumin [13]. The total serum calcium failed to identify 44 of the 109 (40 percent) patients who had low ionized calcium levels, and also failed to identify 6 of the 28 (21 percent) patients who had a high ionized calcium. In addition, 11 percent of patients with normal ionized calcium concentrations were mistakenly identified as having either hypocalcemia or hypercalcemia by using the total serum calcium. Correcting the total calcium for the serum albumin did not substantially improve the reliability of the total serum calcium.

Two major factors contributed to the unreliability of the total serum calcium [13]:

Patients with CKD often have metabolic acidosis, which can lead to an underestimate of the ionized calcium concentration when only the total serum calcium is measured. (See 'Acid-base disorders' above.)

The standard equations used to correct for a low serum albumin frequently overestimated the ionized calcium.

Thus, in patients with reduced GFR who have a low serum bicarbonate and/or a low serum albumin, measuring the ionized calcium is preferable to measuring the total calcium in order to diagnose hypocalcemia or hypercalcemia.

SUMMARY

• The total serum calcium concentration consists of three fractions: (See 'Determinants of the serum calcium concentration' above.)
• 15 percent is bound to organic and inorganic anions.
• 40 percent is bound to albumin.
• 45 percent is physiologically active ionized (or free) calcium.
• Measurement of the total serum calcium concentration alone is sometimes misleading, since this parameter can change without affecting the concentration of ionized calcium, such as with:
• Hypoalbuminemia, because a large fraction of calcium circulates bound to albumin. The total serum calcium can be adjusted for the concentration of albumin using the following equation: (See 'Hypoalbuminemia' above.)
• Corrected [Ca] = Measured total [Ca] + (0.8 x (4.5 - [alb]))
• Hyperalbuminemia, as may occur with extracellular volume depletion or by fluid movement out of the vascular space due to a tight tourniquet, and can also result from a very high protein diet.
• Some cases of multiple myeloma, in which calcium binds to the monoclonal immunoglobulin. (See 'Multiple myeloma' above.)
• The ionized fraction can change without an alteration in the total serum calcium concentration, as with:
• Acid-base disorders, in which an increase in blood pH may enhance binding of calcium to albumin, thereby decreasing the ionized fraction. (See 'Acid-base disorders' above.)
• Hyperparathyroidism, which increases the ionized calcium at the expense of that bound to albumin. (See 'Parathyroid hormone' above.)
• Hyperphosphatemia, which increases the fraction bound to inorganic anions, decreasing ionized calcium. (See 'Hyperphosphatemia' above.)
• In patients who have CKD and a low serum bicarbonate, a low serum albumin, or both, measuring the ionized calcium is preferable to measuring the total calcium in order to diagnose hypocalcemia or hypercalcemia. (See 'Measuring the serum calcium in patients with CKD' above.)

REFERENCES

1. Moore EW. Ionized calcium in normal serum, ultrafiltrates, and whole blood determined by ion-exchange electrodes. J Clin Invest 1970; 49:318.
2. Bushinsky DA, Monk RD. Electrolyte quintet: Calcium. Lancet 1998; 352:306.
3. Ladenson JH, Lewis JW, Boyd JC. Failure of total calcium corrected for protein, albumin, and pH to correctly assess free calcium status. J Clin Endocrinol Metab 1978; 46:986.
4. DENT CE. Some problems of hyperparathyroidism. Br Med J 1962; 2:1419.
5. Mutlu EA, Keshavarzian A, Mutlu GM. Hyperalbuminemia and elevated transaminases associated with high-protein diet. Scand J Gastroenterol 2006; 41:759.
6. Lindgärde F, Zettervall O. Hypercalcemia and normal ionized serum calcium in a case of myelomatosis. Ann Intern Med 1973; 78:396.
7. Merlini G, Fitzpatrick LA, Siris ES, et al. A human myeloma immunoglobulin G binding four moles of calcium associated with asymptomatic hypercalcemia. J Clin Immunol 1984; 4:185.
8. Pearce CJ, Hine TJ, Peek K. Hypercalcaemia due to calcium binding by a polymeric IgA kappa-paraprotein. Ann Clin Biochem 1991; 28 ( Pt 3):229.
9. McCloskey EV, Galloway J, Morgan MA, Kanis JA. Pseudohyperphosphataemia in multiple myeloma. BMJ 1989; 299:1381.
10. Oberleithner H, Greger R, Lang F. The effect of respiratory and metabolic acid-base changes on ionized calcium concentration: in vivo and in vitro experiments in man and rat. Eur J Clin Invest 1982; 12:451.
11. Wang S, McDonnell EH, Sedor FA, Toffaletti JG. pH effects on measurements of ionized calcium and ionized magnesium in blood. Arch Pathol Lab Med 2002; 126:947.
12. Krapf R, Jaeger P, Hulter HN. Chronic respiratory alkalosis induces renal PTH-resistance, hyperphosphatemia and hypocalcemia in humans. Kidney Int 1992; 42:727.
13. Gauci C, Moranne O, Fouqueray B, et al. Pitfalls of measuring total blood calcium in patients with CKD. J Am Soc Nephrol 2008; 19:1592.
14. Evenepoel P, Bammens B, Claes K, et al. Measuring total blood calcium displays a low sensitivity for the diagnosis of hypercalcemia in incident renal transplant recipients. Clin J Am Soc Nephrol 2010; 5:2085.
15. Movilli E, Zani R, Carli O, et al. Direct effect of the correction of acidosis on plasma parathyroid hormone concentrations, calcium and phosphate in hemodialysis patients: a prospective study. Nephron 2001; 87:257.
16. Kaye M, Somerville PJ, Lowe G, et al. Hypocalcemic tetany and metabolic alkalosis in a dialysis patient: an unusual event. Am J Kidney Dis 1997; 30:440.
17. Ladenson JH, Lewis JW, McDonald JM, et al. Relationship of free and total calcium in hypercalcemic conditions. J Clin Endocrinol Metab 1979; 48:393.
18. Nordenström E, Katzman P, Bergenfelz A. Biochemical diagnosis of primary hyperparathyroidism: Analysis of the sensitivity of total and ionized calcium in combination with PTH. Clin Biochem 2011; 44:849.