Albumin calcium-binding

Low total serum calcium (hypocalcemia) may be due to either a reduction in the albumin-bound calcium, the free firaction of calcium, or both (Box 49-Hypoalbu-minemia is the most common cause of pseudohypocalcemia (decreased total and norma free calcium) because 1 g/dL of albumin binds approximately 0.8 mg/dL of calcium. Common clinical conditions associated with low serum... 

Extracellularly, calcium ions circulate in the blood plasma and interstitial fluid (Sect. 3.3.1). In blood plasma, calcium ions are chelated to albumin and citrate. Albumin (mol. wt. 66,700 kDa) is present at 50-60 mg/mL in plasma, corresponding to 0.9 m mol/L. Although plasma albumin has many different sites that can chelate calcium ions in vitro, only one site binds to calcium ions at physiological albumin concentrations and pH. Thus, albumin binds 0.9 mmol/L of free plasma Ca2+. In addition, citrate (Fig. 10.7), a tricarboxylic acid that the liver secretes into plasma, chelates a free calcium ion to two of its three carboxyl groups, replacing two Na+ ions. Citrate has a molar concentration of 0.08 mM in venous blood and therefore binds to an equivalent concentration of free calcium. Because the total calcium ion concentration of venous blood is 1.14 mmol/L (range 0.2), and the free calcium ion concentration is 0.1 mM, it appears that 0.15 mM of the plasma calcium ion concentration is bound to other plasma components. 

A healthy person has a total scrum calcium of around 2.4 mmol/1. About half is bound to protein, mostly to albumin. Binding is pH dependent and is decreased in acidosis, because the amino acid side chains on albumin become more positively charged. Conversely, binding is increased if an alkalosis is present. Hence, the percentage unbound calcium increa.ses in acidosis and decreases if there is an alkalosis. 

Bone chemistry Calcium Albumin Phosphate Alkaline phosphatase Serum or plasma mmoll gi- Mmol ui- Yes No Bone metabolism Correct for Ca + protein binding Bone metabolism Bone building cell activity... 

Calcium Albumin Walser(1961) Calcium binding protein Huang et al. (1975)... 

Another important function of albumin is its ability to bind various ligands. These include free fatty acids (FFA), calcium, certain steroid hormones, bilirubin, and some of the plasma tryptophan. In addition, albumin appears to play an important role in transport of copper in the human body (see below). A vatiety of drugs, including sulfonamides, penicilhn G, dicumarol, and aspirin, are bound to albumin this finding has important pharmacologic implications. 

More than 99% of total body calcium is found in bone the remaining less than 1% is in the ECF and ICE Calcium plays a critical role in the transmission of nerve impulses, skeletal muscle contraction, myocardial contractions, maintenance of normal cellular permeability, and the formation of bones and teeth. There is a reciprocal relationship between the serum calcium concentration (normally 8.6 to 10.2 mg/dL [2.15 to 2.55 mmol/L]) and the serum phosphate concentration that is regulated by a complex interaction between parathyroid hormone, vitamin D, and calcitonin. About one-half of the serum calcium is bound to plasma proteins the other half is free ionized calcium. Given that the serum calcium has significant protein binding, the serum calcium concentration must be corrected in patients who have low albumin concentrations (the major serum protein). The most commonly used formula adds 0.8 mg/dL (0.2 mmol/L) of calcium for each gram of albumin deficiency as follows ... 

A similar approach for detecting the presence of specific proteins has also been reported by Nilsson and coworkers [26]. In this study, a complex between a calmodulin, a small calcium-binding protein, and the zwitter-ionic polythiophene POWT was used to detect the presence of calcineurin. The interaction between the POWT-camodulin complex and calcineurin changed the emission profile from POWT, and no observable changes were observed upon exposure of the complex human serum albumin, suggesting that the complex could be used for the specific detection of calcineurin. 

Figure 5.26 pH dependence of calcium binding to plasma albumin... 

C. Lead can substitute for calcium in the bone crystal lattice, resulting in bone brittleness. Bone may become a reservoir for other substances as well. Several drugs, such as chlorpromazine, may accumulate in the eye. Drugs with extremely high Upid-water partition coefficients tend to accumulate in fat, while basic amines tend to accumulate in the lungs. Many agents bind avidly to albumin in the blood. 

Hypoproteinemia may result in low levels of serum calcium, ceruloplasmin, and transferrin. Because losses of iron are at most 0.5-1.0 mg/24 hr, even with the heaviest proteinuria, other factors must operate to produce iron deficiency and microcytic hypochromic anemia. Although the copper-binding protein ceruloplasmin is lost in the urine in nephrotic subjects and its plasma levels are low, plasma and red cell copper concentrations are usually normal. Zinc circulates mainly bound to albumin and also to transferrin, and thus the reported reduction zinc concentration in plasma, hair, and white cells in nephrotic patients is not surprising. 

Albumin also acts as a transport medium for a variety of substances. It is the principal, if not the only, means of transport for free bilirubin (breakdown product of heme) and free fatty acids. It also binds calcium ions, hematin, steroids, thyroxine, and various drugs and dyes. 

The Isolated, vascularly perfused rat intestine system has been used to investigate the influence of various zinc-binding ligands on zinc absorption. With this approach the functional integrity of the intestine with respect to several minerals, including calcium, iron and zinc uptake, and subsequent transfer of these minerals to their respective serum transport proteins is maintained (32,33). The intestinal perfusion system allows the simultaneous measurement of both mucosal zinc uptake (retention) and transfer to the portal circulation (absorption), and thus provides detailed information on the nature of the mechanisms of both uptake from the lumen and transfer to albumin in the portal circulation. 

About 40% of serum calcium is protein bound, with most of it 80%) being bound to albumin. Generally, one or two calcium ions are associated with serum albumin. Albumin serves as a calcium buffer. Jt can bind more calcium ions when excessive concentrations of calcium appear in the bloodstream. About 13% of the calcium in scrum is weakly complexed with phosphate, citrate, and sulfate. About half (47%) of serum calcium occurs as the free calcium ion. The level of free scrum Ca is maintained within narrow limits, 1.0 to 1.25 mM (40 to 50 pg/mJ). The normal concentration of total serum calcium (bound plus free) is 85 to 105 pg/ml. Conditions in which the level of free serum calcium fails below and rises above the normal range are called hypocalcemia and hypercalcemia, respectively. The term ionized calcium is often used to refer to the concentrations of free calcium. This term is not scientifically accurate, because all of the calcium in the body is ionized. Calcium does not engage in the formation of covalent bonds (Cotton and Wilkinson, 1966). 

It has been postulated that cardiac pump function can be reduced by binding of free calcium to albumin (6). 

Figure 6-2 Bioactivation of the calcium channel opener maxipost in rat and human to a reactive quinone-methide, which covalently binds to albumin in vivo.

If the increase in pH is great enough, increased neuromuscular activity may be seen, and above pH 7.55, tetany may develop even in the presence of a normal serum total calcium concentration. The cause of the tetany is a decreased concentration of ionized calcium due to increased binding of calcium ions by protein (mainly albumin) and other anions. Measurement of CL status can be helpful, as causes of metabolic alkalosis fall into Cfr responsive, CL resistant, and exogenous base categories (Box 46-1 see also Figure 46-4). 

The binding of calcium by protein and small anions is influenced by pH in vitro and in vivo. Albumin, with up to 30 binding sites for calcium,accounts for approximately 80% of the protein-bound calcium. Increasing the pH of a specimen in vitro increases the ionization and negative charge on albumin and other proteins, leading to an increase... 

Free calcium has proved to be more useful than total calcium in the diagnosis of hypercalcemia. Patients with subsequently surgically proven primary hyperparathyroidism more often have increases of free calcium than of total calcium (Figure 49-7). Free calcium is more sensitive than total calcium in detecting hypercalcemia associated with malignancy, as may be expected in patients who frequently have decreased serum albumin. Less commonly, paraproteins produced in myeloma may bind calcium, complicating the interpretation of total or corrected calcium measurements. 

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