The principal considerations driving iron status evaluation are clinical concern for anemia and the possibility of iron-storage disease. Most often, the circulating levels of transferrin (or total iron binding capacity) and serum iron are measured and the percentage of transferrin saturation (TSAT) is then computed. Optimally, reference ranges for these analytes should exclude the effects of the acute phase response, nutritional status, estrogen effect, specific genetic disorders, liver disease, and blood transfusion. The current study reports reference ranges for serum iron and TSAT within a cohort of over 55,000 Caucasians from northern New England, tested in our laboratory between 1994 and 1999. Measurements were standardized against serum reference material (SRM) 937 (for iron) and certified reference material (CRM) 470 (also called reference preparation for proteins in human serum (RPPHS)) (for transferrin), and analyzed using a previously published approach. Individual cases with evidence of inflammation (C-reactive protein > or =10 mg/L), or iron overload (TSAT >80% for males and >70% for females) or serum iron values <5 micro mol/L, were removed. Among the referent individuals, iron and TSAT levels rose slightly until the teen years, at which time levels in males increased while those in females remained essentially constant. Between 20 and 70 years of age, males had 10-15% higher iron levels and 15-20% higher TSAT levels than females. When values were expressed as multiples of the age- and gender-specific median levels, the serum iron and TSAT observations fit log-Gaussian distributions reasonably well from the 20th to 99th centile, and the 10th to the 99th centile, respectively. After normalization, the Gaussian parameters can be used to assign a corresponding centile to an individual's measurement, simplifying interpretation. These data provide new and more detailed reference ranges for serum iron and TSAT.
The two serum proteins of the complement cascade in the highest concentrations, C3 and C4, respond to various conditions in much the same manner as do other positive acute-phase proteins. A major difference is that they are relatively sluggish in response to cytokine drive, requiring several days rather than hours to be detectably elevated by serial measurements. As with other acute-phase proteins, there are many processes that up- or down-regulate synthesis, including infection or inflammation, hepatic failure, and immune-complex formation. Clinicians may find it difficult to distinguish among these processes, because they often occur simultaneously. The situation is further complicated by genetic polymorphism, with rare instances of markedly reduced synthesis and circulating levels, and consequent vulnerability to infection. C3 and C4 are measured for clinical purposes to help define certain rheumatic and immunologically mediated renal diseases. Interpreting the measured blood levels of these two components requires one to consider the intensity of the inflammatory drive, the timing of the suspected clinical process, the production of complement-consuming immune complexes, and the possible existence of benign circumstances. In this fifth article in a series, reference ranges for serum levels of two complement proteins (C3 and C4) are examined. The study is based on a cohort of over 55,000 Caucasian individuals from northern New England, who were tested in our laboratory in 1994-1999. Measurements were standardized against certified reference material (CRM) 470/reference preparation for proteins in human serum (RPPHS), and analyzed using a previously described statistical approach. Individuals with unequivocal laboratory evidence of inflammation (C-reactive protein of 10 mg/L or higher) were excluded. Our results show that the levels of C3 and C4 change little during life and between the sexes, except that they increase slightly and then fall after age 20 in males and at about age 45 in females. When values were expressed as multiples of the age- and gender-specific median levels, the resulting distributions fitted a log-Gaussian distribution well over a broad range. When patient data are normalized in this manner, the distribution parameters can be used to assign a centile corresponding to an individual's measurement, thus simplifying interpretation.
Quality-control surveys in recent years, in various parts of the world, have shown poor between-laboratory agreement for measurements of plasma proteins. Despite the existence of international reference materials distributed by the World Health Organization, standards produced by diagnostics manufacturers and professional organizations differ significantly in their ascribed values. The reasons for this are complex but include poor availability of the primary materials, confusion about their use, and the fact that their turbidity on reconstitution precludes their use in modern optical immunoassays. This unfortunate situation led to an important initiative to produce sufficient quantities of a widely available, optically clear secondary reference material for plasma proteins that could be used worldwide by manufacturers, professional organizations, and laboratories. Here we present an overview on how the laboratory community, including manufacturers, clinical laboratories, professional societies, and regulators, has reached what we consider is a successful conclusion to a difficult problem.
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