Summary
Extensive laboratory analysis in the anemic patient from the general population enables to establish an etiology diagnosis more often. We found that 22% of patients have multiple etiologies defining their anemia. Moreover, many combinations of etiologies of anemia are possible. This study also estimated that age, sex and anemia severity are related to several anemia etiologies.
Comparison with existing literature
We found that ACD, IDA and renal anemia were the most common etiologies of anemia among the studied population, which is in line with previous studies [3 – 6]. The etiology of the anemia was uncertain for 20% of patients, which proportion is much lower than the 26 – 44% reported in previous studies [3 – 6]. An explanation could be our inclusion of suspected bone marrow disease, hemoglobinopathy and suspected hemolysis as anemia etiologies, which was not done in previous studies [3 – 5]. Another explanation could be a lower incidence of uncertain anemia when a more regular extensive laboratory analysis is performed. This hypothesis is supported by a previous study in which only 8% of hospitalized anemia patients had an uncertain anemia etiology, most likely due to a more extensive laboratory analysis [9, 10]. Nevertheless, for most patients an anemia etiology can be diagnosed based on the laboratory tests results. This information is of great relevance for the general practitioners as it provides insight in the additional diagnostic work-up and prevents unnecessarily (hematology) referral.
To date, data on multiple etiologies of anemia has been scarce. In our study, a multiple etiology was found in 22% of patients from the general population. Especially vitamin B12 deficiency and folic acid deficiency were often part of a multiple anemia etiology. Therefore, extensive laboratory analysis might yield results that were not expected based on history and clinical presentation, but which may have treatment implications. Performing an extensive laboratory analysis in case of low hemoglobin concentrations is therefore recommended. This will reduce the number of missed causes of anemia and creates an optimal treatment framework. Furthermore, the laboratory protocol used for this study has shown to be effective at a minimal increase in costs [8]. In conclusion, an extensive laboratory analysis should be a standard first step during the diagnostic work-up of a newly diagnosed anemia patient, independently of the clinical presentation.
In this study, the distribution of anemia etiologies among specific patient characteristics showed a number of interesting trends. The peak of IDA etiology in the younger age group might be due to the arbitrary age cut-off of 50 years for inclusion. We offset this cut-off to exclude hypermenorrhea as predominant cause of IDA, but hypermenorrhea might still be present in some patients above 50 years. Furthermore, IDA is predominantly seen in patients with severe anemia, which might be explained by the more insidious course of anemia often seen in patients with IDA. As a consequence of the insidious course, the patient presents with symptoms at a later stage, resulting in a more severe anemia at moment of diagnosis. We also found that other etiologies presented more frequently with severe anemia. This finding highlights the relevance of additional tests (i.e. genetic screening or bone marrow biopsy) based on the clinical suspicion and family history. The mild anemia seen in patients with uncertain anemia etiology has been described in literature before [16]. Overall, Andres et al noted no correlation between the severity of anemia and its underlying cause. We were able to demonstrate significant associations, which might be due to our large cohort resulting in a more precision of observed point estimates [10]. Regarding associations with the patients’ sex, we observed a trend towards twice as many ACD etiologies among men compared with women. Previous studies showed a broad range in this ratio [3, 5]. The trend we observed might have resulted from the strict definition of ACD including ferritin > 100 µg/L. The median ferritin level in the women in our study was lower than that in men (table 2: 81 µg/L versus 157 µg/L, respectively). Therefore, women might be less likely to meet our definition of ACD.
Strengths and limitations
A major strength of our study design is that it permitted to establish the onset of anemia. This was achieved by excluding patients already known with anemia two years previously. Another strength is the large cohort, which increased the precision of observed point estimates. Eighty-one out of 151 GP practices registered at our laboratory system participated in the study. These 81 GP practices can be considered reflective of all 151 GP practices in the area of Dordrecht. Therefore, we assume that there are no considerable differences between the distribution of anemia etiology among participating and non-participating GP practices.
As a limitation of our study, we did not know the indications for blood analysis; these are not registered. We, therefore, could not match a patient’s clinical information with the results of the blood analysis. We used a laboratory-orientated uniform enforcement when defining the etiologies and acknowledge the limitation of the missing clinical information. Still, our approach means a solid step forward in the anemia diagnostic work-up and we encourage the use of clinical information during the diagnostic process. On top of that, we are aware of the fact that the gold standard for anemia etiology diagnosis would be a bone marrow biopsy. However, this examination would be non-ethical to apply on each patient and can’t be performed in general practice setting.
We are aware of the fact that the WHO uses slightly different cut-off values of hemoglobin for anemia and not all laboratories have the same reference values. However, we decided to maintain the reference values according to the participating laboratory. A limitation is a gap in the analysis of ferritin values between 20/25 – 100 µg/L and vitamin B12 levels between 130 – 200 pmol/L, which is a consequence of our strict definitions. In the current study design, it was not possible to add additional parameters such as serum transferrin receptor, methylmalonic acid and homocysteine as additional parameters for further interpretation. This might have resulted in an underestimation of IDA, ACD and vitamin B12 deficiencies.
Although we defined a standard extensive laboratory protocol to be performed in each patient, data were missing for a proportion of patients. We applied single imputation to avoid selection bias and thus could include data of all patients in the analysis.
Conclusions
In clinical practice, the extensive laboratory analysis during the diagnostic work-up of anemia patients seems to be valuable. Not only because more patients can be assigned an etiology, but also because the possible multiple aspect of etiologies can be effectively analyzed. Moreover, a patient’s age, sex and the severity of anemia may serve as markers that can guide the diagnostic work-up, resulting in a faster diagnosis and treatment initiation of the underling disease causing anemia.