Reticulocyte Hemoglobin Content As a Diagnostic Tool for Myelodysplastic Syndrome: Findings from a 20-Year Retrospective Study
Authors: Khan Muhammad Haseeb , Malik Uzair Ahmad , Niaz Nimra , Thalody Vimala , Mehdi Syed , Pasquale Donald 
Published: December 2024

Introduction:
Myelodysplastic syndromes (MDS) are a group of hematological malignancies primarily characterized by abnormal cellular maturation, clonal hematopoiesis, and cytopenia (i.e., anemia, neutropenia, and/or thrombocytopenia). Approximately one-third of MDS cases can progress and transform into acute myeloid leukemia (AML), a group of aggressive blood cancers, and therefore early identification of MDS is crucial. Presently, to diagnose MDS, the gold standard procedure is a bone marrow biopsy to obtain a tissue sample; however, these procedures are invasive, painful, and pose the risk of bleeding and infections. There is no literature available on the role of reticulocyte hemoglobin content (CHr) as a screening/diagnostic tool in the work-up of suspected MDS. Anecdotally, we had observed elevated CHr levels in a number of our patients with MDS and had not noted elevated levels in patients without MDS. If a strong correlation could be proven, this research would establish the sensitivity and specificity of CHr and would allow for more timely diagnosis and management of MDS, prior to transformation into malignant AML.
Methods:
We looked at 130 patients who either had a diagnosis of MDS or who had a workup done for any condition that included a reticulocyte panel at the Stratton VA Medical Center from January 2003 to December 2022. Six patients were excluded as five of them were positive for MDS but never had a reticulocyte panel performed at our hospital, and one was being followed outside the VA, so none of the records were available to us. The results of the rest were recorded in a 2x2 table, and analysis was done using the Wilson score method to calculate confidence intervals.
Results:
We collected data from a total of 124 patients: 27 diagnosed with MDS (17 with high CHr, 10 with normal CHr) and 97 without MDS (87 with normal CHr, 10 with high CHr). The sensitivity of high CHr for diagnosing MDS was 62.96% (95% CI: 44.23% to 78.47%), and the specificity was 89.69% (95% CI: 82.05% to 94.30%). The Positive Predictive Value (PPV) was 62.96% (95% CI: 44.23% to 78.47%), and the Negative Predictive Value (NPV) was 89.69% (95% CI: 82.05% to 94.30%).
Out of the 10 patients with high CHr but no MDS diagnosis, several had significant comorbidities complicating their diagnosis, including chronic iron deficiency anemia, deep vein thrombosis (DVT), hereditary hemochromatosis, metastatic castrate-resistant prostate cancer, and multiple cerebrovascular accidents (CVAs). One patient with biopsy-confirmed MDS had consistently low to normal CHr levels. After excluding those who could not undergo a biopsy or complete the MDS workup due to other health conditions, the refined analysis included 118 patients: 27 with MDS (17 with high CHr, 10 with normal levels) and 91 without MDS (87 with normal CHr, 4 with high levels). The recalculated sensitivity remained at 62.96% (95% CI: 44.23% to 78.47%), but the specificity increased significantly to 95.60% (95% CI: 89.24% to 98.28%). The PPV was 80.95% (95% CI: 60.00% to 92.33%), and the NPV was 89.69% (95% CI: 82.05% to 94.30%).
Discussion:
Presently, there are no known laboratory markers that can screen for MDS. One theoretical explanation for high CHr in MDS is that the ineffective erythropoiesis can lead to suppression of hepcidin, which results in inappropriate reabsorption of iron throughout the body and a state of iron overload. Serum iron, ferritin, and transferrin saturation are routinely used to estimate a patient's iron levels; however, serum iron is variable, and ferritin is an acute phase reactant and therefore can have great variations secondary to external factors such as acute illness and physiological stress. The CHr is a useful measure of the body's iron content in real-time as the reticulocyte lifespan is two to three days. CHr is used in the evaluation of iron content to assess iron deficiency anemia; however, our findings suggest that elevated CHr (with its very high specificity) could be a valuable diagnostic tool for MDS, particularly in patients with complicating health conditions.
Conclusion: These preliminary results indicate that the Reticulocyte Hemoglobin content has moderate sensitivity and very high specificity for diagnosing Myelodysplastic Syndrome (MDS) in the veteran population at our hospital. Further analysis and a larger sample size may help refine these findings and improve the diagnostic accuracy.