Higher hypochromic red cell concentration predicts mortality in systemic sclerosis
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Key findings:
- Concentration of hypochromic red cells may serve as a prognostic biomarker for patients with systemic sclerosis.
- Hypochromic red cell concentrations greater than 2% may indicate worse survival outcomes.
A hypochromic red cells concentration of more than 2% is an independent predictor of mortality in patients with systemic sclerosis, according to data published in Arthritis Research & Therapy.
“The percentage of hypochromic erythrocytes or red cells (% HRC) was shown to be one of the most reliable markers for early identification of functional [iron deficiency (ID)], as it reflects the iron status of the previous three months,” Panagiota Xanthouli, MD, of the Center for Pulmonary Hypertension at Heidelberg University Hospital, in Germany, and colleagues wrote.
“It was successfully used for the observation of functional ID in rheumatoid arthritis and for monitoring of therapeutic response to iron supplementation in advanced chronic kidney disease,” they added. “Furthermore, previous data indicate that HRC > 2% could be relevant for the prognosis of patients with pulmonary arterial hypertension (PAH).”
To investigate the connection between hypochromic red cell concentrations and survival rates in patients with SSc, Xanthouli and colleagues conducted a retrospective cohort study of patients from a single clinic center who were referred to receive pulmonary hypertension screening by a rheumatologist. Included patients were screened from 2010 through 2020. Those aged younger than 18 years, could not consent to participation, had other connective tissue diseases or had no data regarding hypochromic red cell concentrations at baseline were excluded.
Patients underwent a clinical workup that included a medical history, a current clinical evaluation and blood tests. Blood tests evaluated factors including liver and renal function, in addition to inflammatory markers and analysis for iron deficiencies. Patients also completed pulmonary function tests, ECGs, 6-minute walking distance tests and right-heart catheterization.
The analysis included a total of 171 patients who were followed for a median of 2.4 years. According to the researchers, a baseline hypochromic red cell concentration of more than 2% was “significantly” associated with worsened survival rates in both the univariable (P = .018) and multivariable (P = .031) analyses, independent of pulmonary hypertension or pulmonary parenchymal manifestations. Additionally, the combination of a hypochromic red cell concentration greater than 2% and a low diffusion capacity for carbon monoxide — 65% or less — was “significantly” associated with survival (P < .0001).
“This is the first study investigating the importance of % HRC as a marker of deranged iron supply demonstrating that a concentration of more than 2% of HRC is a strong predictor for worse survival in SSc patients independent from the presence of [interstitial lung disease (ILD)] and/or PH,” Xanthouli and colleagues wrote. “On the contrary, ferritin, hemoglobin and serum iron as conventional parameters of ID were not associated with mortality in our cohort.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
Erythrocytes contain approximately half the body’s iron (Fe) at any one time. The red cell indices offered by more recent analyzers can be predictive in diagnosing Fe deficiency (ID) and response to Fe. These advanced parameters include percentage of hypochromic red blood cells (%HRC) and the reticulocyte mean Hemoglobin (Hb) content. Methods and nomenclature for these indices vary by analyzer, but a high %HRC or low reticulocyte mean Hb content in persons without thalassemia indicate that Fe is not adequately available to the newly developed red cells. This can be due to Fe deficiency or Fe restriction.
The %HRC monitors the amount of Fe available (hemoglobinization) for the past 3 months and is useful for observation of functional ID in rheumatoid arthritis and for monitoring therapeutic response to Fe supplementation in advanced chronic kidney disease. A retrospective observational study of patients undergoing hemodialysis showed that an increase in %HRC was associated with a decrease in Hb levels in the future. Particularly, %HRC was found to be an independent predictor of anemia, defined as an Hb level that is 15% or less of baseline. A %HRC value of greater than 5% suggests ID.
The %HRC is affected by sample transport time and should only be used in laboratories that can reliably ensure analysis within 3 to 4 hours of phlebotomy.
Bone marrow biopsy is the most accurate way to measure Fe storage. For this reason, multiple biochemical markers of Fe metabolism have been developed to estimate the status of Fe stores, such as serum Fe, ferritin and transferrin saturation (TSAT, or performed as TIBC). Serum Fe measures only the oxidized ferric form bound to transferrin and not the functional Fe component of Hb. An individual with ID will usually exhibit a low concentration of serum Fe, but it is a dynamic parameter with well-established day-to-day variability.
Ferritin, as an acute phase reactant, rises in response to inflammatory states and is often elevated without regard to the Fe stores. In health, there is a direct relationship between reticuloendothelial Fe stores and serum ferritin, making it a powerful laboratory test when free of confounders. Levels of less than 15 µg/L predict a high likelihood of ID.
TIBC and transferrin rise in ID. Transferrin is a negative acute phase protein so its concentration may be reduced in inflammation. TIBC and transferrin have less variability than serum Fe quantitation, but specificity remains poor. The TSAT is the ratio of serum Fe to transferrin (or TIBC) expressed as a percentage, representing the proportion of serum transferrin binding sites occupied with Fe molecules. It relies on serum Fe concentration and so it carries a similar caveat regarding variability and lack of specificity. Diurnal fluctuations can be up to 70%.
Clinical disorders such as malnutrition and chronic disease cause a decrease in transferrin synthesis and therefore increase the TSAT, reducing its usefulness. A TSAT of less than 16% can support the diagnosis of ID.
There is great interest in %HRC as a new marker for Fe deficiency and to predict ID anemia, and a study like this one will continue to enlighten us on new markers of illness.
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