Polycythemia in Patients With Hereditary Hemochromatosis: Real or Myth?

Abstract

Background Hereditary hemochromatosis (HH) is an autosomal recessive disorder affecting iron metabolism, resulting in iron accumulation in tissue parenchymal cells. Missense mutations result in homozygosity or heterozygosity for substitutions in the HFE gene, with the most common being C282Y and H63D. Methods With an aim to evaluate an association between polycythemia and HH, retrospective chart review was performed for 152 patients with known HFE mutations. Parameters reviewed included individual HFE genotypes, gender distribution, hemoglobin (Hgb) and hematocrit (Hct) levels, median ferritin levels and whether or not phlebotomy was required. Results Of 152 patients, 96 (63.2%) were men and 56 (36.8%) were women. Median Hgb and Hct were noted to be higher in men compared to women irrespective of HFE status. Mean age was 60.5 years (range 22 - 93 years). Regarding HFE mutation, 44 (28.9%) patients were C282Y/C282Y, 10 (6.6%) were H63D/H63D and 27 (17.8%) had one copy of each mutation. One patient in the study group was H63D/S65C. Median Hgb and Hct were noted to be 15.5 g/dL and 44.9% respectively in C282Y/C282Y subjects, 16.0 g/dL and 47% in H63D/H63D subjects, 15.8 g/dL and 46% in C282Y/H63D subjects, 16g/dL and 47% in those with single C282Y mutation and 16.6g/dL and 48% in those with single H63D mutation. A total of 67.1% subjects received phlebotomy. A total of 21.7% patients in this cohort were active tobacco users and only 8.6% had an established pulmonary diagnosis, including obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD). Elevated Hgb levels were noted despite absence of an established reason for secondary polycythemia. Anemia was not encountered despite concurrent medical conditions that would usually be associated with anemia, including gastrointestinal bleeding or end-stage renal disease (ESRD). Conclusions Elevated Hgb and Hct levels in HH may be secondary to increased iron uptake by erythroid cell precursors in the bone marrow, in setting of increased availability of both transferrin-bound as well as non-transferrin-bound iron (NTBI). Additional studies need to be pursued to explore the association between HFE mutations and secondary polycythemia.

Polycythemia and Anemia in Hereditary Hemochromatosis

“…Beutler et al report only a slightly increased mean hemoglobin level in patients with hereditary hemochromatosis screened in the ambulatory setting [10]. Asif et al observed a median hemoglobin level of 15.5 mg/dL in their homozygous C282Y population, which is closely reflective of the hemoglobin values reported by our study [11]. Another study by Barton et al reports that only patients with C282Y homozygosity (and not other genotypic variants) have higher mean hemoglobin values when compared to healthy matched controls; the mean hemoglobin levels of their untreated homozygous C282Y probands was reported to be 15.0 mg/dL (±1.3), which also closely matches that reported in our study [6].…”

“…Polycythemia has been previously explored in various studies in the context of hereditary hemochromatosis [6,11]. Polycythemia in this setting is thought to be a consequence of elevated transferrin saturation levels, resulting in increased iron uptake by erythroid precursor cells.…”

Hemochromatosis Gene Mutation in Persons Developing Erythrocytosis on Combined Testosterone and SGLT-2 Inhibitor Therapy

“…11,17 Furthermore, previous studies have demonstrated that individuals with heterozygosity for H63D gene will have normal to slightly elevated biochemical indices of iron overload compared with wild-type individuals 18,19 or may tend to have higher baseline hemoglobin levels when compared with persons with C282Y or compound C282Y/H63D heterozygosity. 20 In addition, it was previously shown that high-volume transfusion donors (super donors) who had the H63D heterozygosity were characterized by significant reduction in hepcidin production compared with the wildtype super donors. 21 On the contrary, both testosterone and SGLT-2i in in vivo and clinical studies have been shown to suppress hepcidin and increase erythropoietin levels thus promoting environment stimulating hematopoiesis and erythrocytosis.…”

Identification of Variants Associated With Rare Hematological Disorder Erythrocytosis Using Targeted Next-Generation Sequencing Analysis

“…Recently, several research groups found HFE variants at higher frequencies among patients with unexplained erythrocytosis, i.e., idiopathic erythrocytosis (IE), compared with the general population (Biagetti et al, 2018;Burlet et al, 2019;Gurnari et al, 2019). Similarly, patients with the HFE variants had significantly higher Hb and Ht values than normal (Barton et al, 2000;Asif et al, 2019). It was suggested that HFE mutations could induce erythropoiesis through higher iron bioavailability, since iron is dedicated to the synthesis of Hb (Hentze et al, 2010;Biagetti et al, 2018;Burlet et al, 2019).…”