The heights of iron absorption: Erythrocytosis in patients with heterozygous HFE mutations at altitude Free

Background:

Hemochromatosis (HC) is a disorder characterized by increased iron absorption from the intestines and increased recycling of iron from red blood cells. HC typically manifests with elevated serum ferritin and transferrin saturation. Iron overload can result, leading to end organ damage most notably in the liver, potentially leading to cirrhosis, pancreas, heart, and joints, among others. Therapies for HC include phlebotomy to remove excessive iron along with iron chelation if necessary.1 There are four types of HC and type 1 is a disorder of homeostatic iron regulator (HFE). HFE regulates production of hepcidin through interactions with transferrin receptors 1 and 2.2 Typically HFE-HC has been characterized as an autosomal recessive disorder with heterozygous patients being asymptomatic.1 The most common variants in the HFE gene associated with HFE-HC are C282Y (80-85%), H63D, and S65C.3 Patients with HC have been shown to either have polycythemia or normal hemoglobin in the setting of significant risk factors for anemia.3 Polycythmia in this context is thought to be due to elevated transferrin saturation levels leading to increased uptake by erythroid precursor cells. Prior studies of polycythemia in HC have been conducted in homozygous or compound heterozygous HFE gene mutations but never in heterozygous mutations.

It is well known that living at altitude can lead to erythrocytosis. This is normally an initial response to an increase in elevation thought to be due to an increase in erythropoietin production in the setting of relative hypoxia. It is not, however, demonstrated in all populations and not typically persistent, possibly due to changes in blood flow, respiration, NO metabolism, and O2 diffusion among other compensatory mechanisms.4

Cases:

We present five patients presenting with polycythemia and heterozygous HFE mutations. Four patients are male and one is female. Four are of caucasian background and one of hispanic background. Basic hematologic labs were obtained initially by their primary care physicians for either preventative screening or complaints of fatigue. HFE genetic workup was subsequently obtained either due to family history of HC or due to persistent polycythemia. Hemoglobin values ranged from 15.6-19.6 g/dL. Iron saturations were between 40 and 130% with ferritins ranging from 41 to 124 ng/mL. There was no significant increase or decrease in TIBC measured across all patients. The highest average hemoglobin was found in a patient with a heterozygous C282Y mutation. The lowest average hemoglobin was in our only female patient; however, she had concomitant celiac disease and heavy menstruation without anemia. One patient was tested for JAK2 mutation which was negative.

Discussion: While it is commonly taught that patients with heterozygous mutations in HFE are unaffected, this cohort shows that each of the three most common HFE variants, C282Y, H63D, and S65C may cause mild polycythemia at elevation with hemoglobin values ranging from 15.9 to 19.6 g/dL. The patient with a heterozygous C282Y mutation showed the highest hemoglobin, between 18.3 and 19.6 g/dL. C282Y is the most common mutation in HFE and has been shown most commonly to be associated with polycythemia in patients with homozygous mutations. It is possible that this mutation results in a significant decrease in HFE protein, while not enough to produce severe iron overload, to persistently elevate transferrin mobilization and utilization of iron in erythrocyte precursors in the setting of hypoxemia. If polycythemia is found in patients living at altitude, known presence of heterozygous HFE mutations may reduce the need for further work up for other etiologies such as Polycythemia Vera via JAK2 testing.

Conclusion:HC, and especially HFE-HC, has typically been presented as an autosomal recessive disorder. We consider the possibility that, at altitude, patients with heterozygous mutations in HFE can present with increased iron absorption, storage, and utilization leading to polycythemia.