Anemia at Altitude: Iron Deficiency and Other Acquired Anemias

Introduction

Many diseases can lead to anemia. Iron deficiency is one of the most common causes of anemia in the world and can have many effects on going to altitude beyond anemia. Other disorders such as underlying inflammatory states and renal disease can lead to anemia. Often for travelers with these disorders, the anemia is only part of their disease complex; so planning needs to be focused on the underlying disease.

Iron Deficiency

The most common correctable cause of anemia is iron deficiency. The incidence of iron deficiency can be as high as 51% in active women and up to 17% in active men (Rowland et al., 1987; Dubnov and Constantini, 2004; Fallon, 2004). Women are especially prone to iron deficiency due to obligate menstrual losses, which often exceed oral iron intake. Athletes are also at risk for iron deficiency due to greater gastrointestinal blood loss and exercise-induced inflammation inducing synthesis of hepcidin—a protein that decreases gastrointestinal iron absorption and restricts iron release from stores (Pagani et al., 2019).

Iron deficiency can have profound effects on altitude performance due to anemia, decreased exercise performance and response to hypoxia. As noted above, anemia leads to impaired exercise performance. Importantly, it is now recognized that low tissue iron stores can have deleterious performance effects even with a normal blood count. Studies show decreased athletic performance with low iron stores, and performance improves with iron repletion (Burden et al., 2015). This may be due to depletion of muscle iron stores, including smooth and cardiac (Lakhal-Littleton, 2019). Iron depletion has also been shown to result in fatigue—two randomized trials have shown improvement in fatigue with repletion of iron stores in nonanemic patients presenting with ferritins of less than 50 ng/dl (Verdon et al., 2003; Vaucher et al., 2012).

A consistent normal physiologic response of going to altitude is a 3%–8% increase in red cell mass, which leads to improved oxygen-carrying capacity (Ryan et al., 2014; Garvican-Lewis et al., 2015). Studies have shown this response is blunted in iron-deficient patients—presumably due to lack of iron for the increased red cell production (Hannon et al., 1969; Stray-Gundersen et al., 1992).

Low iron stores also lead to impaired thermoregulation, with one study showing lower body temperatures and metabolism in response to a cold challenge than controls; this effect improved with iron supplementation (Beard et al., 1990). This is thought to be due to impaired thyroid hormone production.

A fundamental connection exists between iron metabolism and the body's response to hypoxia (Gassmann and Muckenthaler, 2015). The overall response to hypoxia is mediated by protein transcription factors known as hypoxia-inducible factor 1 and 2 (HIF). HIF is constantly synthesized, but then is targeted for destruction, so normally, the half-life of the protein is very short—less than 5 minutes (Huang et al., 1998). Under hypoxic conditions, HIF is no longer targeted for degradation and cellular levels rise rapidly, inducing a wide variety of adaptations to hypoxia. The proteins responsible for marking HIF for destruction are prolyl hydroxylases (PHD), which require iron to function. Hypoxia also reduces synthesis of hepcidin, which functions to allow more iron to be transferred from iron stores to the developing red cells (Talbot et al., 2012).

Iron deficiency leads to HIF stabilization and increased expression of hypoxia-related genes. There are abundant data that this can lead to exaggerated pulmonary hypoxic vasoconstriction. In Chuvash polycythemia—an inherited state of HIF overactivation—there is an increased incidence of pulmonary hypertension and thrombotic complications leading to early death (Frise and Robbins, 2015). Conversely, Tibetans have variants in the HIF pathway that lead to decreased expression (Peng et al., 2017). A study of 13 iron-deficient volunteers showed that, compared to matched controls, pulmonary artery systolic pressure in the iron-deficient volunteers had a greater rise when exposed to hypoxia—16.1 mmHg versus 10.7 mmHg (Frise et al., 2016). Both groups that received intravenous iron had blunting of the hypoxic vasoconstriction response—but this decrease was greater in the iron deficiency group. A study in iron-replete volunteers also demonstrated a 50% decrease in hypoxic PASP pressure rise after intravenous iron (Bart et al., 2016). Finally, in a study of normal volunteers taken to 4,340 m, the group that received intravenous iron again showed dampening of the hypoxic response by 40% (Smith et al., 2009).

Given the benefits of iron in reducing pulmonary vasoconstriction, it is tempting to speculate that iron infusions may have a role in the prevention of acute mountain sickness (AMS). A preliminary randomized clinical trial in 24 people ascending rapidly to 4,340 m showed that 200 mg of intravenous iron reduced the increase in AMS score by 65%, with negative correlation between change in score and serum ferritin (Talbot et al., 2011). Obviously, more studies are needed to verify this fascinating observation.

Data demonstrate that iron supplementation is helpful for going to attitude. One study demonstrated that the routine use of oral iron supplements in athletes with ferritins <100 ng/dl allows for expansion of red cell mass compared to controls at altitude (Govus et al., 2015). Hannon et al. (1969) also noted that iron supplementation resulted in an improved red cell mass response to higher altitudes. Okazaki et al. (2019) showed that low iron stores hindered erythropoietic response to altitude training, but that iron supplementation stabilized the serum ferritin and allowed for an increase in red cell volume at altitude. It takes ∼250 mg of storage iron to support a 1 g/dl increase in hemoglobin. This amount of storage iron would be represented by 25–32 ng/dl of serum ferritin. Since it has been suggested that an “ideal” hemoglobin for altitude should be 2.5 g/dl higher than the usual range, increasing the hemoglobin by that amount would require a serum ferritin of 62–80 ng/dl (Berglund et al., 2002; Grissom et al., 2017).

Traditionally, the diagnosis of iron deficiency has been made by documenting a microcytic anemia, but we know now that this is a late finding. Currently, the most effective means of diagnosis is by measuring a serum ferritin as this is the protein that best reflects body iron stores (DeLoughery, 2017). Current lower limits of “normal” ferritin in many laboratory will vastly underestimate iron deficiency. Given that data from both fatigue and athletic studies show levels below 50 ng/dl are deficient, this should be the cutoff for treatment in people considering going to altitude. For those considering extreme altitude, a level of 100 ng/dl may be more appropriate. Given the prevalence of low iron stores—especially in athletes—screening should be considered for those at risk of iron deficiency, especially for women.

Treatment starts with oral iron (Table 1). Data show that one pill daily is adequate for restoring iron stores as more frequent dosing does not lead to an increase in iron absorption due to increased hepcidin levels induced by the oral iron (Moretti et al., 2015; DeLoughery, 2017). Taking the iron with 500 mg vitamin C and meat protein will also increase iron absorption. In addition, iron absorption is increased when going to altitude due to suppressed hepcidin synthesis. For patients who are unable to replete with oral iron, the use of intravenous iron, which innumerable studies have shown to be safe and effective (Auerbach and Deloughery, 2016), is being considered more often.

Anemia of Inflammation

With any inflammatory state, ranging from infection to inflammatory arthritis, anemia can be seen (Ganz, 2019). While it goes by several different names, anemia of inflammation is the most accurate description. Inflammation leads to anemia by several different mechanisms. One is that inflammatory cytokines increase the levels of serum hepcidin. Hepcidin blocks iron absorption, and the release of iron from stores results in iron-restricted erythropoiesis (Camaschella et al., 2020). Normally, a membrane protein known as ferroportin allows export of iron from enterocytes, macrophages, and hepatocytes. Hepcidin binds to and leads to the degradation of ferroportin, which blocks iron export. Second, these cytokines also suppress the production of erythropoietin. So for a given degree of anemia, serum erythropoietin levels will be lower than predicted. Finally, the half-life of the red cell is shorter.

The degree of anemia varies with the degree of inflammation; most patients will have hemoglobin in the 8–10 g/dl range. Diagnosis is made by establishing no other causes for anemia and the presence of adequate iron stores (serum ferritin >100 ng/dl). Serum levels of erythropoietin are lower than would be expected for the degree of anemia. In the future, it is hope that measurement of serum hepcidin levels can help in the diagnosis by findings raised levels in patients with anemia of inflammation. It is unknown how patients with anemia of inflammation will respond to hypoxic stimulus, but given the pathophysiology of the disease, one can expect the erythropoietic response to altitude will be blunted.

There are some data that altitude may make certain inflammatory conditions worse, potentially augmenting anemia. The best studies are in those with inflammatory bowel disease. Patients with inflammatory bowel disease will have worsened control of their disease with altitude exposure (Vavricka et al., 2014, 2016). Also, patients who develop inflammatory conditions at altitude such as infections will become more anemic.

Preparation for travel should include ensuring that the underlying disease is controlled as well as possible. Patients should be screened for iron deficiency—in inflammatory conditions, ferritins should be over 100 ng/dl. Another group of patients with anemia of inflammation that can benefit from aggressive iron repletion are patients with heart failure. Several studies show benefit in exercise ability with replacing iron when the ferritin is under 100 ng/dl, or under 300 ng/dl, with an iron saturation below 30% (von Haehling et al., 2019).

Renal Disease

A hallmark of kidney disease is anemia. The kidneys are the main site of production for erythropoietin and as the kidneys fail, erythropoietin synthesis falls off with resulting anemia. The use of exogenous erythropoietic stimulating agents (ESA) such as erythropoietin formulations and PHD inhibitors aids dialysis patients in maintaining blood counts. Interestingly, while use of these agents to raise the hematocrit has been shown to improve quality of life, raising blood counts to normal or near normal levels is associated with increased risk of thrombosis, especially stroke. Because of this adverse effect, current guidelines recommend hemoglobin goals of 11 g/dl.

It has been observed that with altitude, dialysis patients require less erythropoietin, suggesting that hypoxia can induce endogenous erythropoietin production from extra-renal sources (Brookhart et al., 2008; Sibbel et al., 2017). Increase in altitude was associated with lower requirements for intravenous iron and erythropoietin and patients still maintained higher hemoglobin levels. The reason for this may be found in the liver—it normally produces ∼10% of erythropoietin, but can be upregulated. Interestingly, multiple studies have shown decreased mortality and decreased cardiovascular events in high-altitude dialysis patients (Brookhart et al., 2008; Winkelmayer et al., 2012; Sibbel et al., 2017). For travel to altitude, dosing of erythropoietin should be timed to right before travel to maintain hemoglobin. For patients with chronic renal disease not on dialysis, iron stores should be screened as iron replacement can improve anemia.

Myelodysplasia

Myelodysplasia is a clonal bone marrow disorder resulting in decreased production in all blood lines. There are multiple subtypes, ranging from preleukemic states, which rapidly evolve into frank leukemia in weeks to refractory anemias where survival can be many years. Patients with more advanced disease are treated with chemotherapy or stem cell transplant, while patients with milder forms receive erythropoiesis-stimulating agents or transfusions.

Several strategies can be used for patients with myelodysplasia, who want to travel to altitude. For those who are transfusion dependent, timing the transfusion before travel should help improve altitude tolerance. Patients on ESA can travel in between therapy or if feasible can inject themselves during the journey. Those on chemotherapy can time their travels between therapies, but need to be at a point where their neutrophil counts are stable to avoid infection.

Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia is a rare cause of anemia. There are two main types—Immunoglobulin G (IgG) mediated (“warm”) and Immunoglobulin M (IgM) mediated (“cold”). For IgG hemolysis, treatment starts with prednisone, with the anti-CD20 antibody rituximab often included as this has been shown to increase response rates. IgM disease is not steroid responsive so rituximab is the most commonly given therapy. Some patients may require chemotherapy agents such as bendamustine to achieve disease control.

Patients with acute autoimmune hemolytic anemia, whose red cell counts are not stable, should be advised not to go to altitude. Those just off prednisone or on low doses are immunosuppressed. One side effect of rituximab is that responses to vaccinations are impaired for 6–12 months after treatment so travel-required vaccination may not be effective.

Summary

Given the close connections between iron status, exercise performance, and response to hypoxia, screening for iron deficiency needs to be an essential part of any evaluation for travel to altitude. For patients with other causes of anemia, the underlying etiology will dictate their travel plans.