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Pearls and Pitfalls

Pondering the Perils of Too Much Iron and Round Red Cells

Randy Eichner, E. MD, FACSM

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Current Sports Medicine Reports: January 2019 - Volume 18 - Issue 1 - p 2-3
doi: 10.1249/JSR.0000000000000559
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Introduction

Recently, I was asked practical questions about managing fairly common inborn conditions in three athletes, one with possible hereditary hemochromatosis and two with hereditary spherocytosis. Bearing in mind that some questions are harder to answer than others, and there are more questions than answers in life, let me begin.

Hereditary Hemochromatosis

I am asked about a female college runner who, taking a regular iron supplement, has a serum iron as high as 263 μg·dL−1 and a percent saturation (with iron) of transferrin of 90%, which also is high. Her serum ferritin is normal at 55 μg·L−1 and her liver chemistries also are normal. Last year, when she was not taking an iron supplement, her serum iron was lower, 115 μg·dL−1, with percent saturation of transferrin also lower, at 38%. She says she has a grandfather and two aunts with hemochromatosis. What to do for this athlete?

First, the latest on hemochromatosis. Hereditary hemochromatosis (HH) is an autosomal recessive iron-overload disorder caused by lifelong excessive dietary iron absorption. It is the most common single-gene disorder in whites from northern Europe, due to mutations of the HFE gene on chromosome 6. Of the many HFE mutations known, only two, C282Y and H63D, have clinical impact. C282Y may have originated by chance in a single Viking ancestor 5,000 years ago. Homozygosity for it accounts for 85% to 100% of patients with clinical HH, or features of iron overload in the liver, pancreas, heart, joints, or hypothalamus. In contrast, H63D homozygosity or compound heterozygosity with C282Y may cause a slow increase in serum ferritin over the years, but rarely causes clinical HH. Homozygosity for C282Y, “the cause” of HH, exists in about 5 of every 1,000 persons of northern European descent, a prevalence 10 times that of cystic fibrosis genotypes.

How does an HFE mutation cause iron overload? Inappropriately low hepcidin levels are key. Normally, plasma iron level (transferrin saturation) regulates the synthesis of hepcidin (in the liver) by a feedback signaling pathway that includes HFE. Normally, when plasma iron rises, hepcidin is secreted into the blood. Hepcidin then degrades the “iron exporter” ferroportin, in duodenal enterocytes and in macrophages that hold iron from senescent red cells. This in turn inhibits the absorption of dietary iron and the release of iron from macrophages, so the plasma iron level falls.

This “fine-tuning” of plasma iron level is disrupted in HH, however, by a deficiency of hepcidin. The HFE gene seems somehow to interfere with the “reading” of high plasma iron level by transferrin receptors on cell surfaces. This impairs hepcidin synthesis, allowing excess uptake of dietary iron and increased egress of iron from macrophages. This keeps the plasma iron level high and slowly increases the body burden of iron, which over decades can lead to clinical HH (1).

Now, how to manage this young athlete with a high serum iron? First, genotype for HFE. She will want to know, and it will provide practical information, for her and for any offspring. Unless she is homozygous for C282Y, she can relax, forget about HH. Other genotypes of HFE do not really matter clinically; even H63D, if homozygous or a compound heterozygote with C282Y, rarely if ever leads to clinically important tissue iron overload (2).

What if she is homozygous for C282Y? Her ferritin is normal at 55 μg·L−1; the news may still be good. Half of female homozygotes have a normal ferritin at diagnosis, and may never need phlebotomy therapy (3). In one study, 20 of 22 such adults (18 females) were followed for up to 23 years (median, 4 years) and only two had noteworthy rises in serum ferritin (4). So you could make a strong case just to follow her ferritin (maybe twice a year at first) for the next few years, and do nothing else if her ferritin stays “flat” or at least does not rise >200 μg·L−1.

If she is C282Y homozygous, just in case, I would teach her dietary and lifestyle tips: Avoid iron pills; go light on red meat and alcohol; avoid vitamin C pills; be smart about avoiding hepatitis C and other threats to the liver; avoid raw shellfish (risk of dire Vibrio vulnificus infection with high serum iron); and periodically volunteer as a blood donor (3).

Finally, what about benefits? Studies suggest that, compared to controls, mean hemoglobin is higher in homozygotes for C282Y, in compound heterozygotes (with H63D), and even in heterozygotes for C282Y. Researchers propose that increased iron supply from these HFE mutations protects against iron deficiency anemia (5–7). Also, two studies suggest that elite endurance athletes more commonly have HFE gene mutations (8,9). Because performance-limiting iron deficiency anemia is common in female athletes, this female runner — with a high serum iron and a family history of HH — may be a top athlete in part because she has the genetic makeup for HH.

Hereditary Spherocytosis

I am asked about two athletes with hereditary spherocytosis (HS). One is a college lacrosse player hospitalized for “influenza and anemia,” where his HS was uncovered. He got a blood transfusion and was discharged with splenomegaly and a hemoglobin 11 g·dL−1, his baseline. The other is a downhill ski racer in high school with newly diagnosed HS. In both cases, physicians favor return to play but ask about the chance of splenic rupture.

HS is the most common hemolytic anemia caused by a defect in red-cell membranes; usually autosomal dominant, it affects about 1 per 2,000 persons of northern European ancestry. Deficiencies in membrane or associated cytoskeletal proteins (most commonly ankyrin and/or spectrin or band 3) lead to membrane loss, rounding up (into spherocytes), and the trapping and destruction of the round red cells in the spleen.

Up to 30% of patients have very mild HS with “compensated hemolysis” (their rate of red-cell production matches that of destruction), so they are not anemic. They usually have no symptoms, few spherocytes, mild reticulocytosis, and mild splenomegaly.

The diagnosis of mild HS can be elusive, and it does not preclude top athleticism. A recent illustrative case is a 28-year-old man with bilirubin gallstones and mild splenomegaly, but a normal hemoglobin of 15 g·dL−1 (10). A high-profile case is the German speedskater Claudia Pechstein (five-time Olympic gold-medal winner) who for nearly 10 years has fought being banned (for 2 years) when she was “caught” in 2009 with high reticulocyte counts (but normal hemoglobin levels), based only on the then-new “biologic passport.” She was the first athlete “caught” by this indirect method; despite more than 500 tests over her long career, she has never tested positive for any performance-enhancing drug. She — and several German hematologists — claim she has mild HS, from her father, who also has it. She may be right; it could be a bum rap.

What about the spleen in HS? As I review the literature, splenic rupture is very rare in HS. Compared to infectious mononucleosis (IM), the spleen in HS is “firmer, less friable,” so the risk of rupture is lower in HS than in IM. In fact, there are very few reports in the medical literature of splenic rupture in HS, and one of the few involved a major car wreck that likely could have ruptured even a normal spleen (11). A recent authoritative review concludes there is no evidence to support limiting activity (in children) with splenomegaly due to HS (12). I agree.

Final pearl: Medicine is a humbling profession, and practicing medicine long-distance is a fool’s game. Current consensus discourages splenectomy in mild HS, because the risks associated with some resultant immunocompromise outweigh the risks of hemolytic complications (10). In my opinion, both athletes in question here, despite HS and mild splenomegaly, can return to play.

References

1. Leitman SF. Hemochromatosis: the new blood donor. Hematology Am. Soc. Hematol. Educ. Program. 2013; 2013:645–50. doi:10.1182/asheducation-2013.1.645.
2. Radford-Smith DE, Powell EE, Powell LW. Haemochromatosis: a clinical update for the practising physician. Intern. Med. J. 2018; 48:509–16.
3. Adams PC, Barton JC. How I treat hemochromatosis. Blood. 2010; 116:317–25.
4. Yamashita C, Adams PC. Natural history of the C282Y homozygote for the hemochromatosis gene (HFE) with a normal serum ferritin level. Clin. Gastroenterol. Hepatol. 2003; 1:388–91.
5. Barton JC, Bertoli LF, Rothenberg BE. Peripheral blood erythrocyte parameters in hemochromatosis: evidence for increased erythrocyte hemoglobin content. J. Lab. Clin. Med. 2000; 135:96–104.
6. Rossi E, Olynyk JK, Cullen DJ, et al. Compound heterozygous hemochromatosis genotype predicts increased iron and erythrocyte indices in women. Clin. Chem. 2000; 46:162–6.
7. Datz C, Haas T, Rinner H, et al. Heterozygosity for the C282Y mutation in the hemochromatosis gene is associated with increased serum iron, transferrin saturation, and hemoglobin in young women: a protective role against iron deficiency? Clin. Chem. 1998; 44:2429–32.
8. Chicharro JL, Gómez-Gallego F, Villa JG, et al. Mutations in the hereditary haemochromatosis gene HFE in professional endurance athletes. Br. J. Sports Med. 2004; 38:418–21.
9. Hermine O, Dine G, Genty V, et al. Eighty percent of French sport winners in Olympic, World and Europeans competitions have mutations in the hemochromatosis HFE gene. Biochimie. 2015; 119:1–5.
10. Rencic J, Zhou M, Hsu G, Dhaliwal G. Circling back for the diagnosis. N Engl. J. Med. 2017; 377:1778–84.
11. Berne JD, Asensio JA, Falabella A, Gomez H. Traumatic rupture of the spleen in a patient with hereditary spherocytosis. J. Trauma. 1997; 42:323–6.
12. Bolton-Maggs PH, Langer JC, Iolascon A, et al. Guidelines for the diagnosis and management of hereditary spherocytosis—2011 update. B. J. Haematol. 2012; 156:37–49.
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