Can Iron Treatments Aggravate Epistaxis in Some Patients With Hereditary Hemorrhagic Telangiectasia?

Abstract

Objectives/hypothesis: To examine whether there is a rationale for iron treatments precipitating nosebleeds (epistaxis) in a subgroup of patients with hereditary hemorrhagic telangiectasia (HHT).

Study design: Survey evaluation of HHT patients, and a randomized control trial in healthy volunteers.

Methods: Nosebleed severity in response to iron treatments and standard investigations were evaluated by unbiased surveys in patients with HHT. Serial blood samples from a randomized controlled trial of 18 healthy volunteers were used to examine responses to a single iron tablet (ferrous sulfate, 200 mg).

Results: Iron tablet users were more likely to have daily nosebleeds than non-iron-users as adults, but there was no difference in the proportions reporting childhood or trauma-induced nosebleeds. Although iron and blood transfusions were commonly reported to improve nosebleeds, 35 of 732 (4.8%) iron tablet users, in addition to 17 of 261 (6.5%) iron infusion users, reported that their nosebleeds were exacerbated by the respective treatments. These rates were significantly higher than those reported for control investigations. Serum iron rose sharply in four of the volunteers ingesting ferrous sulfate (by 19.3-33.1 μmol/L in 2 hours), but not in 12 dietary controls (2-hour iron increment ranged from -2.2 to +5.0 μmol/L). High iron absorbers demonstrated greater increments in serum ferritin at 48 hours, but transient rises in circulating endothelial cells, an accepted marker of endothelial damage.

Conclusions: Iron supplementation is essential to treat or prevent iron deficiency, particularly in patients with pathological hemorrhagic iron losses. However, in a small subgroup of individuals, rapid changes in serum iron may provoke endothelial changes and hemorrhage.

Level of evidence: 4. Laryngoscope, 126:2468-2474, 2016.

Keywords: Epistaxis; iron.

© 2016 The Authors. The Laryngoscope published by Wiley Periodicals, Inc. on behalf of American Laryngological, Rhinological and Otological Society Inc, “The Triological Society” and American Laryngological Association (ALA).

Figures

Figure 1

Nosebleed frequency in study respondents, categorized by iron use. (A) Percentage (%) of the 1,080 respondents in whom hereditary hemorrhagic telangiectasia could be confidently assigned, reporting any nosebleed ever, nosebleeds in childhood, or nosebleeds in response to trauma or injury. Open circles indicate the 299 patients who had never used iron tablets, diamonds indicate the 781 users of iron tablets, and filled circles indicate the 359 who had used iron tablets without intravenous iron or blood transfusions. Mean and standard error are indicated. (B) Percentage (%) of groups reporting no nosebleeds ever (“never”),

Figure 2

Reported exacerbation of nosebleeds after treatments and investigations. Percentage (%) of patients reporting that iron tablets, infusions, or blood transfusions exacerbated nosebleeds compared to a subgroup of 460 reporting responses to the control investigations in the second survey. N indicates number of respondents reporting responses for the treatment or investigation. *P < .05 compared to equivalent responses in control investigations. Note that the iron and transfusion data are from all 1,288 participants with confident and likely hereditary hemorrhagic telangiectasia (HHT), as this group was more comparable to the control survey population, although the proportions reporting exacerbation by iron treatments were marginally lower than in the 1,080 participants with rigorously defined HHT (see text).

Figure 3

Iron treatment trial. (A) Study protocol. Black arrows indicate time of blood samples, red arrows indicate the time of administration of ferrous sulfate (FeSO4) 200 mg, and blue dotted arrows indicate the time of administration of the dietary supplement (Diet supp; molasses). (B) Serum iron concentrations (normal range = 7–27 μmol/L) in the 18 healthy volunteers before (T = 0) and after ingestion of ferrous sulfate (solid lines), molasses (dotted lines), or no agent (dashed lines). Note all four rapid increases were in individuals receiving ferrous sulfate.

Figure 4

Biomarkers in iron treatment trial. (A) Change in serum iron (upper graph) and transferrin saturation index (TfSI, lower panel) in the first 2 hours after iron administration, categorized by absorber groups. Boxplots display interquartile range and 2 standard deviations. Probability values for iron absorber status were calculated by two‐way analysis of variance using T = 0 and T = 2 hours data. (B) Circulating endothelial cells (ECs; viable CD34+CD45−CD146+ cells) in the iron treatment and control groups, categorized by iron absorption status. Boxplots display median, interquartile range, and 2 standard deviations; dots at extremes represent outliers. At each of the 4‐5 and 7‐hour time points, one of the molasses group also demonstrated circulating EC rises (data not shown).