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

Abstract

Objectives/HypothesisTo examine whether there is a rationale for iron treatments precipitating nosebleeds (epistaxis) in a subgroup of patients with hereditary hemorrhagic telangiectasia (HHT).Study DesignSurvey evaluation of HHT patients, and a randomized control trial in healthy volunteers.MethodsNosebleed 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).ResultsIron 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.ConclusionsIron 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 Evidence4. Laryngoscope, 126:2468–2474, 2016

Dietary supplement use and nosebleeds in hereditary haemorrhagic telangiectasia ‒ an observational study

“…enhanced in iron-deficiency (3)). It may be of concern however, that for five iron users, serum iron concentrations were at least twice the upper limit of normal ( Figure 2B), in keeping with recent data from a healthy volunteers study (5). One in 20 HHT iron users report nosebleeds are worse after iron treatments (5,27), and recent data suggest one plausible biological explanation through activation of endothelial DNA damage response pathways by 10 µM iron (28), an order of magnitude lower than examined in recent iron toxicity studies (29,30).…”

“…Despite a battery of potential interventional, surgical, and medical approaches (4), HHT patients are commonly iron deficient and/or anaemic because replacing iron lost through recurrent haemorrhage demands very high iron intakes (3). In a recently surveyed international group, 273 of 1,288 (21.2%) had received iron infusions and 396 (30.8%) had received blood transfusions, 105 (8.1%) on at least 10 occasions (5). Additionally, arterial rate bleeds can cause acute haemodynamic disturbances (3,4,6,7); epistaxis severity is a major predictor of reduced quality of life (8)(9)(10)(11); and epistaxis is the primary outcome measure in nine of ten clinical trials of new therapeutic agents recruiting in HHT (12).…”

Reported cardiac phenotypes in hereditary hemorrhagic telangiectasia emphasize burdens from arrhythmias, anemia and its treatments, but suggest reduced rates of myocardial infarction

“…We cannot rule out an alternate, and not mutually exclusive possibility that the anemia treatments may aggravate the cardiac phenotypes. This is important to consider in the light of two sets of recent data: first 5-7% of HHT patients report immediate exacerbation of nosebleeds by iron treatments and transfusions [45], and multiple studies emphasize the rapid increases in serum iron after iron treatments [45][46][47][48][49][50][51][52]. Secondly, an RNASeq-based study demonstrates that 10 μM iron generates rapid molecular and cellular changes in primary human endothelial cells, compatible with activation of DNA damage response pathways [53] the concentration required is similar to clinical concentrations of nontransferrin bound iron (NTBI) after iron treatments [47][48][49][50][51][52], and much lower than those used in previous studies of endothelial iron toxicity [54,55].…”

No effects without causes: the Iron Dysregulation and Dormant Microbes hypothesis for chronic, inflammatory diseases

“…Iron can have negative effects, as reviewed extensively elsewhere (e.g. Altamura & Muckenthaler, ; Anderson & Wang, ; Berg & Youdim, ; Bush & Tanzi, ; Castellani et al ., ; Chifman, Laubenbacher & Torti, ; Collingwood & Davidson, ; Crichton, ; Crichton, Dexter & Ward, ; Dixon & Stockwell, ; Farina et al ., ; Ganz & Nemeth, ; Hansen, Moen & Mandrup‐Poulsen, ; Jellen, Beard & Jones, ; Kell, , ; Kell & Pretorius, ; Koskenkorva‐Frank et al ., ; Lehmann et al ., ; Levi & Finazzi, ; Mollet et al ., ; Muhoberac & Vidal, ; Muller & Leavitt, ; Nikonorov et al ., ; Núñez et al ., ; Oliveira, Rocha & Fernandes, ; Peters, Connor & Meadowcroft, ; Pisano, Lombardi & Fracanzani, ; Rouault, ; Schneider, ; Shovlin et al ., , ; Simcox & McClain, ; Stankiewicz, Neema & Ceccarelli, ; Stephenson et al ., ; Sullivan, ; Thuret, ; Vinchi et al ., ; Weinreb et al ., ; Yin et al ., ; Zhao et al ., ; Zhuang, Han & Yang, ), as well as being an essential nutrient for cell growth ( cf . Posey & Gherardini, ).…”