Immunological Effects of Iron Supplementation in HHT Disease

Immunological Effects of Iron Supplementation in HHT Disease

Hereditary haemorrhagic telangiectasia (HHT), is a rare genetic vascular disorder with autosomal dominant inheritance. Its prevalence is estimated at approximately 1 in 6,000 individuals in France. Clinical manifestations include recurrent nosebleeds (epistaxis), cutaneous telangiectasias, and visceral arteriovenous malformations (AVMs) that may affect the lungs, gastrointestinal tract, liver, and brain.

Beyond vascular abnormalities, patients often present with a decrease in circulating T lymphocytes (T-cell lymphopenia), which can be profound but remains unexplained. There is also a distinct infectious risk profile associated with the disease: brain abscesses in the presence of pulmonary AVMs (pAVMs), and osteoarticular infections in patients with the longest durations of epistaxis. However, no definitive correlation has been established between T-cell lymphopenia and infection risk.

Iron-deficiency anemia is a frequent complication in HHT, affecting about 50% of patients, with a mean age of onset around 36 years. Its prevalence increases with age. These patients typically require prolonged and high-dose iron supplementation, administered either orally or intravenously, which may expose them to side effects not observed in other clinical contexts. In a previous study, we identified a correlation between the level of iron supplementation (none, oral, or intravenous) and the severity of T-cell lymphopenia.

This association may be explained by two potential mechanisms linking iron metabolism to immune function:

• A direct toxic effect of iron on immune system homeostasis
• Impaired lymphocyte production resulting from iron deficiency, with the type of supplementation serving as an indirect marker of deficiency severity We propose a prospective study designed to differentiate between these two hypotheses. The aim of the study is to characterize the impact of iron deficiency and iron supplementation on the immune system of patients with HHT.

Inclusion Criteria:

• For all three groups:

  • Adult patient diagnosed with HHT (meeting 3 or 4 Curaçao criteria).
  • Documented pathogenic mutation in one of the following genes: ENG, ACVRL1, or MADH4.
  • Patient enrolled in the CIROCO cohort.
  • Written informed consent freely given and signed by the patient.
  • Patient covered by a social security scheme or equivalent.
  • Routine biological follow-up for HHT performed within the 15 days preceding the inclusion visit (complete blood count, reticulocytes, ferritin, CRP, calcium, phosphorus).

• Specific to Group 1:

  • Ferritin > 25 µg/L
  • No iron supplementation (oral or intravenous) in the past 3 months
  • No red blood cell transfusion in the past 3 months

• Specific to Group 2:

  • Ferritin > 25 µg/L
  • Ongoing oral iron therapy, or at least one intravenous iron infusion, or at least one red blood cell transfusion within the past 3 months

• Specific to Group 3:

  • Ferritin < 25 µg/L
  • No iron supplementation (oral or intravenous) in the past 3 months
  • No red blood cell transfusion in the past 3 months

Exclusion Criteria:

• Patients with hemoglobin levels < 90 g/L.
• Patients with active cancer or recent cancer remission (< 3 months) that may alter the immune profile.
• Patients with an active infection or recent infection recovery (< 3 months) that may alter the immune profile.
• Patients with an autoimmune or autoinflammatory disease, either active or recently treated (< 3 months), requiring immunosuppressive therapy and potentially altering the immune profile.
• Pregnant, postpartum, or breastfeeding women.
• Minors.
• Individuals deprived of liberty by judicial or administrative decision.
• Individuals undergoing psychiatric care.
• Individuals admitted to a healthcare or social institution for reasons other than research participation.
• Adults under legal protection (guardianship, curatorship).
• Individuals participating in another interventional clinical trial with an exclusion period still in effect at the time of pre-inclusion.