How to manage high iron levels in patients with Hereditary Hemorrhagic Telangiectasia (HHT)?

Management of High Iron Levels in HHT Patients

High iron levels are exceedingly rare in HHT patients and should trigger immediate investigation for alternative causes, as approximately 50% of HHT patients typically present with iron deficiency anemia from chronic bleeding rather than iron overload. 1

Critical Distinction: HHT Typically Causes Iron Deficiency, Not Overload

The question of "high iron" in HHT represents an unusual clinical scenario that warrants careful evaluation:

• HHT patients overwhelmingly present with anemia and iron deficiency due to chronic bleeding from telangiectasias, making iron overload the opposite of the expected presentation 2
• Iron deficiency anemia affects approximately 50% of HHT patients and is the primary hematologic manifestation requiring treatment 2, 1
• If true iron overload is documented in an HHT patient, this represents a coincidental condition requiring separate evaluation 1

Diagnostic Approach When Iron Overload is Suspected

Rule Out Measurement Artifacts

• Ferritin can be falsely elevated as an acute phase reactant during inflammation or infection, which does not represent true iron overload 2
• Confirm iron overload with transferrin saturation and consider hepatic iron concentration if diagnosis remains uncertain 2

Screen for Coexisting Conditions Causing True Iron Overload

Evaluate for hereditary hemochromatosis:

• Test for HFE gene mutations (C282Y and H63D) as this represents a separate genetic condition that could coincidentally occur with HHT 2
• Hemochromatosis requires phlebotomy therapy targeting ferritin levels of 50-100 μg/L 2

Assess for secondary causes of erythrocytosis that might suggest iron overload:

• Pulmonary arteriovenous malformations (PAVMs) causing chronic hypoxemia can drive erythrocytosis 1
• Hepatic AVMs may contribute to altered iron metabolism 1
• Screen with contrast echocardiography or chest CT for PAVMs 1

Management Algorithm

If Hereditary Hemochromatosis is Confirmed

Therapeutic phlebotomy is the treatment of choice:

• Weekly or biweekly phlebotomy (500 mL blood removal) until ferritin reaches 50-100 μg/L 2
• Check hemoglobin/hematocrit before each phlebotomy and allow no more than 20% decline from baseline 2
• Monitor ferritin every 10-12 phlebotomies 2
• Critical caveat: Phlebotomy in HHT patients with active bleeding is extremely high-risk and may precipitate severe anemia 2

Dietary modifications:

• Avoid vitamin C supplements, which accelerate iron mobilization and increase oxidative stress 2
• Avoid iron supplements 2
• No specific dietary iron restrictions are necessary as dietary modification has minimal impact (2-4 mg/day) 2

If PAVMs are Causing Erythrocytosis

• Percutaneous transcatheter embolization should be performed regardless of feeding artery size due to stroke and cerebral abscess risk 1
• This addresses the underlying hypoxemia driving erythrocytosis 1

If No Secondary Cause is Identified

• Refer to hematology for evaluation of primary polycythemia vera or other myeloproliferative disorders 1
• JAK2 mutation testing and bone marrow evaluation may be indicated 1

Critical Pitfalls to Avoid

Do not initiate phlebotomy without confirming true iron overload:

• HHT patients with iron deficiency may have normal or slightly elevated ferritin if inflammation is present 2
• Inappropriate phlebotomy will worsen the underlying iron deficiency anemia that is the hallmark of HHT 2

Monitor for transition to iron deficiency:

• Even if iron overload is initially present, HHT patients may transition to iron deficiency as bleeding manifestations progress 1
• Reassess hemoglobin and iron studies at 1-month intervals 1
• Establish baseline iron studies, ferritin, and transferrin saturation even in the presence of apparent iron overload 1

Consider chelation therapy only in specific circumstances:

• Iron chelation with deferoxamine or deferasirox is indicated for secondary iron overload due to ineffective erythropoiesis (e.g., thalassemia), not for HHT 2
• Chelation is not appropriate for HHT-related iron abnormalities 2

Anticoagulation Considerations in HHT with Coexisting Thrombotic Risk

Bleeding in HHT is not an absolute contraindication to anticoagulation when indicated:

• Anticoagulation should be provided when there is a clear indication, with individualized assessment of bleeding risk 2
• Paradoxically, severe iron deficiency in HHT can cause hypercoagulability through elevated factor VIII levels 3
• Avoid dual antiplatelet therapy and combination antiplatelet/anticoagulation therapy wherever possible 2, 1
• Consider left atrial appendage closure for atrial fibrillation in patients who cannot tolerate anticoagulation 2, 1