Can HHT Cause Chronic Fatigue?
Yes, HHT commonly causes chronic fatigue, primarily through iron deficiency anemia resulting from chronic bleeding, which affects approximately 50% of HHT patients. 1
Primary Mechanism: Iron Deficiency Anemia
Iron deficiency anemia from chronic bleeding is the dominant cause of fatigue in HHT, with recurrent epistaxis and gastrointestinal bleeding leading to typical symptoms including fatigue, reduced exercise tolerance, pica, restless leg syndrome, and hair loss. 1
The prevalence of anemia in HHT patients reaches approximately 50%, making fatigue one of the most common manifestations of the disease. 1
Fatigue severity correlates with the degree of iron deficiency and anemia, not just hemoglobin levels alone—ferritin and transferrin saturation must also be assessed and normalized. 1
Secondary Contributors to Fatigue
High-output cardiac failure from hepatic arteriovenous malformations can considerably worsen fatigue symptoms in patients with significant liver involvement, creating an additional hemodynamic burden beyond anemia alone. 1
Chronic hypoxemia from pulmonary arteriovenous malformations may contribute to fatigue through reduced oxygen delivery to tissues, though this is less common than anemia-related fatigue. 2
The psychosocial burden of chronic bleeding causes significant morbidity, social isolation, and difficulties with employment and daily activities, which compounds physical fatigue with psychological exhaustion. 2, 3
Diagnostic Approach to Fatigue in HHT
All adults with HHT should be tested for iron deficiency and anemia regardless of symptoms (strong recommendation, high quality evidence). 1
Assess complete iron studies including hemoglobin, ferritin, and transferrin saturation—not just hemoglobin alone, as iron deficiency without anemia still causes fatigue. 1
Screen for pulmonary AVMs with contrast echocardiography or chest CT if hypoxemia is suspected as a contributor. 2
Evaluate for hepatic AVMs with Doppler ultrasonography if high-output cardiac symptoms are present. 2
Management Algorithm for Fatigue
Step 1: Iron Replacement
- Start with oral iron (35-65 mg elemental iron daily), escalating dose or frequency if inadequate response. 1
- Switch to intravenous iron for patients with inadequate absorption, intolerance, or severe anemia—expect to need regularly-scheduled infusions unless bleeding is controlled. 1
- Reassess at 1 month for adequate response (hemoglobin rise ≥1.0 g/dL, normalization of ferritin and transferrin saturation). 1
Step 2: Control Bleeding Source
- Begin with nasal moisturization (air humidification, topical saline gels) for epistaxis. 2, 3
- Add oral tranexamic acid (500 mg twice daily, titrating to 1000 mg four times daily) if moisturization fails—this reduces epistaxis duration by 17.3% and composite endpoints by 54%. 2, 3
- Reserve systemic bevacizumab (5 mg/kg IV every 2 weeks for 4-6 doses, then maintenance every 1-3 months) for refractory bleeding—this produces a 50% reduction in epistaxis severity score and mean hemoglobin improvement of 3.2 g/dL. 1, 3
Step 3: Treat Underlying AVMs
- Perform percutaneous transcatheter embolization for pulmonary AVMs causing hypoxemia, regardless of feeding artery size. 2, 4
- Consider systemic antiangiogenic therapy for symptomatic hepatic AVMs with high-output cardiac failure, though invasive therapies should be avoided unless medical management fails. 2
Critical Pitfalls
Do not focus solely on hemoglobin levels—treatment decisions should prioritize quality of life, as even mild anemia with iron deficiency causes significant fatigue and functional impairment. 2, 3
Evaluate for additional causes of anemia if response to iron replacement is inadequate, as concomitant hemolysis may contribute in a subset of patients. 1
Never perform liver biopsy in HHT patients due to catastrophic hemorrhage risk, even when investigating hepatic involvement. 1, 2
Recognize that fatigue may persist despite hemoglobin normalization if iron stores (ferritin, transferrin saturation) remain depleted. 1