Hereditary Hemorrhagic Telangiectasia Medical Services in China

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a rare, autosomal dominant genetic disorder characterized by abnormal blood vessel formation—specifically, direct connections between arteries and veins without intervening capillaries (arteriovenous malformations, or AVMs) and fragile, dilated small vessels (telangiectasias). These vascular anomalies occur predominantly in the skin, mucosa (especially nasal and oral), lungs, brain, liver, and gastrointestinal tract. Pathogenesis stems from mutations in genes involved in transforming growth factor-beta (TGF-β) signaling, most commonly ENG (encoding endoglin, HHT type 1), ACVRL1 (encoding ALK1, HHT type 2), and less frequently SMAD4 (HHT–juvenile polyposis overlap syndrome) or GDF2. Dysfunctional TGF-β signaling impairs endothelial cell maturation and vascular stabilization, leading to progressive telangiectasia development and AVM formation. Epidemiologically, HHT affects approximately 1 in 5,000 to 1 in 8,000 individuals worldwide, with no significant gender or ethnic predilection; however, underdiagnosis remains widespread—up to 80% of cases may go unrecognized due to variable expressivity and mild early presentations. Key risk factors include family history (nearly 100% penetrance by age 40), consanguinity (rarely), and specific genotype–phenotype correlations: ENG mutations confer higher risk of pulmonary AVMs (20–30%), while ACVRL1 mutations correlate with hepatic AVMs (70–80%) and lower pulmonary involvement. Clinical manifestations range from recurrent spontaneous epistaxis (present in >90% of adults), which often begins in childhood or adolescence, to life-threatening complications including ischemic stroke (from paradoxical embolism via pulmonary AVMs), cerebral hemorrhage (from cerebral AVMs), high-output heart failure (due to hepatic shunting), and severe iron-deficiency anemia from chronic GI bleeding. Quality of life is significantly impaired: patients report chronic fatigue, social embarrassment from visible telangiectasias and nosebleeds, anxiety about sudden hemorrhage or stroke, limitations in physical activity, frequent medical visits, and reduced work productivity. Psychological burden—including depression and health-related anxiety—is prevalent, particularly among those with untreated pulmonary or cerebral AVMs. Early diagnosis using the Curaçao criteria (spontaneous recurrent epistaxis, multiple mucocutaneous telangiectasias, visceral AVMs, and first-degree family history) enables timely screening (e.g., contrast echocardiography for pulmonary AVMs, brain MRI, hepatic Doppler) and preventive interventions, substantially reducing morbidity and mortality.

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant vascular disorder characterized by abnormal direct connections between arteries and veins—termed arteriovenous malformations (AVMs)—and mucocutaneous telangiectasias. These lesions predispose patients to recurrent epistaxis, gastrointestinal bleeding, ischemic stroke, brain abscess, and high-output cardiac failure. Management requires a multidisciplinary approach coordinated by hematologists, interventional radiologists, otolaryngologists, gastroenterologists, pulmonologists, and genetic counselors. Treatment strategies are tailored to lesion location, size, symptom burden, and complication risk—not disease stage—since HHT is lifelong and progressive.

Conservative treatment forms the cornerstone of long-term management, particularly for mild or asymptomatic cases. Nasal humidification using saline nasal sprays and ointments (e.g., petrolatum-based emollients) reduces mucosal dryness and fragility, thereby decreasing epistaxis frequency and severity. Patients are advised to avoid nasal trauma, NSAIDs, anticoagulants, and thrombolytics unless strongly indicated; aspirin may be cautiously continued in select cardiovascular indications after shared decision-making. Iron supplementation—oral ferrous sulfate or intravenous ferric carboxymaltose—is essential for iron-deficiency anemia secondary to chronic blood loss. Regular monitoring of hemoglobin, ferritin, and transferrin saturation guides replacement therapy. Endoscopic nasal cautery (silver nitrate or electrocautery) provides short-term control of anterior nasal telangiectasias but carries recurrence risk. For gastrointestinal telangiectasias, endoscopic argon plasma coagulation (APC) offers targeted ablation with low complication rates, though repeat sessions are often needed.

Pharmacologic interventions remain adjunctive and evidence-limited. Antifibrinolytic agents such as tranexamic acid (500–1,000 mg orally three times daily) reduce epistaxis duration and volume by inhibiting plasmin-mediated clot lysis; it is contraindicated in active thromboembolic disease or history of venous thromboembolism (VTE). Bevacizumab—a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF)—has demonstrated efficacy in severe hepatic AVMs and refractory epistaxis. Intravenous bevacizumab (5–10 mg/kg every 2–3 weeks for 4–6 doses, then maintenance) improves hepatic perfusion, reduces cardiac output, and decreases transfusion dependence. However, its use requires rigorous VTE and hypertension screening and monitoring due to prothrombotic and hypertensive risks. Thalidomide has shown modest benefit in reducing epistaxis and improving hemoglobin in small trials, likely via anti-angiogenic and immunomodulatory effects, but teratogenicity, neuropathy, and sedation limit its utility. Pazopanib and other tyrosine kinase inhibitors are under investigation but not yet standard-of-care.

Surgical and interventional therapies target high-risk or symptomatic AVMs. Pulmonary AVMs (PAVMs) carry significant risks of paradoxical embolism and brain abscess; therefore, all PAVMs ≥3 mm in diameter should undergo transcatheter embolization using detachable coils or vascular plugs. Embolization reduces stroke and abscess incidence by >90% when performed at experienced centers. Cerebral AVMs require individualized assessment: asymptomatic small lesions may be observed, while large or hemorrhagic AVMs may warrant stereotactic radiosurgery, microsurgical resection, or endovascular embolization—often in combination. Hepatic AVMs rarely require intervention unless causing high-output heart failure, portal hypertension, or biliary ischemia; in such cases, selective hepatic artery embolization or liver transplantation may be considered. Severe, refractory epistaxis unresponsive to conservative and endoscopic measures may necessitate surgical options including septodermoplasty (nasal mucosal replacement with skin grafts) or endoscopic sphenopalatine artery ligation (ESPAL), which achieves durable control in >80% of cases. Gastrointestinal bleeding refractory to APC may require segmental resection, though this is reserved for focal, surgically accessible lesions.

China offers distinct advantages in HHT management, particularly through centralized, multidisciplinary HHT Centers of Excellence established under the Chinese HHT Alliance (founded 2018). These centers—located in Beijing, Shanghai, Guangzhou, and Chengdu—employ standardized diagnostic protocols aligned with the Curacao criteria and integrate next-generation sequencing for *ENG*, *ACVRL1*, *SMAD4*, and *GDF2* mutation analysis with <72-hour turnaround. Interventional radiology expertise is highly advanced, with widespread availability of real-time cone-beam CT-guided embolization for complex PAVMs and hepatic AVMs. China’s national health insurance now covers bevacizumab for HHT-related complications (since 2022), significantly improving access compared to many Western countries. Additionally, large-scale prospective registries (e.g., the China HHT Registry, n > 2,400 patients) facilitate rapid clinical trial enrollment and evidence generation specific to Asian populations, revealing differences in *ACVRL1* predominance and lower PAVM prevalence than Western cohorts. Telemedicine networks enable rural patients to receive specialist consultation and coordinate local transfusion support, enhancing continuity of care.

Recovery and long-term follow-up emphasize patient empowerment and prevention. All diagnosed individuals should undergo baseline screening: contrast-enhanced chest CT for PAVMs, brain MRI for cerebral AVMs, abdominal ultrasound/Doppler for hepatic involvement, and upper/lower endoscopy if GI symptoms exist. Screening intervals depend on initial findings—e.g., PAVM-negative patients repeat chest CT every 5 years; those with treated PAVMs require annual contrast echocardiography. Patients must receive antibiotic prophylaxis (e.g., amoxicillin 2 g pre-procedure) before dental or invasive procedures to prevent brain abscess. Genetic counseling and cascade testing are recommended for first-degree relatives. Lifestyle modifications include avoiding scuba diving (risk of nitrogen bubble embolism through PAVMs), maintaining adequate hydration, and using humidifiers year-round. Annual hematologic evaluation—including complete blood count, serum ferritin, and reticulocyte count—is mandatory. Psychosocial support is integral: chronic epistaxis and fatigue contribute to anxiety and depression, and structured programs incorporating cognitive behavioral therapy and peer support groups are increasingly available in major academic hospitals. With proactive, protocol-driven care, most HHT patients achieve stable hemoglobin levels, preserved organ function, and near-normal life expectancy.