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 dysplasia characterized by abnormal direct connections between arteries and veins—termed arteriovenous malformations (AVMs) and telangiectasias—without intervening capillaries. The primary cause of HHT is pathogenic germline variants in genes critical for transforming growth factor-beta (TGF-β) signaling pathway integrity, particularly in endothelial and mural cell development and vascular stabilization. Approximately 85–90% of clinically definite HHT cases are attributable to loss-of-function mutations in one of three major genes: ENG (encoding endoglin, chromosome 9q34.11), ACVRL1 (encoding activin receptor-like kinase 1, ALK1, chromosome 12q13.13), or SMAD4 (chromosome 18q21.1). ENG and ACVRL1 mutations account for ~50% and ~40% of cases respectively; SMAD4 mutations cause a combined syndrome of HHT and juvenile polyposis (JP-HHT), with distinct gastrointestinal and colorectal cancer risks. Rarely, mutations in GDF2 (encoding BMP9) or RASA1 (associated with capillary malformation–arteriovenous malformation syndrome, though phenotypically overlapping) may underlie atypical HHT presentations. These genetic defects impair TGF-β/BMP-mediated endothelial cell quiescence, migration, and pericyte recruitment, resulting in fragile, dilated microvascular structures prone to rupture.

Triggers of clinical manifestations are largely mechanical or hemodynamic. Epistaxis—the most common presenting symptom—often initiates during childhood or adolescence and worsens with puberty, pregnancy, or hormonal fluctuations due to estrogen-mediated vascular proliferation and increased nasal mucosal blood flow. Trauma (e.g., nose picking, dry air, nasal instrumentation), environmental desiccation (low humidity, high altitude), and upper respiratory infections provoke telangiectasia bleeding. Pulmonary AVM hemorrhage may be triggered by chest trauma, Valsalva maneuvers, or pulmonary hypertension exacerbations. Cerebral AVM rupture risk increases with systemic hypertension, anticoagulation, or thrombolytic therapy. Gastrointestinal bleeding episodes frequently follow NSAID use, corticosteroids, or iron-deficiency anemia–induced mucosal fragility.

Established risk factors include family history—first-degree relatives of affected individuals have a 50% inheritance probability—and specific genotype–phenotype correlations. ACVRL1 mutation carriers exhibit higher prevalence of pulmonary AVMs (up to 50%) and hepatic AVMs (70–80%), often with high-output cardiac failure or portal hypertension. ENG mutation carriers demonstrate greater frequency of cerebral AVMs (10–20%) and severe epistaxis. SMAD4 carriers face elevated lifetime risk of colorectal adenocarcinoma (up to 50% by age 60) and gastric polyposis. Age is a strong modifier: telangiectasias typically appear by age 10–20 years, while visceral AVMs may remain asymptomatic until adulthood or be unmasked by pregnancy, surgery, or diagnostic imaging. Female sex confers increased epistaxis severity and earlier onset of pulmonary AVM complications, likely due to hormonal influences on angiogenesis and vascular permeability.

Environmental factors play a contributory rather than causative role. Chronic exposure to dry, low-humidity environments (e.g., heated indoor air in winter, arid climates) promotes nasal mucosal desiccation and telangiectasia fissuring. High-altitude residence (>1,500 meters) may augment hypoxia-driven VEGF upregulation, accelerating telangiectasia formation and bleeding. Occupational or recreational exposures involving repetitive nasal trauma (e.g., dust inhalation, scuba diving with barotrauma) or systemic vasodilators (e.g., excessive alcohol, certain herbal supplements) may exacerbate symptoms. While no definitive environmental mutagen has been linked to HHT de novo mutation, advanced paternal age modestly increases the likelihood of sporadic pathogenic variants. Importantly, modifiable cardiovascular risk factors—including uncontrolled hypertension, smoking (which impairs endothelial repair and promotes oxidative stress), and obesity-related chronic inflammation—may accelerate AVM progression and increase hemorrhagic or thromboembolic complications. Routine screening for visceral AVMs (especially pulmonary and cerebral) and anticipatory management of modifiable triggers and comorbidities are essential components of multidisciplinary hematologic care.

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant vascular dysplasia characterized by abnormal direct connections between arterioles and venules—termed arteriovenous malformations (AVMs)—and mucocutaneous telangiectasias. It predominantly affects the pulmonary, cerebral, hepatic, and gastrointestinal vasculature, with manifestations varying widely in age of onset, severity, and organ involvement. Early symptoms typically emerge in childhood or adolescence but may be subtle and overlooked. Epistaxis—recurrent, spontaneous, and often bilateral nasal bleeding—is the most common initial presentation, occurring in over 90% of affected individuals by age 20. These episodes usually begin between ages 6 and 12 years and progressively increase in frequency and duration due to progressive telangiectasia formation on the nasal septum (especially Kiesselbach’s plexus). Mild, intermittent epistaxis may initially be attributed to environmental dryness or trauma; however, its recurrent, unprovoked nature—often requiring nasal packing, cautery, or transfusion support in severe cases—is highly suggestive. Cutaneous telangiectasias may appear concurrently or slightly later, commonly on the lips, oral mucosa, fingertips, and face, becoming more prominent with age and sun exposure. They are small (0.5–3 mm), blanchable, spider-like lesions that may bleed with minor trauma.

Typical symptoms reflect systemic AVM burden and cumulative microvascular fragility. Chronic, recurrent epistaxis remains the hallmark, frequently leading to iron-deficiency anemia—manifesting as fatigue, pallor, exertional dyspnea, tachycardia, and reduced exercise tolerance. Gastrointestinal (GI) telangiectasias develop in approximately 20–30% of adults with HHT, typically after age 40, and present with occult or overt GI bleeding: melena, hematochezia, or chronic iron loss. Hepatic AVMs occur in up to 75% of patients but are clinically silent in most; symptomatic involvement (hepatic HHT) may cause high-output cardiac failure (due to intrahepatic shunting), portal hypertension, biliary ischemia (leading to cholangitis or secondary sclerosing cholangitis), or hepatomegaly with abdominal bruits. Pulmonary AVMs (PAVMs), present in ~40–50% of genetically confirmed cases, are particularly critical: they predispose to paradoxical embolism, resulting in ischemic stroke or transient ischemic attack (TIA) in up to 30–40% of untreated individuals, brain abscess (10–15%), and hemoptysis or hemothorax (less common). Cerebral AVMs (CAVMs), found in ~10% of patients, may remain asymptomatic or cause seizures, focal neurological deficits, intracranial hemorrhage, or headache. Spinal AVMs are rare but can produce myelopathy or radicular pain.

Accompanying symptoms include migraine headaches (reported in up to 60%, possibly linked to microemboli or nitric oxide dysregulation), dyspnea on exertion (from anemia, PAVM-induced hypoxemia, or high-output heart failure), orthostatic dizziness (secondary to chronic anemia or autonomic dysregulation), and digital clubbing (in advanced hepatic or pulmonary disease). Patients may report cyanosis or platypnea (dyspnea worsened in upright position, relieved by lying supine)—a classic sign of right-to-left shunting through PAVMs. Some exhibit telangiectasia-associated arthropathy, though causality remains debated. Neurocognitive complaints—including memory lapses, executive dysfunction, or 'brain fog'—are increasingly recognized, potentially reflecting chronic cerebral microembolization or hypoxemia.

Complications arise from hemorrhage, shunting, or embolic phenomena. Severe, refractory epistaxis can lead to transfusion-dependent anemia, iron overload (particularly with repeated IV iron or transfusions), and nasoseptal perforation or atrophy. GI bleeding may necessitate endoscopic ablation, angiographic embolization, or surgery, with risk of rebleeding and nutritional deficiencies. PAVMs confer a 10-fold increased risk of ischemic stroke and a 1,000-fold higher incidence of brain abscess compared to the general population; mortality from untreated large PAVMs approaches 10% per decade due to hemorrhage or embolism. CAVMs carry a lifetime hemorrhage risk of ~1–3% per year, with significant morbidity and mortality. Hepatic AVMs may progress to cirrhosis, portopulmonary hypertension, or cardiac decompensation. Pregnancy poses heightened risks—including accelerated telangiectasia growth, exacerbated epistaxis, PAVM rupture, and maternal stroke—mandating preconception counseling and multidisciplinary surveillance.

Diagnosis relies on the Curaçao Criteria: (1) spontaneous, recurrent epistaxis; (2) multiple mucocutaneous telangiectasias at characteristic sites (lips, oral cavity, fingers, nose); (3) visceral AVMs (pulmonary, cerebral, hepatic, GI, spinal); and (4) first-degree relative with HHT. Definite HHT requires ≥3 criteria; possible HHT is assigned with 2 criteria; and unlikely with ≤1. Genetic testing identifies pathogenic variants in *ENG* (HHT1), *ACVRL1* (HHT2), *SMAD4* (JP-HHT overlap syndrome), or *GDF2* (HHT5) in >85% of clinically definite cases and is recommended for confirmation, family screening, and prognostication (*ENG* mutations associate with earlier PAVM onset and higher stroke risk; *ACVRL1* with later-onset, more hepatic involvement). Screening modalities include contrast-enhanced transthoracic echocardiography (cTTE) with agitated saline for PAVM detection (sensitivity >95% for shunts >1.5 mm), followed by CT pulmonary angiography for characterization. Brain MRI with contrast is standard for CAVM screening. Hepatic Doppler ultrasound and contrast-enhanced MRI assess hepatic shunting. GI evaluation involves video capsule endoscopy or bidirectional endoscopy if bleeding or anemia is present. Pulmonary function tests may reveal diffusion impairment (DLCO reduction) even without radiographic PAVMs.

Differential diagnosis includes other causes of recurrent epistaxis and telangiectasias: Ataxia-Telangiectasia (ATM gene mutations; features cerebellar ataxia, immunodeficiency, radiosensitivity, and elevated AFP); generalized essential telangiectasia (benign, non-hereditary, no visceral AVMs or epistaxis); collagen vascular diseases (e.g., systemic sclerosis—associated with Raynaud’s, skin tightening, autoantibodies); and acquired conditions such as chronic liver disease (spider angiomata, but no epistaxis or AVMs) or chronic sun damage. Hereditary hemorrhagic disorders (e.g., von Willebrand disease, platelet function defects) must be excluded via coagulation studies and platelet function assays—though these do not explain telangiectasias or visceral AVMs. SMAD4-related juvenile polyposis–HHT overlap syndrome requires distinction from isolated juvenile polyposis (absence of telangiectasias/epistaxis) and familial adenomatous polyposis (different polyp histology and APC mutation). Accurate differentiation guides surveillance intensity, genetic counseling, and therapeutic interventions.

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.