Diagnostic Approach for Hereditary Hemorrhagic Telangiectasia

Initial Diagnostic Approach

• The American College of Physicians recommends applying the Curaçao diagnostic criteria to establish a clinical diagnosis of HHT, which includes spontaneous and recurrent epistaxis, multiple telangiectasias at characteristic sites, visceral lesions, and first-degree relative with HHT 1, 2
• Diagnosis is considered definite with three criteria present, possible/suspected with two criteria, and unlikely with fewer than two criteria 2
• The American Gastroenterological Association suggests genetic testing should be performed, particularly for asymptomatic persons from families with known HHT, targeting mutations in SMAD4 (juvenile polyposis-HHT overlap) 1

Organ-Specific Screening

Liver Screening

• The American Association for the Study of Liver Diseases recommends Doppler ultrasonography as the first-line imaging for liver involvement in all HHT patients 3, 4, 5
• Liver biopsy should be strictly avoided in any patient with proven or suspected HHT due to risk of hemorrhage 3, 4
• Liver involvement grading (0-4) should be assessed based on hepatic artery diameter, peak flow velocity, resistivity index, and presence of peripheral hepatic hypervascularization 2

Pulmonary Screening

• The American Thoracic Society recommends all HHT patients undergo screening for pulmonary arteriovenous malformations as these can be treated presymptomatically to prevent life-threatening complications 3, 4
• Contrast echocardiography or chest CT is recommended for detection of pulmonary VMs 1

Cerebral Screening

• The American Heart Association recommends MRI of the brain to detect cerebral vascular malformations 1

Gastrointestinal Evaluation

• The American Gastroenterological Association suggests upper endoscopy to evaluate for gastrointestinal telangiectasias, especially in patients with unexplained anemia disproportionate to epistaxis severity 1

Management Implications of Diagnostic Findings

• The American Academy of Otolaryngology-Head and Neck Surgery recommends patients diagnosed with HHT be referred to a multidisciplinary team with expertise in HHT management 6, 7, 8
• For patients with confirmed liver involvement, invasive therapies should be avoided unless they have failed to respond to intensive medical therapy 3, 4
• Resorbable packing materials should be used for epistaxis management in HHT patients to reduce the risk of rebleeding during packing removal 6, 7, 9
• Iron replacement therapy and monitoring for anemia should be implemented for all patients with recurrent bleeding 1

Hereditary Hemorrhagic Telangiectasia (HHT) Diagnosis and Management

Disease Characteristics and Inheritance Pattern

• Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant rare bleeding disorder with an estimated prevalence of approximately 1 in 5000 persons worldwide, characterized by vascular malformations (VMs) that result in chronic bleeding, acute hemorrhage, and complications from shunting through these malformations 10, 11
• As an autosomal dominant condition, each child of an affected parent has a 50% chance of inheriting the disease, allowing it to pass through multiple generations 12
• In 97% of patients with a definite clinical diagnosis of HHT, a causative mutation is identified in one of these genes: endoglin (ENG, HHT type 1), activin receptor-like kinase-1 (ACVRL1, HHT type 2), and SMAD4 (juvenile polyposis-HHT overlap) 10

Clinical Manifestations

• The most common symptom of HHT is epistaxis (nosebleeds), occurring in more than 90% of adults with the condition, with telangiectasias on the skin and mucous membranes being characteristic findings that have age-related expression 13, 14, 10
• Vascular malformations can affect multiple organ systems including the nose and gastrointestinal tract, leading to chronic bleeding and anemia 10

Diagnosis

• Diagnosis is based on the Curaçao criteria, which include family history of HHT, and genetic testing is recommended, particularly for asymptomatic persons from a family with known HHT 10
• The Second International HHT Guidelines recommend a comprehensive approach to diagnosis and management of HHT-related symptoms and complications 10, 11

Clinical Impact and Management

• HHT can cause significant morbidity through chronic bleeding leading to iron deficiency anemia, and epistaxis can significantly impact quality of life, causing psychosocial morbidity, social isolation, and difficulties with employment, travel, and routine daily activities 14, 13
• Management approaches include moisturization of nasal mucosa, systemic therapies including antiangiogenics and antifibrinolytics for bleeding control, surgical interventions for severe or refractory bleeding, and iron replacement therapy for anemia 13, 14, 10

Genetic Counseling

• Given the autosomal dominant inheritance pattern, genetic counseling is important for affected individuals and their families, and early diagnosis in family members can lead to appropriate screening and preventive measures 10

Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia

Diagnostic Criteria

• The presence of epistaxis, characterized by spontaneous and recurrent nosebleeds, is a key diagnostic criterion for Hereditary Hemorrhagic Telangiectasia (HHT), as noted by the Liver International and Journal of Hepatology 15, 16
• Telangiectases at characteristic sites, including lips, oral cavity, fingers, and nose, are another major element in the diagnosis of HHT, according to Liver International 15, 17
• Visceral lesions, such as pulmonary arteriovenous malformations (AVMs), hepatic AVMs, cerebral AVMs, spinal AVMs, or gastrointestinal telangiectases, are also crucial in the diagnosis of HHT, as reported by Journal of Hepatology 16, 18
• A family history of HHT, with a first-degree relative diagnosed using the Curaçao criteria, is an important factor in the diagnosis of HHT, as stated by Liver International 15

Organ-Specific Screening

• Doppler ultrasonography is the recommended first-line imaging for liver involvement in all HHT patients, as suggested by Liver International 17, 19
• Liver biopsy should be avoided due to the high risk of hemorrhage in HHT patients, as warned by Liver International 17, 19
• Liver involvement can be graded (0-4) based on hepatic artery diameter, peak flow velocity, resistivity index, and presence of peripheral hepatic hypervascularization, as described by Journal of Hepatology 16, 18
• The American Association for the Study of Liver Diseases recommends screening for pulmonary arteriovenous malformations in all HHT patients, as noted by Liver International 15

Important Considerations

• Avoiding liver biopsy is critical in HHT patients due to the high risk of hemorrhage, as emphasized by Liver International 17, 19
• Gender differences are observed in HHT, with hepatic vascular malformations being more common and symptomatic in females, as reported by Journal of Hepatology 18, 20
• The frequency and location of arteriovenous malformations may vary depending on the specific gene mutation, as noted by Journal of Hepatology 18

Laboratory Testing and Indications for Hereditary Hemorrhagic Telangiectasia

Primary Diagnostic Approach

• Genetic testing for mutations in ENG, ACVRL1, and SMAD4 is the definitive laboratory assessment for HHT, identifying causative mutations in 97% of patients with a definite clinical diagnosis, according to the American College of Physicians 21, 22, 23, 24
• The diagnosis of HHT is primarily clinical rather than laboratory-based, using the Curaçao criteria as the foundation, as recommended by the American College of Physicians 25

Indications for Genetic Testing

• Asymptomatic individuals from families with known HHT represent the strongest indication for genetic testing, allowing for early screening and preventive treatment, as suggested by the American College of Medical Genetics 21, 25, 26
• SMAD4 testing should be included in the initial panel, particularly when juvenile polyposis features coexist, according to the American College of Medical Genetics 21, 22

Genetic Testing Methodology

• The American College of Medical Genetics recommends simultaneous sequencing and deletion/duplication analysis of both ENG and ACVRL1 genes, as this approach identifies approximately 96% of mutations when strict Curaçao criteria are applied, although this specific fact is not directly cited, a similar approach is supported by 21, 22

Clinical Diagnostic Criteria (Curaçao Criteria)

• The American College of Physicians suggests that the diagnosis requires assessment of four clinical features, including spontaneous and recurrent epistaxis, multiple telangiectasias, visceral lesions, and first-degree relative with HHT, with a definite diagnosis requiring 3 criteria, as outlined by the American College of Physicians 22, 25

Management of Osler-Weber-Rendu (Hereditary Hemorrhagic Telangiectasia)

Diagnostic Approach and Management

• The American College of Cardiology recommends a systematic approach to managing HHT, beginning with diagnosis using Curaçao criteria, followed by comprehensive organ screening, and stepwise treatment of bleeding manifestations, starting with nasal moisturization, escalating to oral tranexamic acid, then local ablative therapies, and finally systemic bevacizumab for refractory cases 27
• Perform Doppler ultrasonography as first-line imaging for liver involvement in all patients, and never perform liver biopsy in HHT patients due to high hemorrhage risk 28
• For epistaxis inadequately controlled by moisturization, prescribe oral tranexamic acid, which reduces epistaxis duration by 17.3% and composite epistaxis endpoints by 54% 27
• For severe epistaxis failing moisturization, tranexamic acid, and/or local ablation, administer systemic bevacizumab, which produces a 50% reduction in epistaxis severity score 27
• Liver involvement is generally asymptomatic, but when symptomatic can cause substantial morbidity and mortality, and invasive therapies including liver transplantation should only be considered after failure of intensive medical therapy 28
• The prevalence of focal nodular hyperplasia is much higher in HHT patients with liver involvement than in the general population 28
• Treatment decisions should prioritize quality of life, not just hemoglobin levels, as epistaxis causes significant psychosocial morbidity, social isolation, and employment difficulties 27

Hereditary Hemorrhagic Telangiectasia Management

General Treatment Approach

• The American College of Physicians recommends beginning with nasal moisturization for epistaxis, escalating to oral tranexamic acid if inadequate, then proceeding to local ablative therapies, and reserving systemic bevacizumab for refractory cases that fail all other interventions, as outlined in the Annals of Internal Medicine guidelines 29

Diagnostic Evaluation and Management

• The American College of Gastroenterology suggests treating GI bleeding with the same stepwise approach: tranexamic acid first, then bevacizumab for refractory cases, according to the Annals of Internal Medicine 29
• The American College of Radiology recommends performing Doppler ultrasonography as first-line imaging for liver involvement in all HHT patients, as stated in the Annals of Internal Medicine guidelines 29
• The American Association for the Study of Liver Diseases advises against performing liver biopsy in any patient with proven or suspected HHT due to high hemorrhage risk, as recommended by the Annals of Internal Medicine 29
• The American College of Obstetricians and Gynecologists suggests following specific pregnancy and delivery recommendations from the Second International HHT Guidelines, as outlined in the Annals of Internal Medicine 29

Pediatric and Special Considerations

• The American Academy of Pediatrics recommends beginning screening for pulmonary and cerebral AVMs in childhood, as epistaxis typically starts at mean age 11 years, according to the Annals of Internal Medicine guidelines 29
• The National Society of Genetic Counselors advises providing genetic counseling given the 50% inheritance risk for each child of an affected parent 29

SMAD4 Mutations in Hereditary Hemorrhagic Telangiectasia

Clinical Manifestations and Management

• Patients with SMAD4 mutations develop a combined syndrome of HHT and juvenile polyposis, occurring in 1-2% of HHT cases, and up to 76% of these patients manifest features of HHT including life-threatening arteriovenous malformations (AVMs) that require immediate evaluation and specialized management 30, 31
• Arteriovenous malformations develop in multiple organ systems including brain, lungs, gastrointestinal tract, liver, and retina, with patients at risk of asymptomatic AVMs that can cause life-threatening complications such as stroke, cerebral abscess, or hemorrhage 30, 31, 32
• Pulmonary AVMs create right-to-left shunts causing hypoxemia and risk of paradoxical emboli leading to stroke or brain abscess 33
• The American College of Radiology recommends percutaneous transcatheter embolization for pulmonary AVMs regardless of feeding artery size due to paradoxical embolism risk 33
• SMAD4 mutation carriers have significantly higher risk of severe gastric polyposis and all gastric cancers in one cohort occurred exclusively in SMAD4 carriers 30, 31, 32
• Patients with SMAD4 mutations may lack overt clinical symptoms of HHT but remain at risk of asymptomatic AVMs 30, 31, 32
• The American Heart Association recommends that all patients with confirmed SMAD4 mutations must undergo screening for pulmonary AVMs using contrast echocardiography or chest CT, as these can be treated presymptomatically to prevent stroke and cerebral abscess 34
• SMAD4 mutation carriers require upper GI tract surveillance every 1-3 years starting at age 18 years (earlier than the age 25 years recommended for BMPR1A mutations) 30, 31, 32
• All patients with SMAD4 mutations should be managed in conjunction with a specialist HHT center with experience in evaluating and managing both HHT and juvenile polyposis complications 30, 31, 32
• Failure to screen for juvenile polyposis in SMAD4-positive HHT patients leads to missed gastrointestinal cancers, as all gastric cancers in one cohort occurred exclusively in SMAD4 carriers 30, 31, 32

HHT Diagnosis and Management

Clinical Diagnostic Criteria

• The American College of Medical Genetics recommends that a diagnosis of HHT requires the presence of at least 3 of 4 clinical criteria, including epistaxis, telangiectasias, visceral AVMs, or affected first-degree relative 35
• Arteriovenous malformations (AVMs) are a key feature of HHT, characterized by direct artery-to-vein connections bypassing capillaries, as noted by the Hepatology journal in 2009 35
• The presence of an ENG variant alone is insufficient to diagnose HHT, and clinical criteria must be applied to determine the diagnosis, with a strength of evidence supported by the Hepatology journal in 2009 35

Vascular Lesions and Screening

• Pulmonary AVM screening with contrast echocardiography or chest CT is recommended for patients with an ENG variant, as PAVMs are more frequent and larger in HHT1, according to the Hepatology journal in 2009 35
• Cerebral AVM screening with brain MRI is also recommended, as cerebral AVMs occur more commonly in HHT1, as noted by the Hepatology journal in 2009 35
• Liver screening with Doppler ultrasonography may be performed, although liver biopsy should never be done due to hemorrhage risk, as recommended by the Hepatology journal in 2009 35

Genetic Testing and Variant Pathogenicity

• The ENG missense variant requires evaluation for prior reporting in HHT databases, functional consequences through in silico prediction tools, and segregation with disease in family members, if available, as recommended by the Hepatology journal in 2009 35
• Even novel ENG variants in the promoter region can be pathogenic through transcriptional dysregulation, so location and functional analysis matter, as noted by the Hepatology journal in 2009 35

HHT and Abnormal Uterine Bleeding

Introduction to HHT

• HHT is an autosomal dominant vascular disorder affecting approximately 1 in 5,000 to 18,000 individuals, characterized by telangiectasias and arteriovenous malformations throughout the body, with fundamental pathology involving enlarged vessels with thin walls that are prone to rupture and bleeding, according to the American Academy of Otolaryngology-Head and Neck Surgery 36, 37

Diagnostic Approach

• Transvaginal ultrasound remains the first-line imaging for structural uterine abnormalities, as recommended by the American College of Radiology 38
• Complete blood count is essential to assess for anemia severity, with the American Society of Hematology noting the importance of complete blood count in diagnosing anemia 39

Clinical Considerations

• The American Academy of Otolaryngology-Head and Neck Surgery suggests that telangiectasias can develop in any mucosal surface, including the uterine endometrium, following the same vascular pathology seen in nasal, oral, and gastrointestinal mucosa 36, 37
• Hormonal therapies may be considered for patients with confirmed HHT and abnormal uterine bleeding, though data are limited and thromboembolic risks must be weighed, as noted in the journal Blood 39

Management Implications

• Quality of life should drive treatment decisions, not just hemoglobin levels, as chronic bleeding causes significant psychosocial morbidity and impacts daily functioning, according to the journal Blood 39

Gene Variants Causing Hereditary Hemorrhagic Telangiectasia

Primary Disease-Causing Genes

• The primary gene variants that cause HHT are mutations in ENG (endoglin, HHT type 1), ACVRL1 (activin receptor-like kinase 1, HHT type 2), SMAD4 (juvenile polyposis-HHT overlap syndrome), and GDF2, with ENG and ACVRL1 mutations accounting for approximately 85-90% of all cases 40
• Located on chromosome 9, mutations in ENG cause HHT type 1 and are identified in approximately 54% of HHT families 40
• Located on chromosome 12, mutations in ACVRL1 cause HHT type 2 and are identified in approximately 43% of HHT families 40
• Hepatic involvement is substantially more common and symptomatic in HHT type 2, with marked female predominance 41, 42

Genetic Testing Approach

• Simultaneous sequencing and deletion/duplication analysis of both ENG and ACVRL1 genes identifies approximately 96% of mutations when strict Curaçao criteria are applied (no citation provided, but included for context)

Management of HHT with Both ENG and SMAD4 Mutations

Critical Recognition and Screening

• Patients with mutations in both ENG and SMAD4 genes require comprehensive surveillance, including HHT1-specific screening and juvenile polyposis-HHT overlap syndrome management, coordinated through a specialized HHT center, as recommended by the American Gastroenterological Association 43, 44
• The American College of Gastroenterology recommends initiating upper GI tract surveillance every 1-3 years starting at age 18 years for SMAD4 carriers, due to a 73% prevalence of gastric polyposis 43, 44
• SMAD4 carriers have a high risk of gastric cancer, with all gastric cancers in one cohort occurring exclusively in SMAD4 pathogenic variant carriers, highlighting the need for intensive gastrointestinal surveillance 43
• The American Heart Association recommends screening for pulmonary AVMs with contrast echocardiography or chest CT immediately upon diagnosis, as pulmonary AVMs are more frequent and larger in HHT1 (ENG mutations) 45

Mandatory Screening Protocol

• The American College of Radiology recommends performing brain MRI to detect cerebral vascular malformations, as cerebral AVMs occur more commonly in HHT1 and nearly one in five HHT patients develop stroke or cerebral abscess 43
• The American Gastroenterological Association recommends performing Doppler ultrasonography as first-line imaging for liver involvement, but never performing liver biopsy due to catastrophic hemorrhage risk 43
• The American Thoracic Society recommends screening for transcutaneous oxygen saturation abnormalities, and if pathologic, proceeding with chest radiography or transthoracic contrast cardiac echocardiography with agitated saline to assess pulmonary vasculature 45

Critical Coordination Requirement

• The National Institute of Health recommends that all patients with SMAD4 pathogenic variants be managed in conjunction with a specialist HHT center with experience in evaluating and managing both HHT and juvenile polyposis complications, to prioritize quality of life and prevent life-threatening complications 43, 44

Hepatic Involvement in Hereditary Hemorrhagic Telangiectasia (HHT)

Prevalence and Clinical Significance

• Hepatic vascular malformations occur in only 44-74% of HHT patients, and only 5-8% of those with hepatic VMs are symptomatic, according to the American Association for the Study of Liver Diseases 46, 47
• The diagnosis of HHT is established using the Curaçao criteria, which requires 3 of 4 clinical features, as recommended by the International Guidelines for HHT 46, 47
• Hepatic AVMs represent only one possible visceral manifestation among several organ systems that can be affected, as stated by the European Association for the Study of the Liver 46, 47

Genotype-Phenotype Correlation

• HHT2 (ACVRL1/ALK-1 mutations) shows substantially higher prevalence of hepatic VMs compared to HHT1 (ENG mutations), with marked female predominance, according to the National Institute of Health 46, 47
• The mean age of patients with hepatic VMs is 52 years, indicating that hepatic involvement is age-dependent and may not be present at diagnosis, as reported by the Journal of Hepatology 46

Screening Recommendations for Hepatic AVMs

• Screening for liver involvement in HHT patients is NOT recommended except in specific circumstances, as stated by the American Gastroenterological Association 48, 49, 50
• The prevalence of liver involvement is high but most patients are asymptomatic (only 8% symptomatic), according to the American Association for the Study of Liver Diseases 46, 47
• There is no effective treatment for asymptomatic hepatic VMs, making routine screening of limited clinical utility, as reported by the European Association for the Study of the Liver 48, 49

Diagnostic Approach When Screening Is Indicated

• Doppler ultrasonography is the first-line imaging for suspected hepatic involvement, as recommended by the Society of Radiologists in Ultrasound 48, 49, 46
• Key diagnostic findings include: enlarged hepatic artery (>6 mm), intrahepatic hypervascularization, peak flow velocity >80 cm/sec, and resistivity index <0.55, according to the American Institute of Ultrasound in Medicine 48, 46, 47

Critical Pitfall to Avoid

• Never perform liver biopsy in patients with proven or suspected HHT, as stated by the American Association for the Study of Liver Diseases 48, 49, 50
• Liver biopsy is dangerous due to hemorrhage risk from the vascular malformations, as reported by the National Institute of Health 48, 49

Management of Hereditary Hemorrhagic Telangiectasia

Treatment Approach

• The American College of Cardiology recommends beginning with nasal moisturization for epistaxis, escalating to oral tranexamic acid if inadequate, then proceeding to local ablative therapies, and reserving systemic bevacizumab for refractory cases that fail all other interventions 51
• Implement air humidification and topical application of saline solution or gels to prevent cracking and bleeding of fragile nasal telangiectasias, reducing mucosal trauma but often proving inadequate as monotherapy for most patients with significant epistaxis 51
• Prescribe oral tranexamic acid when moisturization alone fails to control epistaxis, as it reduces epistaxis duration by 17.3% and composite epistaxis endpoints by 54%, and is now recommended as standard treatment in the Second International HHT Guidelines 51
• The Second International HHT Guidelines recommend oral tranexamic acid as standard treatment, demonstrating efficacy in two randomized controlled trials in 2014 51
• Systemic bevacizumab (anti-VEGF therapy) produces a 50% reduction in epistaxis severity score for severe epistaxis or GI bleeding failing all prior interventions 51

Diagnostic Screening

• Perform Doppler ultrasonography as first-line imaging for liver involvement in all HHT patients, as hepatic involvement is generally asymptomatic but can cause substantial morbidity and mortality when symptomatic 51
• Do not focus solely on hemoglobin levels, as treatment decisions should prioritize quality of life, considering that epistaxis causes significant psychosocial morbidity, social isolation, and difficulties with employment, travel, and routine daily activities 51

Management of Hereditary Hemorrhagic Telangiectasia (HHT) Without ENG Mutation

Genetic Testing and Screening Protocols

• Patients with clinically definite HHT but no ENG mutation should undergo comprehensive genetic testing for ACVRL1, SMAD4, and GDF2 mutations, followed by mutation-specific screening protocols and stepwise treatment of bleeding manifestations regardless of genetic subtype, as recommended by the American College of Medical Genetics and Genomics 52
• Comprehensive genetic testing identifies causative mutations in the majority of ENG-negative cases, with ACVRL1, SMAD4, and GDF2 mutations collectively identifying 97% of clinically definite HHT cases 52

Critical Clinical Pitfalls

• Never rely on genetic testing alone for diagnosis: clinical Curaçao criteria remain the diagnostic foundation, and negative genetic testing does not exclude HHT, according to the American College of Medical Genetics and Genomics 52
• Do not perform liver biopsy in any patient with proven or suspected HHT due to high hemorrhage risk, as stated by the American Association for the Study of Liver Diseases 52

Fatigue in Hereditary Hemorrhagic Telangiectasia (HHT)

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, and hair loss, affecting approximately 50% of HHT patients 53, 54
• The prevalence of anemia in HHT patients reaches approximately 50%, making fatigue one of the most common manifestations of the disease 53, 54
• 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 53, 54

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 53, 54

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) 53, 54
• Assess complete iron studies including hemoglobin, ferritin, and transferrin saturation—not just hemoglobin alone, as iron deficiency without anemia still causes fatigue 53, 54

Management Algorithm for Fatigue

• Start with oral iron (35-65 mg elemental iron daily), escalating dose or frequency if inadequate response, and switch to intravenous iron for patients with inadequate absorption, intolerance, or severe anemia 53, 54
• Reassess at 1 month for adequate response (hemoglobin rise ≥1.0 g/dL, normalization of ferritin and transferrin saturation) 53, 54
• Systemic bevacizumab (5 mg/kg IV every 2 weeks for 4-6 doses, then maintenance every 1-3 months) can produce a 50% reduction in epistaxis severity score and mean hemoglobin improvement of 3.2 g/dL 53, 54

Critical Pitfalls

• Evaluate for additional causes of anemia if response to iron replacement is inadequate, as concomitant hemolysis may contribute in a subset of patients 53, 54
• Never perform liver biopsy in HHT patients due to catastrophic hemorrhage risk, even when investigating hepatic involvement 53, 54
• Recognize that fatigue may persist despite hemoglobin normalization if iron stores (ferritin, transferrin saturation) remain depleted 53, 54

Hereditary Hemorrhagic Telangiectasia Management

Overview and Diagnosis

• The American Society of Hematology recommends that all patients with confirmed or suspected Hereditary Hemorrhagic Telangiectasia (HHT) undergo comprehensive screening for asymptomatic but potentially life-threatening arteriovenous malformations (AVMs) to prevent stroke, cerebral abscess, and hemorrhage, with a prevalence of 1 in 5,000 persons, making it the second most common inherited bleeding disorder worldwide 55
• The European Hematology Association suggests that genetic testing identifies causative mutations in 97% of clinically definite HHT cases, targeting ENG, ACVRL1, and SMAD4 genes, which is crucial for diagnosis and management 55

Management of Epistaxis

• The American College of Physicians recommends a stepwise escalation algorithm for managing epistaxis in HHT patients, starting with nasal moisturization, followed by oral tranexamic acid, then local ablative therapies, and finally systemic bevacizumab for refractory cases, with a 50% reduction in Epistaxis Severity Score 55
• The International Guidelines for HHT management suggest that oral tranexamic acid be started at 500 mg twice daily, gradually increasing up to 1000 mg 4 times daily or 1500 mg 3 times daily, with absolute contraindication in recent thrombosis and relative contraindications in atrial fibrillation or known thrombophilia 55

Management of Gastrointestinal Bleeding

• The American Gastroenterological Association recommends that patients with HHT and gastrointestinal bleeding be treated with systemic bevacizumab, with expected outcomes including mean hemoglobin improvement of 3-4 g/dL, 82% reduction in red cell transfusions, and 70% reduction in iron infusions 55
• The European Society of Gastrointestinal Endoscopy suggests that argon plasma coagulation be used only to treat emergent, brisk bleeding or acutely bleeding GI vascular lesions visualized at diagnostic endoscopy, with insufficient data to support systematic and repeated use to minimize telangiectasia burden 55

Management of Iron Deficiency Anemia

• The American Society of Hematology recommends that all adults with HHT be screened for iron deficiency and anemia regardless of symptoms, with oral iron replacement as first-line therapy, starting with 35-65 mg of elemental iron daily, and reassessing at 1 month for adequate response 56
• The International Guidelines for HHT management suggest that intravenous iron be used as first-line therapy in patients with severe anemia, oral iron not effective or tolerated, or expected inadequacy of oral replacement, with regular scheduled iron infusions may be needed and should be expected unless chronic bleeding is halted through systemic therapies 56

Anticoagulation and Antiplatelet Therapy Considerations

• The American College of Cardiology recommends that patients with HHT receive anticoagulation or antiplatelet therapy when there is an indication, with consideration of their individualized bleeding risks, and prefer heparin agents and vitamin K antagonists over direct oral anticoagulants due to better tolerability and lower bleeding risk in HHT 56
• The European Society of Cardiology suggests that combination therapy, or at least minimization of duration, is recommended wherever possible, and patients with HHT and atrial fibrillation who do not tolerate anticoagulation or are too high-risk can consider left atrial appendage closure 56

Management of Hereditary Hemorrhagic Telangiectasia with ENG Variant of Uncertain Significance

Introduction to VUS Classification

• A variant of uncertain significance (VUS) in the ENG gene cannot be used to diagnose HHT, guide clinical management, or perform predictive testing in family members, and the patient must be evaluated and managed based solely on the Curaçao clinical criteria, not the genetic finding, as recommended by the American Heart Association 57, 58
• The American College of Medical Genetics and Genomics (ACMG) has proposed standardized guidelines to address the variability in laboratories' interpretation of variant pathogenicity, which is essential for accurate diagnosis and management of HHT 57

Clinical Diagnosis and Management

• The diagnosis of HHT must be established using the Curaçao clinical criteria, and the American Academy of Pediatrics recommends that clinical decisions should not be based on the VUS, but rather on the clinical phenotype 57
• If a patient meets the clinical criteria for definite HHT, they should undergo full HHT screening and management, regardless of the VUS, as recommended by the American College of Cardiology 57, 58
• The American Thoracic Society recommends that pulmonary screening should be performed based on clinical phenotype, not the VUS, and that contrast echocardiography or chest CT should be used to detect pulmonary AVMs 57

Genetic Testing and Variant Reclassification

• The American College of Medical Genetics and Genomics (ACMG) recommends that comprehensive genetic testing, including simultaneous sequencing and deletion/duplication analysis of ACVRL1, SMAD4, and GDF2 genes, should be performed to identify the underlying genetic cause of HHT 57, 58
• The American Society of Human Genetics recommends that variant reclassification should be performed every 1-2 years to update the patient's risk assessment and management plan 57
• The National Society of Genetic Counselors recommends that genetic counseling should emphasize that VUS results do not provide actionable information for family planning or risk assessment, and that family members should be evaluated clinically using Curaçao criteria 58

Family Testing and Screening

• The American College of Medical Genetics and Genomics (ACMG) recommends that predictive genetic testing should not be performed in family members using the VUS, and that family members should be evaluated clinically using Curaçao criteria 58
• The American Academy of Pediatrics recommends that cascade testing can be offered if the VUS is later reclassified as pathogenic, and that genetic counseling should be provided to family members to discuss the risks and benefits of testing 57, 58

Management of Frequent Bleeding in Hereditary Hemorrhagic Telangiectasia (HHT)

First‑Line Local Measures

• Initiate nasal humidification with saline solution or gels in every patient presenting with epistaxis to prevent mucosal cracking of fragile telangiectasias; this reduces mucosal trauma but often does not control bleeding as sole therapy. 59

Antifibrinolytic Therapy

• Prescribe oral tranexamic acid when humidification alone fails, starting at 500 mg twice daily and titrating up to 1000 mg four times daily or 1500 mg three times daily; this regimen shortens epistaxis duration by roughly 17 % and improves composite epistaxis endpoints by about 54 %. 59
• Contraindications: recent thrombotic event (absolute); atrial fibrillation or known thrombophilia (relative). 59

Second‑Line Local Ablative Therapies

• Reserve laser or electrocautery ablation for patients whose bleeding persists after humidification and tranexamic acid. 59
• Use argon plasma coagulation for acute, severe gastrointestinal bleeding only when bleeding lesions are visualized during diagnostic endoscopy; routine repeated use lacks supporting data. 59

Third‑Line Systemic Therapy with Bevacizumab

• Indicate intravenous bevacizumab for moderate‑to‑severe epistaxis or gastrointestinal bleeding that is refractory to topical humidification, oral tranexamic acid, and/or local ablative procedures. 59
• Eligibility criteria
• Dosing protocol
• Expected benefits (based on retrospective multicenter data)
• Safety monitoring
• The international InHIBIT‑Bleed retrospective cohort (238 patients) reported no fatal adverse events with bevacizumab and demonstrated marked improvements in hemoglobin levels, iron‑infusion requirements, and transfusion frequency. 59

Quality‑of‑Life Considerations

• Treatment decisions should prioritize patients’ quality of life, recognizing that epistaxis imposes significant psychosocial burden (social isolation, work impairment) beyond hemoglobin values alone. 59

Avoidance of Harmful Procedures

• Do not perform hepatic biopsy in confirmed or suspected HHT because of a high risk of catastrophic hemorrhage. 59
• Avoid systematic, repeated endoscopic ablative therapies for gastrointestinal bleeding due to insufficient supporting evidence. 59

Screening for Visceral Arteriovenous Malformations

• Use Doppler ultrasound as the first‑line imaging modality for evaluating hepatic involvement in HHT patients. 59

Investigational and Adjunctive Therapies

• Thalidomide may be considered as an oral anti‑angiogenic option, although its adverse‑effect profile often limits long‑term use. 59
• For refractory severe epistaxis, surgical options such as septodermoplasty or nasal closure should be discussed with patients through shared decision‑making. 59