Conjunctival Findings
Conjunctival telangiectasia: The most common ocular finding in HHT patients, seen in up to half of patients.
Dilated vessels: Tortuous and dilated vessels are observed on the conjunctival surface.
Ocular Findings in Hereditary Hemorrhagic Telangiectasia
Key Points at a Glance
Section titled “Key Points at a Glance”1. Ocular Findings in Hereditary Hemorrhagic Telangiectasia
Section titled “1. Ocular Findings in Hereditary Hemorrhagic Telangiectasia”Hereditary hemorrhagic telangiectasia (HHT), also known as Osler–Weber–Rendu disease, is an autosomal dominant vascular malformation disorder. Its prevalence is estimated at 1 in 5,000 to 10,000 people, making it the second most common hereditary hemorrhagic disorder 1).
HHT is characterized by systemic telangiectasias and arteriovenous malformations (AVMs). Telangiectasias are small vascular lesions that appear on the skin and mucous membranes, while AVMs are large vascular lesions that form in internal organs. Both involve direct connections between arterioles and venules without intervening capillaries.
In ophthalmology, HHT presents with various findings including conjunctival and retinal telangiectasias, retinal aneurysms, retinal neovascularization, orbital AVMs, and orbital vein thrombosis. Intraocular lesions are relatively rare and often stable, but when retinal neovascularization or hemorrhage occurs, they can threaten vision.
Genetic Background
Section titled “Genetic Background”The causative genes of HHT are mainly involved in the TGF-β/BMP signaling pathway. Mutations in ENG and ACVRL1 account for over 96% of all cases 1).
The correspondence between major HHT types and causative genes is shown below.
| Type | Causative gene | Features |
|---|---|---|
| HHT type 1 | ENG | Frequent pulmonary and cerebral AVMs3) |
| HHT type 2 | ACVRL1 | Frequent hepatic AVMs1) |
| JP-HHT | SMAD4 | Associated with juvenile polyposis1) |
Affected individuals have elevated serum levels of VEGF and TGF-β1, which form the basis of abnormal angiogenesis3).
Q
Is HHT hereditary? What should be done if a family member has HHT?
A
HHT is an autosomal dominant disorder, with a 50% chance of inheritance in children of affected individuals. If a first-degree relative has HHT, genetic testing and screening are recommended even in the absence of symptoms1).
2. Main Symptoms and Clinical Findings
Section titled “2. Main Symptoms and Clinical Findings”Subjective Symptoms
Section titled “Subjective Symptoms”Ocular subjective symptoms are as follows:
- Conjunctival injection: Chronic redness due to conjunctival telangiectasia.
- Decreased vision: Occurs when retinal hemorrhage or retinal neovascularization affects the macula.
- Proptosis: Seen in the presence of orbital AVM.
- Diplopia: May present with ocular motility disorders due to orbital lesions.
- Visual field defect: May cause visual field loss corresponding to the site of retinal hemorrhage.
Many ocular lesions are asymptomatic and are often discovered incidentally during dilated fundus examination.
Clinical Findings (Findings Confirmed by Physician Examination)
Section titled “Clinical Findings (Findings Confirmed by Physician Examination)”Retinal Findings
Retinal telangiectasia: Seen in 2–10% of patients. May resemble hypertensive retinopathy.
Retinal neovascularization and aneurysms: Detected by dilated fundus examination. Cause retinal hemorrhages.
Parafoveal telangiectasia: Appears around the macula.
Orbital Findings
Proptosis: Due to orbital AVM (rare). Accompanied by conjunctival edema.
Orbital vein thrombosis: Thrombosis of the superior ophthalmic vein or orbital AVM. Manageable with anticoagulation.
Retinal AVMs appear as tortuous vessels on fluorescein angiography. Fluorescein angiography (FA) is useful for identifying dilated vessels and telangiectasias, and is valuable for monitoring retinal lesions. Since retinal hemorrhages can occur, detailed examination for identification and monitoring of abnormal vessels is important.
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”HHT is caused by mutations in genes such as ENG, ACVRL1, and SMAD4, which disrupt the TGF-β/BMP signaling pathway. These mutations impair vascular endothelial cell integrity, leading to abnormal smooth muscle differentiation and cytoskeletal defects 3). As a result, blood vessel walls become fragile, forming abnormal vessels prone to bleeding.
Formation of AVMs in specific vascular beds is thought to require a “second hit” (e.g., trauma, inflammation, or acquisition of somatic mutations) 2).
The clinical manifestations of HHT progress with age. Epistaxis typically appears in the teenage years, and telangiectasias become noticeable in the 20s–30s 1). Since children may not meet the Curaçao criteria, genetic testing is useful. Pregnancy increases the risk of AVM rupture due to hemodynamic changes, and serious complications such as hemoptysis and hemothorax can occur in the third trimester 7).
4. Diagnosis and Testing Methods
Section titled “4. Diagnosis and Testing Methods”Curaçao Diagnostic Criteria
Section titled “Curaçao Diagnostic Criteria”The clinical diagnosis of HHT is based on the Curaçao diagnostic criteria1).
| Criterion | Description |
|---|---|
| Epistaxis | Recurrent, spontaneous |
| Telangiectasias | Lips, oral cavity, fingers, nose |
| Visceral lesions | Pulmonary, hepatic, cerebral, spinal AVM |
| Family history | First-degree relative with HHT |
Three or more criteria confirm the diagnosis, two criteria indicate suspected HHT, and fewer than two criteria make HHT unlikely. However, in children, the negative predictive value of the criteria is low, and genetic testing is recommended1).
Genetic Testing
Section titled “Genetic Testing”It is performed using a multi-gene panel including ENG, ACVRL1, SMAD4, RASA1, GDF2, and EPHB4. A positive result confirms the diagnosis of HHT. In 10–15% of clinically diagnosed cases, mutations may not be identified 1).
Ophthalmic Examination
Section titled “Ophthalmic Examination”- Slit-lamp microscopy: Observation of conjunctival telangiectasias.
- Dilated fundus examination: Detection of retinal telangiectasias, neovascularization, and aneurysms. Frequent examinations are recommended.
- Fluorescein angiography (FA): Useful for identifying dilated vessels and monitoring retinal lesions over time.
Systemic Screening
Section titled “Systemic Screening”When HHT is diagnosed, the following screening is recommended 1).
- Brain MRI/MRA: Evaluation of cerebral AVMs and aneurysms
- Transthoracic echocardiography (bubble test): Evaluation of pulmonary AVMs
- Liver Doppler ultrasound: Evaluation of hepatic AVMs
- Upper and lower gastrointestinal endoscopy: Evaluation of gastrointestinal telangiectasias
Q
Can HHT be diagnosed by ophthalmic examination alone?
A
HHT cannot be confirmed by ophthalmic findings alone. Conjunctival telangiectasias may raise suspicion of HHT, but definitive diagnosis requires the Curaçao criteria or genetic testing 1). If an ophthalmologist observes conjunctival or retinal telangiectasias, they should consider the possibility of HHT and recommend systemic evaluation.
5. Standard Treatment
Section titled “5. Standard Treatment”Treatment of HHT is basically symptomatic, and multidisciplinary collaboration is essential.
Ophthalmic Treatment
Section titled “Ophthalmic Treatment”Intraocular lesions are rare and often stable, but when retinal neovascularization occurs, the following treatments are selected.
- Intravitreal injection of anti-VEGF drugs: Used for retinal neovascularization and macular edema.
- Panretinal photocoagulation (PRP): Laser treatment for retinal neovascularization.
- Photodynamic therapy (PDT): Reported use in one case.
For orbital AVMs, embolization may be performed, with expected regression of the lesion and symptom relief. Anticoagulation therapy is applied for orbital vein thrombosis.
Systemic Treatment (Bleeding Management and Anemia Management)
Section titled “Systemic Treatment (Bleeding Management and Anemia Management)”More than 50% of HHT patients have anemia due to epistaxis or gastrointestinal bleeding 1). Treatment is performed stepwise.
- Iron supplementation: Correction of iron deficiency anemia. Target maintenance of ferritin ≥50 ng/mL 1).
- Antifibrinolytics: Topical or oral administration of tranexamic acid 1).
- Intravenous bevacizumab: Antiangiogenic therapy for severe/refractory cases. Reduction of bleeding and improvement of hemoglobin levels have been reported 2).
Treatment of Visceral AVMs
Section titled “Treatment of Visceral AVMs”- Pulmonary AVMs: Coil embolization is standard treatment. Indicated for feeding artery diameter ≥2-3 mm 6).
- Cerebral AVMs: Embolization, surgical resection, or radiotherapy (e.g., Gamma Knife) are selected 1). Spinal AVMs are rare (prevalence <1%) but can cause paralysis in childhood, requiring caution 8).
- Hepatic AVM: Hepatic artery embolization is not recommended due to high risk of complications9); liver transplantation or systemic bevacizumab therapy may be considered5).
Q
How often should ocular complications of HHT be monitored?
A
For early detection of retinal lesions, patients diagnosed with HHT are recommended to undergo regular dilated fundus examinations. If retinal telangiectasias or neovascularization are found, treatment described in the “Standard Treatment” section should be promptly considered.
6. Pathophysiology and Detailed Mechanisms
Section titled “6. Pathophysiology and Detailed Mechanisms”HHT is a vascular malformation disorder caused by abnormalities in the TGF-β/BMP signaling pathway. Over 700 causative gene mutations have been identified2).
Molecular Mechanisms
Section titled “Molecular Mechanisms”Both ENG and ACVRL1 encode receptors of the TGF-β/BMP signaling pathway that are predominantly expressed in vascular endothelial cells2). Heterozygous loss-of-function mutations in these receptors lead to the following abnormalities:
- Increased VEGF expression: The regulatory mechanism of angiogenesis is disrupted3).
- Weakening of the extracellular matrix: The supporting structure of the vessel wall is impaired2).
- Abnormalities in SMAD and non-SMAD signaling pathways: Vascular remodeling becomes uncontrolled3).
Mechanisms of AVM Formation
Section titled “Mechanisms of AVM Formation”Genetic mutations alone do not form AVMs; a local “second hit” is required 2). Second hits include trauma, inflammation, angiogenic stimuli, and acquisition of somatic mutations. This “two-hit model” explains why different AVM patterns can occur in different organs within the same patient.
Special Pathologies Related to Hepatic AVMs
Section titled “Special Pathologies Related to Hepatic AVMs”There are three shunt types in hepatic AVMs 5).
Hepatic artery to portal vein
Portal hypertension: Increased pressure in the portal vein, causing gastrointestinal bleeding and ascites.
Hepatic artery to hepatic vein
High-output heart failure: The most common complication. Blood shunting to the heart increases cardiac load 5).
Portal vein to hepatic vein
Portosystemic encephalopathy: Extremely rare. Ammonia bypasses the liver and reaches the brain 5).
Kawabata et al. (2021) reported a case of a 72-year-old woman with portosystemic encephalopathy (PSE) due to hepatic AVMs 5). Serum ammonia levels rose to 270 mg/dL and improved with lactulose and branched-chain amino acid administration. Only 12 cases of PSE have been reported in the literature.
Manganese Deposition in the Brain
Section titled “Manganese Deposition in the Brain”Over 23% of HHT patients with hepatic AVMs show basal ganglia T1 hyperintensity (manganese deposition) 4). Iron deficiency may promote manganese absorption and deposition. It can present with Parkinson-like neurological symptoms 4).
7. Latest Research and Future Perspectives (Research-stage Reports)
Section titled “7. Latest Research and Future Perspectives (Research-stage Reports)”Novel antiangiogenic drugs
Section titled “Novel antiangiogenic drugs”In the treatment of HHT, bevacizumab is currently the most widely used antiangiogenic drug, but the burden of intravenous administration is a challenge. Several new drugs, including oral agents, are in clinical trials2).
In the PATH-HHT trial (Al-Samkari et al. 2024), oral pomalidomide significantly improved the epistaxis severity score by -1.84 in a randomized controlled trial of 144 patients, and also improved quality of life2).
Pazopanib (oral tyrosine kinase inhibitor) achieved transfusion independence in all 13 transfusion-dependent patients, with a mean improvement in epistaxis severity score of -4.772). The dose required for HHT was about one-eighth of the oncological dose.
Other investigational drugs include nintedanib (oral tyrosine kinase inhibitor), VAD044 (AKT inhibitor), sirolimus (mTOR inhibitor), and tacrolimus (SMAD pathway activator)2).
Measures against cerebral infarction complicated by PAVM
Section titled “Measures against cerebral infarction complicated by PAVM”Tang et al. (2024) reported a 58-year-old woman with recurrent cerebral infarction due to paradoxical embolism from PAVM4). Manganese deposition in the basal ganglia was a clue to the diagnosis of HHT. She had a good outcome after PAVM embolization. Iron supplementation may be effective in preventing manganese deposition.
8. References
Section titled “8. References”- Hammill AM, Wusik K, Kasthuri RS. Hereditary hemorrhagic telangiectasia (HHT): a practical guide to management. Hematology. 2021;2021:469-477.
- Eswaran H, Kasthuri RS. Potential and emerging therapeutics for HHT. Hematology. 2024;2024:724-727.
- Han Y, Ding B, Li M, Song X, Liu L, Zhou H. A case of hereditary hemorrhagic telangiectasia and literature review. J Clin Lab Anal. 2022;36:e24571.
- Tang Q, Xia P, Hu X, Shao Y. Hereditary haemorrhagic telangiectasias with recurrent ischemic stroke hinted by manganese deposition in the basal ganglia: a case report and literature review. BMC Neurol. 2024;24:375.
- Kawabata H, Hamada Y, Hattori A, Tanaka K. Hereditary Hemorrhagic Telangiectasia Induced Portosystemic Encephalopathy: a case report and literature review. Intern Med. 2021;60:1541-1545.
- Li X, Duan L, Mu S, Dong X, Lu X, Cao D. Massive hemothorax induced by pulmonary arteriovenous malformation rupture: a case report and literature review. J Cardiothorac Surg. 2024;19:342.
- Liu S, Zhang Q, Liu W, Zheng L, Zhou J, Huang X. Hereditary haemorrhagic telangiectasia with atrial septal defect and pulmonary hypertension during advanced pregnancy: a case report and literature review. J Int Med Res. 2022;50(4):1-10.
- Devara J, Iyer VN, Warad DM, Brinjikji W, Aljobeh A, Lanzino G, Demirel N. Acute thrombosis of a giant perimedullary arteriovenous fistula in a pediatric HHT patient. Interv Neuroradiol. 2022;28(2):132-135.
- L’Huillier R, Garnaud A, Monneuse O. Spontaneous Ischemic Cholecystitis in a Patient with Hereditary Hemorrhagic Telangiectasia (HHT). J Clin Med. 2024;13:6653.