Hereditary Hemorrhagic Telangiectasia: Genetics, Pathophysiology, Diagnosis, and Management
Abstract
:1. Introduction
History and Epidemiology
2. Pathophysiology
2.1. Regulation of Angiogenesis
2.2. Pathogenesis in HHT
2.3. Relationship between Inflammation and Hereditary Hemorrhagic Telangiectasia
2.4. Relationship between Hemostasis and Hereditary Hemorrhagic Telangiectasia
3. Clinical Manifestations
Clinical Presentation
4. Vascular Malformations and Its Complications
4.1. Pulmonary Arteriovenous Malformations (PAVMs)
4.2. Hepatic Vascular Malformations
4.3. AVMs of the Gastrointestinal System
4.4. AVMs of the Nervous System
5. Pulmonary Hypertension and HHT
6. Diagnosis
6.1. Diagnostic Criteria
6.2. Screening and Follow up for HHT
7. Treatment
7.1. Management of Epistaxis
7.1.1. Care of the Nasal Mucosa
7.1.2. Invasive Treatments
7.2. Approach to Pulmonary AVMs
7.3. Approach to Gastrointestinal AVMs
7.4. Management of Central Nervous System AVMs
7.5. Pharmacological Treatment
7.5.1. Antifibrinolytic Strategy
7.5.2. Drugs That Stimulate ENG and ACVRL1 Gene Expression
7.5.3. Angiogenesis Inhibitor Drugs
7.5.4. Potential New Treatments in HHT
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Gen | Affected Protein | Location | Phenotype | Frequency |
---|---|---|---|---|
ENG | Endoglin | 9q34.11 | HHT1 | 39–59% |
ACVRL1 | ALK1 | 12q13.13 | HHT2 | 25–57% |
MADH4 | Smad4 | 18q21.1 | HHT-juvenile polyposis syndrome | 1–2% |
GDF2 | BMP9 | 10q11.22 | HHT-like | <1% |
RASA-1 | p120-RasGAP | 5q14.3 | RASA-1 related disorders (CM-AVM) | Unknown |
Clinical Manifestations | Prevalence (%) | Comments |
---|---|---|
Epistaxis | 90–95 | Most limiting symptom for patients. |
Telangiectasias | 95 | It can produce recurrent bleeding in the bearing areas of the body or those in contact with external surfaces such as the fingertips. |
Anemia | 50 | It is associated with asthenia and chronic fatigue. |
Pulmonary AVMs | 15–50 | Chronic hypoxaemia is only present in case of large pulmonary AVMs. Prevalence 10–20% in HT-II, 60% in HHT-I. |
Hepatic AVMs | 47–74 | Three different types. Depending on their predominance, they increase the risk of HOHF, portal hypertension, hepatic encephalopathy, biliary ischemia, mesenteric ischemia, and hepatic cirrhosis. |
Cerebral AVMs | 2–20 | Nonspecific symptoms (headaches or seizures) |
Digestive AVMs | 13–30 | AVMs predominate in the stomach and duodenum. |
Pulmonary hypertension | 1–5 | Can be caused by different mechanisms including hereditary group 1 PAH, or due to high cardiac output in the setting of liver AVMs (mostly associated with ACVRL1 mutation). |
Manifestations | Treatment | Comments |
---|---|---|
Epistaxis | Moisturizing (Topical hydration) Use of oral tranexamic acid if continuous bleeding despite moisturizing topical therapies | Recent evidence shows no superiority on all topical therapy (tranexamic acid, estrogens, propranolol, and bevacizumab) compared to placebo. |
Ablative treatments (laser, radiofrequency ablation, electrosurgery and sclerotherapy). Systemic therapy could be considered: beta blockers, thalidomide, tacrolimus. Antiangiogenics (Bevacizumab) | Consider if epistaxis persists despite topical treatments. Consider systemic therapy before surgery. | |
Septodermoplasty | Consider in patients who do not respond to previous treatments. | |
Digestive bleeding | Endoscopic procedures are diagnostic and therapeutic. Consider capsule endoscopy if endoscopic bleeding is not identified. | Repeat sessions are discouraged to avoid repeated iatrogenic injury to the intestinal mucosa. |
In mild cases, oral antifibrinolytics may be considered. | ||
If, despite previous treatments, bleeding persists, anemia requiring transfusions, antiangiogenic drugs (bevacizumab) can be initiated. | ||
Anemia | Oral ironIV iron if intolerant or lack of response to oral iron. Red blood cell transfusion. | A usual dose of 35 mg elemental iron tablets daily indicated. |
Pulmonary AVMs | Transcatheter embolization: Consider in any AVM with afferent vessel >2 mm in diameter. | |
Chest CT is recommended to identify possible recanalization. | Follow-up with CT scan after embolization every 6 months, then every 3–5 years. | |
Cerebral abscess | If TTCE identifies the presence of a short circuit (although pulmonary AVM is not identified in CT): Antibiotic prophylaxis is recommended prior to dental procedures. Avoid administering air bubbles when cannulating veins. | |
Pulmonary hypertension | Extend study to identify primary cause and address management (multidisciplinary consultation). | |
Hepatic VMs | Most patients with symptomatic hepatic AVMs can be managed with medical treatment. Consider bevacizumab for patients who fail medical treatment. | |
Refer to referral center to consider liver transplantation in patients with refractory symptomatic hepatic AVMs (HOHF, biliary ischemia, or complicated portal hypertension). | Liver biopsies should be avoided in patients with HHT. | |
Cerebral AVMs | Treated depending on risk of bleeding and expertise of the neurosurgical team. Embolization or stereotactic radiosurgery depending on the size, location, and symptomatology. |
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Viteri-Noël, A.; González-García, A.; Patier, J.L.; Fabregate, M.; Bara-Ledesma, N.; López-Rodríguez, M.; Gómez del Olmo, V.; Manzano, L. Hereditary Hemorrhagic Telangiectasia: Genetics, Pathophysiology, Diagnosis, and Management. J. Clin. Med. 2022, 11, 5245. https://doi.org/10.3390/jcm11175245
Viteri-Noël A, González-García A, Patier JL, Fabregate M, Bara-Ledesma N, López-Rodríguez M, Gómez del Olmo V, Manzano L. Hereditary Hemorrhagic Telangiectasia: Genetics, Pathophysiology, Diagnosis, and Management. Journal of Clinical Medicine. 2022; 11(17):5245. https://doi.org/10.3390/jcm11175245
Chicago/Turabian StyleViteri-Noël, Adrian, Andrés González-García, José Luis Patier, Martin Fabregate, Nuria Bara-Ledesma, Mónica López-Rodríguez, Vicente Gómez del Olmo, and Luis Manzano. 2022. "Hereditary Hemorrhagic Telangiectasia: Genetics, Pathophysiology, Diagnosis, and Management" Journal of Clinical Medicine 11, no. 17: 5245. https://doi.org/10.3390/jcm11175245
APA StyleViteri-Noël, A., González-García, A., Patier, J. L., Fabregate, M., Bara-Ledesma, N., López-Rodríguez, M., Gómez del Olmo, V., & Manzano, L. (2022). Hereditary Hemorrhagic Telangiectasia: Genetics, Pathophysiology, Diagnosis, and Management. Journal of Clinical Medicine, 11(17), 5245. https://doi.org/10.3390/jcm11175245