Search Results (16)

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler–Weber–Rendu disease, is an autosomal dominant vascular disorder caused most commonly by pathogenic variants in the ENG and ACVRL1/ALK1 genes. It is characterized by mucocutaneous telangiectasias and arteriovenous malformations (AVMs) in various organs, leading to recurrent epistaxis, gastrointestinal bleeding, and iron deficiency anemia. Diagnosis relies on the Curaçao Criteria, which include recurrent nosebleeds, characteristic telangiectasias, visceral AVMs, and family history. This review aims to present current therapeutic approaches and emerging treatment strategies for HHT. Traditional surgical and laser-based methods are increasingly complemented or replaced by targeted pharmacological interventions. Antiangiogenic agents such as bevacizumab and thalidomide have demonstrated efficacy in reducing bleeding frequency and transfusion requirements, although adverse effects may limit long-term use. Novel therapies under investigation target molecular pathways involved in vascular remodeling, including tyrosine kinase inhibitors (sorafenib, nintedanib), anti-ANGPT2 antibodies, and modulators of BMP9/ALK1 signaling (tacrolimus, sirolimus). Preclinical and early clinical studies suggest that these agents may provide disease-modifying benefits. Continued research should focus on optimizing treatment efficacy, reducing toxicity, and developing individualized therapeutic regimens based on genetic and clinical characteristics. Full article

Background/Objectives: Rendu–Osler disease is a rare genetic disease, characterized by widespread telangiectasia that can involve the skin and mucous membranes. The diagnosis is based on spontaneous and recurrent epistaxis; various mucosal and cutaneous telangiectasia at typical sites; visceral manifestations including gastrointestinal telangiectasia or pulmonary, cerebral, or hepatic arteriovenous malformation; and a first-degree relative with hereditary hemorrhagic telangiectasia. Squamous cell carcinoma of the larynx generally develops in patients with a smoking history. It is most often treated by surgery and/or radiotherapy. To our knowledge, these two entities were never reported in the same patient. Methods: We herein report a case of a 51-year-old man with Rendu–Osler disease. He was subsequently diagnosed with a locally advanced well-differentiated squamous cell carcinoma of the vocal cord. Results: The patient received a neo-adjuvant chemo-immunotherapy, with nine weekly injections of paclitaxel (60 mg/m²/week), cisplatin (30 mg/m²/week), and cetuximab (250 mg/m²/week), and three injections of pembrolizumab (200 mg every 3 weeks). This controlled tumor bleeding, and then cisplatin-enhanced radiotherapy helped obtain a complete remission. Conclusions: Locally advanced squamous cell carcinoma of the larynx treatment in the context of active Rendu–Osler disease is challenging. If the wide curative surgical approach is deemed too risky, neo-adjuvant chemo-immunotherapy may present a helpful alternative as it may enhance the conditions in order to perform classical radiotherapy with concomitant cisplatin. Full article

Background: Heyde syndrome is a rare condition characterized by the triad of severe aortic stenosis, gastrointestinal bleeding, and acquired type 2A von Willebrand syndrome. This case report highlights the diagnostic and therapeutic approach for a 72-year-old woman presenting with exertional chest pain, dyspnea, fatigue, and a history of melena. Methods: The diagnostic workup revealed severe microcytic anemia and a reduced vWF ristocetin-to-antigen ratio. Imaging confirmed severe degenerative aortic stenosis, while video capsule endoscopy identified angiodysplasia and telangiectasias in the small bowel as the source of gastrointestinal bleeding. Following evaluation by a multidisciplinary Heart Team, the patient underwent transcatheter aortic valve replacement (TAVR) with an Evolut Fx self-expanding prosthesis. Results: Post-procedural echocardiography showed mild paravalvular regurgitation. The patient’s clinical course was favorable, with resolution of anemia and no further gastrointestinal bleeding episodes. Conclusions: Heyde syndrome requires a high index of suspicion for diagnosis in patients with severe aortic stenosis and unexplained anemia or gastrointestinal bleeding. TAVR offers an effective treatment option that not only resolves valvular pathology, but also mitigates associated bleeding risks. Full article

Background: Hereditary Hemorrhagic Telangiectasia (HHT) is a vascular autosomically inherited rare disease. Epistaxis (nose bleeds) is the most common symptom in HHT, leading to anemia and affecting the patient’s quality of life. In addition to epistaxis, gastrointestinal bleeding (GI), more often at older ages, may lead to severe anemia and the need for blood transfusions. Thus, finding drugs to control both types of bleeding is a primary necessity in HHT. Methods: A cross-sectional observational study was conducted in a series of 11 HHT patients treated with low tacrolimus doses (0.5–2 mg/day) on an off-label prescription basis. Patients showed refractory bleeding to previous treatments. The epistaxis severity score (ESS) and hemoglobin levels were the parameters used to evaluate the impact of tacrolimus. The occurrence of side effects was also recorded. Results: Tacrolimus was well tolerated in all of the patients except 2 (who stopped the treatment). The remaining patients tolerated the treatment, with a general improvement in their health condition. Epistaxis was significantly reduced when comparing the ESS before and after the treatment. Hemoglobin levels significantly increased, overcoming the anemia, during the course of the treatment. Conclusion: Tacrolimus at low doses should be considered as a promising treatment for epistaxis and gastrointestinal bleeding in HHT. Full article

Herein, we present the first described hereditary hemorrhagic telangiectasia (HHT) patient treated with aflibercept for severe GI involvement after tachyphylaxis to bevacizumab, with promising results. HHT is a rare genetic disease characterized by systemic vascular malformations. Gastrointestinal telangiectasia is one of the major involvements that can produce chronic severe iron-deficiency anemia. Nowadays, support treatment with iron replacement therapy, red blood cell transfusions, and antiangiogenic drugs—mainly bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF)—are the main therapeutic options for this complication. The evidence of alternative drugs in patients with failure to this approach, such as tachyphylaxis to bevacizumab, is scarce. Aflibercept is a VEGF inhibitor with antiangiogenic properties approved for the treatment of different types of cancer and ocular neovascularization diseases. Full article

Haploinsufficiency for Endoglin (ENG) and activin A receptor type II-like I (ACVRL1/ALK1) lead to the formation of weak and abnormal vessels in hereditary hemorrhagic telangiectasia (HHT). These cause epistaxis (nosebleeds) and/or gastrointestinal blood loss. In vitro in cultured endothelial cells, tacrolimus has been shown to increase ENG and ALK1 expression. It is, therefore, a potential treatment option. We report here a proof-of-concept study in patients with HHT and severe epistaxis and/or gastrointestinal bleeding who were treated daily with orally-administered tacrolimus for twenty weeks. Twenty-five patients with HHT (11 females (44%)) and median age of 59 years were enrolled. Five patients (20%) stopped the trial prematurely-four due to (serious) adverse events ((S)AE). Twenty patients were included in further analyses. Hemoglobin levels increased during tacrolimus treatment from 6.1 (IQR 5.2–6.9) mmol/L at baseline (9.8 g/dL) to 6.7 (6.5–7.1) mmol/L (10.8 g/dL), p = 0.003. The number of blood transfusions over the twenty weeks decreased from a mean of 5.0 (±9.2) to 1.9 (±3.5), p = 0.04. In 64% of the patients, at least one AE occurred. Oral tacrolimus, thus, significantly increased hemoglobin levels and decreased blood transfusion needs, epistaxis and/or gastrointestinal bleeding in patients with HHT. However, side-effects were common. Further investigation of the potential therapeutic benefit is justified by the outcome of the study. Full article

Hereditary hemorrhagic telangiectasia is a rare autosomal dominant vascular disease defined by the presence of mucosal and cutaneous telangiectasia and visceral arterio-venous malformations. The latter are abnormal capillary-free direct communications between the pulmonary and systemic circulations with the following consequences: arterial hypoxemia caused by right-to-left shunts; paradoxical embolism with transient ischemic attack or stroke and brain abscess caused by the absence of the normally filtering capillary bed; and hemoptysis or hemothorax due to the rupture of the thin-walled arterio-venous malformations (particularly during pregnancy). It is frequently underdiagnosed, commonly presenting as complications from shunting through arterio-venous malformations: dyspnea, chronic bleeding, or embolism. Arterio-venous malformations are present not only in the lungs, but can also be found in the liver, central nervous system (mainly in the brain), nasal mucosa, or the gastrointestinal tract. The first choice of therapy is embolization of the afferent arteries of the arterio-venous malformations, a minimally invasive procedure with a high efficacy, a low morbidity, and low mortality. Other therapeutic modalities are surgery (resection) or stereotactic radiosurgery (using radiation). Routine screening for arterio-venous malformations is indicated in patients diagnosed with this condition and can prevent severe complications such as acute hemorrhages, brain abscesses, or strokes. Clinicians should provide a long-term follow-up for patients with arterio-venous malformations, in an effort to detect their growth or reperfusion in case of previously treated malformations. In spite of two experts’ consensuses, it still possesses multiple therapeutic challenges for physicians, as several aspects regarding the screening and management of arterio-venous malformations still remain controversial. Multidisciplinary teams are especially useful in complex cases. Full article

Osler-Weber-Rendu disease, also known as hereditary hemorrhagic telangiectasia (HHT), is a rare, autosomal dominant condition that affects approximately 1 in 5000 patients causing abnormal blood vessel formation. HHT patients have mucocutaneous telangiectasias and arteriovenous malformations in various organs. The most prominent symptom of HHT is epistaxis, which, together with gastrointestinal bleeding, may cause iron deficiency anemia. This study is a case report of a 62-year-old patient who was admitted to the Department of Gastroenterology due to acute upper gastrointestinal bleeding and a history of recurrent epistaxis and melena for 4 days, which was confirmed in digital rectal examination. Urgent upper gastrointestinal endoscopy revealed active bleeding from multiple angioectatic spots with bright-looking salmon-colored patches in the antrum and the body suggestive of HHT. The bleeding from two angioectatic spots was stopped by argon plasma coagulation, and four clips were placed to provide good hemostasis. The patient was treated with a proton pomp inhibitor infusion and iron infusion. She was discharged with no signs of GI bleeding, normalized iron levels and a diagnosis of HHT. She was referred to further genetic testing, including evaluation of first-degree relatives. She also had performed unenhanced thin-cut computed tomography (CT) with angiography to exclude the presence of pulmonary arteriovenous malformations (PAVMs). Due to the fact that the patient did not manifest any other HHT-related symptoms and that the instrumental screening discloses no silent AVMs in other organs, the “watch-and-wait strategy” was applied. Although, Osler-Weber-Rendu syndrome is widely described in the medical literature, effective treatment of gastrointestinal telangiectasias is not always available and still lacks standardization to date, which makes the management of gastroenterological involvement still a challenging issue. Full article

Flavonoids are a subclass of polyphenols which are attractive, due to possessing various physiological activities, including a radioprotective effect. Tumor suppressor p53 is a primary regulator in the radiation response and is involved in the pathogenesis of radiation injuries. In this study, we revealed that isorhamnetin inhibited radiation cell death, and investigated its action mechanism focusing on DNA damage response. Although isorhamnetin moderated p53 activity, it promoted phosphorylation of ataxia telangiectasia mutated (ATM) and enhanced 53BP1 recruitment in irradiated cells. The radioprotective effect of isorhamnetin was not observed in the presence of ATM inhibitor, indicating that its protective effect was dependent on ATM. Furthermore, isorhamnetin-treated mice survived gastrointestinal death caused by a lethal dose of abdominal irradiation. These findings suggested that isorhamnetin enhances the ATM-dependent DNA repair process, which is presumably associated with the suppressive effect against GI syndrome. Full article

Background: Recurrent bleeding in patients with hereditary hemorrhagic telangiectasia (HHT) can lead to chronic iron deficiency anemia (CIDA). Existing research points to CIDA as a contributing factor in restless leg syndrome (RLS). The association between HHT-related symptoms and the prevalence of RLS was analyzed. Methods: An online survey was conducted whereby the standardized RLS-Diagnostic Index questionnaire (RLS-DI) was supplemented with 82 additional questions relating to HHT. Results: A total of 474 persons responded to the survey and completed responses for questions pertaining to RLS (mean age: 56 years, 68% females). Per RLS-DI criteria, 48 patients (48/322, 15%; 95% confidence interval (CI): 11–19%) self-identified as having RLS. An analysis of physician-diagnosed RLS and the RLS-DI revealed a relative frequency of RLS in HHT patients of 22% (95% CI: 18–27%). In fact, 8% (25/322; 95% CI: 5–11%) of the HHT patients had RLS which had not been diagnosed before. This equals 35% of the total amount of patients diagnosed with RLS (25/72; 95% CI: 25–46%). HHT patients with a history of gastrointestinal bleeding (prevalence ratio (PR) = 2.70, 95% CI: 1.53–4.77), blood transfusions (PR = 1.90, 95% CI: 1.27–2.86), or iron intake (PR = 2.05, 95% CI: 0.99–4.26) had an increased prevalence of RLS. Conclusions: Our data suggest that RLS is underdiagnosed in HHT. In addition, physicians should assess CIDA parameters for possible iron supplementation. Full article

Hereditary haemorrhagic telangiectasia (HHT) is characterised by arteriovenous malformations (AVMs). These vascular abnormalities form when arteries and veins directly connect, bypassing the local capillary system. Large AVMs may occur in the lungs, liver and brain, increasing the risk of morbidity and mortality. Smaller AVMs, known as telangiectases, are prevalent on the skin and mucosal lining of the nose, mouth and gastrointestinal tract and are prone to haemorrhage. HHT is primarily associated with a reduction in endoglin (ENG) or ACVRL1 activity due to loss-of-function mutations. ENG and ACVRL1 transmembrane receptors are expressed on endothelial cells (ECs) and bind to circulating ligands BMP9 and BMP10 with high affinity. Ligand binding to the receptor complex leads to activation of the SMAD1/5/8 signalling pathway to regulate downstream gene expression. Various genetic animal models demonstrate that disruption of this pathway in ECs results in AVMs. The vascular abnormalities underlying AVM formation result from abnormal EC responses to angiogenic and haemodynamic cues, and include increased proliferation, reduced migration against the direction of blood flow and an increased EC footprint. There is growing evidence that targeting VEGF signalling has beneficial outcomes in HHT patients and in animal models of this disease. The anti-VEGF inhibitor bevacizumab reduces epistaxis and has a normalising effect on high cardiac output in HHT patients with hepatic AVMs. Blocking VEGF signalling also reduces vascular malformations in mouse models of HHT1 and HHT2. However, VEGF signalling is complex and drives numerous downstream pathways, and it is not yet clear which pathway (or combination of pathways) is critical to target. This review will consider the recent evidence gained from HHT clinical and preclinical studies that are increasing our understanding of HHT pathobiology and informing therapeutic strategies. Full article

Hereditary hemorrhagic telangiectasia (HHT), a rare autosomal dominant disease mostly caused by mutations in three known genes (ENG, ACVRL1, and SMAD4), is characterized by the development of vascular malformations (VMs). Patients with HHT may present with mucocutaneous telangiectasia, as well as organ arteriovenous malformations (AVMs) of the central nervous system, lungs, and liver. Genotype–phenotype correlations have been well described in adults with HHT. We aimed to investigate genotype–phenotype correlations among pediatric HHT patients. Demographic, clinical, and genetic data were collected and analyzed in 205 children enrolled in the multicenter Brain Vascular Malformation Consortium HHT Project. A chi-square test was used to determine the association between phenotypic presentations and genotype. Among 205 patients (age range: 0–18 years; mean: 11 years), ENG mutation was associated with the presence of pulmonary AVMs (p < 0.001) and brain VM (p < 0.001). The presence of a combined phenotype—defined as both pulmonary AVMs and brain VMs—was also associated with ENG mutation. Gastrointestinal bleeding was rare (4.4%), but was associated with SMAD4 genotype (p < 0.001). We conclude that genotype–phenotype correlations among pediatric HHT patients are similar to those described among adults. Specifically, pediatric patients with ENG mutation have a greater prevalence of pulmonary AVMs, brain VMs, and a combined phenotype. Full article

Background: We aimed to describe risk factors for gastrointestinal (GI) bleeding and endoscopic findings in patients with hereditary hemorrhagic telangiectasia (HHT). Methods: This is a prospective study from a referral HHT unit. Endoscopic tests were performed when there was suspicion of GI bleeding, and patients were divided as follows: with, without, and with unsuspected GI involvement. Results: 67 (27.9%) patients with, 28 (11.7%) patients without, and 145 (60.4%) with unsuspected GI involvement were included. Age, tobacco use, endoglin (ENG) mutation, and hemoglobin were associated with GI involvement. Telangiectases were mostly in the stomach and duodenum, but 18.5% of patients with normal esophagogastroduodenoscopy (EGD) had GI involvement in video capsule endoscopy (VCE). Telangiectases ≤ 3 mm and ≤10 per location were most common. Among patients with GI disease, those with hemoglobin < 8 g/dL or transfusion requirements (65.7%) were older and had higher epistaxis severity score (ESS) and larger telangiectases (>3 mm). After a mean follow-up of 34.2 months, patients with GI involvement required more transfusions and more emergency department and hospital admissions, with no differences in mortality. Conclusions: Risk factors for GI involvement have been identified. Patients with GI involvement and severe anemia had larger telangiectases and higher ESS. VCE should be considered in patients with suspicion of GI bleeding, even if EGD is normal. Full article

Endoglin is a 180-kDa glycoprotein receptor primarily expressed by the vascular endothelium and involved in cardiovascular disease and cancer. Heterozygous mutations in the endoglin gene (ENG) cause hereditary hemorrhagic telangiectasia type 1, a vascular disease that presents with nasal and gastrointestinal bleeding, skin and mucosa telangiectases, and arteriovenous malformations in internal organs. A circulating form of endoglin (alias soluble endoglin, sEng), proteolytically released from the membrane-bound protein, has been observed in several inflammation-related pathological conditions and appears to contribute to endothelial dysfunction and cancer development through unknown mechanisms. Membrane-bound endoglin is an auxiliary component of the TGF-β receptor complex and the extracellular region of endoglin has been shown to interact with types I and II TGF-β receptors, as well as with BMP9 and BMP10 ligands, both members of the TGF-β family. To search for novel protein interactors, we screened a microarray containing over 9000 unique human proteins using recombinant sEng as bait. We find that sEng binds with high affinity, at least, to 22 new proteins. Among these, we validated the interaction of endoglin with galectin-3, a secreted member of the lectin family with capacity to bind membrane glycoproteins, and with tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin-protein ligase. Using human endothelial cells and Chinese hamster ovary cells, we showed that endoglin co-immunoprecipitates and co-localizes with galectin-3 or TRIM21. These results open new research avenues on endoglin function and regulation. Full article

In hereditary hemorrhagic telangiectasia (HHT), frequent episodes of nasal and gastrointestinal bleeding commonly lead to irondeficiency with or without anemia. In the retrospective study presented here we assessed the iron stores, as determined by analysis of plasma ferritin, during oral and intravenous iron supplementation, respectively, in a population of iron-deficient non-anemic HHT patients who were inadequately iron-repleted by oral supplementation. A switch from oral to intravenous iron supplementation was associated with a significant increase in ferritin in this patient population. Full article