Epistaxis due to hereditary hemorrhagic telangiectasia: A case report and literature review

Abstract

Characterized by abnormalities of the blood vessel wall, hereditary hemorrhagic telangiectasia is an autosomal dominant disorder. Recurrent or spontaneous epistaxis is the most prevalent symptom of hereditary hemorrhagic telangiectasia, whose severity varies greatly, ranging from moderate self-limiting epistaxis to severe, life-threatening epistaxis, which often requires multiple treatments and is therefore a challenge for otorhinolaryngologists. This case report retrospectively analyzed the clinical data and family history of a patient who presented to the Department of Otorhinolaryngology, Hangzhou First People’s Hospital, with recurrent epistaxis for 60 years. The patient was treated with Little’s area septomucotomy combined with electrocoagulation for epistaxis, and her clinical symptoms and specialty findings showed significant improvement after four postoperative follow-up visits. This article reviews the possible mechanisms and treatment progress of epistaxis caused by hereditary hemorrhagic telangiectasia, with the aim of improving diagnosis and clinical management of this disease.

Introduction

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu–Osler–Weber disease, is an unusual autosomal dominant vascular disorder with a global prevalence of approximately 1/5000. HHT is distinguished by dilated capillaries in the nose, skin, and mucous membranes of the gastrointestinal (GI) tract and visceral arteriovenous malformations (AVMs). ¹ The disease is more prevalent in adults, with only 30% of cases occurring before the age of 20 years, and the double whammy hypothesis helps explain this phenomenon: somatic mutations in the capillaries induced by environmental stresses (e.g. sun exposure) lead to more localized lesions. In hemodynamic disorders, endothelial glycoproteins, which are adhesion molecules for leukocyte infiltration, are excised, and their soluble fraction (sol-Eng) can mediate platelet adhesion through integrin αIIbβ3 on platelets. This could explain why patients with HHT exhibit a prolonged bleeding time and a greater volume of hemorrhage in addition to an increased risk of hemorrhage. ² Epistaxis is the most common symptom in patients with HHT, and they often seek initial medical attention in an ear, nose, and throat (ENT) department. Clinically, the severity of epistaxis symptoms can be assessed by the Epistaxis Severity Scale (ESS), which relies on patients’ self-reports of the seriousness of epistaxis. This scale has been created by analyzing the independently associated risk factors of patients, including six questions about the duration of epistaxis, frequency of epistaxis, and whether they were anemic, with scores ranging from 0 (none) to 10 (severe epistaxis). ³ HHT can be diagnosed via genetic testing or according to the Curaçao criteria, which include the presence of epistaxis, telangiectasis, visceral lesions, or family history. A definitive diagnosis is made when three or more criteria are met, a suspected diagnosis when two are met, and a diagnosis is excluded when fewer than two are met. ⁴

This article reports a case of epistaxis due to HHT and systematically describes its clinical presentation, diagnostic process, and treatment options. Comprehensive knowledge of HHT-induced epistaxis is important to prevent the clinical risks associated with delayed diagnosis and incomplete treatment.

We adhered to the Case Report (CARE) guidelines during the preparation of this manuscript. ⁵

Case presentation

An East Asian woman aged <70 years was admitted to our hospital in mid-2024 with recurrent bilateral epistaxis for 60 years, aggravated for 1 month. The patient had a history of recurrent nosebleeds for 60 years. She recorded the frequency and time of nosebleeds using daily paper adsorption as a reference and reported that the bleeding occurred mostly at night, alternated bilaterally, 1–2 times per day, with a bleeding volume of approximately 50 mL each time, which could often be stopped by herself. She visited the local hospital several times and was given symptomatic treatment such as nasal electrocoagulation for hemostasis, but the postoperative control was not optimal. One month ago, the patient experienced nasal bleeding again without any obvious triggers, with a bleeding volume of approximately 100 mL, 1–2 times/day. The patient had a history of hypertension, and a pursuing history revealed that her sister, cousin, and uncle had recurrent nosebleeds and telangiectases of the nasal mucosa; the family tree was mapped (Figure 1). On examination, mucosal erosion and diffuse exudation of blood were observed at the anterior end of the nasal septum bilaterally, and a large number of multiple hemorrhagic spots and nodular protrusion were noted in the Little’s area, inferior turbinate, and middle turbinate bilaterally (Figure 2). Scattered telangiectases were noted on the lips, tongue, and soft palate (Figure 3). Laboratory test results were as follows: erythrocyte count, 3.6 × 10¹²/L; hemoglobin level, 94 g/L; mean corpuscular hemoglobin, 26 pg; serum iron level, 5.2 μmol/L; and transferrin saturation, 7.07%; the remaining results were not significant. Other imaging findings included the following: 1. Computed tomography (CT) of paranasal sinuses showed bilateral inflammation of the maxillary sinus, ethmoid sinus, and right frontal sinus. The right inferior turbinate was enlarged, and the nasal septum was deviated to the left. 2. Abdominal ultrasound showed portal vein widening in the image of chronic liver disease, gallbladder stones with cholecystitis, multiple polypoid lesions of the gallbladder, splenomegaly, and a small amount of fluid in the abdominal cavity. 3. E-gastroscopy showed reflux esophagitis and chronic superficial atrophic gastritis. 4. Chest CT showed mild bronchitis and no other unusual findings.

Figure 1.

Distribution of hereditary hemorrhagic telangiectasia in the patient’s family.

Figure 2.

Endoscopic examination revealing vascular dilation of the nasal mucosa.

Figure 3.

Telangiectases (indicated by arrows) are observed on the patient’s lips (a), tongue (b), and soft palate (c).

The patient’s cousin, who had previously been diagnosed with HHT, underwent genetic testing (ACVRL1(+)), nasal electrocoagulation for hemostasis under general anesthesia, and Little’s area septomucotomy on 1 April 2021 at our hospital. Nasal endoscopy was performed on admission to observe scattered telangiectases in the nasal cavity, and his laboratory test results were as follows: hemoglobin level of 34 g/L, activated partial thromboplastin time of 23.7 s, and ferritin level of 3.71 μg/L. He had been hospitalized with multiple transfusions due to severe anemia, including suspended red blood cells.

Based on family history and clinical manifestations and signs, the patient was diagnosed with HHT. The patient and her family refused to undergo genetic testing during the consultation process. The patient was fully informed of her condition and actively cooperated with the treatment plan. She received preoperative prophylactic intravenous antibiotics and antihypertensive therapy and underwent Little’s area septomucotomy and electrocoagulation of epistaxis under general anesthesia. During the operation, bipolar electrocoagulation was used to extensively cauterize the submucosal capillary mass and protect the normal mucosa as much as possible, and small pieces of nasopore sponge were used to fill in the operative cavity locally. The patient did not exhibit serious adverse reactions after the operation and continued to receive intravenous administration of cefalosporin at a dosage of 1.5 g once daily for anti-infective treatment, with the treatment course lasting 2 days. The patient’s nasal cavity was closely observed, and she was discharged after no active bleeding was seen. Instructions for the patient’s discharge included the following: (a) use a humidifier to maintain sufficient humidity in the air to avoid drying out the nasal or oral mucosa; (b) use nasal saline rinses in a gentle manner to prevent crusting and drying; (c) use an ointment to keep the nasal mucosa oily; and (d) avoid the triggers. The postoperative follow-up at 3 months revealed that the patient strictly complied with the doctor’s instructions for nasal care, and the nasal bleeding was recorded in detail on the Osler calendar. The patient reported a small amount of bilateral nasal bleeding at 2 weeks after the operation, and an outpatient follow-up examination showed that the wound was adherent to the crusts (Figure 4), accompanied by a small number of bleeders; at the fourth follow-up visit, the symptoms of nasal bleeding had been basically controlled.

Figure 4.

Endoscopic presentation of the patient’s nasal mucosa 2 weeks after surgery.

Discussion

HTT often presents as telangiectasis and AVMs in the clinic. Telangiectasis can appear anywhere; it is most commonly seen on the face, nose, tongue, fingertips, lips, oral cavity, and GI tract mucous membranes. They are pink to red in color and approximately 0.5–1.0 mm in diameter. Unlike purpura, which has a similar appearance, these lesions whiten when pressure is applied and return to the colored form once the pressure is released. ⁶ The most common symptom of HTT is epistaxis associated with dilated capillaries in the nose, which, in severe cases, may lead to anemia. The prevalence and severity of epistaxis often increase with advancing age. The pathological changes are manifested by remodeling of the vascular endothelium of the nasal mucosa occurring in an uncontrolled manner, resulting in loss of vascular elasticity. Dilation of thin-walled capillaries occurs in areas of the nasal cavity exposed to high airflow, and nodular dilations form at weak points of the vessels under the constant impact of blood flow. ⁷ HHT is also usually characterized by the presence of larger AVMs. These lesions can be up to several centimeters in size and are most often found in the lungs, liver, and brain. Approximately 13%–56% of patients with pulmonary AVMs present as asymptomatic, or they may present with signs and symptoms of intrapulmonary hemorrhage or right-to-left shunting (e.g. hypoxemia and dyspnea). ⁸ Hepatic AVMs are usually present in 30%–70% of cases and may result in congestive heart failure and hepatic encephalopathy. ⁹ In the central nervous system, AVMs may occur in either the brain or spinal cord, potentially leading to the development of brain accesses, transient ischemic attacks, or ischemic strokes. GI lesions are usually evaluated by GI endoscopy and may present with symptoms such as hemorrhage or anemia. ¹⁰

HHT is a progressive condition characterized by a diverse array of clinical symptoms related to age, organ involvement, and severity of the attack. For decades, the lack of awareness among patients and their family members regarding available screening methods and treatment options has hindered the early detection and treatment of the disease. The clinical diagnosis of HHT is established based on the Curaçao criteria. A definitive diagnosis is made when three or more criteria are fulfilled, a suspected diagnosis when two are fulfilled, and a diagnosis of exclusion when fewer than two are fulfilled. The criteria are as follows: (a) recurrent and spontaneous epistaxis; (b) presence of typical dilated capillaries in the skin or mucous membranes (most often in the lips, nose, fingers, mouth and GI tract); (c) visceral lesions, represented by AVMs, occurring in the GI tract, liver, lungs, brain, or spinal cord; and (d) a family history of first-degree relatives with HHT. ¹¹

All identified relevant genes for HHT encode proteins involved in the transforming growth factor β signaling pathway. These proteins are crucial for maintaining the integrity of the vascular wall. When protein function is impaired, blood vessels are more likely to dilate and remodel during development and after repair of injury. There are currently five subtypes of HHT: HHT1 (ENG gene), HHT2 (ACVRL1 gene), ¹² HHT3 (unknown gene located on chromosome 5q31), ¹³ HHT4 (unknown gene localized on chromosome 7p14), ¹⁴ and HHT5 (GDF2 gene). Mutations in ENG and AVRL1 are present in approximately 80% of patients with HHT, with significant phenotypic variability between HHT1 and HHT2. Patients with HHT1 tend to exhibit an early onset of epistaxis and pulmonary AVMs, whereas those with HHT2 are more predisposed to GI and hepatic AVMs. ¹⁵ Another possible genetic alteration is mutations in GDF2, which encodes bone morphogenetic protein 9. ¹⁶ In addition, alterations in SMAD4 have been detected in a subset of patients with HHT and juvenile polyposis (approximately 2% of cases). Recent studies have reported a potential pathogenic role of mutations in RASA1, with a close overlap between capillary malformation–AVM syndrome and HHT, both of which are associated with mutations in RASA1 but express different phenotypes. ¹⁷ Not all patients with HHT have a positive genetic test result, and genetic testing is expensive; hence, it is only recommended in certain situations, such as prenatal screening, when family members with known HHT have identified some symptoms or for ruling out HHT to make a definitive diagnosis.

Currently, there is no cure for HHT-induced recurrent epistaxis, but preventive and targeted treatments are available depending on the amount of epistaxis. A sequential treatment approach is advised, commencing with conservative topical treatments and advancing to more invasive surgical treatments. As the first line of treatment for nasal bleeding, topical moisturizing therapy is recommended to moisturize the nasal mucosa and minimize damage to the nasal mucosa. In the case of bilateral bleeding, nasal tamponade is a safe option; however, the thinness of the patient’s nasal mucosa and the fragility of the capillaries may lead to secondary bleeding when the tamponade is removed, and absorbable gelatin sponges can avoid this damage. ¹⁸ Another interesting method of nasal plugging is the silicone olive customized for both nostrils; however, it has the disadvantages of being time consuming and costly and requiring repeated manipulation in the nasal vestibule. ¹⁹

Regarding pharmacological treatment, bevacizumab functions as an antiangiogenic drug by inhibiting the vascular endothelial growth factor (VEGF) receptor. In a randomized clinical trial, Dupuis-Girod et al. ²⁰ found that treatment with bevacizumab nasal spray did not reduce the duration of epistaxis in patients with HHT, whereas submucosal injections did. ²¹ In another study, pazopanib, an oral multikinase angiogenesis inhibitor, was observed to significantly improve symptoms in patients with HHT, including epistaxis, decreased blood transfusions, and iron requirements. ²² Another antiangiogenic drug used to treat HHT-related bleeding is thalidomide. As an immunomodulatory drug, thalidomide makes the blood vessels of patients with HHT stronger and less prone to rupture, and clinical trials have shown positive results in reducing the frequency of iron-deficiency anemia and lowering ESS scores in patients. ²³ The mechanism of action of tacrolimus (FK506) may involve partial correction of haploinsufficiency of endothelin and ALK1; therefore, it may be a potentially useful drug for use in patients with HHT undergoing transplantation. ²⁴ Antifibrinolytic agents have been incorporated into the first-line treatment of HHT. By inhibiting fibrinolysis associated with telangiectasis, enhancing coagulation, and increasing endothelin and ALK1 levels, tranexamic acid could significantly shorten the duration of epistaxis. Its systemic use has clearly shown benefit by reducing the frequency of epistaxis, but it is difficult to assess the potential risks of this treatment, such as the generation of blood clots. ²⁵ As a selective estrogen receptor modulator, tamoxifen inhibits neovascularization and reduces the formation and growth of AVMs while inducing the conversion of columnar epithelium to a thicker keratinized squamous epithelium, thereby enhancing mucosal tolerance to local trauma. In a previous trial, tamoxifen effectively reduced the frequency and volume of nosebleeds with few side effects. ²⁶ As a β-blocker, propranolol reduces cell migration and tubular structure formation, exhibits fibrinolytic activity, and is accompanied by reduced RNA and protein levels of ENG and ALK1. ²⁷ It exerts its antiangiogenic effects by downregulating VEGF expression and inducing vasoconstriction and endothelial cell apoptosis. In addition, several cases have reported systemic and topical use of propranolol, both showing a reduction in ESS. ²⁸ Recent studies have also emphasized the antiangiogenic potential of the antifungal agent itraconazole in HHT. By selectively inhibiting endothelial cells by targeting multiple pathways, including VEGF, its oral treatment significantly reduced the frequency and duration of nosebleeds in patients with HHT, but moderate side effects were observed. ²⁹ Studies have shown that acetylcysteine, an antioxidant, is effective in reducing epistaxis in male patients and HHT1 patients with ENG mutations, whereas only a trend toward improvement has been observed in female patients with HHT2 and ALK1 mutations. ³⁰

Surgical and invasive treatments are used when conservative methods and medications fail. Ablative therapies include laser therapy, sclerotherapy, radiofrequency ablation, bipolar electrocoagulation, and cryotherapy, while septal perforations and increased crusting, decreased airflow through the nostrils, loss of sense of smell, and atrophic rhinitis are known complications of these techniques. ³¹ As a newer technique, sclerotherapy results in fewer complications than laser therapy and can be performed under local anesthesia in an outpatient setting; however, local submucosal and subchondral injections of polydocanol can result in vascular occlusion. A camera can also be used to access the turbinate and ablate capillary dilation by radiofrequency. ³² Bipolar cauterization is used in the treatment of acute unilateral nosebleeds and lowers the risk of septal perforation. In this case, a modified Little’s area septomucotomy was combined with bipolar cauterization. The mucosal surface of the Little’s area was incised or scratched using a peeler to disrupt the hemorrhagic point, abnormal blood vessels, and the surrounding superficial mucosa of the nasal septum’s Little’s area while also promoting repair by stimulating local angiogenesis and epithelial regeneration. This Chinese modified mucosal dissection is an original novel method that is complementary to existing studies; it has not been reported in the literature on the surgical treatment of nasal hemorrhage associated with HHT. Cryotherapy is a therapeutic method in which low temperatures are applied to various tissues. Exposure of the nasal mucosa to temperatures as low as −70°C causes intracellular electrolyte shifts and cellular protein denaturation. Similar reactions in endothelial cells result in the formation of microthrombi in the vasculature, which leads to impaired perfusion and subsequent intermittent ischemia, transient hemostasis, and nasal mucosa reepithelialization. Over time, chronic recurrent bleeding decreases. ³³ The septal skin graft technique, in which the nasal mucosa is replaced with skin graft tissue or oral mucosa while leaving the basic perichondrium intact, is only advised in extreme cases because it cannot control bleeding from the sidewalls, and the main complications include worsening sinus infections and crusting. ³⁴ The Young’s procedure is used in patients with hemodynamically compromised epistaxis or those who continue to require transfusion after medication, and it avoids airflow through the nasal passages and drying out of the nasal mucosa and has a higher rate of recovery than septoplasty, with complications that include partially reopening or cracking and worsening of sinus infections. ³⁵ In addition, a technique of coagulation of the pterygopalatine arteries on both sides, followed by covering the area of the large arteriovenous fistula in the lateral wall of the nose with a hemostatic collagen mesh, has been reported in the literature to minimize mucosal injury and acute hemorrhage in this vulnerable area. However, hemostasis is only temporary due to collateral vessel formation. ³⁶

The success of patient-specific treatments can also be monitored clinically by means of systematic questionnaires, and adjustments to treatment are influenced by the level of the score and the patient’s personal intentions. The MFI-20 is a 20-question test used to gauge weariness. Lower ratings indicate fewer complaints of weariness. Scores vary between 0 and 20. ³⁷ The 36 quality-of-life items on the SF-36 evaluate eight health themes, with a composite score ranging from 0 to 100, with higher scores representing better self-reported health status. ³⁸ In addition, the Osler calendar, a treatment plan for patients with HHT and their treatment physicians, has begun to be used abroad. Its purpose is to educate patients about the most typical HHT symptoms, document how frequently they occur as well as their management, and remind patients of necessary follow-up visits. The calendar also summarizes the notes of the treating physician and tracks the patient’s outcome, facilitating the measurement of the effectiveness of current treatment strategies. ³⁹

This article reports a rare case of epistaxis due to HHT in an elderly woman and systematically analyzes its clinical features, diagnosis, and treatment process. The case meets the diagnostic criteria for HHT and provides a typical clinical example, which helps deepen the understanding of the characteristic manifestations of the disease and provides a reference for the treatment decision of similar patients. There are limitations in this study. The sample size of this single case report is limited, which makes it difficult to fully reflect the individual differences in age, organ involvement, and severity of HHT; genetic testing was not performed due to the refusal of the patient and her family. We will continue to communicate with the patient and her family to seek their cooperation. If consent is obtained, we will further conduct family genetic analysis to lay the groundwork for genetic studies of this disease in families.

Conclusion

Patients with HHT have a long disease course, and the clinical picture is sometimes characterized only by symptoms of recurrent epistaxis. The 60-year delay in diagnosis in this case reflects the lack of knowledge of the patient and her family about the disease as well as the limitations of the current healthcare system in terms of disease screening and allocation of resources to specialties. In this regard, otolaryngologists need to strengthen history taking (especially family history) and perform genetic testing as early as possible when there is a high degree of suspicion to avoid delays in treatment. In addition, multidisciplinary evaluation and treatment are needed to reduce the risk factor. Treatment for HHT-induced epistaxis ranges from conservative, nonsurgical measures to further surgical treatments and should be tailored to the individual patient. Moreover, it requires close follow-up and clinical counseling due to the chronic nature of the disease. In conclusion, a comprehensive understanding of HHT-induced epistaxis is important to prevent the clinical risks associated with delayed diagnosis and incomplete treatment.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605251374630 - Supplemental material for Epistaxis due to hereditary hemorrhagic telangiectasia: A case report and literature review

Supplemental material, sj-pdf-1-imr-10.1177_03000605251374630 for Epistaxis due to hereditary hemorrhagic telangiectasia: A case report and literature review by Xiangnan Du, Yuting Lu, Xiaoxiao Luo and Xiaolin Cao in Journal of International Medical Research