Hormonal and antihormonal therapy for epistaxis in hereditary hemorrhagic telangiectasia

OBJECTIVES/HYPOTHESIS: Objectives were to assess available information on hormonal therapy for bleeding in hereditary hemorrhagic telangiectasia (HHT), to determine whether there is a role for hormonal therapy as an initial therapeutic option, and to report the second known case of response in HHT to antihormonal therapy. Study Design: Literature review and case report. METHODS: The literature on hormonal and antihormonal therapy for HHT was reviewed. Medical records for the case reported in the present study were evaluated to confirm the diagnosis and assess responses to surgical and nonsurgical treatments. RESULTS: All reports of success using hormonal therapy for HHT-related bleeding were either retrospective or uncontrolled with the exception of two. Anecdotal evidence with high-dose estrogen appeared to show success, but serious side effects have discouraged use. One controlled trial found no benefit for intermediate dose, single-agent estrogen. The other controlled trial appeared to show benefit with low-dose estrogen-progesterone in HHT with gastrointestinal tract bleeding and was supported by an uncontrolled study showing efficacy in epistaxis. The case reported in the present study demonstrated long-term cessation of epistaxis with tamoxifen in a postmenopausal woman. CONCLUSIONS: Systemic estrogen-progesterone at doses used for oral contraception may eliminate bleeding in symptomatic HHT and is a reasonable initial option in fertile women. There is no information on possible effects of lower-dose estrogen-progesterone used in postmenopausal women for hormone replacement therapy. Tamoxifen has dramatically eliminated HHT-related bleeding in two cases. It is well tolerated in postmenopausal women and should be considered for randomized clinical trials.     

遗传性出血性毛细血管扩张症1例及家系报告

患者,男,47岁。因左侧鼻腔反复出血1个月于2009年11月入院。     

Outcome of septal dermoplasty in patients with hereditary hemorrhagic telangiectasia

OBJECTIVES/HYPOTHESIS: Septal dermoplasty has been recommended as the treatment of choice for life-threatening epistaxis in patients with hereditary hemorrhagic telangiectasia. The purpose of the study was to evaluate the effectiveness and outcomes of septal dermoplasty for management of transfusion-dependent epistaxis. STUDY DESIGN: Retrospective study. METHODS: Between 1994 and 2004, septal dermoplasty was performed on 67 consecutive patients with severe epistaxis attributable to hereditary hemorrhagic telangiectasia. The numbers of units of blood received 1 year before and 1 year after septal dermoplasty were obtained. A subjective appraisal of the results of the surgery as well as second procedures after septal dermoplasty was determined. Patients were screened for pulmonary and cerebral arteriovenous malformations, gastrointestinal tract bleeding, and symptomatic liver disease. RESULTS: Data were obtained in 66 of 67 (98%) patients with a mean age of 61.5 years (mean follow-up, 3.9 y). Accurate transfusion requirements 1 year before and 1 year after septal dermoplasty were available in 32 of 66 (48%) patients. In these 32 patients, the mean units of blood received decreased from 21 units (range, 2-100 units) 1 year before septal dermoplasty to 1 unit (range, 0-10 units) in the year after septal dermoplasty (P < .001). Improved quality of life was claimed in 57 patients. Second therapies, ranging from cautery to repeat partial septal dermoplasty, were required in 15 patients during follow-up. Among the 67 patients, 31 (46%) had pulmonary arteriovenous malformation, 14 (21%) had gastrointestinal tract bleeding, 7 (10%) had symptomatic liver disease, and 5 (7%) had cerebral arteriovenous malformation. During the follow-up, 14 patients died of other complications of hereditary hemorrhagic telangiectasia (11 patients) and unrelated causes (3 patients). CONCLUSION: Septal dermoplasty remains an effective way of reducing transfusion requirements in patients with hereditary hemorrhagic telangiectasia and subjectively improves their quality of life. The otolaryngologist caring for patients with hereditary hemorrhagic telangiectasia should be familiar with other organ involvement by hereditary hemorrhagic telangiectasia to prevent complications during surgery.     

贝伐珠单抗治疗遗传性出血性毛细血管扩张症所致家族性鼻出血的疗效观察北大核心CSCD

目的： 观察贝伐珠单抗治疗遗传性出血性毛细血管扩张症（hereditary hemorrhagic telangiectasia,HHT）所致家族性鼻出血的临床效果。 方法： 回顾性分析2016年12月至2019年12月期间于北京安贞医院、解放军总医院第一医学中心和滨州医学院附属滨州市中心医院接受静脉滴注贝伐珠单抗治疗的27例HHT所致家族性鼻出血患者的相关资料,其中男性14例,女性13例,年龄（55.3±11.2）岁。按5 mg/kg体重计算贝伐珠单抗剂量,观察第一次用贝伐珠单抗治疗1个月后的疗效。用视觉模拟量表（VAS）对比治疗前后患者全身症状自我评分;用鼻出血严重程度量表（epistaxis severity score,ESS）对治疗前后患者的6个问题（鼻出血频率、持续时间、出血强度、治疗需求、是否贫血、是否输血）进行对比分析;对比治疗前后患者的血红蛋白水平变化情况。采用SPSS 20.0统计软件处理数据。 结果： 第一次贝伐珠单抗治疗1个月后,27例患者中22例自诉鼻出血严重程度明显改善,5例自诉治疗效果不显著,治疗有效率81.5%（22/27）。用药效果显著的22例患者疗效维持时间5～24个月,中位时间11.23个月。全身症状VAS评分较治疗前明显下降,差异有统计学意义［（2.41±2.55）分比（8.19±1.47）分,t=9.708,P<0.01］。ESS的6个问题的得分及ESS标准化评分较治疗前均明显下降［鼻出血频率（1.78±1.22）分比（3.44±0.80）分,t=6.814,P<0.01;出血持续时间（0.85±0.91）分比（3.00±0.73）分,t=8.845,P<0.01;出血强度（0.19±0.40）分比（1.00±0.00）分,t=10.696,P<0.01;治疗需求（0.22±0.42）分比（1.00±0.00）分,t=9.539,P<0.01;是否贫血（0.41±0.50）分比（0.89±0.32）分,t=4.914,P<0.01;是否输血（0.11±0.32）分比（0.41±0.50）分,t=3.309,P<0.01;ESS标准化评分（2.50±2.45）分比（7.60±1.30）分,t=9.344,P<0.01］。治疗后血红蛋白水平较治疗前明显提高,差异有统计学意义［（105.48±24.31） g/L比（73.07±23.71） g/L,t=6.864,P<0.01］。27例患者中HHT1型（ENG基因）8例,HHT2型（ACVRL1基因）19例;药物应用后鼻出血改善持续时间前者为（4.76±5.12）个月,后者为（7.60±10.84）个月,后者长于前者,但差异无统计学意义（P>0.05）。治疗前后ESS评分在两组基因型患者中的差异无统计学意义（P>0.05）。第一次用药治疗后2例女性患者出现停经,所有患者均未出现其他不良反应。 结论： 贝伐珠单抗静脉滴注治疗HHT所致家族性鼻出血疗效显著、安全性高。.;Objective: To observe the clinical effects of bevacizumab in the treatment of familial epistaxis caused by hereditary hemorrhagic telangiectasia (HHT). Methods: The data of 27 patients with familial epistaxis caused by HHT who were treated with bevacizumab intravenously from Beijing Anzhen Hospital, the First Clinical Center of Chinese People's Liberation Army General Hospital and Binzhou Central Hospital between December 2016 and December 2019 were retrospectively analyzed. There were 14 males and 13 females, aged (55.3±11.2) years. The dose of bevacizumab was calculated according to the body weight of 5 mg/kg. The curative effect was observed one month after the first treatment. Visual analogue scale (VAS) was used to compare patients' self-scores of systemic symptoms before and after treatment. Epistaxis severity score (ESS) was used to compare and analyze the six problems (including the frequency, duration, intensity, treatment demand, anemia and blood transfusion) of the patients before and after treatment. The changes of hemoglobin levels before and after treatment were compared. SPSS 20.0 statistical software was used to process the data. Results: Among the 27 patients at one month after the first bevacizumab treatment, 22 cases reported that the severity of epistaxis was improved significantly, and 5 cases reported that the treatment effect was not significant. The effective rate was 81.5% (22/27). The significant effect in 22 patients lasted for 5-24 months, with a median duration of 11.23 months. The VAS score of systemic symptoms decreased significantly compared with that before treatment (2.41±2.55 vs 8.19±1.47, t=9.708, P<0.01). The scores of six aspects and standardized scores of ESS were significantly decreased after treatment (epistaxis frequency: 1.78±1.22 vs 3.44±0.80, t=6.814, P<0.01;epistaxis duration: 0.85±0.91 vs 3.00±0.73, t=8.845, P<0.01;epistaxis intensity: 0.19±0.40 vs 1.00±0.00, t=10.696, P<0.01;treatment demand: 0.22 ± 0.42 vs 1.00±0.00, t=9.539, P<0.01;anemia: 0.41±0.50 vs 0.89±0.32, t=4.914, P<0.01;blood transfusion: 0.11±0.32 vs 0.41±0.50, t=3.309, P<0.01;ESS standardized score: 2.50±2.45 vs 7.60±1.30, t=9.344, P<0.01). The hemoglobin level after treatment was significantly higher than that before treatment ((105.48±24.31) g/L vs (73.07±23.71) g/L, t=6.864, P<0.01). Among the 27 patients, there were 8 cases of HHT1 (ENG gene) and 19 cases of HHT2 (ACVRL1 gene). The improvement duration of epistaxis in group HHT1 and group HHT2 was (4.76±5.12) months and (7.60±10.84) months, respectively, which was in group HHT2 longer than that of group HHT1, but there was no significant difference between the two groups (P>0.05). There was no significant difference in ESS scores between the two groups before and after treatment (P>0.05). Two female patients had amenorrhea after the first medication. All patients had no other adverse reactions and complications. Conclusion: Intravenous bevacizumab is significantly effective and safe in the treatment of familial epistaxis caused by HHT.     

Manifestations of hereditary hemorrhagic telangiectasia in children and adolescents

The medical literature provides little information on manifestations of hereditary hemorrhagic telangiectasia (HHT) in children. The presented investigation was initiated to analyze early presenting symptoms in HHT, which should help to make the diagnosis at a young age and thus prevent potential complications from occult visceral arteriovenous malformations (AVM), which have commonly been described in HHT. A series of 15 children and adolescents with a suspicious diagnosis of HHT were examined clinically for typical signs and symptoms of the disorder. If the diagnosis of HHT seemed to be likely, recommendations for non-invasive screening procedures were given. Screening was directed at the detection of occult visceral AVMs. Main outcome measures were the definition of principal signs of HHT in children and adolescents. Family history was positive for HHT in 13 persons. The principal sign of recurrent epistaxis was present in 10/15 individuals and the earliest age of onset with regard to epistaxis was 4 years. Cutaneous vascular lesions were present in 5/15 patients. Screening for AVMs was performed in six individuals and revealed vascular lesions of the brain in two patients and vascular lesions of the lung in two patients. Gastrointestinal hemorrhages were present in one infant. Based on these findings, diagnosis of HHT seemed likely in ten individuals and unlikely in five individuals. Signs and symptoms of HHT in children and adolescents may be discrete, but are detectable at an earlier age than previously thought. Clinical examinations in children from HHT families may help identify candidates who will benefit from molecular genetic testing or screening imaging studies.     

Management of epistaxis in hereditary hemorrhagic telangiectasia by Nd:YAG laser and quality of life assessment using the HR-QoL questionnaire

The purpose of this study was to describe the results of Nd:YAG laser application in hereditary hemorrhagic telangiectasia (HHT) patients and to measure the Health-Related Quality of Life (HR-QoL) in patients with HHT before and after Nd:YAG laser application in a prospective, clinical trial at a university hospital. Twenty-seven consecutive patients with HHT and mild to moderate degrees of epistaxis were followed-up for 2 years after Nd:YAG laser treatments. Recurrence of epistaxis after Nd:YAG laser application and measurement of HR-QoL using the International Quality of Life Assessment questionnaire, version 1.1 (IQOLA 1.1), was found. Eight patients (30%) received only one Nd:YAG laser treatment, 15 (56%) had a recurrence and received a second treatment and 4 (14%) had two recurrences and received three Nd:YAG laser treatments. HR-QoL was improved 2 years after the first Nd:YAG laser application in both its Physical Health Dimension (47.5±2.9 vs. 38.1±2.3 before treatment, P <0.05) and Mental Health Dimension (45.1±2.7 vs. 39.6±2.4 before treatment, P <0.05). Although no curative treatment for HHT exists, Nd:YAG laser treatment seems to constitute a simple and efficient method of epistaxis control, resulting in a significant improvement in quality of life.     

Hereditary hemorrhagic telangiectasia type 1 and 2 mutations in Finland

Conclusion. The finding of several new unique mutations suggests that the genes causing hereditary hemorrhagic telangiectasia (HHT), i.e. endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1), have a relatively high mutation rate. As no single founder mutation was found, analysis of the whole coding sequences of ENG and ACVRL1 genes remains the first choice in genetic testing of new index patients with HHT. Objectives. Our aim was to characterize specific mutations causing HHT in our hospital in Helsinki serving a population of 1 million inhabitants. Patients and methods. HHT patients were searched from our hospital discharge records and their diagnoses were verified by review of patient records and interviews. Eight index patients who fulfilled HHT phenotypic criteria were tested. ENG and ACVRL1 mutations were identified by DNA sequencing of ENG and ACVRL1 coding regions. Results: Of the eight index patients, four had a mutation in the ENG gene, three in the ACVRL1 gene, and one had no mutations. All the mutations were different and all the four ENG mutations and one of the ACVRL1 mutations were new and had not been described previously in other populations. All the affected first-degree relatives had the same mutation as the index case.