Defective Flow-Migration Coupling Causes Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia.

BACKGROUND: Activin receptor-like kinase 1 (ALK1) is an endothelial transmembrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. Loss-of-function mutations in the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasia, a devastating disorder that leads to arteriovenous malformations. Here, we show that ALK1 controls endothelial cell polarization against the direction of blood flow and flow-induced endothelial migration from veins through capillaries into arterioles. METHODS: Using Cre lines that recombine in different subsets of arterial, capillary-venous, or endothelial tip cells, we show that capillary-venous Alk1 deletion was sufficient to induce arteriovenous malformation formation in the postnatal retina. RESULTS: ALK1 deletion impaired capillary-venous endothelial cell polarization against the direction of blood flow in vivo and in vitro. Mechanistically, ALK1-deficient cells exhibited increased integrin signaling interaction with vascular endothelial growth factor receptor 2, which enhanced downstream YAP/TAZ nuclear translocation. Pharmacologic inhibition of integrin or YAP/TAZ signaling rescued flow migration coupling and prevented vascular malformations in Alk1-deficient mice. CONCLUSIONS: Our study reveals ALK1 as an essential driver of flow-induced endothelial cell migration and identifies loss of flow-migration coupling as a driver of arteriovenous malformation formation in hereditary hemorrhagic telangiectasia disease. Integrin-YAP/TAZ signaling blockers are new potential targets to prevent vascular malformations in patients with hereditary hemorrhagic telangiectasia.

Pulmonary Abnormalities in Liver Disease: Relevance to Transplantation and Outcome.

Pulmonary disease in liver cirrhosis and portal hypertension (PH) constitutes a challenging clinical scenario and may have important implications with regard to prognosis, liver transplantation (LT) candidacy, and post-LT outcome. Pre-LT evaluation should include adequate screening for pulmonary diseases that may occur concomitantly with liver disease as well as for those that may arise as a complication of end-stage liver disease and PH, given that either may jeopardize safe LT and successful outcome. It is key to discriminate those patients who would benefit from LT, especially pulmonary disorders that have been reported to resolve post-LT and are considered "pulmonary indications" for transplant, from those who are at increased mortality risk and in whom LT is contraindicated. In conclusion, in this article, we review the impact of several pulmonary disorders, including cystic fibrosis, alpha 1-antitrypsin deficiency, hereditary hemorrhagic telangiectasia, sarcoidosis, coronavirus disease 2019, asthma, chronic obstructive pulmonary disease, pulmonary nodules, interstitial lung disease, hepatic hydrothorax, hepatopulmonary syndrome, and portopulmonary hypertension, on post-LT survival, as well as the reciprocal impact of LT on the evolution of lung function.

Life expectancy and comorbidities in patients with hereditary hemorrhagic telangiectasia.

There are only a few published studies that demonstrate associations between life expectancy, severe comorbidities, and their complications in patients with hereditary hemorrhagic telangiectasia (HHT). Relatives of 73 deceased patients with suspected HHT completed a questionnaire about causes of death, and symptoms and comorbidities that the patients had developed. We compared the data for 55 cases where HHT had been clinically confirmed with the general population. Patients suffering from HHT lost, on average, 19 years (SD 11 years) of potential life compared to the general population. Among the deceased HHT patients, 35% (95% CI: 23-48%) died from sepsis, 26% (95% CI: 16-38%) from cardiac failure, 20% (95% CI: 9-28%) from a severe bleeding episode, and 13% (95% CI: 6-24%) from terminal cancer. Congestive heart failure (69%, 95% CI: 56-80%) and pulmonary hypertension (23%, 95% CI: 14-36%) were the main non-fatal comorbidities in patients with HHT. Patients with HHT appear to have a lower life expectancy than the general population. Sepsis and cardiac failure were the main causes of death. Optimized and targeted screening programs for the most frequent comorbidities followed by improved management of infectious complications may increase life expectancy.

Liver transplantation for hereditary hemorrhagic telangiectasia: a systematic review.

AIM: To evaluate the indications, timing and results of liver transplantation in patients affected by hereditary hemorrhagic telangiectasia (HHT), by undertaking a systematic review of the current literature. METHODS: Electronic bibliographical databases were searched on MEDLINE and Pubmed according to the PRISMA criteria. A total of 58 articles were initially found, 11 have been excluded because of single center series later included in the European Liver transplant Registry (ELTR), already reported in this study. Thirty-eight articles have been excluded because they did not report specifically new cases of liver transplantation for hereditary hemorrhagic telangiectasia. Finally 9 articles were included in the analysis. RESULTS: A total of 56 patients who underwent liver transplantation for HHT are present in the English literature. One additional patient is presented in this article, for a total of 57 patients worldwide. To date, the most consistent published series is the one of the ELTR, including patients from 15 liver transplantation centers in the period 1985-2003 with a mean follow-up of 69 months. Ten-year patient and graft survival is 82.5% CONCLUSION: Liver transplantation should be considered as a radical but definitive treatment option in patients affected by HHT with liver or cardiac involvement not responsive to medical treatment.

Natural history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary hemorrhagic teleangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia is a genetic disease characterized by teleangiectasias involving virtually every organ. There are limited data in the literature regarding the natural history of liver vascular malformations in hemorrhagic telangiectasia and their associated morbidity and mortality. AIM: This prospective cohort study sought to assess the outcome of liver involvement in hereditary hemorrhagic telangiectasia patients. METHODS: We analyzed 16 years of surveillance data from a tertiary hereditary hemorrhagic telangiectasia referral center in Italy. We considered for inclusion in this study 502 consecutive Italian patients at risk of hereditary hemorrhagic telangiectasia who presented at the hereditary hemorrhagic telangiectasia referral center and underwent a multidisciplinary screening protocol for the diagnosis of hereditary hemorrhagic telangiectasia. Of the 502 individuals assessed in the center, 154 had hepatic vascular malformations and were the subject of the study; 198 patients with hereditary hemorrhagic telangiectasia and without hepatic vascular malformations were the controls. Additionally, we report the response to treatment of patients with complicated hepatic vascular malformations. RESULTS: The 154 patients were included and followed for a median period of 44 months (range 12-181); of these, eight (5.2%) died from VM-related complications and 39 (25.3%) experienced complications. The average incidence rates of death and complications were 1.1 and 3.6 per 100 person-years, respectively. The median overall survival and event-free survival after diagnosis were 175 and 90 months, respectively. The rate of complete response to therapy was 63%. CONCLUSIONS: This study shows that substantial morbidity and mortality are associated with liver vascular malformations in hereditary hemorrhagic telangiectasia patients.

Long-term outcome of patients with hereditary hemorrhagic telangiectasia and severe hepatic involvement after orthotopic liver transplantation: a single-center study.

Hepatic involvement occurs in up to 74% of patients with hereditary hemorrhagic telangiectasia (HHT) and is characterized by a spectrum of arteriovenous malformations. Three different types of intrahepatic shunting may be present: hepatic artery to hepatic veins, hepatic artery to portal vein, and portal vein to hepatic vein. Hepatic involvement in HHT may lead to biliary ischemia, portal hypertension, or high-output cardiac failure (HOCF). Orthotopic liver transplantation (OLT) has been proposed as the only definitive curative treatment. The aim of this study was to evaluate the long-term outcome of patients with hepatic involvement due to HHT after OLT with respect to mortality, cardiac and hepatic status, epistaxis, and quality of life. Patients with HHT and severe hepatic vascular malformations who underwent OLT in the Lyon Liver Transplant Unit (LLTU) from 1993 to 2007 were followed at the LLTU and the French Reference Center for HHT. Quality of life was evaluated with the Short Form 36 questionnaire. There were 13 patients who fulfilled the entry criteria of the study (12 women and 1 man). The mean age at the time of OLT was 51.8 years (range = 33-65 years). Indications for OLT were cardiac failure (n = 9), biliary necrosis (n = 2), both cardiac failure and biliary necrosis (n = 1), and hemobilia (n = 1). The mean duration of follow-up was 109 months (range = 1-200 months). Twelve patients (92.3%) are still alive. For the 9 patients with HOCF, the mean cardiac index decreased from 5.4 L/minute/m(2) before OLT to 3.0 L/minute/m(2) after OLT. No severe hepatic complications were observed after OLT. Nine of the surviving patients (75%) experienced dramatic improvements in epistaxis and quality of life, including an ability to undertake more physical activity. In conclusion, OLT is an important therapeutic option for patients with HHT who have severe hepatic involvement. In the reported cohort, the mortality after OLT for this indication was low.

[Mortality attributed to hereditary haemorrhagic telangiectasia and geographical variability in Spain (1981-2016)]. / Mortalidad atribuida a telangiectasia hemorrágica hereditaria y variabilidad geográfica en España (1981-2016).

OBJECTIVE: To identify the mortality directly attributed to hereditary haemorrhagic telangiectasia (HHT) in Spain, and to analyze its time trends and geographic variability. METHOD: Population-based deaths due to HHT were selected from the Spanish National Statistics Institute: codes 448.0 (ICD-9, 1981-1998) and I78.0 (ICD-10, 1999-2016) as the basic cause of death. Specific and age-adjusted mortality rates were calculated by sex, as well as standardized mortality ratios (SMR) by province and district, and smoothed SMR. RESULTS: We identified 327 deaths attributed to HHT (49.5% women), with the highest mortality at 80-84 years in men (0.220 per 100,000 inhabitants) and at 75-79 years in women (0.147 per 100,000 inhabitants). Age-adjusted mortality rates did not show any significant time trend between 1981 and 2016 in Spain. The provinces of Navarra, Cantabria, Guipúzcoa, Pontevedra and Las Palmas had higher than expected mortality, as well as the regions of Monte Sur (Ciudad Real) and Ripollès (Girona). CONCLUSIONS: This study has identified some regions with higher risk of death due to HHT in Spain. It is unknown whether these differences are associated with the distribution of types HHT1 and HHT2, and further studies will be necessary to know the determinants of this geographical variability. These findings are useful to complement the information provided by other studies and registries, and for health planning.

Liver Transplantation Trends and Outcomes for Hereditary Hemorrhagic Telangiectasia in the United States.

BACKGROUND: Liver arteriovenous malformations (AVM) in hereditary hemorrhagic telangiectasia (HHT) can necessitate liver transplantation. There is limited data on HHT patients undergoing liver transplantation (LT) in the United States. METHODS: Two sources of data were used: (1) Scientific Registry of Transplant Recipients (SRTR) database (1998-2016) (2) Single center liver transplant database (Mayo Clinic Rochester, MN). The aims of this study were (1) to determine trends in LT for HHT-related liver involvement in the United States using the SRTR database; (2) to identify clinical characteristics, indications, and outcomes for LT in HHT. RESULTS: Thirty-nine HHT patients were listed for LT in the SRTR database from 1998-2016 to 1998-2001 (n = 1); 2002-2005 (n = 4); 2006-2010 (n = 10), and 2011-2016 (n = 24). Twenty-four underwent LT at a median age of 47.5 years (interquartile range, 37.0-58.5 years). Median calculated MELD score at time of LT was 8.0 (interquartile range, 7.0-9.5), and 75% received an exception MELD score. Two status-1 patients died during transplant surgery. Nineteen (86%) patients were alive after a median post-LT follow-up of 48 months, whereas 2 patients were lost to follow-up. Five of the aforementioned HHT patients underwent LT at Mayo Clinic, 4 with high output cardiac failure, and 1 with biliary ischemia. All 5 were alive at the time of last follow-up with good graft function and resolution of heart failure. CONCLUSIONS: Outcomes after LT for HHT patients are excellent with 86% survival after a median follow-up of 48 months and resolution of heart failure. LT listing for HHT has increased in substantially in more recent eras.

Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): suggested approach for obstetric services.

OBJECTIVES: Hereditary haemorrhagic telangiectasia (HHT) affects 1 in 5-8000 individuals. Pregnancy outcomes are rarely reported. The major reason is that most women do not have their HHT diagnosed prior to pregnancy. Using a large well-characterised series, we studied all pregnancies known to have occurred in HHT-affected women, whether or not their diagnosis was known at the time of pregnancy. Our aim was to estimate rates and types of major complications of HHT in pregnancy, to guide management decisions. DESIGN: Cohort study, with prospective, retrospective and familial components. SETTING/POPULATION: Tertiary referral centre population. METHODS: All 262 pregnancies in the 111 women with HHT and pulmonary arteriovenous malformations (PAVMs) reviewed between 1999 and 2005 were studied. Eighty-two women (74%) did not have a diagnosis of HHT/PAVM at the time of pregnancy. 222 pregnancies in their 86 HHT-affected relatives were also studied. MAIN OUTCOME MEASURES: PAVM bleed, stroke and maternal death. RESULTS: Thirteen women experienced life-threatening events during pregnancy: 1.0% (95% CI 0.1-1.9) of pregnancies resulted in a major PAVM bleed; 1.2% (0.3-2.2%) in stroke (not all were HHT related); and 1.0% (0.13-1.9%) in maternal death. All deaths occurred in women previously considered well. In women experiencing a life-threatening event, prior awareness of HHT or PAVM diagnosis was associated with improved survival (P = 0.041, Fisher's exact test). CONCLUSIONS: Most HHT pregnancies proceed normally. Rare major complications, and improved survival outcome following prior recognition, means that pregnancy in a woman with HHT should be considered high risk. Recommendations for pregnancy management are provided.

Brain abscess and hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder that can lead to serious central nervous system complications including hemorrhage, ischemia, and infection. Symptoms can be mild, making diagnosis problematic. Fifty-three prior cases of HHT and brain abscess are described, in addition to two new cases. The clinical manifestations and current methods for diagnosis and management of patients with HHT are reviewed. Early recognition of HHT is important because screening in these patients and affected family members may help prevent complications. In addition, advancements in imaging, surgical techniques, antibiotics, and genetic testing may improve outcomes.

The role of liver transplantation in the treatment of hereditary hemorrhagic telangiectasia: a short literature review.

The liver is involved in up to 73% of patients suffering from hereditary hemorrhagic telangiectasia (HHT), but only some of them become symptomatic. Although management is often conservative, sometimes a more aggressive approach is required. The role of surgery is still undefined. Open ligation, banding, or closure of the arteriovenous malformation feeding artery have been proposed but rejected, as they are followed by an unacceptably high incidence of complications, derived from ischemia of the biliary tree. Orthotopic liver transplantation (OLT) has been successfully attempted in 28 patients with cardiac, biliary, or portal hypertension as well as mixed clinical presentations. Twenty-four were alive at time of data collection. Cardiovascular and pulmonary functions have improved after the operation in most cases. Intrahepatic relapse of the hallmark lesion of the disease (telangiectasia and arterovenous malformation) has been recently described in two cases. OLT represents a valuable therapeutic option for hepatic-based HHT, provided early diagnosis and referral to a specialized unit.

[Embolization of localized pulmonary arteriovenous malformations in adults]. / Embolisation des malformations artérioveineuses pulmonaires localisées de l'adulte.

OBJECTIVES: To report our experience using embolization in managing localized pulmonary arteriovenous malformations in adults. MATERIAL: and methods. All patients presenting with localized pulmonary arteriovenous malformations treated with embolization were included in the study. Clinical presentation (respiratory symptoms and previous history of paradoxical embolism) and the characteristics of pulmonary arteriovenous malformations (single or multiple, location, diameter of the afferent artery and simple or complex angioarchitecture) before embolization were analyzed. The details of the procedure, including the number of pulmonary arteriovenous malformations embolized, the number of coils used, and the type of intraoperative complications were recorded. Postembolization clinical and imaging follow-up were described. RESULTS: Forty-two patients (26 women, 16 men; mean age, 45 years), including 36 with hereditary hemorrhagic telangiectasia were treated with embolization. Twenty-two patients (53%) were dyspneic and 12 (29%) had a previous history of paradoxical embolism prior to embolization. Forty-seven procedures were carried out on a total of 99 pulmonary arteriovenous malformations (mean, 2.3 per patient), using 530 coils (12.6 per patient). The pulmonary arteriovenous malformations were located in the lower lobes in 60% of cases and a simple architecture was reported in 81% of cases. The average diameter of the afferent artery was 6mm. No preoperative complications were reported. After embolization, two patients (5%) presented with a paradoxical embolism and five patients out of 22 (23%) remained dyspneic. The rate of complete occlusion of treated arteriovenous malformations was 92% using computer tomography. CONCLUSION: Embolization is a highly effective and safe technique for treating pulmonary arteriovenous malformations. Improvement in dyspnea and prevention of paradoxical embolism can be expected. A high technical success rate can be obtained by experienced interventional radiologists.

Pulmonary hypertension subtypes associated with hereditary haemorrhagic telangiectasia: Haemodynamic profiles and survival probability.

BACKGROUND: Different pulmonary hypertension (PH) mechanisms are associated with hereditary haemorrhagic telangiectasia (HHT). METHODS AND RESULTS: We conducted a retrospective study of all suspected cases of PH (echocardiographically estimated systolic pulmonary artery pressure [sPAP] ≥ 40 mmHg) in patients with definite HHT recorded in the French National Reference Centre for HHT database. When right heart catheterization (RHC) was performed, PH cases were confirmed and classified among the PH groups according to the European guidelines. Among 2,598 patients in the database, 110 (4.2%) had suspected PH. Forty-seven of these 110 patients had RHC: 38/47 (81%) had a confirmed diagnosis of PH. The majority of these had isolated post-capillary PH (n = 20). We identified for the first time other haemodynamic profiles: pre-capillary pulmonary arterial hypertension (PAH) cases (n = 3) with slightly raised pulmonary vascular resistances (PVR), and combined post- and pre-capillary PH cases (n = 4). Compared to controls, survival probability was lower in patients with PAH. CONCLUSION: This study revealed the diversity of PH mechanisms in HHT. The description of combined post- and pre-capillary PH with/or without high cardiac output (CO) suggests either a continuum between the pre- and post-capillary haemodynamic profiles or a different course in response to high CO.

Hereditary hemorrhagic telangiectasia is caused by the Q490X mutation of the ACVRL1 gene in a large Arab family: support of homozygous lethality.

In a large Saudi Arabian family with hereditary hemorrhagic telangiectasia (HHT), we identified ACVRL1 (ALK1) nonsense mutation Q490X in 40 HHT patients and three healthy children, but neither in 11 individuals with epistaxis, 41 other healthy family members, nor in 50 healthy unrelated Saudi Arabian controls. Sequence analysis of the entire coding region of the ACVRL1 and ENG genes in five of the 11 epistaxic individuals did not reveal any other disease-causing mutation. Epistaxis seems to be a relatively common phenocopy of HHT in the family under study. One couple, both affected by HHT and carriers of Q490X, had 12 pregnancies. Three of them ended in spontaneous abortion, four in early neonatal death, and only five yielded living offspring, all of which had HHT and were Q490X heterozygous. This observation corroborates previous claims that homozygosity for HHT-causing mutations is lethal.

Life expectancy in patients with hereditary haemorrhagic telangiectasia.

BACKGROUND: There are few data on life expectancy in patients with hereditary haemorrhagic telangiectasia (HHT), a disorder with life-threatening complications. METHODS: Seventy HHT patients provided data on age and age at death of their HHT-affected parent, which was compared with that of the parent's non-affected partner. RESULTS: At the time of the study, 40 HHT parents (57.1%) vs. 36 (51.4%) non-HHT parents had died (p = 0.404). Median age at death was lower in HHT vs. non-HHT parents (63.2 vs. 70.0 years, respectively). The mortality of HHT parents showed an early peak in the under 50s and a late peak at 60-79 years. HHT was the main risk factor influencing life expectancy after 30 years (p < 0.05). No differences in survival probability were found in HHT patients with respect to sex (p = 0.37), or ENG vs. ALK-1 genotype (p < 0.9). DISCUSSION: Life expectancy appears to be significantly lower in HHT patients than in their partners. Prevention of HHT complications with screening programs could increase life expectancy.

Life expextancy of parents with Hereditary Haemorrhagic Telangiectasia.

BACKGROUND: Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant disease associated with epistaxis, arteriovenous malformations and telangiectasias. Disease complications may result in premature death. METHOD: We investigated life-expectancies of parents of HHT patients compared with their non-HHT partners using self- or telephone-administered questionnaires sent to their children. Patients were extracted from the databases of 2 participating HHT Centres: the Toronto HHT Database (Toronto, Canada) and the St. Antonius Hospital HHT Database (Nieuwegein, The Netherlands). RESULTS: Two hundred twenty five/407 (55%) of respondents were included creating HHT- (n = 225) and control groups (n = 225) of equal size. Two hundred thirteen/225 (95%) of the HHT group had not been screened for organ involvement of the disease prior to death. The life expectancy in parents with HHT was slightly lower compared to parents without (median age at death 73.3 years in patients versus 76.6 years in controls, p0.018). Parents with ACVRL 1 mutations had normal life expectancies, whereas parents with Endoglin mutations died 7.1 years earlier than controls (p = 0.024). Women with Endoglin mutations lived a median of 9.3 years shorter than those without (p = 0.04). Seven/123 (5%) of deaths were HHT related with a median age at death of 61.5 years (IQ range 54.4-67.7 years). CONCLUSION: Our study showed that the life expectancy of largely unscreened HHT patients was lower than people without HHT. Female patients with Endoglin mutations were most strikingly at risk of premature death from complications. These results emphasize the importance of referring patients with HHT for screening of organ involvement and timely intervention to prevent complications.

20-year follow-up study of Danish HHT patients-survival and causes of death.

BACKGROUND: Hereditary Haemorrhagic Telangiectasia (HHT) is a dominantly inheritable disorder, with a wide variety of clinical manifestations due to presence of multiple arteriovenous manifestations. The most common mutations are found in HHT1 (ENG) and HHT2 (ACVRL1) patients, causing alterations in the TGF-ß pathway which is responsible for angiogenesis. Modulations of angiogenesis may influence cancer rates. The objective of the study was to evaluate 20-year survival according to HHT subtype, as well as to evaluate differences in causes of death comparing HHT patients and controls. We also wanted to investigate whether cancer morbidity among HHT patients differs from that among controls. RESULTS: We included all HHT patients in the County of Fyn, Denmark, prevalent as of January 1st 1995 in total 73 HHT patients. In addition three age- and sex- matched controls per HHT patient were evaluated, in total 218 controls (one was lost due to registration failure). The controls were defined at start of follow-up in 1995. Information on lifestyle factors was not available. A total of 32 (44%) HHT patients and 97 (44%) controls passed away during follow-up. The survival curves were evenly distributed showing similar survival rates in the two groups. Cancer diagnoses had been registered in the follow-up period in 4 (5%) HHT patients and in 38 (17%) controls. CONCLUSION: The mortality was not increased among Danish HHT patients compared to controls. This study is based on a clinical unselected series of HHT patients with the whole spectrum of severity, independent of need for medical care. Our data also suggest that HHT patients to a lesser degree than the background population are affected by cancer.

Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterised by mucocutaneous telangiectasis, epistaxis, gastrointestinal haemorrhage, and arteriovenous malformations in the lung and brain. Causative mutations for HHT have been identified in two genes, endoglin and ALK1, which encode proteins involved in serine-threonine kinase signalling in the endothelial cell. METHODS: A number of people affected with HHT had completed a postal questionnaire as part of an international study to delineate the HHT phenotype. We identified questionnaires completed by subjects in whom we had identified a mutation in endoglin or ALK1. Further questionnaires were sent to families with known mutations. Data were only included from questionnaires returned by people known to carry disease causing mutations. RESULTS: Questionnaires were completed by 83 subjects with known mutations. Of these, 49 had endoglin mutations (HHT1) and 34 had ALK1 mutations (HHT2). Subjects with HHT1 reported an earlier onset of epistaxis (p=0.01) and telangiectasis (p=0.0001) than those with HHT2. Pulmonary arteriovenous malformations were only reported in the endoglin mutation group in our study (p<0.001). CONCLUSIONS: Our questionnaire based study provides evidence that the HHT phenotype caused by mutations in endoglin (HHT1) is distinct from, and more severe than, HHT caused by mutations in ALK1 (HHT2). This has significant implications for diagnosis, screening, and treatment in the two different forms of HHT, as well as for understanding the pathogenesis of the disease.

Mortalidad atribuida a telangiectasia hemorrágica hereditaria y variabilidad geográfica en España (1981-2016) / Mortality attributed to hereditary haemorrhagic telangiectasia and geographical variability in Spain (1981-2016)

OBJETIVO: Conocer la mortalidad directamente atribuida a la telangiectasia hemorrágica hereditaria (THH) en España, su tendencia temporal y la posible variabilidad geográfica. MÉTODO: El total de los fallecidos por THH de base poblacional se obtuvo del Instituto Nacional de Estadística, seleccionando los códigos 448.0 (CIE 9-MC, 1981-1998) y I78.0 (CIE 10, 1999-2016) como causa básica de defunción. Se calcularon las tasas de mortalidad específicas y ajustadas por edad para cada sexo, las razones de mortalidad estandarizadas (RME) por provincia y comarca, y las RME suavizadas. RESULTADOS: Se identificaron 327 fallecimientos por THH (el 49,5% eran mujeres), siendo la mortalidad más alta a los 80-84 años en los hombres (0,220 por 100.000 habitantes) y a los 75-79 años en las mujeres (0,147 por 100.000 habitantes). No se detectaron cambios temporales entre 1981 y 2016. Las provincias de Navarra, Cantabria, Guipúzcoa, Pontevedra y Las Palmas presentaron un riesgo significativamente superior con respecto a lo esperado para el total nacional, así como las comarcas de Monte Sur (Ciudad Real) y Ripollès (Girona). CONCLUSIONES: Este trabajo ha permitido identificar algunas regiones con mayor riesgo de defunción por THH, si bien se desconoce si estas diferencias se asocian a la distribución de los tipos THH1 y THH2, por lo que son necesarios estudios posteriores para profundizar en las causas de la variabilidad geográfica. Estos hallazgos complementan la información proporcionada por otros estudios y registros, además de ser útiles para la planificación sanitaria

OBJECTIVE: To identify the mortality directly attributed to hereditary haemorrhagic telangiectasia (HHT) in Spain, and to analyze its time trends and geographic variability. METHOD: Population-based deaths due to HHT were selected from the Spanish National Statistics Institute: codes 448.0 (ICD-9, 1981-1998) and I78.0 (ICD-10, 1999-2016) as the basic cause of death. Specific and age-adjusted mortality rates were calculated by sex, as well as standardized mortality ratios (SMR) by province and district, and smoothed SMR. RESULTS: We identified 327 deaths attributed to HHT (49.5% women), with the highest mortality at 80-84 years in men (0.220 per 100,000 inhabitants) and at 75-79 years in women (0.147 per 100,000 inhabitants). Age-adjusted mortality rates did not show any significant time trend between 1981 and 2016 in Spain. The provinces of Navarra, Cantabria, Guipúzcoa, Pontevedra and Las Palmas had higher than expected mortality, as well as the regions of Monte Sur (Ciudad Real) and Ripollès (Girona). CONCLUSIONS: This study has identified some regions with higher risk of death due to HHT in Spain. It is unknown whether these differences are associated with the distribution of types HHT1 and HHT2, and further studies will be necessary to know the determinants of this geographical variability. These findings are useful to complement the information provided by other studies and registries, and for health planning

Complications and mortality in hereditary hemorrhagic telangiectasia: A population-based study.

OBJECTIVES: Studies report that the risks of significant neurologic complications (including stroke, cerebral abscess, and migraine) and hemorrhagic sequelae are high in patients with hereditary hemorrhagic telangiectasia (HHT), and that life expectancy in this cohort is reduced. However, most published cohorts derive from specialist centers, which may be susceptible to bias. METHODS: We used a population-based approach to estimate the risks of developing neurologic and hemorrhagic complications of HHT, the association of a diagnosis of HHT with common cardiovascular and malignant comorbidities, and also long-term survival of those with the disease. RESULTS: From a UK primary care database of 3.5 million patients (The Health Improvement Network), we identified 675 cases with a diagnosis of HHT and compared them with 6,696 controls matched by age, sex, and primary care practice. Risks of stroke (odds ratio [OR] 1.8, 95% confidence interval [CI] 1.2-2.6), cerebral abscess (OR 30.0, CI 3.1-288), and migraine (OR 1.7, CI 1.3-2.2) were elevated over controls. Bleeding complications including epistaxis (OR 11.6, CI 9.1-14.7) and gastrointestinal hemorrhage (OR 6.1, CI 2.8-13.4) were more common in cases with HHT. Survival of cases with HHT was poorer than controls with a hazard ratio for death of 2.0 (CI 1.6-2.6) and a median age at death 3 years younger. CONCLUSIONS: Patients with HHT are at substantially increased risk of serious neurologic and hemorrhagic complications of the disease. Because a diagnosis of HHT is associated with a significantly poorer survival compared with those who have no disease, evaluation of new strategies to improve clinical management is required.