Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia

OBJECTIVE: Gastrointestinal bleeding occurs in a number of patients with hereditary hemorrhagic telangiectasia (HHT) and may lead to a high transfusion need. The aim of this study was to estimate the occurrence and severity of gastrointestinal bleeding in a geographically well defined HHT population. METHODS: All HHT families in the county of Fyn, Denmark, (470,000 population) have been identified. Probands and their first degree relatives, and all descendants from probands for whom one parent had HHT were eligible for inclusion in the study. A total of 77 patients with HHT were identified; of these, 76 patients (mean age: 52 yr) were evaluated and interviewed with regard to gastrointestinal bleeding, that is, a history of either hematemesis or melena. Patients charts were reviewed. RESULTS: A total of 25 HHT patients (33%) had a history of either hematemesis or melena. Of these, 12 (48%) had received blood transfusions. Seven patients had severe bleeding (that is, > or =6 units of blood within 6 months before inclusion in the study). Endoscopy had been performed in 16 of the 25 (64%) patients. Telangiectatic lesions were documented in nine at upper endoscopy and in one at sigmoidoscopy. Telangiectatic lesions were observed in all patients with severe bleeding, but in two patients epistaxis is likely to have contributed to the anemia. Among 51 HHT patients without a history of gastrointestinal bleeding, only five (10%) had previously received blood transfusions; however, none fulfilled the definition of severe bleeding. In the HHT population 29 patients were > or =60 yr old, but all patients with severe bleeding were > or =60 yr. CONCLUSIONS: A history of gastrointestinal bleeding is common in patients with HHT (33%). This study documents that 25% of HHT patients > or =60 yr suffer from severe gastrointestinal bleeding.     

Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia

Pulmonary arteriovenous malformations (PAVMs) associated with hereditary hemorrhagic telangiectasia may cause severe cerebral complications that may be prevented by embolization therapy. We retrospectively compared the diagnostic value of noninvasive tests for the screening of treatable (amenable to embolization) PAVMs in a series of 105 patients, using chest computerized tomography (CT) and/or pulmonary angiography as a "gold standard." Patients had assessment of dyspnea, chest radiograph, alveolar-arterial PO2 gradient under 100% oxygen (AaPO2), contrast echocardiography, and radionuclide perfusion lung scanning. Contrast echocardiography in the supine position was the most sensitive test (93%). The sensitivity of self-reported dyspnea (59%), chest radiograph alone (70%), measurement of AaPO2 by the 100% oxygen method (62%), or radionuclide lung scanning (71%), was not suitable for efficient screening. A 100% sensitivity and negative predictive value could be obtained when combining anteroposterior chest radiograph and contrast echocardiography. Our data support a screening algorithm based on the combined use of contrast echocardiography and anteroposterior chest radiograph, followed by chest CT if either test is positive. An alternative is to screen directly by chest CT. However, this algorithm may obviate the need for chest CT in patients without PAVM, who represent a majority of patients with hereditary hemorrhagic telangiectasia.     

Familial juvenile polyposis syndrome with a novel SMAD4 germline mutation

Juvenile polyposis syndrome (JPS) is a dominantly inherited disorder characterized by the development of numerous juvenile polyps (JPs) of the gastrointestinal tract, and associated with a mutation of the SMAD4 or BMPR1A gene. Here, we report a mother?daughter case of familial JPS. A 29-year-old female patient with severe iron deficiency anemia and hypoproteinemia had numerous polyps in the stomach and a few polyps in the ileum and colon that were detected endoscopically. Biopsy specimens from the gastric polyps were diagnosed as JPs. The patient underwent a laparoscopy-assisted total gastrectomy, and her anemia and hypoproteinemia improved. Her mother also had multiple JPs in the stomach, duodenum, jejunum, and colon. We then diagnosed them as having familial JPS. Moreover, germline mutation analysis of the 2 patients presented a novel pathogenic SMAD4 variant.     

High prevalence of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

ObjectiveHereditary hemorrhagic telangiectasia (HHT) is a vascular disorder causing mucocutaneous telangiectases and visceral arteriovenous malformations (AVMs). Pulmonary hypertension (PH) is considered an uncommon complication of HHT whose impact on the survival of these patients is currently unknown.MethodsFrom January 1995 to December 2008, 29 hospitalized patients with definite HHT were included and followed until January 2011. Data on demographics, clinical symptoms and survival were recorded. PH was classified according to echocardiographic probability.ResultsA CT angiogram was performed in 24 of the 29 patients with HHT and AVMs were detected in 16 of them (67%): hepatic in 58%, pulmonary in 33% and spinal in 3%; 37% had both pulmonary and hepatic AVMs. Transthoracic Doppler echocardiography (TTE) was performed in 21 patients. PH was considered possible in 4 (14%) and probable in 9 (31%). The mean age at diagnosis was lower in patients with PH than in patients without PH (54 ± 16.5 years vs 73 ± 8.8 years, p = 0.002). PH was more prevalent in patients with AVMs (56 vs. 23%, p = 0.036). The mean follow-up of the entire cohort was 6 ± 4.4 years (range: 2 months–17 years), during this time 18 patients died (62%; mean age 73 ± 8.1 years). Patients with PH died at a younger age (68 ± 8.4 vs. 79 ± 2.7 years, p = 0.015) than those without PH.ConclusionsPH is a severe condition that significantly reduces survival on HHT patients. PH should be suspected in all HHT patients with dyspnea and hepatic AVMs.     

Diagnosis and management of gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia

OBJECTIVE: Our aim was to report our experience with treating GI bleeding in patients with hereditary hemorrhagic telangiectasia (HHT). METHODS: Consecutive patients with GI bleeding referred to the Yale University Vascular Malformation Center underwent clinical evaluation and endoscopy. Hb and blood transfusion requirements for 1 yr before and after evaluation were documented. Patients with a mean Hb or= 12 units packed red blood cells (PRBC)/yr were defined as patients with significant bleeding. Drug therapies, including ethinyl estradiol/norethindrone, danazol, and aminocaproic acid, were prescribed on an individual patient basis. RESULTS: The study included 43 HHT patients with a mean age of 57 yr. Endoscopy revealed telangiectases in the esophagus (1/41), stomach (33/41), duodenum (33/41), jejunum (5/9), and colon (10/32). Patients with > 20 telangiectases visualized on esophagogastroduodenoscopy had a significantly lower mean Hb of 7.9, compared with 9.4 (p = 0.007), and a trend toward higher blood transfusion requirements. Non-HHT-related causes of GI bleeding were diagnosed in four patients. During a mean follow up of 18.9 months, the group of 40 patients with HHT-related bleeding had improvements in their mean Hb and blood transfusion requirements. CONCLUSIONS: Some HHT patients with GI bleeding improve on drug therapies, but others fail. Transfusion-dependent GI bleeding is difficult to manage, and optimal management may include both medical and endoscopic treatments.     

Hereditary polyposis syndromes and hereditary non-polyposis colorectal cancer

Colorectal cancer due to hereditary syndromes comprises approximately 5% of the overall colorectal cancer burden. Conditions fall into two distinct categories, the polyposis syndromes and hereditary non-polyposis colorectal cancer. It is important for the clinician to have a working knowledge of both as screening and surveillance recommendations differ significantly from those applicable to the general population. The polyposis syndromes include familial adenomatous polyposis, Peutz-Jeghers syndrome, juvenile polyposis, and Cowden syndrome. For each condition, a review of both the intestinal and extra-intestinal clinical findings is presented as well as the genetic basis, genetic testing, screening, surveillance and treatment options. As genetic testing for several of these conditions has recently become both commercially available and standard practice, special attention is given to indications and strategies for genetic testing in hereditary colorectal cancer syndromes.     

Adrenomedullin as a potential biomarker involved in patients with hereditary hemorrhagic telangiectasia

BackgroundAdrenomedullin (AM) is a vasoactive peptide mostly secreted by endothelial cells with an important role in preserving endothelial integrity.  The relationship between AM and hereditary hemorrhagic telangiectasia (HHT) is unknown. We aimed to compare the serum levels and tissue expression of AM between HHT patients and controls.MethodsSerum AM levels were measured by radioimmunoassay and compared between control and HHT groups. AM levels were also compared among HHT subgroups according to clinical characteristics. The single nucleotide polymorphism (SNP) rs4910118 was assessed by restriction analysis and sequencing. AM immunohistochemistry was performed on biopsies of cutaneous telangiectasia from eight HHT patients and on the healthy skin from five patients in the control group.ResultsForty-five HHT patients and 50 healthy controls were included, mean age (SD) was 50.7 (14.9) years and 46.4 (9.9) years (p = 0.102), respectively. HHT patients were mostly female (60% vs 38%, p = 0.032). Median [Q1-Q3] serum AM levels were 68.3 [58.1–80.6] pg/mL in the HHT group and 47.7 [43.2–53.8] pg/mL in controls (p<0.001), with an optimal AM cut-off according to Youden's J statistic of 55.32 pg/mL (J:0.729). Serum AM levels were similar in the HHT subgroups. No patient with HHT had the SNP rs4910118. AM immunoreactivity was found with high intensity in the abnormal blood vessels of HHT biopsies.ConclusionsWe detected higher AM serum levels and tissue expression in patients with HHT than in healthy controls. The role of AM in HHT, and whether AM may constitute a novel biomarker and therapeutic target, needs further investigation.     

Evaluation of previously nonscreened hereditary hemorrhagic telangiectasia patients shows frequent liver involvement and early cardiac consequences

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by cutaneous, mucosal, and sometimes visceral arteriovenous malformations. Severe hepatic manifestations have been characterized in a subgroup of patients, but few data are available in previously nonscreened patients. We prospectively evaluated liver involvement and its cardiac consequences in such patients. Between 2000 and 2005, we prospectively evaluated the clinical, biological, and hepatic Doppler sonography (DS) characteristics of 102 consecutive HHT patients (mean age, 52.5 years; range, 19-88; 80.4%) with an identified genetic mutation. Patients were segregated into three different severity groups according to DS values. Factors predictive of an abnormal DS, according to predetermined criteria, and of a high cardiac index were identified by logistic and linear regression analysis, respectively. Abnormal liver biology and clinical signs of hepatic involvement were present in 35.3% and 27.5% of cases, respectively. Abnormal DS (defined as at least enlargement of the main hepatic artery) was observed in 56 (54.9%) cases, and direct or indirect signs of significant fistulas were present in 26 (25.5%) cases. Abnormal liver biology and a mutation involving the ACVRL1 gene were predictive of hepatic ultrasound (US) abnormalities. The diameter of the main hepatic artery and the presence of focal nodular hyperplasia (FNH) were predictive of a higher cardiac index. CONCLUSION: This large prospective series of previously nonscreened HHT patients identified a subgroup at risk of liver involvement (patients with abnormal liver biology and ACVRL1 mutations) and a subgroup with a higher cardiac index: future studies will show whether such patients would benefit from systematic DS screening and long-term cardiac surveillance.     

Enteroscopic evaluation of the gastrointestinal tract in symptomatic patients with hereditary hemorrhagic telangiectasia

OBJECTIVES: Hereditary hemorrhagic telangiectasia is an autosomal dominant disease in which 25% to 30% of patients will develop gastrointestinal bleeding from telangiectases. The extent of telangiectases has not been previously evaluated. This cross-sectional study compared the presence, number, and size of telangiectases in the stomach and duodenum to those in the jejunum using enteroscopy. METHODS: At the Yale University Vascular Malformation Center, 30 consecutive, symptomatic adult patients with hereditary hemorrhagic telangiectasia were evaluated using a 220-cm-length enteroscope. The number and size of the telangiectases were documented in the esophagus, proximal and distal stomach, four parts of the duodenum, and every 20 cm in the jejunum. The indication for the procedure was recorded as anemia, gastrointestinal bleeding, or anemia out of proportion to epistaxis. RESULTS: The results of 27 patients were analyzed. A total of 89% of patients had telangiectases in the first 60 cm of the jejunum. In individual patients, there was a strong correlation between the number of telangiectases in the stomach/duodenum when compared with the jejunum. In group analysis, the median number of telangiectases in the stomach and duodenum was significantly higher than in the jejunum (13 vs. 3; Wilcoxon signed rank test, P = 0.001). The presence of large (> or =5 mm) telangiectases in the stomach/duodenum did not necessarily indicate that there would be large telangiectases in the jejunum. CONCLUSIONS: The presence and number of stomach and duodenal telangiectases correlated with the presence and number of jejunal ones. However, the occurrence of large proximal telangiectases was not associated with large distal ones.     

遗传性出血性毛细血管扩张症相关性肺动脉高压六例的临床特征

目的 初步探讨遗传性出血性毛细血管扩张症相关性肺动脉高压的临床特征.方法 回顾性分析6例临床诊断为遗传性出血性毛细血管扩张症相关性肺动脉高压的临床表现.结果 6例患者年龄8～67岁,平均34岁,均有反复鼻出血病史,4例诊断为重度肺动脉高压,2例诊断为中度肺动脉高压.6例患者首次入院诊断均未明确肺动脉高压原因.除2例合并弥漫肝动静脉瘘患者外,其余4例经内科治疗后症状改善明显.结论 遗传性出血性毛细血管扩张症合并肺动脉高压易误诊,需对其相应的病症采用及时有效的治疗.

Abstract：

Objective To investigate the clinical manifestations of patients with pulmonary artery hypertension (PAH) associated with hereditary hemorrhagic telangiectasia (HHT). Methods This retrospective analysis summarized the clinical features of 6 patients with PAH associated with HHT hospitalized at department of cardiology in Cardiovascular Institute and Fuwai Hospital between January 2006 and May 2009. Results The mean age of the 6 patients (3 male) was 34 years (8 -67years). Recurrent epistaxis were present in all patients, there were 4 patients with severe PAH and 2 patients with moderate PAH. All of the six patients with PAH associated with HHT were misdiagnosed at the first hospital visit.Clinical symptoms were significantly improved in 4 patients and remained unchanged in 2 patients combined hepatic venous malformation post medical therapy. Conclusions Misdiagnosis for patients with PAH associated with HHT is a common phenomenon in daily clinical practice. Patients could benefit from the corresponding medical therapy after the establishment of the correct diagnosis.     

Pulmonary arteriovenous malformations, hereditary hemorrhagic telangiectasia, and brain abscess

Hereditary hemorrhagic telangiectasia (HHT) is a systemic angiodysplasia inherited as an autosomal dominant disease. Patients with HHT and pulmonary arteriovenous malformations (PAVMs) are at increased risk for brain abscess (BA), a potentially preventable condition as effective treatment for PAVMs is available. In a center dedicated to HHT, a history of BA was found in 6 out of 128 patients with a definite diagnosis: herewith, their histories are reported focusing on mistakes in the diagnosis and management of the disease. Patients with PAVMs and BA had a higher mean hemoglobin concentration (15.1 g/dl vs. 12.2 g/dl, p < 0.006 by Student's t test) compared to patients with PAVMs alone. Other clinical features (genetics, bacteriology, types of PAVMs, treatments, outcomes) are also discussed. Prompt diagnosis and screening for visceral involvement is pivotal for HHT patients and their relatives.     

Manifestations of juvenile polyposis syndrome in SMAD4 mutation carriers of a kindred

The autosomal dominantly inherited juvenile polyposis syndrome (JPS) leads to the development of multiple hamartomatous polyps in the gastrointestinal tract and is a precancerous condition. In a large family with a newly identified SMAD4 mutation (c.543delC), we describe the clinical manifestations of JPS. Nine affected SMAD4 mutation-positive family members were screened and treated for manifestations of JPS. Two family members were symptomatic at the time of diagnosis; seven were asymptomatic - independent of the severity of the manifestation. Each mutation carrier presented with colonic juvenile polyps, seven out of nine with additional gastric manifestations. One asymptomatic patient had early gastric cancer; another patient had a villous adenoma with high-grade intraepithelial neoplasia in the colon. Three patients had biliary lesions including a bile duct hamartoma in one and gallbladder polyps in two. Three patients had gastrointestinal vascular malformations. All mutation carriers were affected by JPS. Interestingly, the manifestations and their severity differed considerably between the patients, suggesting secondary factors influencing JPS manifestations such as Helicobacter pylori infection.     

Macro- and microcirculation patterns of intrahepatic blood flow changes in patients with hereditary hemorrhagic telangiectasia

AIM To evaluated vascular dynamic processes in the liver of hereditary hemorrhagic telangiectasia(HHT) patients by ultrasound(US) considering quantitative analytic methods. METHODS The imaging features on US and contrast-enhanced ultrasound(CEUS) in 18 patients diagnosed with HHT were retrospectively analyzed. Regarding CEUS, realtime contrast harmonic imaging and sulfur hexafluoridefilled microbubbles were used. RESULTS HVa Ms were identified in all 18 patients. By US, the two major Caselitz criteria could be detected in 55.6% patients. "Color spots" were detected in 72.2% of the cases. Respecting sonographic grading criteria by Buscarini, grade 3 could be demonstrated most frequent(40%). By CEUS, all the patients showed quick and early hyperenhancement during the arterial phase. Significant lowest time to peak(TTP) and highest area under the curve(AUC) values were identified in the hepatic artery(TTP: 69.8%; AUC: 100%) and highest TTP and lowest AUC in the hepatic parenchyma and the portal vein. CONCLUSION For the first time we analyzed CEUS findings of a group of HHT patients regarding macro- and microcirculation. Our data demonstrate significant differences in TTP and AUC values in the four selected regions: hepatic artery, shunt region, portal vein and hepatic parenchyma.     

Vascular endothelial growth factor serum levels are elevated in patients with hereditary hemorrhagic telangiectasia

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a genetic angiodysplasia affecting multiple organs. Two genes involved in the transduction of TGF-beta signalling are responsible for HHT. An additional role for vascular endothelial growth factor (VEGF) has been proposed. Serum VEGF, which has been evaluated in several diseases characterized by aberrant angiogenesis, has never been measured in patients with HHT. AIMS: To evaluate VEGF serum levels in HHT patients as compared to normal subjects. MATERIALS AND METHODS: 32 HHT patients (age 47.7 +/- 16.7 years) and a control group of 37 healthy subjects (age 48.2 +/- 15.5 years) were entered in the study. Each patient underwent serum VEGF dosage using a commercial ELISA specific for the human molecule. RESULTS: The serum level of VEGF in HHT patients was 196.3 +/- 103.2 pg/ml, while it was 152.0 +/- 84.1 pg/ml in the control group. Statistical analysis showed that serum VEGF was significantly higher in HHT patients than in the controls (p < 0.031). CONCLUSIONS: According to a study performed in a murine model, persistence of the activation phase of angiogenesis might be responsible for an increased production of several angiogenic factors, in particular VEGF, in HHT. Our work is the first to suggest an increased expression of VEGF in the serum of subjects with HHT in agreement with the stimulation of VEGF synthesis proposed in the murine model.