Pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: a series of 126 patients

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by epistaxis, telangiectasia, and visceral vascular manifestations. Infectious and ischemic central nervous system (CNS) manifestations due to embolism through pulmonary arteriovenous malformations (PAVMs) represent the main causes of morbidity. To improve the phenotypic characterization of HHT with PAVM, we conducted a retrospective multicenter study of patients with HHT and at least 1 PAVM detected by chest computed tomography (CT) and/or pulmonary angiography, with particular attention to CNS and infectious manifestations. The study included 126 patients (47 men, 79 women), with a mean age of 43.1 +/- 17.4 years; 45 patients had a mutation of the ENG gene and 16 had a mutation of ACVRL1. PAVMs were diagnosed as a result of systematic screening procedures (29%), incidental imaging findings (15%), dyspnea (22%), or CNS symptoms (13%). The PAVMs were diagnosed at a mean age of 43 +/- 17 years, with a linear distribution of diagnosis between 20 and 75 years. Dyspnea on exertion was present in 56% of patients. Four patients had a hemothorax, including 1 during pregnancy. Fifty-three CNS events directly related to HHT (excluding migraine) were observed in 35% of patients: cerebral abscess (19.0%), ischemic cerebral stroke (9.5%), transient cerebral ischemic attack (6.3%), and cerebral hemorrhage (2.4%). The median age of onset was 33 years for cerebral abscesses (range, 11-66 yr), and 53.5 years for ischemic cerebral events (range, 2-72 yr). Migraine was reported in 16% of patients. The diagnoses of PAVM and HHT were made at the time of the cerebral abscess in 13 cases (54%). Forty-three percent of patients were hypoxemic at rest. Contrast echocardiography showed intrapulmonary right-to-left shunting in 87% of tested patients. PAVMs were seen on chest radiograph in 54% of patients, and on the CT scan in all patients. One hundred five patients (83%) underwent treatment of the PAVM, by percutaneous embolization (71%) and/or by surgical resection (23%). A high frequency of CNS and infectious complications was observed in this large series of patients with HHT-related PAVM. Physicians may not be sufficiently aware of the clinical manifestations of this orphan disorder. Patients diagnosed with HHT should be informed by physicians and patient associations of the risk of PAVM-related complications, and systematic screening for PAVM should be proposed, regardless of a patient's symptoms, familial history, or genetic considerations.     

Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease, characterized by a wide variety of clinical manifestations, including epistaxis, gastrointestinal (GI) bleeding, pulmonary arteriovenous malformations (PAVMs) and neurological symptoms. HHT is a genetically heterogeneous disorder involving at least two loci; HHT 1 mapping to chromosome 9 q 34.1 (ENG) and HHT 2 mapping to chromosome 12 q 31 (ALK-1). OBJECTIVE: To evaluate and describe the diversity of clinical manifestations in a Danish population of HHT patients with known HHT 1 or HHT 2 subtype. DESIGN: Prospective clinical examination with genetic evaluation and follow-up. SETTING: Investigation centre was Odense University Hospital. All HHT patients in the County of Fyn were included. METHODS: HHT family members were invited to a clinical examination including registration of HHT manifestations, screening for PAVM and neurological evaluation. Blood tests were performed for analysis of disease-causing mutation, and clinical manifestations in the HHT subtypes were compared. The survival of the patients was studied in the follow-up period. RESULTS: Included in the study were 73 HHT patients representing 18 families. In 14 of the families we identified a disease-causing mutation. Thirty-nine patients (from 10 families) had HHT1 and 16 HHT patients from four families had HHT2. CONCLUSION: Amongst patients with HHT1 genotype the prevalence of PAVM was higher than amongst HHT patients with HHT2 genotype. HHT1 patients had experienced more severe GI bleeding than HHT2 patients. There was no significant difference in severity of epistaxis or age at debut. Finally the mortality over a 90-month observation period was not significantly increased.     

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.     

Multiple pulmonary arteriovenous malformations associated with hereditary hemorrhagic telangiectasia]

A 61-year old asymptomatic woman was admitted to our hospital for the examination of an abnormal shadow in the left lower lung lobe in 1978. Enhanced chest computed tomograms and pulmonary arteriograms revealed a pulmonary arteriovenous malformation (PAVM) composed of feeding artery and draining vein. The patient had suffered brain abscesses 3 times because of paradoxical emboli from PAVMs. A diagnosis of hereditary hemorrhagic telangiectasia (HHT) was made according to the criteria. The patient died of septic shock due to urinary tract infection by Candida albicans. We reviewed cases of PAVMs associated with HHT in the Japanese literature. In Japan, 126 HHT families and 144 HHT patients have been reported to date. PAVMs occur in approximately one-third of HHT patients in Japan. Twenty-four out of 45 patients (44.4%) had multiple PAVMs. We also discussed the diagnosis, complications, and treatment of PAVM-associated HHT.     

Contrast echocardiography for detection of pulmonary arteriovenous malformations

BACKGROUND: Pulmonary arteriovenous malformations (PAVMs) lead to stroke, brain abscess, and hemorrhage in hereditary hemorrhagic telangiectasia (HHT). The current screening approach for PAVMs in HHT patients with chest radiograph (CXR) and oxygen shunt study has not been validated and is thought to be insensitive. We hypothesized that agitated saline contrast echocardiography (ECHO) would be a useful screening test for PAVMs. METHODS AND RESULTS: A total of 106 sequential HHT patients underwent screening for PAVMs with ECHO in a prospective study. If the test was positive, or if the CXR or shunt study suggested PAVMs, pulmonary angiography was performed. A positive ECHO was defined as appearance of bubbles in the left atrium after injection of agitated saline solution. A positive shunt study was defined as a partial pressure of oxygen in arterial blood <500 mm Hg while breathing 100% oxygen. The mean age was 41 years (range 15-80 years); 66% were female. Forty-four patients had positive ECHO. Forty-one of the 44 patients underwent angiography. Three patients declined further testing. Thirty-three of the 41 patients who underwent angiography were diagnosed with PAVMs. Of the 62 patients with a negative ECHO, 18 underwent angiography because of either a shunt study or CXR that was suggestive of PAVMs. Of these 18 patients, 2 had PAVMs. In the total population of 106 patients, 35 (33%) had PAVMs. ECHO was the only positive screening test in 11 of 35 (31%) patients. The diagnosis of PAVMs in these 11 patients would have otherwise been missed. CONCLUSIONS: ECHO is a useful screening tool for PAVMs in HHT.     

Prevalence of pulmonary arteriovenous malformations (PAVMs) and occurrence of neurological symptoms in patients with hereditary haemorrhagic telangiectasia (HHT)

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease. HHT is characterized by a wide variety of clinical manifestations, including pulmonary arteriovenous malformations (PAVMs) and neurological symptoms. OBJECTIVE: To estimate (i) the prevalence of PAVM, and (ii) the occurrence of neurological symptoms in a geographical well-defined population of HHT patients. METHODS: HHT family members were invited to a clinical examination including registration of HHT manifestations, screening for pulmonary arteriovenous malformations and neurological evaluation. Two groups served as controls: (i) first-degree relatives without any signs of HHT; and (ii) age- and gender-matched controls. SETTING: Odense University Hospital. SUBJECTS: HHT patients identified in a cross-sectional family survey carried out in the County of Fyn, Denmark. RESULTS: Included in the study were 169 HHT family members representing 24 families. They included both HHT patients and their first-degree relatives. The criteria of HHT were fulfilled in 75 participants; of these, 59 had a screening procedure performed, and PAVMs were demonstrated at pulmonary angiography (PA) in 18. Seven of the HHT patients had a history of cerebral stroke, compared with none of their healthy first-degree relatives. CONCLUSION: The prevalence of PAVM was 24% amongst HHT patients. The study confirmed an increased prevalence of neurological symptoms amongst HHT patients; the odds ratio was estimated to be 7.6. In order to enable prevention of these complications, screening for PAVM should become an integral part of the medical care for HHT patients.     

Juvenile polyposis, hereditary hemorrhagic telangiectasia, and early onset colorectal cancer in patients with SMAD4 mutation

Background

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder most often caused by mutation in the endoglin or ALK1 genes. A distinct syndrome combines the clinical features of HHT and juvenile polyposis (JP) and has been associated with SMAD4 mutation. The aim of this study was to describe the phenotype of patients with JP–HHT and SMAD4 mutations and to compare this phenotype with HHT or JP patients with mutations other than SMAD4.

Methods

Patients prospectively enrolled in the Toronto HHT and JP databases who underwent genotyping were included. The phenotypic characteristics of JP–HHT patients with SMAD4 mutations and patients with mutations other than SMAD4 were analyzed and compared.

Results

Three hundred and fifty-eight patients underwent genetic testing (HHT, n?=?332; JP, n?=?26). Among fourteen patients identified with SMAD4 mutations, ten met the clinical diagnostic criteria for both JP and HHT (71%). Patients with SMAD4 mutations had 100% penetrance of the polyposis phenotype. All patients with JP and SMAD4 mutation had features of HHT. Three JP–HHT patients developed early onset colorectal cancer (CRC) (mean age 28 years). JP–HHT patients with SMAD4 mutation had a significantly higher rate of anemia than HHT patients with mutations other than SMAD4.

Conclusions

Patients with HHT and SMAD4 mutations are at significant risk of JP and CRC. The gastrointestinal phenotype is similar to JP patients without SMAD4 mutation. It is essential for HHT patients to undergo genetic testing to determine if they have SMAD4 mutations so that appropriate gastrointestinal screening and surveillance for JP and CRC can be completed.     

Oral itraconazole for epistaxis in hereditary hemorrhagic telangiectasia: a proof of concept study

The inhibiting effects of itraconazole, an antifungal drug on vascular endothelial growth factor (VEGF) have recently been discovered. By inhibiting VEGF, itraconazole has shown potential in clinical trials as anti-cancer treatment. In hereditary hemorrhagic telangiectasia (HHT) patients, VEGF levels are elevated and inhibition of VEGF can decrease bleeding. Itraconazole could potentially serve as anti-angiogenic therapy for HHT-related bleeding. We report a proof of concept study with HHT patients and severe epistaxis. Patients were treated with daily 200 mg orally administered itraconazole for sixteen weeks. Twenty-one HHT patients, 8 females (38%), 13 males (62%), median age of 59 years (interquartile range (IQR) 55–69) were enrolled. Of these patients, 13 (62%) were diagnosed with HHT type 1, seven (33%) with HHT type 2 and in one patient (5%), no pathognomonic HHT mutation was found. Four patients (19%) prematurely terminated the study (3 due to mild or moderate side-effects) resulting in 17 patients included in the analyses. The median epistaxis severity score significantly decreased during treatment from 6.0 (IQR 5.1–7.2) to 3.8 (IQR 3.1–5.2) (p?=?0.006). The monthly epistaxis frequency decreased from 56 to 38 epistaxis episodes (p?=?0.004) and the monthly duration from 407 to 278 minutes (p?=?0.005). Hemoglobin levels did not significantly change. The quality of life showed a small but significant improvement. In conclusion, oral itraconazole significantly improved epistaxis in HHT patients. The potential benefit of itraconazole in HHT should be further investigated.

     

Nutcracker esophagus: GERD or an esophageal motility disorder

A retrospective study was performed to determine the frequency of acid-related esophageal dysfunction in an unselected group of patients with nutcracker esophagus (NE). Five hundred seventy-two consecutive patients who underwent esophageal manometry and pH testing at one institution were evaluated. Forty-one percent were referred for evaluation of chest pain, 39% for reflux symptoms, and 20% for dysphagia, nausea, or epigastric pain. Esophageal manometry and 24-h pH monitoring were performed using standard methods. NE was defined as amplitude of phasic contractions of ≥180 mm Hg in any manometric tracing at any level of the esophagus. Abnormal total reflux was defined as >4% of the time with the esophageal pH < 4. A positive symptom index was defined as >50% of periods with pH < 4 coinciding with symptoms of chest pain or heartburn. Esophagitis was defined as an unequivocal mucosal defect if esophagogastroduodenoscopy was performed.
Forty-five patients met criteria for NE, with acid-related abnormalities found in 77%. Forty-nine percent had abnormal acid exposure time, 16% had positive symptom indexes with normal acid exposure, and 5% had endoscopic esophagitis. An additional 7% had only an increased number of reflux episodes with normal acid exposure and symptom indexes. The prevalence of NE was significantly higher in patients referred for chest pain than for typical reflux symptoms (14.3% vs 4.5%). Seventy-four percent of the patients with NE and chest pain did not have classic reflux symptoms. Seventy-six percent of 34 evaluable subjects who had been started on acid suppression were either improved or symptom free at an average of 10.7 months of follow-up.     

Pulmonary arteriovenous malformations: screening procedures and pulmonary angiography in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited disease with a high prevalence of pulmonary arteriovenous malformations (PAVMs). The first symptom of HHT may be stroke or fatal hemoptysis associated with the presence of PAVM. OBJECTIVE: To evaluate different screening methods applied for the identification of PAVMs. SETTING: Odense University Hospital. SUBJECTS: HHT patients with positive findings on contrast echocardiography (CE) who participated in a screening investigation and underwent pulmonary angiography (PA). METHODS: Different screening methods were evaluated against the results of PA. In a group of patients with positive findings on CE, we compared results of PA with the following: severity of dyspnea; results of pulse oximetry arterial oxygen saturation (SaO2) supine and upright; supine PaO2 in room air and while breathing 100% oxygen; size of arteriovenous shunt in supine position; chest radiograph; and intensity of contrast at CE. RESULTS: PA was performed in 25 HHT patients with positive findings on CE, 15 of whom had PAVM. Embolization therapy was recommended in 12 patients, and 3 patients had small PAVMs not accessible for therapy. In 10 patients, PAVM could not be demonstrated at PA. The sensitivity and specificity calculated for the screening procedures are as follows: 53% and 90%, respectively, for SaO2; 60% and 100%, respectively, for chest radiograph; 73% and 80%, respectively, for PaO2 in room air; 100% and 40%, respectively, for PaO2 breathing 100% oxygen; and 64% and 80%, respectively, for shunt measurement. CONCLUSION: Initial screening with CE followed by measurement of PaO2 while breathing 100% oxygen seemed to be the best screening procedure for identification of patients with PAVM. Screening with chest radiograph and pulse oximetry was shown to be insufficient.     

Multimodality evaluation of patients with gastroesophageal reflux disease symptoms who have failed empiric proton pump inhibitor therapy

Patients with symptoms suggestive of gastroesophageal reflux disease (GERD), such as chest pain, heartburn, regurgitation, and dysphagia, are typically treated initially with a course of proton pump inhibitors (PPIs). The evaluation of patients who have either not responded at all or partially and inadequately responded to such therapy requires a more detailed history and may involve an endoscopy and esophageal biopsies, followed by esophageal manometry, ambulatory esophageal pH monitoring, and gastric emptying scanning. To assess the merits of a multimodality ‘structural’ and ‘functional’ assessment of the esophagus in patients who have inadequately controlled GERD symptoms despite using empiric PPI, a retrospective cohort study of patients without any response or with poor symptomatic control to empiric PPI (>2 months duration) who were referred to an Esophageal Studies Unit was conducted. Patients were studied using symptom questionnaires, endoscopy (+ or – for erosive disease, or Barrett's metaplasia) and multilevel esophageal biopsies (eosinophilia, metaplasia), esophageal motility (aperistalsis, dysmotility), 24‐hour ambulatory esophageal pH monitoring (+ if % total time pH < 4 > 5%), and gastric emptying scanning (+ if >10% retention at 4 hours and >70% at 2 hours). Over 3 years, 275 patients (147 men and 128 women) aged 16–89 years underwent complete multimodality testing. Forty percent (n= 109) had nonerosive reflux disease (esophagogastroduodenoscopy [EGD]–, biopsy–, pH+); 19.3% (n= 53) had erosive esophagitis (EGD+); 5.5% (n= 15) Barrett's esophagus (EGD+, metaplasia+); 5.5% (n= 15) eosinophilic esophagitis (biopsy+); 2.5% (n= 7) had achalasia and 5.8% (n= 16) other dysmotility (motility+, pH–); 16% (n= 44) had functional heartburn (EGD–, pH–), and 5.8% (n= 16) had gastroparesis (gastric scan+). Cumulative symptom scores for chest pain, heartburn, regurgitation, and dysphagia were similar among the groups (mean range 1.1–1.35 on a 0–3 scale). Multimodality evaluation changed the diagnosis of GERD in 34.5% of cases and led to or guided alternative therapies in 42%. Overlap diagnoses were frequent: 10/15 (67%) of patients with eosinophilic esophagitis, 12/16 (75%) of patients with gastroparesis, and 11/23 (48%) of patients with achalasia or dysmotility had concomitant pathologic acid reflux by pH studies. Patients with persistent GERD symptoms despite empiric PPI therapy benefit from multimodality evaluation that may change the diagnosis and guide therapy in more than one third of such cases. Because symptoms are not specific and overlap diagnoses are frequent and multifaceted, objective evidence‐driven therapies should be considered in such patients.     

Symptoms and esophageal motility based on phenotypic findings of scleroderma

Scleroderma esophagus is characterized by ineffective peristalsis and reduced esophageal sphincter pressure. Esophageal disease in scleroderma can precede cutaneous manifestations and has been associated with Raynaud's phenomenon (RP) and pulmonary fibrosis (PF). The objective of the study is to evaluate the impact of cutaneous findings, RP, and PF on demographics, symptoms, and esophageal motility in patients with scleroderma. Scleroderma patients with esophageal involvement were included after review of esophageal manometries and charts over a 6‐year period. High‐resolution esophageal manometry was performed. Patients completed a symptom questionnaire. The study enrolled 28 patients (22 females; mean age 50.3 ± 12.8 years) with scleroderma esophagus. Patients without skin involvement (n= 12) reported more severe heartburn (P= 0.02), while those with cutaneous findings (n= 16) had more frequent dysphagia with solids (P= 0.02). Patients with RP (n= 22) had lower amplitude of distal esophageal contractions (P= 0.01) than those without RP (n= 6). Patients with PF (n= 11) reported more severe coughing and wheezing (both P= 0.03) than those without lung disease (n= 17). This study highlights subgroups of patients with scleroderma esophagus according to phenotypic findings of dermatologic changes, RP, and PF. Heartburn and dysphagia are important symptoms that may be associated with different stages of disease progression based on skin changes in scleroderma. RP was associated with greater esophageal dysmotility. Coughing and wheezing were more severe in patients with PF.     

遗传性出血性毛细血管扩张症：一家系研究与文献复习

目的 调查一例遗传性出血性毛细血管扩张症（HHT）患者及其家系，并复习相关文献。方法 调查先证者及其家系，抽取家系4例HHT患者及4名无HHT对照者外周血提取DNA，对活化素受体类激酶1（activin Areceptor type Ⅱ-ike1，ACVRLI）基因常见突变位点外显子3、7、8进行聚合酶链反应（PCR）和直接DNA测序，确定突变位点。结果 （1）家族5代45中人10人有HHT，其祖母死于“心脏病”，父死于“脑溢血”；（2）先证者为73岁女性，因反复自发性鼻衄60年，头昏、胸闷23年，加重2周收住院，临床主要诊断为HHT、高血压病3级（极高危）、腔隙性脑梗塞、高血压性心脏病、心功能Ⅱ级、高醛固酮血症、动脉硬化症、非胰岛素依赖性糖尿病，她的内脏损害包括胃毛细血管扩张症并出血和肾血管扩张并小动静脉瘘；（3）4例HHT患者存在ACVRLI基因第3外显子145鸟嘌呤碱基缺失（delG145），引起框移突变，并导致第53密码子为UAG终止密码子（frameshifi＋Stop：×53），4例对照者未见此突变；（4）文献报道63．4％的HHT患者急诊原因是鼻衄和胃肠道出血，但也可有脑、肺、心、肝等病变。结论 （1）ACVRLI基因delG145突变是这个家系致病的遗传学基础，此突变方式系国内首次报道；（2）HHT是一种慢性病，经常鼻衄会影响患者的生活质量，而血管畸形就有可能突然引起危机生命的情况，因此我们应该关注HHT患者，抓住主要矛盾，即要避免病情恶化，又要兼顾并发症和／或伴随症的处理，同时还要注意家系的调查。     

Malformaciones arteriovenosas pulmonares y complicaciones embólicas en pacientes con telangiectasia hemorrágica hereditaria

Patients with hereditary hemorrhagic telangiectasia (HHT) and pulmonary arteriovenous malformation (PAVM) face higher risk of embolic complications. It is not clear whether poor outcomes are related to PAVM severity or pulmonary symptoms. Furthermore, there is currently no available data on HHT patients in Argentina. We conducted a cross sectional study in a teaching hospital in Buenos Aires, Argentina. We describe baseline characteristics of HHT and compare the prevalence of embolic complications in patients with significant PAVM compared to patients without significant PAVM. One hundred and eight consecutive patients were included. Significant PAVM was defined as: contrast echocardiography grade 2 or greater; bilateral PAVM or feeding artery bigger than 3 mm; or previous PAVM treatment. Primary composite outcome was defined as: cerebrovascular accident, cerebral abscess or peripheral embolism. 20% of participants had embolic complications, the most frequent one was stroke. Embolic complications were associated with significant PAVM and respiratory symptoms.     

Clinical Course and Symptomatology of Angina Pectoris in a Population Study

ABSTRACT The clinical course of angina pectoris was studied in a follow-up study of 427 patients with angina from a general population sample. The subjects were men aged 56-65 years at the time of follow-up. After a mean follow-up time of 5.8 years. 55% were still suffering from angina pectoris, 15% had died and a further 19% were either free from chest pain or had chest pain considered to be of different origin. In the group with definite angina pectoris at follow-up (n = 236), 29% had sustained a myocardial infarction. 23% had symptoms of intermittent claudication, 36% were treated for hypertension and 15% had diabetes. Many of the angina patients suffered from other chest conditions in addition to anginal symptoms, Most of the patients (56%) had infrequent attacks (a few times per month or less often) and were not severely incapacitated by their symptoms. Only one fifth worked full time compared with more than half of those in the same age groups in the general population. Only 16 of those interviewed had undergone bypass surgery and a further 16 had disabling angina but, for various reasons, they had not been operated on. The implications are that most angina patients do well on pharmacological treatment alone even though they are limited socially as well as physically. Precipitating factors other than physical activity were also investigated and associations were found between susceptibility to cold, early morning angina, angina at rest and attacks of long duration, possibly indicating a mechanism of vasospasm superimposed on a fixed stenosis.     

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.     

Primary fibromyalgia. A clinical and laboratory study of 55 patients

The clinical symptoms of 55 patients with primary fibromyalgia (PF) were studied and compared with 30 patients with rheumatoid arthritis (RA). The PF patients expressed a more intense feeling of illness than did the RA patients. Stiffness occurred just as often in PF as in RA. Trigger points occurred less frequently in RA patients. Muscular fatigue appeared to be one of the most disabling symptoms in PF. Neurophysiological studies indicated that the fatigue was at least partly of central origin. Ischemic forearm exercise test gave no evidence of impaired glycogenolysis. Laboratory investigation revealed normal 25-hydroxyvitamin D, cobalamin, folate, estrogen, testosterone, and myoglobin in the PF patients.     

Human platelet factor 4: Preparation from outdated platelet concentrates and application in cerebral vascular disease

Platelet factor 4 (PF4), the platelet antiheparin protein, was isolated from both the supernatant and the cells of recently outdated platelet concentrates. Following purification by affinity chromatography, a competitive binding radioimmunoassay was developed to detect this protein in human plasma. The normal range was determined to be 9.4 ± 4.7 ng/ml (mean ± SD for 52 healthy adults). In order to determine whether individuals with transient ischemic attack (TIA) or stroke had measurable increments of PF4 in their plasma, radioimmunoassay studies were performed on 11 patients with well-documented TIA, 10 patients with well-documented stroke and on 16 age-matched controls hospitalized on a neurology service with disorders unrelated to arterial thrombosis. The 16 hospitalized controls had PF4 levels of 10.3 ± 9.1 ng/ml, a value not significantly different from the 52 normals (P > 0.50). Patients with TIA had PF4 levels of 24.6 ± 12.1 ng/ml, a value significantly higher than both the 52 normals (P < 0.001) and the 16 hospitalized control patients (P < 0.005). Patients with stroke had PF4 levels of 35.4 ± 29.2 ng/ml, a value significantly higher than both the 52 normals (P < 0.001) and the 16 hospitalized control patients (P < 0.005). Outdated platelet concentrates facilitate the development of a reproducible radioimmunoassay for PF4. The elevation of this platelet-derived protein in the plasma of patients with stroke and TIA provides evidence for recent or ongoing platelet activation in the cerebral vascular disease population.     

Outcome of patients with positive heparin–platelet factor-4 antibodies: A retrospective multi-institutional observational study

Studies show increased mortality with positive heparin–platelet factor-4 (H–PF4) antibodies, especially in hemodialysis patients. We aimed to compare mortality and thrombosis in hospitalized patients with positive, equivocal and negative H–PF4 antibody results. Information was collected on these patients using a multi-institutional retrospective electronic medical record review. Patients tested for H–PF4 antibodies by commercial ELISA during the years 2006 to 2010 were identified. We compared 30-day, 90-day and 1-year mortality in patients with negative, equivocal and positive H–PF4 test and evaluated the relationship between H–PF4 status and rate of thrombosis. Four hundred and seventeen patients had ELISA testing for H–PF4 antibodies. Forty-four patients had equivocal (optical density value 0.4–0.9) and 21 had positive (value 1) H–PF4 antibody test. There were no statistically significant differences in mortality between patients with negative, equivocal and positive results at all three time points (p?=?0.22, 0.27 and 0.38, respectively) even after excluding patients with thrombosis (p?=?0.22, 0.24 and 0.31, respectively). Age and Charlson score were associated with increased 30-day, 90-day and 1 year mortality. Odds ratio of having thrombosis was 23.1 for positive vs. equivocal results (p?<?0.001); however, there was no statistically significant difference between equivocal vs. negative results (p?=?0.22). Our results revealed no association between H–PF4 status and mortality, as well as no difference in 1-year survival between the positive and negative groups.     

Esophageal Disease in Patients with Angina-like Chest Pain

To assess the frequency of esophageal disease in patients with angina-like chest pain and normal coronary arteriograms, 16 patients underwent esophageal manometric studies, acid perfusion (Bernstein) tests, upper gastrointestinal series and cholecystograms. Five patients had evidence of esophageal disease. Three of the five had manometric criteria of increased nonperistalsis; one patient had idiopathic diffuse esophageal spasm while the other two patients had acid infusion tests which reproduced the presenting chest pain and the manometric findings were regarded as a motor disturbance of the esophagus secondary to chronic gastroesophageal reflux. The remaining two patients had symptomatic gastroesophageal reflux—one with an acid infusion test positive for pressure-like chest pain and the other with a decreased resting lower esophageal sphincter pressure associated with reflux of barium on upper gastrointestinal series. All five patients had improvement of symptoms during a follow-up period of seven to 17 months. Manometric studies in 18 normal subjects of similar age revealed no evidence of esophageal disease. Since esophageal disorders capable of causing chest pain were diagnosed in one-third of the patients (5/16 or 31%), it is suggested that investigations for esophageal disease, specifically directed at gastroesophageal reflux-induced abnormalities and idiopathic diffuse esophageal spasm, be included in the evaluation of patients with angina-like chest pain of uncertain origin.