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Eker OF, Boccardi E, Sure U, et al., European Reference Network for Rare Vascular Diseases (VASCERN) Position Statement on Cerebral Screening in Adults and Children with Hereditary Haemorrhagic Telangiectasia (HHT), Orphanet Journal of Rare Diseases, ISSN: 1750-1172
Shovlin C, Clarke J, Alikian M, et al., Low grade mosaicism in hereditary haemorrhagic telangiectasia identified by bidirectional whole genome sequencing reads through the 100,000 Genomes Project clinical diagnostic pipeline, Journal of Medical Genetics, ISSN: 0022-2593
Shovlin C, Millar C, Droege F, et al., 2019, Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia, Orphanet Journal of Rare Diseases, Vol: 14, ISSN: 1750-1172
Background: Hereditary haemorrhagic telangiectasia (HHT) is a rare vascular dysplasia resulting in visceral arteriovenous malformations and smaller mucocutaneous telangiectasia. Most patients experience recurrent nosebleeds and become anaemic without iron supplementation. However, thousands may require anticoagulation for conditions such as venous thromboembolismand/or atrial fibrillation. Over decades,tolerance data has been publishedfor almost 200HHT-affected usersof warfarinand heparins, but there are no publisheddata forthe newer direct oralanticoagulants(DOACs)in HHT. Methods: To provide such data, aretrospective audit was conducted across the eight HHT centres of the European Reference Network for Rare Vascular Disorders (VASCERN),in Denmark, France, Germany, Italy, Netherlands and UK. Results: Although HHT Centreshad not specifically recommended the use of DOACs, 32treatment episodes had been initiated by other cliniciansin 28patients reviewed at the centres, at median age 65years(range 30-84). Indications were for atrial fibrillation (16 treatment episodes) and venous thromboembolism (16 episodes).The 32 treatment episodes used Apixaban (n=15), Rivaroxaban (n=14), and Dabigatran (n=3). HHT nosebleeds increased in severity in 24/32 treatment episodes (75%), leading to treatment discontinuation in 11 (34.4%). Treatment discontinuation was required for 4/15(26.7%) Apixabanepisodes and 7/14 (50%)Rivaroxaban episodes.By a 4 point scale of increasing severity,there was a trend for Rivaroxaban to be associated with a greaterbleeding riskboth including and excluding patients who had used more than one agent (age-adjusted coefficients 0.61 (95% confidence intervals 0.11, 1.20) and 0.74 (95% confidence intervals 0.12, 1.36) respectively. Associationswere maintained after adjustment for genderand treatment indication. Extreme haemorrhagic responses, worse thananything
Gawecki F, Strangeways T, Amin A, et al., 2019, Exercise capacity reflects airflow limitation rather than hypoxaemia in patients with pulmonary arteriovenous malformations, QJM: An International Journal of Medicine, Vol: 112, Pages: 335-342, ISSN: 1460-2393
Background: Pulmonary arteriovenous malformations (PAVMs) generate a right-to-left shunt. Impaired gas exchange results in hypoxemia and impaired CO2 clearance. Most patients compensate effectively but a proportion are dyspneic, and these are rarely the most hypoxaemic. Aim: To test degrees of concurrent pathology influencing exercise capacity. Design: Replicate, sequential single centre, prospective studies. Methods: Cardiopulmonary exercise tests (CPET) were performed in 26 patients with PAVMs, including individuals with and without known airflow obstruction. To replicate, relationships were tested prospectively in an independent cohort where self-reported exercise capacity evaluated by the Veterans Specific Activity Questionnaire (VSAQ) was used to calculate metabolic equivalents at peak exercise (METS N = 71). Additional measurements included oxygen saturation (SpO2), forced expiratory volume in 1 second (FEV1), vital capacity (VC), exhaled nitric oxide (FeNO), haemoglobin and iron indices. Results: By CPET, the peak work-rate was only minimally associated with low SpO2 or low arterial oxygen content (CaO2=1.34 x SpO2 x haemoglobin), but was reduced in patients with low FEV1 or VC. Supranormal work-rates were seen in patients with severe right-to-left shunting and SpO2 <90%, but only if FEV1 was >80% predicted. VSAQ-calculated METS also demonstrated little relationship with SpO2, and in crude and CaO2-adjusted regression, were lower in patients with lower FEV1 or VC. Bronchodilation increased airflow even where spirometry was in the normal range: exhaled nitric oxide measurements were normal in 80% of cases, and unrelated to any PAVM-specific variable. Conclusions: Exercise capacity is reduced by relatively mild airflow limitation (obstructive or restrictive) in the setting of PAVMs.
Alsafi A, Jackson JE, Fatania G, et al., 2019, Patients with in-situ metallic coils and amplatzer vascular plugs used to treat pulmonary arteriovenous malformations since 1984 can safely undergo magnetic resonance imaging, The British Journal of Radiology, Vol: 92, ISSN: 0007-1285
OBJECTIVES:To examine the magnetic resonance imaging (MRI) safety of metallic coils and Amplatzer vascular plugs. Currently, concern regarding MR-safety of devices used to treat pulmonary arteriovenous malformations (PAVMs) causes delays in performing emergency MRI in patients presenting with acute neurological symptoms.METHODS:A retrospective audit was performed on all patients who underwent PAVM embolization at our institution between 1984 – 2017. Outcomes of all MRI studies performed at our institution were recorded. In addition, known outcomes of all known MRI studies performed on patients treated with the earliest steel coils (1984 – 1995) were recorded.RESULTS:At our institution, 20 patients underwent 1.5 T MRI after the insertion of 100 steel coils (15.5 – 28.6, median 22 years later), 140 coils designated MR-conditional (0.42 – 12.7, median 9.3 years later), and 54 MRI-conditional Amplatzer vascular plugs (0.17 – 8.0, median 0.75 years later), many in combination. The majority of scans were for cerebral indications, but other body regions scanned included spinal, thoracic, and pelvic regions. No adverse events were reported. Similarly, there were no adverse events in any MR scan known to have been performed in other institutions in seven further patients treated with the earliest steel coils (1984 – 1995). Again, the majority of scans were for cerebral indications.CONCLUSIONS:The findings demonstrate MR safety at 1.5 T of all PAVM embolization devices inserted in a main UK centre since inception in 1984.ADVANCES IN KNOWLEDGE:Magnetic resonance imaging of patients who have had pulmonary AVMs treated by embolization can be implemented without contacting specialist pulmonary arteriovenous malformation treatment centres for approval.
Thielemans L, Layton DM, Shovlin CL, 2019, Low serum haptoglobin and blood films suggest intravascular haemolysis contributes to severe anaemia in hereditary haemorrhagic telangiectasia, Haematologica, Vol: 104, Pages: e127-e130, ISSN: 0390-6078
Buscarini E, Botella LM, Geisthoff U, et al., 2019, Safety of thalidomide and bevacizumab in patients with hereditary hemorrhagic telangiectasia, Orphanet Journal of Rare Diseases, Vol: 14, ISSN: 1750-1172
BackgroundHereditary hemorrhagic telangiectasia (HHT) is a multisystemic inherited vascular dysplasia that leads to nosebleeds and visceral arteriovenous malformations (AVMs). Anti-angiogenic drugs thalidomide and bevacizumab have been increasingly used off-label with variable results. The HHT working group within the ERN for Rare Multisystemic Vascular Diseases (VASCERN), developed a questionnaire-based retrospective capture of adverse events (AEs) classified using the Common Terminology Criteria for Adverse Events.ResultsSixty-nine HHT patients received bevacizumab, 37 (50.6%) for high output cardiac failure/hepatic AVMs, and 32 (49.4%) for bleeding; the 69 patients received bevacizumab for a mean of 11 months for a total of 63.8 person/years treatment. 67 received thalidomide, all for epistaxis and/or gastrointestinal bleeding; they received thalidomide for a mean of 13.4 months/patient for a total of 75 person/years treatment. AEs were reported in 58 patients, 33 with bevacizumab, 37 with thalidomide. 32 grade 1–3 AEs related to bevacizumab were reported with an average incidence rate of 50 per 100 person-years. 34 grade 1–3 AEs related to thalidomide were reported with an average incidence rate of 45.3 per 100 person-years. Bevacizumab AEs were more common in females (27 AEs in 46 women) than males (6 in 23, p < 0.001). Thalidomide AEs occurred at more similar rates in males (25 AEs in 41 men, 60.9%) and females (12 in 26 (46.2%), but were more common in ENG patients (17 in 17) than in ACVRL1 (14 in 34, p < 0.0001). For bevacizumab, the most common reports were of joint pains (7/69, 10%), headache (3/69, 4.4%) and proteinuria (2/69, 3%), and for thalidomide, peripheral neuropathy (12/67, 18%); drowsiness (8/67, 12%); and dizziness (6/67, 9%). Fatal adverse events were more common in males (p = 0.009), and in patients with ENG pathogenic variants (p = 0.012). One fatal AE was
Shovlin C, Bamford K, Sabbà C, et al., 2019, Prevention of serious infections in hereditary hemorrhagic telangiectasia: roles for prophylactic antibiotics, the pulmonary capillaries-but not vaccination, Haematologica, Vol: 104, Pages: e85-e86, ISSN: 0390-6078
Gawecki F, Myers J, Shovlin C, 2019, The Veterans Specific Activity Questionnaire (VSAQ) - a new and efficient method of assessing exercise capacity in patients with pulmonary arteriovenous malformations, BMJ Open Respiratory Research, Vol: 6, ISSN: 2052-4439
INTRODUCTION: Assessment of performance status is an important component of clinical management of patients with pulmonary arteriovenous malformations (PAVMs). Usual methods are time-consuming and insensitive to variationswithinnormal or supranormal exercise capacity.METHODS: TheVeterans Specific Activity Questionnaire (VSAQ) wasmodifiedto facilitate completion by patients independently. Patient-reported activity limitations were converted to the MRC Dyspnea scale, NYHA Classification,and metabolic equivalents (METs) in which 1 MET equals the consumption of 3.5 ml O2per kilogram of body weight. RESULTS: The study population of71 patients with PAVMswas aged 20-85 (median 52) years.SaO2was80-99.5% (median 96%), and haemoglobin73-169g/L in females and 123-197g/L in males (p<0.0001). CaO2(1.34 x (haemoglobin ×SaO2)/100) was maintained unless iron deficiency was present. Most patients(49/71, 69%) did not need to stop until activities more energetic than walking briskly at 4 miles per hour were achieved (VSAQ >5; MRC Dyspnea Scale 1 or 2; NYHA Class I). SaO2was inversely associated with the MRC Dyspnea scale and NYHA class, but not theVSAQ. Raw VSAQ scores captured a marked difference between malesand females. METSwere also higherin malesat 3.97-15.55(median 8.84)kcal/kg/hour, compared to 1.33-14.4(median 8.25)kcal/kg/hour(p=0.0039). There was only a modest association between METsand oxygen saturation (SaO2, p=0.044), but a stronger association between METsand haemoglobin (p=0.001).In crude and sex-adjusted regression, the arterial oxygen content (CaO2) was more strongly associated with METsthan either SaO2or haemoglobin in isolation.CONCLUSION: The VSAQ,capturing patient reported outcome measures,is an efficient and quantifiable measure of exercise capacity that can be readily employed in clinical services particularly wherepatients have normal to high exercise tolerance. In th
Fatania G, Gilson C, Glover A, et al., 2018, Uptake and radiological findings of screening cerebral magnetic resonance scans in patients with hereditary haemorrhagic telangiectasia, Intractable & rare diseases research, Vol: 7, Pages: 236-244, ISSN: 2186-361X
Hereditary haemorrhagic telangiectasia (HHT) results in arteriovenous malformations (AVMs), most commonly in the lungs, liver and brain. Discussion of cerebral vascular malformations is an important element of patient management. The current study objectives were to examine uptake and results of screening cerebral magnetic resonance (MR) scans, excluding symptomatic patients requiring neurological investigations. The remaining non-symptomatic individuals received formal pretest counselling that differed according to family history. For the 603 patients with no neurological symptoms of concern, screening scan uptake was higher after publication of the ARUBA trial. Patients with a family history of cerebral haemorrhage were 4 to 14-fold more likely to have a screening scan than patients with no such family history. For patients without neurological symptoms suggesting cerebral AVMs, none of the 59 screening scans performed at our institution demonstrated a cerebral AVM. Four scans (6.8%) demonstrated small aneurysms. The most common abnormality was cerebral infarction (20/59, 33.9%), predominantly identified in patients with pulmonary AVMs. Of 29 pulmonary AVM patients with no previous history of clinical stroke, 16 (55.2%) had between one and five silent infarcts. For HHT patients with pulmonary AVMs, the most frequently affected sites were the cerebellum (40%) and thalamus (14.3%), and the age-adjusted odds ratio for an infarct was 21.6 (95% confidence intervals 3.7, 126), p = 0.001. We concluded that for cerebral screening programmes in HHT, the findings support informed patient choice incorporating understanding that cerebral AVMs are rare in non-symptomatic HHT patients, but that screening scans commonly detect silent cerebral infarction due to pulmonary AVMs.
Alsafi A, Shovlin CL, Jackson JE, 2018, Acquired Transpleural Systemic Artery-to-Pulmonary Artery Communication Mimicking a Pulmonary Arteriovenous Malformation and Causing a False-Positive Diagnosis of a Pulmonary Embolus, JVIR: Journal of Vascular and Interventional Radiology, Vol: 29, Pages: 1313-1315, ISSN: 1051-0443
Shovlin CL, Buscarini E, Kjeldsen AD, et al., 2018, European Reference Network for Rare Vascular Diseases (VASCERN) outcome measures for hereditary haemorrhagic telangiectasia (HHT), Orphanet Journal of Rare Diseases, Vol: 13, ISSN: 1750-1172
Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia that leads to nosebleeds, anaemia due to blood loss, and arteriovenous malformations (AVMs) in organs such as the lungs, liver and brain. HHT is estimated to affect 85,000 European citizens, but most health care providers have limited prior HHT exposure or training.Outcome Measures were developed and implemented by the HHT Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN), in order to maximise the number of patients receiving good care. The measures specifically target areas where optimal management reduces morbidity and mortality in HHT patients, and were designed to be robust to emerging new evidence. Thresholds are the percentage of patients in particular settings who have been recommended screening, or provided with written advice. The 5 Outcome Measures cover (1) pulmonary AVM screening; (2) written nosebleed advice, (3) assessment of iron deficiency; (4) antibiotic prophylaxis prior to dental and surgical procedures for patients with pulmonary AVMs, and (5) written advice on pregnancy. They are not a blueprint for detailed HHT management, but are suitable for all clinicians to be aware of and implement.In summary, these 5 Outcome Measures provide metrics to identify healthcare providers of good care, and encourage care improvement by all healthcare providers.
Andrejecsk JW, Hosman AE, Botella LM, et al., 2017, Executive summary of the 12th HHT international scientific conference, Angiogenesis, Vol: 21, Pages: 169-181, ISSN: 0969-6970
Hereditary hemorrhagic telangiectasia is an autosomal dominant trait affecting approximately 1 in 5000 people. A pathogenic DNA sequence variant in the ENG, ACVRL1 or SMAD4 genes, can be found in the majority of patients. The 12th International Scientific HHT Conference was held on June 8–11, 2017 in Dubrovnik, Croatia to present and discuss the latest scientific achievements, and was attended by over 200 scientific and clinical researchers. In total 174 abstracts were accepted of which 58 were selected for oral presentations. This article covers the basic science and clinical talks, and discussions from three theme-based workshops. We focus on significant emergent themes and unanswered questions. Understanding these topics and answering these questions will help to define the future of HHT research and therapeutics, and ultimately bring us closer to a cure.
Shovlin CL, Condliffe R, Donaldson JW, et al., 2017, British Thoracic Society Clinical Statement on Pulmonary Arteriovenous Malformations., Thorax, Vol: 72, Pages: 1154-1163, ISSN: 1468-3296
Pulmonary arteriovenous malformations (PAVMs) are structurally abnormal vascular communications that provide a continuous right-to-left shunt between pulmonary arteries and veins. Their importance stems from the risks they pose (>1 in 4 patients will have a paradoxical embolic stroke, abscess or myocardial infarction while life-threatening haemorrhage affects 1 in 100 women in pregnancy), opportunities for risk prevention, surprisingly high prevalence and under-appreciation, thus representing a challenging condition for practising healthcare professionals. The driver for the current Clinical Statement was the plethora of new data since previous hereditary haemorrhagic telangiectasia (HHT) guidelines generated in 2006 and a systematic Cochrane Review for PAVM embolisation in 2011. The British Thoracic Society (BTS) identified key areas in which there is now evidence to drive a change in practice. Due to the paucity of data in children, this Statement focused on adults over 16 years. The Statement spans the management of PAVMs already known to be present (interventional and medical), screening and diagnosis (for PAVMs and HHT) and follow-up of patients following a first diagnosis, intervention or negative screen for PAVMs. The Good Practice Points (in bold) were generated for a target audience of general respiratory, medical and specialist clinicians and were approved by the BTS Standards of Care Committee, before formal peer review and public consultation. The Statement spans embolisation treatment, accessory medical management and issues related to the likelihood of underlying HHT.
Shovlin CL, Condliffe R, Donaldson JW, et al., 2017, Pulmonary arteriovenous malformations emerge from the shadows, Thorax, Vol: 72, Pages: 1071-1073, ISSN: 1468-3296
Shovlin CL, Buscarini E, Hughes JMB, et al., 2017, Long-term outcomes of patients with pulmonary arteriovenous malformations considered for lung transplantation, compared with similarly hypoxaemic cohorts, BMJ Open Respiratory Research, Vol: 4, ISSN: 2052-4439
INTRODUCTION:Pulmonary arteriovenous malformations (PAVMs) may not be amenable to treatment by embolization or surgical resection, and many patients are left with significant hypoxemia. Lung transplantation has been undertaken.There is no guidance on selection criteria.METHODS:To guidetransplantation listingassessments, the outcomes of the six patients who had been considered for transplantation were compared to a similarly hypoxemic patient group recruited prospectively between2005-2016at thesame UK institution.RESULTS: Sixpatientshad been formally considered for lung transplantation purely for PAVMs. One underwent a single lung transplantation for diffuse PAVMs and died within 4 weeks of surgery. Theother five were not transplanted, in four cases at the patients’ request.Their current survival ranges from 16-27 (median 21) years post transplant assessment. Of 444 consecutive patients with PAVMs recruited between 2005-2016, 42 were similarly hypoxemic to the “transplant-considered”cohort (SaO2 <86.5%). Hypoxemic cohorts maintained arterial oxygen content through secondary erythrocytosis and higher haemoglobin. The “transplant-considered” cohort had similar CaO2to the hypoxemic comparator group,but higher MRC dyspnea scores(p=0.023),higher rates of cerebral abscesses (p=0.0043) and higher rates of venous thromboemboli (p=0.0009) that were evident before and after the decision to list for transplantation. CONCLUSIONS: The non-transplanted patients demonstrated marked longevity. Symptoms and co-morbidities were better predictors of health than oxygen measurements. While a case-by-case decision, weighing survival estimates and quality of life will help patients in their decision making, the data suggesta verystrong case must be made before lung transplantation is considered.
Dupuis-Girod S, Cottin V, Shovlin CL, 2017, The Lung in Hereditary Hemorrhagic Telangiectasia, Respiration, Vol: 94, Pages: 315-330, ISSN: 1423-0356
Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited genetic vascular disorder with an estimated prevalence of 1 in 6,000, characterized by recurrent epistaxis, cutaneous telangiectasia, and arteriovenous malformations (AVMs) that affect many organs including the lungs, gastrointestinal tract, liver, and brain. Its diagnosis is based on the Curaçao criteria, and is considered definite if at least 3 of the 4 following criteria are fulfilled: (1) spontaneous and recurrent epistaxis, (2) telangiectasia, (3) a family history, and (4) pulmonary, liver, cerebral, spinal, or gastrointestinal AVMs. The focus of this review is on delineating how HHT affects the lung.
Boother EJ, Brownlow S, Tighe HC, et al., 2017, Cerebral abscess associated with odontogenic bacteremias, hypoxemia, and iron loading in immunocompetent patients with right-to-left shunting through pulmonary arteriovenous malformations., Clinical Infectious Diseases, Vol: 65, Pages: 595-603, ISSN: 1537-6591
Background: Cerebral abscess is a recognised complication of pulmonary arteriovenous malformations (PAVMs) that allow systemic venous blood to bypass the pulmonary capillary bed through anatomic right-to-left shunts. Broader implications and mechanisms remain poorly explored. Methods: Between June 2005 and December 2016, at a single institution, 445 consecutive adult patients with CT-scan confirmed PAVMs (including 403 (90.5%) with hereditary haemorrhagic telangiectasia) were recruited to a prospective series. Multivariate logistic regression, and detailed peri-abscess histories were evaluated to identify potential associations with cerebral abscess. Rates were compared to an earlier non-overlapping series. Results: Thirty-seven (8.3%) of the 445 patients experienced a cerebral abscesses at median age 50 (range 19-76) years. The rate adjusted for ascertainment bias was 27/435 (6.2%). 29/37 (78.4%) abscess patients had no PAVM diagnosis prior to their abscess, a rate unchanged from earlier UK series. 21/37 (56.7%) suffered residual neurological deficits, most commonly memory/cognition impairment; hemiparesis, and visual defects. Isolation of periodontal microbes, and precipitating dental and other interventional events emphasised potential sources of endovascular inoculations. In multivariate logistic regression, cerebral abscess was associated with low oxygen saturation (indicating greater right-to-left shunting); higher transferrin iron saturation index; intravenous iron use for anemia (adjusted odds ratio 5.4 [95% confidence intervals 1.4, 21.1]); male gender; and venous thromboemboli. There were no relationships with anatomic attributes of PAVMs, or red cell indices often increased due to secondary polycythemia. Conclusions: Greater appreciation of the risk of cerebral abscess in undiagnosed PAVMs is required. Lower SaO2 and intravenous iron may be modifiable risk factors.
Shovlin CL, Gossage JR, 2017, Pulmonary arteriovenous malformations: evidence of physician under-education, ERJ Open Research, Vol: 3, ISSN: 2312-0541
PAVMs pose unique management challenges; publication patterns indicate their importance remains poorly recognised http://ow.ly/7iIT304WYl2.
Finnamore H, Silva BM, Hickson BM, et al., 2017, 7-day weighed food diaries suggest patients with hereditary hemorrhagic telangiectasia may spontaneously modify their diet to avoid nosebleed precipitants, ORPHANET JOURNAL OF RARE DISEASES, Vol: 12, ISSN: 1750-1172
Hereditary hemorrhagic telangiectasia (HHT) poses substantial burdens due to nosebleeds and iron deficiency resulting from recurrent hemorrhagic iron losses. Recent studies by our group found surprising links between HHT nosebleeds and certain food groups. In this letter, we report 7-day weighed food diary assessments of an unselected group of 25 UK patients with HHT whose nosebleeds ranged from mild to severe (median epistaxis severity score 4.66, range 0.89– 9.11). The diaries provide evidence that food items most commonly reported to provoke nosebleeds were ingested by fewer HHT patients, compared to food items less commonly reported to provoke nosebleeds (chi-squared p <0.001).
Rizvi A, Macedo P, Babawale L, et al., 2017, Hemoglobin Is a Vital Determinant of Arterial Oxygen Content in Hypoxemic Patients with Pulmonary Arteriovenous Malformations., Annals of the American Thoracic Society, Vol: 14, Pages: 903-911, ISSN: 2329-6933
RATIONALE: Arterial partial pressure of oxygen (PaO2), and oxygen saturation (SaO2) are commonly measured in respiratory practice, but arterial oxygen content (CaO2) refers to the volume of oxygen delivered to the tissues per unit blood volume. CaO2 is calculated from SaO2 and the hemoglobin concentration in blood, recognizing that each gram of hemoglobin can transport approximately 1.34mls of oxygen when fully saturated. OBJECTIVES: To prospectively evaluate serial changes in CaO2 in man, incorporating and excluding dynamic changes to oxygenation and hemoglobin parameters that may occur during life. METHODS: A cohort of 497 consecutive patients at risk of both hypoxemia and anemia were recruited. The patients had radiologically-proven pulmonary arteriovenous malformations (PAVMs) which result in hypoxemia due to right-to-left shunting, and concurrent hereditary hemorrhagic telangiectasia (HHT) which placed them at risk of iron deficiency anemia due to recurrent hemorrhagic iron losses. Presentation SaO2 (breathing room air, by pulse oximetry), hemoglobin, red cell and iron indices were measured, and CaO2 calculated by SaO2*hemoglobin*1.34mls/gram. Serial measurements were evaluated in 100 cases spanning up to 32.1 (median 10.5) years. RESULTS: Presentation CaO2 ranged from 7.6-27.5 (median 17.6) mls/dL. CaO2 did not change appreciably across the SaO2 quartiles. In contrast, hemoglobin ranged from 5.9-21.8g/dL (median 14.1g/dL), with a linear increase in CaO2 across hemoglobin quartiles. Following PAVM embolization and an immediate increase in SaO2, hemoglobin fell and CaO2 was unchanged 1.6-12 (median 4) months later. When hemoglobin fell due to iron deficiency, there was no change in SaO2. Similarly, when hemoglobin rose after iron treatment, there was no change in SaO2, and the expected CaO2 increment was observed. These relationships were not evident during pregnancy when hemoglobin fell, and PAVMs usually deteriorated: In pregnancy SaO2 commonly increased, and
Hosman AE, Shovlin CL, 2016, Cancer and hereditary haemorrhagic telangiectasia, Journal of Cancer Research and Clinical Oncology, Vol: 143, Pages: 369-370, ISSN: 0171-5216
ObjectiveTo examine associations between cancer incidence and hereditary haemorrhagic telangiectasia (HHT).MethodsTwo studies with contrasting conclusions were compared. The first had used a registry-based, matched-pairs approach, while the second utilised HHT family-based, survey methodology.ResultsThe first manuscript captured data on cancer incidence in a total of 316,581 matched cancer patients–non-cancer controls, which included 431 HHT cases. No association was found between HHT and pooled cases of lung, breast, prostate, and colorectal cancer (adjusted OR 0.978, 95% CI [0.795, 1.204]). The second, which was powered to examine these four cancers individually, captured data from 2161 HHT cases and 2817 related controls. Fewer HHT-affected individuals had cancer (398/2161, [18.4%]) compared to 668/2817 (23.7%) related controls (p = 0.0012). Of the four most common cancers, prostate and colorectal cancer rates were equivalent, but lung cancers were significantly less frequent in HHT (adjusted OR 0.48 [0.30, 0.70], p = 0.0012), and breast cancer was more frequent (adjusted OR 1.52 [1.07, 2.14] p = 0.018).ConclusionsThe respective studies had different methodological strengths and weaknesses. Potential reasons for the discrepant conclusions include study power, particularly important to dissect specific cancers where differential contributions from HHT genotypes and environmental confounders might be predicted.
Shovlin CL, Patel T, Elphick A, et al., 2016, Injections of intravenous contrast for computerized tomography scans precipitate migraines in hereditary hemorrhagic telangiectasia subjects at risk of paradoxical emboli: implications for right-to-left shunt risks, Headache, Vol: 56, Pages: 1659-1663, ISSN: 0017-8748
OBJECTIVE: To evaluate if injection of intravenous particles may provoke migraines in subjects with right-to-left shunts due to pulmonary arteriovenous malformations (AVMs).BACKGROUND: Migraine headaches commonly affect people with hereditary hemorrhagic telangiectasia (HHT), especially those with pulmonary AVMs that provide right-to-left shunts. In our clinical practice, patients occasionally reported acute precipitation of migraine headaches following injection of technetium-labelled albumin macroaggregates for nuclear medicine scans.METHODS: Self-reported migraine features and exacerbations were examined in HHT subjects with and without pulmonary AVMs, for a series of noninvasive and invasive investigations, using an unbiased online survey.RESULTS: 166 subjects were classified as having both HHT and migraines. HHT subjects with migraines were more likely to have pulmonary AVMs (p<0.0001). HHT subjects with pulmonary AVMs were more likely to report photophobia (p=0.010); ‘flashes of light’ (p=0.011), or transient visual loss (p=0.040). Pulse oximetry, x-rays, ultrasound and computerized tomography (CT) scans without intravenous contrast medium rarely, if ever, provoked migraines, but unenhanced magnetic resonance imaging (MRI) was reported to exacerbate migraines by 14/124 (11.2%) subjects. 114 had both enhanced and unenhanced CT examinations: studies with contrast media were more commonly reported to start (9/114 [7.8%]), and/or worsen migraines (18/114 [15.7%]) compared to those undertaken without contrast medium (p<0.01), or after simple blood tests (p<0.05). Additionally, migraine exacerbation was reported by 9/90 (10%) after contrast echocardiography, 2/44 (4.5%) after nuclear medicine scans, and 10/154 (6.5%) after blood tests. CONCLUSIONS: HHT subjects frequently report migraine exacerbation following blood tests, contrast e
Shovlin CL, Patel T, Jackson JE, 2016, Embolisation of PAVMs reported to improve nosebleeds by a subgroup of patients with hereditary haemorrhagic telangiectasia, ERJ Open Research, Vol: 2, ISSN: 2312-0541
Shovlin CL, Gilson C, Busbridge M, et al., 2016, Can iron treatments aggravate epistaxis in some patients with hereditary hemorrhagic telangiectasia?, The Laryngoscope, Vol: 126, Pages: 2468-2474, ISSN: 1091-756X
Objectives/HypothesisTo examine whether there is a rationale for iron treatments precipitating nosebleeds (epistaxis) in a subgroup of patients with hereditary hemorrhagic telangiectasia (HHT).Study DesignSurvey evaluation of HHT patients, and a randomized control trial in healthy volunteers.MethodsNosebleed severity in response to iron treatments and standard investigations were evaluated by unbiased surveys in patients with HHT. Serial blood samples from a randomized controlled trial of 18 healthy volunteers were used to examine responses to a single iron tablet (ferrous sulfate, 200 mg).ResultsIron tablet users were more likely to have daily nosebleeds than non–iron-users as adults, but there was no difference in the proportions reporting childhood or trauma-induced nosebleeds. Although iron and blood transfusions were commonly reported to improve nosebleeds, 35 of 732 (4.8%) iron tablet users, in addition to 17 of 261 (6.5%) iron infusion users, reported that their nosebleeds were exacerbated by the respective treatments. These rates were significantly higher than those reported for control investigations. Serum iron rose sharply in four of the volunteers ingesting ferrous sulfate (by 19.3–33.1 μmol/L in 2 hours), but not in 12 dietary controls (2-hour iron increment ranged from −2.2 to +5.0 μmol/L). High iron absorbers demonstrated greater increments in serum ferritin at 48 hours, but transient rises in circulating endothelial cells, an accepted marker of endothelial damage.ConclusionsIron supplementation is essential to treat or prevent iron deficiency, particularly in patients with pathological hemorrhagic iron losses. However, in a small subgroup of individuals, rapid changes in serum iron may provoke endothelial changes and hemorrhage.
Chamali B, Finnamore H, Manning R, et al., 2016, Dietary supplement use and nosebleeds in hereditary haemorrhagic telangiectasia - an observational study., Intractable & rare diseases research, Vol: 5, Pages: 109-113, ISSN: 2186-3644
Understanding potential provocations of haemorrhage is important in a range of clinical settings, and particularly for people with abnormal vasculature. Patients with hereditary haemorrhagic telangiectasia (HHT) can report haemorrhage from nasal telangiectasia in real time, and suggested dietary factors may precipitate nosebleeds. To examine further, nosebleed severity, dietary supplement use, and blood indices were evaluated in an unselected group of 50 HHT patients recruited from a specialist UK service. Using the validated Epistaxis Severity Score, nosebleed severity ranged from 0 to 9.1 out of 10 (median 3.9). Using a Food Frequency Questionnaire, 24/50 (48%) participants reported use of dietary supplements in the previous year. A third (18/50; 36%) had used self prescribed, non-iron containing dietary supplements, ingesting between 1 and 3 different supplements each day. Eight (16%) used fish oils. Despite having more severe epistaxis (p = 0.012), the 12 iron supplement users had higher serum iron concentrations, and were able to maintain their red blood cell indices. In contrast, there was no evident benefit for the participants using non iron supplements. Furthermore, platelet counts and serum fibrinogen tended to be lower in fish oil/supplement users, and one fish oil user demonstrated reduced in vitro platelet aggregation. In conclusion, in this small study, a third of HHT patients used non-iron dietary supplements, and one in six ingested fish oils, unaware of their known anti-platelet activity. The scale of use, and potential of these "natural health supplements" to exacerbate nosebleeds has not been appreciated previously in HHT.
Shovlin CL, Awan I, Cahilog Z, et al., 2016, Reported cardiac phenotypes in hereditary hemorrhagic telangiectasia emphasize burdens from arrhythmias, anemia and its treatments, but suggest reduced rates of myocardial infarction, International Journal of Cardiology, Vol: 215, Pages: 179-185, ISSN: 1874-1754
IntroductionCardiac phenotypes should be pronounced in hereditary hemorrhagic telangiectasia (HHT) due to frequent systemic arteriovenous malformations (AVMs), iron deficiency anemia, hypoxemia, hyperdynamic circulations, venous thromboemboli, and paradoxical emboli through pulmonary AVMs.Methods/resultsIn an international survey, 1025 respondents (median age 55 years) met HHT diagnostic criteria: 942 (91.9%) reported nosebleeds, 452 (44.1%) at least daily. AVMs were commonly reported in pulmonary (544, 53%), hepatic (194, 18.9%) and/or cerebral (92, 9.0%) circulations. 770/1025 (75%) had used iron tablets, 256 (25.0%) intravenous iron, and 374 (36.5%) received blood transfusions. Arrhythmias were reported by 113/1025 (11%, including 44 (4.3%) with atrial fibrillation), angina by 36 (3.5%), and cardiac failure by 26 (2.5%). In multivariate logistic regression, these phenotypes were associated with hepatic AVMs/pulmonary hypertension (relatively interchangeable variables), blood transfusions, and intravenous iron. Cardiac insufficiency/failure often provokes intensive anemia treatments, but associations with arrhythmias, particularly with a greater transfusion burden, were less easy to explain.Myocardial infarction (23/1025; 2.2%), and abnormal coronary angiogram (≤ 31/76, ≤ 54%) rates appeared low. Provocative preliminary data were obtained including HHT-affected respondents' parents and grandparents in whom HHT could be confidently assigned, or excluded based on autosomal dominant inheritance patterns: in crude and survival analyses, myocardial infarctions were reported less frequently for individuals with HHT, particularly for males (p = 0.001).ConclusionArrhythmias are the most common cardiac phenotype in HHT, and likely to be aggravated by iron deficiency anemia, its treatments, and/or high output states due to AVMs. Myocardial infarction rates may be reduced in this apparently high risk population.
Mollet IG, Patel D, Govani FS, et al., 2016, Low Dose Iron Treatments Induce a DNA Damage Response in Human Endothelial Cells within Minutes, PLOS One, Vol: 11, ISSN: 1932-6203
BackgroundSpontaneous reports from patients able to report vascular sequelae in real time, and recognitionthat serum non transferrin bound iron may reach or exceed 10μmol/L in the bloodstream after iron tablets or infusions, led us to hypothesize that conventional iron treatmentsmay provoke acute vascular injury. This prompted us to examine whether a phenotypecould be observed in normal human endothelial cells treated with low dose iron.MethodologyConfluent primary human endothelial cells (EC) were treated with filter-sterilized iron (II) citrateor fresh media for RNA sequencing and validation studies. RNA transcript profiles wereevaluated using directional RNA sequencing with no pre-specification of target sequences.Alignments were counted for exons and junctions of the gene strand only, blinded to treatmenttypes.Principal FindingsRapid changes in RNA transcript profiles were observed in endothelial cells treated with10μmol/L iron (II) citrate, compared to media-treated cells. Clustering for Gene Ontology(GO) performed on all differentially expressed genes revealed significant differences in biologicalprocess terms between iron and media-treated EC, whereas 10 sets of an equivalentnumber of randomly selected genes from the respective EC gene datasets showed no significantdifferences in any GO terms. After 1 hour, differentially expressed genes clusteredto vesicle mediated transport, protein catabolism, and cell cycle (Benjamini p = 0.0016,0.0024 and 0.0032 respectively), and by 6 hours, to cellular response to DNA damage stimulusmost significantly through DNA repair genes FANCG, BLM, and H2AFX. Comet assays demonstrated that 10μM iron treatment elicited DNA damage within 1 hour. This wasaccompanied by a brisk DNA damage response pulse, as ascertained by the developmentof DNA damage response (DDR) foci, and p53 stabilization.SignificanceThese data suggest that low dose iron treatments are sufficient to modify the vascular endothelium,and induce a DNA damage
Shovlin CL, 2015, Circulatory contributors to the phenotype in hereditary hemorrhagic telangiectasia, Frontiers in Genetics, Vol: 06, ISSN: 1664-8021
Yasuda W, Jackson JE, Layton DM, et al., 2015, Hypoxaemia, sport and polycythaemia: a case from Imperial College London., Thorax, Vol: 70, Pages: 601-603, ISSN: 0040-6376
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