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BACKGROUND: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare disorders of heme biosynthesis characterized by severe cutaneous phototoxicity. Afamelanotide, an α-melanocyte-stimulating hormone analogue, is the only approved treatment for protoporphyria and leads to increased light tolerance and improved quality of life (QoL). However, published experience with afamelanotide in the US is limited. METHODS: Here, we report on all adults who received at least one dose of afamelanotide at the Massachusetts General Hospital Porphyria Center from 2021 to 2022. Changes in the time to phototoxic symptom onset, QoL, and laboratory parameters were assessed before and during treatment with afamelanotide. RESULTS: A total of 29 patients with protoporphyria were included, 26 of whom (72.2%) received ≥2 afamelanotide implants. Among the patients who received ≥2 implants, the median time to symptom onset following sunlight exposure was 12.5 min (IQR, 5-20) prior to the initiation of afamelanotide and 120 min (IQR, 60-240) after treatment (p < 0.001). Improvements in QoL during afamelanotide treatment were measured using two QoL tools, with good correlation observed between these two instruments. Finally, we found no improvements in the median levels of metal-free erythrocyte protoporphyrin, plasma protoporphyrin, or liver biochemistries during versus prior to the initiation of afamelanotide treatment. CONCLUSIONS: This study highlights a dramatic clinical benefit of afamelanotide in relation to light tolerance and QoL in protoporphyria, albeit without improvement in protoporphyrin levels or measures of liver function.
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Understanding attitudes towards genetic exceptionalism and confidentiality is important in guiding policies regarding special protections for genetic/genomic information stored in electronic health records (EHR). The goals of this study were to determine biobank participants' attitudes towards genetic exceptionalism and confidentiality and whether those attitudes are related to their preference for return of genetic results. An online questionnaire was distributed to patients with an EHR and email address who had previously enrolled in the BioMe Biobank program. Most participants responded with similar levels of concern in scenarios involving the use of genetic information and other types of health information, suggesting that participants want similar protections for genetic data as other types of sensitive health information, particularly mental health and family history records. Of the 829 respondents, the majority had genetic exceptionalist views when directly asked, even though their concerns about confidentiality were similar for their genetic information and other health information. There were no differences in genetic exceptionalist views between those who had a documented preference to have genetic results returned and those who did not. Notably, for many participants, their recall of preference did not align with their documented preference. The majority of biobank participants were most anxious about the loss of confidentiality for genetic, mental health, and family history information, indicating that certain types of health information are considered more "sensitive" than others. These findings suggest the importance of assuring people participating in biobank research that the confidentiality of their "sensitive" health information is secured.
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Purpose: Erythropoietic protoporphyria (EPP), a rare inherited disorder, presents in early childhood with severe, painful phototoxicity, with significant impacts on health-related quality of life (HRQoL). Previous studies have not captured all concepts important to patients. Therefore, this study sought to develop a novel, comprehensive, and content valid patient-reported outcome (PRO) measure to assess the efficacy of new therapies. Patients and Methods: Qualitative interviews were conducted with EPP participants and clinical experts to obtain views on concepts relevant to patients. Results informed the development of novel PROs, which were debriefed during subsequent combined concept elicitation and cognitive debriefing interviews. Results: Twenty-three interviews were conducted with 17 adults and 6 adolescents with EPP. Concept elicitation revealed that participants experienced many symptoms with significant variability. The most common were burning, pain, swelling, and tingling. Tingling was the most common prodromal symptom, while burning was the most bothersome, and pain was the worst full reaction symptom. Participants reported being negatively impacted in their ability to do daily activities, and social and emotional functioning. Many reported impacted ability to work and be productive at their job. Participants reviewed and completed the newly developed PRO measures assessing full reactions and ability to do activities, as well as items to assess severity and change in severity of prodromal symptoms, full reactions, and EPP overall. All measures were found to be comprehensive, clear, and relevant. Conclusion: PRO measures are needed to assess important aspects of HRQoL and evaluate therapeutic response. These PRO measures are unique in assessing overall severity and change in EPP.
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Pharmacogenomics has the potential to inform drug dosing and selection, reduce adverse events, and improve medication efficacy; however, provider knowledge of pharmacogenomic testing varies across provider types and specialties. Given that many actionable pharmacogenomic genes are implicated in cardiovascular medication response variability, this study aimed to evaluate cardiology providers' knowledge and attitudes on implementing clinical pharmacogenomic testing. Sixty-one providers responded to an online survey, including pharmacists (46%), physicians (31%), genetic counselors (15%), and nurses (8%). Most respondents (94%) reported previous genetics education; however, only 52% felt their genetics education prepared them to order a clinical pharmacogenomic test. In addition, most respondents (66%) were familiar with pharmacogenomics, with genetic counselors being most likely to be familiar (p < 0.001). Only 15% of respondents had previously ordered a clinical pharmacogenomic test and a total of 36% indicated they are likely to order a pharmacogenomic test in the future; however, the vast majority of respondents (89%) were interested in pharmacogenomic testing being incorporated into diagnostic cardiovascular genetic tests. Moreover, 84% of providers preferred pharmacogenomic panel testing compared to 16% who preferred single gene testing. Half of the providers reported being comfortable discussing pharmacogenomic results with their patients, but the majority (60%) expressed discomfort with the logistics of test ordering. Reported barriers to implementation included uncertainty about the clinical utility and difficulty choosing an appropriate test. Taken together, cardiology providers have moderate familiarity with pharmacogenomics and limited experience with test ordering; however, they are interested in incorporating pharmacogenomics into diagnostic genetic tests and ordering pharmacogenomic panels.
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Sistema Cardiovascular , Testes Farmacogenômicos , Humanos , Testes Genéticos , Farmacêuticos , FarmacogenéticaRESUMO
Introduction: The 2019 Coronavirus Disease (COVID-19) pandemic necessitated a mass transition in genetics clinics nationwide from in-person care to virtual care through telehealth. Before the COVID-19 pandemic, there was limited research on the use of telehealth in genetics specialties. Therefore, the COVID-19 pandemic presented a unique opportunity to study this emerging mode of care delivery in the setting of genetics clinics. This study described the scope of telehealth use in genetics clinics nationally and determined how COVID-19 influenced patients' decisions regarding their genetic care. Methods: Two anonymous surveys for patients and providers were developed. The patient survey was offered online to all genetics patients seen through telehealth at a Manhattan-based practice between March and December 2020. The provider survey was distributed through several listservs to genetics providers nationwide. Results: Patients (n = 242) and providers (n = 150) responded. Telehealth was used in all specialty genetics clinics for both initial and follow-up visits. Telehealth was both effective and satisfactory to patients for both visit types and across specialties; however, Asian and Hispanic/Latino patients had significantly lower mean satisfaction scores compared with White patients (p = 0.03 and 0.04, respectively). Patients appreciated telehealth for its convenience and to avoid COVID-19 exposure. Providers across specialties and provider types preferred telehealth for follow-up rather than initial visits. Several clinic initiatives related to telehealth were identified. Discussion: Telehealth was generally well received by both patients and providers, and is expected to become permanent option in genetics clinics. Further studies are needed to identify barriers to accessing telehealth.
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COVID-19 , Telemedicina , Humanos , COVID-19/epidemiologia , Pandemias , Atenção à Saúde , SARS-CoV-2RESUMO
We developed novel electronic phenotyping algorithms for the BioMe biobank data, which accurately identified angiotensin converting enzyme inhibitor (ACEi)-induced angioedema cases and controls. A survey was mailed to all 1075 patients and 91 were returned. Over a third reported that prescribing physicians had not discussed with them the concepts of interindividual drug response variability or adverse event risk, and 73% of patients were previously unaware of pharmacogenomics; however, most patients were interested in having pharmacogenomic testing. Moreover, 67% of patients indicated that pharmacogenomic testing would positively influence their medication compliance. In addition to identifying an innovative approach to define biobank cohorts for pharmacogenomic studies, these results indicate that patients are interested in pharmacogenomic testing, which could translate to improved adherence.
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Angioedema , Inibidores da Enzima Conversora de Angiotensina , Humanos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Farmacogenética , Angioedema/induzido quimicamenteRESUMO
BACKGROUND: Erythropoietic protoporphyria is a rare, inherited disorder presenting in early childhood with severe, painful phototoxicity. EPP has significant impacts on health-related quality of life, though there is variable disease severity. Accurately capturing how much time individuals with EPP can spend outdoors before they develop symptoms is critical to understanding HRQoL and measuring therapeutic response. Therefore, the goal of this study was to develop a comprehensive and content valid sun exposure diary to assess the efficacy of new therapies in individuals with EPP. METHODS: Qualitative interviews were conducted with adult and adolescent EPP participants, as well as five clinical experts, to obtain their input on the content of an existing sun exposure diary. Revisions to the diary were made based on evidence generated in cognitive debriefing interviews analyzed in eight consecutive groups of EPP participant. RESULTS: Interviews were conducted with 17 adults and 6 adolescents with EPP. The average age of adults was 40 years and of adolescents was 14 years. Clinical experts thought the original diary needed clarification on the description of symptoms, how time outdoors was captured, and the distinction between direct vs. indirect sunlight. Participants with EPP also noted these items needed revision, and that the distinction between prodromal symptoms and full reaction symptoms should be clarified. In the final diary version, participants with EPP found most items to be clear and easy to complete/think about. Seventy-six percent of participants (13/17) asked thought the diary was easy to complete. The remainder thought the majority of the diary was easy to complete with the exception of select questions. CONCLUSIONS: Evaluating a new treatment for EPP requires accurately capturing time in sunlight and symptoms in this unique disorder. The newly developed sun exposure diary is content valid and can be used to assess important aspects of symptoms and daily life and therefore evaluate clinically meaningful therapeutic response.
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Dermatite Fototóxica , Protoporfiria Eritropoética , Pré-Escolar , Adolescente , Adulto , Humanos , Protoporfiria Eritropoética/diagnóstico , Qualidade de Vida , Luz Solar/efeitos adversos , Pacientes , Doenças RarasRESUMO
The genetics and disability communities have had a complicated relationship that is rooted in the history of the eugenics movement. Disability scholars claim that in order for healthcare professionals to provide optimal services to disabled patients, disability education must be implemented into healthcare training programs. No studies have explored the perspectives of disability advocates regarding the implementation and use of disability training in genetic counseling. This exploratory study recruited 13 advocates with lived experience of disability and genetic counseling exposure to participate in a semi-structured interview to share their recommendations for disability education opportunities in genetic counseling training programs and their perceived benefits of increased student exposure to disability. All advocates received genetic counseling themselves and four advocates reported working with genetic counselors in the advocacy setting. Advocates recounted their experiences working with genetic counselors, identifying qualities they deemed critical for effective counseling. All the advocates expressed interest in participating in experiential opportunities, with few concerns noted. The most frequently discussed recommendations for disability training included inviting advocates to speak in classrooms, and having students shadow disabled individuals. Advocates noted barriers to consider when implementing such educational opportunities, such as accessibility issues. Potential benefits of implementing disability education for students included providing students with a broader scope of knowledge and a deeper understanding of disability and resources available to the disability community. This novel study found that advocates are interested in participating in genetic counseling education, with recommendations on preferred experiential learning. By increasing a genetic counseling student's exposure to a disability, they may develop a comprehensive understanding of life with a disability, which may improve genetic counseling services to those with newly diagnosed disabilities.
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PURPOSE: The Curaçao criteria are well-established diagnostic criteria for hereditary hemorrhagic telangiectasia (HHT), but they lack details regarding a predictive presentation of epistaxis and telangiectasias. This study collects and compares data in HHT and population cohorts to inform the application of these criteria. METHODS: In-person interviews regarding epistaxis and targeted examination for telangiectases in a general population cohort (n = 204) and an HHT cohort (n = 432) were conducted. RESULTS: Frequency of epistaxis, rather than intensity or duration, was the best discriminator of HHT. A cutoff of ≥4 nosebleeds per year alone yielded a diagnostic sensitivity of 97%, and specificity of 84%. The mean number of telangiectases at the sites investigated was 0.4 in the general population cohort and 26.5 in the HHT cohort. The most distinctive sites for telangiectases in HHT were lips and palmar fingers, whereas telangiectases of the face and dorsum of the hand were comparable in both cohorts. CONCLUSION: We propose that the Curaçao criteria be modified to include the following cutoffs: (1) epistaxis frequency of ≥4 nosebleeds per year and (2) telangiectasia count of at least 2 in characteristic locations (palmar aspect of fingers, lips, and oral cavity), and that cutaneous telangiectases at other sites not be considered relevant for diagnostic purposes.
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Telangiectasia Hemorrágica Hereditária , Telangiectasia , Humanos , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/diagnóstico , Telangiectasia Hemorrágica Hereditária/epidemiologia , Epistaxe/epidemiologia , Epistaxe/etiologia , Epistaxe/diagnóstico , Curaçao , Telangiectasia/diagnóstico , Telangiectasia/epidemiologia , PacientesRESUMO
BACKGROUND AND AIMS: Chronic hepatitis C [CHC] is a risk factor for porphyria cutanea tarda [PCT]. To assess whether ledipasvir/sofosbuvir is effective for treating both PCT and CHC, we treated patients with CHC + PCT solely with ledipasvir/sofosbuvir and followed them for at least 1 year to assess cure of CHC and remission of PCT. METHODS: Between September 2017 and May 2020, 15 of 23 screened PCT + CHC patients were eligible and enrolled. All were treated with ledipasvir/sofosbuvir at recommended doses and durations, according to their stage of liver disease. We measured plasma and urinary porphyrins at baseline and monthly for the first 12 months and at 16, 20, and 24 mos. We measured serum HCV RNA at baseline, 8-12, and 20-24 mos. Cure of HCV was defined as no detectable serum HCV RNA ≥ 12 weeks after the end of treatment (EOT). Remission of PCT was defined clinically as no new blisters or bullae and biochemically as urinary uro- plus hepta-carboxyl porphyrins ≤ 100 mcg/g creatinine. RESULTS: All 15 patients, 13 of whom were men, were infected with HCV genotype 1. 2/15 withdrew or were lost to follow-up. Of the remaining 13, 12 achieved cure of CHC; 1 had complete virological response, followed by relapse of HCV after ledipasvir/sofosbuvir but was subsequently cured by treatment with sofosbuvir/velpatasvir. Of the 12 cured of CHC, all achieved sustained clinical remission of PCT. CONCLUSIONS: Ledipasvir/sofosbuvir [and likely other direct-acting antivirals] is an effective treatment for HCV in the presence of PCT and leads to clinical remission of PCT without additional phlebotomy or low-dose hydroxychloroquine treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT03118674.
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Hepatite C Crônica , Porfiria Cutânea Tardia , Porfirinas , Masculino , Humanos , Feminino , Sofosbuvir/uso terapêutico , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Antivirais/efeitos adversos , Porfiria Cutânea Tardia/diagnóstico , Porfiria Cutânea Tardia/tratamento farmacológico , Porfiria Cutânea Tardia/induzido quimicamente , Fluorenos/uso terapêutico , Hepacivirus/genética , Resultado do Tratamento , Quimioterapia Combinada , RNA , Genótipo , Porfirinas/farmacologia , Porfirinas/uso terapêuticoRESUMO
Elective genetic testing (EGT) to identify disease risk in individuals who may or may not meet clinical criteria for testing is increasingly being offered in clinical practice. However, little is known about how EGT is currently implemented and how genetics professionals perceive this type of testing. We conducted a mixed-methods survey study to evaluate genetics professionals' perspectives and attitudes about EGT and describe the current landscape of EGT practices in the United States (U.S.) and Canada. Six clinical geneticists and 131 genetic counselors responded to the online survey, among whom 44% reported offering EGT in their practice. Over 84% of survey respondents agreed that EGT may improve health outcomes and understanding of genotype-phenotype correlations, and 85% agreed that potential risks include result misinterpretation and contribution to economic health disparities. Though most respondents felt comfortable providing pretest (77%) and post-test (86%) counseling for EGT, lack of provider resources (such as time and personnel) and prioritization of diagnostic testing were cited most frequently in free-text responses as reasons for not offering EGT. Of those offering EGT, 88% reported positive overall experiences. Qualitative analysis of open-ended questions identified benefits of EGT as expanding access to genetic testing, providing potential health benefits, and providing psychological benefits for patients. Disadvantages included prohibitive costs, limited clinical utility, and strain on resources. Overall, we found that genetics providers perceive both potential benefits and harms of EGT and that those offering this testing had generally positive experiences, although ethical reservations and practical limitations exist.
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Conselheiros , Aconselhamento Genético , Humanos , Aconselhamento Genético/psicologia , Testes Genéticos , Aconselhamento , AtitudeRESUMO
Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic delays. Here, we present evidence-based consensus guidelines for the diagnosis, monitoring, and management of erythropoietic protoporphyria and X-linked protoporphyria. A systematic literature review was conducted, and reviewed among subcommittees of experts, divided by topic. Consensus on guidelines was reached within each subcommittee and then among all members of the committee. The appropriate biochemical and genetic testing to establish the diagnosis is reviewed in addition to the interpretation of results. Prevention of symptoms, management of acute phototoxicity, and pharmacologic and nonpharmacologic treatment options are discussed. The importance of ongoing monitoring for liver disease, iron deficiency, and vitamin D deficiency is discussed with management guidance. Finally, management of pregnancy and surgery and the safety of other therapies are summarized. We emphasize that these are multisystemic disorders that require longitudinal monitoring. These guidelines provide a structure for evidence-based diagnosis and management for practicing physicians. Early diagnosis and management of these disorders are essential, particularly given the availability of new and emerging therapies.
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Dermatite Fototóxica , Doenças Genéticas Ligadas ao Cromossomo X , Hepatopatias , Guias de Prática Clínica como Assunto , Protoporfiria Eritropoética , Humanos , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Protoporfiria Eritropoética/diagnóstico , Protoporfiria Eritropoética/genética , Protoporfiria Eritropoética/terapiaRESUMO
The use of iron supplementation for anemia in erythropoietic protoporphyria (EPP) is controversial with both benefit and deterioration reported in single case reports. There is no systematic study to evaluate the benefits or risks of iron supplementation in these patients. We assessed the potential efficacy of oral iron therapy in decreasing erythrocyte protoporphyrin (ePPIX) levels in patients with EPP or X-linked protoporphyria (XLP) and low ferritin in an open-label, single-arm, interventional study. Sixteen patients (≥18 years) with EPP or XLP confirmed by biochemical and/or genetic testing, and serum ferritin ≤30 ng/mL were enrolled. Baseline testing included iron studies, normal hepatic function, and elevated plasma porphyrins and ePPIX levels. Oral ferrous sulfate 325 mg twice daily was administered for 12 months. The primary efficacy outcome was the relative difference in total ePPIX level between baseline and 12 months after starting treatment with iron. Secondary measures included improvement in serum ferritin, plasma porphyrins, and clinical symptoms. Thirteen patients had EPP (8 females, 5 males) and 3 had XLP (all females) and the mean age of participants was 38.8 years (SD 14.5). Ten patients completed all study visits limiting interpretation of results. In EPP patients, a transient increase in ePPIX levels was observed at 3 months in 9 of 12 (75%) patients. Iron was discontinued in 2 of these patients after meeting the protocol stopping rule of a 35% increase in ePPIX. Seven patients withdrew before study end. Ferritin levels increased on iron replacement indicating an improvement in iron status. A decrease in ePPIX was seen in both XLP patients who completed the study (relative difference of 0.67 and 0.5 respectively). No substantial changes in ePPIX were seen in EPP patients at the end of the study (n = 8; median relative difference: -0.21 (IQR: -0.44, 0.05). The most common side effects of iron treatment were gastrointestinal symptoms. Hepatic function remained normal throughout the study. Our study showed that oral iron therapy repletes iron stores and transiently increases ePPIX in some EPP patients, perhaps due to a transient increase in erythropoiesis, and may decrease ePPIX in XLP patients. Further studies are needed to better define the role of iron repletion in EPP. Trial registration: NCT02979249.
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OBJECTIVES: As evidence mounts supporting the utility of pharmacogenomic-guided medication management, incorporating pharmacogenomic genes into secondary finding results from sequencing panels is increasingly under consideration. We studied medical geneticists' attitudes on receiving pharmacogenomic results as secondary finding. METHODS: Four focus groups with 16 medical geneticists total were conducted followed by thematic analysis. RESULTS: All participants ordered genetic sequencing tests; however, the majority had rarely or never ordered pharmacogenomic tests (10/16) or prescribed medications with established response variability (11/16). In total 81.3% expressed low comfort interpreting pharmacogenomic results without appropriate clinical resources (13/16). The positives of receiving pharmacogenomic results as secondary finding included prevention of adverse drug reactions in adults, grateful information-seeking patients, the ability to rapidly prescribe more effective treatments and appreciation of the recent advances in both pharmacogenomic knowledge and available guidelines. Negatives included laboratory reporting issues, exclusivity of pharmacogenomic results to certain populations, lengthy reports concealing pharmacogenomic results in patient charts and laboratories marketing to individuals without prior pharmacogenomic knowledge or targeting inappropriate populations. The most desirable pharmacogenomic resources included a universal electronic health record clinical decision support tool to assist identifying and implementing pharmacogenomic results, a specialized pharmacist as part of the care team, additional pharmacogenomic training during medical/graduate school, and a succinct interpretation of pharmacogenomic results included on laboratory reports. CONCLUSIONS: The majority of participants agreed that adding certain actionable pharmacogenomic genes to the American College of Medical Genetics and Genomics SF list is reasonable; however, this was qualified with a need for additional resources to support implementation.
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Farmacogenética , Médicos , Adulto , Atitude , Humanos , Farmacêuticos , Farmacogenética/métodos , Testes Farmacogenômicos/métodosRESUMO
The increasing number of genetic counselors participating directly in clinical pharmacogenomic post-test counseling prompted our evaluation of pharmacogenomic education across genetic counseling training programs in North America. Thirty-one program leadership participants from both the United States (U.S.) and Canada responded to a survey assessing pharmacogenomics education and the role of genetic counselors. Eighty-five percent of respondents agreed pharmacogenomics is currently within the scope of genetic counseling practice, and 96.3% indicated their training programs currently provide education on pharmacogenomics, with the majority reporting < 7 hr of education. Lectures on pharmacogenomics were the most common method for didactics; however, some programs also included practical modalities (e.g., case studies, clinical rotations) and online resources. Barriers to expanding pharmacogenomic education included the constrained timeline of training, and lack of resources and local expertise. Moreover, participants suggested that genetic counselors ideally should be able to order pharmacogenomic tests and counsel patients on pharmacogenomics, including result interpretation, as they believe pharmacogenomics does fall within the scope of practice of genetic counseling. Our novel results also confirm that training program leadership support a pharmacogenomic service delivery model that includes a combined effort between genetic counselors and pharmacists to utilize their synergistic expertise. However, this model likely still necessitates expanding pharmacogenomic didactics in genetic counseling training programs through more practical training and/or by leveraging online pharmacogenomic courses dedicated to supporting clinical implementation.
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Conselheiros , Aconselhamento Genético , Aconselhamento , Humanos , América do Norte , Farmacogenética , Estados UnidosRESUMO
BACKGROUND AND AIMS: The risk for hepatocellular carcinoma (HCC) is increased in acute hepatic porphyrias (AHP). The aim of this study was to explore the clinicopathologic characteristics, outcomes, and frequency of HCC in patients with AHP in the United States. APPROACH AND RESULTS: This cross-sectional analysis evaluated patients with HCC in a multicenter, longitudinal study of AHP. Among 327 patients with AHP, 5 (1.5%) were diagnosed with HCC. Of the 5 HCC cases, 4 had acute intermittent porphyria and 1 had variegate porphyria, confirmed by biochemical and/or genetic testing. All patients were white females, with a median age of 27 years (range 21-75) at diagnosis. The median age at HCC diagnosis was 69 years (range 61-74). AHP was asymptomatic in 2 patients; 2 reported sporadic attacks; and 1 reported recurrent attacks (>4 attacks/year). All patients had a single HCC lesion on liver imaging that was 1.8-6.5 centimeters in diameter. Serum alpha fetoprotein levels were below 10 ng/mL in all 4 patients with available results. Four patients underwent liver resection, and 1 was treated with radioembolization. No significant inflammation or fibrosis was found in adjacent liver tissues of 3 patients who underwent liver resection. Two patients developed recurrence of HCC at 22 and 26 months following liver resection. All patients are alive with survival times from HCC diagnosis ranging from 26-153 months. CONCLUSION: In this U.S. study, 1.5% of patients with AHP had HCC. HCC in AHP occurred in the absence of cirrhosis, which contrasts with other chronic liver diseases. Patients with AHP, regardless of clinical attacks, should be screened for HCC, beginning at age 50. The pathogenesis of hepatocarcinogenesis in AHP is unknown and needs further investigation.
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Carcinoma Hepatocelular/etiologia , Neoplasias Hepáticas/etiologia , Porfirias Hepáticas/complicações , Adulto , Fatores Etários , Idoso , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/patologia , Estudos Transversais , Feminino , Humanos , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Estudos Longitudinais , Pessoa de Meia-Idade , Porfirias Hepáticas/epidemiologia , Porfirias Hepáticas/patologia , Estados Unidos/epidemiologia , Adulto JovemRESUMO
PURPOSE: Erythropoietic protoporphyria (EPP), characterized by painful cutaneous photosensitivity, results from pathogenic variants in ferrochelatase (FECH). For 96% of patients, EPP results from coinheriting a rare pathogenic variant in trans of a common hypomorphic variant c.315-48T>C (minor allele frequency 0.05). The estimated prevalence of EPP derived from the number of diagnosed individuals in Europe is 0.00092%, but this may be conservative due to underdiagnosis. No study has estimated EPP prevalence using large genetic data sets. METHODS: Disease-associated FECH variants were identified in the UK Biobank, a data set of 500,953 individuals including 49,960 exome sequences. EPP prevalence was then estimated. The association of FECH variants with EPP-related traits was assessed. RESULTS: Analysis of pathogenic FECH variants in the UK Biobank provides evidence that EPP prevalence is 0.0059% (95% confidence interval [CI]: 0.0042-0.0076%), 1.7-3.0 times more common than previously thought in the UK. In homozygotes for the common c.315-48T>C FECH variant, there was a novel decrement in both erythrocyte mean corpuscular volume (MCV) and hemoglobin. CONCLUSION: The prevalence of EPP has been underestimated secondary to underdiagnosis. The common c.315-48T>C allele is associated with both MCV and hemoglobin, an association that could be important both for those with and without EPP.
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Protoporfiria Eritropoética , Bancos de Espécimes Biológicos , Europa (Continente) , Ferroquelatase/genética , Humanos , Mutação , Protoporfiria Eritropoética/diagnóstico , Protoporfiria Eritropoética/epidemiologia , Protoporfiria Eritropoética/genética , Reino Unido/epidemiologiaRESUMO
SARS-CoV-2 infection carries high morbidity and mortality in individuals with chronic disorders. Its impact in rare disease populations such as Gaucher disease (GD) is unknown. In GD, decreased acid ß-glucosidase activity leads to the accumulation of inflammatory glycosphingolipids and chronic myeloid cell immune activation which a priori could predispose to the most severe effects of SARS-CoV-2. To evaluate the determinants of SARS-CoV-2 infection in GD, we conducted a cross-sectional study in a large cohort. 181 patients were enrolled, including 150 adults and 31 children, with a majority of patients on treatment (78%). Information on COVID-19 exposure, symptoms, and SARS-CoV-2 nucleic acid and/or antibody testing was obtained during the peak of the pandemic in the New York City metropolitan area. Forty-five adults reported a primary exposure to someone with COVID-19 and 17 (38%) of these patients reported at least one COVID-19 symptom. A subset of adults was tested (n = 88) and in this group 18% (16/88) were positive. Patients testing positive for SARS-CoV-2 had significantly more symptoms (4.4 vs 0.3, p < 0.001) than patients testing negative. Among patients who were antibody-positive, quantitative titers indicated moderate to high antibody response. In GD adults, male gender, older age, increased BMI, comorbidities, GBA genotype, prior splenectomy and treatment status were not associated with the probability of reporting symptoms or testing positive. No patient required COVID-19-specific treatments and there were no deaths. Our data suggests that GD does not confer a heightened risk for severe effects of SARS-CoV-2 infection feared based on the known chronic inflammatory state in these patients.