Hereditary haemochromatosis: Prevalence and characterization of the disease in a tertiary hospital in Aragon.

BACKGROUND: The main genetic cause of iron overload is haemochromatosis (HC). In recent years, the study of non-HFE genes (HFE2, HJV, HAMP, TRF2, SLC40A1, and BMP6) has become relevant thanks to next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) techniques. Our objectives were to estimate the prevalence of both HFE (C282Y/HY63D variants) and non-HFE variants attending a tertiary hospital in Aragón, to predict the effect of the variants on the protein, and to establish a genotype-phenotype correlation evaluating with the clinical context. METHODS: Retrospective descriptive study from 2006 to 2020 of patients attended at genetic consultation in a reference hospital for HC in Aragon. We calculated prevalence of HFE and non-HFE variants. We analysed non-HFE genes (HFE2, HJV, HAMP, TRF2, SLC40A1, and BMP6), used bioinformatics tools, consulted different databases and measured clinical parameters (laboratory and imaging). RESULTS: The prevalence of C282Y homozygous was 5.95% respect the total of cases and 0.025% respect our population. The prevalence of non-HFE HC variants was 1.94% respect the total of cases and 0.008% respect our population. We found 27 variants in non-HFE genes and 4 in HFE gene, of which 6 were classified as variant of uncertain clinical significance (VUS), or likely pathogenic or pathogenic according to the ACMG classification criteria. CONCLUSION: Our prevalence results are as expected, and similar to those obtained by other studies. Although some of the genetic findings explain the clinical symptoms of some of our patients, we remain have a high number of patients without a clear molecular diagnosis.

Hemofagocitose em cultura de sangue periférico precedendo hemofagocitose em biópsia de medula óssea na síndrome hemofagocítica secundária / Hemophagocytosis in peripheral blood culture preceding hemophagocytosis in bone marrow biopsy in secondary hemophagocytic syndrome

A síndrome hemofagocítica é determinada por desregulação do sistema imunológico, caracterizada por ativação excessiva de macrófagos, resultando em fagocitose de células sanguíneas normais no fígado, baço e medula óssea. Pode ser primária (genética) ou secundária (adquirida). Em adultos quase sempre é secundária, tendo infecções, neoplasias e doenças autoimunes como frequentes desencadeadores. Entre as principais manifestações da síndrome estão febre prolongada e hepatoesplenomegalia. O diagnóstico até o momento é confirmado pelo achado de hemofagocitose em biópsia de medula óssea. Entretanto, é descrito que a biópsia de medula óssea é normal nos primeiros dias de manifestações da síndrome. O presente relato tem como objetivo mostrar a observação de hemofagocitose em cultura de células de sangue periférico de paciente de 29 anos precedendo a hemofagocitose em biópsia de medula óssea. A paciente apresentava diferentes infecções, com grave comprometimento do estado geral e sem melhora com o tratamento das infecções. O achado laboratorial permitiu o tratamento precoce da síndrome hemofagocítica e a melhora da paciente. No presente relato a técnica utilizada está descrita detalhadamente para que possa ser reproduzida, além de ser apresentada uma revisão não sistemática da literatura sobre a síndrome.

Hemophagocytic syndrome, which is caused by dysregulation of the immune system, is characterized by excessive macrophage activation, resulting in phagocytosis of normal blood cells in the liver, spleen, and bone marrow. It can be primary (genetic) or secondary (acquired). In adults, it is almost always secondary, with infections, neoplasms, and autoimmune diseases as frequent triggers. The main manifestations of this syndrome are prolonged fever and hepatosplenomegaly. Currently, diagnosis is confirmed through finding hemophagocytosis in a bone marrow biopsy. However, it has been reported that bone marrow biopsy results are still normal on the first day the syndrome manifests. Here we report observing hemophagocytosis in cultured peripheral blood cells from a 29-year-old patient prior to finding hemophagocytosis in bone marrow biopsy. The patient had various infections and a poor general condition, which did not improve after treating the infections. The laboratory findings allowed early treatment of hemophagocytic syndrome and the patient improved. We describe our technique in detail so it can be reproduced, and we provide a non-systematic review of the literature on the syndrome.

Perfil dos pacientes com hiperferritinemia em acompanhamento ambulatorial em um serviço no sul do Brasil / Profile of patients with hyperferritinemia in ambulatorial follow-up in southern Brazil

O achado de hiperferritinemia é comum na prática clínica. Além de representar os estoques de ferro no organismo, a ferritina se mostra como proteína de fase inflamatória, podendo elevar-se em comorbidades inflamatórias agudas ou crônicas e se associar com a chamada síndrome plurimetabólica. Objetivo: Avaliar as características clínicas de pacientes com hiperferritinemia em acompanhamento ambulatorial no período de janeiro de 2013 a novembro de 2016. Métodos: Estudo observacional transversal, desenvolvido em um serviço de Hematologia na cidade de Tubarão, Santa Catarina. Coletaram-se dados de 136 pacientes com o diagnóstico de hiperferritinemia através de prontuários digitais. Foram realizadas análises descritivas e associações com os testes qui-quadrado e t Student, quando apropriado. Resultados: Houve um predomínio do sexo masculino (83,50%) com idade média de 56,62 anos, a média de ferritina de 693,45mcg/L e de ferro sérico 121,52mcg/dL, sendo as causas secundárias de hiperferritinemia as predominantes. Ao se estratificar os valores de ferritina constatou-se que os pacientes com ferritina >1000mcg/L tiveram um risco 50% maior de possuir alterações ao ultrassom, 70% maior prevalência de HDL<40 e 40% maior prevalência de hipertrigliceridemia. Os pacientes com ferritina >400mcg/L tiveram duas vezes maior chance de apresentar resistência à insulina. Conclusão: As principais causas de hiperferritinemia foram secundárias a doenças crônicas metabólicas

Hyperferritinemia is common in the clinical practice. In aside from representing the stocks of iron in the organism, ferritin is also a inflammatory phase protein, witch can be elevated in chronic or acute inflammatory comorbidities and be associated with plurimetabolic syndrome. This study aims the evaluation of the clinical characteristics of ambulatory patients with hyperferritinemia between January-2013 and November-2016. Methods: It is a cross-sectional, descriptive study, developed in the hematology center of the medical specialities clinic in Tubarão ­ Santa Catarina. Data from 136 patients have been collected and then transferred to an Excel spreadsheet, imported to Epiiinfo 7 and the expressed into absolute and relative numbers, graphics and figures. Results: It was found a predominance of males (83,50%) with a mean age of 56,62 years, a mean ferritin level of 693,45mcg/L and seric iron of 121,52mcg/dL being the secondary causes of hyperferritinemia the most predominant. When stratified the ferritin levels, it was verified that patients with a ferritin >1000mcg/L had 50% more risk of having ultrasound alterations, 70% more prevalence of HDL<40 and 40% more prevalence of having hypertriglyceridemia. Patients with a ferrintin >400mcg/L had twice as many chances of having insulin resistance. Conclusion: The main causes of hyperferritinemia were secondary to chronic metabolic diseases

Relação entre os níveis de ferritina e o prognóstico da COVID-19 / Relationship between ferritin levels and the prognosis of COVID-19

O elevado nível de ferritina sérica tem sido associado à COVID-19 grave devido à sua estimulação por citocinas relacionadas com o processo inflamatório. Embora este aumento seja esperado, esta revisão propõe analisar o quão elevado o nível de ferritina pode estar relacionado com esta severidade. Nesta linha de pensamento, a hiperferritinemia na COVID-19 poderia ser um importante fator de previsão e outra forma de compreender as complicações da COVID-19 - coagulopatia, síndrome do desconforto respiratório agudo (SDRA). Além disso, esta correlação tem sido vista como uma possível quinta síndrome entre as outras "síndromes hiperferritinêmicas", todas caracterizadas por ferritina sérica elevada; esta é uma comparação e análise pertinente em termos de tratamentos. [au]

The high level of serum ferritin has been associated with severe COVID-19 due to its stimulation by cytokines related to the inflammatory process. Although this increase is expected, this review proposes to analyze how high ferritin can be related to this severeness. According to this premise, the hyperferritinemia on COVID-19 could be an important factor of prediction and another way to understand the complications of COVID-19 -coagulopathy, acute respiratory distress syndrome (ARDS). Furthermore, this correlation has been seen as a possible fifth syndrome among the other "hyperferritinemic syndromes", which are all characterized by high serum ferritin; this is an pertinent comparison and analyzation in terms of treatments. [au]

Hyperferritinemia in patients with nonalcoholic fatty liver disease / Hiperferritinemia em pacientes com doença hepática gordurosa não alcoólica

Summary Objective: In liver diseases, hyperferritinemia (HYF) is related to injured cells in acquired and genetic conditions with or without iron overload. It is frequent in patients with nonalcoholic fatty liver disease (NAFLD), in which it is necessary to define the mean of HYF to establish the better approach for them. The present study evaluated the significance of elevated ferritin in patients with NAFLD and steatohepatitis (NASH). Method: The review was performed using search instruments of indexed scientific material, including MEDLINE (by PubMed), Web of Science, IBECS and LILACS, to identify articles published in Portuguese, English and Spanish, from 2005 to May, 2016. Studies eligible included place and year of publication, diagnose criteria to NAFLD, specifications of serum ferritin measurements and/or liver histopathologic study. Exclusion criteria included studies with patients with alcohol consumption ≥ 20 g/day and other liver diseases. Results: A total of 11 from 30 articles were selected. It included 3,564 patients and they were cross-sectional, retrospective, case series and case-control. The result's analyses showed in 10 of these studies a relationship between ferritin elevated serum levels and NAFLD/NASH with and without fibrosis and insulin resistance. Conclusion: Hyperferritinemia in patients with NAFLD/NASH is associated more frequently with hepatocellular injury than hemochromatosis. These data suggest the relevance to evaluate carefully HYF in patients with NAFLD/NASH to establish appropriate clinical approach.

Resumo Objetivo: A hiperferritinemia (HPF) está associada à agressão hepatocelular nas doenças do fígado e à sobrecarga de ferro, em doenças genéticas e adquiridas. A HPF é frequente em pacientes com doença hepática gordurosa não alcoólica (DHGNA) e é necessário definir seu significado para estabelecer as melhores condutas para esses indivíduos. Esta revisão avaliou o significado da HPF em portadores de DHGNA e esteato-hepatite não alcoólica (EHNA). Método: A busca de artigos foi realizada através do PubMed (Medline), Web of Science e Lilacs, e foram selecionados aqueles publicados em português, inglês e espanhol de 2005 a maio de 2016. Os artigos foram elegíveis quando informavam data e local da publicação, critérios diagnósticos para DHGNA, especificações das dosagens de ferritina sérica e/ou estudo histopatológico. Foram excluídos os artigos cujos pacientes relataram ingestão alcoólica ≥ 20 g/dia ou eram portadores de outras doenças do fígado. Resultados: Foram selecionados 11 de 30 artigos, totalizando 3.564 pacientes. Os artigos eram de corte transversal, retrospectivos, série de casos e caso-controles. Em dez artigos, observou-se correlação entre alteração de ferritina e DHGNA/EHNA com e sem fibrose hepática e resistência à insulina. Conclusão: Hiperferritinemia em pacientes com DHGNA/EHNA se associa com maior frequência à agressão hepatocelular do que com sobrecarga de ferro hepático. Os resultados da revisão sugerem a necessidade de um maior cuidado na interpretação da elevação da ferritina sérica em pacientes com DHGNA/EHNA para o estabelecimento de condutas clínicas apropriadas.

Estudio del paciente con hiperferritinemia / Study of the patient with hyperferritinemia

Resumen: la hiperferritinemia, definida por ferritina sérica mayor de 200 µg/L en mujeres y de 300 µg/L en hombres, representa un reto para el clínico. De acuerdo con la etiología, la hiperferritinemia se puede subdividir en tres grupos: el primero correspondiente a la causada por enfermedades frecuentemente asociadas, como el síndrome metabólico, la hepatopatía alcohólica, la hepatopatía no alcohólica y procesos inflamatorios incluidas infecciones, enfermedades inflamatorias crónicas, enfermedades autoinmunes y algunos procesos malignos; el segundo, correspondiente a la causada por enfermedades poco frecuentemente asociadas, como la hemocromatosis hereditaria, algunas enfermedades hematológicas con anemia y la terapia transfusional permanente; y un tercer grupo, correspondiente a la causada por enfermedades raramente asociadas, como el síndrome hereditario de hiperferritinemia y cataratas, la aceruloplasminemia, la atransferrinemia o hipotransferrinemia, la porfiria cutánea tarda, la hemocromatosis neonatal, la sobrecarga de hierro africana y la enfermedad de Gaucher. El aspecto clínico más importante es definir, mediante la clínica y estudios simples y especializados, la causa asociada a la hiperferritinemia e intervenirla como punto de partida para su manejo. Desde el punto de vista del paciente es importante realizar estudios de ferrocinética (ferritina sérica y saturación de transferrina) y medición de sobrecarga de hierro en órganos blanco, mediante resonancia magnética, la cual presenta alta sensibilidad y especificidad. Todo esto significa la aplicación de algoritmos de manejo y seguimiento del paciente con hiperferritinemia. El manejo del síndrome depende de la etiología con la cual está asociada y la ausencia o presencia de sobrecarga de hierro, siendo, exclusivamente en este último caso, la flebotomía la mejor opción. (AU)

µg/L in men, represents a challenge for the clinician. Based on the etiology, hyperferritinemia can be subdivided into three groups: the first corresponds to the caused by diseases frequently associated, including the metabolic syndrome, alcoholic liver disease, non-alcoholic liver disease and inflammatory processes (infections, chronic inflammatory diseases, autoimmune diseases, and some malignant processes); the second corresponds to the initiated by diseases associated in low frequency, which include hereditary hemochromatosis, some hematological diseases characterized by anemia and of permanent transfusional therapies; and a third group corresponding to the induced by diseases rarely associated, among which are the hereditary syndrome of hyperferritinemia and cataracts, the aceruloplasminemia, the atransferrinemia or hypotransferrinemia, the cutaneous porphyria tarda, the neonatal hemochromatosis, the overload of African iron, the Gaucher disease. The most important clinical aspect is to define, through clinical findings and simple and specialized studies, the associated cause of hyperferritinemia and intervene it as starting point of the management. From the patient's point of view it is vital to perform ferrokinetic studies; in particular serum ferritin and transferrin saturation, and iron overload measurement in white organs through magnetic resonance, which presents high sensitivity and specificity. All this means the application of algorithms of handling and monitoring of the patient with hyperferritinemia. The management of the syndrome depends on the associated etiology and the absence or presence of iron overload; being, exclusively in this last case, the phlebotomy the best option. (AU)

Hiperferritinemia como factor pronóstico de inmunosupresión en pacientes con síndrome de inmunodeficiencia adquirida / Hyperferritinemia as a prognostic factor for immnosuppression in patients with acquired immnodeficiency syndrome

Se realiza una investigación prospectiva con el objetivo de determinar si la hiperferritinemia es un factor pronóstico de inmunosupresión en pacientes con síndrome de inmunodeficiencia adquirida (SIDA). La población estuvo conformada por 40 pacientes hospitalizados en el Hospital Universitario de Maracaibo, durante los meses de Enero a Octubre del 2010. 27 (67,50%) pacientes fueron de sexo masculino y 13 (32,50%) femeninos. El 55,00% presentó hiperferritinemia. 22,50% presentaron contaje de linfocitos T CD4+ entre 200-400 cel/mm³ con un promedio de ferritina de 144,2 ± 127,1 ng/mL y, el 77,50% contaje de linfocitos T CD4+ < 200 cel/mm³ con un promedio de ferritina de 1100,0 ± 984,7 ng/mL (p = 0,01). Se demostró una correlación inversamente negativa entre niveles elevados de ferritina con niveles bajos de contaje de linfocitos T CD4+ (r = 0,3135, p = 0,030), cifras bajas de leucocitos (r= 0, 7458, p= 0,012), cifras bajas de proteínas (r= 0,5814, p= 0,01) y una relación directamente proporcional con el aumento de la VSG (r = 0,7422, p= 0,001). En los pacientes fallecidos el promedio de ferritina (1180,0 ± 1.072) estadísticamente (p= 0,018) fue más elevado en comparación con el promedio de ferritina (474 ±440,2) de los pacientes que sobrevivieron. Se concluye que se puede tomar en cuenta a la hiperferritinemia como factor pronóstico de inmunosupresión en pacientes con diagnóstico de SIDA

A prospective study was carried out to determine if hyperferritinemia is a predictive factor for immunosuppression in patients with acquired immunodeficiency syndrome (AIDS). The population consisted of 40 patients hospitalized at the University Hospital of Maracaibo (Hospital Universitario de Maracaibo), from January to October, 2010. Twenty-seven (67.50%) patients were male and 13 (32.50%) were female. 22.50% had a T CD4+ lymphocyte count between 200-400 cells/mm³ with a mean ferritin of 144.2 ± 127.1 ng/mL; 77.50% had a T CD4+ lymphocyte count of <200 cells/mm³ and a ferritin average of 1100.0 ± 984.7 ng/mL (p = 0.01). An inverse negative correlation was found between high ferritin levels and low T CD4+ lymphocyte count (r = 0.3135, p = 0.030), low numbers of leukocytes (r = 0, 7458 p = 0.012), low levels of protein (r = 0.5814, p = 0.01), and a directly proportional relation with the increase of ESR (r = 0.7422, p = 0.001). In patients who died, the mean ferritin level (1180.0 ± 1,072) statistically (p = 0.018) was higher compared with the average ferritin level (474 ± 440.2) of patients who survived. Conclusions are that these results are sufficiently relevant to take hyperferritinemia into account as a prognostic factor for the immunosuppression of diagnosed AIDS patients

Enfermedad de Still del adulto / Still's disease of adult

Se presenta un paciente del sexo masculino de 51 años de edad que fue hospitalizado por odinofagia, fiebre elevada, poliartritis, además de leucocitosis con neutrofilia y eritrosedimentación acelerada. Durante el ingreso se le constata poliserositis, neumonitis y miocarditis con insuficiencia cardiaca izquierda, hipertransaminasemia, hiperferritinemia y factor reumatoideo con anti DNA de doble cadena negativos. Se inició tratamiento con corticoesteroides e inmunosupresores (azatioprina). La respuesta no fue la esperada y hubo que cambiar el inmunosupresor por metotrexate. La poliartritis febril de evolución policíclica es la forma de presentación más frecuente de la enfermedad de Still del adulto. La hiperferritinemia mayor de 1 000 ng/mL es una herramienta útil para el diagnóstico y su normalización es indicador de éxito terapéutico. No existen manifestaciones clínicas, ni pruebas de laboratorio patognomónicas, por lo que el diagnóstico continúa siendo por exclusión

This is the case of man aged 51 admitted due to odynophagia, high fever, polyarthritis, as well as leukocytes with neutrophilia and accelerated erythrosedimentation. During admission it was noted polyserositis, pneumonitis and myocarditis with left cardiac insufficiency, hyper-transaminasemia, hyper-ferritinemia and rheumatoid factor with anti-AND of negative double-chain. Treatment was started with corticosteroids and immunosuppressive agents (azathioprine). Response was not the expected one and it was necessary to change the immunosuppressive agent by methotrexate. Febrile polyarthritis of polycyclic evolution is the more frequent presentation of the Still's disease in adult. Hyper-ferritinemia over 1 000 ng/mL is an useful tool for diagnosis and its normalization is an indicator of therapeutical success. There were neither clinical manifestations nor pathognomonic laboratory tests thus, diagnosis remains by exclusion

Síndrome de ativação macrofágica secundária à infecção aguda pelo vírus Epstein-Barr: [relato de caso] / Macrophage activation syndrome triggered by Epstein-Barr virus: [case report]

A síndrome de ativação macrofágica (SAM) ou síndrome hemofagocítica secundária (reativa) consiste de uma rara, grave e potencialmente fatal complicação das doenças reumáticas crônicas, particularmente da artrite idiopática juvenil de início sistêmico, doença de Still do adulto e lúpus eritematoso sistêmico. É caracterizada pela excessiva ativação dos macrófagos, resultando febre, hepatoesplenomegalia, linfadenomegalia, envolvimento neurológico, graus variáveis de citopenias, hiperferritinemia, distúrbio hepático, coagulação intravascular e freqüente falência de múltiplos órgãos. Também ocorre em associação com neoplasias, imunodeficiências e variedade de agentes infecciosos virais (sobretudo do grupo do herpes), bacterianos e fúngicos. Relatamos um caso de SAM decorrente de infecção viral aguda pelo vírus Epstein-Barr tratado com corticóide oral

The macrophage activation syndrome (MAS) or secondary haemophagocytic syndrome (reactive) is an uncommon, severe and life-threatening complication of chronic rheumatic diseases, especially systemic onset juvenile idiopathic arthritis, adult-onset Still disease and systemic lupus eritematosus. It is characterized by the excessive activation of macrophages, resulting in fever, hepatoesplenomegaly, lymphadenopathy, neurological involvement, variable cytopenias, hyperferritinemia, liver disease, intravascular coagulation, often resulting in fatal multiple organ failure. Besides chronic rheumatic diseases, it is also seen in a heterogeneous group of diseases like neoplasms, imunodeficiencies and viruses (especially the herpes group), bacteria and fungi infections. We describe a case report of one patient with MAS triggered by Epstein-Barr virus infection treated with oral corticosteroid.