Hemocromatosis: revisión de la literatura a propósito de un caso clínico / Hemochromatosis: case report and literature review

Hemochromatosis (HC) is a disorder that alters the body's ability to metabolize iron, increasing its absorption, causing iron overload, and consequently an accumulation of the mineral in multiple organs such as the liver, heart, and pancreas. The amount of total iron in the body is 2-4 g in healthy individuals and remains within these limits throughout life thanks to the control of intestinal absorption. In patients with CH, this amount is increased by at least 10 times, which translates into body deposits of 20-40 grams of iron on average. Factors that increase the risk of having HC: having two copies of the mutated HFE gene, family history, ethnicity or ancestry from Northern Europe (less common in blacks, Hispanics, and Asians), and male gender.

HFE hemochromatosis: an overview about therapeutic recommendations

Abstract Hemochromatosis is currently characterized by the iron overload caused by hepcidin deficiency. Large advances in the knowledge on the hemochromatosis pathophysiology have occurred due to a better understanding of the protein of the iron metabolism, the genetic basis of hemochromatosis and of other iron overload diseases or conditions which can lead to this phenotype. In the present review, the main aims are to show updates on hemochromatosis and to report a practical set of therapeutic recommendations for the human factors engineering protein (HFE) hemochromatosis for the p.Cys282Tyr (C282Y/C282Y) homozygous genotype, elaborated by the Haemochromatosis International Taskforce.

Treatment of iron overload syndrome: a general review

SUMMARY INTRODUCTION Iron overload is a broad syndrome with a large spectrum of causative etiologies that lead to iron deposition. When iron exceeds defenses, it causes oxidative damage and tissular disfunction. Treatment may prevent organ dysfunction, leading to greater life expectancy. METHODS Literature from the last five years was reviewed through the use of the PubMed database in search of treatment strategies. DISCUSSION Different pharmacological and non-pharmacological strategies are available for the treatment of iron overload and must be used according to etiology and patient compliance. Therapeutic phlebotomy is the basis for the treatment of hereditary hemochromatosis. Transfusional overload patients and those who cannot tolerate phlebotomy need iron chelators. CONCLUSION Advances in the understanding of iron overload have lead to great advances in therapies and new pharmacological targets. Research has lead to better compliance with the use of oral chelators and less toxic drugs.

RESUMO INTRODUÇÃO A síndrome de sobrecarga de ferro engloba um grande espectro de etiologias que levam a um aumento da quantidade de ferro nos tecidos. Esse ferro excede a capacidade de proteção dos tecidos, levando a dano oxidativo e lesão tissular. Tratamento pode prevenir esse dano, levando à melhor sobrevida. METODOLOGIA A literatura dos últimos cinco anos foi revisada por meio de pesquisa na base de dados PubMed buscando identificar estratégias de tratamento. DISCUSSÃO Medidas farmacológicas e não farmacológicas estão disponíveis para o tratamento da síndrome de sobrecarga de ferro e devem ser utilizadas de acordo com a etiologia e a aceitação do paciente. A flebotomia terapêutica é base do tratamento dos pacientes com hemocromatose hereditária. Pacientes com sobrecarga transfusional ou aqueles que não toleram flebotomias devem utilizar quelantes de ferro. CONSIDERAÇÕES FINAIS Avanços no entendimento da síndrome de sobrecarga de ferro têm levado a grandes progressos na terapêutica, com promessas de abordagem de novos alvos farmacológicos. A evolução da pesquisa tem possibilitado melhor aderência com o uso de quelantes orais e com possibilidade de drogas menos tóxicas.

Hepatitis aloinmune fetal / Fetal alloimmune hepatitis

La hepatitis aloinmune fetal, conocida anteriormente como hemocromatosis neonatal, ha demostrado en los últimos años ser una enfermedad completamente distinta a la hemocromatosis del adulto, tanto en su etiología como en su la fisiopatología. Este conocimiento abre nuevas perspectivas tanto en la prevención de la enfermedad en futuros embarazos, así como en el tratamiento con inmunoglobulina endovenosa en la madre durante el embarazo y eventualmente el tratamiento postnatal, en el que el trasplante de hígado juega un rol primordial.

Fetal alloimmune hepatitis, until few years ago was known as neonatal hemochromatosis, has shown to be a completely different disease from hemochromatosis in the adult, in its etiology and pathophysiology. This knowledge opens up opportunities of counselling in future pregnancies as well as in the treatment with intravenous immunoglobulin to the mother during pregnancy, and eventually the postnatal treatment, in which liver transplantation plays a primary role.

Hemocromatose hereditária / Hereditary hemochromatosis

A hemocromatose é um distúrbio autossômico recessivo ou dominante que ocorre devido ao aumento inapropriado da absorção de ferro pela mucosa gastrointestinal, resultando no armazenamento excessivo desse elemento no fígado, pâncreas, coração, articulações e gônadas. Afeta a populaçãocaucasiana, com prevalência de até um em 200 descendentes da população nórdica ou celta. O diagnóstico se faz por critérios clínicos, bioquímicos (ferritina, saturação da transferrina, etc.), genéticos epor imagem (ressonância magnética, tomografia e ultrassom).

Hemochromatosis is a disorder autosomal recessive or dominant that occurs inappropriate due to the increased absorption of iron by the gastrointestinal mucosa resulting in excessive storage of this element in the liver, pancreas, heart, joints and gonads. It affects the caucasian population with a prevalence reaching up to 1 in 200 people descendants of the population nordic or celtic. The diagnosis is made by clinical criteria, biochemical (ferritin, transferrin saturation of and so on), genetic and by image (magnetic resonance, tomography and ultrasound).

Neonatal hemochromatosis. case series from Bahrain

To review clinical presentations, diagnosis, response to treatment, and outcome of infants with neonatal hemochromatosis [NH]. This is a retrospective review of all cases admitted to the Pediatric Department at Salmaniya Medical Center, Manama, Bahrain between March 2008 and May 2011. The diagnosis was based on serum iron and ferritin, alpha-fetoprotein levels [AFP], liver and buccal biopsies, and abdominal MRI scan. Ten patients [8 males and 2 females] were diagnosed with NH. Two patients were intrauterine growth restriction [IUGR] and 6 were preterm. The median birth weight was 1.700 grams. The median age at presentation was 16 days, and at diagnosis was 23 days. Two patients had positive consanguinity. Clinical presentations of the infants were hepatosplenomegaly [n=5], ascites [n=3], and hypoglycemia [n=6]. All patients had raised ferritin levels, prolonged prothrombin time, and 9 patients had high serum iron and serum AFP. Abdominal MRI showed iron overload in the liver [n=8]. Liver biopsies showed evidence of hemochromatosis [n=3]. Buccal biopsies stained positive for iron [n=1]. Eight patients received antioxidant therapy and survived. Two patients passed away. Neonatal hemochromatosis is a rare liver disease of newborns with a spectrum of clinical severity. Elevated serum ferritin and AFP support the diagnosis after excluding other causes of neonatal liver failure. The use of antioxidant therapy helps to improve the outcome

Sobrecarga de hierro y enfermedad hepática: aspectos clínicos y terapéuticos / Iron overload and liver disease: clinical and therapeutic issues

Iron accumulation in parenchymal cells results in toxic damage and cell death which can determine a functional organ failure. The prototypical disease is hereditary hemochromatosis (HH). HH has been associated to mutations affecting any of the proteins that regulate iron metabolism. The most common cause of HH is a mutation in the HFE gene [C282Y]. Mutations in the gene for the hormone hepcidin and any of other eight genes that regulate iron biology, including the transferrin receptor 2 (TfR2), hemojuvelin (HJV) and ferroportin (FPN), also cause iron overload and hemochromatosis. Although information is limited, HFE-associated to HH is uncommon in Chile. Evaluation of iron overload in clinical practice should include consideration of co-factors such as alcohol consumption, the presence of virus infection hepatitis C virus and nonalcoholic steatohepatitis, which independently can contribute to iron accumulation. While genetic testing is useful, analysis of liver histology and imaging evaluation of iron overload by MRI are important tools for clinical evaluation. This article reviews current concepts on the clinical diagnosis and management of hepatic iron overload.

La acumulación de hierro en las células parenquimatosas determina la ocurrencia de daño tóxico y muerte celular, lo que puede producir una insuficiencia funcional. La enfermedad prototípica es la hemocromatosis hereditaria (HH). La HH se ha asociado a mutaciones que afectan a cualquiera de las proteínas que regulan el metabolismo del hierro. La causa más común de HH es una mutación en el gen HFE [C282Y]. Mutaciones en el gen de la hormona hepcidina (HAMP) y cualquiera de los 8 genes que regulan su biología, incluyendo el receptor de transferrina 2 (TfR2), hemojuvelina (HJV) y ferroportina(FPN), también causan sobrecarga de hierro y hemocromatosis. Aunque la información es limitada, la HH asociada a HFE es infrecuente en nuestro medio. La evaluación de la sobrecarga de hierro en la práctica clínica debe contemplar la evaluación de otros factores tales como el consumo de alcohol, la presencia de infección por el virus de la hepatitis por virus C y de esteatohepatitis no alcohólica. Si bien el test genético es de utilidad, los análisis de la histología hepática y la evaluación imagenológica de la sobrecarga de hierro mediante resonancia magnética son útiles para la evaluación clínica de la sobrecarga de hierro. El presente artículo revisa conceptos actuales sobre el manejo clínico de la sobrecarga de hierro hepática.

Hemocromatose hereditária relacionada ao gene HFE / Hereditary hemochromatosis HFE gene related

A Hemocromatose Hereditária (HH) é a desordem hereditária mais comum em caucasianos. Mais de 90% dos casos de HH resultam da simples substituição do aminoácido Cisteína pela Tirosina no gene HFE. Essa mutação causa uma doença recessiva que resulta no acúmulo tissular de ferro. O mecanismo através do qual o HFE influencia a homeostase do ferro nas células e no corpo permanece obscuro. A doença é subdiagnosticada na população em geral devido à inespecificidade de sua apresentação clínica. O prognóstico envolve a detecção precoce da doença e a terapêutica adequada utilizando a flebotomia em fase oportuna. Essa revisão descreve os conceitos atuais a respeito das manifestações clínicas, fisiopatologia, prognóstico e tratamento da Hemocromatose Hereditária relacionada ao gene HFE.

Hereditary hemochromatosis (HH) is the most common inherited disorder in caucasians. Over 90% of the cases of HH result from a single mutation of a Cys to Tyr in the HFE gene. This mutation causes a recessive disease resulting in iron acumulation in selected tissues. The mechanism by which HFE influences iron homeostasis in cells and in the body remains elusive. The disease is underdiagnosed in general population due to inespecific clinical manifestations. Prognosis is related to early diagnostic and correct treatment using pheblotomy. This review describe the current concepts concerning the clinical features, pathophisiology, prognosis and treatment of HFE-related hemochromatosis hereditary.

Hemocromatosis Neonatal: una causa de fallo hepático in utero: presentación de dos casos y revisión de la bibliografía / Neonatal Hemochromatosis: a cause of liver failure in utero: report of two cases and review of the literature

La hemocromatosis neonatal es una entidad clínico patológicaque presenta fallo hepático grave, se inicia in útero, asociada a siderosis intrahepática y extrahepática, que respeta el sistema reticulo endotelial.Su causa se desconoce pero se debería a un manejo anormal del hierro fetoplacentario con enfermedad hepática perinatal, relación genética familiar o sería consecuencia de una enfermedad gestacional aloinmunitaria. Es un síndrome con características comunes más que una simple entidad patológica, con transmisión materna y alta recurrencia en la misma progenie. La muerte se produceen los primeros días o semanas de vida por fallomultiorgánico. Presentamos dos recién nacidos con hemocromatosis neonatal. El primero falleció por fallo multiorgánico y el segundo permitió el trasplante hepático. Desde 1993, se emplea un cocktail antioxidantequelantedel hierro, junto al tratamiento de soporteestándar del fallo hepático, pero su uso es polémico. En 2002, una comunicación preliminar sugiere que el tratamiento con inmunoglobulinas endovenosas en la segunda mitad de la gestación, en mujeres con el antecedente de un hijo con hemocromatosis neonatal probada, previene las formas recurrentes letales de la enfermedad. Este trastorno se debe sospechar en todo fallo hepático grave al nacer, acompañado de valores séricos de ferritina elevados; pero debe confirmarse por un aumento de los depósitos hepáticos de hierro y siderosis extrahepática demostrables por resonancia magnética nuclear, en la biopsia de glándulas salivales o en la autopsia. La hemocromatosis neonatal es la indicación específicamás frecuente de trasplante hepático en los primeros 3 meses de vida, que parecería ser el tratamiento de elección por considerar desde el momentoque el soporte médico, incluida la terapia antioxidante-quelante del hierro, sea inefectivo, antes de que surjan complicaciones neurológicas irreversibles

Neonatal hemochromatosis is a rare clinical pathologic entity, defined by severe neonatal liver failure of intrauterine onset associated with intra-and extra hepatic siderosis that spares reticuloendothelial system. It is the most frequently recognized cause of liver failure in neonates. The cause is unknown but it may develop secondary to abnormal fetoplacental iron handling or perinatal liver disease or be familial or as a consequence of gestational alloimmune disease. It’s a syndrome with a common feature rather than a single pathologic entity, with maternal transmission and a high recurrence in the sibship. Death from multisystem organ failure usually occurs in the first few days or weeks of life. We report two newborn with neonatal hemochromatosis. The first died for multiorgan failure, despite aggressive support. The second underwent to liver transplantation. Since 1993, an antioxidant-chelator cocktail has been used in addition to standard supportive care, but this remains controversial. By 2002, a preliminary report suggested that treatment with weekly intravenous immunoglobulin during the later half of pregnancy, for woman whose most recent gestation was affected with proven NH. The diagnosis is suspected in the presence of severely impaired hepatic synthetic function accompanied by high serum ferritin levels, but is confirmed only by demonstration of increased hepatic iron stores, and extra-hepatic siderosis shown by autopsy or in vivo, which can be achieved by biopsy of the minor salivary glands or magnetic resonance imaging. Neonatal hemochromatosis is the most common specific indication for liver transplantation in the first three months of life and appears to be the treatment of choice, and must as well be considered as soon as it becomes apparent that medical support, which should include chelation-antioxidant treatment, is ineffective, before irreversible neurological complications appear.

Hereditary hemochromatosis: An opportunity for gene therapy

Levels of body iron should be tightly controlled to prevent the formation of oxygen radicals, lipoperoxidation, genotoxicity, and the production of cytotoxic cytokines, which result in damage to a number of organs. Enterocytes in the intestinal villae are involved in the apical uptake of iron from the intestinal lumen; iron is further exported from the cells into the circulation. The apical divalent metal transporter-1 (DMT1) transports ferrous iron from the lumen into the cells, while the basolateral transporter ferroportin extrudes iron from the enterocytes into the circulation. Patients with hereditary hemochromatosis display an accelerated transepithelial uptake of iron, which leads to body iron accumulation that results in cirrhosis, hepatocellular carcinoma, pancreatitis, and cardiomyopathy. Hereditary hemochromatosis, a recessive genetic condition, is the most prevalent genetic disease in Caucasians, with a prevalence of one in 300 subjects. The majority of patients with hereditary hemochromatosis display mutations in the gene coding for HFE, a protein that normally acts as an inhibitor of transepithelial iron transport. We discuss the different control points in the homeostasis of iron and the different mutations that exist in patients with hereditary hemochromatosis. These control sites may be influenced by gene therapeutic approaches; one general therapy for hemochromatosis of different etiologies is the inhibition of DMT1 synthesis by antisense-generating genes, which has been shown to markedly inhibit apical iron uptake by intestinal epithelial cells. We further discuss the most promising strategies to develop gene vectors and deliver them into enterocytes.

Hemocromatose hereditária / Hereditary haemochromatosis

Hemocromatose hereditária é o termo usado para identificar uma doença ligada ao complexo maior de histocompatibilidade humana, de herança genética, onde há um inapropriado aumento da absorção intestinal de ferro. Cirrose hepática, diabetes, artrite e cardiopatia são achados frequentes em pacientes com a doença estabelecida. Os autores relatam caso de paciente com essa enfermidade e fazem uma revisão na literatura especializada acerca de sua fisiopatologia, métodos diagnósticos e terapêutica