Liraglutide Impacts Iron Homeostasis in a Murine Model of Hereditary Hemochromatosis.

Classic hereditary hemochromatosis (HH) is an autosomal recessive iron-overload disorder resulting from loss-of-function mutations of the HFE gene. Patients with HH exhibit excessive hepatic iron accumulation that predisposes these patients to liver disease, including the risk for developing liver cancer. Chronic iron overload also poses a risk for the development of metabolic disorders such as obesity, type 2 diabetes, and insulin resistance. We hypothesized that liraglutide, GLP1 receptor agonist, alters iron metabolism while also reducing body weight and glucose tolerance in a mouse model of HH (global HFE knockout, HFE KO) and diet-induced obesity and glucose intolerance. The total body HFE KO and wild-type control mice were fed high-fat diet for 8 weeks. Mice were subdivided into liraglutide and vehicle-treated groups and received daily subcutaneous administration of the respective treatment once daily for 18 weeks. Liraglutide improved glucose tolerance and hepatic lipid markers and reduced body weight in a mouse model of HH, the HFE KO mouse, similar to wild-type controls. Importantly, our data show that liraglutide alters iron metabolism in HFE KO mice, leading to decreased circulating and stored iron levels in HFE KO mice. These observations highlight the potential that GLP1 receptor agonist could be used to reduce iron overload in addition to reducing body weight and improving glucose regulation in HH patients.

Hemocromatosis neonatal: resultado satisfactorio de la terapia con inmunoglobulina por vía intravenosa a partir de la semana 14 de gestación / Neonatal hemochromatosis: Satisfactory outcome of intravenous immunoglobulin therapy from week 14 of pregnancy

La hemocromatosis neonatal es una enfermedad congénita infrecuente que cursa con un fallo hepático severo con alta tasa de mortalidad (80-90%) en el neonato. Su etiología sigue siendo desconocida, aunque cada día cobra más fuerza la hipótesis aloinmune. La terapia con inmunoglobulina por vía intravenosa ha demostrado ser efectiva para disminuir sus consecuencias. Presentamos el caso de una paciente con diagnóstico previo de hijo afectado por la enfermedad que en la gestación actual se realiza tratamiento con inmunoglobulina por vía intravenosa, desde la semana 14 de embarazo, obteniendo resultados satisfactorios (AU)

Neonatal hemochromatosis is a rare congenital disease that causes severe liverfailure, leading to a high mortality rate (80-90%). The cause remains unknown but the alloimmune hypothesis is gaining ground. Intravenous immunoglobulin therapy has been proven to be effective in ameliorating the consequences of this entity. We present the case of a patient who had previously delivered a child with neonatal hemochromatosis. She was treated with intravenous immunoglobulin from week 14 of pregnancy, with a satisfactory outcome (AU)

El nuevo paradigma de la hemocromatosis neonatal: hepatitis fetal aloinmunitaria / The new paradigm of neonatal hemochromatosis: fetal alloimmune hepatitis

El modelo clásico de la hemocromatosis neonatal contemplaba la analogía con la hemocromatosis hereditaria. El tratamiento médico se basaba en un cóctel quelante/antioxidante. La hipótesis actual de un origen aloinmunitario del proceso, en el que la madre gestante monta una respuesta destructiva de tipo IgG contra los hepatocitos fetales, ha ofrecido una mejor explicación fsiopatológica y permite enfocar el tratamiento en el aspecto inmunológico con excelentes resultados, incluso previniendo la enfermedad en embarazos posteriores. Este cambio de paradigma repercute profundamente en el diagnóstico, pronóstico y tratamiento de la enfermedad, que debería denominarse "hepatitis fetal aloinmunitaria".

The classical model of neonatal hemochromatosis was based on the analogy with hereditary hemochromatosis. Medical treatment consisted on the antioxidant-chelator cocktail. The new hypothesis of an alloimmune origin of the process by which the pregnant woman mounts an IgG-based destructive response against fetal hepatocytes offers a pathogenic explanation, allowing treatment to be focused on the immunological aspects, with excellent results, and opens the possibility of preventive treatment in future pregnancies. This new paradigm produces a deep impact in diagnosis, prognosis and treatment of the disease, that should be called "fetal alloimmune hepatitis".

El nuevo paradigma de la hemocromatosis neonatal: hepatitis fetal aloinmunitaria / The new paradigm of neonatal hemochromatosis: fetal alloimmune hepatitis

El modelo clásico de la hemocromatosis neonatal contemplaba la analogía con la hemocromatosis hereditaria. El tratamiento médico se basaba en un cóctel quelante/antioxidante. La hipótesis actual de un origen aloinmunitario del proceso, en el que la madre gestante monta una respuesta destructiva de tipo IgG contra los hepatocitos fetales, ha ofrecido una mejor explicación fsiopatológica y permite enfocar el tratamiento en el aspecto inmunológico con excelentes resultados, incluso previniendo la enfermedad en embarazos posteriores. Este cambio de paradigma repercute profundamente en el diagnóstico, pronóstico y tratamiento de la enfermedad, que debería denominarse "hepatitis fetal aloinmunitaria".(AU)

The classical model of neonatal hemochromatosis was based on the analogy with hereditary hemochromatosis. Medical treatment consisted on the antioxidant-chelator cocktail. The new hypothesis of an alloimmune origin of the process by which the pregnant woman mounts an IgG-based destructive response against fetal hepatocytes offers a pathogenic explanation, allowing treatment to be focused on the immunological aspects, with excellent results, and opens the possibility of preventive treatment in future pregnancies. This new paradigm produces a deep impact in diagnosis, prognosis and treatment of the disease, that should be called "fetal alloimmune hepatitis".(AU)

Hemocromatosis hereditaria. Problemas en el diagnóstico y tratamiento / Hereditary hemochromatosis. Problems in diagnosis and treatment

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Nueva terapia con inmunoglobulinas en un caso de hemocromatosis neonatal / Immunoglobulin therapy for natal hemochromatosis

La hemocromatosis neonatal es una enfermedad hepática muy severa del recién nacido y se asocia a una alta mortalidad. Se cree que su etiología es de tipo aloinmune, debido a la presencia de un anticuerpo materno hasta ahora desconocido que interfiere con el metabolismo férrico del feto, llegando a producir gran morb i mortal ¡dad. Basándonos en esta teoría, el tratamiento materno con inmunoglobulinas intravenosas en gestaciones sucesivas podría prevenir el desarrollo de un nuevo cuadro de hemocromatosis neonatal. Se describe el caso de una gestante con un hijo anterior diagnosticado y fallecido neonatalmente por hemocromatosis, a la que en el embarazo actual se le trató con inmunoglobulinas intravenosas consiguiendo un hijo sano y vivo. Es el primer caso descrito en España y demuestra el éxito de esta terapia, tal como describe la literatura.

Neonatal hemochromatosis is a severe neonatal liver disease with a high mortality and recurrence rate. It is supposed to be a gestational alloimmune disease because of the existence of maternal antibodies against fetal hepatic metabolism. On the basis of this hypothesis, the administration of intravenous immunoglobulin has been reported as a successful treatment during the following pregnancy. We describe the first case of this treatment in Spain which confirms the data available in the literature.

Hemocromatose associada a carcinoma hepatocelular e neoplasias extra-hepáticas / Hemochromatosis combined with hepatocellular carcinoma and extrahepatic neoplasms

A hemocromatose caracteriza-se pelo acúmulo excessivo de ferro no organismo, que é depositado redominantemente no fígado, e resulta ou de um defeito genético determinando uma absorção excessiva de ferro ou da administração parenteral deste íon. O ferro em excesso determina alterações celulares através da peroxidação lipídica, estímulo da deposição de colágeno e interação com o oxigênio reativo e DNA. Os autores relatam um caso de hemocromatose em paciente portador de cirrose hepática associada ao desenvolvimento de hepatocarcinoma, hemangioma hepático, adenocarcinoma prostático e carcinoma renal, e apresentam uma discussão geral deste processo, frequentemente associado ao desenvolvimento de neoplasias.

Hemochromatosis is characterized by excessive accumulation of iron in the body, which is deposited primarily in the liver. It results either from a genetic defect determining an excessive absorption of iron or from parenteral administration of this ion. The excess iron determines cellular changes through lipid peroxidation, stimulation of collagen deposition, and interaction with reactive oxygen and DNA. The authors report a case of hemochromatosis in a patient with liver cirrhosis associated with development of hepatocellular carcinoma, hepatic hemangioma, prostate adenocarcinoma and renal cell carcinoma, and provide a general discussion of this process often associated with the development of neoplasias.

Tratamiento de la hemocromatosis hereditaria tipo 1 con magnesio oral / Treatment of type 1 hereditary haemochromatosis with oral magnesium

Fundamento y objetivo: Parece que un eslabón en la patogenia de la hemocromatosis hereditaria tipo 1 es la sobreexpresión de un transportador de cationes divalentes duodenal (DMT1) causante de la absorción del hierro2+ no hemínico. El objetivo del presente estudio ha sido valorar si el bloqueo competitivo de DMT1 mediante la administración de dosis altas de magnesio2+ por vía oral reduce la absorción de hierro en pacientes homocigotos para la mutación C282Y. Pacientes y método: Mediante un ensayo clínico cruzado se investigó la absorción de hierro mediante el test de absorción de bajas dosis de hierro en un grupo de 15 pacientes antes y después de ingerir durante 2 semanas una dosis de magnesio de 809,6 mg cada 8 h. Resultados: No se observaron efectos secundarios ni diferencias estadísticamente significativas entre la absorción de hierro antes y después del tratamiento experimental (14,7 µmol/l, intervalo de confianza [IC] del 95%, 9,8-19,6, frente a 14,9 µmol/l, IC del 95%, 8,5-21,4; p = 0,7). Conclusiones: El tratamiento con magnesio oral no reduce la absorción de hierro en los pacientes homocigotos C282Y. Dicho tratamiento no puede ser una alternativa terapéutica a las flebotomías

Background and objective: An essential step in the pathogenesis of hereditary hemochromatosis seems to be the increased expression of a duodenal divalent cation transporter (DMT1) responsible for absorption of non-heminic iron2+. The objective of the present study was to ascertain whether the competitive blockade of DMT1 by the administration of high doses of oral Mg2+ reduces iron absorption in patients homozygous for the C282Y mutation. Patients and method: Iron absorption was evaluated by a low dose iron absorption test in 15 patients before and after treatment with oral magnesium (809.6 mg every 8 hours) for two weeks. Results: We did not observe secondary effects or significant differences in iron absorption before or after magnesium treatment (14.7 µmol/L; 95% confidence interval [CI], 9.8-19.6 vs 14.9 µmol/L; 95% CI, 8.5-21.4, P = 0.7). Conclusions: Treatment with oral magnesium does not reduce iron absorption in homozygous C282Y patients. This treatment can not be used in these subjects