RESUMO
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.
Assuntos
Modelos Animais de Doenças , Proteína da Hemocromatose , Hemocromatose , Homeostase , Ferro , Liraglutida , Camundongos Knockout , Animais , Hemocromatose/genética , Hemocromatose/metabolismo , Hemocromatose/tratamento farmacológico , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Ferro/metabolismo , Homeostase/efeitos dos fármacos , Camundongos , Proteína da Hemocromatose/genética , Proteína da Hemocromatose/metabolismo , Fígado/metabolismo , Fígado/efeitos dos fármacos , Masculino , Dieta Hiperlipídica/efeitos adversos , Intolerância à Glucose/metabolismo , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/genética , Obesidade/metabolismo , Obesidade/tratamento farmacológico , Obesidade/genética , Camundongos Endogâmicos C57BL , Peso Corporal/efeitos dos fármacosRESUMO
A 24-year-old man was admitted to our hospital because of severe heart failure. Although he was treated with diuretics and positive inotropic agents, his heart failure progressed. An endomyocardial biopsy revealed iron deposition in his myocytes. Finally, he was diagnosed with hereditary hemochromatosis. After starting administration of an iron-chelating agent in addition to conventional treatment for heart failure, his condition improved. We should consider hemochromatosis in heart failure patients with severe right ventricular dysfunction in addition to left ventricular dysfunction.
Assuntos
Insuficiência Cardíaca , Hemocromatose , Masculino , Humanos , Adulto Jovem , Adulto , Hemocromatose/complicações , Hemocromatose/tratamento farmacológico , Hemocromatose/diagnóstico , Quelantes de Ferro/uso terapêutico , Coração , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , FerroRESUMO
Background: Deferasirox is an active iron chelator, used in the treatment of iron overload such as hemochromatosis. Up to 28% may present adverse reactions to said drug. A desensitization protocol for this drug may be useful when there are no other therapeutic options. Case report: A 52-year-old female with a diagnosis of hemochromatosis who began treatment with phlebotomy, poor response and tolerance, so it was decided to treat with deferasirox 500 mg daily, presenting symptoms of urticaria and angioedema on the third dose. Hospitalization was decided for a desensitization protocol with an initial dose of 0.6mg with a gradual increase in the dose, reaching a maintenance dose of 500 mg per day on the third day. Conclusions: The rapid desensitization protocol for Deferasirox is useful when there is no response or therapeutic alternative.
Antecedentes: Deferasirox es un quelante de hierro activo, indicado en el tratamiento de pacientes con hemocromatosis; sin embargo, se ha informado que el 28% de los casos puede tener reacciones adversas al fármaco. El protocolo de desensibilización para deferasirox puede ser útil cuando no se dispone de opciones terapéuticas adicionales. Reporte de caso: Paciente femenina de 52 años, con diagnóstico de hemocromatosis, quien luego de practicarle una flebotomía se observó poca respuesta y tolerancia al tratamiento, por lo que se decidió indicar deferasirox (500 mg/día), manifestando un cuadro de urticaria y angioedema en la tercera toma. Se decidió hospitalizarla para implementar el protocolo de desensibilización con una dosis inicial de 0.6 mg, con incremento gradual hasta llegar, al tercer día, a una dosis de mantenimiento de 500 mg/día. Conclusiones: El protocolo de desensibilización rápida con deferasirox es útil cuando no se obtiene respuesta satisfactoria con la flebotomía o no se dispone opciones de tratamiento alternativas.
Assuntos
Deferasirox , Hemocromatose , Quelantes de Ferro , Feminino , Humanos , Pessoa de Meia-Idade , Deferasirox/uso terapêutico , Hemocromatose/tratamento farmacológico , Quelantes de Ferro/uso terapêuticoRESUMO
Linezolid (LZD) is an effective drug in treating multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. This study aimed to evaluate the safety of LZD in the treatment of patients with rifampicin resistant tuberculosis. This was a multicenter retrospective study. A total of 184 patients of the rifampicin resistant tuberculosis patients treated with LZD from Jan 2018 to Apr 2020 in three hospitals were involved, and their clinical symptoms were recorded and analyzed. Meanwhile, the types and incidence of adverse effects associated with LZD were evaluated. It showed that peripheral neuritis (51, 27.7%) and hemochromatosis (42, 22.8%) were the most common adverse effects observed among these patients. The median time of symptoms after LZD treatment was 45.5 and 120.0 days, respectively. Furthermore, female patients had a significantly higher risk for leukopenia (P = 0.002) and hemochromatosis (P = 0.033) when compared with male patients. History of underlying disease was the risk factor for thrombocytopenia (P = 0.022). Patients with long duration of medication (RR = 1.004, 95%CI: 1.002-1.006, P < 0.001) and daily dosage ≥600mg (RR = 3.059, 95%CI: 1.238-7.558, P = 0.015) were at higher risk of hemochromatosis. Age was the risk factor for rash (P = 0.008) and nausea and vomiting (P = 0.018). In addition, LZD administration time was the risk factor for optic neuritis (P < 0.001) and peripheral neuritis (P < 0.001). LZD can cause adverse symptoms in patients with rifampicin resistant tuberculosis. Gender, history of underlying disease, LZD use time, LZD dosage, and age are the risk factors in the LZD treatment of these patients. During medication, bone marrow suppression and neuropathy should be closely monitored. This study could potentially provide useful information for the clinical practice.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hemocromatose , Neurite (Inflamação) , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Masculino , Feminino , Linezolida/efeitos adversos , Rifampina/efeitos adversos , Estudos Retrospectivos , Hemocromatose/induzido quimicamente , Hemocromatose/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Neurite (Inflamação)/induzido quimicamente , Neurite (Inflamação)/tratamento farmacológico , Antituberculosos/efeitos adversosRESUMO
In clinical trials, sodium-glucose cotransporter-2 inhibitors (SGLT-2i) use alone in persons with type 2 diabetes (T2D) or testosterone replacement therapy (TRT) prescription alone in men with hypogonadism was shown to lead to a modest but significant increase in red blood cell mass. Recent evidence indicates that combined use of TRT and SGLT-2i in persons with T2D may be associated with risk of erythrocytosis. However, factor(s) that may lead to the development of erythrocytosis in these patients is unknown. We describe here 5 consecutive patients with hypogonadism on chronic TRT who developed erythrocytosis following addition of SGLT-2i empagliflozin for optimization of T2D management. In addition to the careful review of medical history, all patients underwent genetic screening for hereditary hemochromatosis. We have found that none of the patients had C282Y mutation in the HFE (Homeostatic Iron Regulator) gene and 4 out of 5 patients had heterozygosity in the H63D allele. Upon TRT discontinuation or its dose reduction or referral for scheduled phlebotomy, patients showed resolution of erythrocytosis. Our study reaffirms that practitioners should monitor for changes in hematocrit following the initiation of SGLT-2i in persons with T2D and hypogonadism on chronic TRT. Also, for the first time, we showed that in some of the patients receiving combined TRT and SGLT-2i H63D heterozygosity in the HFE gene may mediate the development of new-onset erythrocytosis.
Assuntos
Diabetes Mellitus Tipo 2 , Hemocromatose , Hipogonadismo , Policitemia , Inibidores do Transportador 2 de Sódio-Glicose , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Hemocromatose/tratamento farmacológico , Hemocromatose/genética , Humanos , Hipogonadismo/tratamento farmacológico , Hipogonadismo/genética , Masculino , Mutação , Policitemia/induzido quimicamente , Policitemia/genética , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Testosterona/efeitos adversosRESUMO
OBJECTIVES: We developed a natural polyphenol supplement that strongly chelates iron in vitro and assessed its effect on non-heme iron absorption in patients with hereditary hemochromatosis (HH). METHODS: We performed in vitro iron digestion experiments to determine iron precipitation by 12 polyphenol-rich dietary sources, and formulated a polyphenol supplement (PPS) containing black tea powder, cocoa powder and grape juice extract. In a multi-center, single-blind, placebo-controlled cross-over study, we assessed the effect of the PPS on iron absorption from an extrinsically labelled test meal and test drink in patients (n = 14) with HH homozygous for the p.C282Y variant in the HFE gene. We measured fractional iron absorption (FIA) as stable iron isotope incorporation into erythrocytes. RESULTS: Black tea powder, cocoa powder and grape juice extract most effectively precipitated iron in vitro. A PPS mixture of these three extracts precipitated ~ 80% of iron when 2 g was added to a 500 g iron solution containing 20 µg Fe/g. In the iron absorption study, the PPS reduced FIA by ~ 40%: FIA from the meal consumed with the PPS was lower (3.01% (1.60, 5.64)) than with placebo (5.21% (3.92, 6.92)) (p = 0.026)), and FIA from the test drink with the PPS was lower (10.3% (7.29 14.6)) than with placebo (16.9% (12.8 22.2)) (p = 0.002). CONCLUSION: Our results indicate that when taken with meals, this natural PPS can decrease dietary iron absorption, and might thereby reduce body iron accumulation and the frequency of phlebotomy in patients with HH. TRIAL REGISTRY: clinicaltrials.gov (registration date: 9.6.2019, NCT03990181).
Assuntos
Hemocromatose , Adulto , Estudos Cross-Over , Hemocromatose/tratamento farmacológico , Hemocromatose/genética , Hemocromatose/metabolismo , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Ferro , Ferro da Dieta , Polifenóis/farmacologia , Pós , Método Simples-Cego , CháRESUMO
Iron overload can be the result of either dysregulated iron metabolism in the case of hereditary hemochromatosis or repeated blood transfusions in the case of secondary hemochromatosis (e.g. in ß-thalassemia and sickle cell anemia patients). Under iron overload conditions, transferrin (Tf) saturation leads to an increase in non-Tf bound iron which can result in the generation of reactive oxygen species (ROS). These excess ROS can damage cellular components, resulting in the dysfunction of vital organs including iron overload cardiomyopathy (IOC). Multiple studies have demonstrated that L-type and T-type calcium channels are the main routes for iron uptake in the heart, and that calcium channel blockers, given either individually or in combination with standard iron chelators, confer cardioprotective effects under iron overload conditions. Treatment with antioxidants may also provide therapeutic benefits. Interestingly, recent studies have suggested that mitochondrial dynamics and regulated cell death (RCD) pathways are potential targets for pharmacological interventions against iron-induced cardiomyocyte injury. In this review, the potential therapeutic roles of iron chelators, antioxidants, iron uptake/metabolism modulators, mitochondrial dynamics modulators, and inhibitors of RCD pathways in IOC are summarized and discussed.
Assuntos
Cardiomiopatias , Hemocromatose , Sobrecarga de Ferro , Antioxidantes/uso terapêutico , Cardiomiopatias/tratamento farmacológico , Hemocromatose/complicações , Hemocromatose/tratamento farmacológico , Hemocromatose/metabolismo , Humanos , Ferro/metabolismo , Quelantes de Ferro/metabolismo , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/tratamento farmacológico , Miócitos Cardíacos/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Gestational alloimmune liver disease (GALD) is a materno-fetal alloimmune disorder that targets the fetal liver and often causes neonatal liver failure. GALD most commonly presents as neonatal hemochromatosis (NH), which is a severe neonatal liver injury confirmed by extra-hepatic iron accumulation at various sites. With the discovery of the alloimmune mechanism of GALD, exchange transfusion and intravenous immunoglobulin (IVIG) administration are being used as novel treatments. Here, we present a rare case of an 11-day-old female infant who presented with marked hyperbilirubinemia. Laboratory findings showed significantly elevated direct and indirect bilirubin, high ferritin and alpha fetoprotein levels, high transferrin saturation, and severe coagulopathy. Abdominal magnetic resonance imaging revealed markedly reduced T2 signal intensity in the liver and pancreas compared to the spleen, suggesting iron deposition. The infant was diagnosed with NH and successfully treated with exchange transfusion and four doses of IVIG.
Assuntos
Doenças Fetais , Hemocromatose , Hepatopatias , Feminino , Hemocromatose/diagnóstico , Hemocromatose/tratamento farmacológico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Recém-Nascido , Ferro/uso terapêuticoRESUMO
BACKGROUND: Human hepcidin, produced by hepatocytes, regulates intestinal iron absorption, iron recycling by macrophages, and iron release from hepatic storage. Recent studies indicate that hepcidin deficiency is the underlying cause of the most known form of hereditary hemochromatosis. CASE PRESENTATION: A 44-year-old Asian man who developed type 2 diabetes mellitus had elevated serum ferritin levels (10,191 ng/mL). Liver biopsy revealed remarkable iron deposition in the hepatocytes and relatively advanced fibrosis (F3). Chromosomal analysis confirmed the presence of transferrin receptor type 2 mutations (c.1100T>G, c.2008_9delAC, hereditary hemochromatosis type 3 analyzed by Kawabata). The patient received intravenous infusions of Laennec (672 mg/day, three times/week) or oral administration with Porcine (3.87 g/day) for 84 months as an alternative to repeated phlebotomy. At the end of the treatment period, serum ferritin level decreased to 428.4 ng/mL (below the baseline level of 536.8 ng/mL). Hemoglobin A1c levels also improved after treatment with the same or lower dose of insulin (8.8% before versus 6.8% after). Plural liver biopsies revealed remarkable improvements in the grade of iron deposition and fibrosis (F3 before versus F1 after) of the liver tissue. CONCLUSION: The discovery of hepcidin and its role in iron metabolism could lead to novel therapies for hereditary hemochromatosis. Laennec (parenteral) and Porcine (oral), which act as hepcidin inducers, actually improved iron overload in this hereditary hemochromatosis patient, without utilizing sequential phlebotomy. This suggests the possibility of not only improving the prognosis of hereditary hemochromatosis (types 1, 2, and 3) but also ameliorating complications, such as type 2 diabetes, liver fibrosis, and hypogonadism. Laennec and Porcine can completely replace continuous venesection in patients with venesection and may improve other iron-overloading disorders caused by hepcidin deficiency.
Assuntos
Diabetes Mellitus Tipo 2 , Hemocromatose , Preparações Farmacêuticas , Adulto , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Hemocromatose/tratamento farmacológico , Hemocromatose/genética , Humanos , Masculino , Flebotomia , Placenta , Gravidez , SuínosRESUMO
Morus nigra L. is a plant popularly known as 'amoreira preta', very used in folk medicine. Iron overload (hemochromatosis) is a clinical condition that causes damage to various tissues due to oxidative stress. Therapy to control iron overload is still unsatisfactory. The protective effect on oxidative stress induced by iron overload was verified. Phytochemical characterization was evaluated by UHPLC-MS/MS. The in silico toxicity predictions of the main phytochemicals were performed via computer simulation. To induce iron overload, the animals received iron dextran (50 mg/kg/day). The test groups received doses of 500 and 1000 mg/kg of M. nigra extract for six weeks. Body weight, organosomatic index, serum iron, hepatic markers, cytokines, interfering factors in iron metabolism, enzymatic and histopathological evaluations were analyzed. Vanillic acid, caffeic acid, 6-hydroxycoumarin, p-coumaric acid, ferulic acid, rutin, quercitrin, resveratrol, apigenin and kaempferol were identified in the extract. In addition, in silico toxic predictions showed that the main compounds presented a low probability of toxic risk. The extract of M. nigra showed to control the mediators of inflammation and to reduce iron overload in several tissues. Our findings illustrate a novel therapeutic action of M. nigra leaves on hemochromatosis caused by iron overload.
Assuntos
Hemocromatose , Sobrecarga de Ferro , Morus , Animais , Morus/química , Morus/metabolismo , Quempferóis/análise , Quempferóis/farmacologia , Resveratrol/farmacologia , Hemocromatose/tratamento farmacológico , Apigenina/análise , Apigenina/farmacologia , Ácido Vanílico/farmacologia , Espectrometria de Massas em Tandem , Simulação por Computador , Dextranos/análise , Dextranos/metabolismo , Dextranos/farmacologia , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Estresse Oxidativo , Sobrecarga de Ferro/prevenção & controle , Compostos Fitoquímicos/análise , Rutina/farmacologia , Ferro/toxicidade , Ferro/análise , Citocinas/metabolismo , Mediadores da Inflamação/metabolismoAssuntos
Hemocromatose/diagnóstico , Ferro/sangue , Cardiomiopatias/etiologia , Diabetes Mellitus/etiologia , Diagnóstico Diferencial , Edema/etiologia , Evolução Fatal , Fadiga/etiologia , Hemocromatose/complicações , Hemocromatose/tratamento farmacológico , Hemocromatose/genética , Humanos , Ferro/metabolismo , Quelantes de Ferro/uso terapêutico , Perna (Membro) , Masculino , Pessoa de Meia-Idade , Transferrina/metabolismoRESUMO
The flavonol rutin has been shown to possess antioxidant and iron chelating properties in vitro and in vivo. These dual properties are beneficial as therapeutic options to reduce iron accumulation and the generation of reactive oxygen species (ROS) resultant from excess free iron. The effect of rutin on iron metabolism has been limited to studies performed in wildtype mice either injected or fed high-iron diets. The effect of rutin on iron overload caused by genetic dysregulation of iron homoeostasis has not yet been investigated. In the present study we examined the effect of rutin treatment on tissue iron loading in a genetic mouse model of iron overload, which mirrors the iron loading associated with Type 3 hereditary haemochromatosis patients who have a defect in Transferrin Receptor 2 (TFR2). Male TFR2 knockout (KO) mice were administered rutin via oral gavage for 21 continuous days. Following treatment, iron levels in serum, liver, duodenum and spleen were assessed. In addition, hepatic ferritin protein levels were determined by Western blotting, and expression of iron homoeostasis genes by quantitative real-time PCR. Rutin treatment resulted in a significant reduction in hepatic ferritin protein expression and serum transferrin saturation. In addition, trends towards decreased iron levels in the liver and serum, and increased serum unsaturated iron binding capacity were observed. This is the first study to explore the utility of rutin as a potential iron chelator and therapeutic in an animal model of genetic iron overload.
Assuntos
Hemocromatose/tratamento farmacológico , Ferro/sangue , Fígado/efeitos dos fármacos , Receptores da Transferrina/deficiência , Rutina/farmacologia , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Ferritinas/metabolismo , Hemocromatose/sangue , Hemocromatose/genética , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores da Transferrina/sangue , Receptores da Transferrina/genética , Transferrina/metabolismoRESUMO
Phlebotomies are performed in hereditary hemochromatosis (HH) to maintain normal iron concentrations. Proton-pump inhibitors (PPIs) can reduce the number of phlebotomies in patients with HH. However, in patients without HH, the iron concentrations do not appear to be compromised when using PPIs. Therefore, we aim to explain the differences in iron absorption between patients with and without HH. In 10 p.cysteine282tyrosine (p.C282Y) homozygous HH patients with normalized iron stores and 10 healthy control subjects (HCs), the iron parameters and hepcidin concentrations were determined before ingestion of a pharmacological dose of 50 mg iron [ferric iron (Fe3+)] polymaltose and hourly for 4 h afterward. This was repeated after 7 days of treatment with pantoprazole 40 mg once daily. Serum iron concentrations and transferrin saturation percentages dropped significantly during PPI use in the patients with HH, whereas no changes were observed in the HCs. Hepcidin concentrations were lower in the patients with HH compared with the HCs both before and during PPI use. In both groups, hepcidin levels did not significantly decrease during the treatment. Seven-day PPI use significantly reduces iron absorption in patients with HH but not in HCs. Changes in hepcidin concentrations could not explain these different PPI effects on iron absorption probably due to a small sample size.NEW & NOTEWORTHY This study confirms that lowering gastric acidity by proton pump inhibitors results in a reduction in iron absorption in patients with hemochromatosis and not in healthy control subjects. The presupposition that a decrease in hepcidin concentration in healthy control subjects in response to lowering gastric acidity can explain the difference in iron absorption between these groups could not be confirmed probably because of a small sample size.
Assuntos
Ferritinas/sangue , Hemocromatose/sangue , Hepcidinas/sangue , Ferro/sangue , Adulto , Índice de Massa Corporal , Feminino , Hemocromatose/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Pantoprazol/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêuticoRESUMO
Hemochromatosis is an iron overload disease, which lacks nutritional intervention strategies. This study explored the protective effect of quercetin on hemochromatosis and its possible mechanism through network pharmacology. We used Online Mendelian Inheritance in Man to screen the disease targets of hemochromatosis, and further constructed a potential protein interaction network through STITCH. The above-mentioned targets revealed by Gene enrichment analysis have played a significant role in ferroptosis, mineral absorption, basal cell carcinoma, and related signal pathways. Besides, the drug likeness of quercetin obtained by Comparative Toxicogenomics Database was evaluated by Traditional Chinese Medicine Systems Pharmacology, and potential drug targets identified by PharmMapper and similar compounds identified by PubChem were selected for further research. Moreover, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed the relationship between quercetin and glycosylation. Furthermore, we performed experiments to verify that the protective effect of quercetin on iron overload cells is to inhibit the production of reactive oxygen species, limit intracellular iron, and degrade glycosaminoglycans. Finally, iron-induced intracellular iron overload caused ferroptosis, and quercetin and fisetin were potential ferroptosis inhibitors. In conclusion, our study revealed the correlation between hemochromatosis and ferroptosis, provided the relationship between the target of quercetin and glycosylation, and verified that quercetin and its similar compounds interfere with iron overload related disease. Our research may provide novel insights for quercetin and its structurally similar compounds as a potential nutritional supplement for iron overload related diseases.
Assuntos
Antioxidantes/farmacologia , Ferroptose , Hemocromatose/metabolismo , Fígado/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Quercetina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Hemocromatose/tratamento farmacológico , Hemocromatose/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Simulação de Acoplamento Molecular , RatosRESUMO
INTRODUCTION: Postinfantile giant cell hepatitis is a rare entity in adult hepatopathy caused by various etiologies that can be summarized by their characteristic giant cells in histopathologic examination. Frequently, association with autoimmune, infectious and hepatotoxic events is described. Therefore, therapy consists in treatment of underlying diseases and immunosuppression. HISTORY: We saw an 76-year-old patient due to histologically proven Postinfantile giant cell hepatitis. Despite administering budesonid as an initial attempt of treatment, no improvement in hepatitis was achieved. Hence, the patient was forwarded to us. FINDINGS: Neither regarding the patient's history nor in laboratory and serological tests, nor in histopathological analysis of liver biopsies an underlying cause of giant cell hepatitis was identified. THERAPY AND COURSE: Despite immunosuppressive therapy with glucocorticoids alone, cyclophosphamide and a monoclonal anti-CD20-antibody, giant cell hepatitis was not controlled. Hence, we started treatment with the calcineurin inhibitor Tacrolimus combined with low-dose prednisolone and thus were able to lower patient's liver values and stabilize hepatitis. CONCLUSION: The good effectiveness of tacrolimus in our patient underlines the important role of calcineurin inhibitors in treating Postinfantile giant cell hepatitis, although rarely reported to date.
Assuntos
Inibidores de Calcineurina/uso terapêutico , Hemocromatose , Idoso , Feminino , Hemocromatose/diagnóstico , Hemocromatose/tratamento farmacológico , Hemocromatose/patologia , Humanos , Fígado/patologiaRESUMO
Hemochromatosis (iron overload) encompasses a group of diseases that are characterized by a toxic hyperaccumulation of iron in parenchymal organs. Currently, only few treatments for this disease have been approved; however, all these treatments possess severe side effects. In this study, a paradigm for hemochromatosis maintenance/preventive therapy is investigated: polymers with negligible systemic biological availability form stable complexes with iron ions in the gastrointestinal tract, which reduces the biological availability of iron. Macroporous polymer beads are synthesized with three different iron-chelating moieties (benzene-1,2-diol, benzene-1,2,3-triol, and 1,10-phenanthroline). The polymers rapidly chelate iron ions from aqueous solutions in vitro in the course of minutes, and are noncytotoxic and nonprooxidant. Moreover, the in vivo biodistribution and pharmacokinetics show a negligible uptake from the gastrointestinal tract (using 125 I-labeled polymer and single photon emission computed tomography/computed tomography), which generally prevents them from having systemic side effects. The therapeutic efficacy of the prepared polymers is successfully tested in vivo, and exhibits a significant inhibition of iron uptake from the gastrointestinal tract without any noticeable signs of toxicity. Furthermore, an in silico method is developed for the prediction of chelator selectivity. Therefore, this paradigm can be applied to the next-generation maintenance/preventive treatment for hemochromatosis and/or other diseases of similar pathophysiology.
Assuntos
Hemocromatose/tratamento farmacológico , Quelantes de Ferro/farmacologia , Ferro/metabolismo , Modelos Teóricos , Benzeno/química , Benzeno/farmacologia , Trato Gastrointestinal/efeitos dos fármacos , Hemocromatose/diagnóstico por imagem , Hemocromatose/patologia , Humanos , Quelantes de Ferro/química , Fenantrolinas/química , Fenantrolinas/farmacologia , Polímeros/química , Polímeros/farmacologia , Tomografia Computadorizada de EmissãoRESUMO
Iron homeostasis is essential for health; moreover, hepcidin-deficiency results in iron overload in both hereditary hemochromatosis and iron-loading anemia. Here, we identified iron modulators by functionally screening hepcidin agonists using a library of 640 FDA-approved drugs in human hepatic Huh7 cells. We validated the results in C57BL/6J mice and a mouse model of hemochromatosis (Hfe-/- mice). Our screen revealed that the anti-rheumatoid arthritis drug auranofin (AUR) potently upregulates hepcidin expression. Interestingly, we found that canonical signaling pathways that regulate iron, including the Bmp/Smad and IL-6/Jak2/Stat3 pathways, play indispensable roles in mediating AUR's effects. In addition, AUR induces IL-6 via the NF-κB pathway. In C57BL/6J mice, acute treatment with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling and decreased serum iron and transferrin saturation. Whereas chronically treating male Hfe-/- mice with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling, decreasing systemic iron overload, but less effective in females. Further analyses revealed that estrogen reduced the ability of AUR to induce IL-6/hepcidin signaling in Huh7 cells, providing a mechanistic explanation for ineffectiveness of AUR in female Hfe-/- mice. Notably, high-dose AUR (25 mg/kg) induces ferroptosis and causes lipid peroxidation through inhibition of thioredoxin reductase (TXNRD) activity. We demonstrate the ferroptosis inhibitor ferrostatin significantly protects liver toxicity induced by high-dose AUR without comprising its beneficial effect on iron metabolism. In conclusion, our findings provide compelling evidence that TXNRD is a key regulator of ferroptosis, and AUR is a novel activator of hepcidin and ferroptosis via distinct mechanisms, suggesting a promising approach for treating hemochromatosis and hepcidin-deficiency related disorders.
Assuntos
Auranofina/farmacologia , Ferroptose/efeitos dos fármacos , Hemocromatose , Sobrecarga de Ferro , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Feminino , Ferroptose/genética , Células HEK293 , Hemocromatose/tratamento farmacológico , Hemocromatose/genética , Hemocromatose/metabolismo , Hemocromatose/patologia , Humanos , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/patologia , Masculino , Camundongos , Camundongos Knockout , Transdução de Sinais/genéticaRESUMO
Patients with hereditary hemochromatosis and non-transfusion-dependent hereditary anemia develop predominantly liver iron-overload. We present a unique method allowing quantification of liver iron retention in humans during first-pass of 59Fe-labeled iron through the portal system, using standard ferrokinetic techniques measuring red cell iron uptake after oral and intravenous 59Fe administration. We present data from patients with iron deficiency (ID; N = 47), hereditary hemochromatosis (HH; N = 121) and non-transfusion-dependent hereditary anemia (HA; N = 40). Mean mucosal iron uptake and mucosal iron transfer (±SD) were elevated in patients with HH (59 ± 18%, 80 ± 15% respectively), HA (65 ± 17%, 74 ± 18%) and ID (84 ± 14%, 94 ± 6%) compared to healthy controls (43 ± 19%, 64 ± 18%) (p < 0.05) resulting in increased iron retention after 14 days compared to healthy controls in all groups (p < 0.01). The fraction of retained iron utilized for red cell production was 0.37 ± 0.17 in untreated HA, 0.55 ± 0.20 in untreated HH and 0.99 ± 0.22 in ID (p < 0.01). Interestingly, compared to red blood cell iron utilization after oral iron administration, red blood cell iron utilization was higher after injection of transferrin-bound iron in HA and HH. Liver iron retention was considerably higher in HH and HA compared to ID. We hypothesize that albumin serves as a scavenger of absorbed Fe(II) for delivering albumin-bound Fe(III) to hepatocytes.
Assuntos
Anemia Hemolítica Congênita/tratamento farmacológico , Anemia Ferropriva/tratamento farmacológico , Hemocromatose/tratamento farmacológico , Radioisótopos de Ferro/administração & dosagem , Fígado/química , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Idoso , Anemia Hemolítica Congênita/metabolismo , Anemia Ferropriva/metabolismo , Estudos de Casos e Controles , Feminino , Hemocromatose/metabolismo , Humanos , Radioisótopos de Ferro/farmacocinética , Masculino , Pessoa de Meia-Idade , Albumina Sérica Humana/metabolismo , Transferrina/metabolismo , Adulto JovemRESUMO
Hemochromatosis is an imbalance of excessive serum iron and is a life-threatening condition if left untreated. Due to different causes, primary and secondary hemochromatosis have different patient care considerations for the infusion nurse. Understanding the pathophysiology and how the body absorbs iron is imperative for providing the highest quality care. Since primary (hereditary) hemochromatosis originates from a gene mutation, and secondary (acquired) from excessive intake, the treatment and education must be adjusted accordingly to deliver successful outcomes for both diagnoses.