鐵調素，作為關鍵的鐵調節激素，在維持外周系統的鐵平衡中具有重要作用。外周鐵調素的表達受到多種因素的平衡調節，包括鐵的狀態，炎症，造血活動和缺氧。這一激素肽在腦內的存在和廣泛分佈，提示它可能在腦鐵平衡中也發揮作用。本研究檢測了炎症是否對腦內鐵調素表達起調節作用，從而影響腦鐵代謝。 / 在本研究的第一部分，我們檢測了炎症是否調節腦內鐵調素的表達，以及這種調節作用在腦內是否具有區域特異性。利用脂多糖（一種廣泛使用的炎症誘導劑）誘導的炎症模型，我們發現腦室內注射脂多糖可區域特異性地誘導腦內鐵調素的表達，即誘導皮層和黑質的鐵調素表達，而海馬的鐵調素水準無顯著改變。與此相伴隨的是腦內膜鐵轉運蛋白區域特異性的表達下降。此外，我們發現脂多糖處理引起的腦內鐵調素表達升高發生在神經元而不是星形膠質細胞內。這些發現提示，炎症能夠區域特異性地上調腦內鐵調素表達，上調的鐵調素轉而下調特定腦區膜鐵轉運蛋白的表達。 / 在本研究的第二部分，我們檢測了離體水準上炎症對原代皮層神經元和MES23.5多巴胺能細胞鐵調素表達的影響。我們觀察了炎症對這些細胞鐵調素和膜鐵轉運蛋白表達的作用。我們發現脂多糖不增加原代皮層神經元鐵調素的表達。但在與BV-2小膠質細胞共培養的條件下，原代皮層神經元的鐵調素表達水準經脂多糖刺激後上升。我們檢測了一系列可能由小膠質釋放的促炎細胞因數對神經元鐵調素表達的影響。結果表明，白介素-6介導了脂多糖誘導的神經元鐵調素表達升高的作用。我們進一步發現，白介素-6在短時間內直接增加神經元鐵調素表達和降低膜鐵轉運蛋白表達。最後我們進一步探究了白介素-6對腦內鐵調素表達的調控機制，發現在原代皮層神經元和MES23.5多巴胺能細胞中白介素-6誘導的鐵調素表達是通過信號轉導和轉錄啟動因數3信號通路介導的。 / 綜上所述，我們的研究結果表明，炎症在調節腦內鐵調素表達和控制腦內鐵轉運中發揮重要的作用。在腦內，炎症區域特異性地誘導鐵調素表達上調和膜鐵轉運蛋白表達下調。白介素-6/ 信號轉導和轉錄啟動因數3這一信號通路介導了在炎症情況下腦內鐵調素表達。這些發現加強了我們對於腦內鐵調素表達的調節過程的理解，並提供了一種新的關於鐵調素在腦內抗炎作用的治療觀點。 / Hepcidin, as the central iron regulatory hormone, plays a key role in maintaining peripheral iron homeostasis. The expression of hepcidin in the periphery is regulated by multiple factors homeostatically, including iron status, inflammation, erythropoietic activity and hypoxia. The presence and widespread distribution of this peptide in the brain suggests that hepcidin may also have an essential role in brain iron homeostasis. In this study we tested the hypothesis that inflammation exerts an important role in the regulation of brain hepcidin expression, which might alter brain iron metabolism. / To investigate whether inflammation could regulate brain hepcidin expression and whether this regulatory role is regionally specific in the brain, in the first part of study, we explored the effects of lipopolysaccharides (LPS), a widely used inflammation-inducing agent, on hepcidin expression in different brain regions of the rat brain in vivo. We found that intracerebroventricular (i.c.v.) injection of LPS induced brain hepcidin expression regionally specifically, that is, in the cortex and substantia nigra but not in the hippocampus. This effect was accompanied by a regionally specific decrease in brain ferroportin expression. Besides, brain hepcidin was found to be increased in neurons but not in astrocytes by LPS treatment. These findings indicate that inflammation could up-regulate brain hepcidin expression regionally specifically in the brain, which in turn down-regulates ferroportin expression in specific brain regions. / In the second part, we investigated the effects of inflammation on hepcidin expression in primary cortical neurons and MES23.5 dopaminergic cells in vitro. The expression of hepcidin as well as ferroportin was observed. We found that LPS did not increase hepcidin expression in primary cortical neurons. However, LPS induced neuronal hepcidin expression with the presence of BV-2 microglia cells. We examined the effects of a series of pro-inflammatory cytokines which could be released by microglia cells, on hepcidin expression, and found that interleukin-6 (IL-6) mediated neuronal hepcidin expression induced by LPS. Furthermore, we found that IL-6 directly increased hepcidin expression and decreased ferroportin expression in an acute manner. Finally, we further investigated the mechanisms underlying the regulatory effects of IL-6 on brain hepcidin expression, and found that IL-6-induced hepcidin expression is via signal transducer and activator of transcription-3 (STAT3) signaling in primary cortical neurons and MES23.5 dopaminergic cells. / In conclusion, the results of the present study implied that inflammation plays an important role in regulating brain hepcidin expression and controlling brain iron transport. In the brain, hepcidin up-regulation and ferroportin down-regulation is induced by inflammation in a regionally specific way. IL-6/ STAT3 signaling pathway is essential for brain hepcidin expression during inflammation. These findings enhance our understanding of the regulatory process of hepcidin in the brain, and provide a new therapeutic perspective of hepcidin in anti-inflammation in the brain. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / He, Xuan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 110-128). / Abstracts also in Chinese. / ABSTRACT OF THESIS ENTITLED --- p.II / ACKNOWLEDGENENTS --- p.VII / TABLE OF CONTENTS --- p.VIII / LIST OF FIGURES --- p.XII / LIST OF ABBREVIATIONS --- p.XV / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Introductory statement --- p.1 / Chapter 1.2 --- Hepcidin in the periphery --- p.1 / Chapter 1.2.1 --- Biological functions of hepcidin --- p.3 / Chapter 1.2.2 --- Regulation of hepcidin synthesis --- p.10 / Chapter 1.2.2.1 --- Regulation of hepcidin by iron --- p.10 / Chapter 1.2.2.2 --- Regulation of hepcidin by inflammation --- p.17 / Chapter 1.2.2.3 --- Regulation of hepcidin by anemia, erythropoiesis and hypoxia --- p.21 / Chapter 1.2.3 --- Misregulation of hepcidin --- p.25 / Chapter 1.2.3.1 --- Hepcidin deficiency --- p.25 / Chapter 1.2.3.2 --- Hepcidin excess --- p.27 / Chapter 1.3 --- Hepcidin in the brain --- p.28 / Chapter 1.4 --- Neuroinflammation --- p.30 / Chapter 1.5 --- Summary --- p.33 / Chapter 1.6 --- Objectives . --- p.34 / Chapter CHAPTER 2 --- MATERIALS AND METHODS --- p.36 / Chapter 2.1 --- Animal experiments --- p.36 / Chapter 2.1.1 --- Intracerebroventricular LPS injection --- p.36 / Chapter 2.1.2 --- Animal sacrifice and sample collection --- p.37 / Chapter 2.2 --- Cell cultures --- p.38 / Chapter 2.2.1 --- Primary cortical neurons culture --- p.38 / Chapter 2.2.2 --- BV-2 microglia cells --- p.39 / Chapter 2.2.3 --- MES23.5 dopaminergic cells --- p.39 / Chapter 2.3 --- Western blot analysis --- p.40 / Chapter 2.4 --- ELISA measurement --- p.42 / Chapter 2.5 --- Immunohistochemistry --- p.43 / Chapter 2.6 --- Statistical analysis --- p.44 / Chapter CHAPTER 3 --- IN VIVO STUDY OF THE EFFECTS OF INFLAMMATION ON BRAIN HEPCIDIN EXPRESSION --- p.46 / Chapter 3.1 --- ABSTRACT. --- p.46 / Chapter 3.2 --- INTRODUCTION --- p.47 / Chapter 3.3 --- MATERIALS AND METHODS --- p.48 / Chapter 3.4 --- RESULTS --- p.50 / Chapter 3.4.1 --- LPS injection induced hepcidin expression in neurons in the cortex and substantia nigra but not in the hippocampus of the rat brain --- p.50 / Chapter 3.4.2 --- LPS injection did not induce hepcidin expression in astrocytes in the cortex, hippocampus and substantia nigra of the rat brain --- p.51 / Chapter 3.4.3 --- LPS injection induced hepcidin up-regulation and ferroportin down-regulation in the cortex and substantia nigra but not in the hippocampus of the rat brain --- p.52 / Chapter 3.4.4 --- LPS injection induced IL-6 production and STAT3 phosphorylation in the cortex, hippocampus and substantia nigra of the rat brain --- p.53 / Chapter 3.5 --- DISCUSSION --- p.54 / Chapter CHAPTER 4 --- IN VITRO STUDY OF THE MECHANISMS UNDERLYING THE EFFECTS OF INFLAMMATION ON BRAIN HEPCIDIN EXPRESSION --- p.72 / Chapter 4.1 --- ABSTRACT --- p.72 / Chapter 4.2 --- INTRODUCTION --- p.73 / Chapter 4.3 --- MATERIALS AND METHODS --- p.74 / Chapter 4.4 --- RESULTS --- p.76 / Chapter 4.4.1 --- IL-6 mediated LPS-induced hepcidin expression in primary cortical neurons with the presence of BV-2 microglia --- p.76 / Chapter 4.4.2 --- IL-6 induced hepcidin up-regulation and ferroportin down-regulation in primary cortical neurons in an acute manner --- p.77 / Chapter 4.4.3 --- Inhibition of STAT3 activity suppressed IL-6-induced hepcidin up-regulation and ferroportin down-regulation in primary cortical neurons --- p.79 / Chapter 4.4.4 --- IL-6 rather than other cytokines induced STAT3 activation in primary cortical neurons --- p.80 / Chapter 4.4.5 --- Inhibition of STAT3 activity suppressed IL-6-induced hepcidin up-regulation and ferroportin down-regulation in MES23.5 dopaminergic cells --- p.80 / Chapter 4.5 --- DISCUSSION --- p.81 / Chapter CHAPTER 5 --- GENERAL DISCUSSION --- p.102 / REFERENCE --- p.110

Wu, Xinggang. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 124-161). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

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<p>Hronična bubrežna bolest (HBB) je globalni zdravstveni problem ne toliko zbog svoje masovnosti, koliko zbog hroničnog, progresivnog toka i udrženosti sa značajnim komorbiditetima. Anemija u sklopu HBB povezana je sa smanjenim kvalitetom života, povećanjem kardiovaskularnog morbiditeta, kognitivnim poremećajima, povećanjem broja hospitalizacija i sa povećanim mortalitetom. Incidencija anemije raste sa napredovanjem HBB, tako da u petom stadijumu zahvata gotovo sve obolele. Hepcidin je centralni regulator metabolizma gvožđa u organizmu, koji može uticati na razvoj i lečenje anemije u sklopu HBB. Cilj istraživanja je bio da se utvrdi nivo hepcidina kod ispitivanih bolesnika, kao i njegova povezanost sa parametrima metabolizma gvožđa, markerima inflamacije i odgovorom na agense za stimulaciju eritropoeze (ESA). Istovremeno smo želeli da utvrdimo koji faktori utiču na nivo hemoglobina u ispitivanoj populaciji, kao i &scaron;ta utiče na indeks rezistencije na eritropoetin (ERI). U ispitivanje je uključeno 77 bolesnika koji su lečeni hroničnim programom hemodijalize, tokom najmanje tri meseca pre uključivanja u ispitivanje. Ispitanicima je metodom ELISA određen nivo hepcidina u serumu. Ostali ispitivani podaci su dobijeni anamnezom, fizikalnim pregledom, analizom medicinske dokumentacije i standardnim laboratorijskim ispitivanjima. Sprovedenim ispitivanjem smo utvrdili postojanje pozitivne korelacije između serumskog nivoa hepcidina i interleukina-6, dok ostali ispitivani parametri inflamacije nisu korelirali sa nivoom hepcidina. Od parametara metabolizma gvožđa, sa serumskim nivoom hepcidina pozitivno su korelirali nivo gvožđa u serumu, feritin i saturacija transferina, dok je utvrđena negativna korelacija sa transferinom i ukupnim kapacitetom za vezivanje gvožđa. Serumski nivo hepcidina pozitivno je korelirao sa prosečnom nedeljnom dozom ESA. Nije utvrđena korelacija sa ERI, ukupnom dužinom lečenja sa ESA, kao ni sa vrstom ESA. Od svih ispitivanih parametara koji su značajno korelirali sa nivoom hepcidina u serumu, multivarijantna analiza je izdvojila jedino nivo feritina kao signifikantan i nezavisan činilac. Hemoglobin u krvi bolesnika koji su uključeni u ispitivanje nezavisno pozitivno korelira sa vrednostima leukocita i albumina u serumu. Vrednosti ERI u ispitivanoj grupi pozitivno koreliraju sa paratiroidnim hormonom, a negativno sa vrednostima leukocita i indeksom telesne mase.</p> / <p>Chronic kidney disease (CKD) is a global health problem not so much because of its massiveness, as a chronic, progressive course and association with significant comorbidities. Anemia associated with the CKD leads to reduced quality of life, increase in cardiovascular morbidity, cognitive impairment, an increase in the number of hospitalizations and increased mortality. The incidence of anemia increases with the progression of CKD, and in the fifth stage affects almost all the patients. Hepcidin is a central regulator of iron metabolism in the body, which may affect the development and treatment of anemia in CKD. The aim of this study was to determine the level of hepcidin in the patients, as well as its association with parameters of iron metabolism, markers of inflammation and response to erythropoiesis-stimulating agents (ESA). Also, we wanted to determine what factors influence the level of hemoglobin in the study population, as well as what affects the erythropoietin resistance index (ERI). The study included 77 patients who were treated with chronic hemodialysis for at least three months prior to inclusion in the study. Serum hepcidin levels were determined by the ELISA procedure. Other test data were obtained by anamesis, physical examination, analysis of medical history and standard laboratory tests. In our study we have found a positive correlation between serum levels of hepcidin and interleukin-6, while the other parameters of inflammation did not correlate with the level of hepcidin. Serum hepcidin levels were positively correlated values of serum iron, ferritin, transferring saturation, and negatively correlated with transferring and total iron binding capacity. Serum hepcidin levels positively correlated with average weekly dose of ESA. There was no correlation with ERI, the total length of treatment with ESA, as well as the type of ESA. Of all the tested parameters that were significantly correlated with the level of hepcidin in serum, multivariate analysis has allocated only ferritin level as a significant and independent factor. The hemoglobin in the blood of the patients involved in the study, positively correlated with the values of the white cell count and serum albumin. ERI values in the study group positively correlated with parathyroid hormone, and negatively with the values of leukocytes and body mass index.</p>

<p>Anemija predstavlja problem svetskih razmera sa značajnim zdravstvenim, socijalnim i ekonomskim konsekvencama. Iako je pre mnogo godina prepoznata kao javnozdravstveni problem, malo je učinjeno u uspostavljanju kontrole anemije i prevalenca je ostala neprihvatljivo visoka. Deficit gvožđa predstavlja najče&scaron;ći uzrok anemije, deca uzrasta od 6-24 meseca i adolescenti predstavljaju vulnerabilne grupe. Hepcidin je peptidni hormon niske molekularne težine koji ima ključnu ulogu u metabolizmu gvožđa. Cilj istraživanja je bio da se odredi serumska koncentracija hepcidina kod dece uzrasta od 6 meseci do 2 godine i adolescenata uzrasta od 11 do 19 godina koji boluju od sideropenijske anemije i uporedi sa serumskim koncentracijama hepcidina u kontrolnim grupama, kao i da se utvrdi njegova povezanost sa parametrima metabolizma gvožđa. Ispitivanjem je obuhvaćeno ukupno 173 ispitanika, 89 ispitanika koji su bolovali od sideropenijske anemije i 84 ispitanika koji nisu bolovali od sideropenijske anemije i koji su predstavljali kontrolnu grupu. Svim ispitanicima je venepunkcijom uzorkovana krv za određivanje kompletne krvne slike i prametara metabolizma gvožđa. ELISA metodom je određen nivo hepcidina u serumu. Ispitivanjem je utvrđeno da je koncentracija hepcidina statistički značajno niža u dece i adolescenata koji boluju od sideropenijske anemije u poređenju sa decom i adolescentima koji ne boluju od sideropenijske anemije. Potvrđena je pozitivna korelacija između koncentarcije serumskog hepcidina i gvožđa u serumu, feritina, srednjeg volumena eritrocita i saturacije transferina, a negativna korelacija između koncentracije serumskog hepcidina i transferina i broja retikulocita. Koncentracija transferina i nezasićeni kapacitet vezivanja gvožđa, ukupni kapacitet za vezivanje gvožđa i broj retikulocita su međusobno u pozitivnoj korelaciji, a korelacija koncentracije transferina sa parametrima saturacija transferina, koncentracije gvožđa i hemoglobina je negativna. Na vrednost serumskog hepcidina ne utiču niti pol niti uzrast ispitanika &scaron;to ga čini senzitivnijim pokazateljem stanja gvožđa u organizmu i pouzdanijim biolo&scaron;kim markerom u dijagnostici sideropenijske anemije.</p> / <p>Anemia represents a worldwide problem which leads to substantial health, social and economic issues. Although it was identified as a common health problem many years ago, not a lot has been done in controlling anemia and its prevalence has stayed unacceptably high. The iron deficit is the most frequent cause of anemia, 6-24 month-old children and adolescents are vulnerable groups. Hepcidin is a peptide hormone of a low molecular weight which has a main role in the iron metabolism. The aim of the research was to determine the serum concentration of hepcidin in children aged from 6 months to 2 years and in adolescents from the age of 11 to 19 which suffer from iron deficiency anemia and compare it with the serum concentration of hepcidin in the control groups, as well as to determine its connection with the parameters of the iron metabolism. The research included 173 examinees, 89 of them suffered from iron deficiency anemia and 84 did not suffer from iron deficiency anemia. The latter represented the control group. All the examinees had their blood sampled intravenously in order for full blood count results and parameters of iron metabolism to be determined. Also, ELISA method was used for establishing the level of hepcidin in the serum. The research showed that the concentration of hepticin is statistically lower in children and adolescents who suffer from iron deficiency anemia in comparison with children and adolescents who do not have this condition. The positive correlation between the level of serum hepcidin and iron in the serum, ferritin, the medium volume of erythrocytes and transferrin saturation was confirmed but the negative one occurred in the level of the serum hepcidin, transferrin and reticulocyte. Transferrin and the unsaturated capacity of iron binding, the total capacity of iron binding and reticulocytes are in a positive correlation but the correlation of transferrin with the parameters of transferrin saturation, iron and hemoglobin is negative. The sex and the age of the examinees do not influence the level of serum hepcidin which makes it a more sensitive indicator of the level of iron in the body. Besides this, serum hepcidin is a reliable biological marker in the iron deficiency anemia diagnosis.</p>

Introdução: A hiperferritinemia (HF) pode refletir o estado inflamatório do paciente com doença hepática gordurosa não alcoólica (DHGNA) e obesidade, porém em cerca de 33% reflete uma real sobrecarga de ferro hepática. A síndrome dismetabólica relacionada ao depósito de ferro (SDDF) é caracterizada por HF, saturação de transferrina normal, alterações metabólicas e um discreto depósito de ferro hepático. O método padrão ouro para o diagnóstico de sobrecarga de ferro é a biópsia hepática. Por se tratar de método invasivo, novos métodos se tornam necessários. Dentre eles a ressonância nuclear magnética (RM) é o mais disponível. Pacientes e Métodos: O presente estudo avaliou pacientes com HF, excesso de peso, e DHGNA comprovada por biópsia hepática. Os pacientes realizaram RM pela técnica de relaxometria (análise de gordura/ferro - máquina 3T), dosagem de marcadores inflamatórios (IL-6 e TNF-alfa), análise da expressão das subunidades da ferritina (FP - cadeia pesada e FL - cadeia leve) e dosagem de hepcidina. Os dados foram comparados com a biópsia hepática. Estes pacientes foram classificados segundo os níveis de ferritina e siderose. Foram classificados em ferritina normal (FN), hiperferritinemia dismetabólica (HFD) e SDDF. O grupo de FN foi caracterizado por ferritina < 200 ng/mL em mulheres e 300 ng/mL em homens, já os pacientes do grupo HFD têm níveis elevados de ferritina e ausência de siderose hepática. Os pacientes também foram avaliados considerando somente a siderose hepática. Resultados: Foram avaliados 152 pacientes com DHGNA comprovada pela biópsia hepática, sendo 67 incluídos no estudo. A frequência de SDDF e HFD foi de 37% e 16%, respectivamente. O nível de corte da ferritina sérica, a fim de identificar depósito de ferro, foi de 180.4 ng/mL para mulheres (sensibilidade de 76,9%, especificidade de 64,3%) e 350,7 ng/mL para homens (sensibilidade de 72,7% e especificidade de 75,5%). Os pacientes com SDDF E HFD não apresentaram piores características metabólicas e histológicas. Os níveis de hepcidina foram maiores nos grupos SDDF E HFD, se correlacionando com o conteúdo de ferro hepático quando > 30,2 ng/mL. Os marcadores inflamatórios (IL-6 e TNF-alfa) foram semelhantes entre os grupos. A expressão de FP e FL se comportaram de modo semelhante entre os grupos. A FL se correlacionou com síndrome metabólica e circunferência abdominal, enquanto a FP se correlaciona com níveis maiores de esteatose. A RM foi capaz de identificar o conteúdo de ferro destes pacientes, sendo o ponto de corte de R2* 58,9s-1. A porcentagem de gordura, identificada pela RM, foi de 17% nos grupos HFD e SDDF e de 13% no grupo FN. Conclusão: 1) RM utilizando a técnica de relaxometria com correção da interferência de gordura se mostrou acurado na avaliação de discreto depósito de ferro em pacientes com SDDF; 2) HF pode refletir depósito de ferro hepático quando acima de 180,4 ng/mL para mulheres e 350,7 ng/mL para homens, não foi encontrada relação entre HF e características piores metabólicas ou histológicas; 3) FL se correlacionou com síndrome metabólica e circunferência abdominal, enquanto a FP se correlaciona com esteatose; 4) Hepcidina se correlacionou com siderose e ferritina sérica nos pacientes com DHGNA / Introduction: Hyperferritinemia (HF) may reflect the inflammatory status of patients with NAFLD and obesity, but about 33 % reflects a real hepatic iron overload. The dysmetabolic iron overload syndrome (DIOS) definition is HF, normal transferrin saturation, and mild hepatic iron overload in a patient with metabolic disorders. The gold standard for diagnosis of iron overload is the liver biopsy. As it is an invasive method, new methods are necessary. Among them, magnetic resonance imaging (MRI) is the most available one. Patients and Methods: This study evaluated patients with HF, overweight and NAFLD. All patients were submitted to liver biopsy. MRI relaxometry (fat/iron analysis - 3T machine), measurement of inflammatory markers (TNF-alpha and IL-6), analysis of the expression of ferritin light and heavy chain subunits (FL and FP) and serum hepcidin were held. Data were correlated with liver biopsy. The patients were classified considering the ferritin levels and siderosis. They were classified in three groups: normal ferritin (NF), dysmetabolic hyperferrinemia (DHF) and DIOS. The NF group has serum ferritin (SF) below 200 ng/dL for women and 300 ng/dL for men, DHF must have SF above those values and negative siderosis, and DIOS have hyperferritinemia and positive siderosis. They are also classified considering only the iron status Results: 152 biopsy-proven NAFLD patients were screened but only 67 were included in this study. DIOS and HFD frequency in our sample were 37% and 16%, respectively. The cut-off of ferritin levels were correlated with iron overload in liver biopsy was 180.4 ng/mL for women (sensibility of 76.9% and specificity of 64.3%) and 350 ng/mL for men (sensibility of 72.7% and specificity of 75.5%). Although, DHF and DIOS patients did not have worst metabolic or histological characteristics, hepcidin levels were higher in DHF and DIOS groups, correlating with hepatic siderosis when hepcidin is above 30,2 ng/mL. The inflammatory markers (IL- 6 and TNF-alpha) were similar among the groups. The expression of FP and FL were similar in role sample. FL correlates with metabolic syndrome and abdominal circumference, while FP correlates with in higher fat scores. The MRI was able to identify mild iron overload. The R2* cut off level was 58,9 s -1. The fat percentage in DIOS and HFD was of 17% each and in NF 13%. Conclusion: 1) MRI using relaxometry method is accurate to evaluate mild iron overload in DIOS patients; 2) HF may reflect iron overload when above 180.4 ng/mL for women and 350.7 ng/mL for men, however, this study didn´t find correlation between HF and insulin resistance and worst NAFLD histological characteristics; 3) FL correlates with metabolic syndrome and abdominal circumference while FP correlates with in higher fat scores 4) Hepcidin correlates with iron and serum ferritin in NAFLD patients

Introdução: A hiperferritinemia (HF) pode refletir o estado inflamatório do paciente com doença hepática gordurosa não alcoólica (DHGNA) e obesidade, porém em cerca de 33% reflete uma real sobrecarga de ferro hepática. A síndrome dismetabólica relacionada ao depósito de ferro (SDDF) é caracterizada por HF, saturação de transferrina normal, alterações metabólicas e um discreto depósito de ferro hepático. O método padrão ouro para o diagnóstico de sobrecarga de ferro é a biópsia hepática. Por se tratar de método invasivo, novos métodos se tornam necessários. Dentre eles a ressonância nuclear magnética (RM) é o mais disponível. Pacientes e Métodos: O presente estudo avaliou pacientes com HF, excesso de peso, e DHGNA comprovada por biópsia hepática. Os pacientes realizaram RM pela técnica de relaxometria (análise de gordura/ferro - máquina 3T), dosagem de marcadores inflamatórios (IL-6 e TNF-alfa), análise da expressão das subunidades da ferritina (FP - cadeia pesada e FL - cadeia leve) e dosagem de hepcidina. Os dados foram comparados com a biópsia hepática. Estes pacientes foram classificados segundo os níveis de ferritina e siderose. Foram classificados em ferritina normal (FN), hiperferritinemia dismetabólica (HFD) e SDDF. O grupo de FN foi caracterizado por ferritina < 200 ng/mL em mulheres e 300 ng/mL em homens, já os pacientes do grupo HFD têm níveis elevados de ferritina e ausência de siderose hepática. Os pacientes também foram avaliados considerando somente a siderose hepática. Resultados: Foram avaliados 152 pacientes com DHGNA comprovada pela biópsia hepática, sendo 67 incluídos no estudo. A frequência de SDDF e HFD foi de 37% e 16%, respectivamente. O nível de corte da ferritina sérica, a fim de identificar depósito de ferro, foi de 180.4 ng/mL para mulheres (sensibilidade de 76,9%, especificidade de 64,3%) e 350,7 ng/mL para homens (sensibilidade de 72,7% e especificidade de 75,5%). Os pacientes com SDDF E HFD não apresentaram piores características metabólicas e histológicas. Os níveis de hepcidina foram maiores nos grupos SDDF E HFD, se correlacionando com o conteúdo de ferro hepático quando > 30,2 ng/mL. Os marcadores inflamatórios (IL-6 e TNF-alfa) foram semelhantes entre os grupos. A expressão de FP e FL se comportaram de modo semelhante entre os grupos. A FL se correlacionou com síndrome metabólica e circunferência abdominal, enquanto a FP se correlaciona com níveis maiores de esteatose. A RM foi capaz de identificar o conteúdo de ferro destes pacientes, sendo o ponto de corte de R2* 58,9s-1. A porcentagem de gordura, identificada pela RM, foi de 17% nos grupos HFD e SDDF e de 13% no grupo FN. Conclusão: 1) RM utilizando a técnica de relaxometria com correção da interferência de gordura se mostrou acurado na avaliação de discreto depósito de ferro em pacientes com SDDF; 2) HF pode refletir depósito de ferro hepático quando acima de 180,4 ng/mL para mulheres e 350,7 ng/mL para homens, não foi encontrada relação entre HF e características piores metabólicas ou histológicas; 3) FL se correlacionou com síndrome metabólica e circunferência abdominal, enquanto a FP se correlaciona com esteatose; 4) Hepcidina se correlacionou com siderose e ferritina sérica nos pacientes com DHGNA / Introduction: Hyperferritinemia (HF) may reflect the inflammatory status of patients with NAFLD and obesity, but about 33 % reflects a real hepatic iron overload. The dysmetabolic iron overload syndrome (DIOS) definition is HF, normal transferrin saturation, and mild hepatic iron overload in a patient with metabolic disorders. The gold standard for diagnosis of iron overload is the liver biopsy. As it is an invasive method, new methods are necessary. Among them, magnetic resonance imaging (MRI) is the most available one. Patients and Methods: This study evaluated patients with HF, overweight and NAFLD. All patients were submitted to liver biopsy. MRI relaxometry (fat/iron analysis - 3T machine), measurement of inflammatory markers (TNF-alpha and IL-6), analysis of the expression of ferritin light and heavy chain subunits (FL and FP) and serum hepcidin were held. Data were correlated with liver biopsy. The patients were classified considering the ferritin levels and siderosis. They were classified in three groups: normal ferritin (NF), dysmetabolic hyperferrinemia (DHF) and DIOS. The NF group has serum ferritin (SF) below 200 ng/dL for women and 300 ng/dL for men, DHF must have SF above those values and negative siderosis, and DIOS have hyperferritinemia and positive siderosis. They are also classified considering only the iron status Results: 152 biopsy-proven NAFLD patients were screened but only 67 were included in this study. DIOS and HFD frequency in our sample were 37% and 16%, respectively. The cut-off of ferritin levels were correlated with iron overload in liver biopsy was 180.4 ng/mL for women (sensibility of 76.9% and specificity of 64.3%) and 350 ng/mL for men (sensibility of 72.7% and specificity of 75.5%). Although, DHF and DIOS patients did not have worst metabolic or histological characteristics, hepcidin levels were higher in DHF and DIOS groups, correlating with hepatic siderosis when hepcidin is above 30,2 ng/mL. The inflammatory markers (IL- 6 and TNF-alpha) were similar among the groups. The expression of FP and FL were similar in role sample. FL correlates with metabolic syndrome and abdominal circumference, while FP correlates with in higher fat scores. The MRI was able to identify mild iron overload. The R2* cut off level was 58,9 s -1. The fat percentage in DIOS and HFD was of 17% each and in NF 13%. Conclusion: 1) MRI using relaxometry method is accurate to evaluate mild iron overload in DIOS patients; 2) HF may reflect iron overload when above 180.4 ng/mL for women and 350.7 ng/mL for men, however, this study didn´t find correlation between HF and insulin resistance and worst NAFLD histological characteristics; 3) FL correlates with metabolic syndrome and abdominal circumference while FP correlates with in higher fat scores 4) Hepcidin correlates with iron and serum ferritin in NAFLD patients