Research advances in ferroptosis in the pathogenesis and treatment of nonalcoholic fatty liver disease / 临床肝胆病杂志

Ferroptosis is a pattern of non-apoptotic cell death characterized by iron dependence and lipid peroxidation. Nonalcoholic fatty liver disease (NAFLD) is a metabolic disease with fat infiltration as its main pathological feature, and it is closely associated with insulin resistance and genetic susceptibility. The mechanism of transition from hepatic steatosis alone to steatohepatitis remains unclear, and studies have shown that ferroptosis in hepatocytes may be the trigger for the inflammatory initiation of steatohepatitis. This article reviews the role of abnormal iron metabolism and lipid peroxidation in promoting the development and progression of NAFLD and summarizes the application prospect of ferroptosis-related inhibitors in the treatment of NAFLD.

Effects of iron metabolism and oxidative stress level on blood glucose control during pregnancy in patients with gestational diabetes mellitus / 中国基层医药

Objective:To investigate the effects of iron metabolism and oxidative stress level on blood glucose control during pregnancy in patients with gestational diabetes mellitus (GDM).Methods:A total of 139 pregnant women who received prenatal examination between January 2020 and June 2021 in Wenzhou Central Hospital were included in this study. They were divided into GDM group ( n = 68) and control group ( n = 71) according to oral glucose tolerance test results at 24-48 weeks of gestation. Clinical data were collected. Iron metabolism, oxidative stress and blood glucose levels were measured. The relationships between iron metabolism and oxidative stress levels and blood glucose control in GDM were analyzed. Results:There was no significant difference in age between the GDM and control groups ( P > 0.05). Body mass index, fasting blood glucose, fasting insulin, glycosylated hemoglobin, nuclear factor-κB (NF-κB), malondialdehyde (MDA), ferritin (SF), serum iron, transferrin (TRF) and insulin resistance index (IRI) in the GDM group were (24.11 ± 3.05) kg/m 2, (4.92 ± 0.67) mmol/L, (10.56 ± 2.21) pmol/mL, (6.15 ± 0.62)%, (20.50 ± 1.72) μg/L, (20.34 ± 2.92) μmol/L, (70.77 ± 7.01) μg/L, (30.18 ± 4.25) μmol/L, (3.93 ± 0.69) g/L and (2.50 ± 1.03), respectively, which were significantly higher than those in the control group [(21.41 ± 2.86) kg/m 2, (4.69 ± 0.62) mmol/L, (5.76 ± 2.09) pmol/mL, (5.37 ± 0.58)%, (15.43 ± 1.55) μg/L, (12.93 ± 2.17) μmol/L, (42.53 ± 8.86) μg/L, (18.81 ± 3.85) μmol/L, (2.89 ± 0.53) g/L and (1.74 ± 0.89)] ( t = 5.39, 2.10, 13.16, 7.66, 18.27, 17.03, 20.78, 16.54, 9.99, 4.66, all P < 0.05). Superoxide dismutase (SOD), total antioxidant capacity (TAOC) and insulin sensitivity index in the GDM group were (21.49 ± 3.52) U/L, (10.87 ± 1.34) kU/L and (3.28 ± 0.46), respectively, which were significantly lower than those in the control group [(26.28 ± 3.95) U/L, (13.28 ± 1.52) kU/L, (3.86 ± 0.53), t = 7.54, 9.90, 6.88, all P < 0.05]. Multivariate logistic regression analysis revealed that SOD, TAOC, NF-κB, MDA, SF and TRF were independent influential factors of GDM occurrence [ OR (95% CI) = 1.57 (1.09-2.26), 3.15 (1.71-5.80), 2.18 (1.32-3.61), 3.27 (1.58-6.76), 2.12 (1.29-3.50), 1.23 (0.99-1.53), 3.65 (1.89-7.04), all P < 0.05]. SOD and TAOC levels were negatively correlated with IRI ( r = -0.75, -0.84, both P < 0.05), while NF-κB, MDA, SF, serum iron and TRF were positively correlated with IRI ( r = 0.93, 0.96, 0.98, 0.07, 0.92, all P < 0.05). Conclusion:Increased levels of iron metabolism and oxidative stress are risk factors for the occurrence of GDM, and they are closely related to the degree of insulin resistance. GDM screening should be carried out in advance in pregnant women with increased levels of iron metabolism and oxidative stress indicators, which plays a positive role in clinical diagnosis and treatment of GDM.

Brazilian family with hyperferritinemia-cataract syndrome: case report

ABSTRACT Hereditary hyperferritinemia-cataract syndrome is a rare autosomal dominant disease caused by a genetic mutation in the iron responsive element in the 5' untranslated region of the ferritin light chain gene. Hereditary hyperferritinemia-cataract syndrome is characterized by elevated serum ferritin levels and bilateral cataract development early in life and may be misdiagnosed as hemochromatosis. This case report describes a Brazilian family with a clinical diagnosis of hereditary hyperferritinemia-cataract syndrome, which was submitted to ferritin light chain gene sequencing. The genetic mutation c.-164C>G was identified in the 5' untranslated region. In conclusion, genetic testing can be used for accurate diagnosis of hereditary hyperferritinemia-cataract syndrome to avoid misdiagnosis of hemochromatosis, other diseases associated with iron overload or ophthalmic diseases.

The strategy change of targeting iron homeostasis for leukemia therapy: from iron chelation to iron overload as a therapeutic strategy to induce ferroptosis / 白血病·淋巴瘤

Iron, an indispensable element for life, is involved in all kinds of vital physiological activities. Due to its potential toxicity, the body has a strict regulation mechanism of iron metabolism to maintain the "iron homeostasis". Dysregulation of iron metabolism and subsequent accumulation of excess iron are closely associated with the development and progression of leukemia. Specifically, due to the pro-oxidative nature of iron and its damaging effects on DNA, excess iron promotes the progression of leukemia; on the other hand, leukemia cells need to obtain more iron than normal cells to maintain rapid growth and proliferation, which is known as "iron addiction". Iron chelators can remove iron in leukemia cells and induce differentiation and apoptosis of leukemia cells. However, "iron addiction" makes leukemia cells more susceptible to iron overload, and is more sensitive to a new form of iron-catalyzed cell death which was named ferroptosis. According to the different needs of leukemia cells and normal cells for iron, the method of selectively killing leukemia cells through iron overload may become a new strategy for leukemia treatment. This paper reviews the strategy of targeting iron homeostasis for leukemia therapy.

A study on the relationship between serum transferrin and prognosis of elderly patients with sepsis / 中华老年医学杂志

Objective:To investigate the relationship between serum transferrin(TRF)and the characteristics and prognosis of elderly patients with sepsis.Methods:A retrospective analysis was conducted on 49 elderly patients with sepsis treated at the Department of Critical Medicine and the Department of Respiratory and Critical Medicine of the First Affiliated Hospital of Suzhou University between October 2020 and March 2022 who had met the inclusion criteria.These patients were divided into a shock group(n=18)and a non-shock group(n=31); Based on outcomes, they were also divided into a death group(n=16)and a survival group(n=33).Through the random number table method, 30 healthy elderly people from the physical examination center of our hospital were selected as the control group.TRF and ferritin(SF)were measured on the 1st, 3rd and 7th day after admission, and the correlation between TRF and the sequential organ failure assessment score(SOFA)was analyzed.The predictive value of TRF on prognosis was evaluated via the receiver operating characteristic curve.Finally, the influence of multiple factors on prognosis was analyzed using the binary logistic regression model.Results:Compared with the control group at admission, SF levels of elderly patients with sepsis increased[709.20(402.40, 2000.00)μg/L vs.102.05(79.55, 199.75)μg/L, Z=-5.482, P<0.01], but TRF levels decreased[1.43(1.12, 1.72)g/L vs.2.23(1.80, 3.12)g/L, Z=5.395, all P<0.01], with statistical significance.On the 3rd and 7th day, TRF levels in the shock group were lower than in the non-shock group[(1.25±0.35)g/L vs.(1.55 ±0.51)g/L, 1.15(9.68, 1.34)g/L vs.1.56(1.19, 2.03)g/L]( t=-2.186, Z=3.258, P<0.05).There was a linear correlation between TRF and SOFA score on the 1st, 3rd and 7th day( R2=0.177, 0.176, 0.275, all P<0.01).TRF levels in the death group were lower than in the survival group on the 3rd and 7th day( Z=2.208, 3.423, P<0.05 for both).TRF levels on the 3rd and 7th day in elderly patients with sepsis had predictive value in evaluating the prognosis[area under receiver operating characteristic curve( AUC)values=0.696, 0.804, P<0.05, P<0.01].The survival curves based upon the best cutoff values(TRF=1.085 g/L on the 3rd day, TRF=1.330 g/L on the 7th day)between the two groups were statistically significantly( χ2=10.903, 13.318, P<0.01 for both).With TRF<1.085 g/L on the 3rd day, the risk of death in elderly patients with sepsis on the 28th day was 9.388 times the usual risk( OR=9.388, P<0.01), and with TRF<1.330 g/L on the 7th day, the risk of death was 14.625 times the usual risk on the 28th day( OR=14.625, P<0.01). Conclusions:Increased SF in elderly patients with sepsis is not related to disease severity, but the level of TRF is related to disease severity, and the level of TRF on the 3rd and 7th day is related to the prognosis and is an independent risk factor for all-cause death on the 28th day.

Hereditary hemochromatosis associated with the development of liver cirrhosis / Hemocromatose hereditária associada ao desenvolvimento da cirrose hepática

ABSTRACT Hereditary hemochromatosis (HH) is an autosomal recessive disease, most often associated with mutations in the HFE gene, which result in continuous absorption of iron, causing its overload. Liver tissue is the main site of iron deposition; thus, high levels of iron, when interacting with oxygen, induce the formation of free radicals that will act on proteins, lipids, and deoxyribonucleic acid (DNA), which may trigger deleterious effects at cellular and tissue levels. In order to elucidate the development and progression of liver cirrhosis due to iron overload, the purpose of this study is to describe the pathophysiology of the hepatic system in patients diagnosed with HH. For this purpose, searches for scientific articles were carried out in the main academic databases. We found that patients diagnosed with HH are more likely to develop liver cirrhosis, since chronic iron deposition in liver tissue induces injury and consequent tissue regeneration, progressing to collagen fibers synthesis surrounding the hepatocytes, leading to loss of liver function and development of cirrhosis. Therefore, it is necessary to carry out tests such as iron, ferritin and transferrin measurements, to evaluate body's iron stores, aiming at an early diagnosis of iron overload, thus avoiding deleterious damage at cellular and tissue levels.

RESUMEN La hemocromatosis hereditária (HH) es uma enfermedad autosómica recesiva, asociada, la mayoría de las veces, a mutaciones del gen HFE, que producen absorción continua de hierro, con sobrecarga de esa sustancia. El tejido hepático es el principal sitio de almacenamiento de hierro; así, niveles elevados de hierro, al interactuar con oxígeno, inducen la formación de radicales libres que actuarán sobre proteínas, lípidos y ácido desoxirribonucléico (ADN), pudiendo acarrear efectos dañosos a nível celular y tisular. Para aclarar el mecanismo de desarrollo de la cirrosis hepática debido a sobrecarga de hierro, el objetivo de este estudio es describir la fisiopatologia del sistema hepático en pacientes diagnosticados con HH. Para eso, se efectuaron búsquedas por artículos científicos en los principales bancos de datos acadêmicos. Verificamos que pacientes diagnosticados con HH presentan mayor predisposición a desarrollar cirrosis hepática, porque el depósito crônico de hierro en el tejido hepático causa lesión y consecuente regeneración de tejido, progresando a la formación de fibras de colágeno que rodean los hepatocitos, llevando la pérdida de la función hepática y al desarrollo de la cirrosis. Ante esto, es necesario medir hierro, ferritina y transferrina para evaluación de las provisiones de hierro del cuerpo, buscando un diagnóstico temprano de la sobrecarga de hierro, para evitar efectos deletereos a nível celular y tisular.

RESUMO A hemocromatose hereditária (HH) é uma doença autossômica recessiva, associada, na maioria das vezes, a mutações do gene HFE, que resultam em absorção contínua de ferro, ocasionando a sobrecarga dessa substância. O tecido hepático é o principal sítio de depósito do ferro; dessa forma, níveis elevados de ferro, ao interagir com o oxigênio, induzem a formação de radicais livres que irão agir sobre proteínas, lipídios e ácido desoxirribonucleico (DNA), podendo desencadear efeitos deletérios a níveis celulares e teciduais. Visando elucidar o mecanismo de desenvolvimento da cirrose hepática decorrente da sobrecarga de ferro, o objetivo deste estudo é descrever a fisiopatologia do sistema hepático em pacientes diagnosticados com HH. Para isso, foram realizadas buscas por artigos científicos nos principais bancos de dados acadêmicos. Verificamos que pacientes diagnosticados com HH apresentam maior predisposição de desenvolver cirrose hepática, pois o depósito crônico de ferro no tecido hepático provoca lesão e consequente regeneração tecidual, progredindo para formação de fibras de colágeno que circundam os hepatócitos, levando à perda da função hepática e ao desenvolvimento da cirrose. Diante disso, faz-se necessária a realização de exames como dosagem de ferro, ferritina e transferrina para avaliação dos estoques de ferro do organismo, objetivando um diagnóstico precoce da sobrecarga de ferro, a fim de evitar danos deletérios a níveis celulares e teciduais.

Analysis of Iron Metabolism in Chronic Chagasic Cardiomyopathy / Análise do Metabolismo do Ferro na Cardiomiopatia Chagásica Crônica

Abstract Changes in iron metabolism in heart failure (HF) have been described as an important prognostic marker. To check if the markers of iron kinetics are related to the morbidity and etiology of chagasic cardiomyopathy. Patients with Chronic Chagasic Cardiomyopathy (CCC, n = 40), with indeterminate form (IND, n = 40), besides non-chagasic cardiomyopathy (NCh, n = 40). The mean age was 50.98 ± 5.88 in CCC, 50% were male, 49.68 ± 5.28 in IND, 52.2% were male, and 49.20 ± 10.09 in NCh, 12.5% were male. Lower levels of iron (FeSe) were observed in the CCC groups (93.15 ± 36.53), when compared to IND (125.30 ± 22.79) and NCh (114.77 ± 18.90) (p = 0.0004), lower IST transferrin saturation index in CCC (29.48 ± 6.59), when compared to IND (30.95 ± 7.06) and in the NCh group (39.70 ± 7.54) p = 0.0001), total binding capacity of the lower CTLF iron in the CCC group (297.30 ± 36.46), when compared to the IND group (196.52 ± 56.95) and the NCh group (275.18 ± 33, 48) (p = 0.0001), lower ferritin in the CCC group (134.55, 1.56-42.36), when compared to the IND group (156,25, 1,72-42,20) and the NCh group (112.95, 2.88-42.66) (p = 0.0004). It was also observed that FeSe (95% CI 1.00-1.04, p = 0.0014), IST (95% CI 1.02-1.22) (p = 0.0012) and gender (95% CI 1.07-14.43 p = 0.0038) were independently associated with the degree of ventricular dysfunction in chagasic cardiomyopathy. CCC patients showed greater change in iron metabolism regarding the indeterminate form and other forms of cariomyopathies.

Resumo A alteração do metabolismo do ferro na insuficiência cardíaca (IC) tem sido descrita como um importante marcador prognóstico. Verificar se os marcadores da cinética do ferro guardam relação com a morbidade e a etiologia da cardiomiopatia chagásica. Pacientes com cardiomiopatia chagásica crônica (CCC, n = 40), com a forma indeterminada (IND, n = 40), além de cardiomiopatia não chagásica (NCh, n = 40). A idade média foi de 50,98 ± 5,88 no CCC, 50% eram do sexo masculino, 49,68 ± 5,28 no IND, 52,2% eram do sexo masculino e 49,20 ±10,09 no NCh, 12,5% eram do sexo masculino. Observaram-se níveis de ferro (FeSe) menores no grupos CCC (93,15 ± 36,53), quando comparados ao IND (125,30 ± 22,79) e NCh (114,77 ± 18,90) (p = 0,0004), índice de saturação de transferrina (IST) menor no CCC (29,48 ± 6,59), quando comparado ao IND (30,95 ± 7,06) e no grupo NCh (39,70 ± 7,54) (p= 0,0001), capacidade total de ligação do ferro CTLF menor no grupo CCC (297,30 ± 36,46), quando comparado ao grupo IND (196,52 ± 56,95) e ao grupo NCh (275,18 ± 33,48) (p = 0,0001), ferritina menor no grupo CCC (134,55, 1,56-42,36), quando comparada ao grupo IND (156,25, 1,72 - 42,20) e ao grupo NCh (112,95, 2,88-42,66) (p = 0.0004). Verificou-se também que o FeSe (IC% 95% 1,00-1,04; p = 0,0014), o IST (IC 95% 1,02-1,22) (p = 0,0012) e o sexo (IC 95% 1,07-14,43 p = 0,0038) associaram-se independentemente ao grau de disfunção ventricular na cardiomiopatia chagásica. Os pacientes com CCC demonstraram maior alteração no metabolismo do ferro em relação a forma indeterminada e outras formas de miocardiopatias.

Progress of the relationship between iron metabolism and solid tumors / 肿瘤研究与临床

Iron is an important nutrient element which is involved in a variety of physiological processes. The potential toxicity of excess iron requires that cells should evolve a robust, tightly regulated mechanism for maintaining iron homeostasis. At the same time, iron plays an indispensable role in the process of tumorigenesis and progression. The mechanism involved in iron homeostasis can make changes to adapt to its metabolic level and to maintain the activity of the tumor cells. This paper reviews iron metabolism and its role in the maintaining of iron homeostasis, as well as the importance of iron metabolism in solid cancers.

Progress of the relationship between iron metabolism and solid tumors / 肿瘤研究与临床

Iron is an important nutrient element which is involved in a variety of physiological processes. The potential toxicity of excess iron requires that cells should evolve a robust, tightly regulated mechanism for maintaining iron homeostasis. At the same time, iron plays an indispensable role in the process of tumorigenesis and progression. The mechanism involved in iron homeostasis can make changes to adapt to its metabolic level and to maintain the activity of the tumor cells. This paper reviews iron metabolism and its role in the maintaining of iron homeostasis, as well as the importance of iron metabolism in solid cancers.

Prognostic Impact of Iron Metabolism Changes in Patients with Acute Coronary Syndrome / Impacto Prognóstico das Alterações do Metabolismo do Ferro em doentes com Síndrome Coronária Aguda

Abstract Background: Iron metabolism disorders have been associated with an increased risk of cardiovascular events. However, the prognostic impact on patients (pts) with acute coronary syndrome (ACS) has yet to be clarified. Objective: To determine the prognostic value of serum iron and ferritin levels in pts with ACS in the short and long-term. Methods: Consecutive pts admitted to a coronary care unit with a diagnosis of ACS, for a period of 2 years, were evaluated. The population was divided into tertiles of serum iron and ferritin distribution. The primary adverse events were the occurrence of in-hospital death or heart failure (HF) and death or HF at 1 year of follow-up. Results: We studied 280 pts (73% males; mean age 68 ± 13 years). The mean levels of serum iron and ferritin were 59 ± 34 mcg/dL and 205 ± 185 ng/mL, respectively. Patients included in the 1st tertile of serum iron (≤ 40 mcg/dL) had a higher rate of adverse events, in-hospital and after 1 year. Lower and higher levels of ferritin (1st and 3rd tertiles, ≤ 110; >219 ng/ml, respectively) were associated with a higher incidence of HF during hospitalization and death at 1 year. A ferritin value >316 ng /mL was an independent risk factor for death at 1 year (adjusted OR: 14; 95%CI: 2.6 to 75.9). Conclusion: In this population, iron metabolism alterations were associated with a higher rate of adverse events and higher ferritin levels constituted an independent mortality predictor in the long-term.

Resumo Fundamento: Alterações do metabolismo do ferro têm sido associadas a um aumento do risco de eventos cardiovasculares. No entanto, o impacto prognóstico em doentes (dts) com síndrome coronária aguda (SCA) encontra-se ainda pouco esclarecido. Objetivo: Determinar o valor prognóstico a curto e longo prazo dos níveis séricos do ferro e ferritina em dts com SCA. Métodos: Foram avaliados doentes consecutivos admitidos numa Unidade Coronária com o diagnóstico de SCA no período de 2 anos. A população foi agrupada segundo os tercis de distribuição de ferro e ferritina. Os eventos adversos primários foram a ocorrência de morte intrahospitalar e a 1 ano, bem como, insuficiência cardíaca (IC) intrahospitalar e a 1 ano de follow-up. Resultados: Estudaram-se 280 dts (73% sexo masculino; idade média de 68 ± 13 anos). O nível médio de ferro sérico e de ferritina foi 59 ± 34 mcg/dl e 205 ± 185 ng/ml, respetivamente. Os doentes incluídos no 1º tercil (≤ 40 mcg/dl) de ferro sérico apresentaram maior percentagem de eventos adversos intrahospitalares e a 1 ano. Níveis mais baixos e mais elevados de ferritina (1º e 3º tercil, respetivamente, ≤ 110; > 219 ng/ml) estiveram associados a uma maior ocorrência de IC em internamento e de morte a 1 ano. Um valor de ferritina > 316 ng/mL constituiu fator de risco independente de morte a 1 ano (OR ajustado 14 IC 95% 2,6-75,9). Conclusão: Nesta população alterações do metabolismo do ferro estiveram associadas a uma maior ocorrência de eventos adversos e níveis elevados de ferritina constituíram preditor independente de mortalidade a longo prazo.

Mechanism research progress of iron removal by eltrombopag / 中国医师进修杂志

Eltrombopag is a kind of human thrombopoietin receptor agonist, which is used to treat thrombocytopenia and severe aplastic anemia. In recent years, it highlights the huge advantage in iron removal. It regulates the acidification of glucuronidation in the body, removing it from feces and urine before iron conjugates to the liver, so as to effectively reduce the overload of iron in the body.

Basic Understanding of Iron Metabolism / 임상소아혈액종양

Iron is critical for almost all living organisms because it serves as a cofactor for many proteins and enzymes necessary for oxygen and energy metabolism. Disruption of iron homeostasis is associated with a wide range of diseases. Thus mammals have developed sophisticated mechanisms to maintain optimal range of iron concentration. Iron regulation involves processes at the systemic and cellular levels. These processes are regulated by hepcidin and iron regulatory proteins. Hepcidin modulates systemic iron homeostasis with ability to impede cellular iron export via interaction with the iron export protein, ferroportin. Whereas, iron regulatory proteins control cellular iron homeostasis by translational regulation of proteins which involve iron metabolism. Recent advances in the study of iron metabolism have shown promising results that hepcidin-targeted strategies may help to improve the diagnosis and treatment of iron related diseases. Although these strategies are now under development, ongoing studies can help to elucidate its application possibilities.

Exploration of gender differences in correlation between iron metabolism and bone turnover markers in elderly patients with fragility fractures / 中华老年医学杂志

Objective To explore the gender differences in the association between iron metabolism and bone turnover markers in elderly patients with fragility fracture.Methods A total of 271 patients admitted in our hospital from Aug 2014 to Oct 2017 with osteoporotic fractures were divided into two groups:109 males and 162 females,aged from 60 to 92 years.Both groups were further divided into 3 age groups(60 to 70,71 to 80,and ≥81 year group).Biochemical indicators,serum ferritin and bone turnover markers were detected eight hours after admission.Results In the male group,there were no statistical differences in serum ferritin and serum procollagen type Ⅰ Nterminal propeptide(PINP) among age groups (all P ＞ 0.05).Serum β-carboxy terminal telopeptide of collagen type Ⅰβ-CTX(β-CTX)was elevated with ageing.In the female group,serum ferritin,PINP,and β-CTX were elevated with ageing.There was a significant positive correlation between serum ferritin and β-CTX in two gender groups (all P ＜ 0.05)without gender difference.Gender difference was observed in the correlation between serum ferritin and PINP between two gender groups:a significant positive correlation in the female group (r =0.255,P =0.001)whereas a significant negative correlation in the male group(r=-0.207,P=0.031).Conclusions There are gender differences in correlations of serum ferritin with bone turnover markers.Increased iron accumulation in postmenopausal women is closely correlated with high bone turnover rate.

Characteristics of gene mutation in Chinese patients with hereditary hemochromatosis / 临床肝胆病杂志

ObjectiveTo investigate the characteristics of gene mutation in Chinese patients with hereditary hemochromatosis (HH). MethodsA total of 9 patients with HH who visited Beijing Friendship Hospital, Capital Medical University from January 2013 to December 2015 were enrolled. The genomic DNA was extracted, and PCR amplification and Sanger sequencing were performed for all the exons of four genotypes of HH, i.e., HFE (type Ⅰ), HJV (type ⅡA), HAMP (type ⅡB), TFR2 (type Ⅲ), and SLC40A1 (type Ⅳ) to analyze gene mutations. A total of 50 healthy subjects were enrolled as control group to analyze the prevalence of identified gene mutations in a healthy population. ResultsOf all patients, 2 had H63D mutation of HFE gene in type Ⅰ HH, 1 had E3D mutation of HJV gene in type ⅡA HH, 2 had I238M mutation of TFR2 gene in type Ⅲ HH, and 1 had IVS 3+10 del GTT splice mutation of SLC40A1 gene in type Ⅳ HH. No patients had C282Y mutation of HFE gene in type Ⅰ HH which was commonly seen in European and American populations. Five patients had no missense mutation or splice mutation. In addition, it was found in a family that a HH patient had E3D mutation of HJV gene, H63D mutation of HFE gene, and I238M mutation of TFR2 gene, but the healthy brother and sister carrying two of these mutations did not had the phenotype of HH. ConclusionHH gene mutations vary significantly across patients of different races, and non-HFE-HH is dominant in the Chinese population. There may be HH genes which are different from known genes, and further investigation is needed.

Mechanism of iron metabolism disorder in patients with chronic hepatitis C / 临床肝胆病杂志

Since the liver is the major iron storage organ in human body, iron metabolism disorder is closely related to chronic hepatitis. So far, the mechanisms underlying iron overload in chronic hepatitis C (CHC) have not been fully elucidated. Highly complex regulation of hepcidin relies on a number of variables, including hepatic inflammatory conditions of different stages, transferrin-bound iron circulation, and intracellular iron storage. All these factors are associated with variations in hepatic iron concentrations among patients with hepatitis C virus (HCV)-related chronic liver disease. This paper discusses the regulation of systemic iron homeostasis, the relationship between CHC and iron metabolism disorder, and the mechanism of inducing iron overload. In-depth understanding about iron homeostasis and the relationship between relevant signaling pathways will contribute to the control and therapy of HCV-related diseases.

Nonalcoholic fatty liver disease in severe obese patients, subjected to bariatric surgery / Doenca hepatica gordurosa nao alcoolica em pacientes com obesidade morbida, submetidos a cirurgia bariatrica

Context Nonalcoholic fatty liver disease encompasses a spectrum of histopathological changes that range from simple steatosis to nonalcoholic steatohepatitis. Works suggest that iron (Fe) deposits in the liver are involved in the physiopathology of nonalcoholic steatohepatitis. Objective The aim of this study was to determine the prevalence of simple steatosis and nonalcoholic steatohepatitis in patients with morbid obesity, subjected to bariatric surgery and to establish a correlation of the anatomopathological findings with the presence of liver fibrosis. Methods A total of 250 liver biopsies were conducted in the transoperation of the surgeries. Results Steatosis was present in 226 (90.4%) of the samples, 76 (30.4%) being classified as mild; 71 (28.4%) as moderate and 79 (31.6%) as intense. Nonalcoholic steatohepatitis was diagnosed in 176 (70.4%) cases, where 120 (48.4%) were mild; 50 (20%) were moderate, and 6 (2.4%) cases were intense. Fibrosis was referred to in 108 (43.2%) biopsies, 95 of which (38%) were mild; 2 (0.8%) were moderate; 7 (2.8%) were intense, and cirrhosis was diagnosed in 4 (1.6%) cases. There was a correlation between the degree of steatosis and the level of inflammatory activity (rs = 0.460; P<0.001) and between the degree of this activity and the degree of fibrosis (rs = 0.583; P<0.001). Only 13 (5.2%) samples showed Fe deposits. Conclusion There is a high prevalence of nonalcoholic steatohepatitis in these patients and a positive correlation of the degrees of nonalcoholic steatohepatitis with the intensity of fibrosis. The low prevalence of Fe deposits found makes it questionable that the presence of this ion has any participation in the physiopathogeny of nonalcoholic fatty liver disease. .

Contexto A doença hepática gordurosa não alcoólica engloba um espectro de alterações histopatológicas que abrangem desde a esteatose simples até a esteato-hepatite não alcoólica. Trabalhos sugerem que depósitos de ferro (Fe) no fígado estão envolvidos na fisiopatologia da esteato-hepatite não alcoólica. Objetivo Determinar a prevalência de esteatose simples e de esteato-hepatite não alcoólica nos pacientes com obesidade mórbida, submetidos à cirurgia bariátrica e estabelecer uma correlação dos achados anatomopatológicos com a presença de fibrose hepática. Método Foram analisadas 250 biópsias hepáticas realizadas no transoperatório das cirurgias. Resultados A esteatose esteve presente em 226 (90,4%) das amostras, sendo 76 (30,4%) classificadas como leves; 71 (28,4%), como moderadas e, 79 (31,6%) como intensas. A esteato-hepatite não alcoólica esteato-hepatite não alcoólica foi diagnosticada em 176 (70,4%) dos casos, nos quais 120 (48,4%) eram de grau leve; 50 (20%) moderado e, 6 (2,4%) intenso. A fibrose foi referida em 108 (43,2%) biópsias, das quais 95 (38%) eram leves; 2 (0,8%), moderadas; 7 (2,8%) intensas e, em 4 (1,6%) casos, foi diagnosticado cirrose. Observou-se uma correlação entre o grau de esteatose e o nível de atividade inflamatória (rs = 0,460; P<0,001) e entre o grau dessa atividade com o de fibrose (rs = 0,583; P<0,001). Apenas 13 (5,2%) amostras apresentaram depósitos de Fe. Conclusão Existe uma prevalência elevada de esteato-hepatite não alcoólica nesses pacientes e uma correlação positiva dos graus de esteato-hepatite não alcoólica com a intensidade da fibrose. A baixa prevalência de depósitos de Fe encontrada torna questionável que a presença deste ...

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.

Correlation study between MR quantitative cardiac iron accumulated and serum ferritin, liver iron concentration in patients with β-thalassemia major / 中华放射学杂志

Objective Using MRI-T2 * method to quantify the cardiac iron overload in patients with β-thalassemia major and to evaluate the correlation between cardiac T2 * values and serum ferritin (SF),liver iron concentration(LIC).Methods Fifty-eight over 10 years old transfusion-dependent patients with β-thalassemia major were underwent MRI heart measurement to obtain T2 * values.Spearman rank correlation was used to analyze the relationship between cardiac T2*,SF,and LIC.Patients were divided into two groups based on standard setting (SF ＞2500 μg/L or LIC ＞ 15 mg/g of dry tissue).Differences of cardiac T2 * values between two groups were evaluated by Wilcoxon rank sum test with cardiac T2 * ＜ 20 ms as diagnosis standard.The sensibilities and specificities of prediction for cardiac iron deposition with the index of SF ＞ 2500 μg/L or LIC ＞ 15 mg/g dry tissue were calculated,and receiver operating characteristic (ROC) curve analysis was performed.Results The range (median) of cardiac T2 * values,SF and LIC in 58 patients were 4.7-51.1 ms (14.0 ms),1345-23 640 μg/L (5741 μg/L),9.0-＞43.0 mg/g dry tissue (41.4 mg/g),respectively.There was no linear correlation between cardiac T2 * values and SF (r =-0.240,P =0.070).Cardiac T2 * values and LIC was weakly correlated (r =-0.420,P =0.002).The range (median) of cardiac T2 * values was 6.1-47.6 ms (23.7 ms) in 7 patients of SF ≤ 2500 μg/L group.The range (median) of cardiac T2 * values was 4.7-51.1 ms(13.5 ms) in 51 patients of SF ＞2500 μg/L group.There was no statistically significant difference between two groups (Z =-0.489,P =0.625).The range (median) of cardiac T2 * values was 24.4-51.1 ms (44.8 ms) in 5 patients of the LIC ≤15 mg/g dry tissue group.The range (median) of cardiac T2 * values was 4.7-45.5 ms (13.2 ms) in 53 patients of HIC ＞ 15 mg/g dry tissue group.There was significant difference between T2 * values of the two groups(Z =-2.895,P =0.004).To predict cardiac iron deposition,the sensibilities and specificities were 90.9％ (30/33) and 16.0％ (4/25) for the index of SF ＞2500 μg/L,100.0％ (33/33) and 20.0％(5/25) for LIC ＞ 15 mg/g dry tissue respectively.The areas under the ROC curve were 0.652 with the index of SF and 0.775 with the index of LIC.Conclusions MRI-T2 * method can directly quantify the cardiac iron overload in patients with β-thalassemia major.There is no linear correlation between cardiac T2 * values and SF.Cardiac T2 * values and LIC is weakly correlated.Using SF or LIC as an indirect index to predict cardiac iron deposition is not reliable in clinical.

Effects of manganese exposure on iron metabolism in peripheral blood of exposed population / 解放军医学杂志

Objectives To investigate the adverse effect of manganese exposure on the iron metabolism in peripheral blood of professionally exposed workers. Methods The manganese in air was collected using personal air sampler, and the time weighted average (TWA) concentration of exposure to manganese was then calculated. The subjects were divided into exposure group (n=85) and control group (n=80) based on the exposure doses they received. The concentrations of iron and manganese in the plasma and blood cells of the subjects were determined using flame atomic absorption detector and graphite furnace atomic absorption detector. Serum ferritin, transferrin, transferrin receptor and total iron binding capacity were determined using enzyme linked immunosorbent assay. Results The manganese contents in both plasma and blood cells were much higher in exposure group than in control group (P0.05). It was revealed by linear correlation analysis that no linear correlation existed between the professional exposure time and manganese and iron contents in both plasma and blood cells, serum ferrin, transferrin, transferring receptor and total iron binding capacity (P>0.05). Conclusion The long-term exposure to high dose manganese may result in an imbalance of iron metabolism in the peripheral blood in exposed population, manifesting a decrease of plasma iron and serum transferrin receptors, and an increase of serum transferrin.

Non-HFE hemochromatosis

Hereditary hemochromatosis (HH) is an autosomal recessive disorder classically related to HFE mutations. However, since 1996, it is known that HFE mutations explain about 80% of HH cases, with the remaining around 20% denominated non-HFE hemochromatosis. Nowadays, four main genes are implicated in the pathophysiology of clinical syndromes classified as non-HFE hemochromatosis: hemojuvelin (HJV, type 2Ajuvenile HH), hepcidin (HAMP, type 2B juvenile HH), transferrin receptor 2 (TFR2, type 3 HH) and ferroportin (SLC40A1, type 4 HH). The aim of this review is to explore molecular, clinical and management aspects of non-HFE hemochromatosis.