BACKGROUND It is not easy to identify the cause of various iron overload diseases because the phenotypes overlap.Therefore,it is important to perform genetic testing to determine the genetic background of patients.AIM...BACKGROUND It is not easy to identify the cause of various iron overload diseases because the phenotypes overlap.Therefore,it is important to perform genetic testing to determine the genetic background of patients.AIM To investigate the genetic background of a patient with hemochromatosis complicated by psoriasis on both lower extremities.METHODS Ten years ago,a 61-year-old male presented with iron overload,jaundice,hemolytic anemia and microcytic hypochromic anemia.Computed tomography of the left knee joint showed enlargement of the tibial medullary cavity and thinned bone cortices.Magnetic resonance imaging showed hepatic hemochromatosis,extensive abnormal signals from bone marrow cavities and nodular lesions in the lateral medullary cavity of the upper left lateral tibia.Single photon emission computed tomography showed radial dots of abnormal concentration in the upper end of the left tibia and radial symmetry of abnormal concentrations in joints of the extremities.The patient showed several hot spot mutations of the HFE and G6PD genes detected by next-generation sequencing,but no responsible gene mutation was found.The thalassemia gene was detected by gap-PCR.RESULTS The patient was found to carry the-α4.2 and--SEA deletion mutations of the globin gene.These two mutations are common causes of Southeast Asianα-thalassemia,but rarely cause severe widespread non-transfusion secondary hemochromatosis osteoarthropathy.The simultaneous presence of an auxiliary superposition effect of a rare missense mutation of the PIEZO1 gene(NM_001142864,c.C4748T,p.A1583V)was considered.Moreover,several rare mutations of the IFIH1,KRT8,POFUT1,FLG,KRT2,and TGM5 genes may be involved in the pathogenesis of psoriasis.CONCLUSION The selection of genetic detection methods for hemochromatosis still needs to be based on an in-depth study of the clinical manifestations of the disease.展开更多
Advances in recent years in the understanding of, and the genetic diagnosis of hereditary hemochromatosis (HH) have changed the approach to iron overload he-reditary diseases. The ability to use a radiologic tool (MRI...Advances in recent years in the understanding of, and the genetic diagnosis of hereditary hemochromatosis (HH) have changed the approach to iron overload he-reditary diseases. The ability to use a radiologic tool (MRI) that accurately provides liver iron concentration determination, and the presence of non-invasive sero-logic markers for fibrosis prediction (ser um ferritin, platelet count, transaminases, etc), have diminished the need for liver biopsy for diagnosis and prognosis of this disease. Consequently, the role of liv er biopsy in iron metabolism disorders is changing. Furthermore, the irruption of transient elastography to assess liver stiffness, and, more recently, the ability to determine liver f ibrosis by means of MRI elastography will change this role even more, with a potential drastic decline in hepatic biopsies in years to come. This review will provide a brief summary of the different non-invasive methods available nowadays for diagnosis and prognosis in HH, and point out potential new techniques that could come about in the next years for fibrosis prediction, thus avoiding the need for liver biopsy in a greater number of patients. It is possible that liver biopsy will remain useful for the diagnosis of associated diseases, where other non-invasive means are not po-ssible, or for those rare cases displaying discrepancies between radiological and biochemical markers.展开更多
This review focuses on the management of iron metabolism and iron overload experienced in the hereditary condition, human factors engineering(HFE)-associated hemochromatosis. Hemochromatosis refers to a group of genet...This review focuses on the management of iron metabolism and iron overload experienced in the hereditary condition, human factors engineering(HFE)-associated hemochromatosis. Hemochromatosis refers to a group of genetic diseases that result in iron overload; the major one globally is HFE-associated hemochromatosis. The evolution in understanding of the most common form of hereditary hemochromatosis, being the substation of cysteine to a tyrosine at position 282 in the HFE gene, has been extensively studied Novel mutations in both HFE and non-HFE genes have been indicated in this disease which hold significance in its application for the Asia-Pacific region. In conditions with iron overload, the storage of excess iron in various body tissues leads to complications and toxic damage. The most common presenting complaint for this disease is malaise, lethargy and other non-specific symptoms. In order to diagnose hereditary hemochromatosis, there are biochemical, imaging and genetic testing options. Currently, cascade screening of affected families is preferred over population-level screening. The mainstay of treatment is venesection and the appropriate approach to treatment has been consolidated over the years. Recently, the indications for venesection therapy of hemochromatosis have been challenged and are the subject of ongoing research.展开更多
Juvenile hemochromatosis(JH) is a rare condition classified as an autosomal recessive disorder that leads to severe iron absorption. JH usually affects people under the age of 30 and presents symptoms such as chronic ...Juvenile hemochromatosis(JH) is a rare condition classified as an autosomal recessive disorder that leads to severe iron absorption. JH usually affects people under the age of 30 and presents symptoms such as chronic liver damage,hypogonadotropic hypogonadism,cardiac diseases and endocrine dysfunctions. The present case reports a 29-year-old Brazilian woman with JH condition due to HAMP mutation(g.47G>A),treated with phlebotomies and deferasirox. She presented symptoms such as weakness,skin hyperpigmentation,joint pain in the shoulders and hands and amenorrhea. First laboratory tests showed altered biochemical parameters [serum ferritin(SF): 5696 ng/mL,transferrin saturation(TS): 85%]. After sessions of phlebotomies(450 mL every 15 d),the patient presented partial symptomatic improvements and biochemical parameters(SF: 1000 ng/mL,Hb: 11 g/dL). One year later,deferasirox(15 mg/kg per day) was introduced to the treatment,and the patient showed total symptomatic improvement,with significant clearing of the skin,SF: 169 ng/mL,and TS: 50%. Furthermore,after the combined deferasirox-phlebotomy therapy,magnetic resonance imaging measurements revealed normalized level for liver iron(30 μmol/g; reference value < 36 μmol/g). In conclusion,combined deferasirox-phlebotomy treatment was able to normalize iron levels and improve symptoms.展开更多
BACKGROUND Patients with hepatitis C virus(HCV) and hepatocellular carcinoma(HCC) may or not develop iron overload(IO),which is associated with worst prognosis,because can cause serious damage to organs.HFE gene contr...BACKGROUND Patients with hepatitis C virus(HCV) and hepatocellular carcinoma(HCC) may or not develop iron overload(IO),which is associated with worst prognosis,because can cause serious damage to organs.HFE gene controls the iron uptake from gut,particularly in patients with hereditary hemochromatosis(HH).AIM To identify associations between HFE coding region in patients exhibiting hereditary hemochromatosis and in diseases associated with acquired IO.METHODS We sequenced exons 2 to 5 and boundary introns of HFE gene,evaluating all polymorphic sites in patients presenting hereditary(hemochromatosis) or acquired iron overload HCV and HCC) and in healthy controls,using Sanger sequencing.We also determined the ensemble of extended haplotype in healthy control individuals,including several major histocompatibility complex loci,using sequence specific probes.Haplotype reconstruction was performed using the Arlequin and Phase softwares,and linkage disequilibrium(LD) between histocompatibility loci and HFE gene was performed using the Haploview software.RESULTS The HFE*003 allele was overrepresented(f = 71%) and HFE*001 allele was underrepresented(f = 14%) in HH patients compared to all groups.A strong linkage disequilibrium was observed among the H63 D-G,IVS2(+4)-C and C282 YG gene variants,particularly in HH;however,the mutation IVS2(+4)T>C was not directly associated with HH susceptibility.The HFE*001/HFE*002 genotype conferred susceptibility to HCC in HCV patients exhibiting IO(P = 0.02,OR =14.14).Although HFE is telomeric to other histocompatibility genes,the H63 DG/IVS2(+4)-C(P ≤ 0.00001/P ≤ 0.0057) combination was in LD with HLA-B*44 allele group in healthy controls.No LD was observed between HFE alleles and other major histocompatibility loci.CONCLUSION A differential HFE association was observed for HH and for diseases associated with acquired IO(HCV,HCC).Since HFE is very distant from other histocompatibility loci,only weak associations were observed with these alleles.展开更多
BACKGROUND Hereditary hemochromatosis(HH)has an increased risk of hepatocellular cancer(HCC)both due to genetic risks and iron overload as iron overload can be carcinogenic;HH impacts the increasing risk of HCC,not on...BACKGROUND Hereditary hemochromatosis(HH)has an increased risk of hepatocellular cancer(HCC)both due to genetic risks and iron overload as iron overload can be carcinogenic;HH impacts the increasing risk of HCC,not only through the development of cirrhosis but concerning hepatic iron deposition,which has been studied further recently.AIM To evaluate HH yearly trends,patient demographics,symptoms,comorbidities,and hospital outcomes.The secondary aim sheds light on the risk of iron overload for developing HCC in HH patients,independent of liver cirrhosis complications.The study investigated HH(without cirrhosis)as an independent risk factor for HCC.METHODS We analyzed data from National Inpatient Sample(NIS)Database,the largest national inpatient data collection in the United States,and selected HH and HCC cohorts.HH was first defined in 2011 International Classification of Disease-9th edition(ICD-9)as a separate diagnosis;the HH cohort is extracted from January 2011 to December 2019 using 275.01(ICD-9)and E83.110(ICD-10)diagnosis codes of HH.Patients were excluded from the HH cohort if they had a primary or secondary diagnostic code of cirrhosis(alcoholic,non-alcoholic,and biliary),viralhepatitis,alcoholic liver disease,non-alcoholic fatty liver disease(NAFLD),and non-alcoholic steatohepatitis(NASH).We removed these patients from the HH cohort to rule out bias or ICD-10 diagnostic errors.The HCC cohort is selected from January 2011 to December 2019 using the ICD-9 and ICD-10 codes of HCC.We selected a non-HCC cohort with the 1:1 fixed ratio nearest neighbor(greedy)propensity score method using the patients'age,gender,and race.We performed multivariate analysis for the risk factors of HCC in the HCC and non-HCC matched cohort.We further analyzed HH without cirrhosis(removing HH patients with a diagnosis of cirrhosis)as an independent risk factor of HCC after adjusting all known risk factors of HCC in the multivariate model.RESULTS During the 2011-2019 period,a total of 18031 hospitalizations with a primary or secondary diagnosis of HH(excluding liver diseases)were recorded in the NIS database.We analyzed different patients’characteristics,and we found increments in inpatient population trend with a Ptrend<0.001 and total hospital cost of care trend from$42957 in 2011 to$66152 in 2019 with a Ptrend<0.001 despite no change in Length of Stay over the last decade.The multivariate analyses showed that HH without cirrhosis(aOR,28.8;95%CI,10.4–80.1;P<0.0001),biliary cirrhosis(aOR,19.3;95%CI,13.4–27.6;P<0.0001),non-alcoholic cirrhosis(aOR,17.4;95%CI,16.5–18.4;P<0.0001),alcoholic cirrhosis(aOR,16.9;95%CI,15.9–17.9;P<0.0001),hepatitis B(aOR,12.1;95%CI,10.85–13.60;P<0.0001),hepatitis C(aOR,8.58;95%CI,8.20–8.98;P<0.0001),Wilson disease(aOR,4.27;95%CI,1.18–15.41;P<0.0001),NAFLD or NASH(aOR,2.96;95%CI,2.73–3.20;P<0.0001),alpha1-antitrypsin deficiency(aOR,2.10;95%CI,1.21–3.64;P<0.0001),diabetes mellitus without chronic complications(aOR,1.17;95%CI,1.13–1.21;P<0.0001),and blood transfusion(aOR,1.80;95%CI,1.69–1.92;P<0.0001)are independent risk factor for liver cancer.CONCLUSION Our study showed an increasing trend of in-hospital admissions of HH patients in the last decade.These trends were likely related to advances in diagnostic approach,which can lead to increased hospital utilization and cost increments.Still,the length of stay remained the same,likely due to a big part of management being done in outpatient settings.Another vital part of our study is the significant result that HH without cirrhosis is an independent risk factor for HCC with adjusting all known risk factors.More prospective and retrospective large studies are needed to re-evaluate the HH independent risk in developing HCC.展开更多
We report the case of a 7 years old girl with Juvenile Hemochromatosis, due to homozygous mutation of HJV, which had increased serum iron indices and liver iron overload in the absence of any clinical sign of disease....We report the case of a 7 years old girl with Juvenile Hemochromatosis, due to homozygous mutation of HJV, which had increased serum iron indices and liver iron overload in the absence of any clinical sign of disease. Oral iron chelation with low dose deferasirox showed good efficacy and no side effects. The oral iron chelator deferasirox could be a valid option for removing excess iron in early Juvenile Hemochromatosis.展开更多
Objective: To evaluate the auditory function of an individual with genetically confirmed hemochromatosis.Methods: A 57 year old male with mildly impaired sound detection thresholds underwent a range of behavioural, el...Objective: To evaluate the auditory function of an individual with genetically confirmed hemochromatosis.Methods: A 57 year old male with mildly impaired sound detection thresholds underwent a range of behavioural, electroacoustic and electrophysiologic assessments. These included the recording of otoacoustic emissions and auditory brainstem responses, measurement of monaural temporal resolution and evaluation of binaural speech processing. Findings for this patient were subsequently compared with those of 80 healthy controls with similar audiometric thresholds.Results: The patient showed the three cardinal features of auditory neuropathy, presenting with evidence of normal cochlear outer hair cell function, disrupted neural activity in the auditory nerve/brainstem and impaired temporal processing. His functional hearing ability(speech perception) was significantly affected and suggested a reduced capacity to use localization cues to segregate signals in the presence of background noise.Conclusion: We present the first case of an individual with hemochromatosis and auditory neuropathy. The findings for this patient highlight the need for careful evaluation of auditory function in individuals with the disorder.展开更多
AIM To investigat the influence of hemochromatosis gene(Hfe) mutation on ^(59)Fe labelled duodenal heme absorption in mice.METHODS Heme absorption was measured in Hfe wild type and Hfe^((-/-)) mice by the duodenal tie...AIM To investigat the influence of hemochromatosis gene(Hfe) mutation on ^(59)Fe labelled duodenal heme absorption in mice.METHODS Heme absorption was measured in Hfe wild type and Hfe^((-/-)) mice by the duodenal tied loop and by oral gavage methods. The m RNA expression of heme oxygenase(HO-1), Abcg2 and Flvcr1 genes and levels were determined by quantitative polymerase chain reaction.RESULTS Heme absorption was significantly increased in homozygous Hfe^((-/-)) mice despite significant hepatic and splenic iron overload. While duodenal HO-1 mRNA was highly expressed in the wild type and Hfe^((-/-)) heme-treated group following 24 h heme administration, Flvcr1 a mRNA decreased. However, Abcg2 mRNA expression levels in duodenum remained unchanged. CONCLUSION Heme absorption was enhanced in Hfe^((-/-)) mice from both duodenal tied-loop segments and by oral gavage methods. HO-1 m RNA levels were enhanced in mice duodenum after 24 h of heme feeding and may account for enhanced heme absorption in Hfe^((-/-)) mice. Implications for dietary recommendations on heme intake by Hfe subjects to modulate iron loading are important clinical considerations.展开更多
Hemochromatosis,either hereditary hemochromatosis(HH)or secondary hemochromatosis,consists of the accumulation of iron in the liver,heart,and other organs.It leads to end-organ damage in a proportion of affected subje...Hemochromatosis,either hereditary hemochromatosis(HH)or secondary hemochromatosis,consists of the accumulation of iron in the liver,heart,and other organs.It leads to end-organ damage in a proportion of affected subjects.Although liver-related morbidity(cirrhosis and hepatocellular carcinoma[HCC])and mortality are well established,the frequency of these complications remains controversial.The aim of this study is to examine the rate of hospitalization and the incidence of iron overload-related comorbidities in patients with hemochromatosis between the years of 2002 and 2010.We queried the Nationwide Inpatient Sample(NIS)database from the year 2002 to 2010.We included adults(age≥18 years)and used the ICD-CM 9 code 275.0x to identify hospitalized patients with a diagnosis of hemochromatosis.Data analysis for this study was generated using SAS software version 9.4.A total of 168,614 hospitalized patients between 2002 and 2010 had a diagnosis of hemochromatosis.The majority were males(57%)with a median age of 54 years(37–68),with a predominance of white patients(63.3%)followed by black(26.8%).The rate of hospitalization among patients with hemochromatosis increased by 79%between the years 2002 and 2010(34.5/100,000 in 2002 vs 61.4/100,000 in 2010).The main associated diagnoses were diabetes mellitus(20.2%),cardiac disease,including arrhythmias(14%)and cardiomyopathy(dilated 3.8%;peri-,endo-,myocarditis 1.3%),liver cirrhosis(8.6%),HCC(1.6%),and acute liver failure(0.81%).Of note,HCC was associated with cirrhosis in 1188 patients(43%of HCC patients)and male sex(87%).Diagnostic biopsies were performed in 6023(3.6%)of those patients and liver transplant was performed in 881(0.5%).In-hospital mortality occurred in 3638(2.16%)patients.In this large database study,we found a rising trend in hospitalization for hemochromatosis,possibly due to the increased recognition of this entity and billing for the condition.The incidence of cirrhosis in hemochromatosis was found to be similar to other studies(8.6%vs 9%).However,the rate of HCC was lower than previous reports(1.6%vs 2.2%–14.9%),and only 43%of HCC was associated with cirrhosis.This raises important pathophysiologic questions regarding the impact of iron overload in HCC.There has been an increase in the rate of hospitalization for patients with a diagnosis of hemochromatosis.This may be related to an increased recognition of hemochromatosis as the underlying etiology for conditions such as diabetes,cardiomyopathy,cirrhosis,and HCC.Further prospective studies are needed to clarify the burden of liver disease in HH and secondary iron overload.展开更多
We report a patient with refractory ascites because of portal hypertension caused by hemochromatosis secondary to osteopetrosis.To our knowledge,this is the first well-documented case of this association.A 46-year-old...We report a patient with refractory ascites because of portal hypertension caused by hemochromatosis secondary to osteopetrosis.To our knowledge,this is the first well-documented case of this association.A 46-year-old male patient who was repeatedly infused with red blood cells for anemia secondary to osteopetrosis suffered from refractory ascites.The serum-ascites albumin gradient was 29.9 g/L.Abdominal computed tomography(CT)showed a large amount of ascites,hepatomegaly,and splenomegaly.Bone marrow biopsy showed a small bone marrow cavity with no hematopoietic tissue.A peripheral blood smear showed tear drop red blood cells and metarubricytes.Serum ferritin was 8,855.0 ng/mL.Therefore,we considered that the ascites resulted from portal hypertension caused by hemochromatosis secondary to osteopetrosis.We simultaneously performed the transjungular intrahepatic portal-systemic shunt(TIPS)and obtained a transjungular liver biopsy.The portal pressure gradient before TIPS was 28 mmHg,and iron staining was strongly positive on liver biopsy,which confirmed our diagnosis.After TIPS,both abdominal distention and ascites gradually resolved,and no recurrence as observed after the 12-month postoperative follow-up was observed.This case indicated that regular monitoring of iron load is important for patients with osteopetrosis.TIPS is safe and effective for portal hypertension complications due to osteopetrosis.展开更多
Iron homeostasis is a complex process in which iron uptake and use are tightly balanced.Primary Type 1 or HFE hemochromatosis results from homozygous mutations in the gene that encodes human homeostatic iron regulator...Iron homeostasis is a complex process in which iron uptake and use are tightly balanced.Primary Type 1 or HFE hemochromatosis results from homozygous mutations in the gene that encodes human homeostatic iron regulator(known as human factors engineering,HFE)protein,a regulator of hepcidin,and makes up approximately 90%of all hemochromatosis cases.However,four types of hemochromatosis do not involve the HFE gene.They are non-HFE hemochromatosis type 2A(HFE2,encoding HJV),type 2B(HAMP,encoding hepcidin),type 3(TFR2,encoding transferring receptor-2),and types 4A and B(SLC40A1,encoding ferroportin.NonHFE hemochromatosis is extremely rare.Pathogenic allele frequencies have been estimated to be 74/100,000 for type 2A,20/100,000 for type 2B,30/100,000 for type 3,and 90/100,000 for type 4 hemochromatosis.Current guidelines recommend that the diagnosis be made by ruling out HFE mutations,history,physical examination,laboratory values(ferritin and transferrin saturation),magnetic resonance or other imaging,and liver biopsy if needed.While less common,non-HFE hemochromatosis can cause iron overload as severe as the HFE type.In most cases,treatment involves phlebotomy and is successful if started before irreversible damage occurs.Early diagnosis and treatment are important because it prevents chronic liver disease.This review updates the mutations and their pathogenetic consequences,the clinical picture,diagnostic guidelines,and treatment of hemochromatosis.展开更多
Background:Red blood cell transfusions are critical in burn management.The subsequent iron overload that can occur from this treatment can lead to secondary hemochromatosis with multi-organ damage.Case Presentation:Wh...Background:Red blood cell transfusions are critical in burn management.The subsequent iron overload that can occur from this treatment can lead to secondary hemochromatosis with multi-organ damage.Case Presentation:While well recognized in patients receiving chronic transfusions,we present a case outlining the acute development of hemochromatosis secondary to multiple transfusions in a burn patient.Conclusions:Simple screening laboratory measures and treatment options exist which may significantly reduce morbidity;thus,we believe awareness of secondary hemochromatosis in those treating burn patients is critical.展开更多
Hepatocellular carcinoma(HCC)is a significant global health problem with high morbidity and mortality.Its incidence is increasing exponentially worldwide with a close overlap between annual incidence and death rates.E...Hepatocellular carcinoma(HCC)is a significant global health problem with high morbidity and mortality.Its incidence is increasing exponentially worldwide with a close overlap between annual incidence and death rates.Even though significant advances have been made in HCC treatment,fewer than 20%of patients with HCC are suitable for potentially curative treatment.Hereditary hemochromatosis(HH)is an important genetic risk factor for HCC.HH is an autosomal recessive disorder of iron metabolism,characterised by elevated iron deposition in most organs including the liver,leading to progressive organ dysfunction.HCC is a complication of HH,nearly always occurring in patients with cirrhosis and contributes to increased mortality rates.Identifying the susceptibility of development of HCC in HH patients has gained much traction.This review summarises the current knowledge with regard to the association of HH and HCC in order to encourage further research.In this review,we focus particularly on HFE gene-related HH.Herein,we highlight and discuss emerging clinical research which addresses the prevalence of HCC in HH patients and the coincidence of HH with other risk factors for HCC development.We also focus on the therapeutic tools in the management of HCC associated with HH.展开更多
Accurate evaluation of iron overload is necessary to establish the diagnosis of hemochromatosis and guide chelation treatment in transfusion-dependent anemia. The liver is the primary site for iron storage in patients...Accurate evaluation of iron overload is necessary to establish the diagnosis of hemochromatosis and guide chelation treatment in transfusion-dependent anemia. The liver is the primary site for iron storage in patients with hemochromatosis or transfusion-dependent anemia, therefore, liver iron concentration (LIC) accurately re? ects total body iron stores. In the past 20 years, magnetic resonance imaging (MRI) has emerged as a promising method for measuring LIC in a variety of diseases. We review the potential role of MRI in LIC determination in the most important disorders that are characterized by iron overload, that is, thalassemia major, other hemoglobinopathies, acquired anemia, and hemochromatosis. Most studies have been performed in thalassemia major and MRI is currently a widely accepted method for guiding chelation treatment in these patients. However, the lack of correlation between liver and cardiac iron stores suggests that both organs should be evaluated with MRI, since cardiac disease is the leading cause of death in this population. It is also unclear which MRI method is the most accurate since there are no large studies that have directly compared the different available techniques. The role of MRI in the era of genetic diagnosis of hemochromatosis is also debated, whereas data on the accuracy of the method in other hematological and liver diseases are rather limited. However, MRI is a fast, non-invasive and relatively accurate diagnostic tool for assessing LIC, and its use is expected to increase as the role of iron in the pathogenesis of liver disease becomes clearer.展开更多
BACKGROUND: The liver, as the main iron storage compartment and the place of hepcidin synthesis, is the central organ involved in maintaining iron homeostasis in the body. Excessive accumulation of iron is an importan...BACKGROUND: The liver, as the main iron storage compartment and the place of hepcidin synthesis, is the central organ involved in maintaining iron homeostasis in the body. Excessive accumulation of iron is an important risk factor in liver disease progression to cirrhosis and hepatocellular carcinoma.Here, we review the literature on the molecular pathogenesis of iron overload and its clinical consequences in chronic liver diseases.DATA SOURCES: Pub Med was searched for English-language articles on molecular genesis of primary and secondary iron overload, as well as on their association with liver disease progression. We have also included literature on adjuvant therapeutic interventions aiming to alleviate detrimental effects of excessive body iron load in liver cirrhosis.RESULTS: Excess of free, unbound iron induces oxidative stress, increases cell sensitivity to other detrimental factors,and can directly affect cellular signaling pathways, resulting in accelerated liver disease progression. Diagnosis of liver cirrhosis is, in turn, often associated with the identification of a pathological accumulation of iron, even in the absence of genetic background of hereditary hemochromatosis. Iron depletion and adjuvant therapy with antioxidants are shown to cause significant improvement of liver functions in patients with iron overload. Phlebotomy can have beneficial effects on liver histology in patients with excessive iron accumulation combined with compensated liver cirrhosis of different etiology.CONCLUSION: Excessive accumulation of body iron in liver cirrhosis is an important predictor of liver failure and available data suggest that it can be considered as target for adjuvant therapy in this condition.展开更多
Safe trafficking of iron across the cell membrane is a delicate process that requires specific protein carriers. While many proteins involved in iron uptake by cells are known, only one cellular iron export protein ha...Safe trafficking of iron across the cell membrane is a delicate process that requires specific protein carriers. While many proteins involved in iron uptake by cells are known, only one cellular iron export protein has been identified in mammals: ferroportin(SLC40A1). Ceruloplasmin is a multicopper enzyme endowed with ferroxidase activity that is found as a soluble isoform in plasma or as a membrane-associated isoform in specific cell types. According to the currently accepted view, ferrous iron transported out of the cell by ferroportin would be safely oxidized by ceruloplasmin to facilitate loading on transferrin. Therefore, the ceruloplasminferroportin system represents the main pathway for cellular iron egress and it is responsible for physiological regulation of cellular iron levels. The most recent findings regarding the structural and functional features of ceruloplasmin and ferroportin and their relationship will be described in this review.展开更多
BACKGROUND: Liver steatosis and iron overload, which are frequently observed in chronic hepatitis C (CHC), may contribute to the progression of liver injury. This study aimed to evaluate the correlation between liver ...BACKGROUND: Liver steatosis and iron overload, which are frequently observed in chronic hepatitis C (CHC), may contribute to the progression of liver injury. This study aimed to evaluate the correlation between liver steatosis and iron overload in Polish patients with CHC compared to non- alcoholic fatty liver disease (NAFLD) and HFE-hereditary hemochromatosis (HH) patients. METHODS: A total of 191 CHC patients were compared with 67 NAFLD and 21 HH patients. Liver function tests, serum markers of iron metabolism, cholesterol and triglycerides were assayed. The inflammatory activity, fibrosis, iron deposits and steatosis stages were assessed in liver specimens. HFE gene polymorphisms were investigated by PCR-RFLP. RESULTS: Liver steatosis was associated with obesity and diabetes mellitus. This disease was confirmed in 76/174 (44%) CHC patients, most of whom were infected with genotype 1. The average grade of steatosis was higher in NAFLD patients. CHC patients had significantly higher iron concentrations and transferrin saturations than NAFLD patients. Compared with CHC patients, HH patients had higher values of serum iron parameters and more intensive hepatocyte iron deposits without differences in the prevalence and intensity of liver steatosis. In the CHC group, lipids accumulation in hepatocytes was significantly associated with the presence of serummarkers of iron overload. No correlation between the HFE gene polymorphism and liver steatosis in CHC patients was found. CONCLUSIONS: Liver steatosis was diagnosed in nearly half of CHC patients, most of whom were infected with genotype 1. The intensity of steatosis was lower in CHC patients than that in NAFLD patients because of a less frequent diagnosis of metabolic syndrome. Only in CHC patients were biochemical markers of iron accumulation positively correlated with liver steatosis; these findings were independent of HFE gene mutations.展开更多
Due to blood transfusions,thalassemics are often infected with either hepatitis C virus(HCV)or hepatitis B virus and often have hemochromatosis.Hepatocellular carcinoma(HCC)has emerged in thalassemics only recently as...Due to blood transfusions,thalassemics are often infected with either hepatitis C virus(HCV)or hepatitis B virus and often have hemochromatosis.Hepatocellular carcinoma(HCC)has emerged in thalassemics only recently as a result of the improvement in thalassemia outcomes.In fact,a prospective study estimated an HCC incidence inβ-thalassemia of about 2%.Although data are scanty,HCC screening in thalassemics with risk factors for HCC should be carried out.HCV treatments have some efficacy in HCV infected thalassemics despite partial contraindication to ribavirin and iron overload.However,there are no data on how HCV treatment translates into HCC prevention.Preliminary data suggest that HCC treatment in thalassemics should generally have the same outcomes as in nonthalassemics.Although coexistence of severe comorbidities makes liver transplantation challenging,this therapeutic possibility should not be precluded for well selected HCCβ-thalassemia patients.In fact,2 transfusion dependent adult HCCβ-thalassemia patients have recently undergone successful liver transplantation with a good outcome.In conclusion,HCC seems to be a developing issue in thalassemia and HCC screening should be carried out.HCC treatment,including liver transplantation,can be performed in selected patients. A multidisciplinary effort is needed for management.展开更多
BACKGROUND Congenital dyserythropoietic anemia type 1(CDA1)is an autosomal recessive disorder of ineffective erythropoiesis,resulting in increased iron storage.CDA1 is usually diagnosed in children and adolescents but...BACKGROUND Congenital dyserythropoietic anemia type 1(CDA1)is an autosomal recessive disorder of ineffective erythropoiesis,resulting in increased iron storage.CDA1 is usually diagnosed in children and adolescents but can rarely present in the neonatal period with severe anemia at birth.There are no prior reports of neonatal liver histologic findings of CDA1.We report a case of CDA1 in a newborn presenting with severe anemia,cholestasis and liver failure,where liver biopsy helped confirm the diagnosis.CASE SUMMARY A term infant,born via emergency Cesarean section,presented with cholestasis,hepatosplenomegaly,multiorgan failure and severe anemia at birth.A prior pregnancy was significant for fetal demise at 35 wk without autopsy or known etiology for the fetal demise.Parents are both healthy and there is no history of consanguinity.On further evaluation,the patient was found to have severe ferritin elevation and pulmonary hypertension.An extensive infectious and metabolic work-up was negative.Salivary gland biopsy was negative for iron deposition.At 2 wk of age,a liver biopsy showed findings consistent with CDA1.A genome rapid sequencing panel revealed novel variants in the CDAN1 gene.The patient’s liver dysfunction,cholestasis and organomegaly resolved,however she remains transfusion-dependent.CONCLUSION We report liver pathology findings of CDA1 with a novel genetic mutation for the first time in a newborn.展开更多
基金Supported by National Natural Science Foundation of China,No.81874379Fujian Province Medical Innovation Foundation,No.2019-CXB-3 and 2019-CXB-4.
文摘BACKGROUND It is not easy to identify the cause of various iron overload diseases because the phenotypes overlap.Therefore,it is important to perform genetic testing to determine the genetic background of patients.AIM To investigate the genetic background of a patient with hemochromatosis complicated by psoriasis on both lower extremities.METHODS Ten years ago,a 61-year-old male presented with iron overload,jaundice,hemolytic anemia and microcytic hypochromic anemia.Computed tomography of the left knee joint showed enlargement of the tibial medullary cavity and thinned bone cortices.Magnetic resonance imaging showed hepatic hemochromatosis,extensive abnormal signals from bone marrow cavities and nodular lesions in the lateral medullary cavity of the upper left lateral tibia.Single photon emission computed tomography showed radial dots of abnormal concentration in the upper end of the left tibia and radial symmetry of abnormal concentrations in joints of the extremities.The patient showed several hot spot mutations of the HFE and G6PD genes detected by next-generation sequencing,but no responsible gene mutation was found.The thalassemia gene was detected by gap-PCR.RESULTS The patient was found to carry the-α4.2 and--SEA deletion mutations of the globin gene.These two mutations are common causes of Southeast Asianα-thalassemia,but rarely cause severe widespread non-transfusion secondary hemochromatosis osteoarthropathy.The simultaneous presence of an auxiliary superposition effect of a rare missense mutation of the PIEZO1 gene(NM_001142864,c.C4748T,p.A1583V)was considered.Moreover,several rare mutations of the IFIH1,KRT8,POFUT1,FLG,KRT2,and TGM5 genes may be involved in the pathogenesis of psoriasis.CONCLUSION The selection of genetic detection methods for hemochromatosis still needs to be based on an in-depth study of the clinical manifestations of the disease.
文摘Advances in recent years in the understanding of, and the genetic diagnosis of hereditary hemochromatosis (HH) have changed the approach to iron overload he-reditary diseases. The ability to use a radiologic tool (MRI) that accurately provides liver iron concentration determination, and the presence of non-invasive sero-logic markers for fibrosis prediction (ser um ferritin, platelet count, transaminases, etc), have diminished the need for liver biopsy for diagnosis and prognosis of this disease. Consequently, the role of liv er biopsy in iron metabolism disorders is changing. Furthermore, the irruption of transient elastography to assess liver stiffness, and, more recently, the ability to determine liver f ibrosis by means of MRI elastography will change this role even more, with a potential drastic decline in hepatic biopsies in years to come. This review will provide a brief summary of the different non-invasive methods available nowadays for diagnosis and prognosis in HH, and point out potential new techniques that could come about in the next years for fibrosis prediction, thus avoiding the need for liver biopsy in a greater number of patients. It is possible that liver biopsy will remain useful for the diagnosis of associated diseases, where other non-invasive means are not po-ssible, or for those rare cases displaying discrepancies between radiological and biochemical markers.
文摘This review focuses on the management of iron metabolism and iron overload experienced in the hereditary condition, human factors engineering(HFE)-associated hemochromatosis. Hemochromatosis refers to a group of genetic diseases that result in iron overload; the major one globally is HFE-associated hemochromatosis. The evolution in understanding of the most common form of hereditary hemochromatosis, being the substation of cysteine to a tyrosine at position 282 in the HFE gene, has been extensively studied Novel mutations in both HFE and non-HFE genes have been indicated in this disease which hold significance in its application for the Asia-Pacific region. In conditions with iron overload, the storage of excess iron in various body tissues leads to complications and toxic damage. The most common presenting complaint for this disease is malaise, lethargy and other non-specific symptoms. In order to diagnose hereditary hemochromatosis, there are biochemical, imaging and genetic testing options. Currently, cascade screening of affected families is preferred over population-level screening. The mainstay of treatment is venesection and the appropriate approach to treatment has been consolidated over the years. Recently, the indications for venesection therapy of hemochromatosis have been challenged and are the subject of ongoing research.
文摘Juvenile hemochromatosis(JH) is a rare condition classified as an autosomal recessive disorder that leads to severe iron absorption. JH usually affects people under the age of 30 and presents symptoms such as chronic liver damage,hypogonadotropic hypogonadism,cardiac diseases and endocrine dysfunctions. The present case reports a 29-year-old Brazilian woman with JH condition due to HAMP mutation(g.47G>A),treated with phlebotomies and deferasirox. She presented symptoms such as weakness,skin hyperpigmentation,joint pain in the shoulders and hands and amenorrhea. First laboratory tests showed altered biochemical parameters [serum ferritin(SF): 5696 ng/mL,transferrin saturation(TS): 85%]. After sessions of phlebotomies(450 mL every 15 d),the patient presented partial symptomatic improvements and biochemical parameters(SF: 1000 ng/mL,Hb: 11 g/dL). One year later,deferasirox(15 mg/kg per day) was introduced to the treatment,and the patient showed total symptomatic improvement,with significant clearing of the skin,SF: 169 ng/mL,and TS: 50%. Furthermore,after the combined deferasirox-phlebotomy therapy,magnetic resonance imaging measurements revealed normalized level for liver iron(30 μmol/g; reference value < 36 μmol/g). In conclusion,combined deferasirox-phlebotomy treatment was able to normalize iron levels and improve symptoms.
基金"Conselho Nacional de Desenvolvimento Cientifico e Tecnologico"(CNPq,Brazil),No.304931/2014-1 and No.148638/2010-4
文摘BACKGROUND Patients with hepatitis C virus(HCV) and hepatocellular carcinoma(HCC) may or not develop iron overload(IO),which is associated with worst prognosis,because can cause serious damage to organs.HFE gene controls the iron uptake from gut,particularly in patients with hereditary hemochromatosis(HH).AIM To identify associations between HFE coding region in patients exhibiting hereditary hemochromatosis and in diseases associated with acquired IO.METHODS We sequenced exons 2 to 5 and boundary introns of HFE gene,evaluating all polymorphic sites in patients presenting hereditary(hemochromatosis) or acquired iron overload HCV and HCC) and in healthy controls,using Sanger sequencing.We also determined the ensemble of extended haplotype in healthy control individuals,including several major histocompatibility complex loci,using sequence specific probes.Haplotype reconstruction was performed using the Arlequin and Phase softwares,and linkage disequilibrium(LD) between histocompatibility loci and HFE gene was performed using the Haploview software.RESULTS The HFE*003 allele was overrepresented(f = 71%) and HFE*001 allele was underrepresented(f = 14%) in HH patients compared to all groups.A strong linkage disequilibrium was observed among the H63 D-G,IVS2(+4)-C and C282 YG gene variants,particularly in HH;however,the mutation IVS2(+4)T>C was not directly associated with HH susceptibility.The HFE*001/HFE*002 genotype conferred susceptibility to HCC in HCV patients exhibiting IO(P = 0.02,OR =14.14).Although HFE is telomeric to other histocompatibility genes,the H63 DG/IVS2(+4)-C(P ≤ 0.00001/P ≤ 0.0057) combination was in LD with HLA-B*44 allele group in healthy controls.No LD was observed between HFE alleles and other major histocompatibility loci.CONCLUSION A differential HFE association was observed for HH and for diseases associated with acquired IO(HCV,HCC).Since HFE is very distant from other histocompatibility loci,only weak associations were observed with these alleles.
文摘BACKGROUND Hereditary hemochromatosis(HH)has an increased risk of hepatocellular cancer(HCC)both due to genetic risks and iron overload as iron overload can be carcinogenic;HH impacts the increasing risk of HCC,not only through the development of cirrhosis but concerning hepatic iron deposition,which has been studied further recently.AIM To evaluate HH yearly trends,patient demographics,symptoms,comorbidities,and hospital outcomes.The secondary aim sheds light on the risk of iron overload for developing HCC in HH patients,independent of liver cirrhosis complications.The study investigated HH(without cirrhosis)as an independent risk factor for HCC.METHODS We analyzed data from National Inpatient Sample(NIS)Database,the largest national inpatient data collection in the United States,and selected HH and HCC cohorts.HH was first defined in 2011 International Classification of Disease-9th edition(ICD-9)as a separate diagnosis;the HH cohort is extracted from January 2011 to December 2019 using 275.01(ICD-9)and E83.110(ICD-10)diagnosis codes of HH.Patients were excluded from the HH cohort if they had a primary or secondary diagnostic code of cirrhosis(alcoholic,non-alcoholic,and biliary),viralhepatitis,alcoholic liver disease,non-alcoholic fatty liver disease(NAFLD),and non-alcoholic steatohepatitis(NASH).We removed these patients from the HH cohort to rule out bias or ICD-10 diagnostic errors.The HCC cohort is selected from January 2011 to December 2019 using the ICD-9 and ICD-10 codes of HCC.We selected a non-HCC cohort with the 1:1 fixed ratio nearest neighbor(greedy)propensity score method using the patients'age,gender,and race.We performed multivariate analysis for the risk factors of HCC in the HCC and non-HCC matched cohort.We further analyzed HH without cirrhosis(removing HH patients with a diagnosis of cirrhosis)as an independent risk factor of HCC after adjusting all known risk factors of HCC in the multivariate model.RESULTS During the 2011-2019 period,a total of 18031 hospitalizations with a primary or secondary diagnosis of HH(excluding liver diseases)were recorded in the NIS database.We analyzed different patients’characteristics,and we found increments in inpatient population trend with a Ptrend<0.001 and total hospital cost of care trend from$42957 in 2011 to$66152 in 2019 with a Ptrend<0.001 despite no change in Length of Stay over the last decade.The multivariate analyses showed that HH without cirrhosis(aOR,28.8;95%CI,10.4–80.1;P<0.0001),biliary cirrhosis(aOR,19.3;95%CI,13.4–27.6;P<0.0001),non-alcoholic cirrhosis(aOR,17.4;95%CI,16.5–18.4;P<0.0001),alcoholic cirrhosis(aOR,16.9;95%CI,15.9–17.9;P<0.0001),hepatitis B(aOR,12.1;95%CI,10.85–13.60;P<0.0001),hepatitis C(aOR,8.58;95%CI,8.20–8.98;P<0.0001),Wilson disease(aOR,4.27;95%CI,1.18–15.41;P<0.0001),NAFLD or NASH(aOR,2.96;95%CI,2.73–3.20;P<0.0001),alpha1-antitrypsin deficiency(aOR,2.10;95%CI,1.21–3.64;P<0.0001),diabetes mellitus without chronic complications(aOR,1.17;95%CI,1.13–1.21;P<0.0001),and blood transfusion(aOR,1.80;95%CI,1.69–1.92;P<0.0001)are independent risk factor for liver cancer.CONCLUSION Our study showed an increasing trend of in-hospital admissions of HH patients in the last decade.These trends were likely related to advances in diagnostic approach,which can lead to increased hospital utilization and cost increments.Still,the length of stay remained the same,likely due to a big part of management being done in outpatient settings.Another vital part of our study is the significant result that HH without cirrhosis is an independent risk factor for HCC with adjusting all known risk factors.More prospective and retrospective large studies are needed to re-evaluate the HH independent risk in developing HCC.
文摘We report the case of a 7 years old girl with Juvenile Hemochromatosis, due to homozygous mutation of HJV, which had increased serum iron indices and liver iron overload in the absence of any clinical sign of disease. Oral iron chelation with low dose deferasirox showed good efficacy and no side effects. The oral iron chelator deferasirox could be a valid option for removing excess iron in early Juvenile Hemochromatosis.
基金supported by the HEARing CRC(established and supported under the Australian Government's Cooperative Research Centres Program)
文摘Objective: To evaluate the auditory function of an individual with genetically confirmed hemochromatosis.Methods: A 57 year old male with mildly impaired sound detection thresholds underwent a range of behavioural, electroacoustic and electrophysiologic assessments. These included the recording of otoacoustic emissions and auditory brainstem responses, measurement of monaural temporal resolution and evaluation of binaural speech processing. Findings for this patient were subsequently compared with those of 80 healthy controls with similar audiometric thresholds.Results: The patient showed the three cardinal features of auditory neuropathy, presenting with evidence of normal cochlear outer hair cell function, disrupted neural activity in the auditory nerve/brainstem and impaired temporal processing. His functional hearing ability(speech perception) was significantly affected and suggested a reduced capacity to use localization cues to segregate signals in the presence of background noise.Conclusion: We present the first case of an individual with hemochromatosis and auditory neuropathy. The findings for this patient highlight the need for careful evaluation of auditory function in individuals with the disorder.
文摘AIM To investigat the influence of hemochromatosis gene(Hfe) mutation on ^(59)Fe labelled duodenal heme absorption in mice.METHODS Heme absorption was measured in Hfe wild type and Hfe^((-/-)) mice by the duodenal tied loop and by oral gavage methods. The m RNA expression of heme oxygenase(HO-1), Abcg2 and Flvcr1 genes and levels were determined by quantitative polymerase chain reaction.RESULTS Heme absorption was significantly increased in homozygous Hfe^((-/-)) mice despite significant hepatic and splenic iron overload. While duodenal HO-1 mRNA was highly expressed in the wild type and Hfe^((-/-)) heme-treated group following 24 h heme administration, Flvcr1 a mRNA decreased. However, Abcg2 mRNA expression levels in duodenum remained unchanged. CONCLUSION Heme absorption was enhanced in Hfe^((-/-)) mice from both duodenal tied-loop segments and by oral gavage methods. HO-1 m RNA levels were enhanced in mice duodenum after 24 h of heme feeding and may account for enhanced heme absorption in Hfe^((-/-)) mice. Implications for dietary recommendations on heme intake by Hfe subjects to modulate iron loading are important clinical considerations.
文摘Hemochromatosis,either hereditary hemochromatosis(HH)or secondary hemochromatosis,consists of the accumulation of iron in the liver,heart,and other organs.It leads to end-organ damage in a proportion of affected subjects.Although liver-related morbidity(cirrhosis and hepatocellular carcinoma[HCC])and mortality are well established,the frequency of these complications remains controversial.The aim of this study is to examine the rate of hospitalization and the incidence of iron overload-related comorbidities in patients with hemochromatosis between the years of 2002 and 2010.We queried the Nationwide Inpatient Sample(NIS)database from the year 2002 to 2010.We included adults(age≥18 years)and used the ICD-CM 9 code 275.0x to identify hospitalized patients with a diagnosis of hemochromatosis.Data analysis for this study was generated using SAS software version 9.4.A total of 168,614 hospitalized patients between 2002 and 2010 had a diagnosis of hemochromatosis.The majority were males(57%)with a median age of 54 years(37–68),with a predominance of white patients(63.3%)followed by black(26.8%).The rate of hospitalization among patients with hemochromatosis increased by 79%between the years 2002 and 2010(34.5/100,000 in 2002 vs 61.4/100,000 in 2010).The main associated diagnoses were diabetes mellitus(20.2%),cardiac disease,including arrhythmias(14%)and cardiomyopathy(dilated 3.8%;peri-,endo-,myocarditis 1.3%),liver cirrhosis(8.6%),HCC(1.6%),and acute liver failure(0.81%).Of note,HCC was associated with cirrhosis in 1188 patients(43%of HCC patients)and male sex(87%).Diagnostic biopsies were performed in 6023(3.6%)of those patients and liver transplant was performed in 881(0.5%).In-hospital mortality occurred in 3638(2.16%)patients.In this large database study,we found a rising trend in hospitalization for hemochromatosis,possibly due to the increased recognition of this entity and billing for the condition.The incidence of cirrhosis in hemochromatosis was found to be similar to other studies(8.6%vs 9%).However,the rate of HCC was lower than previous reports(1.6%vs 2.2%–14.9%),and only 43%of HCC was associated with cirrhosis.This raises important pathophysiologic questions regarding the impact of iron overload in HCC.There has been an increase in the rate of hospitalization for patients with a diagnosis of hemochromatosis.This may be related to an increased recognition of hemochromatosis as the underlying etiology for conditions such as diabetes,cardiomyopathy,cirrhosis,and HCC.Further prospective studies are needed to clarify the burden of liver disease in HH and secondary iron overload.
文摘We report a patient with refractory ascites because of portal hypertension caused by hemochromatosis secondary to osteopetrosis.To our knowledge,this is the first well-documented case of this association.A 46-year-old male patient who was repeatedly infused with red blood cells for anemia secondary to osteopetrosis suffered from refractory ascites.The serum-ascites albumin gradient was 29.9 g/L.Abdominal computed tomography(CT)showed a large amount of ascites,hepatomegaly,and splenomegaly.Bone marrow biopsy showed a small bone marrow cavity with no hematopoietic tissue.A peripheral blood smear showed tear drop red blood cells and metarubricytes.Serum ferritin was 8,855.0 ng/mL.Therefore,we considered that the ascites resulted from portal hypertension caused by hemochromatosis secondary to osteopetrosis.We simultaneously performed the transjungular intrahepatic portal-systemic shunt(TIPS)and obtained a transjungular liver biopsy.The portal pressure gradient before TIPS was 28 mmHg,and iron staining was strongly positive on liver biopsy,which confirmed our diagnosis.After TIPS,both abdominal distention and ascites gradually resolved,and no recurrence as observed after the 12-month postoperative follow-up was observed.This case indicated that regular monitoring of iron load is important for patients with osteopetrosis.TIPS is safe and effective for portal hypertension complications due to osteopetrosis.
文摘Iron homeostasis is a complex process in which iron uptake and use are tightly balanced.Primary Type 1 or HFE hemochromatosis results from homozygous mutations in the gene that encodes human homeostatic iron regulator(known as human factors engineering,HFE)protein,a regulator of hepcidin,and makes up approximately 90%of all hemochromatosis cases.However,four types of hemochromatosis do not involve the HFE gene.They are non-HFE hemochromatosis type 2A(HFE2,encoding HJV),type 2B(HAMP,encoding hepcidin),type 3(TFR2,encoding transferring receptor-2),and types 4A and B(SLC40A1,encoding ferroportin.NonHFE hemochromatosis is extremely rare.Pathogenic allele frequencies have been estimated to be 74/100,000 for type 2A,20/100,000 for type 2B,30/100,000 for type 3,and 90/100,000 for type 4 hemochromatosis.Current guidelines recommend that the diagnosis be made by ruling out HFE mutations,history,physical examination,laboratory values(ferritin and transferrin saturation),magnetic resonance or other imaging,and liver biopsy if needed.While less common,non-HFE hemochromatosis can cause iron overload as severe as the HFE type.In most cases,treatment involves phlebotomy and is successful if started before irreversible damage occurs.Early diagnosis and treatment are important because it prevents chronic liver disease.This review updates the mutations and their pathogenetic consequences,the clinical picture,diagnostic guidelines,and treatment of hemochromatosis.
文摘Background:Red blood cell transfusions are critical in burn management.The subsequent iron overload that can occur from this treatment can lead to secondary hemochromatosis with multi-organ damage.Case Presentation:While well recognized in patients receiving chronic transfusions,we present a case outlining the acute development of hemochromatosis secondary to multiple transfusions in a burn patient.Conclusions:Simple screening laboratory measures and treatment options exist which may significantly reduce morbidity;thus,we believe awareness of secondary hemochromatosis in those treating burn patients is critical.
文摘Hepatocellular carcinoma(HCC)is a significant global health problem with high morbidity and mortality.Its incidence is increasing exponentially worldwide with a close overlap between annual incidence and death rates.Even though significant advances have been made in HCC treatment,fewer than 20%of patients with HCC are suitable for potentially curative treatment.Hereditary hemochromatosis(HH)is an important genetic risk factor for HCC.HH is an autosomal recessive disorder of iron metabolism,characterised by elevated iron deposition in most organs including the liver,leading to progressive organ dysfunction.HCC is a complication of HH,nearly always occurring in patients with cirrhosis and contributes to increased mortality rates.Identifying the susceptibility of development of HCC in HH patients has gained much traction.This review summarises the current knowledge with regard to the association of HH and HCC in order to encourage further research.In this review,we focus particularly on HFE gene-related HH.Herein,we highlight and discuss emerging clinical research which addresses the prevalence of HCC in HH patients and the coincidence of HH with other risk factors for HCC development.We also focus on the therapeutic tools in the management of HCC associated with HH.
文摘Accurate evaluation of iron overload is necessary to establish the diagnosis of hemochromatosis and guide chelation treatment in transfusion-dependent anemia. The liver is the primary site for iron storage in patients with hemochromatosis or transfusion-dependent anemia, therefore, liver iron concentration (LIC) accurately re? ects total body iron stores. In the past 20 years, magnetic resonance imaging (MRI) has emerged as a promising method for measuring LIC in a variety of diseases. We review the potential role of MRI in LIC determination in the most important disorders that are characterized by iron overload, that is, thalassemia major, other hemoglobinopathies, acquired anemia, and hemochromatosis. Most studies have been performed in thalassemia major and MRI is currently a widely accepted method for guiding chelation treatment in these patients. However, the lack of correlation between liver and cardiac iron stores suggests that both organs should be evaluated with MRI, since cardiac disease is the leading cause of death in this population. It is also unclear which MRI method is the most accurate since there are no large studies that have directly compared the different available techniques. The role of MRI in the era of genetic diagnosis of hemochromatosis is also debated, whereas data on the accuracy of the method in other hematological and liver diseases are rather limited. However, MRI is a fast, non-invasive and relatively accurate diagnostic tool for assessing LIC, and its use is expected to increase as the role of iron in the pathogenesis of liver disease becomes clearer.
基金supported by a grant from Polish National Science Centre(2011/01/B/NZ6/00320)
文摘BACKGROUND: The liver, as the main iron storage compartment and the place of hepcidin synthesis, is the central organ involved in maintaining iron homeostasis in the body. Excessive accumulation of iron is an important risk factor in liver disease progression to cirrhosis and hepatocellular carcinoma.Here, we review the literature on the molecular pathogenesis of iron overload and its clinical consequences in chronic liver diseases.DATA SOURCES: Pub Med was searched for English-language articles on molecular genesis of primary and secondary iron overload, as well as on their association with liver disease progression. We have also included literature on adjuvant therapeutic interventions aiming to alleviate detrimental effects of excessive body iron load in liver cirrhosis.RESULTS: Excess of free, unbound iron induces oxidative stress, increases cell sensitivity to other detrimental factors,and can directly affect cellular signaling pathways, resulting in accelerated liver disease progression. Diagnosis of liver cirrhosis is, in turn, often associated with the identification of a pathological accumulation of iron, even in the absence of genetic background of hereditary hemochromatosis. Iron depletion and adjuvant therapy with antioxidants are shown to cause significant improvement of liver functions in patients with iron overload. Phlebotomy can have beneficial effects on liver histology in patients with excessive iron accumulation combined with compensated liver cirrhosis of different etiology.CONCLUSION: Excessive accumulation of body iron in liver cirrhosis is an important predictor of liver failure and available data suggest that it can be considered as target for adjuvant therapy in this condition.
文摘Safe trafficking of iron across the cell membrane is a delicate process that requires specific protein carriers. While many proteins involved in iron uptake by cells are known, only one cellular iron export protein has been identified in mammals: ferroportin(SLC40A1). Ceruloplasmin is a multicopper enzyme endowed with ferroxidase activity that is found as a soluble isoform in plasma or as a membrane-associated isoform in specific cell types. According to the currently accepted view, ferrous iron transported out of the cell by ferroportin would be safely oxidized by ceruloplasmin to facilitate loading on transferrin. Therefore, the ceruloplasminferroportin system represents the main pathway for cellular iron egress and it is responsible for physiological regulation of cellular iron levels. The most recent findings regarding the structural and functional features of ceruloplasmin and ferroportin and their relationship will be described in this review.
基金supported by agrant from Medical University of Gdansk(W-175)
文摘BACKGROUND: Liver steatosis and iron overload, which are frequently observed in chronic hepatitis C (CHC), may contribute to the progression of liver injury. This study aimed to evaluate the correlation between liver steatosis and iron overload in Polish patients with CHC compared to non- alcoholic fatty liver disease (NAFLD) and HFE-hereditary hemochromatosis (HH) patients. METHODS: A total of 191 CHC patients were compared with 67 NAFLD and 21 HH patients. Liver function tests, serum markers of iron metabolism, cholesterol and triglycerides were assayed. The inflammatory activity, fibrosis, iron deposits and steatosis stages were assessed in liver specimens. HFE gene polymorphisms were investigated by PCR-RFLP. RESULTS: Liver steatosis was associated with obesity and diabetes mellitus. This disease was confirmed in 76/174 (44%) CHC patients, most of whom were infected with genotype 1. The average grade of steatosis was higher in NAFLD patients. CHC patients had significantly higher iron concentrations and transferrin saturations than NAFLD patients. Compared with CHC patients, HH patients had higher values of serum iron parameters and more intensive hepatocyte iron deposits without differences in the prevalence and intensity of liver steatosis. In the CHC group, lipids accumulation in hepatocytes was significantly associated with the presence of serummarkers of iron overload. No correlation between the HFE gene polymorphism and liver steatosis in CHC patients was found. CONCLUSIONS: Liver steatosis was diagnosed in nearly half of CHC patients, most of whom were infected with genotype 1. The intensity of steatosis was lower in CHC patients than that in NAFLD patients because of a less frequent diagnosis of metabolic syndrome. Only in CHC patients were biochemical markers of iron accumulation positively correlated with liver steatosis; these findings were independent of HFE gene mutations.
文摘Due to blood transfusions,thalassemics are often infected with either hepatitis C virus(HCV)or hepatitis B virus and often have hemochromatosis.Hepatocellular carcinoma(HCC)has emerged in thalassemics only recently as a result of the improvement in thalassemia outcomes.In fact,a prospective study estimated an HCC incidence inβ-thalassemia of about 2%.Although data are scanty,HCC screening in thalassemics with risk factors for HCC should be carried out.HCV treatments have some efficacy in HCV infected thalassemics despite partial contraindication to ribavirin and iron overload.However,there are no data on how HCV treatment translates into HCC prevention.Preliminary data suggest that HCC treatment in thalassemics should generally have the same outcomes as in nonthalassemics.Although coexistence of severe comorbidities makes liver transplantation challenging,this therapeutic possibility should not be precluded for well selected HCCβ-thalassemia patients.In fact,2 transfusion dependent adult HCCβ-thalassemia patients have recently undergone successful liver transplantation with a good outcome.In conclusion,HCC seems to be a developing issue in thalassemia and HCC screening should be carried out.HCC treatment,including liver transplantation,can be performed in selected patients. A multidisciplinary effort is needed for management.
文摘BACKGROUND Congenital dyserythropoietic anemia type 1(CDA1)is an autosomal recessive disorder of ineffective erythropoiesis,resulting in increased iron storage.CDA1 is usually diagnosed in children and adolescents but can rarely present in the neonatal period with severe anemia at birth.There are no prior reports of neonatal liver histologic findings of CDA1.We report a case of CDA1 in a newborn presenting with severe anemia,cholestasis and liver failure,where liver biopsy helped confirm the diagnosis.CASE SUMMARY A term infant,born via emergency Cesarean section,presented with cholestasis,hepatosplenomegaly,multiorgan failure and severe anemia at birth.A prior pregnancy was significant for fetal demise at 35 wk without autopsy or known etiology for the fetal demise.Parents are both healthy and there is no history of consanguinity.On further evaluation,the patient was found to have severe ferritin elevation and pulmonary hypertension.An extensive infectious and metabolic work-up was negative.Salivary gland biopsy was negative for iron deposition.At 2 wk of age,a liver biopsy showed findings consistent with CDA1.A genome rapid sequencing panel revealed novel variants in the CDAN1 gene.The patient’s liver dysfunction,cholestasis and organomegaly resolved,however she remains transfusion-dependent.CONCLUSION We report liver pathology findings of CDA1 with a novel genetic mutation for the first time in a newborn.
