AIM:To investigate the role of genetic polymorphisms in the progression of hepatic fibrosis in hereditary haemochromatosis.METHODS:A cohort of 245 well-characterised C282Y homozygous patients with haemochromatosis was...AIM:To investigate the role of genetic polymorphisms in the progression of hepatic fibrosis in hereditary haemochromatosis.METHODS:A cohort of 245 well-characterised C282Y homozygous patients with haemochromatosis was studied,with all subjects having liver biopsy data and DNA available for testing.This study assessed the association of eight single nucleotide polymorphisms(SNPs)in a total of six genes including toll-like receptor 4(TLR4),transforming growth factor-beta(TGF-β),oxoguanine DNA glycosylase,monocyte chemoattractant protein 1,chemokine C-C motif receptor 2 and interleukin-10 with liver disease severity.Genotyping was performed using high resolution melt analysis and sequencing.The results were analysed in relation to the stage of hepatic fibrosis in multivariate analysis incorporating other cofactors including alcohol consumption and hepatic iron concentration.RESULTS:There were significant associations between the cofactors of male gender(P=0.0001),increasing age(P=0.006),alcohol consumption(P=0.0001),steatosis(P=0.03),hepatic iron concentration(P<0.0001)and the presence of hepatic fibrosis.Of the candidate gene polymorphisms studied,none showed a significant association with hepatic fibrosis in univariate or multivariate analysis incorporating cofactors.We also specifically studied patients with hepatic iron loading above threshold levels for cirrhosis and compared the genetic polymorphisms between those with no fibrosis vs cirrhosis however there was no significant effect from any of the candidate genes studied.Importantly,in this large,well characterised cohort of patients there was no association between SNPs for TGF-βor TLR4and the presence of fibrosis,cirrhosis or increasing fibrosis stage in multivariate analysis.CONCLUSION:In our large,well characterised group of haemochromatosis subjects we did not demonstrate any relationship between candidate gene polymorphisms and hepatic fibrosis or cirrhosis.展开更多
Haemochromatosis is a genetic disease caused by hepcidin deficiency,responsible for an increase in intestinal iron absorption.Haemochromatosis is associated with homozygosity for the HFE p.Cys282Tyr mutation.However,r...Haemochromatosis is a genetic disease caused by hepcidin deficiency,responsible for an increase in intestinal iron absorption.Haemochromatosis is associated with homozygosity for the HFE p.Cys282Tyr mutation.However,rare cases of haemochromatosis(non-HFE haemochromatosis)can also be caused by path-ogenic variants in other genes(such as HJV,HAMP,TFR2 and SLC40A1).A working group of the International Society for the Study of Iron in Biology and Medicine(BIOIRON Society)has concluded that the classification based in different molecular subtypes is difficult to be adopted in clinical practice and has proposed a new classification approaching clinical questions and molecular complexity.The aim of the present review is to provide an update on classification,pathophysiology and therapeutic recommendations.展开更多
Haemochromatosis is the most common genetic condition among people of European descent,resulting in iron overload and multi-organ dysfunction.Despite early detection and treatment advances,affected individuals experie...Haemochromatosis is the most common genetic condition among people of European descent,resulting in iron overload and multi-organ dysfunction.Despite early detection and treatment advances,affected individuals experience significant morbidity impacting their quality of life(QoL).To scope the literature for QoL issues and rank them in order of relevance by professional bodies.A literature search was conducted using PubMed,EMBASE,and MEDLINE in addition to a grey literature search against the eligibility criteria up to July 2023.Inclusion cri-teria included original articles with data concerning symptoms and QoL in patients with haemochromatosis.Nineteen issues were identified from 47 articles and scored by a haemochromatosis special interest group using a scale of 1 to 10(10=highest importance).Mean scores were then calculated for each issue.Fatigue,joint pain and sexual issues were key factors associated with impaired QoL.The least relevant were weight changes and abdominal pain.Other issues raised were anxiety,the development of diabetes,and concerns about genetics and family.This is the first scoping review examining common symptoms affecting QoL of patients with hereditary haemochromatosis.Further studies,including patient interviews and a randomised controlled trial,will inform a validated QoL questionnaire.展开更多
Iron is an essential element involved in various biological pathways. When present in excess within the cell, iron can be toxic due to its ability to catalyse the formation of damaging radicals, which promote cellular...Iron is an essential element involved in various biological pathways. When present in excess within the cell, iron can be toxic due to its ability to catalyse the formation of damaging radicals, which promote cellular injury and cell death. Within the liver, iron related oxidative stress can lead to fibrosis and ultimately to cirrhosis. Here we review the role of excessive iron in the pathologies associated with various chronic diseases of the liver. We also describe the molecular mechanism by which iron contributes to the development of hepatic fibrosis.展开更多
The carcinogenic potential of iron in colorectal cancer(CRC) is not fully understood.Iron is able to undergo reduction and oxidation,making it important in many physiological processes.This inherent redox property of ...The carcinogenic potential of iron in colorectal cancer(CRC) is not fully understood.Iron is able to undergo reduction and oxidation,making it important in many physiological processes.This inherent redox property of iron,however,also renders it toxic when it is present in excess.Iron-mediated generation of reactive oxygen species via the Fenton reaction,if uncontrolled,may lead to cell damage as a result of lipid peroxidation and oxidative DNA and protein damage.This may promote carcinogenesis through increased genomic instability,chromosomal rearrangements as well as mutations of proto-oncogenes and tumour suppressor genes. Carcinogenesis is also affected by inflammation which is exacerbated by iron.Population studies indicate an association between high dietary iron intake and CRC risk.In this editorial,we examine the link betweeniron-induced oxidative stress and inflammation on the pathogenesis of CRC.展开更多
Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of exc...Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of excess hepatic iron in non-haemochromatotic chronic liver diseases. Indeed, some authors have proposed iron removal in liver diseases other than hereditary haemochromatosis. However, the pathogenesis of secondary iron overload remains unclear. The High Fe （HFE） gene has been implicated, but the reported data are controversial. In this article, we summarise current concepts regarding the cellular role of the HFE protein in iron homeostasis. We review the current status of the literature regarding the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C, hepatitis B, alcoholic and non- alcoholic fatty liver diseases and porphyria cutanea tarda. We discuss the evidence regarding the role of HFE gene mutations in these liver diseases. Finally, we summarize the common and specific features of iron overload in liver diseases other than haemochromatosis.展开更多
AIM： To discover the causes of markedly raised ferritin levels in patients seen at a teaching hospital in Newcastle Upon Tyne, United Kingdom. METHODS： Demographic and medical data were collected for all patients ov...AIM： To discover the causes of markedly raised ferritin levels in patients seen at a teaching hospital in Newcastle Upon Tyne, United Kingdom. METHODS： Demographic and medical data were collected for all patients over 18 years who had a serum ferritin levels recorded as ≥ 1500 μg/L during the period January to September 2002. The cause or causes for their hyperferritinaemia were identified from their medical notes. Patients from a defined local population were identified. RESULTS： A total of 19 583 measurements were provided of which 406 from 199 patients were ≥ 1500 μg/L. An annual incidence for the local population was determined to be 0.44/1000. 150/199 medical notes were scrutinised and 81 patients were identified as having a single cause for their raised ferritin level. The most common single cause was alcoholic liver disease in the local population and renal failure was the most common single cause in the overall population. Confirmed hereditary haemochromatosis was the 10^th most common cause. Liver disease contributed to hyperferritinaemia in 44% of the patients. Weight loss may have contributed to hyperferritinaemia in up to 11%. CONCLUSION： Alcohol related liver disease, haematological disease, renal failure and neoplasia are much more common causes of marked hyperferritinaemia than haemochromatosis. The role of weight loss in hyperferritinaemia may warrant further investigation.展开更多
Hepatocellular carcinoma (HCC) is a major and increasing cause of clinical and economic burden worldwide. Now that there are effective therapies to control or eradicate viral aetiologies, the landscape of HCC is chang...Hepatocellular carcinoma (HCC) is a major and increasing cause of clinical and economic burden worldwide. Now that there are effective therapies to control or eradicate viral aetiologies, the landscape of HCC is changing with alcoholic and metabolic liver diseases becoming major catalysts. The pathogenesis of HCC is complex and incompletely understood, hampering improvements in therapy. Animal models are essential tools for advancing study on the cellular and molecular processes in HCC and for screening potential novel therapies. Many models of hepatocarcinogenesis have been established using various methods including genetic engineering, chemotoxic agents and dietary manipulation to direct implantation of tumour cells. However, none of these can accurately replicate all features found in human diseases. In this review, we provide an overview of different mouse models of HCC with a particular focus on cancer arising from alcoholic liver disease, non-alcoholic fatty liver disease and hereditary haemochromatosis. We also highlight their strengths and limitations and provide perspectives for future study.展开更多
基金Supported by NHMRC Medical Postgraduate Scholarship and the Royal Brisbane and Women’s Hospital Research Foundation to Wood MJthe National Health and Medical Research Council(NHMRC)to Ramm GA and Powell LW+1 种基金the recipient of an NHMRC Senior Research Fellowship,1024672 to Subramaniam VNan NHMRC Senior Research Fellowship,No.552409 to Ramm GA
文摘AIM:To investigate the role of genetic polymorphisms in the progression of hepatic fibrosis in hereditary haemochromatosis.METHODS:A cohort of 245 well-characterised C282Y homozygous patients with haemochromatosis was studied,with all subjects having liver biopsy data and DNA available for testing.This study assessed the association of eight single nucleotide polymorphisms(SNPs)in a total of six genes including toll-like receptor 4(TLR4),transforming growth factor-beta(TGF-β),oxoguanine DNA glycosylase,monocyte chemoattractant protein 1,chemokine C-C motif receptor 2 and interleukin-10 with liver disease severity.Genotyping was performed using high resolution melt analysis and sequencing.The results were analysed in relation to the stage of hepatic fibrosis in multivariate analysis incorporating other cofactors including alcohol consumption and hepatic iron concentration.RESULTS:There were significant associations between the cofactors of male gender(P=0.0001),increasing age(P=0.006),alcohol consumption(P=0.0001),steatosis(P=0.03),hepatic iron concentration(P<0.0001)and the presence of hepatic fibrosis.Of the candidate gene polymorphisms studied,none showed a significant association with hepatic fibrosis in univariate or multivariate analysis incorporating cofactors.We also specifically studied patients with hepatic iron loading above threshold levels for cirrhosis and compared the genetic polymorphisms between those with no fibrosis vs cirrhosis however there was no significant effect from any of the candidate genes studied.Importantly,in this large,well characterised cohort of patients there was no association between SNPs for TGF-βor TLR4and the presence of fibrosis,cirrhosis or increasing fibrosis stage in multivariate analysis.CONCLUSION:In our large,well characterised group of haemochromatosis subjects we did not demonstrate any relationship between candidate gene polymorphisms and hepatic fibrosis or cirrhosis.
文摘Haemochromatosis is a genetic disease caused by hepcidin deficiency,responsible for an increase in intestinal iron absorption.Haemochromatosis is associated with homozygosity for the HFE p.Cys282Tyr mutation.However,rare cases of haemochromatosis(non-HFE haemochromatosis)can also be caused by path-ogenic variants in other genes(such as HJV,HAMP,TFR2 and SLC40A1).A working group of the International Society for the Study of Iron in Biology and Medicine(BIOIRON Society)has concluded that the classification based in different molecular subtypes is difficult to be adopted in clinical practice and has proposed a new classification approaching clinical questions and molecular complexity.The aim of the present review is to provide an update on classification,pathophysiology and therapeutic recommendations.
文摘Haemochromatosis is the most common genetic condition among people of European descent,resulting in iron overload and multi-organ dysfunction.Despite early detection and treatment advances,affected individuals experience significant morbidity impacting their quality of life(QoL).To scope the literature for QoL issues and rank them in order of relevance by professional bodies.A literature search was conducted using PubMed,EMBASE,and MEDLINE in addition to a grey literature search against the eligibility criteria up to July 2023.Inclusion cri-teria included original articles with data concerning symptoms and QoL in patients with haemochromatosis.Nineteen issues were identified from 47 articles and scored by a haemochromatosis special interest group using a scale of 1 to 10(10=highest importance).Mean scores were then calculated for each issue.Fatigue,joint pain and sexual issues were key factors associated with impaired QoL.The least relevant were weight changes and abdominal pain.Other issues raised were anxiety,the development of diabetes,and concerns about genetics and family.This is the first scoping review examining common symptoms affecting QoL of patients with hereditary haemochromatosis.Further studies,including patient interviews and a randomised controlled trial,will inform a validated QoL questionnaire.
文摘Iron is an essential element involved in various biological pathways. When present in excess within the cell, iron can be toxic due to its ability to catalyse the formation of damaging radicals, which promote cellular injury and cell death. Within the liver, iron related oxidative stress can lead to fibrosis and ultimately to cirrhosis. Here we review the role of excessive iron in the pathologies associated with various chronic diseases of the liver. We also describe the molecular mechanism by which iron contributes to the development of hepatic fibrosis.
基金Supported by Grants from the Cancer Council of Western Australia and Fremantle Hospital Medical Research Foundation
文摘The carcinogenic potential of iron in colorectal cancer(CRC) is not fully understood.Iron is able to undergo reduction and oxidation,making it important in many physiological processes.This inherent redox property of iron,however,also renders it toxic when it is present in excess.Iron-mediated generation of reactive oxygen species via the Fenton reaction,if uncontrolled,may lead to cell damage as a result of lipid peroxidation and oxidative DNA and protein damage.This may promote carcinogenesis through increased genomic instability,chromosomal rearrangements as well as mutations of proto-oncogenes and tumour suppressor genes. Carcinogenesis is also affected by inflammation which is exacerbated by iron.Population studies indicate an association between high dietary iron intake and CRC risk.In this editorial,we examine the link betweeniron-induced oxidative stress and inflammation on the pathogenesis of CRC.
文摘Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of excess hepatic iron in non-haemochromatotic chronic liver diseases. Indeed, some authors have proposed iron removal in liver diseases other than hereditary haemochromatosis. However, the pathogenesis of secondary iron overload remains unclear. The High Fe （HFE） gene has been implicated, but the reported data are controversial. In this article, we summarise current concepts regarding the cellular role of the HFE protein in iron homeostasis. We review the current status of the literature regarding the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C, hepatitis B, alcoholic and non- alcoholic fatty liver diseases and porphyria cutanea tarda. We discuss the evidence regarding the role of HFE gene mutations in these liver diseases. Finally, we summarize the common and specific features of iron overload in liver diseases other than haemochromatosis.
文摘AIM： To discover the causes of markedly raised ferritin levels in patients seen at a teaching hospital in Newcastle Upon Tyne, United Kingdom. METHODS： Demographic and medical data were collected for all patients over 18 years who had a serum ferritin levels recorded as ≥ 1500 μg/L during the period January to September 2002. The cause or causes for their hyperferritinaemia were identified from their medical notes. Patients from a defined local population were identified. RESULTS： A total of 19 583 measurements were provided of which 406 from 199 patients were ≥ 1500 μg/L. An annual incidence for the local population was determined to be 0.44/1000. 150/199 medical notes were scrutinised and 81 patients were identified as having a single cause for their raised ferritin level. The most common single cause was alcoholic liver disease in the local population and renal failure was the most common single cause in the overall population. Confirmed hereditary haemochromatosis was the 10^th most common cause. Liver disease contributed to hyperferritinaemia in 44% of the patients. Weight loss may have contributed to hyperferritinaemia in up to 11%. CONCLUSION： Alcohol related liver disease, haematological disease, renal failure and neoplasia are much more common causes of marked hyperferritinaemia than haemochromatosis. The role of weight loss in hyperferritinaemia may warrant further investigation.
文摘Hepatocellular carcinoma (HCC) is a major and increasing cause of clinical and economic burden worldwide. Now that there are effective therapies to control or eradicate viral aetiologies, the landscape of HCC is changing with alcoholic and metabolic liver diseases becoming major catalysts. The pathogenesis of HCC is complex and incompletely understood, hampering improvements in therapy. Animal models are essential tools for advancing study on the cellular and molecular processes in HCC and for screening potential novel therapies. Many models of hepatocarcinogenesis have been established using various methods including genetic engineering, chemotoxic agents and dietary manipulation to direct implantation of tumour cells. However, none of these can accurately replicate all features found in human diseases. In this review, we provide an overview of different mouse models of HCC with a particular focus on cancer arising from alcoholic liver disease, non-alcoholic fatty liver disease and hereditary haemochromatosis. We also highlight their strengths and limitations and provide perspectives for future study.
