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1.
Clin Gastroenterol Hepatol ; 18(8): 1851-1857, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-31622736

RESUMEN

BACKGROUND & AIMS: Fibrosis stage can decrease following treatment in patients with hemochromatosis caused by mutations in the homeostatic iron regulator gene (HFE), but the effects on cirrhosis are not clear. We assessed regression of severe fibrosis and the ensuing risk of liver cancer after treatment. METHODS: We performed a retrospective analysis of data from 106 patients in France or Australia who were homozygous for the C282Y mutation in HFE with F3 fibrosis (n = 40) or F4 fibrosis (n = 66) at diagnosis and from whom at least 1 liver biopsy was collected during follow up. We collected data from the time of first biopsy and during follow-up period on patient demographics, treatment, smoking habits, alcohol consumption, infection with hepatitis B or C viruses, and other diseases. The median time between first and last liver biopsy was 9.5 years (range, 3.5-15.6 years). We collected results of tests for liver function, markers of iron stores, and platelet levels. Patients were followed for a median 17.6 years (range, 9.8-24.1 years) for development of liver cancer occurrence. RESULTS: At last liver biopsy, 41 patients (38.6%) had fibrosis scores of F2 or less. Liver cancer occurred in 34 patients (52.3%) with F3 or F4 fibrosis at last liver biopsy vs 2 patients (4.8%) with fibrosis scores of F2 or less at last liver biopsy (P < .001). Liver cancer incidences were 32.8 per 1000 person-years (95% CI, 22.7-45.9 per 1000 person-years) in patients with F3 or F4 fibrosis and 2.3 per 1000 person-years (95% CI, 0.2-8.6 per 1000 person-years) in patients with fibrosis scores of F2 or less (P < .001). In multivariate analysis, male sex (hazard ratio [HR], 6.09; 95% CI, 1.21-30.4), age at diagnosis (HR, 1.16; 95% CI, 1.09-1.25), presence of diabetes (HR, 3.07; 95% CI, 1.35-6.97), excess alcohol consumption (HR, 3.1; 95% CI, 1.47-6.35), serum level of ferritin at diagnosis (P < .01), and regression to fibrosis scores of F2 or less (HR, 0.08; 95% CI, 0.01-0.62) were significantly associated with risk of liver cancer. CONCLUSIONS: In a retrospective analysis of patients with hemochromatosis caused by the C282Y mutation in HFE, we found that severe liver fibrosis can regress with treatment. In patients with fibrosis regression to a stage F2 or less, the long-term risk for liver cancer is significantly reduced.


Asunto(s)
Hemocromatosis , Neoplasias Hepáticas , Genes Reguladores , Hemocromatosis/complicaciones , Hemocromatosis/epidemiología , Hemocromatosis/genética , Proteína de la Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Hígado/patología , Cirrosis Hepática/patología , Neoplasias Hepáticas/patología , Masculino , Proteínas de la Membrana/genética , Mutación , Estudios Retrospectivos
2.
Blood ; 132(1): 101-110, 2018 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-29743178

RESUMEN

The clinical progression of HFE-related hereditary hemochromatosis (HH) and its phenotypic variability has been well studied. Less is known about the natural history of non-HFE HH caused by mutations in the HJV, HAMP, or TFR2 genes. The purpose of this study was to compare the phenotypic and clinical presentations of hepcidin-deficient forms of HH. A literature review of all published cases of genetically confirmed HJV, HAMP, and TFR2 HH was performed. Phenotypic and clinical data from a total of 156 patients with non-HFE HH was extracted from 53 publications and compared with data from 984 patients with HFE-p.C282Y homozygous HH from the QIMR Berghofer Hemochromatosis Database. Analyses confirmed that non-HFE forms of HH have an earlier age of onset and a more severe clinical course than HFE HH. HJV and HAMP HH are phenotypically and clinically very similar and have the most severe presentation, with cardiomyopathy and hypogonadism being particularly prevalent findings. TFR2 HH is more intermediate in its age of onset and severity. All clinical outcomes analyzed were more prevalent in the juvenile forms of HH, with the exception of arthritis and arthropathy, which were more commonly seen in HFE HH. This is the first comprehensive analysis comparing the different phenotypic and clinical aspects of the genetic forms of HH, and the results will be valuable for the differential diagnosis and management of these conditions. Importantly, our analyses indicate that factors other than iron overload may be contributing to joint pathology in patients with HFE HH.


Asunto(s)
Proteína de la Hemocromatosis/genética , Hemocromatosis , Hepcidinas/genética , Mutación Missense , Fenotipo , Receptores de Transferrina/genética , Índice de Severidad de la Enfermedad , Adulto , Femenino , Hemocromatosis/genética , Hemocromatosis/patología , Humanos , Masculino
3.
Hepatology ; 56(3): 904-11, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22422567

RESUMEN

UNLABELLED: The risk of hepatic fibrosis and cirrhosis in hereditary hemochromatosis relates to the degree of iron loading, but iron alone does not explain the variability in disease penetrance. This study sought to identify clinical cofactors that increase the risk of progressive liver disease. We identified 291 patients from our database who were homozygous for the C282Y mutation in HFE and had undergone a liver biopsy with quantification of hepatic iron concentration (HIC) and fibrosis staging. Data were collected from a retrospective chart review, including age, gender, alcohol consumption, medical therapy, smoking history, metabolic risk factors, mobilizable iron, and laboratory results. Male gender, excess alcohol consumption, HIC, and the presence of diabetes were independently associated with increasing fibrosis stage in multivariate analysis. Of these, the presence of diabetes showed the strongest association (odds ratio, 7.32; P = 0.03). The presence of steatosis was associated with higher fibrosis scores, but this was of borderline statistical significance. Risk factors for hepatic steatosis were male gender, impaired glucose tolerance, and increased body mass index. CONCLUSION: The presence of diabetes was associated with more severe hepatic fibrosis independent of iron loading, male gender, and alcohol consumption. The mechanism for this association is unknown and deserves further evaluation; however, it is possible that diabetes produces an additional hepatic oxidative injury from hyperglycemia. Thus, management of such cofactors in patients with hemochromatosis is important to reduce the risk of liver injury and fibrosis.


Asunto(s)
Complicaciones de la Diabetes/complicaciones , Hemocromatosis/complicaciones , Cirrosis Hepática/etiología , Adulto , Femenino , Hemocromatosis/genética , Proteína de la Hemocromatosis , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Masculino , Proteínas de la Membrana/genética , Estudios Retrospectivos , Factores de Riesgo
4.
Arch Intern Med ; 166(3): 294-301, 2006 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-16476869

RESUMEN

BACKGROUND: Hemochromatosis in white subjects is mostly due to homozygosity for the common C282Y substitution in HFE. Although clinical symptoms are preventable by early detection of the genetic predisposition and prophylactic treatment, population screening is not currently advocated because of the discrepancy between the common mutation prevalence and apparently lower frequency of clinical disease. This study compared screening for hemochromatosis in subjects with or without a family history. METHODS: We assessed disease expression by clinical evaluation and liver biopsy in 672 essentially asymptomatic C282Y homozygous subjects identified by either family screening or health checks. We also observed a subgroup of untreated homozygotes with normal serum ferritin levels for up to 24 years. RESULTS: Prevalence of hepatic iron overload and fibrosis were comparable between the 2 groups. Disease-related conditions were more common in male subjects identified by health checks, but they were older. Hepatic iron overload (grades 2-4) was present in 56% and 34.5% of male and female subjects, respectively; hepatic fibrosis (stages 2-4) in 18.4% and 5.4%; and cirrhosis in 5.6% and 1.9%. Hepatic fibrosis and cirrhosis correlated significantly with the hepatic iron concentration, and except in cases of cirrhosis, there was a 7.5-fold reduction in the mean fibrosis score after phlebotomy. All subjects with cirrhosis were asymptomatic. CONCLUSIONS: Screening for hemochromatosis in apparently healthy subjects homozygous for the C282Y mutation with or without a family history reveals comparable levels of hepatic iron overload and disease. Significant hepatic fibrosis is frequently found in asymptomatic subjects with hemochromatosis and, except when cirrhosis is present, is reversed by iron removal.


Asunto(s)
Hemocromatosis/diagnóstico , Tamizaje Masivo , Adolescente , Adulto , Factores de Edad , Anciano , Alanina Transaminasa/sangre , Australia/epidemiología , Biopsia , Niño , Estudios de Cohortes , Femenino , Ferritinas/sangre , Hemocromatosis/genética , Hemocromatosis/metabolismo , Homocigoto , Humanos , Sobrecarga de Hierro/metabolismo , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/metabolismo , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Curva ROC , Sensibilidad y Especificidad , Factores Sexuales
5.
Best Pract Res Clin Haematol ; 18(2): 221-34, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15737886

RESUMEN

Hereditary haemochromatosis is a primary inherited disorder of iron metabolism leading to progressive iron loading of parenchymal cells of the liver and other organs with diverse clinical manifestations, including cirrhosis, diabetes and skin pigmentation. This chapter will focus on HFE-associated hereditary haemochromatosis, which accounts for approximately 90% of cases in Caucasian populations. Penetrance is incomplete, with variable clinical expression. The majority of cases demonstrate biochemical expression, but a much lower proportion develop advanced disease. Clinical disease--especially hepatic fibrosis--is related to the level of body iron stores, which is reflected primarily in the liver. The available evidence indicates that adequate screening and diagnostic strategies ensure that early case detection and treatment occur prior to the development of irreversible end-organ damage. The most cost-effective methods of early case detection are family (cascade) screening and evaluation of potential cases by primary care physicians with a high index of clinical suspicion.


Asunto(s)
Pruebas Genéticas/métodos , Hemocromatosis/diagnóstico , Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Proteínas de la Membrana/genética , Hemocromatosis/terapia , Proteína de la Hemocromatosis , Antígenos de Histocompatibilidad Clase I/clasificación , Humanos , Hierro/metabolismo , Proteínas de la Membrana/clasificación , Penetrancia , Prevalencia
6.
Haematologica ; 90(2): 254-5, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15710580

RESUMEN

Juvenile hemochromatosis is a severe form of hereditary iron overload. It can be caused by mutations in either hepcidin or hemojuvelin genes. In this study we identified the molecular basis of juvenile hemochromatosis in three Australian families and assessed the role of potential modifying genes in individuals carrying HFE mutations.


Asunto(s)
Hemocromatosis/metabolismo , Sobrecarga de Hierro , Proteínas de la Membrana/metabolismo , Mutación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Péptidos Catiónicos Antimicrobianos/metabolismo , Australia , Salud de la Familia , Femenino , Proteínas Ligadas a GPI , Proteína de la Hemocromatosis , Hepcidinas , Humanos , Masculino , Persona de Mediana Edad , Linaje
7.
BMJ Open ; 5(8): e008938, 2015 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-26270952

RESUMEN

INTRODUCTION: HFE p.C282Y homozygosity is the most common cause of hereditary haemochromatosis. There is currently insufficient evidence to assess whether non-specific symptoms or hepatic injury in homozygotes with moderately elevated iron defined as a serum ferritin (SF) of 300-1000 µg/L are related to iron overload. As such the evidence for intervention in this group is lacking. We present here methods for a study that aims to evaluate whether non-specific symptoms and hepatic fibrosis markers improve with short-term normalisation of SF in p.C282Y homozygotes with moderate elevation of SF. METHODS AND ANALYSIS: Mi-iron is a prospective, multicentre, randomised patient-blinded trial conducted in three centres in Victoria and Queensland, Australia. Participants who are HFE p.C282Y homozygotes with SF levels between 300 and 1000 µg/L are recruited and randomised to either the treatment group or to the sham treatment group. Those in the treatment group have normalisation of SF by 3-weekly erythrocytapheresis while those in the sham treatment group have 3-weekly plasmapheresis and thus do not have normalisation of SF. Patients are blinded to all procedures. All outcome measures are administered prior to and following the course of treatment/sham treatment. Patient reported outcome measures are the Modified Fatigue Impact Scale (MFIS-primary outcome), Hospital Anxiety and Depression Scale (HADS), Medical Outcomes Study 36-item short form V.2 (SF36v2) and Arthritis Impact Measurement Scale 2 short form (AIMS2-SF). Liver injury and hepatic fibrosis are assessed with transient elastography (TE), Fibrometer and Hepascore, while oxidative stress is assessed by measurement of urine and serum F2-isoprostanes. ETHICS AND DISSEMINATION: This study has been approved by the Human Research Ethics Committees of Austin Health, Royal Melbourne Hospital and Royal Brisbane and Women's Hospital. Study findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION: Trial identifier: NCT01631708; Registry: ClinicalTrials.gov.


Asunto(s)
Eliminación de Componentes Sanguíneos , Transfusión de Eritrocitos , Ferritinas/sangre , Antígenos de Histocompatibilidad Clase I/genética , Homocigoto , Sobrecarga de Hierro/terapia , Proteínas de la Membrana/genética , Adolescente , Adulto , Anciano , Proteína de la Hemocromatosis , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Adulto Joven
8.
World J Gastroenterol ; 19(48): 9366-76, 2013 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-24409064

RESUMEN

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-ß), 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-ß or TLR4 and 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.


Asunto(s)
Hemocromatosis/genética , Cirrosis Hepática/genética , Polimorfismo de Nucleótido Simple , Receptor Toll-Like 4/genética , Factor de Crecimiento Transformador beta/genética , Adulto , Biopsia , Distribución de Chi-Cuadrado , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Hemocromatosis/complicaciones , Hemocromatosis/inmunología , Homocigoto , Humanos , Cirrosis Hepática/inmunología , Cirrosis Hepática/patología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Fenotipo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Adulto Joven
9.
Vaccine ; 25(13): 2375-8, 2007 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-17030079

RESUMEN

This study reports a 16-year prospective surveillance of invasive disease isolates in central Australian Aborigines. There were 621 (89.6% of total) isolates recovered from Aborigines. The mortality in children less than 5 years of age was 4% but rose to 34.5% in those over 49 years of age. The study documented continuing high rates of disease overall, but with significant reductions in incidence rates for children. In children under 2 years of age, the incidence fell by 32% from 2053 per 100,000 in the period 1985-1990 to 1184 per 100,000 in the period 1996-2000. Rates of disease in adults showed no reduction despite an adult immunisation programme with 23 valent vaccine which occurred in the 1990s. Epidemics of serotypes 1, 5 and 12F were documented during the study period.


Asunto(s)
Nativos de Hawái y Otras Islas del Pacífico , Infecciones Neumocócicas/etnología , Infecciones Neumocócicas/epidemiología , Vacunas Neumococicas/uso terapéutico , Streptococcus pneumoniae/aislamiento & purificación , Adolescente , Adulto , Anciano , Australia/epidemiología , Niño , Preescolar , Brotes de Enfermedades , Humanos , Incidencia , Lactante , Persona de Mediana Edad , Infecciones Neumocócicas/prevención & control , Estudios Prospectivos , Factores de Riesgo , Vacunas Conjugadas/uso terapéutico
10.
J Hepatol ; 46(5): 921-6, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17383046

RESUMEN

BACKGROUND/AIMS: Hereditary iron overload is associated with mutations in a number of genes involved in the regulation of iron metabolism. In this study we examined the molecular basis of iron overload in an individual from New Zealand and characterised the molecular and cellular defect. METHODS: We analysed the ferroportin gene and a control population was screened using allele-specific PCR and denaturation analysis. Molecular characterisation was performed by immunofluorescence microscopy analysis of transfected cells. We analysed the ferritin levels of cells expressing wild-type and mutant ferroportin to define the nature of the molecular defect on iron transport. RESULTS: We identified a novel nucleotide substitution (c. 1014T>G) in the ferroportin gene leading to the S338R mutation. This mutation is not a common polymorphism. Cellular analysis of the mutant protein indicates that this amino acid change does not affect the localisation of the protein or its ability to transport iron. CONCLUSIONS: The S338R mutation results in a mutated ferroportin associated with iron overload and is predicted insensitive to regulation by the iron regulatory hormone hepcidin.


Asunto(s)
Proteínas de Transporte de Catión/genética , Ferritinas/metabolismo , Sobrecarga de Hierro/genética , Proteínas Reguladoras del Hierro/metabolismo , Mutación/genética , Anciano , Sustitución de Aminoácidos , Biopsia con Aguja , Células Cultivadas , Humanos , Sobrecarga de Hierro/patología , Hígado/metabolismo , Hígado/ultraestructura , Masculino , Nueva Zelanda
11.
Clin Gastroenterol Hepatol ; 4(11): 1403-10, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16979952

RESUMEN

BACKGROUND & AIMS: Two major mutations are defined within the hemochromatosis gene, HFE. Although the effects of the C282Y substitution have been well characterized, the clinical significance of the C282Y/H63D state remains unclear. This study assessed the phenotypic expression in C282Y/H63D subjects as compared with C282Y homozygotes. METHODS: Data were obtained from 91 C282Y/H63D probands, 158 C282Y/H63D subjects identified through family screening, and 483 C282Y homozygotes. Subjects underwent clinical evaluation, genotyping, biochemical assessment, and liver biopsy examination where clinically indicated. RESULTS: C282Y/H63D probands had significantly less clinical and biochemical expression than C282Y homozygotes. Biochemical expression was higher in C282Y/H63D probands than in C282Y/H63D subjects identified through family screening (P < .001). Of the C282Y/H63D subjects with serum ferritin levels greater than 1000 mug/L, all had known comorbid factors that could have contributed to the increased ferritin level. Of the 51 C282Y/H63D subjects who underwent liver biopsy examination, significantly increased iron stores were present in 9 subjects and hepatic fibrosis was present in 13. Twelve of the 13 had evidence of hepatic steatosis, excess alcohol consumption, or diabetes. The mobilizable iron level was significantly higher in C282Y homozygous males than in compound heterozygous males (P < .001). Genetic screening of C282Y/H63D first-degree relatives detected 5 C282Y homozygotes. CONCLUSIONS: C282Y/H63D subjects referred for assessment had a high prevalence of increased iron indices but did not develop progressive clinical disease without comorbid factors such as steatosis, diabetes, or excess alcohol consumption. When fibrosis was seen, 1 or more comorbid factors almost always were present. Thus, phlebotomy therapy is warranted and cascade screening of relatives should be performed because expressing C282Y homozygotes may be detected.


Asunto(s)
Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Proteínas de la Membrana/genética , Adulto , Comorbilidad , Progresión de la Enfermedad , Femenino , Ferritinas/sangre , Hemocromatosis/sangre , Hemocromatosis/epidemiología , Proteína de la Hemocromatosis , Heterocigoto , Homocigoto , Humanos , Hierro/metabolismo , Hígado/química , Masculino , Persona de Mediana Edad , Fenotipo
12.
J Genet Couns ; 14(6): 453-63, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16388326

RESUMEN

This study assessed psychological adjustment and quality of life relative to population-based norms and knowledge about hereditary hemochromatosis in a sample of 101 patients who attended a hemochromatosis clinic. Participants were assessed prior to their clinic visit, and two weeks and 12 months after attendance, using self-administered questionnaires. Mean Mental Health Component Scores from the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) (45.3, 95% CI 43.2, 47.4) were as compromised as those found amongst stroke victims (45.9, 95% CI 42.8, 49.0) who had participated in a national health survey. Recall of the genetic testing result was less than optimal, in that only 69.3% of those with genetic testing results knew whether they carried one or two mutations. This study demonstrates that patients would benefit from routine assessment of psychological distress and referral to mental health professionals of those whose levels of distress suggest a need for clinical intervention. Results also show that patients may benefit from strategies aimed at improving recall of genetic testing results.


Asunto(s)
Adaptación Psicológica , Concienciación , Asesoramiento Genético/psicología , Pruebas Genéticas/psicología , Hemocromatosis/genética , Hemocromatosis/psicología , Antígenos de Histocompatibilidad Clase I/genética , Proteínas de la Membrana/genética , Adolescente , Adulto , Anciano , Actitud Frente a la Salud , Femenino , Estudios de Seguimiento , Genotipo , Encuestas Epidemiológicas , Proteína de la Hemocromatosis , Humanos , Masculino , Persona de Mediana Edad , Cooperación del Paciente/psicología , Estudios Prospectivos , Calidad de Vida/psicología , Encuestas y Cuestionarios
13.
Gastroenterology ; 129(6): 1937-43, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16344062

RESUMEN

BACKGROUND & AIMS: Obesity-related steatosis is an increasingly common histologic finding and often coexists with other chronic liver diseases. Although obesity and steatosis are recognized risk factors for more advanced fibrosis in chronic hepatitis C and alcoholic liver disease, it has not been determined whether these factors influence the progression of other diseases in which steatosis is not a feature of the primary liver insult. METHODS: We studied 214 patients with hemochromatosis who were homozygous for the C282Y substitution in HFE and had undergone liver biopsy prior to phlebotomy. RESULTS: Steatosis was present in 41.1% of these patients, and 14.5% had moderate or severe steatosis. Median serum alanine aminotransferase (ALT) and ferritin levels were higher (P < .001), and median transferrin saturation (P = .01) and hepatic iron concentration (HIC) were lower (P = .003) in subjects with steatosis compared with subjects without steatosis. Bivariate analysis revealed a significant association between steatosis and fibrosis (P = .001). Following multiple logistic regression, steatosis was independently associated with fibrosis (odds ratio [OR] 4.3, 95% confidence interval [CI]: 2.1-8.8; P < .001) along with male sex (OR, 5.1; 95% CI: 2.0-12.5; P < .001), excess alcohol consumption (males > or = 50 g/day, females > or = 40 g/day) (OR, 3.9; 95% CI: 1.8-8.5; P = .001), and hepatic iron content (OR, 1.4; 95% CI: 1.2-1.6; P < .001). Both higher BMI (OR, 3.3; 95% CI: 1.8-6.3; P < .001) and alcohol consumption (males > or = 30 g/day, females > or = 10 g/day) (OR, 3.4; 95% CI: 1.2-10.0; P = .023) were independently associated with the presence of steatosis. CONCLUSIONS: These findings indicate that obesity-related steatosis may have a role as a cofactor in liver injury in hemochromatosis. This has important clinical implications and suggests that obesity should be actively addressed in the management of patients with hemochromatosis, as well as other liver diseases.


Asunto(s)
Hígado Graso/patología , Hemocromatosis/patología , Hepatopatías/patología , Obesidad/patología , Adolescente , Adulto , Anciano , Consumo de Bebidas Alcohólicas , Biopsia , Índice de Masa Corporal , Hígado Graso/fisiopatología , Femenino , Fibrosis/patología , Hemocromatosis/genética , Hemocromatosis/fisiopatología , Proteína de la Hemocromatosis , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Hierro/metabolismo , Hepatopatías/genética , Hepatopatías/fisiopatología , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Obesidad/etiología , Mutación Puntual , Factores de Riesgo
14.
Gastroenterology ; 122(2): 281-9, 2002 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11832443

RESUMEN

BACKGROUND & AIMS: The progression of fibrosis to cirrhosis is the most significant prognostic factor in hereditary hemochromatosis. We aimed to determine the range of hepatic iron concentration associated with cirrhosis in the absence of alcohol and other pro-fibrogenic cofactors and to quantify the contribution of excess alcohol consumption to the development of cirrhosis. METHODS: Liver biopsy data were evaluated on 224 C282Y homozygous hemochromatosis subjects. To determine the effect of alcohol alone on the development of fibrosis, subjects with viral hepatitis or nonalcoholic steatohepatitis were excluded. Subjects were divided into those who consumed less than 60 g alcohol per day and those who consumed 60 g per day or more. RESULTS: Seven percent of subjects who consumed less than 60 g per day had severe fibrosis/cirrhosis compared with 61% of excess alcohol consumers. CONCLUSIONS: Hemochromatosis subjects who drink more than 60 g alcohol per day are approximately 9 times more likely to develop cirrhosis than those who drink less than this amount, and the range of hepatic iron concentration associated with cirrhosis in the absence of cofactors was 233-675 micromol/g dry weight.


Asunto(s)
Consumo de Bebidas Alcohólicas/efectos adversos , Hemocromatosis/epidemiología , Cirrosis Hepática/epidemiología , Adulto , Anciano , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Femenino , Ferritinas/sangre , Hemocromatosis/genética , Hemocromatosis/patología , Humanos , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , Prevalencia , gamma-Glutamiltransferasa/sangre
15.
Blood ; 100(2): 692-4, 2002 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-12091366

RESUMEN

Hemochromatosis is a common disorder characterized by excess iron absorption and accumulation of iron in tissues. Usually hemochromatosis is inherited in an autosomal recessive pattern and is caused by mutations in the HFE gene. Less common non-HFE-related forms of hemochromatosis have been reported and are caused by mutations in the transferrin receptor 2 gene and in a gene localized to chromosome 1q. Autosomal dominant forms of hemochromatosis have also been described. Recently, 2 mutations in the ferroportin1 gene, which encodes the iron transport protein ferroportin1, have been implicated in families with autosomal dominant hemochromatosis from the Netherlands and Italy. We report the finding of a novel mutation (V162del) in ferroportin1 in an Australian family with autosomal dominant hemochromatosis. We propose that this mutation disrupts the function of the ferroportin1 protein, leading to impaired iron homeostasis and iron overload.


Asunto(s)
Proteínas de Transporte de Catión/genética , Hemocromatosis/genética , Eliminación de Secuencia , Adulto , Anciano , Australia , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Genes Dominantes , Hemocromatosis/metabolismo , Hemocromatosis/patología , Humanos , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/genética , Sobrecarga de Hierro/patología , Hígado/patología , Masculino , Persona de Mediana Edad , Fenotipo
16.
J Hepatol ; 36(4): 474-9, 2002 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11943417

RESUMEN

BACKGROUND/AIMS: HFE-related haemochromatosis is a common disorder of iron metabolism. Most affected individuals are homozygous for the C282Y mutation of HFE. Some are compound heterozygotes for C282Y/H63D. A small proportion have neither of these genotypes. We have investigated the phenotype of compound heterozygotes for C282Y and another missense mutation S65C. METHODS: Genotype for the S65C mutation was determined in 309 subjects heterozygous for C282Y and negative for H63D, referred because of increased serum iron indices or family screening. A control sample comprising 315 individuals was also studied. RESULTS: Twelve individuals were compound heterozygotes for C282Y and S65C. Seven, referred for family screening, had normal serum iron indices. Five subjects had elevated serum iron indices; three of these had elevated hepatic iron and have received treatment for iron overload. Transferrin saturation was significantly elevated in C282Y/S65C compound heterozygotes compared with simple C282Y heterozygotes. CONCLUSIONS: Some C282Y/S65C compound heterozygotes have elevated serum iron indices and iron overload. The penetrance of this genotype is low and other genetic and environmental factors may influence the expression of iron loading. Screening for S65C may be useful in individuals with iron overload who are not homozygous for C282Y or compound heterozygous for C282Y/H63D.


Asunto(s)
Frecuencia de los Genes , Antígenos HLA/genética , Heterocigoto , Antígenos de Histocompatibilidad Clase I/genética , Sobrecarga de Hierro/genética , Proteínas de la Membrana , Mutación/genética , Adulto , Anciano , Alelos , Femenino , Proteína de la Hemocromatosis , Humanos , Hierro/sangre , Hierro/metabolismo , Sobrecarga de Hierro/sangre , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Transferrina/metabolismo
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