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V Byrnes

Publications and source records attributed to V Byrnes.

8 recordsLinked to original sources
PubMed2004

Increased DMT1 but not IREG1 or HFE mRNA following iron depletion therapy in hereditary haemochromatosis.

BACKGROUND AND AIMS: While upregulation of divalent metal transporter 1 (DMT1) and iron regulated gene 1 (IREG1) within duodenal enterocytes is reported in patients with hereditary haemochromatosis (HH), these findings are controversial. Furthermore, the effect of HFE, the gene mutated in HH, on expression of these molecules is unclear. This study examines duodenal expression of these three molecules in HH patients (prior to and following phlebotomy), in patients with iron deficiency (ID), and in controls. METHODS: DMT1, IREG1, and HFE mRNA were measured in duodenal tissue of C282Y homozygous HH patients, in ID patients negative for the C282Y mutation with a serum ferritin concentration less than 20 microg/l, and in controls negative for C282Y and H63D mutations with normal iron indices, using real time polymerase chain reaction. RESULTS: DMT1 and IREG1 mRNA levels were not significantly different in non-phlebotomised (untreated) HH patients compared with controls. DMT1 expression was significantly increased in HH patients who had undergone phlebotomy therapy (treated) and in patients with ID compared with controls. IREG1 was significantly increased in ID patients relative to controls, and while IREG1 expression was 1.8-fold greater in treated HH patients, this was not statistically significant. HFE mRNA expression was not significantly different in any of the groups investigated relative to controls. CONCLUSIONS: These findings demonstrate that untreated HH patients do not have increased duodenal DMT1 and IREG mRNA, but rather phlebotomy increases expression of these molecules, reflecting the effect of phlebotomy induced erythropoiesis. Finally, HFE appears to play a minor role in the regulation of iron absorption by the duodenal enterocyte.

Adult↗
PubMed2002

Underdiagnosis of hereditary haemochromatosis: lack of presentation or penetration?

BACKGROUND: The majority of hereditary haemochromatosis (HH) patients are homozygous for the C282Y mutation in the HFE gene. We have demonstrated a homozygote frequency of 1 in 83 for the C282Y mutation in a retrospective analysis of Irish neonates. However, a fully developed phenotype is not observed at the same frequency clinically, suggesting that a large proportion of Irish HH patients may remain undiagnosed. AIMS: To determine whether underdiagnosis of HH results from the non-specific nature of early symptoms or incomplete penetrance of the C282Y mutation. METHODS: Seventy nine C282Y homozygous individuals identified from family screening for HH and 30 HH probands were investigated. Non-specific symptoms (fatigue, arthropathy, and impotence) and their association with iron indices (transferrin saturation and serum ferritin) and hepatic iron deposition were analysed. RESULTS: We found that 78% of men (mean age 42 years) and 36% of women (mean age 39 years) who were identified as C282Y homozygotes following family screening had iron overload, as defined by a transferrin saturation >or=52% combined with a serum ferritin >or=300 microg/l for men and >or=200 microg/l for women. The frequency of reports of non-specific symptoms in those individuals with iron overload was not significantly different from those who did not have iron overload. CONCLUSIONS: Our findings indicate that underdiagnosis of HH may be due to the non-specific nature of early symptoms and less frequently to the incomplete penetrance of the C282Y mutation.

Adult↗
PubMed2001

Genetic hemochromatosis, a Celtic disease: is it now time for population screening?

In populations of northern European ancestry, hereditary hemochromatosis (HH) is tightly linked to mutations within the hemochromatosis gene (HFE gene). Over 93% of Irish HH patients are homozygous for the HFE gene C282Y mutation, providing a reliable diagnostic marker of the disease in this population. However, the prevalence of the C282Y mutation and that of the second HFE gene mutation, H63D, have yet to be determined within the Irish population. The objective of this study was to identify the true prevalence of the genetic form of HH in the Irish population. DNA was extracted from 1002 randomly selected newborn screening cards and analyzed for the C282Y and H63D mutations within the HFE gene. Complete results were obtained from 800 cards. Mutations were identified in 364 (46%) neonates. Eight (1%) neonates were homozygous for C282Y and 8 (1%) were homozygous for H63D. One hundred and fifty-five (19%) neonates were C282Y heterozygous and 226 (28%) were H63D heterozygous. Of these, 33 (4%) carried one copy of both C282Y and H63D mutations, i.e., compound heterozygous. Allele frequencies for C282Y and H63D were 11% and 15%, respectively. The high C282Y allele frequency in the Irish population together with its close linkage to HH indicate that C282Y genotyping is the preferred screening strategy for this disease in Ireland.

Ethnicity↗
PubMed2000

Immunohistochemistry of the Hfe protein in patients with hereditary hemochromatosis, iron deficiency anemia, and normal controls.

In 1996 two mutations in Hfe, the gene affected in hereditary hemochromatosis, were identified as C282Y (c.845G. A) and H63D (c.187C. G). Immunohistochemical studies have localized the protein product of Hfe to the deep crypts of the duodenum, the maximum site of iron absorption. To date, there are no published data on the cellular location and regulation of Hfe in patients with hemochromatosis who are homozygous for C282Y. The aim of this study was to identify the cellular localization of Hfe in genotyped individuals and to study possible regulation of this protein by the mutations described in the Hfe gene locus and iron deficiency. Duodenal biopsy specimens and serum for iron, ferritin, and transferrin saturation were taken from controls (n = 10) and patients with hereditary hemochromatosis (n = 10) and iron deficiency anemia (n = 10). All participants were genotyped for C282Y and H63D mutations. Expression of Hfe in the duodenum was demonstrated by immunohistochemistry. Hfe was expressed in the deep crypts of the duodenum in all three groups in a perinuclear fashion. Hfe staining was weaker in the hemochromatosis and iron deficiency patients (mean transferrin saturation 69.6%, SD 23% and 15%, SD 11%, respectively) when compared to controls (mean transferrin saturation 33.1%, SD 15%). There was no difference in the intensity of Hfe staining within the hemochromatosis group who were iron overloaded when compared to their iron-depleted counterparts. In summary, Hfe is expressed strongly in the deep crypts of the small intestine of normal subjects. Homozygosity for C282Y and conditions of iron deficiency result in a downregulation of Hfe. Furthermore, Hfe is not regulated by therapeutic iron depletion in patients with hemochromatosis who are homozygous for the C282Y mutation.

Anemia, Iron-Deficiency↗
PubMedDate not supplied

Increased duodenal DMT-1 expression and unchanged HFE mRNA levels in HFE-associated hereditary hemochromatosis and iron deficiency.

HFE-associated hereditary hemochromatosis is characterized by imbalances of iron homeostasis and alterations in intestinal iron absorption. The identification of the HFE gene and the apical iron transporter divalent metal transporter-1, DMT-1, provide a direct method to address the mechanisms of iron overload in this disease. The aim of this study was to evaluate the regulation of duodenal HFE and DMT-1 gene expression in HFE-associated hereditary hemochromatosis. Small bowel biopsies and serum iron indices were obtained from a total of 33 patients. The study population comprised 13 patients with hereditary hemochromatosis (C282Y homozygous), 10 patients with iron deficiency anemia, and 10 apparently healthy controls, all of whom were genotyped for the two common mutations in the HFE gene (C282Y and H63D). Total RNA was isolated from tissue and amplified via RT-PCR for HFE, DMT-1, and the internal control GAPDH. DMT-1 protein expression was additionally assessed by immunohistochemistry. Levels of HFE mRNA did not differ significantly between patient groups (P = 0.09), specifically between C282Y homozygotes and iron deficiency anemic patients, when compared to controls (P = 0.09, P = 0.9, respectively). In contrast, DMT-1 mRNA levels were at least twofold greater in patients with hereditary hemochromatosis and iron deficiency anemia when compared to controls (P = 0.02, P = 0.01, respectively). Heightened DMT-1 protein expression correlated with mRNA levels in all patients. Loss of HFE function in hereditary hemochromatosis is not derived from inhibition of its gene expression. DMT-1 expression in C282Y homozygote subjects is consistent with the hypothesis of a "paradoxical" duodenal iron deficiency in hereditary hemochromatosis. The observed twofold upregulation of the DMT-1 is consistent with the slow but steady increase in body iron stores observed in those presenting with clinical features of hereditary hemochromatosis.

Cation Transport Proteins↗
PubMedDate not supplied

Drug induced liver injury secondary to interferon-beta (IFN-beta) in multiple sclerosis.

Post marketing studies of Interferon-beta (IFN beta) therapy in multiple sclerosis (MS) have demonstrated surprisingly high rates of hepatotoxicity. Grade 3 hepatotoxicity (AST and ALT > 5 to 20 upper limit normal) or higher has been observed in as many as 1.4% of MS patients on IFN beta. We report three cases of IFN beta induced hepatitis in MS and discuss the pathology findings and possible mechanisms of drug-induced liver injury.

Adjuvants, Immunologic↗