Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal).

Iron overload is associated with acquired and genetic conditions, the most common being hereditary hemochromatosis (HH) type-I, caused by HFE mutations. Here, we conducted a hospital-based case-control study of 41 patients from the São Miguel Island (Azores, Portugal), six belonging to a family with HH type-I pseudodominant inheritance, and 35 unrelated individuals fulfilling the biochemical criteria of iron overload compatible with HH type-I. For this purpose, we analyzed the most common HFE mutations- c.845G>A [p.Cys282Tyr], c.187C>G [p.His63Asp], and c.193A>T [p.Ser65Cys]. Results revealed that the family's HH pseudodominant pattern is due to consanguineous marriage of HFE-c.845G>A carriers, and to marriage with a genetically unrelated spouse that is a -c.187G carrier. Regarding unrelated patients, six were homozygous for c.845A, and three were c.845A/c.187G compound heterozygous. We then performed sequencing of HFE exons 2, 4, 5 and their intron-flanking regions. No other mutations were observed, but we identified the -c.340+4C [IVS2+4C] splice variant in 26 (74.3%) patients. Functionally, the c.340+4C may generate alternative splicing by HFE exon 2 skipping and consequently, a protein missing the α1-domain essential for HFE/ transferrin receptor-1 interactions. Finally, we investigated HFE mutations configuration with iron overload by determining haplotypes and genotypic profiles. Results evidenced that carriers of HFE-c.187G allele also carry -c.340+4C, suggesting in-cis configuration. This data is corroborated by the association analysis where carriers of the complex allele HFE-c.[187C>G;340+4T>C] have an increased iron overload risk (RR = 2.08, 95% CI = 1.40-2.94, p<0.001). Therefore, homozygous for this complex allele are at risk of having iron overload because they will produce two altered proteins--the p.63Asp [c.187G], and the protein lacking 88 amino acids encoded by exon 2. In summary, we provide evidence that the complex allele HFE-c.[187C>G;340+4T>C] has a role, as genetic predisposition factor, on iron overload in the São Miguel population. Independent replication studies in other populations are needed to confirm this association.

Acute lower gastrointestinal bleeding management in Portugal: a multicentric prospective 1-year survey.

INTRODUCTION: Acute lower gastrointestinal bleeding (ALGIB) is a common event, which consumes considerable human and economic resources. Its incidence is expected to rise in the coming years due to an increasing aging population. PATIENTS AND METHODS: Multicentric prospective analysis of patients was carried out with ALGIB in 13 Portuguese hospitals from April 2008 to May 2009, using a protocol designed by the French Association Nationale des Hépato-Gastroentérologues des Hôpitaux Généraux. Statistical analysis was carried out with SPSS 16.0. RESULTS: In a total of 371 hemorrhagic events in 364 patients (51.4% men, mean age: 72 years), 28.4% patients showed hemodynamic instability and 54.2% were under single/combined medication with antiaggregants/NSAIDs/heparin/anticoagulants; blood transfusion was administered in 34.8% of patients. Sigmoidoscopy was the first endoscopic procedure performed in 61.3% of patients and rectal enema was the first method of bowel preparation in 67.3% of them. Endoscopic hemostasis was performed in 22.2% of all cases with efficacy ranging from 84.6 to 96.2%. Most frequent diagnoses were ischemic colitis (23.7%), diverticulosis (20.8%), and colorectal malignancies (12.4%). Surgery was needed in 8% of patients, and global mortality rate was 2.2%. Risk factors for poor outcome on multivariate analysis were heparin use before bleeding (hazards ratio: 10.6; 95% confidence interval: 0.94-119.48) and in-hospital bleeding (hazards ratio: 5.6; 95% confidence interval: 1.01-19.70). CONCLUSION: ALGIB seems to occur frequently in Portugal with a low mortality rate. Previous heparin use and in-hospital bleeding are associated with worse prognosis. Our management relies on early endoscopic examinations, which are highly available, safe, and accurate. A successful endoscopic therapeutic approach was possible in one fifth of the patients.