Valentina Paolini

Expression of hepcidin and other iron-related genes in type 3 hemochromatosis due to a novel mutation in transferrin receptor-2

This brief report describes the decreased hepatic and urinary expression of hepcidin in type 3 hemochromatosis. Transferrin receptor-2 (TFR2) regulates hepatic hepcidin secretion and when mutated causes type-3 hemochromatosis. No functional study is available in humans. We studied a 47 year-old woman with hemochromatosis. TFR2 DNA and its hepatic transcript were directly sequenced. Hepatic expression of hepcidin and other iron-related genes were measured by qRT-PCR. Urinary hepcidin was measured at baseline and after an oral iron challenge (ferrous sulfate, 65 mg) by SELDI-TOF-MS. A novel homozygous TFR2 mutation was identified in the splicing donor site of intron 4 (c.614+4 A>G) causing exon 4 skipping. Hepcidin and hemojuvelin expression were markedly reduced. Urinary hepcidin was lower than normal and further decreased after iron challenge. This is the first description of iron-related gene expression profiles in a TFR2 mutated patient. The decreased hepatic and urinary expression of hepcidin and lack of acute response to iron challenge confirms the primary role of TFR2 in iron homeostasis.

Hepcidin response to acute iron intake and chronic iron loading in dysmetabolic iron overload syndrome

Background: The pathogenesis of dysmetabolic iron overload syndrome (DIOS) is still unclear. Hepcidin is the key regulator of iron homeostasis controlling iron absorption and macrophage release.

Genetic and metabolic factors are associated with increased hepatic iron stores in a selected population of p.Cys282Tyr heterozygotes

Heterozygosity for p.Cys282YTyr is not ordinarily associated with a hemochromatosis phenotype, unless associated in the compound heterozygous state with other HFE mutations. The aims of the study were to identify factors responsible for iron overload in patients who were only heterozygous for p.Cys282Tyr at first genetic testing. Since 2001, twelve p.Cys282Tyr heterozygous patients with iron overload, defined by increased transferrin saturation, serum ferritin and hepatic iron stores, were identified. Four patients showed rare nonsense or missense HFE mutations in the compound heterozygous state with p.Cys282Tyr. One mutation (p.Gln233X) was never described before. The other 8 patients did not carry any other causal mutations in iron-related genes, but showed a very high prevalence of hepatic steatosis and steato-hepatitis, and metabolic alterations. Serum ferritin levels did not differ between the two groups, but transferrin saturation, hepatic iron amount and distribution significantly did. These last indices should be then strongly considered to decide for additional genetic characterization in p.Cys282Tyr heterozygotes. Our results also highlights the influence of metabolic alterations on serum iron indices and pattern of hepatic iron accumulation.

Reduced expression of hepcidin in patients with myelodysplastic syndrome and myelofibrosis: the causes might be more heterogeneous than in thalassaemia.

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Positive end expiratory pressure in acute hypoxemic respiratory failure due to community acquired pneumonia: do we need a personalized approach?

Background Acute respiratory failure (ARF) is a life-threatening complication in patients with community acquired pneumonia (CAP). The use of non-invasive ventilation is controversial. With this prospective, observational study we aimed to describe a protocol to assess whether a patient with moderate-to-severe hypoxemic ARF secondary to CAP benefits, in clinical and laboratoristic terms, from the application of a positive end expiratory pressure (PEEP) + oxygen vs oxygen alone. Methods Patients who benefit from PEEP application (PEEP-responders) were defined as those with partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2/FiO2) increase >20% and/or reduction of respiratory distress during PEEP + oxygen therapy compared to oxygen therapy alone. Clinical characteristics and outcomes were compared between PEEP-responders and PEEP-non responders. Results Out of 41 patients, 27 (66%) benefit from PEEP application (PEEP-responders), the best response was obtained with a PEEP of 10 cmH2O in 13 patients, 7.5 cmH2O in eight and 5 cmH2O in six. PEEP-responders were less likely to present comorbidities compared to PEEP-non responders. No differences between groups were found in regards to endotracheal intubation criteria fullfillment, intensive care unit admission and in-hospital mortality, while PEEP-responders had a shorter length of hospital stay. Discussion The application of a protocol to evaluate PEEP responsiveness might be useful in patients with moderate-to-severe hypoxemic ARF due to CAP in order to personalize and maximize the effectiveness of therapy, and prevent the inappropriate PEEP use. PEEP responsiveness does not seem to be associated with better outcomes, with the exception of a shorter length of hospital stay.

Surgical and endoscopic treatment for COPD: patients selection, techniques and results

Chronic obstructive pulmonary disease (COPD) is a very heterogeneous disease characterised by an obstructive lung pattern that constitutes worldwide a major cause of high morbidity and mortality. In the last decades, lung volume reduction surgery (LVRS) has demonstrated to be a potential good alternative to transplantation in patients affected by COPD. The trend toward minimally invasive techniques resulted not only in surgical procedures better tolerated by the patients but also in several endoscopic treatments modality that are rapidly gaining ground.

436 ANALYSIS OF POLYMORPHISMS OF GENES REGULATING HEPCIDIN TRANSCRIPTION IN HFE- HEMOCHROMATOSIS

analyzed. In 6 patients ESLD was due to biliary atresia, mean age 44 months (range 8−60), the remaining 5 to miscellaneous causes (one patient to Wilson’s disease, one biliary cirrhosis, one congenital hepatic fibrosis, one cryptogenic chronic hepatitis, one acute liver failure of unknown origin), mean age 127 months (range 72–191). 9 out of 11 patients had varices. 6 patients had F1 esophageal varices, 1 patient had F3 esophageal varices, two patients with no esophageal varices on EGDS had large perigastric and peri-esophageal varices detected on CT scan. Results: Catheterization of hepatic veins was done under deep sedation and was technically possible in all patients without complications. HVPG values were elevated in all patients, ranging between 8 and 33mmHg (mean 13.5mmHg), thus indicating a sinusoidal component in the portal hypertension. A salient finding was the presence of hepatic venous-venous shunts in 5 out of 6 patients with biliary atresia; these were identical to those described in idiopathic portal hypertension. The presence of venousvenous shunts frequently precludes adequate HVPG measurements; however HVPG could still be measured distally to the shunts in 4 patients using ultrathin catheters, but in two patients (both HVPG 8mmHg) was determined in an area with a small venous-venous communication still visible, therefore underestimating the actual portal pressure gradient. Actually both patients had esophageal varices. No venous-venous shunts were detected in the non biliary atresia patients. Conclusion: HVPG is a feasible procedure in pediatric patients. Patients with biliary atresia very frequently have venous-venous shunts between hepatic veins. This hitherto unrecognized finding can lead to underestimation of the portal pressure by HVPG measurement.