Acquired Refractory Iron Deficiency Anemia.

Anemia is a global health problem affecting one-third of the world population, and half of the cases are due to iron deficiency (ID). Iron deficiency anemia (IDA) is the leading cause of disability in several countries. Although multiple mechanisms may coexist, ID and IDA causes can be classified as i) insufficient iron intake for the body requirement, ii) reduced absorption, and iii) blood losses. Oral iron represents the mainstay of IDA treatment. IDA is defined as "refractory" when the hematologic response after 4 to 6 weeks of treatment with oral iron (an increase of >=1 g/dL of Hb) is absent. The cause of iron-refractory anemia is usually acquired and frequently related to gastrointestinal pathologies, although a rare genetic form called iron-refractory iron deficiency anemia (IRIDA) exists. In some pathological circumstances, either genetic or acquired, hepcidin increases, limiting the absorption in the gut, remobilization, and recycling of iron, thereby reducing iron plasma levels. Indeed, conditions with high hepcidin levels are often under-recognized as iron refractory, leading to inappropriate and unsuccessful treatments. This review provides an overview of the iron refractory anemia underlying conditions, from gastrointestinal pathologies to hepcidin dysregulation and iatrogenic or provoked conditions, and the specific diagnostic and treatment approach.

Prognostic role of transferrin saturation in heart failure patients.

AIMS: In heart failure (HF) iron deficiency (ID) is frequently observed and represents a major mortality risk factor. Purpose of this study was to evaluate the correlation between mortality and ID in a cohort of 661 consecutive patients hospitalized for HF worsening. METHODS AND RESULTS: Patients were grouped: (i)according to presence(+)/absence(-) of anaemia (A) and ID defined following World Health Organization (WHO) and European Society of Cardiology (ESC)-American College of Cardiology/American Heart Association/HF society of America (ACC/AHA/HFSA) definitions, respectively: Group A-ID- (n = 123), Group A+ID- (n = 80), Group A+ID+ (n = 247), and Group A-ID+ (n = 211); (ii) according to presence of absolute (serum ferritin < 100µg/L) and functional ID [ferritin between 100 and 300µg/L and transferrin saturation (TSAT) < 20%]; and (iii) according to TSAT <20% and ≥20%. Groups were not different for several clinical features but age, gender, kidney function, and chronic obstructive pulmonary disease. Average follow-up was 1.94 year (±420 days). Overall 5 years mortality rate was 29.5%. Only anaemia and functional ID but not ID as defined by guidelines showed an impact on prognosis. Transferrin saturation <20% (n = 360) patients showed worst prognosis compared to TSAT ≥20% (n = 301) patients. In addition, functional ID patients showed worse prognosis compared patients with ferritin <100µg/L and TSAT <20% or ≥20% likely due to more severe chronic inflammatory status [C-reactive protein, 7.4 (interquartile range 2.7-22.6) and 3.2 (1.4-8.7) mg/L, P < 0.0001 respectively]. CONCLUSION: We confirmed that in HF anaemia is associated to a poor prognosis. Moreover, we showed that patients with TSAT <20% had worse prognosis compared to those with TSAT ≥20% but the composite of ferritin between 100 and 300 µg/L and TSAT <20% identifies HF patients with the poorest survival rate.

Liver damage and sickle cell disease: genotype relationship.

Sickle hepatopathy is a severe and not rare complication of sickle cell disease (SCD), showing mainly a cholestatic pattern. So far, no effective approaches to prevent or treat this condition have been recognized. We conducted a single-center observational study in 68 adult sickle cell patients, encompassing 17 with sickle cell anemia (SCA), 38 with sickle cell thalassemia (HbS/ß-Thal), and 13 with HbSC disease. The aim of our study was to assess liver damage in the three main forms of SCD, through the evaluation of clinical, laboratory, and imaging findings. In our population, the role of hepatotropic viruses, high BMI, and alcohol consumption in liver damage was ruled out. SCA and HbS/ß-Thal patients with lower Hb (p < 0.001), higher HbS (p < 0.001), and frequent vaso-occlusive crises showed functional (GGT values: SCA and HbS/ß-Thal vs HbSC p = 0.047 and p = 0.009, respectively) and structural liver abnormalities, defined by abdominal ultrasound and vibration-controlled transient elastography (liver stiffness values: SCA and HbS/ß-Thal vs HbSC p 0.022 and p 0.19, respectively), more severe than HbSC patients. Through univariate and multivariate analyses, male sex, SCA genotype, lower HbF, frequent transfusions, increased GGT values, and abnormal liver ultrasound and stiffness were identified as potentially early markers of sickle hepatopathy.

Treatment with ferric carboxymaltose in stable patients with severe iron deficiency anemia in the emergency department.

The AABB Choosing Wisely Campaign recommends "don't transfuse for iron deficiency without hemodynamic instability". However, the management of iron deficiency anemia (IDA) in the emergency department (ED) is heterogeneous and patients are often over-transfused. Intravenous iron is effective in correcting anemia and new formulations, including ferric carboxymaltose (FCM), allow the administration of high doses with low immunogenicity. The aim of this retrospective study was to analyze the management of hemodynamically stable patients aged 18-55 years with severe IDA (hemoglobin < 8 g/dL), who presented to the ED from January 2014 to July 2018. Patients who received FCM (FCM1) and those who did not receive FCM (FCM0) were compared. Efficacy and safety of FCM at follow-up were evaluated. Seventy-one subjects fulfilled the inclusion criteria (FCM0 n = 48; FCM1 n = 23). The mean Hb at admission was 6.6 g/dL. 40% in the FCM0 and 13% in FCM1 were transfused (p = 0.02). 21% of FCM0 patients were admitted to the ward, while all FCM1 were discharged (p = 0.02). Within 2 weeks, the Hb increase was 2.8 ± 1 g/dL in the FCM1 group. Sixteen FCM1 patients were evaluated at 52 ± 28 days (median 42, range 27-122): the average Hb increase was 5.3 ± 1.4 g/dL. In summary, we showed that FCM administration in the ED in hemodynamically stable patients was associated with fewer transfusions and hospital admissions compared to the FCM0 group; moreover, it succeeded in safely, effectively and rapidly increasing Hb levels after discharge from the ED. Further studies are needed to develop recommendations for IDA in the ED and to identify transfusion thresholds for non-hospitalized patients.

Red blood cell distribution width as a prognostic factor of mortality in elderly patients firstly hospitalized due to heart failure.

BACKGROUND: Red blood cell distribution width (RDW) is a risk factor related to adverse outcome in patients with heart failure (HF). Less is known about its influence in patients in their first hospitalization by HF.   Aims: Our objective was to investigate the prognostic role of RDW in elderly patients firstly hospitalized for acute HF. METHODS: We reviewed all patients ≥ 65 years old admitted to a tertiary care university hospital with a main diagnosis of acute HF during a two year period (January 2013 to December 2014). Patients were divided in two different groups according to admission RDW values (< or ≥ 15%). RESULTS: A total of 897 patients were included in the study. Mean age was 80.25 ± 7.6 years. Admission RDW was ≥ 15% in 474 (52.8%) patients, with a mean RDW of 15.5 % ± 2.3. Multivariate analysis confirmed the relationship between a higher admission RDW and a previous diagnostic history of diabetes and admission higher serum sodium concentrations. All-cause mortality was significantly higher among patients with RDW  15% at one year of follow-up (29.6% vs. 23.2%, p 0.026). Multivariate analysis confirmed the association between RDW and higher risk of one-year mortality, as well as with older age, higher Charlson comorbidity Index, higher potassium serum concentrations and no hypertension as a previous diagnosis. CONCLUSIONS: In elderly patients experiencing their first admission due to acute HF, a higher RDW at baseline might help identify patients at higher risk for one-year all-cause mortality.

Correction to: Prognostic influence of prior chronic obstructive pulmonary disease in patients admitted for their first episode of acute heart failure.

In the original publication, the given name and family name of the fifth author Dr Margherita Migone De Amicis were incorrectly published. The correct given name and family name should read as 'Margherita' and 'Migone De Amicis', respectively.

Prognostic influence of prior chronic obstructive pulmonary disease in patients admitted for their first episode of acute heart failure.

Chronic obstructive pulmonary disease (COPD) is a frequent comorbidity in heart failure (HF) patients. Whether a prior COPD diagnosis influences patients' prognosis in early stages of HF is unknown. We reviewed patients > 50 years old admitted because of a first episode of acute HF. We divided the sample into two groups according to the existence of a prior diagnosis of COPD. We used regression analysis to identify the baseline patients' characteristics associated with the presence of COPD, and Cox mortality analysis to identify baseline and discharge data related to higher risk of a combined outcome of 1-year all-cause readmission or mortality. Finally, 985 patients were included in the analysis; 212 (21.5%) with a prior diagnosis of COPD. Baseline characteristics were similar between both groups except for a much higher prevalence of male gender, higher number of chronic therapies, and lower prevalence of atrial fibrillation among COPD patients. The combined primary outcome is significantly more prevalent in COPD patients (68.4 vs. 59.8%, p = 0.022). Cox analysis identified this prior diagnosis of COPD (HR 1.282, 95% CI 1.063-1.547; p = 0.001) as an independent risk factor for 1-year readmission and mortality, together with older age, higher admission creatinine and potassium values, and a higher number of chronic therapies. Our study confirms that in a "real-life" cohort of elderly patients experiencing a first episode of acute HF, the presence of a prior diagnosis of COPD is common, and confers a higher risk of adverse outcomes (death or readmission) during the year following discharge.

Anemia is a mortality prognostic factor in patients initially hospitalized for acute heart failure.

Anemia is a risk factor related to morbidity and mortality in patients with chronic heart failure (HF). Less is known about its influence in patients in an early stage of HF. Our aim is to investigate the prognostic role of anemia in patients initially hospitalized for acute HF. We reviewed all consecutive patients admitted within a 18-month period with a main diagnosis of acute HF. We collected demographic, clinical and treatment data. Anemia is defined as Hemoglobin <12/13 g/dL upon admission in female/male patients, respectively. 719 patients were included (55.5% female), with a mean age of 78.7 ± 9 years. Anemia was present in 59.6% of patients upon admission, with a mean Hb of 10.4 ± 1.4 g/dL. Multivariate analysis confirms the relationship between the presence of anemia and older age, a previous diagnostic history of diabetes, and the presence of chronic kidney disease. In-hospital mortality is similar for anemic and non-anemic patients (6.8 vs 3.8%, p = n.s.) However, the difference is significant when one-year mortality is evaluated (31% in anemic patients vs 19% in non-anemic patients, p < 0.001). Cox regression analysis confirms the association between anemia and higher risk of one-year mortality, as well as with older age and a higher Charlson comorbidity index. Our study confirms that the presence of anemia is an independent factor for mid-term (1-year) mortality even in patients experiencing a first admission due to acute HF.

Anemia in elderly hospitalized patients: prevalence and clinical impact.

Anemia is a common finding in elderly individuals. Several studies have shown a strong relationship between anemia, morbidity and mortality, suggesting anemia as a significant independent predictor of adverse outcome in elderly hospitalized patients. The pathophisiology of anemia in the elderly is not yet completely understood. Several mechanisms are involved. We investigated the prevalence of anemia in a cohort of 193 elderly patients admitted to the Internal Medicine Ward of Ca'Granda Policlinico Hospital along 6 months, and its relationship to comorbidities and to the length of hospitalization. Anemia was classified according to the WHO criteria. The majority of patients (48 %) had a mildmoderate, normocytic anemia; severe anemia was found in 8 out of 92 anemic patients. In a subgroup of patients erythropoietin was tested and resulted statistically higher if compared to non-anemic controls (p = 0.003). Considering the most common cause of anemia, nutritional deficiency, chronic renal disease and anemia of chronic disease were found respectively in 36, 15 and 25 % of cases. Unexplained anemia was diagnosed in 24 % of patients, according to the literature. Anemia was independently associated with increased length of hospital stay. Our study confirmed a high prevalence of anemia in elderly patients, and its association with a higher number of comorbidities and a longer stay. A correct clinical approach to anemia in elderly hospitalized patients is essential, considering its negative impact on patients' quality of life, and its social burden in term of healthcare needs and costs.

Anemia of chronic disease: a unique defect of iron recycling for many different chronic diseases.

Anemia of chronic disease (ACD) is frequently observed in patients with chronic diseases as a significant contributor to morbidity and mortality, which can aggravate the severity of symptoms of the underlying inflammatory status. The pathophysiology of ACD is multifactorial, including three mechanisms: shortened erythrocyte survival, impaired proliferation of erythroid progenitor cells, and abnormalities of iron metabolism. These mechanisms are "immune and inflammation"-driven, but several other factors, including chronic blood loss, hemolysis, or vitamin deficiencies, can aggravate anemia. All the abnormalities of iron metabolism observed in ACD can be explained by the effect of hepcidin upregulation. Hepcidin is a small liver peptide, that inhibits the cellular macrophage efflux of iron and intestinal iron absorption, binding to ferroportin and inducing its internalization and degradation. In ACD the synthesis of hepcidin is upregulated by increased inflammatory cytokines, causing the two main principal features: the macrophage iron sequestration and the iron-restricted erythropoiesis. ACD is the most complex anemia to treat. The recommended approach is the treatment of the underlying disease, which can lead to a major improvement or even resolution of ACD. Currently available treatments (transfusion, iron, and erythropoiesis-stimulating agents) can ameliorate anemia, but a considerable percentage of non-responders exist. On this evidence new treatment strategies might arise from the knowledge of the pathophysiology of ACD, in which hepcidin plays the central role. Prospective studies are needed to evaluate the safety and the efficacy of the new emerging treatments, which modulate hepcidin expression through different mechanisms.