Association between Allergies and Hypercholesterolemia: A Systematic Review.

BACKGROUND: There is controversy in the literature regarding the potential relationship between atopic predisposition (AP) and serum cholesterol levels. To this purpose, we reviewed human studies that investigated this possible link. METHODS: Following PRISMA guidelines, a literature search of PubMed and Science Direct for peer-reviewed journal articles in English from January 2003, with updates through to August 2016, was conducted. Relevant publications were reviewed that included pediatric and adult populations. Information on the study design, sample, intervention, comparators, outcome, time frame, and risk of bias were abstracted for each article. RESULTS: Of 601 reviewed reports, 18 were included in this systematic review. Fifteen studies assessed the relationship between AP and serum cholesterol levels. Due to the lack both of observational and cross-sectional studies from the literature search at this time (only 8 studies also analyzed confounding factors) there is a high possibility of confounding variables (familial and genetic predisposition, age, gender, BMI, comorbidity, and medication status) that could not be ruled out. CONCLUSION: Existing studies are heterogeneous, making it difficult to draw broad conclusions. Future studies and more detailed analyses, considering confounding variables and including a larger and homogeneous population, are needed to strengthen the argument for a link between lipid metabolism and atopy.

High mobility group box 1: Biomarker of inhaled corticosteroid treatment response in children with moderate-severe asthma.

BACKGROUND: High mobility group box 1 (HMGB1) is abnormally expressed in serum and sputum of patients with allergic asthma. OBJECTIVE: The aim of this study was to investigate the role of HMGB1 as guidance for treatment management of children with asthma. METHODS: Thirty children with asthma and 44 healthy children were enrolled. The patients were classified according to Global Initiative for Asthma Guideline disease severity criteria. Sputum HMGB1 levels and lung function index (percentage forced expiratory volume in 1 second [FEV1%]) were recorded in the cohort study at baseline (T0) and after 3 (T3) and 6 (T6) months of inhaled corticosteroids (ICS) treatment. RESULTS: Sputum HMGB1 levels were significantly higher in all the patients with asthma (p < 0.001). An inverse correlation between sputum HMGB1 levels and pulmonary function parameters was observed only in the children with moderate asthma (T0: FEV1%, r = -0.9891, p < 0.001; T3: FEV1%, r = -0.6763, p < 0.001; T6: FEV1%, r = -0.5419, p < 0.05) and in the children with severe asthma (T0: FEV1%, r = -0.8696, p < 0.001; T3: FEV1%, r = -0.6477, p < 0.05; T6: FEV1%, r = -0.8627, p < 0.001). After ICS treatment, a significant decrease of sputum HMGB1 levels was noted in moderate (T0 [93.44 ± 20.65 ng/mL] versus T3 [77.96 ± 1.81 ng/mL] versus T6 [67.75 ± 3.01 ng/mL]; p < 0.0001) and in the children with severe asthma (T0 [130.3 ± 7.48 ng/mL] versus T3 [156.9 ± 1.09 ng/mL] versus T6 [116.08 ± 4.77 ng/mL]; p < 0.0001) data are mean ± standard deviation, respectively. The area under the receiver operating characteristic curve, performed to define the diagnostic profile of sputum HMGB1 levels in identifying the children with asthma, was 0.713. CONCLUSION: In addition to the findings that HMGB1 is a sensitive biomarker of allergic asthma in children, our data demonstrated a significant correlation between the decrease of HMGB1 levels and a successful treatment response.

Breastfeeding and IL-10 levels in children affected by cow's milk protein allergy: A restrospective study.

AIM: To assess the protective role of breast-feeding in infants with CMPA-related AEDS as well as IL-10 utility as marker of disease evolution. METHODS: 64 breast-feeding children with CMPA-related AEDS (31 males and 33 females; mean age 5.56±2.41months; 21 mild AEDS; 25 moderate AEDS; 18 severe AEDS) and 60 artificial feeding babies (33 males and 27 females; mean age 6.01±2.08months; 26 mild AEDS; 19 moderate AEDS; 15 severe AEDS) were evaluated. In all patients serum IL-10 levels were detected. RESULTS: Significant Score Atopic Dermatitis (SCORAD) index point differences between breastfed and not breastfed children (p<0.001) have been detected. The serum IL-10 levels were lower in children with CMPA-related AEDS as compared to the healthy control group (p<0.001). Moreover, a significant inverse correlation between serum IL-10 levels and SCORAD in both enrolled groups has been also noted. In particular, IL-10 levels, in both groups, were significantly lower in children with severe symptoms. Conversely, serum IL-10 levels were significantly increased in children with mild-severe symptoms in both groups. Furthermore, breastfed children, with lower severe symptoms, had higher serum IL-10 levels. Finally, serum total IgE levels were negatively correlated with serum IL-10 levels in both breastfed and non-breastfed children with CMPA-related AEDS (p<0.001). CONCLUSIONS: We reported that exclusive breast-feeding induces hyposensitization in children with CMPA-related AEDS and it is associated with minor disease severity and higher serum IL-10 levels, resulting as useful disease-monitor marker.

Atopy and autoimmune thyroid diseases: melatonin can be useful?

Recently, there has been growing interest in the relationship between allergic and autoimmune diseases. Allergy and autoimmunity can be considered two potential outcomes of dysregulated immunity and analysis of literature data shows a strong positive association between a history of Th2-mediated allergic disorders and Th1-mediated autoimmune disorders.Autoimmune thyroid diseases are the most common of all autoimmune pathological conditions.Currently, the mechanisms explaining an association among atopy, autoimmunity, and thyroid diseases are not fully understood.There are data in literature pointing to the relationship between melatonin and thyroid activity. Several studies have suggested a paracrine role for this molecule in the regulation of thyroid activity, documenting that administration, as an antioxidant, in thyroid tissues under conditions of increased oxidative stress, could be helpful to reduce the oxidative processes involved in autoimmune thyroid diseases.Although thyroid autoimmunity has been regularly associated with atopic conditions in children, the possible protective role of melatonin has not yet been investigated.This review summarizes what is known regarding the connection between atopy and autoimmune thyroid diseases, and analyses the probable beneficial action of melatonin.

"Cumulative Stress": The Effects of Maternal and Neonatal Oxidative Stress and Oxidative Stress-Inducible Genes on Programming of Atopy.

Although extensive epidemiological and laboratory studies have been performed to identify the environmental and immunological causes of atopy, genetic predisposition seems to be the biggest risk factor for allergic diseases. The onset of atopic diseases may be the result of heritable changes of gene expression, without any alteration in DNA sequences occurring in response to early environmental stimuli. Findings suggest that the establishment of a peculiar epigenetic pattern may also be generated by oxidative stress (OS) and perpetuated by the activation of OS-related genes. Analyzing the role of maternal and neonatal oxidative stress and oxidative stress-inducible genes, the purpose of this review was to summarize what is known about the relationship between maternal and neonatal OS-related genes and the development of atopic diseases.

Mode of delivery and atopic phenotypes: Old questions new insights? A retrospective study.

BACKGROUND: To date studies on the relation between mode of delivery and atopic diseases in are controversial. OBJECTIVE: The aim of the study was to determine a possible relationship between mode of delivery and risk of atopic phenotypes and, to assess the critical role of some pre-and post-natal parameters as a link between mode of delivery and risk of atopy. METHODS: 1516 children were assessed by skin prick tests, serum total and specific IgE levels. Parental reports on demographic and clinical data were also recorded. RESULTS: Of the 1516 children enrolled for the study, clinical and laboratory informations were obtained from 917 children. 460 children of them were born via CD and 457 via VD. Mode of delivery did not modify the prevalence of immune sensitization and/or allergic diseases. However, CD was associated with increased risk of atopy (p<0.001). Moreover, some parameters such as familiar history of atopy (p<0.001), habits smoking (p<0.05), exclusive artificial feeding (p<0.001); and breast-feeding time (<3months) (p<0.001) were associated with a major risk of atopy in CD group. Additionally, although our study confirmed that breast-feeding is associated to lower serum total IgE levels than artificial-feeding (p<0.001), it seems that the protective role of breast-feeding is negatively influenced from CD. Also in artificial-feeding subjects CD is related to a significant higher levels of IgE than VD (p<0.001). CONCLUSIONS: Our findings suggest that CD influences only the risk of atopy but no prevalence of immune sensitization and allergic diseases.

Visfatin: New marker of oxidative stress in preterm newborns.

BACKGROUND: Oxidative stress is involved in several neonatal conditions characterized by an upregulation in the production of oxidative or nitrative free radicals and a concomitant decrease in the availability of antioxidant species. Oxygen, which is obviously vital to survival, can be highly damaging to neonatal tissue which is known to be poorly equipped to neutralize toxic derivatives. Thus, exposure of the newborn infant to high oxygen concentrations during resuscitation at birth increases oxidative damage. Visfatin is an adipocytokine involved in oxidative stress and an important mediator of inflammation that induces dose-dependent production of both pro-inflammatory and anti-inflammatory cytokines. To our knowledge, the diagnostic value of visfatin as a marker of oxidative stress in preterm newborns has not been investigated. OBJECTIVE: The aim of this study was to evaluate visfatin levels in preterm neonates resuscitated with different concentrations of oxygen in the delivery room. PATIENTS: Fifty-two preterm newborns with gestational age less than 32 weeks, resuscitated randomly with different oxygen concentrations (40%, 60%, or 100%) were enrolled at the University Hospital of Messina, over a 12-month period to evaluate serum visfatin levels at T0 (within 1 h after birth), T24 h, T72 h, and T168 h of life. RESULTS: At T72 h and T168 h, higher serum visfatin values in the high-oxygen group compared to the low- and mild-oxygen subjects (P=0.002 and P<0.001, respectively) were noted. CONCLUSION: The results of this study suggest that visfatin could be a new marker of oxidative stress in preterm newborns.

New patients with Temple syndrome caused by 14q32 deletion: Genotype-phenotype correlations and risk of thyroid cancer.

Temple syndrome (TS) is caused by abnormal expression of genes at the imprinted locus 14q32. A subset of TS patients carry 14q32 deletions of paternal origin. We aimed to define possible genotype-phenotype correlations and to highlight the prevalence of thyroid dysfunction, which is a previously unreported feature of TS. We described four new patients who carry deletions of paternal origin at 14q32 detected by array-CGH and reviewed nine patients reported in the medical literature. We compared clinical features with respect to deletion size and position. Expression of DLK1 is altered in all the patients with TS, but intellectual disability (ID) is present only in patients with larger deletions extending proximally to the imprinted locus. This study led to the identification of an ID "critical region" containing four annotated genes including YY1 as the strongest candidate. Furthermore, we described three patients with thyroid dysfunction, which progressed to papillary carcinoma at a very young age in two of them. We conclude that DLK1 loss of function is likely to be responsible for the core features of TS, while haploinsufficiency of a gene outside the imprinted region causes ID. Thyroid cancer may be an unrecognized feature and monitoring for thyroid dysfunction should thus be considered in TS patients.

Role of prebiotics and probiotics in pediatric diseases.

The increasing knowledge about the composition and activities of the microflora has shown the close link between the bacteria and the health of the human organism. For this reason it has focused attention on the possibility of modulating the gut flora. The use of probiotics and prebiotics has increased enormously in recent years, more for real beneficial effects demonstrated in patients than for their safety profiles. However, it is recorded an indiscriminate use also in conditions in which there are no scientific evidence to support. Their use in case of immunocompromised patients or with severe and debilitating chronic diseases should be very prudent, because of the risk of complications including sepsis. The use of a probiotic cannot ignore the knowledge of the genus and species of the strain and in pediatric patients has been demonstrated their role for treating acute viral gastroenteritis and preventing antibiotic-associated diarrhea in healthy children. Moreover probiotics are considered as an option for recurrent and relapsing antibiotic sensitive pouchitis and in select patients with mild ulcerative colitis. Further studies are needed to evaluate clinical conditions that may require their use and to define the optimal doses and intake durations.

Mode of delivery and risk for development of atopic diseases in children.

Atopic diseases are a major public health problem worldwide, and several factors are thought to contribute to this rapid increase. The observed association between mode of delivery and risk of atopy in childhood has had a great deal of interest during the past few decades. In fact, even during delivery, exposure to antigens can index immune system in newborn, which induces the release of biologically active molecules, which are polarizing immune responses toward the T-helper 2 atopic profile. However, to date, studies on the relationship between mode of delivery and atopy have produced conflicting findings. The aim of this review was to summarize what is known about the relationship between mode of delivery and risk of atopic diseases in children. A literature search of electronic databases was undertaken for the major studies published from 1994 to today. The databases searched were PubMed, EMBASE, Medline, and Cochrane Library. The following key words were used: mode of delivery, cesarean section, vaginal delivery, atopy, and atopic diseases.

Sputum high mobility group box-1 in asthmatic children: a noninvasive sensitive biomarker reflecting disease status.

BACKGROUND: The monitoring of asthma is based mainly on clinical history, physical examination, and lung function test evaluation. To improve knowledge of the disease, new biomarkers of airway inflammation, including high mobility group box-1 (HMGB1), are being developed. OBJECTIVE: To evaluate sputum HMGB1 levels in children with stable, off-therapy, allergic asthma and to evaluate the relation between HMGB1 levels and lung function parameters. METHODS: Fifty children with asthma (28 boys and 22 girls, median age 11.56 ± 1.41 years) and 44 healthy children (22 boys and 22 girls, median age 11.07 ± 2.12 years) were enrolled. Sputum HMGB1 was assessed in the cohort study. Lung function (predicted percentage of forced expiratory volume in 1 second [FEV1%] and forced expiratory flow between 25% and 75% [FEF25%-75%]), serum total IgE levels, and asthma severity by validated Global Initiative for Asthma criteria were recorded. RESULTS: Sputum HMGB1 levels were higher in children with asthma than in healthy controls (100.68 ± 10.03 vs 9.60 ± 3.76 ng/mL, P < .0001). Sputum HMGB1 levels also were positively related to total IgE levels in children with asthma (r = 0.6567, P < .0001). An inverse and strict correlation between sputum HMGB1 levels and pulmonary function indices also were observed in children with mild (FEV1%, r = -0.86544, P < .0001; FEF25%-75%, r = -0.53948, P < .05), moderate (FEV1%, r = -0.99548, P < .0001; FEF25%-75%, r = -0.48668, P < .05), and severe (FEV1%, r = -0.90191, P < .0001; FEF25%-75%, r = -0.66777, P < .05) asthma. CONCLUSION: The present study provides evidence that sputum HMGB1 is a sensitive biomarker of allergic asthma in children because it was increased and correlated directly with asthma severity and inversely with lung function indices.

Thalassaemia major and infectious risk: High Mobility Group Box-1 represents a novel diagnostic and prognostic biomarker.

High mobility group box -1 (HMGB1) represents a common causal agent for various types of diseases, including infective pathologies. This study aimed to investigate the role of HMGB1 in ß-thalassemia major (TM) by evaluating its diagnostic and prognostic role. Fifty-one TM patients and 30 healthy subjects (HS) were enrolled. Receiver operating characteristics (ROC) analysis was employed to calculate the area under the curve (AUC) for HMGB1 to determine the best cut-off values capable of identifying infectious episodes. Adjusted risk estimates for infective events were calculated using univariate followed by multivariate Cox proportional hazard regression analysis. Serum HMGB1 levels were higher in TM patients than in HS (14·6 ± 8·7 vs. 2·08 ± 0·9 ng/ml, P < 0·0001). Patients who underwent splenectomy were characterized by lower levels of HMGB1, when compared with patients with an intact spleen (10·2 ± 8 vs. 19·1 ± 7 ng/ml, P = 0·004). ROC analyses revealed an AUC for serum HMGB1 of 0·801, with a sensitivity and specificity of 92·3% and 68·2% to detect an infectious episode. Low HMGB1 levels predicted high risk of infective events (HR: 0·81; P = 0·006). HMGB1 represents a prognostic marker for TM patients and a predictive factor for infectious events.

Increase in the Level of Proinflammatory Cytokine HMGB1 in Nasal Fluids of Patients With Rhinitis and its Sequestration by Glycyrrhizin Induces Eosinophil Cell Death.

OBJECTIVES: The nuclear protein high mobility group protein box 1 (HMGB1) is a proinflammatory mediator that belongs to the alarmin family of proinflammatory mediators, and it has recently emerged as a key player in different acute and chronic immune disorders. Several lines of evidence demonstrate that HMGB1 is actively released extracellularly from immune cells or passively released from necrotic cells. Because of the ability of HMGB1 to sustain chronic inflammation, we investigated whether the protein is present in nasal fluids of patients with different forms of rhinitis. METHODS: HMGB1 levels were evaluated in nasal fluids of healthy subjects or rhinitis patients who were treated or not treated with different treatments. RESULTS: We report that the level of HMGB1 was significantly increased in nasal fluids of patients with allergic rhinitis, patients with NARES (nonallergic rhinitis with eosinophiliac syndrome), as well as patients with polyps. We also found that a formulation containing the HMGB1-binding compound glycyrrhizin (GLT) reduced the HMGB1 content in nasal fluids of rhinitis patients to an extent similar to that with nasal budesonide treatment. We also found that among the cultured human leukocyte populations, eosinophils released higher amounts of HMGB1. Based on the ability of HMGB1 to sustain eosinophil survival and the ability of GLT to inactivate HMGB1, we report that GLT selectively killed cultured eosinophils and had no effect on neutrophils, macrophages, and lymphocytes. CONCLUSION: Collectively, these data underscore the role of HMGB1 in rhinitis pathogenesis and the therapeutic potential of GLT formulations in treatment of chronic inflammatory disorders of the nasal mucosa.

A de novo 0.63 Mb 6q25.1 deletion associated with growth failure, congenital heart defect, underdeveloped cerebellar vermis, abnormal cutaneous elasticity and joint laxity.

Deletions of the long arm of chromosome 6 are rare and are characterized by great clinical variability according to the deletion breakpoint. We report a on 6-year-old girl with a de novo 0.63 Mb deletion on chromosome 6q25.1 who demonstrated multiple congenital anomalies including a ventricular septal defect and an underdeveloped cerebellar vermis. She presented with severe pre- and post-natal growth failure, hyperextensible small joints (Beighton scores = 8/9; with normal parental scores), and an abnormally elastic, redundant skin. Abnormally high upper/lower segment ratio (i.e., 1.34 = > 3SD), mild dysmorphic facial features and developmental delay were also present. The girl's phenotype was compared with: (i) two girls, each previously reported by Bisgaard et al. and Caselli et al. with similar albeit larger (2.6-7.21 Mb) deletions; (ii) seven additional individuals (6 M; 1 F) harboring deletions within the 6q25.1 region reported in the literature; and (iii) ten further patients (5 M; 4 F; 1 unrecorded sex) recorded in the DECIPHER 6.0 database. We reported on the present girl as her findings could contribute to advance the phenotype of 6q deletions. In addition, the present deletion is the smallest so far recorded in the 6q25 region encompassing eight known genes [vs. 41 of Bisgaard et al., and 23 of Caselli et al.,], including the TAB2 (likely responsible for the girl's congenital heart defect), LATS1 gene, and the UST gene (a regulator of the homeostasis of proteoglycans, which could have played a role in the abnormal dermal and cartilage elasticity).

Sudden cardiac arrest in a child with nemaline myopathy.

BACKGROUND: Nemaline myopathy is a rare, non progressive congenital skeletal muscle disorder defined by the presence of inclusions known as nemaline rods in muscle fibers. Several clinical subtypes have been described, according to degree of muscle weakness, severity and age at onset. The course of nemaline myopathy is very slowly progressive, and death is usually due to respiratory failure. Cardiac involvement is rare and generally considered to be the result of ACTA1 mutations. PATIENT: We report the case of a 6 year old boy with typical congenital nemaline myopathy. Nemaline myopathy was confirmed at 3 years of age by muscle biopsy. No mutation of ACTA1, TPM2 and TNNT1 genes was detected. The child died suddenly of cardiac arrest and associated hypoxic-ischemic brain injury, in absence of acute respiratory failure or swallowing difficulties. RESULTS: Nemaline cardiomyopathy was suspected, but post mortem cardiac biopsy did not show findings consistent with nemaline myopathy. CONCLUSIONS: Congenital typical nemaline myopathy is not necessarily a static or very slowly progressive disorder and acute cardiac deterioration can lead to early death.

Analgesic, anxiolytic and anaesthetic effects of melatonin: new potential uses in pediatrics.

Exogenous melatonin is used in a number of situations, first and foremost in the treatment of sleep disorders and jet leg. However, the hypnotic, antinociceptive, and anticonvulsant properties of melatonin endow this neurohormone with the profile of a drug that modulates effects of anesthetic agents, supporting its potential use at different stages during anesthetic procedures, in both adults and children. In light of these properties, melatonin has been administered to children undergoing diagnostic procedures requiring sedation or general anesthesia, such as magnetic resonance imaging, auditory brainstem response tests and electroencephalogram. Controversial data support the use of melatonin as anxiolytic and antinociceptive agents in pediatric patients undergoing surgery. The aim of this review was to evaluate available evidence relating to efficacy and safety of melatonin as an analgesic and as a sedative agent in children. Melatonin and its analogs may have a role in antinociceptive therapies and as an alternative to midazolam in premedication of adults and children, although its effectiveness is still controversial and available data are clearly incomplete.

Serum interleukin 17, interleukin 23, and interleukin 10 values in children with atopic eczema/dermatitis syndrome (AEDS): association with clinical severity and phenotype.

To date cytokines profile in AEDS is poorly described in children. We evaluated the interleukin (IL)-17, IL-23, and IL-10 levels in atopic eczema/dermatitis syndrome (AEDS) children and healthy controls, in atopic AEDS (aAEDS) and nonatopic (naAEDS) subtypes and their relationship with disease severity. A total of 181 children with aAEDS and 93 healthy children were evaluated. According to the skin-prick test (SPT) for allergens and serum total IgE, all patients were subdivided in two groups: 104 aAEDS and 77 naAEDS. In all patients, serum IL-17, IL-23, and IL-10 levels were detected. Serum IL-17 and IL-23 levels were significantly higher, and serum IL-10 levels were significantly lower in AEDS children than healthy group (p < 0.001). Moreover, serum IL-17 and IL-23 levels were significantly higher in aAEDS than in naAEDS subtypes (p < 0.001). Differently, serum IL-10 levels resulted similar in both subtypes. There was a correlation between Score Atopic Dermatitis (SCORAD) index and both IL-17 and IL-23 and an inverse correlation between SCORAD index and IL-10 in aAEDS and naAEDS types. Serum IL-17 and IL-23 values were positively related to total IgE levels (p < 0.0001) in aAEDS. Further increase of IL-17 and IL-23 levels was detected in aAEDS subjects with atopic diseases such as asthma and rhinitis than children with only allergic sensitization. Our study confirms the role of IL-17, IL-23, and IL-10 and their relationship with the severity of AEDS. We firstly found a correlation between high IL-17/IL-23 axis levels and different phenotypes of AEDS in children, suggesting its role as marker of "atopic march" and disease severity.

Role of the diet as a link between oxidative stress and liver diseases.

Oxidative stress is caused by an imbalance between the production of reactive oxygen (free radicals) and the body's ability (antioxidant capacity) to readily detoxify the reactive intermediates or easily repair the resulting damage. An adequate diet, characterized by daily intake of foods associated with improvements in the total antioxidant capacity of individuals and reduced incidence of diseases related to oxidation, can modulate the degree of oxidative stress. In fact, diet-derived micronutrients may be direct antioxidants, or are components of antioxidant enzymes, leading to improvement of some indicators of hepatic function. However, although their increased dietary intake might be beneficial, literature data are still controversial. This review summarizes what is known about the effects of diet nutrients on oxidative stress, inflammation and liver function. Moreover, we have analyzed: (1) the main nutritional components involved in the production and/or removal of free radicals; and (2) the role of free radicals in the pathogenesis of several hepatic diseases and related comorbidities.

Obesity and breastfeeding: The strength of association.

UNLABELLED: Obesity and attendant co-morbidities are an emergent problem in public health. Much attention has focused on prevention, especially during the perinatal period. Breastfeeding is considered a possible protective factor for obesity in childhood, influencing gene-neuroendocrine-environment-lifestyle interaction. Therefore, breastfeeding and its longer duration are probably associated with lower development of childhood obesity. Through human milk, but not formula, the child assumes greater bioactive factors contributing to immunological, endocrine, development, neural and psychological benefits. Contrarily, other studies did not confirm a critical role of breast milk. Confounding factors, especially maternal pre-pregnancy overweight, may influence breastfeeding effects. This review summarises what is known about the possible relationship between breastfeeding and prevention of obesity development. CONCLUSION: Breastfeeding appears to represent a protective factor for obesity in childhood, although evidence is still controversial and underlying mechanisms unclear. Further research is needed to improve knowledge on overweight/obesity and breastfeeding.

Endocrinopathies, metabolic disorders, and iron overload in major and intermedia thalassemia: serum ferritin as diagnostic and predictive marker associated with liver and cardiac T2* MRI assessment.

INTRODUCTION: Endocrinopathies and metabolic disorders-characterized ß thalassemic (ßT) patients and the prevention and treatment of these comorbidities are important targets to be achieved. The aim of the study was to analyze the diagnostic and prognostic role of ferritin for endocrinopathies and metabolic disorders in ßT patients. The ability of iron chelators to treat iron overload and to prevent or reverse metabolic disorders and endocrinopathies was also evaluated. PATIENTS AND METHODS: Seventy-two ßT patients were treated with different chelation strategies during the study. Receiver operating characteristics analysis was employed to calculate the area under the curve for serum ferritin to find the best cutoff values capable of identifying endocrine dysfunction in thalassemic patients. Kaplan-Meier curves were generated to assess the incidence of endocrinopathy. Adjusted risk estimates for endocrinopathy were calculated using univariate followed by multivariate Cox proportional hazard regression analysis. RESULTS: High ferritin levels were observed in patients with hypothyroidism [1500 (872.5-2336.5) µg/L], hypogonadism [878 (334-2010) µg/L], and in patients with hypoparathyroidism or osteoporosis [834 (367-1857) µg/L]. A strict correlation between ferritin and T2* magnetic resonance imaging of heart (r = -0.64; P:0.0006) and liver (r = -0.40; P:0.03) values was observed. Patients with ferritin values above 1800 µg/L experienced a significantly faster evolution to hypothyroidism [log-rank (χ(2) ):7.7; P = 0.005], hypogonadism [log-rank (χ(2) ):10.7; P = 0.001], and multiple endocrinopathies [log-rank (χ(2) ):5.72; P = 0.02]. Ferritin predicted high risk of endocrine dysfunction independently of confounding factors (HR:1.23; P < 0.0001). The intensification of chelation therapy led to an amelioration of hypothyroidism. CONCLUSIONS: Ferritin represents a prognostic marker for ßT patients and a predictive factor for progression to endocrine dysfunctions. Intensive chelation therapy allows the reversibility of hypothyroidism.