Hyperferritinemia—a clinical overview

Ferritin is one of the most frequently requested laboratory tests in primary and secondary care, and levels often deviate from reference ranges. Serving as an indirect marker for total body iron stores, low ferritin is highly specific for iron deficiency. Hyperferritinemia is, however, a non-specific finding, which is frequently overlooked in general practice. In routine medical practice, only 10% of cases are related to an iron overload, whilst the rest is seen as a result of acute phase reactions and reactive increases in ferritin due to underlying conditions. Differentiation of the presence or absence of an associated iron overload upon hyperferritinemia is essential, although often proves to be complex. In this review, we have performed a review of a selection of the literature based on the authors’ own experiences and assessments in accordance with international recommendations and guidelines. We address the biology, etiology, and epidemiology of hyperferritinemia. Finally, an algorithm for the diagnostic workup and management of hyperferritinemia is proposed, and general principles regarding the treatment of iron overload are discussed.publishedVersio

Substantial reduction in severe diarrheal morbidity by daily zinc supplementation in young north Indian children

Objective: To evaluate the impact of 4 months of daily zinc supplementation on the incidence of severe and recurrent diarrhea in children 6 to 30 months of age. Methods: A double-blind, randomized, placebo-controlled trial was conducted on children who were identified by a door-to-door survey to be aged 6 to 30 months and residing in the urban slum of Dakshinpuri, New Delhi. They were randomized to receive daily zinc gluconate (elemental zinc 10 mg to infants and 20 mg to older children) or placebo. A field attendant administered the syrup daily at home for 4 months except on Sundays, when the mother did so. One bottle that contained 250 mL was kept in the child's home and replaced monthly. Field workers visited households every seventh day during the 4-month follow-up period. At each visit, information was obtained for the previous 7 days on history of fever, number and consistency of stools, and presence of cough. When the child was ill, illness characteristics and treatment seeking outside the home were determined. If the child had diarrhea or vomiting, then dehydration was assessed. At household visits, 2 packets of oral rehydration salts were given when a child had diarrhea. Children who visited the study clinic spontaneously for illness or were referred by the field workers were treated according to the standard national program guidelines. Antibiotics were advised only for diarrhea with bloody stools or for associated illnesses. For using generalized estimating equations for longitudinal analysis of a recurring event such as diarrhea, the follow-up data for each child was divided into 17 child-periods of 7 days each and presence or absence of an incident episode of diarrhea or severe diarrhea within each 7-day period was coded. This method of analysis does not assume independence of events and therefore prevents underestimation of variance that results because of correlation of morbidity within the same child. A logistic generalized estimating equations model with exchangeable correlation covariance-variance matrix was then used to estimate the effect size. Results: Zinc or placebo doses were administered on 88.8% and 91.2%, respectively, of study days during the 4 months of follow-up. There was a small but significant increase in the average number of days with vomiting in the zinc group (4.3 [standard deviation (SD): 5.8] vs 2.6 [SD 3.9] days; difference in means: 1.7 [95% confidence interval (CI): 1.3-2.1] days). At the baseline, mean plasma zinc was 62.0 microg/dL (SD: 14.3 microg/dL) in the zinc and 62.0 microg/dL (SD: 11.2 microg/dL) in the placebo group; 45.8% and 42%, respectively, had low plasma zinc levels below 60 microg/dL. At the end of the study, plasma zinc levels were substantially higher in the zinc group (ratio of geometric means: 1.94 [95% CI: 1.86-2.03]) and the proportion with low plasma zinc was lower (difference in proportions: -46.7% [95% CI: -41.8% to -51.4%]). The incidence of diarrhea during follow-up was lower in the zinc-supplemented as compared with the placebo group (odds ratio [OR]: 0.88; 95% CI: 0.82-0.95). The beneficial impact of zinc was greater on the incidence of diarrhea with progressively increasing duration: episodes of diarrhea that lasted 1 to 6 days (OR: 0.92; 95% CI: 0.85-1.00), 7 to 13 days (OR: 0.79; 95% CI: 0.65-0.95), and > or =14 days (OR: 0.69; 95% CI: 0.48-0.98). The impact was also greater on the incidence of episodes with progressively higher stool frequency: 3 to 5 stools per day (OR: 0.90; 95% CI: 0.83-0.98), 6 to 9 stools per day (OR: 0.87; 95% CI: 0.77-0.98), and > or =10 per day (OR: 0.77; 95% CI: 0.63-0.94). In the zinc group, significantly more children experienced no diarrheal episode during the study period (risk ratio [RR]: 1.22; 95% CI: 1.02-1.44). Furthermore, substantially fewer children (RR: 0.51; 95% CI: 0.36-0.73) experienced recurrent diarrhea, defined as >6 diarrheal episodes in the follow-up period as compared with children in the placebo group. The number of children who were hospitalized for any cause tended to be lower in the zinc group, but the difference was not statistically significant (1.79% vs 2.43%; RR: 0.74; 95% CI: 0.43-1.27). The baseline mean plasma copper (microg/dL) was similar in the 2 groups (difference in means: 1.6; 95% CI: -2.9 to 6.1). The end study plasma copper levels were significantly lower in the zinc group (difference in means: -15.5; 95% CI: -19.9 to - 11.1). Conclusions: Zinc supplementation substantially reduced the incidence of severe and prolonged diarrhea, the 2 important determinants of diarrhea-related mortality and malnutrition. This intervention also substantially reduced the proportion of children who experienced recurrent diarrhea. Prompt measures to improve zinc status of deficient populations are warranted. The potential approaches to achieve this goal include food fortification, dietary diversification, cultivation of plants that are zinc dense or have a decreased concentration of zinc absorption inhibitors, and supplementation of selected groups of children. Future studies should assess the impact of increased zinc intakes on childhood mortality in developing countries. For facilitating intervention, there is a need to obtain reliable estimates of zinc deficiency, particularly in developing countries. The functional consequences of the effect of various doses of zinc on plasma copper levels merits additional study

Effectiveness and efficacy of zinc for the treatment of acute diarrhea in young children

Intervention trials have shown that zinc is efficacious in treating acute diarrhea in children of developing countries. In a randomized, placebo-controlled trial, we assessed the effectiveness and efficacy of giving 3 Recommended Daily Allowances of elemental zinc to 6- to 35-month-old children with acute diarrhea. Methods: Seventeen hundred ninety-two cases of acute diarrhea in Nepalese children were randomized to 4 study groups. Three groups were blinded and the children supplemented daily by field workers with placebo syrup, zinc syrup, or zinc syrup and a massive dose of vitamin A at enrollment. The fourth group was open and the caretaker gave the children zinc syrup daily. Day-wise information on morbidity was obtained by household visits every fifth day. Results: The relative hazards for termination of diarrhea were 26% (95% confidence interval [CI]: 8%, 46%), 21% (95% CI: 4%, 38%), and 19% (95% CI: 2%, 40%) higher in the zinc, zinc-vitamin A, and zinc-caretaker groups, respectively, than in the placebo group. The relative risks of prolonged diarrhea (duration >7 days) in these groups were 0.57 (95% CI: 0.38, 0.86), 0.53 (95% CI: 0.35, 0.81), and 0.55 (0.37, 0.84); zinc accordingly reduced the risk of prolonged diarrhea with 43% to 47%. Five percent and 5.1% of all syrup administrations were followed by regurgitation in the zinc and zinc-vitamin A group, respectively, whereas this occurred after only 1.3% of placebo administrations. Vomiting during diarrhea was also more common in children receiving zinc. Conclusions: Three Recommended Daily Allowances of zinc given daily by caretakers or by field workers substantially reduced the duration of diarrhea. The effect of zinc was not dependent on or enhanced by concomitant vitamin A administration

Hyperferritinemia—a clinical overview

Ferritin is one of the most frequently requested laboratory tests in primary and secondary care, and levels often deviate from reference ranges. Serving as an indirect marker for total body iron stores, low ferritin is highly specific for iron deficiency. Hyperferritinemia is, however, a non-specific finding, which is frequently overlooked in general practice. In routine medical practice, only 10% of cases are related to an iron overload, whilst the rest is seen as a result of acute phase reactions and reactive increases in ferritin due to underlying conditions. Differentiation of the presence or absence of an associated iron overload upon hyperferritinemia is essential, although often proves to be complex. In this review, we have performed a review of a selection of the literature based on the authors’ own experiences and assessments in accordance with international recommendations and guidelines. We address the biology, etiology, and epidemiology of hyperferritinemia. Finally, an algorithm for the diagnostic workup and management of hyperferritinemia is proposed, and general principles regarding the treatment of iron overload are discussed

Bloodlettings in Hemochromatosis Result in Increased Blood Lead (Pb) Concentrations

Hemochromatosis is a hereditary disorder, most often associated with mutations of the HFE (High FErrum) gene. If left untreated, it can result in severe parenchymal iron accumulation. Bloodletting is the mainstay treatment. We have previously shown that treatment of hemochromatosis by repeated bloodlettings may induce changes in the serum levels of several trace elements. The aim of this work was to evaluate if whole blood concentrations of the environmental pollutants lead (Pb), mercury (Hg), and cadmium (Cd) could be affected by bloodlettings. We recruited 28 patients and 21 healthy individuals (control group). Whole blood and urine levels of Pb, Hg, and Cd were measured before the start and after the completion of treatment using inductively coupled plasma mass spectrometry, together with serum iron and liver function tests. Concentrations of blood Pb, but not Hg or Cd, were significantly increased after treatment. The increase in Pb was higher in C282Y homozygous patients than in the other patients, and it was positively correlated with the serum concentration of alkaline phosphatase. Bloodlettings in hemochromatosis result in an increase in the blood concentration of Pb. Augmented absorption due to iron loss or Pb mobilization from bone may contribute to the higher blood Pb level.publishedVersio

Quantitative proteomics comparison of arachnoid cyst fluid and cerebrospinal fluid collected perioperatively from arachnoid cyst patients

Background: There is little knowledge concerning the content and the mechanisms of filling of arachnoid cysts. The aim of this study was to compare the protein content of arachnoid cysts and cerebrospinal fluid by quantitative proteomics to increase the understanding of arachnoid cysts. Methods: Arachnoid cyst fluid and cerebrospinal fluid from five patients were analyzed by quantitative proteomics in two separate experiments. In a label-free experiment arachnoid cyst fluid and cerebrospinal fluid samples from individual patients were trypsin digested and analyzed by Orbitrap mass spectrometry in a label-free manner followed by data analysis using the Progenesis software. In the second proteomics experiment, a patient sample pooling strategy was followed by MARS-14 immunodepletion of high abundant proteins, trypsin digestion, iTRAQ labelling, and peptide separation by mix-phase chromatography followed by Orbitrap mass spectrometry analysis. The results from these analyzes were compared to previously published mRNA microarray data obtained from arachnoid membranes. Results: We quantified 348 proteins by the label-free individual patient approach and 1425 proteins in the iTRAQ experiment using a pool from five patients of arachnoid cyst fluid and cerebrospinal fluid. This is by far the largest number of arachnoid cyst fluid proteins ever identified, and the first large-scale quantitative comparison between the protein content of arachnoid cyst fluid and cerebrospinal fluid from the same patients at the same time. Consistently in both experiment, we found 22 proteins with significantly increased abundance in arachnoid cysts compared to cerebrospinal fluid and 24 proteins with significantly decreased abundance. We did not observe any molecular weight gradient over the arachnoid cyst membrane. Of the 46 proteins we identified as differentially abundant in our study, 45 were also detected from the mRNA expression level study. None of them were previously reported as differentially expressed. We did not quantify any of the proteins corresponding to gene products from the ten genes previously reported as differentially abundant between arachnoid cysts and control arachnoid membranes. Conclusions: From our experiments, the protein content of arachnoid cyst fluid and cerebrospinal fluid appears to be similar. There were, however, proteins that were significantly differentially abundant between arachnoid cyst fluid and cerebrospinal fluid. This could reflect the possibility that these proteins are affected by the filling mechanism of arachnoid cysts or are shed from the membranes into arachnoid cyst fluid. Our results do not support the proposed filling mechanisms of oncotic pressure or valves

Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 years: randomised controlled trial in an urban slum

OBJECTIVES: To evaluate the effect of daily zinc supplementation in children on the incidence of acute lower respiratory tract infections and pneumonia. DESIGN: Double masked, randomised placebo controlled trial. SETTING: A slum community in New Delhi, India. PARTICIPANTS: 2482 children aged 6 to 30 months. INTERVENTIONS: Daily elemental zinc, 10 mg to infants and 20 mg to older children or placebo for four months. Both groups received single massive dose of vitamin A (100 000 IU for infants and 200 000 IU for older children) at enrolment. MAIN OUTCOME MEASURES: All households were visited weekly. Any children with cough and lower chest indrawing or respiratory rate 5 breaths per minute less than the World Health Organization criteria for fast breathing were brought to study physicians. RESULTS: At four months the mean plasma zinc concentration was higher in the zinc group (19.8 (SD 10.1) v 9.3 (2.1) μmol/l, P<0.001). The proportion of children who had acute lower respiratory tract infection during follow up was no different in the two groups (absolute risk reduction −0.2%, 95% confidence interval −3.9% to 3.6%). Zinc supplementation resulted in a lower incidence of pneumonia than placebo (absolute risk reduction 2.5%, 95% confidence interval 0.4% to 4.6%). After correction for multiple episodes in the same child by generalised estimating equations analysis the odds ratio was 0.74, 95% confidence interval 0.56 to 0.99. CONCLUSIONS: Zinc supplementation substantially reduced the incidence of pneumonia in children who had received vitamin A

The prevalence of anemia and iron deficiency is more common in breastfed infants than their mothers in Bhaktapur, Nepal

Background/Objectives: Iron deficiency anemia is a widespread public health problem, particularly in low- and middle-income countries. Maternal iron status around and during pregnancy may influence infant iron status. We examined multiple biomarkers to determine the prevalence of iron deficiency and anemia among breastfed infants and explored its relationship with maternal and infant characteristics in Bhaktapur, Nepal. Subjects/Methods: In a cross-sectional survey, we randomly selected 500 mother–infant pairs from Bhaktapur municipality. Blood was analyzed for hemoglobin, ferritin, total iron-binding capacity, transferrin receptors and C-reactive protein. Results: The altitude-adjusted prevalence of anemia was 49% among infants 2–6-month-old (hemaglobin (Hb) <10.8 g/dl) and 72% among infants 7–12-month-old (Hb <11.3 g/dl). Iron deficiency anemia, defined as anemia and serum ferritin <20 or <12 μg/l, affected 9 and 26% of infants of these same age groups. Twenty percent of mothers had anemia (Hb <12.3 g/dl), but only one-fifth was explained by depletion of iron stores. Significant predictors of infant iron status and anemia were infant age, sex and duration of exclusive breastfeeding and maternal ferritin concentrations. Conclusions: Our findings suggest that iron supplementation in pregnancy is likely to have resulted in a low prevalence of postpartum anemia. The higher prevalence of anemia and iron deficiency among breastfed infants compared with their mothers suggests calls for intervention targeting newborns and infants

Discovery and initial verification of differentially abundant proteins between multiple sclerosis patients and controls using iTRAQ and SID-SRM

In the present study, we aimed to discover cerebrospinal fluid (CSF) proteins with significant abundance difference between early multiple sclerosis patients and controls, and do an initial verification of these proteins using selected reaction monitoring (SRM). iTRAQ and Orbitrap MS were used to compare the CSF proteome of patients with clinically isolated syndrome (CIS) (n = 5), patients with relapsing–remitting multiple sclerosis that had CIS at the time of lumbar puncture (n = 5), and controls with other inflammatory neurological disease (n = 5). Of more than 1200 identified proteins, five proteins were identified with significant abundance difference between the patients and controls. In the initial verification using SRM we analyzed a larger patient and control cohort (n = 132) and also included proteins reported as differentially abundant in multiple sclerosis in the literature. We found significant abundance difference for 11 proteins after verification, of which the five proteins alpha-1-antichymotrypsin, contactin-1, apolipoprotein D, clusterin, and kallikrein-6 were significantly differentially abundant in several of the group comparisons. This initial study form the basis for further biomarker verification studies in even larger sample cohorts, to determine if these proteins have relevance as diagnostic or prognostic biomarkers for multiple sclerosis.acceptedVersio