Normal Ferritin Levels Research Articles

Effect of Omeprazole on Response to Oral Ferrous Sulphate in Iron Deficient Patients: 2010 Presidential Poster

Purpose: Proton pump inhibitors are very commonly prescribed medications in gastrointestinal practice. One of the debated effects of proton pump inhibitors is on oral iron absorption. Their effect on absorption of oral iron supplementation in iron deficient patients has not been studied. Methods: We reviewed patient charts seen in Cooper Outpatient offices for iron deficiency anemia on omeprazole within the last three years. We then selected fifty patients based on following criteria: Having no apparent ongoing blood loss; having other causes of anemia especially that of chronic disease ruled out; and had follow-up iron studies done. The iron studies at the start of oral ferrous sulfate therapy and at three months follow up were compared to evaluate the response. Results: There were 74% males and 36% females in the study group. Mean age of the study group was 50.5+/-15.3 years. Mean hemoglobin and ferritin at baseline, and at three months follow up along with their paired t-test results and p-values are shown in table 1. The mean hemoglobin change was 0.8+/-1.2 g/L, while the mean ferritin change was 10.2+/-7.8 ug/L. These results indicate that there was a significant change in both hemoglobin and ferritin levels. But only 40% of the patients had a normal response to ferritin levels, defined as a rise of >20 ug/L; and only 15% had a normal response to hemoglobin levels; defined as a rise of > 2 g/L. Also on further follow up almost all who were continued on iron and omeprazole achieved a normal ferritin and hemoglobin levels in a year. Also 15 patients were switched to iv iron therapy and 13 of them responded. Further 5 patients had no compelling reason to be on omeprazole and 4 of them responded to ferrous sulfate after stopping omeprazole. Conclusion: Omeprazole and possibly all proton pump inhibitors seem to decrease the absorption of oral iron supplementation, to a level where either they may have to be continued for a long term or may have to be given the iron supplementation intravenously. Patients who need to be on long term PPI, especially who may have ongoing occult blood loss should be checked regularly for iron deficiency anemia, as they most certainly also significantly decrease dietary iron absorption. And if found to be iron deficient, they should either be treated with high dose iron therapy or for susceptible patients with iv iron therapy. Further, prospective studies are needed to support this preliminary finding.Table: Serum hemoglobin and ferritin levels before and after oral iron supplementation

Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency

Chronic cerebrospinal venous insufficiency (CCSVI) has been suggested to be a possible cause of multiple sclerosis (MS). If the presumed mechanism of venous stasis-related parenchymal iron deposition and neurodegeneration were true, then upregulation of intrathecal iron transport proteins may be expected. This was a cross-sectional (n = 1,408) and longitudinal (n = 29) study on CSF ferritin levels in patients with MS and a range of neurologic disorders. Pathologic (>12 ng/mL) CSF ferritin levels were observed in 4% of the control patients (median 4 ng/mL), 91% of patients with superficial siderosis (75 ng/mL), 73% of patients with a subarachnoid hemorrhage (59 ng/mL), 10% of patients with relapsing-remitting MS (5 ng/mL), 11% of patients with primary progressive MS (6 ng/mL), 23% of patients with secondary progressive MS (5 ng/mL), and 23% of patients with meningoencephalitis (5 ng/mL). In MS, there was no significant change of CSF ferritin levels over the 3-year follow-up period. These data do not support an etiologic role for CCSVI-related parenchymal iron deposition in MS.

CC-007 Ascites due to unusual cause with unusual mode of therapy

<h3>Introduction</h3> 40 years old married goldsmith presented with features of numbness of both lower limbs, swelling of the neck, bilateral pedal oedema and abdominal distension of 4 months duration. In addition he had asthenia, effort dyspnoea and pigmentation. Systemic inquiry revealed no other significant symptoms and he was on treatment for hypertension. He was a non-alcoholic and a non-smoker. He had many social and psychological problems due to his current illness. Examination revealed mild pallor, pigmentation not involving oral mucosa but involving skin creases, generalised lymphadenopathy in the cervical, supraclavicular and inguinal areas rubbery and non-discrete in certain areas, leuconychia without clubbing, ankle oedema. CVS and respiratory system examination were normal. Abdomen revealed non-tender hepatomegaly 4 cm below right costal margin shifting dullness, while CNS examination revealed presence of peripheral neuropathy with bilateral foot drop without thickened nerves and bilateral papilloedema. Following were the results of laboratory investigations; FBC: Hb-9.3 g/dl, MCV-70.2 fl and rest normal. LFT: normal. Renal profile normal. ESR:40 mm first hour, C-RP 48 mg/dl. FBS-100 mg/dl. Normal ferritin, calcium and ceruloplasmin levels. Clotting profile: INR-1.6, rest normal. UFR normal. HIV screening negative. CXR-PA normal. Abdomen and pelvic USS: minimal hepatomegaly and splenomegaly with ascites. Mantoux negative. OGD: no evidence of portal hypertension. Bone marrow normal. Nerve conduction study and EMG: severe demyelinating sensory and motor neuropathy. 2D echo: moderate LVH and pulmonary hypertension with small pericardial effusion. TSH- 23.8 μiu/l (0.4–4.0 μiu/l) Ascitic fluid analysis: 64.5 g/l, white cells- 344/mm³ 90% lymphocytes and 10% neutrophils. LDH and amylase levels normal. Screening for mycobacterium negative. Liver biopsy: interphase hepatitis. Immunoglobulin Profile – elevated α 2 Globulins and a mild polyclonal gammopathy Free κ light chains 569.0 mg/dl (138–375) Free λ light chains 258.7 mg/dl (93–242) Lymph node biopsy revealed unifying diagnosis which was compatible with other clinical and laboratory findings. The patient was treated with a single drug for 6 months which resulted in improvement of his clinical features and resolution of ascites. <h3>Conclusion</h3> Ascites is a common condition encountered by a Gastroenterologist with or without other signs, and the aeotiology could be unusually extraordinary as in this report with an unusual therapeutic strategy. <h3>Methods</h3> BSG – interactive case presentation <h3>Results</h3> BSG – interactive case presentation <h3>Conclusion</h3> BSG – interactive case presentation

Iron Status in Female Athletes Participating in Team Ball-Sports

Iron deficiency anemia is the most prevalent micronutrient deficiency in the world, affecting 20-50% of the world's population. It is estimated that 10 and 20% of male and female athletes are iron deficient, respectively. Iron deficiency has deleterious effects on the physical performance of athletes. It decreases aerobic capacity, increases heart rate and elongates the recovery time after exercise. In this cross-sectional study, 42 semi-professional female athletes who had been playing in basketball, volleyball and handball super league teams served as subjects. Data on socioeconomic and fertility status as well as the type of sport were obtained through a questionnaire. Nutritional data were gathered with a 3 day dietary recall. Total intake of calorie, iron, zinc, folate, vitamin C and B12 were also analyzed. In addition, ferritin and TIBC were measured and a CBC test was done for each subject. The results showed that the mean total calorie intake of women was 2049.79 +/- 735.12 kcal, where their iron intake was 22.33 +/- 9.24 mg day(-1). There was a significant difference between the iron intake of basketball and volleyball players (p = 0.036). Of our subjects, 33.33% had low ferritin levels (< 30 ng mL(-1)) and it was lowest in handball players. Higher than normal ferritin levels were seen in 12.5% of the subjects. We saw a significant difference in ferritin levels of basketball and handball players (p = 0.047). We conclude that the intake of calorie and iron is low in female athletes and therefore, their hematological indices such as ferritin level are below standard values.

Hepcidin and inflammatory bowel disease: dual role in host defence and iron homoeostasis

Hepcidin is an endogenous antimicrobial peptide with a key role in iron homoeostasis. Hepcidin is similar to defensin, the deficiency of which is associated with Crohn's disease. To date there has been no validated method to reliably assay serum hepcidin. We studied iron indices in inflammatory bowel disease (IBD) including hepcidin. We assessed serum hepcidin concentrations (using a newly developed competitive radioimmunoassay) and ferritin in patients with IBD. Haematinics including serum soluble transferrin receptor, serum iron, serum vitamin B12 and red cell folate levels were also measured. The hepcidin results were compared with a control group of healthy volunteers from the local community. This study was based in a hospital. Sixty-one patients with IBD (51 patients with ulcerative colitis and 10 with Crohn's disease). Their mean hepcidin results were compared with 25 healthy controls. hepcidin concentration in serum samples in IBD patients compared with normal volunteers. We found significantly low serum hepcidin levels in patients with IBD. The hepcidin levels were low in IBD patients without iron deficiency anaemia as evidenced by normal ferritin and serum iron levels (n=41, mean hepcidin 6.81 ng/ml, SEM 1.2) and in IBD patients with iron deficiency anaemia (n=18, mean hepcidin 4.14 ng/ml, SEM 0.72) compared with healthy controls (n=25, mean hepcidin 15.3 ng/ml, SEM 3.14) (P=0.0045 and P=0.0050 on unpaired t-tests, respectively). We also measured IL-6 (enzyme-linked immunosorbent assay method, Abcam plc) in 21 of the 61 patients with IBD and compared the results with samples from 10 healthy volunteers. The IL-6 level was significantly higher (P=0.0222 on unpaired t-tests) in this group of IBD patients (n=21, IL-6 mean 2.94 pg/ml, SEM 0.64) compared with controls (n=10, IL-6 mean 0.663 pg/ml SEM 0.14). A significant positive correlation (Pearson's correlation coefficient r=0.6331) was present between hepcidin and IL-6, but not between hepcidin and serum soluble transferrin receptor (r=-0.235). The low hepcidin results in IBD patients may reflect a causal or perpetuator effect on intestinal inflammation.

Extrinsic factors modifying expressivity of the HFE variant C282Y, H63D, S65C phenotypes in 1,294 Danish men

This study analysed the influence of extrinsic factors on the phenotypic expression of HFE gene variants in ethnic Danish men. A cohort of 6,020 men aged 30-53 years was screened for HFE C282Y, H63D and S65C variants. Serum iron, serum transferrin, transferrin saturation, and serum ferritin were analysed in 1,452 men and 1,294 men completed a questionnaire on factors, which could influence iron balance. The C282Y allele was present in 5.6%, H63D in 12.8% and S65C in 1.8% of the men. In the entire series, 3% had elevated iron status markers (transferrin saturation > or =50%, ferritin > or =300 microg/L). Self-reported liver disease had an elevating effect and peptic ulcer a lowering effect on iron status markers. Age increased the fraction of men with elevated ferritin from 8.3% at 32-38 years to 16.2% at 46-53 years of age (p = 0.002). Blood donation had a lowering effect on iron status markers (p = 0.0001). Alcohol consumption elevated serum iron and serum ferritin (p = 0.001). Meat consumption had an elevating effect (p = 0.02) and milk consumption a lowering effect (p = 0.03) on serum ferritin. There was no influence of vitamin-mineral tablets on iron status markers. In adjusted logistic regression analysis, the HFE genotype had the highest impact on iron status markers; high alcohol consumption was significantly associated with elevated transferrin saturation. High age and high alcohol consumption were significantly associated with elevated ferritin and high egg consumption and blood donation was significantly associated with normal ferritin levels. In conclusion, the expressivity of HFE variant phenotypes in Danish men was enhanced by alcohol and meat consumption and decreased by milk and egg consumption and blood donation.

Quantification by Superconducting Quantum Interference Device (SQUID) of Iron Overload after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT).

Introduction. Iron overload (IO) is an adverse prognostic factor in patients who undergo allogeneic HSCT for thalassemia and appears to play a similar role in patients with other hematological disorders. Estimation of IO is primarily based on serum ferritin, however many confounding factors particularly in HSCT recipients may result in frequent ferritin overestimation. Aim of the study was to quantify IO by SQUID after HSCT and evaluate the impact on hepatic function and infections. Additionally, the feasibility of iron-depletion has been investigated.Methods. Between December 2005 and December 2007, 102 consecutive pts who were admitted at our outpatient department have been analyzed. Patients received HSCT from a matched sibling (n=66), a partially matched relative (n=4) or a matched unrelated donor (n=32). Primary diagnosis included acute leukemia/MDS in 61% of cases. Assessment of IO after HSCT included serum ferritin and in those with hyperferritinemia (> 1000 ng/ml), liver iron concentration (LIC) was evaluated by SQUID magnetic susceptometry. Iron removal therapy was offered to patients with moderate (LIC 1000–2000 microg/gww) or severe (LIC >2000 microg/gww) IO.Results. Patients who were in complete remission underwent ferritin assessment at a median time of 578 days from transplantation. Fifty-seven had a ferritin level below the threshold of 1000 ng/ml; in this cohort the median time from HSCT to ferritin assessment was 1006 days, significantly different from the median time of 183 days of the 45 patients who had a ferritin level > 1000 ng/ml. LIC evaluated by SQUID was available for 42/45 patients with elevated ferritin values. Overall, 29 patients had moderate to severe IO: median LIC values were 1493 microg/gww (range 1030–3253 microg/gww). Thirteen patients had normal LIC values (LIC<400 microg/gww) despite high serum ferritin levels. Multivariate analysis showed a significant correlation between ferritin levels > 1000 ng/ml and the occurrence of liver dysfunction defined by the presence of at least one abnormal liver function test (LFT) on two or more occasions (OR 6.8; 95%CI 2.2–20.6); the correlation hold the statistical significance even including into the multivariate model the different time of ferritin assessment. In addition, the rate of proven/probable invasive fungal disease was significantly higher among patients with hyperferritinemia as compared to patients with normal ferritin levels (13% vs 0%; p=.006). Nineteen of the 23 patients considered eligible to iron depletion, underwent regular phlebotomy: 9 patients completed the program after a median time of 10 months (range 3–13 months), reaching the target of ferritin < 500 ng/ml; for 6 patients the program is still ongoing, while 4 patients discontinued the phlebotomy protocol (relapse n=2; hypotension, n=1; progressive anemia, n=1). In 8/9 patients who were revaluated by SQUID at the end of iron depletion program there was a significant decrease of LIC (median 1368 microg/gww to 606 microg/gww; p=.005) that parallels changes of serum ferritin; one patient did not show e remarkable reduction of LIC despite serum ferritin normalization.. Three of the 4 patients ineligible to phlebotomy were successfully treated with deferasirox and 1 patient was treated with deferoxamine.Conclusion. The measurement of LIC obtained by SQUID documented the presence of moderate/severe IO in 69% of the patients with high ferritin levels. Our preliminary data showed that in HSCT recipients, high ferritin level is an independent risk factor for the occurrence of abnormal LFTs and IO may be considered a potential risk factor for fungal infections. A phlebotomy program resulted feasible in 65% of the patients who might benefit from a procedure of iron depletion

Anemia without Low Ferritin – Do They Warrant a GI Workup? a Preliminary Hospital Based Study

Purpose: Endoscopic evaluation of the gastrointestinal tract in patients with iron deficiency in men and postmenopausal women is warranted by most guidelines. The yield of endoscopy in patients with normal and high ferritin levels is unknown. In hospitalized patients with other acute medical problems, the ferritin levels can be elevated and may mask a true iron deficiency anemia. The aim of the study is to analyze the yield of endoscopy in patients with anemia but with a normal or high ferritin. Methods: Retrospective review of adult men and postmenopausal women that were admitted with anemia to a teaching community hospital for a period of nine months. Only the patients who had an anemia workup with hematological indices were included. A ferritin level of over 100 ng/ml was considered as normal or high. Endoscopic procedure reports and pathology reports were analyzed. Gastrointestinal (GI) lesions that were counted as a cause or contributing to the anemia were malignancy, angiodysplasias, polyps, colitis, high grade esophagitis, erosive and hemorrhagic gastritis and extensive diverticulosis. Results: In the nine month period 340 patients had anemia work up with hematological indices documented. The mean age was 62.2 years with 34% males and 66% females. 209 patients fit the subset of anemia with normal or high ferritin levels. 70 of these patients had a GI workup. 50% had both upper endoscopy and colonoscopy. 32% had upper endoscopy alone and 18% had colonoscopy alone. The findings were: malignancy 11% (10% colon carcinoma and 1% gastric carcinoma), colitis 2.8%, erosive/hemorrhagic gastritis 14%, grade C esophagitis 4%, peptic ulcer 2.8% and angiodysplasia 4.2%. Conclusion: Anemia with normal or high ferritin does not conclusively rule out anemia due to blood loss in a hospitalized patient. GI workup will be beneficial in these patients especially because of the incidence of malignancies noted. A prospective or large retrospective study will need to be undertaken to prove this hypothesis.

Serum hepcidin levels are innately low in HFE‐related haemochromatosis but differ between C282Y‐homozygotes with elevated and normal ferritin levels

HFE C282Y-homozygosity has been associated with low hepcidin expression, leading to increased ferritin levels. However, serum hepcidin protein levels have not been documented in humans. In the current study, we compared serum hepcidin levels of newly diagnosed HFE C282Y-homozygotes with (N = 15) and without (N = 7) elevated serum ferritin levels to levels of 40 controls (20 heterozygotes and 20 wild types). In addition, hepcidin levels of four C282Y homozygotes were investigated during the course of all phlebotomy treatment phases. Serum hepcidin levels were lower in HFE C282Y-homozygotes (median; 25th-75th percentile: 1.88; 0.78-2.77 nmol/l) compared to controls (2.74; 1.45-5.39). Hepcidin/ferritin ratios were also lower in homozygotes. Homozygotes with an elevated serum ferritin had a higher serum hepcidin but a lower hepcidin/ferritin ratio than those with normal ferritin (2.28; 1.62-3.23 nmol/l hepcidin vs. 0.80; 0.60-1.29 and 3.63; 2.72-7.59 pmol hepcidin/microg ferritin vs. 13.2; 5.15-14.2). Serum hepcidin decreased during the depletion phase of phlebotomy and remained low during maintenance. This study showed that serum hepcidin is innately low in HFE-related haemochromatosis. Elevated ferritin levels were associated with increased hepcidin levels while erythropoiesis lead to lower hepcidin levels. During depletion, therefore, hepcidin levels are decreased, which may exacerbate intestinal iron absorption.

Oxidative stress and ferritin levels in haemodialysis patients

Increased oxidative stress (OS) and inflammation are associated with atherosclerotic coronary artery disease in haemodialysis (HD) patients. Ferritin may have other effects in addition to its role in storing intracellular iron. This study was performed to determine any relationships between markers of OS, nutrition and inflammation in HD patients with normal and high ferritin levels. Our cohort comprised 34 maintenance dialysis patients on erythropoietin therapy and 22 healthy controls. HD patients were divided into two groups: 17 with normal (<800 ng/ml) and 17 with high (>800 ng/ml) ferritin levels, and we measured lipid profile, albumin, highly sensitive C-reactive protein (hsCRP), anti-oxidant enzymes [whole blood glutathione peroxidase (Gpx), serum superoxide dismutase (SOD), paraoxonase, arylestherase (AE) and total anti-oxidant status (TAOC)], anti-oxidants (vitamin C) and lipid peroxidation products [red blood cell malondialdehyde (RBC MDA)]. Compared with controls, the HD patients had higher serum urea, blood pressure, triglyceride, hsCRP, RBC MDA, SOD and TAOC values and lower albumin, low-density lipoprotein cholesterol, apolipoprotein AI, paraoxonase, AE and whole blood Gpx activities. Serum vitamin C, uric acid, apolipoprotein B, total- and high-density lipoprotein cholesterol, apolipoprotein B MDA, and lymphocyte levels in the HD patients with normal and high ferritin levels were similar. The OS markers of HD patients did not differ, whether or not they received intravenous iron supplementation or had transferrin saturations < 50% or > or = 50%. HD patients are in a higher oxidative state, which results in the reduction of total anti-oxidant capacity and also have an increased inflammation status. We could not find a relationship between ferritin level and OS markers in HD patients receiving erythropoietin.

Ferritin levels during structured treatment interruption of highly active antiretroviral therapy

The aim of the study was to investigate the influence of highly active antiretroviral therapy (HAART) on iron status and, conversely, the influence of iron status on the response to HAART. Ferritin levels were retrospectively determined in stored plasma from 138 HAART-naïve, moderately immunosuppressed HIV-infected Thai patients participating in a structured treatment interruption trial. Ferritin levels were determined at three predefined time-points: (1) HAART initiation; (2) HAART discontinuation; and (3) HAART resumption. At baseline, 31% and 16% of the HIV-infected patients included in the study had high (>200 ng/mL) and low (<30 ng/mL) ferritin levels, respectively. Ninety-five per cent of patients with low ferritin levels were female. Ferritin decreased significantly during the interruption phase of HAART (-8.8 ng/mL; P=0.0005) but remained elevated in 62% of the patients with high baseline levels. A low baseline ferritin level was associated with a shorter time (P=0.041) to reach the CD4 cell target for HAART interruption (350 cells/microL), compared with a normal or high baseline ferritin level. Moreover, in a multivariate model, the relative risk (RR) of arriving at this CD4 cell target was significantly higher [RR 1.81; 95% confidence interval (CI) 1.05-3.14] in patients with low baseline ferritin. It is unlikely that inflammation affected ferritin in our patients, as mean levels of C-reactive protein were not elevated in patients with either high or low ferritin levels. Both high and low ferritin levels were highly prevalent in moderately immunosuppressed HIV-positive Thai patients. Structured treatment interruption of HAART resulted in a significant decrease in overall ferritin levels. Furthermore, subjects with low baseline ferritin levels had a faster and greater CD4 response to HAART, suggesting a potential beneficial effect of iron deficiency on immunological recovery after initiation of HAART.

Refinement of the genetic cause of ATR-16

Alpha thalassemia retardation associated with chromosome16 (ATR-16 syndrome) is defined as a contiguous gene syndrome resulting from haploinsufficiency of the alpha-globin gene cluster and genes involved in mental retardation (MR). To date, only few cases have been described which result from pure monosomy for a deletion of 16p. In most of these cases the deletion was identified by densitometric analysis of Southern blot results or by Fluorescent In Situ Hybridization analysis, and these alterations have not been mapped in detail. In this study, we have fine mapped deletions causing alpha-thalassemia within 2 Mb from the telomere of 16p by multiplex ligation-dependent probe amplification (MLPA). We have developed a rapid and simple test for high resolution mapping of rearrangements involving the tip of the short arm of chromosome 16 by incorporating 62 MLPA probes spaced approximately 10-200 kb over a region of 2 Mb from the telomere. One deletion of approximately 900 kb without MR was identified in addition to three de novo deletions varying between 1.5 and 2 Mb causing ATR-16 in three patients having mild MR and alpha-thalassemia. Two were found by chance to be ATR-16 because they were included in a study to search for telomeric loss in MR and not by hematological analysis. This would plead for more alertness when a persistent microcytic hypochromic anemia at normal ferritin levels is observed as suggestive for the ATR-16 syndrome. The region on chromosome 16p for which haploinsufficiency leads to the dysmorphic features and MR typical for ATR-16, has been narrowed down to a 800 kb region localized between 0.9 and 1.7 Mb from the telomere.

The relationship between depression and serum ferritin level

This study looks at the association of depression and serum ferritin level. Case-control study. University hospital. Two hundred and five female medical students of Free University of Medical Sciences in Tehran were selected for the study (mean age; 24.5+/-1.6 years). Of these, 13 subjects were excluded and finally 192 subjects took part in the study. A questionnaire was filled in by each participant for the diagnosis of depression to be made. Based on the Beck score, the students were grouped as depressed and healthy (67 depressed students and 125 healthy controls). The participants were evaluated in terms of hemoglobin (Hgb) level, serum ferritin, ESR (erythrocyte sedimentation rate), CRP (C-reactive protein), folic acid, vitamin B12 and Hgb simultaneously. The prevalence of depression in the study population was 34.7%. The mean ferritin level in students with depression was significantly lower than the healthy ones (P<0.001). By changing the status from normal ferritin level to low ferritin level, odds of depression was increased by 1.92 (P<0.05). The study implies a possible association between depression and decreased ferritin level before the occurrence of anemia. Free University of Medical Sciences.

Zinc Status But Not Iron Stores Are Inversely Associated With Soluble Vascular Cell Adhesion Molecule‐1 (sVCAM‐1) Levels in Children With Sickle Cell Disease (SCD)

VCAM-1, a protein expressed on endothelial cells, increases the risk of vasooclusion in SCD patients through adhesion of sickle red blood cells. Suboptimal zinc status and iron overload due to blood transfusion have been implicated in disease severity through oxidative stress. However, the influence of these factors on VCAM-1 has not been previously investigated. We measured sVCAM-1, zinc, hemoglobin [Hb], hematocrit [Hct], and serum ferritin in 76 SCD children and 96 non-SCD children, mean age 7.73 y and 11.24 y, respectively. Although mean zinc levels of both groups were within the normal range (≈14.5 μmol/l), 14.5 % of SCD and 11% of non-SCD children had levels below normal (10.7 μmol/L). As expected, mean Hb and Hct of SCD children were below normal and serum ferritin levels were 2–3 fold higher than those usually seen in healthy children. Mean sVCAMs1 levels of SCD children (837 μg/l) were higher than those of controls (627 μg/l) (p <0.0001). Differences persisted after taking into account age, Hb phenotypes, and inflammation (α1-acid glycoprotein >1g/l and C-reactive protein >10 mg/l). sVCAM-1 negatively correlated with serum (r=−0.444) and red blood cells zinc (r=−0.242, p <0.05), but not acute phase proteins. Hb and Hct, but not serum ferritin levels tended to inversely correlate with sVCAM-1 in children with SS and Sβthal Hb phenotypes (r≤−0.3364, p >0.05). Data suggest that zinc, but not body high iron stores may modulate SCD clinical status through VCAM-1 expression, and zinc supplementation may be beneficial in these patients. Funds: Pediatrics

Three Kinships with ALAS2 P520L Mutations, Two in Association with Severe Iron Overload, and One with Sideroblastic Anemia and Severe Iron Overload.

Aminolevulinate synthase 2 (ALAS2) is an erythroid-expressed gene located on chromosome Xp11.21. Mutations in ALAS2 have been shown to be associated with sideroblastic anemia. We have identified a novel mutation in ALAS2, P520L, in three kinships. The P520L mutation was not found in 316 white male control subjects. The proline in this position is highly conserved across species from humans to zebrafish.In the C kinship, the P520L mutation was first identified in a white man who presented with severe iron overload at an early age and was a HFE C282Y homozygote. Genetic analyses of members of the C kinship suggest that the presence of P520L alone in hemizygous males, or simple heterozygosity in females, is not associated with anemia or iron overload. Females heterozygous for both HFE C282Y and ALAS2 P520L also had normal ferritin levels. Only subjects homozygous for HFE C282Y and hemizygous or heterozygous for ALAS2 P520L had severe iron overload. Sequencing studies revealed that the propositus did not have missense mutations in HAMP, HJV, FPN1, ABC7, IL6, or RAG1.In the H kinship, the propositus was a white woman with severe iron overload who was heterozygous for ALAS2 P520L; she had a wildtype HFE genotype. The pedigree of the H kinship identified 5 additional females who were heterozygous for the P520L ALAS2 mutation. Only the propositus had iron overload and none of the subjects with P520L had sideroblastic anemia. The propositus did not have missense mutations in FPN1, HAMP, HJV, TFR2, B2M, IRP2, ABC7, or SFT. We speculate that the propositus in the H kinship has a mutation in a currently unknown gene that contributes to her severe iron overload. In the S kinship, the P520L mutation was identified in a white man with sideroblastic anemia and severe iron overload. The patient had a second mutation in ALAS2, R560H, a mutation previously described in two brothers with sideroblastic anemia of variable penetrance (Blood 100:4236–4238, 2002). It is not possible to determine the effect of the P520L mutation on the penetrance of the R560H-associated sideroblastic anemia and iron overload.We conclude that the ALAS2 P520L occurs at a very low allele frequency in the white population. The present observations also suggest that there is no distinctive phenotype associated with the P520L mutation alone, but that P520L may act as a modifier of iron overload in the presence of HFE homozygosity, other missense mutations of ALAS2, or mutations of uncharacterized iron regulatory genes.

Leflunomide and Azathioprine Combination in Refractory Adult-Onset Still's Disease

To present a case of Adult-onset Still's disease (ASD) in a patient who was successfully treated with leflunomide and azathioprine. A 24-year-old woman with ASD was initially treated with indomethacin, corticosteroids, and hydroxychloroquine; there was no clinical improvement. Methotrexate was added to the regimen, followed by azathioprine. The patient still experienced disease flares with this treatment, and cyclophosphamide was started. However, because of persisting disease activity, leflunomide combined with azathioprine was given. Only on this regimen was complete disease control achieved, with a normal erythrocyte sedimentation rate as well as normal C-reactive protein and ferritin levels. No recurrences or adverse effects attributable to leflunomide or azathioprine were observed at the one-year follow-up. Clinical experience concerning leflunomide and azathioprine combination in ASD is limited. This combination may be modifying the clinical expression of ASD through its effects on T lymphocyte clonal expansion and production of proinflammatory cytokines. Leflunomide combined with azathioprine appears to be an effective and safe treatment of ASD.

Iron deficiency with normal ferritin levels in restless legs syndrome

This report describes a patient with iron deficiency in bone marrow examination and iron-responsive restless legs syndrome (RLS), in whom serum ferritin levels were well above the conventional cutoff for considering iron deficiency. The predictive value of serum ferritin for iron deficiency in RLS depends on the cutoff employed, on the pre-test likelihood of iron deficiency and on coexisting inflammatory conditions. Bone marrow examination is helpful when ferritin levels are equivocal.

The Diagnostic Value of Gastrointestinal Endoscopy in Anemic Patients with Low Normal Ferritin Level.

Purpose: Our objective is to investigate the yield of upper and lower gastrointestinal(GI) endoscopic evaluations in anemic patients with serum ferritin levels between 40 and 100 ng/ml.Subjects and Methods: Most practice guidelines recommend endoscopic evaluation of the GI tract in men and post menopausal women with anemia and a serum ferritin level less than 20–40 ng/ml. However, as ferritin is an acute phase reactant, iron deficiency anemia (IDA) can be present with ferritin greater than 40 ng/ml. The diagnostic yield of GI endoscopy in patients with anemia, no GI symptoms or signs, and low normal ferritin. Some patients at the Veterans Affairs (VA) Connecticut Healthcare System undergo endoscopic evaluation as part of their anemia work up even when the ferritin is in the low normal range (40–100 ng/ml). We retrospectively reviewed the data on this population of patients over a 42-month period (1999–2003) to determine the incidence of GI findings.Results: All 522 patients who had undergone endoscopic examination for anemia over a 42 month period were screened. We identified 54 male patients who had a serum ferritin level between 40 and 100 ng/ml, no GI symptoms, and no evidence of GI bleeding. Significant lower GI findings, including large tubular adenomas and arterio-venous malformation (AVM), were identified in 3/53 cases (6.7%). Upper GI findings, including malignancy, peptic ulcers, Helicobacter Pylori gastritis, and AVM, were found in 14/47(30%) of cases.Conclusion: In this retrospective study on male anemic patients with low normal serum ferritin but lack of GI symptoms or known bleeding, the prevalence of upper and lower GI lesions was 30% and 6.7%, respectively. Our study supports a GI endoscopic evaluation in anemic patients with ferritin between 40 to 100 ng/ml, even in the absence of GI symptoms, or evidence for GI bleeding.Table 1: Ferritin, hematocrit (HCT), mean corpuscular volume (MCV) and prevalence of GI lesions in patients with borderline ferritin levelsTotal number of pateientsN=54Age(YO)72.4±10.3Ferritin (ng/ml)63.6±16.7HCT(%)35.5% + 2.4 (range 34–40%)MCV(fL)85.9±7.6Upper GI findings17/47Lower GI findings22/53* In the majority of the patients, more than one serum ferritin level was measured, and the one closest to the endoscopic procedure was used.Table 2: Endoscopic Findings in Anemic Patients with Serum Ferritin Levels between 40–100 ng/mL without significant GI symptoms or signs.LOWER GI FINDINGSNumber/percentageMALIGNANCY0/53ADENOMA>1CM2/53ADENOMA<1CM15/53*EXTENSIVE DIVERTICULOSIS4/53ARTERIOVENOUS MALFORMATION1/53ULCER0/53UPPER GI FINDINGSMALIGNANCY1/47ESOPHAGITIS/BARRETT'S ESOPHAGUS1/47LARGE HIATAL HERNIAS WITH EROSION2/47ESOPHAGEAL VARICES1/47CHRONIC ACTIVE GASTRITIS/DUODENITIS, H PYLORI+5/47GASTRIC OR DUODENAL PEPTIC ULCER5/47ARTERIOVENOUS MALFORMATION1/47ATROPHIC GASTRITIS1/47TA = tubular adenoma. *In 13/15 cases, TAs were found proximal to the splenic flexure, in 6/15 cases multiple TAs were found.

Screening for hemochromatosis in Turkey.

In this study we screened 3060 consecutive blood donors for an unbound iron-binding capacity level of <28 microM and then performed HFE mutation analysis in these subjects. Sixty-five of the 75 subjects with a low initial unbound iron-binding capacity (all had normal ferritin levels) came back and only 5 (8%) had a low fasting unbound iron-binding capacity. Mutational analysis revealed H63D heterozygosity in two of five subjects. Four of five subjects had liver biopsy indication and none had increased liver iron. HFE genotyping of 60 subjects with a low initial but normal fasting unbound iron-binding capacity revealed heterozygote H63D in seven (11.6%). No allelic variant of position 282 or 63 was found in three previously diagnosed patients with hereditary hemochromatosis. In conclusion, full phenotypic expression of hereditary hemochromatosis is very rare in Turkey. The absence of HFE mutations in three patients with hereditary hemochromatosis suggests that hereditary hemochromatosis in Turkey occurs without common HFE mutations.

Autonomic function and serum erythropoietin levels in chronic fatigue syndrome

Objective Given previous findings, we wished to investigate whether there was evidence of autonomic dysfunction in patients with chronic fatigue syndrome, and whether this could be related to reduced erythropoietin levels and altered red blood cell indices. Methods We assessed autonomic function and analysed blood parameters (including erythropoietin) in 22 patients with chronic fatigue syndrome who were medication-free and without comorbid depression or anxiety. Results were compared to 23 iron-deficiency anaemia patients and 18 healthy individuals. Results Autonomic testing in patients with chronic fatigue syndrome yielded a significantly greater increase in heart rate together with a more pronounced systolic blood pressure fall on standing compared to healthy individuals. Heart rate beat-to-beat variation on deep breathing and responses to the Valsalva manoeuvre were normal. Two of 22 patients with chronic fatigue had mild normochromic normocytic anaemia with normal ferritin, vitamin B12 and folate levels. Serum erythropoietin levels were within reference range. Conclusion Some autonomic dysfunction is present in chronic fatigue syndrome (CFS) patients; the explanation remains uncertain, but could relate to cardiovascular deconditioning. There were no major haematological, biochemical or immunological abnormalities in these patients.