Low Transferrin Saturation Research Articles

Is Obesity Associated With Anemia of Chronic Disease? A Population‐based Study

Obesity is characterized by chronic, low-grade, systemic inflammation, which, in turn, has been associated with anemia of chronic disease. We hypothesized that obesity may be associated with the features of anemia of chronic disease, including low hemoglobin concentration, low serum iron and transferrin saturation (TS), and elevated serum ferritin. We compared normal-weight to overweight and obese adult participants of the third National Health and Nutrition Examination Survey with respect to hemoglobin concentration and levels of serum iron, TS, and ferritin. Measured BMI was used to categorize participants into normal weight (BMI < 25 kg/m(2), n = 6,059), overweight (BMI 25 to <30 kg/m(2), n = 5,108), mildly obese (BMI 30 to <35 kg/m(2), n = 2,366), moderately obese (BMI 35 to <40 kg/m(2), n = 850), and severely obese (BMI > or = 40 kg/m(2), n = 465). After adjustment for age, gender, menstruation, race/ethnicity, education, alcohol consumption, smoking, blood donation, and dietary iron intake, serum ferritin was progressively higher with increasing BMI category, whereas serum iron and TS were progressively lower. However, compared to normal-weight persons, those in all other higher BMI categories did not have a significant change in hemoglobin concentration after adjustment for the above-mentioned confounders. Overweight and obesity were associated with changes in serum iron, TS, and ferritin that would be expected to occur in the setting of chronic, systemic inflammation. However, overweight and obese persons were not more likely to be anemic compared with normal-weight persons.

Prevalence of von Willebrand disease in women with iron deficiency anaemia and menorrhagia in Taiwan

Iron deficiency anaemia (IDA) is a frequently encountered disease, which can be attributed to menorrhagia. Most female patients with von Willebrand disease (VWD) have menorrhagia. The aim of this study was to investigate the prevalence of VWD in women with both IDA and menorrhagia in Taiwan. From January to December 2005 and November 2006 to January 2007, 56 consecutive patients with both IDA and menorrhagia were enrolled in this study. Their median age was 41 years (range 18-53). IDA was diagnosed by anaemia plus either low ferritin or transferrin saturation. Menorrhagia was evaluated by patient's menses history. Both von Willebrand factor antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo) were measured for each patient. Bleeding time (BT) and platelet function analyser (PFA)-100 assay were determined as ancillary tests. The VWD diagnosis was established if: (i) both VWF:Ag (<50%) and VWF:RCo (<50%) were low; (ii) either VWF:Ag or VWF:RCo was low plus prolonged BT or prolonged PFA closure times. VWF multimer analysis was performed for subtype confirmation of VWD. Nine of the 56 (16.1%) patients were identified to have VWD. VWD patients with menorrhagia might develop IDA at younger age (34.3 vs. 39.7, P = 0.09) and had more IDA recurrence (75% vs. 16%, P = 0.03) than those patients without VWD. Of the eight VWD patients with VWF multimer analyses, all were revealed to have type I VWD. Our study demonstrates that VWD was not uncommon in women with both IDA and menorrhagia in Taiwan.

Anemia ferropriva e estado nutricional de crianças de creches de Guaxupé

To evaluate the nutritional status and the prevalence of iron deficiency anemia in children attending public day care centers in the city of Guaxupé (MG), Brazil. Children of both genders, from 6 to 72 months, registered in public day-care centers in the city of Guaxupé, were studied. Nutritional evaluation was conducted using the Z-score for height-to-age and weight-to-height relationships. Hemoglobin dosage, serum iron, total iron binding capacity and the transferrin saturation index were used for diagnosis of anemia. Z score < - 2 was observed in 3.3% of the children for the height-to-age relationship and of 0.4% for the weight-to-height relationship. Prevalence of total iron deficiency anemia was of 16.1%. In the age span from 6 to 36 months it was of 44.6%. The entire sample showed 45% with low serum iron, 37.9% with high total iron binding capacity and 43.1% with a low transferrin saturation index. Malnutrition was not considered to be a problem due to its low prevalence; however, an important prevalence of iron deficiency was observed. Iron deficiency anemia is more prevalent in children between 6 and 36 months confirming that this age span is more vulnerable. No association between iron deficiency anemia and the Z score of the studied anthropometry relationships was found.

Ferric Gluconate Reduces Epoetin Requirements in Hemodialysis Patients with Elevated Ferritin

The Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) study demonstrated the efficacy of intravenous ferric gluconate to improve hemoglobin levels in anemic hemodialysis patients who were receiving adequate epoetin doses and who had ferritin levels between 500 and 1200 ng/ml and transferrin saturation (TSAT) < or = 25%. The DRIVE-II study reported here was a 6-wk observational extension designed to investigate how ferric gluconate impacted epoetin dosage after DRIVE. During DRIVE-II, treating nephrologists and anemia managers adjusted doses of epoetin and intravenous iron as clinically indicated. By the end of observation, patients in the ferric gluconate group required significantly less epoetin than their DRIVE dose (mean change of -7527 +/- 18,021 IU/wk, P = 0.003), whereas the epoetin dose essentially did not change for patients in the control group (mean change of 649 +/- 19,987 IU/wk, P = 0.809). Mean hemoglobin, TSAT, and serum ferritin levels remained higher in the ferric gluconate group than in the control group (P = 0.062, P < 0.001, and P = 0.014, respectively). Over the entire 12-wk study period (DRIVE plus DRIVE-II), the control group experienced significantly more serious adverse events than the ferric gluconate group (incidence rate ratio = 1.73, P = 0.041). In conclusion, ferric gluconate maintains hemoglobin and allows lower epoetin doses in anemic hemodialysis patients with low TSAT and ferritin levels up to 1200 ng/ml.

Revaluation of clinical and histological criteria for diagnosis of dysmetabolic iron overload syndrome

To re-evaluate the diagnostic criteria of insulin resistance hepatic iron overload based on clinical, biochemical and histopathological findings. We studied 81 patients with hepatic iron overload not explained by known genetic and acquired causes. The metabolic syndrome (MS) was defined according to ATPIII criteria. Iron overload was assessed by liver biopsy. Liver histology was evaluated by Ishak's score and iron accumulation by Deugnier's score; steatosis was diagnosed when present in >or=5% of hepatocytes. According to transferrin saturation levels, we observed significant differences in the amount of hepatic iron overload and iron distribution, as well as the number of metabolic abnormalities. Using Receiving Operating Curve analysis, we found that the presence of two components of the MS differentiated two groups with a statistically significant different hepatic iron overload (P<0.0001). Patients with >or=2 metabolic alterations and steatosis had lower amount of hepatic iron, lower transferrin saturation and higher sinusoidal iron than patients with <2 MS components and absence of steatosis. In our patients, the presence of >or2 alterations of the MS and hepatic steatosis was associated with a moderate form of iron overload with a prevalent sinusoidal distribution and a normal transferrin saturation, suggesting the existence of a peculiar pathogenetic mechanism of iron accumulation. These patients may have the typical dysmetabolic iron overload syndrome. By contrast, patients with transferrin saturation>or=60% had more severe iron overload, few or no metabolic abnormalities and a hemochromatosis-like pattern of iron overload.

Subpopulations with Iron Deficiency, Liver Disease, or HFE Mutations Revealed by Statistical Mixture Modeling of Transferrin Saturation and Serum Ferritin Concentration in Asians, African Americans, Hispanics, and Whites.

In previous investigations, we modeled the distribution of transferrin saturation (TS) in Caucasians and demonstrated a strong association between HFE genotype and TS subpopulations. Extending this approach, we now have analyzed joint population distributions of TS and serum ferritin concentration (SF) measured in the multi-ethnic Hemochromatosis and Iron Overload Screening (HEIRS) Study and examined the association of these distributions with the presence of HFE C282Y and H63D mutations, self-reported liver disease, and iron deficiency (defined as SF <15 μg/L). Based on separate models for each race/ethnicity by gender, four components with successively increasing age-adjusted means for TS and SF were identified in data from 26,832 African Americans, 12,620 Asians, 12,264 Hispanics, and 43,254 Whites. Fig. 1 illustrates age-adjusted values from 16,662 White men. Superimposed 95% confidence ellipses reflect component probability densities and show separation of the 1st and 4th components that had the lowest and highest means for TS and SF, respectively. Table 1 presents the range of estimates from individual models and indicates that the 2nd (largest) component had TS means of 22–26% for women (29–30% for men) and SF means of 43–82 μg/L for women (165–242 μg/L for men). The 3rd and 4th components had progressively smaller proportions and higher mean values of TS and SF, while the 1st component in each model had mean TS <16% for women (<20% for men), and mean SF <28 μg/L for women (<47 μg/L for men). Compared to the 2nd component:1.adjusted odds of iron deficiency were significantly higher in the 1st component (15–48 for women, 61–3530 for men);2.adjusted odds of self-reported liver disease were significantly higher in the 3rd and 4th components for African-American women and all men; and3.adjusted odds of any HFE mutation were increased in the 3rd component (1.4–1.8 for women, 1.2–1.9 for men) and in the 4th component for Hispanic and White women (1.5, 5.2, respectively) and men (2.8, 4.7, respectively).Joint mixture modeling identifies one component with lower mean SF and TS at risk for iron deficiency and two components with higher mean SF and TS at risk for liver disorders and HFE mutations. This approach permits characterization of the aggregate effects of hereditary or acquired factors that influence these serum iron measures in populations, and complements and enhances genetic and phenotypic testing for assessment of disease characteristics. [Display omitted]

Predictors of the response to treatment in anemic hemodialysis patients with high serum ferritin and low transferrin saturation

Treating hemodialysis patients to combat anemia corrects hemoglobin but exacerbates iron deficiency by utilizing iron stores. Patients needing iron should receive this by intravenous (i.v.) means. The Dialysis patients' Response to IV iron with Elevated ferritin (DRIVE) trial investigated the role of i.v. iron in anemic patients with high ferritin, low transferrin saturation, and adequate epoetin doses. We examined whether baseline iron and inflammation markers predict the response of hemoglobin to treatment. Patients (134) were randomized to no added iron or to i.v. ferric gluconate for eight consecutive hemodialysis sessions spanning 6 weeks with epoetin increased by 25% in both groups. The patients started with hemoglobin less than or equal to 11 g/dl, ferritin between 500 and 1200 ng/ml, and transferrin saturation of less than 25%. Significantly, patients with a reticulocyte hemoglobin content greater than or equal to 31.2 pg were over five times more likely to achieve a clinically significant increase in hemoglobin of greater than 2 g/dl. Lower reticulocyte hemoglobin contents did not preclude a response to i.v. iron. Significantly higher transferrin saturation or lower C-reactive protein but not ferritin or soluble transferrin receptor levels predicted a greater response; however their influence was not clinically significant in either group. We conclude that none of the studied markers is a good predictor of response to anemia treatment in this patient sub-population.

The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease

AbstractFerroportin disease is caused by mutation of one allele of the iron exporter ferroportin (Fpn/IREG1/Slc40a1/MTP1). All reported human mutations are missense mutations and heterozygous null mutations in mouse Fpn do not recapitulate the human disease. Here we describe the flatiron (ffe) mouse with a missense mutation (H32R) in Fpn that affects its localization and iron export activity. Similar to human patients with classic ferroportin disease, heterozygous ffe/+ mice present with iron loading of Kupffer cells, high serum ferritin, and low transferrin saturation. In macrophages isolated from ffe/+ heterozygous mice and through the use of Fpn plasmids with the ffe mutation, we show that Fpnffe acts as a dominant negative, preventing wild-type Fpn from localizing on the cell surface and transporting iron. These results demonstrate that mutations in Fpn resulting in protein mislocalization act in a dominant-negative fashion to cause disease, and the Fpnffe mouse represents the first mouse model of ferroportin disease.

Rationale and Design of the IRON-HF Study: A Randomized Trial to Assess the Effects of Iron Supplementation in Heart Failure Patients With Anemia

Anemia is a common finding in heart failure (HF) patients and has been associated with increased morbidity and mortality. It is generally denominated as anemia of chronic disease (ACD), but the association with true ferropenic anemia is common. Many studies have investigated the effects of treating anemia in HF patients with either erythropoietin alone or combination of erythropoietin and intravenous iron. However, the effect of iron supplementation alone in HF patients with ACD, ferropenic anemia, or both is unknown. IRON-HF study is a multicenter, investigator initiated, randomized, double-blind, placebo controlled trial that will enroll anemic HF patients with relatively preserved renal function, low transferrin saturation, low iron levels, and low to moderately elevated ferritin levels. Interventions are iron sucrose intravenously 200 mg once per week for 5 weeks, ferrous sulfate 200 mg by mouth 3 times per day for 8 weeks, or placebo. The primary objective is to assess the impact of iron supplementation (intravenously or by mouth) compared with placebo in HF patients with anemia from deficient iron availability. The primary end point is variation of peak oxygen consumption assessed by ergospirometry over 3-month follow-up. Secondary end points include functional class, brain natriuretic peptide levels, quality of life scores, left ventricular ejection fraction, adverse events, HF hospitalization, and death. The results of IRON-HF should help to clarify the potential clinical impact of mild to moderate anemia correction in HF patients.

Ferric Gluconate Is Highly Efficacious in Anemic Hemodialysis Patients with High Serum Ferritin and Low Transferrin Saturation

Few data exist to guide treatment of anemic hemodialysis patients with high ferritin and low transferrin saturation (TSAT). The Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) trial was designed to evaluate the efficacy of intravenous ferric gluconate in such patients. Inclusion criteria were hemoglobin <or=11 g/dl, ferritin 500 to 1200 ng/ml, TSAT <or=25%, and epoetin dosage >or=225 IU/kg per wk or >or=22,500 IU/wk. Patients with known infections or recent significant blood loss were excluded. Participants (n=134) were randomly assigned to no iron (control) or to ferric gluconate 125 mg intravenously with eight consecutive hemodialysis sessions (intravenous iron). At randomization, epoetin was increased 25% in both groups; further dosage changes were prohibited. At 6 wk, hemoglobin increased significantly more (P=0.028) in the intravenous iron group (1.6 +/- 1.3 g/dl) than in the control group (1.1 +/- 1.4 g/dl). Hemoglobin response occurred faster (P=0.035) and more patients responded after intravenous iron than in the control group (P=0.041). Ferritin <or=800 or >800 ng/ml had no relationship to the magnitude or likelihood of responsiveness to intravenous iron relative to the control group. Similarly, the superiority of intravenous iron compared with no iron was similar whether baseline TSAT was above or below the study median of 19%. Ferritin decreased in control subjects (-174 +/- 225 ng/ml) and increased after intravenous iron (173 +/- 272 ng/ml; P<0.001). Intravenous iron resulted in a greater increase in TSAT than in control subjects (7.5 +/- 7.4 versus 1.8 +/- 5.2%; P<0.001). Reticulocyte hemoglobin content fell only in control subjects, suggesting worsening iron deficiency. Administration of ferric gluconate (125 mg for eight treatments) is superior to no iron therapy in anemic dialysis patients receiving adequate epoetin dosages and have a ferritin 500 to 1200 ng/ml and TSAT <or=25%.

Role of C‐reactive protein, reticulocyte haemoglobin content and inflammatory markers in iron and erythropoietin administration in dialysis patients

C-reactive protein (CRP) is an acute phase reactant protein, which becomes elevated in response to inflammation, infections or malignancies. These conditions are well known causes of bone marrow hyporesponsiveness and erythropoietin resistance in dialysis patients. The role of iron-deficiency as a cause of hyporesponsiveness under these conditions is not clear. Reticulocyte haemoglobin content (CHr) is one of several iron indices used to determine iron deficiency in dialysis patients. The aim of this study is to evaluate the role of CRP and CHr in iron administration and anaemia management in dialysis patients. In 47 haemodialysis patients with ferritin levels of >500 ng/mL, CRP, CHr, transferrin saturation (TSAT), other markers and erythropoietin dose were evaluated. Patients with CRP < 5 mg/L (Group A) were compared to patients with CRP > 5 mg/L (Group B). Ferritin levels in the two groups were not different. Weekly erythropoietin was significantly different between the two groups. Group B required an average of 121% more erythropoietin than Group A to maintain similar haemoglobin levels of 11-12 g/dL 36% of Group B had CHr < 29 pg versus 7% of patients in Group A. 39% of patients in Group B also had TSAT < 20% versus 0% in Group A. Group A also had more arteriovenous (AV) fistulae as dialysis access than group B. Data indicate that low CHr, similar to low TSAT, could be associated with inflammatory process and erythropoietin resistance, but not necessarily with iron-deficiency. High CRP association with low CHr and low TSAT levels can explain the lack of response to further IV iron therapy. AV grafts, contrary to AV fistulae, are associated with high inflammatory markers and also with a higher erythropoietin requirement.

Increased Adipose Tissue Expression of Hepcidin in Severe Obesity Is Independent From Diabetes and NASH

Hepcidin is an acute-phase response peptide. We have investigated the possible involvement of hepcidin in massive obesity, a state of chronic low-grade inflammation. Three groups of severely obese patients with or without diabetes or nonalcoholic steatohepatitis were investigated. Hepcidin expression was studied in liver and adipose tissue of these patients. Hepcidin regulation was investigated in vitro by adipose tissue explant stimulation studies. Hepcidin was expressed not only in the liver but also at the messenger RNA (mRNA) and the protein levels in adipose tissue. Moreover, mRNA expression was increased in adipose tissue of obese patients. The presence of diabetes or NASH did not modify the hepcidin expression levels in liver and adipose tissue. In adipose tissue, mRNA expression correlated with indexes of inflammation, interleukin-6, and C-reactive protein. Interleukin-6 also promoted in vitro hepcidin expression. A low transferrin saturation ratio was observed in 68% of the obese patients; moreover, 24% of these patients presented with anemia. The observed changes in iron status could be due to the role of hepcidin as a negative regulator of intestinal iron absorption and macrophage iron efflux. Interestingly, a feedback control mechanism on hepcidin expression related to low transferrin saturation occurred in the liver but not in the adipose tissue. Hepcidin is a proinflammatory adipokine and may play an important role in hypoferremia of inflammation in obese condition.

Iron Deficiency in Goitrous Schoolchildren of Semirom, Iran

Background: Iodine deficiency produces the spectrum of iodine deficiency disorders (IDDs): endemic goiter, hypothyroidism, cretinism, and congenital anomalies. Other factors, including goitrogens and micronutrient deficiencies, may influence the prevalence and severity of IDDs and response to iodine supplementation. This cross-sectional, descriptive study was performed in 2003 on elementary school children of Semirom, a mountainous region of Iran, where goiter was hyper-endemic in 1994, but the goiter prevalence had not decreased as expected many years after salt iodization and iodine injection. Some possible risk factors associated with goiter in that area were evaluated, and the results of iron study are presented here. Methods: 1,869 cases were selected by a multistage cluster sampling procedure. Grade 2 goitrous children were compared with equal number of nongoitrous children for serum iron, ferritin, transferrin, thyroxin, TSH and urine iodine concentrations (UIC). Results: 210 children (105 goiter grade 0 and 105 goiter grade 2) entered this sub-study. Of 210 participants, 70 children had low transferrin saturation, 13 had low serum ferritin and 9 children had both problems. There was no significant difference in goiter rate between children with low iron indices and others.There was no significant correlation between serum iron, ferritin or transferrin saturation with other variables including T4, UIC and goiter stage. Conclusion: The present study reveals that in the area studied, iron deficiency cannot explain the high prevalence of goiter, so other responsible factors should be investigated.

Iron Status of Female Collegiate Athletes Involved in Different Sports

Iron status was assessed in 70 female athletes aged 18-25 yr participating in collegiate cross-country track, tennis, softball, swimming, soccer, basketball, and gymnastics. No significant differences in mean hemoglobin, hematocrit, serum iron, total iron-binding capacity, transferrin saturation, and ferritin were found among teams. The mean concentrations of each parameter for each of the teams were within the normal ranges. However, several athletes from different sports had suboptimal iron status indexes. Of 17 athletes with a serum ferritin concentration < or = 15 microg/L, 8 (4 freshmen, 2 sophomores, 2 unknown) also exhibited low serum iron concentrations (< 60 microg/dL) and low transferrin saturation (< 16%). Thirteen (6 freshmen, 3 sophomores, 2 juniors, 2 seniors) of 51 (25%) athletes failed to consume two-thirds of the Recommended Dietary Allowance for iron and exhibited suboptimal serum concentrations of ferritin, iron, and/or transferrin saturation. Of nine athletes taking iron supplements, one exhibited suboptimal iron status. In summary, nonanemic iron depletion was present among female collegiate athletes involved in many different sports and in all years of participation (freshmen, sophomore, junior, and senior athletes). Female athletes should continue to be individually and routinely evaluated for nutritional deficiencies throughout their collegiate athletic careers.

Melatonin corrects reticuloendothelial blockade and iron status in haemodialysed patients

Treatment of anaemia in haemodialysed patients in the setting of inflammation usually displays high levels of serum ferritin (>800 ng/mL) and low transferrin saturation (TSAT) (<20%) despite i.v. iron supplementation, thus proving iron trapping in the reticuloendothelial system. Melatonin has been reported to reduce cytokine production and, in dialysis patients, to prevent oxidative stress resulting from iron and erythropoietin treatment. In this study, we evaluated a group of 10 patients undergoing haemodialysis who displayed elevated serum ferritin (981 +/- 44.6 ng/mL) and TSAT <20% (15.6 +/- 3.8%) after having received 1.2 g of i.v. iron dextran over a period of 8 weeks. These patients received oral melatonin, 6 mg/day at night for 30 days. After this treatment, all of them markedly increased TSAT values, reaching 35.5 +/- 6.7% (P < 0.0001 vs basal values). In addition, ferritin values decreased to 754.4 +/- 263.7 ng/mL (P < 0.05), and serum iron dramatically increased in all of the patients under study (42.4 +/- 9.4 vs 109.7 +/- 24.3 microg/dL; P < 0.0001). Values for haematocrit (28.6 +/- 2.7 vs 31.9 +/- 3.57%; P < 0.05) and haemoglobin (9.19 +/- 0.97 vs 10.04 +/- 1.29 g/dL; P < 0.05) were also improved. Measurements were then repeated 2 weeks after melatonin withdrawal, showing an impressive decrease in TSAT (16.4 +/- 5.3%; P < 0.00001) and serum iron (48 +/- 14.7 microg/dL; P < 0.0001) values and an almost significant increase in ferritin values (954.4 +/- 86 ng/mL; P < 0.054). The present study demonstrates that melatonin may strongly correct the reticuloendothelial blockade seen in dialysis patients under an inflammatory status, thus allowing a better management of iron derangements and renal anaemia.

A novel ferroportin mutation in a Canadian family with autosomal dominant hemochromatosis

We report a new mutation, Asn185Asp, in exon 6 of the ferroportin gene ( FPN1) in 15 members of three successive generations of a Canadian family of Scandinavian origin with autosomal dominant hemochromatosis. Hyperferritinemia with low transferrin saturation was noted in younger family members, seven of whom were aged 20 years or less at the time of diagnosis. In those individuals first diagnosed with hemochromatosis in later life, marked hyperferritinemia was accompanied by high transferrin saturation. In contrast to the phenotype of high ferritin with low saturation first reported for ferroportin disease, this family demonstrates a phenotype of iron indices that varies with age.

Blunted erythropoietin production and defective iron supply for erythropoiesis as major causes of anaemia in patients with chronic heart failure

Anaemia is often observed in patients with chronic heart failure (CHF), and it may be associated with a worse prognosis. Aim of this study was to identify the individual mechanisms of anaemia in CHF patients. One hundred and forty-eight consecutive patients with haemoglobin concentration <13 g/dL (if males) or <12 g/dL (if females) were enrolled. Factors responsible for anaemia were investigated by evaluating endogenous erythropoietin (Epo) production, serum cytokines levels, body iron status, and iron supply for erythropoiesis. Most patients (57%) presented anaemia of chronic disease and among them, 92% showed evidence of a defective endogenous Epo production. This was indicated by an observed/predicted log(serum Epo) ratio less than 0.8 and/or a defective iron supply for erythropoiesis diagnosed by low transferrin saturation and/or increased value of soluble transferrin receptor. According to regression analysis sex, renal failure, and serum Epo were correlated with anaemia. According to our study, about half of anaemic CHF patients showed anaemia of chronic disease with blunted endogenous Epo production and/or a defective iron supply for erythropoiesis. Determination of the individual mechanisms of anaemia in CHF could justify a rational therapeutic approach to anaemia.

Hepcidin-The Culprit Explaining Disturbed Iron Homeostasis in Chronic Renal Disease?: IL-6 Mediates Hypoferremia of Inflammation by Inducing the Synthesis of the Iron Regulatory Hormone Hepcidin. J Clin Invest 113:1271-1276, 2004.

Hepcidin-The Culprit Explaining Disturbed Iron Homeostasis in Chronic Renal Disease?: IL-6 Mediates Hypoferremia of Inflammation by Inducing the Synthesis of the Iron Regulatory Hormone Hepcidin. J Clin Invest 113:1271-1276, 2004.

A Japanese Family with Ferroportin Disease Caused by a Novel Mutation of SLC40A1 Gene: Hyperferritinemia Associated with a Relatively Low Transferrin Saturation of Iron

Ferroportin disease, autosomal-dominant reticuloendothelial iron overload, may be more prevalent than hemochromatosis in Japan. Hyperferritinemia of 822 ng/ml with 24.8% transferrin saturation of iron was incidentally noted in a 43-year-old man. His iron overload was selective in Kupffer cells of the liver. Subsequently, his father was found to have asymptomatic hyperferritinemia of 2,283 ng/ml with 62.1% saturation. These affected subjects were heterozygous for 1467A>C (R489S) in SLC40A1, and without other mutations of the hemochromatosis genes. Here, we report a Japanese family with ferroportin disease, characterized by hyperferritinemia with relatively low transferrin saturations of iron.

HLA haplotype A*03-B*07 in hemochromatosis probands with HFE C282Y homozygosity: frequency disparity in men and women and lack of association with severity of iron overload

Before the discovery of HFE, reports suggested that hemochromatosis patients with the ancestral haplotype (or some element thereof) have more severe iron overload than those without the haplotype. We performed univariate and multivariate analyses of the relationships of human leukocyte antigen (HLA)-A*03 and HLA haplotype A*03-B*07 to iron measures (serum iron concentration, transferrin saturation, and serum ferritin concentration at diagnosis and units of phlebotomy to achieve iron depletion) in hemochromatosis probands homozygous for HFE C282Y diagnosed in medical care. Iron overload was defined by demonstration of hepatic iron index of ≥1.9 or removal of ≥2.0 g Fe by therapeutic phlebotomy. We tabulated the phenotype frequencies of HLA-A*03 and the frequencies of common HLA haplotypes A*01-B*08, A*02-B*44, A*03-B*07, and A*03-B*14 in three groups of white adults: (1) 141 hemochromatosis probands with C282Y homozygosity; (2) 195 index cases with IgG subclass deficiency (IgGSD) or common variable immunodeficiency (CVID), disorders typically linked to Ch6p, and (3) 750 control subjects. Among probands, 86 men and 42 women had iron overload. Frequencies of HLA-A and -B alleles in probands did not depart significantly from Hardy-Weinberg equilibrium. The phenotype frequency of A*03 did not differ significantly between men and women in the each of the respective three groups. The frequency of haplotype A*03-B*07 was greater in men than women with hemochromatosis (0.3081 vs. 0.1455; P = 0.0019). The frequency of A*03-B*014 was significantly greater in women than men with hemochromatosis (0.1182 vs. 0.0407, respectively; P = 0.0134). Mean values of most iron measures were not affected by numbers of copies of A*03 or by presence of A*03-B*07 in either men or women in univariate analysis. ANOVA models of sex, age at diagnosis, and all HLA alleles and haplotypes in probands were used to determine effects of these variables on iron measures. ANOVA models revealed that (1) there were no significant predictors for serum iron concentration; (2) B*14 is associated with higher transferrin saturation in women and lower transferrin saturation in men; (3) A*01-B*08 is associated with a trend of higher serum ferritin levels; and (4) A*03-B*14 is associated with exaggeration of the age-associated upward trend in units of phlebotomy to achieve iron depletion. In hemochromatosis probands with HFE C282Y homozygosity, we conclude that (1) disparate frequencies of HLA haplotypes A*03-B*07 and A*03-B*14 occur in men and women and (2) HLA-A*03 and HLA-A*03-B*07 are not independent variables associated with iron overload severity.