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.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2672-2672
Author(s):  
Christine E. McLaren ◽  
Victor R. Gordeuk ◽  
Wen-Pin Chen ◽  
James C. Barton ◽  
Ronald T. Acton ◽  
...  
Keyword(s):  
At Risk ◽  
Liver Disease ◽  
African Americans ◽  
Iron Deficiency ◽  
Serum Ferritin ◽  
Transferrin Saturation ◽  
Mixture Modeling ◽  
Ferritin Concentration ◽  
Serum Ferritin Concentration ◽  
Hfe Mutations

Abstract 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: adjusted odds of iron deficiency were significantly higher in the 1st component (15–48 for women, 61–3530 for men); adjusted odds of self-reported liver disease were significantly higher in the 3rd and 4th components for African-American women and all men; and 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. Table 1 Range of estimates from models.

Unexplained Serum Ferritin Elevations in Primary Care Patients with Elevated Serum Ferritin Concentrations and High Normal Transferrin Saturations.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3729-3729
Author(s):  
Onyinye C. Onyekwere ◽  
Tiffany N. Johnson ◽  
Margaret Fadojutimi-Akinsiku ◽  
Fitzroy Dawkins ◽  
Victor Gordeuk
Keyword(s):  
Primary Care ◽  
African Americans ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Transferrin Saturation ◽  
Elevated Serum ◽  
Ferritin Concentration ◽  
Serum Ferritin Concentration ◽  
Primary Care Patients ◽  
Hfe Mutations

Abstract Non-HFE primary iron overload exists in African Americans and other ethnic groups, but the prevalence and spectrum of clinical manifestations are not known. In the HEIRS (Hereditary Hemochromatosis and Iron Overload Screening) Study, participants were considered for further evaluation if the serum ferritin concentration was elevated and the transferrin saturation was more than 45% for women or 50% for men. We hypothesized that these screening criteria would miss a substantial number of African Americans and members of other ethnic groups with increased iron stores. In the process of screening 21,231 predominantly African-American and Hispanic primary care patients at the Howard University field center of the HEIRS Study, we identified 161 non-HFE-C282Y homozygotes ≥ 25 years of age with serum ferritin concentrations above the 97.5 percentile for the population (>700 ng/ml for men and >500 ng/ml for women) but transferrin saturations in the upper part of the normal range (35–50% for men and 30–45% for women). Of the 123 participants we were able to contact, 68 (55%) participated in a clinical evaluation, including 64 African Americans, three Hispanics and one Asian American with a mean ± SD age of 57 ± 13 years. Thirty-eight (56%) were females, 6 (9%) were HFE H63D heterozygotes and 2 (3%) were C282Y heterozygotes. Seven patients (10%) had normal serum ferritin concentration on repeat testing while 42 (62%) had potential reasons for elevated serum ferritin concentration other than a primary increase in body iron including (sequentially) multiple blood transfusions (>10 lifetime; n = 4), abnormal liver function tests (hepatitis C positive or AST >60 IU/L and AST>ALT; n = 17), hemoglobin < 10 g/dL men or 9 g/dL women (n = 1), elevated C-reactive protein with transferrin saturation not elevated (n = 17), and excessive alcohol use (n = 3). Nineteen patients did not have these explanations for increased serum ferritin concentration and were considered to have a possible primary iron-loading process (see Table). One of the patients with unexplained elevated serum ferritin concentration (an African American) had a diagnostic liver biopsy showing 2-3+ hepatocellular iron and heavy iron deposition in Kupffer cells and is on phlebotomy therapy; the others have been advised to have diagnostic liver biopsy or quantitative phlebotomy. We conclude that there are substantial numbers of African Americans with elevated serum ferritin concentration and normal transferrin saturation who have transfusional iron overload or a probable primary increase in body iron stores. Characteristics of 19 Patients with Unexplained Serum Ferritin Elevations No. (%) of Women 8 (42) Age inyears (mean ± SD) 63 ± 14 Race (African American:Hispanic:Asian) 16:2:1 Hemoglobin in g.dL (mean ± SD) Men 13.8 ±1.5 Hemoglobin in g.dL (mean ± SD) Women 12.9 ± 0.8 HFE mutations in no. (%) C282Y heterozygotes 0 (0) HFE mutations in no. (%) H63D heterozygotes 2 (11) Ferritin category in no. (%) < 500 ng/ml 7 (37) Ferritin category in no. (%) 500–1000 ng/ml 9(57) Ferritin category in no. (%) 1000 ng/ml> 3 (16)

Extreme hyperferritinaemia; clinical causes

2013 ◽  
Vol 66 (5) ◽  
pp. 438-440 ◽  
Author(s):  
Martin A Crook ◽  
Patrick L C Walker
Keyword(s):  
Liver Disease ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Malignant Disease ◽  
Hepatic Disease ◽  
Blood Transfusions ◽  
Still’S Disease ◽  
Ferritin Concentration ◽  
Serum Ferritin Concentration ◽  
Multiple Blood

There are many causes of raised serum ferritin concentrations including iron overload, inflammation and liver disease to name but a few examples. Cases of extreme hyperferritinaemia (serum ferritin concentration equal to or greater than 10 000 ug/l) are being reported in laboratories but the causes of this are unclear. We conducted an audit study to explore this further. Extreme hyperferritinaemia was rare with only 0.08% of ferritin requests displaying this. The main causes of extreme hyperferritinaemia included multiple blood transfusions, malignant disease, hepatic disease and suspected Still's disease.

scholarly journals Reduction of tissue iron stores and normalization of serum ferritin during treatment with the oral iron chelator L1 in thalassemia intermedia

Blood ◽  
1992 ◽  
Vol 79 (10) ◽  
pp. 2741-2748 ◽  
Author(s):  
NF Olivieri ◽  
G Koren ◽  
D Matsui ◽  
PP Liu ◽  
L Blendis ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Dramatic Improvement ◽  
Thalassemia Intermedia ◽  
Ferritin Concentration ◽  
Iron Stores ◽  
Tissue Iron ◽  
Serum Ferritin Concentration

Abstract In patients with thalassemia intermedia in whom hyperabsorption of iron may result in serious organ dysfunction, an orally effective iron- chelating drug would have major therapeutic advantages, especially for the many patients with thalassemia intermedia in the Third World. We report reduction in tissue iron stores and normalization of serum ferritin concentration after 9-month therapy with the oral chelator 1,2- dimethyl-3-hydroxypyrid-4-one (L1) in a 29-year-old man with thalassemia intermedia and clinically significant iron overload (SF 2,174 micrograms/L, transferrin saturation 100%; elevated AST and ALT, abnormal cardiac radionuclide angiogram) who was enrolled in the study with L1 75 mg/kg/day after he refused deferoxamine therapy. L1-Induced 24-hour urinary iron excretion during the first 6 months of therapy was (mean +/- SD, range) 53 +/- 30 (11 to 109) mg (0.77 mg/kg), declining during the last 3 months of L1 to 24 +/- 14 (13–40) mg (0.36 mg/kg), as serum ferritin decreased steadily to normal range (present value, 251 micrograms/L). Dramatic improvement in signal intensity of the liver and mild improvement in that of the heart was shown by comparison of T1- weighted spin echo magnetic resonance imaging with images obtained immediately before L1 administration was observed after 9 months of L1 therapy. Hepatic iron concentration decreased from 14.6 mg/g dry weight of liver before L1 therapy to 1.9 mg/g liver after 9 months of therapy. This constitutes the first report of normalization of serum ferritin concentration in parallel with demonstrated reduction in tissue iron stores as a result of treatment with L1. Use of L1 as a therapeutic option in patients with thalassemia intermedia and iron overload appears warranted.

Hepatic computed tomography for monitoring the iron status of haemodialysis patients with haemosiderosis treated with recombinant human erythropoietin

1991 ◽  
Vol 81 (1) ◽  
pp. 113-121 ◽  
Author(s):  
Sergio De Marchi ◽  
Emanuela Cecchin
Keyword(s):  
Computed Tomography ◽  
Serum Ferritin ◽  
Recombinant Human Erythropoietin ◽  
Chelation Therapy ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Ferritin Concentration ◽  
Human Erythropoietin ◽  
Serum Ferritin Concentration ◽  
Erythropoietin Treatment

1. A randomized, partial-crossover study was conducted in uraemic patients with dialysis-associated anaemia and transfusional iron overload to evaluate the effects of desferrioxamine chelation therapy and of recombinant human erythropoietin treatment on hepatic iron storage determined by computed tomography, as well as by serum ferritin concentration and transferrin saturation. 2. Twenty-one haemodialysis patients with moderate iron overload, confirmed by values of serum ferritin concentration, transferrin saturation and hepatic computed tomography density exceeding 1000 μg/l, 45% and 68 Hounsfield units respectively, were randomly allocated to three groups and were followed for 12 months. 3. During the first 6 months group 1 (n = 7) received desferrioxamine chelation therapy (30 mg/kg intravenously three times a week) and group 2 (n = 7) underwent recombinant human erythropoietin treatment (36 units/kg intravenously three times a week). Thereafter, in the second 6 months of observation patients in group 1 were switched to receive recombinant human erythropoietin. Because of a poor response in the desferrioxaminetreated group in the initial 6 months, patients in group 2 continued on the maintenance dose of recombinant human erythropoietin (18 units/kg three times a week) until the end of the trial. Patients in group 3 (n = 7) were maintained on placebo throughout the study. 4. In comparison with placebo, recombinant human erythropoietin treatment, but not desferrioxamine chelation therapy, reduced serum ferritin concentration, transferrin saturation and hepatic computed tomography density, and was associated with a rise in haemoglobin and packed cell volume. Hepatic computed tomography density, serum ferritin concentration and transferrin saturation decreased in 13 out of 14 patients (93%) during treatment with recombinant human erythropoietin. However, when the changes in hepatic computed tomography density were compared with those in the biochemical indices, we observed that the decreases in serum ferritin concentration and transferrin saturation were much slower and delayed. More specifically, within 6 months of starting recombinant human erythropoietin treatment, hepatic computed tomography density was normalized in 13 out of 14 patients (93%), whereas serum ferritin concentration and transferrin saturation were within the normal limits in only two (14%) and six patients (43%), respectively. 5. In conclusion, the strategies for monitoring the iron status of haemodialysis patients with transfusional haemosiderosis may evolve to a new level of sophistication with the introduction of computed tomography scanning. This technique has the advantage of estimating directly the effect of recombinant human erythropoietin treatment on hepatic iron storage. Hepatic computed tomography density is complementary to serum ferritin concentration and transferrin saturation in monitoring the iron status of haemodialysis patients treated with recombinant human erythropoietin.

Correlation between Diagnostic 59Fe2+-Absorption and Serum Ferritin Concentration in Man

1977 ◽  
Vol 32 (11-12) ◽  
pp. 1023-1025 ◽  
Author(s):  
H. C. Heinrich ◽  
J. Brüggemann ◽  
E. E. Gabbe ◽  
M. Gläser ◽  
Fatima Icagic ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Deficiency ◽  
Correlation Coefficient ◽  
Serum Ferritin ◽  
Inverse Relationship ◽  
Sensitive Indicator ◽  
Ferritin Concentration ◽  
Iron Stores ◽  
Serum Ferritin Concentration ◽  
The Relationship

Abstract A high correlation coefficient r = -0.832 (Pr≠0 <0.0001) was estimated in man for the inverse relationship between the diagnostic 59Fe2+-absorption and the serum ferritin concentration which is very close to the correlation r = - 0.88 as described for the relationship between the diagnostic 59Fe2+-absorption and the diffuse cytoplasmic storage iron in the bone marrow macrophages. The increase of the diagnostic 59Fe2+-absorption seems to be an earlier and more sensitive indicator of depleted iron stores whereas the serum ferritin decreases somewhat later during the development of iron deficiency.

scholarly journals Enzyme-linked Immunosorbent Assay to Measure Serum Ferritin and the Relationship between Serum Ferritin and Nonheme Iron Stores in Cats

1994 ◽  
Vol 31 (6) ◽  
pp. 674-678 ◽  
Author(s):  
G. A. Andrews ◽  
P. S. Chavey ◽  
J. E. Smith
Keyword(s):  
Iron Deficiency ◽  
Serum Ferritin ◽  
Immunosorbent Assay ◽  
Serum Iron ◽  
Nonheme Iron ◽  
Enzyme Linked Immunosorbent Assay ◽  
Ferritin Concentration ◽  
Iron Stores ◽  
Tissue Iron ◽  
Serum Ferritin Concentration

Serum ferritin concentration correlates with tissue iron stores in humans, horses, calves, dogs, and pigs but not in rats. Because serum iron and total iron-binding capacity can be affected by disorders unrelated to iron adequacy (such as hypoproteinemia, chronic infection, hemolytic anemia, hypothyroidism, and renal disease), serum ferritin is probably the most reliable indicator of total body iron stores in larger species. To test the hypothesis that serum ferritin might be correlated with tissue iron levels in cats, we developed a quantitative enzyme-linked immunosorbent assay that uses two monoclonal antibodies in a sandwich arrangement to measure feline serum ferritin. The recovery of purified ferritin added to feline sera ranged from 94% to 104%; the within-assay coefficient of variability was 8.4%, and the assay-to-assay variability was 13.2%. Mean serum ferritin from 40 apparently healthy cats was 76 ng ml (SD = 24 ng/ml). Serum ferritin concentration was significantly correlated ( P < 0.001, n = 101, r = 0.365) with the nonheme iron in the liver and spleen (expressed as milligrams of iron per kilogram of body weight), as determined by Pearson product-moment correlation analysis. Because serum iron can decrease in diseases other than iron deficiency, the combination of serum iron and serum ferritin should provide sufficient evidence to differentiate anemia of chronic inflammation from anemia of iron deficiency in the cat.

Hereditary Hemochromatosis in an Adult Due to H63D Mutation: The Value of Estimating Iron Deposition By MRI T2* and Dissociation Between Serum Ferritin Concentration and Hepatic Iron Overload

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4891-4891
Author(s):  
Mohamed A. Yassin ◽  
Ashraf T Soliman ◽  
Vincenzo Desanctis ◽  
Sandara Abusamaan ◽  
Ahmed Elsotouhy ◽  
...  
Keyword(s):  
Iron Overload ◽  
Basal Ganglion ◽  
Serum Ferritin ◽  
Normal Values ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Iron Deposition ◽  
Ferritin Concentration ◽  
H63d Mutation ◽  
Serum Ferritin Concentration

Abstract Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excessive intestinal absorption of dietary iron, causing iron overload in different organs, especially the liver. Hemochromatosis may not be recognized until later in life. Patients are usually asymptomatic but may present with a variety of signs and symptoms. These include: hyper-pigmented skin, hepatomegaly, arthralgia, diabetes mellitusand/or heart failure/arrhythmia. The risk of HH related morbidity in HFE compound homozygotes patients (H63D /H63D) is considered rare, we report a male patient with H63D mutation who developed impaired glucose tolerance, and high hepatic enzymes due to significant iron accumulation in the liver as well as Parkinsonian-like syndrome due to iron deposition in the basal ganglia. A 40 year old Qatari male was referred for evaluation of a rise in hemoglobin and hematocrit values with normal MCV, total leucocyte and platelet counts. The patient was asymptomatic with normal vital signs, no depigmentation or hepato-splenomegaly. Hematologic findings included a hemoglobin concentration of Hb 16.5 g/dL, hematocrit 53%, mean corpuscular volume (MCV) 93 fL/red cell, leucocyte count of 7200/ μL and a platelet count of 199000/μL. His serum ferritin was 359 μg/l ( normal values: < 336 μg/l), serum iron: 37 μmol/l ( normal values <28.6μmol/l), fasting transferrin saturation: 64% (normal < 50%). A random glucose 6.5 and 6.4 mmol/L (normal values 5.5mmol/L ), A1C of 5,4 %, normal creatinine and electrolytes, alanine aminotransferase (ALT) of 66 U/l (normal < 40U/l), mild elevation of bilirubin 39 umol/l (normal <24umol/l), normal U&E Hepatitis B and C antibodies were negative. OGTT revealed impaired glucose tolerance. Thyroid function, morning serum cortisol, LH and FSH and serum total testosterone concentrations were in the normal range. A diagnosis of polycythemia vera was excluded on the basis of WHO Criteria 2008. The polymerase chain restriction assay was negative for the common mutation (C282Y) but positive for H63 D mutation. Family screening confirmed HH in his brother (homozygous), whereas his mother, two brothers and the sister were carriers (heterozygous). His four offspring were carriers. This suggested an autosomal recessive mode of inheritance. Conventional MRI study showed a normal liver size with diffuse fatty changes and focal areas of fatty sparing with some evidence of iron deposition. Whereas, T2-star (T2*) sequences showed a diffuse and significant decrease in liver signal intensity. A LIC liver concentration of 27 mg Fe/g dry wt was found (normalvalues:< 2 mg Fe/g dry wt; severe iron overload: ≥15 mg Fe/g dry wt). No significant iron deposition in the spleen, heart or pancreas was observed. At the age of 41 years the patient complained of tremors in both hands and arms while sitting or standing still (resting tremor) that improved with hands movements. A brain MRI revealed iron deposition in the basal ganglion. It was concluded that basal ganglionicn iron deposition mediated the neurological decline. Currently, the transferrin saturation and serum ferritin levels are within normal. Discussion: This is the first case of HH secondary to H63 D among an Arab family and the first reported case of Parkinsonism tremors secondary to this mutation. The H63D HFE variant is less frequently associated with HH, but its role in the neurodegenerative diseases has received a great attention. An accurate evaluation of iron overload is necessary to establish the diagnosis of HH and to guide iron chelation in HH by determination of liver iron concentration (LIC) by means of T2* MRI. Although serum ferritin concentration was only mildly increased a significant siderosis in the liver was detected by MRI T2* technique occurred. Liver siderosis was associated with mild impairment of liver function (increased serum ALT and bilirubin ). Conclusion: Our data further confirm that serum ferritin levels are not an accurate measure of total body iron stores in HH. Iron deposition in the liver and basal ganglion occurred despite mild elevation of ferritin. changes in basal ganglion may present by parkinsonian like tremors in these patients Use,T2* MRI should be encouraged in patients with HH for better evaluation of Iron overload and avoidance of Complications since serum ferritin can be misleading in these conditions. Disclosures Yassin: Qatar National research fund: Patents & Royalties, Research Funding. Aldewik:Qatar Ntional Research Fund: Patents & Royalties, Research Funding.

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