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Importance of Iron
1. Serve as both electron donor and acceptor in the Electron Transport Chain. 2. Needed by peroxidase enzymes as catalysts to convert harmful peroxides into water. 3. Needed in oxidative phosphorylation (oxidation of nutrients into ATP) by iron-sulfur proteins. 4. Main Importance: Oxygen Transport (incorporated in heme in hemoglobin)
Distribution of Iron
3-5 g of iron is in the body (total)
Ferritin water-soluble complex of ferric salt (Fe+3) and the protein apoferritin. Present in blood.
- a positive acute phase reactant/protein increases in inflammation.
tissues.
Iron Metabolism
1.Iron (Ferric) from foods is ingested. 2.To be absorbed by the intestinal cells, ferric ions (Fe+3) must be reduced to ferrous ions (Fe+2) by agents like Vitamin C (ascorbate).
3. Ferrous ions (Fe+2) are bound to apoferritin then oxidized to ferric ions (Fe+3) by ceruloplasmin to become bound as ferritin.
4. Ferritin is carried into blood (plasma) and releases its ferric ions (Fe+3). 2 ferric ions (Fe+3) are then absorbed by the protein apotransferrin to become transferrin.
5. Ferric (Fe+3) ions are then incorporated into the bone marrow for hemoglobin production.
* methemoglobin reductase reduces (Fe+3) to (Fe+2)
6. RBCs are degraded by the spleen, liver and macrophages. Iron leftovers from RBCs are carried by transferrin and recycled.
However, some iron is lost and excreted in the feces or urine. Women lose 20-40 mg of iron due to menstruation...
Implication
Diagnosis of conditions/diseases - sort out the diseases - most common: iron deficiency anemia Assess nutritional status of the patient.
Specimen must be collected as serum: - Oxalate, citrate and EDTA as anticoagulant is unacceptable chelators that can bind to iron.
Early morning samples are preferred diurnal variation in iron concentration. 25% lower in the evening.
- specimens are burned to break the bonds and liberate free unexcited atoms. - light from the hollow-cathode lamp passes through the atoms to shift into excited state. - the excited atoms then release light and shifts to ground state again measured by light detectors.
Ferritin Measurement
Radioimmunoassay (RIA) - highly sensitive test
- uses radioisotopes as labels to detect the presence of antigen (ferritin) or antibody in a sample. - Unlabeled ("cold") antigens compete for the antibodies. Radioactive antigens are displaced from the antibodies. - The antibody-bound antigen is separated from the free antigen in the supernatant fluid. - The radioactivity of each bound antigen is measured.
Ferritin Measurement
Enzyme-linked immunosorbent assay (ELISA)
- Patients serum containing the antigen (ferritin) is added in Microwell strips (which contains the antibody)
- 2nd antibody coupled to an enzyme is then added (forming a sandwich) - substrate (chromogen) solution is added and will be cleaved by the enzyme to form a colored product. - measured quantitatively by a spectrophotometer.
Transferrin Measurement
Total Iron Binding Capacity (TIBC) ability of
transferrin to bind iron in a saturated state.
Transferrin Measurement
Percent/Transferrin Saturation ratio of the serum iron to
the TIBC.
- The amount of light scatter is determined by collecting the light at an angle (usually about 70-75) by detectors.
FEP Measurement
Free
protoporphyrin IX in which ferrous (Fe+2) iron is added to form heme.
Erythrocyte
Protoporphyrin
(FEP)
FEP Measurement
Zinc protoporphyrin (ZPP) - compound found in RBCs
when heme production is inhibited or if iron is deficient.
- Instead of incorporating a ferrous ion, to form heme, protoporphyrin IX, incorporates a zinc ion, forming ZPP.
- normally present in trace amounts.
Measured by:
- High Performance Liquid Chromatography (HPLC) - FEP is extracted from the heme and measured.
measured using fluorescent spectrophotometer (Protoporphyrin + Iron will not fluoresce).
Reference Values
Patient Population Adult Male Serum Iron Transferrin (g/dL) (mg/dL) Ferritin (g/L) % Saturation TIBC (g/dL)
Infant
40-100
200-360
200-600
12-50
100-400
Child
50-120
200-360
7-140
12-50
100-400
Condition Iron Deficiency Anemia Thalassemia Major Anemia of Chronic Disease Sideroblastic Anemia Lead Poisoning Hemochromatosis / Iron Overload Malnutrition
Ferritin
% Transferrin Saturation
TIBC
Serum Iron
FEP/ ZPP
N/ N
N N N/
Variable
N N/ N/ N N
N N/ N/ N N
N N/
N
Variable
N N
Malignancy
- Most common cause of anemia on the planet, affecting at least 1/3 of the world's population
Condition
Stage 3 (IDA)
Iron Overload
Ferritin
> 12
< 12
< 12
< 12
> 300
TIBC
300-360
360
390
410
< 300
Serum Iron
65-165
115
< 60
< 40
> 175
% Saturation FEP
20-50
30
< 15
< 10
> 60
< 50
< 50
100
200
< 50
Rapid growth of infants and children. Pregnancy, lactation. Iron-deficient diet Inadequate absorption (achlorhydria, decreased absorptive surface)
Menstruation Gastrointestinal bleeding Hemorrhoids Regular blood donation Hemolysis
Inadequate intake:
Blood loss:
Fatigue, breathlessness and dizziness due to Pica persistent compulsive desire of eating substances
Disturbances in the gastrointestinal system swallowing difficulties (due to webbing of esophageal tissue), stomatitis (cracks in the mouth corners), tongue abnormalities (soreness and papillary atrophy) and gastritis (may progress to gastric atrophy which results in achlorhydria).
Plummer-Vinson Syndrome
Plummer-Vinson syndrome (US) or Paterson-Brown Kelly syndrome (UK) is a rare disease defined by severe, long-term iron deficiency anemia, which causes swallowing difficulty (dysphagia) due to web-like membranes of tissue growing in the throat (esophageal webs). Currently, the cause and the epidemiology of this syndrome are unknown, however, genetic factors and nutritional deficiencies were pointed out to play a role. Clinical findings include almost all those mentioned in iron deficiency anemia. This may progress to squamous cell carcinoma of the oral cavity, esophagus and hypopharynx. The 1st step in the management of the disease is to clarify the cause of iron deficiency in order to exclude active hemorrhage, malignancy or celiac disease.
Journal
Iron Deficiency in Children With Attention-Deficit/Hyperactivity Disorder by Eric Konofal, MD, et al. (From Archives of Pediatrics and Adolescent Medicine, December 17, 2004)
Background: Iron deficiency causes abnormal dopaminergic neurotransmission and may contribute to the physiopathology of attentiondeficit/hyperactivity disorder (ADHD). Objective: To evaluate iron deficiency in children with ADHD VS iron deficiency in an age and sex-matched control group. Design: Controlled group comparison study.
Setting: Child and Adolescent Psychopathology Department in European Pediatric Hospital, Paris, France.
Patients (Subjects): 53 children with ADHD aged 4 to 14 years (mean SD, 9.2 2.2 years) and 27 controls (mean SD, 9.5 2.8 years).
Journal
Main Outcome Measures: Serum ferritin levels evaluating iron stores and Conners Parent Rating Scale scores measuring severity of ADHD symptoms have been obtained. Results: The mean serum ferritin levels were lower in the children with ADHD (mean SD, 23 13 ng/mL) than in the controls (mean SD, 44 22 ng/mL; P < 0.001).
Serum ferritin levels were abnormal (<30 ng/mL) in 84% of children with ADHD and 18% of controls (P < 0.001).
In addition, low serum ferritin levels were correlated with more severe general ADHD symptoms measured with Conners Parent Rating Scale (Pearson correlation coefficient, r = -0.34; P < 0.02) and greater cognitive deficits (r = -0.38; P < 0.01). Conclusion: The results suggest that low iron stores contribute to ADHD and that ADHD children may benefit from iron supplementation.
Journal
Double Burden of Iron Deficiency in Infancy and Low Socioeconomic Status: A Longitudinal Analysis of Cognitive Test Scores to Age 19 Years by Betsy Lozoff, MD, et al. (From
Archives of Pediatrics and Adolescent Medicine, July 8, 2006)
Objective: To assess change in cognitive functioning after iron deficiency in infancy, depending on socioeconomic status (SES; middle VS low).
Design: Longitudinal study. Setting: Urban community in Costa Rica (infancy phase [July 26, 1983, through February 28, 1985] through 19-year follow-up [March 19, 2000, through November 4, 2002]). Participants: A total of 185 individuals enrolled at 12 to 23 months of age (no pre-term or low-birth-weight infants or infants with acute or chronic health problems).
Journal
The participants were assessed by various cognitive assessment score tests in infancy and at 5, 11 to 14, 15 to 18, and 19 years of age. A total of 97% were evaluated at 5 or 11 to 14 years and 78% at 15 to 18 or 19 years. Iron status in infancy was determined by venous concentrations of hemoglobin, % saturation, FEP, and serum ferritin. Individuals who had chronic iron deficiency in infancy (iron deficiency with hemoglobin concentrations 10.0 g/dL or, with higher hemoglobin concentrations, not fully corrected within 3 months of iron therapy) were compared with those who had good iron status as infants (hemoglobin concentrations 12.0 g/dL and normal iron measures before and/or after therapy). Main Outcome Measures: Cognitive change over time (composite of standardized scores at each age).
Journal
Results: For middle-SES participants, scores averaged 101.2 in the group with chronic iron deficiency VS 109.3 in the group with good iron status in infancy and remained 8 to 9 points lower through 19 years (95% confidence interval [CI], -10.1 to -6.2).
For low-SES participants, the gap widened from 10 points (93.1 VS 102.8; 95% CI for difference, -12.8 to -6.6) to 25 points (70.4 VS 95.3; 95% CI for difference, 20.6 to 29.4). Conclusions: The group with chronic iron deficiency in infancy did not catch up to the group with good iron status in cognitive scores over time. There was a widening gap for those in low-SES families. The results suggest the value of preventing iron deficiency in infancy.
References
Bishop, M. L., et al. (2006) Clinical Chemistry: Principles, Procedures, Correlation (2nd Edition). USA: Lippincott Williams and Wilkins. Hillman, R. S., et al. (2005) Hematology in Clinical Practice (4th Edition). USA: McGraw-Hill
Lehman, C. A. (1998) Saunders Manual of Clinical Laboratory Science. USA: W.B. Saunders
McPherson, R. A., Pincus, M. R. (2006) Henrys Clinical Diagnosis and Management by Laboratory Methods (21st Edition). USA: Elsevier Stiene-Martin, E. A., et al. (1997) Clinical Hematology: Principles, Procedures, Correlation (2nd Edition). USA: Lippincott.
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