Iron and Anemia in Human Biology: A Review of Mechanisms
Handelman GJ, et al.
Heart Fail Rev.; 2008; 13(4):393-404.
The biology of iron in relation to anemia is best understood by a review of the iron cycle, since the majority of
iron for erythropoiesis is provided by iron recovered from senescent erythrocytes. In iron-deficiency anemia,
storage iron declines until iron delivery to the bone marrow is insufficient for erythropoiesis. This can be
monitored with clinical indicators, beginning with low plasma ferritin, followed by decreased plasma iron and
transferrin saturation, and culminating in red blood cells with low-Hb content. When adequate dietary iron is
provided, these markers show return to normal, indicating a response to the dietary supplement. Anemia of
inflammation (also known as anemia of chronic disease, or ACD) follows a different course, because in this form
of anemia storage iron is often abundant but not available for erythropoiesis. The diagnosis of ACD is more
difficult than the diagnosis of iron-deficiency anemia, and often the first identified symptom is the failure to show a
response to a dietary iron supplement. Confirmation of ACD is best obtained from elevated markers of
inflammation. The treatment of ACD, which typically employs erythropoietin (EPO) supplements and
intravenous iron (i.v.-iron), is empirical and often falls short of therapeutic goals. Dialysis patients show a
complex pattern of anemia, which results from inadequate EPO production by the kidney, inflammation, changes
in nutrition, and blood losses during treatment. EPO and i.v.-iron are the mainstays of treatment. Patients with
heart failure can be anemic, with incidence as high as 50%. The causes are multifactorial; inflammation now
appears to be the primary cause of this form of anemia, with contributions from increased plasma volume, effects
of drug therapy, and other complications of heart disease. Discerning the mechanisms of anemia for the heart
failure patient may aid rational therapy in each case.
Bioavailability as an Issue in Risk Assessment and Management of Food Cadmium: A
Review
Reeves PG, et al.
Sci Total Environ.; July 2008; 398(1-3):13-9.
The bioavailability of cadmium (Cd) from food is an important determinant of the potential risk of this toxic
element. This review summarizes the effects of marginal deficiencies of the essential nutrients zinc (Zn), iron (Fe),
and calcium (Ca) on the enhancement of absorption and organ accumulation and retention of dietary Cd in
laboratory animals. These marginal deficiencies enhanced Cd absorption as much as ten-fold from
diets containing low Cd concentrations similar to that consumed by some human populations,
indicating that people who are nutritionally marginal with respect to Zn, Fe, and Ca are at higher
risk of Cd disease than those who are nutritionally adequate. Results from these studies also suggest that
the bioavailability of Cd is different for different food sources. This has implications for the design of food safety
rules for Cd in that if the dietary source plays such a significant role in the risk of Cd, then different foods would
require different Cd limits. Lastly, the importance of food-level exposures of Cd and other potentially toxic
elements in the study of risk assessment are emphasized. Most foods contain low concentrations of Cd that are poorly absorbed, and it is neither relevant nor practical to use toxic doses of Cd in experimental diets to study
food Cd risks. A more comprehensive understanding of the biochemistry involved in the bioavailability of Cd from
foods would help resolve food safety questions and provide the support for a badly needed advance in international
policies regarding Cd in crops and foods.
Hematological Manifestations of Copper Deficiency: A Retrospective Review
Bodnar L, et al.
Eur J Cancer, 2008 Sep 14.
Copper deficiency is an established cause of hematological abnormalities but is frequently misdiagnosed. Copper
deficiency can present as a combination of hematological and neurological abnormalities and it may masquerade as
a myelodysplastic syndrome. We reviewed the records of patients with hypocupremia and hematologic
abnormalities identified between 1970 and 2005. Patients with hypocupremia unrelated to copper deficiency (e.g.
Wilson's disease) were excluded. Forty patients with copper deficiency and hematological abnormalities were
identified. Ten patients (25%) had undergone bariatric (weight reduction) surgery and an additional 14 patients
(35%) had undergone surgery on the gastrointestinal tract, most commonly gastric resection. In 12 cases, no cause
for copper deficiency was identified. Anemia and neutropenia were the most common hematologic abnormalities
identified and the majority of the patients also had neurologic findings, most commonly due to myeloneuropathy.
Abnormalities observed on bone marrow examination including vacuoles in myeloid precursors, iron-containing
plasma cells, a decrease in granulocyte precursors and ring sideroblasts may be valuable clues to the diagnosis.
Copper deficiency is an uncommon but very treatable cause of hematologic abnormalities.
Heme Iron Uptake by Caco-2 Cells is a Saturable, Temperature Sensitive and
Modulated by Extracellular pH and Potassium
Arredondo M, et al.
Biol Trace Elem Res (2008) 125:109-119.
It is known that heme iron and inorganic iron are absorbed differently. Heme iron is found in the diet mainly in
the form of hemoglobin and myoglobin. The mechanism of iron absorption remains uncertain. This study focused
on the heme iron uptake by Caco-2 cells from a hemoglobin digest and its response to different iron
concentrations. We studied the intracellular Fe concentration and the effect of time, K+ depletion, and cytosol
acidification on apical uptake and transepithelial transport in cells incubated with different heme Fe
concentrations. Cells incubated with hemoglobin-digest showed a lower intracellular Fe concentration than cells
grown with inorganic Fe. However, uptake and transepithelial transport of Fe was higher in cells incubated with
heme Fe. Heme Fe uptake had a low Vmax and Km as compared to inorganic Fe uptake and did not compete with
nonheme Fe uptake. Heme Fe uptake was inhibited in cells exposed to K+ depletion or cytosol acidification. Heme
oxygenasc 1 expression increased and DMTI expression decreased with higher heme Fe concentrations in the
media. The uptake of heme iron is a saturable and temperature-dependent process and, therefore, could occur
through a mechanism involving both a receptor and the endocytic pathway.
The Study of Cu and Zn Serum Levels in Idiopathic Dilated Cardiomyopathy (IDCMP)
Patients and its Comparison with Healthy Volunteers
Salehifar E, et al.
Biol Trace Elem Res (2008) 125:97-108
Changes in the cupper (Cu) and zinc (Zn) concentrations have been reported previously in idiopathic dilated
cardiomyopathy (IDCMP). As a result of controversial results, the aim of this study was to compare the Zn and Cu
concentrations and Zn/Cu ratio of IDCMP patients to healthy volunteers. In addition, the correlation of Cu and
Zn levels with age has been evaluated. The study population consisted of 18 IDCMP patients and 27 healthy
volunteers. IDCMP patients had normal angiography with echocardiography supporting cardiomyopathy without
pericardial and valvular diseases. Exclusion criteria were renal or hepatic insufficiency, alcohol usage, and intake of
supplements containing Cu or Zn within 1 week ago. Cu and Zn levels have been assayed with atomic absorption
spectrophotometry. Statistical analysis was performed with SPSS 10 software with independent sample t test for
comparing the level of Cu and Zn of IDCMP patients with normal subjects and Pearson correlation to determine
the correlation between numeric data. P<0.05 was considered as significant differences. There was a trend for a
lower Zn level in IDCMP patients compared to healthy volunteers. (0.97 ± 0.25 mg/l vs. 1.12 ± 0.42 mg/l,
respectively). The mean Cu levels of IDCMP and normal subjects were 1.33 ± 0.20 mg/l and 1.31 ± 0.23 mg/l,
respectively. There was a significant difference in Zn/Cu ratio among patients based on the NYHA classification of
heart failure (P = 0.003). Age was negatively correlated with Zn levels in IDCMP group (P = 0.037) and
positively with Cu levels in healthy volunteers (P = 0.012). A lower Zn level in IDCMP patients compared to
healthy volunteers and especially a significant difference in Zn/Cu ratio of patients based on their NYHA
classification would suggest a critical role of zinc and Cu imbalance in development of IDCMP.
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