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The first study on this page is not an iron reduction study. We've selected it to demonstrate how marked variations in iron and antioxidant status markers relate to the significant health differences in two elderly male populations. We are unfortunately unable to provide the full published text of this article due to publisher's copyright restrictions; however, we will provide the author's manuscript.
Oxidative stress, and iron and antioxidant status in elderly men: differences between the Mediterranean south (Crete) and northern Europe (Zutphen) (1) Manuscript PDF
This research team from the Netherlands provided the following as background for their study: "Oxidative stress may accelerate ageing and increase the risk of chronic diseases, such as coronary heart disease (CHD). We assessed differences in oxidative stress, and iron and antioxidant status between elderly men living in Mediterranean southern Europe (Crete, Greece) and northern Europe (Zutphen, The Netherlands)." "Non-fasting blood samples were drawn in 2000 from 105 men from Crete and 139 men from Zutphen, all aged 79 years or over." "After multiple adjustments, serum levels of the markers of oxidative stress were lower in Cretan men than in men from Zutphen, as indicated by lower mean levels of hydroperoxides (33.2 versus 57.3 micromol/l; P=0.005) and gamma-glutamyltransferase (GGT) (20.3 versus 26.1 U/l; P=0.003). The most pronounced difference in iron status was a twofold lower mean serum ferritin level in Cretan men (69.8 ng/mL) compared with men from Zutphen (134.2 ng/mL; P<0.0001). Men from Crete had consistently higher plasma levels of major plasma antioxidants than the Zutphen men, including a nearly fourfold higher mean level of lycopene (15.3 versus 4.1 microg/100 ml; P<0.0001)." The researchers concluded, " "Elderly men from Crete had consistently lower levels of the indicators of oxidative stress and iron status and higher concentrations of major antioxidants than men from Zutphen. These differences may contribute to the lower rate of CHD and total mortality that has been observed in this cohort of Cretan men." [Health-e-Iron note: Tables 2 and 3 from the manuscript are below]
Health-e-Iron note: The following three papers (#s 2-4) were based on the largest, controlled iron-reduction investigation undertaken to date (VA Cooperative Study #410). A total of 1,277 patients with peripheral arterial disease (PAD) were randomized and assigned to one of two groups, iron reduction (n = 636) or control (n = 641). All patients had no history of cancer for 5 years prior to the study; patients were followed for 4.5 years. Various disease endpoints and mortality measures were evaluated for each subject age quartile. Each age quartile independently represented larger patient populations than those studied in previous iron reduction studies. Of note, iron reduction was targeted to reduce serum ferritin levels to approximating those of the comparatively healthy Cretan male population described above. The following information is relevant to each of studies 2, 3 and 4 below: Patients with serum ferritin above 400 ng/mL were excluded from the study. "Ferritin levels were similar in both groups at baseline but were lower in iron reduction patients than control patients across all 6-month visits (mean = 79.7 ng/mL... vs 122.5 ng/mL...)."
Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial (2) Free full text
The object of this 2008 report from this large VA study to determine the "Occurrence of new visceral malignancy and cause-specific mortality data were collected prospectively. Cancer and mortality outcomes in the two arms were compared using intent-to-treat analysis..." "Risk of new visceral malignancy was lower in the iron reduction group than in the control group (38 vs 60...), and, among patients with new cancers, those in the iron reduction group had lower cancer-specific and all-cause mortality (HR = 0.39, ...) than those in the control group. Mean ferritin levels across all 6-monthly visits were similar in patients in the iron reduction and control groups who developed cancer but were lower among all patients who did not develop cancer than among those who did (76.4 ng/mL, ..., vs 127.1 ng/mL, ...)."The results ... appear to show reduced risk of new cancer in patients having greater than about 60% compliance with phlebotomy, corresponding to a ferritin level of less than 54.8 ng/mL, 95% CI = 51.6 to 57.9 ng/mL. Seventy-five percent of new cancers occurred among patients having mean ferritin levels during followup of greater than about 57 ng/mL." The investigators concluded, "Iron reduction was associated with lower cancer risk and mortality. Further studies are needed to define the role of body iron in cancer risk." [Health-e-Iron note: There are several illustrative tables and charts in the "Free full text" available using the above link. Two of them are reproduced below.]
Health-e-Iron note: For those with the interest and time to learn more about the iron/cancer investigation in this study, we suggest viewing this Video Link in which Leo R. Zacharski MD, the lead investigator in each of studies 2, 3 and 4 discusses, "Iron and Diseases of Aging" – Medical Grand Rounds July 2009 Presented at – Norris Cotton Cancer Center Dartmouth - Hitchcock Medical Center. (We believe you'll find this video very informative. It covers oxidative stress and many other topics relevant to our website, and is even very humorous at times as well.)
Reduction of iron stores and cardiovascular outcomes in patients with peripheral arterial disease: a randomized controlled trial (3) Free full text
This 2007 paper was the first findings report from VA Cooperative Study #410. The stated objective was: "To test the hypothesis that reducing body iron stores through phlebotomy will influence clinical outcomes in a cohort of patients with symptomatic peripheral arterial disease (PAD)."The primary end point was all-cause mortality; the secondary
end point was death plus nonfatal myocardial infarction and stroke." Although the results for the entire 1,277 patient cohort did not achieve statistically significance for the primary and secondary endpoint objectives, there were 23 more mortalities in the control group than in the iron-reduction group. Notably however, statistically significant results were observed in the youngest cohort (ages 43 - 61 years). Among 169 patients in the the youngest control quartile, there were 28 mortalities versus 13 in the iron reduction cohort. When the mortalities in the youngest cohort were combined with nonfatal myocardial infarction and stroke as events, 21 events were attributed to the iron-reduction group and 49 to the control group. [Health-e-Iron note: The investigators reviewed their findings to ascertain what, if anything, could have caused the significantly disparate outcomes observed among age quartiles. They published a follow-up study in 2011 that describes the "age-specific effect" observed in the overall study. That paper is # 4 below. Figure 3 from this study appears below]
Effect of controlled reduction of body iron stores on clinical outcomes in peripheral arterial disease (4) Free full text
The results from the large randomized control study described above "found improved outcomes with iron (ferritin) reduction among middle-aged subjects but not the entire cohort." The investigators analyzed these findings in detail. The initial study reported "Iron reduction improved outcomes in youngest age quartile patients (primary outcome hazard ratio [HR] 0.44, 95% CI 0.21-0.92, P = .028; secondary outcome HR 0.34, 95% CI 0.19-0.61, P < .001)." Put another way, iron-reduction patients between the age of 43 and 61 experienced a 56% reduction in the rate of death and a 66% reduction in the incidence of combined death, nonfatal myocardial infarction, and stroke, when compared to age-matched control patients. The results of the investigation showed, "Mean follow-up ferritin levels (MFFL) declined with increasing entry age in controls. Older age... and higher ferritin ... at entry predicted poorer compliance with phlebotomy and rising MFFL in iron-reduction patients. Intervention produced greater ferritin reduction in younger patients. Improved outcomes with lower MFFL were found in iron-reduction patients...; secondary outcome ... and the entire cohort...). Improved outcomes occurred with MFFL below versus above the median of the entire cohort means" for both primary and secondary outcomes ..." (although this secondary outcome finding for the entire cohort was slightly less than statistically significant). The investigators concluded, "Lower iron burden predicted improved outcomes overall and was enhanced by phlebotomy. Controlling iron burden may improve survival and prevent or delay nonfatal myocardial infarction and stroke." [Health-e-Iron note: In separate analysis, unrelated to this patient cohort, Health-e-Iron analyzed more than 230,000 ferritin/age data points derived from multiple cross-sectional studies conducted throughout the world. As demonstrated in this large study, serum ferritin measures from aggregated studies demonstrate a peak, particularly for males around 50 years of age, and a decline thereafter for about 20 years. However paradoxically, all longitudinal studies (i.e. two or more data points for individuals over time), although far fewer in number, show that ferritin increases with age over time beyond age 50 (in males and females). Health-e-Iron hypothesizes this dichotomy is a result of premature deaths that cause the removal of (particularly) men with higher ferritin from the population at an earlier age than those with lower ferritin. If correct, this would at least in part explain the convergence of ferritin measures with increasing age in both the iron-reduction and control groups (e.g., as demonstrated in the VA study). Or put more succinctly, if premature death occurs, the decedent is no longer available to participate in a study at a more advanced age! (also, as noted in nearly all the large GGT studies detailed on this web site, the significant fatalities related to elevated GGT appear to "disappear" when subjects are above ~ age 65 -70 years at study baseline). Table II from this research appears below]
Iron Overload Is Associated with Hepatic Oxidative Damage to DNA in Nonalcoholic Steatohepatitis (5) Free full text
In 2009 this research team reported on their study of oxidative stress and iron reduction in a group of 38 non-alcoholic steatohepatitis (NASH) patients. They measured markers of oxidative stress, baseline clinical and biochemical factors in the NASH patient cohort and compared them to the same measurements in 24 simple steatosis (fatty liver disease) patients and 10 healthy controls. "Levels of oxidative stress were significantly higher in NASH compared with simple steatosis. Oxidative stress "was significantly related to iron overload condition, glucose-insulin metabolic abnormality, and severities of hepatic steatosis in NASH patients." The researchers concluded, "After the iron reduction therapy (by phlebotomy), hepatic 8-oxodG levels (a good measure of oxidative stress) were significantly decreased (from 20.7 to 13.8) ... with concomitant reductions of serum transaminase levels in NASH patients. "In conclusion, iron overload may play an important role in the pathogenesis of NASH by generating oxidative DNA damage and iron reduction therapy may reduce hepatocellular carcinoma incidence in patients with NASH." [Health-e-Iron note: Figure 2 from this study appears below]
Figure 2. Correlations between 8-oxodG–positive hepatocytic nuclear counts and clinical variables in 38 NASH or 24 simple steatosis patients. A. 8-oxodG counts and serum glucose levels in NASH. B. 8-oxodG counts and HOMA-IR in NASH. C. 8-oxodG counts and serum iron levels in NASH. D. 8-oxodG counts and TIS in hepatic tissues in NASH. Dotted vertical line indicates that the TIS is 0. E-1. 8-oxodG counts and extent of hepatic steatosis in NASH. E-2. 8-oxodG counts and extent of hepatic steatosis in simple steatosis.
Iron Depletion by Phlebotomy Improves Insulin Resistance in Patients With Nonalcoholic Fatty Liver Disease and Hyperferritinemia: Evidence from a Case-Control Study (6) Free full text
In this 2007 study conducted in Italy, the aims of the study were defined as follows: "...to define the relationship between ferritin and iron stores in patients with NAFLD, the effect of iron depletion on insulin resistance, and whether basal ferritin levels influence treatment outcome." "Subjects were included if ferritin and/or ALT were persistently elevated after 4 months of standard therapy. Sixty-four phlebotomized subjects were matched 1:1 for age, sex, ferritin, obesity, and ALT levels with patients who underwent lifestyle modifications only. Insulin resistance was evaluated by insulin levels, determined by RIA and the HOMA-R index, at baseline and after 8 months." "Baseline ferritin levels were associated with body iron stores (P < 0.0001). Iron depletion produced a significantly larger decrease in insulin resistance (P = 0.0016 for insulin, P = 0.0042 for HOMA-R) compared with nutritional counseling alone, independent of changes in BMI, baseline HOMA-R, and the presence of the metabolic syndrome. Iron depletion was more effective in reducing HOMA-R in patients in the top two tertiles of ferritin concentrations (P < 0.05 vs controls), and in carriers of the mutations in the HFE gene of hereditary hemochromatosis (P < 0.05 vs noncarriers). The researchers concluded, "Given that phlebotomy reduces insulin resistance, which is associated with liver tissue damage, future studies should evaluate the effect of iron depletion on liver histology and cardiovascular end points." [Health-e-Iron note: a number of such "future studies" have been reported and are summarized on this page and in other sections of this website. Table 2, Figures 2 and 3 from this research appear below]
Figure 2. Effect of therapy on BMI, HOMA-R, insulin, and ALT levels according to basal ferritin tertiles. (A) Basal and final values. (B) Variation—white bars: phlebotomized subjects, grey bars: nonphlebotomized subjects. Data are shown as mean ± SE. ∗P < 0.05 versus controls.
Effects of phlebotomy-induced reduction of body iron stores on metabolic syndrome: Results from a randomized clinical trial (7) Free full text
In 2012 this research group reported on their study to test the hypothesis that, "...phlebotomy-induced reduction of body iron stores would alter clinical manifestations of METS (metabolic syndrome)..." "In a randomized-controlled single-blinded clinical trial 64 patients with METS (aged 25 to 70 Years) were randomly assigned to iron reduction by phlebotomy (n=33) or to a waiting-list control group (n=31). Iron reduction patients had 300ml of blood removed at entry and between 250-500ml removed after 4 weeks depending on entry ferritin levels. Primary outcomes were change of systolic blood pressure (SBP) and of insulin sensitivity as measured by HOMA-Index after 6 weeks. Secondary outcomes included HbA1c, plasma-glucose, blood lipids and heart rate." "In the iron reduction group...mean hemoglobin decreased from 14.3 ± 1.2 at baseline to 13.3 ± 1.1 mg/dl after 6 weeks, and similarly, mean serum ferritin concentration decreased from 188.3 ± 212.4 to 104.6 ± 132.5 mg/dl." The researchers further reported "SBP decreased from 148.5 ± 12.3 mmHg to 130.5 ± 11.8 mmHg in the phlebotomy group, and from 144.7 ± 14.4 mmHg to 143.8 ± 11.9 mmHg in the control group (difference -16.6 mmHg; 95% CI -20.7 to -12.5; P < 0.001). No significant effect on HOMA index was seen. With regard to secondary outcomes, blood glucose, HbA1c, low-density lipoprotein/high-density lipoprotein ratio, and HR (heart rate) were significantly decreased by phlebotomy. Changes in BP and HOMA index correlated with ferritin reduction. The researchers concluded, "In patients with METS, phlebotomy, with consecutive reduction of body iron stores, lowered BP and resulted in improvements in markers of cardiovascular risk and glycemic control. Blood donation may have beneficial effects for blood donors with METS." [Health-e-Iron note: Table 2 from this study appears below]
Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target (8) Free full text
In 2011 this group of researchers discussed the emergent trend in a condition referred to as the dysmetabolic iron overload syndrome (DIOS), which they refer to as, "a frequent finding in the general population, as is detected in about one third of patients with nonalcoholic fatty liver disease (NAFLD) and the metabolic syndrome. In the U.S. that amounts to many millions of people. In this review, the authors state the following: "Evidence is accumulating that excessive body iron plays a causal role in insulin resistance through still undefined mechanisms that probably involve a reduced ability to burn carbohydrates and altered function of adipose tissue. Furthermore, DIOS may facilitate the evolution to type 2 diabetes by altering beta-cell function, the progression of cardiovascular disease by contributing to the recruitment and activation of macrophages within arterial lesions, and the natural history of liver disease by inducing oxidative stress in hepatocytes, activation of hepatic stellate cells, and malignant transformation by promotion of cell growth and DNA damage." In the full text, the authors describe the results and findings of iron reduction trials that they have conducted. The researchers conclude, "iron depletion, most frequently achieved by phlebotomy, has been shown to decrease metabolic alterations and liver enzymes in controlled studies in NAFLD." [Health-e-Iron note: Figure 2 from the above paper appears below]
Fig. 2. Proposed mechanisms explaining iron induced liver damage associated with steatosis and DIOS in hepatocytes (brown), macrophages (gray), and hepatic stellate cells (yellow). Cp, ceruloplasmin; Cu, copper; Fe-Tf, ferric-transferrin; Fp-1, ferroportin-1; HCC, hepatocellular carcinoma; HFE, hemochromatosis gene; HSCs, hepatic stellate cells; MDA, malonyl-dialdehyde; ROS, reactive oxygen species; SOD2, Mn superoxide dismutase; Tf-R, transferrin receptor.
The role of oxidative stress in the metabolic syndrome (9)
In a second 2011 review of metabolic syndrome, iron and oxidative stress, researchers at the Harry S. Truman VA Medical Center in Columbia, Missouri state, "Loss of reduction-oxidation (redox) homeostasis and generation of excess free oxygen radicals play an important role in the pathogenesis of diabetes, hypertension, and consequent cardiovascular disease. Reactive oxygen species are integral in routine in physiologic mechanisms. However, loss of redox homeostasis contributes to proinflammatory and profibrotic pathways that promote impairments in insulin metabolic signaling, reduced endothelial-mediated vasorelaxation, and associated cardiovascular and renal structural and functional abnormalities. Redox control of metabolic function is a dynamic process with reversible pro- and anti-free radical processes. Labile iron is necessary for the catalysis of superoxide anion, hydrogen peroxide, and the generation of the damaging hydroxyl radical. Acute hypoxia and cellular damage in cardiovascular tissue liberate larger amounts of cytosolic and extracellular iron that is poorly liganded; thus, large increases in the generation of oxygen free radicals are possible, causing tissue damage. The understanding of iron and the imbalance of redox homeostasis within the vasculature is integral in hypertension and progression of metabolic dysregulation that contributes to insulin resistance, endothelial dysfunction, and cardiovascular and kidney disease.
The role of iron in the pathophysiology and treatment of chronic hepatitis C (10) Free full text
This 2009 article "reviews the prevalence and risk factors for hepatic iron overload in chronic hepatitis C, with emphasis on the available data regarding the efficacy of iron depletion in the treatment of this common liver disease." The authors also discuss "The presence of hemochromatosis gene mutations is associated with increased hepatic iron accumulation and may lead to accelerated disease progression. Hepatic iron depletion has been postulated to decrease the risk of hepatocellular carcinoma in patients with cirrhosis due to chronic hepatitis C. It is possible that iron depletion stabilizes or improves liver histology and slows disease progression in these individuals."
A case–control histological study on the effects of phlebotomy in patients with chronic hepatitis C (11) Free full text
Reported in 2011, this Italian research was undertaken to, "assess the actual effectiveness of long-term phlebotomy by comparing histological improvement (HI) in 69 Caucasian HCV-RNA-positive CHC (chronic hepatitis C) patients undergoing phlebotomy or receiving an interferon-based therapy without virological response [non responders to interferon therapy (IBT-NR)]." The study cohort was compared to a 39 patient (non-phlebotomized) control group. Based on initial study biopsies of patients in each groups, liver damage assessments were compared both prior to phlebotomy treatments and approximately 5-6 years later. "Univariate and multivariate analysis showed that histological grading score before therapy (P=0.001) and phlebotomy (P=0.002) were independently predictors of HI." The researchers concluded, "HI was observed in 15 of 30 (50%) patients treated with phlebotomy and in six of 39 (15%) IBT-NR subjects (P=0.002). "Furthermore, AST, ALT, and GGT serum levels were significantly reduced only in phlebotomized patients (P ≤ 0.003) at the time of the second biopsy." [Health-e-Iron note: Table 3 from this study appears below]
Phlebotomy improves histology in chronic hepatitis C males with mild iron overload (12) Free full paper
In this 2010 study, 28 Caucasian, chronic hepatitis C patients who had not responded to (or were unsuitable for) traditional antiviral therapy "underwent mild iron depletion (ferritin < or = 70 ng/mL) by long-term phlebotomy." "Phlebotomy showed an excellent safety profile. Histological (liver damage) improvement occurred in 12/28 phlebotomized patients. Only males responded to phlebotomy." The researchers concluded, "Male CHC Caucasian non-responders to antiviral therapy with low-grade iron overload can benefit from mild iron depletion by long-term phlebotomy." [Health-e-iron note; Table 2 from this study appears below]
Increased oxidative stress, decreased total antioxidant capacity, and iron overload in untreated patients with chronic hepatitis C (13)
This was a 2010 study reported by a Brazilian research team, "The aim of this study was to determine oxidative stress in patients with untreated chronic hepatitis C (CHC), relating the obtained results with iron status and disease activity markers. Two groups (CHC patients and controls) were studied. CHC patients presented significantly higher values than the control group in some parameters: ALT, AST, GGT, iron, ferritin, and transferrin saturation, and also in tert-butyl hydroperoxide initiate chemiluminescence and thiobarbituric acid-reactive substances (TBARS) as well as lower values in total radical-trapping antioxidant parameter (TRAP). TBARS showed a significant correlation with serum AST and with transferrin saturation, whereas TRAP correlated inversely with serum albumin. Serum ferritin correlated with ALT and GGT, whereas serum iron did so with GGT. "In conclusion, lower antioxidant capacity, higher levels of pro-oxidants activity, and iron overload occur in untreated patients with CHC. This greater oxidative activity could play an important role in pathogenesis and evolution of hepatitis C and thus further investigations."
Long term effects of phlebotomy on biochemical and histological parameters of chronic hepatitis C (14)
This was a 2002-reported study from Japan. "There is considerable evidence that iron is a risk factor for liver injury in chronic hepatitis C. Known as iron reduction therapy, phlebotomy reduces serum ALT activity. This effect might continue with maintenance phlebotomy and result in slower progression of liver fibrosis." "We examined the biochemical parameters and liver histology of patients with chronic hepatitis C treated by maintenance phlebotomy. For biochemical evaluation, 25 patients were treated by initial phlebotomy to reduce serum ferritin levels to 10 ng/ml or less and then observed for 5 yr with maintenance phlebotomy to maintain the iron-deficient state. For histological evaluation, liver biopsies were performed before and after the study period in 13 of the patients. Thirteen patients who were virological nonresponders to interferon alone and had undergone second liver biopsies after more than 3 yr served as histological controls." "Serum aminotransferase levels were decreased significantly by initial phlebotomy and remained at the same levels during the study period (p < 0.05). The grading scores were improved significantly in the study group (p < 0.05) and unchanged in the controls. The staging scores remained unchanged in the study group but were increased in the controls (p < 0.005). Disease progression was significantly different between the two groups (p < 0.05). The investigators concluded, "These results suggest that phlebotomy with maintenance lowers serum aminotransferase levels, improves liver inflammation, and suppresses the progression of liver fibrosis in chronic hepatitis C."
Patients with chronic hepatitis C may be more sensitive to iron hepatotoxicity than patients with HFE-hemochromatosis (15) Free full text
The investigators in this 2010-reported study from Japan first noted, "In chronic hepatitis C, iron might play an important role as a hepatotoxic co-factor. Therefore, venesection, a standard treatment for hemochromatosis, has been proposed as an alternative for patients who respond poorly to anti-viral therapy. To improve our understanding of iron-induced hepatotoxicity, we compared the responses to venesection between patients with chronic hepatitis C and those with HFE-hemochromatosis." "Fourteen Japanese patients with chronic hepatitis C and eight Italian patients with HFE-hemochromatosis underwent repeated venesection with a serum ferritin endpoint of 20 and 50 ng/mL, respectively. Serum iron indices and liver function tests were measured in pre- and post treatment blood samples from each patient. Body iron stores were calculated using the removed blood volume." "In both patients with hepatitis and hemochromatosis, serum ferritin, aminotransferase and hepcidin 25 were reduced after venesection. The serum aminotransferase activity, but not the serum ferritin level, was predictive of effective iron removal treatment. Hepcidin regulation was set at an inappropriately low level in hemochromatosis patients (11.1 ± 9.2 ng/mL), but not so in hepatitis patients (30.7 ± 14.5 ng/mL). Inversely, the estimated body iron stores of hemochromatosis patients were 5,960 ± 2,750 mg, while those of hepatitis patients were 730 ± 560 mg. Judging from the liver enzyme reduction ratio, patients with hepatitis seemed to be more sensitive to iron hepatotoxicity than hemochromatosis patients." The investigators concluded, "Even though the threshold of iron hepatotoxicity and benefit of its removal differ between patients with chronic hepatitis C and those with HFE-hemochromatosis, venesection is a valid choice of treatment to reduce liver disease activity in both diseases." [Health-e-Iron note: the important juxtaposition of response to treatment as measured by ferritin reduction compared to improvement in inflammation demonstrate the the differences between hemochromatosis and hepatitis C patients as described by the authors in the full paper. These differences are depicted below in Figures 2 and 3 from this article.]
Relation between iron stores and non-insulin dependent diabetes in men: case-control study (16) Free full text
In 1998 a group of Finnish investigators "...tested the hypothesis that the accumulation of iron in the body predicts the development of insulin dependent diabetes. We followed 1,038 randomly selected men from eastern Finland aged 42-60 for four years." "...all potential participants who had diabetes or who could have been classed as prediabetic were excluded." "In a logistic regression model, men with high stores of iron...were 2.4 times more likely...to develop diabetes than men with lower stores of iron. In a step up model in which baseline concentrations of serum triglycerides and glycosylated proteins were adjusted for as continuous variables, the odds ratio for developing diabetes was 2.5 (1.1 to 6.0, P = 0.04)." The researchers concluded, "This is the first study to show an association between stores of iron and the incidence of diabetes. Our data support the theory that increased iron stores, even in the range not considered to be associated with haemochromatosis, contribute to the development of non-insulin dependent diabetes."
Blood Letting in High-Ferritin Type 2 Diabetes; effects on insulin sensitivity and Beta-cell function (17) Free full text
The aim of this 2002 Spanish study "was to evaluate insulin sensitivity and insulin secretion after blood letting in patients who had high-ferritin type 2 diabetes and were randomized to blood letting (three phlebotomies [500 ml of blood] at 2-week intervals, group 1) or to observation (group 2). Insulin secretion and sensitivity were tested at baseline and 4 and 12 months thereafter." The researchers reported, "As expected, serum ferritin, transferrin saturation index, and blood hemoglobin decreased significantly at 4 months only in patients who received blood letting. In parallel to this changes, blood HbA1c decreased significantly only in group 1 subjects,...(and) AUCc-peptide (a marker of total insulin secretion) decreased... after blood letting. In contrast, an... increase...in group 2 subjects at 4 months." "At 4 months, the change in insulin sensitivity from baseline was significantly different between the two groups." "At 12 months, the differences between the two groups were even more marked..." "A statistically significant increase in insulin sensitivity was observed in the blood-letting group...at 4 months,...at 12 months;...in contrast with group 2 subjects." With regard to excess iron storage in patients with diabetes, the researchers concluded, "an adequate and safe therapy will be needed for these patients, and blood letting might be one of them." [Health-e-Iron note: Table 2 and Figures 1 and 2 from this study appear below. Note also that phlebotomy treatment was limited to the first month of the study only.]
Blood letting in high-ferritin type 2 diabetes: effects on vascular reactivity (18) Free full text
In a second 2002 paper by the researchers in the study reported directly above, the authorss noted that, "In a recent study, iron chelation with deferoxamine led to improvement of endothelial dysfunction in patients with coronary artery disease. We tested the hypothesis that decreasing circulating iron stores might improve vascular dysfunction in patients with type 2 diabetes and increased serum ferritin concentration." "A total of 28 type 2 diabetic male patients with serum ferritin levels >200 ng/ml... were randomized to iron depletion (three extractions of 500 ml blood at 2-week intervals; group 1A) or to observation (group 1B)." "The two groups of patients were matched for age, BMI, pharmacological treatment, and chronic diabetic complications." "Endothelium-dependent vasodilation remained essentially unchanged in both groups of patients. In contrast, the vasodilation induced by glyceryl trinitrate (GTN) improved significantly after iron depletion (P = 0.006). These changes occurred in parallel to decreases in transferrin saturation index and HbA(1c) levels (-0.6%, P < 0.05) only in group 1A patients. The best predictor of the modifications in endothelium-independent vasodilation was the change in HbA(1c) levels. Changes in endothelium-independent vasodilation also correlated with the change in serum ferritin (r = -0.45, P = 0.04). At 12 months, transferrin saturation index and GTN-induced vasodilation returned to values similar to those at baseline in both groups of subjects." The researchers concluded, "Iron depletion improves vascular dysfunction in type 2 diabetic patients with high ferritin concentrations. The mechanisms by which these changes occur should be further investigated." [Health-e-Iron note: as noted in the above study, phlebotomy treatments of Group 1A patients was limited to the first month of the study only. Table 1 from this study appears below]
Association of High Serum Ferritin Concentration with Glucose Intolerance and Insulin Resistance in Healthy People (19) Free full text
The objection of this 2003 letter that comments on the study described directly above was "to analyze the relationship between iron variables and glucose tolerance, insulin sensitivity, and Beta-cell function in non-diabetic persons." The researchers found, "Serum ferritin level was positively correlated with 2-hour glucose concentration and negatively correlated with insulin sensitivity.... These associations remained statistically significant ... after transferrin saturation, age, sex, body mass index, waist-to-hip ratio, leukocyte count, and C-reactive protein level were included as covariates in a multivariate linear regression analysis. There was no significant correlation between serum ferritin concentration and either estimated (from the oral glucose tolerance test) or measured Beta-cell function ...."The researchers concluded, "It may become advisable to routinely screen for mildly elevated or even high-normal serum ferritin concentrations in the context of glucose intolerance. If prospective and interventional studies confirm an etiologic role of iron overload in the pathogenesis of insulin resistance and type 2 diabetes, reduced dietary iron intake, especially in men and postmenopausal women (9) with additional risk factors for type 2 diabetes, would appear to be a logical consequence. In the future, actively lowering body iron stores may become a tool in preventing type 2 diabetes in selected subgroups." [Health-e-Iron note: since this 2003 letter, a number of such "prospective and interventional studies" have been reported and are summarized on this page and in other sections of this website. The Figure from this study appears below]
Association Between Blood Donation Frequency, Antioxidant Enzymes and Lipid Peroxidation (no abstract) (20) Free full text
This 2008 Iranian research was based on reported findings that linked iron as a pro-oxidant cofactor to atherosclerosis progression and the hypothesis that, "Reduction of body iron stores secondary to blood donation has been hypothesized to reduce lipid peroxidation" The researchers divided 150 male volunteer blood donor subjects between 30 and 60 years of age into five groups according to annual frequency of blood donations. The researchers concluded, "The current findings demonstrate evidence of greater reduction of body iron stores, increase activity of SOD, decreased oxidative stress, and decrease lipid peroxidation in high frequency blood donors when compared with low frequency blood donors." [Health-e-Iron note: Table 2 from this study appears below]
Iron Stores, Blood Donation, and Insulin Sensitivity and Secretion (21) Free full text
In this 2005 study from Spain, the researchers, "investigated the relationship between iron stores and insulin sensitivity, after controlling for known confounding factors, and compared insulin sensitivity between blood donors and individuals who had never donated blood (nondonors). In 181 men, insulin sensitivity and insulin secretion were evaluated through frequently sampled intravenous glucose tolerance tests with minimal model analysis. Men who donated blood between 6 months and 5 years before inclusion (n = 21) were carefully matched with nondonors (n = 66) for age, body mass index, waist-to-hip ratio, and cardiovascular risk profile, including blood lipids, blood pressure, and smoking status." "Blood donors were classified as occasional donors (1 blood donation in the period 6 months to 5 years before the study; group 1) and frequent blood donors (at least 2 blood donations in the same period, median = 4 donations; group 2; Table 1). The number of blood donations correlated with insulin sensitivity (r = 0.28; P = 0.01; n = 87), and this association was more statistically significant when only blood donors were considered (r = 0.60; P = 0.003; n = 21). This result was mainly attributable to the men who had given at least 2 blood donations in the previous 6 months to 5 years." "Frequent blood donors (2-10 donations) had increased insulin sensitivity [ 3.42 (1.03) vs 2.45 (1.2) x 10(-4) x min(-1) x mIU/L; P = 0.04], decreased insulin secretion [186 (82) vs 401.7 (254) mIU/L x min; P <0.0001], and significantly lower iron stores [serum ferritin, 101.5 (74) vs 162 (100) microg/L; P = 0.017] than nondonors." The researchers concluded, "Blood donation is simultaneously associated with increased insulin sensitivity and decreased iron stores. Stored iron seems to impact negatively on insulin action even in healthy people, and not just in classic pathologic conditions associated with iron overload (hemochromatosis and hemosiderosis). According to these observations, it is imperative that a definition of excessive iron stores in healthy people be formulated." "In addition, blood donation or phlebotomy may be indicated as adequate and safe therapy for prevention of type 2 diabetes among persons with high-normal serum ferritin." [Health-e-Iron note: Figures 1 and 2 and Table 1 from this study appear below]
Iron status of regular blood donors (22) Free full text
In this 2008 study from a voluntary donor blood bank in India, researchers reviewed the "iron status of regular voluntary donors who donated their blood at least twice in a year." The study included 220 males and 30 females. "After investigation, 85 males and 56 females having haemoglobin (Hb) levels above 12.5 g/dl were selected as controls." "Donors were divided into 50 blood donation categories. Majority of the donors in >50 donation category donated blood four times in a year, whereas the remaining donors donated two to three times per year." A respective "Significant increase or decrease was observed in mean values of various haematological and iron parameters in donors who donated blood for >20 times (P < 0.001), compared to controls." [Health-e-Iron note: this study was undertaken in a population with relatively low iron stores in non-blood donors (e.g. SF ~59 men; 39 women). The researchers noted that frequent donation totaling more than ~20 times can cause iron deficiency and that in their population "there is a need to educate regular blood donors about iron deficiency."]
Iron stores and vascular function in voluntary blood donors (23) Free full text
In this U.S. study of blood donors reported in 2005, "Forty high-frequency voluntary blood donors (≥8 donations in past 2 years) and 42 low-frequency blood donors (1 to 2 donations in past 2 years) aged 50 to 75 years were randomly selected from American Red Cross of Connecticut blood donor records. Flow-mediated dilation in the brachial artery, serum markers of iron stores, vascular inflammation and oxidative stress, and cardiac risk factors were assessed in all subjects. Serum ferritin was significantly decreased in high-frequency blood donors when compared with low-frequency blood donors (median values 17 versus 52 ng/mL..., but hematocrit did not differ between groups. Flow-mediated dilation in the brachial artery was significantly greater in high-frequency donors when compared with low-frequency donors in univariate analysis... and in multivariate analysis adjusting for cardiac risk factors and other potential confounders. The researchers concluded, "High-frequency blood donors had evidence of decreased body iron stores, decreased oxidative stress, and enhanced vascular function when compared with low-frequency donors. These findings support a potential link between blood donation and reduced cardiovascular risk that warrants further investigation in prospective outcome studies." [Health-e-Iron note: Table 2 and Model 1 from this study appear below]
Model 1. Estimates of differences in flow-mediated dilation (absolute difference in units of % with 95% confidence intervals shown) between high-frequency blood donors and low-frequency blood donors for all subjects and in subgroups defined by median age in years, gender, presence of hyperlipidemia, use of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) and median C-reactive protein (CRP) levels in mg/dL.
Low iron status and enhanced insulin sensitivity in lacto-ovo vegetarians (24) Free full text
In this 2001-reported study form California, the investigators reported, "the efficacy of insulin in stimulating whole-body glucose disposal (insulin sensitivity) was quantified using direct methodology in thirty lacto-ovo vegetarians and in thirty meat-eaters. All subjects were adult, lean (BMI <23 kg/m2), healthy and glucose tolerant. Lacto-ovo vegetarians were more insulin sensitive than meat-eaters, with a steady-state plasma glucose (mmol/l) of 4.1 (95 % CI 3.5, 5.0) v. 6.9 (95 % CI 5.2, 7.5; respectively. In addition, lacto-ovo vegetarians had lower body Fe stores, as indicated by a serum ferritin concentration (microg/l) of 35 (95 % CI 21, 49) compared with 72 (95 % CI 45, 100) for meat-eaters. To test whether or not Fe status might modulate insulin sensitivity, body Fe was lowered by phlebotomy in six male meat-eaters to levels similar to that seen in vegetarians, with a resultant approximately 40 % enhancement of insulin-mediated glucose disposal. Our results demonstrate that lacto-ovo vegetarians are more insulin sensitive and have lower Fe stores than meat-eaters. In addition, it seems that reduced insulin sensitivity in meat-eaters is amenable to improvement by reducing body Fe." The investigators concluded,"The latter finding is in agreement with results from animal studies where, no matter how induced, Fe depletion consistently enhanced glucose disposal." [Health-e-Iron note: Figures 1 & 2 from this study are below]
Effect of iron depletion in carbohydrate-intolerant patients with clinical evidence of nonalcoholic fatty liver disease (25) Free full text
In this 2002 study, body iron stores were measured in 42 carbohydrate-intolerant patients (without hemochromatosis genotypes) with nonalcoholic fatty liver disease (NAFLD) and a serum iron saturation lower than 50%. Seventeen patient with higher than normal body iron stores were phlebotomized to bring their iron stores to a level of "near-iron deficiency (NID)." "...at NID, there was a 40%-55% improvement (P = 0.05-0.0001) of both fasting and glucose-stimulated plasma insulin concentrations, and near-normalization of serum alanine aminotransferase activity (from 61 +/- 5 to 32 +/- 2 IU/L; P < 0.001). The researchers concluded, "These results reflect the insulin-sparing effect of iron depletion and indicate a key role of iron and hyperinsulinemia in the pathogenesis of NAFLD." [Health-e-Iron note: Tables #1, 2, and 3 from this study are available below along with Figures #2, 3 and 5]
Iron metabolism in Nonalcoholic Fatty Liver Disease (26)
In this 2012 paper this team of investigators, who are highly experienced in iron reduction, reported the following: "Non-Alcoholic Fatty Liver Disease (NAFLD) is a common worldwide clinical and major public health problem affecting both adults and children in developed nations. Increased hepatic iron stores are observed in about one-third of adult NAFLD patients. Iron deposition may occur in parenchymal and/or non-parenchymal cells of the reticuloendothelial system (RES). Similar patterns of iron deposition have been associated with increased severity of other chronic liver diseases including HCV infection and dysmetabolic iron overload, suggesting there may be a common mechanism for hepatic iron deposition in these diseases. In NAFLD, iron may potentiate the onset and progression of disease by increasing oxidative stress and altering insulin signaling and lipid metabolism. The impact of iron in these processes may depend upon the sub-cellular location of iron deposition in hepatocytes or RES cells. Iron depletion therapy has shown efficacy at reducing serum aminotransferase levels and improving insulin sensitivity in subjects with NAFLD."
Venesection therapy of insulin resistance-associated hepatic iron overload (27)
The researchers in this 2001 study reiterated, "The association of hepatic iron overload with metabolic disorders has been coined as the insulin resistance-associated hepatic iron overload syndrome (IR-HIO). "Fifty-six IR-HIO patients were phlebotomized either weekly (n = 14) or bimonthly (n = 42) and compared with C282Y homozygotes (Classic hemochromatosis genotype) and with ten IR-HIO patients treated by a low calorie diet alone." "When compared with C282Y homozygotes, IR-HIO patients had a similar amount of mobilized iron, but three-fold serum ferritin levels. The presenting symptoms (chronic fatigue and/or polyarthralgias) improved in 6/7 patients. Phlebotomies were well tolerated. In patients treated by a low calorie diet, serum ferritin levels remained stable. Mean serum ferritin levels were 519 ng/dL prior to phlebotomy and dropped to 80.5 ng/mL after treatments. The researcher concluded, "In IR-HIO patients, body iron stores are significantly increased, overestimated by serum ferritin, not modified by a low calorie diet, and safely removed by phlebotomies. Based on these data and on studies indicating that iron excess is associated with increased risk for hepatic fibrosis, cancer and cardiovascular disorders, venesection therapy can be recommended in IR-HIO patients."
Effects of venesections and restricted diet in patients with the insulin-resistance hepatic iron overload syndrome (28)
In 2004, this Italian research group, "evaluated the effect of venesections (phlebotomy) and restricted diet on iron and metabolic indices and liver function tests in patients with insulin-resistance hepatic iron overload (IR-HIO)." Patients were divided in three groups: patients without phlebotomy therapy, patients phlebotomized, and patients on dietary treatment. Patients were followed up for approximately 3 years. "In each group baseline and end-point levels of serum iron and metabolic indices, and liver function tests were compared..." "In the follow-up group, iron and metabolic indices did not change over time. Serum alanine aminotransferase, gamma-glutamyl transferase, cholesterol and triglycerides significantly decreased after iron depletion. Serum glucose, cholesterol, triglyceride, ferritin and liver function tests significantly decreased after dietary treatment. Transferrin saturation decreased below 20% during phlebotomy treatment in 52% of the patients." The researchers concluded, "our results show that IR-HIO patients had relatively low amount of iron overload that seems not to increase even after a long follow-up period. Both venesections and diet improved iron, metabolic and hepatic indices. Data suggest a relationship between hepatic iron overload and insulin resistance, and a role for both iron overload and insulin resistance in hepatocellular damage."
Diagnostic and therapeutic implications of the association between ferritin level and severity of nonalcoholic fatty liver disease (29) Free full text
The researchers who published this review in 2012 noted that, "Evidence has shown that increased ferritin levels are associated with the metabolic insulin resistance syndrome, and higher hepatic iron and fat content. Hyperferritinemia and iron stores have been associated with the severity of liver damage in NAFLD, and iron depletion reduced insulin resistance and liver enzymes." "Recently, Kowdley et al (see next paper below) demonstrated in a multicenter study in 628 adult patients with NAFLD from the NAFLD-clinical research network database with central re-evaluation of liver histology and iron staining that the increased serum ferritin level is an independent predictor of liver damage in patients with NAFLD, and is useful to identify NAFLD patients at risk of non-alcoholic steatohepatitis and advanced fibrosis. These data indicate that incorporation of serum ferritin level may improve the performance of noninvasive scoring of liver damage in patients with NAFLD, and that iron depletion still represents an attractive therapeutic target to prevent the progression of liver damage in these patients." "...the accumulated available evidence allows to validate the effect of iron depletion on the prevention of hepatic, metabolic and cardiovascular complications of NAFLD." [Health-e-Iron note:Figure 1 from this study is below]
Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease (30) Free full text
In this 2012 research from the U.S., the researchers noted, "Serum ferritin (SF) levels are commonly elevated in patients with nonalcoholic fatty liver disease (NAFLD) because of systemic inflammation, increased iron stores, or both. The aim of this study was to examine the relationship between elevated SF and NAFLD severity. Demographic, clinical, histologic, laboratory, and anthropometric data were analyzed in 628 adult patients with NAFLD (age, ≥ 18 years) with biopsy-proven NAFLD and an SF measurement within 6 months of their liver biopsy. A threshold SF >1.5 × upper limit of normal (ULN) (i.e., >300 ng/mL in women and >450 ng/mL in men) was significantly associated with male sex, elevated serum alanine aminotransferase, aspartate aminotransferase, iron, transferrin-iron saturation, iron stain grade, and decreased platelets (P < 0.01). Histologic features of NAFLD were more severe among patients with SF >1.5 × ULN, including steatosis, fibrosis, hepatocellular ballooning, and diagnosis of NASH (P < 0.026). On multiple regression analysis, SF >1.5 × ULN was independently associated with advanced hepatic fibrosis (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.05-2.62; P = 0.028) and increased NAFLD Activity Score (NAS) (OR, 1.99; 95% CI, 1.06-3.75; P = 0.033). CONCLUSIONS: A SF >1.5 × ULN is associated with hepatic iron deposition, a diagnosis of NASH, and worsened histologic activity and is an independent predictor of advanced hepatic fibrosis among patients with NAFLD. Furthermore, elevated SF is independently associated with higher NAS, even among patients without hepatic iron deposition. We conclude that SF is useful to identify NAFLD patients at risk for NASH and advanced fibrosis." " We suggest that SF, an inexpensive convenient clinical test, should be included in the laboratory evaluation of NAFLD patients." [Health-e-Iron note: Tables 1 and 2 from this study appear below]
A Low-Iron-Available, Polyphenol-Enriched, Carbohydrate-Restricted Diet to Slow Progression of Diabetic Nephropathy (31) Free full text
This 2003 reported research was preformed at the University of California-San Francisco. The researchers noted, "The present investigation was initiated to evaluate whether a carbohydrate-restricted, low-iron-available, polyphenol-enriched (CR-LIPE) diet may delay and improve the outcome of diabetic nephropathy to a greater extent than standard protein restriction." "To this aim, 191 diabetic patients, all with type 2 diabetes, were randomized to either CR-LIPE or standard protein restriction and the following outcomes monitored: doubling of serum creatinine, cumulative incidence of end-stage renal disease, and all cause mortality. Over a mean follow-up interval of 3.9 +/- 1.8 years, serum creatinine concentration doubled in 19 patients on CR-LIPE (21%) and in 31 control subjects (39%) (P < 0.01). Renal replacement therapy or death occurred in 18 patients on CR-LIPE (20%) and in 31 control subjects (39%) (P < 0.01). These differences were independent from follow-up interval, sex, mean arterial blood pressure, HbA(1c), initial renal dysfunction, and angiotensin system inhibitor use. In conclusion, CR-LIPE was 40-50% more effective than standard protein restriction in improving renal and overall survival rates." [Health-e-Iron note: Chart C from this study's Figure 1 appears below. Note the significant reduction in serum ferritin achieved by a low-iron diet with iron absorption inhibitors.]
FIG. 1. Longitudinal changes of mean ... serum ferritin (C) [Red line = Protein restricted diet; Blue line = Low-iron- available, polyphenol-enriched diet.
Effect of iron depletion on cardiovascular risk factors: studies in carbohydrateintolerant patients (32)
This 2002 study reported on iron reduction be phlebotomy on 31 carbohydrate-intolerant subjects with atherosclerosis. Iron levels were reduced to near-deficiency levels. "...a significant increase of HDL-cholesterol (p < 0.001) and reductions of blood pressure (p < 0.001), total and LDL-cholesterol (p < 0.001), triglyceride (p < 0.001), fibrinogen (p < 0.001) and glucose and insulin responses to oral glucose loading (p < 0.001) were noted, while homocysteine plasma concentration remained unchanged. These effects were largely reversed by a 6-month period of Fe repletion with reinstitution of Fe sufficiency." The researchers concluded, "...although individuals at high risk for ASCVD (atherosclerosis) are not Fe (iron) -overloaded, they seem to benefit, metabolically and hemodynamically, from lowering of body Fe (iron) to levels commonly seen in premenopausal females."
High iron stores and the relationship between metabolic syndrome and proteinuria (33) Free full text
Dr. Jerome Sullivan and colleagues wrote the following in a letter to the editor regarding metabolic syndrome research reported in Japan. "Miyatake and colleagues found a close relation between metabolic syndrome and proteinuria in a Japanese population. We suggest that elevated body iron stores may have a role in this synergistic pathological association. Serum ferritin, a good indicator of iron stored in the body, has been reported to correlate both with components of metabolic syndrome and overt proteinuria. The elevated levels of serum ferritin in patients with overt proteinuria could not be explained as an acute phase response. On the other hand, withdrawal of red meat (a rich source of heme iron) from the usual diet has been shown to reduce the urinary albumin excretion rate in patients with type 2 diabetes and proteinuria. Moreover, induction of near iron deficiency in carbohydrate intolerant subjects has been shown to improve insulin sensitivity and other cardiac risk factors. Another intervention study in type 2 diabetic patients with elevated ferritin levels demonstrated that even a lesser degree of iron removal by blood letting, resulting in 50% reduction of serum ferritin concentrations, improved glycemia, insulin sensitivity and vascular dysfunction. High iron stores should be considered as an adjunctive risk factor for the development of proteinuria in individuals with metabolic syndrome. Induction and maintenance of a state of iron depletion should be evaluated as a practical modality in the treatment of metabolic syndrome."
Near-iron deficiency-induced remission of gouty arthritis (34) Free full text
The investigator in this 2003 study noted that, "previous evidence supports a role of iron in the pathogenesis of gout." "The objective of the present study was to investigate whether or not iron removal may improve the outcome of gouty arthritis in humans..." Mean ferritin levels at baseline were 301 ng/mL ± 98 in 12 patients. Mean ferritin was reduced to 26 ng/mL ± 10 by quantitative phlebotomy. All patients were hyperuricaemic with gouty arthritis. The protocol was aimed at maintaining body iron at near-iron deficiency (NID) levels (i.e. the lowest body iron store compatible with normal erythropoiesis and therefore absence of anaemia)." "During maintenance of NID for 28 months, gouty attacks markedly diminished in every patient, from a cumulative amount of 48 and 53 attacks per year before (year -2, -1), to 32, 11 and 7 during induction (year 0) and maintenance (year +1, +2) of NID, respectively. During NID, attacks were also more often of milder severity." The investigator concluded, "During a 28-month follow-up, maintenance of NID was found to be safe and beneficial in all patients, with effects ranging from a complete remission to a marked reduction of incidence and severity of gouty attacks." [Health-e-Iron note: Table 1 and Figures 1 & 2 from this study are below]
Comment on: Gout: an independent risk factor for all-cause and cardiovascular mortality (35) Free full text
This was a 2010 commentary on a study identifying the association of Gout with for all-cause and cardiovascular mortality independent of age, gender, metabolic syndrome and proteinuria. That abstract and the link to its full text paper to which this commentary was directed can be accessed here. The authors of this commentary suggest, based on several lines of evidence, that gout is a disease of iron overload. Among several papers making the association of gout with cardiovascular disease and mortality, the authors cite the iron-reduction trial described in the study noted above. The authors concluded, "Therefore, iron may represent an important biological link between gout and cardiovascular disease."
Remission of paroxysmal atrial fibrillation with iron reduction in haemophilia A (36)
In this 2010 study, "Two male first cousins with mild haemophilia A had baseline factor VIII levels of 12-15% and experienced bleeding requiring coagulation factor infusion therapy with trauma and surgical procedures. Both the patients with haemophilia A also had electrocardiographically documented symptomatic paroxysmal atrial fibrillation (PAF) for several years that had become resistant to pharmacological suppression." The investigators that, "Remission of arrhythmias has been reported in patients with iron-overload syndromes." "Calibrated reduction of iron stores by serial phlebotomy, avoiding iron deficiency, was followed by remission of symptomatic PAF in both cases." The authors concluded, "Iron reduction may be an effective treatment for arrhythmias apart from the classic iron-overload syndromes and deserves further study particularly in patients with bleeding disorders who might be at risk for arrhythmias and other diseases of ageing."
Back to past leeches: repeated phlebotomies and cardiovascular risk (37) Free full text
This 2012 review from Italy first notes, "In patients with metabolic syndrome, body iron overload exacerbates insulin resistance, impairment of glucose metabolism, endothelium dysfunction and coronary artery responses. Conversely, iron depletion is effective to ameliorate glucose metabolism and dysfunctional endothelium. Most of its effectiveness seems to occur through the amelioration of systemic and hepatic insulin resistance." The authors describe the study directly below and the finding relative to hypertension in the context of the existing body of knowledge. They note that, "Michalsen et al. (see above study #7) demonstrated a dramatic improvement of blood pressure, serum glucose and lipids after removing 550 to 800 ml of blood in subjects with metabolic syndrome. This effect was apparently independent of changes in insulin resistance, in contrast to previous cross-sectional and cohort studies investigating the association between iron overload, insulin resistance and cardiovascular disease." "Despite drawbacks in the study design, its findings may lead the way to investigations aimed at exploring iron-dependent regulatory mechanisms of vascular tone in healthy individuals and patients with metabolic disease, thus providing a rationale for novel preventive and therapeutic strategies to counteract hypertension." "In conclusion, findings from Michalsen’s study give
new perspectives for prevention and treatment of the metabolic syndrome demonstrating that repeated phlebotomies, a low-cost and minimally invasive technique, are effective in reducing blood pressure with a mechanism that is independent of insulin resistance. Routine phlebotomies in these patients may enormously reduce health care costs related to the epidemic metabolic syndrome and, importantly, also contribute to increase the rate of blood donations."
Iron restriction improves type 2 diabetes mellitus in Otsuka Long-Evans Tokushima fatty rats (38) Free full text
This was a 2010 study of lab rats reported in Japan. The researchers, "...examined the effect of iron depletion in a model of type 2 diabetes, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Age-matched Long-Evans Tokushima Otsuka (LETO) rats were used as controls for all experiments. Iron restriction was performed by eliminating iron in the diet from 15 wk of age or by phlebotomy. Phlebotomy was commenced at 29 wk of age by removing 4 and 3 ml of blood from the tail vein every week in OLETF and LETO rats, respectively." "The plasma ferritin concentration was markedly higher in OLETF rats and decreased in iron-deficient (ID) diet and phlebotomy rats. Hemoglobin A(1c) (Hb A(1c)) was decreased significantly in OLETF rats fed the ID diet and in the phlebotomy group. Increased levels of triglycerides, glucose, free fatty acids, and total cholesterol were found in ID OLETF rats. Plasma, liver, and pancreas lipid peroxidation and hepatic superoxide production decreased in both groups. Pancreatic fibrosis and insulin levels improved in both groups of OLETF rats. Pancreatic levels of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) ligands and hypoxia-inducible factor (HIF)-1alpha were decreased significantly in OLETF rats. These factors were normalized in both rats fed ID and phlebotomy groups of OLETF rats. In conclusion, iron depletion improved diabetic complications by inhibition of oxidative stress and TGFbeta signal pathways and the maintenance of pancreatic PPARbeta/delta and HIF-1alpha pathways.
Donation of blood is associated with reduced risk of myocardial infarction. The Kuopio Ischaemic Heart Disease Risk Factor Study (39) Free full text
This research from Finland was reported in 1998. "Because high body iron stores have been suggested as a risk factor for acute myocardial infarction, donation of blood could theoretically reduce the risk by lowering body iron stores. For this reason, the authors tested the hypothesis that voluntary blood donation is associated with reduced risk of acute myocardial infarction in a prospective epidemiologic follow-up study in men from eastern Finland. The subjects are all participants of the Kuopio Ischaemic Heart Disease Risk Factor Study. A cohort of 2,862 men aged 42-60 years were followed for an average of almost 9 years. One man (0.7%) out of 153 men who had donated blood in 24 months preceding the baseline examination experienced an acute myocardial infarction during 1984 to 1995, whereas 316 men (12.5%) of 2,529 non-blood donors had an acute myocardial infarction (p < 0.0001 for difference between proportions). In a Cox proportional hazards model adjusting for age, examination years and all other predictive coronary disease risk factors, blood donors had a 88% reduced risk (relative hazard = 0.12, 95% confidence interval 0.02-0.86, p = 0.035) of acute myocardial infarction, compared with non-blood donors. The researchers concluded, "These findings suggest that frequent blood loss through voluntary blood donations may be associated with a reduced risk of acute myocardial infarction in middle-aged men." [Health-e-Iron note: Tables 1 - 4 from this paper are below]
Iron stores, liver transaminase levels and metabolic risk in healthy teenagers (40)
Thia Austrian study was published in 2010. The investigators noted, "Iron overload may contribute to the pathogenesis of insulin resistance. We aimed to investigate the relationship among iron stores, liver transaminases and components of the metabolic syndrome in healthy teenagers in a cross-sectional study." "We determined body mass index (BMI), waist-to-hip-ratio (WHR), blood pressure, liver ultrasound, serum lipids, insulin, fasting glucose, liver transaminase levels, hsCRP, iron parameters in 325 of 341 (95.3%) students (234 men, 16.7 +/- 1.7 years; 91 women, 16.5 +/- 1.7 years) of one single high school." "In male students, BMI, WHR, systolic and diastolic blood pressure, serum triglyceride levels and hsCRP were higher in the top sTfR/ferritin and ALT quartiles compared with the lowest quartiles (P < 0.01 for all parameters). In female students, sTfR/ferritin were not associated with antropomorphic cardiometabolic risk factors but with insulin resistance (HOMA-IR, P = 0.046). Moreover, ALT levels were independently related to BMI, waist and hip circumference, systolic blood pressure, serum triglyceride and insulin concentrations (P < 0.05 for all parameters) in female students." The investigators concluded, "These results provide evidence for linkage among body iron stores, transaminase activity and the prevalence of cardiometabolic risk factors in apparently healthy, non-obese adolescents even within the range of normal laboratory and anthropomorphic values and suggest that iron stores should be investigated as a potentially modifiable risk factor in healthy teenagers."