Iron loading in humans: A risk factor for enhanced morbidity and mortality

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DOI: 10.1080/13590840601167685
Cite this publication
Abstract
Purpose. To develop an overview of the kinds of disease that can be exacerbated by excessive/misplaced iron; to briefly consider mortality data on iron‐loaded persons; and to summarize methods for the prevention and therapy of iron loading. Design. Literature review. Materials and methods. A survey of clinical and research medical journals of the past decade was carried out. The diseases were categorized by medical specialty and by currently proposed types of iron association. Results. A remarkably diverse assemblage of diseases have been reported to be associated with and/or exacerbated by excessive or misplaced iron in specific tissue sites. Reduced longevity was associated with iron loading in two studies, but not in a third. Behavioral factors, as well as genetic modifiers, have been described that can result in an increase in inhaled, ingested and injected iron. Conclusions. Our present knowledge strongly indicates that methods for the reduction of iron loading could contribute considerably to the improved health and longevity of human populations.
ORIGINAL ARTICLE
Iron loading in humans: A risk factor for enhanced
morbidity and mortality
E. D. WEINBERG, PhD
Department of Biology and Program in Medical Sciences, Indiana University, Bloomington, IN 47405,
USA
Abstract
Purpose. To develop an overview of the kinds of disease that can be exacerbated by excessive/
misplaced iron; to briefly consider mortality data on iron-loaded persons; and to summarize methods
for the prevention and therapy of iron loading.
Design. Literature review.
Materials and methods. A survey of clinical and research medical journals of the past decade was
carried out. The diseases were categorized by medical specialty and by currently proposed types of
iron association.
Results. A remarkably diverse assemblage of diseases have been reported to be associated with
and/or exacerbated by excessive or misplaced iron in specific tissue sites. Reduced longevity was
associated with iron loading in two studies, but not in a third. Behavioral factors, as well as
genetic modifiers, have been described that can result in an increase in inhaled, ingested and
injected iron.
Conclusions. Our present knowledge strongly indicates that methods for the reduction of iron loading
could contribute considerably to the improved health and longevity of human populations.
Key words: Inhaled iron, iron-associated diseases, iron chelation, iron-enhanced morbidity, iron-
enhanced mortality, iron loading
Introduction
Excessive iron in specific tissue sites promotes infection and neoplasia. Moreover, elevated
iron is also a risk factor for cardiomyopathy, arthropathy, and an array of endocrine,
neurodegenerative and other chronic diseases. The metal, which cannot substantially be
excreted, is hazardous in several ways. Non-protein-bound ferric ions are reduced by
superoxide and the ferrous product is reoxidized by peroxide to regenerate ferric ions and
yield hydroxyl radicals. The latter attack all classes of macromolecules. Hydroxyl radicals
can depolymerize polysaccharides, inactivate enzymes, initiate lipid peroxidation and, not
least, cause DNA strand breaks [1].
Correspondence: E. D. Weinberg, Biology Department, Indiana University, Bloomington, IN 47405, USA. Email: eweinber@
indiana.edu
Journal of Nutritional & Environmental Medicine
February 2007; 16(1): 43–51
ISSN 1359-0847 print/ISSN 1364-6907 online #2007 Informa UK Ltd
DOI: 10.1080/13590840601167685
Furthermore, overabundant iron can serve as a readily available nutrient for invading
neoplastic cells, as well as for bacterial, fungal and protozoan pathogens. Even microbial
strains that are usually not dangerous can cause disease when present in iron-loaded tissues,
fluids or cells [2]. Vertebrate hosts maintain an iron-withholding defense system [3]
designed to prevent the accumulation of non-protein-bound (free) iron in sensitive sites
and to sequester the metal in innocuous packages in ferritin. However, numerous
behavioral factors and genetic modifiers can result in contravention of the iron-withholding
defense system.
Method
A survey of clinical and medical research journals of the past decade was carried out. The
diseases were categorized by medical specialty and by currently proposed types of iron
association.
Iron enhances morbidity
In Table I, iron-associated diseases are grouped by medical specialty. As is evident,
the iron-loaded patient might be diagnosed and treated not only by the family practitioner
but also by a considerable variety of medical specialists. Possible mechanisms whereby
excessive or misplaced iron can initiate or exacerbate a disease are summarized in
Table II.
Diseases can often be subdivided with regard to the initiating condition. For instance,
among established causes of osteoporosis are deficiencies in vitamin D, ascorbic acid or
calcium; hyperparathyroidism; or prolonged therapy with thyroid hormone or steroids [4].
Recently, an additional cause has become well documented, i.e. iron loading. In animal
models and in human patients, iron per se can, by specifically suppressing osteoblast
formation, cause osteoporosis in the absence of the conditions listed above [5]. Indeed the
term ‘siderotic osteoporosis’ might be an appropriate designation. Similarly, the adjective
‘siderotic’ might be applied to a subset of such other diseases as cardiomyopathy and
growth deficiency when, in specific cases, iron is established to be the sole initiator.
Iron enhances mortality
Three studies have presented data on mortality rate in untreated iron-loaded persons.
In one, the percentage of C282Y heterozygote hemochromatotic carriers in a Danish
population of 376 women decreased from 19.5 to 9.9% between age 45 and 74 years;
in 363 men from 12.4 to 8.1% (Table III) [38]. Some, but not all, carriers tend
to acquire excess iron [39]. Unfortunately, in this study, body iron levels were not
ascertained.
In another study [40], in a set of 10,714 US adults, 2.3% had transferrin iron saturation
(Tfsat%) values .55%. During the subsequent 22 years, the rate of mortality of the iron-
loaded group was accelerated (Table IV). Except for a higher amount of diabetes and
hepatic cirrhosis in persons with Tfsat% .55%, the causes of death were similar to those
with Tfsat% ,55%.
In a different study of 41,038 US adults, which included 152 C282Y homozygotes,
selective loss of the latter as the population aged was not observed [41].
44 E. D. Weinberg
Behavioral and genetic factors can increase body iron burden
Examples of behavioral and genetic factors that can enhance body iron loading are listed in
Tables V and VI. Among patients who have a particular factor, there is much variation in
specific tissue sites of iron deposition. Moreover, combinations of factors can result in
synergistic rather than merely additive damage.
Table I. Examples of diseases for which excessive/misplaced iron can be a risk factor.
Cardiovascular
atherosclerosis
cardiomyopathy
hypertension
Dermal
porphyria cutanea tarda
Endocrine
diabetes
growth deficiency
hypogonadism
hypothyroidism
Gastrointestinal
colorectal cancer
Hepatic
cirrhosis
hepatoma
steatohepatitis
viral hepatitis
Infectious
microbial infections of all body systems
Neurologic
ALS
Alzheimer’s
depression
Friedreich’s ataxia
Huntington’s
multiple sclerosis
PKAN
Obstetric
neonatal hemochromatosis
pre-eclampsia
Ophthalmic
macular degeneration
Orthopedic
gout
hemophilic synovitis
osteoarthritis
osteoporosis
Otologic and Renal
aminoglycoside toxicity
Pediatric & Neonatal
Down syndrome
epilepsy
sudden infant death
Pulmonary
cystic fibrosis
lung cancer
pneumoconiosis
Iron-associated morbidity and mortality 45
For example, in a group of 3410 US adults, 27.3% had serum levels of low-density
lipoprotein (LDL) .160 mg dl
21
and 1.64% had Tfsat% .55% [42]. If only LDL or
Tfsat% was elevated, the relative risk of dying with atherosclerosis was 1.4 or 1.57,
respectively. However, if both factors were high, the relative risk was 5.21. An animal
model has confirmed this observation. Rabbits with both hypercholesterolemia and an
Table II. Examples of mechanisms of iron-associated disease.
Iron, by itself, has been observed to initiate:
cardiomyopathy [6]
growth deficiency [7]
hemophilic synovitis [8]
hypogonadism [9]
lung cancer [10]
osteoporosis [5]
pneumoconiosis [11]
Iron can be a cofactor in promoting:
Alzheimer’s disease [12]
bacterial infections [13]
diabetes [14]
fungal infections [15]
gout [16]
hepatoma [17]
multiple sclerosis [18]
protozoan infections [15]
osteoarthritis [19]
oto- and renal toxicity [20]
Iron deposits are observed in disease-associated tissue sites:
basal ganglia in Hallervorden–Spatz (PKAN) disease [21]
hepatocytes in viral- and steato-hepatitis [22,23]
retina in macular degeneration [24]
mitochondria in Friedreich’s ataxia [25]
pulmonary secretions in cystic fibrosis [26]
substantia nigra in Parkinson’s disease [27]
Body iron loading is associated with above-normal incidence of:
amyotrophic lateral sclerosis [28]
atherosclerosis [29]
colorectal cancer [30]
Down syndrome [31]
epilepsy [32]
hypertension [33]
pre-eclampsia [34]
porphyria cutanea tarda [35]
sudden infant death syndrome [36]
Maternal antibodies can impair fetal iron metabolism
fetal or neonatal death in neonatal hemochromatosis [37]
Table III. Decline in frequency of C282Y carriers with age.
45–54 years 55–64 years 65–74 years
Number %C282Y Number %C282Y Number %C282Y
Women 200 19.5 85 17.6 91 9.9
Men 161 12.4 91 8.8 111 8.1
Data from Table 2 in [38].
46 E. D. Weinberg
elevated iron level had significantly more aortic atherosclerosis than rabbits that were above
normal in either one of the two factors [43].
Nevertheless, in patients with a common cause of iron loading, i.e. hemochromatosis, the
incidence of atherosclerosis uniquely is not raised [44]. A possible reason for this anomaly
Table IV. Enhanced mortality associated with elevated transferrin iron saturation (Tfsat).
Time (years) after initial transferrin test
Mortality (%)
Tfsat ,55% Tfsat .55%
225
4 3.5 6
6 5.5 13
8816
10 10 19
12 13 24
14 16 27
16 20 32
18 23 33
20 25.5 34
22 26.5 36
The initial population was comprised of American adults aged 24–74 years: 10,468 had Tfsat ,55%; 246 had
Tfsat .55%. Data from Figure 1 in [40].
Table V. Behavioral factors that enhance body iron loading.
Inhalation
Mining: iron; iron-contaminated coal or sand; iron silicates in amosite, crocidolite or tremolite asbestos
Processing: steel grinding or polishing; asbestos in building materials
Painting: iron silicate in tremolite
Smoking: iron-contaminated tobacco smoke
Urban habitation: iron-contaminated urban and subway air particulates
Ingestion
Iron additives in processed foods
Iron supplements
Heme iron in red meats
Ascorbic acid supplements consumed with iron-containing items
Ethanol consumed with iron-containing items
Injection
Iron saccharates
Erythrocytes or whole blood
Table VI. Examples of genetic disorders associated with body iron loading.
Enhancement of intestinal absorption of ingested iron
Aceruloplasminemia
African siderosis
Juvenile or adult hemochromatosis
Thalassemia
Requirement for periodic blood transfusions
Myelodysplasia
Sicklemia
Thalassemia
Iron-associated morbidity and mortality 47
is that, in this specific iron disorder, macrophage iron remains low, apparently due to a lack
of hepcidin. For the development of atherosclerosis, iron-rich macrophages are considered
to be important components [45].
The oxidative role of iron in lipid peroxidation may be critical, not only in the
development of atherosclerosis, but also in such neurodegenerative conditions as
Alzheimer’s disease [27]. Oxidized LDL induces neuronal cell death [46]. In a group of
6558 US adults aged .40 years, followed for 20 years, the relative risk of developing
Alzheimer’s disease when both total cholesterol and Tfsat% were at the 75th percentile was
3.19 [47]. When only one of the factors was elevated, there was no increased risk for
Alzheimer’s disease.
Prevention of iron loading
All persons, not only those with mutations that enhance body iron loading, should
minimize as much as possible the behavioral factors listed in Table V. Industrial workers
exposed to airborne iron should be advised to wear masks. Their on-the-job clothing should
be carefully laundered to prevent their families or laundry workers from being exposed to
iron dust. Home owners should be warned against applying tremolite paint to the inner and
outer walls of their houses [48]. Curtailment of active and passive inhalation of tobacco
smoke is essential for the prevention of iron toxicity to respiratory tract tissue [10].
Persons whose diets include high amounts of non-heme iron can lower the quantity
absorbed by concurrent consumption of the natural phenolic iron chelators in tea [49] and
of phytates in whole grains [50]. A reduction in heme iron intake can be achieved by
lowering the ingestion of red meat [50]. Men of all ages, as well as post-menopausal
women, should consider periodic donations of blood; each unit drawn results in a reduction
in the iron burden of 250 mg [51].
An increasingly large number of clinical reports on the hazards of iron loading continue
to emphasize the necessity of including the Tfsat% level in routine biochemical profiles of
adults of all ages. Individuals with high iron values should be counseled to take prompt
action. Just as persons predisposed to hypertension or hypercholesterolemia are urged to
take hypotensive or cholesterol-lowering drugs, respectively, while their cardiovascular
system has not yet become damaged, so must hyperferremic persons be urged to lower their
iron burden while their general health has not yet been compromised.
Therapy of iron loading
In hemochromatosis, hemoglobin is normal; thus blood transfusions are not required and
iron loading can be treated appropriately by phlebotomies. In contrast, in hemoglobino-
pathies, such as thalassemia and sicklemia, as well as in myelodysplasia, specific iron-
chelating drugs must be administered to reduce the transfusion-associated iron burden.
Presently in most countries, subcutaneous deferoxamine (DF), oral deferiprone (DP) and
their combinations are the established iron-chelating drugs [52]. A combination of DP
during the day and DF at least three nights per week can achieve a negative iron balance
and the clearance of cardiac iron.
A more recently developed oral iron chelator, deferasirox, is in clinical trials. Combinations
of DF or DP with deferasirox may be necessary to increase the ability of the latter to maintain a
negative iron balance and cardiac iron clearance [52]. Among other iron chelators in
preliminary stages of development are deferitrin, L1NA11, and starch DF polymers.
48 E. D. Weinberg
Two natural product protein iron chelators, transferrin and lactoferrin, are becoming
available for therapy of iron loading at specific sites. Transferrin has been extracted from
human serum, de-ironed and purified [53]. The product is employed in conditions in
which iron saturation of the patient’s transferrin has become highly elevated. Moreover, in
pre-term infants, such oxygen radical injury as retinopathy and bronchopulmonary
dysplasia might be alleviated by the injection of apotransferrin [54].
Recombinant human lactoferrin is produced in molds as well as in cells of plants and
animals [55]. Another source of the protein is bovine lactoferrin extracted from cow’s milk.
Lactoferrin is being tested/employed in a considerable diversity of nutraceutical,
preservative and pharmaceutical applications. In most, but not all, the mechanism of
action of lactoferrin is considered to be that of iron chelation.
Acknowledgment
This review is dedicated to Gu¨ nter Weiss, MD, in recognition of his fundamental research
on the anemia of chronic disease.
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Iron-associated morbidity and mortality 51
  • ... Actualmente, el hierro por sí mismo, puede iniciar o ser un decisivo cofactor para el desarrollo de enfermedad (24,25). Por ejemplo, inclusive en presencia de reservas normales de hierro, una simple ingestión exógena de hierro incrementa el riesgo de infección (26,24), y ello, concretamente, por aumentar la Resistencia a la Insulina,el evento hormonal predictor de Enfermedad Crónica-, y por ser un poderoso activador del factor NFkB, cuya señalización se reconoce cada vez más como decisiva en la promoción de tumorigénesis: el NFkB es un poderoso factor que confiere resistencia para la muerte programada de la célula tumoral; es decir, es un potente Anti-apoptótico , confiriendo supervivencia a la célula neoplásica y promoviendo su poder metastásico (27). ...
    Research
    Full-text available
    Iron is physiologically essential for life but biochemically dangerous. Chronic accumulation of iron causes pantropic organ damage and excess body iron play an important role in carcinogenesis, coronary artery disease, neurodegenerative disease, stroke. and inflammatory disorders. Iron is very slowly excreted from humans once it is absorbed into the body. The significance of iron excess has been markedly underestimated, despite the fact that iron overloading disorders are as common place in the US white population (Conrad, 2002). Iron-overload and catalytic iron promotes activation of oxidative responsive transcription factors and pro-inflammatory cytokines that increase cancer extension and aggravate them. There is accumulative evidence for iron as a carcinogenic metal in epidemiological, clinical, animal, and cell culture studies. The role of iron in various cancers, such as colorectal and liver cancer was demonstrated. Recent advancements on the molecular mechanisms of iron carcinogenesis evolved the Insulin-resistance generation and promotion, fisiopatologic condition that is not only permissive, but may be generated cancer and promoting it. Unlike other nutritional metals, iron is highly conserved: toxicity due to excess iron can occur either acutely after a single dose or chronically due to excessive accumulation in the body from diet. In vivo studies have demonstrated that an iron deficiency induced by either feeding a low iron diet injecting the iron chelator deferoxamine mesylate decreases tumor growth (Wang F, Elliott RL, Head JF: Inhibitory effect of deferoxamine mesylate and low iron diet on the 13762NF rat mammary adenocarcinoma Anticancer Res. 1999 Jan-Feb;19(1A):445-50). Iron supplementation has at times proven ineffective and even detrimental to health (Dao, 2013). Thus, iron excess may mediate the increased cancer risk associated with insulin resistance and heme-rich diets, and subjects who are insulin resistant can minimize any health risk associated with iron overload by avoiding heme-rich flesh foods and donating blood regularly (McCarty, 2003). The energy that sustains cancer cells derived preferentially from glycolysis (Matoba, 2006) depends on the gene p53 deficiency-iron induced. This nutrient is postulated to contribute to the initiation of cancer in vivo (Nakano 2003, Tuomainen 2007, Rockfield, 2017), but iron overload initiates and sustain cancer development if chronic infection or insulin resistance conditions are present. Cancer cells require considerably more iron than normal cells. Since iron catalytic can induce driver point mutation and create fusion genes through chromosomal translocations, iron overload is one of the most important risk factors in human carcinogenesis (Toyokuni, 2014). Because free iron may play a catalytic role in “spontaneous” mutagenesis, moderately elevated iron stores increased overall risk for cáncer (McCarthy, 2003). Overactivity of inflammatory cytokines is responsible for anemia of inflammation in different chronic diseases and cancer (Vela, J Transl Med. 2018), and exogenous iron is ever detrimental in sikness. In US, a daily intake of dietary iron more than 18 mg is associated with an increased risk of cancer (Manous, 2014)
  • ... Actualmente, el hierro por sí mismo, puede iniciar o ser un decisivo cofactor para el desarrollo de enfermedad (24,25). Por ejemplo, inclusive en presencia de reservas normales de hierro, una simple ingestión exógena de hierro incrementa el riesgo de infección (26,24), y ello, concretamente, por aumentar la Resistencia a la Insulina,el evento hormonal predictor de Enfermedad Crónica-, y por ser un poderoso activador del factor NFkB, cuya señalización se reconoce cada vez más como decisiva en la promoción de tumorigénesis: el NFkB es un poderoso factor que confiere resistencia para la muerte programada de la célula tumoral; es decir, es un potente Anti-apoptótico , confiriendo supervivencia a la célula neoplásica y promoviendo su poder metastásico (27). ...
    Article
    Full-text available
    Iron is physiologically essential for life but biochemically dangerous. Chronic accumulation of iron causes pantropic organ damage and excess body iron play an important role in carcinogenesis, coronary artery disease, neurodegenerative disease, stroke. and inflammatory disorders. Iron is very slowly excreted from humans once it is absorbed into the body. The significance of iron excess has been markedly underestimated, despite the fact that iron overloading disorders are as common place in the US white population (Conrad, 2002). Iron-overload and catalytic iron promotes activation of oxidative responsive transcription factors and pro-inflammatory cytokines that increase cancer extension and aggravate them. There is accumulative evidence for iron as a carcinogenic metal in epidemiological, clinical, animal, and cell culture studies. The role of iron in various cancers, such as colorectal and liver cancer was demonstrated. Recent advancements on the molecular mechanisms of iron carcinogenesis evolved the Insulin-resistance generation and promotion, fisiopatologic condition that is not only permissive, but may be generated cancer and promoting it. Unlike other nutritional metals, iron is highly conserved: toxicity due to excess iron can occur either acutely after a single dose or chronically due to excessive accumulation in the body from diet. In vivo studies have demonstrated that an iron deficiency induced by either feeding a low iron diet injecting the iron chelator deferoxamine mesylate decreases tumor growth (Wang F, Elliott RL, Head JF: Inhibitory effect of deferoxamine mesylate and low iron diet on the 13762NF rat mammary adenocarcinoma Anticancer Res. 1999 Jan-Feb;19(1A):445-50). Iron supplementation has at times proven ineffective and even detrimental to health (Dao, 2013). Thus, iron excess may mediate the increased cancer risk associated with insulin resistance and heme-rich diets, and subjects who are insulin resistant can minimize any health risk associated with iron overload by avoiding heme-rich flesh foods and donating blood regularly (McCarty, 2003). The energy that sustains cancer cells derived preferentially from glycolysis (Matoba, 2006) depends on the gene p53 deficiency-iron induced. This nutrient is postulated to contribute to the initiation of cancer in vivo (Nakano 2003, Tuomainen 2007, Rockfield, 2017), but iron overload initiates and sustain cancer development if chronic infection or insulin resistance conditions are present. Cancer cells require considerably more iron than normal cells. Since iron catalytic can induce driver point mutation and create fusion genes through chromosomal translocations, iron overload is one of the most important risk factors in human carcinogenesis (Toyokuni, 2014). Because free iron may play a catalytic role in “spontaneous” mutagenesis, moderately elevated iron stores increased overall risk for cáncer (McCarthy, 2003). Overactivity of inflammatory cytokines is responsible for anemia of inflammation in different chronic diseases and cancer (Vela, J Transl Med. 2018), and exogenous iron is ever detrimental in sikness. In US, a daily intake of dietary iron more than 18 mg is associated with an increased risk of cancer (Manous, 2014)
  • ... Actualmente, el hierro por sí mismo, puede iniciar o ser un decisivo cofactor para el desarrollo de enfermedad (24,25). Por ejemplo, inclusive en presencia de reservas normales de hierro, una simple ingestión exógena de hierro incrementa el riesgo de infección (26,24), y ello, concretamente, por aumentar la Resistencia a la Insulina,el evento hormonal predictor de Enfermedad Crónica-, y por ser un poderoso activador del factor NFkB, cuya señalización se reconoce cada vez más como decisiva en la promoción de tumorigénesis: el NFkB es un poderoso factor que confiere resistencia para la muerte programada de la célula tumoral; es decir, es un potente Anti-apoptótico , confiriendo supervivencia a la célula neoplásica y promoviendo su poder metastásico (27). ...
    Thesis
    Full-text available
    Iron is physiologically essential for life but biochemically dangerous. Chronic accumulation of iron causes pantropic organ damage and excess body iron play an important role in carcinogenesis, coronary artery disease, neurodegenerative disease, stroke and inflammatory disorders. Iron is very slowly excreted from humans once it is absorbed into the body. The significance of iron excess has been markedly underestimated, despite the fact that iron overloading disorders are as common place in the US white population. Iron-overload and catalytic iron promotes activation of oxidative responsive transcription factors and pro-inflammatory cytokines that increase cancer extension and aggravate them. There is accumulative evidence for iron as a carcinogenic metal in epidemiological, clinical, animal, and cell culture studies. The role of iron in various cancers, such as colorectal and liver cancer was demonstrated. Recent advancements on the molecular mechanisms of iron carcinogenesis evolved the insulin-resistance generation and promotion, fisiopatologia condition that is not only permissive, but may be generated cancer and promoting it. Unlike other nutritional metals, iron is highly conserved: toxicity due to excess iron can occur either acutely after a single dose or chronically due to excessive accumulation in the body from diet. In vivo studies have demonstrated that an iron deficiency induced by either feeding a low iron diet or injecting the iron chelators deferoxamine mesylate decreases tumor growth. Iron supplementation has at times proven ineffective and even detrimental to health. Thus, iron excess may mediate the increased cancer risk associated with insulin resistance and heme-rich diets, and subjects who are insulin resistant can minimize any health risk associated with iron overload by avoiding heme-rich flesh foods and donating blood regularly. The energy that sustains cancer cells derived preferentially from glycolysis depends on the gene p53 deficiencyiron induced.
  • ... including the pancreas and liver. 6 Both insulin deficiency and resistance are reported in patients with β-thalassemia. [7][8][9] Suggested risk factors for development of DM in patients with β-thalassemia include old age, increased amount and duration of blood transfusion, type and dose of iron-chelating therapy, high serum ferritin, family history of DM, hepatic impairment, and genetic modifiers of iron overload. ...
    Article
    Background Disturbances of glucose metabolism are common in β‐thalassemia major (β‐TM). Aim This study was conducted to assess the pattern of glucose homeostasis in pediatric β‐TM patients comparing oral glucose tolerance test (OGTT) and continuous glucose monitoring system (CGMS). Methods Two‐hundred β‐TM patients were studied and those with random blood glucose (RBG) ≥7.8 mmol/L (140 mg/dL) were subjected to OGTT, insertion of CGMS and measurement of fasting C peptide, fasting insulin and HbA1c. Results Twenty patients (10%) had RBG ≥7.8 mmol/L. Using OGTT, 6 out of 20 patients (30%) had impaired glucose tolerance (IGT) while 7 (35%) patients were in the diabetic range. CGMS showed that 7/20 (35%) patients had IGT and 13 (65%) patients had diabetes mellitus (DM); 10 of the latter group had HbA1c readings within diabetic range. The percentage of diabetic patients diagnosed by CGMS was significantly higher than that with OGTT (p=0.012). Serum ferritin was the only independent variable related to elevated RBG. All β‐TM patients with DM were noncompliant to chelation therapy. Conclusions The use of CGMS in the diagnosis of early glycemic abnormalities among pediatric patients with β‐TM appears to be superior to other known diagnostic modalities. This article is protected by copyright. All rights reserved.
  • ... Nishida (2009) reported that the high concentration of iron is responsible for renal carcinoma and tissue damage. Studies in the context of iron toxicity have also reported diseases like gastrointestinal effects including diarrhoea, nausea, vomiting and epigastric, genetical metabolic disease, repeated blood transfusion ( Weinberg E.D., 2007). Wilson's disease in human is occurring due to the copper and the analogous disorder Bedlington Terries is also characterised by the increase in copper concentration (Crawford et al., 1985). ...
    Research
    Full-text available
    This study evaluates temporal peculiarity of Fe and Cu in river Gomti during three consecutive years and assesses the efficiency of two native macrophytes T. natans and M. glabratus in accumulation/removal of pollutants under in-situ and ex-situ. During the year 2009 Fe concentration ranged between 1.110-1.339 mg L-1 and Cu from 0.008-0.021 mg L-1 throughout pre-monsoon period whereas during post-monsoon Fe concentration was between 1.103-1.185 mg L-1 and Cu was recorded from 0.003-0.008 mg L-1. During the year 2010 and 2011, Fe concentration ranged between 1.122-1.384 mg L-1 and Cu ranged from 0.010-0.023 mg L-1 in pre-monsoon period and in post-monsoon Fe ranged from 1.082-1.184 mg L-1 and Cu ranged from 0.04-0.09 mg L-1 in Gomti river water. Removal of Fe by T. natans was 64.4% in net house and accumulation was 56% and at river site the accumulation was 45% whereas in M. glabratus 56.6% removal and 47.6% accumulation was noted in net house and at river site 36% accumulation was noticed. T. natans removed Cu by 60% and accumulated 46.6% whereas M. glabratus removed 53% and accumulated 33% in net house and at river site Cu accumulation was 37% in T. natans and 29% increment of Cu was observed in M. glabratus. It resulted that T. natans showed more potential than M. glabratus in bio-accumulation of Fe and Cu from water.
  • ... Especially for women, tobacco consumption even at low doses impairs Fe homeostasis, causing a condition known as iron-deficiency anemia that can be harmful to their unborn children. Besides these findings, it is also suggested that elevated Fe could be hazardous and promotes cardiomyopathy, arthropathy, and an array of endocrine, neurodegenerative, and other chronic diseases [9] . Within our studied tobacco products, manganese levels varied significantly. ...
    Article
    We identified and quantified a variety of mineral elements in 18 tobacco samples purchased from a Tunisian market. In total, 25 mineral elements have been measured in cigarettes, water pipe tobacco, and smokeless tobacco using inductively coupled plasma-optical emission spectroscopy following microwave-assisted digestion. Statistical analyses were performed using SPSSTM, version 18.0. The lowest concentrations of all studied elements were observed in water pipe tobacco. Significantly higher concentrations of Al, Fe, Mg, Na, Ca, Cr, and Co were found in smokeless tobacco, while cigarettes brands contained the highest concentrations of K, Mn, Ni, Ba, and Sr. There was no significant difference between the mineral contents of local and foreign cigarettes and conventional and light cigarettes. Our findings demonstrated that local smokeless tobacco appears to be the most hazardous tobacco type. The concentration of minerals in light cigarettes was not significantly different from the concentration in conventional cigarettes. © 2017 The Editorial Board of Biomedical and Environmental Sciences
  • ... Suggested risk factors for development of DM in patients with BTM include old age, increased amount of blood transfusion, high serum ferritin level, family history of DM, hepatic impairment, and genetic modifiers of iron overload. [8][9][10][11][12][13] The relationship between glucose concentrations in interstitial fluid (ISF) and blood has generated great interest due to its importance in minimally invasive and non-invasive techniques for measuring blood glucose. The relationship between glucose levels in dermal ISF, and glucose levels in capillary and venous blood measured simultaneously was studied. ...
    Data
    Full-text available
    Glycemic abnormalities in Adolescents with thalassemia detected by CGMS versus OGTT
  • ... Suggested risk factors for development of DM in patients with BTM include old age, increased amount of blood transfusion, high serum ferritin level, family history of DM, hepatic impairment, and genetic modifiers of iron overload. [8][9][10][11][12][13] The relationship between glucose concentrations in interstitial fluid (ISF) and blood has generated great interest due to its importance in minimally invasive and non-invasive techniques for measuring blood glucose. The relationship between glucose levels in dermal ISF, and glucose levels in capillary and venous blood measured simultaneously was studied. ...
    Article
    Full-text available
    Both insulin deficiency and resistance are reported in patients with β-thalassemia major (BTM). The use of continuous blood glucose monitoring (CGM), among the different methods for early detection of glycemic abnormalities, has not been studied thoroughly in these adolescents. To assess the oralglucose tolerance (OGT) and 72-h continuous glucose concentration by the continuous glucose monitoring system (CGMS) and calculate homeostatic model assessment (HOMA), and the quantitative insulin sensitivity check index (QUICKI) was conducted in 16 adolescents with BTM who were receiving regular blood transfusions every 2-4 weeks and iron-chelation therapy since early childhood. SIXTEEN ADOLESCENTS WITH BTM (AGE: 19.75 ± 3 years) were investigated. Using OGTT, (25%) had impaired fasting blood (plasma) glucose concentration (BG) (>5.6 mmol/L). 2-h after the glucose load, one of them had BG = 16.2 mmol/L (diabetic) and two had impaired glucose tolerance (IGT) (BG > 7.8 and <11.1 mmol/L). Monitoring the maximum (postprandial) BG using CGMS,4 adolescents were diagnosed with diabetes (25%) (BG >11.1 mmol/L) and 9 with IGT (56%). HOMA and QUICKI revealed levels <2.6 (1.6 ± 0.8) and >0.33 (0.36 ± 0.03), respectively, ruling out significant insulin resistance in these adolescents. There was a significant negative correlation between the β-cell function (B%) on one hand and the fasting and the 2-h BG (r=-0.6, and - 0.48, P < 0.01, respectively) on the other hand. Neither fasting serum insulin nor c-peptide concentrations were correlated with fasting BG or ferritin levels. The average and maximum blood glucose levels during CGM were significantly correlated with the fasting BG (r = 0.68 and 0.39, respectively, with P < 0.01) and with the BG at 2-hour after oral glucose intake (r = 0.87 and 0.86 respectively, with P < 0.001). Ferritin concentrations were correlated with the fasting BG and the 2-h blood glucose levels in the OGTT (r = 0.52, and r = 0.43, respectively, P < 0.01) as well as with the average BG recorded by CGM (r = 0.75, P < 0.01). CGM has proven to be superior to OGTT for the diagnosis of glycemic abnormalities in adolescents with BTM. Defective β-cell function rather than insulin resistance appeared to be the cause for these abnormalities.
  • Thesis
    Full-text available
    Old age comes coupled with frailty and disease and, thus, the ageing of the World’s population has spurred the interest on the causes and mechanisms of senescence. Senescence has long been a mystery, with no single universally accepted theory accounting for its ultimate evolutionary causes (if indeed these causes exist). Perhaps two of the most popular evolutionary explanations proposed so far are the Mutation Accumulation Theory proposed by Peter Medawar in 1951 and the Antagonistic Pleiotropy Theory, suggested by George C. Williams in 1957. The large amount of data derived from Genome-Wide Association Studies (GWAS) obtained over the last decade allows testing both theories, provided that they can make predictions in terms of the genetic architecture of complex human disease. However, if we want to take advantage from GWAS data, we need to assure that they are sound, replicable and that they contain information that is useful for our purposes. This PhD thesis deals with both goals: we first assess the quality and replicability of information on genome-disease associations and then we use it to explore the Mutation Accumulation and Antagonistic Pleiotropy theories of senescence. Knowledge about the impact of these theories will be important for an increasingly ageing population.
  • Chapter
    Taken together, these observations suggest that mechanisms to sequester iron have evolved as part of the host response to infection. It is possible that ACD represents a side effect of this response when it persists over a period of months. (1) INTRODUCTION Excessive and misplaced iron in specific cells and tissues promotes infection, neoplasia, cardiomyopathy, arthropathy and an array of endocrine and neurodegenerative diseases. Vertebrate hosts maintain an iron withholding defense system designed to: (a) prevent accumulation of nonprotein bound (free) iron in sensitive sites and (b) sequester the metal in innocuous packages. Manifestations of iron withholding are most evident in defense against diseases that are associated with known (or yet to be discovered) microbial cell invaders, with neoplastic cell invaders, and with other inflammatory conditions.
  • Conference Paper
    Background and Objectives: Evidence suggests that cardiovascular disease (CVD) is accelerated by the oxidation of low-density lipoprotein (LDL) in the presence of iron. This study examined whether adults with elevated iron, as measured by transferrin saturation (TS), and elevated LDL are at an increased risk for mortality. Methods: This is a cohort study of the adult US population using the National Health and Nutrition Examination Survey 1976-1980 (NHANES II) merged with the NHANES II Mortality Study in 1992. Multivariate Cox regression was performed to determine hazard ratios (HR)for CVD and all-cause mortality for high (>55%) or low (<55%) levels of TS and high (>160mg/dl) or low (<160mg/dl) levels of LDL. Results: An elevated LDL alone did not significantly increase CVD mortality or all-cause mortality in the adjusted model. Individuals with elevated LDL and elevated TS had a statistically significant increase in both CVD mortality and all-cause mortality (HR=5.74 and 3.53, respectively) compared to the low LDL and low TS group. Conclusions: The results of this study indicate an increased risk associated with the combination of elevated LDL and elevated TS, which suggests that iron-mediated oxidation of LDL may be a significant factor in the progression of CVD.
  • Article
    Neurodegeneration in Parkinson's, Alzheimer's, and other neurodegenerative diseases seems to be multifactorial, in that a complex set of toxic reactions including inflammation, glutamatergic neurotoxicity, increases in iron and nitric oxide, depletion of endogenous antioxidants, reduced expression of trophic factors, dysfunction of the ubiquitin-proteasome system, and expression of proapoptotic proteins leads to the demise of neurons. Thus, the fundamental objective in neurodegeneration and neuroprotection research is to determine which of these factors constitutes the primary event, the sequence in which these events occur, and whether they act in concurrence in the pathogenic process, This has led to the current notion that drugs directed against a single target will be ineffective and rather a single drug or cocktail of drugs with pluripharmacological properties may be more suitable. Green tea catechin polyphenols, formerly thought to be simple radical scavengers, are now considered to invoke a spectrum of cellular mechanisms of action related to their neuroprotective activity. These include pharmacological activities like iron chelation, scavenging of radicals, activation of survival genes and cell signaling pathways, and regulation of mitochondrial function and possibly of the ubiquitin-proteasome system. As a consequence these compounds are receiving significant attention as therapeutic cytoprotective agents for the treatment of neurodegenerative and other diseases.
  • Article
    BACKGROUND A large proportion of US adults have elevated transferrin saturation, an indicator of a predisposition for iron overload. The purpose of this study was to evaluate the relationship between elevated serum transferrin saturation and mortality. METHODS This cohort study was conducted using data from the First Health and Nutrition Examination Survey I (1971–1974) (NHANES I) merged with the NHANES I Epidemiologic Followup Study (1992) (N = 10,714). We used SUDAAN and appropriate weights to make population estimates for the adult US population (aged 25 to 74 years at baseline). All-cause mortality was evaluated in relation to serum transferrin saturation of greater than 45%, greater than 50%, greater than 55%, and greater than 60% using Cox proportional hazards regression. RESULTS In a Cox proportional hazards model controlling for potential confounders, including comorbid diseases, smoking, and cholesterol, all-cause mortality is significantly greater for persons with a serum transferrin saturation of more than 55%, compared with those with saturations below this cutoff (hazards ratio [HR] =1.60, 95% confidence interval [CI], 1.17–2.21). No one who died had hemochromatosis as any of the 20 listed causes of death. Many of the underlying causes of death for persons with serum transferrin saturation levels of more than 55% are common causes of death in the general population, although these persons were more likely to have died of cirrhosis and diabetes, a finding consistent with iron overload. CONCLUSIONS In this nationally representative cohort of adults, those with elevated serum transferrin saturation, more than 2% of the adult US population, were at increased risk for all-cause mortality.
  • Article
    Low-density lipoprotein (LDL) exists within the brain and is highly vulnerable to oxidative modifications. Once formed, oxidized LDL (oxLDL) is capable of eliciting cytotoxicity, differentiation, and inflammation in nonneuronal cells. Although oxLDL has been studied primarily for its role in the development of atherosclerosis, recent studies have identified a possible role for it in neurological disorders associated with oxidative stress. In the present study application of oxLDL, but not LDL, resulted in a dose- and time-dependent death of cultured rat embryonic neurons. Studies using pharmacological inhibitors implicate the involvement of calcium, reactive oxygen species, and caspases in oxLDL-induced neuronal death. Coapplication of oxLDL with either amyloid β-peptide or glutamate, agents that enhance oxidative stress, resulted in increased neuronal death. Taken together, these data demonstrate that oxLDL induces neuronal death and implicate a possible role for oxLDL in conditions associated with increased levels of reactive oxygen species, including Alzheimer's disease.
  • Article
    Objective. —To examine the prevalence of coronary artery disease (CAD) in autopsies of patients with iron-overload syndromes.Design. —Retrospective autopsy study of CAD in cases of hemochromatosis and multiorgan hemosiderosis.Setting. —Registry of nearly 48000 autopsies performed at The Johns Hopkins Hospital between 1889 and 1992.Subjects. —One hundred twenty-three subjects were studied. In a 2:1 control-case ratio, 82 controls matched by age, race, and sex were compared with 41 cases with iron overload.Main Outcome Measure. —Severity of CAD.Results. —Pathological description of the coronary arteries were recorded as advanced or severe in 12% of iron-overload cases(n=41) (mean age, 57.6±13.2 years) compared with 38% of controls (n=82) (mean age, 57.0±13.8 years) (P=.01). The prevalence of three-vessel disease assessed by postmortem coronary arteriography was 11.1% in iron-overload cases (n=18) (mean age, 61.7±12.2 years) compared with 33.3% in controls (n=36) (mean age, 61.1±12.5 years) (P=.04). The odds ratio of CAD with iron overload was 0.18 (95% confidence interval, 0.04 to 0.73).Conclusions. —Iron overload resulting from hemochromatosis or multiorgan hemosiderosis is not associated with an increased prevalence of CAD.(JAMA. 1994;272:231-233)
  • Article
    OBJECTIVE:The aim of this study was to define in patients with hyperferritinemia and normal transferrin saturation the relationships among hyperferritinemia, iron overload, HFE gene mutations, the presence of metabolic alterations, and nonalcoholic steatohepatitis (NASH).METHODS:Forty patients with increased serum ferritin, resistant to dietary restriction and normal transferrin saturation, 90 with ultrasonographic evidence of hepatic steatosis, and 60 obligate heterozygotes for hemochromatosis, all negative for alcohol abuse, hepatitis virus infections, and inflammation were studied. Transferrin saturation, serum ferritin, uric acid, lipids, glucose tolerance, insulin resistance, HFE gene mutations, liver histology, and hepatic iron concentration were analyzed.RESULTS:Of the 40 patients with hyperferritinemia, 29 (72%) had biochemical metabolic abnormalities, 18 of the 26 examined (69%) had insulin resistance, 26 (65%) had the presence of one of the two HFE gene mutations (normal controls, 33 of 128 [26%], p < 0.0001), and all had increased liver iron concentration. Thirty-one patients (77%) had histology compatible with NASH. At univariate analysis, NASH was significantly associated with the presence of metabolic alterations, the C282Y mutation, and severity of fibrosis. At multivariate analysis, NASH was associated with the coexistence of multiple metabolic alterations (odds ratio = 5.2, 95% CI = 0.95–28.7). The risk of having NASH augmented in the presence of higher values of ferritin and liver iron concentration. Among the 90 patients with ultrasonographic evidence of hepatic steatosis, 24 (27%) had increased serum ferritin with normal transferrin saturation, but only six remained hyperferritinemic after dietary restriction.CONCLUSION:Increased ferritin with normal transferrin saturation is frequently found in patients with hepatic steatosis, but it reflects iron overload only in those patients in whom it persists despite an appropriate diet. The simultaneous disorder of iron and glucose and/or lipid metabolism, in most of the cases associated with insulin resistance, is responsible for persistent hyperferritinemia and identifies patients at risk for NASH.
  • Article
    Five cases of hemochromatosis arthropathy are presented and the distinctive radiological features of the disease are described. Although the condition is typically degenerative, showing subchondral cyst formation, sclerosis, and thinning of cartilage, its distribution is characteristic. Selective degenerative changes of the second and third metacarpophalangeal joints are striking, particularly in the hands, while abnormalities in the intercarpal joints are variable and the interphalangeal joints are spared. Chondrocalcinosis involving both fibrous and hyaline cartilage is frequently seen as well, particularly in the large joints. The calcification is due to deposition of calcium pyrophosphate crystals, perhaps resulting from iron inhibition of pyrophosphatase.