Iron in neoplastic disease

Normal and neoplastic cells have similar needs for iron, but the latter may exhibit altered mechanisms of iron acquisition that permit continued multiplication in host iron-restricted tissues. For example, neoplastic cells may form low molecular weight siderophores as well as increase the number of transferrin binding glycoproteins on their cell surfaces. The hosts attempt to withhold iron from neoplastic cells by preventing the return of the metal to plasma and diverting it to storage, by increasing the synthesis of ferritin to accommodate the added stores, and by surrounding tumor cells with macrophages that can ingest lactoferrin-bound iron, but these mechanisms are often not effective against the iron-accumulating mechanisms of the tumor. Persons or animals with iron overload (via ingestion, inhalation, injection, or pathophysiologic process) tend to be at greater risk than normal hosts in the development of neoplasms. The tumors are often associated with the site(s) of deposition of the metal. In addition to its neoplastic cell nutrient function, excess iron might suppress tumorcidal action of macrophages and interfere with lymphocyte traffic. Severe iron deficiency can interfere with the ability of the host to detoxify potential carcinogens as well as with its ability to activate antitumor lymphocytes.     

Iron storage disease

Iron overload causes impaired function of tissues and organs due to the increased iron storage in them. Hereditary hemochromatosis is the most frequent hereditary metabolic disorder, with lethal outcome without treatment. The genetic disorder is a mutation on the short arm of the 6. chromosome, which resulted a cysteine-tyrosine substitution on the 282. amino acid position (C282Y). This mutation is less frequent in the non-Caucasian population, in opposition to the other reported mutation (H63D). The risk of the development of the disease is the highest in people who are C282Y homozygotes or C282Y/H63D compound heterozygotes. The prevalence of hemochromatosis is 1.5-5.9 per thousand. Liver disease/cirrhosis, diabetes mellitus and hyperpigmentation are the classic signs of the disease. Primer hepatocellular cancer occurs in 30% of patients with liver cirrhosis, that it is the most common cause of death among them. The diagnosis is based on the detection of iron overload (transferrin saturation, serum ferritin level, iron concentration of the liver tissue) and on the genetic examinations. Early diagnosis makes the causal therapy possible, which is the removal of the iron excess by phlebotomy. Furthermore, the early detection of iron overload allows of prevention of the development of the disease. Based in these facts population screening seems to be necessary and cost-effective, but further studies are required to determine the exact screening strategy.     

Iron loading and disease surveillance.

Iron is an oxidant as well as a nutrient for invading microbial and neoplastic cells. Excessive iron in specific tissues and cells (iron loading) promotes development of infection, neoplasia, cardiomyopathy, arthropathy, and various endocrine and possibly neurodegenerative disorders. To contain and detoxify the metal, hosts have evolved an iron withholding defense system, but the system can be compromised by numerous factors. An array of behavioral, medical, and immunologic methods are in place or in development to strengthen iron withholding. Routine screening for iron loading could provide valuable information in epidemiologic, diagnostic, prophylactic, and therapeutic studies of emerging infectious diseases.     

Iron as a co-morbid factor in nonhemochromatotic liver disease.

Heavy iron overload, in both primary and secondary hemochromatosis, may cause fibrosis of parenchymal organs, especially the liver. The toxicity of iron is believed to involve increased oxidative stress, with iron-catalyzed production of reactive oxygen species causing oxidative damage to lipids, proteins, and nucleic acids. Lesser degrees of hepatic iron deposition are also associated with, and seem to be risk factors for, certain nonhemochromatotic liver diseases. Porphyria cutanea tarda is associated with hepatic iron overload and responds to iron-reduction therapy. Results of recent studies have demonstrated high prevalences (about 60%-80%) of HFE gene mutations in patients with porphyria cutanea tarda. Chronic hepatitis C is another risk factor for porphyria cutanea tarda. Other recent evidence indicates that the prevalence of HFE gene mutations is increased in chronic viral hepatitis and that patients with chronic hepatitis C harboring especially the C282Y mutation are more likely to suffer from advanced hepatic fibrosis or cirrhosis and to do so at younger ages. A role for modest iron overload in increasing severity of alcohol-induced liver disease has been well established from results of experimental studies. However, it is currently unresolved whether mild-to-moderate hepatic iron deposition or heterozygosity for the C282Y mutation plays a role in human alcoholic liver disease or in nonalcoholic fatty liver disease or nonalcoholic steatohepatitis. There is persuasive evidence that iron reduction decreases insulin resistance, and it likely also decreases oxidative stress, two key pathogenic features of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Iron loading has also been described after portosystemic shunts and in end-stage liver disease.     

Iron status of children with sickle cell disease

BACKGROUND: Dietary iron requirements are unclear in children with SS-type sickle cell disease. METHODS: Iron status was assessed in 104 nontransfused African American children (aged 0.5 to 17.6 years) with sickle cell disease who receive no iron supplement. Dietary iron intake was not measured at the time of this study. RESULTS: Serum ferritin was normal or high in all children. Other hematologic and biochemical indicators of iron deficiency were in the normal range in most children. CONCLUSIONS: Unlike previous studies, this sample of children and adolescents did not show signs of iron deficiency.     

Iron, oxidative stress, and disease risk

Based on epidemiologic evidence citing excess iron as a risk factor for many diseases, and oxidative stress as an underlying cause for those diseases, iron-induced oxidative stress has recently gained attention. Although iron can participate in oxidative reactions to generate free radicals under in vitro conditions, its involvement in vivo in the cause or progression of diseases is questionable.     

Iron and its relation to immunity and infectious disease

The continuing unresolved debate over the interaction of iron and infection indicates a need for quantitative review of clinical morbidity outcomes. Iron deficiency is associated with reversible abnormalities of immune function, but it is difficult to demonstrate the severity and relevance of these in observational studies. Iron treatment has been associated with acute exacerbations of infection, in particular, malaria. Oral iron has been associated with increased rates of clinical malaria (5 of 9 studies) and increased morbidity from other infectious disease (4 of 8 studies). In most instances, therapeutic doses of oral iron were used. No studies in malarial regions showed benefits. Knowledge of local prevalence of causes of anemia including iron deficiency, seasonal malarial endemicity, protective hemoglobinopathies and age-specific immunity is essential in planning interventions. A balance must be struck in dose of oral iron and the timing of intervention with respect to age and malaria transmission. Antimalarial intervention is important. No studies of oral iron supplementation clearly show deleterious effects in nonmalarious areas. Milk fortification reduced morbidity due to respiratory disease in two very early studies in nonmalarious regions, but this was not confirmed in three later fortification studies, and better morbidity rates could be achieved by breast-feeding alone. One study in a nonmalarious area of Indonesia showed reduced infectious outcome after oral iron supplementation of anemic schoolchildren. No systematic studies report oral iron supplementation and infectious morbidity in breast-fed infants in nonmalarious regions.     

Iron status in association with cardiovascular disease risk in 3 controlled feeding studies

BACKGROUND: The role of body iron stores in free radical-induced peroxidation and cardiovascular disease risk has been debated, but controlled feeding studies using measurements of non-transferrin-bound iron (NTBI) and LDL oxidation have not been conducted. OBJECTIVE: We tested the hypothesis that NTBI and other measures of iron status do not affect oxidative susceptibility in healthy subjects with normal iron status. DESIGN: Plasma samples were analyzed from 77 healthy men and women aged 20-65 y who participated in 3 controlled feeding studies in which the type and amount of dietary fat were controlled. Iron status and in vitro LDL oxidation were assessed at baseline and at the end of each feeding period (4-8 wk). RESULTS: No significant relations were found between any measure of iron status (ferritin: 83 +/- 8.9 micro g/L; iron: 20.9 +/- 5.4 micro mol/L; TIBC: 74.4 +/- 11.0 micro mol/L; NTBI: 0.184 +/- 0.15 micro mol/L) and the in vitro measures of LDL oxidation (total dienes: 485 +/- 55 micro mol/mg LDL protein; lag time: 51.7 +/- 15.9 min; and rate of oxidation: 25.4 +/- 6.8 micro mol dienes.min(-1).g LDL protein(-1)). Equal-iron peanut butter-based diets were associated with higher plasma iron in men (22.4 +/- 3.8 micro mol/L) than was the olive oil diet (17.7 +/- 4.5 micro mol/L) (P = 0.02), but this slight elevation did not alter LDL oxidation. CONCLUSIONS: Diet composition may affect plasma iron in men, but LDL oxidative susceptibility is unaffected by the subtle variation in iron status. Thus, the results do not support a relation between iron status and LDL oxidative susceptibility, a possible risk factor for cardiovascular disease.     

Relevance of microRNA-s in neoplastic diseases

MicroRNA molecules consisting of 19-23 nucleotides influence numerous basic physiological and pathophysiological processes as endogenous mediators of RNA interference. These molecules are capable of specifically inhibiting the translation of messenger RNA molecules, but in some cases also promote the degradation of mRNA-s. Altered microRNA expression profiles were noted in several human diseases, most data, however, are known for neoplasms. Characteristic microRNA profiles are known both in solid and haematologic malignancies. MicroRNA profiles enable the distinction of benign follicular adenomas from follicular neoplasms of the thyroid. The micro-RNA expression patterns could be associated with the clinical behaviour of certain neoplasms (e.g. lung tumours and chronic lymphocytic leukemia) as well. It is possible that small molecular weight RNA-s may be used for therapeutical purposes in the future.     

Iron versus cholesterol-Perspectives on the iron and heart disease debate

Focusing only on the limited question of whether stored iron is a valid heart disease risk factor inappropriately narrows the scope of the debate on the “iron hypothesis.” Framing the debate in this way ignores the broad explanatory power of the hypothesis that iron depletion protects against ischemic heart disease. The iron hypothesis provides a conceptual tool for study of the mechanisms by which age and gender influence the development of ischemic heart disease. The assumption that age and gender exert unalterable effects has diverted attention from these strong risk factors, and has led to intense preoccupation with weaker risk factors such as cholesterol. The notion that cholesterol is of central importance has become a rigid and institutionalized point of view. Increased mortality from some cholesterol-lowering drugs is but one of the potential dangers of continued promotion of the flawed idea that heart disease is a function of the cholesterol concentration. The more serious risk is that alternative approaches to the problem of ischemic heart disease will be suppressed. Consideration of the relationship between the iron and cholesterol hypotheses provides important perspectives on the current debate on the role of iron in the development of ischemic heart disease.     

IARC multicenter study on neoplastic disease caused by man-made vitreous mineral fibers (MMVF)]

Man-made vitreous fibres (MMVF) showed carcinogenic potential in experimental animals. Epidemiological data suggested an increased mortality from lung cancer among production workers, but the interpretation is still a matter of controversy. A European study encompassing 13 plants in 7 countries pointed towards a moderate excess of lung cancer among workers employed longer than 1 year in the production of rock/slag wool (SMR = 1.34, 95% CI = 1.08-1.63) and glass wool (SMR = 1.27, 95% CI = 1.07-1.50); the latter increase was not confirmed after applying local rates to calculate expected deaths. The elevated risk among rock/slag wool producers was present even in comparison with local rates, and was associated with increasing time from first exposure, and duration of exposure. Glass wool results exhibited a less definite pattern. Smoking was excluded, although indirectly, as a sufficient alternative explanation of the increased lung cancer risk. In a few plants, exposure to asbestos had occurred in limited periods for some workers, and might have contributed to the findings. Case-control studies are under way to thoroughly investigate the relative and possibly combined role of the different exposures, either occupational or not. Cohort studies in the USA produced results closely consistent with those of the European study.