Iron Overload Toxicity and Chronic Disease

Paul L. Reller L.Ac. / Last Updated: August 03, 2017

Iron overload toxicity is just beginning to be taken seriously in standard medicine around the world. This is because the subject of iron overload toxicity is difficult to understand. Many experts believe that we have operated for decades with diagnostic and treatment guidelines that are inadequate, and rely on assumptions rather than facts when considering iron overload toxicity as a cause of symptoms. Iron overload, like many heavy metal toxicities, may cause or contribute to a variety of disorders, though, and perhaps explain many chronic cases of fatigue, abdominal discomfort, menstrual irregularities, hormonal imbalances, chronic pain, and abnormalities in heart rate, that elude the normal diagnostic workup. Iron overload toxicity has also been tied to the complex etiopathology of Parkinson's disease and other neurodegenerative disorders, as well as Diabetes, joint arthropathy, and cancer. By utilizing a too simplistic view of iron overload, namely that it is the opposite in every way from iron deficiency, we have ignored the source of the problem, altered iron homestasis, or the regulation of iron transport, storage and utilization.

Problems with iron homeostasis and iron status are integral to this slowly developing health problem. Iron overload is almost never the result of an acute poisoning by iron, but rather the slow and chronic development of dysfunction in iron homeostasis. The problems may lie in a group of factors, the modern diet, changes in mineral content of the soils from modern farming techniques, environmental pollutants, and ill health of the gastrointestinal system, as well as liver dysfunction, chronic inflammatory disease and genetic propensities. Since iron is the most abundant mineral in our planet, simple supply is not the problem. The World Health Organization (WHO) has alerted the world to the widespread problems of nutritional deficiencies that affect every country on the planet, and iron deficiency and utilization, iodine deficiency and utilization, and disorders of the Vitamin A metabolism have been the focus of health experts around the world since 1992. Experts at this time stated: "Iron deficiency affects a significant part, and often a majority, of the population in nearly every country in the world." The outline for this problem addressed the complexity of iron homeostasis and disease, or iron status, which was considered "as a continuum from iron deficiency with anaemia, to iron deficiency with no anaemia, to normal iron status with varying amounts of stored iron, and finally to iron overload- which can cause organ damage when severe." Obviously, standard medicine has not taken a serious approach, or a holistic approach, to this medical problem, even though it was emphasized as a very prevalent worldwide problem by the best medical experts in the world in 1992. These problems of iron and iodine utilization, and the metabolism of the chemicals in the Vitamin A family, which include both chemicals that transform into Vitamin A chemicals in the body, as well as the familiar chemicals we call Vitamin A, which are integral to utilization and regulation of iron storage in the body, are still treated as simple dietary deficiencies, and the eventual problem of iron overload toxicity is still both denied in prevalence, as well as diagnosed as a genetic disease alone, ignoring the decades of evidence to the contrary.

The World Health Organization (WHO) has stated in a 2001 assessment of diseases of iron homeostasis that iron deficiency with anemia and iron overload toxicity are just two ends of a continuum of problems with iron homeostasis. The panel of experts agreed that the term anemia is often used synonymously with iron deficiency anemia, ignoring the problems of iron homeostasis in the individual. They stated that there "are about 2-5 times more iron-deficient than iron-deficient-anaemic individuals". This iron deficiency is often unrelated to simple dietary insufficiency of iron, but involves a variety of factors contributing to defective iron homeostasis. Defective iron homeostasis may not only lead to iron deficiency, but to iron overload toxicity as well. There is a clear link between altered gastrointestinal function, imbalance of the gut microbiota, and altered iron homeostasis with iron overload toxicity. Correction of this homeostasis of iron, related health problems, and chelation of iron accumulation, with holistic medicine, is needed to fully resolve health problems related to iron overload toxicity.

The World Health Organization has found that iron deficiency is a problem related to long-term defects in iron homeostasis, and that with chronic iron deficiency, the homeostatic mechanisms of iron transport are negatively affected. When this occurs the body may have trouble with strongly binding the iron in transport, and weakly bound or free iron in circulation may end up accumulating in body tissues, especially organ tissues, creating problems. Iron deficiency was defined by the WHO not as a simple matter of deficient iron in the diet, but "the result of long-term negative iron balance. Iron stores in the form of Haemosiderin and ferritin are progressively diminished and no longer meet the needs of normal iron turnover. From this critical point onward, the supply of iron to the transport protein apoferritin is compromised. This condition results in a decrease in transferrin saturation and increase in transferrin receptors (expressed on cells) in the circulation and on the surface of cells, including (but not limited to) the erythron (circulating erythrocytes or red blood cells, or their precursors, including platelets). Iron deficiency is defined as a condition in which there are no mobilizable iron stores and in which signs of a compromised supply of iron to the tissues, including the erythron, are noted. The more severe stages of iron deficiency are associated with anaemia." In other words, iron deficiency is a slowly developing problem, where eventually the diminishing of usable iron may lead to an increase in cell receptors for the iron transporting protein, and iron overload toxicity in some cells of the body with increased transferrin receptors. The eventual iron overload may occur locally in the body, or systemically. It may or may not be associated with the various genetic propensities we have defined iron overload syndromes in the past by, termed hemochromatosis with genetic component.

The implications are that iron deficiency is often a problem with iron homeostasis, not intake of iron, and that most iron deficiency in the population has not reached a severe stage that results in actual anemia, or worse, an imbalance of iron homeostasis that results in local or systemic iron overload toxicity. This report of the WHO states that mild deficiency of iron homeostasis may result in poor cognitive performance, behavioral problems, stunted growth, immune pathologies, and fatigue and weak muscle function. The report also stated: "Moreover, iron-deficient animals and humans have impaired gastrointestinal functions and altered hormone production and metabolism. The latter include those for neurotransmitters and thyroidal hormones which are associated with neurological, muscular, and temperature-regulatory alterations that limit the capacity of individuals exposed to the cold to maintain their body temperature. In addition, DNA replication and repair involve iron-dependent enzymes." (WHO/NHD/01.3 Iron Defiency Anaemia Assessment, Prevention, and Control 2001). In other words, once again, many of the chronic health problems that we see clinically, but often are inexplicable, could be attributed to problems with iron homeostasis. How long the medical field, and the public, will ignore this confusing situation, is the question. The implications of this WHO report are not binary, not a judgement of whether iron supplementation is wrong or right, but a need to properly assess iron homeostasis and anemias, and give serious consideration not only to iron deficiency with anemia, but also to the continuum of problems with iron homeostasis, including iron overload toxicity, which could be much more prevalent than we believe. We need to correct problems with iron homeostasis, preferably at an early stage. While such an approach is complex, and the standard approach to the problem is much simpler, ignoring the problem until it is more severe, then using too simplistic therapeutic strategies to manage the problems of anemia or iron overload toxicity, there is no denying the need for a more complex and holistic approach to correct this potentially serious metabolic problem.

Gaining a better understanding of iron homeostasis is the first step in diagnosis and treatment

Problems with iron homeostasis, or the assimilation, transport and utilization of iron in the body, are thus linked to a chronic and gradual iron deficiency in the majority of the population in most countries in the world, as well as to the problems of iron overload toxicity in a small percentage of the population. This problem, iron deficiency and dysfunction with iron homeostasis, may indeed result in iron overload toxicity over time, and it may indeed be linked to inherited genetic propensities that are triggered by epigenetic and environmental factors, as well as genetic mutations caused by disease. Although the progression, or continuation, of problems with iron homeostasis, from deficiency to toxic overload, is well documented, this does not mean that simple supplementation with common iron supplements should be utilized by everyone to correct this problem. Supplementation with a type of iron that is difficult to assimilate and may be toxic to the gastrointestinal tract, as has been commonly prescribed for decades, may only exacerbate, or contribute to, an iron overload toxicity. In 2011, the Iowa Women's Health Study found in a large study of health supplements and risk that iron supplementation was practically the only common supplement associated with increased health risk and mortality in older women. The simplistic iron supplementation currently prescribed in standard medicine was perhaps causing more harm than good. The key to correction of this health problem is utilization of a holistic treatment regimen that is thoughtful, individually tailored, and uses the latest research and best products to restore iron homeostasis and simultaneously chelate unwanted iron accumulation in our bodies. Simple chelation and detox therapy alone is also not the answer. If the problems that lead to iron overload toxicity are not corrected, the problem will recur. If a problem with both iron overload toxicity and iron deficiency and dysfunction in assimilation of iron from the diet is suspected, a step-by-step protocol to first chelate iron, then resolve ill health of the gastrointestinal tract, and finally to restore iron with a formula utilizing plant-based iron with supplements supporting iron assimilation may be needed. Of course, utilizing professional assessment and guidance in such therapy is highly recommended.

Since iron is a highly charged and attractive element, with a potential oxidation state (potential electrical charge), of 2 to 8, and reacts easily with oxygen, it may cause problems when accumulating in tissues. Iron, as a very electric and magnetic mineral in the body, is well used and well controlled in the human organism, but problems with iron homeostasis may occur due to a variety of factors. The use of iron by the red blood cells to attract and bind oxygen for transport and supply to our cells, perhaps our chief source of bioelectrical energy, is well known, but iron is also the metal used at active sites of many important redox enzymes, controlling the rate of oxidation and reduction (loss or gain of electrons) in cellular respiration. The WHO report cited above stated that about 14 percent of iron in a normal iron homeostasis, or healthy individual, is used for other physiological functions than hemoglobin and oxygen transport in red blood cells. Iron is the central atom in heme, a cyclic porphoryn carbon ring that attracts and carries oxygen in the hemoglobin protein. The measurement of hemoglobin (Hgb), the respiratory protein of red blood cells (erythrocytes), is most important to gauge anemia, or a blood deficiency, but the actual meaning of anemia is perhaps not well known in the patient population. For most patients, a diagnosis of anemia indicates a need for more iron, but simple iron supplementation is usually not what the body needs, and often, iron supplementation is not only not helpful, but may cause a variety of problems, especially if the type of iron supplement is difficult to absorb and assimilate. Use of such an iron supplement can lead to constipation and ill health of the gastrointestinal system, and to potential iron overload. Excessive supplementation and poor iron asssimilation is not the only cause of iron overload toxicity, though, and most cases involve a gradual onset and have a complex array of causative factors.

The subject of anemia and iron deficiency is complex, and the complete spectrum of problems with iron homeostasis, from iron deficiency to iron overload, which may occur together, may contribute to various types of anemia

A number of different types of anemia are associated with iron overload toxicity, and when anemia is suspected and confirmed with blood tests, a thorough differential diagnosis needs to be assessed, not just an assumption that you have iron deficient anemia that will resolve by taking a simple standard iron supplement. Today, signs of anemia are almost always responded to with iron supplement, though, not a differential diagnosis to clarify whether the anemia may be a type associated with iron overload toxicity, or due to a number of other causes, especially problems with absorption and assimilation of key nutrients. Anemia indicates a variety of conditions in which the amount of hemoglobin, the number of red blood cells per volume of blood, or the volume of packed red blood cells per volume of blood are deficient. Generally, the concern is for the ability to transport oxygen in the body, rather than the deficiency of volume of blood (oligemia), although decreased volume of blood could stress this system. This ability of oxygen transport is tied to iron and hemoglobin, and when dysfunctions occur in the iron transport metabolism, weakly bound iron in circulation may lead to accumulation of iron molecules in the body, especially the liver, endocrine organs, kidney and heart, which may, in turn, lead to, or contribute to, a wide variety of disorders and disease. Even with iron deficiency, weakly bound, or unbound iron in circulation may deposit in tissues and cause disease. There are many types of anemia, and although it has been part of standard guidelines for decades that the most common type of anemia is iron deficiency anemia, in most populations with a reasonable diet the intake of iron is not the problem. Misshapen blood cells may cause anemia, as in thallasemias or sickle cell anemia, or poor production of blood cells (erythropoiesis) may be the problem. Deficiencies of key nutrients needed to make blood cells (pernicious anemias), such as Vitamin B12 and folates, leucine, isoleucine, zinc, cobalamin, cobalt or iron, may be involved, and often are due to gastrointestinal dysfunction. Gradual iron overload toxicity is associated with thalassemia, sickle cell disease, and myelodysplastic syndromes (problems with hematopoiesis in the bone marrow).

When signs of anemia occur, a differential diagnosis to determine the type of, or cause of, the anemia is very important, both to proper restoration of health, and to avoid problems with iron overload toxicity. In true iron-deficient anemia a decreased concentration of blood serum iron, and increased concentration of TIBC (total iron binding capacity), and a matching low degree of transferrin saturation (the ratio of iron to TIBC times 100), is needed on blood tests. Since the concentration of iron and iron-binding protein (transferrin) in serum varies markedly in different conditions, as well as diurnal variation, these blood test values must be considered in relation to the individual, and the individual's current health, and may need to be repeated to compare values to be sure of the diagnosis. Including analysis of the concentration of serum ferritin more accurately evaluates this chronic deficiency of iron storage and homeostasis. This type of iron deficiency that has caused anemia can only be detected when it is relatively advanced, or chronic, and more persistent and holistic therapy is needed to correct the iron homeostasis when it is diagnosed. We also know from this researched fact that many individuals that receive a normal blood test have a type of iron deficiency that has not yet caused anemia. When your doctor states that the blood test rules out iron deficiency, this is not completely true.

In types of anemia where red blood cells are defective and unable to carry sufficient iron, such as the many types of thalassemia, where the types of hemoglobin proteins that bind and carry iron to release electrons for energy are defective or poorly expressed by the DNA, a simplistic assessment often leads to a misdiagnosis of iron deficient anemia. In these types of anemia, when iron supplement is prescribed, increased iron accumulation and toxicity occurs. Even when properly diagnosed, in more severe cases, blood transfusion and standard iron chelation often is inadequate to prevent problems with iron overload toxicity, especially in liver tissues. While a number of simple and safe natural chelators are proven to work, and are inexpensive, compared to the very expensive and harsh chelators normally used, this type of integrative medicine is rarely utilized.

As with any disease mechanism, there is a differential diagnosis with iron overload toxicity that focuses on the array of causes and types of disease. There is not just one cause for, or type of, iron overload toxicity, and these anemias are just potential explanations. Patients without these anemias or myodysplastic disorders are not exempt from iron overload toxicity. One area of scientific study is the relationship between inflammatory bowel disorders and iron overload toxicity. Inflammatory bowel disorders may not only lead to nutritional deficiencies associated with anemias, but may also induce the creation of excess apoferritin in the intestinal mucosa independently from the iron intake, resulting in too much of the dietary iron bound to apoferritin. This could cause a dysfunction in the feedback regulation of iron homeostasis. An array of health disorders that could contribute to iron overload toxicity may also be seen in a single patient, and a holistic diagnostic view is important. These various disorders that show a prevalence of iron overload toxicity are explained more fully later in this article.

The Question of Hemochromatosis, the role of genetic inheritance, and the often too easy diagnosis of Classic Hemochromatosis without proper diagnostic testing when Iron Overload Toxicity is found

In the United States, if one researches iron overload toxicity, the search results are basically limited to the relatively rare disease called hemochromatosis. Hemochromatosis is the term for an iron storage disease, which should be distinguished from iron overload toxicity. Toxicity may occur over time in hemochromatosis, causing fatigue, weakness, weight loss, abdominal discomfort, and joint pains, but hemochromatosis is not the only potential cause of iron overload toxicity. Most cases of hemochromatosis diagnosed in the United States have been related to a genetic defect, with both parents passing on a defective allele. This is called "classic" hemochromatosis. Even this inherited form is poorly understood, though. It is estimated that only 1 in 100 with this inherited mutation from both parents will experience symptoms. Studies have predicted a range from 1 to 50 in 100 individuals inheriting alleles from both parents of the defective gene becoming symptomatic, though, according to the U.S. Centers for Disease Control and Prevention (CDC). Obviously, the data on this inherited disease is unclear, but we may assume from these statistics that with inherited classic hemochromatosis, which is rare and perhaps only a few percent of patients will exhibit symptoms, that this is not the cause of the many patients now known to be afflicted with altered iron homeostasis and iron overload toxicity. An explanation for this variance in expressed symptoms in classic hemochromatosis is found in the complex array of factors that are associated with iron overload toxicity. Other types of hemochromatosis besides "classic" hemochromatosis do exist, but are largely ignored by a medical community that apparently is unable of reluctant to put two and two together. These types of iron overload toxicity may have both genetic component and an underlying disease mechanism as well. Metabolic syndromes with insulin resistance, hepatitis C related hemochromatosis, iron overload related to fatty liver disease, and other types of iron accumulation and toxicity may be accompanied by genetic causes, but not primarily caused by them. Fully clarifying the diagnosis is the first step in designing an effective treatment protocol. Inherited hemochromatosis is still largely being diagnosed without genetic testing, which is now inexpensive, which is absurd. Even when genetic testing is better utilized, though, to improve preventive treatment, and to clearly diagnose the type of iron overload toxicity, genetic counseling and integration of Complementary Medicine strategies to treat or prevent the manifestation of the disease are not being employed.

In recent years, an attempt to clarify the subject of inherited hemochromatosis has been undertaken, recognizing the problem of the complexity of the disease and the oversimplified diagnostic protocol. The patient should be aware that the classic type 1 form of the hereditary disease, associated with the genetic mutation HFE C282Y, represents about 85 percent of the cases of genetic disease in past studies, and mostly affects patients of Northern European descent. This type of the disease almost alway onset between the ages of 40 to 60, and in women may be associated with hormonal imbalances. To date, four types of genetic hemochromatosis have been identified, with types 2-4 still considered rare. Type 2 (mutations in the HFE2 or HAMP gene, Hepcidin Antimicrobial Peptide gene) is mostly seen as onset in juveniles, and detected with menstrual irregularity and amenorrhea in the teens, type 3 (mutations in the TFR2 gene) is seen mainly in women in the late 20s, and type 4 (mutations in the SLC40A1 gene) is called ferroportin disease, and is generally without symptoms, but with aging may result in liver fibrosis. These types, 2-4, are rare. To demonstrate their rarity, type 4 is seen more often than types 2 and 3, yet by 2010, fewer than 200 cases were reported in scientific literature worldwide. The Type 2 hemochromatosis, onset between the ages of 10-29 clinically, results in deficient production of hepcidin by the liver, which can be measured on blood tests, and prevents regulation of iron absorption in the gut, requiring the patient to limit iron in the diet, as well as address problems with liver health and chronic low-grade microbial inflammation. Chelation of iron to prevent damage to the liver and heart is important. Type 3 hemochromatosis involves the transferrin receptor 2 gene, and may result in poor expression of transferrin receptors, or expressions of proteins that regulate iron homeostasis, related to difficulties with certain amino acid deficiencies. Type 4 hemochromatosis is the only type that is autosomal dominant, meaning that only one parent may have the genetic allele that is passed on.

It is now well recognized that about 75 percent of patients with hereditary hemochromatosis are asymptomatic, or without clinical symptoms. The most prevalent early symptoms of this disease are fatigue (74 percent), impotence (45 percent), and arthralgia (44 percent). The most common diagnostic signs are liver enlargement (hepatomegaly), changes in skin pigmentation (darkening), and arthritis. The most commonly seen arthritic changes were erosions (84 percent), synovitis (77 percent), joint-space narrowing (73 percent), osteophytes or bone spurs (59 percent), bone marrow edema (38 percent), subchondral cysts (30 percent), and tenosynovitis (30 percent). These are detected with MRI. The only approved treatments in standard medicine are phlebotomy (clearing of iron from the blood), and chemical chelation, with side effects. More and more patients are realizing, though, that more can be done than this, and are integrating Complementary Medicine. More and more patients are also realizing that their medical doctors may not have performed a thorough diagnostic testing protocol, and that they may have been misdiagnosed. Patients with genetic testing are starting to realize that this is not a definitive finding of clinical hemochromatosis, as 75 percent or more of patients with these genetic mutations do not experience clinical symptoms, and that there may be a combination of genetic and non-genetic components to their disease. While the complexity of the subject of iron overload toxicity is stressful, this does not mean that the patient cannot find the understanding of their disease that is so important to proper care and prevention.

Standard medicine has stuck to an easy explanation for iron overload toxicity that is not "classic". People obviously sometimes take too much iron supplement, or too much Vitamin C, which may affect iron absorption from the diet. For many experts, though, these flimsy explanations are not sufficient, and so much scientific study has been conducted worldwide to explore the subject of iron overload toxicity.

Standard tests for iron overload associated with hemochromatosis include two simple blood tests, serum transferrin saturation and ferritin level, but many experts state that this is just the first step in such a diagnosis, not the definitive test. Ferritin is an apoprotein that can bind many atoms of iron for storage, especially in the liver. As iron from the diet leaves the intestinal epithelial cells of the membrane, it is attracted to, and binds to ferritin for storage. If, for some reason, the binding sites for iron on the ferritin are full (saturated), the ability to regulate iron stores is diminished, or if the protein that attracts and carries iron in the intestine to ferritin, apoferritin, is overexpresssd and excessively binds dietary iron, the ferritin saturation may be deficient, and ferritin expression decreased. This dysfunction of iron binding and transport in the intestinal membranes may be thus due to problems with apoferritin expression, with increased apoferritin induced by chronic inflammation independent of iron intake causing excess apoferritin binding and deficient ferritin saturation. Transferrin is a glycoprotein in blood circulation (plasma) that controls the level of free iron in fluids. Although the iron bound to transferrin makes up less that 0.1 percent of the total iron in the body, transferrin is still effective in a normal iron homestasis for regulation of free iron, because iron is quickly bound to hemoglogin, myoglobin (muscles), enzymes, and ferritin stores. If the iron homeostasis is abnormal, problems of iron regulation may occur. The total iron binding capacity (TIBC) of blood plasma is the sum of the iron binding sites on transferrin. Normally we take in 1-2 milligrams per day of iron in food, store or use about 3 milligrams in the body, and excrete 1-2 milligrams of iron per day. These blood tests thus show us if we have sufficient ferritin, and whether the sites for iron binding on the transferrin are properly saturated. Of course, there may be more to the picture than this, and a variety of factors could contribute to iron overload toxicity besides the total ferritin and transferrin saturation (TIBC). A number of histological studies (biopsied tissue samples) have shown that iron accumulation and toxicity occur in various disease states even when the diagnostic levels of circulating blood plasma ferritin and transferrin are not at levels needed to meet clinical guidelines to diagnose a hemochromatosis and iron overload. Unfortunately, most experts in standard clinical practice explore the pathology no further.

The objective diagnosis of iron overload toxicity presents problems. A definitive diagnosis assesses iron accumluation in actual tissue samples, but the use of tissue biopsy in all cases is not possible. The use of ferritin and transferrin saturation alone, or even just the ferritin level, is just the first step in diagnosis, and does not rule out iron overload toxicity. Relying on ferritin levels alone is irresponsible. In intial diagnosis and evaluation of iron overload, not only the ferritin level and total iron binding capacity of transferrin (TIBC), but the level of transferrin in the blood plasma is also important. A patient with excess serum transferrin may suffer from iron deficiency anemia, while a patient with deficient serum transferrin may suffer from iron overload toxicity, and possibly protein malnutrition. Abnormalities in circulating transferrin levels may indicate other pathological problems, though. Transferrin are also implicated in some cancer pathologies, with the transferrin receptors attracting antibodies, as well as depriving some cancer cells of the iron needed to spur excess growth. Transferrin has also now been shown to interact with insulin-like growth factor 2 (IGF2), and insulin-like growth factor binding protein 3 (IGFBP3), perhaps slowing the development of certain cancers, such as prostate cancer, where the levels of IGFCP3 are decreased in cases where the benign prostatic hypertrophy (BPH) progresses to metastatic prostate cancer. IGF2 is a protein hormone involved in ovarian function, gestation and ovulation, promoting progesterone secretion during the luteal phase to regulate the menstrual cycle. IGF2 is also involved in a variety of hormonal processes of the body, though, and is linked to neurohormonal pathologies as well. These pathological stressors may alter the transferrin levels. We see that a number of different health problems may be associated with, or caused by, dysfunction of the transferrin homeostasis, and the iron metabolism. A holistic analysis of the problem of iron overload toxicity is required to reach a sensible conclusion.

For patients with chronic inflammatory and rheumatoid diseases, the level of iron stores becomes painfully important. A 1981 research article in the British Medical Journal (BMJ vol 283: 1147-1149; Blake, Waterworth, Bacon) showed that in chronic inflammatory states iron may be redistributed to inflamed membranes and reticuloendothelial cells, and that changes in iron homeostasis, or iron kinetics, occurs. This may be due to an immune mechanism that attempts to deprive iron from pathogenic bacteria by creating more iron storage, to the effects of free iron as a stimulator of reactive oxidative reactions, or to the effects of the inflammatory process and dysfunction on the production of apoferritin and iron transporters in membranes. The normal methods of assessing iron levels, tracking red blood cells and hemoglobin concentration, are insufficient to assess this problem. These normal blood tests adequately assess iron levels in normal healthy patients. In these chronic inflammatory diseases states, though, red blood cell variables, serum iron concentration, and transferrin concentrations do not serve to adequately assess problems with iron homeostasis. Greater amounts of iron are stored in cellular apoferritin proteins as ferritin in these disease states, rendering the normal tests inadequate. This may describe the phenomenon of iron overload toxicity in many cases. Studies conducted decades ago have proven that intracellular iron stimulates increased apoferritin production, and that inflammation may induce synthesis of apoferritin independently of iron levels. A patient with chronic inflammation may have normal levels of red blood cells, hemoglobin, and serum ferritin, yet be both iron deficient, and subject to iron overload toxicity. Today, further assessment of iron homeostasis in these patients, and a recommendation for correction of this important homeostatic mechanism, are not provided.

The first step in improving the assessment of iron overload toxicity when evaluating chronic diseases and difficult or unclear diagnoses is to adopt a more thorough and thoughtful diagnostic testing. As with many type of difficult diagnoses, a step-by-step approach in diagnosis is needed. The WHO report cited above states: "Measurements of heaemoglobin, serum ferritin, serum iron, and transferrin (total iron-binding capacity) enable iron status to be characterized in detail. However, each of these determinations has well-recognized limitations under field conditions, i.e. single or combined measurements of iron status show that response to therapeutic trials is greater than expected. As previously noted, iron deficiency anaemia represents the extreme low end of the spectrum of iron status." These experts recommend that medical doctors go further in evaluation of iron status than simply noting that these basic tests are normal, or near normal. Recognizing that test data does not complete the diagnostic picture, and that a thoughtful and specialized analysis and further testing is needed, is the first step in taking a serious look at problems of iron homeostasis, and developing a holistic protocol to correct them. Integrating with Complementary Medicine would allow standard medicine to achieve this type of holistic and thorough correction of these problems of iron status. The introduction of genetic testing is very helpful in this evaluation, but again does not give a definitive diagnosis, as a majority of cases of inherited genetic mutation, even from both parents, do not result in clinical hemochromatosis. Jumping too quickly to an assumption in diagnosis does not help formulate a correct treatment plan.

Diagnosis: symptoms, signs, and objective testing

The first step in diagnosis of iron overload toxicity is the consideration that this health problem could be responsible for signs and symptoms. Iron accumulation in the organs may cause menstrual problems, hormonal imbalances, hair loss, shortness of breath, and liver dysfunction. If the disease and toxicity progresses to a serious state, liver cirrhosis, cancer, arthritis, diabetes, irregular heart beat, chronic heart failure, and chronic fatigue syndrome may occur. Iron accumulation and toxicity in the gastrointestinal tract may contribute to irritable bowel syndrome and its many variable symptoms. Obviously, this is a big picture of potential signs and symptoms. While standard medicine may only test the serum ferritin to assess the patient, or just the serum ferritin and transferrin saturation, which is called the total iron-binding capacity (TIBC), these tests are useful, but not definitive.

In diagnostic assessment, the potential of iron overload toxicity must consider this within the framework of a continuum of iron homeostasis disorders, often progressing from iron deficiency with anemia, to iron deficiency without anemia, to normal iron status but variable amounts of stored iron, to iron overload toxicity. The iron overload toxicity may be causing the symptoms and associated diseases (comorbidities), or it may be the result of another disease. A thoughtful analysis is needed.

Standard medicine continues to stick with a religiously simplified diagnosis when iron overload is found, considering only the genetic types of hemochromatosis. This is gradually changing as more cases are being diagnosed, and the incidence of insulin resistant liver iron toxic overload is recognized. It is well known that among the genetic types of hemochromatosis, that type 1 C2H2Y +/+ accounts for 95 percent of these cases, but this typically onsets in men between the age of 40 and 60, and in women postmenopausally. For the many patients experiencing problems at a young age, but without evidence of juvenile onset Type 2, which usually is noticed as the sexual hormones become deficient and menstruation stops in the teenage years, the diagnosis of genetic hemochromatosis may be given without sufficient thought and analysis.

Two blood tests that are helpful, serum iron (SI) and transferrin, with a look at transferrin saturation, or total iron-binding capacity, are problematic, in that these have a diurnal variability that is considerable. When testing and evaluating, the net reduction in transferrin saturation is important, as well, as are changes over time. These may be indicated as SI/TIBC. In addition, there is a marked overlap in these values between normal and iron-deficient, and iron overload, subjects. This makes these tests valuable only as a first consideration in building a step-by-step diagnosis and assessment. It is necessary for the patient and physician to realize that they are looking for more than a diagnosis of hemachromatosis, as iron overload toxicity may occur outside of this health problem. A patient with excess serum transferrin may suffer from iron deficiency anemia, while a patient with deficient serum transferrin may suffer from iron overload toxicity, and possibly protein malnutrition. Abnormalities in circulating transferrin levels may indicate other pathological problems, though. These tests indicate potential problems, but do not affirm or rule out iron overload toxicity, or even iron deficiency. More tests are needed, and as always, this objective test data must be applied to the more important signs and symptoms of the individual.

Tests may analyze the serum transferrin receptors as well. These receptors will increase in number as the iron deficiency progresses, and an analysis of receptor level, as well as receptor saturation, provides valuable data. The most common testing method is based on the ELISA assay (enzyme-linked immunosorbant assay). Measurement of transferrin receptors is used to evaluate both iron deficiency and iron excess. Serum transferrin receptor levels increase progressively as the supply of iron to the tissues becomes progressively deficient, but decrease in the prescence of iron overload. The ranges of transferrin receptor levels in the iron deficient patients and iron overload patients do overlap slightly, making this test valuable in the overall testing picture, not a definitive test for diagnosis by itself. Other tests include reticulocyte hemoglobin content, percentage of hypochromic red cells, and hepcidin. Hepcidin is a protein peptide hormone produced by the liver that appears to be a master regulator of iron homeostasis, functioning to regulate iron absorption and transport across the intestinal mucosa, and it also serves as an antifungal. Hepcidin deficiency is associated with iron overload toxicity in cases of beta-thalassemia, a type of anemia where there is deficient iron binding proteins in the red blood cells. Problems with liver function could also lead to a deficient expression of hepcidin. Hepcidin is measured with blood tests (hepcidin-S), immunoassay (ELISA), or in urine (hepcidin-U). An advantage to soluble transferrin receptor levels is that, unlike ferritin levels, this value is not affected by infection or inflammatory processes.

In summary, the diagnosing physician may test for ferritin, TIBC (total iron binding capacity of transferrin), level of serum iron, level of serum transferrin, SI/TIBC (serum iron and total iron binding capacity ratio), level of serum transferrin receptors (ELISA assay), reticulocyte hemoglobin content, percentage of hypochromic red cells, and hepcidin. Of course, these blood tests merely point to problems associated with iron overload toxicity, and are not definitive. The definitive test is a biopsy of tissue and cytological assessment of iron ion accumuluation, especially in the liver tissue. Even if the iron overload toxicity is not fully explored with objective tests and biopsy, suspected iron overload toxicity may be treated with safe and effective strategies in Complementary Medicine that do not present the harsh adverse effects and risks of allopathic medicine and pharmaceutical chelators. The side effects of these Complementary Medicine protocols is better overall health.

In addition to this more thorough diagnostic workup, which is rarely performed, the American Hemochromatosis Society recommends inexpensive genetic testing now. Since many individuals may carry the genetic alleles that are passed on to potentially affect an array of genes that are linked to iron homeostasis, not only the patient, but the parents may be tested. The company 23 and me (www.23andme.com) offers 99 dollar tests now, and the company Gene Track (www.hemochromatosisdna.com) is also recommended at about 195 dollars. Home kits that collect saliva samples are used, eliminating the expense of the doctor office visit and consult fees. While the finding of these genes or genetic alleles does not mean that one has hemochromatosis, the absence of this finding would certainly imply that the iron overload toxicity is indeed caused by something other than an inherited disorder. The increasing recognition of insulin resistant, or metabolic, liver iron toxicity as a common cause of hemochromatosis, now called IR-HIO (insulin resistant hepatic iron overload), but there is still poor diagnostic evidence to confirm this type of the disease.

Types of disease with clear association of iron overload toxicity

Irritable Bowel Syndrome (IBS) and iron overload toxicity

Iron overload toxicity may directly affect the intestinal mucosa. Iron is an extremely corrosive substance in the gastrointestinal tract, and such stomach and bowel irritation may result in nausea, bleeding, abdominal pain and diarrhea. Systemic iron overload toxicity may cause cellular toxicity, dysfunction of the liver and kidney, and metabolic acidosis. Taking too much iron supplement, a caustic or difficult to absorb form of iron, or acquiring problems with iron absorption and assimilation may result in iron overload in the intestinal mucosa. Assessment of iron status may be an important diagnostic consideration in IBS.

Transferrin is associated with the innate immune system. Transferrin located in the intestinal mucosa binds iron to withhold it from bacteria that need it to grow, or overgrow. This is one method to control the biota, or vast symbiotic bacterial colony in the intestines. Thus, problems with iron overload toxicity may be associated with unhealthy intestinal function and IBS. Formation of ferritin iron stores occurs when a protein in the intestinal wall, called apoferritin, joins to iron. Accumuluation of protein fragments, or peptides, in the intestinal wall, or mucosa, may inhibit this apoferritin function. Poor protein digestion is seen in most cases of food allergies, celiac disease, poor digestion of glutens, dairy, and nuts, and even in lectin excesses. This can contribute to problems with apoferritin and iron assimilation.

Iron accumulation and cytotoxicity in the intestinal walls is also associated with chronic parasitic overgrowth such as amebiasis. For example, the intestinal protozoan parasite Entamoeba histolytica is a cause of amebiasis, and may produce colitis. Iron is an essential element for growth of almost all microorganisms, especially these protozoal amoebas, as well as synthesis of toxins and virulence determinants in parasitic bacteria. Protozoal parasites such as Trichomonas vaginalis, a common cause of vaginal disease, are aided by iron accumulation, enhancing growth, abscess formation, and cytoadherence (see study link below). Such research demonstrates that the relationship between iron overload toxicity and gastrointestinal dysfunctions such as IBS, even in inherited hemochromatosis, may be a two-way street, with genetic propensities contributing to altered iron homeostasis affecting pathogenic parasites and bacteria, and these pathogenic biotic imbalances triggering the pathogenic expressions of genes associated with hemochromatosis. While the study of iron overload toxicity is still largely confined to subjects with these genetic propensities, it is clear that we need to study the gut microbiota and the dysfunctions of iron absorption in the gut membrane to really understand this health problem. The funding for such study has not appeared.

There is a clear association between altered gut function, imbalances in the gut microbiota, and iron overload toxicity. Altered iron homeostasis involves elevation in both transferrin saturation and serum ferritin levels, with increased iron absorption by the intestine. Although the HFE gene and its altered regulatory HFE protein appears to modulate the transferrin receptor and is associated with other aspects of iron regulation, its precise role in the body remains obscure, and multiple cell types are involved in this iron metabolism. Scientific studies in 2012, at the Technion-Israel Institute of Technology, Haifa, Israel (PMID: 22580926) found that there are indeed consistent microbiotic imbalances in mice with the most common genetic mutations, Hfe and Irp2, that relate to dysfunctional iron metabolism and iron absorption in the intestinal membrane. Whether this relationship is due to the genetic alterations, or rather, the biotic imbalances lead to the altered gene expressions, is still unclear. Either way, restoring gut microbiotic balance appears very important. These imbalances in the gut flora and fauna, or Biota, may explain the link between IBS and iron overload toxicity.

Iron overload toxicity in chronic Hepatitis C

Studies at Hokuriku University and Nogoya University School of Medicine, in 2002, have shown that a majority of patients with chronic hepatitis C are exposed to iron-induced oxidative stress, or iron overload toxicity. Iron reduction therapy has been successful in the treatment of chronic active hepatitis C (Journal of Health Science, 48(3) 227-231). Biopsy specimens of patients with hepatitis C showed that almost all patients had some lysosomal iron load in the liver, and most patients had complications of iron deposition in histochemical study. Although few patients had diagnostic criteria indicating clinical iron overload toxicity, these researchers found that any patient with a serum ferritin level higher than 10ng/ml had an accumulation of iron in the liver that generated free radicals and contributed to hepatitis. These modestly elevated serum ferritin levels were correlated with serum liver enzyme ALT, indicating a relationship between mild cellular iron deposition and liver dysfunction. The authors stated: "The present observations suggest that slight iron overload, although unlikely to be cytotoxic in healthy individuals, may contribute to hepatic injury in patients with CHC (chronic hepatitis C)." Iron reduction for these patients consisted of phlebotomy (bloodletting) and a low iron diet, which brought about sustained improvement in patient health. Since this time, other treatments have been researched and found promising for chelation and reduction of iron overload.

In 2013, studies at the University of Gdansk and the Medical University of Gdansk, in Poland, found that in patients with chronic hepatitis C, fatty liver disease occurred in approximately half of the patients, and that the intensity of the fatty liver disease was milder than in patients with non-alcoholic fatty liver diseases due to the less frequent diagnosis of Metabolic Syndrome in these patients with hepatitis C. Biochemical markers of iron overload toxicity were seen only in the patients with hepatitis C and fatty liver disease, not in those with non-alcoholic fatty liver disease. A correlation exists between the fatty liver disease combined with the inflammatory disease that precludes iron overload. It has also been noted that even moderate alcohol consumption may lead to increased blood serum iron indices, thought to be related to increased oxidative stress causing the decreased expression of a hormone regulator or iron metabolism called hepcidin.

Alcoholic fatty liver disease and iron overload toxicity

Iron overload toxicity is observed in most cases of alcoholic liver disease. Why this occurs and how it contributes to the disease progression has not been well understood. Study of this phenomenon in recent years has revealed that a combination of factors may be needed to exacerbate this liver toxicity, or hepatotoxicity. Iron overload, accumulation and imbalance of polyunsaturated fatty acids (PUFA), and oxidative stress, combine to overwhelm the liver in advanced alcoholism. These polyunsaturated fatty acids, including the essential fatty acids we call omega-3 and omega-6, are not metabolized properly in liver disease. Fatty liver, or hepatic steatosis, is a major feature of both alcoholic and non-alcoholic fatty liver disease, and studies have shown that a depletion of long-chain PUFA, both omega-6 and omega-3 essential fatty acids, occurs in the liver triacylglycerols with a relative decrease in omega-6, while a relative decrease in omega-3 and higher omega-6 occur in the liver phospholipids, or cell membranes. This relative excess of omega-6 in the omega-6/omega-3 ratio, combined with deficient metabolism of essential fatty acids, favors lipid synthesis over oxidation and secretion, leading to fatty liver disease, according to these experts. Such imbalance of essential fatty acids is typical of the modern diet that is dominated by consumption of red meat and simple carbohydrates, but other homeostatic imbalances may also contribute as well, such as liver stress induced by overuse of medicating drugs, aldehyde toxicity, chronic low-grade infection, and of course, excess alcohol consumption.

Normally, with acute iron overload, hormonal and peptide controls regulate the absorption and accumulation of iron. These regulatory chemicals are hepcidin (a peptide hormone discovered in 2000), hemojuvelin (a membrane-bound regulatory protein), and leap-2 (a liver expressed antimicrobial protein). Both increased iron and alcohol up-regulates the genetic expression or leap-2, but in contrast to increased iron intake, alcohol downregulates both liver hepcidin and and hemojuvelin gene expression. Therefore, when excess iron is consumed, or released in the body, excess alcohol intake will nullify the normal controls of iron homeostasis. We see that a variety of factors explain iron overload toxicity in alcoholic fatty liver disease. Obviously, a holistic therapeutic protocol is needed to correct or prevent this problem.

Thalassemia, Sickle cell disease, and iron overload toxicity - the prevalence of concurrent anemia and iron overload toxicity

Thalassemia is considered a type of anemia with a genetic cause, resulting in poor expression of the globin proteins in hemoglobin. Most cases of thalassemia go undiagnosed due to the lack of symptoms, but in studied populations, the incidence is often very high. For example, in the Maldives and Cyprus, island communities in the Indian Ocean and the Mediterranean, where the population was heavily affected by malaria in the past, the genetic allele that would infer potential for thalassemia occurs in 16-18 percent of the population. The genetic allele (autosomal recessive trait) occurs in 3-8 percent of the populations of China, India, Pakistan, Malaysia and Bangladesh, and is very prevalent as well in most of the Mideast. Studies of ancient mummies from Egypt and the Nile delta reveal an incidence of 40 percent. Populations not affected by malaria, as in northern Europe, show an inherited propensity in just 0.1 percent. Another type of anemia associated with monogenesis, or inheritance of a single recessive allele, and is associated with the parasitic disease malaria in the population, is Sickle cell disease, which is also an anemia associate with poor expression of the globin proteins. The essential difference between thalassemia and sickle cell disease is that in thalassemia, the quantity of globins is underexpressed, whereas in sickle cell disease the globins are misshapen, and often dysfunctional. Both of these anemias are highly associated with iron overload toxicity, though. This is because the globins in hemoglobin are the strong binding molecules for circulating iron, and when this system is deficient, iron in the daily diet is weakly bound to various proteins, amino acids and glycoproteins, or circulating freely. In addition, Sickle Cell anemia presents an episodic problem with excess hemolysis, or destruction of problematic red blood cells, overloading the spleen and liver and releasing too much iron into the tissues. A lack of oxygen enhances the pathological mechanism, creating fragility in the hardened and damaged membranes of the red blood cells. Since iron attracts oxygen, this is a somewhat circular problem.

Iron overload toxicity is very prevalent with Thalassemia and Sickle cell disease, as well as other anemias associated with poor quality of red blood cells. As stated, many of these diseases go undiagnosed. The World Health Organization estimates that alpha and beta thalassemias are the most common inherited single-gene (allele) disorders in the world. Obviously, in the environment we have created in the modern civilization, one may be affected by genetic mutations or defects from a variety of environmental chemical and drug effects, as well as radiation, and heavy metal toxicities in the air, water and food crops, and simple inheritance may not explain all of these cases. The threat is real and growing for modern civilization, and hence, the threat of iron overload toxicity related to blood cell quality is also growing.

Iron overload cytotoxicity in Parkinson's Disease and other neurodegenerative disorders

In 2004, the Eve Topf and USA National Parkinson Foundation Centers for Neurodegenerative Diseases Research released a report on findings of the complex pathology of Parkinsonism and other neurodegenerative diseases, and the finding of free iron, or iron accumulation, in the central nervous system, was central to the cascade of events that lead to Parkinson's disease (see study link cited below). These researchers found that the abnormal accumulation of iron in the brain, especially the substantia nigra pars compacta and melanin-containing dopamine neurons. Lewy body, a hallmark of Parkinson's disease, is composed of redox-active iron, altered lipids, and aggregated alpha-synuclein, and it was found that this iron accumulation induces the aggregation, or clumping of alpha-synuclein protein into toxic aggregates in Lewy body. Iron accumulation and cytotoxicity also increases oxidative stress and the generation of reactive oxygen radicals, another hallmark of the disease. The accumulation of iron and reactive oxygen species (ROS) in these cells also degrades iron regulatory proteins via ubiquitination, where the protein ubuquitin (not to be confused with ubiquitol, or CoQ10 enzyme), inactivates regulatory proteins within the cells. These researchers noted: "Radical scavengers such as R-apomorphine and green tea catechin polyphinol (-)epigallocatechin-3-gallate, as well as recently developed brain-permeable VK-28 series derivative iron chelators, which are neuroprotective against these neurotoxins in mice and rats, prevent the the accumulation of iron and alpha-synuclein in substantia nigra pars compacta. This study supports the notion that a combination of iron chelation and antioxidant therapy, as emphasized on several occasions, might be a significant approach to neuroprotection in Parkinson's disease and other neurodegenerative diseases."

In 2009, an Italian vascular surgeon, Dr. Paolo Zamboni, hypothesized that multiple sclerosis could be linked to iron overload toxicity, and proposed that chronic cerebrospinal venous insufficiency (CCSVI) was responsible for insufficient iron clearing, leading to, or contributing to sclerosis of the myelin sheaths in parts of the brain. While this theory is controversial, it is being further studied, and many hospital clinics now offer venous stent surgery to counter CCSVI for a subset of MS patients. Since iron overload is associated with inflammatory disorders, the root of the pathology of Multiple Sclerosis, such research could reveal new complexities to this already complex and confusing pathology. So far, studies have revealed that at least half of MS patients may be diagnosed with CCSVI to some extent, and that about 40 percent of patients with other neurological disorders show signs of CCSVI as well. Whether this venous insufficiency could be the reason for iron overload toxicity is another question altogether. Geneticists have identified polymorphisms in the genes encoding for iron binding and transport proteins that may account for some MS phenotypes (Gemmati D. et al; BMC Med Gen 2012 Aug 10;13(10):70), and have evidence that local iron overload toxicity could affect these genetic controls. Study at Cairo University, in Cairo, Egypt, in 2008, found that iron overload toxicity and upregulation of iron-handling proteins, such as Transferrin receptor, could contribute to the pathology of MS in conjunction with oxidative stress and a proinflammatory environment (e.g. a Th1/Th2 imbalance in autoimmune disease) (Abo-Krysha N, Rashed L; Mult Scler 2008 Jun;14(5):602-8). In other words, iron chelation could be an important part of a holistic treatment protocol in the future.

The role of iron overload cytotoxicity in cancer

Tumor cell growth may be enhanced by iron, and iron deprivation or chelation has been proposed by many cancer experts as a treatment in certain types of cancer. In 2004, the Department of Cancer Biology at Wake Forest University in Winston-Salem, North Carolina, studied the effect of an iron chelator as an effective anti-cancer strategy (see study link below). These experts found that an iron chelator, tachpyridine, exhibited both anti-cancer and cytotoxic effects, and that the iron chelator initiated tumor cell apoptosis (programmed cell death) in cancer cells with a defective p53 (tumor protein 53). These experts noted that defective p53 proteins (tumor-suppressing protein regulators) are found in about 50 percent of all cancer cells, reducing sensitivity to common chemotherapeutic agents. This iron chelator thus presented a new effective strategy for killing cancer cells. Further research found that zinc chelation may also play a role in the effects of tachpyridine. Such studies confirm the role that iron overload toxicity may play in many cancer cell lines, and suggests that iron and heavy metal chelation may be an important strategy for cancer prevention. Of course, a definitive diagnosis, or at least a high probability of iron overload toxicity, should be obtained to justify the use of toxic chemical agents such as tachpyridine or desferrioxamine (Desferal). On the other hand, Compelementary Medicine is providing more and more proven iron and heavy metal chelators that are not toxic.

In 2014, the Harvard School of Public Health did a follow-up to the Nurses' Health Study II (NSHII), which found that the level of red meat consumption is associated with breast cancer risk in premenopausal women, and speculated that the iron in the red meat may play a role in this risk, and that a common genetic mutation, HFE SNP (15 hemochromatosis gene singel nucleotide polymorphism), which is thought to represent about 85 percent of all cases of hemochromatosis, may also be associated and triggered by the amount of red meat consumption. These research experts concluded that ferritin levels and HFE SNPs were not associated with the breast cancer risk in a study of about 2000 patients tests between 1996 and 1999. The study concluded that other chemicals in the red meat were likely responsible for the increased cancer risk. This study does not rule out the role of altered iron homeostasis for all cancers, but does reveal that dietary iron may not be the problem. It also highlights the fact that the most common type of genetic hemochromatosis affects women during the perimenopausal state, and may be highly associated with hormonal changes and imbalance.

Iron and copper overload toxicity, linked to chronic zinc and copper deficiencies, are implicated in the pathology of diabetes

In 2008, studies at the Jilin University First Clinical College in Changchun, China, found that problems with iron homeostasis that led to iron overload toxicity were implicated in diabetes and diabetic complications. Zinc, copper and iron were found to be essential minerals that were required for healthy function of many cells, but that excess accumulation could create toxicity and excessive oxidative stress. Diabetic cellular dysfunction was found to be associated with deficiency of zinc and copper, and overload cytotoxicity of iron and copper. In 2009, the University of Louisville, Kentucky, took up this study and confirmed that dysfunction of iron homeostasis, and iron overload toxicity, did indeed correlate with diabetic pathology, and that iron chelation could be an effective therapy for diabetes (see study link below).

In 2002, a study in France (cited below) found that around 40 percent of patients with type 2 diabetes, or Metabolic Syndrome, with insulin resistance, tested positive for iron overload toxicity (in biopsy studies). Since this type of Metabolic disease is now very prevalent in the U.S. such study presents an alarming red flag concerning problems with iron homeostasis. A study in 2004, at the University of Turin, Italy, found that with non-diabetic patients with nonalcoholic fatty liver disease and without obesity, that 9 percent had signs of iron overload toxicity affecting the liver, and 7.4 percent had signs of peripheral iron overload toxicity. The genetic mutations of hemochromatosis, C282Y and H63D HFE mutations, were similar in these patients to the general population. High serum ferritin levels were markers of severe liver damage, or fibrosis, in hisologic study (biopsy). While iron overload was not correlated with liver fibrosis in these non-diabetic patients, high serum ferritin was. In addition, the findings that nearly 10 percent of non-diabetic patients tested positive for iron overload toxicity in the liver shows the prevalence of this problem (PMID: 14752836 Hepatology 2004 Jun;39(6)).

Treatment strategy for Iron Overload Toxicity

This confusing condition, iron overload toxicity, requires a thoughtful and holistic treatment strategy. The problem is one of gradual dysfunction in iron homeostasis and iron status, and is related to a dysfunctional homeostasis of other essential minerals. Our bodies operate on a complex feedback system of regulation, and this must be restored in a systematic manner. Important molecules, such as minerals and hormones, are highly regulated to prevent health problems. Underlying health problems that may contribute to iron overload toxicity must also be individually assessed and treated. The stress of the modern civilization, dietary problems, environmental pollutants, radiation, etc. lead to prevalent problems of homeostatic regulation. Restoring a healthy metabolism is essential. Correcting both the underlying causes of iron overload toxicity, and the present accumulations in tissues that are causing, or may cause, health problems, are both important. This may be integrated with standard therapies, such as phlebotomy, which temporarily clears excess iron from the circulation, but does not clear it from the accumulation in the organ and muscle tissues. Phlebotomy is increasingly used, and is relatively safe, although some instances of motor or sensory nerve injury, commonly observed vasovagal reactions (drop in blood pressure, fainting), and infection (an increasing threat in hospitals), do occur. Complementary Medicine allows the patient to integrate a thorough and holistic plan to achieve a healthy iron status and homeostasis, as well as to resolve symptoms, and to resolve any underlying causes of the disorder. The treatment plan must address both the chelation of iron accumulation and the restoration of essential mineral balance, as a first line, but also provide a step-by-step approach to correcting causative health problems and restoring iron homeostasis.

Obviously, to restore iron homeostasis, the healthy function of the gastrointestinal tract, site of iron absorption and initial transport, is the first consideration. If symptoms of gastrointestinal dysfunction and irritable bowel syndrome, or inflammatory bowel disease, is apparent, restoration of GI function, regulation of the inflammatory processes, and restoration of the healthy biota are an important step in reestablishing a healthy iron homeostasis. Since iron overload toxicity first affects organ tissues and functions, especially the liver, attention to liver health and function, decrease in fatty liver accumulations, detoxification and restoration of glutathione metabolism, and promotion of a healthy system of inflammatory modulation and regulation are important considerations. Since the liver is the metabolic center of our bodies, aiding liver health and function will increase the ability of the whole body to cope with iron overload toxicity. Since iron overload toxicity is linked to problems in the essential mineral balance of the body, suspected mineral imbalances should be addressed with a proper assimilatable essential mineral supplement formula. Since mineral supplementation may be a problem, use of the best type of professional supplement formula is highly recommended. The carriers of these essential minerals, and the cofactors for absorption are very important. If there are signs of anemia, these should be addressed, as well as signs of simple iron deficiency. Lastly, if there are signs of iron toxicity, adequate measures to chelate iron from the tissues should be implemented.

Treatment of Iron Overload Toxicity

Standard treatment for iron overload still depends on the expensive drug Desferrioxamine (Deferoxamine), which is limited with oral use by poor bioavailability, and hence a treatment with prolonged subcutaneous delivery is used in clinical practice. Other synthesized iron chelators have also had problems in clinical practice, with toxicity from inhibition of iron-containing enzymes, or promotion of iron-mediated free radical damage, which could promote cancer. A 2010 FDA black box warning was issued for the newer iron-chelating drug Deferasirox (Exjade), for risk of kidney or liver failure, liver impairment, gastrointestinal hemmorrhage, and death from myelodysplastic syndrome. Due to failures in drug treatment for iron overload toxicity, the FDA fast-tracked approval in 2011 for another drug, Deferiprone (Ferriprox), approved for thalassemia-related iron overload that has not responed favorably to other drugs. This newer iron chelator showed efficacy in only half of the 236 patients studied, with a 20 percent decrease in serum ferritin achieved. The common side effects included agranulocytosis in 2 percent (lowered white blood cell count), and greater than 5 percent experiencing neutropenia, chromaturia, elevated liver enzymes, joint pain, abdominal pain and nausea. In some studies, greater than half of the patients experienced arthropathy (joint pathology), and 16 percent developed neutropenia, or white blood cell immunodeficiency (V.P. Choudry et al). The search for a safer pharmaceutical iron chelator continues. In the meantime, when the condition becomes severe, the treatment includes removing some of the blood, or inducing anemia. The need for a safer and more effective iron chelation therapy has prompted much research into benign chelators in Complementary Medicine, and an array of adjunct therapeutic protocols to integrate for a more thorough treatment outcome. Not only chelation, but the addressing of associated diseases and health problems, alleviation of symptoms, and correction of the causative underlying problems is important.

One simple product useful in chelation is EDTA. EDTA binds metal and mineral ions, especially iron and calcium, and studies show that while this does not eliminate the heavy metal toxins from the body, they do exhibit diminished reactivity. This form of chelation may not decrease lead and mercury accumulation, but would help with patients that are suspected of having calcified tissue irritation, or problems related to iron ion accumulation. Various herbal chemicals and chlorella are also proven to be potent iron chelators, and provide antixodiant and anti-inflammatory effects as well. These may be combined to achieve a more successful outcome.

Iron ion accumulation is associated with neurodegenerative disorders, tinnitus, postmenopausal osteoporosis, liver cirrhosis, cancer, heart disease, hypothalamic insufficiency, anemia hemochromatosis, and more, and so this form of chelation may be beneficial. EDTA is a widely used initialism for the organic compound ethylenediaminetetraacetic acid, which is a polyamino carboxylic acid, and forms strong complexes with metal ions by donation of electron pairs from the nitrogen and oxygen atoms to the metal ion to form multiple chelate rings. Today, EDTA is a component of natural chelation formulas, which combine a number of researched herbs and nutrient supplement. The World Health Organization paper on iron homeostasis pathologies, including iron overload toxicity, cited above, recommends: "Expand research on iron-EDTA to include not only its current areas of application, but also its use in non-traditional vehicles (e.g. an adequate fortificant, its effect on absorption of other minerals, and the effectiveness of its absorption to influence meal iron bioavailability compared with that from ferrous sulphate). Continue research to determine how EDTA promotes absorption of the non-haem iron pool." EDTA may not only aid chelation of iron toxicty from tissues, but support the healthy homeostasis of iron absorption. We see that the subject of iron overload toxicity is not one of simply adding or subtracting iron from the diet, but of correcting the total iron homeostasis. Iron deficiency and iron overload toxicity may be concurrent, and the use of common iron supplements may present problems for iron homeostasis. Our bodies are not machines with a tank of iron that needs to be filled, but a complex organism with complicated regulation of iron homeostasis. A second simple metal chelator, DMSA (dimercaptosuccinic acid), is also useful in helping your body to chelate iron, and has been found to be less depleting of normal iron stores than EDTA. Since higher dosages of either EDTA or DMSA may be depleting of normal metal ion stores in the body, and even of some other nutrient molecules associated with these metal ions, supplementation with an essential mineral complex after completing therapy, and perhaps even an essential vitamin complex, may be sensible. Concurrent use of N-acetyl cysteine may also aid the iron chelation, as well as benefit the intestinal mucosa and glutathione detoxification. These natural iron chelation protocols have been used for many decades, are safe and fairly effective. Monitoring by a physician is recommended, though, as there are always possibilities of adverse effects, depending on the individual.

Herbal chemicals are being studied and show much promise as well in iron chelation. Scutellaria baicalensis, or Huang qin, a commonly used Chinese herb, is shown to be a strong chelator of iron accumulation, with the active chemical baicalein studied by numerous institutions (see study links below). Quercetin, a component of many Chinese herbs, is also shown to effectively modulate iron biochemistry and aid iron chelation, and is found in the herbs Lou bu ma (Apocynum venetum), Sang ji sheng (Loranthus parasiticus), Fan shi liu (Psidium guajava, or Apple guava), Di er cao (Hypericum, or Saint Johns Wort), and Man shan hong (Rhododendron dahuricum). Milk thistle, or sylmarin, has also been found effective to aid the liver in detoxification of heavy metals. Curcumin, a chemical is a few Chinese herbs, such as Yu jin (Curcuma longa) and E zhu (Curcuma zedoaria), as well as the spice turmeric (Jiang huang), have also been identified as potential iron chelators, reducing levels of ferritin protein in the liver in animal studies. Research into the herbal chemical curcumin has uncovered patented methods of enhancing the effective bioavailability of curcumin, and the product Longvida has been shown to produce much higher circulating levels without adverse effects. In 2009, research at Wake Forest University School of Medicine, in Winston-Salem, North Carolina, U.S.A. found that high dose curcumin acted broadly to affect iron homeostasis, reducing hepcidin, iron accumulation in the liver and spleen, transferrin saturation and serum iron in circulation (Blood Jan.8, 2009; 113(2): 462-469). Of course, iron chelation should not be used long term, as this was proven to potentially contribute to iron deficiency, lowered hematocrit and hemoglobin. In professional herbalism, such herbal clearing herbs and formulas are prescribed in short courses, while blood tonic formulas are prescribed in longer courses as a follow-up in chelating and clearing therapies. Such research demonstrates that with proper and intelligent use of herbal medicine that both iron chelation and improvement in the iron metabolism and production of healthy red blood cells can be achieved. These and other herbs proven to achieve iron chelation are found in scientific studies below in Additional Information with links to the actual studies. Correct dosage, form and quality, as well as the correct combination with other herbs in formula is important in these therapies. As always, acupuncture is symbiotic with herbal therapy to enhance effects. Herbal medicine and acupuncture may also be utilized to treat the many diseases associated with iron overload toxicity, as well as to aid restoration of the gastrointestinal functions, provide antioxidant support, benefit liver function and clear inflammation, etc. The benefits of Traditional Chinese Medicine include the broad array of benefits that fit into an individualized package of holistic care.

Research has uncovered some unique aids to iron homeostasis. Lactoferrin, also known as lactotransferrin, is a glycoprotein that is widely used in our bodies, and an essential part of colostrum, or the part of mother's milk that helps establish the programmed immune system. Lactoferrin is widely used in the adult human, as we see it as a major component of blood plasma, neutrophils, saliva, tears, gallbladder and pancreatic secretions. A lower concentration of lactoferrin is found in cow's milk, but modern methods of homogenization may destroy the integrity of this glycoprotein. Lactoferrin is also a component of whey protein. Supplements are now available to achieve an effective dosage and concentration, as well as to aid utilization and supply the safest and most effective form of lactoferrin. One form, apolactoferrin is preferred by experts because it is iron-depleted, and thus better able to bind free iron, as well as zinc, copper and other metals. The affinity for free iron is 300 times that of other transferrins, and this affinity is boosted in a weakly acidic medium, such as is found in many inflamed tissues, where the pH is decreased due to accumulation of lactic acid and other acids. Lactoferrin is a transferrin protein, and acts by binding and transporting iron ions, but it is also able to bind with nucleic acids, more directly aiding cell nucleus functions. This ability gives lactoferrin the potential to inhibit retrovirus expression, potentially aiding the inhibition of herpes, HIV, and even some common cancer cell lines. Potentially, the use of lactoferrin could greatly aid diseases caused by, or aggravated by, iron overload toxicity.

The USDA website of Dr. David Duke, entitled Dr. Duke's Phytochemical and Ethnobotanical Databases, lists a number of herbs with chelator activity, including Ze xie (alisma plantago), Aloe vera, Scutellaria lateriflora and churchilliana (Skullcap and hybrid Skullcap), Acacia catechu and many species of acacia, Yarrow, and Acorus calamus (Calamus), as well as date palm fruit and carob. Plant lignins, tannins, and polyphenols, components of many Chinese medicinal herbs, are listed as the chelators. Green tea catechins have also been studied as significant iron chelators. Use of a comprehensive treatment protocol, rather than dependence on just one herb, is highly recommended. While simple chelation methods may not yield dramatic results, incorporation into diet and lifestyle over time is recommended as well, with consumption of green tea, date and carob, aloe vera, whey protein supplement, and raw milk, or cheeses made from raw milk.

Detoxification

Many claims are made of simple herbal products to detox the body and this is very appealing to the public. The herbs do not directly detox the body, though, unless they are direct chelaters, able to conjugate with and transport heavy metal toxicities. Instead, the herbs useful in detoxification aid the body's own processes of detoxification, which are highly developed in the human physiology, and often need to be optimized with healthy choices in medical treatment as well as diet and lifestyle. Utilizing a professional Complementary Medicine physician, such as a Licensed Acupuncturist with extensive herbal knowledge as well as experience with nutrient medicine, insures that this process of detoxification is achieved.

To make the most intelligent choice of products to detox, it is best to understand what this process really is. Detoxification in the body is mostly performed by the liver, which houses Kupfer cells that contain rich quantities of macrophages to clear unwanted cells and toxins from the blood, and is also able to conjugate difficult toxins to bile salts to facilitate excretion if these chemical cannot be broken down. The other major way of clearing in the body is thus by excretion from the intestines and bowel. Excretion of toxins via the fluids, by sweating and urination is a much less effective way of elimination in the body. Health of the liver and intestinal tract is therefore of utmost importance in detoxification. The kidney plays a less potent role to excrete, ridding the body of excesses of normal chemicals that are broken down in the detoxification process, but many toxins are not able to pass the blood filters into the kidney.

Standard detox regimens include 1) aiding the liver to cleanse the blood more efficiently with diet, herbs, supplements and acupuncture, and 2) aiding the bowels in the elimination and excretion of stored toxins through fasting, colon cleanse, diet, herbs, probiotics, and acupuncture. Added to this is 3) tissue clearing through antioxidant activity and chemicals that attract and bind to heavy metals, such as EDTA (chelation). Clearing of toxins via sweating is touted but has little significant effect in studies. The number of ways that we might help the detoxification processes in the body are numerous, and should be tailored to the individual goals. Standard modern medical practice utilizes activated charcoal and milk thistle to detoxify the liver when acute liver toxicity threatens the health, utilizing both methods with great success, and both of these products are available and safe in standard practice. Chelation therapy using strong intravenous chemicals is also becoming a popular practice across the world, although it is still not accepted by the standard medical community in the United States except with acute threatening toxicities. For nontoxic chelation a formula utilizing EDTA and chlorella is now standard and effective for helping the body to eliminate heavey metal toxin accumulation. For patients concerned with accumulated toxicity that is less acute, and simpler, such as toxicity from cigarette smoking, alcohol abuse, or common environmental pollutants, a course of herbs and key nutrient supplements to enhance the liver glutathione and enzyme metabolism may be the focus of therapy, and acupuncture may enhance this process greatly.

Addressing liver health is of prime importance in detoxification. It is best to decrease the stress on the liver by decreasing the amount of chemicals in the body, by adopting a more natural diet and home environment, and by decreasing medication dependency whenever possible. Most drugs are immediately broken down by a certain percentage in the liver (over 4-12 hours), although some directly deposit in the body tissues, such as muscle, fat and bone, and may accumulate, just as other chemical toxins do. The rate of immediate breakdown, or catabolism, is called the half-life, implying that half of the drug is broken down into metabolites in a short period of time. This determines the time between dosage of the drug. The more prescription drugs that are taken the more stress is placed upon the liver detoxification system, probably resulting in less efficiency in detoxifying unwanted chemicals or pollutants that we ingest by eating, drinking or breathing, as well as the other drug metabolites. When the liver is unable to clear toxins and chemicals efficiently, these environmental toxins and drug catabolites may circulate and deposit in the body tissues, often with fatty encapsulations to prevent contact with normal tissues. This type of tissue accumulation increases over time and eventually contributes to degeneration, disease and aging.

The rate, or efficiency, of toxin breakdown, or catabolism, in the liver is primarily determined by the enzyme metabolism. Enzymes are a class of molecules, mostly proteins, that regulate rates of metabolism and catabolism. When the liver is dysfunctional, the blood tests show that the liver enzyme transanimases are high in circulating blood. These are termed AST and ALT on your blood tests. High transanimases in circulation implies a problem with liver function, and/or high stress put upon the liver. Normal levels are exceeded in liver disease, but even levels in the high end of the normal range imply liver stress of a subclinical nature. More important enzymes of detoxification, such as glutathione peroxidase, are not routinely analyzed in blood tests. Enzyme metabolism may be normal on the blood test, but the liver may still have problems affecting detoxification metabolism. If the liver tissues accumulate toxic metabolites, such as oxidant free radicals, the tissues may become inflamed, and may harden (cirrhosis), and this may decrease efficiency of liver metabolism significantly. Fatty accumulation in the liver in the form of stored glycogen may also decrease the capacity of the liver to detoxify, as well as trap toxins in fatty accumulations. Excess consumption of fructose contributes greatly to this fatty liver accumulation, and poor liver function, or excess liver stress impairs the ability to the liver to catabolize glycogen stores at a fast enough rate. Therapy is directed toward clearing antioxidants and protein fragments, increasing circulation, and aiding the enzyme and glutathione metabolism in the liver. The degree of ill health of the liver is determined by the physician, who then prescribes the most tailored logical combination of herbs and supplements. Typically, a short course of herbal formula, with milk thistle, Vitamin B6, L-cysteine, L-glutamine, OptiZinc, alpha-lipoic acid, and N-acetylcysteine optimize the goals above. Proteolytic enzymes may also benefit tissue clearance in the liver. This course of nutrients optimizes various antioxdant pathways and provides the best bioavailability of glutathione, the key antioxidant.

The subject of detoxification is not as simple as many advertisers would lead you to believe. A simple change in diet with a mild herbal formula that aids the intestinal tract helps, but is only mildly effective. Once again, the medical advice presented on medical websites such as this one is more complicated than we would wish for. The idea that the human physiology is simple, and correcting problems with our health can be achieved with the magic pill or simple routine, is a fairy tale, though, that we all buy into in a consumer society. It's easier to advertise simple solutions, and so this is what we repeatedly hear. Reality is more complicated, but can be simplified by putting the process into the hands of a professional and following the professional advice.

So what about all these advertised products to detox and colon cleanse?

We see that products with a few simple herbs may help but are not the complete answer to detox. The claims are overblown. Be especially wary of products that don't list the ingredients, spend too much on advertising, and support the product with the endorsement of a single M.D. Standard medical schools provide no instruction in herbal medicine and little nutritional medicine. Trust the professional herbalist that has graduated from a medical college specializing in Traditional Chinese Medicine (acupuncture et al) or Naturopathy. To really achieve detox one should work to develop a complete program. Guidance by a professional holistic or naturopathic physician is highly recommended due to the complexity of the process. There are a number of products that can be very potent and valuable in detox, though. Let's discuss a few of these most valuable products I use and see and how they work.

Glutathione S transferase is a family of enzymes of the liver that is used by cells to detoxify and clear toxins and drugs from the body. The P450 and glucuronosyl transferase are emphasized in drug clearing metabolism, but the glutathione enzyme activity has a greater relationship to clearing toxins and cancer causing compounds. Sandalwood essential oil (most safely taken as alcohol extract or double boil water extraction), St. Johnswort and other herbs are found to be potent in increasing this enzymatic activity, as well as the combination of nutrient supplements already mentioned. St. John's Wort (Di er cao), contains a high level of quercetin and quercitrin as well, potent antioxidants, as do many Chinese herbs used to clear and protect the liver. Milk thistle has been well studied and found to benefit liver function and speed enzymatic detox, as have schisandra berries (wu wei zi), turmeric (jiang huang), and alpha lipoic acid (R-lipoic acid is the more active form). Schisandra chinensis berries have been proven to significantly increase the liver glutathione level and glutathione reductase enzyme activity. A percentage of the population lacks the 2D6 gene and has difficulty in liver detox metabolism, and these people are especially in need of herbal and nutrient aids. Studies also confirm that a percentage of the population lacks other significant genetic coding for liver detoxifying enzymes, P450, glutathione S-transferase, and N-acetyl transferase, increasing their risk for leukemia and stomach cancers significantly. The benefits of these detoxifying regimens in preventative medicine appear great in recent scientific study (see citations below).

Activated charcoal is very effective to attract toxins from the intestinal tract. Flax, fennel and fenugreek seeds have long been used in traditional medicine to cleanse the intestinal tract. The best way is to mix the seeds, take a heaping tablespoon each day, soak in warm water, and then chew thoroughly and swallow. This tastes weird because of the mucilage, but will be very effective if taken for a week or so daily.

Most advertised herbal detox formulas use simple herbal strategies with fennel, dandelion root, etc. These herbs are beneficial but not extremely effective chemically in aiding liver function or bowel elimination, and they certainly do little to aid chelation. These herbal products are often based on the most common herbs appearing in research, are very gentle, and may have little noticeable impact, and thus generate less complaint of the common clearing effects sometimes seen when the body goes through a more vigorous detoxification, which may include itching, stomach upset, or loose bowel movements. Does the patient know that these products are working? The answer is no. These products are kept simple and achieve mild stimulation, giving the patient the impression that they are detoxing because they feel a little better when a healthy diet and herbal supplements are used. Most often these simple commercial products do not utilize sound science and have exagerrated claims of effectiveness. While commonly advertised detox herbal products may not provide a strong detox stimulation, they can't hurt. Dandelion, burdock, fennel, fenugreek, and nettle can all be added to your diet and give benefit in aiding the body's natural detoxifying mechanisms. To achieve a potent detoxification, though, utilizing professional individualized protocol to achieve specific detox goals is recommeded.

To reiterate, detoxification and removal of stored heavy metals (chelation) are processes that each healthy body engages in daily. The patient may want to increase the rate of detoxification and chelation, and a variety of strategies, ranging from very gentle, to very strong, are available. Very potent chelation and detoxification needs to be supervised in a clinic, while gentle protocols can be utilized at home, or with therapy from a professional herbalist and Complementary Medicine physician utilizing nutrient medicine. Products on the grocery or drugstore shelf may not be dependable, or may be too gentle. A TCM physician with knowledge of this therapy may utilize three strategies. One, herbs and supplements that are proven to aid the liver in its natural detoxification processes, and the glutathione system in its cellular detox can be prescribed; two: intestinal clearing may be aided by herbal formulas, activated charcoal, and various specific herbs and nutrients, individually prescribed on a case-by-case protocol; and three: chelation of heavy metal and toxin accumulation in tissues can be stimulated with a variety of herbal and nutrient products. You may read more about chelation of heavy metals, and heavy metal environmental toxins on another article on this website, and you may read more about the glutathione metabolism as well.

Information Resources / Additional Information

  1. By 2014, many University Medical School programs, such as this at the Polytechnic Institute of Porto, Portugal, expanded their teaching of iron overload syndromes and the continuity of pathologies of iron metabolism in light of research findings in the last decade that overturned the standard guidelines and diagnostic ideas that iron overload toxicity was merely and simply a genetic disorder that prevented normal iron storage regulation. These researchers are also noting that new therapeutic strategies are being implemented to address problems with iron homeostasis: http://www.ncbi.nlm.nih.gov/pubmed/24478115
  2. As far back as 1986 researchers were aware that iron overload toxicity is highly associated with chronic inflammatory diseases. In this study, patients with the autoimmune inflammatory disorder ankylosing spondylitis were evaluated, and researchers found that the levels of cellular iron corresponded to ESR and IgA/IgG, markers of inflammation, as well as circulating transferrin, lactoferrin, and total iron, but not to the serum ferritin, the test most commonly relied upon to assess iron status: http://www.ncbi.nlm.nih.gov/pubmed/3789818
  3. By 2012, research had discovered that levels of the immune cytokine TNF-alpha were associated with iron deficiency in early stages of inflammatory disease, and that the hormone hepcidin deficiency with iron deficiency and iron overload toxicity in later stages: http://www.ncbi.nlm.nih.gov/pubmed/22842669
  4. A 2015 study by experts at the Icahn School of Medicine at Mount Sinai, in New York, U.S.A. and the University of Melbourne and the University of Technology Sydney, in Australia, noted that iron overload toxicity is associated with neurodegenerative disorders such as Parkinsonism and Alzheimer's disease, and suggested that excess iron supplement in infant formula could contribute. Iron accumulation is known to gradually increase with age, and infant formula could be one of the contributors, with a variety of factors potentially contributing: http://www.ncbi.nlm.nih.gov/pubmed/26100754
  5. In 2015, experts at the University of Rome, Italy, confirmed that iron accumulation overload is associated with lipid imbalance and liver function in obesity independent of weight changes. Much research has linked iron overload toxicity to insulin resistance and obesity, but it has been unclear whether this is a result of the obesity and insulin resistance of a cause: http://www.ncbi.nlm.nih.gov/pubmed/25843660
  6. A 2014 showed that dysfunction of iron homeostasis and elevated ferritin (iron) in blood circulation affects glucose homeostasis and contributes to insulin resistance and type 2 Diabetes, or Metabolic Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/25842584
  7. A study in 2003, at the University of Patras Medical School, in Patras, Greece, shows that infants born of patients with Metabolic Syndrome, or Type 2 Diabetes, had a significantly higher risk of iron overload toxicity, showing the connection between metabolic systems and iron homeostasis: http://www.ncbi.nlm.nih.gov/pubmed/17003017
  8. This 2008 report, by experts at the Harvard School of Public Health, the University of Buffalo, and the University of Florida, shows the the hormone hepcidin, mainly expressed in the liver to negatively regulate iron uptake and release into circulation at both the transferrin and intestinal membrane enterocytes, is expressed via a complex feedback system, demonstrating how iron homeostasis is not a simple process. These experts point out that hepcidin is also expressed in monocytes and alveolar macrophages, fat cells, and cells of the kidney, spleen and heart, with a number of poorly understood functions. These studies show how hepcidin and iron homeostasis is tied to the inflammatory processes in such as complex way that we still do not fully understand the whole system: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764359/
  9. A 2015 study at the National University of del Sur, in San Juan, Argentina, showed that both iron deficiency and iron overload toxicity, or dyshomeostasis of iron metabolism, is involved in several forms of chronic lung disease, and that iron detoxification is facilitated by ferroportin and ferritin, showing that both iron deficiency and iron overload do occur simultaneously, and that elevated levels of ferritin and ferroportin may indicate an ongoing process of iron detoxification, especially when other signs of iron deficient anemia are absent: http://www.ncbi.nlm.nih.gov/pubmed/26047483
  10. A review of one type of CNS disorder linked to altered iron homeostasis, Restless Leg Syndrome, by experts at Johns Hopkins University School of Medicine, shows that localized iron deficiency can exist in spite of normal serum iron levels. This shows clearly that iron homeostasis is much more complex than simple iron deficiency and dysfunction in this iron metabolism may contribute to a variety of diseases, including CNS disorders. This iron deficiency localized in the brain has also been linked to Multiple Sclerosis and other pathologies: http://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/restless-legs-syndrome/what-is-rls/causes.html
  11. By 2007, research in France established a clear diagnostic guideline for the differentiation of the two most common types of hemochromatosis, genetic or insulin resistant, with insulin resistant hepatic iron overload (IR-HIO) finally recognized as a prevalent cause of the disease: http://www.ncbi.nlm.nih.gov/pubmed/18584923
  12. Also in 2007, meta-analysis of research concerning hemochromatosis, or iron overload toxicity, associated with Hepatitis C, by researchers at the University of Milan, Italy, noted that while genetic basis for these syndromes are common, often the genetic component (HFE gene mutation, or High Ferrous Iron protein) contributes to the disease, while a large percentage of cases are actually linked to Hepatitis C and Metabolic Syndrome, as well as development of fatty liver disease. The HFE genetic mutation concerns a protein that regulates iron metabolism by affecting the interactions of the transferrin receptors on our cells with transferrin, and is associated with the most common form of hemochromatosis, the C282Y genetic variant, and the regulation of the iron storage hormone hepcidine: http://www.ncbi.nlm.nih.gov/pubmed/17640859
  13. While there is still much disagreement concerning hemochromatosis, this 2007 meta-review of the pathology by experts at the London Health Science Center elucidates some of the data and disagreements. It was noted that 1 in 227 Caucasians in North America may test positive for the most common related gene mutation of C282Y, seen in up to 90 percent of patients, yet the diagnosis of hemochromatosis is still relatively rare. Population studies have also noted that about 10 percent of patients, serum ferritin is elevated, but only about a third of these patients will test positive for the genetic mutation. Most physicians still rush to diagnose a patient with high serum ferritin as hemochromatosis patients, without genetic testing, and prescribe phlebotomy, despite the fact that no randomized clinical human trials of the effectiveness of phlebotomy have been performed, and many documented patients have been followed and suffered no increase in serum ferritin from their baseline diagnosis, or liver damage, despite refusing phlebotomy: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2657669/
  14. In 2014, the subject of poor standards of assessment and care in the diagnosis of hemochromatosis was finally addressed by experts at the University do Porto, Porto, Portugal, revealing that while finally medical doctors are utilizing genetic testing to assess diagnosis of hereditary hemochromatosis, that genetic counseling is not being requested. Since a great majority of cases of genetic mutations of the iron homeostasis controlling genes do not result in a clinical disease, and that a vast majority of the most common types of genetic mutation associated with hemochromatosis do not express clinically till the age 40-60, this pattern clearly shows that while testing guidelines are finally improved, the sensible course of counseling and treatment in early prevention is not being addressed: http://www.ncbi.nlm.nih.gov/pubmed/24399095
  15. In 2013, this review of non-HFE hemochromatosis (not the most typical type 1 genetic hemochromatosis), was presented by experts at the University of Rennes, Rennes, France, and concluded that biologic and imaging tools, such as genetic testing and MRI, should be utilized, and that a multidisciplinary approach is essential to support the diagnosis and treatment, or management, of this usually slowly progressing and rare disease. Complementary Medicine is gradually being considered as a part of this multidisciplinary approach: http://www.ncbi.nlm.nih.gov/pubmed/24321703
  16. Simplistic supplementation with common iron supplements are not the complete answer to problems with iron metabolism, and used alone may in fact contribute to problems with the health, as well as the iron metabolism. This 2005 study at the University of Innsbruck, Austria, found that in laboratory mice with the genetic abnormalities observed in classic hemochromatosis, that iron supplements increased the expression of hepcidin in the liver, as well as decreased the iron regulatory protein (IRP), one of the main genetic abnormalities noted in hemochromatosis. The simplistic iron supplementation also reduced genetic expression of divalent metal transporter-1 (DMT-1) and duodenal cytochrome b (Dcytb) in the intestinal membrane cells, or enterocytes. These findings clearly show that a complex feedback system is involved in the disease, not just the inherited genetic alleles and altered regulatory protein expression. A more holistic view is necessary to correct such a feedback cycle, even in patients with a genetic mutation diagnosed: http://www.ncbi.nlm.nih.gov/pubmed/15744772
  17. As far back as 1989, studies such as this one, at the Department of Clinical Biochemistry, in Zeist, The Netherlands, in a large randomized controlled human clinical trial of 166 children with a similar anemia and Vitamin A deficiency, found that supplementation with Vitamin A precursors in children with low serum ferritin and hemoglobin concentration resulted in restoration of homeostasis of retinol, retinol-binding protein, serum ferritin, and saturation of transferrin in just 2 months. A recommendation that large dosage of Vitamin A precursors, such as beta-carotene, lycopene, anthocyanins, Retin-A, etc. be used periodically to control iron overload toxicity was noted: http://www.ncbi.nlm.nih.gov/pubmed/2756920
  18. A 2014 study in Australia, found that lactoferrin in bovine colostrum binds strongly to iron and could suppress reactive oxygen species related to iron toxicity and inflammation in heme, as well as ferritin bound iron that accompanies chronic inflammation: http://www.ncbi.nlm.nih.gov/pubmed/25280951
  19. A 2012 study at Brigham Young University, in Provo, Utah, U.S.A. found that high phospate levels inhibit iron homeostasis by decreasing iron ions (Fe3+) from loading onto iron transport proteins (transferrin), and that a high dose Vitamin C could prevent this disruption of iron homeostasis. High phosphates are derived in the diet from carbonated sodas, canned iced teas, beer, high protein diets, chocolate sweets, ice cream, candy, skim milk powder, commercial bakery goods, and processed cheeses and meats. Lowered kidney function, chronic infections, thyroid and parathyroid problems, chemotherapy, magnesium deficiency, COPD, and statin drugs may cause excess phosphate, or hyperphosphatemia, in the blood circulation: http://chemocare.com/chemotherapy/side-effects/hyperphosphatemia-high-phosphate.aspx#.VH4w39Z4SSA
  20. A 2003 dissertation submitted to the Swiss Federal Institute of Technology Zurich, provided evidence that poor iron homeostasis significantly decreased the utilization of iodine and that supplementation with iron could dramatically reduced thyroid goiter in children who were receiving standard iodine supplementation in salt: http://e-collection.library.ethz.ch/eserv/eth:26314/eth-26314-02.pdf
  21. A number of herbal and nutrient chemicals have been studied and found effective in reduction of iron overload toxicity. This study at the University of Massachusetts, in 2007, found that quercetin, chrysin, rutin and a number of phenolic flavonoids in Chinese herbs show promise, and that quercetin appears to effect iron chelation as well as reduction of free radical oxidants associated with iron overload toxicity: http://www.ncbi.nlm.nih.gov/pubmed/17992280
  22. A 2009 study at the University of Massachusetts Department of Chemistry and Biochemistry found that baicalein and baicalin, 2 active chemicals in the Chinese herb Huang qin (Scutellaria baicalensis) are strong iron chelators. These herbal chemicals act via a combination of chelation and free radical reactive oxidant scavenging mechanisms, and may play a vital role in modulating the body's iron homeostasis. These researchers also found that the herbal chemicals inhibit Fenton chemistry, by which free iron in the body is oxidized to active iron and reactive oxygen molecules: http://www.ncbi.nlm.nih.gov/pubmed/19108897
  23. An 2012 article in Clinical Chemistry shows that transferrrin receptor levels do provide a reliable indicator of iron status, indicating either deficiency or excess. Some overlap in the ranges of the patients with either deficiency or excess indicate a need for other tests as well, but make this test valuable in the overall evaluation of iron status: http://www.clinchem.org/content/44/1/40.long
  24. A 2006 article in the Clinical Journal of the American Society of Nephrology shows how the need for a more thorough testing of iron status has become apparent. The use of serum ferritin and transferrin saturation (TIBC) alone has been recognized as inadequate, especially with the rise of serum ferrition levels greater than 800, indication iron overload, but potentially affected by inflammatory disease. These experts recommended tests for reticulocyte hemoglobin content, soluble transferrin receptor levels, percentage of hypochromic red cells, and hepcidin, a liver peptide.: http://cjasn.asnjournals.org/content/1/Supplement_1/S4.full
  25. Problems with iron homeostasis may affect more than just hemoglobin and red blood cells. Here, a 2003 study at the University of Oulu, Finland, found that transferrin receptors and iron regulatory proteins were also expressed in platelets, clear cell erythrons that regulate blood clotting factors, and express growth factors: http://www.ncbi.nlm.nih.gov/pubmed/12656741
  26. A 2008 study by the Yonsei University College of Medicine in Seoul, South Korea, found that iron cytotoxicity is integral to parasitic growth and intestinal disease, as well as growth and adherence of various protozoal and bacterial infections throughout the body: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2526291/
  27. A 2004 study by the Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research found that iron overload, or cytotoxicity, was integral to the etiopathology of Parkinson's disease and other neurodegenerative diseases, both by inducing "sticky protein" accumulation and promoting oxidative stress that may degenerate neurons and inhibit protein regulation in the brain cells: http://www.ncbi.nlm.nih.gov/pubmed/15655262
  28. A 2008 study at Cairo University in Egypt found that dysfunction of the iron metabolism related to iron overload toxicity is associated with all stages of Multiple Sclerosis. Although the iron levels were within normal levels, the serum transferrin receptor levels were significantly higher, indicating increased iron turnover, a finding associated with active inflammation and oxidative stress.: http://www.ncbi.nlm.nih.gov/pubmed/18408021
  29. A 2014 report by experts at the University of Florida School of Medicine, Department of Psychiatry, noted that up to a third of patients with a substance abuse disorder now report abuse of medications to treat ADHD, and perhaps more than a third of adults with a diagnosis of ADHD report a history of substance abuse disorder! This may be a conservative estimate, according to some sources. The creation of drug addicts in the treatment of ADHD is amazing and alarming, but the public seems not to notice. These psychiatric experts now recommend Complementary and Integrative Medicine in the the standard treatment protocols, both to prevent drug abuse and addiction, and to improve treatment results of ADHD, which is being ignored as well. The evidence-based treatments recommended include herbal medicine, diet and nutritional medicine, iron supplements and neurofeedback: http://www.ncbi.nlm.nih.gov/pubmed/24393762
  30. A 2013 study at the University of Gdansk and Medical University of Gdansk, in Poland, found that iron overload toxicity correlated with fatty liver disease in half of patients with chronic hepatitis C, but not with patients with non-alcoholic fatty liver disease: http://www.ncbi.nlm.nih.gov/pubmed/23924495
  31. A 2003 study by the National Institutes of Health (NIH) of the United States of America, noted that iron overload is frequently observed in alcoholic liver disease, although this was poorly understood in 2003. Subsequent study found that a combination of essential fatty acid imbalance in liver cells drove fatty liver accumulation and decreased oxidative metabolism, and deregulation of the synthesis of hormones and hepcidin may also be associated. Hepcidin is expressed in the liver and regulates iron absorption and metabolism by inhibiting iron release from cells, and it was found that even moderate alcohol consumption leads to increased serum iron: http://www.ncbi.nlm.nih.gov/pubmed/12957293
  32. A 2013 study at Tongji Medical College, in Wuhan, China, found that the Chinese herbal chemical quercetin exerted a significant iron-chelating antioxidant effect on laboratory animals with induced alcoholic fatty liver disease, especially when combined with ferric nitrilotriacetate. Quercetin is now standardized and often combined with resveratrol, another Chinese herbal chemical which is proven to aid cellular detoxification, glutathione metabolism and oxidative damage induced by iron overload. A combination of quercetin, resveratrol and milk thistle may do much to alleviate iron overload in liver disease: http://www.ncbi.nlm.nih.gov/pubmed/23928830
  33. A 2004 study at Wake Forest University Department of Cancer Biology found that an iron chelator, tachpyridine, has an anticancer and cytotoxic effect that would inhibit cancer cell growth and promote apoptosis (programmed cell death) in cancer cells affected by iron overload toxicity: http://www.ncbi.nlm.nih.gov/pubmed/15081867
  34. Iron overload toxicity, as well as accumulation of copper metal toxins, were found to lead to diabetes and diabetic complications, and that zinc and copper deficiency led to a higher risk of these metal overload toxicities: http://www.ncbi.nlm.nih.gov/pubmed/18274991
  35. In 2009, the University of Louisville, Kentucky, confirmed that dysfunction of iron homeostasis and iron overload toxicity was implicated in diabetic pathology, and that iron chelation could be an important part of the treatment protocol for both diabetes and metabolic syndrome: http://www.ncbi.nlm.nih.gov/pubmed/19149565
  36. A 2002 report from the Department of Internal Medicine and Hepato-gastro-enterology in Gad Cedex, France, found that the most prevalent disorder associated with iron overload toxicity was insulin resistance in the liver, and that around 40 percent of type 2 diabetics (Metabolic Syndrome) were found to have iron overload toxicity: http://www.ncbi.nlm.nih.gov/pubmed/12442073
  37. A 2013 study at Southern Medical University, Guangdong, China, found that the Chinese herb Plastrum testudinis (Gui ban, or fresh water turtle shell extract) may be very effective in the adjunct treatment of various anemias associated with iron overload toxicity, including beta-thalassemia and Sickle Cell anemia, both in promotion of the key red blood cell types, generation of healthy hemoglobin, and activation of anti-inflammatory pathways associated with these diseases (p38 MAPK pathway and histone expression): http://www.ncbi.nlm.nih.gov/pubmed/23588991
  38. A 2013 study at the University of North Carolina, School of Pharmacy, found that chemicals in the Chinese herb prepared Rehmannia Radix (Shu di and Sheng di huang) have been found to be beneficial in treating Sickle Cell anemia, a cause of iron overload toxicity, and that these chemicals are currently in phase 1 human clinical trials in the United States: http://www.ncbi.nlm.nih.gov/pubmed/18404317
  39. Lactoferrin, or lactotransferrin, is increasingly studied as a potent aid to iron homeostasis and immune health. The studies on lactoferrin have noted significant benefit in decreasing parasitic overgrowth, restoring the innate immune system, supporting immune cytokine balance, preventing deep viral infections, inhibiting overgrowth of many problematic bacteria, and even explored in cancer adjunct therapy. The research has prompted the National Institutes of Health to set up targeted human research to evaluate this supplement. Perhaps the most important aspect of benefit from lactoferrin supplement is the effect on regulation and maturation of macrophages, which are integral to blood cell production. Besides this essential benefit, lactoferrin aids maturation and function of lymphocytes as well, potentially benefitting recovery in autoimmune disorders: http://www.vrp.com/immune-system/lactoferrin-natures-premier-immune-boosting-protein
  40. In 2014, researchers at Harvard Medical School, in Boston, Massachusetts, U.S.A., the University of Pretoria, South Africa, and Manchester University, United Kingdom, proposed that iron chelation may be beneficial to a number of diseases and problems associated with iron overload toxicity, whether systemic or localized. Their focus was on fibrins, thromboses, and red blood cell deformation. Their research also revealed that the realm of iron chelators now included selenite (selenium compounds), salicylates, and clioquinol (an anti-fungal and anti-protozoal drug). In addition, research has revealed that IP6 may be a useful iron chelator, and such investigation has opened up a realm of herbal and nutrient medicines that may be helpful in this regard, integrating Complementary Medicine: http://www.ncbi.nlm.nih.gov/pubmed/24416376
  41. A 2012 study at the Bose Institute, in Calcutta, India, found that the Chinese herb Terminalia chebula (He zi), in alcohol extract, was a potent chelator of free iron: http://www.biomedcentral.com/1472-6882/12/144
  42. A study of herbal and nutrient iron chelators, at the University of Mazandaran Medical College, in Sari, Iran, showed that a variety of such has presented evidence of effectiveness, including EDTA, Pterocarpa fraxinifolia, and Craetagus pentagyna (Shan zha), with further study around the world surely turning up more viable examples: http://www.ajol.info/index.php/ajb/article/viewFile/59257/47555
  43. An example of medication breakdown, or catabolism, in the liver, which produces even more harmful chemicals than the medication itself, is cited in this study of AZT catabolites: http://molpharm.aspetjournals.org/cgi/content/abstract/39/2/258
  44. A conservative but informative article from the American Heart Association explains some of the pharmacodynamics of prescription drugs and the effect on the liver, with drug-drug contraindications and explanation of ill effects on the liver metabolism with statin drugs to lower cholesterol: http://circ.ahajournals.org/cgi/content/full/109/23_suppl_1/III-50
  45. A 2000 FDA labeling approval for a synthetic estradiol oral contraceptive reveals that concentrations of drugs in the body vary considerable from person to person depending on the individual health of the liver metabolism and competition for detox pathways: http://www.fda.gov/cder/ogd/rld/19190s34.pdf
  46. A 2008 study published in the European Journal of Cancer Prevention showed that a percentage of the population is born with genetic polymorphisms, or tendency to express misshapen protein enzymes, related to alleles expressing P450, glutathione S-transferase and N-acetyl transferase. In the population with deficient expression of both the glutathione and acetyl transferase enzymes, risk of acquiring acute myeloid leukemia, or bone marrow cancer, increased nearly 12 percent: http://www.ncbi.nlm.nih.gov/pubmed/18287869. Another study in 2000 found a significant relationship between deficient expression of P450 and glutathione transferase enzymes and esophageal cancers: http://www.ncbi.nlm.nih.gov/pubmed/10868687. These studies were a follow-up to a 1997 study of glutathione deficiency genotypes and the relationship to cancer susceptibility by the University of Pennsylvania School of Medicine: http://www.ncbi.nlm.nih.gov/pubmed/9298582?
  47. A 2014 follow-up to the Nurses Health Study II findings that the level of red meat consumption was correlated with increased breast cancer risk in premenopausal women, by the Harvard School of Public Health, concluded that the iron in red meat was not associated with the increased breast cancer risk, nor was the expression of the most common hemochromatosis genetic mutation HFE SNP. The conclusion was that other factors associated with red meat consumption were the problem: http://www.ncbi.nlm.nih.gov/pubmed/24443403