Iron Overload Disorders

Iron is an essential micronutrient. However, free iron rapidly catalyzes the generation of damaging free radicals and subsequent oxidant stress. In fact, excess iron can damage cells and tissues, and iron overload is associated with increased risk of cancer and heart disease along with neurological, endocrine, and musculoskeletal disorders (Jellinger 1992; Kew 2009; Shima 1997; Siddique 2012; Huang 2003).

Iron is unusual among dietary nutrients in that both iron deficiency and iron excess are relatively common health concerns; however, little-understood or recognized is that the difference between iron deficiency or overload is often a question of a scant few milligrams of iron (Heli 2011; Cogswell 2009; Fleming 2001).

Conditions that predispose to accumulation of excess iron can be hereditary (e.g., hemochromatosis) or acquired (e.g., excess iron ingestion, chronic liver disease). Poorly appreciated by mainstream medicine is the fact that iron has a tendency to accumulate within cells during the aging process (Killilea 2003; Brittenham 2008), further exacerbating the detrimental impact of aging in our body.

Iron overload is not typically detected until 40 - 60 years of age (Borgaonkar 2003). However, recent advances in the understanding of the genetic basis of hereditary iron overload disorders, availability of blood markers, and development of non-invasive techniques to assess tissue iron stores have facilitated early detection and faster treatment of iron overload disorders (Fischer 2009; Muñoz 2011; Fleming 2012; Santos 2012).

This protocol will present an overview of iron overload disorders (acquired and hereditary), and will highlight state of the art methods in diagnosing and treating excess iron stores. Additionally, advances in dietary approaches to managing iron intake will be reviewed.

The body absorbs 10% (1 to 2 mg) of the iron encountered in dietary sources each day, but has no efficient means of rapidly eliminating excess iron, other than loss of blood. Iron absorption is regulated in the GI tract at the initial part of the small intestine called the duodenum, which lies just beyond the stomach in the digestive tract (Murray 2003; Heli 2011; Geissler 2011).

Following absorption, iron is normally bound to specific storage or transport proteins when not in use; this limits the possibility of excess free iron catalyzing generation of damaging free radicals. Iron travels through the bloodstream bound to transferrin (an iron transport protein).

Cells that require iron (e.g., red blood cells) express a transferrin receptor on their surface, which captures circulating transferrin and pulls it into the cell, causing it to release the bound iron.

Iron, in excess of what is needed to satisfy metabolic demand, is stored bound to the iron storage protein ferritin (Geissler 2011; Fisher 2007).

Both ferritin and transferrin are used as blood markers to monitor iron load (see Diagnosis below).

Iron overload results from an elevated total body iron pool. There are primary (inherited) and secondary (acquired) causes of iron overload; many involve dysregulation of iron absorption from the gut. However, iron overload secondary to repeated blood transfusions can occur in patients with certain types of anemia (Pietrangelo 2010; Heli 2011).

Despite its many important metabolic roles, iron is a potent free-radical generator. Damaging reactive oxygen species are constantly produced during cellular energy generation. Antioxidant enzymes (e.g., superoxide dismutase and catalase) normally eliminate these pro-oxidant compounds, sparing cells from oxidative damage. Iron, however, can readily convert these reactive oxygen species into damaging hydroxyl radicals that are not cleared by antioxidant enzymes. Hydroxyl radicals can damage DNA and cellular proteins, as well as decrease the integrity of cellular membranes (Marx 1996; Emerit 2001; Heli 2011). Iron balance (homeostasis) in humans is predominantly controlled by limiting intestinal absorption, as well as efficient recycling of the body pool because virtually no iron is excreted (Heli 2011). Iron is unique among dietary nutrients in that both iron deficiency and iron excess are relatively common health concerns; in fact, iron deficiency or overload is a question of a few milligrams of iron (Heli 2011; Cogswell 2009; Fleming 2001).

Iron balance is regulated by the peptide hormone hepcidin (Pigeon 2001). Hepcidin, produced by the liver in response to high iron stores or inflammation, travels though the blood stream to the intestines where it reduces iron absorption. It is thought both genetic and acquired causes of iron overload may share a common mechanism of low hepcidin production (Siddique 2012).

Normal iron absorption (1-2 mg/day) and dysregulated iron absorption differ by only a few milligrams each day, yet this is sufficient to outpace iron loss - approximately 1 mg/day in adult men - which occurs very slowly through the sloughing of gastrointestinal and skin cells (Heli 2011; Murray 2003).

As the total body iron pool rises, its levels exceed the capacity of iron storage and transport proteins (ferritin and transferrin, respectively) to keep it safely bound (Brissot 2012). Increased levels of non-transferrin bound iron in the blood can enter cells, thus increasing free cellular iron levels. It is this free iron that is available for generating free radicals within cells, and is responsible for the cellular and tissue toxicities characteristic of iron overload (Brissot 2012).

Primary Iron Overload

Primary iron overload results from inherited defects in genes involved in iron absorption, transport, or regulation. Hemochromatosis, the most common disease of primary iron overload, can be partitioned into 4 types. The most common is Classic (Type I) or HFE hemochromatosis. HFE hemochromatosis results from the inheritance of two mutant copies of the HFE or High Fe (iron) gene (C282Y and H63D) (Borgaonkar 2003; Sebastiani 2007). These defective genes are thought to increase iron absorption by lowering production of hepcidin, and increasing iron uptake from intestinal cells.

The other three types of hemochromatosis are much more rare: Type II is a more severe iron overload due to defective production of hepcidin; Type III is a defect in the transferrin receptor (unable to uptake iron from the blood); and Type IV results in defects in the removal of iron from certain cells (liver macrophages). Type IV may also cause the intestines to become insensitive to hepcidin, resulting in uncontrolled iron absorption (Pietrangelo 2010).

Other hereditary iron overload disorders are extremely rare. They include atransferrinemia (lack of the transferrin iron transporter), mutation in the ferritin gene, and neurodegeneration with brain iron accumulation (NBIA) (Pietrangelo 2010; Gregory 2011).

Secondary Iron Overload

Secondary iron overload can result from a variety of conditions, including repeated blood transfusion for treating certain types of anemia (Heli 2011). Additional iron is introduced with each transfusion, and since humans have no mechanism for its excretion, iron overload becomes possible. Iron overload in transfusion patients presents additional treatment challenges, as phlebotomy, the gold standard for iron overload treatment in hereditary hemochromatosis, is usually not feasible in anemic patients (Bring 2008).

Chronic liver disease. Chronic liver disease, caused by, for example, alcoholic fatty liver and the hepatitis C virus, can compromise the liver’s ability to produce the iron regulatory hormone hepcidin and the iron transport protein transferrin (Siddique 2012; Brissot 2012).

Other sources of secondary iron overload include excessive dietary intake, parenteral iron (such as intravenous iron for anemia management), and long-term hemodialysis (Pietrangelo 2010; Muñoz 2011).

The classic symptom of iron overload is skin hyperpigmentation (to a bronze or grey color), due to deposits of iron and melanin complexes in the skin. The liver, as a primary source of iron storage, is particularly susceptible to iron overload and related damage, which may range from enlargement (hepatomegaly) and elevated serum liver enzymes, to fibrosis or cirrhosis (Siddique 2012).

Long-term iron overload can result in liver cancer (Kew 2009). High serum iron (measured as greater than 60% transferrin saturation) increases the 10-year absolute risk of liver cancer almost six-fold and risk of any cancer over three-fold (Ellervik 2012).

Iron accumulation in endocrine organs has been associated with diabetes, hypogonadism (decreased production of sex hormones), and less commonly hyper- or hypothyroidism; some of these may be reversed by bringing iron levels back into a healthy range (Siddique 2012; NIH MedlinePlus 2010).

Osteoporosis is possible with severe iron overload, and may be due to hypogonadism (Valenti 2009; Siddique 2012).

Arthropathy (joint disease with or without inflammation) is common with iron overload, causing pain with minimal inflammation in the joints of the hands, wrists, elbows, shoulders, and hips (Siddique 2012).

Iron deposition in the heart can cause cardiomyopathy, arrhythmia, heart failure, and sudden cardiac death (Kremastinos 2011; Klintschar 2004). It can also increase vascular damage and atherosclerosis risk (Dongiovanni 2011).

The brain is another potential site of excess iron accumulation, as it requires iron for several neuron-specific reactions, e.g. the synthesis of myelin, which sheaths neuronal axons, and the production of neurotransmitters (Williams 2012). Excess iron can form complexes with melanin in the substantia nigra of the brain in much the same way it does in skin; this has been observed in the brains of Parkinson’s disease patients, and may be related to progression of the disease (Nandar 2011; Shima 1997; Jellinger 1992). Iron deposits in the amyloid plaques of Alzheimer’s disease patients may contribute to neurodegeneration through free-radical toxicity (Crichton 2011). Abnormal brain iron deposition has also been observed in Multiple Sclerosis as well as other neurodegenerative movement disorders (Williams 2012; Gregory 2011).

Bacteria require iron for many of the same reactions as humans; excess iron in the blood or tissues can stimulate the growth of invading pathogens (Pietrangelo 2010).

Given the potential involvement of elevated tissue iron in the progression of several seemingly unrelated diseases, surveillance of total body iron content may present an important measure of disease prevention. Historically, excessive iron has been diagnosed only after sufficient damage has occurred to reveal characteristic symptoms (hyperpigmentation, liver enlargement, and joint problems); however, there are several tests that can monitor iron status before signs & symptoms of frank iron overload occur. Annual blood testing for iron load can allow early detection of sub-clinical elevations that can be addressed by diet, lifestyle changes, and/or conventional therapies (Heli 2011; Fleming 2012; Muñoz 2011).

Diagnosis

Serum ferritin and transferrin saturation are blood tests that can detect iron overload, even before symptoms appear (Heli 2011; Fleming 2012; Muñoz 2011).

Serum ferritin. This test measures the iron storage protein ferritin in the blood serum. While typically an intracellular storage protein, blood levels of ferritin increase proportionally to body stores (1 ng/ml of serum ferritin represents approximately 8 mg of stored iron) (Muñoz 2011). Infection, inflammation or liver disease can elevate serum ferritin levels, complicating measurements in individuals with these conditions; a high-sensitivity C-reactive protein (hs-CRP) test can be used to rule out inflammation (Heli 2011).

Transferrin Saturation. Transferrin saturation (TSAT) measures the ratio of serum iron and total iron-binding capacity of transferrin multiplied by 100 (Muñoz 2011). Elevated TSAT is seen in several genetic causes of iron overload (Fleming 2012).

Other important tests include:

Serum Iron. Serum iron measures the total iron in blood serum (Muñoz 2011).

Total Iron Binding Capacity. Total iron binding capacity (TIBC) measures total binding capacity of transferrin (the iron transport protein) in the serum (an indirect measurement of transferrin) (Muñoz 2011).

HFE Test. A HFE test is a genetic test for the presence of either of the two main mutations (C282Y and H63D) of the HFE gene. These mutations are the most common causes of hereditary hemochromatosis. An individual with Type I hemochromatosis generally carries two copies of the C282Y gene, or one copy of each mutant gene (Santos 2012). Positive HFE analysis confirms the clinical diagnosis of hemochromatosis in asymptomatic individuals with blood tests showing increased iron stores; it is also predictive of risk in individuals with a family history of hemochromatosis (Pietrangelo 2010).

Liver biopsy. Liver biopsy can be used as a direct measure of non-heme iron and for the diagnosis of non-HFE hemochromatosis. Liver iron concentrations of greater than 15 mg/g dry weight increase the risk of iron-associated cardiovascular disease and early death. The threshold for liver injury and fibrosis is about 22 mg/g (Muñoz 2011).

The development of MRI (magnetic resonance imaging) of the liver and heart now offers a non-invasive method for assessing iron stores in these organs. R2-MRI (also known as FerriScan) is now specifically recommended as a method to measure liver iron concentrations in clinical practice guidelines. It is also used for monitoring the efficacy of iron chelation therapy (Taher 2008; Fischer 2009; Muñoz 2011).

Phlebotomy The standard treatment for patients with iron overload is bloodletting (phlebotomy or venesection) in the absence of anemia and chelation in the iron-loading anemias (Fleming 2012; Pietrangelo 2010). One unit (about 450 ml) of blood contains approximately 200-250 mg of iron, depending upon the hemoglobin concentration; it is often recommended to remove one unit per week (as tolerated). In patients who have very high total body iron stores greater than 30 g, therapeutic phlebotomy (i.e., removal of blood) may take up to 1-2 years to adequately reduce iron stores, until serum ferritin levels and transferrin saturation values fall within normal ranges. Ferritin levels are then typically maintained by removal of 2-4 units of blood per year (Pietrangelo 2010).

A potential drawback of phlebotomy is a decrease in hepcidin levels and excess iron absorption (Fleming 2012). Removal of blood initiates the compensatory synthesis of new red blood cells in bone marrow. These new red blood cells have increased iron requirements through enhanced production of the oxygen-carrying protein hemoglobin. Thus, hepcidin levels may be further decreased so additional iron can be absorbed to meet increased demand (van Dijk 2008).

In one study among patients with hereditary hemochromatosis, phlebotomy was associated with decreased hepcidin levels; although subjects’ hepcidin levels were low initially (van Dijk 2008; Galesloot 2011). Targeting a serum ferritin level slightly above the recommended range during maintenance phlebotomy may help some patients avoid increased iron absorption caused by low hepcidin levels (van Dijk 2008).

Iron Chelation For patients refractory to phlebotomy treatment, or for those in which blood removal is not feasible (e.g., iron-loading anemia patients), iron chelation is the standard therapy.

Currently, there are three FDA approved iron chelating agents. Desferoxamine mesylate (Desferal®) is an injectable iron chelator that has been in use since the 1960’s. It can bind and remove iron from ferritin stores or abnormal tissue deposits, but not from sites of active metabolic iron usage (such as transferrin or hemoglobin). Desferoxamine has some considerable drawbacks; it can elicit hypersensitivity and systemic allergic reactions, and its short half-life requires treatment via a slow injection over a period of 4-12 hours (Heli 2011).

The development of oral iron chelators has enabled more convenient dosing and improved patient compliance. Deferiprone (Ferriprox®) is a synthetic analog of mimosine (a naturally occurring iron chelating compound, originally derived from the Mimosa pudica plant) (Hider 2005; Heli 2011). Its rapid metabolism by the liver requires that it be taken in high doses for efficacy. Side effects of deferiprone include gastrointestinal discomfort and skin rash. Deferasirox (Exjade®), an orally bioavailable chelator with a longer half-life and smaller effective dose than deferiprone, has been approved in the United States for treatment of secondary iron overload due to ineffective erythropoiesis since 2005. It exhibits some of the same side effects as deferiprone, with the possibility of more serious side effects (e.g., liver failure and renal dysfunction). It is also very expensive. Due to its small molecular size (compared to desferoxamine), deferasirox is able to move throughout the body, removing iron from the active sites of several critical iron-containing enzymes (Hider 1995; Heli 2011).

The evolution of the therapeutic treatment for iron overload has been slow. Almost a hundred years passed between the first description of hemochromatosis in 1889 and the establishment of phlebotomy as a treatment; only recently have more precise metabolic and genetic mechanisms of iron overload been elucidated (Pietrangelo 2010).

Iron chelating agent development. There appears to be increasing interest in the development of safer iron chelators with enhanced iron-clearing activity (Zhou 2011). High molecular weight derivatives of desferoxamine, attached to natural or synthetic fibers, retain the iron-binding activity of the classic drug, while offering reduced toxicity and longer time in circulation, thus overcoming some of the shortcomings of desferoxamine alone (Zhou 2011). A new oral chelator (FBS0701) is currently in clinical trials. It has an activity similar to the FDA approved desferasirox, but with a significantly better safety profile (especially for kidney function) (Neufeld 2012). Restoring iron regulatory function through the administration of transferrin, hepcidin, or modified hepcidin molecules (minihepcidin) is also being explored as a potential therapy (Preza 2011; Fleming 2012).

Erythrocytapheresis. Erythrocytapheresis, selective removal of red blood cells from blood while preserving blood volume, has been investigated as an alternative to conventional phlebotomy (Rombout-Sestrienkova 2012). Erythrocytapheresis can remove more red blood cells per procedure (achieving desired reductions in serum ferritin in fewer procedures), with no significant differences in cost, quality of life, or frequency of adverse events (Rombout-Sestrienkova 2012). However, it may demonstrate some of the same drawbacks as phlebotomy (e.g., lowering hepcidin levels).

Bone marrow transplantation and novel stem cell therapies. Understanding genetic iron regulatory mechanisms may allow practitioners another therapeutic direction to address iron overload. Restoration of functional iron regulatory genes in patients with hereditary iron dysregulation may prove a viable treatment. Bone marrow transplantation has already proven to be an effective approach for treating young patients with β-thalassemia. In a survey of 115 transplant procedure patients between 1983 and 2006, 89% (103) survived to an average 15 year follow up, with 96% (99) of those survivors no longer requiring blood transfusions (Di Bartolomeo 2008). Stem cells from bone marrow may also be used to reconstitute iron regulation elsewhere in the body. When type I hemochromatotic mice (containing 2 mutant copies of the HFE gene) were transplanted with bone marrow from healthy donor mice, donor stem cells were detected in the liver (constituting 11% of total liver cells) and intestine after 6 months. In both cases, the stem cells had transformed (differentiated) into cell types appropriate for those organs (liver hepatocytes and intestinal myofibroblasts), partially restored the expression of iron regulatory genes (including HFE), and reduced iron content in these tissues compared to control animals (Morán-Jiménez 2008).

Population studies suggest limiting dietary iron intake may lower serum iron burden. In one study of men and women with a high incidence of HFE mutations (approximately 40% of the test group had at least one mutation in their HFE gene), the frequency of red meat and alcohol consumption was associated with higher serum ferritin levels, and non-citrus fruits with lower serum ferritin levels in men (Milward 2008). Similarly, a study of women saw modest associations between the intake of alcohol, red meat and heme iron as well as serum ferritin (Cade 2005). In addition to the heme form of iron found in meats, non-heme iron can be found in plant-based foods (e.g., leafy greens, legumes, and fortified breads and cereals) (USDA 2011). The contribution of non-heme iron to iron overload is unclear; neither of the above studies reported significant increases in serum ferritin levels associated with non-heme iron consumption (Cade 2005; Milward 2008). The long-term effects of low-iron diets on disease progression are unknown; and clinical studies of dietary iron restriction are lacking.

Foods high in ascorbic (vitamin C) and citric acid (e.g., citrus fruits) may enhance the absorption of non-heme iron (Crawford 1995). Supplemental vitamin C greater than 500 mg per day should be avoided in patients with iron overload (Barton 1998) and especially avoided at mealtimes.

Yearly blood donation may also help to maintain iron levels. Blood donors had an average 33% decrease in serum ferritin levels compared to non-donors in one study (Cade 2005).

Life Extension advises against taking supplemental iron unless needed (i.e., due to a deficiency). Iron needs should be determined with yearly blood testing. Because excessive iron intake may be associated with, or increase the risk of several degenerative diseases, Life Extension multivitamins are formulated without iron. Pregnant women, due to increased iron requirements, should consult their physician to determine if iron supplementation is appropriate.

Several dietary constituents have been investigated for their ability to treat iron overload. They work by either reducing or inhibiting iron absorption from the gut, or binding excess iron in the blood and tissues to help draw it out of the body. Additionally, the significant contribution of free radical damage to the progression of iron-overload associated diseases suggests a role for increasing antioxidant consumption.

Polyphenols. Polyphenols such as chlorogenic acid (Kono 1998), quercetin, rutin, chrysin (Guo 2007), punicalagins (from pomegranate) (Kulkarni 2007), and proanthocyanidins (from cranberry) have been shown to bind iron in vitro (Lin 2011). In an in vitro binding study of 26 flavonoids (a type of polyphenol) isolated from a variety of sources (including tea catechins, hesperidin, naringenin, and diosmin), several were nearly as effective as deferoxamine at chelating ferrous iron when supplied at a 10:1 flavonoid/iron ratio. When supplied at a 1:1 ratio, quercetin, myricetin, and baicalein (a flavonoid from skullcap) continued to chelate iron with the same efficiency as desferoxamine (Mladěnka 2011). As antioxidants, polyphenols may also reduce iron-catalyzed free-radical generation (Minakata 2011).

In a mouse model of iron overload (over 2,000 mg iron/g of liver weight), both quercetin and baicalin (fed as 1% of water, which is roughly equivalent to 15 grams for a 70 kg human) reduced iron-induced lipid peroxidation and protein oxidation in the liver, decreased liver iron stores as well as serum ferritin, and increased fecal excretion of iron (Zhang 2006). Clinical studies are necessary to confirm polyphenol’s effect(s) in humans.

Pectin. Pectin is an indigestible fiber that binds tightly to non-heme iron, thus interfering with its absorption. In a small study of 13 patients with idiopathic hemochromatosis (conducted before the genetics of hemochromatosis had been discovered), iron absorption decreased by nearly half following a loading dose of 9 grams/m² of pectin (about 15 grams for the average adult). Cellulose fiber had no effect on iron binding (Monnier 1980).

Milk Thistle. Milk thistle and its flavonoid constituent (i.e., silymarin) have iron chelation and hydroxyl radical quenching properties (Borsari 2001; Abenavoli 2010). In HFE hemochromatosis patients, 140 mg of silybin (the main component of silymarin) taken with a test meal containing about 14 mg of non-heme iron reduced iron absorption by over 40% (Hutchinson 2010). When combined with soy phosphatidylcholine, silybin treatment for 12 weeks demonstrated a modest (13%) reduction in serum ferritin (indicative of reduced total body iron stores) in patients with chronic hepatitis C (Bares 2008). When combined with the injectable iron chelator desferoxamine, silymarin resulted in more effective reductions in serum ferritin than desferoxamine alone in patients with β-thalassemia (Gharagozloo 2009).

Curcumin. Curcuminoids, which are derived from the spice turmeric, are antioxidants and iron chelators. In experimental models, they have been shown to reduce iron-catalyzed oxidative damage of DNA (García 2012), liver damage associated with iron-associated lipid peroxidation (Reddy 1996), and free-radical damage due to iron in amyloid plaques characteristic of Alzheimer’s disease (Atamna 2006). In β-thalassemic mice, curcumin bound iron in the blood reduced cardiac iron deposits in mice fed a high-iron diet (Thephinlap 2011), and reduced iron-associated lipid peroxidation when combined with the IV chelator deferiprone (Thephinlap 2009). The iron chelation effects of curcumin in the liver depend upon total iron intake. At low dietary iron concentrations, curcumin demonstrated a significant reduction in transferrin saturation and plasma iron in mice given curcumin as 2% of their diet (Jiao 2009). Mice on high iron diets, however, saw significant decreases in liver ferritin (indicative of a decrease in iron storage capacity), but no changes in total plasma iron or transferrin saturation when given curcumin as 2% of their diet (Jiao 2006; Jiao 2009).

Green tea. Green tea catechins are potent antioxidants that demonstrate an iron chelating activity similar to the injectable chelator desferoxamine in test tube studies (Mandel 2006). The addition of green tea extract with a high epigallocatechin gallate (EGCG) content to blood samples from β-thalassemia patients rapidly chelated non-transferrin bound iron, and modestly reduced markers of lipid peroxidation (Srichairatanakool 2006). The ability of green tea catechins to cross the blood-brain barrier implicates them as possible agents for the chelation of abnormal iron deposits characteristic of several neurodegenerative disorders (Mandel 2006). Studies examining the effect(s) of green tea consumption on iron status in humans are conflicting. Several studies have shown no association between tea consumption and iron absorption, serum ferritin, or hemoglobin levels in individuals with adequate iron intake (Mennen 2007; Temme 2002; Cheng 2009). However, two studies did show reductions in serum ferritin and iron absorption with high consumption levels of green tea (Imai 1995) and green tea extract (Samman 2001) respectively.

Alpha lipoic acid. Alpha lipoic acid is an important antioxidant and enzyme co-factor. In cell culture, alpha-lipoic acid (in its reduced form, dihydrolipoic acid) protects neurons against oxidative damage catalyzed by iron or Alzheimer’s beta amyloid (Lovell 2003). In a preclinical trial, R-alpha-lipoic acid (R-LA) was fed to older rats with age-related accumulation of iron in the cerebral cortex. Following 2 weeks of R-LA supplementation, iron levels dropped to those indicative of younger rats (Suh 2005).

Carnitine. Carnitine is an internal shuttle that helps move fatty acids into the mitochondria for conversion into energy. Carnitine esters (acetyl-L-carnitine and propionyl-L-carnitine) are derivatives, which may have additional antioxidant activities that confer advantages over carnitine alone (Mingorance 2011). When combined with alpha lipoic acid, acetyl-L-carnitine attenuated the production of free radicals in cultures of iron-overloaded human fibroblasts (Lal 2008). In test tube studies, propionyl-L-carnitine inhibits superoxide radicals, and reduces lipid peroxidation catalyzed by hydrogen peroxide (Vanella 2000). It is also proposed that propionyl-L-carnitine can reduce the production of hydroxyl radicals generated by iron, because of its iron-chelating activity (Reznick 1992).