How should the diet be composed in persons with iron overload?

Vegetarians in general have a low body iron status [19, 20], even though the iron content in their diet often is distinctly above the recommended intake [65-67]. The reason for this discrepancy is that all the iron contained in a diet based on plant foods is nonheme ferric iron, which basically has a poor availability and furthermore many plant foods are rich in compounds that inhibit iron absorption, e.g., phytates, polyphenols and some plant proteins (see above). Studies have also shown that iron absorption is significantly lower from a vegetarian diet than from a meat-rich diet [21]. This knowledge encourages to recommend a predominantly plant-based, semi-vegetarian style of diet also containing dairy products and eggs, a “veggie-lacto-ovo” style diet to persons with iron overload or predisposition to iron overload. The diet should be varied, and balanced to fulfill the demands for proteins, vitamins and minerals.

In a standard diet, approximately 10-20% of the total iron content consists of heme iron, contained in animal meat together with meat factors [10, 25, 29]. Meat is a rich source of protein, containing 20 - 30 g protein/100 g, depending on the fat content [34]. The heme iron is present in the myoglobin and in the variable amount of hemoglobin in blood, which remains captured in the blood vessels in the muscles after butchering and exsanguinating the animals. The most widely consumed sorts of meat are pork, beef, veal, lamb and poultry. Both myoglobin and hemoglobin are red pigments that give the meat its red color, i.e., the redder the meat, the higher the content of myoglobin/hemoglobin and heme iron [68]. The content of myoglobin in the muscles increases with the age of the animal [68]. Most animals are butchered at a young age, varying from 2 months (chicken) to 3 months (pigs) and 6 - 10 months (calves and lambs). In Denmark, beef cattle is butchered after the age of 10 - 20 months. Dairy cows are butchered after 65 - 68 months [67] and their meats have a high content of myoglobin and heme iron [68], the so-called “red meat”, in contrast to the “white meat” from poultry, e.g., chicken breast.

Beef contains more total iron (2.2 mg/100 g) than veal (1.5 mg/100 g), leg of lamb (1.5 mg/100 g), pork chops (1.0 mg/100 g) and chicken breast (0.9 mg/100 g) [35]. The iron content of the meat in the specific animal also varies between different muscle groups; the iron content in the red meat in chicken legs (1.8 mg/100 g) is twice as high as in the white meat in chicken breast; duck meat contains 1.2 mg iron/100 g, while duck breast has a high iron content of 4.5 mg/100 g [35]. Ground beef is predominantly produced from old dairy cows [67] and therefore has a high content of heme iron. Of the total iron content, heme iron constitutes 83% in beef, 63% in pork chops and 33-44% in chicken [36]. Mammals and birds killed by shooting are not exsanguinated, and game meat is therefore very rich in iron and should be avoided.

Offal, also called variety meats, pluck or organ meats, is the viscera and entrails of an animal. Offal and products containing blood, e.g., blood sausage have a high heme and nonheme iron content as well as meat factors and should be avoided by persons with hemochromatosis. As examples, the total iron content in pork offal is: in liver 13.4 mg/100 g, liver pate 5.6 mg/100 g, heart 6.0 mg/100 g, kidney 3.3 mg/100 g and in blood sausage 16.2 mg/100 g [35]. Ideally, the consumption of meat should be as low as possible, and not be consumed on a daily basis. If the meal includes meat, the red meat must be avoided and the white meat from poultry, young pigs and young calves should be preferred and consumed in moderate quantities not more than two times per week.

In general, white fish meat has a low iron content, whereas the red meat from the big skipjack tuna contains myoglobin and has a higher iron content [34, 35]. Fish meat has a high content of protein of 20 - 30 g/100 g [34], equal to the content in mammal meat. Fish is therefore an important source of protein, and fat fish in addition contains essential fatty acids. The total iron content in lean fish meat is 0.2 mg/100 g in cod, 0.1 mg/100 g in plaice and 0.8 mg/100 g in redfish, and in fat fish meat 0.2 mg/100 g in farm raised salmon, 0.8 mg/100 g in mackerel, 0.7 - 1.3 mg/100 g in herring and 1.6 mg/100 g in tuna [34, 35]. Cod fillet contains no heme iron, while 30-40% of the iron content in the other fish species is heme iron [36]. Fish meat in addition contains meat factors [42, 69], so the iron has a quite good bioavailability. For persons with iron overload, it may therefore be an advantage to replace the intake of mammal meat with white poultry meat and lean fish meat from cod, plaice, and redfish, as well as occasional fat fish meat from mackerel and salmon two to four times per week. A “veggie-lacto-ovo-poultry-pescetarian” style diet will also ensure a sufficient intake of proteins and essential fatty acids.

Shellfish like blue mussels, oysters, crabs and lobsters are generally rich in iron [25] and should be avoided or consumed in small quantities, and all shellfish should be well cooked. Raw mussels including oysters can harbor bacteria like Vibrio vulnificus, which may cause severe food poisoning infections both in apparently healthy persons [70] but especially in patients with chronic diseases, and liver affection, e.g., hemochromatosis [71, 72].

Healthy persons are recommended to consume 0.8 - 1.0 g protein/kg body weight per day [23]. In a phlebotomy of 500 mL blood, 130 - 140 g of protein are lost, equivalent to 2 days recommended intake. During the induction phase [1] where patients are phlebotomized weekly or every other week, it is essential to compensate for the extra protein losses and increase the protein intake to approximately 1.3 - 1.5 g/kg body weight per day.

White poultry meat and white fish meat are recommended good sources of protein (see above). Eggs contain approximately 14 g protein/100 g [34], so one to two eggs a day can be a source of protein, unless egg yolk should be avoided due to hyperlipidemia and/or cardiovascular disease. Milk contains approximately 3.4 g protein/100 mL and harbors all the nine essential amino acids, so drinking 1 L of low-fat milk will provide the body with 34 g protein [34]. Low-fat, protein-rich lactic acid fermented milk products such as the Icelandic inspired “Skyr” or yoghurt containing up to 11 g protein/100 g are good sources of additional protein. The lactic acid contained in fermented milk does not appear to enhance iron absorption, i.e., cannot overrule the inhibiting effects of calcium and milk proteins [10]. The diet can also be supplemented with whey protein powder in an appropriate amount, e.g., 30 - 40 g per day. The lactic acid in fermented milk does not increase iron absorption, because the iron content in milk is negligible [34], and both the proteins [10, 52] and the calcium contained in milk [10, 55] inhibit iron absorption.

There are a plethora of protein drinks or shakes on the market. However, most of these contain added minerals often including iron, and vitamins often including vitamin C. It is important to check the declaration and avoid products containing iron and vitamin C.

Pulses and legumes, especially beans, contain between 21% and 25% proteins by weight, which is much higher than the protein content in other vegetables [34-36]. The high protein content is due to the atmospheric nitrogen capturing activity occurring in the root nodules in symbiosis with Rhizobia bacteria [73]. Especially kidney beans, soya beans and soya bean derived products have a high protein content of 24 - 36 g protein/100 g [34] and can be consumed on a daily basis, in order to increase protein intake. Soya bean milk has almost the same protein content as bovine milk, 3.3 g/100 mL [34].

Tempeh is a traditional Indonesian product that is based on fermented soya beans. It is made by a natural culturing and a controlled fermentation process with Rhizopus oligosporus that binds soya beans into a cake form. It has a high protein content of 18 g/100 g [34]. Tofu, also known as bean curd, is a food prepared by coagulating soya bean milk and then pressing the resulting curds into solid white blocks of varying softness. The protein content is about 8 g/100 g [34]. Some species of soya beans may be rich in iron, probably due to the culturing conditions [10]. However, there appear to be no reasons for not using soya bean protein supplements, as both soya bean protein, and the high content of intrinsic phytate as well as calcium will inhibit iron absorption [10]. A diet rich in soya bean products containing native phytate significantly decreases body iron status (serum ferritin) in postmenopausal women [74].

Whole grains contain phytic acids/phytates [10, 48], of which the major part is present in the shell parts of the grain, germ and bran. It is therefore important to choose flour-based products, which contain a high proportion of whole grain flour, e.g., whole grain bread and whole grain pasta and other products based on whole grain flour. Likewise, cereals based on whole grain should be preferred.

When baking at home, whole grain should be used and it is also possible to increase the content of phytates by adding extra wheat bran to the flour. It is important to use yeast-based fermentation of the dough and not lactic acid fermentation as in sourdough [10]. Lactic acid is a potent promoter of iron absorption by itself, due to its acidity [10, 41]. Furthermore, lactic acid fermentation by itself produces phytase, and can activate the dormant intrinsic phytase activity in the flour [75], two mechanisms, which can reduce the phytate content in grains [76]. When purchasing industrially baked bread and other grain products, it is important to check the declaration concerning the content of whole grain flour and use of sourdough as well as whether the flour or bread has been enriched with iron.

Regular consumption of alcohol predisposes to iron overload, depending on the amount consumed, and especially if the consumption is higher than recommended by the health authorities [10, 43, 44]. In population studies, there are clear positive associations between the quantity of alcohol intake and the iron status marker serum ferritin, both in men and women. An increased alcohol intake is associated with an increase in ferritin [77-79]. In persons with HFE-hemochromatosis, alcohol consumption increases both the biochemical and clinical disease expression, as well as the risk of liver cirrhosis and liver cancer [80].

Alcohol seems to increase ferric iron absorption from the meal, possibly due to the stimulating effect on gastric acid secretion [81]. However, the enhancing influence of alcohol on iron absorption is more likely due to its inhibition of hepcidin expression/synthesis in the liver [10, 44]. Alcohol induced decrease in hepcidin synthesis has been demonstrated both in patients with alcoholic liver disease [44], as well as in animal studies [10]. Both acute and chronic alcohol exposures suppress hepcidin expression in the liver [82]. Persons with hemochromatosis a priori have low hepcidin levels, but it has not yet been evaluated whether alcohol consumption may contribute to a further reduction of hepcidin expression in these patients.

White wines and red wines contain varying amounts of iron depending on the grape varieties, the iron content in the soil in which the grapes are cultured, the iron content in fertilizers and the wine production processes. The average iron content in white wine is 3 mg/L and in red wine is 5 mg/L [34]. Furthermore, wines contain various amounts of phenols and polyphenols, including tannins, depending on the grape varieties, growth conditions including climatic conditions, fertilizers and the wine production processes.

White wines have a significant increasing effect on food iron absorption, which is even higher than can be explained solely by its alcohol content [83]. This is probably due to its low content of phenols and tannins and its high content of organic acids, as well as the low pH, which all promote iron absorption [10, 83].

Red wines also contain organic acids but have a higher pH than white wines. The coloring in red wines is due to their content of phenols and tannins, which inhibit food iron absorption [10, 49, 50]. The higher the content of phenols and tannins, the higher the inhibition of iron uptake. If occasionally, red wine is consumed, choose heavy bodied red wines with a high content of tannins; enjoy with a selection of cheeses, which due to their low content of iron and their high contents of milk protein and calcium, inhibit iron absorption [10]. Do not drink wine with a selection of cold cuts and sausages, which due to their high content of heme- and nonheme iron and meat factors, stimulate iron absorption.

The Danish Health Authority recommends a maximum of seven standard drinks (each containing 12 g alcohol) per week in healthy women and a maximum of 14 standard drinks per week in healthy men [84]. This amount of intake is, however, not recommended to persons with hemochromatosis. Considering the present evidence, in hemochromatosis, it is clearly best to abstain from alcohol, or at least the consumption should be restricted to a minimum, and alcoholic beverages should be replaced by their non-alcoholic counterparts.

The beverages consumed with the meal can significantly influence the absorption of food iron, i.e., either increase or decrease absorption. Drinking alcoholic beverages increases iron absorption (see above). Drinking fruit juices, both processed and fresh, containing vitamin C, and having a low pH due to the content of organic acids and possibly a high content of sucrose and/or fructose will significantly increase iron uptake (see above). Consequently, this kind of beverages should not be taken with the meals. Fresh fruit juices are healthy foods containing antioxidants, vitamins and minerals; they should not be avoided but instead consumed between the meals. Milk proteins and calcium both inhibit food iron absorption [10], so drinking a glass of milk with the meals may be beneficial for persons with iron overload.

Recommended beverages to the meals are green- or black tea, coffee, low-fat milk, or water. In Denmark, tap water is potable and contains no iron. Some bottled mineral water may contain iron, check the declaration.

Polyphenols contained in tea and coffee are strong inhibitors of iron absorption [10]. The infusion of 1.5 g of the black Ceylon Wewesse tea contains 90 - 100 mg polyphenols [85], so a standard cup or mug (250 mL) of this tea contains about 90 - 100 mg polyphenols. In general, the polyphenol content in a cup of green- or black teas is depending on the variety of tea, the processing of the tea leaves, the type of brewing (tea leaves or tea bags) and the strength (grams of tea leaves per mL of water) of the infusion [85, 86]. One of the few controlled, nutritional studies in persons with hemochromatosis showed that regular tea drinking with the three daily main meals decreased food iron absorption on the long term, resulting in a reduced yearly rate of phlebotomies in the maintenance phase of the disease [85].

In patients with impaired liver function, i.e., significantly elevated liver enzymes, liver fibrosis or liver cirrhosis, heavy green tea drinking and/or the consumption of green tea extract food supplements may induce severe liver damage, and in some even acute liver failure [87]. Therefore, no more than three cups of green tea should be consumed per day and food supplements of green tea extract should be avoided.

Coffees (with caffeine) also contain polyphenols, varying from 30 to 300 mg per cup of coffee, depending on the variety of coffee beans, the processing of the beans and the strength of the coffee brew (grams of coffee beans per mL of water) [88]. Furthermore, regular coffee drinking appears to be beneficial for the overall liver function, see review [89]. “Moderate coffee consumption may be related to a slower progression of chronic liver disease. Patients who consumed a higher quantity of coffee have been found to display a milder course of fibrosis, especially in those with alcohol related liver disease. The association between moderate coffee consumption and a slower rate of fibrosis has also been seen in patients with hepatic fibrosis, cirrhosis, non-alcohol related liver disease and hepatitis” [89]. Likewise, regular coffee drinking has a protective effect against non-alcoholic fatty liver disease [90]. In conclusion, regular coffee drinking with meals (three to four cups daily) can replace regular tea drinking with meals, possibly with benefits especially in patients with impaired liver function, liver fibrosis or liver cirrhosis.

Nowadays, most cooking utensils, like pots and pans/skillets have a non-stick coating, and no metal is released from the utensils during the cooking process, whether boiling or frying. However, previously there was a widespread use of cast iron pots and pans without coating, which still are used by many people, depending of the regional cooking habits. Iron utensils release iron during the cooking process, especially if the prepared foods are acidic with a low pH. As an example, the iron content increased from 0.6 mg to 5.7 mg/100 g in spaghetti sauce after being cooked in a cast iron pot [91]. Consequently, the message is clear: do not use uncoated iron utensils in cooking!

In healthy people, the needs for vitamins are usually covered by eating a healthy, varied and balanced diet [92]. In hemochromatosis, during the induction phase, the patients are phlebotomized with 1 week or 2 weeks intervals. Depending on the magnitude of iron overload at diagnosis, the induction treatment can vary greatly, e.g., from 6 to 24 months. Frequent phlebotomies are associated with loss of various vitamins in the blood, but none has so far measured or tried to estimate these losses.

Some Danish centers monitor the blood concentrations of vitamin B₁₂, folate and vitamin D during the induction treatment of hemochromatosis patients and prescribe vitamin supplements according to the vitamin levels. Although not confirmed in controlled studies, common sense, the benefit of doubt, and the absence of side effects concerning vitamin intake motivate the author to consider a regular daily intake of multivitamin tablets in the induction phase, in order to secure an adequate body “vitamin status”.

In the maintenance phase, where patients are phlebotomized two to four times in a year, the intake of multivitamin tablets may according to the author’s suggestion be reduced to three times a week or alternatively to a daily intake in 1 week or 2 weeks in connection with phlebotomies. The multivitamin tablets should be checked for having an adequate content of the various vitamins, especially vitamin D₃ and vitamin E. It is also important to emphasize that the tablets should be taken between meals, due to their content of vitamin C. According to the Nordic nutrition recommendations, the recommended intake of vitamin C in adults is 75 mg/day [23]. Therefore, the multivitamin tablets should not contain more than 200 mg vitamin C per day, as suggested by the Iron Disorders Institute [93].

Osteopenia and osteoporosis occur frequently; among patients with clinical hemochromatosis, 41% have osteopenia and 25% osteoporosis [1]. The frequency of osteoporosis increases with increasing iron overload [1], and it is therefore important to have an adequate intake of vitamin D₃ (and calcium, see mineral section below) to prevent bone decalcification [94]. The plasma vitamin D level should be checked for vitamin deficiency/adequacy. The recommended intake of vitamin D₃ according to the Nordic nutrition recommendations is 10 µg/day for adults and 20 µg for adults above 75 years [23]. If the multivitamin tablets have a lower content of vitamin D₃, additional vitamin D₃ supplements should be taken; in most persons, a supplement of 20 µg/day will be sufficient. Furthermore, a bone mineral (dual energy X-ray absorptiometry (DEXA)) scan should be performed, in order to check for osteopenia/osteoporosis [1].

Vitamin E (d-alfatocoferol) is an important antioxidant [95]. The recommended intake of vitamin E according to the Nordic nutrition recommendations is 10 mg/day for men and 8 mg/day for women [23], while the US National Institutes of Health recommend a higher dose of 15 mg/day in both genders [95]. Many multivitamin tablets contain 20 - 30 mg of vitamin E, which is adequate. If necessary, an extra vitamin E supplement should be taken.

In healthy people, the needs for minerals are usually covered by eating a healthy, varied and balanced diet [92]. Many multivitamin tablets also contain the essential minerals (multivitamin-multimineral tablets). Taking combined multivitamin-multimineral tablets will cover the need for essential minerals in most people.

Selenium is an essential micronutrient, which is a component of the important antioxidant enzymes glutathione peroxidase and thioredoxin reductase [23]. The recommended intake of selenium according to the Nordic nutrition recommendations is 60 µg/day and the intake must not exceed 300 µg/day [23]. Check whether the selenium content in the multivitamin-multimineral tablets is adequate, i.e., 60 µg or higher; if not, an extra selenium supplement may be indicated.

Due to the high risk of osteoporosis, it is important to have an adequate intake of calcium (and vitamin D₃, see vitamin section above). The recommended intake of calcium according to the Nordic nutrition recommendations is 800 mg/day [23]. The richest food sources of calcium are milk and milk products including cheese [23]. One liter of milk contains 1,200 mg calcium [34]. Depending on the consumption of milk products, calcium supplement should be taken in the form of calcium citrate. Calcium tablets are marketed with and without additional vitamin D₃. As calcium inhibits iron absorption [10], calcium supplements should be taken with meals.

In hemochromatosis, the surplus amount of iron in the cells and organs induces oxidative stress by the formation of free radicals through the Fenton reaction, which is assumed to be the basis for inflammation, cell necrosis and the development of connective tissue and fibrosis in various organs [1]. Anti-inflammatory and anti-oxidative diets [96] have become increasingly popular in recent years and are promoted by many nutritionists and rheumatic associations [97]. The concept is that a high intake of anti-oxidative-rich macronutrients and a favorable balance between omega-6 and omega-3 fatty acids in the diet can decrease the expression of inflammatory genes [96, 98]. Omega-3 fatty acids (eicosapentaenoic acid plus docosahexaenoic acid) have both anti-oxidative [99] and anti-inflammatory properties [96, 98], and exert favorable effects on inflammatory arthritis, e.g., rheumatoid arthritis [96, 98].

An anti-inflammatory diet should contain adequate amounts of omega-3 fatty acids at the level of a total of 2 - 3 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day [96]. Even a high daily intake of fat fish can hardly fulfill these requirements, so it is necessary to take supplementary fish oil capsules with the meals [96]. Furthermore, an anti-oxidative diet should be rich in colorful, non-starchy vegetables and fruits, which will contribute adequate amounts of polyphenols to help inhibit nuclear factor kappa beta, a primary molecular target of inflammation, and activate 5' adenosine monophosphate-activated protein kinase that plays an important role in cellular energy homeostasis [96].

From a empirical point of view, it seems likely that an anti-oxidative/anti-inflammatory diet comprising tea/coffee and many colorful vegetables, fruits and berries containing plant pigments acting as natural antioxidants, such as polyphenols (flavonoids and anthocyanins), as well as carotenoids [96], and providing adequate amounts of vitamin E and selenium, as well as anti-inflammatory supplements of omega-3 fatty acids [96], will be of benefit for persons with hemochromatosis. However, until now no systematic studies have been performed to explore this issue.