Tipos y estados de operación Las etapas de la transferencia de masa, las cuales bajo ciertas condiciones manipulables de operación determinan la velocidad a la

Because iron absorption is homeostatically regulated, at least in adults, the risk of iron overload from dietary iron is mainly limited to individuals with hereditary (primary) haemochromatosis, a relatively common disor- der in the Nordic countries with a reported frequency of homozygosity for

NORDIC NUTRITION RECOMMENDATIONS 2012

the C282Y mutation ranging from 0.20% to 0.75% (2, 119). In primary haemochromatosis, iron absorption is increased 2 to 3 times in homozy- gotes due to a genetic defect in the HFE gene. Three mutations have been described, and for the two most common, C282Y and H63D, the frequen- cies of homozygotes are about 0.4% and 2%, respectively, in Scandinavia (2, 119, 120). Individuals who are heterozygous for the C282Y mutation do not appear to respond abnormally to dietary iron and, therefore, do not need to change their diet to prevent accumulation of iron in the body (121). Homozygosity for the C282Y mutation is most often associated with clinical signs of haemochromatosis and risk of developing serious symp- toms even at the iron levels normally present in the diet. These symptoms include hepatomegaly, hepatic fibrosis, and hepatoma in addition to joint inflammation, diabetes mellitus, cardiomyopathy, and cardiac failure. The treatment is phlebotomy. If untreated, the risk of symptoms is five times higher in men than in women due to a constantly higher loss of iron among women via menstrual bleeding. The penetrance of the C282Y mutation, which is the most frequent one leading to haemochromatosis, has been estimated to be between 1% and 25% depending on the study design and the endpoints used (122).

Studies have found moderate and slight liver fibrosis in several cases with hepatic iron concentrations of 51 mmol/g to 240 mmol/g dry weight (123, 124). Hepatic fibrosis and iron concentration have also been cor- related to s-ferritin levels. In the study by Bell et al, a dose response curve for severity of fibrosis and s-ferritin was found, and s-ferritin was mostly above 1000 mg/L in those with liver fibrosis (124). The median s-ferritin concentration for the mildest form of fibrosis was 858 mg/L with values as low as 520 mg/L. Åsberg et al found a clear correlation between hepatic iron and s-ferritin with quite a wide distribution (123). To keep hepatic iron below 400 mmol/g of dry weight, the limit for s-ferritin would be about 250 mg/L. In this study, 4 of 12 patients with moderate liver fibrosis had s-ferritin concentrations below 1000 mg/L and ranged from 311 mg/L to 629 mg/L.

Earlier reports have described secondary haemochromatosis caused by high intake of iron, e.g. as part of a habitual intake of iron-contami- nated beer or as pharmaceutical iron, over a period of several years. Iron doses thought to stimulate secondary haemochromatosis might exceed 150 mg/d (77).

Iron

Iron and risk of cardiovascular disease

In the NNR 2004 a possible relationship between iron overload and car- diovascular disease was discussed, but no stable or causal relationship between iron and risk of cardiovascular disease had been established (77). In the recent SR (24), an association between both hypertension and cardiovascular disease was explored. The evidence for a relationship between haem iron intake and cardiovascular disease was determined to be suggestive based on the SACN report of 2010 that evaluated iron and cardiovascular disease and iron and health (82). This relationship between iron overload and cardiovascular disease has also been shown in the Iowa women’s health study cohort in women using more than 10 g of alcohol per day and even more clearly in women using more than 30 g of alcohol per day (125). Some studies have indicated a protective effect of iron intake against high blood pressure, but no conclusions (24) could be drawn about associations between high iron intake and lower blood pressure either as intake during pregnancy vs. blood pressure in the offspring (126, 127) or as intake vs. blood pressure in adults (128, 129).

Iron and risk of cancer

According to a recent meta-analysis, individuals carrying the C282Y hae- mochromatosis mutation have an increased risk of hepatocellular carci- noma (130). Regarding extra-hepatic malignancies in the general popu- lation, there were studies cited in NNR 4 indicating an increased risk of colon cancer and other cancers related to high iron stores (77). However, a causal relationship between iron and extra-hepatic cancer could not be established. Several new studies have examined the possible relationship between dietary iron intake and various forms of cancer (131–140). How- ever, no convincing evidence that dietary iron intake is associated with increased risk of colon cancer, lung cancer, breast cancer, oesophageal cancer, or other cancers could be found (24).

Iron and risk of diabetes

Based on the SR undertaken for NNR 5, there is probable evidence for an association between haem iron intake and type 2 diabetes (T2D) as well as gestational diabetes mellitus (GDM). Three recent large epidemiologi- cal studies have examined the association between iron intake and T2D (141–143). The studies reported similar figures for the lowest and the highest quintile of haem iron intake and they arrived at the exact same relative risk for T2D (RR = 1.28). No effect or an inverse effect on the risk

NORDIC NUTRITION RECOMMENDATIONS 2012

of T2D was seen for non-haem iron and for total iron intake. Two case studies looking mainly at the association between markers of iron stores and risk of T2D (144, 145) also found that cases with T2D had the highest intake of haem iron.

High intake of haem iron before or during pregnancy seems to increase the risk of developing GDM (146, 147). The studies on the association between haem iron intake and T2D and GDM adjusted their data for many confounders, but the facts that haem iron intake is closely related to the in- take of red or processed meat and that subjects with high haem iron intake had significantly less healthy behaviour in terms of diet, physical activity, smoking, and BMI (142), as well as an absence of an effect of total iron intake, suggest that there are other dietary or lifestyle factors rather than iron that increase the risk of T2D. Haem iron intake might be an indirect marker of T2D development, but a meta-analysis found that the intake of both unprocessed and processed red meat was positively associated with T2D risk after adjustment for age, BMI, and lifestyle such as smoking (148). The association between haem iron and T2D could, therefore, be related to the increased risk of T2D that is associated with the intake of red meat.

There is probable evidence for the association of haem iron intake with the risk of T2D and GDM even though these associations might not be causal. Because there is no evidence that total iron intake is associated with increased risk of T2D, this does not have any implication for recom- mended daily intakes of iron.

There is no conclusive evidence for an association between iron intake and type1 diabetes (24).

Reasoning behind the recommendation

Requirements and recommendations for iron were based on calculations including the body’s estimated basal loss of iron (taking body size into account), the requirements for growth of a child, an adolescent and fetus and maternal growth in pregnancy, and the estimated menstrual losses of a woman in fertile age. Varying absorption of different groups depending on possible iron status was taken into account. The recommendations of iron in NNR 2012 are maintained unchanged from NNR 2004 since no strong scientific evidence to change has emerged.

Iron