Ординатура / Офтальмология / Английские материалы / Handbook of Nutrition and Ophthalmology_Semba_2007
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Table 1
Causes of Hyperhomocysteinemia
A.Inherited defects
1.Enzyme deficiencies
a.Cystathionine β-synthase
b.Methylenetetrahydrofolate reductase
c.Methionine synthase
d.Cobalamin coenzyme synthesis
2.Transport defects
a.Transcobalamin II deficiency
b.Cobalamin lysosomal transporter
B.Acquired defects
1.Nutritional
a.Cobalamin (vitamin B12) deficiency
b.Folic acid deficiency
c.Pyridoxine (vitamin B6) deficiency
2.Metabolic
a.Chronic renal disease
b.Hypothyroidism
3.Drug-induced
a.Methotrexate and other folate antagonists
b.Nitrous oxide and other cobalamin antagonists
c.Azaribine and other pyridoxine antagonists
d.Estrogen antagonists
Reproduced from ref. 4, with permission of Routledge/Taylor & Francis Group, LLC.
cies of these B complex vitamins (5). There are other factors that can alter homocysteine metabolism and cause hyperhomocysteinemia, including inborn errors of metabolism, such as cystathionine β-synthase deficiency, methionine synthase deficiency, transcobalamin II deficiency, chronic renal disease, hypothyroidism, and some drugs (Table 1). Homocystinuria due to cystathionine β-synthase deficiency is presented elsewhere in Chapter 12.
Homocysteine appears to inhibit several different anticoagulant systems, such as the protein C anticoagulant pathway, antithrombin III, human umbilical vein endothelial cells ecto-ADPase, and endothelial cell tissue plasminogen activator (6). Disruption of these vessel wall-related anticoagulant systems by homocysteine may potentially account for the increased thrombosis that occurs with hyperhomocysteinemia.
2.3. Relationship Between Folate Status and Homocysteine
An inverse relationship has generally been found between folate concentrations and total homocysteine concentrations in serum or plasma. An inverse relationship between serum folate and total homocysteine concentrations was described in 1987 by Kang and colleagues (7). Subjects with subnormal serum folate concentrations had more than a 1.65 higher concentration of serum total homocysteine than those with normal serum folate concentrations. An inverse correlation was also found between low serum vitamin B12 concentrations and serum total homocysteine when those with serum folate >18 ng/mL
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Fig. 2. Impact of folate supplementation on total homocysteine concentrations among women. Mean plasma total homocysteine (tHcy) concentrations during 4 wk of folic acid supplementation and 4 and 8 wk after the end of the intervention period in 144 healthy, nonpregnant women, by intervention group. (Reproduced from ref. 14, with permission of American Journal of Clinical Nutrition. Copyright © Am J Clin Nutr. American Society for Nutrition.)
were excluded (7). Elevated serum total homocysteine was described in 18 of 19 patients with folate deficiency (8). A significant inverse relationship was found between plasma folate and plasma homocysteine concentrations among men with and without coronary artery disease (9). Suboptimal folate status was found in 59.1% of men with hyperhomocysteinemia (10). Studies in the Framingham Heart Study cohort also showed that plasma homocysteine was inversely correlated with plasma folate concentrations (11).
Randomized clinical trials have shown that folic acid supplementation will reduce serum or plasma total homocysteine concentrations (12–14). In a randomized controlled clinical trial of folate supplementation, 500 μg per day, 500 μg every other day, or placebo, total homocysteine concentrations decreased among women taking either dose of folate compared with placebo (14) (Fig. 2). Meta-analysis of twelve randomized clinical trials
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Fig. 3. Reductions in blood homocysteine concentrations with folic acid supplements, stratified by pretreatment blood concentrations of homocysteine, folate, and vitamin B12. (Reproduced from ref. 15, with permission of BMJ Publishing Group.)
of folic acid showed that folic acid supplementation lowered blood homocysteine concentrations, and greater effects of folic acid were noted when subjects started out with lower folate concentrations or higher blood homocysteine concentrations before treatment (15) (Fig. 3). Dietary folic acid reduced blood homocysteine concentrations by 25% (95% confidence interval [CI], 23–28%), and the effect of folic acid was similar for doses from 0.5 to 5 mg per day. In a placebo-controlled, dose ranging study, the effect of low dose folic acid on plasma homocysteine concentrations was examined in 95 patients with documented coronary artery disease (16). The doses consisted of 400 μg, 1 mg, or 5 mg of folate or placebo for 3 mo, in addition to vitamin B12 and vitamin B6. A similar decrease in homocysteine concentrations was found in all three folate treatment groups, and there was no change in the placebo group (16).
In 1996, the Food and Drug Administration issued a regulation that required all enriched flour, rice, pasta, cereal and other grain products to be fortified with folic acid (140 μg per 100 g) in order to reduce the risk of neural tube defects in newborns. Plasma folate and total homocysteine concentrations were compared in archived samples from the Framingham Offspring Study cohort between subjects who were seen before and after mandatory folic acid fortification went into effect. Between these two periods, among those who did not take vitamin supplements, the prevalence of high homocysteine concentrations (>13 μmol/L) decreased significantly from 18.7 to 9.8%, and prevalence of low plasma folate concentrations significantly decreased from 22.0 to 1.7% (17).
2.4. Relationship Between Vitamin B6 Status and Homocysteine
Vitamin B6 serves as a coenzyme in the transsulfuration of homocysteine to cysteine, but clinical studies suggest that the relationship between plasma total homocysteine
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concentrations and vitamin B6 is not as strong as that between plasma total homocysteine and folate or vitamin B12, respectively. Administration of vitamin B6 (pyridoxine) has been shown to improve the response to the methionine loading test among subjects with vascular disease and elevated total homocysteine concentrations (18).
2.5. Relationship Between Vitamin B12 Status and Homocysteine
Plasma or serum total homocysteine concentrations are usually elevated among patients with vitamin B12 deficiency (19). Asymptomatic vitamin B12-deficient subjects had higher total plasma homocysteine concentrations compared with controls (23.8 vs 11.5 μmol/L, respectively p < 0.0001) (20). Plasma total homocysteine concentrations returned to normal after administration of hydroxycobalamin to vitamin B12-deficient subjects (20). The relationship between total homocysteine and vitamin B12 deficiency is sufficiently strong that total homocysteine concentrations may be useful in the diagnosis of cobalamin deficiency (21), and elevated serum total homocysteine concentrations may facilitate the diagnosis of cobalamin deficiency among individuals who have cobalamin deficiency with normal serum cobalamin concentrations (22) or cobalamin deficiency without anemia (23).
2.6. Epidemiology of Hyperhomocysteinemia
Plasma homocysteine concentrations are generally higher in men than women, and mean concentrations increase with age (24) (Fig. 4). Among individuals receiving vitamin supplements, the normal frequency distribution and reference range for plasma homocysteine concentrations has been predicted, with a 95% reference range for plasma homocysteine of 4.9 to 11.7 μmol/L (25). In the third National Health and Nutrition Examination Survey (NHANES), age-adjusted geometric mean total homocysteine concentrations among non-Hispanic men and women were 9.6 and 7.9 mmol/L, among non-Hispanic black men and women were 9.8 and 8.2 mmol/L, and among Mexican-American men and women were 9.4 and 7.4 mmol/L (24). The risk for hyperhomocysteinemia may need to be reassessed, since mandatory folate enrichment was implemented in the United States in 1996. Individuals who are carriers or heterozygotes for cystathionine β-synthase deficiency can have slightly elevated plasma total homocysteine concentrations (26), which may put them at higher risk for retinal vascular disease. The frequency of carriers is estimated to be 1 of 200 in the US population. Other inborn errors of metabolism that may cause hyperhomocysteinemia are relatively rare and include vitamin B12 defects (CbC, D, E, F, G) and methylenetetrahydrofolate reductase deficiency (MTHFR). Recently, thermolabile variants of the enzyme MTHFR recently discovered, and 5% to 16% of individuals may be homozygous for the enzyme and up to 50% may be heterozygous (27). MTHFR polymorphism does not seem to be associated with increased risk of vascular disease (28,29). Other factors that may influence plasma total homocysteine concentrations include medications such as fibrates, carbamazepine, phenytoin, methotrexate, and trimethoprim (30).
2.7. Hyperhomocysteinemia and Cardiovascular Disease
Elevated plasma or serum total homocysteine concentrations are associated with an increased risk for cardiovascular disease. The number of studies that examined the relationship between homocysteine and cardiovascular disease has accelerated at a steep
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Fig. 4. Smoothed geometric mean serum homocysteine concentration by age group, sex, and raceethnicity in males (---) and females (—) in the third National Health and Nutrition Examination Survey. (From ref. 24, with permission of the American Journal of Clinical Nutrition. Copyright © Am J Clin Nutr. American Society for Nutrition.)
pace over the last two decades (31), and meta-analysis of over two dozen of these studies suggests that 10% of the population risk for coronary artery disease is related to elevated total homocysteine concentrations (32). Another recent meta-analysis suggests that lower blood homocysteine concentrations are associated with a modest 11% lower risk for ischemic heart disease and 19% lower risk of stroke (33).
Subjects with coronary artery disease have been shown to have significantly higher plasma or serum total homocystene concentrations than controls (9,34). A case-control study from Great Britain showed that subjects who died with ischemic heart disease had higher serum homocysteine levels than controls, 13.1 vs 11.8 μmol/L, respectively (35).
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Fig. 5. Estimated survival among patients with coronary artery disease, according to plasma total homocysteine levels. (Reprinted from ref. 37. Copyright © 1997, Massachusetts Medical Society. All rights reserved.)
Higher plasma total homocysteine concentrations are associated with an increased risk of myocardial infarction. In the Physicians’ Health Study, 271 of 14,916 male physicians had a myocardial infarction during 5 yr of follow-up (36). A case control study showed that those who had a myocardial infarction had significantly higher plasma homocysteine than matched controls (11.1 ± 4.0 vs 10.5 ± 2.9 μmol/L, respectively, p = 0.03). Individuals with plasma homocysteine above the 95th percentile of the control distribution had a three-fold increased risk of myocardial infarction (36). A prospective study of 587 patients with angiographically confirmed coronary artery disease showed a graded relationship between plasma homocysteine concentrations and subsequent mortality (Fig. 5), and 3.8% of those with plasma homocysteine <9 μmol/L died vs 24.7% of those with plasma homocysteine ≥15 μmol/L (37).
Other studies have shown relationships between serum folate concentrations and myocardial infarction or risk of death from heart disease. In a case-control study of 130 patients hospitalized for their first myocardial infarction, mean plasma homocysteine concentrations were higher in cases than controls, and plasma homocysteine was inver-
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sely correlated with plasma folate and vitamin B12 concentrations, but not with plasma vitamin B6 (38). Adults with decreased serum folate concentrations had an increased risk of death from fatal coronary heart disease in the Nutrition Canada Survey (39). In another study from the Physicians’ Health Study, risk of acute myocardial infarction or death from coronary artery disease was associated with folate and vitamin B6 concentrations (40). Men with the lowest 20% of folate levels (<2.0 ng/mL) had a relative risk of 1.4 (95% CI 0.9–2.3) for acute myocardial infarction or death due to coronary artery disease compared with those in the top 80%. For those the lowest 20% compared with top 80% of vitamin B6, the relative risk was 1.5 (95% CI 1.0–2.2) (40).
2.8. Hyperhomocysteinemia and Peripheral Vascular Disease
Elevated plasma or serum total homocyteine concentrations have been associated with an increased risk for venous and recurrent thrombotic disease in many different studies, as reviewed elsewhere (41). In a case control study of 185 patients with history of recurrent venous thrombosis and 220 controls, homocysteine concentrations were measured after oral methionine loading (42). Hyperhomocysteinemia was defined as >90th percentile of homocysteine concentration post-methionine dose in the controls. Of 185 patients with recurrent thrombosis, 25% had fasting homocysteine concentrations above the 90th percentile of the controls (odds ratio [OR] 3.1, 95% CI 1.8–5.5) (42). In the Leiden Thrombophilia Study, plasma homocysteine concentrations were higher among 269 patients with a first episode of deep venous thrombosis compared with 269 healthy controls matched by age and sex (43). 10% of cases and 4.8% of controls had homocysteine >18.5 μmol/L (OR 2.5, 95% CI 1.2–5.2).
2.9. Hyperhomocysteinemia and Cerebrovascular Disease
Hyperhomocysteinemia is associated with increased carotid artery intimal-medial wall thickening (44) and increased risk of stroke (45). In a study from the United Kingdom, serum was collected from 5661 men, aged 40–59 yr, who were randomly selected from population of one general practice in each of 18 towns. During follow-up, there were 141 incident cases of stroke among those with no history of stroke at screening. Serum total homocysteine was determined in 107 cases and 118 control men. Total homocysteine concentrations were 13.7 vs 11.9 μmol/L ( p = 0.004) in cases and controls. The relative risk of stroke increased in a dose-response fashion from the 2nd, 3rd, and 4th quartiles of the homocysteine distribution, relative to the first. The relationship between homocysteine and stroke was strong, even after adjusting for other factors such as cigarette smoking, hypertension, and high-density lipoprotein (HDL) cholesterol (45).
Both elevated plasma homocysteine concentrations and low plasma folate or vitamin B6 concentrations were associated with increased risk of stroke, peripheral vascular disease, and coronary artery disease (46). In a case control study conducted in nine European countries, 750 cases of atherosclerotic vascular disease were matched with 800 controls (47). The relative risk for vascular disease in the top fifth compared with the bottom four fifths of the control fasting total homocysteine distribution was 2.2 (95% CI 1.6–2.9) (47).
2.10. Hyperhomocysteinemia and Retinal Vascular Disease
Hyperhomocysteinemia is associated with retinal vascular disease, including central retinal vein occlusion, branch retinal vein occlusion, and central retinal artery occlusion.
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Prior to more widespread recognition of hyperhomocysteinemia as a risk factor for retinal vascular disease, epidemiological studies showed that risk factors for retinal vein occlusion included hypertension, diabetes mellitus, ischemic heart disease, and cerebrovascular disease (48). In a study from the Wilmer Institute, 197 patients with central retinal vein occlusion were compared with National Health Interview Survey patients, and diabetes mellitus and hypertension were risk factors for central retinal vein occlusion (49). The Eye Disease Case-Control Study Group investigated 270 patients with branch retinal vein occlusion and 1142 control patients, and risk factors for branch retinal vein occlusion included a history of hypertension, glaucoma, increased body mass index at 20 yr of age, and higher serum levels of α2-globulin (50). Risk factors for hemiretinal vein occlusion included hypertension and diabetes mellitus (51). In the Blue Mountains Eye Study, glaucoma, hypertension, history of stroke, and history of angina were associated with retinal vein occlusion (52). Diabetes mellitus, glaucoma, and hypertension have also been identified as risk factors for retinal vein occlusions in another case-control study (53). Increased blood viscosity has been identified as a risk factor for central retinal vein occlusion (54, 55), and other potential risk factors have been discussed elsewhere (56,57).
An association between homocystinuria and retinal artery occlusions has appeared in case reports. Bilateral central retinal vein occlusions were described in a 6-yr-old child with homocystinuria (58), and early reports of optic atrophy and sclerotic arteries in homocystinuria may have been late findings related to retinal artery occlusion (59,60). In a case report, a 24-yr-old man developed bilateral central retinal vein occlusions, and plasma homocysteine concentrations were found to be 26.2 μmol/L (61). Retinal vein occlusions as reported in series of children and young adults (62,63) may have included cases of unrecognized hyperhomocystinuria. Elevated homocysteine was found in a 33-yr-old man with central retinal vein occlusion who had no vascular risk factors except cigarette smoking (64).
In a study of 19 patients under the age of 50 yr who had retinal vein occlusion or retinal artery occlusion, 4 of 19 patients had elevated homocysteine concentrations after methionine loading test, leading the investigators to conclude that hyperhomocysteinemia was associated with increased risk of premature retinal artery and retinal vein occlusions (65). In a case-control study, 74 patients with central retinal vein occlusion were found to have plasma homocysteine concentrations of 11.58 μmol/L compared with 9.49 μmol/L in controls (66). Plasma homocysteine concentrations were studied in 74 cases with nonarteritic anterior ischemic optic neuropathy, central retinal vein occlusion, and central retinal artery occlusion and 81 controls, and significantly elevated plasma homocysteine concentrations were found among the cases with retinal vascular disease (67). Elevated plasma homocysteine was associated with nonarteritic ischemic optic neuropathy in two younger adults without diabetes (68). In a case-control study, 87 cases of central retinal vein occlusion, hemiretinal vein occlusion, branch retinal vein occlusion, or central retinal artery occlusion were matched with 87 controls (69). Mean plasma homocysteine concentrations were significantly higher in all disease groups compared with controls, and when adjusted for other factors, OR, 2.85, 95% CI 1.43–5.68. Mean plasma homocysteine in cases and controls was 12.9 vs 10.7 μmol/L (p < 0.0001) (69). Although the homozygous genotype for the thermolabile methylenetetrahydrofolate reductase enzyme (TT genotype) has been associated with vascular occlusive disease, in a recent case-control study, the TT genotype was not associated with increased risk of retinal vascular disease (70).
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In contrast, a study from Israel of 59 patients with retinal vein occlusion showed a significant association between the TT genotype and retinal vein occlusion (71).
2.11. Prevention of Hyperhomocysteinemia
Several studies have shown that serum or plasma total homocysteine concentrations can be reduced to normal following folate supplementation (14,15,72) or a combination of folate and other B vitamin supplements (73). There may be a potential benefit of reducing 13,500 to 50,000 deaths from coronary artery disease annually by increasing the intake of folic acid (32). Clinical trials are currently in progress to examine the effects of B vitamin supplementation on risk of recurrent stroke or death from cardiovascular disease (74–76).
3. DISORDERS OF IRON METABOLISM
Although iron deficiency and iron deficiency anemia are extremely common, there have only been isolated case reports where severe iron deficiency has been associated with retinal vascular disease. Excess iron stores have been implicated in the pathogenesis of the retinopathy of prematurity.
3.1. Iron Deficiency
Iron is essential for oxygen and energy metabolism and is a constituent of hemoglobin, myoglobin, cytochromes, and other iron-containing enzymes. Iron deficiency is the most common micronutrient deficiency worldwide, affecting a large proportion of children and women in both developed and low income countries. Iron deficiency may potentially contribute to retinal vascular disease through anemia and compromised oxygen delivery to the retina, but such a biological mechanism has not been well elucidated.
3.1.1. BIOCHEMISTRY OF IRON
Iron is element 26 in the periodic table and has an atomic weight of 55.85. Iron exists in two oxidation states in aqueous solution, either Fe2+, the ferrous form, or Fe3+, the ferric form. Iron can change between these forms, enabling it to serve as a catalyst in redox reactions by donating or accepting electrons. Iron-containing compounds play key roles in oxygen and energy metabolism. The role of iron in oxidative stress is presented in further detail under Subheading 3.2.1.
3.1.2. DIETARY SOURCES OF IRON
Foods that are rich in iron include liver, beef, veal, fish, eggs, soybeans, broccoli, green beans, and pasta. The absorption of iron depends on factors which include overall iron status, the mixture of foods in the meal, and the presence of vitamin C. From an economic standpoint, animal foods that contain heme iron tend to be more expensive and may be a barrier to obtaining iron-rich sources of food in low income situations.
3.1.3. ABSORPTION, STORAGE, AND METABOLISM OF IRON
Foods that contain iron are absorbed via two different pathways, one for heme iron found in animal products, and the second for absorption of non-heme iron, mostly iron salts, that are found in dairy products and plant foods. The bioavailability of heme iron in foods of animal origin is higher than that for iron from foods of vegetable origin. The absorption of iron in the upper intestine is regulated by the body’s need for iron, and the iron content
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Table 2 |
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Dietary Reference Intakes for Iron (mg/d) |
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Age and Gender Category |
AI |
EAR |
RDA |
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Infants, 0–6 mo |
0.27 |
– |
– |
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Infants, 7–12 mo |
6.9 |
– |
11.0 |
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Children, 1–3 yr |
– |
3.0 |
7.0 |
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Children, 4–8 yr |
– |
4.1 |
10.0 |
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Boys, 9–13 yr |
– |
5.9 |
8.0 |
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Girls, 9–13 yr |
– |
5.7 |
8.0 |
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Boys, 14–18 yr |
– |
7.7 |
11.0 |
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Girls, 14–18 yr |
– |
7.9 |
15.0 |
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Adult men ≥19 yr |
– |
6.0 |
8.0 |
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Adult women, 19–50 yr |
– |
8.1 |
18.0 |
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Adult women >50 yr |
– |
5.0 |
8.0 |
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Pregnant women, 14–18 yr |
– |
23.0 |
27.0 |
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Pregnant women, 19–50 yr |
– |
22.0 |
27.0 |
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Lactating women, 14–18 yr |
– |
7.0 |
10.0 |
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Lactating women, 19–50 yr |
– |
6.5 |
9.0 |
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AI, Adequate Intake; EAR, Estimated Average Requirement; RDA, Recommended Dietary Allowance. Based on ref. 77.
of the body is highly conserved. Factors that enhance the absorption of dietary iron include vitamin C. Phytates and polyphenols in plant foods can inhibit the absorption of dietary iron. Iron is taken up by duodenal enterocytes and transferred into the plasma in the form of bilirubin and iron transported by transferrin. About two-thirds of the total iron of the human body is found in the form of hemoglobin in circulating erythrocytes, with the remainder in liver stores and in myoglobin in muscle tissue.
3.1.4. FUNCTIONS
Hemoglobin, myoglobin, and cytochromes contain a heme protein, or iron-porphyrin prosthetic group, that bind iron in the center of a porphyrin ring. Hemoglobin combines with oxygen in the pulmonary circulation and becomes largely deoxygenated in the capillary circulation, where it delivers oxygen to tissues. In severe anemia, the hemoglobin content of erythrocytes is reduced, decreasing oxygen delivery to tissues and leading to chronic tissue hypoxia. Myoglobin in muscle transports and stores oxygen needed for muscular contraction. Cytochromes a, b, and c are involved in oxidative phosphorylation and the production of cellular energy. Cytochromes serve as electron carriers in transforming adenosine disphosphate (ADP) to adenosine triphosphate (ATP), the primary energy storage compound. Cytochrome P450 is found in microsomal membranes of liver and intestinal mucosal cells. Other non-heme, iron-containing enzymes include NADH dehydrogenase and succinate dehydrogenase, hydrogen peroxidases, catalase, peroxidase, aconitase, phosphoenolpyruvate carboxykinase, and ribonucleotide reductase.
3.1.5. REQUIREMENTS FOR IRON
The Food and Nutrition Board of the Institute of Medicine has made new recommendations for iron intake by life stage and gender group (77) (Table 2). The Adequate Intake