Ординатура / Офтальмология / Английские материалы / Handbook of Nutrition and Ophthalmology_Semba_2007

(AI) is the recommended level of intake for infants. The Estimated Average Requirement (EAR) is the daily intake value that is estimated to meet the requirement of half the healthy individuals in a group. The Recommended Dietary Allowance (RDA) is defined as the EAR plus twice the coefficient of variation (CV) to cover 97–98% of individuals in any particular group.

3.1.6. EPIDEMIOLOGY OF IRON DEFICIENCY

Iron deficiency is the most common nutritional deficiency worldwide, affecting half of children and women and a quarter of men in developing countries (78) and 7–12% of children and women in industrialized countries (79,80). In the United States, iron deficiency remains a major problem of women. Among women aged 20–49 yr in NHANES III (1988–1994), iron deficiency and iron deficiency anemia were found in 11% and 5% of women, respectively (81). These data, which used a conservative estimate for iron deficiency, suggest that at least 7.8 million women of childbearing age have iron deficiency and 3.3 million have iron deficiency anemia in the United States (81). There is a common, erroneous perception that iron deficiency and iron deficiency anemia are no longer important nutritional problems in the United States, but the prevalence rates for iron deficiency and iron deficiency anemia have not changed in the last 30 yr and may actually be increasing (82). Low income and minority women of childbearing age are the highest risk group for iron deficiency in the United States (81).

3.1.7. ASSESSMENT OF IRON STATUS

Iron deficiency is often diagnosed using laboratory indicators such as serum or plasma ferritin, total iron-binding capacity, transferrin saturation, erythrocyte protoporphyrin, serum or plasma transferrin receptor, and red cell indices (5,83). Use of these laboratory indicators have been described in detail elsewhere (5,83) and can be briefly summarized as follows. A serum or plasma ferritin <12 μg/L is considered to be consistent with iron deficiency among individuals >15 yr of age. Ferritin is a positive acute phase reactant, thus, in the presence of inflammation or infection, ferritin concentrations can be elevated in the presence of iron deficiency. Thus, serum or plasma ferritin should be considered as a conservative indicator of iron deficiency. Recent data suggest that a cut-off of 30 μg/L may be more appropriate for defining iron deficiency in adults (84–87). Among adults, a transferrin saturation <16%, total iron-binding capacity >400 μg/dL, erythrocyte protoporphyrin >70 μg/dL, and serum transferrin receptor >8.5 mg/L, have been used, separately or in combination, to define iron deficiency (5). Many of these indicators can also be affected by infection or inflammation. Red cell indices showing a microcytic, hypochromic anemia are consistent with iron deficiency. Iron deficiency anemia is usually defined as anemia in combination with one or more iron status indicators that are consistent with iron deficiency. According to World Health Organization criteria for the diagnosis of anemia, the cut-off points for hemoglobin are as follows: children aged 6 mo–6 yr, <110 g/L; children aged 6–14 yr, <120 g/L; adult males, <130 g/L; adult females, nonpregnant, <120 g/L; and adult females, pregnant, <110 g/L (5).

3.1.8. CLINICAL MANIFESTATIONS OF IRON DEFICIENCY

The main manifestation of iron deficiency is anemia, and anemia may cause fatigue, reduced work capacity, and reduced capacity for thermoregulation in cold environments. Among pregnant women, iron deficiency anemia has been associated with low birth weight,

prematurity, and increased fetal death. Iron deficiency in children is associated with impaired psychomotor and cognitive development and behavioral abnormalities. Nonspecific symptoms and signs of iron deficiency anemia include shortness of breath and pallor. Conjunctival pallor, especially in the cul-de-sacs, is a nonspecific ocular sign of severe iron deficiency.

3.1.9. RETINAL VASCULAR DISEASE ASSOCIATED WITH IRON DEFICIENCY ANEMIA

Severe iron deficiency anemia may compromise oxygen delivery to the retina, and there have been occasional case reports of iron deficiency anemia associated with background retinopathy, venous stasis retinopathy, central retinal artery occlusion, central retinal vein occlusion, and non-arteritic ischemic optic neuropathy. Chronic severe iron deficiency anemia has been associated with retinal hemorrhages and cotton wool spots (88), and there do not appear to be differences in the retinopathy associated with iron deficiency versus the anemia of chronic disease (89). Central retinal vein occlusion was reported in a 44-yr- old woman who presented with blurred vision, dyspnea, and a hemoglobin concentration of 62 g/L (90). Venous stasis retinopathy was described in a 36-yr-old woman who presented with acute onset of blurred vision in one eye, a microcytic, hypochromic anemia, and a hemoglobin concentration of 72 g/L (91). The patient had a 1-yr history of heavy menstrual flow in which she would typically use 20 pads per day for 5 d. The venous stasis retinopathy improved rapidly after blood transfusion, and further investigation showed that her menorrhagia was due to a large leiomyoma (91). A partial central retinal artery occlusion was described in a 13-yr-old girl with iron deficiency anemia (92). Central retinal vein occlusion was reported in a 37-yr-old woman with iron deficiency anemia and hemoglobin concentration of 94 g/L (93). The patient had no history of glaucoma, cardiovascular disease, hyperlipidemia, diabetes mellitus, cigarette smoking, intravenous drug use, oral contraceptive use, or use of any other medication. The patient was treated with oral ferrous sulfate and fibrinolytic therapy. By 2 wk, her vision had improved to 20/20 and had remained stable (93). Nonarteric ischemic optic neuropathy was reported in a 50-yr-old woman with hypermenorrhea, serum ferritin <5 μg/L, and hemoglobin concentration of 73 g/L (93). Severe iron deficiency anemia may also potentially accelerate the course of diabetic retinopathy (94).

3.1.10. PAPILLEDEMA ASSOCIATED WITH IRON DEFICIENCY ANEMIA

There have been rare case reports of papilledema associated with iron deficiency anemia (95–97). In one case report, a 42-yr-old man developed iron deficiency from bleeding hemorrhoids and presented with iron deficiency anemia, papilledema, and severe thrombocytosis (98). All three findings responded to treatment with oral iron supplementation (98).

3.2. Excess Iron Stores

Excess iron stores, or iron overload, is the opposite end of the spectrum and is less common than iron deficiency. A recent study conducted among exclusively white, older men and women living in the community of Framingham, Massachusetts showed that elevated iron stores were found in 12.9% of the subjects, and iron overload was considered more of a problem than iron deficiency among older white Americans (99). Although iron overload, an excess of total body iron, has been linked with accelerated disease processes (100), including heart disease (101), cancer (102), and diabetes (103), strong evidence showing a definitive causal relationship is lacking.

3.2.1. EXCESS IRON STORES AND RETINOPATHY OF PREMATURITY

Iron has been hypothesized to cause oxygen radical injury and increase the risk of retinopathy of prematurity (104,105). Retinopathy of prematurity is a fibrovascular proliferation of the retina found mainly in very premature infants. Premature infants may lack effective antioxidant systems, which may allow greater damage to tissues from free radicals. Much of the antioxidant activity of plasma is associated with two iron-associated antioxidants, ceruloplasmin and transferrin (105). Ceruloplasmin catalyzes the oxidation of ferrous to ferric iron, and apotransferrin serves as an antioxidant by binding ferric ions. Preterm infants have low plasma concentrations of ceruloplasmin and transferrin and high levels of transferrin saturation (106). Sullivan has hypothesized that retinopathy of prematurity is primarily a disorder of iron-associated antioxidant deficiency, thus, he termed the condition the “oxygen radical disease of prematurity” (105). The capacity of the ironassociated antioxidant system in premature infants may be unable to handle exogenous iron, and oxygen radical injury may increase because of the role of iron in the formation of highly reactive hydroxyl radical (•OH) from superoxide (O2−), known as the HaberWeiss reaction:

O2− + Fe3+ → O2 + Fe2+

2O2− + 2H+ → O2 + H2O2 Fe2+ + H2O2 → Fe3+ + OH− + •OH

Several studies have been conducted to examine the hypothesis that iron status is related to the retinopathy of prematurity. In a study of 184 very low-birthweight infants conducted in two neonatal intensive care units in Liverpool, frequency of blood transfusion and gestational age were independently associated with retinopathy of prematurity (107). Two previous studies had suggested an association between blood transfusion and retinopathy of prematurity in low-birthweight infants (108,109). In a prospective study of 56 very low-birthweight infants, those who developed retinopathy of prematurity had significantly high serum iron (OR, 1.90, 95% CI 1.06–3.90) and transferrin saturation (OR 1.73, 95% CI 1.03–3.27) in the first week of life than those without retinopathy, after controlling for potential confounding variables (110). An observational study involving 114 very low-birthweight infants showed that the relative risk of developing retinopathy of prematurity was 6.4 (95% CI 1.2–33.4) for infants who received 16.45 mL/kg and 12.3 (95% CI 1.6–92.5) for infants who received >45 mL/kg of blood transfusion (111). Infants who developed retinopathy of prematurity had significantly higher serum ferritin concentrations and lower transferrin concentrations than infants without retinopathy of prematurity, but these differences were not significant after adjusting for transfusion volume (111).

In a study of 230 preterm infants who were randomly allocated to receive treatment with recombinant human erythropoietin and iron (1 mg/kg/d intravenously from the second to the fourth week, and then 12 mg/kg/d orally until the seventh week) or no treatment (control), 43.8% of the treated group and 21.7% of the control group developed retinopathy of prematurity (p = 0.0007) (112). There was a significant positive correlation between serum ferritin concentrations at the second, fourth, and sixth week of treatment and the severity of the retinopathy of prematurity. The investigators suggested that iron supplementation increased retinal free iron and may have contributed to the oxidative injury to retinal vessels (112).

3.2.2. EXCESS IRON STORES AND MACULAR DEGENERATION

Aceruloplasminemia is a rare autosomal recessive disease that is associated with iron overload. A mutation in the ceruloplasmin gene results in impaired iron export from several tissues and the accumulation of iron in the retina, brain, and pancreas. In a case report from Japan, a 56-yr-old man was found to have a retinal degeneration with yellowish discoloration of the fundus and midperipheral retinal pigment epithelium cell atrophy (113). Multiple subretinal yellowish-white lesions and retinal pigment epithelium cell atrophy was described in a Caucasian man with aceruloplasminemia (114). Biopsy of the conjunctival epithelium revealed Perls’ Prussian blue-positive epithelial cells, indicating tissue iron overload.

4. ANOREXIA NERVOSA

Anorexia nervosa, a disorder characterized by self-imposed weight loss, endocrine dysfunction, and an altered view of eating and weight, usually in young women, has rarely been associated with retinal vascular disease and cataracts in case reports. Anorexia nervosa is similar to a state of semistarvation, and accompanying changes include elevated plasma carotenoids, hypercholesterolemia, altered thyroid hormone and cateocholamine metabolism, amenorrhea, reduced libido, and constipation. Anorexia nervosa has been associated with central retinal vein occlusion and cataracts. Whether these eye conditions are causally related to anorexia nervosa or are chance associations is not clear. A 21-yr-old woman with anorexia nervosa presented with central retinal vein occlusion and vision of 20/200 (115). In the year after the divorce of her parents, the patient lost 18 kg, and at presentation, her body mass index (weight/height2) was 16.1. She had severe iron deficiency anemia with a hemoglobin concentration of 65 g/L. Following treatment with oral ferrous sulfate and a high calorie and protein rich diet, the vision returned to 20/20 (115). Bilateral subcapsular cataracts have also been described in women with anorexia nervosa (116,117). Anorexia nervosa has not been associated with ocular signs of vitamin A deficiency, despite low levels of vitamin A intake (118).

5. HYPERLIPIDEMIAS AND LIPEMIA RETINALIS

Lipemia retinalis is a rare fundus abnormality that is associated with primary and secondary hyperlipidemia. The condition is characterized by pale, creamy or milky white retinal blood vessels and a salmon-colored fundus due to elevated triglycerides in the retinal and choroidal circulation.

5.1. Hyperlipidemias

Lipemia retinalis has been described in different primary hyperlipidemias: Type I (exogenous hyperlipemia), Type III (remnant hyperlipidemia), Type IV (endogenous hyperlipemia), and Type V (mixed hyperlipemia) and with secondary hyperlipidemias. Primary disorders associated with Type I are familial lipoprotein lipase deficiency and C-II apolipoprotein deficiency. Type III is associated with familial dysbetalipoproteinemia. Type IV is associated with familial hypertriglyceridemia (mild form), familial multiple lipo- protein-type hyperlipidemia, sporadic hypertriglyceridemia, and Tangier disease. Type V is associated with mixed hyperlipemia are familial hypertriglyceridemia (severe form), familial lipoprotein lipase deficiency, and C-II apolipoprotein deficiency. These disorders

LDL, low-density lipoprotein; VLDL, very low-density lipoprotein. Modified from refs. 119,120.

have been reviewed in detail elsewhere (119). The hyperlipidemias that have been associated with lipemia retinalis are summarized in Table 3 (119,120). The most common secondary hyperlipidemia associated with lipemia retinalis is chylomicronemia that results from uncontrolled diabetes mellitus.

5.2. Historical Background

In 1880, the ophthalmologist Albert G. Heyl (1847–1895) presented a case report at the Philadelphia County Medical Society of a 20-yr-old man with diabetes mellitus and wasting who complained of dimness of sight (121). Fundus examination revealed light salmon-colored retinal blood vessels. Heyl noted: “On pricking the finger, a drop of blood would escape, having very much the color of a piece of pink coral, followed by a thick, whitish fluid, of the color and consistence of an oil-emulsion...” Since Heyl’s description, there have been numerous case reports in the literature of lipemia retinalis (122–139). In most of these cases, lipemia retinalis was associated with severe diabetes mellitus.

5.3. Clinical Presentation

Idiopathic hyperlipemia is associated with lipemia retinalis, lid xanthelasmas, and corneal arcus, and is rarely associated with lipid interstitial keratitis (140), iris xanthomas (135), and yellowish lesions in the deep retina that are thought to represent small intraretinal xanthomas (141). Type III hyperlipoproteinemia has been associated with Schnyder central stromal corneal dystrophy and lipemia of the limbal vessels (142). In a experimental canine model, hyperlipoproteinemia caused deposition of lipid in peripheral cornea but did not any appreciable fundus lesions (143). Lipemia retinalis has been described in rhesus monkeys with thyroid suppression and long-term ingestion of a high-cholesterol diet (144). A grading system was developed for lipemia retinalis, consisting of Grade I

tionships between nutritional disorders and the retinal vascular diseases discussed in this chapter, this would suggest that a large proportion of retinal vascular disease may be preventable with better nutrition. Studies are needed to determine whether mandatory folic acid fortification of bread flour and other food products since 1996 has had an apparent impact on the incidence of retinal artery or retinal vein occlusion in the United States. It is unclear whether daily folic acid or B complex vitamin supplementation in patients with retinal vein occlusion will reduce the risk of having a subsequent retinal vein occlusion in the opposite eye. Although iron deficiency and iron deficiency anemia could theoretically contribute to retinal hypoxia and progression of diabetic retinopathy, it is unclear whether such a relationship may exist among young women with diabetes mellitus who have iron deficiency or iron deficiency anemia. Further studies are needed to determine whether milder forms of hyperlipidemia are associated with an increased risk of retinal vascular disease. Controlled clinical trials may be needed to confirm the hypothesis that excess iron stores are involved in the pathogenesis of the retinopathy of prematurity.

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