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

Fig. 1. Metabolism of n-6 and n-3 fatty acids.

of AA and DHA in the retina and brain appears to be largely dependent on the maternal supply (27). About 85% of DHA and more than 90% of the AA in the brain accrues between 26 and 40 wk of gestation (25).

In pregnant women, overall maternal essential fatty acid status declines continuously from the first trimester until delivery (28). The absolute plasma concentrations of phospho- lipid-associated AA and DHA increase by about 20% and 40%, respectively (28). The relative fatty acid concentration of linoleic acid does not change during pregnancy from 10 wk of gestation until delivery, however, the relative concentrations of arachodonic acid and DHA as percent of total fatty acids decrease progressively during pregnancy. At the same time, indicators of a relative essential fatty acid deficiency increase during gestation (28). The plasma phospholipid DHA content of multigravidae is lower than primigravidae (29). During lactation, the mother loses about 70–80 mg of DHA per day in breast milk, but there is little evidence that this loss causes any maternal depletion of DHA (30).

The essential fatty acid status of preterm infants is much lower than that for term infants. Preterm infants have significantly lower levels of PUFAs in umbilical vessel walls than term infants (31). The essential fatty acid composition of umbilical vessel walls is considered to reflect more long-term essential fatty acid status of the fetus (31). The concentrations of n-3 and n-6 LC-PUFAs were lower among preterm compared with term infants (31). Preterm infants also have much lower total body fat content compared with term

Table 2

Percent Fatty Acid Composition of Human Milk Compared With Oils Used in Infant Formula

Reprinted from ref. 23, with permission of Elsevier.

shown in Table 2 (23). Seed oils such as corn oil and safflower oil are rich in linoleic acid and α-linolenic acid. A rich source of AA is egg yolk. Fatty fish is a good source of DHA, especially salmon and mackerel (Table 3) (44,45). For vegetarians, the only source of dietary n-3 fatty acids is linolenic acid, because the long-chain PUFAs of the n-3 family, such as eicosapentaenoic acid and DHA, are found in fish and shellfish.

7. ASSESSMENT OF ESSENTIAL FATTY ACID STATUS

Laboratory methods that can be used for the assessment of essential fatty acid status include measurement of 5,8,11-eicosatrienoic acid, the “Mead” acid (46), measurement of osbond acid (47), use of the triene/tetraene ratio (20:3 n-9 to 20:4 n-6 ratio) (48,49), and use of the essential PUFA index (50). The total amount of essential fatty acids and long-chain polyenes in plasma or red blood cell phospholipids may be a useful indicator of essential fatty acid status of an individual (50). In healthy individuals, 5,8,11-eicosatri- enoic acid is only found in trace amounts in plasma, but in the absence of adequate dietary intake of linoleic acid, an increase in plasma 5,8,11-eicosatrienoic acid may occur. In the absence of DHA, the body will synthesize a larger amount of osbond acid, or docosoapentanoic acid (22:5 n-6), and the ratio of DHA to osbond acid can be used as an indicator

422 Handbook of Nutrition and Ophthalmology

Table 3

Linolenic Acid and Docosahexaenoic Acid Content of Selected Foods

Adapted from refs. 44,45.

of DHA status (50). The triene/tetraene ratio has been used to identify essential fatty acid deficiency among patients who are receiving total parenteral nutrition and among children with protein energy malnutrition (51). The PUFA index is the ratio between all essential PUFAs (the sum of all n-3 and n-6 fatty acids) and all of the nonessential unsaturated fatty acids (the sum of all n-7 and n-9 fatty acids). A higher essential PUFA index is thought to reflect better essential PUFA status (50,52).

8. DIETARY REQUIREMENTS FOR ESSENTIAL FATTY ACIDS

A workshop was convened in April 1999 by groups that included the International Society for the Study of Fatty Acids and Lipids (ISSFAL), the US National Institute on Alcohol Abuse and Alcoholism, the US Office of Dietary Supplements at the National Institutes of Health, and the Center for Genetics, Nutrition and Health. The purpose of the

Fig. 3. Relationship of a rhodopsin molecule to disk membranes of the outer segments. The chromophore is 11-cis retinal which is bound within the rhodopsin molecule. The rhodopsin molecule is surrounded by membrane phospholipids that are rich in docosahexaenoic acid. (Reproduced from ref. 68, with permission of Elsevier.)

conserves DHA through a tight mechanism of recycling. This mechanism maintains the high concentrations of DHA in the retina, even under conditions of n-3 and n-6 fatty acid deficiency (62–65). The high concentrations and tight recycling of DHA suggests that there must be an important role for this fatty acid (66), and the precise roles of DHA in retinal function are currently being elucidated.

The photoreceptor outer segments are specialized for absorbing photons of light and consist of stacks of membranous discs that are rich in DHA-containing phospholipids. The rod outer segment membranes contain major phospholipids which include phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine, in addition to smaller amounts of phosphatidylinositol, phosphatidic acid, and sphingomyelin. Phosphatidylethanolamine and phosphatidylserine are particularly rich in DHA. Approximately 60 molecules of DHA-rich phospholipid surround each visual pigment molecule in the disc membranes of rods and cones (67). Rhodopsin comprises seven transmembrane helices and includes an intradiskal domain, a transmembrane domain, and a cytoplasmic domain. The relationship of rhodopsin to the disk membranes of the rod outer segment is shown in Fig. 3 (68).

10.2. Animal Studies of DHA Depletion and Retinal Function

Early animal studies showed that rats raised on a fat-free diet had abnormally low concentrations of DHA in the retina and diminished a-wave amplitudes on the electroretinogram (ERG) (69), an effect that was reversible with n-3 fatty acid supplementation (70). Subsequent studies have shown that retinal function, as assessed by the ERG, also declines in guinea pigs (71) and nonhuman primates (47,72,73) that are deficient in DHA. Infant rhesus monkeys that were deficient in n-3 fatty acids had significantly decreased visual acuity compared with control monkeys (Fig. 4). The a-wave of the ERG originates largely in the

Fig. 4. Visual acuity thresholds (mean ± standard error of the mean) as determined by the preferential looking method for control and omega-3 fatty acid-deficient infant monkeys. Mean values for the deficient group (black dot) and control group (circles). (Adapted from ref. 47, with permission of the author.)

photoreceptors, thus, DHA deficiency appears to be causing an abnormality in photoreceptor function (67).

10.3. Potential Functions for DHA in the Retina

DHA has been hypothesized to play a role in the regeneration of rhodopsin (66). When the chromophore of rhodopsin, 11-cis retinal, is stimulated by light, it undergoes isomerization to all-trans retinal and leads to the formation of metarhodopsin II. Metarhodopsin II is deactivated, and some of the all-trans retinal is converted to all-trans retinol, or vitamin A. In the regeneration of rhodopsin, all-trans retinol is transferred to the retinal pigment epithelium, and a new 11-cis retinal molecule made within the retinal pigment epithelium is transferred to the rod outer segment. 11-cis retinal combines with opsin to form a new rhodopsin molecule. The transfer of 11-cis retinal and all-trans retinol across the aqueous interphotoreceptor matrix involves interphotoreceptor retinoid-binding proteins (IRBP) (74). DHA has a high affinity for IRBP and is noncovalently bound to IRBP, and DHA is found in high concentrations in rod outer segment and relatively lower concentrations in the retinal pigment epithelium. Thus, a concentration gradient exists for DHA between the rod outer segments and the retinal pigment epithelium.

Chen and colleagues have proposed that DHA modulates the transfer of retinoids between the rod outer segments and retinal pigment epithelium (75). In this model, as IRBP is near the retinal pigment epithelium, it binds a saturated fatty acid, giving a high affinity for binding 11-cis retinal. When the IRBP approaches the rod outer segment, DHA displaces the saturated fatty acid, causing a dissociation of 11-cis retinal from IRBP and binding with all-trans retinol. 11-cis retinal then moves into the rod outer segment to combine with opsin and form rhodopsin. When IRBP returns to the retinal pigment epithelium with all-trans retinol, saturated fatty acids displace DHA, releasing all-trans retinol. IRBP then binds with 11-cis retinal to begin the cycle anew.

DHA has been proposed to have other roles in the retina, such as providing the optimal physical environment in the membranes for the activation of rhodopsin in rod outer segments (76–78) and playing a role in the normal phagocytosis of rod outer segments by the retinal pigment epithelium (79,80). DHA may provide the proper mechanical property for rhodopsin function in the lipid bilayer (76). It has been hypothesized that DHA acts as a “molecular spring” in the rod outer segment membrane when rhodopsin absorbs a photon of light and the membrane expands (68). Alternatively, DHA may provide the proper fluid environment in the membranes for the function of rhodopsin (78). In vitro studies suggest that DHA may also protect photoreceptors against apoptosis, or programmed cell death (81).

11. ESSENTIAL FATTY ACIDS IN VISUAL DEVELOPMENT OF INFANTS

11.1. Methods Used for Assessing Visual Development of Infants

The three main tools that have been used for the assessment of visual development among infants have been the ERG, the visual evoked potential (VEP), and preferential looking, a behavioral test (67). The ERG is an electrical potential across the retina that is elicited by light, and it consists of an initial negative component, the a-wave, generated primarily by photoreceptors, followed by a positive component, the b-wave, generated by the inner retina (Fig. 5) (82). The ERG is recorded in a pharmacologically dilated eye using a contact-lens electrode and topical anesthetic. The subject is presented with full field stimulation with flashes of light (83). The rod and cone responses of the ERG can be separated by adjusting the conditions of light and dark adaptation, wavelength of light, flash rate, and stimulus intensity. The measurements from the ERG that are often compared in clinical studies include the amplitude of the wave, the threshold (intensity of light needed to reach a particular amplitude), and peak latency (the time from the flash until the peak of the response), as reviewed in detail elsewhere (67). The ERG does not provide any information regarding visual acuity.

The VEP is a measure of the electrical activity of the brain that is elicited by a change of a visual stimulus and represents the overall processing of visual information from the retina to the visual cortex (84). The VEP is recorded using small disk electrodes applied to the scalp. The subject is usually placed before a video display that shows a checkerboard or grating pattern. When the pattern reverses from dark to light and light to dark, this stimulus elicits a signal that can be recorded. With rapid reversal rates, a steady-state response is obtained, and the waveform resembles a continuous sine wave. The spatial frequency of a pattern can be derived from the amplitude of the VEP using linear regression. The VEP cannot give the locality of any lesion that may be causing decreased visual acuity, but instead provides an overall measurement of visual acuity as perceived by the visual system from the retina to the visual cortex.

Preferential looking methods of visual acuity are based on the natural tendency of infants to look at a patterned target, such as a stripe or checkerboard pattern, rather than a blank target of equal luminance (85). Most studies have relied on the Teller acuity card procedure, a rapid version of the preferential looking method (86). In this test, the infant is held in front of a panel that has two openings for presenting cards. The infant is presented with a card that contains a black and white grating of a particular spatial frequency or a blank gray card that is matched in luminance with the grating card. The observer looks through

Fig. 6. Teller acuity card procedure. The infant is held in front of gray screen; shield located at chosen test distance assists in positioning infant and prevents person from holding the infant from seeing the grating. Adult observer holds acuity cards up to opening in screen and watches child through peephole in card. (Reprinted from ref. 86, with permission of Developmental Medicine and Child Neurology.)

In a study from Australia, breast-fed term infants had significantly better VEP acuity compared with formula-fed term infants at 22 wk of age (87). In addition, with all infants from the study combined, there was a significant correlation between DHA content of erythrocytes and VEP acuity. The infant formula in the Australian study contained about 6–8% energy as linoleic acid and 0.5–0.8% energy as α-linolenic acid (87). In a longitudinal comparison of term infants in Denmark, the increase in visual acuity as assessed by Teller cards was more rapid in breast-fed compared with formula-fed infants from 1 to 4 mo of age (88).

Most observational studies of term infants have shown no difference in visual acuity of infants who were breast-fed or formula-fed with formula that did not contain LC-PUFAs (Table 5) (89–92). There was no difference in visual acuity assessed by Teller cards between breast-fed and formula-fed term infants at 14 d and 3 mo (89). The investigators concluded that infant formula which contained α-linolenic acid as about 1% of total energy was adequate for normal visual development (89). Further investigators of a larger group of infants who had been breast-fed for various lengths of time or fed formula without AA or DHA had no differences in visual acuity assessed by Teller cards at 9 mo of age (90). A multicenter study of term infants conducted in seven centers in the United States and Canada demonstrated no difference in visual acuity assessed by Teller cards at 3 mo of age between breast-fed infants and infants fed either of two formulas. Formula 1 and 2 had a linoleic acid and α-linolenic acid content of 18.0% and 1.9% vs 34.2% and 4.7%, respectively, and neither formula contained AA or DHA (91). No differences were found between