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

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Fig. 1. Structural formulas of L-ascorbic acid and L-dehydroascorbic acid.

3. BIOCHEMISTRY OF VITAMIN C

Vitamin C is a generic term for ascorbic acid, dehydroascorbic acid, and all compounds that have the biological activity of ascorbic acid. Ascorbic acid, or L-ascorbic acid, is chemically defined as 2-oxo-L-theo-hexono-4-lactone-2,3-enediol and consists of a five-mem- ber ring with two enolic hydrogens (Fig. 1). The enolic hydrogens are important in the structure of L-ascorbic acid, because they provide electrons for its function as an antioxidant. These electrons can be lost easily, providing strong reducing power for L-ascorbic acid. L-ascorbic acid can be oxidized to L-dehydroascorbic acid via the ascorbyl radical, a relatively stable free radical. L-dehydroasorbic acid can be reduced back to the intermediate free radical and then to L-ascorbic acid. Dehydroascorbic acid can be hydrolyzed irreversibly to diketogulonic acid. Humans, other primates, guinea pigs, and bats are among the few mammals that cannot synthesize ascorbic acid from glucose because of a lack of the enzyme gulonolactone oxidase (23). Obsolete names for vitamin C include hexuronic acid, cevitamic acid, antiskorbutin, and scorbutamin.

4. DIETARY SOURCES OF VITAMIN C

Rich dietary sources of vitamin C include peppers, citrus fruits, broccoli, brussel sprouts, and cauliflower (Table 1) (24,25). Orange juice is rich in vitamin C, and many commercially available fruit drinks that have a small proportion of fruit juice are fortified with vitamin C. Vitamin C is also available in the form of multivitamins and also as megadose supplements. The vitamin C content of vegetables can be reduced by long cooking at high temperature. Ascorbate is the main form of vitamin C in most foods, constituting about 80–90% of the total vitamin C (25).

5. ABSORPTION, STORAGE, AND METABOLISM OF VITAMIN C

Ascorbic acid is absorbed in the intestine through a sodium-dependent, active transport process that is dose dependent and saturable and also by the process of simple diffusion (25). Simple diffusion predominates with high intakes of ascorbic acid. About 70–90% of ascorbic acid is absorbed with the usual dietary intake of ascorbic acid, but the amount absorbed may drop to 50% with higher doses, as with vitamin C supplements of 1 g. Larger megadoses of vitamin C may cause diarrhea and abdominal discomfort because a significant proportion of the unabsorbed ascorbic acid is degraded in the intestinal lumen. Vitamin C circulates as ascorbic acid free in the plasma, bound to albumin, within erythrocytes,

Table 1

Vitamin C Content of Selected Foods

Adapted from refs. 24,25.

and concentrated within neutrophils, lymphocytes, and platelets. Dehydroascorbic acid accounts for <2% of total vitamin C concentrations in the blood (25). Dehydroascorbic acid is readily reduced back to ascorbic acid, thus maintaining the total body stores of vitamin C, but some dehydroascorbic acid is hydrolyzed to diketogulonic acid and metabolized to other products that include oxalic acid, threonic acid, L-xylose, and ascorbate- 2-sulfate (26). There is little renal excretion of ascorbic acid when the dietary intake of vitamin C is less than about 80 mg/d, but renal excretion of ascorbic acid increases at higher intakes (27). The symptoms of scurvy may occur when the total body pool of ascorbic acid is less than 300 mg (28). The vitamin C content of some human tissues and fluids is shown in Table 2 (26,29). The cornea epithelium and crystalline lens contain some of the highest concentrations of vitamin C in the human body.

6. FUNCTIONS OF VITAMIN C

Vitamin C is known to play a role as electron donor for several important enzymes in humans that are involved variously in collagen biosynthesis, Cq1 complement synthesis, carnitine biosynthesis, cephalosporin synthesis, norepinephrine biosynthesis, pyridine metabolism, tyrosine metabolism, and the activation of peptide hormones (26). L-ascorbic acid functions as a protective antioxidant for reactions that require reduced iron (Fe2+) or copper (Cu1+) metalloenzymes (30). In collagen biosynthesis, the enzyme prolyl hydroxylase requires oxygen, ascorbic acid, iron, and α-ketoglutarate in order to convert peptidebound proline to hydroxyproline. Ascorbic acid is required as a cofactor for the enzymes 6-N-trimethyl-L-lysine hydroxylase and γ -butyrobetaine hydroxylase in the two-step

Table 2

Vitamin C Content of the Human Eye and Cornea Related to Other Tissues

From refs. 26,29.

hydroxylation of 6-N-trimethyl lysine to carnitine. In the biosynthesis of norepinephrine, dopamine-β-hydroxylase requires ascorbic acid in the conversion of dopamine to norepinephrine. Some peptide hormones have a terminal amide group which requires α-amidation in order to have biological activity. The enzyme peptidyl glycine hydroxylase requires ascorbic acid as an electron donor in α-amidations of hormones such as thyrotropinreleasing hormone, adrenocorticotropic hormone, vasopressin, oxytocin, and cholecystokinin (31). Vitamin C is a strong antioxidant and has been shown to protect against lipid peroxidation and DNA damage in a wide variety of studies (26).

7. REQUIREMENT FOR VITAMIN C

The Food and Nutrition Board of the Institute of Medicine has made new recommendations of vitamin C intake by life stage and gender group (Table 3) (32). For definitions of Adequate Intake (AI), Estimated Average Requirement (EAR), and Recommended Dietary Allowance (RDA), see Chapter 1, Subheading 3.4. The requirement for vitamin C is an estimated 35 mg/d higher among smokers because of increased oxidative stress and metabolic differences (32).

8. EPIDEMIOLOGY OF VITAMIN C DEFICIENCY

Scurvy is rare in developed countries, but it is occasionally seen among individuals who have odd food habits with little consumption of fruits or vegetables, in situations of alcoholism or drug abuse, in heavy smokers, in patients with cancer, and in elderly men who live alone. In developing countries, scurvy may occur in refugee camps, prisons, and during periods of drought and food shortage. Scurvy has been described in a subject on a Zen macrobiotic diet (33). The clinical presentation of such patients may be unusual, as in hemarthrosis in a patient who shunned fruits and vegetables (34), purpura in an “unrepentant carnivore,” (35), painful gait with bruising in a child with peculiar dietary habits (36), lower extremity rash in a heavy smoker (37), and purpura and gingivitis in older adult patients with cancer (38,39). Scurvy may be increasing among the institution-

AI, Adequate Intake; EAR, Estimated Average Requirement; RDA,

Recommended Dietary Allowance. Based on the Food and Nutrition

Board (32).

alized elderly and alcoholics in the United States (40). Borderline to deficient vitamin C status is relatively more common among some risk groups in developed countries, such as institutionalized older women (41) and elderly men living alone in the community (42). In the National Health and Nutrition Examination Survey (NHANES) II, 3% of the overall population aged 3–74 yr and 16% of black males aged 55–74 yr had low plasma vitamin C concentrations (43). A higher prevalence of low vitamin C concentrations was also found among cigarette smokers and among those with low incomes (43).

Infantile scurvy is a condition that occurs among infants and young children who do not receive sufficient amounts of vitamin C. The disease was more common in the late 19th century and early 20th century, when infant formula or weaning diet did not contain adequate amounts of vitamin C (44,45). The disease is also known as Barlow disease, after a clinical description made in 1883 by Sir Thomas Barlow (1845–1945) (46). Occasional cases of infantile scurvy still occur in developed countries (47,48), usually among infants who were fed cow’s milk and no formula or supplements containing vitamin C.

9. ASSESSMENT OF VITAMIN C STATUS

The laboratory diagnosis of vitamin C deficiency is usually made either by measurement of serum or leukocyte ascorbic acid concentrations. Serum ascorbic acid concentrations usually reflect short term intake of vitamin C, whereas leukocyte ascorbic acid concentrations are considered to reflect more long term vitamin C status (49). In NHANES II, serum ascorbic acid concentrations were classified as deficient, low, and acceptable, based on ranges of <11, 11–23, and >23 μmol/L, respectively (50). The preferred method for measurement of ascorbic acid concentrations in serum is by high performance liquid chromatography. Leukocyte ascorbic acid concentrations have been defined as deficient, low, and adequate based on ranges of <57, 57–114, and >114 nmol/108 cells (49).

Fig. 2. Marked hematoma of the left eyelid in infantile scurvy. Hematoma is masking the exophthalmos. Note characteristic flexion of the leg, or “frog position” of infantile scurvy. (From ref. 52, with permission of the Archives of Ophthalmology.)

10. CLINICAL MANIFESTATIONS OF VITAMIN C DEFICIENCY

10.1. General Systemic Manifestations of Scurvy

Scurvy in adults is characterized by petechiae, ecchymoses, inflamed and bleeding gums, follicular hyperkeratosis, coiled hairs, perifollicular hemorrhages, arthralgias, joint effusions, and impaired wound healing. Old, formerly healed scars and fractures may spontaneously recur (51). Fatigue, dyspnea, gingivitis, and loosening of teeth are often present. Anemia is associated with scurvy. Infantile scurvy is typically characterized by subperiosteal and intramuscular hemorrhages. The gums may be red, swollen, and prone to bleeding. The condition is often described in badly nourished infants with poor weight gain. The infant often lies on his back in the “frog position” with one thigh everted and flexed at the abdomen in order to reduce pressure on a painful, swollen leg (Fig. 2) (52). Petechiae and ecchymoses are less common among infants than adults with scurvy.

10.2. Ophthalmological Findings During Scurvy

Ocular findings during scurvy are rare and are usually related to bleeding complications, as hemorrhages have been described in the eyelids, conjunctiva, orbit, iris, and retina. The most common ocular finding in infantile scurvy is unilateral proptosis, sometimes associated with eyelid ecchymoses. Over the last 125 yr, there have been numerous case reports of proptosis in infantile scurvy since an early clinical description made by Hugo Magnus (1842–1907) in 1878 (52–77). The average age of infants and young children who presented with exophthalmos and scurvy has been 10.5 mo (range 7–24 mo) (52). The subperiosteal regions of long bones and the orbit appear to be prone to hemorrhage because of their rapid physiologic growth. The exophthalmos is firm, nonpulsatile, and occurs spontaneously, usually with no history of trauma. The orbital plate of the frontal bone is the most frequent site of hemorrhage, and for unknown reasons, the left eye seems to be more susceptible (52,60). The exophthalmos will usually resolve within 1–3 wk with vitamin C therapy (Fig. 3) (52,64). Corneal ulceration has been described in one case of severe exophthalmos and exposure (73). Eyelid ecchymoses may also occur without proptosis, causing a “black eye” (60,65).

Fig. 3. Spontaneous exophthalmos in an infant with scurvy, before and after treatment. (From ref. 64, with permission of the Journal of the American Medical Association.)

In a collective report of infantile scurvy in North American in the late 19th century, a committee of the American Pediatric Society reported “swelling or protrusion of one or both eyes” in 49 of 379 cases, or 12.9% (78). This report and others (68) suggest that orbital hemorrhage with exophthalmos was not uncommon at a time when infantile scurvy was more prevalent. Other ocular findings that have been described in infantile scurvy include retinal hemorrhages (56,79) and hemorrhage into the anterior chamber (62). Orbital hemorrhages rarely may occur in adults with scurvy (66). Bilateral superior subperiosteal orbital hematomas were recently described in a 13-yr-old girl with spontaneous unilateral proptosis and scurvy (Fig. 4) (80). Orbital hemorrhage with proptosis has also been found in monkeys with experimental scurvy (81,82). From a medico-legal point of view, infantile scurvy should be considered in the differential diagnosis of “battered baby” or “shaken baby” syndrome, as eyelid ecchymoses, orbital hemorrhage, hyphema, and retinal hemorrhages can occur in a poorly nourished infant with scurvy in the absence of any physical trauma.

The most common finding among adults with scurvy is subconjunctival hemorrhage (83). Ocular lesions such as conjunctival hemorrhages and small conjunctival varicosities have been described in adults who were experimentally deprived of vitamin C after 74– 95 d (83). Retinal hemorrhages have been occasionally described among adults with scurvy (84–92). The fundus appearance is characterized by retinal hemorrhages, exudates, and cotton wool spots (91,92). The retinopathy of scurvy is similar to both background diabetic retinopathy and the retinopathy of HIV infection, and it should be considered in the differential diagnosis in poorly nourished adults and among infants with failure to thrive. In a typical case, a 48-yr-old white, divorced, unemployed man developed painful bruising in the leg muscles (92). He did not have any ocular complaints, but he noted that his gums were bleeding, and one tooth had recently fallen out. For the last 2 yr, the patient had not eaten any fresh fruits or vegetables and had subsisted on tinned foods, meat pies, boiled

Fig. 4. Coronal computed tomographic scan of a 13-yr-old girl with scurvy reveals bilateral superior subperiosteal orbital hematomas. (From ref. 80, with permission of the Archives of Ophthalmology.)

eggs, white bread, and milk. Physical findings included gum hemorrhages, extensive muscle bruising, and petechiae. Ocular examination revealed retinal hemorrhages and exudates (Fig. 5A). The retinal hemorrhages and exudates resolved after 3 wk of vitamin C treatment (Fig. 5B). In one case report, the hemorrhagic diathesis of scurvy was severe enough to complicate cataract surgery (93).

10.3. Vitamin C and Corneal Wound Healing

Vitamin C, through its essential function in collagen synthesis and metabolism, appears to play an important role in corneal wound healing. The corneal epithelium contains the highest concentration of vitamin C found in the human body, 1100 μmol/100 g wet weight, or about three hundred times the concentration of ascorbic acid found in the plasma (29). High concentrations of ascorbic acid have also been described in the corneal epithelium of many different mammals (94–99). The concentrations of ascorbic acid are lower in the corneal stroma, corneal endothelium, and aqueous humor than in the corneal epithelium (29,99). Ascorbic acid is concentrated through active transport by the ciliary body into the aqueous humor (100–107). The concentrations of ascorbic acid in the aqueous humor are about 20–25 times higher in the aqueous humor than in the plasma. The corneal endothelium takes up L-dehydroascorbic acid from aqueous humor, transports it into the cornea, and reduces it to ascorbic acid (108,109). The physiological mechanisms that account for the extremely high concentrations of vitamin C in the corneal epithelium have not been well characterized. The transport and metabolism of vitamin C in ocular tissues has been reviewed in detail elsewhere (110–112).

The importance of vitamin C to corneal integrity was shown in guinea pigs that developed corneal epithelial edema, disruption of the normal collagen pattern in the stroma,