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

controls. Serum thiamine and TPP effect (TPPE) were normal in only 38% of the patients and 45% of controls, indicating widespread deficiency of thiamin in the population (308). Both patients with neuropathy and unaffected control patients had biochemical evidence of thiamin depletion, and the severity of thiamin deficiency was higher in Pinar del Rio, where the disease was most common, and lower in Havana, where the prevalence of disease was less (326). Two years after the epidemic, vitamin B intake was assessed among 141 healthy middle-aged men in Havana (329). The subjects were seen every 3 mo for 1 yr, and dietary intake and status of thiamin, riboflavin, pyridoxine, folate, and vitamin B12 were measured. Deficient status was noted for all B complex vitamins that were studied except for pyridoxine (329). Further studies also showed that dietary intakes of zinc, vitamin C, and vitamin E were also low in comparison with international reference ranges (329). In another study conducted after the epidemic, smokers were found to have lower concentrations of circulating α-carotene, β-carotene, β-cryptoxanthin, and riboflavin than nonsmokers (330).

The recent epidemic in Cuba is reminiscent of a previous epidemic of amblyopia and peripheral neuropathy that began during the Spanish-American War (331). Domingo L. Madan reported an epidemic increase in cases of amblyopia and peripheral neuropathy characterized by numbness and pain in the toes and feet, accompanied by muscle weakness. The food supply was disrupted during the war, and in May 1898, the United States began a naval blockade of Cuba after declaring war on Spain. This blockade was considered to have contributed to the food shortage and poor quality of food, and the outbreak of eye disease was considered amblyopia due to malnutrition, informally called “amblyopia of the blockade” (331). In 1993, there is no doubt that the social, political, and economic circumstances in 1993 contributed to widespread food shortages, and arguments arose regarding how the collapse of the Soviet Union, the US trade embargo with Cuba, natural disasters, and national government contributed to the epidemic (332–334).

6.7.7. CONCLUSIONS FROM THE CASE STUDY

Nearly one century after Henry Strachan made an early description of nutritional amblyopia in Cuba in 1897 (2), the island was revisited by the largest known epidemic of nutritional amblyopia. Although various etiologies were considered, the circumstances of food rationing, widespread B complex vitamin deficiencies, epidemiological characteristics of the epidemic, clinical presentation of disease, therapeutic response to B complex vitamins, and prevention of further cases with widespread distribution of multivitamin supplements all demonstrate that the underlying etiology of this epidemic was nutritional in nature.

7. DIAGNOSIS OF NUTRITIONAL AMBLYOPIA

The diagnosis of nutritional amblyopia is based on the clinical features of decreased vision, and central or cecocentral scotoma as described under Subheading 5 above. None of the ophthalmological findings are specific for nutritional amblyopia, and the diagnosis should be based on clinical findings, history, and laboratory biochemical evidence of a B vitamin deficiency or combined B complex vitamin deficiencies. Early findings may include slight hyperemia of the optic disc and occasional retinal hemorrhages. Dilation and tortuosity of small retinal vessels with the arcuate areas of the nerve fiber layer have been described as early changes (335). The absolute scotoma rarely exceeds five degrees in diameter. In the late stage of disease, temporal disc pallor and loss of the papillomacular

Based on US Department of Agriculture National Nutrient Database for

Standard Reference (http://www.nal.usda.gov/fnic/foodcomp/search) (31).

The riboflavin content of some selected foods is shown in Table 13 (31). The extent of riboflavin bioavailability from foods has not been well characterized (350). It is estimated that 95% of food flavin or a maximum of about 27 mg of riboflavin can be absorbed per single meal or dose (351). Most of the riboflavin in foods is found in the form of FAD and FMN.

9.4. Absorption, Storage, and Metabolism of Riboflavin

The upper ileum is the main site for riboflavin absorption. Prior to absorption, FAD and FMN are hydrolyzed in the gut. Absorption of flavins occurs through a saturable, sodiumdependent, active transport system, rather than passive diffusion. Riboflavin is best absorbed in the presence of food (352). In the blood, flavins are transported either tightly bound to immunoglobulins or are more loosely bound to albumin. The metabolism of riboflavin is tightly regulated. There is no body storage of riboflavin, thus, megadoses of riboflavin, as used by some vitamin enthusiasts, are rapidly excreted in the urine.

9.5. Functions of Riboflavin

Riboflavin is a precursor to the coenzymes FMN and FAD and other covalently bound flavins. These flavoenzymes play a role in many oxidation-reduction reactions. FAD is part of the respiratory chain and is involved in energy production. Flavoenzymes are involved in one-electron transfers, dehydrogenase reactions, hydroxylations, oxidative decarboxylations, and dioxygenations. Riboflavin also has strong antioxidant activity through its role in the glutathione redox cycle. Glutathione peroxidase breaks down reactive lipid peroxides, a process that requires reduced glutathione. Reduced glutathione is produced by the FAD-containing enzyme glutathione reductase. Riboflavin deficiency may lower the FAD

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

Recommended Dietary Allowance. Based on ref. 42.

available for glutathione reductase and inhibit the ability to deal with reactive lipid peroxides and oxidative stress. There are many different flavoenzymes, and these include mitochondrial electron-transfer flavoprotein, mitochondrial NADH dehydrogenase, glutathione reductase, monoamine oxidase, and microsomal FAD-containing mono-oxygenase (353). There are complex interactions between some micronutrients, as niacin requires FAD for the formation of niacin from tryptophan, and FMN is needed for the conversion of vitamin B6 to pyridoxal 5'-phosphate.

9.6. Requirements for Riboflavin

The Food and Nutrition Board of the Institute of Medicine has made new recommendations of riboflavin intake by life stage and gender group (42) (Table 14). The AI is the recommended level of intake for infants. The EAR is the daily intake value that is estimated to meet the requirement of half the healthy individuals in a group. The RDA is defined as the EAR plus twice the CV to cover 97–98% of individuals in any particular group. The requirements for riboflavin increase with pregnancy and lactation. Physical activity may increase the requirement for riboflavin, but there is still insufficient evidence to change general recommendations for riboflavin intake (Food and Nutrition Board 1998).

9.7. Epidemiology of Riboflavin Deficiency

Inadequate riboflavin status, as defined by laboratory assessment and dietary intake, is highly prevalent in many parts of the world, and specific reports have come from Great Britain (354), Spain (355), Saudi Arabia (356), The Gambia (357), Nigeria (358,359), Zimbabawe (360), China (361), Brazil (362), Mexico (363), and Guatemala (364). Riboflavin deficiency is relatively common in countries that do not require the fortification of foods, such as flour, with riboflavin. Individuals who eat a diet low in dairy products and meat are at more likely to develop riboflavin deficiency, and strict vegetarians who do not take vitamin supplements with riboflavin are at especially higher risk of riboflavin deficiency (365). Diseases such as diabetes mellitus, cancer, and cardiac disease may

increase the risk of riboflavin deficiency (367–369). Phototherapy with ultraviolet light for certain skin disorders and neonatal jaundice may increase the risk of riboflavin deficiency, as riboflavin can be deactivated by ultraviolet light.

9.8. Assessment of Riboflavin Deficiency

Laboratory tests for riboflavin status include urinary excretion of riboflavin and erythrocyte glutathione reductase activity (52). The body does not store riboflavin, thus, riboflavin in excess of requirements is excreted in the urine. Urinary excretion of riboflavin is negligible if the dietary intake of riboflavin is low. Riboflavin status in adults has been defined as deficient, marginal, and acceptable for urine riboflavin of <40, 40–119, and ≥120 μg, respectively, per 24-h urine collection (52). If 24-h urine collection cannot be undertaken, riboflavin can be measured in a random urine sample and expressed as μg riboflavin per gram creatinine. Using random urine samples, riboflavin status in adults has been defined as deficient, marginal, and acceptable for urine riboflavin of <27, 27–79, and ≥80 μg, respectively, per gram creatinine (52). Urine riboflavin measurements are limited in that they are influenced by sudden withdrawal of riboflavin from the diet, are relatively insensitive to low and moderate intakes of riboflavin, and do not necessarily reflect long term riboflavin status.

The method of choice for assessment of riboflavin status is the erythrocyte glutathione reductase assay. Erythrocyte glutathione reductase is a flavoenzyme that is present within red blood cells, and it requires FAD as a cofactor. Holo-glutathione reductase consists of the enzyme associated with FAD. With long term riboflavin deficiency, there is a progressive loss of FAD from the enzyme, leaving intact apo-glutathione reductase. The assay measures the amount of unsaturated, or apo-glutathione reductase activity, in a blood sample. A fresh blood sample is taken and lysed, and glutathione reductase activity is measured both with and without FAD added to the blood sample. In riboflavin deficiency, the added FAD combines with apo-glutathione reductase and forms functional holo-glutathione reductase, and there is a resulting increase in activity. In the riboflavin-sufficient state, there is mostly holo-glutathione reductase present, thus the added FAD will not cause much change in activity of the enzyme. The result of this test is expressed as the activity coefficient (AC), or the activity with added FAD over the activity without added FAD. For all ages, the activity coefficients that define deficient, marginal, and acceptable riboflavin status are 1.40, 1.20–1.40, and <1.20, respectively (52).

9.9. Clinical Manifestations of Riboflavin Deficiency

9.9.1. GENERAL SIGNS AND SYMPTOMS OF HUMAN RIBOFLAVIN DEFICIENCY

Riboflavin deficiency is characterized by soreness and burning of the lips, mouth, and tongue, cheilosis, angular stomatitis, seborrheic dermatitis, and glossitis (370–372). These findings are not specific for riboflavin deficiency and also occur in pellagra, or niacin deficiency, and folate deficiency. Cheilosis is defined as shallow ulcerations or crusting and chapping of the lips. Angular stomatitis consists of redness and maceration of the angles of the mouth, and this may progress to bleeding fissures, fissures covered with yellow crusts, and scars at the angles of the mouth. The seborrheic dermatitis is found in the nasolabial and nasomalar folds, the alae nasi, the vestibule of the nose, and around the outer and inner canthi of the eyes. The glossitis is characterized by a purplish-red or magenta-

colored tongue with smooth, flattened papillae. Although these oral and facial lesions have been considered by some to be specific for riboflavin deficiency alone (373), there has never been conclusive evidence to separate these lesions from pellagra. Riboflavin deficiency is so widely distributed in small amounts that absolute, total depletion apparently never occurs, and there have been no reports of deaths from riboflavin deficiency (374).

9.9.2. PERIPHERAL CORNEAL VASCULARIZATION IN HUMANS

Riboflavin deficiency has been reportedly associated with peripheral corneal vascularization in humans (375–385), but despite numerous reports, it is uncertain whether this ocular finding can be definitively attributed to riboflavin deficiency. Burning and itching of the eyes, photophobia, and a subepithelial keratitis have also been described in riboflavin deficiency (378,386,387). Angular blepharitis may be present and accompany angular stomatitis (388). Peripheral corneal vascularization is not considered pathognomonic for riboflavin deficiency and has been reported to occur among individuals who are more severely riboflavin-deficient. The corneal vascularity that occurs in riboflavin deficiency has been defined as a condition in which newly formed blood vessels leave the limbic plexus and centripetally enter the subepithelial space of the true cornea (389), and a slit lamp is necessary to see these vessels (376) (Fig. 18). In areas of the world where riboflavin deficiency was more common, there have been large case series of patients with superficial keratitis and corneal vascularization who responded well to riboflavin therapy (390,391).

Initially, there was a great deal of confusion caused by the inappropriate use of the terms “conjunctivitis,” “engorgement of the limbic plexus,” and “circumcorneal injection” to describe corneal lesions associated with riboflavin deficiency (382,392,393). These vague descriptions led to apparent misdiagnosis and overdiagnosis of ocular signs of riboflavin deficiency (394), with some surveys reporting a prevalence of riboflavin deficiency of 50–100% based on the particular interpretation of the vascular abnormality (395–400). One study in The Gambia reported that 37% of 536 Europeans and 5% of 1700 Africans had corneal vascularity, but the prevalence of angular stomatitis, cheilosis, and glossitis was much higher among Africans than Europeans (401). With slit lamp examination and strict criteria for peripheral corneal vascularization, i.e., actual invasion of clear cornea by vessels from the limbus, the prevalence of riboflavin deficiency based on ocular criteria has been much lower in various surveys (382,392,402). Corneal vascularization from riboflavin deficiency was reportedly common in India (403) and China (404). Other corneal conditions, such as previous trauma and trachomatous pannus, have been reported to flare up under conditions of riboflavin deficiency (405,406). Recently, riboflavin deficiency has been linked with the maintenance of the corneal and conjunctival epithelium and goblet cells in riboflavin-deficient rats (407).

The differential diagnosis of peripheral corneal vascularization includes acne rosacea, phlyctenular keratitis, trachoma, chemical burns, and previous infections of the cornea, such as bacterial and viral keratitis. The purported cornea vascularization of riboflavin deficiency has been reported to be accompanied by other signs of riboflavin deficiency, such as angular stomatitis, cheilosis, and glossitis. The purported corneal vascularization seen in riboflavin deficiency reportedly resolves within 3–6 wk with daily oral riboflavin therapy (389). It is not known whether long-standing riboflavin deficiency results in a more refractory state of corneal vascularization to riboflavin therapy. Riboflavin therapy has been attempted for many conditions with corneal vascularity, including acne rosacea,

Fig. 18. Corneal vascularization purportedly associated with riboflavin deficiency. (From ref. 376, with permission.)

syphilitic keratitis, phlyctenular keratitis, and herpes zoster keratitis, with mostly negative results (377,408–414). Riboflavin therapy did not reverse the corneal vascularization of patients that were considered to have the signs of riboflavin deficiency, but it appears that most of these patients had corneal vascularization associated with rosacea keratitis (415).

9.9.3. PERIPHERAL CORNEAL VASCULARIZATION IN EXPERIMENTAL DEFICIENCY

Early investigations showed that peripheral corneal vascularization could be produced in riboflavin-deficient rats (Fig. 19) (416–419). Riboflavin deficiency in rats has been used as an experimental model for the study of corneal vascularization (420). After 12 wk on a riboflavin-deficient diet, rats develop a slight polymorphonuclear infiltrate beneath the corneal epithelium, and by 14 wk, the leukocytes extend into the deeper corneal stroma. By the 16th week of deficiency, blood vessels grow into the cornea stroma from the limbus. The leukocytes disappear by 24 wk of riboflavin deficiency, leaving persistent corneal vascularization (420). The presence of keratitis in the experimental animal model is consistent with reports of a subepithelial keratitis in humans with riboflavin deficiency (378) and provides some clues as to the presence of abnormal blood vessels in the cornea. The healing of the cornea in riboflavin deficiency may be exacerbated by ultraviolet light exposure (421).

Attempts have been made to produce riboflavin deficiency experimentally in humans by a low-riboflavin diet (422–425) or by administration of galactoflavin, a riboflavin antagonist (426–428). In four adult subjects kept on a low-riboflavin diet of 0.8–0.9 mg riboflavin/d for 9 mo, no signs of riboflavin deficiency developed, including glossitis,

Fig. 19. Drawing of peripheral corneal vascularization in a riboflavin-deficient rat. (From ref. 417, with permission of the Rockefeller University Press.)

angular stomatitis, or corneal vascularization (422). No corneal vascularity was noted in six subjects who received a diet containing 0.9 mg riboflavin per day (423). The daily intake of riboflavin in these studies (422,423) was close to the EAR of riboflavin (0.9 mg/ d for women, 1.1 mg/d for men) (42), and perhaps it is not surprising that no signs of riboflavin deficiency occurred in these so-called “deficiency” experiments. Corneal vascularization was not found in three subjects who had a diet of about 0.5 mg riboflavin per day, but the study was terminated after only 5 wk (424). In another study, fifteen male subjects were given 0.6 mg riboflavin per day for over 1 yr, and no subjects developed corneal vascularization (429).

Galactoflavin-induced riboflavin deficiency resulted in a syndrome of sore throat, cheilosis, angular stomatitis, glossitis, seborrheic dermatitis, and anemia, and these changes were reversible with administration of riboflavin (426–428). Some of the patients developed peripheral neuropathy. The signs and symptoms of riboflavin deficiency were induced rapidly after 10–25 d of galactoflavin administration, but peripheral corneal vascularization and cataracts were not found among the 11 study subjects during this short time period (427,428).

9.9.4. RIBOFLAVIN DEFICIENCY AND CATARACTS

Riboflavin was once known as the “cataract-protective factor” after studies demonstrated that riboflavin deficiency would produce cataracts in many different species of

animals, including mice (430), rats (416,432–441), cats (442), dogs (443), and pigs (444). In the early stages of cataract formation, the cataracts are reversible with administration of riboflavin (435). Early efforts were made to apply these findings to humans by treatment of senile cataract with riboflavin therapy (445,446). The flavins FAD and FMN are found in high concentrations in the lens, cornea, and retina (447,448), suggesting an important role for riboflavin in the eye. Riboflavin deficiency has been shown to alter the composition of lens proteins in rats (449) and to lower the glutathione reductase activity of the lens (450–452). Reduced glutathione protects the lens from photo-oxidative stress, and riboflavin is required by glutathione reductase for the regeneration of reduced glutathione. A controlled clinical trial in China suggests that riboflavin/niacin supplements may protect against nuclear cataracts (453). The epidemiological studies regarding nutrition and cataract in humans are discussed in detail in Chapter 3.

9.9.5. RIBOFLAVIN DEFICIENCY AND RETINAL VASCULAR DISEASE

Recent studies suggest that riboflavin could potentially be involved in the pathogenesis of vascular disease, including retinal vascular disease, through its role in the metabolism of homocysteine (455). High plasma concentrations of homocysteine have been associated with diabetic retinopathy (456,457). Animal studies suggest that riboflavin metabolism is altered in diabetes (458,459), and riboflavin deficiency has been described among children with diabetes mellitus (367). The relationships between riboflavin status, homocysteine, and diabetic retinopathy have not been well characterized in humans.

9.9.6. RIBOFLAVIN DEFICIENCY AND NUTRITIONAL AMBLYOPIA

Nutritional amblyopia has been described among children and adults with pellagra. It has been difficult to distinguish pellagra from riboflavin deficiency in these reports, as multiple deficiencies in B complex vitamins were probably present. Some clinicians have classified glossitis and angular stomatitis without dermatitis as pellagra sine pellagra, and others have considered that this syndrome actually represents pure riboflavin deficiency. Riboflavin deficiency was also present among prisoners-of-war in South and Southeast Asia during World War II, where a significant proportion of prisoners developed nutritional amblyopia (Subheading 6.6.).

9.10. Treatment of Riboflavin Deficiency

Riboflavin deficiency can be treated with oral riboflavin, 5 mg, two or three times daily. Nutrition education, with emphasis on increasing intake of food sources rich in riboflavin, i.e., meat and dairy products, should be part of an integrated approach to long term prevention of riboflavin deficiency. Riboflavin deficiency can be prevented in strict vegetarians by a daily multivitamin supplement.

10. CONCLUSIONS

Nutritional amblyopia may occur among individuals who have a diet poor in B complex vitamins, and the general settings include alcoholism and malnutrition, dietary deprivation in prisoners, and nutritional deficiencies following natural or man-made disasters such as crop failures and economic hardships. Although some have argued that nutritional amblyopia is due to one specific B deficiency, there are multiple examples from the clinical and experimental literature that suggest that nutritional amblyopia may occur with