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

Fig. 8. Pellagrous dermatitis in a young women. (From ref. 128.)

6.2.10. NUTRITIONAL AMBLYOPIA ASSOCIATED WITH PELLAGRA

Nutritional amblyopia has been described in patients with pellagra and in patients who had the signs and symptoms of pellagra combined with beriberi. In Italy in the nineteenth century, there were several reports of reduced vision and optic atrophy among adults with pellagra (129–131). Decreased vision and optic atrophy were described in 55 patients with pellagra (132). In 1917, Phinizy Calhoun described decreased vision, central scotomas, and mild optic atrophy in adults with pellagra in Georgia (133). He later expanded his investigation to the Georgia State Sanitarium in Milledgeville, where the superintendent allowed him to perform eye examinations on many of the several hundred inmates with pellagra. At the time, many pellagra patients with mental alterations and dementia were placed in asylums. Calhoun described ten cases with reduced vision, central or paracentral scotomas, optic atrophy, and loss of the papillomacular bundle (134). He also thought that the visual fields were mildly contracted in some patients (133,134). In a report from Savannah, Georgia, 58 patients with pellagra were examined at the US Marine Hospital, and the patients typically presented with red tongue, diarrhea, and a burning sensation in the feet. One-third of the patients complained of “dimness of vision,” and it is unclear whether the patients had an eye examination (135). In a study of 55 patients at the Illinois State Hospital for the Insane in Bartonsville, Illinois, several patients were found to have

Fig. 9. Symmetrical dermatitis of the hands. (From ref. 128.)

optic atrophy (136). Reduced vision, central scotomas, and retrobulbar neuritis were described in three patients with pellagra, of whom one originally presented with retrobulbar neuritis before the signs of pellagra appeared (137). Other case reports in the literature have described an association between pellagra and optic neuritis or optic atrophy (138–141).

The nutritional amblyopia described among patients with pellagra in Italy and the United States is similar to some of the disorders that have been loosely described as “tropical amblyopia.” In 1917, Henry Harold Scott (1874–1956) observed an outbreak of visual loss among laborers on sugar cane estates in Jamaica. The disorder consisted of decreased vision, glossitis, angular stomatitis, numbness in the lower extremities, burning in the feet, and decreased deep tendon reflexes (142). The epidemic was originally noted in the neighborhood of Spanish Town (St. Jago de la Vega), the old capital of Jamaica, among both men and women cane cutters who were previously in good health. The epidemic began during the cutting and carrying of the crop and ceased after the cane had been cut. Scott noted that the laborers did not generally eat breakfast prior to coming to the fields, preferring to eat sugar cane for breakfast and then throughout the day. Scott remarked that the “central neuritis” of the affected plantation laborers and the disorder described by Strachan (1,2) were similar and thought that those affected in the sugar plantation had signs and symptoms of both pellagra and beriberi (142).

A disorder characterized by dimness of vision, glossitis, angular stomatitis, and paresthesias in the extremities was also described in Sierra Leone (143). The condition was brought to the attention of the medical officer, when he was asked to investigate an outbreak of the disease among students in a girls school that was “notorious for its bad diet.” The condition was treated successfully using cod-liver oil, a rich source of vitamin A, and marmite, a rich source of B complex vitamins. The author believed that the disease was similar to the disorder described in Jamaica by Scott (142), but the condition became known later as the “A and B avitaminosis of Sierra Leone” (144).

From 1929 to 1937, D. G. Fitzgerald Moore, a colonial medical officer, observed more than 5000 cases of nutritional amblyopia associated with pellagra in Nigeria (145). The syndrome was well-known in areas of Nigeria and had a fairly consistent presentation of glossitis, angular stomatitis, scrotal or vulvar dermatitis, and decreased vision. Typically the patient would complain of decreased central vision for both reading and distance, and the first visible ophthalmic finding would be a slight temporal pallor of the optic disc. The problem was originally called to his attention when he found young adolescents with the disease in certain boarding schools (146). In schools with established dietaries there was no disease, but in other schools with no controlled dietary the disease could be rampant with over one-quarter of the students affected (147).

When Moore first encountered cases, he used cod-liver oil with malt and an iron-rich tonic without much effect, but then found that patients would recover quickly when marmite was added to the treatment (147). Moore later realized that the disease in Nigeria was the same as that described by Wright in Sierra Leone (148). In the boarding schools, the syndrome occurred among the “self-feeders” who made their own food every day: “The boys began the day by eating a cabin (dog) biscuit in the early morning, followed at noon by a very badly-prepared mixture, cooked by themselves, of gari (kassava or manioc) soup, with little or no green food; of meat, they had 1 oz. only every three days; there was very little protein of any kind. Their evening meal was little better. In fact, these boys were living on gari (kassava) as their main food, which was almost entirely carbohydrate” (149). The disease would often improve after the school children went home to their parents for the holidays.

Moore thought that the disease was due to a dietary deficiency, but he also thought that the boys were consuming cassava of bad quality (149). In another school in southern Nigeria with 80 pupils, Moore found that all the girls had nutritional amblyopia, but none of the boys were affected (150). The school was located in a remote area and had provisions brought by canoe twice a week, and food was distributed equally to students of each sex. The food in the school was “seriously deficient in proteins.” “Further inquiry showed that the boys augmented their diet daily by the simple expedient of catching and roasting the land crabs that existed in countless numbers in the vicinity. This was not permissible to the girls, who were kept in strict seclusion” (151). The authorities in Nigeria recognized the problem with their boarding schools, and they formed special dietetic committees to make recommendations for approved dietaries in the schools (152). These measures were aimed at terminating the bad feeding practices applying to the “boarding-in” and “self-feeder” type of students in the boarding schools.

A similar condition was described in epidemic form among children following a devastating hurricane and subsequent period of food shortage in Jamaica (153). Affected children presented with “dark eyes,” glossitis, angular stomatitis, abnormal dry, and thickened

skin lesions, and the condition responded well to cod-liver oil and a liberal diet. The disease also occurred in endemic form among children from poor urban families, and in 1945, 74 children were seen with the disease at the School Clinic in Kingston, Jamaica (153). Unless discovered by routine school exam, children did not complain of “dark eyes” until their vision dropped to 6/24, 6/60 or less. “Dark eyes” in local terms meant that the child was not able to see the blackboard, or that the print was running together. Altered color vision was common. In the early stages of the disease, the fundus was normal, but later there was temporal pallor of the disc. Ataxia was found in one child, and 10 of the 74 children developed deafness. Most of the children recovered with a treatment of brewer’s yeast, and impaired vision did not improve unless the glossitis and angular stomatitis were also cured. One visiting ophthalmologist noted the similarity between the condition among children in Jamaica and the clinical presentation of nutritional amblyopia in pris- oners-of-war (154).

In the 1930s, Landor and Pallister conducted studies among inmates of Singapore and Johore prisons that suggested niacin could be used to treat nutritional amblyopia (155). Autoclaved yeast could prevent experimental black tongue in dogs but would not prevent polyneuritis (156). Under the high temperature of autoclaving, the niacin in yeast was stable but thiamin was destroyed. A syndrome of nutritional amblyopia, paresthesias, and scrotal dermatitis was found in about 7% and 6.4% of prisoners who had been interned for more than 1 yr in the Singapore and Johore prisons, respectively (155). Prisoners in both prisons received parboiled rice, which has been found to be protective against thiamin deficiency since it contains a relatively large portion of the germ. Yeast, whether autoclaved or fresh, was found to be effective in treatment of this syndrome (155). The heatstable portion of yeast was later shown by other investigators to contain riboflavin and vitamin B6, thus adding to the difficulties in attributing the therapeutic effect to niacin alone.

6.2.11. MACULOPATHY ASSOCIATED WITH MEGADOSES OF NIACIN

(NIACIN MACULOPATHY)

Megadose niacin therapy has been associated with a reversible maculopathy that is characterized by cystoid macular edema (157). High dose niacin therapy is sometimes used in patients with hypercholesterolemia. It has been reported that niacin maculopathy occurs in about 0.67% of patients who are taking high doses of niacin (158). Niacin maculopathy causes cystoid spaces in the inner nuclear and outer plexiform layers, and these abnormalities resolve with discontinuation of niacin (159).

6.3. Folate Deficiency

Folate is a generic term used to describe a family of compounds with the activity of folic acid, including folylpolyglutamates and folic acid (pteroylglutamic acid) and its derivatives. Folate plays an important role as coenzymes in the synthesis of nucleic acids and amino acids, thus, cells that undergo more rapid synthesis such as hematopoietic cells and epithelial cells are affected more early in folate deficiency. Nutritional amblyopia has been associated with folate deficiency, and several reports demonstrate that folate alone can be used to treat the disease.

6.3.1. HISTORICAL BACKGROUND

In the 1930s, Lucy Wills (1888–1964) described megaloblastic anemia among pregnant women in Bombay, India, and the anemia responded to injections of liver or to yeast

Fig. 10. Structure of pteryolglutamic acid.

and marmite taken orally (160–162). This unknown hematopoietic factor became known as “Wills’ factor.” A growth factor in spinach was termed “folic acid” in 1941 (163). The factor that cured megaloblastic anemia was isolated from liver and yeast, and pteroylglutamic acid was synthesized in 1945 (164). Megaloblastic anemia was attributed to folate deficiency alone until subsequent work led to the isolation of vitamin B12, the second major dietary factor that prevented this type of anemia. The fortification of cereal grains with folate became mandatory in the United States after January 1, 1998 (42), and fortification appears to have had an impact on overall improvement of folate status among adults in the United States (165).

6.3.2. BIOCHEMISTRY OF FOLATE

Folates are compounds that contain pteroylglutamic acid, a 2-amino-4-hydroxy-pterid- ine moiety linked via a methylene group to a p-aminobenzoylglutamate moiety (Fig. 10). This family of compounds differs in the pyrazine ring, which can contain other forms of substitutions, and by the p-aminobenzoylglutamate moiety, which can contain additional glutamates. In foods, the number of glutamates can number from one to nine. Pteryolmonoglutamic acid is not common in foods but is the form of folate used in vitamin supplements and in food fortification. Obsolete names for folate include Wills factor, vitamin M, factor U, and vitamin Bc.

6.3.3. DIETARY SOURCES OF FOLATE

The richest natural sources of folate are liver, yeast, dark green leafy vegetables, legumes, and certain fruits. The folate content of certain foods is shown in Table 5 (31). It is currently recognized that the folate content in available food composition databases are generally inaccurate and tend to underestimate the amount of folate contained in foods. The folate yield from foods is higher than contained in most databases, as recent methods have shown that traditional methods did not yield a complete release of folate from the food matrix (42). The bioavailability of naturally occurring folates in mixed diets is about 50% (166).

6.3.4. ABSORPTION, STORAGE, AND METABOLISM OF FOLATE

Most folates in food consist of reduced polyglutamates, and these are hydrolyzed in the gut to monoglutamates. Absorption of folate takes place in the small intestine, primarily in the jejunum. Folates are transported across the intestinal mucosa by a saturable, carrier-mediated system and also by passive diffusion. The metabolism of folate involves the reduction of the pyrazine ring to the active tetrahydro form, the elongation of the glutamate chain by addition of glutamates, and the acquisition and oxidation or reduction of one-carbon units at the N-5 and/or N-10 positions of the 2-amino-4-hydroxy-pteridine moiety (167). In the circulation, folate occurs as free folate in plasma, folate bound to

Based on US Department of Agriculture National Nutrient Database for Standard Reference (http://www.nal.usda.gov/fnic/ foodcomp/search) (31).

albumin and other plasma proteins, and folate within erythrocytes. The normal adult human body contains about 5–10 mg, with about half of the total body folate found in the liver. The enterohepatic recirculation of folate plays an important role in folate balance. About 0.1 mg of biologically active folate is excreted in the bile each day and a large proportion is reabsorbed and reutilized. Excessive alcohol use interferes with the enterohepatic recirculation of folates. Most of the folate that enters the glomerulus is reabsorbed in the proximal renal tubule, thus most secreted folate is reabsorbed (167).

6.3.5. FUNCTIONS OF FOLATE

Folate coenzymes are involved in the transfer of one-carbon units in nucleic acid and amino acid metabolism. These reactions include (1) the de novo synthesis of purines, (2) the methylation of deoxyuridylic acid to thymidylic acid in pyrimidine synthesis, (3) the interconversion of serine and glycine, (4) the catabolism of histidine, (5) the conversion of homocysteine to methionine, (6) the generation of formate into the formate pool, and

(7) the methylation of transfer RNA in mitochondrial protein synthesis. Both vitamin B12 and folate are required for the synthesis of thymidylic acid. The conversion of 5-methyl- tetrahydrofolate to tetrahydrofolate by methionine synthetase requires vitamin B12 as a cofactor, and vitamin B12 deficiency can result in a megaloblastic anemia that is clinically indistinguishable from the megaloblastic anemia of folate deficiency. The relationship between vitamin B12 and folate has been explained by the methyl trap hypothesis, where non-functional 5-methyl-tetrahydrofolate accumulates and the level of other metabolically active folate coenzymes undergo a concomitant reduction (167).

6.3.6. REQUIREMENT FOR FOLATE

The Food and Nutrition Board of the Institute of Medicine has made new recommendations of folate intake by life stage and gender group (42) (Table 6).

Table 6

Dietary Reference Intakes for Folate (μg/d of Dietary Folate Equivalents)

AI, Adequate Intake; EAR, Estimated Average Requirement; RDA, Recommended Dietary Allowance. Based on ref. 42.

6.3.7. EPIDEMIOLOGY OF FOLATE DEFICIENCY

The risk of folate deficiency is increased with insufficient dietary intake of folates, alcoholism, and malabsorption. The demand of folate is increased under conditions of pregnancy, lactation, and malignancy. Alcohol and certain drugs may play a role in reducing the absorption of folates through inhibition of folate hydrolase in the brush border of the intestine. Some drugs can interfere with absorption or utilization of folates, such as phenytoin, barbiturates, metformin, methotrexate, pentamidine, sulfasalazine, trimethoprim, and triamterene (168,169).

6.3.8. ASSESSMENT OF FOLATE STATUS

Folate status is usually assessed through measurement of plasma folate concentrations, erythrocyte folate concentrations, plasma homocysteine concentrations, hypersegmentation of neutrophils, and the deoxyuridine suppression test (52). The earliest stage of folate deficiency involves a drop in serum folate, followed by a decrease in erythrocyte folate. With further depletion of folate, the deoxyuridine suppression will be abnormal and homocysteine concentrations are elevated. Megaloblastic anemia occurs in the most advanced stage of folate deficiency. The different criteria for folate deficiency are shown for each test (52) Table 7. Plasma folate concentrations are sensitive to acute decreases in folate intake, whereas erythrocyte folate concentrations reflect body folate stores at the time of erythropoiesis.

6.3.9. CLINICAL MANIFESTATIONS OF FOLATE DEFICIENCY

The classic finding in folate deficiency is a megaloblastic anemia that is indistinguishable from the megaloblastic anemia caused by vitamin B12 deficiency. Other clinical manifestations that have been associated with folate deficiency include fatigue, weakness, dyspnea, and anorexia. Angular stomatitis, recurrent aphthous ulcers, and glossitis have been described in folate deficiency. Pallor of the skin and mucous membranes may occur in the presence of anemia.

aLobe average. Based on ref. 52.

6.3.10. NUTRITIONAL AMBLYOPIA ASSOCIATED WITH FOLATE DEFICIENCY

It is reasonable to surmise that many of the patients who were thought to have so-called “tobacco alcohol amblyopia” may actually have had other nutritional problems that included folate deficiency, either isolated or combined with other deficiencies. The effect of chronic alcoholism on folate metabolism is well documented. In a study of 26 patients with nutritional amblyopia and 36 control patients, serum folate and red blood cell folate concentrations were significantly lower in the cases than the controls, whereas vitamin B12 concentrations were not significantly different between the two groups (170). Six patients with bilateral progressive visual loss, poor color vision, and central or cecocentral scotomas, had laboratory evidence of folate deficiency and had normal vitamin B12 levels. Treatment with oral folic acid, 1 mg/d, resulted in visual improvement in all patients (171). All patients consumed tobacco, alcohol, or both, and did not alter their use of these substances during folic acid therapy. Other case reports exist in which patients with nutritional amblyopia and folate deficiency responded to folate treatment (172,173). Folate deficiency has also been associated with a neuropathy (174), but the pathophysiology has not been well elucidated.

6.4. Vitamin B12 Deficiency

Vitamin B12, or cobalamin, is a generic term for corrinoids that have the biological activity of cyanocobalamin. Vitamin B12 is essential for normal formation of the blood and for neurological function. On the molecular level, vitamin B12 plays an important role in amino acid and fatty acid metabolism and in DNA synthesis. Deficiency of vitamin B12, like deficiency of folate, will result in impaired production of tetrahydrofolate necessary for thymidine synthesis, hence, a similar clinical picture of megaloblastic anemia can occur with either deficiency. In addition, vitamin B12 deficiency is characterized by glossitis, papillary atrophy of the tongue, and in advanced deficiency, by neuropathy and spinal cord dysfunction.

6.4.1. HISTORICAL BACKGROUND

Early descriptions of a fatal anemia were made by James Combe (1796–1883) in 1824 (175) and Thomas Addison (1793–1860) in 1849 (176). The anemia became known as pernicious anemia because of its high mortality, and in 1884, subacute combined degenera-

Fig. 11. Structure of cyanocobalamin.

tion of the spinal cord was described in associated with pernicious anemia by Otto Leichtenstern (1845–1900) (177). Optic atrophy was noted in a patient with pernicious anemia in 1895 (178). In 1926, George Minot and William Murphy demonstrated that a diet of beef liver would cure pernicious anemia (179). Pernicious anemia was attributed to the absence of an intrinsic factor in gastric juice by William Castle (b. 1897) (180). Cobalamin was crystallized by Edward Rickes and associates in 1948 (181). The history of vitamin B12 has been recounted in detail elsewhere (182).

6.4.2. BIOCHEMISTRY OF VITAMIN B12

The term “vitamin B12 ” is used by nutritionists to describe cobalamins with the activity of cyanocobalamin, but, strictly speaking, the chemical definition refers to cyanocobalamin, or α-(5,6-dimethyl-benzimidazolyl)-cobamide cyanide (Fig. 11). Cyanocobalamin consists of four reduced pyrroles in a macrocyclic ring termed a corrin, linked to a nucleotide that lies nearly perpendicular to the corrin. Inside the ring is a central cobalt atom. Corrinoids refer to compounds that contain a corrin nucleus with a tetrapyrrolic ring structure. Cyanocobalamin bears some structural relationship with other cyclic tetrapyrroles in nature, such as heme and chlorophyll.

6.4.3. DIETARY SOURCES OF VITAMIN B12

Vitamin B12 is synthesized solely by bacteria. It is not produced by plants and does not occur in vegetables or fruit, unless bacterial or fecal contamination is present in these plant foods. Vitamin B12 is found in animal tissues, and the original source of the vitamin B12 in animal tissues is bacteria. Rich sources of vitamin B12 include liver, beef, lamb, shellfish, fish, egg yolk, and fermented cheeses. The vitamin B12 content of some foods is shown in Table 8 (31).

6.4.4. ABSORPTION, STORAGE, AND METABOLISM OF VITAMIN B12

Vitamin B12 is released from the protein matrix of foods through mastication and pepsin digestion. Cobalamins are then bound by high-affinity glycoproteins, including intrin-

Based on US Department of Agriculture National Nutrient Database for

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

sic factor (IF). IF is secreted chiefly by parietal cells in the stomach and is necessary for the absorption of cobalamin in the ileum. Other glycoproteins, such as haptocorrins (Hc) and transcobalamin (TC) II, bind to cobalamin. In the duodenum, Hc bind mostly to inactive corrinoids and cobalamin analogues and facilitates their excretion in the feces. The IF-cobalamin complex is taken up by specific receptors in ileal mucosal cells, and this uptake is limited to about 1.5–2.0 μg of cobalamin per meal. In the ileal cell, the cobalamin moiety is converted to methyl-cobalamin and adenosyl-cobalamin, and these cobalamins are then released in the blood bound to TC II. Cobalamin is taken up by cells in the body by a receptor specific for TC II. The total body content of vitamin B12 is 3–5 mg, of which half is found in the liver. Vitamin B12 is secreted in the bile and is largely reabsorbed and available for metabolic use. This tight enterohepatic cycle can be interrupted if intrinsic factor is reduced or absent, in which case most or all of the vitamin B12 is lost in the feces.

6.4.5. FUNCTIONS OF VITAMIN B12

Vitamin B12 serves as an essential cofactor for methylmalonyl-CoA mutase and methionine synthetase. Methylmalonyl-CoA mutase requires adenosyl-cobalamin to convert L-methylmalonyl-CoA to succinyl-CoA, a step that occurs in the degradation of amino acids (valine, isoleucine, methionine, and threonine) and odd-numbered fatty acids. Methionine synthetase requires methyl-cobalamin in the folate-dependent methylation of homocysteine to methionine. Thus, vitamin B12 is linked to nucleic acid metabolism with its role in the conversion of methyltetrahydrofolate to tetrahydrofolate. Tetrahydrofolate is involved in the synthesis of thymidylate (see Subheading 6.3.5.).

6.4.6. REQUIREMENT FOR VITAMIN B12

The Food and Nutrition Board of the Institute of Medicine has made new recommendations of vitamin B12 intake by life stage and gender group (42) (Table 9). Although the RDA is calculated to meet the requirements of nearly all individuals for the maintenance of hematological status and normal vitamin B12 concentrations, about 10–30% of older