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

factors, race with AMD). Only a few modifiable risk factors have been found (e.g., smoking with AMD). Finding specific associations of dietary factors with AMD, cataract and other chronic eye diseases are important because diet is modifiable and such modifications may have the potential of reducing the burden associated with these diseases. With this in mind, the new book by Semba will be important to dieticians, ophthalmologists, optometrists, and the lay public interested in role of nutrition in eye disease. It examines the historical and recent evidence concerning the role of dietary changes in preventing both acute and chronic eye disease.

Dr. Semba’s text covers the broad field of nutrition and ophthalmology. The content of the 12 chapters covers specific disease entities e.g., AMD and age-related cataract, diabetic retinopathy, and inborn errors of metabolism) and specific nutrients (e.g., vitamins C, E, A, and B-complex, zinc, fatty acids) and their relation to ocular disease. It is a unique text, in that all chapters were written by one author and cover a large area of material ranging from an historical overview, epidemiology, pathology and treatment of the condition. There are three identified themes within the text, the first emphasizing the efficacy of long-term “healthy” diet, the second the importance of historical perspective of diet and eye disease, and the third the importance of two putative pathogenetic mechanisms, oxidative stress and inflammation. The text provides important and new authoritative information on the relation of nutrition to ocular disorders which will reward the reader with a wealth of insightful information.

Ronald Klien, MD, MPH

Rita Costa Gomes, helped in many ways with works from the French, Portuguese, Spanish, and Italian scientific literature. I thank Kelly Barry and Christopher Wild, Anna Berchidskaia, and Michael Stern, respectively, for their translations of papers from the German, Russian, and Dutch scientific literature. Frank Corl provided the original illustrations and figures, and the staff members of Wilmer Ophthalmic Photography were helpful in preparing photographs.

The preparation of the Handbook of Nutrition and Ophthalmology was greatly facilitated by the superb assistance and expertise of the staff of the National Library of Medicine, especially Stephen Greenberg, Elizabeth Tunis, Kenneth Niles, Crystal Smith, and Khoi Le. I also thank Mike Piorunski of the Friedenwald-Romano Library, and the staff of the Bibliothèque Nationale de France, the Österreichische Nationalbibliothek, and the Wellcome Library in London. I also thank Dana Totin Moncrief, Barbara Dancheck, Amanda Ray, Margaret Dayhoff-Brannigan, and Caitlin Howard for moving our laboratory work forward with innovative investigations of nutrition, oxidative stress, and inflammation. Finally, this work would not be possible without the support of the National Institute on Aging (R01 AG02712 and the National Institute on Child Health and Human Development (R01 HD30042, R01 HD32247) of the National Institutes of Health and a Lew R. Wasserman Merit Award from Research to prevent blindness.

Richard D. Semba, MD, MPH

“O que ha de muito curioso no historico da xerophthalmia por vicio de nutrição, é que todos ou quasi todos os autores que a observaram e descreveram, presumiram fazel- o pela primeira vez.”

“It is very curious in the history of xerophthalmia due to nutritional disorders that all or nearly all authors who have observed and described it believed themselves to be the first to do so” (3).

This view from the late 19th century should be well considered, as in the last three decades, many so-called “new” findings in the field of vitamin A are rediscoveries or refinements of previous observations that were made in the 19th and early 20th centuries when vitamin A deficiency was a public health problem in Europe and the United States. This recurring theme is emphasized throughout the chapter.

2.1. Early Perspectives on Xerophthalmia

Night blindness, a clinical manifestation of vitamin A deficiency, has been known from antiquity. In the Hippocratic writings, Epidemics VI, night blindness was described among children with whooping cough (4). In the first century AD, Celsus noted the ingestion of animal liver (a rich source of vitamin A) as a treatment for night blindness in De Medicina (5). During the European era of exploration and colonization, night blindness was found to be indigenous among populations in Africa (6,7), the East Indies (8), Brazil (9), and China (10). Night blindness appeared to be common among some groups of poorly nourished soldiers, sailors, slaves, pregnant women, and children in the 18th and 19th centuries (11–14). In 1816, the French physiologist François Magendie (1783– 1855) fed dogs an experimental diet of sugar and water alone and noted that they developed corneal ulcers and died (15). A few years later in France, Félix-Séverin Ratier (1797–1866) observed bilateral corneal ulcers in a poorly nourished 6-mo-old infant who developed diarrhea and died (16). The British physician Joseph Brown (1784–1868) (17) and the French physician Charles Billard (1800–1832) (18) observed corneal ulcers in poorly fed infants. Later, in the 1840s, the British ophthalmologist William Bowman (1816–1892) also described a case of keratomalacia in an infant whose mother stopped breast-feeding when she was sent to the workhouse (19). It is notable that all four physicians drew comparisons with the corneal ulcers in Magendie’s dogs and raised the question whether this was related to faulty nutrition. As noted by Brown: “Compare this case with Magendie’s account of the dogs fed, or rather starved, on sugar” (17).

In 1863, Pierre Bitot (1822–1888), Professor of Anatomy at the School of Medicine in Bordeaux, described “une tache nacrée ou argentée” (“a pearly or silvery patch”) on the conjunctiva among children suffering from night blindness at the Hospice des Enfants Assistés in Bordeaux (20). He observed 29 children, mostly orphans and abandoned children between the ages of 6 and 19 yr, from 1859 through 1861. Bitot provided a detailed description of the location of the patches and the clinical course of the lesions, and described the reappearance of the lesions after the patches were scraped off the conjunctiva. He examined the lesions microscopically and described the findings as “une altération non encore décrite, une production squameuse spéciale de l’épithélium conjonctival” (“a yet undescribed alteration, a specific squamous production of the conjunctival epithelium”) (20). His classic description of the lesions is reproduced under Subheading 3.2.1. Bitot was born in Podensac, a small town southeast of Bordeaux. He finished his

medical studies in Bordeaux and received his doctor of medicine in Paris in 1848. Bitot became physician for the Bureaux de Charité in 1849 and professor of anatomy at the School of Medicine in Bordeaux in 1854. In 1856 he became chief surgeon of the Bordeaux homes, and during his tenure he made his important clinical observations of xerophthalmia. The patches of keratinized, squamous metaplasia that occur on the bulbar conjunctiva are considered pathognomonic for vitamin A deficiency and are now known as Bitot spots.

Bitot’s report was followed three weeks later in the same journal by a report by a military physician, Jean-Antoine Villemin (1827–1892), who had made similar observations and noted that the epithelial changes affected the cornea in addition to the conjunctiva (21). Abraham Netter (1818–1904), a physician in the military hospital in Strasbourg, had also observed the conjunctival lesions in adults with night blindness. He proposed that the conjunctival spot was an epiphenomenon, and that it was not the cause of night blindness but was rather related to sunlight exposure (22). In 1866, Robert Blessig (1830– 1878), an ophthalmologist from St. Petersburg who had studied at the University of Dorpat, described the entire spectrum of disease, from conjunctival xerosis, to Bitot spots, corneal xerosis, keratomalacia, and formation of a corneal opacity (23). Blessig sometimes observed conjunctival xerosis and Bitot spots among individuals who also had signs of scurvy (23). Other detailed descriptions were made in Brazil by Manuel da Gama Lobo (1832–1883), who termed the condition “ophthalmia brasiliana” (24). In his report, Gama Lobo noted that four children with cornea ulceration, diarrhea, and malnutrition later died, and “in our view, these children died of inanition as a consequence of nutritionally limited fare which was given in insufficient quantity” (24).

Earlier descriptions exist of pathological changes of the conjunctiva among individuals with night blindness, but none of the descriptions are as complete as those provided by Bitot. For example, in 1855, Mecklenburg, a physician for the Deutsch-Krone (now present-day Walcz, Poland) district prison, described “constant dryness of the eyes” and conjunctival changes among poorly nourished prisoners who had night blindness: “Die Augen hatten etwas Gläsernes, Gläzendes, nie fand sich Röthung der Conjunctiva, sie erschien im Gegentheil gläzend weiss, fast perlmutterartig” (“The eyes had something glassy, shining about them, there was never a redness in the conjunctiva, on the contrary it appeared a shiny white, almost like mother-of-pearl”) (25). “Gegen Abend—eine bestimmte Stunde konnte Niemand angeben—schwand bei Allen das Sehvermögen, bei den meisten in so hohem Grade, dass sie sich führen und sich manchen Schabernack, wie sie sagten, gefallen lassen mussten; ein Theil dieser letzteren konnte weder bei Mond-noch Kerzenlicht sehen” (“Toward evening—no one could indicate a precise hour—vision disappeared in all of the patients, for most to such a high degree that they had to be led about and had to put up with many a practical joke, as they said; a portion of this last group could see neither by moonlight or candlelight”) (25).

Anton Christian August von Huebbenet (1822–1873), Chief Physician of the Russian Army in the Crimea, described his experiences with epidemics of night blindness among laborers and soldiers in Russia to his colleagues of the Medical Society of the Hospitals of Paris in 1860 (26). Von Huebbenet was born in Gute Ulpich, Livland (Baltic region) and studied medicine at the University of Dorpat. He was professor at Vladimir University in Kiev and director of the surgical department of the Hospitalklinik, where he had an interest in eye diseases. Von Huebbenet took part in the Crimean War in Sebastopol

in 1854–1855 and became concerned with the health of soldiers. In Russia, Von Huebbenet noticed “certain changements dans l’aspect du globe oculaire; sa surface présente un certain degré de sécheresse, la conjonctive s’altère et devient le siege d’une desquamation épithéliale. Ce sont de petites écailles qui se dessèchent et dont les cellules sont atteintes de dégénérescence graisseuse, d’atrophie” (“some changes in the appearance of the eyeball, its surface presents a certain degree of dryness, the conjunctiva changes and is the site of epithelial destruction. These are little scales that become dessicated; their cells have experienced fatty degeneration and atrophy”) (26). Von Huebbenet observed that night blindness and eye changes usually appeared during the Lenten fasts and disappeared after the fast was broken (26).

In Portugal, a year before Bitot published his report of conjunctival lesions associated with night blindness, the military ophthalmologist João Clemente Mendes (b. 1819) clearly described the association between xerophthalmia and night blindness (27). He detailed an outbreak of night blindness that affected 16 boys and 6 girls in an orphanage that housed 93 boys and 109 girls aged 7 to 15 yr. Mendes reported: “Uma doença, a xerophthalmia, que não vimos mencionada por ninguem como acompanhando a cegueira crepuscular, foi observada entre nós no asylo dos orphãos da febre amarella em novembro de 1860” (“An illness, xerophthalmia, that we have not heard mentioned before as accompanying night blindness, was observed by us in an asylum among orphans with yellow fever in November of 1860”). “Em todos os casos se manifestou a alteração da conjunctiva em maior ou menor grau, sendo para notar que algumas creanças tiveram a xerophthalmia sem hemeralopia” (“In all cases there was an alteration of the conjunctiva of greater or lesser degree, being notable that some children had xerophthalmia without night blindness”) (27).

2.2. Characterization of Vitamin A

The existence of vitamin A was shown through a long process that spanned a period of over 130 yr. More than 60 yr after Magendie’s experiments with dogs, Nicolai Lunin (1853–1937) and Carl Socin at the University of Dorpat showed that mice could not survive on purified protein, fat, carbohydrate, and mineral salts alone, but were able to survive if supplemented with milk or egg yolk (28,29). Cornelis Pekelharing (1848–1922) and Frederick Hopkins (1861–1947) both conducted studies that also suggested there was something essential in milk that supported life (30,31). Wilhelm Stepp (1882–1964) extracted lipids from milk with alcohol-ether that contained the active substance (32,33), and Elmer McCollum (1879–1967) and Marguerite Davis, working at the University of Wisconsin, used ether to extract these lipids from cod-liver oil (34). At Yale University, Thomas Osborne (1859–1929) and Lafayette Mendel (1872–1935) made the seminal observation that infectious diseases in vitamin A-deficient animals were quickly alleviated by introduction of butter fat or cod-liver oil in the diet (35,36). In 1916, this growthpromoting and anti-infectious substance was termed “fat-soluble A” (37). The search for vitamin A in other foods revealed that certain plant foods, such as spinach and cabbage (38), carrots (39), and alfalfa and clover (40) had the same properties as “fat-soluble A” in experimental animal studies. In 1929, Thomas Moore (1900–1999) demonstrated that β-carotene could be converted to vitamin A (41). The structure of vitamin A was deduced in 1931 by Paul Karrer (1889–1971) (42,43), and vitamin A was crystallized in 1937 (44). The synthesis of pure vitamin A was not achieved until 1947 (45,46). The role of vitamin

A as a precursor for the visual pigment, rhodopsin, was elucidated by George Wald (1906– 1997). The investigations by Wald helped to complete a long line of investigation that began with early observations relating night blindness with lack of vitamin A (47).

2.3. Vitamin A Deficiency and Increased Mortality in Children: Lessons From Denmark

From 1909 to 1920, the Danish ophthalmologist Olaf Blegvad (1888–1961) documented cases of xerophthalmia, or clinical vitamin A deficiency, among children in Denmark (48). From 1911 to 1917, there was a strong, gradual increase in the number of cases of keratomalacia, the most severe eye lesion of vitamin A deficiency, followed by a decline in 1918 and 1919 and then an increase in 1920. During the same period in neighboring Sweden, there was no epidemic of xerophthalmia. Blegvad showed that the export of butter and cheese from Denmark and increased consumption of margarine within the country were linked with the increase in vitamin A deficiency. The manufacture of margarine ceased in 1917 after a German submarine blockade halted importation of raw materials, and butter, which was produced in Denmark at an expensive price, was then rationed at a more affordable cost for the poor after December 21, 1917. On May 1, 1919, butter rationing ceased (Fig. 1) (48). The mortality rate observed among 434 children with xerophthalmia was about 21%, with the highest mortality noted among younger infants. The high mortality of children was attributed to infections and the lack of vitamin A, and it resembled the infections and mortality found in animals experimentally raised on a vitamin A-deficient diet (48). Blegvad concluded that efficacious treatment with whole milk or cod-liver oil containing vitamin A reduced the mortality of children with xerophthalmia (49).

Carl Bloch (1872–1952), a pediatrician in Copenhagen, also dealt with the epidemic of xerophthalmia and provided important descriptions of the epidemiology and treatment of vitamin A deficiency (50). Bloch observed that the number of cases of children admitted with xerophthalmia at the State Hospital in Copenhagen rose from 1912 to 1917 and then dropped dramatically in 1918 (Fig. 2) (51). The abrupt decline in cases of xerophthalmia in 1918 coincides with butter rationing for the poor in 1918 (Fig. 1). Bloch noted that xerophthalmia was associated with lack of milk and green vegetables in the diet and that children with xerophthalmia had retarded growth. He concluded that vitamin A deficiency was characterized by a decline in immunity, increased severity of infections, and a higher risk of death. Child mortality was reduced by providing foods containing vitamin A. Bloch advocated the provision of milk, cream, butter, and cod-liver oil to treat eye disease, promote growth and development, and to reduce infectious diseases of children (50,52). Bloch noted that “the death rate among children is considerable after recovery from xerophthalmia; hardly two thirds of these children reach the age of 8 years” (52).

The concerns about vitamin A deficiency clearly extended beyond children who had xerophthalmia, or clinical vitamin A deficiency. The concept of subclinical vitamin A deficiency was widely discussed in major medical journals in the 1920s. Based on the observations in Denmark and animal studies, Erik Widmark (1889–1945), Professor of Medical and Physiological Chemistry at the University of Lund, concluded in The Lancet “...there must be in a population in which xerophthalmia occurs a much larger number of cases in which the deficiency in vitamin A, without producing the eye disease, is the