THERAPEUTICS UPDATE Nutritional Deficiencies As the number of bariatric procedures in the US rises, clinicians must be aware of the ocular manifestations of deficiencies and their treatment.

BY GINNY KULLMAN, MD; JEFFREY L. BENNETT, MD, PHD; NARESH MANDAVA, MD; AND MALIK Y. KAHOOK, MD

here is a well-recognized connection between vitamin deficiencies and ophthalmic .1 Although the reported prevalence of nutritional deficiencies in the US varies depending on the studyT population and specific nutrients studied,2 a defi- ciency in remains the leading cause of prevent- able blindness in developing countries.3 Vitamin deficiencies commonly result from poor nutri- tion due to poverty, drug abuse, and alcoholism. Recent Figure 1. Humphrey Visual Field 24-2 testing (Carl Zeiss reports, however, suggest that nutritional deficiencies Meditec, Inc., Dublin, CA) reveals a peripheral ring scotoma due to malabsorption from gastric bypass procedures are from vitamin A deficiency in the patient’s left eye. increasing in frequency. A prevalence of obesity in the US has increased interest in surgical procedures for weight become a more clinically recognized phenomenon sec- loss. For instance, the number of gastric bypass surgeries ondary to malabsorption as the demand for bariatric rose more than 600% from 1993 to 2003. Metabolic and surgery grows.7 This nutritional lack has a wide range nutritional derangements are common sequelae follow- of ocular manifestations. Impaired dark , ing these procedures. The Roux-en-Y, the gold-standard leading to night blindness (), is the earliest bariatric surgery, is known to cause vitamin B12, folate, and most common symptom. Up to 60% of patients and iron deficiencies; more aggressive diverting proce- with vitamin A deficiency due to fat-malabsorption dures may lead to deficiencies in the fat-soluble conditions, cholestasis, small-bowel bypass, or inflam- A, D, E, and K due to a malabsorption of fat.4 Although matory bowel disease may have subclinical dark-adap- patients are routinely prescribed multivitamins and sup- tation abnormalities.8 , which is nearly plements following bariatric procedures, inadequate pathognomonic, results from keratinization of the eyes adherence to this therapy would place them at risk for and involves dehydration of the and cor- developing metabolic deficiencies.5 nea. The cornea becomes infiltrated and hazy at an Vitamin deficiencies may produce a wide range of sys- early stage. Keratomalacia involves liquefaction of part temic . Ophthalmologists must screen of or the entire cornea, which can ultimately lead to for and recognize the ophthalmic manifestations of the phthisis bulbi. In advanced deficiency, Bitot’s spots, various states of deficiency in patients who have under- areas of proliferating abnormal squamous cells and gone gastric bypass procedures. This article discusses gen- keratinization of the conjunctiva develop and are eral ocular and visual field abnormalities related to nutri- pathognomonic.9 tional deficiencies involving vitamin A, vitamin B12, folate, In the , vitamin A deficiency preferentially affects and vitamin C as well as adequate replacement therapy. the rod photoreceptors. Rods peak in density in a ring pattern 18º or 5 mm from the center of the fovea.10 As a VITAMIN A result, visual field testing will classically reveal a midpe- Although vitamin A deficiency is common in the ripheral ring scotoma (Figure 1). Alternative field abnor- developing world,6 it is rarely seen in the US but may malities include the bilateral constriction of the peripher-

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al visual fields or generalized depression.11 Scotopic, full- field, electroretinographic wave forms are typically reduced.12 The World Health Organization recognizes vitamin A deficiency as the single most important cause of child- hood blindness in developing countries. A strategy to combat this global concern is based on its prevention through the fortification, diversification, and supplemen- tation of food as well as public health measures.3 For treatment, the World Health Organization recommends oral vitamin A replacement, from 50,000 to 200,000 IU Figure 2. Humphrey Visual Field 24-2 testing shows a ceco- 13 per day, depending on the age of the patient. Intra- central depression from vitamin B12 in the patient’s left eye. muscular injections in symptomatic patients may help

expedite the nutrient’s absorption and accelerate the The diagnosis of is confirmed by patient’s visual recovery.7 For individuals with vitamin A the presence of inadequate serum levels, although the deficiencies following bariatric surgery, a complete rever- normal levels of this nutrient are quite variable across the sal of the problem’s signs and symptoms can occur as adult population. When highly suspicious for clinical dis- quickly as 3 days following treatment.11 ease, therefore, clinicians should obtain methylmalonic acid and homocysteine levels, because the presence of

VITAMIN B12 elevated amounts of metabolites is a sensitive marker of Although the prevalence of vitamin B12 deficiency in functional . Standard treatment entails the general population is unknown, its incidence ap- intramuscular injections of 1,000 mcg of vitamin B12; the pears to increase with age. Up to 15% of adults older initial dose is administered daily for 3 days and then than 60 years have laboratory evidence of a deficiency monthly for life.16 14 in vitamin B12, usually resulting from malabsorption, the inability to split cobalamin from food, or the defi- FOLATE ciency of intestinal transport proteins. Gastric atrophy, The mandatory fortification of cereal-grain products the chronic carriage of Helicobacter pylori, and the use with folic acid began in the US in 1998 to decrease the of antacids impedes the enteral absorption of food- number of children born with neural tube defects. Sub-

bound vitamin B12 in the elderly population. Individuals sequently, the prevalence of dropped with small-bowel inflammatory disease or with a history from 16% to 0.5%.17 Currently, the most common caus- of surgical removal of the small bowel may also experi- es of deficiency are an inadequate intake of this nutri-

ence impeded absorption of vitamin B12. ent, usually associated with or alcoholism, Ocular manifestations of this entity may occur in an increased demand for folate due to or concert with megaloblastic anemia but often appear in lactation, and impaired absorption, as seen with tropi- isolation. Patients typically present with reduced visual cal sprue or as a consequence of certain medications acuity that is painless, symmetrical, and progressive, (eg, phenytoin).18 Absorption occurs in the duodenum but the optic neuropathy occasionally may be unilater- and upper jejunum, and the ’s stores provide only a al and subacute. Affected individuals’ color vision is fre- 3 to 6 months’ reserve. quently impaired, and a relative afferent pupillary de- A lack of folate may produce a megaloblastic anemia fect is often absent due to bilateral impairment. A for- and optic neuropathy that is indistinguishable from

mal evaluation of the patient’s visual fields often re- that caused by low vitamin B12. Clinically, one may be veals central or cecocentral defects (Figure 2). The able to distinguish a deficiency in folate versus vitamin

optic disc may be normal or slightly hyperemic in the B12 by an absence of associated neurologic symptoms, early stages of the deficiency. Several months to years but a lack of vitamin B12 may result in an isolated optic later in the course of the disease, disc-related changes neuropathy. As occurs with low levels of vitamin B12, involve a loss of the nerve fiber layer in the papillomac- folate deficiency results in a nutritional optic neuropa- ular bundle, temporal disc pallor, and optic atrophy.15 thy characterized by bilaterally symmetrical, cecocentral Associated neurologic abnormalities include spastic vision loss with preferential involvement of the papillo- paraparesis, ataxia, and a loss of vibratory and position- macular bundle.15 al sensation due to subacute combined degeneration Daily doses of oral folate 400 to 1,000 µg replenish tis- of central nervous system myelin. sues and are usually successful remedies, even if the

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patient’s deficiency resulted from malabsorption. The (303) 315-7579; [email protected]. normal requirement of folate is 400 µg per day. Malik Y. Kahook, MD, is Assistant Professor of Ophthalmology and Director of Clinical Re- VITAMIN C search in the Department of Ophthalmology at A recent study determined that the prevalence of vita- the University of Colorado at Denver & Health min C deficiency in the US is 14% among males and 10% Sciences Center. He acknowledged no financial among females.19 The deficiency occurs in severely mal- interest in the product or company mentioned herein. nourished individuals, drug and alcohol abusers, and Dr. Kahook may be reached at (720) 848-5029; those living in poverty. results from low levels of [email protected]. ascorbic acid, largely due to impaired collagen synthesis, Ginny Kullman, MD, is a second-year ophthalmology resi- which depends on ascorbate. Symptoms can occur as dent at the University of Colorado at Denver & Health early as 3 months after deficient intake. Ocular involve- Sciences Center. She acknowledged no financial interest in the ment is primarily due to hemorrhages caused by in- product or company mentioned herein. Dr. Kullman may be creased capillary fragility. Proptosis secondary to orbital reached at (720) 848-5029; [email protected]. hemorrhage occurs in 10% of cases of infantile scurvy but Naresh Mandava, MD, is Associate Professor and Interim is rarely seen in adults.20 Petechiae or larger hemorrhages Chair of the Department of Ophthalmology at the Uni- can occur in the conjunctiva, eyelids, orbit, anterior versity of Colorado at Denver & Health Sciences Center. He chamber, vitreous, and other ocular structures. Despite acknowledged no financial interest in the product or com- the high concentration of ascorbic acid in the crystalline pany mentioned herein. Dr. Mandava may be reached at lens, cataracts are not common. There are no known visu- (720) 848-5029; [email protected]. al field defects that are classically associated with scurvy. Treatment entails the oral replacement of vitamin C with 1. Hoyt CS. Vitamin metabolism and therapy in ophthalmology. Surv Ophthalmol. 100 mg four times a day for 10 to14 days, followed by a 1979;24:177-190. maintenance dose of at least 60 mg per day until the rec- 2. Alaimo D, McDowell MA, Briefel RR, et al. Dietary intake of vitamins, minerals, and fiber of persons ages 2 months and over in the United States: Third National Health and Nutrition ommended dietary allowance (approximately 120 mg per Examination Survey, phase 1, 1988-91. In: Advance Data. Centers for Disease Control and day, depending on the person’s sex and age) is resumed.21 Prevention. 1994:258:1-28. 3. Indicators for assessing vitamin A deficiency and their application in monitoring and eval- uating intervention programmes. Geneva, Switzerland: World Health Organization; 1996. CONCLUSION 4. Stater GH, Ren CJ, Siegel N, et al. Serum fat-soluble vitamin deficiency and abnormal cal- cium metabolism after malabsorptive bariatric surgery. J Gastrointest Surg. 2004;8:48-55. Clinicians should be aware of the ocular signs and 5. Brolin BE, Leung M. Survey of vitamin and mineral supplementation after gastric bypass symptoms associated with vitamin deficiencies. Alcohol and biliopancreatic diversion for morbid obesity. Obes Surg. 1999;9:150-154. 6. Williams SR. Nutrition and Diet Therapy. 8th ed. St Louis, MO: Mosby; 1997:159. abuse, inflammatory bowel disease, and 7. Chae T, Foroozan R. Vitamin A deficiency in patients with a remote history of intestinal are a few conditions known to predispose patients to surgery. Br J Ophthalmol. 2006;90:955-956. 8. Russell RM. The vitamin A spectrum: from deficiency to toxicity. Am J Clin Nutr. vitamin deficiencies. A history of bariatric surgery can 2000;71:878-884. now be added to this list. The appropriate treatment for 9. Sommer A. Xerophthalmia and vitamin A status. Prog Retin Eye Res. 1998;17:9-31. 10. Curcio CA, Sloan KR, Kalina RE, et. al. Human photoreceptor topography. J Comp vitamin deficiencies requires closely monitored replace- Neurol. 1990;292:497-523. ment, because excessive supplementation may be toxic, 11. Spits Y, De Laey JJ, Leroy BP. Rapid recovery of night blindness due to obesity surgery 22 after vitamin A repletion therapy. Br J Ophthalmol. 2004;88:583-585. especially with fat-soluble vitamins. 12. McBain VA, Egan CA, Pieris SJ. Functional observations in vitamin A deficiency: diag- A careful clinical examination, formal visual field testing, nosis and time course of recovery. Eye. 2007;21:367-376. 13. Andersson M. Vitamin A deficiency control: WHO/UNICEF strategy. Available at: and laboratory testing are indicated in patients at risk for http://www.euro.who.int/ppt/nut/vad.pdf. Accessed July 20, 2007. nutritional deficiencies. The role of imaging to detect early 14. Andrès E, Affenberger S, Vinzio S, et al. Food-cobalimin malabsorption in elderly patients: clinical manifestations and treatment. Am J Med. 2005;118:1154-1159. and optic nerve disease remains to be elucidated. 15. Sadun AA. Metabolic optic neuropathies. Semin Ophthalmol. 2002;17:29-32. Further research examining the utility of intraocular imag- 16. Hvas A, Nexo E. Diagnosis and treatment of vitamin B12 deficiency—an update. Haematologica. 2006;91:1506-1512. ing (such as ocular coherence tomography and confocal 17. Pfeiffer CM, Caudill SP, Gunter EW, et al. Biochemical indicators of B vitamin status in scanning laser ophthalmoscopy) in patients with nutrition- the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000. Am J Clin Nutr. 2005;82:442-450. al deficiencies may shed light on how these disease states 18. Rampersaud GC, Kawell GP, Bailey LB. Folate: a key to optimizing health and reducing affect the overall health of their and optic nerves. ❏ disease risk in the elderly. J Am Coll Nutr. 2003;22:1-8. 19. Hampl JS, Taylor CA, Johnston CS. Vitamin C deficiency and depletion in the United States: the Third National Health and Nutrition Examination Survey, 1988 to 1994. Am J Jeffrey L. Bennett, MD, PhD, is Associate Professor in the Public Health. 2004;94:870-875. 20. Dunnington JH. Exophthalmos in infantile scurvy. Trans Am Ophthalmol Soc. Departments of Neurology and Ophthalmology at the Uni- 1931;29:37-47. versity of Colorado at Denver & Health Sciences Center. He 21. US Department of Health and Human Services and US Department of Agriculture. Dietary Guidelines for Americans. 6th ed. Washington, DC: US Government Printing Office; 2005. acknowledged no financial interest in the product or com- 22. Omaye ST. Safety of . Advances in experimental medicine and biol- pany mentioned herein. Dr. Bennett may be reached at ogy. Adv Exp Med Biol. 1984;177:169-203.

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