Carotenemia Associated with Vitamin Supplementation Used for Treatment of Age-related Macular Degeneration

DECEMBER 08, 2007
Daniel G. Federman, MD and Jeffrey D. Kravetz, MD

Daniel G. Federman, MD
Associate Professor of Medicine
Yale University School of Medicine
New Haven, Conn
Staff Physician
VA Connecticut Health Care System
West Haven, Conn
Jeffrey D. Kravetz, MD
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, Conn
Staff Physician
VA Connecticut Health Care System
West Haven, Conn

Guest Editor: H. Ralph Schumacher, Jr, MD
Professor of Medicine
University of Pennsylvania, School of Medicine

Case Presentation

A74-year-old white man presented for routine care. His medical history included early age-related macular degeneration (AMD), hypothyroidism, hypertension, atrial fibrillation, cerebrovascular accident, and dyslipidemia. He denied pruritis, dark urine, light stool, abdominal pain, fever, excessive alcohol intake, or diarrhea. He had been taking warfarin sodium (Coumadin, Jantoven), long-acting diltiazem HCl (Cardizem LA), digoxin (Digitek, Lanoxin), ranitidine HCl (Zantac), levothyroxine (eg, Levothroid, Levoxyl, Synthroid), simvastatin (Zocor), and an over-the-counter daily supplement containing 20,000 IU vitamin A as betacarotene, 1200 mg vitamin C, 440 IU vitamin E, 117 mg calcium, 60 mg zinc, 120 ?g selenium, 8 mg copper, 200 ?g chromium, and 383 mg lutein complex. With the exception of calcium, all these amounts are greater than the recommended daily allowances.

His physical examination was significant for a deep yellow discoloration of the skin (Figure), most prominently on the hands and soles, without icteric mucous membranes or sclerae. No splenomegaly or hepatomegaly was detected. Laboratory testing showed normal values for hemoglobin, white blood cell count, liver function, creatinine, blood glucose, and thyroid-stimulating hormone. His serum vitamin A level was normal, but his carotene level was markedly elevated, at 238 ?g/dL (normal, 40-150 ?g/dL). He was instructed to discontinue the betacarotene supplement, and his skin discoloration resolved within 2 weeks.

Discussion

Carotenemia is most often seen after the excessive consumption of foods or juices containing carotene (eg, carrots, squash, asparagus, alfalfa, cantaloupes, mangoes, papaya, sweet potatoes, yellow turnips, tomatoes), but it can also occur with excessive intake of carotene-containing supplements. Carotenemia causes a yellow skin discoloration and must be distinguished from jaundice, which is much more likely to be a sign of serious illness. Physicians must be able to distinguish between these 2 entities, since clinical recognition of carotenemia obviates the need to evaluate for causes of jaundice.

Unlike patients with jaundice, those with carotenemia do not have pigmentation of the sclera and mucous membranes,1 although it has been suggested that subconjunctival or submucosal fat might be stained, leading to confusion.2 In carotenemia, the yellow pigmentation tends to be more pronounced in the palms, soles, and nasolabial folds than in other areas. Constitutional symptoms, such as weight loss, pruritus, or malaise, are absent. Hypervitaminosis A may cause alopecia, bone pain, skin desquamation, anorexia, or hepatomegaly,3 but carotenemia is thought to be a benign disorder, causing only skin discoloration.4

Our patient had been diagnosed with AMD?deterioration of the central portion of the retina?a common cause of vision loss that usually affects patients older than 60 years.5 Several risk factors for AMD have been identified: older age, white race, family history of AMD, cigarette smoking, and low dietary intake or reduced plasma concentrations of zinc or antioxidant vitamins.6 Vitamins containing beta-carotene are sometimes recommended for patients with AMD, since a randomized, placebo-controlled clinical trial showed that supplementation with vitamins C and E, beta-carotene, and zinc benefited patients older than 55 years.7

It is interesting to note that our patient developed carotenemia while taking recommended dosages of beta-carotene and consuming a normal diet. Although hypothyroidism has been shown to be a risk for carotenemia,8 our patient was clinically and biochemically euthyroid while taking levothyroxine as prescribed. None of the other medical conditions that may be associated with carotenemia?diabetes mellitus, panhypopituitarism, hypothalamic amenorrhea, anorexia nervosa, inborn errors of metabolism, malaria, or liver or kidney disease9?were present.

Conclusion

Carotenemia is an uncommon disorder that may be mistaken for jaundice. With the increasing use of supplements to treat patients with AMD and other conditions, physicians should increase their awareness of this entity.


1. Roche SP, Kobos R. Jaundice in the adult patient. Am Fam Physician. 2004;69:299-304.

2. Jeghers H. Skin changes of nutritional origin. N Engl J Med. 1943;228:677-686.

3. Expert Group on Vitamins and Minerals. Safe Upper Levels for Vitamins and Minerals. London, England: Medicines and Healthcare products Regulatory Agency (MHRA); May 2003. Available at www.food.gov.uk/multimedia/webpage/vitandmin/.

4. Arya V, Grzybowski J, Schwartz RA. Carotenemia. Cutis. 2003;71:441-442, 448.

5. Evans J, Wormald R. Is the incidence of registrable age-related macular degeneration increasing? Br J Ophthalmol. 1996;80:9-14.

6. Fine SL, Berger JW, Maguire MG, et al. Age-related macular degeneration. N Engl J Med. 2000;342:483-492.

7. Age-Related Eye Disease Study Research Group. Arandomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta-carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436.

8. Aktuna D, Buchinger W, Langsteger W, et al. Beta-carotene, vitamin A and carrier proteins in thyroid diseases [in German]. Acta Medica Austriaca. 1993;20:17-20.

9. Leung AC. Carotenemia. Adv Pediatr. 1987;34:223-248.


Commentary

Michael D. Cirigliano, MD, FACP
Associate Professor of Medicine
Division of General Internal Medicine
University of Pennsylvania School of Medicine
University City

This case not only highlights the use and potential side effects of beta-carotene supplements but also demonstrates the importance of asking about and knowing which natural products our patients are taking.

In this particular case, the patient was by all accounts taking beta-carotene on the advice of his physicians, and using the correct dosage. Despite this, he developed the classic clinical signs and symptoms of carotenoderma.

A number of natural products, including vitamins, minerals, and herbal remedies, have been studied over the past 10 years in randomized, controlled trials that have produced mixed results. In the case of beta-carotene, various studies have evaluated its use for age-related macular degeneration (AMD). In studies published in peer-reviewed journals, the use of beta-carotene combined with vitamin C, vitamin E, and elemental zinc has been shown to reduce the risk of loss of visual acuity by as much as 27% and the risk of progression of advanced AMD by as much as 25%.1,2 However, several studies have shown no benefit when zinc was not included as part of the vitamin supplementation.1,3 This appears to indicate the presence of a more complex mechanism regarding efficacy in this disorder. Other studies have shown positive effects with high levels of dietary beta-carotene as well as use of supplemental lycopene and lutein.4,5

The exact pharmacology of beta-carotene is still being investigated. Beta-carotene consists of a number of isomers. The most common form used in clinical trials to date is synthetic beta-carotene, consisting of all "trans" forms as opposed to natural beta-carotene, which contains several cis-beta-carotene isomers.6

Beta-carotene appears to be beneficial because of its antioxidant activities in preventing lipid peroxidation.7 Several studies have indicated that there may be a reduction in free radical-induced DNA damage as well as in inflammatory markers, including C-reactive protein.8,9 Reduced risk for some cancers has been postulated, but data are lacking. In fact, taking betacarotene may result in an increased risk for lung cancer because of the production of metabolites.10

Finally, taking high dosages of beta-carotene along with other nutrients, such as selenium, vitamin C, and vitamin E, may lower high-density lipoprotein levels, resulting in a less-optimal lipid profile.11

In this particular patient, although his reversible carotenoderma was most likely benign, there were reasons to stop his supplemental beta-carotene in addition to the skin discoloration. The patient had a history of cardiovascular and lipid abnormalities. Several studies have shown a decrease in the efficacy of statins and niacin with concomitant use of beta-carotene.11,12 Therefore, increasing this patient's dietary intake of fruits and vegetables would be a more prudent approach.

Almost every patient seen in a physician's office or in the hospital will be taking some natural product these days. It is critical that as physicians we ask each and every patient about such use. Drug-supplement interactions can and do occur. Known and idiosyncratic reactions are also possible. There is most certainly a role for natural products that have been proven to be safe and effective by scientific research; however, it is our responsibility to inform our patients that just because something is "natural" does not necessarily mean it is safe.


1. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical-trial of high-dose supplementation with vitamins C and E, beta-carotene, and zinc for age-related macular degeneration and vision loss. AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436.

2. Age-Related Eye Disease Study Research Group. Potential public health impact of Age-Related Eye Disease Study results: AREDS report no. 11. Arch Ophthalmol. 2003;121:1621-1624.

3. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta-carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001;119: 1439-1452.

4. Kim MK, Ahn SH, Lee-Kim YC. Relationship of serum α-tocopherol, carotenoids and retinal with the risk of breast cancer. Nutr Res. 2001;21:797-809.

5. Seddon JM, Ajani UA, Sperduto RD, et al, for the Eye Disease Case-Control Study Group. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. JAMA. 1994;272:1413-1420.

6. Neuman I, Nahum H, Ben-Amotz A. Prevention of exercise-induced asthma by a natural isomer mixture of beta-carotene. Ann Allergy Asthma Immunol. 1999;82:549-553.

7. Omenn GS. Chemoprevention of lung cancer: the rise and demise of beta-carotene. Annu Rev Public Health. 1998;19:73-99.

8. Krajcovicova-Kudlackova M, Dusinska M. Oxidative DNA damage in relation to nutrition. Neoplasma. 2004;51:30-33.

9. Ford ES, Gillespie C, Ballew C, et al. Serum carotenoid concentrations in US children and adolescents. Am J Clin Nutr. 2002;76:818-827.

10. Russell RM. The vitamin A spectrum: from deficiency to toxicity. Am J Clin Nutr. 2000;71:878-884.

11. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1593.

12. Cheung MC, Zhao XQ, Chait A, et al. Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL. Arterioscler Throm Vasc Biol. 2001;21:1320-1326.




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