Dietary Supplements and the Ophthalmologist

Stephen G. Schwartz, MD; Pamela S. Chavis, MD

Compr Ophthalmol Update. 2005;6(3):153-159. 

Abstract and Introduction

Dietary supplements are commonly used by patients in an ophthalmology practice. Many of these agents have direct toxic effects on the eye and visual system or may interfere with elective surgery. A high index of suspicion should be maintained. The authors review common preparations and discuss them in three contexts: direct ocular effects (beneficial and deleterious); bleeding effects that may affect ocular surgery; and effects on medications.

The actions of dietary supplements are diverse and may be adverse. Their prevalence and their potential toxicity are underappreciated among ophthalmologists. With a high index of suspicion, both vision-threatening and life-threatening interactions may be avoided.

The ocular toxicity of pharmaceutical preparations is well documented.[1] In contrast, the ocular effects of dietary supplements are less well described, although recognition of their potential toxicity is increasing.[2,3] In the literature, the terms "herbal," "supplement," and "complementary and alternative medicines (CAM)" are all used, which may lead the reader to confusion. They refer to a heterogeneous group that may include minerals, nutrients, botanical supplements, or ingredients or extracts of plant or animal origin.

We will use the broader term "dietary supplements" in this manuscript, although the regulation of each classification of medication varies, depending on the labeling and on the disease treatment claims made by each agent. The distinction between a "drug" and a supplement may be difficult. For example, cardiac glycosides are derived from foxglove (Digitalis purpurea), and cyclosporine (Sandimmune®; Novartis, Basel, Switzerland) is derived from the fungus Tolypocladium inflatum Gams (later renamed Beauveria nivea).

The 1938 Food, Drug, and Cosmetic Act regulates any substance that claims to diagnose, prevent, treat, cure, or mitigate any disease ("disease claims"). The 1994 Dietary Supplement Health and Education Act (DSHEA, revised in 2000) regulates any substance that claims to affect the structure or function of any organ or system ("structure/function" claims) without specifically claiming efficacy against any particular disease. For example, a substance that makes no medicinal claims is not regulated; a substance that claims to "maintain healthy eyes" would be regulated by DSHEA; and a substance that claims to treat age-related macular degeneration (AMD) would be regulated by the Food, Drug, and Cosmetic Act. Enforcement of these acts is carried out by two federal agencies. The Food and Drug Administration (FDA) controls claims made on the bottle and package insert. The Interstate Commerce Commission (ICC) oversees claims made through advertisements.

The net effect is that most dietary supplements are brought to market with less regulation, and in most cases less rigorous scientific investigation, than pharmaceuticals. Thus, the ophthalmologist should have a working knowledge of these preparations, which are in common use among the general public.

Prevalence of Dietary Supplement Usage

Dietary supplements are commonly used by ophthalmology patients, both to treat specific eye conditions and to treat nonocular disease. Five percent of glaucoma patients use supplements to lower intraocular pressure (IOP).[4] Up to 42% of patients with uveitis use dietary supplements, prayer, and/or acupuncture specifically for their eye condition.[5]

Patients undergoing elective ambulatory surgical procedures commonly use dietary supplements. The prevalence rate is reported at approximately one-third, but this is probably underestimated,[6] as up to 70% of patients withhold this information from their physicians. The layperson may not think of supplements as "medications," may lack awareness of potential risks, and may fear lack of support from physicians.

An additional concern, also related to the less stringent oversight of dietary supplements, is mislabeling of the product. Overdoses, underdoses, and contamination with Western prescription-style pharmaceutical products are unfortunately not uncommon.[7]

Effects of Dietary Supplements

The effects of dietary supplements are diverse and may be adverse. These preparations have been in use for thousands of years and predate modern pharmaceuticals.[8] Most of these agents are relatively safe, although the FDA recently reported that ephedra (Ephedra sinesis, ma huang), a weight loss agent, poses "an unreasonable risk to human health" due to its increased risk of sudden cardiac death.

Although an exhaustive review of the potential toxicity of dietary supplements is beyond the scope of this manuscript, certain effects are important for the practicing ophthalmologist. These are divided here into three categories: direct ocular effects; bleeding effects that may affect ocular surgery; and effects on medications used frequently by patients in a typical ophthalmologic practice.

Direct Ocular Effects

Dietary supplements that have demonstrated direct ocular effects, either beneficial or deleterious, are listed here in alphabetical order. Several preparations appear to demonstrate at least some therapeutic effect. However, with the exception of the vitamin combination from the Age-Related Eye Disease Study (AREDS) Group, none of these supplements has accumulated enough evidence in the peer-reviewed literature to be considered standard of care at this time.

Bilberry (Vaccinium myrtillus) has been used for a variety of purposes, including as an astringent to treat diarrhea, and to induce diuresis. It also stimulates the regeneration of rhodopsin, although its clinical effects on young, healthy volunteers appear negligible.[9]

Canthaxanthine is a carotenoid pigment used in the treatment of photosensitivity disorders and vitiligo; it is also marketed as an oral tanning agent (Orobronze; DeWitte, Greenville, SC). It may cause a characteristic retinopathy, with a ring of yellow-orange crystalline material in the macula.[10] Although the retinopathy is frequently asymptomatic, subnormal responses on electroretinography and dark adaptometry may be noted.[11] Although the long-term effects are unknown, the crystals typically resorb upon discontinuation of the agent.

Chamomile (Matricaria spp.), an anxiolytic, is occasionally used topically as a folk remedy for ocular infections. It may cause an IgE-mediated conjunctivitis with lid edema.[12] Treatment consists of discontinuation of the agent, as well as nonspecific supportive measures.

Echinacea (Echinacea spp.), used to treat viral upper respiratory tract infections, is also occasionally used topically. Similar to chamomile, it may cause a self-limited allergic conjunctivitis.[2,13]

The fish oils eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) appear to have myriad effects on the eye. Docosahexaenoic acid, when combined with vitamin A, has been claimed to slow progression of retinitis pigmentosa (RP) in certain patients: For example, in patients beginning treatment with 15,000 IU/day vitamin A (retinyl palmitate), adding 1,200 mg/day DHA slows progression of RP for 2 years.[14] A diet high in omega-3 fatty acids and fish and low in linoleic acid is associated with a relatively decreased risk of advanced AMD.[15]

Forskolin (Coleus forskohlii) is an aqueous human secretin suppressant and lowers IOP.[16]

Ginkgo (Ginkgo biloba) is mainly used to increase memory function. It appears to be neuroprotective through beneficial effects on blood flow, serum viscosity, and vasospasm. It has direct antiplatelet activity and has been linked to spontaneous hyphema, retinal hemorrhage, and orbital hemorrhage.[2] Ginkgo increases ocular blood flow, but does not affect IOP.[17] In one small placebo-controlled trial, patients with normal-tension glaucoma receiving 120 mg/day of ginkgo extract had short-term improvement of pre-existing visual field defects.[18]

Kava (Piper methysticum) has been used as an anxiolytic and as an antigonorrheal agent. It may cause impaired accommodation.[19]

Licorice (Glycyrrhiza glabra), used to treat gastric ulcer, may cause blood vessel spasm. It has been linked to one case of central retinal vein occlusion[20] and several cases of transient visual loss, presumably secondary to retinal and/or cortical vasospasm.[21]

Lily of the valley (Convallaria majalis), a cardioactive agent, is structurally similar to cardiac glycosides and may cause similar disturbances in color vision.[2]

Marijuana (Cannabis sativa), when inhaled, may lower IOP by as much as 25% for up to 4 hours,[22] although there is significant systemic toxicity.[23] A recent small, uncontrolled, nonrandomized trial suggested some efficacy, but both oral and inhaled preparations studied were not tolerated for more than a few months.[24]

Niacin (nicotinic acid, vitamin B3), used to lower serum lipids, has a well documented dose-related association with pseudocystoid macular edema (CME), usually at doses greater than 1.5 mg/day. Clinically, niacin maculopathy is similar to typical CME, but the two entities may be differentiated by fluorescein angiography. Niacin toxicity does not show leakage of fluorescein in the macula, which therefore represents intracellular fluid accumulation rather than true (extracellular) edema. Maculopathy typically resolves upon discontinuation of the agent.[25]

Valerian (Valeriana spp.), used as an anxiolytic, may cause mydriasis.[26]

Vitamins affect various ocular structures, particularly the retina. The Age-Related Eye Disease Study (AREDS) Group reported a beneficial effect for patients with at least intermediate AMD and without medical contraindications (e.g., smokers) with the following daily dose: 28,640 IU of beta-carotene, 452 mg of vitamin C (ascorbic acid), 400 IU of vitamin E (alphatocophorol), 69.6 mg of zinc oxide, and 1.6 mg of copper (cupric oxide).[27] Vitamin A (retinol), when combined with DHA, may have a positive effect on RP (see fish oils). One trial reported increased tear production in patients with Sjogren syndrome using essential fatty acid precursors of prostaglandin E1, vitamin C, and vitamin B6 (pyridoxine).[28] Potential adverse effects of vitamins include pseudotumor cerebri with vitamin A[29] and corneal pigmentation with beta-carotene.[30]

The various ocular effects, stratified by ocular structure, are summarized in (beneficial effects) and (deleterious effects).

  Beneficial Ocular Effects of Dietary Supplements

  Deleterious Ocular Effects of Dietary Supplements

Bleeding Effects That May Affect Ocular Surgery

Several dietary supplements may increase clinical bleeding, which may be important when evaluating an ocular hemorrhage or scheduling elective surgery.

Gingko has been linked with postoperative hemorrhage in general surgery, and increased risk is associated with the following agents:[31] feverfew (Tanacetum parthenium), used to treat headache; garlic (Allium sativum), used as an antibiotic and diuretic; ginger (Zingiber officinale), an antiemetic; and ginseng (Panax spp.), used to treat anxiety and gastric upset.

In various experimental models, the following agents demonstrate at least some antiplatelet activity, although their clinical effects may be highly variable: chondroitin sulfate,[32] used to treat osteoarthritis; fenugreek (Trigonella foenum-graecum),[33] used as an antibiotic and to treat diabetes mellitus; and fish oils.[34]

Many supplements may potentiate the anticoagulant effects of warfarin (Coumadin®, Bristol-Myers Squibb, Princeton, NJ), including:[35] borage seed oil (Borago officinalis), a diuretic; chamomile; fenugreek; feverfew; garlic; and ginger. On the other hand, a recent small clinical trial found no significant clinical effect of Coenzyme Q10 (a provitamin and antioxidant) and ginkgo on warfarin.[36]

Effects on Medications

Many dietary supplements impact the cytochrome P450 oxidase system, thus affecting pharmaceuticals that are metabolized by these pathways. The cytochrome P450 3A4 (CYP3A4) isoform metabolizes many common medications, including calcium channel blockers and 3-hydroxy, 3-methylglutaryl coenzyme A reductase inhibitors (statins). Many agents demonstrate in vitro inhibition of the CYP3A4 isoform, resulting in increased serum levels of these medications, including chamomile; echinacea; garlic; goldenseal (Hydrastis canadensis), used as an antibiotic; and licorice.[37,38]

Conversely, the antidepressant, St. John's wort (Hyperium perforatum), induces the CYP3A4 isoform and therefore decreases serum concentrations of these compounds. St. John's wort also induces the CYP1A2 and CYP2C9 isoforms as well as the transport protein, P-glycoprotein.[3,39] This reduces the serum concentrations of cardiac glycosides, oral contraceptive agents, warfarin, HIV protease inhibitors (such as saquinavir, Invirase®, Hoffman-LaRoche, Inc., Nutley, NJ), and HIV non-nucleoside reverse transcriptase inhibitors (such as efavirenz, Sustiva®, DuPont, Wilmington, DE).

The effects of various dietary supplements on the cytochrome P450 system are summarized in . Certain supplements may interact with medications through mechanisms other than hepatic metabolism. Licorice may potentiate the cardiac glycosides, possibly through effects on blood electrolyte levels.[40] This is important to the ophthalmologist because overdoses of cardiac glycosides may cause direct retinal toxicity, typically manifesting as xanthopsia.[41]

  Dietary Supplements and the Cytochrome P450 System

Various agents (such as echinacea, ginseng, and licorice) have known or proposed stimulatory effects on the immune system, and may inhibit corticosteroids and other immunosuppressive agents.[42]

Recommendations

The most important step is to maintain a high level of suspicion for the use of dietary supplements. Ophthalmologists should instruct office staff to specifically question patients about supplement use while taking a medication history.

Patients should be counseled that "natural" products are not necessarily "safe." Dietary supplements, like pharmaceuticals, may cause significant unintended consequences even when used properly. Patients are advised not to use ephedra for any reason, or canthaxanthine for tanning purposes.

Supplements thought to increase risks of bleeding (chondroitin sulfate, fenugreek, feverfew, fish oils, garlic, ginkgo, ginger, and ginseng) should be identified and discussed with the patient prior to elective eye surgery. The decision to discontinue a supplement is complex and should be individualized for the patient and the procedure, similar to the decision to discontinue a pharmaceutical anticoagulant such as aspirin, warfarin, or ticlopidine (Ticlid®, Hoffman-LaRoche, Inc., Nutley, NJ).

For example, clear-cornea phacoemulsification has a low risk of bleeding, and it is not always necessary to discontinue pharmaceutical anticoagulants[43] or dietary supplements with this procedure. Alternatively, pars plana vitrectomy is associated with a relatively higher risk of bleeding,[44] so there is more of a rationale to discontinue a supplement. There is no consensus regarding timing of discontinuation, although a conservative preoperative washout of 2 weeks has been proposed for orthopedic procedures.[3] Furthermore, there is no consensus in the peer-reviewed literature regarding reinstitution of supplements following surgery, although a similar 2-week interval appears reasonable.

A poster that alerts patients to the importance of disclosing their dietary supplement use to the ophthalmologist is available at the American Academy of Ophthalmology (AAO) website at http://www.aao.org/aao/education/library/cta/nutr_supp_peri.cfm , or by going to the main web page ( http://www.aao.org ) and entering "herbals" into the search function.

The AAO has established a national monitoring process to collect information regarding adverse ocular effects from dietary supplement use. A HIPAA-compliant copy of the reporting form is available through the AAO website ( http://www.aao.org ). Completed for ms may be sent to the AAO via FAX.

An additional resource, both for further information and to report dietary supplement-related adverse effects, is the National Registry of Drug-Induced Ocular Side Effects ( http://www.eyedrugregistry.com ).

Sidebar: Focus Points

  1. Dietary supplements include a heterogeneous group of substances derived from plant and animal sources.

  2. Dietary supplements typically come to market with less rigorous scientific testing than is expected for pharmaceutical preparations.

  3. Several dietary supplements, such as vitamin combinations[27] and fish oils,[14] appear to have direct beneficial effects on the visual system.

  4. Several dietary supplements, including canthaxanthine[10] and niacin,[25] have direct deleterious effects on the visual system.

  5. Several dietary supplements, including ginkgo and ginseng,[31] have anticoagulant or antiplatelet properties.

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