Optometry & Vision Science:
Smoking and Age-Related Macular Degeneration: Biochemical Mechanisms and Patient Support
Willeford, Kevin T.*; Rapp, Jerry†
Department of Biological Sciences, SUNY College of Optometry, New York, New York.
Abstract: A small percentage of the population associates smoking with ocular disease. Most optometrists do not stress the importance of smoking cessation to their patients, and the centrality of smoking regarding the risk for ocular disease is not emphasized in optometric education. Age-related macular degeneration has strong epidemiological associations with smoking, and so serves as an appropriate model for the adverse effects of cigarette smoke on the eye. This article aims to provide basic scientific information to optometrists and optometry students so that they can better understand the pathogenesis of age-related macular degeneration and provide education and support to their patients wishing to stop smoking.
The associations between cigarette smoking and conditions such as lung cancer and cardiovascular disease are well known among the general population.1 However, despite people fearing blindness more than other smoking-related conditions,2 only a small percentage of the population realizes that smoking can lead to irreversible vision loss. 76% of a sample from the US population believed this association to be false, 14% did not know, and only 9% believed smoking could be detrimental to ocular health.3 Additionally, although optometrists and optometry students are aware of the ocular health risks, most do not assess whether their patients want to stop smoking or provide support for cessation4 because they do not believe it is their role, do not have enough time or forget to ask.5 Using age-related macular degeneration (AMD) as a focus, this article aims to outline the possible biochemical processes by which cigarettes can adversely affect the eye and provide smoking cessation strategies so that optometrists and optometry students can better understand the basic pathological mechanisms involved and provide better support to their patients.
SMOKING AND AMD
The smoke that is inhaled contains many pro-oxidant compounds,6 including heavy metals and toxic mineral elements, which are known to be poisonous in high concentrations.7 The smoke is composed of 2 phases: a gaseous phase and a tar phase.8 The gaseous phase contains both organic and inorganic free radicals, including reactive oxygen species (ROS), epoxides, peroxides, nitric oxide, nitrogen dioxide, peroxynitrite, and peroxynitrates.9 One puff of cigarette smoke contains >4700 individual chemicals10 and 1015 free radicals,9 which is a far cry from the singular nicotine often associated with cigarette smoking. Although most cancers are the result of an interactive effect of genetics and the environment, the chemicals and free radicals in cigarette smoke are a direct cause of lung cancer, regardless of the smoker’s genetic susceptibility.11 The effects of smoking are not limited to the lungs, however, as they have been associated with other cancers and many ocular diseases.11 Moreover, there is evidence for a dose-response effect of smoking on ocular morbidity.12
The deleterious effects of cigarettes span the entire globe. Considering the anterior structures of the eye, it has been shown that there is a higher prevalence of ocular surface disease in smokers when compared with controls. Smokers also demonstrate a reduced tear break up time, irregularities in the lipid layer of the tear film, significant loss of conjunctival goblet cells, and significant conjunctival neutrophil infiltration.13 Nicotine deposits have also been shown to adhere to soft contact lenses.14 Considering the globe as a whole, smoking has been associated with Graves’ ophthalmopathy, glaucoma, cataracts, and the focus of the current discussion—AMD.11
Cigarette smoking is an independent and avoidable risk factor for both wet and dry AMD. The relationship is dose dependent, with one study showing a 2 to 3 times enhanced risk of AMD in current smokers.11 As with the development of any disease, the duration and intensity of the exposure to the harmful stimulus must be considered. A study from Japan showed that smokers who experienced a stronger intensity (i.e., inhaled deeply or did not use a filter) or longer duration (i.e., started smoking at age 20 or younger or have smoked for >40 years) of smoking had the highest risk of developing AMD.11 Furthermore, smoking is the strongest epidemiologic risk factor for developing AMD,8 but our understanding of the mechanism(s) involved is limited. Three distinct mechanisms are likely involved, including direct oxidative damage, indirect oxidative damage, and pathological vascular changes.
Types of Damage
The retina represents a high oxidative stress environment,8 and studies suggest that high levels of exposure to blue and visible light late in life may be associated with AMD development.15 In addition to oxidative light damage, the pro-oxidant compounds in cigarette smoke act as an additional source of stress. Individual variations play a role in this regard, as genetic polymorphisms may enhance susceptibility to oxidative damage from smoking.16 Direct oxidative damage disrupts the structure of retinal layers, with the retinal pigment epithelium (RPE), Bruch’s membrane, and the choriocapillaris being of prime concern in AMD (although all retinal layers are affected by oxidative damage). To study disease progression, oxidized compounds like carboxyethylpyrrole (oxidized docosohexanoic acid) are used to tag oxidatively damaged tissue.17 Damaged tissue was noted in mice chronically exposed to cigarette smoke, using the development of emphysema as a marker that exposure had been sufficient. Oxidative damage was noted in the RPE and Bruch’s membrane; an increased rate of RPE apoptosis was noted as well.18 A shorter duration/higher concentration of smoke induced changes similar to early AMD; that is, only Bruch’s membrane and the choriocapillaris were affected.19 There was no damage to the RPE under these conditions, presumably because the RPE’s antioxidant capability may ward off damage in the early stages of AMD. Chronic exposure to cigarette smoke, however, may overwhelm this protective capability.8
Oxidative stress is always present in the retina, but does not necessarily cause damage. Retinal cells are protected from oxidative stress by antioxidant scavenging systems that utilize two basic chemical reactions. Phase I reactions oxidize and reduce compounds, and phase II reactions conjugate phase I products with hydrophilic molecules, such as glutathione, the most effective and abundant quencher of ROS.8 If antioxidant defense capabilities are lowered to a critical level, indirect oxidative damage occurs—named as such because free radicals have not directly caused structural changes in tissue. Smoking stresses this protective system, both systemically and in the eye. Decreased concentrations of scavenging enzymes have been found in the alveolar macrophages20 and erythrocytes21 of smokers. Male smokers have reduced vitamin A and E (both antioxidants) concentrations in their internal mammary artery,22 and there is a reduction in antioxidant signaling in the ocular NRF2 pathway of smokers.8
The NRF2 signaling pathway provides direct evidence of the eye’s capability to alter protein synthesis in response to ROS. When this pathway is downregulated, it can leave the retina in a vulnerable state. NRF2 is a leucine zipper transcription factor that, when activated by ROS, is released by a protein named Keap1 to bind to antioxidant response elements along with MAF proteins. This results in the transcription of cytoprotective enzymes. The NRF2 antioxidant signaling pathway has been shown to exist in the RPE and is hypothesized to be a central component of the RPE’s defense mechanisms.8 Some of the NRF2 pathway’s functions include glutathione synthesis and thioredoxin induction to reduce acute light toxicity.23 Gao and Talalay provided additional support for the link between the RPE and the NRF2 pathway by showing that sulforaphane, an activator of the NRF2 transcription factor, had a protective effect on RPE cells from oxidative injury.24 The efficiency of this signaling system decreases with age; this decline is compounded by smoking. It appears that the signaling pathway in a young patient is more resilient to the effects of smoking, whereas older patients appear less able to cope. Further, NRF2 mRNA is downregulated in older smokers compared with that of older non-smokers,25 indicating that there is a decreased amount of NRF2 transcription factor available to induce antioxidant mechanisms in the former group. Thus, it is apparently critically important to preserve the protective effects of this system in order to allow the RPE to function normally despite the aging process.
When considering wet AMD, vascular changes become important. It has been shown that nicotine and carbon monoxide, two noxious gases in cigarette smoke, may induce profound vasospasm and platelet aggregation.13 Other documented effects of cigarette smoking on vascular tissue include increased levels of cholesterol, low-density lipoprotein, triglycerides, fibrinogen, and decreased levels of high-density lipoprotein.11 These changes in compound concentration can cause atherosclerosis and hypoxic damage to the choroidal vasculature, which increase the probability of a microinfarction.26 This hypoxic environment may also stimulate the development and progression of new subretinal vessels,27 a process often associated with wet AMD that can lead to macular bleeding, leaking, and scarring. Hypoxia may also be induced by carboxyhemoglobin, which is formed when carbon monoxide from cigarette smoke and hemoglobin combine. Carboxyhemoglobin, found in higher concentrations in the retinal vessels of smokers, reduces choroidal blood flow and can ultimately hinder the delivery of oxygen to the retina. These events also increase the probability of neovascular growth.28 Antivascular endothelial growth factor injections, one of the possible therapies for neovascular growth, may become ineffective when nicotine is present systemically. When comparing control mice with nicotine-fed mice, Davis et al. showed that treatment with adiponectin peptide II or bevacizumab yielded a 61 to 86% decrease in choroidal neovascularization in control mice compared with no significant reduction in nicotine-fed mice.29 This suggests that smoking cessation must be permanent after AMD diagnosis if vascular health is to improve with antiangiogenic treatment.
Current smokers, who have not yet developed AMD, can decrease their probability of developing the disease by adopting dietary strategies that are intimately linked to the aforementioned retinal biochemistry. Carotenoid supplementation with lutein and zeaxanthin can help protect against oxidative damage in the macula.30 This protective effect has been well documented, and in one study, reduced smokers’ risk of developing AMD to the equivalent of non-smokers.31 Boosting the activity of the antioxidant NRF2 pathway is also possible with supplementation. Sulforaphane, a potent activator of the antioxidant NRF2 system,8 is found in broccoli sprouts. Although still currently being researched, triterpenoids are steroid-like molecules found in plants that can cross the blood eye barrier. Triterpenoids function in enabling NRF2 to be released from Keap1.8 Lastly, (R)-alpha lipoic acid supplementation has been shown to restore the age-related decrease in NRF2 transcriptional and nuclear translocational efficiency to normal levels in mice.8 If this system can be restored to maximum efficiency, it may allow the RPE to better respond to an oxidative insult, such as cigarette smoking, regardless of age.
PATIENT EDUCATION AND SUPPORT
Although shown to be scientifically efficacious, dietary supplements do not encourage smokers to quit. Just as optometrists (approximately 4 decades ago) began to successfully incorporate first diagnostic and then therapeutic drugs into clinical care, they are also capable of setting up programs that will instruct clinicians in counseling techniques. This will enable optometrists to effectively discuss the importance of smoking cessation with their patients. It may be beneficial for clinicians to approach cessation counseling with two understandings. First, tobacco dependence is not unique to any age (20% of both adolescents and adults are dependent32) or racial group, and with few exceptions, interventions are effective for all groups.32 Second, tobacco dependence often has a chronic nature,33 resulting in multiple quit attempts and relapses before permanent cessation.34
Health and behavior counseling is most effective in terms of patient adherence if the physician communicates clearly as part of a reciprocal conversation with the patient.35 This conversation can be conducted during the case history and can also serve to strengthen the patient-clinician bond. A useful mnemonic to guide the conversation is the “5A’s”33 (Table 1). After initiating the conversation regarding smoking status, the clinician can integrate his/her own clinical and scientific knowledge into the discussion to help advise the patient. At the end of the discussion, asking ‘‘Are you ready to quit today?’’ is an appropriate question and helps determine the next course of action. If the patient is ready to quit, the last 2 A’s (assist and arrange) can be pursued as part of the clinician’s assessment and plan. A clinician might say, ‘‘In addition to your eye drop prescription, I would also like to write down some options to help you quit smoking.’’ By addressing the issue at the beginning and end of the optometric examination, the issue of smoking becomes integrated into the visual component and helps the patient see the two as related.
Both face-to-face and telephone counseling from 3 to 10 min long can be effective with the 10 min session, resulting in a doubling of abstinence rates.34 A plan should be developed that includes a quit date and coping strategies.34 A tangible quit date solidifies the treatment plan and becomes less ominous if coping strategies such as changing routines, deep breathing exercises, and/or removing all tobacco products from the home are implemented.34 Phone lines such as 1-800-QUIT-NOW may also be recommended to the patient. A discussion of pharmacotherapy may be warranted, in which case patients can be advised that they have both over-the-counter and prescription options. The combination of counseling and medication together was found to be more effective than medication alone.36
If the patient is not yet ready to quit, a motivational intervention known as the ‘‘5R’s’’ should be provided32 (Table 2). This sort of motivational intervention technique can become part of a clinician’s repertoire of questions for current smokers. With the appropriate questions and treatment strategies, the next issue for optometrists becomes how to integrate themselves into current health care systems for treating tobacco dependence. There are a few simple strategies that might help to accomplish this goal:
1. Using prompt and reminder systems in the electronic medical record that alert the clinician to screen the patient for tobacco use;
2. Handing out pamphlets with referral sites and/or phone numbers to those in need;
3. Providing appropriate education to students and clinicians.
As part of a multicomponent effort to improve smoking cessation services, Shelley et al.37 showed that this approach resulted in increased adoption and implementation of smoking cessation treatment guidelines in six New York City dental clinics. In addition, a pilot study in Canada has concluded that most students and optometrists are open to change and can function effectively as a component of a smoking cessation health care network if given proper training and education.37 Schools and colleges of optometry and providers of continuing optometric education should be encouraged to develop courses and programs that will instruct students and practitioners in techniques of motivational interviewing and counseling to encourage patients to quit smoking. In addition, there are helpful resources on the Web offering practical guides to smoking cessation.32
Basic scientific investigations and clinical studies together form the foundation for successful smoking cessation interventions. A study of the effect of informing women smokers of a link between smoking and cervical cancer concluded that higher perceived vulnerability to cervical cancer was associated with greater intention to quit smoking only among women who received a detailed coherent explanation of the link between smoking and cervical cancer.38 Therefore, it is critically important for clinicians to understand the possible pathological mechanisms underlying the development of disease which then afford them the opportunity and, hence, responsibility to provide patients with enough reliable information so that each patient can make an informed decision.
Cigarette smoke is a highly toxic entity that can adversely affect many biochemical processes in the eye. Since smoking is a modifiable risk factor, current smokers should consider the serious deleterious effects of cigarette smoke on retinal structure, defense mechanisms, and nutrient supply. Abnormalities in any of these domains may result in the development of AMD. With regard to treatment strategies, it takes <30 s of discussion to prompt a successful quit attempt,39 and if knowledge of a positive genetic risk for AMD is made available, patients are more likely to consider quitting.40 A quantification of the clinical significance of treatment paradigms, the number to treat, estimates how many patients would need to be treated before one avoids an early death. For treatment of tobacco dependence, the number to treat is comparable to that of daily aspirin treatment for avoidance of early death from heart disease.41 In addition, treatments for smoking cessation are relatively inexpensive, relatively harmless, and require short amounts of time.41
In the case of smoking and AMD, the scientific literature has provided evidence for both the pathological relationship between the two and the efficacy of preventative measures. It is the clinician’s role to synthesize these two areas of knowledge (pathology and prevention) and apply them in optometric practice. For the best clinical care, it is incumbent on eye care practitioners to educate their patients and be educated themselves—physician and patient education both improve patient health outcomes.42
Kevin T. Willeford
Department of Biological Sciences
SUNY College of Optometry
33 West 42nd Street
New York, New York 10036
The bulk of this paper was written by Kevin Willeford in partial fulfillment of the requirements for Dr. Jerry Rapp’s Ocular Biochemistry Graduate Seminar entitled ‘‘Biochemical and Nutritional Implications in Age-Related Ocular Disease’’ at SUNY College of Optometry. The authors would like to thank Ms. Krystine Olszewski and Mr. Anthony Zarella for their help in editing the manuscript.
Received April 5, 2012; accepted July 8, 2012.
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cigarette smoke; age-related macular degeneration (AMD); reactive oxygen species (ROS); antioxidant defense mechanisms; public health awareness
© 2012 American Academy of Optometry
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