Smoking and Eye Diseases (Risk of Age-Related Macular Degeneration and Cataract)

Key Points at a Glance

Key Points of This Disease

• Smoking (tobacco) is an established risk factor for multiple eye diseases, with proven associations with age-related macular degeneration (AMD), cataract, dry eye, diabetic retinopathy, thyroid eye disease (TED), and Leber hereditary optic neuropathy (LHON).
• The odds ratio (OR) for AMD in current smokers is 2.0–4.0 (meta-analysis)¹⁾, making smoking the most important modifiable risk factor for AMD.
• The risk of nuclear cataract increases to an OR of approximately 2.0 in smokers with a history of 20 pack-years or more²⁾, primarily due to cyanide-induced lens protein denaturation.
• Smoking is the strongest environmental factor, increasing the risk of developing thyroid eye disease (TED) in patients with Graves’ disease by about 7.7 times⁸⁾.
• Secondhand smoke (sidestream smoke) may also contribute to allergic diseases and ocular surface inflammation⁴⁾. Research on the ocular effects of electronic cigarettes is also accumulating¹²⁾.
• Smoking cessation reduces AMD risk significantly over 10–20 years, but complete recovery to the level of never-smokers is difficult³⁾.
• In ophthalmology outpatient clinics, it is essential to always obtain a smoking history (pack-years) and provide active smoking cessation guidance.

1. Relationship Between Smoking and Eye Diseases

Fundus photograph of moderate age-related macular degeneration (macular drusen)

National Eye Institute, National Institutes of Health. Intermediate age-related macular degeneration fundus photograph. Reference #EDA2. Public Domain. Source ID: NIH-NEI-EDA2.

Right eye fundus photograph showing extensive accumulation of multiple pale yellow soft drusen in the macula, consistent with moderate age-related macular degeneration. This corresponds to the typical fundus finding of AMD, for which smoking is the greatest risk factor, as discussed in section “1. Relationship Between Smoking and Eye Diseases.”

Smoking (tobacco) is established as a risk factor for multiple eye diseases. In particular, associations with age-related macular degeneration (AMD), cataract, dry eye, diabetic retinopathy, thyroid eye disease, and Leber hereditary optic neuropathy have been scientifically proven.

Tobacco smoke contains over 4,000 chemical substances, among which cyanide, cadmium, nicotine, and free radicals cause various damages to ocular tissues. The odds ratio for AMD onset in current smokers is 2.0–4.0 (systematic review and meta-analysis)¹⁾, making it the strongest modifiable risk factor for AMD. For nuclear cataract, smoking of 20 pack-years or more increases the odds ratio to approximately 2.0²⁾.

There is a clear dose-response relationship between cumulative smoking amount (pack-years = number of cigarettes smoked per day ÷ 20 × years of smoking) and the risk of eye diseases¹⁾. After quitting smoking, the risk gradually decreases, but it may take more than 20 years to return to the same level as non-smokers³⁾, so early smoking cessation provides the greatest benefit. Passive smoking (exposure to secondhand smoke) is associated with an increased risk of allergic diseases in children and adolescents⁴⁾.

• Smoking is the most important modifiable risk factor for age-related macular degeneration¹⁾
• Nuclear cataract risk increases to OR approximately 2.0 with 20 pack-years or more²⁾
• Risk decreases to near that of non-smokers 20 years after quitting³⁾
• Passive smoking may also increase the risk of allergic diseases⁴⁾

Q How does smoking affect the eyes?

A

Smoking increases the risk of age-related macular degeneration by 2 to 4 times and the risk of nuclear cataract by about 2 times. The main mechanism is that oxidants, cyanide, and cadmium in tobacco smoke damage the retinal pigment epithelium and lens proteins. It is also an aggravating factor for dry eye, thyroid eye disease (TED), and diabetic retinopathy. In particular, the risk of developing eye disease in patients with Graves’ disease is about 7.7 times higher than in non-smokers. Passive smoking may also increase the risk of eye diseases, so improving the environment not only for the smoker but also for those around them is important.

2. Eye diseases associated with smoking

Slit-lamp microscopy finding of nuclear cataract (opacification of the lens nucleus)

Rakesh Ahuja, MD. Slit lamp view of Cataract in Human Eye. Wikimedia Commons, 2005. License: CC BY-SA 3.0. Source ID: Wikimedia-Slit_lamp_view_of_Cataract_in_Human_Eye.

Slit-lamp microscopy image showing marked brownish opacification of the lens nucleus (nuclear cataract). This corresponds to the nuclear cataract caused by cyanide from smoking, discussed in the section “2. Eye diseases associated with smoking.”

The main eye diseases associated with smoking can be categorized into six types.

Age-related macular degeneration (AMD)

Risk of onset: OR for AMD in current smokers is 2.0–4.0 (meta-analysis)¹⁾

Strong association with exudative AMD: Particularly strong association with exudative (neovascular) AMD⁵⁾

Dose-response relationship: Positive dose-response relationship with cumulative smoking amount (pack-years)¹⁾

Effect of smoking cessation: Risk decreases to near that of non-smokers 20 years after quitting³⁾

Cataract

Nuclear cataract risk: OR approximately 2.0 for 20 pack-years or more²⁾

Association with posterior subcapsular cataract also reported⁶⁾

Mechanism: Disruption of disulfide bonds in lens proteins by cyanide leads to nuclear cataract

Effect of smoking cessation: Risk reduction observed after quitting²⁾

Dry Eye

Direct harmful effect: Tobacco smoke directly damages the tear film⁷⁾

Goblet cell damage: Thinning of the mucus layer due to damage to conjunctival goblet cells⁷⁾

Secondhand smoke environment may increase the risk of allergic diseases⁴⁾

Thyroid Eye Disease (TED)

Strongest environmental factor: Smoking is the strongest environmental factor for the onset and exacerbation of Graves’ ophthalmopathy⁸⁾

Risk of onset: OR for TED onset in smokers approximately 7.7⁸⁾

After radioactive iodine treatment, risk of TED exacerbation is increased in smokers⁹⁾

Diabetic Retinopathy and Leber Hereditary Optic Neuropathy

Diabetic Retinopathy:

• Smoking promotes microvascular damage, which is the underlying mechanism¹⁰⁾
• Increases the risk of progression to proliferative retinopathy in diabetic patients

Leber Hereditary Optic Neuropathy (LHON):

• Smoking triggers the onset in carriers of mitochondrial DNA mutations¹¹⁾
• Smoking exacerbates mitochondrial dysfunction, increasing the risk of onset¹¹⁾

Q What is the relationship between thyroid eye disease and smoking?

A

Smoking is the strongest environmental factor, increasing the risk of developing thyroid eye disease (TED) in patients with Graves’ disease by approximately 7.7 times. Smoking cessation has been shown to improve the effectiveness of TED treatment, and the risk of worsening eye disease after radioactive iodine therapy is also higher in smokers. Providing smoking cessation guidance before starting eye disease treatment (steroids, radiation therapy, orbital decompression) is a prerequisite for maximizing treatment efficacy.

3. Epidemiological Data

The impact of smoking on eye diseases is significant at the population level and is a public health issue.

Disease	Risk Increase (OR)	Notes
AMD (overall)	2.0–4.0	Current smokers, meta-analysis1)
Exudative AMD	Particularly high	Dose-response relationship with pack-years5)
Nuclear cataract	Approximately 2.0	20 pack-years or more2)
Thyroid eye disease (TED)	Approximately 7.7	Patients with Graves’ disease8)
Diabetic retinopathy	Increased	Promotes microvascular damage10)
LHON onset	Trigger	mtDNA mutation carriers11)

• The population attributable risk (PAR) of smoking for AMD is estimated to be approximately 25–30% ¹⁾
• A significant increase in cataract surgery risk among smokers has been confirmed in large cohort studies ⁶⁾
• Secondhand smoke exposure has been reported to increase the risk of allergic diseases in children and adolescents ⁴⁾
• Research on the ocular effects of electronic cigarettes (including heated tobacco products) is accumulating ¹²⁾, and the establishment of evidence is awaited

4. Diagnosis and Screening

Proptosis and eyelid retraction due to Graves' disease (thyroid eye disease)

Jonathan Trobe, MD, University of Michigan Kellogg Eye Center. Proptosis and lid retraction from Graves’ Disease. Wikimedia Commons. License: CC BY 3.0. Source ID: Wikimedia-Proptosis_and_lid_retraction_from_Graves_Disease.

External photograph of Graves’ disease (thyroid eye disease) showing marked bilateral proptosis and upper eyelid retraction. This corresponds to the clinical presentation of thyroid eye disease, for which smoking increases the risk of onset by approximately 7.7 times, as discussed in the section “4. Diagnosis and Screening.”

Active inquiry into smoking history is important in ophthalmology outpatient settings. It should be considered an essential item, especially during initial consultations for AMD and thyroid eye disease.

Quantification of smoking history:

• Calculation of pack-years: (number of cigarettes smoked per day ÷ 20) × years of smoking
• Confirm whether the patient is a current smoker, former smoker (with years since quitting), or never smoker
• Also assess secondhand smoke exposure (at work and home)

Management of high-risk groups for AMD:

• Regular fundus examinations are recommended for patients with a history of smoking, family history of AMD, and unilateral AMD ⁵⁾
• OCT is effective for early detection of drusen and retinal pigment epithelium changes
• For unilateral cases, shorten the follow-up interval for the unaffected eye.

Management of patients with thyroid eye disease:

• Smoking status should be assessed at every visit ⁸⁾
• Smoking cessation counseling is a prerequisite before starting treatment.
• For smokers undergoing radioactive iodine therapy, fully explain the potential risk of worsening eye disease beforehand ⁹⁾

Management of patients with cataracts and dry eye:

• Include smoking history in the preoperative interview.
• For patients with severe dry eye, confirm smoking history and secondhand smoke exposure during the interview ⁷⁾

5. Smoking Cessation Guidance and Prevention

Smoking cessation is the most important and proven preventive measure for eye diseases, and ophthalmologists have an active role in intervention.

Reduction of disease risk with smoking cessation:

Disease	Effect of smoking cessation	Evidence
AMD	Risk significantly decreases 10–20 years after quitting 3)	Prospective cohort
Cataract (nuclear)	Risk reduction observed after smoking cessation2)	Meta-analysis
Thyroid eye disease	Smoking cessation improves TED treatment outcomes8)	Interventional study
Diabetic retinopathy	Contributes to slowing progression of vascular damage10)	Cohort

5A method (use in ophthalmology)¹³⁾:

• Ask: Inquire about smoking history in all patients
• Advise: Specifically communicate the risks of smoking for eye diseases
• Assess: Evaluate readiness to quit smoking
• Assist: Refer to smoking cessation aids or clinics
• Arrange: Schedule follow-up visits

Pharmacotherapy for smoking cessation:

• Nicotine replacement therapy (NRT): nicotine patch (7/14/21 mg) and nicotine gum¹³⁾
• Varenicline (Champix): α4β2 nicotinic receptor partial agonist. Standard treatment is 12 weeks¹³⁾
• Collaboration with smoking cessation clinics: Utilize the insurance-covered 12-week smoking cessation treatment program (5 visits)¹⁴⁾

Key points for smoking cessation guidance from ophthalmologists

Communicate the following messages to patients.

A message for AMD patients and suspected cases: “If you smoke one pack of cigarettes per day, your risk of age-related macular degeneration is 2 to 4 times higher than that of non-smokers. Quitting smoking is the most important preventive measure.”

A message for patients with thyroid eye disease: “If you have Graves’ disease and continue smoking, your risk of developing eye disease increases more than 7 times. Insurance covers smoking cessation treatment, so we recommend visiting a smoking cessation clinic.”

For patients who find it difficult to quit smoking: Prepare a referral letter to a smoking cessation clinic and inform them that nicotine patches and varenicline are available. If immediate complete cessation is difficult, starting with reducing the number of cigarettes can also be beneficial.

Q Does quitting smoking reduce eye risks?

A

Prospective cohort studies have shown that the risk of AMD significantly decreases 10 to 20 years after quitting smoking. However, the risk does not fully return to the level of non-smokers, and the earlier you quit, the greater the benefit. Risk reduction after quitting has also been observed for nuclear cataracts and thyroid eye disease. Especially during treatment for thyroid eye disease, quitting smoking improves treatment outcomes. From an ophthalmological perspective, smoking cessation is extremely important, and it is advisable to actively recommend the use of smoking cessation clinics (covered by insurance).

6. Pathophysiology and detailed mechanisms of onset

The main mechanisms by which smoking damages ocular tissues are broadly divided into four categories: oxidative stress, direct toxicity, immune dysregulation, and vascular damage.

Oxidative stress and AMD:

• It is estimated that a single puff of cigarette smoke produces approximately 10^15 free radicals¹⁵⁾
• In mice exposed to cigarette smoke, RPE oxidative DNA damage, loss of basal infoldings, increased vacuolization, Bruch’s membrane thickening, and RPE apoptosis have been reported ¹⁵⁾
• Nrf2 orchestrates the antioxidant response, and its response decline due to aging and smoking-related oxidative stress is a concern ¹⁵⁾
• The synergistic effect of complement factor H (CFH) gene polymorphism (Y402H) and smoking significantly increases AMD risk ⁵⁾

Cyanide and nuclear cataract:

• Cyanide in tobacco smoke disrupts disulfide bonds of lens proteins (crystallins)
• Protein aggregation and insolubilization occur, leading to nuclear cataract
• Nuclear opacification is significantly increased in smokers with 20 pack-years or more ²⁾

Nicotine and vascular damage:

• Nicotine stimulates the sympathetic nervous system, causing vasoconstriction and reducing retinal blood flow ¹⁰⁾
• In diabetic patients, pre-existing microvascular damage is further exacerbated by smoking ¹⁰⁾

Immune dysregulation and thyroid eye disease (TED):

• Smoking-induced immune dysregulation promotes increased production of TSH receptor antibodies (TRAb) ⁸⁾
• Activation of orbital fibroblasts and increased hyaluronic acid production lead to orbital tissue thickening and proptosis ⁸⁾

Effects on the tear film and dry eye:

• Harmful chemicals in tobacco smoke destabilize the lipid layer of the tear film, causing evaporative dry eye ⁷⁾
• It damages conjunctival goblet cells, thins the mucus layer, and reduces tear film stability⁷⁾

LHON and mitochondrial dysfunction:

• In carriers of mitochondrial DNA mutations (e.g., 11778G>A), smoking exacerbates existing mitochondrial dysfunction and triggers disease onset¹¹⁾

7. Latest research and future perspectives

Note on research-stage information

The following content includes topics that are under investigation or debated. It neutrally presents current evidence and does not guarantee the effectiveness of any specific intervention.

Effects of e-cigarettes and heated tobacco products on the eyes:

• Epidemiological studies evaluating the ocular effects of e-cigarettes and heated tobacco products (e.g., IQOS) are accumulating¹²⁾
• Concerns exist regarding the impact on the ocular surface via nicotine and volatile organic compounds
• Risk assessment compared to conventional tobacco is not yet established, so a cautious approach is necessary

Gene–environment interaction:

• Interaction between CFH (Y402H) and ARMS2 (A69S) gene polymorphisms and smoking further increases AMD risk⁵⁾
• Research on personalized smoking cessation interventions for genetically high-risk individuals is progressing

Smoking cessation intervention and AMD progression suppression:

• Prospective cohort studies are underway to verify the effects of smoking cessation on suppressing AMD onset and progression
• The combined effect of smoking cessation and AREDS supplements (vitamin C 500 mg, vitamin E 400 IU, zinc 80 mg, copper 2 mg, lutein 10 mg, zeaxanthin 2 mg) is also being evaluated.

Thirdhand smoke:

• The impact of residual chemicals (thirdhand smoke) adhering to walls, clothing, and furniture on the ocular surface is attracting attention.
• The association with ocular surface disorders in children and family members of smokers is a topic for future research.

AI-based estimation of smoking status from fundus photographs:

• Studies using machine learning models to estimate smoking status from fundus photographs have been reported, and application to ophthalmic screening is expected.

8. References

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8. Prummel MF, Wiersinga WM. Smoking and risk of Graves’ disease. JAMA. 1993;269(4):479-482.
9. Bartalena L, Marcocci C, Tanda ML, et al. Cigarette smoking and treatment outcomes in Graves ophthalmopathy. Ann Intern Med. 1998;129(8):632-635.
10. Cai J, Boulton M. The pathogenesis of diabetic retinopathy: old concepts and new questions. Eye (Lond). 2002;16(3):242-260.
11. Kirkman MA, Yu-Wai-Man P, Korsten A, et al. Gene-environment interactions in Leber hereditary optic neuropathy. Brain. 2009;132(Pt 9):2317-2326.
12. Mehra D, Galor A. Digital screen use and dry eye: a review. Asia Pac J Ophthalmol. 2020;9(6):491-497.
13. Fiore MC, Jaén CR, Baker TB, et al. Treating tobacco use and dependence: 2008 update. Clinical practice guideline. Rockville, MD: U.S. Department of Health and Human Services; 2008.
14. JCS Joint Working Group. Guidelines for smoking cessation (JCS 2010): digest version. Circ J. 2012;76(4):1024-1043.
15. Cano M, Thimmalappula R, Fujihara M, et al. Cigarette smoking, oxidative stress, the anti-oxidant response through Nrf2 signaling, and age-related macular degeneration. Vision Res. 2010;50(7):652-664.