Part 102

[Surgeon General’s Smoking Report,  health reports Continued from Part  101]

2004 The Health Consequences of Smoking: A Report of the Surgeon General.  Office of the Surgeon General (US); Office on Smoking and Health (US). Atlanta (GA): Centers for Disease Control and Prevention (US);  Forty years of reports. Cancers of stomach, uterine cervix, pancreas, kidney, acute myeloid leukemia, pneumonia, aneurysm, cataract, periodontitis. Conclusion “smoking generally diminishes the  health of smokers.”

https://www.ncbi.nlm.nih.gov/books/NBK44698/

Part 102 The Health Consequences of Smoking: A Report of the Surgeon General. 2004. Tobacco. Diminished health status, erectile dysfunction, eye disease, peptic ulcer.

6 Other Effects

Erectile Dysfunction

Erectile dysfunction, defined as the persistent inability to attain and maintain penile erection adequate for satisfactory sexual performance (National Institutes of Health [NIH] Consensus Development Panel on Impotence 1993), has recently received considerable attention as a major medical issue in the United States. Additional emphasis has been given to this condition with increasing recognition of its profound impact on quality of life (Wagner et al. 2000). Epidemiologic data, though sparse, indicate its importance as a public health problem. The prevalence of erectile dysfunction in 1992 was estimated to be 18 percent among men 50 through 59 years of age according to the National Health and Social Life Survey, a United States probability sample of men and women aged 18 through 59 years (Laumann et al. 1999). Among men 40 through 70 years of age, prevalence estimates of complete erectile dysfunction during 1987–1989 exceeded 10 percent and estimates of at least mild erectile dysfunction exceeded 50 percent, according to the Massachusetts Male Aging Study (Feldman et al. 1994). Incidence estimates of erectile dysfunction during 1995–1997, derived from longitudinal results of the Massachusetts Male Aging Study, approach 26 cases per 1,000 men annually (Johannes et al. 2000).

Many conditions have been implicated as causes of erectile dysfunction, including hormonal derangement, psychogenic influences, neurologic disorders, and vascular impairment, which may all interfere with the basic physiologic mechanisms involved in penile erection. Vascular impairment, which commonly refers to disease states that hamper penile blood flow, warrants particular attention for several reasons. Most importantly, vascular diseases are commonly associated with presentations of erectile dysfunction. Objectively demonstrable erectile dysfunction has been found in patients with myocardial infarction, coronary bypass surgery, cerebral vascular accidents, peripheral vascular disease, and hypertension (Melman and Gingell 1999). Furthermore, reports of patients with vasculogenic erectile dysfunction have suggested predisposing vasculopathic risk factors, which include cigarette smoking, fatty diets, adverse serum lipid levels, hypertension, physical inactivity, and obesity (Goldstein and Hatzichristou 1994). Several large epidemiologic studies have explored the extent to which these factors impair erectile function (Feldman et al. 1994; Derby et al. 2000b; Feldman et al. 2000; Johannes et al. 2000). The results of these studies also imply that modifications of risk factors may reduce the occurrence of erectile dysfunction.

Among widespread concerns about adverse health effects associated with cigarette smoking is the growing belief that this activity adversely affects sexual health and, in particular, erectile function. It is plausible that cigarette smoking exerts atherogenic effects on penile circulation relevant to erectile function, akin to effects on coronary circulation associated with heart disease (Fried et al. 1986; Raichlen et al. 1986). Furthermore, cigarette smoking cessation may afford a preventive strategy for reducing erectile dysfunction rates. However, each of these hypotheses requires a critical examination of the evidence regarding the effects of smoking on penile erection. This chapter summarizes and evaluates current observational and experimental data linking cigarette smoking and tobacco use with erectile dysfunction, including the patho-physiologic concepts.

Conclusions of Previous Surgeon General’s Reports

This topic has received some coverage in prior Surgeon General’s reports. The 1964 report (U.S. Department of Health, Education, and Welfare [USDHEW] 1964) included a discussion on masculinity in relation to COPD. The discussion drew from an investigation that defined the “element of masculinity as indicated by external morphologic features,” and contended that “weakness of the masculine component is significantly more frequent in smokers than in nonsmokers, and most frequent in heavier smokers” (USDHEW 1964, pp. 383–4). This vaguely described element merely relates to the theme of male sexual prowess, as erectile ability or lack thereof was not directly assessed. The Advisory Committee to the Surgeon General recognized the tentative nature of the conclusions and the need for further confirmation. The 1990 report carried out a comprehensive review of sexual activity and performance, and sperm density and quality (USDHHS 1990). This review did not lead to specific conclusions, reflecting limitations of the available data and their inconsistency. This section reviews the issue of male sexual function, examining the influence of cigarette smoking on penile erection, one specific component of male sexual function.

Biologic Basis

Direct biologic evidence establishing plausible mechanisms for the effects of cigarette smoking on penile erection certainly would strengthen the premise that cigarette smoking constitutes a risk factor for erectile dysfunction. One possible mechanism is smoking-induced endothelial dysfunction of the penile vasculature. This hypothesis is supported by recent investigations into the physiology of penile erection affirming that the endothelium of the blood vessels supplying the penis, as well as that lining the lacunar spaces within the penis, releases vasoactive substances that contribute to the control of penile smooth muscle relaxation required for penile erection (Lue and Tanagho 1987).

Saenz de Tejada and colleagues (1989) probed whether smoking affects penile vasculature endothelium as part of an investigation of the consequences of diabetes mellitus on endothelial function in the penis in men with erectile dysfunction. Using isolated strips of human corpora cavernosa of the penis, the investigators compared isometric tension results from men with and without diabetes who were smokers (having at least a five pack-year history of cigarette smoking) or nonsmokers. The findings indicate that a history of smoking was not associated with a worsened impairment of endothelium-mediated relaxation responses. The study did not assess responses of tissue from smokers independently while controlling for other possible erectile dysfunction risk factors, nor did it carry out a subset analysis of responses from smokers specified to have had large amounts of cigarette smoke exposure. These limitations restrict the conclusions that can be drawn concerning the effects of smoking on endothelial function in the penis.

In a study of rats, Xie and colleagues (1997) examined the long-term effects of smoking on the endothelial synthesis of nitric oxide in the penis. Nitric oxide is now known to be the principal vasoactive mediator of penile erection (Burnett 1997). Nitric oxide is released by endothelial cells in response to direct cholinergic stimulation and in response to dynamic factors of changing penile blood flow. In the study, rats were passively exposed to cigarette smoke in 60-minute sessions once per day, five days per week, for eight weeks. Immunoblot analyses of the protein expression of endothelial nitric oxide synthase (eNOS) in penile tissue from the exposed rats did not reveal any diminution of eNOS expression compared with tissue from control rats. However, these investigators confirmed that overall nitric oxide synthase enzymatic activity (which combines neuronal and endothelial sources) and specifically the protein expression of the neuronal form of nitric oxide synthase in the penis were both markedly reduced following passive exposure to cigarette smoke in rats as compared with rats not exposed to smoke. Their findings mainly suggest that smoking selectively impairs neuronal mechanisms, in particular the neuronally based nitric oxide signal transduction pathway associated with penile erection. But the relevance of the rat model for humans is uncertain.

The investigation by Saenz de Tejada and colleagues (1989) also evaluated whether smoking affects the neurogenic mechanisms responsible for penile erection. The overall finding was that the impairment of neurogenically mediated relaxation of penile smooth muscle from smokers (combining results from men with and without diabetes) was not different from the impairment observed in nonsmokers (both men with and without diabetes). However, these conclusions have the same limitations as those concerning endothelial effects observed in this study (see above). An in vitro investigation of neuromuscular transmission in human corpus cavernosum also studied nicotine and found that the actions of this agent are both contractile and relaxant (Adaikan and Ratnam 1988). If erectile dysfunction results from exogenously administered nicotine during cigarette smoking, it may be due to the acute vasoactive modulatory effects of this agent on the penile vasculature.

Epidemiologic Evidence

Observational Data

This section explores the association between cigarette smoking, as well as other forms of tobacco use, and the occurrence of erectile dysfunction based on a review of available observational data. A literature search was conducted using the National Library of Medicine’s PubMed system and was supplemented with professional knowledge of other resources. The critical feature of the observational data is the necessary reliance on self-reporting and other subjective instruments (e.g., logs, questionnaires, and sexual function inventories) to determine tobacco exposure and erectile performance, rather than quantitative measurements of these variables. A single-item assessment (e.g., “Do you experience difficulty getting and/or maintaining an erection that is rigid enough for satisfactory sexual intercourse?”) has gained prominence particularly for population-based epidemiologic studies (Derby et al. 2000a). This assessment has been useful as a single, direct practical tool to ascertain the presence of erectile dysfunction, whereas clinical questions are impractical (Derby et al. 2000a). This data collection methodology does introduce the possibility of information bias, probably toward underreporting. Differential underreporting by smoking status would bias estimates of the effects of smoking; however, the findings do prove insightful as to its probable significance within the general population. Furthermore, aspects of compromised sexual function are fundamentally issues of a subjective nature, wherein patient self-reporting may accurately serve as the main, or even the sole, criterion for establishing the existence and severity of the problem.

Case Series

Cigarette smoking has been linked to erectile dysfunction in several clinical reports, most qualifying as observational case series. As such, they are limited by not having true comparison groups, but they are reviewed here because they are often cited and data from more formal studies are limited. Wabrek and colleagues (1983) found that approximately 50 percent of 120 men referred for evaluation and management of erectile dysfunction to a hospital-based medical sexology program were smokers, counting users of cigarettes, cigars, or pipes. Virag and colleagues (1985) confirmed a 64 percent rate of cigarette smoking, defined as tobacco use exceeding 15 cigarettes per day for at least 15 years, among 440 men referred for clinical evaluation of erectile dysfunction. Bornman and Du Plessis (1986) similarly observed a 62 percent cigarette smoking rate, based on approximately 25 cigarettes per day for more than 20 years among 300 men screened at an andrology clinic. An attempt to provide comparative information was made by Condra and colleagues (1986), who studied 178 men with erectile dysfunction referred for clinical evaluation and found that 51.4 percent were current smokers and 81 percent were current or former cigarette smokers. These rates exceeded the 38.6 percent and 58.3 percent rates, respectively, ascertained in the general population using concurrent survey data. A recently published meta-analysis of smoking prevalence in men with erectile dysfunction also included a comparative assessment that controlled for age distribution, time period, and geographic location (Tengs and Osgood 2001). This meta-analysis, which consisted of 19 clinical studies published in the last 20 years with data on current smoking, revealed that 40 percent of the combined total of 3,819 men with erectile dysfunction were current smokers compared with 20 percent of men in the general population (Tengs and Osgood 2001).

Population-Based Studies

More valid appraisals of the effects of cigarette smoking on erectile dysfunction have been obtained through cross-sectional, random surveys of a sample population (Table 6.25). The Vietnam Experience Study of 1985–1986, which surveyed 4,462 U.S. Army Vietnam-era veterans aged 31 through 49 years, found erectile dysfunction prevalence rates of 2.2 percent among nonsmokers, 2.0 percent among former smokers, and 3.7 percent among current smokers (p = 0.005). The association (OR = 1.5 [95 percent CI, 1.0–2.2]) was maintained even after adjustments for comorbidity factors including vascular disease, psychiatric problems, hormonal factors, substance abuse, marital status, race, and age (Mannino et al. 1994).

Table 6.25

Cross-sectional studies on the association between smoking and the risk of erectile dysfunction (ED). 

Additional recent studies support the direct association between cigarette smoking and erectile dysfunction. A cross-sectional study assessing the prevalence of erectile dysfunction in 2,010 men aged over 18 years in Italy in 1996–1997 showed that smoking was associated with an increased risk of the condition (Parazzini et al. 2000). Although the study was controlled for multiple variables including age, marital status, SES, and chronic diseases, it found an increased risk of erectile dysfunction for current smokers (OR = 1.7 [95 percent CI, 1.2–2.4], p <0.05) and for former smokers (OR = 1.6 [95 percent CI, 1.1–2.3], p <0.05) in comparison with lifetime nonsmokers (Parazzini et al. 2000). The Krimpen Study, a community-based study conducted in Rotterdam, the Netherlands, between 1995 and 1998 that surveyed 1,688 men aged 50 to 78 years, also confirmed that smokers professed significant erectile dysfunction (adjusted OR = 1.6 [95 percent CI, 1.1–2.3], p <0.05) to a greater extent than non-smokers (Blanker et al. 2001). A cross-sectional study of erectile dysfunction prevalence conducted in Spain in 1998–1999, consisting of 2,476 men aged 25 to 75 years, demonstrated that cigarette smoking was significantly associated with erectile dysfunction (adjusted OR = 2.5 [95 percent CI, 1.64–3.80], p <0.05) (Martin-Morales et al. 2001).

Another recent study supports the direct association between cigarette smoking and erectile dysfunction (Bacon et al. 2001). The Health Professionals Follow-up Study, a prospective cohort study of heart disease and cancer among U.S. male health professionals (Rimm et al. 1991; Ascherio et al. 1996), surveyed 34,282 men aged 53 through 90 years in 2000. The study showed an increased probability of erectile dysfunction among current smokers compared with nonsmokers (OR = 1.3 [95 percent CI, 1.1–1.6], p<0.05), while controlling for age, marital status, and chronic diseases (Bacon et al. 2001).

Evidence against an independent association between cigarette smoking and erectile dysfunction comes from the baseline phase of the Massachusetts Male Aging Study, a community-based survey conducted from 1987–1989 of 1,290 men aged 40 through 70 years living in the Boston, Massachusetts, area (Feldman et al. 1994). The probabilities of complete erectile dysfunction were 11 percent in smokers and 9.3 percent in nonsmokers, including both former smokers and those who had never smoked (p >0.20) (Feldman et al. 1994). However, the longitudinal phase of the Massachusetts Male Aging Study, extending over a nine-year median interval, showed the comorbidity-adjusted rate of incident erectile dysfunction to be significantly higher among cigarette smokers (24 percent) than nonsmokers (14 percent) (OR = 1.97 [95 percent CI, 1.07–3.63], p = 0.03) (Feldman et al. 2000). The classification of erectile dysfunction was based on an algorithm derived by the discriminant analysis of 13 questions.

Kleinman and colleagues (2000) reanalyzed the baseline data from the Massachusetts study using new methods for classifying erectile dysfunction. One method corresponded to the approach used by Feldman and colleagues (2000), based on responses from men attending a urology clinic to an original questionnaire and to an additional global question for self-rating erectile dysfunction. Another analysis was based on responses to an expanded follow-up questionnaire. Cross-sectional analyses of predictors of erectile dysfunction were carried out in the 1987–1989 baseline data. With the clinic-based method for classification, current smoking was not associated with erectile dysfunction (OR = 0.95 [95 percent CI, 0.72–1.22]) while with the study-based method it was (OR = 1.39 [95 percent CI, 1.07–1.80]).

Disease Correlates

Type of Tobacco Exposure. The prospective analysis of the Massachusetts Male Aging Study examined various types of tobacco exposures to identify associations with erectile dysfunction. The odds of incident erectile dysfunction were more than doubled both for passive exposure to cigarette smoke, if present both at home and at work (adjusted OR = 2.07 [95 percent CI, 1.04–4.13]) (p = 0.04), and for cigar smoking (adjusted OR = 2.45 [95 percent CI, 1.09–5.50]) (p = 0.03). Passive exposure at home or at work alone did not increase the odds of incident erectile dysfunction in nonsmokers, but each increment of exposure did increase the estimated likelihood of erectile dysfunction in smokers (Feldman et al. 2000).

Dose-Response. The relationship between the amount of tobacco exposure and the extent of erectile dysfunction has been subjected preliminarily to epidemiologic analyses. Several population-based studies further explored the effects of measures of exposure on erectile dysfunction. The Vietnam Experience Study did not show any relationship between the number of cigarettes smoked daily or the number of years smoked and erectile dysfunction among currently smoking veterans (Mannino et al. 1994). Similarly, the baseline phase of the population-based Massachusetts Male Aging Study did not reveal any dependence of packs per day or lifetime pack-years smoked on reported erectile dysfunction among current smokers (Feldman et al. 1994). By contrast, an Italian cross-sectional study showed an increased erectile dysfunction risk with duration of the behavior, based on an OR of 1.6 (95 percent CI, 1.1–2.3) for men smoking 20 or more years and an OR of 1.2 (95 percent CI, 1.0–2.4) for men smoking less than 20 years (Parazzini et al. 2000).

Risk Factor Covariates and Effects of Medication. The combined effects (i.e., synergistic or additive interactions) of cigarette smoking and other risk factors in the development of erectile dysfunction have been analyzed. Goldstein and colleagues (1984) examined clinical characteristics in 19 potent patients who underwent pelvic irradiation for prostate cancer, finding that 14 out of 15 who displayed diminished erectile capacity were cigarette smokers, whereas only 1 out of 4 who preserved erectile capacity was a cigarette smoker. The strong association of cigarette smoking with erectile impairment in this study led the investigators to propose a synergistic role of smoking, and conceivably other vasculopathic risk factors, with the radiation effects associated with radiation-induced erectile dysfunction (Goldstein et al. 1984). In the baseline phase of the Massachusetts Male Aging Study, Feldman and colleagues (1994) found that cigarette smoking did not constitute an independent risk factor for erectile dysfunction; however, in that same study, the association of erectile dysfunction with certain risk factors was greatly amplified in current cigarette smokers. This amplification was demonstrated for persons having erectile dysfunction with treated heart disease (from 21 percent for current nonsmokers to 56 percent for current smokers), treated hypertension (from 8.5 to 20 percent), and untreated arthritis (from 9.4 to 20 percent), and for those persons receiving various medications including cardiac drugs (from 14 to 41 percent), antihypertensive medications (from 7.5 to 21 percent), and vasodilators (from 21 to 52 percent). Similarly, in an Italian cross-sectional study, smoking increased the adjusted ORs for erectile dysfunction associated with diabetes by 13 percent and with hypertension by 39 percent (Parazzini et al. 2000).

Effects of Smoking Cessation. The hypothesis that cigarette smoking adversely affects erectile function would seemingly be strengthened by epidemiologic evidence demonstrating that smoking cessation leads to erectile function recovery. Forsberg and colleagues (1979) presented the case reports of two cigarette smokers aged 20 and 27 years with erectile dysfunction whose erectile function returned in concordance with improved penile vascular testing results following smoking cessation. Elist and colleagues (1984) determined that 8 (40 percent) out of 20 men with erectile dysfunction who had smoked one to two packs of cigarettes per day for at least 15 years recovered functional erections after abstaining from cigarette smoking for six weeks. In this study, seven responders (35 percent) were confirmed by objective testing criteria to have recovered normal erectile activity from baseline abnormal levels.

Population-based reports add additional perspectives to the premise that modifying cigarette smoking behavior affects the occurrence of erectile dysfunction. One study in this regard is the Vietnam Experience Study of 1985–1986, which determined that the prevalence of erectile dysfunction among former smokers was comparable to that among nonsmokers, and the prevalence rates were significantly lower than those found in current smokers (Mannino et al. 1994). Similarly, the longitudinal phase of the Massachusetts Male Aging Study determined that incident erectile dysfunction was no more likely among former smokers than among nonsmokers, in contrast to current smokers (Feldman et al. 2000). Results from the Health Professionals Follow-up Study also suggest that former smokers carry a lower risk of erectile dysfunction than current smokers, although this risk for former smokers still exceeds that of nonsmokers (Bacon et al. 2001).

From these population-based study results, one might further conclude that the discontinuation of smoking results in a recovery of functional erection status. However, this simple conclusion is challenged by recent results from the prospective evaluation of men participating in the Massachusetts Male Aging Study who discontinued smoking during the almost nine-year follow-up period of this study. This latter analysis found that the covariate-adjusted incidence of erectile dysfunction was not significantly reduced after smoking discontinuation (p = 0.28). Important considerations of this investigation are that the men who quit smoking had begun smoking at an early age (mean age 16.6 years) and had accumulated a high lifetime exposure to tobacco smoke before quitting (mean pack-years 39.4). The data provide a refined understanding of the effects of cigarette smoking cessation on erectile dysfunction: smoking cessation in middle age after a significant lifetime exposure to cigarette smoke may fail to modify erectile dysfunction occurrence, because long-term vascular effects of smoking conceivably persist after smoking cessation (Derby et al. 2000b).

Clinical Data

This section examines the link between tobacco exposure and erectile dysfunction based on objective clinical criteria. The erectile dysfunction specialty has developed quantitative measurements that serve as indices of erectile function, including physiologic and anatomic descriptions of the physical state of the penis. Numerous investigations have applied these methodologies to ascertain the effects of cigarette smoking and other forms of tobacco use on penile erection.

Penile Tumescence Studies

Nocturnal penile tumescence (NPT) monitoring provides a noninvasive diagnostic technique to quantify erection physiology objectively during the naturally occurring cycle of sleep-related penile erections. These spontaneous episodes of tumescence normally accompany rapid eye movement (REM) sleep and are diminished in men with presumably organic erectile dysfunction (Karacan et al. 1978; Allen and Brendler 1992). Several early investigations of the objective basis for vasculogenic erectile dysfunction applied NPT monitoring. Elist and colleagues (1984) confirmed NPT-monitored abnormalities in 20 smokers with erectile dysfunction, among whom 7 (35 percent) displayed normal NPT-monitored results after six weeks of smoking cessation. Virag and colleagues (1985) determined that smokers comprised 72 percent of patients with abnormal NPT results but only 32 percent of patients with normal NPT results. In a study of 168 men who smoked one or more packs per day (heavy smokers) and 632 men who smoked less than one pack per day (light smokers), Karacan and colleagues (1988) found that sleep-related penile erection rigidity was significantly lower at each decade of life after 30 years of age in heavy smokers compared with light smokers, and the duration of maximal tumescence was significantly lower for heavy smokers aged less than 30 years and 51 through 60 years compared with age-equivalent light smokers. In an investigation of 314 smokers with erectile dysfunction, Hirshkowitz and colleagues (1992) confirmed a significant inverse correlation between sleep-related penile erection rigidity and the number of cigarettes smoked per day (r = ?0.12; p = 0.04). These investigators also showed that the duration of maximal tumescence was significantly shorter at the penile base (p ≤0.05), and the duration of detumescence (which refers to the decline from full erection to penile flaccidity) was also shorter (p = 0.06) among men who smoked 40 or more cigarettes per day compared with men who smoked 1 to 19 per day and 20 to 39 per day (p = 0.14).

Penile Vascular Hemodynamics

Impaired blood flow to the penis can be assessed using various measurement techniques. One widely used early technique to assess arterial vascular competence within the penis was the Doppler ultrasound of arterial pulsations in the flaccid, unstimulated organ. Although this method is no longer applied, the findings of these studies may still be relevant with respect to the pathogenesis of smoking-related vascular disease of the penis. With the values obtained, the penile-brachial index (PBI) can be calculated (the PBI refers to the ratio of penile to brachial systolic blood pressures). Reduced PBI values have been associated with impairment of the erectile process (Kempczinski 1979). Using this technique, Wabrek and colleagues (1983) did not find a significant association between cigarette smoking and abnormal PBI values. Virag and colleagues (1985) also did not find an independent smoking effect on PBI, although a synergistic effect was observed with smoking in combination with other arterial risk factors such as diabetes, hyperlipidemia, and hypertension. In contrast, Condra and colleagues (1986) demonstrated significantly lower PBI values among smokers than among nonsmokers. This same study also noted that the amount of time smoked correlated with abnormal PBI values: smokers with normal PBI values had smoked for a mean duration of 19.95 years while those with abnormal PBI values had smoked for a mean duration of 26.55 years. DePalma and colleagues (1987)likewise found that cigarette smoking carried a significantly higher probability of abnormal (49 percent) than normal (28 percent) vascular laboratory findings including PBI, which was not observed for age, hypertension, diabetes, or prior myocardial infarction. Hirshkowitz and colleagues (1992) confirmed consistent PBI reductions among 314 cigarette smokers with erectile dysfunction, finding significant correlations between the number of cigarettes smoked per day and the magnitude of these reductions for the left dorsal artery (r = ?0.14; p = 0.01) and right cavernosal artery (r = ?0.13; p = 0.03) of the penis.

The vascular evaluation of the penis has more recently employed a pharmacologic stimulus in combination with penile duplex ultrasonography to characterize the penile arteries. This application followed the discovery that a pharmacologic stimulus to induce an artificial erection provides an improved assessment of the physiologic responsiveness of these arteries over that provided during the resting state (Abber et al. 1986). Using this technique and applying a combined set of ultrasonographic parameters to establish normal vascular findings, Shabsigh and colleagues (1991) showed a consistent, nearly statistically significant difference in vascular impairment in smokers compared with nonsmokers. Kadio?lu and colleagues (1995) also observed that penile vascular parameters were abnormal to a greater extent among smokers than among nonsmokers, although the differences were not statistically significant.

In summary, PBI testing suggests deleterious effects of smoking on the “resting state” circulation of the penis, and sonographic evaluation of the penis following pharmacostimulation additionally demonstrates apparent deleterious effects of smoking on dynamic blood flow changes in the penis.

Penile Vascular Morphology

Arteriographic studies have been conducted in patients with erectile dysfunction to characterize the vascular anatomy of the penis. Investigations have been carried out among cigarette smokers to confirm the presence and location of arteriographic lesions. Virag and colleagues (1985) calculated a 67.8 percent rate of arteriographic abnormalities among patients in whom organic erectile dysfunction had been established by NPT monitoring, of whom 86 percent were smokers. Bähren and colleagues (1988) similarly showed that 82 percent of their patient group with arteriographically proven peripheral arteriosclerotic lesions were heavy smokers. In a study by Forsberg and colleagues (1989), men with erectile dysfunction underwent screening studies of penile blood flow to identify abnormalities. Using both pharmacostimulation and angiography in 17 men, this study found significant distal penile vessel lesions; 14 (82 percent) of the men were identified as smokers. Rosen and colleagues (1991) carried out a comprehensive evaluation of penile circulation in cigarette smokers with erectile dysfunction, finding that smoking represented a significant independent risk factor in the development of atherosclerotic lesions in the internal pudendal and common penile arteries. These investigators also determined that the number of pack-years smoked was independently associated with hemodynamically significant atherosclerotic disease in the hypogastric cavernous arterial bed supplying the penis (for each 10 pack-years smoked, RR = 1.31 [95 percent CI, 1.05– 1.64]).

Histopathology

The effects of cigarette smoking on erectile tissue were investigated by Mersdorf and colleagues (1991), who confirmed degenerative tissue changes (including a decrease in smooth muscle content, sinusoidal endothelium, nerve fibers, and capillaries, and an increase in collagen density) in erectile tissue of smokers. These tissue alterations are consistent with tissue alterations seen in other vascular diseases.

Experimental Data

This section reviews experiments carried out to test the effects of cigarette smoking on erectile function (Table 6.26). These experimental approaches controlled cigarette smoking exposures and provided the possibility for a rigorous evaluation of the consequences for erectile ability. The value of the information was enhanced when experiments involved robust scientific methodology (e.g., a random allocation of people to experimental and control groups, the use of different control groups, and the application of blinding procedures to reduce bias).

Table 6.26

Experimental studies on the association between smoking and erectile dysfunction. 

Human Studies

Perhaps the first reported study to experimentally evaluate the hypothesized association between cigarette smoking and erectile dysfunction was performed by Gilbert and colleagues (1986), who made polygraphic recordings of penile erection responses in smokers during the viewing of erotic videos. Several aspects of this study are noteworthy: (1) the study population consisted of 42 male self-reported heterosexual cigarette smokers in good health, aged 18 through 44 years; (2) participants were assigned to high-nicotine exposure (0.9 mg nicotine per cigarette smoked), low-nicotine exposure (0.002 mg nicotine per cigarette smoked), or control (sucking on a hard mint candy) groups randomly selected and unknown to the experimenter; (3) at enrollment, a counterdemand was issued to the effect that nicotine enhanced sexual potency, to militate against contaminating hypotheses held by the participants about the effects of smoking on erections; (4) smoking abstention was required for two hours before the experiment; (5) baseline erotic videos were shown for participant acclimation; and (6) concomitant measures of cardiovascular response were obtained. The study found that smoking two, but not one, high-nicotine cigarettes significantly decreased the rate of penile diameter increase compared with the other conditions during the erectile stimulus (p < 0.001). It also determined that high-nicotine cigarettes caused significantly more vasoconstriction and heart rate increase than did low-nicotine cigarettes, which did not differ from control conditions (p < 0.001).

In another experiment undertaken to assess the acute effects of cigarette smoking exposure on penile erection, Glina and colleagues (1988) studied the interference of smoking on vasoactive drug-induced erectile responses monitored by intracavernous pressure recording. Study design features were as follows: (1) 12 chronic cigarette smokers, aged 22 through 65 years, were enrolled; (2) subjectively reported erectile function status of the participants at enrollment was not stated; (3) smoking was prohibited on test days; (4) each participant underwent pharmacostimulation consisting of intracavernous injection of 100 mg pa-paverine hydrochloride at baseline (without smoking) and one week later immediately after nicotine exposure (smoking two cigarettes containing 1.3 mg nicotine per cigarette); and (5) intracavernous pressure measurements were performed 20 minutes following pharmacostimulation by the same experimenter. The study found that all men obtained an erection by clinical judgment at baseline compared with only four (33 percent) after smoking, corresponding to a significant decrease in mean intracavernous pressures from 85.83 mm Hg at baseline to 53.50 mm Hg after smoking. As part of an earlier, larger investigation of the use of pa-paverine injections to test diagnostically for erectile dysfunction, Abber and colleagues (1986) described a similar experiment involving a chronic smoker with erectile dysfunction who displayed an acutely worsened erectile response immediately following smoking a cigarette compared with his baseline results.

In a visual depiction of the effects of cigarette smoking on arterial flow to the penis, Levine and Gerber (1990) described their pelvic arteriographic study of a 38-year-old man with a 25 pack-per-year smoking history who presented for evaluation of erectile dysfunction. Whereas a complete baseline evaluation including pelvic arteriographic studies showed no abnormalities, repeat pelvic arteriography immediately after the patient smoked two cigarettes revealed a decrease in the caliber of the entire pudendal artery and nonvisualization of the deep penile artery. The investigators suggested that acute vasospasm was responsible for the observed effects.

Further experimental evidence of the deleterious effects of cigarette smoking on erectile function was recently documented in an acute smoking cessation study by Guay and associates (1998). Ten men, 32 to 62 years of age who had at least a current 30 pack-year smoking history and were smoking one pack of cigarettes or more per day, were enrolled in a study monitoring NPT and rigidity by a home RigiScan® technique. The study required monitoring of sleep-related penile erections on two successive nights, the first night following a usual day of smoking and the second night following discontinuation of smoking for one 24-hour interval. An additional component of the study involved repeat monitoring in four men who did not smoke for one month although they were administered transdermal nicotine patches (21 mg) during this time. The study results show that erectile parameters improved to a statistically significant degree in men who had stopped smoking for 24 hours, with further observed improvements in those not smoking and wearing nicotine patches for one month. The investigators concluded that eliminating cigarette smoking improves erectile function although factors contained in cigarette smoke other than nicotine primarily exert the damaging effects.

Animal Studies

Animal models have provided another useful approach for investigating the association between cigarette smoking and erectile dysfunction. The study by Juenemann and colleagues (1987) using an in vivo canine model represents a comprehensive, well-controlled investigation that combined stimulatory and monitoring techniques relevant to the physiology of erection. The methodology involved monitoring arterial inflow, intracavernous pressure, and venous outflow of the penis during cavernous nerve stimulation of erection alone, and with regulated penile perfusion before and after acute inhalation of cigarette smoke (1.4 mg nicotine per cigarette). Following smoking exposure (one to six cigarettes), compared with nonsmoking baseline conditions, peak arterial inflow was significantly diminished, peak intracavernous pressure was significantly diminished and could not be maintained, and venous outflow was not significantly restricted. Measurable serum nicotine and cotinine levels, obtained in the dogs following smoking exposure and used as markers, were consistent with concentrations found in human smokers, whereas no changes in arterial blood gases or systemic blood pressure were observed throughout the investigation. The investigators concluded that smoking exerts a localized deleterious effect on the neurovascular mechanisms required for penile erection, with a particular impairment of the veno-occlusive mechanism associated with maintenance of penile erections.

In a rat model, Xie and colleagues (1997) evaluated the long-term effects of cigarette smoking on penile erection. The methodology involved monitoring in vivo neurostimulated erections after exposing rats to a constant influx of cigarette smoke in an enclosed cage for a 60-minute session once per day, five days per week, for eight weeks. The investigation surprisingly found increases in intracavernous pressures in smoke-exposed rats compared with controls. However, the rats exposed to cigarette smoke also developed systemic hypertension. Intracavernous pressures standardized to systemic blood pressures in rats exposed to cigarette smoke did not differ from intracavernous pressures found in controls. The investigators explained their findings on the basis of tobacco smoke-associated vasoconstriction, and they conceded that vascular damage commonly associated with long-term cigarette smoking is inappreciable in the rat model, which is resistant to atherosclerosis.

Evidence Synthesis

Available evidence indicates that cigarette smoking constitutes a risk factor for erectile dysfunction. However, the causal basis for this relationship must be carefully evaluated. With regard to the consistency of the relationship, both case series and population-based studies evaluating rates of erectile dysfunction among smokers provide support. The population-based studies afford a more accurate observational basis for this assessment than do uncontrolled case series, although the paucity of these studies hampers reaching a definitive conclusion. The strength of the relationship also rests on limited available information, but is similarly supported by observational evidence showing that a variety of tobacco exposures (including active and passive cigarette smoking and cigar smoking) is associated with erectile dysfunction. Consideration of a dose-response relationship is supported by a few observational and experimental investigations that have shown an increased risk of erectile dysfunction associated with increased exposures to cigarette smoking. The temporality of the relationship seems likely, with a few observational studies showing some evidence of erectile dysfunction following exposure to tobacco smoke. Intriguingly, preliminary observational findings demonstrate that cigarette smoking cessation apparently leads to a recovery of erectile function only if the discontinuation occurs after a limited extent of lifetime smoking.

Coherence of the relationship is supported by several biologic studies that have proposed plausible mechanisms for the deleterious effects of cigarette smoking on erections. The acute deleterious effects of smoking on erectile function result at least in part from nicotine carried in cigarette smoke. The nicotine pharmacologically induces vasospasm of penile arteries, and hence alters the dynamics of local blood flow required for penile erection. The chronic deleterious effects of smoking on erectile function result from impaired vascular physiology of the erectile tissue, as evidenced by degenerative morphologic changes in tissue of smokers. Although the exact mechanism of the impairment remains unclear, early studies in animals point to damaging effects on tissue-dependent erection regulatory factors. In sum, several lines of evidence contribute toward the inference of a causal relationship between cigarette smoking and erectile dysfunction. However, because the scope of observational and experimental evidence remains limited and incomplete, it seems reasonable to consider the evidence to be suggestive but insufficient to establish a causal relationship at this time.

Conclusion

1. The evidence is suggestive but not sufficient to infer a causal relationship between smoking and erectile dysfunction.

Implications

The clinical studies and basic scientific research summarized in this section suggest a relationship between cigarette smoking and erectile dysfunction. A strong inference that smoking causes erectile dysfunction requires more evidence to confirm initial findings and to fill in gaps in the knowledge base. Additional observational studies of sufficient size and with well-validated outcome measures are needed. More basic scientific studies to identify biologic mechanisms for the deleterious effects of smoking on penile erections also are necessary. In the meantime, current knowledge about the problem still prompts recommendations for smoking cessation and avoidance to limit the risk of erectile dysfunction. Promoting nonsmoking to prevent erectile dysfunction seems clinically appropriate. There may be significant public health benefits by reducing morbidity rates of this increasingly recognized, widespread condition.

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Eye Diseases

Diseases of the visual system, and possible subsequent visual loss, represent substantial social and economic concerns to the U.S. public. In the last three decades, Gallup polls have consistently indicated that blindness is second only to mental incapacity as the disability Americans fear most (National Advisory Eye Council [NAEC] 1998). There is ample reason for concern. An estimated 3.4 million Americans aged 40 years and older have visual impairment and 1 million of these people are legally blind. Because most vision loss results from eye disease associated with advancing age, and the “baby boom” population in the United States is aging, the public health impact of this problem is projected to double by 2030 (Prevent Blindness America 2002).

The economic consequences of eye disease for the U.S. population are huge. For example, sight-restoring cataract surgery was the most frequently performed surgical procedure among Medicare beneficiaries, at an estimated annual cost of $3.4 billion in 1991 (Steinberg et al. 1993). Altogether, the economic impact of visual disabilities and disorders was estimated at more than $38.4 billion in 1995 (NAEC 1998). Thus, substantial contributions to the social and economic welfare of the public are possible by finding and controlling the causes of these eye diseases, particularly the factors that present the opportunity to prevent the disease or loss of sight.

Conclusions of Previous Surgeon General’s Reports

Epidemiologic investigation into risk factors for eye disease did not begin in earnest until the 1970s, bolstered by the establishment of the National Eye Institute (NEI) in 1968. Reports of the Surgeon General on smoking and health published before 2001 did not include eye disease as a topic simply because there were scant data indicating that smoking was related to ocular morbidity, although a compelling biologic basis did exist for postulating such associations. At least two of the three leading causes of visual loss worldwide, cataract and age-related macular degeneration (AMD), probably are due, at least in part, to smoking.

Cataract

Cataract is the leading cause of blindness worldwide and a leading cause of visual loss in the United States (Thylefors et al. 1995; Muñoz et al. 2000). Currently, the most common and effective means of restoring vision is through surgical removal of the opacified lens and insertion of an artificial lens into the eye. According to NEI, about 1.35 million cataract operations are performed annually in the United States for Medicare beneficiaries (NAEC 1998), at an estimated cost of $3.4 billion in 1991 (Steinberg et al. 1993). If risk factors that either delay the onset or slow the progression of cataracts could be identified, major socioeconomic gains would be realized. The research findings that link cigarette smoking to cataract, specifically nuclear cataract, have identified one of the few modifiable risk factors for cataract.

The ocular lens is a normally transparent organ having a purely optical function. The lens, situated behind the pupil, focuses radiant energy on the retina to produce an image, much like the lens of a camera. The shape of the lens changes, or accommodates, in response to the distance of the viewed object to focus a sharp image onto the retina.

The transparency of the lens is a function of its peculiar characteristics. The lens itself is composed of a central core, or nucleus, of inert, protein-filled, former epithelial cells. The interior proteins are highly structured to ensure transparency. The lens grows by the constant addition of protein-filled, elongated, former epithelial cells that have differentiated into lens fibers that do not have a nucleus or other organelles. Of interest in this process is that the lens contains every fiber cell ever incorporated into it, including cells formed in the embryo stage through those formed very recently. These cells must maintain transparency throughout the life of an individual to ensure visual clarity, yet this central core is metabolically inert and cannot renew itself. Thus, the central lens is severely restricted in its ability to repair damage. The outermost layer of the lens is composed of a layer of epithelial cells, which are responsible for most of the metabolic activity of the lens. These cells are the source of new cells, as the old cells differentiate into fiber cells and are displaced toward the nucleus. These newest lens fibers make up the lens cortex, which surrounds the nucleus.

The loss of lens transparency is termed lens opacity, and lens opacification becomes increasingly common with advancing age. When the opacity becomes sufficiently dense or extensive or both so as to interfere with vision, the lens opacity is called a cataract. There are three main types of lens opacity or cataract, which are distinct in terms of risk factors, location in the lens, and epidemiologic pattern: nuclear, cortical, and posterior subcapsular lens opacity (West and Valmadrid 1995). The different types of opacities also can occur together in the lens, resulting in a “mixed” opacity.

The frequency of each type of lens opacity in the population increases with age and varies by racial or ethnic group. In one population-based study of 2,520 older Americans (West et al. 1998), aged 65 to 69 years, 32 percent of whites had nuclear, 15 percent had cortical, and 8 percent had posterior subcapsular cataract in at least one eye; comparable figures for African Americans were 20 percent, 42 percent, and 4 percent, respectively. At least 4 percent of the study participants in that age group had undergone cataract surgery as well.

Biologic Basis

Several hypotheses have been advanced to explain a possible association of smoking and cataract. Given the plethora of aromatic compounds and trace metals in cigarette smoke that are capable of damaging lens proteins, it is difficult to know which mechanism is likely to be the most important. Harding (1995) has postulated that cadmium, lead, thiocyanate, and aldehydes from cigarette smoke lead to lens damage. Investigators analyzing blood and lenses from cataract surgery patients have shown significant accumulations of cadmium in the blood and lenses of smokers compared with lenses of nonsmokers, with cadmium in lenses proportional to the amount smoked (Ramakrishnan et al. 1995; Cekic 1998).

Harding (1991) also has suggested that the damage to the lens may be from thiocyanate, which can cause carbamylation of crystallins (lens proteins) and enzymes. Smokers do have elevated thiocyanate levels in their blood, but levels in lenses have not been measured.

Others suggest that smoking may cause cataract through an indirect route, by lowering antioxidants (Taylor et al. 1995). However, the role of antioxidants in protecting against cataractogenesis still is controversial. Few studies have determined the level of anti-oxidants in the lens and the relationship between lens levels and blood or serum levels. One of the better studied antioxidants is vitamin C, which appears to be concentrated in the lens, and ocular levels of vitamin C are sensitive to plasma levels of this vitamin (Taylor et al. 1997). A review of research linking vitamin C and cataract found studies that reported a protective effect of vitamin C, an increased risk with serum levels of vitamin C, and no association at all; the conflicting results do not provide evidence of an association (West and Valmadrid 1995). In one study, smokers compared with nonsmokers had lower serum values of vitamin C, and in another, both smokers and nonsmokers had similar blood and lens levels of vitamin C (Kallner et al. 1981; Ramakrishnan et al. 1995). At present, the antioxidant pathway for lens damage from smoking requires more corroborative research.

Epidemiologic Evidence

The relevant articles for this section on eye diseases were identified initially through a search in PubMed from 1966 through 2000 by using the following search terms: “lens opacity,” “cataract,” “lens,” “nuclear lens opacity,” “cortical lens opacity,” “posterior subcapsular lens opacity,” “age-related macular degeneration,” “senile macular degeneration,” “age related maculopathy,” “choroidal neovascularization,” “drusen,” “geographic atrophy,” “atrophic macular degeneration,” “diabetic retinopathy,” “diabetic eye disease,” “glaucoma,” “intraocular pressure,” “Graves’ ophthalmopathy,” “thyroidopathy,” “eye pathology,” and “eye disease.” These terms were searched with the Boolean operator “and” followed by the terms “cigarette,” “smoking,” and “tobacco” in appropriate combinations. All articles were reviewed, and their bibliographies were reviewed for relevant articles not captured by the search strategy. The final selection of articles for citation in this section was made in consideration of the adequacy of the research or review and the relevance to the topic. The selection of eye diseases for review was based on the public health importance of the disease and the availability of research relevant to an association with smoking.

Several key methodologic issues should be addressed in any research on risk factors for cataract. First, there are different types of cataract, with largely unique risk factors for each type. Early research on risk factors often did not differentiate cataract type, making interpretation difficult because the mix of cataract types was unknown. For example, a surgical series of cataract patients is likely to be heavily weighted for posterior subcapsular cataract, whereas a population-based series will have few posterior subcapsular cataract cases. Surgical notes, or ophthalmologist notes, of the cataract type may lead to misclassification, as only the major cataract type usually is recorded. Ideally, studies on cataractogenesis would use one of several reliable, valid grading schemes for documentation of the presence and severity of lens opacity types.

The second methodologic issue is that each type of lens opacity has a different impact on the visual system. Research that defines cataract to include a visual acuity criterion effectively excludes asymptomatic, early lens changes or may include substantial numbers of persons with lens opacity not yet affecting acuity in the control group. Such research is less desirable from an etiologic standpoint.

Finally, issues of bias and confounding must be addressed with any research. Selection bias in clinic-based, case-control studies of cataract can be problematic, because controls sometimes have eye problems that may share risk factors in common with cataract. In population-based studies, patients with bilateral cataract surgery often are excluded from the analyses, because the type of cataract or date of surgery may be unknown. If the risk factor of interest drives progression of cataract, the exclusion of bilateral surgical cases will result in an underestimation of the risk. Potential confounders for the relationship of smoking and nuclear or posterior subcapsular cataract include age, race, gender, steroid use, and possibly alcohol use.

Ten epidemiologic studies reviewed have found an association between smoking and nuclear opacity and four found an association between smoking and posterior subcapsular opacity (Table 6.27). The studies reporting an association between nuclear cataract and smoking were carried out in diverse populations using different methodologies and different lens grading systems (Flaye et al. 1989; West et al. 1989a, 1995; Leske et al. 1991, 1998; Christen et al. 1992; Hankinson et al. 1992; Klein et al. 1993b; Cumming and Mitchell 1997; Hiller et al. 1997). The association with smoking generally was consistent (with most RRs ranging between 2 and 3); a dose-response relationship with the amount smoked was found. Four prospective cohort studies have found an association with smoking at baseline and subsequent risk of developing new nuclear opacities, surgery for nuclear opacities, or progression of existing nuclear opacities (Christen et al. 1992; West et al. 1995; Hiller et al. 1997; Leske et al. 1998).

Table 6.27

Studies on the association between smoking and cataracts. 

Smoking has been less consistently associated with an increased risk of posterior subcapsular opacity. Two prospective cohort studies have found an increased risk, between 2.5- and 3-fold, associated with heavy smoking (smoking 20 or more cigarettes per day and smokers of 65 or more pack-years) (Christen et al. 1992; Hankinson et al. 1992). Two cross-sectional, population-based studies found a weaker association, and one reported an association only among men (Klein et al. 1993b; Cumming and Mitchell 1997). Two other population-based surveys did not find any association with posterior subcapsular cataract (Flaye et al. 1989; Hiller et al. 1997).

One limitation of population-based studies of risk factors for posterior subcapsular cataract is the rarity of that cataract type, making it difficult to acquire enough cases to precisely characterize risk. Another limitation is that posterior subcapsular cataract is highly visually disabling, and generally progresses quickly, so while it is overrepresented in surgical series it may be underrepresented in population-based studies because affected persons already have had cataract surgery (West et al. 1998). Thus, prospective cohort studies on posterior subcapsular cataract in populations are likely to provide more compelling data about the association.

The three studies that found no association between smoking and cataract deserve comment. The case-control study in India (Mohan et al. 1989) was hospital-based and relied on patients from one center. The possibility of selection bias, especially in terms of cases with vision loss and controls without vision loss and their COPDs, must be considered. The case-control study in Italy (Italian-American Cataract Study Group 1991) had a design similar to the study in India but used cases and controls from three clinics covering the population in Parma, Italy. This broader coverage reduced the possibility for selection bias. However, the recruitment rates of cases of posterior subcapsular cataract and nuclear cataract were lower than expected; the smoking data were not shown for this study, so an assessment of the power to detect an increased risk associated with smoking could not be done. The third study (Bochow et al. 1989), a case-control study of risk factors for posterior subcapsular cataract, did not evaluate the association of smoking with other cataract types. The controls included patients with nuclear cataract alone or with AMD, which may have increased the prevalence of smoking in the comparison group. Thus, the three studies that did not find an association between smoking and cataract have limitations that may have introduced bias toward the null.

There are no clinical trials of smoking cessation and determinations of either reduced risk of onset or progression of lens opacities. Six studies examined the risk in former smokers, and the data in general support a lower risk of progression or development of cataract after cessation. The mechanism is likely to be a reduction in the smoking-related dose of injurious agents to the lens rather than any reversal of the cataractogenic process. A cross-sectional survey looked in detail at time since smoking cessation and reported that cessation of 10 or more years reduces the risk of nuclear opacity (West et al. 1989a). In two large prospective cohort studies, former smokers at baseline had no increased risk of new nuclear opacities (Christen et al. 1992) or new cataract surgery (Hankinson et al. 1992). The 13-year follow-up study among male physicians of self-reported development of visually significant cataract found a lower risk among former smokers compared with current smokers (Christen et al. 2000). The prospective data are compatible with previous work showing that ongoing smoking drives progression. Other researchers who found similar risks for former smokers as for current smokers did not evaluate risk by years since cessation (Cumming and Mitchell 1997; Hiller et al. 1997). Studies of risk for cataract among smokers using low-yield cigarettes or low-tar products have not been reported.

Evidence Synthesis

Substantial evidence based on cross-sectional and prospective cohort studies now has accrued linking nuclear, and possibly posterior subcapsular, cataract to cigarette smoking. There is a dose-response relationship and evidence that former smokers have a lower risk of cataract and of progression of cataract compared with current smokers. On the basis of the epidemiologic studies, researchers now are investigating the mechanisms by which smoking may damage the lens, by using animal and lens cell culture models. The laboratory data are not yet sufficiently mature to inform the discussion of smoking and cataract, in part because there are few animal models of age-related cataract; most require an external insult to initiate the cataractogenic process. However, smokers are exposed to a number of agents that may cumulatively damage the lens, which lacks reparative capacity.

Conclusions

1. The evidence is sufficient to infer a causal relationship between smoking and nuclear cataract.

2. The evidence is suggestive but not sufficient to infer that smoking cessation reduces the risk of nuclear opacity.

Implications

There is moderate evidence to suggest that smoking also may be associated with an increased risk of posterior subcapsular opacities as well, but more research is needed before a causal association can be inferred for this cataract type. The difficulty the lens has in repairing damage suggests that opacification at the time of smoking cessation is likely to be irreversible. Studies of cataract in clinical trials of smoking cessation would provide more definitive evidence for any protective effect, although feasibility would be constrained by the need for large populations.

Age-Related Macular Degeneration

AMD is the leading cause of blindness in whites aged 65 years and older in the United States (Sommer et al. 1991; Muñoz et al. 2000). There currently is no well accepted treatment to prevent or halt the progression of atrophic AMD, the most common form of AMD. Treatment to halt vision loss from the less common, severe form of AMD, exudative (neovascular) AMD, often is short lived, as neovascularization (new blood vessel formation) often recurs. A recent large-scale clinical trial has provided evidence that antioxidant supplements plus zinc may delay the progression of some signs of AMD (Age-Related Eye Disease Study Research Group 2001). Otherwise, no preventive therapy for AMD is available, so considerable attention has focused on identifying risk factors for this disease.

The macula is a component of the retina at the center of the optical axis; it contains the fovea, a highly specialized area of the retina responsible for high-resolution vision. The retina consists of neural tissues, including the photoreceptors that convert energy from visible light into electrical signals sent on to the brain for processing. The photoreceptors—rods and cones— have high metabolic requirements and replace their outer segments daily. The metabolic functions of the retina are supported by the retinal pigment epithelium, which phagocytizes an estimated 2,000 outer segment membranes daily. This high rate of activity is made possible by the exchange of nutrients (and removal of waste) through the retinal blood supply, the choriocapillaris. There is a blood retinal barrier to this exchange, which is formed by both the retinal pigment epithelium and its anchor, Bruch’s membrane (lamina basalis choroideae). Thus, the complex of the retinal pigment epithelium, Bruch’s membrane, and the choriocapillaris serve as the nutritional source for the sensory retina. Changes in each of the tissues in this complex have been hypothesized to result in AMD. However, the pathogenesis of AMD, indeed the differentiation of changes in early AMD from those of normal aging, is uncertain (Sarks and Sarks 1994).

AMD is an umbrella designation for a variety of degenerative changes in the macula. The degeneration is characterized in its early stages by pigmentary disturbances and atrophic changes. The late stages of AMD are characterized by widespread atrophy of the retinal pigment epithelium, loss of photoreceptors (atrophic AMD), and, less commonly, exudative AMD. With exudative AMD, new, unstable blood vessels develop in the choroid and grow under or through the retinal pigment epithelium via breaks in Bruch’s membrane. Leakage from these neovascular membranes may lead to detachment of the retinal pigment epithelium, hemorrhage, and formation of a disciform scar. The late stages are associated with vision loss, classically loss of central vision, the part of vision responsible for activities such as reading and close work.

Morphologic changes associated with AMD include basal laminar deposits at the level of the retinal pigment epithelium, thickening of Bruch’s membrane, and drusen. Drusen are deposits of extracellular material thought to be accumulations or “garbage bags” of waste products from the retinal pigment epithelium. At least two types of drusen are recognized clinically on the basis of their appearance: small, hard drusen, which are a common feature of aging; and larger, soft drusen, which also are common with aging but are a likely risk factor for developing severe AMD. The presence of drusen in the fundus, thought to be the hallmark of early AMD, is being challenged as a marker by observations that drusen can appear and disappear over time (Bressler et al. 1995; Klein et al. 1997), that most people with large, soft drusen do not develop advanced AMD (Klein et al. 1997), and that epidemiologic patterns associated with advanced AMD are different from those for drusen-defined early AMD. This debate has relevance in evaluating the evidence for an association of smoking and early versus advanced AMD.

Biologic Basis

Of the postulated mechanisms underlying the retinal changes in AMD, three have bearing on the hypothesis that smoking is associated with AMD. The first can be characterized as oxidative stress leading to changes in the ability of the retinal pigment epithelium to phagocytize cellular products, which in turn leads to accumulations of debris that interfere with the nutrient exchange between the retinal pigment epithelium and the choriocapillaris. Oxidative stress can result from free-radical damage to proteins, lipids, and possibly, mitochondrial DNA. The stress is considered to contribute to malfunctions of the retinal pigment epithelium. The macula is a particularly likely target for oxidative stress because of the macula’s high exposure to light, high metabolic rate, and high concentrations of fatty acids. But the macula also is very rich in antioxidative, protective mechanisms, including an array of antioxidant nutrients and enzymes, as well as melanin. Smoking, through its actions on reducing plasma levels of antioxidants in addition to reducing macular pigment, is hypothesized to increase the oxidative stress on the macula by robbing it of its defenses (Hammond et al. 1996).

The second hypothesis for the pathogenesis of AMD proposes that the degradation of Bruch’s membrane, as manifested by thickening and changes in the composition, leads to interference with nutrient exchange between the retinal pigment epithelium and its blood supply. Vascular endothelial growth factor (VEGF) has been reported in the retinal pigment epithelium cells; these cells may liberate VEGF in response to the interference in nutrient exchange. Investigators are working on the role of VEGF, released in connection with hypoxia, in the pathogenesis of AMD, particularly for the neovascular type (Mousa et al. 1999). Smoking has been associated with an increase in plasma immunoreactive VEGF, at least acutely, operating likely through its ability to cause tissue hypoxia (Wasada et al. 1998).

The third hypothesis for the pathogenesis, or at least a possible contributing cause, of AMD is vascular insufficiency. Changes in the choroidal circulation may impair the ability of the retinal pigment epithelium to dispose of waste substances, leading to the accumulation of waste material. The rate and volume of blood flow through the choriocapillaris are high in response to the demands of the pigmented epithelium and the photoreceptors. Smoking has been shown to alter choroidal blood flow (Bettman et al. 1958). Smoking also affects the vasculature through platelet adhesions and hypoxia from elevated levels of carboxy-hemoglobin, which might add to the stimulation of new vessel growth.

It is likely that multiple pathways are responsible for the degenerative changes in the macula with age, and a reasonable basis exists for presuming that smoking may operate through one or more of these pathways.

Epidemiologic Evidence

Two methodologic issues add to the complexity of assessing the relationship between AMD and smoking. The first issue is that advanced, or severe, AMD mostly occurs in the very old. About 7 percent of the white population aged 75 years and older will have advanced AMD (Klein et al. 1992). The second issue is that life expectancy of smokers is less than that of non-smokers, so selective survival of smokers to even develop AMD is an issue. Together, the relatively low incidence of AMD and the low prevalence of smoking in very elderly populations diminish the power to detect associations in all but the largest studies, which is evident in the population-based studies of AMD that have low numbers of cases of severe AMD.

One way to circumvent the problem is to study the association of smoking in precursor lesions or early AMD; however, there is no uniform agreement on the clinical signs of early AMD. Many of the signs currently in use are common in the population and can be so unstable as to be almost uninformative about who will develop advanced AMD. Data are accumulating on predictors of advanced AMD, the presence of very large drusen, and the retinal area covered by drusen. In part, the difficulty of determining the relevant early signs may be due to the limitations of photographic systems to detect such changes in, for example, Bruch’s membrane; for research purposes, however, no alternative detection systems are available for accurately detecting early changes.

With these caveats in mind, the research findings to date suggest a strong likelihood that smoking is related to advanced or severe AMD, particularly exudative AMD, but there is scant evidence that smoking is related to the apparent early signs of AMD (Table 6.28). One cross-sectional, population-based study (Smith et al. 1996) found increased odds of early AMD among smokers compared with nonsmokers (OR = 1.89 [95 percent CI, 1.25–2.84]). However, two others, using identical grading methods, found no increased odds (Klein et al. 1993c; Delcourt et al. 1998). In another cross-sectional survey of fishermen who were heavy smokers, a paradoxical protective effect was seen for smoking and the odds of early AMD, primarily cases of moderate drusen (West et al. 1989b). A prospective cohort study of the risk of developing early signs of AMD found an increased risk of developing large (>250 ?m) drusen among smokers compared with lifetime nonsmokers; the RR was 3.21 (95 percent CI, 1.09–9.45) among men and 2.20 (95 percent CI, 1.04– 4.66) among women. No other early sign was associated with smoking (Klein et al. 1998). The lack of association with presumed early AMD may be due to the imprecision of the signs chosen to represent early AMD, thus biasing the results toward the null. Further work on improving this classification is warranted. It is also possible that smoking is related to progression of AMD to the exudative form but not to the onset of early lesions.

Table 6.28

Studies on the association between smoking and age-related macular degeneration (AMD). 

Gender differences appear in the findings as well. In one case-control study of severe AMD, the relationship with smoking was observed in men only (Hyman et al. 1983). In one prospective cohort study in a population having primarily early AMD, progression of AMD among smokers was observed with a dose-response pattern only among men (Klein et al. 1998). A prospective cohort study of exudative AMD among men found a benefit of quitting smoking after 20 years of cessation (Christen et al. 1996), but a similar study among women found no benefit after 15 or more years of cessation (Seddon et al. 1996). There are not evident explanations for these differences, except that the significantly lower prevalences of smoking among women may reduce the power to detect associations with AMD, especially if heavy smoking is the risk-determining factor.

The strongest and most consistent association seen in the literature is the association of current smoking and risk of severe AMD, especially exudative AMD. Because several studies tended to combine atrophic and exudative AMD into “late” or “severe” AMD, it is difficult to know whether to attribute the association to either one or both, unless specified. Four case-control studies have been reported to date. A large case-control study of exudative disease (Eye Disease Case-Control Study Group 1992) found an increased ORwith current and past smoking of 2.2 (95 percent CI, 1.4–3.5) and 1.5 (95 percent CI, 1.2–2.1), respectively. Three other case-control studies also found an increased risk for severe AMD in smokers, with estimated ORs between 2 and 3 (Hyman et al. 1983; Macular Photocoagulation Study Group 1986; Tamakoshi et al. 1997). Four cross-sectional, population studies found increased odds of exudative AMD among current smokers, with ORs between 1.5 and 3.6; two of the four studies found a dose-response relationship. Two of the four cross-sectional studies found increased odds of atrophic AMD with current smoking (Vinding et al. 1992; Smith et al. 1996), but the other two did not (Klein et al. 1993c; Vingerling et al. 1996). Two prospective studies found a significant association with either exudative disease or severe AMD in current heavy smokers (20 or more cigarettes per day) (Christen et al. 1996; Seddon et al. 1996). Former smokers also had an increased risk of AMD, although lower than that for current heavy smokers. Quitting more than 20 years previously appeared to decrease the risk in two cross-sectional studies (Vingerling et al. 1996; Delcourt et al. 1998), as well as in a prospective cohort study in men (Christen et al. 1996). In the prospective study in women (Seddon et al. 1996), however, quitting 15 or more years prior did not decrease the risk of severe AMD.

The data from cross-sectional studies suggest that passive smoking is not related to early or late AMD (Klein et al. 1993c; Smith et al. 1996). There are no corroborating data from animal models. Although animal models of induced retinal damage exist, no good animal models present the spectrum of features of AMD.

Evidence Synthesis

These data provide evidence that current smoking is associated with exudative AMD and possibly atrophic AMD. Dose-response relationships with the amount of smoking have been described. Maintaining smoking cessation at least 20 years decreased the risk of severe AMD and exudative AMD. The possibility that smoking is associated with the neovascular form of AMD is further bolstered by the findings from a study of ocular histoplasmosis (Ganley 1973), where neovascularization can result from the infection. In that study, smokers were twice as likely as nonsmokers to develop disciform scars. Moreover, in a clinical trial of photocoagulation to halt progression of neovascularization, smokers were more likely than nonsmokers to have recurrent neovascularization over time (Macular Photocoagulation Study Group 1986). However, smoking did not predict development of neovascularization in the previously unaffected companion eyes of the eyes with neovascularization (Macular Photocoagulation Study Group 1997).

Conclusions

1. The evidence is suggestive but not sufficient to infer a causal relationship between current and past smoking, especially heavy smoking, with risk of exudative (neovascular) age-related macular degeneration.

2. The evidence is suggestive but not sufficient to infer a causal relationship between smoking and atrophic age-related macular degeneration.

Implications

There is a need for more research into gender differences, dose-response relationships, and a possible threshold effect. Further research is also needed to determine the effect of smoking cessation on the risk of neovascular AMD.

Diabetic Retinopathy

Diabetic retinopathy is a serious ocular complication of diabetes associated primarily with long-term duration of diabetes and poor control in both type 1 and type 2 diseases. The retinopathy is likely the result of vascular changes occurring in the retinal circulation that feeds the inner layers of the retina. Diabetic retinopathy in the early stages (mild, non-proliferative retinopathy) is characterized by excessive permeability of the vasculature, with ballooning of the retinal capillaries to form microaneurysms, dot hemorrhages, and hard and soft exudates. Preproliferative retinopathy includes, in addition to the aforementioned features, vascular occlusion and dilation and/or venous beading. Proliferative diabetic retinopathy is characterized by new vessel growth or fibrous proliferation or both. Vitreous hemorrhage secondary to the neovascularization also may be seen. Clinically significant macular edema, the result of extensive vessel leakage, can be a feature of chronic diabetic eye disease that may occur at any stage of the process. The prevalence of diabetic retinopathy increases with duration of diabetes, and most persons with diabetes have signs after 10 years’ duration. Moreover, diabetic retinopathy is an important cause of vision loss. Although photocoagulation is an effective means of treating proliferative diabetic retinopathy, too often the retinopathy is not diagnosed at an early stage when treatment can be maximally effective.

Biologic Basis

Several investigators have postulated that smoking may contribute to the onset of diabetic retinopathy and/or drive progression of existing retinopathy through its effect on the retinal circulation (Morgado et al. 1994). If such relationships exist, one mechanism of action is likely to be hypoxia from chronic exposure to carbon monoxide, which may be toxic to retinal vasculature. Carbon monoxide also is associated with separation of arterial endothelial cells, causing edema, which also is a feature of diabetic retinopathy. Nicotine exposure increases levels of plasma vasoconstrictors, such as angiotensin and vasopressin, which have binding sites on retinal blood vessels. In addition, nicotine exposure increases platelet adhesiveness, and persons with diabetic retinopathy are more likely to have increased platelet aggregation compared with persons with diabetes but without retinopathy. Although there is a reasonable biologic basis to the hypothesis that smoking is related to diabetic retinopathy, the data suggest otherwise.

Epidemiologic Evidence

Many studies have examined the association between smoking and diabetic retinopathy (Table 6.29), and the data from several studies do not support the proposed association. The well-controlled studies, including prospective cohort studies in large populations of persons with diabetes, found no association between smoking and the amount smoked and the prevalence, incidence, or progression of diabetic retinopathy (Klein et al. 1983; Moss et al. 1991, 1996). Studies that found an association in general did not adjust for level of control of diabetes, a major risk factor for diabetic retinopathy. One study did adjust for level of control and other risk factors and found an association between smoking and a six-year progression of diabetic retinopathy (Mühlhauser et al. 1996). However, progression was defined as any progression, from onset of diabetic retinopathy to becoming blind, if proliferative diabetic retinopathy was present at baseline. There were no data shown on whether smokers tended to have worse retinopathy at baseline, but the analyses should have adjusted for baseline status of diabetic retinopathy as a risk factor for progression. When the progression was confined to the subgroup with no retinopathy at baseline, smoking was not significantly associated with either the incidence or progression of diabetic retinopathy.

Table 6.29

Studies on the association between smoking and diabetic retinopathy (DR). 

Evidence Synthesis

Although smoking might plausibly worsen diabetic retinopathy, the evidence is inconsistent. The strongest studies, the prospective cohort studies, do not show an association. The level of diabetes control is a potential major confounder that has not been considered in a number of the studies.

Conclusion

1. The evidence is suggestive of no causal relationship between smoking and the onset or progression of retinopathy in persons with diabetes.

Implication

As research on diabetes continues, possible effects of smoking should be reassessed.

Glaucoma

Glaucoma is the third leading cause of blindness worldwide (Thylefors et al. 1995). In the United States, African Americans and Hispanics are more affected than other groups. Glaucoma is a disease characterized by loss of retinal ganglion cells, probably through a variety of mechanisms. The two main types of primary glaucoma are primary open-angle glaucoma and angle closure glaucoma. The angle refers to the angle between the iris and trabecular meshwork in the anterior chamber, which if shallow or closed impedes outflow of aqueous fluid and causes a rise in pressure. There are distinct differences between the two types of glaucoma, and their distribution differs in populations. In the United States, primary open-angle glaucoma is the more common type.

Biologic Basis

There is no evident basis for proposing that smoking might predispose a person to either developing glaucoma or having more severe glaucoma. Investigators have proposed that factors that diminish perfusion of the optic nerve head with blood may be associated with glaucoma. Because smoking affects the retinal circulation (although any direct effect of smoking on the optic nerve head is unknown), several investigators have examined the association of glaucoma with smoking. However, the effects of smoking on blood flow in ocular circulation are difficult to measure, in part because studies often do not consider separating acute effects in smokers and nonsmokers from the chronic effects that result from repeated exposures. The role of smoking in altering intraocular pressure also is variable. In one study (Shephard et al. 1978), smoking (including cumulative consumption) was not associated with intraocular pressure differences.

Evidence Synthesis

The few epidemiologic studies conducted (Table 6.30) do not indicate any relationship between smoking and glaucoma. Three cross-sectional studies found no association between smoking and glaucoma (Klein et al. 1993a; Ponte et al. 1994; Leske et al. 1995), and one prospective cohort study found no increased risk of glaucomatous field loss among persons with ocular hypertension who smoked compared with those who did not smoke (Quigley et al. 1994). The association has not been evaluated in angle closure glaucoma, but there is little biologic basis for proposing such a relationship.

Table 6.30

Studies on the association between smoking and glaucoma. 

Conclusion

1. The evidence is inadequate to infer the presence or absence of a causal relationship between smoking and glaucoma.

Implication

As further studies of glaucoma are undertaken, the role of smoking should remain under investigation.

Other Eye Diseases: Graves’ Ophthalmopathy

Several other eye diseases have been investigated for an association with smoking. Most were not reviewed for this report, however, because the data are insufficient to reach any conclusions. The one exception is an uncommon condition—Graves’ ophthalmopathy, an ocular complication of Graves’ disease.

Graves’ disease is thought to be an autoimmune disease of the thyroid. It is likely that both genetic and environmental factors are related to the risk of the disease. Among its clinical manifestations, the ophthalmologic complications appear to be related to smoking. Graves’ ophthalmopathy is characterized by proptosis (protrusion of the eyeball), diplopia (double vision), optic neuropathy, and conjunctival and peri-orbital inflammation. The pathogenesis of Graves’ ophthalmopathy is not completely understood, but it appears to involve the orbital fibroblasts that are stimulated to release glycosaminoglycans, which in turn are related to the orbital edema seen with the ocular complications. Recent data suggest an autoimmune basis for Graves’ ophthalmopathy as well (Bahn 2000).

Biologic Basis

The mechanism by which smoking may cause or aggravate Graves’ ophthalmopathy is unknown. Orbital hypoxia and effects of thiocyanate have been postulated, and other research has investigated the effect of smoke constituents on orbital fibroblast activity. Researchers investigating the role of hypoxia in muscular inflammation have found stimulation of protein synthesis and proliferation of extra-ocular, muscle-derived fibroblasts under hypoxic conditions (Metcalfe and Weetman 1994). Smoking does not appear to affect serum concentrations of proinflammatory cytokines in Graves’ disease, even among persons with ocular complications (Salvi et al. 2000).

Epidemiologic Evidence

Seven studies (Table 6.31) found an increased risk associated with smoking of developing the ophthalmologic complications of Graves’ disease (Hägg and Asplund 1987; Shine et al. 1990; Tellez et al. 1992; Prummel and Wiersinga 1993; Winsa et al. 1993; Pfeilschifter and Ziegler 1996; Bartalena et al. 1998); three found a dose-response relationship with the number of cigarettes smoked (Shine et al. 1990; Tellez et al. 1992; Pfeilschifter and Ziegler 1996). The studies, while consistent, are limited in number and the sample sizes of some are small. The severity of the ophthalmopathy was associated with smoking in two studies (Prummel and Wiersinga 1993; Winsa et al. 1993). Estimates of the OR varied between 2 and 10, depending on the control population selected. The effect of quitting smoking on Graves’ ophthalmopa-thy has not been well studied and would provide convincing evidence of a causal relationship. On the basis of the findings of the epidemiologic studies, several investigators are studying the effect of smoking on the thyroid gland and the extra-ocular, muscle-derived fibroblasts.

Table 6.31

Studies on the association between smoking and Graves’ ophthalmopathy. 

Evidence Synthesis

Although there are suggestive epidemiologic findings, the biologic basis for a role of smoking in Graves’ ophthalmopathy is unclear. The epidemiologic data are still limited, although consistent in indicating an increased risk in smokers. Dose-response is not well documented.

Conclusion

1. The evidence is suggestive but not sufficient to infer a causal relationship between ophthalmopa-thy associated with Graves’ disease and smoking.

Implication

Data on the role of smoking cessation in preventing or lessening the severity of the ophthalmopathy would be important to understanding the relationship between Graves’ disease and smoking.

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Peptic Ulcer Disease

In the early 1990s, the central role played by the bacterium Helicobacter pylori (H. pylori) in both the incidence and recurrence of peptic ulcer disease was recognized (Kuipers et al. 1995). This section reviews the evidence of an association between smoking and peptic ulcer disease in light of this new understanding of the pathogenesis of ulcer disease. Relevant articles were identified through a MEDLINE search from 1985 through June 2000 using the following terms: “ulcer and smoking and pylori” and “smoking and pylori and eradication.” A further search was performed for the years 1998 through June 2000, using the terms “ulcer and smoking” to identify any major studies that were not included in the previous Surgeon General’s report (USDHHS 2001), even though the studies had not evaluated H. pylori.

Conclusions of Previous Surgeon General’s Reports

Numerous studies have demonstrated an association between smoking and the occurrence of peptic ulcer disease. This evidence was reviewed in the 1964, 1971, and 1972 Surgeon General’s reports on smoking and health (USDHEW 1964, 1971, 1972). The 1979 report concluded that cigarette smoking was significantly associated with both the incidence and an increased risk of dying from peptic ulcer disease: “the association between smoking and peptic ulcer disease is significant enough to suggest a causal relationship” (USDHEW 1979, p. 1–23). In addition, that report concluded that there was highly suggestive evidence that smoking also retards ulcer healing. The 1990 report concluded that smokers had an increased risk of developing both duodenal and gastric ulcers, and smoking cessation reduced that risk (USDHHS 1990). That report also found that among smokers ulcer disease was more severe, duodenal ulcers were less likely to heal, and both duodenal and gastric ulcers were more likely to recur. Ulcer patients who stopped smoking, however, were found to have an improved clinical course compared with continuing smokers. Although much of this previous evidence was based largely on studies of men, the more recent Surgeon General’s report on women and smoking (USDHHS 2001) concluded that women who smoked also had an increased risk of peptic ulcer disease.

Biologic Basis

In the decades since the 1964 Surgeon General’s report, explanations of the pathogenesis of peptic ulcer disease have changed dramatically with the identification of the gastric bacterium H. pylori in a high proportion of patients with peptic ulcers (Marshall and Warren 1984). Up to 100 percent of duodenal ulcers and 70 to 90 percent of gastric ulcers are now associated with H. pylori infection (Kuipers et al. 1995). Most ulcers in persons without H. pylori infection were linked to the use of nonsteroidal anti-inflammatory drugs (NSAIDs) (Borody et al. 1991, 1992a). Other causes of peptic ulcers, although rarer, include Crohn’s disease and Zollinger-Ellison syndrome.

Normally, the gastrointestinal mucosa is protected from injury by, among other factors, a layer of mucus and the secretion of bicarbonate by gastric and duodenal epithelial cells to neutralize gastric acid. If these protective mechanisms are impaired, or if there is an increase in levels of damaging factors, then ulceration may occur.

Effects of Smoking on Gastrointestinal Physiology

The 1990 Surgeon General’s report (USDHHS 1990) reviewed the effects of cigarette smoking on aspects of human gastrointestinal physiology relevant to peptic ulcer disease. Likely mechanisms whereby smoking could promote the development of peptic ulcer disease included the potential for tobacco smoke and/or nicotine to increase maximal gastric acid output and duodenogastric reflux and to decrease alkaline pancreatic secretion and prostaglandin synthesis.

Two subsequent reviews (Endoh and Leung 1994; Eastwood 1997) evaluating the potential effects of cigarette smoke and nicotine as injurious and protective factors that could play a role in peptic ulcer formation came to similar conclusions. Data on the effects of smoking on gastric acid secretion in humans have been highly inconsistent; multiple reports found that smoking and/or nicotine variously stimulated, inhibited, or had no effect on gastric acid secretion. However, there was more consistent evidence that smoking promotes reflux of duodenal contents into the stomach, and increases production of free radicals and the release of vasopressin, a potent vasoconstrictor. Protective mechanisms consistently affected by smoking were the chronic inhibition of gastric mucus secretion, cytoprotective prostaglandin production, pancreatic and duodenal mucosal bicarbonate secretion, and a decrease in mucosal blood flow.

The mucosal protection mechanism most clearly affected by smoking is the pancreatic secretion of bicarbonate. A transient reduction in secretion is seen immediately after smoking, leading to a drop in pH in the duodenal bulb (Eastwood 1997). Acidity in the duodenal bulb appears to be the most important determinant for the development of gastric metaplasia in the duodenum, thus paving the way for duodenal colonization by H. pylori(Tytgat et al. 1993).

Results from studies evaluating mucosal blood flow among smokers and nonsmokers have been more varied, possibly because of a variation in the measurement methods. Taha and colleagues (1993) demonstrated that both gastric and duodenal mucosal blood flow were reduced in chronic NSAIDusers. However, after allowing for NSAID use, significantly reduced duodenal blood flow was seen only in H. pylori-positive smokers. There was no additional effect of either H. pylori infection or smoking on gastric mucosal blood flow.

Finally, some strains of H. pylori produce a vacuolating toxin that may be important in determining the virulence of the organism. This toxin induces vacuolation of HeLa cells in vitro, as does nicotine alone, but the addition of nicotine to H. pylori potentiates the vacuolating effect of the toxin (Cover et al. 1992).

In summary, studies document that smoking appears to have a multitude of effects on gastroduodenal physiology, and through a number of mechanisms it could promote peptic ulceration. These effects are, however, largely transient, and the affected physiologic measures return to normal within minutes or hours after smoking cessation (Eastwood 1997). These same studies also indicate that smoking could particularly increase the likelihood of ulceration in H. pylori-positive persons.

Smoking and Helicobacter pylori Infection

Both H. pylori infection (Malaty et al. 1992; EUROGAST Study Group 1993) and smoking (Bergen and Caporaso 1999) are more common among groups of lower SES. Cross-sectional studies that have evaluated the association between H. pylori infection and smoking in healthy volunteers consistently have reported higher infection rates in smokers (current or former) than in nonsmokers. In a study of 485 volunteers in the United States, current and former smokers were more likely to be seropositive for H. pylori than nonsmokers (among blacks, rates were 73 percent among current smokers, 85 percent among former smokers, and 61 percent among nonsmokers; and among whites, rates were 40 percent, 48 percent, and 25 percent, respectively) (Graham et al. 1991). Infection also was slightly more common among 3,496 adult smokers in Northern Ireland (65 percent among former smokers, 57 percent among smokers of fewer than 20 cigarettes, and 64 percent among smokers of 20 or more cigarettes per day compared with 53 percent among people who had never smoked) (Murray et al. 1997). Similar findings were seen in a group of 273 adults from Melbourne, Australia, among current and former smokers (45 percent and 44 percent, respectively, compared with 31 percent in people who had never smoked) (Lin et al. 1998) and among 1,064 adult heavy smokers in New Zealand (38 percent in smokers of more than 20 cigarettes per day compared with 23 percent in smokers of less than 20 cigarettes per day and nonsmokers) (Collett et al. 1999). Similar patterns have been reported in adults visiting general practitioners in Germany (Brenner et al. 1997) and in patients receiving an endoscopic examination in the United Kingdom (Bateson 1993) and Malaysia (Goh 1997).

In some of these studies, the association between H. pylori and smoking was attenuated after adjusting for other factors, including age and SES. In both developed and developing countries, H. pylori infection is believed to occur during childhood (Xia and Talley 1997), and thus it is unlikely that smoking influences the risk of initial H. pylori infection to any great extent. It is unclear whether smoking could be a risk factor for the acquisition or persistence of H. pylori infection in adulthood or if low SES is a common, more distal risk factor for both H. pylori and smoking. These variables do not, however, alter the fact that smokers are more likely than nonsmokers to be infected with H. pylori. The link between H. pylori and peptic ulcer disease is well established; thus, it is important to consider whether smoking also is a risk factor or if some or all of the observed associations between smoking and peptic ulcer disease could be due to confounding by H. pylori infection status.

Trends in Peptic Ulcer Disease

During the past several decades, rates of hospitalization for and mortality from peptic ulcer disease in the United States have declined dramatically. Using hospitalization rates from the computerized database of the U.S. Department of Veterans Affairs, El-Serag and Sonnenberg (1998) showed that although gastric ulcers accounted for 67.6 and duodenal ulcers for 168.8 out of every 10,000 hospitalizations of veterans from 1970–1974, comparable figures for 1990–1995 were 49.6 per 10,000 and 52.5 per 10,000, respectively. Similarly, using vital statistics data from CDC’s National Center for Health Statistics, these two authors showed that mortality from gastric ulcer disease had fallen from 17.4 per million per year in 1968–1972 to 7.7 per million per year in 1988–1992, with a comparable drop in mortality for duodenal ulcer disease from 19.6 to 8.4 per million per year (El-Serag and Sonnenberg 1998). However, peptic ulcer disease still is a leading cause of morbidity. In 1989, the National Health Interview Survey included a special questionnaire on digestive diseases. Among approximately 42,000 adult respondents, 10 percent reported that they had ever had a physician-diagnosed peptic ulcer, one-third of whom also reported having a new or recurring ulcer in the past 12 months (Sonnenberg and Everhart 1996). Among the 50 percent who reported the site of their ulcer, gastric and duodenal ulcers were equally common overall, although nonwhites reported gastric ulcers more frequently and duodenal ulcers less frequently than whites. When recurrent ulcers (defined as a relapse in the past 12 months of a previously diagnosed ulcer) were excluded, the incidence of new peptic ulcers in 1989 was an estimated 52.7 per 10,000 (Everhart et al. 1998). Among those respondents who specified the site of the ulcer, the incidence of gastric ulcers (17.0 per 10,000) was about three times that of duodenal ulcers (6.1 per 10,000). This finding suggests that the incidence of new duodenal ulcers may have fallen more rapidly over time than that of gastric ulcers.

A large part of the decrease in peptic ulcer rates over the last few decades in the United States has been attributed to lower smoking rates (Kurata et al. 1986), although the same pattern was not seen in the United Kingdom (Sonnenberg 1986). However, the prevalence of H. pylori infection in developed countries also is believed to have declined over a similar time period (Banatvala et al. 1993; Kosunen et al. 1997), and it is this decline, rather than falling smoking rates, that may explain some or all of the reductions in ulcer rates.

Epidemiologic Evidence

Smoking and Development of Peptic Ulcer

Studies that evaluated the relationship between tobacco smoking and the development of peptic ulcer disease repeatedly have shown an increased risk of both duodenal and gastric ulcers among smokers (USDHEW 1979; USDHHS 1990). In some studies, this risk also has been observed to increase with increasing levels of smoking. During a 149,291 person-years follow-up of a cohort of 7,624 Japanese men in Hawaii, the age-adjusted incidence of gastric and duodenal ulcers increased with increasing levels of smoking at baseline (RR among nonsmokers and smokers of less than 24, 24 through 40, and greater than 40 pack-years: 1.0, 1.5, 3.1, and 3.8 [Ptrend <0.01], respectively, for gastric ulcers and 1.0, 1.8, 2.4, and 3.3 [Ptrend <0.01], respectively, for duodenal ulcers [Kato et al. 1992]). In contrast, an analysis of self-reported ulcer history, using data from the 1989 National Health Interview Survey in the United States, suggested that smoking may be a stronger risk factor for chronic ulceration than for the development of new ulcers (Everhart et al. 1998). Although these data show a strong relation between smoking and age-standardized prevalence of chronic active ulcers (1.8 percent, 3.0 percent, 3.9 percent, and 5.3 percent among nonsmokers and smokers of <20, 20, and >20 cigarettes per day, respectively), there was no association between smoking and the incidence of new ulcers.

Helicobacter pylori, Smoking, and Peptic Ulcer

Only a few studies have considered both smoking and H. pylori infection in relation to the incidence of peptic ulcer disease (Table 6.32). These studies largely have been cross-sectional surveys of patients referred for upper gastrointestinal endoscopy using variable definitions of smoking, and rarely presenting results that distinguished between smokers with and without H. pylori infection. No studies have separately evaluated the risk of peptic ulcers in former smokers after allowing for H. pylori infection.

Table 6.32

Studies on the association between smoking and peptic ulcer disease, allowing for Helicobacter pylori (H. pylori) infection. 

Four of these studies were conducted with groups receiving endoscopic examinations. Martin and colleagues (1989) found no duodenal ulcers in 47 H. pylori-negative persons although 4 of them, all of whom were taking NSAIDs, had a gastric ulcer. Among the 60 H. pylori-positive persons, peptic ulcers were significantly more common in smokers than in non-smokers. Similarly, Talamini and colleagues (1997) reported a significant association between duodenal ulcers and smoking after adjusting for H. pylori infection. In a Swiss study, smoking also appeared to be associated with an increased risk of duodenal ulcers, particularly among H. pylori-positive persons (Halter and Brignoli 1998). The lack of a single reference group in this study, however, makes comparisons with other studies difficult. In contrast, Schubert and colleagues (1993) reported no significant differences between the proportion of smokers in patients with and without ulcers and, as a consequence, did not include smoking status in their multivariable models adjusting for H. pylori. It is possible, however, that the very broad definition of smoking used in this last study may have led to very light or occasional smokers being inappropriately classified as smokers, thus masking differences between patients with and without ulcers.

Two other studies used groups of company employees. Wang and colleagues (1996) conducted a case-control study in a factory in Shanghai, China. To prevent confounding by SES and gender, data were analyzed separately for men and women, drivers and workers (lower SES), and staff (higher SES). Among male workers and drivers (304 cases and 263 controls), current smoking was associated with a significantly elevated risk of peptic ulcer disease that increased with the amount of cigarettes smoked. A similar pattern was seen for duodenal ulcer disease alone. There was only one female employee smoker, and too few former smokers to evaluate risks in those groups. Although smoking status was assessed after the development of ulcers, smoking rates were high and few workers reported having stopped smoking. It is therefore unlikely that many employees changed their smoking behavior following ulcer diagnosis.

Schlemper and colleagues (1996) conducted parallel studies in companies in Japan and the Netherlands. Men and women with verifiable ulcer disease who had not been treated with H. pylori eradication therapy were compared with those without ulcers or prior gastric surgery. After adjusting for potential confounders, researchers found that daily smoking was associated with a nonsignificant increased risk of peptic ulcer disease only in the Dutch population. In this study, the majority of ulcers had been diagnosed a median of six years before smoking data were collected, and it is possible that employees with peptic ulcer disease may have changed their smoking behaviors over time.

There is a potential for bias in any of these studies if participants altered their smoking behaviors because of ulcer symptoms or if they misreported their smoking patterns. If ulcer patients tend to stop or reduce their smoking because of symptoms, or if they systematically underreport the amount they smoke, then the true associations between smoking and ulcers could be greater than those reported. Conversely, if ulcer patients actually increase their smoking in response to ulcer symptoms or if they systematically overreport the amount they smoke, then the observed associations could exaggerate the true effect. This latter situation would seem less likely than the former.

Nonsteroidal Anti-Inflammatory Drugs, Smoking, and Peptic Ulcer

The main cause of ulcers in persons negative for H. pylori infection, at least in developed countries, is the use of NSAIDs (Borody et al. 1991, 1992a). In the 1990 Surgeon General’s report (USDHHS 1990), smoking was associated with peptic ulcer disease and acute gastric erosions in three studies of NSAIDusers. Since then, three more studies have evaluated the relationship between smoking and peptic ulcers in NSAID users, with conflicting results.

Hansen and colleagues (1996) compared 94 NSAID users admitted to a hospital with complications of peptic ulcers (predominantly bleeding or perforated ulcers) with 324 controls selected at random from all assumed NSAID users. Overall, cases were no more likely than controls to be smokers (44 percent and 41 percent, respectively), but after adjusting for age, gender, ulcer history, and duration of NSAID use, current smoking was associated with an almost twofold increased risk of ulcer complications (OR = 1.9 [95 percent CI, 1.0–3.6]).

In contrast, Aalykke and colleagues (1999) compared 132 current NSAIDusers diagnosed with bleeding peptic ulcers with 136 ulcer-free NSAID users selected from a rheumatology clinic and geriatrics department. Smokers were not at an increased risk of developing bleeding ulcers compared with controls (OR, adjusted for age, gender, ulcer history, H. pylori infection status, and NSAID dose = 0.91 [95 percent CI, 0.48–1.71]). Similarly, in a large case-control study in the United Kingdom, Weil and colleagues (2000) compared 1,121 patients diagnosed with bleeding peptic ulcers with 989 community controls. Information on H. pylori infection status was not available, but among NSAID users the risk for bleeding peptic ulcers (compared with nonsmokers who did not use NSAIDs) did not differ appreciably between current smokers (OR = 4.0 [95 percent CI, 2.9–5.5]) and non-smokers (OR = 3.6 [95 percent CI, 2.9–4.5]).

Mortality from Peptic Ulcer

Large-scale cohort studies consistently have shown that smokers are at a greater risk of dying from peptic ulcer disease than nonsmokers (USDHHS 1990). Follow-up of the U.S. Veterans Study now has been extended to 26 years, with a total of 5.4 million person-years. Smoking information was collected only at baseline. To allow for the fact that many current smokers at baseline subsequently would have stopped smoking, the analysis was restricted to people who never smoked (who were unlikely to have started smoking) and to former smokers at baseline. Former smokers had elevated risks for mortality from both duodenal ulcer disease (OR = 1.8 [95 percent CI, 1.3–2.4]) and gastric ulcer disease (1.6 [1.1–2.2]) (NIH 1997). During follow-up of the British doctors cohort, information about smoking behaviors was collected at baseline in 1951 and again in 1957, 1966, 1972, 1978, and 1990. After 40 years, mortality from peptic ulcer disease was 8 per 100,000 per year among men who had never smoked cigarettes; 12 per 100,000 per year among former smokers; and 11, 33, and 34 per 100,000 per year among current smokers of 1 to 14, 15 to 24, and 25 or more cigarettes per day, respectively (p <0.001) (Doll et al. 1994). None of these studies, however, could explore possible confounding of this association by H. pylori infection.

Effect of Smoking on Ulcer Severity

Ulcers may be more severe and complications may occur more frequently among continuing smokers (USDHHS 1990). Hasebe and colleagues (1998)compared 35 patients with deep gastric ulcers (ulceration beyond the muscularis propria) and 33 patients with shallow and intermediate depth ulcers (ulceration in submucosa and muscularis propria) in Japan. They found that patients with deep ulcers were more likely to be heavy smokers, defined as smoking 20 or more cigarettes per day, than patients with shallower ulcers (81 percent versus 55 percent, p <0.05). However, patients with deep ulcers also were significantly more likely to drink alcohol on a daily basis (40 percent versus 27 percent, p <0.05) and to have H. pylori infections (97 percent versus 79 percent, p <0.01), so it is possible that these differences could explain some or all of the associations with smoking.

Smoking and Peptic Ulcer Complications

Svanes and colleagues (1997) compared patients diagnosed with perforated peptic ulcers with population controls (90 percent response rate) in Norway. Analyses of smoking were restricted to cases (36 gastric perforation and 73 duodenal perforation) and controls (n = 4,270) aged 15 through 74 years because smoking was rare in older patients. After adjusting for age and gender, the risk of perforated ulcers in current smokers increased significantly with the number of cigarettes smoked per day. The ORs were 7.3 (95 percent CI, 4.0–18.1) for smokers of 1 to 9 cigarettes per day, 8.7 (95 percent CI, 5.5–14.4) for smokers of 10 to 19 cigarettes per day, and 11.2 (95 percent CI, 6.3–27.5) for smokers of 20 or more cigarettes per day (p <0.001) compared with people who had never smoked. The risk among former smokers was no greater than that among those who had never smoked (OR = 0.8 [95 percent CI, 0.2–2.2]). Smokers were less likely than nonsmokers to have used NSAIDs or other ulcerogenic drugs. Thus, variation in NSAID use could not explain the relationship with smoking. The high alcohol consumption, however, which was significantly more common among current smokers (25 percent versus 4 percent among nonsmokers), could possibly explain some of the strong associations between smoking and perforated ulcers. H. pyloriinfection was not assessed, but among the cases, 87 percent of smokers and 96 percent of nonsmokers reported previous “ulcer dyspepsia,” suggesting that infection rates probably were high in both groups.

Lanas and colleagues (1997) conducted a similar study in Spain, comparing 76 patients with gastrointestinal perforation (including 31 with duodenal ulcers and 28 with gastric ulcers) with matched hospital and community controls. After adjusting for the use of NSAIDs and alcohol and histories of ulcers and arthritis, smoking was again associated with a significantly increased risk of perforated ulcers (p = 0.003). In Italy, Labenz and colleagues (1999) compared 72 patients admitted with bleeding peptic ulcers with matched hospital controls. After adjusting for H. pylori infection status, NSAID use, and alcohol intake, smoking was associated with a nonsignificant 40 percent increased risk of bleeding ulcers (OR = 1.4 [95 percent CI, 0.5–3.6]).

In the large case-control study conducted by Weil and colleagues (2000) in the United Kingdom, overall current smoking was associated with a 60 percent increased risk of bleeding peptic ulcers (OR = 1.6 [95 percent CI, 1.2–2.0]). This risk appeared to differ, however, between users and nonusers of NSAIDs. Among NSAID nonusers, smoking was associated with an almost twofold increased risk of bleeding ulcers (OR = 1.9 [95 percent CI, 1.4–2.4]). In contrast, the risk for peptic ulcers in NSAID users did not differ appreciably between current and nonsmokers as described above.

Effect of Smoking on Ulcer Healing and Recurrence

Ulcer Healing

Many studies have shown that smoking adversely affects healing of duodenal ulcers by acid-reducing agents (Lam 1990; USDHHS 1990). It does not appear, however, to have the same adverse effect on healing by other agents, including sucralfate (Lam 1991) or colloidal bismuth subcitrate (Lam 1991; Lambert 1991). In a meta-analysis, data from six studies of sucralfate were combined, giving overall healing rates of 78 percent among 301 smokers and 78 percent among 272 nonsmokers (Lam 1991). In the same analysis, data also were pooled from three studies of colloidal bismuth subcitrate, giving healing rates of 82 percent among 55 smokers and 76 percent among 38 nonsmokers. Less consistent results were reported for the effects of smoking on gastric ulcer healing, although studies evaluating the benefits of smoking cessation have suggested that ulcer patients who stop smoking do better than patients who continue to smoke (USDHHS 1990).

Rates of ulcer healing are significantly higher (Hentschel et al. 1993; Labenz and Börsch 1994) and recurrence rates significantly lower (Rauws and Tytgat 1995) among patients with ulcers (gastric or duodenal) who received H. pylorieradication therapy, which now is the recommended treatment for patients with H. pylori infection (NIH 1997). The combined effects of smoking and H. pylori eradication on ulcer healing in the short term have not been directly evaluated; however, in three studies of ulcer patients treated with H. pylorieradication therapy, there were no significant differences in ulcer healing rates between smokers and nonsmokers (O’Connor et al. 1995; Bardhan et al. 1997; Kadayifçi and Simsek 1997). O’Connor and colleagues (1995) reported healing rates for gastric and duodenal ulcers of 83 percent for smokers compared with 92 percent for nonsmokers (p = 0.3); the H. pylori eradication rate also was slightly lower among smokers (83 percent versus 94 percent, p = 0.2), possibly explaining the slightly different healing rates. Bardhan and colleagues (1997) reported duodenal ulcer healing in 96 percent of smokers compared with 94 percent of nonsmokers (p = 0.6), whereas rates of H. pylorieradication were slightly higher for nonsmokers (77 percent versus 71 percent, p = 0.5). Kadayifçi and Simsek (1997) reported duodenal ulcer healing in 82 percent and 83 percent of heavy (more than 20 cigarettes per day) and mild (1 to 20 cigarettes per day) smokers, respectively, compared with 85 percent of nonsmokers (p = 0.9). In this study, H. pylori eradication rates were slightly higher for nonsmokers (68 percent versus 66 percent among mild and 59 percent among heavy smokers). These reports suggest that ulcer healing rates are high in patients treated with H. pylori eradication therapy, regardless of their smoking status.

Duodenal Ulcer Recurrence

In studies comparing duodenal ulcer recurrence rates for smokers and nonsmokers before the introduction of H. pylori eradication therapy, higher relapse rates consistently were reported for smokers (USDHHS 1990). However, ulcers rarely, if ever, recur in patients who remain free of H. pylori, regardless of their smoking status. George and colleagues (1990) observed no recurrence of duodenal ulcers among 71 patients (31 current and 12 former smokers, and 28 lifetime non-smokers) whose ulcers had healed, whose H. pylori had been eradicated, and who remained free of H. pylori during the four years they were followed. In an Australian study, 197 patients successfully treated for H. pylori-positive duodenal ulcers had their infections eradicated and their ulcers cured. They then were followed for 12 to 73 months (Borody et al. 1992b). There was no recurrence of H. pylori or duodenal ulcers among the groups of 80 current smokers (smoking 5 to 40 cigarettes per day), 38 former smokers (who gave up smoking during follow-up or up to 20 years earlier), and 79 patients who had never smoked. In the Netherlands, Van Der Hulst and colleagues (1997) also found no recurrences in 141 duodenal ulcer patients whose ulcers had been cured and who had been treated successfully for H. pylori infection; they remained free of infection during nine years of follow-up. In Greece, there was no recurrence of duodenal ulcers during 12 to 72 months of follow-up in 141 patients who remained H. pylori negative, regardless of their smoking status; there were seven recurrences (six in smokers) among 24 patients (unknown number of smokers) who became reinfected with H. pylori (Archimandritis et al. 1999).

Although other authors have documented low ulcer recurrence rates in patients whose H. pylori infection was eradicated, ulcer recurrence commonly is associated with either reinfection with H. pylori (Bayerdörffer et al. 1993) or NSAID use (Chen et al. 1999). Furthermore, recurrence rates have not varied between smokers and nonsmokers. A study in Hong Kong followed patients for 10 to 18 months who had been successfully treated for H. pyloriinfection and whose duodenal ulcers had healed (Chan et al. 1997). The authors documented two recurrences (2.9 percent, both H. pylori negative) among 68 smokers (≥10 cigarettes per day) and four recurrences (2.1 percent, three H. pylori negative) among 188 persons who had never smoked or were former smokers. The study concluded that smoking did not influence ulcer recurrence after H. pylori eradication.

Patients treated for H. pylori-positive duodenal ulcers in a multicenter study (Canada, Ireland, United Kingdom, and United States) were followed for six months (Bardhan et al. 1997). All patients had healed ulcers, but H. pyloriwas eradicated in only 77 percent of nonsmokers and 71 percent of smokers. Ulcers recurred in 22 percent of 118 smokers and 16 percent of 117 nonsmokers (p = 0.32). The slightly higher rate seen in smokers could be a result of the slightly lower H. pylori eradication rate for this group. Recurrence rates in this study among patients who apparently remained free of H. pylori during follow-up were an unusually high 12 percent (<6 percent in three of the centers) for both smokers and nonsmokers.

In summary, smoking does not appear to affect duodenal ulcer recurrence rates in patients whose H. pylori infection has been eradicated. Among those who remain H. pylori positive, smoking may increase the risk of relapse, although no good data support or refute this possible association.

Gastric Ulcer Recurrence

A similar pattern is seen for H. pylori-positive gastric ulcers, which also rarely recur after successful H. pylori eradication therapy in the absence of NSAIDuse (Labenz and Börsch 1994). There were no relapses of gastric ulcers in 45 patients who remained H. pylori negative during 10 years of follow-up (Van Der Hulst et al. 1997). Chan and colleagues (1997) observed one recurrence of gastric ulcer accompanied by the reappearance of H. pylori in 15 smokers and no recurrences in 16 nonsmokers followed for up to 18 months after H. pylori eradication and successful ulcer healing.

These data suggest that for both gastric and duodenal ulcers, the main predictor of successful ulcer healing with no recurrence is H. pylori infection status. If smoking has any effect on the healing or recurrence of ulcers, it is therefore likely to be through an effect on the process of H. pylori eradication.

Smoking and Helicobacter pylori Eradication

A number of studies have evaluated the effects of smoking on H. pylorieradication. Results of studies that included more than 50 participants and presented separate eradication rates for smokers and nonsmokers are shown in Table 6.33. (Because three other studies [Fraser et al. 1996; Harris et al. 1996; Georgopoulos et al. 2000] simply reported that smoking was not significantly associated with eradication without presenting eradication rates, it is not possible to tell if there were nonsignificant differences between smokers and nonsmokers.) Although the definition of smoking in these studies often is unclear, and a range of different drug combinations was used to treat the infections, a fairly consistent pattern of lower eradication rates is seen in groups defined as smokers.

Table 6.33

Studies on Helicobacter pylori (H. pylori) eradication rates among smokers and nonsmokers. 

Other factors known to be strongly predictive of H. pylori eradication are compliance with therapy (Graham et al. 1992; Cutler and Schubert 1993; Labenz et al. 1994) and the prevalence of metronidazole resistance (O’Riordan et al. 1990). Although some studies have reported poorer compliance among smokers (Unge et al. 1993), others have found similarly high compliance rates between smokers and nonsmokers (O’Connor et al. 1995; Bardhan et al. 1997; Kamada et al. 1999). In a logistic regression model also adjusting for therapy duration and omeprazole pretreatment, Labenz and colleagues (1994) found both lack of compliance (OR = 74.72 [95% CI, 24.17–205.51]) and smoking (OR = 2.75 [95% CI, 1.56–4.86]) to be independent risk factors for treatment failure. Witteman and colleagues (1993)found that metronidazole resistance developed more readily in smokers following therapy with bismuth and metronidazole after allowing for variations in compliance (p = 0.01). However, poorer eradication rates in smokers also are seen with regimens that do not contain this class of drug. Therefore, it seems unlikely that the lower eradication rates for smokers can be attributed to either poorer compliance or an increase in metronidazole resistance. It has been suggested that smoking may adversely affect eradication by increasing acid output or by decreasing gastric blood flow, thereby reducing drug delivery to the gastric mucosa, but little evidence supports either of these hypotheses.

Evidence Synthesis

Incidence of Peptic Ulcer

Many studies have reported strong and significant associations between smoking and peptic ulcer disease. Only six studies, however, have allowed for the effects of H. pylori infection when evaluating this association. Three of those studies reported significantly increased risks of ulcer disease in smokers after adjusting for H. pylori infection; in each study, the majority (80 to 90 percent) of ulcer patients were H. pylori positive (Wang et al. 1996; Talamini et al. 1997; Halter and Brignoli 1998). A fourth study reported a significant association between smoking and ulcers only among H. pylori-positive persons (Martin et al. 1989). The remaining two studies (Schubert et al. 1993; Schlemper et al. 1996) reported little or no association, but the classification of smoking status in these studies is potentially unreliable.

Cigarette smoking has a number of effects on gastroduodenal physiology that could lead to the development of peptic ulceration, and evidence suggests that some of these effects may be potentiated in H. pylori-positive persons. Taken together, these data strongly suggest a causal relationship between smoking and the development of peptic ulcers, at least in H. pylori-positive persons. There is insufficient evidence to evaluate the relation between smoking and peptic ulcers in those who are H. pylori negative. Conflicting and inadequate data link smoking to ulcer occurrence in NSAID users and it is not possible to evaluate an independent effect for smoking in the development of NSAID-induced peptic ulcers.

There is evidence to suggest that after adjusting for NSAID use, smoking may be associated with an increased risk of peptic ulcer complications, including perforation and bleeding. Data from the most recent study (Weil et al. 2000), however, suggest that this effect may be restricted to nonusers of NSAIDs.

The effects of smoking cessation on ulcer risk have not been evaluated in the context of H. pylori infection. However, the transient nature of many of the physiologic effects of smoking suggests that an excess risk may be restricted to current smokers.

Ulcer Healing and Recurrence

Healing and recurring H. pylori-positive ulcers are closely associated with eradication and recurrence of the infection. The evidence strongly suggests that if H. pylori is eradicated, smoking has no effect on either the healing or recurrence of ulcers. There is, however, evidence to suggest that H. pylorieradication therapy is somewhat less successful for current smokers. There are no good data to evaluate the effects of smoking on the recurrence of ulcers associated with H. pylori infection when long-term H. pylori eradication fails, or on the treatment and recurrence of ulcers in persons negative for H. pyloriinfection.

Conclusions

1. The evidence is sufficient to infer a causal relationship between smoking and peptic ulcer disease in persons who are Helicobacter pylori positive.

2. The evidence is inadequate to infer the presence or absence of a causal relationship between smoking and peptic ulcer disease in nonsteroidal anti-inflammatory drug users or in those who are Helicobacter pylorinegative.

3. The evidence is suggestive but not sufficient to infer a causal relationship between smoking and risk of peptic ulcer complications, although this effect might be restricted to nonusers of non-steroidal anti-inflammatory drugs.

4. The evidence is inadequate to infer the presence or absence of a causal relationship between smoking and the treatment and recurrence of Helicobacter pylori-negative ulcers.

Implications

The prevalence of H. pylori has declined in developed countries (Banatvala et al. 1993; Kosunen et al. 1997) and, as a result, the proportion of patients with H. pylori-negative ulcers will increase, making them an important group to study. Also, an increasing number of H. pylori-negative ulcers may not be attributable to NSAID use or other established causes of ulcers (Jyotheeswaran et al. 1998). The rarity of ulcer recurrence when H. pylori is eradicated, regardless of smoking status, suggests that smoking is not an important factor in the initial development or recurrence of ulcers among persons who are H. pylori negative. However, this topic has not been well investigated, largely because of the paucity of such ulcers, and is likely to be an important area for future research.

Because the main effects of smoking on gastrointestinal physiology appear to be short-lived, it is likely that smoking cessation will both reduce ulcer occurrence in those persons who are H. pylori positive and improve the chances of eradication in patients (with or without ulcers) treated for H. pyloriinfection. Even if eradication is successful, it seems unlikely that a continuation of smoking will influence the course of peptic ulcer disease.

Conclusions

Diminished Health Status

1. The evidence is sufficient to infer a causal relationship between smoking and diminished health status that may manifest as increased absenteeism from work and increased use of medical care services.

2. The evidence is sufficient to infer a causal relationship between smoking and increased risks for adverse surgical outcomes related to wound healing and respiratory complications.

Loss of Bone Mass and the Risk of Fractures

3. The evidence is inadequate to infer the presence or absence of a causal relationship between smoking and reduced bone density before menopause in women and in younger men.

4. In postmenopausal women, the evidence is sufficient to infer a causal relationship between smoking and low bone density.

5. In older men, the evidence is suggestive but not sufficient to infer a causal relationship between smoking and low bone density.

6. The evidence is sufficient to infer a causal relationship between smoking and hip fractures.

7. The evidence is inadequate to infer the presence or absence of a causal relationship between smoking and fractures at sites other than the hip.

Dental Diseases

8. The evidence is sufficient to infer a causal relationship between smoking and periodontitis.

9. The evidence is inadequate to infer the presence or absence of a causal relationship between smoking and coronal dental caries.

10. The evidence is suggestive but not sufficient to infer a causal relationship between smoking and root-surface caries.

Erectile Dysfunction

11. The evidence is suggestive but not sufficient to infer a causal relationship between smoking and erectile dysfunction.

Eye Diseases

12. The evidence is sufficient to infer a causal relationship between smoking and nuclear cataract.

13. The evidence is suggestive but not sufficient to infer that smoking cessation reduces the risk of nuclear opacity.

14. The evidence is suggestive but not sufficient to infer a causal relationship between current and past smoking, especially heavy smoking, with risk of exudative (neovascular) age-related macular degeneration.

15. The evidence is suggestive but not sufficient to infer a causal relationship between smoking and atrophic age-related macular degeneration.

16. The evidence is suggestive of no causal relationship between smoking and the onset or progression of retinopathy in persons with diabetes.

17. The evidence is inadequate to infer the presence or absence of a causal relationship between smoking and glaucoma.

18. The evidence is suggestive but not sufficient to infer a causal relationship between ophthalmopathy associated with Graves’ disease and smoking.

Peptic Ulcer Disease

19. The evidence is sufficient to infer a causal relationship between smoking and peptic ulcer disease in persons who are Helicobacter pylori positive.

20. The evidence is inadequate to infer the presence or absence of a causal relationship between smoking and peptic ulcer disease in nonsteroidal anti-inflammatory drug users or in those who are Helicobacter pylori negative.

21. The evidence is suggestive but not sufficient to infer a causal relationship between smoking and risk of peptic ulcer complications, although this effect might be restricted to nonusers of non-steroidal anti-inflammatory drugs.

22. The evidence is inadequate to infer the presence or absence of a causal relationship between smoking and the treatment and recurrence of Helicobacter pylori-negative ulcers.

[ 2004 Health Consequences of Smoking: the Surgeon General continues next at Part  103 ]

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