Health effects of cigarette smoking

Health effects of cigarette smoking
Yair Skurnik, MDa, , Yehuda Shoenfeld, MDb
a Kaplan Medical Center, Hebrew University–Hadassah Medical School, Jerusalem, Israel
b Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel
http://dx.doi.org.libweb.lib.utsa.edu/10.1016/S0738-081X(98)00037-6, How to Cite or Link Using DOI
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The discovery of America by Christopher Columbus had catastrophic consequences for the natives of the American continent, but they had their revenge: Columbus was offered dried tobacco leaves as a friendly gesture in 1492, and in the following years the Spaniards, Portuguese, and other European explorers spread the habit of tobacco smoking to every continent in the world.1
The Spanish historian Fernandez de Oviedo observed in 1526: “Among other evil practices, the Indians have one that is especially harmful, the inhaling of a certain kind of smoke which they call tobacco.”1 But it was not until the last decades of our century that the health hazards of cigarette smoking became widely known in developed countries. This is astonishing considering the fact that, worldwide, about 2 million people die each year from smoking, half of them before the age of 70. What is so unusual is the social and political acceptability of this lethal habit.
About 20% of all deaths in developed countries are caused by smoking. The overall morbidity is more difficult to quantify, but many nonfatal diseases, which have appreciable disability, inconvenience, and cost, are also caused by smoking.2 Cigarette smoking is now the chief avoidable cause of illness and death in the United States. In 1995 the total number of deaths attributed to smoking was estimated as 150,000 in England, over half a million in the United States, and in all developed countries about 2 million.
In 1990 in developed countries as a whole, tobacco was responsible for 24% of all deaths of men and 7% of all deaths of women, rising to over 40% in men in some former socialist economies and 17% in women in the United States. It is estimated that annual mortality from tobacco will rise from about 3 million in the 1990s to about 10 million in 2020 or early 2030. [2], [3] and [4]
Smoking is responsible for over 75% of deaths from lung cancer and chronic obstructive lung disease, and other cancers are recognized as being caused by smoking (lung, upper respiratory sites, bladder, pancreas, esophagus, stomach, kidney, and leukemia). Smoking is a major risk factor for ischemic heart disease, which is the single leading disease cause of death in the United States and in other developed countries.
The overall morbidity is more difficult to estimate, but many millions of people will suffer illness and disability due to smoking, as smoking is also implicated in nonfatal diseases such as peripheral vascular disease, cataracts, osteoporosis and hip fractures, and periodontal disease. Smoking in pregnancy increases the risk of congenital limb reduction defects, spontaneous abortion, ectopic pregnancy, and low birth weight.4
The impact of smoking is even more extensive when considering the effects of passive smoking along with those of active smoking. It was estimated in 1988 that 53,000 annual deaths in the United States were attributed to passive smoking.5 In conclussion, cigarette smoking is a worldwide pandenic that is completely avoidable.
Cardiovascular diseases
The adverse effects of smoking on the cardiovascular system are well established. Cigarette smoking is a major cause of atherosclerotic disease and is considered one of the major risk factors for coronary heart disease (CHD), along with hypertension and lipid disorders. This finding is most significant because CHD is the most common cause of death in the United States and in most of the industrialized countries. [6] and [7]
Cardiovascular diseases (CVD) encompass many diseases of the heart and blood vessels, including CHD, cerebrovascular disease, peripheral vascular disease, and aortic aneurysm, all of which have been linked to smoking. The relationship of cigarette smoking to these disorders is well established and unequivocal. Evidence linking smoking with CVD has been reliably accumulated from many epidemiological studies, and there is evidence establishing the relationship of tobacco smoking to the physiologic, pathologic, and metabolic factors that contribute to the atherosclerotic and thrombogenic processes.
The death rate for CVD rose steadily throughout the present century until the mid-1960s, when a marked reversal of this trend occurred. Since 1968 there has been a persistent decline in the CVD mortality of approximately 2–3% per year, resulting in nearly a 50% decline. These trends in CVD parallel the trends observed in smoking prevalence in this century, and may be viewed as indirect but impressive evidence for the contribution of smoking to CVD. It was estimated that 24% of the decline in CVD was related to the reduction in cigarette smoking in the United States. [6], [8] and [9]
Much of the high mortality of CHD can be attributed to smoking. In 10 cohort studies including over 20 million person-years of observation, a higher incidence of myocardial infarction and CHD death was found among smokers, averaging 70% above that of nonsmokers (ie, Relative risk (RR) = 1.7).10 There is a strong dose-response effect between smoking and CHD, so that heavier smoking is associated with even higher risk of death and myocardial infarction. In the Pooling Project, men 40 to 59 years of age, who smoked more than a pack per day, had a coronary event RR of 2.5.11 Cigarette smoking has been particularly associated with acute myocardial infarction in younger men and in young and middle-aged women.12 Women in the Nurses’ Health Study who smoked more than 25 cigarettes per day had 5.5 the RR of fatal CHD and 5.8 the RR of nonfatal CHD, of nonsmoking women. In this large cohort, more than 50% of the risk for premature CHD was attributable to smoking.13 Similar results were obtained in a recently published study that demonstrated a sixfold increased incidence of myocardial infarction in women smokers compared with a threefold increase in men smokers relative to nonsmokers.14
Smoking is particularly synergistic with other risk factors; this is especially true for smoking in combination with high LDL cholesterol and low HDL cholesterol and for oral contraceptives in women smokers in whom a 10-fold higher risk for CHD has been demonstrated.15
Cigarette smoking has been associated with premature stroke in both sexes, and the risk for cerebrovascular accident is increased at any level of smoking, but with a dose-response relationship, as in the case of smoking and CHD, it is estimated that the RR of cerebrovascular disease among smokers is approximately 1.5 to 3.0 times the risk observed in nonsmokers.16 The risk of hemorrhagic stroke is substantially increased in smokers, and this increases linearly with the numbers of cigarettes smoked per day, up to a RR of 10.3 in heavy smokers.17 This risk can be reduced by smoking cessation.18 There is much evidence for the association of smoking with cerebral atherosclerosis, both from autopsy studies and from noninvasive studies demonstrating more severe atherosclerosis in the carotid and cranial arteries of smokers, as reflected by wall thickening and by narrowing of the arterial lumen.19 Smokers have decreased cerebral flow, and smoking cessation increases cerebral perfusion. The risk for stroke is also reduced after cessation of smoking, and equals the risk of nonsmokers 5 to 10 years after cessation.
Data from the Framingham Heart Study indicate that cigarette smoking may be responsible for up to 80% of all symptomatic cases of peripheral vascular disease.20 This effect of smoking is mediated by the atherosclerosis induced by smoking and by peripheral vasoconstriction mediated by catecholamines. Cigarette smoking reduces patency rates of femoropopliteal venous grafts and reduces limb salvage rates.21 Smoking cessation, on the other hand, improves the prognosis and performance of patients with peripheral vascular disease (PVD). In patients with claudication, former smokers had a 50% lower rate of complications of PVD than did continuing smokers. Aortic aneurysm, which is considered secondary to atherosclerosis, is relatively rare; mortality rates, however, are five times more common in heavy smokers than in nonsmokers.22
The two major mechanisms involved in coronary heart disease are atherosclerosis, which is a pathologic process that results in stenosis of the arteries, and thrombosis. Atherosclerosis involves endothelial injury, intimal smooth muscle cell proliferation, proliferation of macrophages with lipid accumulation, and formation of foam cells and development of plaques and plaque calcification and rupture. Thrombosis, which causes the acute occlusion of the arteries—usually at the site of a ruptured atherosclerotic plaque—is the final common precipitant of most acute coronary and other vascular events.
Progression of the atherosclerotic lesions involves many metabolic and physiologic processes, most of which are augmented by cigarette smoking (Table 1). Smoking causes endothelial injury, which is considered the antecedent to atherosclerosis.23 It has been demonstrated that nicotine has a desquamating effect on the endothelium, probably by increased shear stress from increased blood viscosity and the rise in heart rate, cardiac output, blood pressure, and vasoconstriction induced by smoking.24 In addition to this endothelial damage by mechanical factors, chemical injury to the endothel, is caused by polycyclic aromatic hydrocarbons in cigarette smoke. Tobacco smoke increases smooth muscle cell proliferation by inducing platelet adherence to the injured endothel, with the resulting release of platelet-derived growth factor (PDGF).
Table 1. The Effects of Cigarette Smoking on Atherosclerosis and Cardiovascular Diseases∗
Pathologic effects
Vascular intimal injury
Smooth muscle cell proliferation
Atherosclerosis initiation and progression cardiomyopathy
Hemodynamic effects
Increased
Heart rate
Blood pressure
Cardiac output
Peripheral vascular resistance
Arrhythmias
Impaired coronary artery flow autoregulation (endothelial dysfunction)
Metabolic effects
Increased
Serum-free fatty acids and VLDL
Postprandial hypertriglyceridemia
Oxidatively modified LDL
Insulin resistance
Glucose
Growth hormone
Cortisol
Decreased
HDL cholesterol
Estrogen levels
Hematologic effects
Release of platelet factors that activate atherosclerotic process
Increased
Thromboxane release
Platelet aggregation
Platelet adhesion
Fibrinogen and factor VII levels
Plasma viscosity
Decreased
Prostacyclin release
Platelet survival
Red cell deformability
Bleeding time
Effects of aspirin on platelets
∗
Modified from McBride.6
Table options

The major hemodynamic effects of smoking are produced by the release of catecholamines by the sympathetic nervous system, which is activated by nicotine. These effects include increased heart rate and blood pressure, cardiac output, and vasoconstriction along with the resulting increased myocardial oxygen demand. These changes contribute to endothelial injury. In addition, carbon monoxide from cigarette smoke reduces the oxygen-carrying capacity of the blood; smoking may also induce coronary spasm, and this can exacerbate myocardial ischemia. [6] and [25]
Smoking has numerous effects on lipoprotein metabolism and composition, which promote atherogenesis. Smoking reduces high density lipoprotein (HDL) cholesterol and may reduce its antiatherogenic effects by altering its composition. The negative effects of smoking on HDL are well documented, and cessation of smoking causes a significant rise in HDL-cholesterol levels.
Smoking is also associated with elevated levels of triglycerides and their primary carrier, namely very low density lipoprotein (VLDL). [26], [27], [28] and [29] A recent study demonstrated postprandial hypertriglyceridemia in smokers whose fasting level of triglycerides did not differ from that of nonsmokers. This “lipid intolerance” may be responsible for the reduced levels of HDL cholesterol in smokers.30
Many of these alterations in lipoprotein metabolism resemble features of the insulin resistance syndrome; as described elsewhere in this report, insulin resistance, which itself is considered a risk factor for CHD, has indeed been documented in smokers.31 Cigarette smoke is known to contain a large number of oxidants; it has been hypothesized that many of the adverse effects of smoking may result from oxidative damage to critical biologic substances. It has been shown that oxidatively modified low density lipoprotein (LDL), but not native LDL, is recognized by scavenger receptors and taken up by macrophages, with development of foam cells. Oxidized LDL is therefore more atherogenic than native LDL. It has been demonstrated that this oxidation of LDL occurs in smokers and that smokers have lower levels of the antioxidant ascorbic acid (vitamin C) and that their risk of CHD correlates inversely with their intake of the antioxidants vitamin E and beta carotene. [32] and [33]
Smoking produces profound changes in the hemostatic system, which contribute to the progression of the atherosclerotic lesions, and to the development of thrombosis, which is responsible for acute cardiovascular events. Platelet activation has a major role in initiation of thrombus formation and contributes to atherogenesis by the release of platelet-derived growth factor (PDGF). This PDGF encourages migration and proliferation of smooth muscle cells in the atherosclerotic lesion. Platelet adhesiveness and aggregability are increased, and platelet survival is shortened in smokers.34 Smoking inhibits prostacyclin and increases thromboxane synthesis; these changes favor vasoconstriction and platelet aggregation. Smoking increases the viscosity of blood and elevates the levels of fibrinogen and factor VII and reduces bleeding time.35
Smoking has many deleterious influences on the heart, in addition to the accelerated coronary atherosclerosis it causes. Smoking increases myocardial demand and reduces oxygen delivery to the myocard. Therefore, angina pectoris symptoms occur at lower workloads following smoking. Cigarette smoking is directly associated with the frequency and duration of ischemia in patients with CHD. The risk of sudden death is increased by smoking both in patients with prior CHD and in patients without known CHD; it is postulated that smoking increases the myocardial vulnerability to ventricular fibrillation.36 Smoking reduces acutely coronary vasodilatory capacity, and this could lower the ischemic threshold in smokers with CHD and contribute to the increased risk for sudden death. [37] and [38] Smoking reduces the effectiveness of antianginal medications and the long-term benefits of thrombolytic therapy for myocardial infarction. Cigarette smoking increased the risk for reinfarction from 6.3% in nonsmokers to 12.5% in smoking patients.39 During 15 years of follow-up of patients who underwent coronary bypass surgery, increased risks for myocardial infarction, recurrence of angina pectoris, and recurrent bypass surgery were documented in patients who continued smoking or started to smoke again after the operation, compared with patients who stopped smoking since surgery and patients who did not smoke.40 The effects of smoking on long-term outcome after successful percutaneous coronary revascularization were similar: During a maximal follow-up of 16 years of patients who underwent various procedures of percutaneous revascularization, nonsmokers and former smokers had similar outcomes. The persistent smokers had a greater relative risk of death and of Q-wave infarction than did nonsmokers. Persistent smokers were also at greater risk for death than were those who stopped smoking after the procedure.41
Pulmonary diseases
Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD)—that is, chronic bronchitis and emphysema. It is estimated that cigarette smoking in the United States was responsible for more than 80,000 pulmonary deaths per year, including COPD, asthma, influenza, pneumonia and other causes. COPD is currently the fifth leading cause of death in the United States, and about 85% of COPD mortality and morbidity are attributable to smoking. Data from both prospective and retrospective studies have consistently shown increased mortality from COPD in cigarette smokers compared with nonsmokers.42 There is a dose-response relationship between COPD death rate and smoking. Depending upon the extent of smoke exposure, male cigarette smokers experience from 4 to 25 times higher mortality secondary to COPD than do nonsmokers.
Recent data from an American Cancer Society report indicates that the age-adjusted death rate for COPD is approximately 10-fold higher among current smokers than among never-smokers.16
Cigarette smoking results in multiple pathophysiologic effects in all the components of the respiratory system (Table 2). In the epithelium of central airways, cigarette smoke causes loss of cilia, mucus gland hyperplasia, and an increase in the number of goblet cells. Normal pseudostratified ciliated epithelium may regress to squamous metaplasia, then transformation to carcinoma in situ and finally to invasive bronchogenic carcinoma.16
Table 2. Pulmonary Pathophysiologic Effects of Cigarette Smoking∗
Alterations of central airways
Loss of cilia
Mucus gland hyperplasia
Increased number of goblet cells
Regression of normal pseudostratified ciliated epithelium to
squamous metaplasia, carcinoma in situ, and eventually invasive bronchogenic carcinoma
Alteration of peripheral airways
Inflammation and atrophy
Goblet cell metaplasia
Squamous metaplasia
Mucus plugging
Smooth muscle hypertrophy
Peribronchial fibrosis
Alterations of alveoli and capillaries
Destruction of peribronchial alveoli
Reduced number of small arteries
Bronchoalveolar lavage fluid abnormalities
Elevated levels of IgA and IgG
Increased percentages of activated macrophages and neutrophils
Alterations and immune function
Higher peripheral leukocyte counts
Elevation in peripheral eosinophils
Increased levels of serum IgE
Lower allergy skin test reactivity
Reduced immune responses to inhaled antigens
∗
Adapted from Sherman.42
Table options

Smaller airways of smokers were observed to have inflammation and atrophy, goblet cell metaplasia, squamous metaplasia, mucus plugging in terminal and respiratory bronchioles, peribronchiolar fibrosis, and smooth muscle hypertrophy.43 Positive correlations between these pathologic changes, as quantified by measurements of peripheral airway wall thickness and alveolar attachment, and bronchial hyperresponsiveness have been documented, and this suggests that exaggerated nonspecific airway narrowing in smokers with COPD is secondary to structural changes caused by the disease.44
Destruction of peribronchiolar alveoli, found in smokers’ lung, may contribute to loss of elastic recoil and to emphysema. Alterations of immune function, which may contribute to the lung damage, were documented in smokers. Current smokers have as much as 30% higher peripheral leukocyte counts with increased numbers of neutrophils, T-lymphocytes, and eosinophils.45 Smokers have higher levels of serum IgE than do nonsmokers, and without the seasonal variations or age-related declines observed in nonsmokers.16
Smoking leads to COPD by accelerating the natural decline in pulmonary function in adults, according to the model proposed by Fletcher and collegues, nearly 20 years ago. This schema was based on data on lung functions in smokers and nonsmokers obtained from cross-sectional and limited longitudinal studies. Longitudinal studies from previous years confirmed the cross-sectional identified effects of smoking on lung function, as assessed by spirometry. These studies showed an accelerated decline of FEV1 (forced expiratory volume in 1 second) in adult smokers. On average, smokers experience a 10 to 20 mL/yr higher loss of FEV1 than do nonsmokers. [46] and [47] This sustained excess decline over many decades is sufficient to result in symptomatic airflow obstruction with the clinical picture of COPD. Yet a subgroup of smokers, defined as “susceptible smokers,” may suffer declines that are more than three times higher than in nonsmokers, and this could lead to severe obstruction within a few years. There is a dose-response relationship between the number of cigarettes smoked and the excess FEV1 decline.47
Data from longitudinal studies on active and passive smoking have led to modification of the schema on smoking and lung function. Active smoking has been shown to affect three components as it leads to COPD:
1.
Diminished growth velocity of FEV1 during adolescence, resulting in a lower maximally attained FEV1;
2.
shortened plateau phase with premature onset of FEV1 decline;
3.
accelerated decline of FEV1 in the middle-aged and elderly.48

Studies such as those of Tager et al, who followed schoolchildren aged 5 to 9 years on enrollment, support the schema by demonstrating reduced growth rate of FEV1 in smoking adolescents. They estimated that a smoking teenager attained an FEV1 level that was on average 340 mL lower for girls and 390 mL lower for boys compared with nonsmokers.49 The data on the effect of in utero exposure to cigarette smoke, and of passive smoking during childhood, on the growth of lung function are more sparse. However, evidence supporting the hypothesis that maternal smoking during pregnancy may adversely affect the offspring’s lung functions and bronchial hyperresponsiveness has also been demonstrated in children exposed in utero to smoking.50
Effects of exposure to household smoking during childhood on growth of lung function have also been identified. Mean level of FEV1 was significantly associated with maternal smoking, and growth rate was associated with number of cigarettes smoked per day by the mother, with a slowing of the annual growth of FEV1 by 0.17% per pack in one study.15
Another study demonstrated projected reductions of lung function growth for a child because of maternal smoking of 28, 51, and 101 mL for 1, 2, and 5 years, respectively.52
Decades ago, the concept of the susceptible smoker was introduced. The distribution of FEV1 decline among smokers led to the hypothesis that some unknown factors inherent in the smoker determine the rate of decline.53 The only firmly established host factor is alpha-1-antitrypsin deficiency, which accounts only for a minority of susceptible smokers.54 However, an imbalance between proteolytic and antiproteolytic enzymes may lead to destruction of lung tissue and emphysema. Cigarette smoke may increase the activity of proteolytic enzymes, and decrease antiprotease activity through smoke-induced oxidants in the lung. Vitamin C is the major antioxidant substance present in the airway surface liquid of the lung, where it could be important in protecting against the oxidants produced by smoking. It is thus possible that relative deficiency of vitamin C increases the lungs’ susceptibility to cigarette smoke, and symptoms of COPD and asthma in smokers appear to decrease by vitamin C supplementation.55
It has been demonstrated in smokers that heightened airway responsiveness is associated with an accelerated decline of pulmonary function, and it was suggested that this hyperresponsiveness may be the factor that makes some smokers more susceptible to the adverse effects of cigarette smoke on the lung. A number of studies have shown that bronchial hyperresponsiveness was associated with faster decline of FEV1 during the study period, but it was not clear from these studies whether the hyperresponsiveness was caused by rapid decline of FEV1 or vice versa. Recent cohort studies, with long follow-up, indicate that hyperresponsiveness at the beginning of the follow-up is indeed a risk indicator for susceptibility of the lung to smoking, as reflected by fast FEV1 decline.56
Cessation of smoking has a beneficial effect on FEV1 decline. Longitudinal studies have shown that the decline of FEV1 returns to that experienced by never smokers. This beneficial effect of smoking cessation is particularly pronounced in younger quitters, but it has also been demonstrated in elderly quitters. Although quitting smoking will result in a return of the decline of FEV1 to that of nonsmokers, the FEV1 will not return to normal, because of the reduction of FEV1 that has already occurred during the period of smoking; thus, it is not surprising that measures of lung function are highest in never smokers, lowest in sustained smokers, and intermediate in those who have stopped smoking. [53], [57] and [58]
Cigarette smoking, in addition to its major role in the pathogenesis of COPD, is also associated with increased morbidity and mortality from acute respiratory illnesses. Smoking increases the risk for lower respiratory tract illness and increases the duration of cough. During outbreaks of influenza, smokers are more likely to experience apparent disease.59 Mortality from influenza and pneumonia is increased in current smokers, and this increased mortality demonstrates a dose-response relationship.60 Postoperative respiratory complications and spontaneous pneumothorax are also more common in smokers.
Cancer
Cigarette smoking is the single most important cause of cancer mortality in the Western world: 30% of all cancer deaths are due to smoking. Smokers have overall cancer death rates two times greater than those of nonsmokers, and these rates are fourfold greater in heavy smokers. Cigarette smoking is considered responsible for the increase in cancer mortality over the past 35 years. [61], [62] and [63] Lung cancer, the most common cause for cancer death in both sexes, has increased 250% since 1950. Over 80% of deaths from lung cancer are caused by smoking, and the RR for death from lung cancer is 15.0 in current smokers.64
In 1985, a review of the carcinogenic effects of tobacco led the International Agency for Research on Cancer to conclude that cigarette smoking was carcinogenic to humans. Smoking was found to be an important cause of eight different cancers: cancers of lung, larynx, oro- and hypopharynx, esophagus, bladder, renal pelvis, and pancreas. Recent review justifies the conclusion that cigarette smoking is also a cause of cancers of the stomach, renal body, liver, and of myeloid leukemia. Pipe smoking is a cause of cancer of the lip. Association between cigarette smoking and cancers of the colon and cervix may be largely explained by confounding.63
Evidence for the association between cigarette smoking and cancer is provided by many epidemiological studies. The data derived from all these studies are very convincing by their consistency, by the strength of the association, as measured by the RR or the ratio of rates of disease between smokers and nonsmokers, and by the biologic gradient, or dose response, which is evident for all cancers: the risk depends upon the intensity of exposure to tobacco smoke (number of cigarettes smoked per day, earlier age at initiation, greater total numbers of years of smoking etc.). Epidemiologic studies also demonstrate that the risks of most smoking-related cancers diminish after quitting smoking and with increasing duration of abstinence. The plausibility of this epidemiologic evidence has been sustained by overall coherence with the natural history of cancer and by studies that provide insights into the mechanisms of carcinogenesis by cigarette smoke.
Cigarette smoke contains more than 4000 compounds. Many of these compounds are known to be toxic, mutagenic, and carcinogenic.65 Two steps are believed to be involved in carcinogenesis: an irreversible initiation phase involving damage to DNA, and a promotion phase, during which initiated cells are converted to malignant phenotype.
Major tumor initiators in cigarette smoke reside in the polyaromatic hydrocarbon subfractions contained in the particulate matter (“tar”). This cigarette tar causes tumors in animals in direct proportion to the dose and frequency in which it is applied. In humans, relative mortality in cigarette smokers for a 15-mg decrease in tar yield per cigarette was 0.75 for lung cancer.66 The action of these initiators is accelerated by promoters and other co-carcinogens found in the weakly acidic and neutral portions of tobacco smoke condensates.67 Tobacco-induced DNA damage may also be promoted by environmental agents, such as asbestos and by alcohol.68
The presence of reversible promoters of carcinogenesis in cigarette smoke is supported by a reduction in risk for all smoking-related cancers following cessation of smoking. Cancer risk among former smokers falls between that of continuing smokers and never smokers.
The greatest carcinogenic effect of cigarette smoke is on tissues directly exposed to the smoke, such as the lining of airways. However, distant organs are also affected by active constituents of the smoke and by active metabolites that may act as organ-specific carcinogens. An example for this is 2-naphthylamine, which concentrates in urine and is associated with increased risk for carcinoma of the bladder.
Lung cancer is the leading cause of cancer death and is directly attributable to smoking in 90% of lung cancer in men and 79% in women.
The increased risk for lung cancer is about 22-fold for current male smokers and 12-fold for female smokers.65 The RR of lung cancer in women smokers has increased over the past decades. This increase reflects an earlier age at initiation of smoking and more cigarettes smoked per day by women smokers. There is a dose-response relation between smoking and the risk for lung cancer in both sexes, so that smokers of 40 cigarettes per day have twice the risk of those who smoke 20 or fewer cigarettes a day. Smoking increases the risk for all four major types of lung cancer (squamous cell, small cell, large cell, and adenocarcinoma). Compared with nonsmokers, male smokers have an increased proportion of squamous cell carcinoma, and female smokers have an increased proportion of small-cell carcinoma.69 Cigar and pipe smoking are also associated with increased risk of lung cancer, and this risk increases with number of cigars and pipefuls of tobacco and degree of inhalation.70
Other organs in direct contact with smoke—the oral cavity, larynx, and esophagus—are also at an increased risk of developing malignancy among smokers. It is therefore not surprising that cancers with strong association to smoking are laryngeal cancer, with a 10-fold increased risk in male smokers, oral cancer (92% and 61% attributable to smoking in men and women, respectively), and esophageal cancer (80% attributable to cigarette smoking). Heavy alcohol consumption augments the carcinogenic effect of cigarette smoking with regard to these three tumors. [62], [71] and [72]
Organs distant from cigarette smoke are also at some increased risk: The risk of kidney and urinary bladder cancer is 2 to 3 times greater in smokers than in nonsmokers. [73] and [74] Cigarette smoking may interact with occupational exposure to chemicals to produce cancers of the kidney and bladder. This has been observed in workers in rubber, paint, and leather industries.75
About 30% of deaths from pancreatic cancer are attributable to cigarette smoking, and heavy smokers have a fivefold increase in the risk for this tumor over that of nonsmokers. There is also an increase of about 50% in the risk of gastric carcinoma in smokers over nonsmokers.
Cervical carcinoma had also been found to be consistently associated with cigarette smoking in many case-control and cohort studies. However, it is not clear whether this relationship is causal or due to confounding with a multiplicity of sexual partners (which is more common in women smokers). It is known that cervical cancer is related to infection with certain types of the human papilloma virus (HPV). One study showed that the relationship of the cancer with smoking does not hold on women positive for HPV types 16 and 18 (the two types most closely related to the development of cervical cancer), but may continue to hold in HPV-negative women.76 The fact that mutagenic components of tobacco smoke can be identified in the cervical mucus of women who smoke77, favors a causal relationship between smoking and the tumor, but the question of whether the relationship between smoking and cervical cancer is causal or due to confounding remains open.
There is a weak relationship between myeloid leukemia and smoking in men but not in women, and cigarette smoke contains two known leukemogens: benzene and isotopes of polonium. [22] and [63] Although cigarette smoking is responsible for only small proportions of cases of myeloid leukemia, it is still the most important avoidable cause.
Cigarette smoking may also increase the risk for cancers of the liver and colon, and a large prospective study published recently found higher death rates from prostate cancer in current smokers. Combined with results of other studies, which did not find increased incidence of this cancer in smokers, these data suggest that smoking may adversely affect survival in patients with prostatic cancer.78
In summary, cigarette smoking has been identified as a definite cause of cancer at many sites, with organs in direct contact with smoke having the greatest risk of malignancy among smokers. The risk of cancer at all mentioned sites increases with increasing exposure to cigarette smoke, and cessation of smoking decreases the risk of all these cancers, although not to the same extent.
Osteoporosis
Daniell was the first to observe the relationship between cigarette smoking and osteoporosis,94 and this relationship was later established by others: The Framingham study demonstrated a significant correlation between smoking and reduction of bone mass.95 The risk for hip fracture was found to be increased in women smokers in a large study conducted in Norway. This study demonstrated that the risk for hip fractures in smoking women was especially high in thin women.96 When bone density was compared in pairs of female monozygotic twins, of whom one in each pair was a smoker, a reduction in bone density was observed in women smokers compared with their nonsmoker twin. This reduction in bone density was proportional to the smoking magnitude, and it was calculated that every 10 pack-years of smoking caused decreases in bone density of 2%, 0.9%, and 1.4% in lumbar vertebrae, neck of femur, and shaft of femur, respectively.97 A reduced effectiveness of hormonal replacement therapy has also been shown in postmenopausal smoking women.
Possible causes for the increased rate of osteoporosis in smoking women are anti-estrogenic effects of smoking, earlier menopause, and lower body mass in smoking women, all of which may accelerate the loss of bone mass.98
Gastrointestinal disorders
Gastric and duodenal ulcer disease is more prevalent in smokers than in nonsmokers. The RR of smokers, compared to lifelong nonsmokers, was 3.4 and 4.1 for gastric and duodenal ulcers, respectively, in a study conducted in Norway.99 Increased mortality from peptic disease among smokers was shown in a follow-up study of British doctors. In this study the excess death from peptic ulcer was about threefold in smokers.64 The association of smoking with peptic ulcer is likely to be largely or wholly causal. Smoking inhibits pancreatic bicarbonate secretion, decreases the pressure of esophageal and pyloric sphincters, impairs spontaneous and drug-induced healing of peptic ulcers, and increases the likelihood of duodenal ulcer recurrence. Histamine-2-receptor antagonist inhibition of nocturnal gastric secretion is also decreased by smoking. Gastroesophageal reflux disease may be aggravated owing to the decreased tone of the esophageal sphincter caused by smoking.
The mortality for cirrhosis of the liver was five times as great in current smokers as in nonsmokers, and five times as great in heavy smokers as in light cigarette smokers, but this relation is largely noncausal. The increased risk is considered due to confounding: The association of cirrhosis with smoking is thought to be secondary to association with alcohol consumption. The close association between smoking and drinking habits was confirmed by a questionnaire, which inquired about smoking and drinking habits among doctors.100 Finally, the RR for Crohn’s disease is 2.1 in smokers compared with nonsmokers. This contrasts with the possible protective effect of smoking on ulcerative colitis, which is consistent though modest.4
Protective effects of smoking
The protective effect of tobacco has been demonstrated with a remarkable consistency for Parkinson’s disease. Smokers have about half the risk for Parkinsonism compared with nonsmokers. This reduction is probably causal, and there is a plausible pharmacological explanation for this negative association. Nicotine stimulates dopamine release, which can ameliorate the disease. Smoking also reduces the risk of endometrial cancer—probably because of its anti-estrogenic effect. Smoking has a protective effect on ulcerative colitis as mentioned in the section on gastrointestinal diseases.4 Smoking mothers have a lower birth prevalence of Down’s syndrome. This may be due to increased risk of abortion in smoking women, which has a disproportionate effect in Down’s syndrome pregnancies compared with normal pregnancies.101
It must be emphasized, however, that, taken as a whole, the “benefits” of smoking are completely negligible compared with the serious and fatal diseases caused by cigarette smoking.
Cigarette smoking and passive exposure to tobacco smoke in children and adolescents
Cigarette smoking by children and adolescents and their passive exposure to tobacco smoke are associated with many harmful effects. These include:

increased neonatal and infant mortality in children whose parents smoke;

increased morbidity from respiratory diseases in children exposed to tobacco smoke102;

adverse physiological and metabolic changes in adolescents who smoke.

Most important, atherosclerosis, endothelial and epithelial injury, and altered lung function—the initiating pathophysiological events that lead to CHD, cancer, and chronic obstructive pulmonary disease—have been described in children exposed to cigarette smoke. Thus, the basis for life-threatening disease later in life is already being laid down in young smokers.
Most of the pathophysiological and metabolic effects of smoking, which were previously described in adult smokers, have also been demonstrated in children exposed to cigarette smoke and in smoking adolescents. These include reduced oxygen transport by the hemoglobin and consistent changes in serum lipoproteins (elevated levels of triglycerides, VLDL cholesterol, LDL cholesterol, and reduced levels of HDL cholesterol: a decline of 3 to 5 mg/dL in HDL cholesterol occurs in children passively exposed to smoke), and increased platelet aggregation and thrombotic potential. Endothelial injury, which is a primary initiating event of atherosclerosis, has been demonstrated after passive exposure to smoke, and in the umbilical arteries of infants born to mothers who smoke.
Pathological evidences for the association of smoking with atherosclerosis in young persons has come from the PDAY (Pathobiological Determinants of Atherosclerosis in Youth) study, which correlated tobacco smoke exposure to arterial lesions in young adults aged 15 to 35 years who died accidentally. Cigarette smoking increased the risk of having atherosclerotic lesions. The likelihood of having these lesions was greater in smokers than the likelihood attributed to a 50-mg/dL increase in LDL cholesterol and a 20-mg/dL decrease in HDL cholesterol.103
Tobacco smoke affects the lungs and respiratory tracts of infants, children, and adolescents by passive exposure in utero caused by maternal smoking,102 by passive exposure to tobacco smoke produced by parents, or by active smoking. Children and adolescents who smoke have increases in respiratory symptoms and reduction in lung function similar to adults who smoke. Exposure to environmental tobacco smoke is especially harmful for the respiratory tract of infants and toddlers. In infancy, exposure to toxic compounds in cigarette smoke is particularly problematic because early lung development seems to be a critical determinant of respiratory health.
Risk of respiratory illness is also increased in infants and children whose parents smoke. Infants exposed to maternal smoking had an increased incidence of lower respiratory tract infection, with a dose-response relationship to maternal smoking. Infants whose mothers smoked at least one pack a day had 2.8 times the risk of developing pneumonia. Bronchiolitis in infants was also associated with maternal smoking. Prenatal effects of maternal smoking on the lungs have been found in infants born to smoking mothers, as evidenced by reduced forced expiratory flows. The decrease in these parameters was correlated with the level of intrauterine exposure to products of cigarette smoke. Postnatal exposure to maternal smoking has the same effect of reduction of lung functions. Researchers have found a reduction of forced expiratory volume in 1 second of 10 mL/g of tobacco per day smoked by the mother.104
Exposure to environmental tobacco smoke in childhood is associated with an increased risk for developing asthma. This risk was found to be about two times higher in youngsters exposed to tobacco smoke than in those free from exposure.105 The development of asthma in these children may be mediated by alteration of the developing lung’s structure and function and by immune mechanisms, as evidenced by eosinophilia, increased levels of IgE, and increased bronchial reactivity and sensitization to allergens. Higher mortality occurs in infants of mothers who smoke compared with those who do not smoke. This higher risk is independent of other factors such as birth weight.
Maternal smoking is also associated with infant death from sudden infant death syndrome (SIDS) and from respiratory deaths. It appears that both intrauterine exposure and postnatal exposure to maternal smoking increase the risk of SIDS.
Researchers have demonstrated a threefold increase of the risk of this syndrome in infants exposed to tobacco smoke in utero and postnatally versus a twofold increase in those with only postnatal exposure, compared with infants not exposed to tobacco smoke.106
Another possible serious health risk in children exposed in utero to tobacco smoke is the risk of developing cancer. However, results of studies investigating this possibility are inconclusive. It is also difficult to solve the question whether childhood exposure to environmental tobacco smoke increases the risk of lung cancer in adult life, owing to the very long latent period between exposure and diagnosis of the cancer. A recent study of lung cancer patients showed that living with two smokers during childhood doubles the risk of lung cancer in nonsmokers, but more studies are needed to clarify this issue. Some evidence shows that active smoking begun before the age of 15 years greatly increases the risk of lung cancer in later life. Other short-term effects of active smoking in children include increased risk of leukoplakia, susceptibility to infection, shaky hands, and increased pulse rate.
Summary
Cigarette smoking, the chief preventable cause of illness and death in the industrialized nations, is a major contributor to morbidity and mortality from cardiovascular and respiratory diseases. It is also the most important preventable factor in the development of lung cancer and various other malignancies, and it may also have a significant role in the pathogenesis of other diseases. Cigarette smoking, the leading cause of morbidity, disability, and death in the Western world, may be considered the most serious pandemic of our century.51
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Address correspondence to Dr. Y. Skurnik, Chaim Sheba Medical Center, Dept. of Medicine B, 52621 Telashomer, Tel-Aviv, Israel
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