Smoking causes death from many diseases that until now have not been linked officially to tobacco use, including digestive disorders, liver cirrhosis, infections, renal failure, and breast and prostate cancers, according to a report published online Feb. 11 in the New England Journal of Medicine.

“Our results suggest that the number of persons in the United States who die each year as a result of smoking cigarettes may be substantially greater than currently estimated,” said Brian D. Carter of the epidemiology research program, American Cancer Society, Atlanta, and his associates.

The 2014 Surgeon General’s report estimated that smoking causes more than 480,000 deaths every year in the United States, based on mortality figures from 21 diseases that have been formally established as caused by smoking: 12 types of cancer, 6 types of cardiovascular disease, diabetes, chronic obstructive pulmonary disease, and pneumonia. Mr. Carter and his associates pooled data from five large cohort studies to examine possible associations between smoking and an additional 31 cause-of-death categories. They now estimate that an additional 60,000-120,000 deaths each year can be attributed to smoking.

For their study, the investigators assessed 421,378 men and 532,651 women aged 55 years and older at baseline whose smoking status was carefully recorded and who were followed from 2000 to 2011 in the Cancer Prevention Study II Nutrition Cohort, the Nurses’ Health Study I, the Health Professionals Follow-up Study, the Women’s Health Initiative, and the National Institutes of Health-AARP Diet and Health Study.

As expected, smokers had a twofold to threefold higher mortality from any cause, compared with nonsmokers. Smokers also had a markedly higher risk of death than nonsmokers from all 21 causes already established as attributable to tobacco use, such as lung cancer, oral cancer, ischemic heart disease, atherosclerosis, and stroke. But approximately 17% of smokers’ excess mortality was accounted for by several diseases that previously have not been attributable to tobacco use.

For example, the risk of death due to intestinal ischemia was approximately six times higher among smokers than among nonsmokers, a remarkably strong association that was also reported in the Million Women Study. “Smoking acutely reduces blood flow to the intestines, and evidence suggests that smoking causes risk factors that can often lead to intestinal ischemia, including atherosclerosis, platelet aggregation, and congestive heart failure,” Mr. Carter and his associates said (N. Engl. J. Med. 2015 Feb. 12 [doi:10.1056/NEJMsa140721]). In this study, smoking also more than doubled the risk of dying from other digestive diseases. Previous studies have suggested a link between smoking and digestive disorders such as Crohn’s disease, peptic ulcers, acute pancreatitis, paralytic ileus, bowel obstruction, choletlithiasis, diverticulitis, and gastrointestinal hemorrhage. “Although these diseases are not common causes of death, they account for millions of hospitalizations each year,” the investigators noted.

The mortality risk from liver cirrhosis, after the data were adjusted to account for alcohol consumption, was more than three times higher in smokers than in nonsmokers. Even smokers who did not drink alcohol were at significantly increased risk of cirrhosis, compared with nonsmokers.

The risk of death due to infection was 2.3 times higher in smokers than in nonsmokers. This strong association was dose-dependent, as infection-related mortality rose with increasing smoking intensity. And among study participants who had quit smoking, infection-related mortality declined as the number of years since cessation increased.

The rate of death due to renal failure was twice as high among smokers as among nonsmokers. And the rate of death due to hypertensive heart disease, the only category of heart disease not already established as smoking related, was 2.4 times higher in smokers. The latter association “is relevant for assessing the public health burden of smoking, since a considerable number of deaths in the United States are attributable to hypertensive heart disease,” according to Mr. Carter and his associates.

Smoking also was strongly associated with “multiple diseases too uncommon to examine individually.” This included all rare cancers combined, rare digestive diseases, and respiratory diseases other than those already known to stem from smoking.

In women, smoking raised breast cancer mortality, with a relative risk of 1.3. This association was strongly dose dependent. In men, smoking raised prostate cancer mortality, with a relative risk of 1.4.

This study was limited in that most of the participants were white and better educated than the general population, which may affect the applicability of the results to other populations.