Only 1% of adults with asymptomatic neoplastic pancreatic cysts developed invasive pancreatic adenocarcinoma after more than 5 years of follow-up, according to a multicenter retrospective study reported in the June issue of Clinical Gastroenterology and Hepatology.

©iStock / ThinkStockPhotos.com

Furthermore, there were no malignant conversions among patients lacking American Gastroenterological Association high-risk features – that is, mural nodules, dilated pancreatic ducts, or cysts measuring more than 3 cm, said Dr. Wilson Kwong at the University of California San Diego Health Sciences in La Jolla. “There is a very low risk of malignant transformation of asymptomatic neoplastic pancreatic cysts after 5 years,” he and his associates wrote.

Up to 20% of cross-sectional imaging studies reveal incidental pancreatic cysts, the researchers noted. Cysts with neoplastic features are recommended for indefinite surveillance, even though there is little or no data on their natural history and malignant potential beyond 5- 10 years, they added. Therefore, they studied 310 patients who underwent endoscopic ultrasound of pancreatic cysts at an academic medical center, a Veterans’ Affairs hospital, and two community health care systems in California between 2002 and 2010. The most common age at enrollment was 66 years, 60% of patients were women, and the median follow-up period was 87 months (range, 60 to 189 months). A total of 90% of patients were followed for 5-10 years, while 10% were followed for more than 10 years (Clin Gastroenterol Hepatol. 2016 Feb 10. doi: 10.1016/j.cgh.2015.11.013).

Source: American Gastroenterological Association

In all, three patients developed invasive pancreatic malignancies after 6, 8, and 11 years of follow-up, for an overall conversion rate of 1%. Conversion rates by subgroup were 0% for patients with no high-risk AGA features, 1% (one case) for patients with one high-risk feature, and 15% (two cases) for patients with two high-risk features. “Because the risk of malignant transformation beyond 5 years is lower than the 1.4% mortality risk of pancreatic resection at high-volume centers, the argument can be made that discontinuing surveillance after 5 years is justified,” the researchers said. Specifically, surveillance could be discontinued after 5 years for neoplastic pancreatic cysts with up to one high-risk feature, particularly if patients have significant comorbidities that increase their risk of imminent death from other causes, they added. In contrast, healthy patients in their 60s and 70s might benefit from long-term surveillance given their longer life expectancy, they said. “Among patients with two high-risk features who remain surgically fit, discussion of surgery or surveillance beyond 5 years should be considered,” they emphasized.

A total of two patients developed high-grade dysplasia – a risk factor for invasive pancreatic cancer – but even so, the aggregate rate of cancer and high-grade dysplasia was 1.6%, only slightly higher than the fatality rate associated with pancreatic resection, the researchers noted. By excluding patients with recent acute pancreatitis (because of the likelihood of pseudocysts), they might have inadvertently excluded “a small number” of patients with pancreatic intraductal papillary mucinous neoplasms, they added.

The University of California San Diego Health Care System supported the study. The investigators had no disclosures.

Only 1% of adults with asymptomatic neoplastic pancreatic cysts developed invasive pancreatic adenocarcinoma after more than 5 years of follow-up, according to a multicenter retrospective study reported in the June issue of Clinical Gastroenterology and Hepatology.

©iStock / ThinkStockPhotos.com

Furthermore, there were no malignant conversions among patients lacking American Gastroenterological Association high-risk features – that is, mural nodules, dilated pancreatic ducts, or cysts measuring more than 3 cm, said Dr. Wilson Kwong at the University of California San Diego Health Sciences in La Jolla. “There is a very low risk of malignant transformation of asymptomatic neoplastic pancreatic cysts after 5 years,” he and his associates wrote.

Up to 20% of cross-sectional imaging studies reveal incidental pancreatic cysts, the researchers noted. Cysts with neoplastic features are recommended for indefinite surveillance, even though there is little or no data on their natural history and malignant potential beyond 5- 10 years, they added. Therefore, they studied 310 patients who underwent endoscopic ultrasound of pancreatic cysts at an academic medical center, a Veterans’ Affairs hospital, and two community health care systems in California between 2002 and 2010. The most common age at enrollment was 66 years, 60% of patients were women, and the median follow-up period was 87 months (range, 60 to 189 months). A total of 90% of patients were followed for 5-10 years, while 10% were followed for more than 10 years (Clin Gastroenterol Hepatol. 2016 Feb 10. doi: 10.1016/j.cgh.2015.11.013).

Source: American Gastroenterological Association

In all, three patients developed invasive pancreatic malignancies after 6, 8, and 11 years of follow-up, for an overall conversion rate of 1%. Conversion rates by subgroup were 0% for patients with no high-risk AGA features, 1% (one case) for patients with one high-risk feature, and 15% (two cases) for patients with two high-risk features. “Because the risk of malignant transformation beyond 5 years is lower than the 1.4% mortality risk of pancreatic resection at high-volume centers, the argument can be made that discontinuing surveillance after 5 years is justified,” the researchers said. Specifically, surveillance could be discontinued after 5 years for neoplastic pancreatic cysts with up to one high-risk feature, particularly if patients have significant comorbidities that increase their risk of imminent death from other causes, they added. In contrast, healthy patients in their 60s and 70s might benefit from long-term surveillance given their longer life expectancy, they said. “Among patients with two high-risk features who remain surgically fit, discussion of surgery or surveillance beyond 5 years should be considered,” they emphasized.

A total of two patients developed high-grade dysplasia – a risk factor for invasive pancreatic cancer – but even so, the aggregate rate of cancer and high-grade dysplasia was 1.6%, only slightly higher than the fatality rate associated with pancreatic resection, the researchers noted. By excluding patients with recent acute pancreatitis (because of the likelihood of pseudocysts), they might have inadvertently excluded “a small number” of patients with pancreatic intraductal papillary mucinous neoplasms, they added.

The University of California San Diego Health Care System supported the study. The investigators had no disclosures.

Only 1% of adults with asymptomatic neoplastic pancreatic cysts developed invasive pancreatic adenocarcinoma after more than 5 years of follow-up, according to a multicenter retrospective study reported in the June issue of Clinical Gastroenterology and Hepatology.

©iStock / ThinkStockPhotos.com

Furthermore, there were no malignant conversions among patients lacking American Gastroenterological Association high-risk features – that is, mural nodules, dilated pancreatic ducts, or cysts measuring more than 3 cm, said Dr. Wilson Kwong at the University of California San Diego Health Sciences in La Jolla. “There is a very low risk of malignant transformation of asymptomatic neoplastic pancreatic cysts after 5 years,” he and his associates wrote.

Up to 20% of cross-sectional imaging studies reveal incidental pancreatic cysts, the researchers noted. Cysts with neoplastic features are recommended for indefinite surveillance, even though there is little or no data on their natural history and malignant potential beyond 5- 10 years, they added. Therefore, they studied 310 patients who underwent endoscopic ultrasound of pancreatic cysts at an academic medical center, a Veterans’ Affairs hospital, and two community health care systems in California between 2002 and 2010. The most common age at enrollment was 66 years, 60% of patients were women, and the median follow-up period was 87 months (range, 60 to 189 months). A total of 90% of patients were followed for 5-10 years, while 10% were followed for more than 10 years (Clin Gastroenterol Hepatol. 2016 Feb 10. doi: 10.1016/j.cgh.2015.11.013).

Source: American Gastroenterological Association

In all, three patients developed invasive pancreatic malignancies after 6, 8, and 11 years of follow-up, for an overall conversion rate of 1%. Conversion rates by subgroup were 0% for patients with no high-risk AGA features, 1% (one case) for patients with one high-risk feature, and 15% (two cases) for patients with two high-risk features. “Because the risk of malignant transformation beyond 5 years is lower than the 1.4% mortality risk of pancreatic resection at high-volume centers, the argument can be made that discontinuing surveillance after 5 years is justified,” the researchers said. Specifically, surveillance could be discontinued after 5 years for neoplastic pancreatic cysts with up to one high-risk feature, particularly if patients have significant comorbidities that increase their risk of imminent death from other causes, they added. In contrast, healthy patients in their 60s and 70s might benefit from long-term surveillance given their longer life expectancy, they said. “Among patients with two high-risk features who remain surgically fit, discussion of surgery or surveillance beyond 5 years should be considered,” they emphasized.

A total of two patients developed high-grade dysplasia – a risk factor for invasive pancreatic cancer – but even so, the aggregate rate of cancer and high-grade dysplasia was 1.6%, only slightly higher than the fatality rate associated with pancreatic resection, the researchers noted. By excluding patients with recent acute pancreatitis (because of the likelihood of pseudocysts), they might have inadvertently excluded “a small number” of patients with pancreatic intraductal papillary mucinous neoplasms, they added.

The University of California San Diego Health Care System supported the study. The investigators had no disclosures.

Women with high circulating levels of interleukin-6 and high-sensitivity C-reactive protein were at significantly greater risk of inflammatory bowel disease (IBD) compared with those testing in the lowest quintiles, according to a prospective nested case-control study.

The findings point to a preclinical state in IBD, in which patients are not yet symptomatic but have positive serologic markers, as occurs in rheumatoid arthritis and systemic lupus erythematosus, said Dr. Paul Lochhead at Massachusetts General Hospital in Boston, and his associates. “To our knowledge, no previous study has examined prediagnostic inflammatory markers in relation to IBD risk,” the investigators added. “Characterizing preclinical inflammation in IBD could give insights into the natural history of [Crohn’s disease] and [ulcerative colitis], and might help identify potential windows for early therapeutic or preventive interventions in high-risk individuals.”

SOURCE: American Gastroenterological Society

The study included 83 patients with Crohn’s disease, 90 patients with ulcerative colitis, and 344 matched controls. Patients were from two national prospective cohort studies – the Nurses’ Health Study, which includes female nurses aged 35-55 years at enrollment, and the Nurses’ Health Study II, which includes female nurses aged 24-42 years at enrollment. Both studies are ongoing, with follow-up rates exceeding 90%. To assemble the cohort, the researchers extracted questionnaire data and then obtained medical records for blinded review. They confirmed diagnoses of Crohn’s disease and ulcerative colitis using standard case definitions, they said (Clin Gastroenterol Hepatol. 2016 Feb 13. doi: 10.1016/j.cgh.2016.01.016).

Participants testing in the highest quintiles for circulating hs-CRP and IL-6 were at greater risk of Crohn’s disease and ulcerative colitis than were those in the lowest quintiles, even after accounting for age, smoking status, body mass index, oral contraceptive use, and cumulative physical activity. For IL-6, odds ratios were 4.7 for Crohn’s disease (95% confidence interval; 1.9-11.5), and 3.4 for ulcerative colitis (95% CI; 1.4-8.2). For hs-CRP, odds ratios were 2.8 for Crohn’s disease (95% CI; 1.15-6.9) and 1.8 for ulcerative colitis (95% CI; 0.8-4.0). The longest interval between testing and diagnosis of IBD was 20 years, Crohn’s disease patients were diagnosed within 10 years, and patients testing in the upper quintile for the inflammatory markers were diagnosed an average of 10.6 years later, the researchers said.

Study participants tended to be in their early 50s when first tested, which exceeds the typical age of Crohn’s disease and ulcerative colitis onset and might limit the generalizability of the findings, the investigators said. They tried to eliminate confounding from undiagnosed baseline IBD by excluding participants diagnosed within 2 years of blood collection, they added. “The differences in overall median inflammatory marker levels between cases and control subjects in our study were small; however, differences of similar magnitude have been reported between groups with disparate outcomes in studies of cardiovascular disease,” they noted. “Moreover, when comparing extreme quintiles of median inflammatory marker levels, where risk of [Crohn’s disease] or [ulcerative colitis] was most evident, the differences were more substantial.”

The study was funded by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Crohn’s and Colitis Foundation of America, and the American Gastroenterological Association. Dr. Lochhead had no disclosures. Two coinvestigators disclosed relationships with Exact Sciences, AbbVie, Cubist Pharmaceuticals, Bayer Healthcare, Pfizer, and Pozen.

Women with high circulating levels of interleukin-6 and high-sensitivity C-reactive protein were at significantly greater risk of inflammatory bowel disease (IBD) compared with those testing in the lowest quintiles, according to a prospective nested case-control study.

The findings point to a preclinical state in IBD, in which patients are not yet symptomatic but have positive serologic markers, as occurs in rheumatoid arthritis and systemic lupus erythematosus, said Dr. Paul Lochhead at Massachusetts General Hospital in Boston, and his associates. “To our knowledge, no previous study has examined prediagnostic inflammatory markers in relation to IBD risk,” the investigators added. “Characterizing preclinical inflammation in IBD could give insights into the natural history of [Crohn’s disease] and [ulcerative colitis], and might help identify potential windows for early therapeutic or preventive interventions in high-risk individuals.”

SOURCE: American Gastroenterological Society

The study included 83 patients with Crohn’s disease, 90 patients with ulcerative colitis, and 344 matched controls. Patients were from two national prospective cohort studies – the Nurses’ Health Study, which includes female nurses aged 35-55 years at enrollment, and the Nurses’ Health Study II, which includes female nurses aged 24-42 years at enrollment. Both studies are ongoing, with follow-up rates exceeding 90%. To assemble the cohort, the researchers extracted questionnaire data and then obtained medical records for blinded review. They confirmed diagnoses of Crohn’s disease and ulcerative colitis using standard case definitions, they said (Clin Gastroenterol Hepatol. 2016 Feb 13. doi: 10.1016/j.cgh.2016.01.016).

Participants testing in the highest quintiles for circulating hs-CRP and IL-6 were at greater risk of Crohn’s disease and ulcerative colitis than were those in the lowest quintiles, even after accounting for age, smoking status, body mass index, oral contraceptive use, and cumulative physical activity. For IL-6, odds ratios were 4.7 for Crohn’s disease (95% confidence interval; 1.9-11.5), and 3.4 for ulcerative colitis (95% CI; 1.4-8.2). For hs-CRP, odds ratios were 2.8 for Crohn’s disease (95% CI; 1.15-6.9) and 1.8 for ulcerative colitis (95% CI; 0.8-4.0). The longest interval between testing and diagnosis of IBD was 20 years, Crohn’s disease patients were diagnosed within 10 years, and patients testing in the upper quintile for the inflammatory markers were diagnosed an average of 10.6 years later, the researchers said.

Study participants tended to be in their early 50s when first tested, which exceeds the typical age of Crohn’s disease and ulcerative colitis onset and might limit the generalizability of the findings, the investigators said. They tried to eliminate confounding from undiagnosed baseline IBD by excluding participants diagnosed within 2 years of blood collection, they added. “The differences in overall median inflammatory marker levels between cases and control subjects in our study were small; however, differences of similar magnitude have been reported between groups with disparate outcomes in studies of cardiovascular disease,” they noted. “Moreover, when comparing extreme quintiles of median inflammatory marker levels, where risk of [Crohn’s disease] or [ulcerative colitis] was most evident, the differences were more substantial.”

The study was funded by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Crohn’s and Colitis Foundation of America, and the American Gastroenterological Association. Dr. Lochhead had no disclosures. Two coinvestigators disclosed relationships with Exact Sciences, AbbVie, Cubist Pharmaceuticals, Bayer Healthcare, Pfizer, and Pozen.

Women with high circulating levels of interleukin-6 and high-sensitivity C-reactive protein were at significantly greater risk of inflammatory bowel disease (IBD) compared with those testing in the lowest quintiles, according to a prospective nested case-control study.

The findings point to a preclinical state in IBD, in which patients are not yet symptomatic but have positive serologic markers, as occurs in rheumatoid arthritis and systemic lupus erythematosus, said Dr. Paul Lochhead at Massachusetts General Hospital in Boston, and his associates. “To our knowledge, no previous study has examined prediagnostic inflammatory markers in relation to IBD risk,” the investigators added. “Characterizing preclinical inflammation in IBD could give insights into the natural history of [Crohn’s disease] and [ulcerative colitis], and might help identify potential windows for early therapeutic or preventive interventions in high-risk individuals.”

SOURCE: American Gastroenterological Society

The study included 83 patients with Crohn’s disease, 90 patients with ulcerative colitis, and 344 matched controls. Patients were from two national prospective cohort studies – the Nurses’ Health Study, which includes female nurses aged 35-55 years at enrollment, and the Nurses’ Health Study II, which includes female nurses aged 24-42 years at enrollment. Both studies are ongoing, with follow-up rates exceeding 90%. To assemble the cohort, the researchers extracted questionnaire data and then obtained medical records for blinded review. They confirmed diagnoses of Crohn’s disease and ulcerative colitis using standard case definitions, they said (Clin Gastroenterol Hepatol. 2016 Feb 13. doi: 10.1016/j.cgh.2016.01.016).

Participants testing in the highest quintiles for circulating hs-CRP and IL-6 were at greater risk of Crohn’s disease and ulcerative colitis than were those in the lowest quintiles, even after accounting for age, smoking status, body mass index, oral contraceptive use, and cumulative physical activity. For IL-6, odds ratios were 4.7 for Crohn’s disease (95% confidence interval; 1.9-11.5), and 3.4 for ulcerative colitis (95% CI; 1.4-8.2). For hs-CRP, odds ratios were 2.8 for Crohn’s disease (95% CI; 1.15-6.9) and 1.8 for ulcerative colitis (95% CI; 0.8-4.0). The longest interval between testing and diagnosis of IBD was 20 years, Crohn’s disease patients were diagnosed within 10 years, and patients testing in the upper quintile for the inflammatory markers were diagnosed an average of 10.6 years later, the researchers said.

Study participants tended to be in their early 50s when first tested, which exceeds the typical age of Crohn’s disease and ulcerative colitis onset and might limit the generalizability of the findings, the investigators said. They tried to eliminate confounding from undiagnosed baseline IBD by excluding participants diagnosed within 2 years of blood collection, they added. “The differences in overall median inflammatory marker levels between cases and control subjects in our study were small; however, differences of similar magnitude have been reported between groups with disparate outcomes in studies of cardiovascular disease,” they noted. “Moreover, when comparing extreme quintiles of median inflammatory marker levels, where risk of [Crohn’s disease] or [ulcerative colitis] was most evident, the differences were more substantial.”

The study was funded by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Crohn’s and Colitis Foundation of America, and the American Gastroenterological Association. Dr. Lochhead had no disclosures. Two coinvestigators disclosed relationships with Exact Sciences, AbbVie, Cubist Pharmaceuticals, Bayer Healthcare, Pfizer, and Pozen.

Women with Crohn’s disease who were prescribed combination oral contraceptive pills for more than 3 years were 68% more likely to need gastrointestinal surgery than patients who did not use oral contraceptives, according to a national prospective cohort study reported in the June issue of Gastroenterology.

“Our data suggest the importance of carefully evaluating contraceptive options among women with established Crohn’s disease. Future studies should focus on mechanisms by which oral contraceptive use alters risk and progression,” said Dr. Hamed Khalili of Harvard Medical School in Boston and his associates at Harvard and Karolinska Institutet, Solna, Sweden.

©Thinkstock

Several studies have linked OC exposure to Crohn’s disease itself. But past studies of OCs and Crohn’s disease progression were small, retrospective, or did not adequately ascertain OC exposure, Dr. Khalili and his associates said. To help fill this gap, they identified 4,036 women with Crohn’s disease aged 16-51 years through the Swedish National Patient Register, and ascertained OC exposure by analyzing Sweden’s national prescription database (Gastroenterology. 2016 Feb 23. doi: 10.1053/j.gastro.2016.02.041).

During a median follow-up period of 58 months, 482 patients (12%) underwent surgery related to Crohn’s disease, the researchers said. Use of OCs was associated with surgery, but the link only reached statistical significance among women prescribed combination (estrogen-containing) regimens for more than 3 years (adjusted hazard ratio, 1.68; 95% confidence interval, 1.06-2.67) or for more than 900 doses (aHR, 1.60; 95% CI, 1.1-2.34). For each additional year that combination OCs were prescribed, surgery risk rose by nearly 30% (aHR, 1.29; 95% CI, 1.05-1.57). Thus, one extra surgery was needed for every 83 patients who received combination OCs for at least 1 year, said the investigators. Progestin-only prescriptions did not increase the likelihood of needing surgery, and there was no link between current or prior OC exposure and the chances of being prescribed steroids, they noted.

Only one other study has linked OC exposure with Crohn’s disease progression, and it included only 158 patients followed for just a year, Dr. Khalili and his associates said. Exactly how estrogen exposure might trigger Crohn’s disease progression is unclear, but OCs have been linked to changes in intestinal barrier function, increased humoral immunity, and modulation of testosterone levels, which in turn affects cytokine function, they added. “Regardless of the potential mechanism, the effect of OCs on Crohn’s disease progression appears to be related to consistent and long-term use of these medications. Similar patterns of associations have also been reported with other chronic illnesses, such as breast cancer and cardiovascular diseases,” said the researchers. Current OC use itself might not have predicted surgery in the study because about one in four women in Sweden stop taking OCs or switch to a nonhormonal form within 6 months of being prescribed them, they added.

The work was funded by the Crohn’s and Colitis Foundation of America, the National Institute of Diabetes and Digestive and Kidney Diseases, the American Gastroenterological Association, and the American College of Gastroenterology. Dr. Khalili reported receiving consulting fees from Abbvie. One coinvestigator reported consulting relationships with Bayer Healthcare, Pfizer, and Pozen. The other investigators had no disclosures.

Women with Crohn’s disease who were prescribed combination oral contraceptive pills for more than 3 years were 68% more likely to need gastrointestinal surgery than patients who did not use oral contraceptives, according to a national prospective cohort study reported in the June issue of Gastroenterology.

“Our data suggest the importance of carefully evaluating contraceptive options among women with established Crohn’s disease. Future studies should focus on mechanisms by which oral contraceptive use alters risk and progression,” said Dr. Hamed Khalili of Harvard Medical School in Boston and his associates at Harvard and Karolinska Institutet, Solna, Sweden.

©Thinkstock

Several studies have linked OC exposure to Crohn’s disease itself. But past studies of OCs and Crohn’s disease progression were small, retrospective, or did not adequately ascertain OC exposure, Dr. Khalili and his associates said. To help fill this gap, they identified 4,036 women with Crohn’s disease aged 16-51 years through the Swedish National Patient Register, and ascertained OC exposure by analyzing Sweden’s national prescription database (Gastroenterology. 2016 Feb 23. doi: 10.1053/j.gastro.2016.02.041).

During a median follow-up period of 58 months, 482 patients (12%) underwent surgery related to Crohn’s disease, the researchers said. Use of OCs was associated with surgery, but the link only reached statistical significance among women prescribed combination (estrogen-containing) regimens for more than 3 years (adjusted hazard ratio, 1.68; 95% confidence interval, 1.06-2.67) or for more than 900 doses (aHR, 1.60; 95% CI, 1.1-2.34). For each additional year that combination OCs were prescribed, surgery risk rose by nearly 30% (aHR, 1.29; 95% CI, 1.05-1.57). Thus, one extra surgery was needed for every 83 patients who received combination OCs for at least 1 year, said the investigators. Progestin-only prescriptions did not increase the likelihood of needing surgery, and there was no link between current or prior OC exposure and the chances of being prescribed steroids, they noted.

Only one other study has linked OC exposure with Crohn’s disease progression, and it included only 158 patients followed for just a year, Dr. Khalili and his associates said. Exactly how estrogen exposure might trigger Crohn’s disease progression is unclear, but OCs have been linked to changes in intestinal barrier function, increased humoral immunity, and modulation of testosterone levels, which in turn affects cytokine function, they added. “Regardless of the potential mechanism, the effect of OCs on Crohn’s disease progression appears to be related to consistent and long-term use of these medications. Similar patterns of associations have also been reported with other chronic illnesses, such as breast cancer and cardiovascular diseases,” said the researchers. Current OC use itself might not have predicted surgery in the study because about one in four women in Sweden stop taking OCs or switch to a nonhormonal form within 6 months of being prescribed them, they added.

The work was funded by the Crohn’s and Colitis Foundation of America, the National Institute of Diabetes and Digestive and Kidney Diseases, the American Gastroenterological Association, and the American College of Gastroenterology. Dr. Khalili reported receiving consulting fees from Abbvie. One coinvestigator reported consulting relationships with Bayer Healthcare, Pfizer, and Pozen. The other investigators had no disclosures.

Women with Crohn’s disease who were prescribed combination oral contraceptive pills for more than 3 years were 68% more likely to need gastrointestinal surgery than patients who did not use oral contraceptives, according to a national prospective cohort study reported in the June issue of Gastroenterology.

“Our data suggest the importance of carefully evaluating contraceptive options among women with established Crohn’s disease. Future studies should focus on mechanisms by which oral contraceptive use alters risk and progression,” said Dr. Hamed Khalili of Harvard Medical School in Boston and his associates at Harvard and Karolinska Institutet, Solna, Sweden.

©Thinkstock

Several studies have linked OC exposure to Crohn’s disease itself. But past studies of OCs and Crohn’s disease progression were small, retrospective, or did not adequately ascertain OC exposure, Dr. Khalili and his associates said. To help fill this gap, they identified 4,036 women with Crohn’s disease aged 16-51 years through the Swedish National Patient Register, and ascertained OC exposure by analyzing Sweden’s national prescription database (Gastroenterology. 2016 Feb 23. doi: 10.1053/j.gastro.2016.02.041).

During a median follow-up period of 58 months, 482 patients (12%) underwent surgery related to Crohn’s disease, the researchers said. Use of OCs was associated with surgery, but the link only reached statistical significance among women prescribed combination (estrogen-containing) regimens for more than 3 years (adjusted hazard ratio, 1.68; 95% confidence interval, 1.06-2.67) or for more than 900 doses (aHR, 1.60; 95% CI, 1.1-2.34). For each additional year that combination OCs were prescribed, surgery risk rose by nearly 30% (aHR, 1.29; 95% CI, 1.05-1.57). Thus, one extra surgery was needed for every 83 patients who received combination OCs for at least 1 year, said the investigators. Progestin-only prescriptions did not increase the likelihood of needing surgery, and there was no link between current or prior OC exposure and the chances of being prescribed steroids, they noted.

Only one other study has linked OC exposure with Crohn’s disease progression, and it included only 158 patients followed for just a year, Dr. Khalili and his associates said. Exactly how estrogen exposure might trigger Crohn’s disease progression is unclear, but OCs have been linked to changes in intestinal barrier function, increased humoral immunity, and modulation of testosterone levels, which in turn affects cytokine function, they added. “Regardless of the potential mechanism, the effect of OCs on Crohn’s disease progression appears to be related to consistent and long-term use of these medications. Similar patterns of associations have also been reported with other chronic illnesses, such as breast cancer and cardiovascular diseases,” said the researchers. Current OC use itself might not have predicted surgery in the study because about one in four women in Sweden stop taking OCs or switch to a nonhormonal form within 6 months of being prescribed them, they added.

The work was funded by the Crohn’s and Colitis Foundation of America, the National Institute of Diabetes and Digestive and Kidney Diseases, the American Gastroenterological Association, and the American College of Gastroenterology. Dr. Khalili reported receiving consulting fees from Abbvie. One coinvestigator reported consulting relationships with Bayer Healthcare, Pfizer, and Pozen. The other investigators had no disclosures.

Answer
The radiograph has several findings, one of which is a nondisplaced proximal fibula fracture. In addition, there is a moderate suprapatellar joint effusion. The patient also has fairly advanced tricompartment degenerative arthrosis. (To review, the tricompartment comprises all three anatomic areas of the knee: the patellofemoral, lateral tibiofemoral, and medial tibiofemoral joints.)

Answer
The radiograph has several findings, one of which is a nondisplaced proximal fibula fracture. In addition, there is a moderate suprapatellar joint effusion. The patient also has fairly advanced tricompartment degenerative arthrosis. (To review, the tricompartment comprises all three anatomic areas of the knee: the patellofemoral, lateral tibiofemoral, and medial tibiofemoral joints.)

Answer
The radiograph has several findings, one of which is a nondisplaced proximal fibula fracture. In addition, there is a moderate suprapatellar joint effusion. The patient also has fairly advanced tricompartment degenerative arthrosis. (To review, the tricompartment comprises all three anatomic areas of the knee: the patellofemoral, lateral tibiofemoral, and medial tibiofemoral joints.)

ANSWER
The correct answer is none of the above (choice “d”). These lesions are all intradermal nevi, which have little, if any, risk for malignant transformation. Deeper nevi are considered quite safe, unless significant change has occurred. Despite the unlikelihood, however, it is risky to declare a 0% chance of skin cancer.

DISCUSSION
Slow growth and increased prominence are not the kinds of changes to look for in skin lesions. Rather, look for marked asymmetry (eg, the growth of a new, darker, macular component) or other change in color or consistency.

Hairs on these lesions are quite normal and are actually reassuring in confirming their benign nature. Skin cancers seldom support hair growth.

Most melanomas don’t come from moles. Instead, they are “de novo” lesions, literally coming from nothing, out of clear skin. It is true that the more moles someone has, the greater his or her risk for skin cancer, though not necessarily in one of the moles. When melanomas do develop from nevi (a collection of a certain type of melanocyte), this usually occurs in superficial types, such as compound or junctional nevi. From an objective standpoint, in this patient’s case, family history means nothing.

What does matter is to pay as much attention to the owner as to the lesion. The more fair-skinned and sun-damaged (freckles, blue eyes, red hair) the patient is, the more worrisome a lesion can be.

This patient had none of those traits, and she will likely have one of her lesions surgically excised to ensure she’s satisfied with the resulting scar. Of course, the tissue sample will be sent for pathologic examination, as any specimen should be.

ANSWER
The correct answer is none of the above (choice “d”). These lesions are all intradermal nevi, which have little, if any, risk for malignant transformation. Deeper nevi are considered quite safe, unless significant change has occurred. Despite the unlikelihood, however, it is risky to declare a 0% chance of skin cancer.

DISCUSSION
Slow growth and increased prominence are not the kinds of changes to look for in skin lesions. Rather, look for marked asymmetry (eg, the growth of a new, darker, macular component) or other change in color or consistency.

Hairs on these lesions are quite normal and are actually reassuring in confirming their benign nature. Skin cancers seldom support hair growth.

Most melanomas don’t come from moles. Instead, they are “de novo” lesions, literally coming from nothing, out of clear skin. It is true that the more moles someone has, the greater his or her risk for skin cancer, though not necessarily in one of the moles. When melanomas do develop from nevi (a collection of a certain type of melanocyte), this usually occurs in superficial types, such as compound or junctional nevi. From an objective standpoint, in this patient’s case, family history means nothing.

What does matter is to pay as much attention to the owner as to the lesion. The more fair-skinned and sun-damaged (freckles, blue eyes, red hair) the patient is, the more worrisome a lesion can be.

This patient had none of those traits, and she will likely have one of her lesions surgically excised to ensure she’s satisfied with the resulting scar. Of course, the tissue sample will be sent for pathologic examination, as any specimen should be.

ANSWER
The correct answer is none of the above (choice “d”). These lesions are all intradermal nevi, which have little, if any, risk for malignant transformation. Deeper nevi are considered quite safe, unless significant change has occurred. Despite the unlikelihood, however, it is risky to declare a 0% chance of skin cancer.

DISCUSSION
Slow growth and increased prominence are not the kinds of changes to look for in skin lesions. Rather, look for marked asymmetry (eg, the growth of a new, darker, macular component) or other change in color or consistency.

Hairs on these lesions are quite normal and are actually reassuring in confirming their benign nature. Skin cancers seldom support hair growth.

Most melanomas don’t come from moles. Instead, they are “de novo” lesions, literally coming from nothing, out of clear skin. It is true that the more moles someone has, the greater his or her risk for skin cancer, though not necessarily in one of the moles. When melanomas do develop from nevi (a collection of a certain type of melanocyte), this usually occurs in superficial types, such as compound or junctional nevi. From an objective standpoint, in this patient’s case, family history means nothing.

What does matter is to pay as much attention to the owner as to the lesion. The more fair-skinned and sun-damaged (freckles, blue eyes, red hair) the patient is, the more worrisome a lesion can be.

This patient had none of those traits, and she will likely have one of her lesions surgically excised to ensure she’s satisfied with the resulting scar. Of course, the tissue sample will be sent for pathologic examination, as any specimen should be.

Electronic cigarettes (e-cigarettes) have become increasingly popular over the last decade. Although they are perceived by many to be safer than traditional cigarettes, many of the devices still contain nicotine, and inhaling their vapors exposes users to toxic substances, including lead, cadmium, and nickel—heavy metals that are associated with significant health problems.¹ (For more on how e-cigarettes work, see “Cigarettes vs e-cigarettes: How does the experience (and cost) compare?”)

In addition, many people use e-cigarettes as a means to stop smoking, but few who do so achieve abstinence.^2,3 They frequently end up utilizing both, increasing their health risks by exposing themselves to the dangers of 2 products instead of one.¹

Further complicating the issue is that the manufacture and distribution of e-cigarettes has not been well regulated. Without regulation, there is no way to know with certainty how much nicotine the devices contain and what else is in them.

Things, however, are changing. The Food and Drug Administration (FDA) recently announced that e-cigarettes and other tobacco products like cigars and hookahs will now be regulated in the same way the government regulates tobacco cigarettes and smokeless tobacco.⁴ The rule will not take effect immediately because companies requested time to comply, but once it is enacted, packaging will be required to list what the products contain, among other changes.

Keeping up on the latest information on e-cigarettes is now—and will continue to be—important as family physicians are increasingly asked about them. What follows is a review of what we know about their potential risks.

© 2016 iStock

A nicotine system developed by a pharmacist

E-cigarettes, or electronic nicotine delivery systems, were patented in 2003 by a Chinese pharmacist.⁵ Since their introduction to North America and Europe in 2007, the devices have become known by over 400 different brand names.⁶ Consumption among adults doubled by 2012, and by 2014, about 4% of US adults used e-cigarettes every day or some days.⁷ Many of them are dual users of tobacco and electronic cigarettes. In fact, Jenkins and colleagues reports in this issue of JFP (see "E-cigarettes: Who's using them and why?") that over half of cigarette smokers (52%) in their study use e-cigarettes, usually to either lower their cigarette consumption or aid in smoking cessation. (Throughout this article, we will use “cigarettes” and “smoking” to refer to the use of traditional tobacco cigarettes.)

In addition to concern over an increase in use among the general population, there is significant concern about the increase in e-cigarette use among US middle and high school students.^1,8,9 In 2015, e-cigarettes were the most commonly used smoking product among middle and high school students, with 620,000 middle school students and nearly 2.4 million high school students using the battery-powered devices in the past 30 days.¹⁰

Many factors have contributed to the growing popularity of e-cigarettes.

• Perceived safety. With tobacco’s dangers so thoroughly documented, many advertising campaigns tout e-cigarettes as less dangerous than conventional cigarettes in terms of their ability to cause cardiac and lung diseases and low birth weights. This is largely because e-cigarettes do not produce the combustion products of tar, ash, or carbon monoxide. In addition, many consumers are mistakenly less fearful about the nicotine added to many e-cigarettes.
• Expectation that it helps smokers quit. Many smokers view e-cigarettes as an aid to smoking cessation.⁶ In fact, testimonials of efficacy in tobacco cessation abound in promotional materials and on the Web, and e-cigarettes are recommended by some physicians as a means to quit or lessen smoking of tobacco cigarettes.¹¹
• Wide availability and opportunities for use. The use of electronic nicotine delivery devices is sometimes permitted in places where smoking of conventional cigarettes is banned, although rules vary widely in different parts of the country. In addition, e-cigarettes are readily available for purchase on the Internet without age verification.
• Extensive advertising. There are increasing concerns that advertising campaigns unduly target adolescents, young adults, and women.^12-155 In addition to advertising, the media and social influences play significant roles in young people’s experimentation with “vaping,” the term for inhaling electronic cigarette aerosols.^14,15
• Regulation, legislation remain controversial. Currently, e-cigarettes are not required to be tested before marketing,¹⁶ but that may change with the FDA’s new regulations. The British National Public Health body, Public Health England, has documented public health benefits of e-cigarettes when used as a way to quit smoking, and provides evidence that the devices are less dangerous than traditional cigarettes.¹⁷ But this issue and public policy are the subject of ongoing debate. In 2015, the United Kingdom made it illegal to sell e-cigarettes or e-liquids to people younger than 18 years of age and urged child-proof packaging.

What’s “in” an e-cigarette—and are the ingredients toxic?

Because e-cigarettes are relatively new to the global marketplace, little research exists regarding the long-term effects and safety of their use, especially among habitual users.

Vapor/refills. E-liquids may contain a variety of substances because they have been largely unregulated, but they generally include some combination of nicotine, propylene glycol, glycerin, and flavorings. In fact, up to 7000 flavors are available,⁶ including such kid-friendly flavors as chocolate, cherry crush, and bubble gum.

Since many individuals continue to use traditional and electronic cigarettes, they end up in double jeopardy of toxicity through exposure to the dangers of both.

When the refills do contain nicotine, users generally derive less of the substance from the electronic devices than they do from a conventional cigarette. Researchers found that individual puffs from an e-cigarette contained 0 to 35 µg nicotine per puff.^1,18 Assuming an amount at the high end of the spectrum (30 µg nicotine), it would take about 30 puffs of an e-cigarette to derive the same amount of nicotine (1 mg) typically delivered by a conventional cigarette.

The chemical make-up of the vapor and the biologic effects on animal models have been investigated using 42 different liquid refills.^19,20 All contained potentially harmful compounds, but the levels were within exposure limits authorized by the FDA. These potentially dangerous chemicals include the known toxins formaldehyde, acrolein, and hydrocarbons.²⁰

An inflammatory response to the inhalation of the vapors was demonstrated in mouse lungs; exposure to e-cigarette aerosols reduced lung glutathione—an important enzyme in maintaining oxidation-reduction balance—to a degree similar to that of cigarette smoke exposure.²⁰ Less of the enzyme facilitates increased pulmonary inflammation.

In addition, human lung cells release pro-inflammatory cytokines when exposed to e-cigarette aerosols.²⁰ Other health risks include:

Harm to indoor air quality/secondhand exposure. Even though e-cigarettes do not emit smoke, bystanders are exposed to the aerosol or vapor exhaled by the user, and researchers have found varying levels of such substances as formaldehyde, acetaldehyde, isoprene, acetic acid, acetone, propanol, propylene glycol, and nicotine in the air. However, it is unclear at this time whether the ultra-fine particles in the e-cigarette vapor have health effects commensurate with the emissions of conventional cigarettes.^1,21,22

Cartridge refill ingestion by children. Accidental nicotine poisonings, particularly among children drawn to the colors, flavors, and scents of the e-liquids, have been problematic. In 2014, for example, over 3500 exposures occurred and more than half of those were in children younger than 6 years of age. (Exposure is defined as contact with the substance in some way including ingestion, inhalation, absorption by the skin/eyes, etc; not all exposures are poisonings or overdoses).²³ Although incidence has tapered off somewhat, the American Association of Poison Control Centers reports that there were 623 exposures across all age groups between January 1, 2016 and April 30, 2016.²³

Many people use e-cigarettes as a means to stop smoking, but few who do so achieve abstinence.

Environmental impact of discarded e-cigarettes. Discarded e-cigarettes filling our landfills is a new and emerging public health concern. Their batteries, as do all batteries, pollute the land and water and have the potential to leach lead into the environment.²⁴ Similarly, incompletely used liquid cartridges and refills may contain nicotine and heavy metals, which add to these risks.²⁴

Explosions. Fires and explosions have been documented with e-cigarette use, mostly due to malfunctioning lithium-ion batteries.²⁵ Thermal injuries to the face and hands can be significant.

Heavy metals. The presence of lead, cadmium, and nickel in inhaled e-cigarette vapor is another area of significant concern, particularly for younger people who might have long-term exposure.¹ All 3 heavy metals are known to be toxic to humans, and safe levels of inhalation have not been established.

Inhalation and/or ingestion of lead, in particular, can cause severe neurologic damage, especially to the developing brains of children.²⁶ Lead also results in hematologic dysfunction. Because of the risks associated with inhalation of this heavy metal, the substance was removed from gasoline years ago.

Inhaled cadmium induces kidney, liver, bone, and respiratory tract pathology²⁷ and can cause organ failure, hypertension, anemias, fractures, osteoporosis, and/or osteomalacia.²⁸ And inhaling nickel produces an inflammatory pulmonary reaction.²⁹

Pregnancy/lactation. Since no clear evidence exists on the safety of e-cigarette use during pregnancy, women should avoid exposure to these vapors during the entire perinatal period. Similarly, the effects of e-cigarettes on infants who are breastfeeding are not established. Pregnant and breastfeeding women should not replace cigarettes with e-cigarettes.^30,31 For pregnant women who smoke, the US Preventive Services Task Force (USPSTF) advises using only behavioral methods to stop cigarette use.³² And until more information becomes available, exposing infants and young children to e-cigarette vapor during breastfeeding is not recommended.

On the flip side, without tobacco, tar, ash, or carbon monoxide, e-cigarettes may have some advantages when compared with the use of traditional cigarettes, but that has not been substantiated.

Don’t substitute one form of nicotine for another

The presence of lead, cadmium, and nickel in inhaled e-cigarette vapor is an area of significant concern.

The USPSTF has not determined the benefit-to-harm ratio of using e-cigarettes as a smoking cessation aid, but recommends prescribing behavioral techniques and/or pharmacologic alternatives instead.³² Because the devices have been promoted as an aid to smoking cessation, intention to quit using tobacco products is a reason often stated for utilizing e-cigarettes.^2,33,34 Indeed, use of e-cigarettes is much more likely among those who already utilize tobacco products.^35-37

At least one study reports that e-cigarettes have efficacy similar to nicotine patches in achieving smoking abstinence among smokers who want to quit.³⁸ Former smokers who used e-cigarettes to quit smoking reported fewer withdrawal symptoms than those who used nicotine skin patches.³⁹ In addition, former smokers were more likely to endorse e-cigarettes than nicotine patches as a tobacco cigarette cessation aid. Significant reduction in tobacco smoke exposure has been demonstrated in dual users of tobacco and electronic cigarettes;^40,41 however, both of these nicotine delivery systems sustain nicotine addiction.

Despite many ongoing studies to determine if e-cigarettes are useful as a smoking cessation aid, the results vary widely and are inconclusive at this time.⁴²

E-cigarettes do not increase long-term tobacco abstinence

Contrary to popular belief, research shows that e-cigarette use among smokers is not associated with long-term tobacco abstinence.¹ E-cigarette users, however, may make more attempts to quit smoking compared with smokers not using them.⁴³ In addition, even though there is some evidence that e-cigarettes help smokers reduce the number of cigarettes smoked per day, simply reducing the daily number of cigarettes does not equate with safety.⁴⁴ Smoking just one to 4 cigarettes per day poses 3 times the risk of myocardial infarction and lung cancer compared with not smoking.⁴⁴ And since many individuals continue to use traditional and electronic cigarettes, they end up in double jeopardy of toxicity through exposure to the dangers of both.

A gateway to other substances of abuse?

Pregnant and breastfeeding women should not replace tobacco cigarettes with e-cigarettes.

There is also fear that nicotine exposure via e-cigarettes, especially in young people, serves as a “gateway” to tobacco consumption and other substance abuses, and increases the risk for nicotine addiction.³⁴ Such nicotine-induced effects are a result of changes in brain chemistry, and have been documented in humans and animals.³⁴

These concerns about negative health consequences, combined with the fact that e-cigarettes are undocumented as a smoking cessation aid, add urgency to the need for legislative and regulatory actions that hopefully can curb all nicotine exposures, particularly for our nation’s youth. In the meantime, it is important for physicians to advise patients—and the public—about the risks of e-cigarettes and the importance of quitting all forms of nicotine inhalation because nicotine—regardless of how it is delivered—is still an addictive drug.

CORRESPONDENCE
Steven Lippmann, MD, University of Louisville School of Medicine, 401 E. Chestnut Street, Suite 610, Louisville, KY 40202; [email protected].

Electronic cigarettes (e-cigarettes) have become increasingly popular over the last decade. Although they are perceived by many to be safer than traditional cigarettes, many of the devices still contain nicotine, and inhaling their vapors exposes users to toxic substances, including lead, cadmium, and nickel—heavy metals that are associated with significant health problems.¹ (For more on how e-cigarettes work, see “Cigarettes vs e-cigarettes: How does the experience (and cost) compare?”)

In addition, many people use e-cigarettes as a means to stop smoking, but few who do so achieve abstinence.^2,3 They frequently end up utilizing both, increasing their health risks by exposing themselves to the dangers of 2 products instead of one.¹

Further complicating the issue is that the manufacture and distribution of e-cigarettes has not been well regulated. Without regulation, there is no way to know with certainty how much nicotine the devices contain and what else is in them.

Things, however, are changing. The Food and Drug Administration (FDA) recently announced that e-cigarettes and other tobacco products like cigars and hookahs will now be regulated in the same way the government regulates tobacco cigarettes and smokeless tobacco.⁴ The rule will not take effect immediately because companies requested time to comply, but once it is enacted, packaging will be required to list what the products contain, among other changes.

Keeping up on the latest information on e-cigarettes is now—and will continue to be—important as family physicians are increasingly asked about them. What follows is a review of what we know about their potential risks.

© 2016 iStock

A nicotine system developed by a pharmacist

E-cigarettes, or electronic nicotine delivery systems, were patented in 2003 by a Chinese pharmacist.⁵ Since their introduction to North America and Europe in 2007, the devices have become known by over 400 different brand names.⁶ Consumption among adults doubled by 2012, and by 2014, about 4% of US adults used e-cigarettes every day or some days.⁷ Many of them are dual users of tobacco and electronic cigarettes. In fact, Jenkins and colleagues reports in this issue of JFP (see "E-cigarettes: Who's using them and why?") that over half of cigarette smokers (52%) in their study use e-cigarettes, usually to either lower their cigarette consumption or aid in smoking cessation. (Throughout this article, we will use “cigarettes” and “smoking” to refer to the use of traditional tobacco cigarettes.)

In addition to concern over an increase in use among the general population, there is significant concern about the increase in e-cigarette use among US middle and high school students.^1,8,9 In 2015, e-cigarettes were the most commonly used smoking product among middle and high school students, with 620,000 middle school students and nearly 2.4 million high school students using the battery-powered devices in the past 30 days.¹⁰

Many factors have contributed to the growing popularity of e-cigarettes.

• Perceived safety. With tobacco’s dangers so thoroughly documented, many advertising campaigns tout e-cigarettes as less dangerous than conventional cigarettes in terms of their ability to cause cardiac and lung diseases and low birth weights. This is largely because e-cigarettes do not produce the combustion products of tar, ash, or carbon monoxide. In addition, many consumers are mistakenly less fearful about the nicotine added to many e-cigarettes.
• Expectation that it helps smokers quit. Many smokers view e-cigarettes as an aid to smoking cessation.⁶ In fact, testimonials of efficacy in tobacco cessation abound in promotional materials and on the Web, and e-cigarettes are recommended by some physicians as a means to quit or lessen smoking of tobacco cigarettes.¹¹
• Wide availability and opportunities for use. The use of electronic nicotine delivery devices is sometimes permitted in places where smoking of conventional cigarettes is banned, although rules vary widely in different parts of the country. In addition, e-cigarettes are readily available for purchase on the Internet without age verification.
• Extensive advertising. There are increasing concerns that advertising campaigns unduly target adolescents, young adults, and women.^12-155 In addition to advertising, the media and social influences play significant roles in young people’s experimentation with “vaping,” the term for inhaling electronic cigarette aerosols.^14,15
• Regulation, legislation remain controversial. Currently, e-cigarettes are not required to be tested before marketing,¹⁶ but that may change with the FDA’s new regulations. The British National Public Health body, Public Health England, has documented public health benefits of e-cigarettes when used as a way to quit smoking, and provides evidence that the devices are less dangerous than traditional cigarettes.¹⁷ But this issue and public policy are the subject of ongoing debate. In 2015, the United Kingdom made it illegal to sell e-cigarettes or e-liquids to people younger than 18 years of age and urged child-proof packaging.

What’s “in” an e-cigarette—and are the ingredients toxic?

Because e-cigarettes are relatively new to the global marketplace, little research exists regarding the long-term effects and safety of their use, especially among habitual users.

Vapor/refills. E-liquids may contain a variety of substances because they have been largely unregulated, but they generally include some combination of nicotine, propylene glycol, glycerin, and flavorings. In fact, up to 7000 flavors are available,⁶ including such kid-friendly flavors as chocolate, cherry crush, and bubble gum.

Since many individuals continue to use traditional and electronic cigarettes, they end up in double jeopardy of toxicity through exposure to the dangers of both.

When the refills do contain nicotine, users generally derive less of the substance from the electronic devices than they do from a conventional cigarette. Researchers found that individual puffs from an e-cigarette contained 0 to 35 µg nicotine per puff.^1,18 Assuming an amount at the high end of the spectrum (30 µg nicotine), it would take about 30 puffs of an e-cigarette to derive the same amount of nicotine (1 mg) typically delivered by a conventional cigarette.

The chemical make-up of the vapor and the biologic effects on animal models have been investigated using 42 different liquid refills.^19,20 All contained potentially harmful compounds, but the levels were within exposure limits authorized by the FDA. These potentially dangerous chemicals include the known toxins formaldehyde, acrolein, and hydrocarbons.²⁰

An inflammatory response to the inhalation of the vapors was demonstrated in mouse lungs; exposure to e-cigarette aerosols reduced lung glutathione—an important enzyme in maintaining oxidation-reduction balance—to a degree similar to that of cigarette smoke exposure.²⁰ Less of the enzyme facilitates increased pulmonary inflammation.

In addition, human lung cells release pro-inflammatory cytokines when exposed to e-cigarette aerosols.²⁰ Other health risks include:

Harm to indoor air quality/secondhand exposure. Even though e-cigarettes do not emit smoke, bystanders are exposed to the aerosol or vapor exhaled by the user, and researchers have found varying levels of such substances as formaldehyde, acetaldehyde, isoprene, acetic acid, acetone, propanol, propylene glycol, and nicotine in the air. However, it is unclear at this time whether the ultra-fine particles in the e-cigarette vapor have health effects commensurate with the emissions of conventional cigarettes.^1,21,22

Cartridge refill ingestion by children. Accidental nicotine poisonings, particularly among children drawn to the colors, flavors, and scents of the e-liquids, have been problematic. In 2014, for example, over 3500 exposures occurred and more than half of those were in children younger than 6 years of age. (Exposure is defined as contact with the substance in some way including ingestion, inhalation, absorption by the skin/eyes, etc; not all exposures are poisonings or overdoses).²³ Although incidence has tapered off somewhat, the American Association of Poison Control Centers reports that there were 623 exposures across all age groups between January 1, 2016 and April 30, 2016.²³

Many people use e-cigarettes as a means to stop smoking, but few who do so achieve abstinence.

Environmental impact of discarded e-cigarettes. Discarded e-cigarettes filling our landfills is a new and emerging public health concern. Their batteries, as do all batteries, pollute the land and water and have the potential to leach lead into the environment.²⁴ Similarly, incompletely used liquid cartridges and refills may contain nicotine and heavy metals, which add to these risks.²⁴

Explosions. Fires and explosions have been documented with e-cigarette use, mostly due to malfunctioning lithium-ion batteries.²⁵ Thermal injuries to the face and hands can be significant.

Heavy metals. The presence of lead, cadmium, and nickel in inhaled e-cigarette vapor is another area of significant concern, particularly for younger people who might have long-term exposure.¹ All 3 heavy metals are known to be toxic to humans, and safe levels of inhalation have not been established.

Inhalation and/or ingestion of lead, in particular, can cause severe neurologic damage, especially to the developing brains of children.²⁶ Lead also results in hematologic dysfunction. Because of the risks associated with inhalation of this heavy metal, the substance was removed from gasoline years ago.

Inhaled cadmium induces kidney, liver, bone, and respiratory tract pathology²⁷ and can cause organ failure, hypertension, anemias, fractures, osteoporosis, and/or osteomalacia.²⁸ And inhaling nickel produces an inflammatory pulmonary reaction.²⁹

Pregnancy/lactation. Since no clear evidence exists on the safety of e-cigarette use during pregnancy, women should avoid exposure to these vapors during the entire perinatal period. Similarly, the effects of e-cigarettes on infants who are breastfeeding are not established. Pregnant and breastfeeding women should not replace cigarettes with e-cigarettes.^30,31 For pregnant women who smoke, the US Preventive Services Task Force (USPSTF) advises using only behavioral methods to stop cigarette use.³² And until more information becomes available, exposing infants and young children to e-cigarette vapor during breastfeeding is not recommended.

On the flip side, without tobacco, tar, ash, or carbon monoxide, e-cigarettes may have some advantages when compared with the use of traditional cigarettes, but that has not been substantiated.

Don’t substitute one form of nicotine for another

The presence of lead, cadmium, and nickel in inhaled e-cigarette vapor is an area of significant concern.

The USPSTF has not determined the benefit-to-harm ratio of using e-cigarettes as a smoking cessation aid, but recommends prescribing behavioral techniques and/or pharmacologic alternatives instead.³² Because the devices have been promoted as an aid to smoking cessation, intention to quit using tobacco products is a reason often stated for utilizing e-cigarettes.^2,33,34 Indeed, use of e-cigarettes is much more likely among those who already utilize tobacco products.^35-37

At least one study reports that e-cigarettes have efficacy similar to nicotine patches in achieving smoking abstinence among smokers who want to quit.³⁸ Former smokers who used e-cigarettes to quit smoking reported fewer withdrawal symptoms than those who used nicotine skin patches.³⁹ In addition, former smokers were more likely to endorse e-cigarettes than nicotine patches as a tobacco cigarette cessation aid. Significant reduction in tobacco smoke exposure has been demonstrated in dual users of tobacco and electronic cigarettes;^40,41 however, both of these nicotine delivery systems sustain nicotine addiction.

Despite many ongoing studies to determine if e-cigarettes are useful as a smoking cessation aid, the results vary widely and are inconclusive at this time.⁴²

E-cigarettes do not increase long-term tobacco abstinence

Contrary to popular belief, research shows that e-cigarette use among smokers is not associated with long-term tobacco abstinence.¹ E-cigarette users, however, may make more attempts to quit smoking compared with smokers not using them.⁴³ In addition, even though there is some evidence that e-cigarettes help smokers reduce the number of cigarettes smoked per day, simply reducing the daily number of cigarettes does not equate with safety.⁴⁴ Smoking just one to 4 cigarettes per day poses 3 times the risk of myocardial infarction and lung cancer compared with not smoking.⁴⁴ And since many individuals continue to use traditional and electronic cigarettes, they end up in double jeopardy of toxicity through exposure to the dangers of both.

A gateway to other substances of abuse?

Pregnant and breastfeeding women should not replace tobacco cigarettes with e-cigarettes.

There is also fear that nicotine exposure via e-cigarettes, especially in young people, serves as a “gateway” to tobacco consumption and other substance abuses, and increases the risk for nicotine addiction.³⁴ Such nicotine-induced effects are a result of changes in brain chemistry, and have been documented in humans and animals.³⁴

These concerns about negative health consequences, combined with the fact that e-cigarettes are undocumented as a smoking cessation aid, add urgency to the need for legislative and regulatory actions that hopefully can curb all nicotine exposures, particularly for our nation’s youth. In the meantime, it is important for physicians to advise patients—and the public—about the risks of e-cigarettes and the importance of quitting all forms of nicotine inhalation because nicotine—regardless of how it is delivered—is still an addictive drug.

CORRESPONDENCE
Steven Lippmann, MD, University of Louisville School of Medicine, 401 E. Chestnut Street, Suite 610, Louisville, KY 40202; [email protected].

Electronic cigarettes (e-cigarettes) have become increasingly popular over the last decade. Although they are perceived by many to be safer than traditional cigarettes, many of the devices still contain nicotine, and inhaling their vapors exposes users to toxic substances, including lead, cadmium, and nickel—heavy metals that are associated with significant health problems.¹ (For more on how e-cigarettes work, see “Cigarettes vs e-cigarettes: How does the experience (and cost) compare?”)

In addition, many people use e-cigarettes as a means to stop smoking, but few who do so achieve abstinence.^2,3 They frequently end up utilizing both, increasing their health risks by exposing themselves to the dangers of 2 products instead of one.¹

Further complicating the issue is that the manufacture and distribution of e-cigarettes has not been well regulated. Without regulation, there is no way to know with certainty how much nicotine the devices contain and what else is in them.

Things, however, are changing. The Food and Drug Administration (FDA) recently announced that e-cigarettes and other tobacco products like cigars and hookahs will now be regulated in the same way the government regulates tobacco cigarettes and smokeless tobacco.⁴ The rule will not take effect immediately because companies requested time to comply, but once it is enacted, packaging will be required to list what the products contain, among other changes.

Keeping up on the latest information on e-cigarettes is now—and will continue to be—important as family physicians are increasingly asked about them. What follows is a review of what we know about their potential risks.

© 2016 iStock

A nicotine system developed by a pharmacist

E-cigarettes, or electronic nicotine delivery systems, were patented in 2003 by a Chinese pharmacist.⁵ Since their introduction to North America and Europe in 2007, the devices have become known by over 400 different brand names.⁶ Consumption among adults doubled by 2012, and by 2014, about 4% of US adults used e-cigarettes every day or some days.⁷ Many of them are dual users of tobacco and electronic cigarettes. In fact, Jenkins and colleagues reports in this issue of JFP (see "E-cigarettes: Who's using them and why?") that over half of cigarette smokers (52%) in their study use e-cigarettes, usually to either lower their cigarette consumption or aid in smoking cessation. (Throughout this article, we will use “cigarettes” and “smoking” to refer to the use of traditional tobacco cigarettes.)

In addition to concern over an increase in use among the general population, there is significant concern about the increase in e-cigarette use among US middle and high school students.^1,8,9 In 2015, e-cigarettes were the most commonly used smoking product among middle and high school students, with 620,000 middle school students and nearly 2.4 million high school students using the battery-powered devices in the past 30 days.¹⁰

Many factors have contributed to the growing popularity of e-cigarettes.

• Perceived safety. With tobacco’s dangers so thoroughly documented, many advertising campaigns tout e-cigarettes as less dangerous than conventional cigarettes in terms of their ability to cause cardiac and lung diseases and low birth weights. This is largely because e-cigarettes do not produce the combustion products of tar, ash, or carbon monoxide. In addition, many consumers are mistakenly less fearful about the nicotine added to many e-cigarettes.
• Expectation that it helps smokers quit. Many smokers view e-cigarettes as an aid to smoking cessation.⁶ In fact, testimonials of efficacy in tobacco cessation abound in promotional materials and on the Web, and e-cigarettes are recommended by some physicians as a means to quit or lessen smoking of tobacco cigarettes.¹¹
• Wide availability and opportunities for use. The use of electronic nicotine delivery devices is sometimes permitted in places where smoking of conventional cigarettes is banned, although rules vary widely in different parts of the country. In addition, e-cigarettes are readily available for purchase on the Internet without age verification.
• Extensive advertising. There are increasing concerns that advertising campaigns unduly target adolescents, young adults, and women.^12-155 In addition to advertising, the media and social influences play significant roles in young people’s experimentation with “vaping,” the term for inhaling electronic cigarette aerosols.^14,15
• Regulation, legislation remain controversial. Currently, e-cigarettes are not required to be tested before marketing,¹⁶ but that may change with the FDA’s new regulations. The British National Public Health body, Public Health England, has documented public health benefits of e-cigarettes when used as a way to quit smoking, and provides evidence that the devices are less dangerous than traditional cigarettes.¹⁷ But this issue and public policy are the subject of ongoing debate. In 2015, the United Kingdom made it illegal to sell e-cigarettes or e-liquids to people younger than 18 years of age and urged child-proof packaging.

What’s “in” an e-cigarette—and are the ingredients toxic?

Because e-cigarettes are relatively new to the global marketplace, little research exists regarding the long-term effects and safety of their use, especially among habitual users.

Vapor/refills. E-liquids may contain a variety of substances because they have been largely unregulated, but they generally include some combination of nicotine, propylene glycol, glycerin, and flavorings. In fact, up to 7000 flavors are available,⁶ including such kid-friendly flavors as chocolate, cherry crush, and bubble gum.

Since many individuals continue to use traditional and electronic cigarettes, they end up in double jeopardy of toxicity through exposure to the dangers of both.

When the refills do contain nicotine, users generally derive less of the substance from the electronic devices than they do from a conventional cigarette. Researchers found that individual puffs from an e-cigarette contained 0 to 35 µg nicotine per puff.^1,18 Assuming an amount at the high end of the spectrum (30 µg nicotine), it would take about 30 puffs of an e-cigarette to derive the same amount of nicotine (1 mg) typically delivered by a conventional cigarette.

The chemical make-up of the vapor and the biologic effects on animal models have been investigated using 42 different liquid refills.^19,20 All contained potentially harmful compounds, but the levels were within exposure limits authorized by the FDA. These potentially dangerous chemicals include the known toxins formaldehyde, acrolein, and hydrocarbons.²⁰

An inflammatory response to the inhalation of the vapors was demonstrated in mouse lungs; exposure to e-cigarette aerosols reduced lung glutathione—an important enzyme in maintaining oxidation-reduction balance—to a degree similar to that of cigarette smoke exposure.²⁰ Less of the enzyme facilitates increased pulmonary inflammation.

In addition, human lung cells release pro-inflammatory cytokines when exposed to e-cigarette aerosols.²⁰ Other health risks include:

Harm to indoor air quality/secondhand exposure. Even though e-cigarettes do not emit smoke, bystanders are exposed to the aerosol or vapor exhaled by the user, and researchers have found varying levels of such substances as formaldehyde, acetaldehyde, isoprene, acetic acid, acetone, propanol, propylene glycol, and nicotine in the air. However, it is unclear at this time whether the ultra-fine particles in the e-cigarette vapor have health effects commensurate with the emissions of conventional cigarettes.^1,21,22

Cartridge refill ingestion by children. Accidental nicotine poisonings, particularly among children drawn to the colors, flavors, and scents of the e-liquids, have been problematic. In 2014, for example, over 3500 exposures occurred and more than half of those were in children younger than 6 years of age. (Exposure is defined as contact with the substance in some way including ingestion, inhalation, absorption by the skin/eyes, etc; not all exposures are poisonings or overdoses).²³ Although incidence has tapered off somewhat, the American Association of Poison Control Centers reports that there were 623 exposures across all age groups between January 1, 2016 and April 30, 2016.²³

Many people use e-cigarettes as a means to stop smoking, but few who do so achieve abstinence.

Environmental impact of discarded e-cigarettes. Discarded e-cigarettes filling our landfills is a new and emerging public health concern. Their batteries, as do all batteries, pollute the land and water and have the potential to leach lead into the environment.²⁴ Similarly, incompletely used liquid cartridges and refills may contain nicotine and heavy metals, which add to these risks.²⁴

Explosions. Fires and explosions have been documented with e-cigarette use, mostly due to malfunctioning lithium-ion batteries.²⁵ Thermal injuries to the face and hands can be significant.

Heavy metals. The presence of lead, cadmium, and nickel in inhaled e-cigarette vapor is another area of significant concern, particularly for younger people who might have long-term exposure.¹ All 3 heavy metals are known to be toxic to humans, and safe levels of inhalation have not been established.

Inhalation and/or ingestion of lead, in particular, can cause severe neurologic damage, especially to the developing brains of children.²⁶ Lead also results in hematologic dysfunction. Because of the risks associated with inhalation of this heavy metal, the substance was removed from gasoline years ago.

Inhaled cadmium induces kidney, liver, bone, and respiratory tract pathology²⁷ and can cause organ failure, hypertension, anemias, fractures, osteoporosis, and/or osteomalacia.²⁸ And inhaling nickel produces an inflammatory pulmonary reaction.²⁹

Pregnancy/lactation. Since no clear evidence exists on the safety of e-cigarette use during pregnancy, women should avoid exposure to these vapors during the entire perinatal period. Similarly, the effects of e-cigarettes on infants who are breastfeeding are not established. Pregnant and breastfeeding women should not replace cigarettes with e-cigarettes.^30,31 For pregnant women who smoke, the US Preventive Services Task Force (USPSTF) advises using only behavioral methods to stop cigarette use.³² And until more information becomes available, exposing infants and young children to e-cigarette vapor during breastfeeding is not recommended.

On the flip side, without tobacco, tar, ash, or carbon monoxide, e-cigarettes may have some advantages when compared with the use of traditional cigarettes, but that has not been substantiated.

Don’t substitute one form of nicotine for another

The presence of lead, cadmium, and nickel in inhaled e-cigarette vapor is an area of significant concern.

The USPSTF has not determined the benefit-to-harm ratio of using e-cigarettes as a smoking cessation aid, but recommends prescribing behavioral techniques and/or pharmacologic alternatives instead.³² Because the devices have been promoted as an aid to smoking cessation, intention to quit using tobacco products is a reason often stated for utilizing e-cigarettes.^2,33,34 Indeed, use of e-cigarettes is much more likely among those who already utilize tobacco products.^35-37

At least one study reports that e-cigarettes have efficacy similar to nicotine patches in achieving smoking abstinence among smokers who want to quit.³⁸ Former smokers who used e-cigarettes to quit smoking reported fewer withdrawal symptoms than those who used nicotine skin patches.³⁹ In addition, former smokers were more likely to endorse e-cigarettes than nicotine patches as a tobacco cigarette cessation aid. Significant reduction in tobacco smoke exposure has been demonstrated in dual users of tobacco and electronic cigarettes;^40,41 however, both of these nicotine delivery systems sustain nicotine addiction.

Despite many ongoing studies to determine if e-cigarettes are useful as a smoking cessation aid, the results vary widely and are inconclusive at this time.⁴²

E-cigarettes do not increase long-term tobacco abstinence

Contrary to popular belief, research shows that e-cigarette use among smokers is not associated with long-term tobacco abstinence.¹ E-cigarette users, however, may make more attempts to quit smoking compared with smokers not using them.⁴³ In addition, even though there is some evidence that e-cigarettes help smokers reduce the number of cigarettes smoked per day, simply reducing the daily number of cigarettes does not equate with safety.⁴⁴ Smoking just one to 4 cigarettes per day poses 3 times the risk of myocardial infarction and lung cancer compared with not smoking.⁴⁴ And since many individuals continue to use traditional and electronic cigarettes, they end up in double jeopardy of toxicity through exposure to the dangers of both.

A gateway to other substances of abuse?

Pregnant and breastfeeding women should not replace tobacco cigarettes with e-cigarettes.

There is also fear that nicotine exposure via e-cigarettes, especially in young people, serves as a “gateway” to tobacco consumption and other substance abuses, and increases the risk for nicotine addiction.³⁴ Such nicotine-induced effects are a result of changes in brain chemistry, and have been documented in humans and animals.³⁴

These concerns about negative health consequences, combined with the fact that e-cigarettes are undocumented as a smoking cessation aid, add urgency to the need for legislative and regulatory actions that hopefully can curb all nicotine exposures, particularly for our nation’s youth. In the meantime, it is important for physicians to advise patients—and the public—about the risks of e-cigarettes and the importance of quitting all forms of nicotine inhalation because nicotine—regardless of how it is delivered—is still an addictive drug.

CORRESPONDENCE
Steven Lippmann, MD, University of Louisville School of Medicine, 401 E. Chestnut Street, Suite 610, Louisville, KY 40202; [email protected].

To the Editor: I appreciated the article on cognitive biases and diagnostic error by Mull et al in the November 2015 issue.¹ They presented an excellent description of the pitfalls of diagnosis as reflected in a case of a patient misdiagnosed with heart failure who ultimately died of pulmonary tuberculosis complicated by pulmonary embolism (the latter possibly from using the wrong form of heparin). To the points they raised,  I would like to add a few of my own about diagnosis in general and heart failure in particular.

First, any initial diagnosis not confirmed objectively within the first 24 hours should be questioned, and other possibilities should be investigated. I have found this to be essential for every day’s stay in the hospital and for every outpatient visit. The authors mention checklists as part of the solution to the problem of misdiagnosis, and I would suggest that confirmation of initial diagnoses be built into these checklists.

In the case of a presumptive diagnosis of an acute exacerbation of heart failure treated empirically with diuretics, the diagnosis should be confirmed by the next day’s response to the diuretics, ie, increased urine output, a lower respiratory rate, and a fall in the pro-B-type natriuretic peptide level. Moreover, a change in the radiographic appearance should be seen, and respiratory and pulmonary function should improve after the first 24 hours on oxygen supplementation plus diuretics. Daily patient weights are also critical in determining response to a diuretic, and are rarely done accurately. I order weights and review them daily for patients like this.

Second, it is good to look at things yourself, including the patient, medication lists, laboratory values, and radiographic films. The attending physician should look at the radiographs together with a senior radiologist. Seeing no improvement or change on the second hospital day, or seeing signs incompatible with heart failure, one could order computed tomography of the chest and begin to entertain pulmonary diagnoses.

Even vital signs can be questionable. For example, in the case presented here, with a temperature of 99°F, a heart rate of 105, and a pulse oxygenation saturation of 89%, a respiratory rate of 24 seems unbelievably low. In my experience, the respiratory rate is recorded erroneously most of the time unless it is recorded electronically or checked at the bedside by the physician using a timepiece with a sweep second-hand.

Additionally, I have found that ordering several days’ laboratory tests (eg, complete blood cell counts, chemistry panels) in advance, in many cases, risks missing important findings and wastes time, energy, and the patient’s blood. I have learned to evaluate each patient daily and to order the most pertinent laboratory tests. With electronic medical records, I can check laboratory results as soon as they are available.  

To the Editor: I appreciated the article on cognitive biases and diagnostic error by Mull et al in the November 2015 issue.¹ They presented an excellent description of the pitfalls of diagnosis as reflected in a case of a patient misdiagnosed with heart failure who ultimately died of pulmonary tuberculosis complicated by pulmonary embolism (the latter possibly from using the wrong form of heparin). To the points they raised,  I would like to add a few of my own about diagnosis in general and heart failure in particular.

First, any initial diagnosis not confirmed objectively within the first 24 hours should be questioned, and other possibilities should be investigated. I have found this to be essential for every day’s stay in the hospital and for every outpatient visit. The authors mention checklists as part of the solution to the problem of misdiagnosis, and I would suggest that confirmation of initial diagnoses be built into these checklists.

In the case of a presumptive diagnosis of an acute exacerbation of heart failure treated empirically with diuretics, the diagnosis should be confirmed by the next day’s response to the diuretics, ie, increased urine output, a lower respiratory rate, and a fall in the pro-B-type natriuretic peptide level. Moreover, a change in the radiographic appearance should be seen, and respiratory and pulmonary function should improve after the first 24 hours on oxygen supplementation plus diuretics. Daily patient weights are also critical in determining response to a diuretic, and are rarely done accurately. I order weights and review them daily for patients like this.

Second, it is good to look at things yourself, including the patient, medication lists, laboratory values, and radiographic films. The attending physician should look at the radiographs together with a senior radiologist. Seeing no improvement or change on the second hospital day, or seeing signs incompatible with heart failure, one could order computed tomography of the chest and begin to entertain pulmonary diagnoses.

Even vital signs can be questionable. For example, in the case presented here, with a temperature of 99°F, a heart rate of 105, and a pulse oxygenation saturation of 89%, a respiratory rate of 24 seems unbelievably low. In my experience, the respiratory rate is recorded erroneously most of the time unless it is recorded electronically or checked at the bedside by the physician using a timepiece with a sweep second-hand.

Additionally, I have found that ordering several days’ laboratory tests (eg, complete blood cell counts, chemistry panels) in advance, in many cases, risks missing important findings and wastes time, energy, and the patient’s blood. I have learned to evaluate each patient daily and to order the most pertinent laboratory tests. With electronic medical records, I can check laboratory results as soon as they are available.  

To the Editor: I appreciated the article on cognitive biases and diagnostic error by Mull et al in the November 2015 issue.¹ They presented an excellent description of the pitfalls of diagnosis as reflected in a case of a patient misdiagnosed with heart failure who ultimately died of pulmonary tuberculosis complicated by pulmonary embolism (the latter possibly from using the wrong form of heparin). To the points they raised,  I would like to add a few of my own about diagnosis in general and heart failure in particular.

First, any initial diagnosis not confirmed objectively within the first 24 hours should be questioned, and other possibilities should be investigated. I have found this to be essential for every day’s stay in the hospital and for every outpatient visit. The authors mention checklists as part of the solution to the problem of misdiagnosis, and I would suggest that confirmation of initial diagnoses be built into these checklists.

In the case of a presumptive diagnosis of an acute exacerbation of heart failure treated empirically with diuretics, the diagnosis should be confirmed by the next day’s response to the diuretics, ie, increased urine output, a lower respiratory rate, and a fall in the pro-B-type natriuretic peptide level. Moreover, a change in the radiographic appearance should be seen, and respiratory and pulmonary function should improve after the first 24 hours on oxygen supplementation plus diuretics. Daily patient weights are also critical in determining response to a diuretic, and are rarely done accurately. I order weights and review them daily for patients like this.

Second, it is good to look at things yourself, including the patient, medication lists, laboratory values, and radiographic films. The attending physician should look at the radiographs together with a senior radiologist. Seeing no improvement or change on the second hospital day, or seeing signs incompatible with heart failure, one could order computed tomography of the chest and begin to entertain pulmonary diagnoses.

Even vital signs can be questionable. For example, in the case presented here, with a temperature of 99°F, a heart rate of 105, and a pulse oxygenation saturation of 89%, a respiratory rate of 24 seems unbelievably low. In my experience, the respiratory rate is recorded erroneously most of the time unless it is recorded electronically or checked at the bedside by the physician using a timepiece with a sweep second-hand.

Additionally, I have found that ordering several days’ laboratory tests (eg, complete blood cell counts, chemistry panels) in advance, in many cases, risks missing important findings and wastes time, energy, and the patient’s blood. I have learned to evaluate each patient daily and to order the most pertinent laboratory tests. With electronic medical records, I can check laboratory results as soon as they are available.  

In Reply: We thank Dr. Field for his insights and personal observations related to diagnosis and biases that contribute to diagnostic errors.

Dr. Field’s comment about the importance of revisiting one’s initial working diagnosis is consistent with our proposed diagnostic time out. A diagnostic time out can incorporate a short checklist and aid in debiasing clinicians when findings do not fit the case presentation, such as lack of response to diuretic therapy. Being mindful of slowing down and not necessarily rushing to judgment is another important component.¹ Of note, the residents in our case did revisit their initial working diagnosis, as suggested by Dr. Field. Questions from learners have great potential to serve as debiasing instruments and should always be encouraged. Those who do not work with students can do the same by speaking with nurses or other members of the healthcare team, who offer observations that busy physicians might miss.

Our case highlights the problem that we lack objective criteria to diagnose symptomatic heart failure. While B-type natriuretic factor (BNP) has a strong negative predictive value, serial BNP measurements have not been established to be helpful in the management of heart failure.² Although certain findings on chest radiography have strong positive and negative likelihood associations, the role of serial chest radiographs is less clear.³ Thus, heart failure remains a clinical diagnosis in current practice.

As Dr. Field points out, the accuracy and performance characteristics of diagnostic testing, such as the respiratory rate, need to be considered in conjunction with debiasing strategies to achieve higher diagnostic accuracy. Multiple factors can contribute to low-performing or misinterpreted diagnostic tests, and inaccurate vital signs have been shown to be similarly prone to potential error.⁴

Finally, we wholeheartedly agree with Dr. Field’s comment on unnecessary testing.  High-value care is appropriate care. Using Bayesian reasoning to guide testing, monitoring the treatment course appropriately, and eliminating waste is highly likely to improve both value and diagnostic accuracy. Automated, ritual ordering of daily tests can indicate that thinking has been shut off, leaving clinicians susceptible to premature closure of the diagnostic process as well as the potential for “incidentalomas” to distract them from the right diagnosis, all the while leading to low-value care such as wasteful spending, patient dissatisfaction, and hospital-acquired anemia.⁵ We believe that deciding on a daily basis what the next day’s tests will be can be another powerful debiasing habit, one with benefits beyond diagnosis.

In Reply: We thank Dr. Field for his insights and personal observations related to diagnosis and biases that contribute to diagnostic errors.

Dr. Field’s comment about the importance of revisiting one’s initial working diagnosis is consistent with our proposed diagnostic time out. A diagnostic time out can incorporate a short checklist and aid in debiasing clinicians when findings do not fit the case presentation, such as lack of response to diuretic therapy. Being mindful of slowing down and not necessarily rushing to judgment is another important component.¹ Of note, the residents in our case did revisit their initial working diagnosis, as suggested by Dr. Field. Questions from learners have great potential to serve as debiasing instruments and should always be encouraged. Those who do not work with students can do the same by speaking with nurses or other members of the healthcare team, who offer observations that busy physicians might miss.

Our case highlights the problem that we lack objective criteria to diagnose symptomatic heart failure. While B-type natriuretic factor (BNP) has a strong negative predictive value, serial BNP measurements have not been established to be helpful in the management of heart failure.² Although certain findings on chest radiography have strong positive and negative likelihood associations, the role of serial chest radiographs is less clear.³ Thus, heart failure remains a clinical diagnosis in current practice.

As Dr. Field points out, the accuracy and performance characteristics of diagnostic testing, such as the respiratory rate, need to be considered in conjunction with debiasing strategies to achieve higher diagnostic accuracy. Multiple factors can contribute to low-performing or misinterpreted diagnostic tests, and inaccurate vital signs have been shown to be similarly prone to potential error.⁴

Finally, we wholeheartedly agree with Dr. Field’s comment on unnecessary testing.  High-value care is appropriate care. Using Bayesian reasoning to guide testing, monitoring the treatment course appropriately, and eliminating waste is highly likely to improve both value and diagnostic accuracy. Automated, ritual ordering of daily tests can indicate that thinking has been shut off, leaving clinicians susceptible to premature closure of the diagnostic process as well as the potential for “incidentalomas” to distract them from the right diagnosis, all the while leading to low-value care such as wasteful spending, patient dissatisfaction, and hospital-acquired anemia.⁵ We believe that deciding on a daily basis what the next day’s tests will be can be another powerful debiasing habit, one with benefits beyond diagnosis.

In Reply: We thank Dr. Field for his insights and personal observations related to diagnosis and biases that contribute to diagnostic errors.

Dr. Field’s comment about the importance of revisiting one’s initial working diagnosis is consistent with our proposed diagnostic time out. A diagnostic time out can incorporate a short checklist and aid in debiasing clinicians when findings do not fit the case presentation, such as lack of response to diuretic therapy. Being mindful of slowing down and not necessarily rushing to judgment is another important component.¹ Of note, the residents in our case did revisit their initial working diagnosis, as suggested by Dr. Field. Questions from learners have great potential to serve as debiasing instruments and should always be encouraged. Those who do not work with students can do the same by speaking with nurses or other members of the healthcare team, who offer observations that busy physicians might miss.

Our case highlights the problem that we lack objective criteria to diagnose symptomatic heart failure. While B-type natriuretic factor (BNP) has a strong negative predictive value, serial BNP measurements have not been established to be helpful in the management of heart failure.² Although certain findings on chest radiography have strong positive and negative likelihood associations, the role of serial chest radiographs is less clear.³ Thus, heart failure remains a clinical diagnosis in current practice.

As Dr. Field points out, the accuracy and performance characteristics of diagnostic testing, such as the respiratory rate, need to be considered in conjunction with debiasing strategies to achieve higher diagnostic accuracy. Multiple factors can contribute to low-performing or misinterpreted diagnostic tests, and inaccurate vital signs have been shown to be similarly prone to potential error.⁴

Finally, we wholeheartedly agree with Dr. Field’s comment on unnecessary testing.  High-value care is appropriate care. Using Bayesian reasoning to guide testing, monitoring the treatment course appropriately, and eliminating waste is highly likely to improve both value and diagnostic accuracy. Automated, ritual ordering of daily tests can indicate that thinking has been shut off, leaving clinicians susceptible to premature closure of the diagnostic process as well as the potential for “incidentalomas” to distract them from the right diagnosis, all the while leading to low-value care such as wasteful spending, patient dissatisfaction, and hospital-acquired anemia.⁵ We believe that deciding on a daily basis what the next day’s tests will be can be another powerful debiasing habit, one with benefits beyond diagnosis.

Nephrolithiasis is common and often recurs. This review focuses on measures to prevent recurrent stone formation. Some measures apply to all patients, and some apply to specific types of stones.

COMMON AND INCREASING

According to data from the 2007–2010 National Health and Nutrition Examination Survey, the prevalence of nephrolithiasis in the United States was 10.6% in men and 7.1% in women. On average, 1 in 11 Americans will develop kidney stones at least once in their lifetime.¹

By race and sex, white men have the highest incidence of nephrolithiasis and Asian women have the lowest. It is less common before age 20 and peaks in incidence in the third and fourth decades of life.

The prevalence has steadily increased in the past few decades (Table 1),^1,2 but the reasons are not clear. The trend may be due to changes in diet and lifestyle, increasing prevalence of obesity and diabetes, migration from rural to urban areas, and global warming, with higher temperature resulting in dehydration and high urinary concentration of calcium and other stone-forming salts.³ Nephrolithiasis is now recognized as a systemic disorder associated with chronic kidney disease, bone loss and fractures, increased risk of coronary artery disease, hypertension, type 2 diabetes mellitus, and metabolic syndrome (Table 2).^4–7

Without medical treatment, the 5-year recurrence rate is high, ranging from 35% to 50% after an initial stone event.⁸ Annual medical costs of care for kidney stones in the United States exceed $4.5 billion, with additional costs from missed work. Therefore, this condition has a considerable economic and social burden, which underscores the importance of prevention.⁹

MOST STONES CONTAIN CALCIUM

About 80% of kidney stones in adults contain calcium, and calcium oxalate stones are more common than calcium phosphate stones. Uric acid and struvite stones account for 5% to 15%, and cystine, protease inhibitor, triamterene, 2,8-dihydroxyadenine (2,8-DHA) and xanthine stones each account for less than 1%.¹⁰

Stones form when the urinary concentration of stone-forming salts, which is inversely proportional to urine volume, is higher than their saturation point, which is affected by urine pH. Acidic urine (low pH) predisposes to the formation of uric acid and cystine stones, whereas alkaline urine (high pH) favors calcium phosphate stones.

INCREASED FLUID INTAKE FOR ALL

High fluid intake, enough to produce at least 2.5 L of urine per day, should be the initial therapy to prevent stone recurrence.¹¹

Borghi et al¹² randomly assigned 199 patients who had a first calcium stone to high oral fluid intake or no intervention and followed them prospectively for 5 years. The recurrence rate was 12% in the treated group and 27% in the control group. Another study, in patients who had undergone shock wave lithotripsy, found a recurrence rate of 8% in those randomized to increase fluid intake to achieve urine output greater than 2.5 L/day, compared with 56% in those assigned to no treatment.¹³

Certain beverages increase the risk of stones and should be avoided. Sugar-sweetened noncola soda and punch are associated with a 33% higher risk of kidney stones, and cola sodas are associated with a 23% higher risk.¹⁴ Prospective studies have shown that the consumption of coffee, beer, wine, and orange juice is associated with a lower likelihood of stone formation.^13,15

Table 3 is a brief summary of the dietary and pharmacologic interventions in the management of recurrent nephrolithiasis.

PREVENTING CALCIUM OXALATE STONES

Major urinary risk factors associated with calcium oxalate stones are hypercalciuria, hyperoxaluria, hyperuricosuria, hypocitraturia, and low urine volume.¹⁶ Preventing calcium stones therefore depends on reducing the urinary concentration of calcium and oxalate, increasing urinary levels of inhibitors such as citrate, and increasing urine volume.

Reducing calcium excretion

Hypercalciuria has been traditionally defined as 24-hour urinary calcium excretion greater than 300 mg/day in men, greater than 250 mg in women, or greater than 4 mg/kg in men or women.¹⁷ It is a graded risk factor, and the cut points used in published research and clinical laboratories vary substantially. Some institutions use the same value for hypercalciuria in both sexes, eg, greater than 200 mg/day.¹⁸

Excessive sodium intake is the most common cause of hypercalciuria. Systemic conditions such as primary hyperparathyroidism, sarcoidosis, and renal tubular acidosis also cause hypercalciuria but are uncommon.¹⁹ Management depends on the underlying cause and includes dietary modifications and pharmacologic therapy.

Dietary modifications have a pivotal role in the management of recurrent stones that are due to hypercalciuria.

Dietary calcium should not be restricted, since calcium reduces the excretion of urinary oxalate by decreasing intestinal absorption of oxalate. Guidelines from the American Urological Association recommend a daily calcium intake of 1,000 to 1,200 mg.^11–20 Moreover, restriction of dietary calcium to less than 800 mg/day (the current recommended daily allowance for adults) can lead to negative calcium balance and bone loss.

Sodium intake also influences hypercalciuria. Calcium is reabsorbed passively in the proximal tubule due to the concentration gradient created by active reabsorption of sodium. A high sodium intake causes volume expansion, leading to a decrease in proximal sodium and calcium reabsorption and enhancing calcium excretion. A low-sodium diet (80–100 mmol/day, or 1,800–2,300 mg/day) is recommended. This enhances proximal sodium and passive calcium absorption and leads to a decrease in calcium excretion.²¹

Dietary protein increases the acid load by production of sulfuric acid and leads to hypercalciuria by its action on bone and kidney. Animal protein has a higher content of sulfur and generates a higher acid load compared with vegetable protein and has been associated with an increased incidence of stone formation, at least in men.^20,22 Borghi et al²³ reported that the combination of restricted intake of animal protein (52 g/day), restricted salt intake (50 mmol, or 2,900 mg/day of sodium chloride), and normal calcium intake (30 mmol/day, or 1,200 mg/day) was associated with a lower incidence of stone recurrence in men with hypercalciuria compared with traditional low-calcium intake (10 mmol, or 400 mg/day). Patients should therefore be advised to avoid excessive intake of animal protein.

Increasing the dietary intake of fruits and vegetables as in the Dietary Approach to Stop Hypertension (DASH) diet is beneficial and reduces the risk of stone recurrence, mainly by increasing citrate excretion.²⁴

Pharmacologic therapy in hypercalciuria. Thiazide diuretics are the mainstay of pharmacotherapy for preventing recurrent stones in patients with idiopathic hypercalciuria. They reduce the risk of stone recurrence by about 50%, as reported in a recent meta-analysis that looked at five trials comparing thiazide diuretics with placebo.²⁵ They lower calcium excretion by causing volume depletion, thereby increasing proximal sodium and passive calcium reabsorption.

Chlorthalidone and hydrochlorothiazide are the thiazides commonly used to treat hypercalciuria. The dosage is titrated to the urinary calcium excretion, and a common mistake is to use doses that are too low. They are usually started at 25 mg/day, but often require an increase to 50 to 100 mg/day for adequate lowering of urinary calcium.

Care should be taken to avoid hypokalemia. If it occurs, it can be corrected by adding the potassium-sparing diuretic amiloride (5–10 mg/day), which increases calcium reabsorption in collecting ducts or, in patients with hypocitraturia, potassium citrate-potassium bicarbonate. (Sodium salts should be avoided, since they increase renal calcium excretion.)²⁶

Management of hypercalciuria with metabolic causes, which include primary hyper­parathyroidism and chronic acidemia. Patients who have hypercalciuria from primary hyperparathyroidism are treated with parathyroidectomy.²⁷ Chronic metabolic acidosis causes hypercalciuria by loss of bone calcium and hypocitraturia by increasing active proximal absorption of citrate. Potassium citrate or potassium bicarbonate is used to prevent stones in such patients; sodium salts should be avoided.²⁸

Reducing oxalate excretion

Hyperoxaluria has traditionally been defined as urinary oxalate excretion of more than 45 mg/day. However, the optimal cutoff point for urinary oxalate excretion is unclear, as is the optimal cutoff for hypercalciuria. The risk of stone formation has been shown to increase with oxalate excretion even above 25 mg/day, which is within the normal limit.¹⁸

Idiopathic hyperoxaluria. High dietary oxalate intake, especially when associated with low calcium intake, leads to idiopathic hyperoxaluria. However, the contribution of abnormal endogenous oxalate metabolism is uncertain. Ingested calcium binds to oxalate in the intestinal tract and reduces both the absorption of intestinal oxalate absorption and the excretion of urinary oxalate.²⁹ High dietary oxalate intake has usually been regarded as a major risk factor for kidney stones.

Taylor and Curhan,³⁰ in a prospective study, reported a mild increase in the risk of stones in the highest quintile of dietary oxalate intake compared with the lowest quintile for men (relative risk [RR] 1.22, 95% confidence interval [CI] 1.03–1.45) and older women (RR 1.21, 95% CI 1.01–1.44). They also demonstrated that eating eight or more servings of spinach per month compared with fewer than one serving per month was associated with a similar increase of stone risk in men (RR 1.30, 95% CI 1.08–1.58) and older women (RR 1.34 95% CI 1.1–1.64). In contrast, spinach and dietary oxalate intake did not increase the risk of nephrolithiasis in young women. The authors concluded that the risk associated with oxalate intake was modest, and their data did not support the contention that dietary oxalate is a major risk factor for kidney stones.

Higher oxalate intake increases urinary oxalate excretion and presumably the risk of nephrolithiasis. Limiting dietary oxalate to prevent stones is recommended if habitually high dietary intake of oxalate is identified or follow-up urine measurements show a decrease in oxalate excretion.³¹ Foods rich in oxalate include spinach, rhubarb, nuts, legumes, cocoa, okra, and chocolate.

The DASH diet, which is high in fruits and vegetables, moderate in low-fat dairy products, and low in animal protein, is an effective dietary alternative and has been associated with a lower risk of calcium oxalate stones.²⁴ Consuming fruits and vegetables increases the excretion of urinary citrate, which is an inhibitor of stone formation. Also, it has been proposed that the DASH diet contains unknown factors that reduce stone risk.

Taylor et al³² prospectively examined the relationship between the DASH diet and the incidence of kidney stones and found that the diet significantly reduced the risk of kidney stones. The relative risks of occurrence of kidney stones in participants in the highest quintile of the DASH score (a measure of adherence to the DASH diet) compared with the lowest quintile were 0.55 (95% CI 0.46–0.65) for men, 0.58 (95% CI 0.49–0.68) for older women, and 0.60 (95% CI 0.52–0.70) for younger women, which the authors characterized as “a marked decrease in kidney stone risk.”

Vitamin C intake should be restricted to 90 mg/day in patients who have a history of calcium oxalate stones. Urivetzky et al³³ found that urinary oxalate excretion increased by 6 to 13 mg/day at doses of ascorbic acid greater than 500 mg.

Pyridoxine (vitamin B₆), a coenzyme of alanine-glyoxylate aminotransferase (AGT), increases the conversion of glyoxylate to glycine instead of oxalate and is used in the treatment of type 1 primary hyperoxaluria (see below).³⁴ However, its effect in preventing stones in idiopathic hyperoxaluria is not well known, and it has not been studied in a randomized controlled trial. In a prospective study, Curhan et al³⁵ reported that high intake of pyridoxine (> 40 mg/day) was associated with a lower risk of stone formation in women, but no such benefit was found in men.

Enteric hyperoxaluria. About 90% of dietary oxalate binds to calcium in the small intestine and is excreted in the stool. The remaining 10% is absorbed in the colon and is secreted in urine. Hyperoxaluria is frequently seen with fat malabsorption from inflammatory bowel disease, short gut syndrome, and gastric bypass surgery. In these conditions, excess fat binds to dietary calcium, leading to increased absorption of free oxalate in the colon.³⁶

Treatment is directed at decreasing intestinal oxalate absorption and should include high fluid intake and oral calcium supplements. Calcium carbonate or citrate causes precipitation of oxalate in the intestinal lumen and is prescribed as 1 to 4 g in three to four divided doses, always with meals. Calcium citrate is preferred over calcium carbonate in stone-formers because of the benefit of citrate and calcium citrate’s higher solubility and greater effectiveness in the presence of achlorhydria.³⁷ Patients should be advised to avoid foods high in oxalate and fat.

Primary hyperoxaluria is caused by inherited inborn errors of glyoxylate metabolism that cause overproduction of oxalate and urinary oxalate excretion above 135 to 270 mg/day.

Type 1 primary hyperoxaluria is the most common (accounting for 90% of cases) and is caused by reduced activity of hepatic peroxisomal AGT.

Type 2 is from a deficiency of glyoxylate reductase-hydroxypyruvate reductase (GRHPR).

Type 3 is from mutations in the HOGA1 gene, which codes for the liver-specific mitochondrial 4-hydroxy-2-oxoglutarate aldolase enzyme involved in degradation of hydroxyproline to pyruvate and glyoxalate.³⁸

High fluid intake to produce a urinary volume of 3 L/day reduces intratubular oxalate deposition and should be encouraged. Potassium citrate (0.15 mg/kg), oral phosphate supplements (30–40 mg/kg of orthophosphate), and magnesium oxide (500 mg/day/m²) inhibit precipitation of calcium oxalate in the urine.^39,40 Pyridoxine, a coenzyme of AGT, increases the conversion of glyoxylate to glycine instead of oxalate and is prescribed at a starting dose of 5 mg/kg (which can be titrated up to 20 mg/kg if there is no response) in patients with type 1 primary hyperoxaluria. About 50% of patients with type 1 respond successfully to pyridoxine, and a 3- to 6-month trial should be given in all patients in this category.³⁴ AGT is present only in hepatocytes, and GRHPR is found in multiple tissues; therefore, combined liver-kidney transplant is the treatment of choice in patients with type 1 primary hyperoxaluria, whereas isolated kidney transplant is recommended in patients with type 2.⁴¹

Reducing uric acid excretion

Hyperuricosuria is defined as uric acid excretion of greater than 800 mg/day in men and greater than 750 mg/day in women.

The association of hyperuricosuria with increased risk of calcium oxalate stone formation is controversial. Curhan and Taylor,¹⁸ in a cross-sectional study of 3,350 men and women, reported that there was no difference in mean 24-hour uric acid excretion in individuals with and without a history of stones.

The mechanism by which uric acid leads to calcium oxalate stones is not completely known and could be the “salting out” of calcium oxalate from the urine.⁴²

Dietary purine restriction, ie, limiting intake of nondairy animal protein to 0.8 to 1 g/kg/day, is the initial dietary intervention.¹¹ Allopurinol is the alternative approach if the patient is not compliant or if dietary restriction fails.⁴³

In a study by Ettinger et al,⁴⁴ 60 patients with hyperuricosuria and normocalciuria were randomized to receive allopurinol (100 mg three times daily) or a placebo. The allopurinol group had a rate of calculus events of 0.12 per patient per year, compared with 0.26 in the placebo group.

Increasing citrate excretion

Hypocitraturia is a well-known risk factor for the formation of kidney stones. It is usually defined as a citrate excretion of less than 320 mg/day for adults.

Citrate prevents formation of calcium crystals by binding to calcium, thereby lowering the concentration of calcium oxalate below the saturation point.⁴⁵

Diet therapy. Patients with calcium oxalate stones and hypocitraturia should be encouraged to increase their intake of fruits and vegetables, which enhances urinary citrate excretion, and to limit their intake of nondairy animal protein.¹¹

The use of citrus products in preventing stones in patients with hypocitraturia is controversial, however, and needs to be studied more.

One study⁴⁶ demonstrated that lemon juice was beneficial in hypocitraturic nephrolithiasis: 4 oz/day of lemon juice concentrate in the form of lemonade was associated with an increase in urinary citrate excretion to 346 mg/day from 142 mg/day in 11 of 12 patients who participated.

Odvina⁴⁷ compared the effects of orange juice with those of lemonade on the acid-base profile and urinary stone risk under controlled metabolic conditions in 13 volunteers. Orange juice was reported to have greater alkalinizing and citraturic effects and was associated with lower calculated calcium oxalate supersaturation compared with lemonade.

Lemonade therapy may be used as adjunctive treatment in patients who do not comply with or cannot tolerate alkali therapy. However, we advise caution about recommending citrus products, as they can increase oxalate excretion.

Pharmacotherapy includes alkali therapy. Barcelo et al⁴⁸ compared the effects of potassium citrate and placebo in 57 patients with calcium oxalate stones and hypocitraturia. Patients treated with potassium citrate had a rate of stone formation of 0.1 event per patient per year, compared with 1.1 in the placebo group.

Many forms of alkaline citrate are available. Potassium citrate is preferred over sodium citrate since the latter may increase urine calcium excretion.⁴⁹ Treatment is usually started at 30 mEq/day and is titrated to a maximal dose of 60 mEq/day for a urinary citrate excretion greater than 500 mg/day.

Common side effects are abdominal bloating and hyperkalemia (especially with renal insufficiency), and in such cases sodium-based alkali, sodium citrate, or sodium bicarbonate can be prescribed.

PREVENTING CALCIUM PHOSPHATE STONES

Risk factors for calcium phosphate stones are similar to those for calcium oxalate stones (other than hyperoxaluria), but calcium phosphate stones are formed in alkaline urine (usually urine pH > 6.0), often the result of distal renal tubular acidosis. Preventive measures are similar to those for calcium oxalate stones.

Alkali therapy should be used with caution because of its effect on urinary pH and the risk of precipitation of calcium phosphate crystals.⁵⁰ Use of potassium citrate was found to be associated with increases in both urinary citrate excretion and calcium phosphate supersaturation in hypercalciuric stone-forming rats.⁵¹ It is therefore challenging to manage patients with calcium phosphate stones and hypocitraturia. Alkali administration in this setting may diminish the formation of new stones by correcting hypocitraturia, but at the same time it may increase the likelihood of calcium phosphate stone formation by increasing the urinary pH. When the urine pH increases to above 6.5 with no significant change in urine citrate or urine calcium excretion, we recommend stopping alkali therapy.

PREVENTING URIC ACID STONES

Clinical conditions associated with uric acid stones include metabolic syndrome, diabetes mellitus, gout, chronic diarrheal illness, and conditions that increase tissue turnover and uric acid production, such as malignancies. Other risk factors for uric acid stone formation are low urine volume, low uric pH, and hyperuricosuria.

Abnormally acidic urine is the most common risk factor. Metabolic syndrome and diabetes mellitus reduce ammonia production, resulting in a lower urinary pH, which predisposes to uric acid stone formation. Chronic diarrhea also acidifies the urine by loss of bicarbonate. Similarly, in gout, the predisposing factor in uric acid stone formation is the persistently acidic urine due to impaired ammonium excretion.⁵² Uric acid precipitates to form uric acid stones in a low urinary pH even with normal excretion rates of 600 to 800 mg/day and a urinary volume of 1 to 1.5 L.⁵³

Therefore, apart from increasing fluid intake, urinary alkalization is the cornerstone of management of uric acid stones. Potassium citrate is the preferred alkali salt and is started at a dose of 30 mEq/day for a goal urinary pH of 6 to 6.5.⁴⁷

Patients with hyperuricosuria are also advised to restrict their protein intake to no more than 0.8 to 1 mg/kg/day.

If the above measures fail, patients are treated with a xanthine oxidase inhibitor, ie, allopurinol or febuxostat, even if their uric acid excretion is normal.⁵⁴

PREVENTING STRUVITE STONES

Struvite stones contain magnesium ammonium phosphate and are due to chronic upper urinary tract infection with urea-splitting bacteria such as Proteus, Klebsiella, Pseudomonas, and enterococci. Urea hydrolysis releases hydroxyl ions, resulting in alkaline urine that promotes struvite stone formation. Early detection and treatment are important, since struvite stones are associated with morbidity and rapid progression.

Medical treatment of struvite stones is usually unsuccessful, and the patient is referred to a urologist for surgical removal of the stones, the gold standard treatment.⁵⁵ Long-term use of culture-specific antibiotics to prevent new stone growth is not well studied. Medical therapy by itself is preferred in patients who refuse stone removal or cannot tolerate it. Urease inhibitors such as acetohydroxamic acid have been successful in preventing or slowing stone growth, but their use is limited by frequent side effects such as nausea, headache, rash, and thrombophlebitis.⁵⁶

CYSTINE STONES

Cystine stones occur in people with inherited defects of renal tubular and intestinal transport of cysteine and dibasic amino acids that cause excessive excretion of urinary cystine, ie, 480 to 3,600 mg/day.

Cystine is formed from two cysteine molecules linked by a disulfide bond. The solubility of cystine is pH-dependent, with increased solubility at higher urinary pH. The goal is to maintain a urinary cystine concentration below its solubility level by keeping the cystine concentration below 243 mg/L and the urine cystine supersaturation (the ratio of the urine cysteine concentration to the cysteine solubility in the same sample) less than 0.6.⁵⁷ Therapy is aimed at increasing daily urinary volume to 3 L and urine alkalization to pH above 7, in order to increase cystine solubility by 300%.⁵⁸

Overnight dehydration should be prevented, and patients should be encouraged to wake up at least once a night to void and drink additional water. Sodium restriction to 100 mmol/day (2,300 mg/day) and moderate protein restriction to 0.8 to 1 g/kg/day are associated with decreased cystine excretion, but long-term studies demonstrating their benefit in preventing cystine stones are lacking.⁵⁹

A thiol-containing drug, eg, D-penicillamine (0.5–2 g/day) or tiopronin (400–1,200 mg/day), should be added to the conservative measures if they have not been effective for 3 months or if there is history of noncompliance.⁶⁰ Thiol-containing drugs have a sulfhydryl group that reduces the disulfide bond, and they form soluble disulfide cysteine-drug complexes with greater ability to solubilize cystine in alkaline urine. They must always be used in conjunction with fluid and alkali therapy.⁶¹

Both drugs have severe and common adverse effects including leukopenia, aplastic anemia, fever, rash, arthritis, hepatotoxicity, pyridoxine deficiency, and proteinuria (membranous nephropathy). However, tiopronin seems to have a lesser incidence of side effects.⁶² Regular monitoring of complete blood cell counts, liver enzymes, and urine protein should be done.

Captopril contains a sulfhydryl group, and the captopril-cysteine disulfide is more soluble than cysteine alone. The amount of captopril that appears in the urine is low, and doses of 150 mg/day are usually required to reduce cysteine excretion, which can lead to hypotension. The efficacy of captopril in treating cystine stones is unproven, and this drug is used only if patients cannot tolerate other thiol-containing drugs.⁶³

Nephrolithiasis is common and often recurs. This review focuses on measures to prevent recurrent stone formation. Some measures apply to all patients, and some apply to specific types of stones.

COMMON AND INCREASING

According to data from the 2007–2010 National Health and Nutrition Examination Survey, the prevalence of nephrolithiasis in the United States was 10.6% in men and 7.1% in women. On average, 1 in 11 Americans will develop kidney stones at least once in their lifetime.¹

By race and sex, white men have the highest incidence of nephrolithiasis and Asian women have the lowest. It is less common before age 20 and peaks in incidence in the third and fourth decades of life.

The prevalence has steadily increased in the past few decades (Table 1),^1,2 but the reasons are not clear. The trend may be due to changes in diet and lifestyle, increasing prevalence of obesity and diabetes, migration from rural to urban areas, and global warming, with higher temperature resulting in dehydration and high urinary concentration of calcium and other stone-forming salts.³ Nephrolithiasis is now recognized as a systemic disorder associated with chronic kidney disease, bone loss and fractures, increased risk of coronary artery disease, hypertension, type 2 diabetes mellitus, and metabolic syndrome (Table 2).^4–7

Without medical treatment, the 5-year recurrence rate is high, ranging from 35% to 50% after an initial stone event.⁸ Annual medical costs of care for kidney stones in the United States exceed $4.5 billion, with additional costs from missed work. Therefore, this condition has a considerable economic and social burden, which underscores the importance of prevention.⁹

MOST STONES CONTAIN CALCIUM

About 80% of kidney stones in adults contain calcium, and calcium oxalate stones are more common than calcium phosphate stones. Uric acid and struvite stones account for 5% to 15%, and cystine, protease inhibitor, triamterene, 2,8-dihydroxyadenine (2,8-DHA) and xanthine stones each account for less than 1%.¹⁰

Stones form when the urinary concentration of stone-forming salts, which is inversely proportional to urine volume, is higher than their saturation point, which is affected by urine pH. Acidic urine (low pH) predisposes to the formation of uric acid and cystine stones, whereas alkaline urine (high pH) favors calcium phosphate stones.

INCREASED FLUID INTAKE FOR ALL

High fluid intake, enough to produce at least 2.5 L of urine per day, should be the initial therapy to prevent stone recurrence.¹¹

Borghi et al¹² randomly assigned 199 patients who had a first calcium stone to high oral fluid intake or no intervention and followed them prospectively for 5 years. The recurrence rate was 12% in the treated group and 27% in the control group. Another study, in patients who had undergone shock wave lithotripsy, found a recurrence rate of 8% in those randomized to increase fluid intake to achieve urine output greater than 2.5 L/day, compared with 56% in those assigned to no treatment.¹³

Certain beverages increase the risk of stones and should be avoided. Sugar-sweetened noncola soda and punch are associated with a 33% higher risk of kidney stones, and cola sodas are associated with a 23% higher risk.¹⁴ Prospective studies have shown that the consumption of coffee, beer, wine, and orange juice is associated with a lower likelihood of stone formation.^13,15

Table 3 is a brief summary of the dietary and pharmacologic interventions in the management of recurrent nephrolithiasis.

PREVENTING CALCIUM OXALATE STONES

Major urinary risk factors associated with calcium oxalate stones are hypercalciuria, hyperoxaluria, hyperuricosuria, hypocitraturia, and low urine volume.¹⁶ Preventing calcium stones therefore depends on reducing the urinary concentration of calcium and oxalate, increasing urinary levels of inhibitors such as citrate, and increasing urine volume.

Reducing calcium excretion

Hypercalciuria has been traditionally defined as 24-hour urinary calcium excretion greater than 300 mg/day in men, greater than 250 mg in women, or greater than 4 mg/kg in men or women.¹⁷ It is a graded risk factor, and the cut points used in published research and clinical laboratories vary substantially. Some institutions use the same value for hypercalciuria in both sexes, eg, greater than 200 mg/day.¹⁸

Excessive sodium intake is the most common cause of hypercalciuria. Systemic conditions such as primary hyperparathyroidism, sarcoidosis, and renal tubular acidosis also cause hypercalciuria but are uncommon.¹⁹ Management depends on the underlying cause and includes dietary modifications and pharmacologic therapy.

Dietary modifications have a pivotal role in the management of recurrent stones that are due to hypercalciuria.

Dietary calcium should not be restricted, since calcium reduces the excretion of urinary oxalate by decreasing intestinal absorption of oxalate. Guidelines from the American Urological Association recommend a daily calcium intake of 1,000 to 1,200 mg.^11–20 Moreover, restriction of dietary calcium to less than 800 mg/day (the current recommended daily allowance for adults) can lead to negative calcium balance and bone loss.

Sodium intake also influences hypercalciuria. Calcium is reabsorbed passively in the proximal tubule due to the concentration gradient created by active reabsorption of sodium. A high sodium intake causes volume expansion, leading to a decrease in proximal sodium and calcium reabsorption and enhancing calcium excretion. A low-sodium diet (80–100 mmol/day, or 1,800–2,300 mg/day) is recommended. This enhances proximal sodium and passive calcium absorption and leads to a decrease in calcium excretion.²¹

Dietary protein increases the acid load by production of sulfuric acid and leads to hypercalciuria by its action on bone and kidney. Animal protein has a higher content of sulfur and generates a higher acid load compared with vegetable protein and has been associated with an increased incidence of stone formation, at least in men.^20,22 Borghi et al²³ reported that the combination of restricted intake of animal protein (52 g/day), restricted salt intake (50 mmol, or 2,900 mg/day of sodium chloride), and normal calcium intake (30 mmol/day, or 1,200 mg/day) was associated with a lower incidence of stone recurrence in men with hypercalciuria compared with traditional low-calcium intake (10 mmol, or 400 mg/day). Patients should therefore be advised to avoid excessive intake of animal protein.

Increasing the dietary intake of fruits and vegetables as in the Dietary Approach to Stop Hypertension (DASH) diet is beneficial and reduces the risk of stone recurrence, mainly by increasing citrate excretion.²⁴

Pharmacologic therapy in hypercalciuria. Thiazide diuretics are the mainstay of pharmacotherapy for preventing recurrent stones in patients with idiopathic hypercalciuria. They reduce the risk of stone recurrence by about 50%, as reported in a recent meta-analysis that looked at five trials comparing thiazide diuretics with placebo.²⁵ They lower calcium excretion by causing volume depletion, thereby increasing proximal sodium and passive calcium reabsorption.

Chlorthalidone and hydrochlorothiazide are the thiazides commonly used to treat hypercalciuria. The dosage is titrated to the urinary calcium excretion, and a common mistake is to use doses that are too low. They are usually started at 25 mg/day, but often require an increase to 50 to 100 mg/day for adequate lowering of urinary calcium.

Care should be taken to avoid hypokalemia. If it occurs, it can be corrected by adding the potassium-sparing diuretic amiloride (5–10 mg/day), which increases calcium reabsorption in collecting ducts or, in patients with hypocitraturia, potassium citrate-potassium bicarbonate. (Sodium salts should be avoided, since they increase renal calcium excretion.)²⁶

Management of hypercalciuria with metabolic causes, which include primary hyper­parathyroidism and chronic acidemia. Patients who have hypercalciuria from primary hyperparathyroidism are treated with parathyroidectomy.²⁷ Chronic metabolic acidosis causes hypercalciuria by loss of bone calcium and hypocitraturia by increasing active proximal absorption of citrate. Potassium citrate or potassium bicarbonate is used to prevent stones in such patients; sodium salts should be avoided.²⁸

Reducing oxalate excretion

Hyperoxaluria has traditionally been defined as urinary oxalate excretion of more than 45 mg/day. However, the optimal cutoff point for urinary oxalate excretion is unclear, as is the optimal cutoff for hypercalciuria. The risk of stone formation has been shown to increase with oxalate excretion even above 25 mg/day, which is within the normal limit.¹⁸

Idiopathic hyperoxaluria. High dietary oxalate intake, especially when associated with low calcium intake, leads to idiopathic hyperoxaluria. However, the contribution of abnormal endogenous oxalate metabolism is uncertain. Ingested calcium binds to oxalate in the intestinal tract and reduces both the absorption of intestinal oxalate absorption and the excretion of urinary oxalate.²⁹ High dietary oxalate intake has usually been regarded as a major risk factor for kidney stones.

Taylor and Curhan,³⁰ in a prospective study, reported a mild increase in the risk of stones in the highest quintile of dietary oxalate intake compared with the lowest quintile for men (relative risk [RR] 1.22, 95% confidence interval [CI] 1.03–1.45) and older women (RR 1.21, 95% CI 1.01–1.44). They also demonstrated that eating eight or more servings of spinach per month compared with fewer than one serving per month was associated with a similar increase of stone risk in men (RR 1.30, 95% CI 1.08–1.58) and older women (RR 1.34 95% CI 1.1–1.64). In contrast, spinach and dietary oxalate intake did not increase the risk of nephrolithiasis in young women. The authors concluded that the risk associated with oxalate intake was modest, and their data did not support the contention that dietary oxalate is a major risk factor for kidney stones.

Higher oxalate intake increases urinary oxalate excretion and presumably the risk of nephrolithiasis. Limiting dietary oxalate to prevent stones is recommended if habitually high dietary intake of oxalate is identified or follow-up urine measurements show a decrease in oxalate excretion.³¹ Foods rich in oxalate include spinach, rhubarb, nuts, legumes, cocoa, okra, and chocolate.

The DASH diet, which is high in fruits and vegetables, moderate in low-fat dairy products, and low in animal protein, is an effective dietary alternative and has been associated with a lower risk of calcium oxalate stones.²⁴ Consuming fruits and vegetables increases the excretion of urinary citrate, which is an inhibitor of stone formation. Also, it has been proposed that the DASH diet contains unknown factors that reduce stone risk.

Taylor et al³² prospectively examined the relationship between the DASH diet and the incidence of kidney stones and found that the diet significantly reduced the risk of kidney stones. The relative risks of occurrence of kidney stones in participants in the highest quintile of the DASH score (a measure of adherence to the DASH diet) compared with the lowest quintile were 0.55 (95% CI 0.46–0.65) for men, 0.58 (95% CI 0.49–0.68) for older women, and 0.60 (95% CI 0.52–0.70) for younger women, which the authors characterized as “a marked decrease in kidney stone risk.”

Vitamin C intake should be restricted to 90 mg/day in patients who have a history of calcium oxalate stones. Urivetzky et al³³ found that urinary oxalate excretion increased by 6 to 13 mg/day at doses of ascorbic acid greater than 500 mg.

Pyridoxine (vitamin B₆), a coenzyme of alanine-glyoxylate aminotransferase (AGT), increases the conversion of glyoxylate to glycine instead of oxalate and is used in the treatment of type 1 primary hyperoxaluria (see below).³⁴ However, its effect in preventing stones in idiopathic hyperoxaluria is not well known, and it has not been studied in a randomized controlled trial. In a prospective study, Curhan et al³⁵ reported that high intake of pyridoxine (> 40 mg/day) was associated with a lower risk of stone formation in women, but no such benefit was found in men.

Enteric hyperoxaluria. About 90% of dietary oxalate binds to calcium in the small intestine and is excreted in the stool. The remaining 10% is absorbed in the colon and is secreted in urine. Hyperoxaluria is frequently seen with fat malabsorption from inflammatory bowel disease, short gut syndrome, and gastric bypass surgery. In these conditions, excess fat binds to dietary calcium, leading to increased absorption of free oxalate in the colon.³⁶

Treatment is directed at decreasing intestinal oxalate absorption and should include high fluid intake and oral calcium supplements. Calcium carbonate or citrate causes precipitation of oxalate in the intestinal lumen and is prescribed as 1 to 4 g in three to four divided doses, always with meals. Calcium citrate is preferred over calcium carbonate in stone-formers because of the benefit of citrate and calcium citrate’s higher solubility and greater effectiveness in the presence of achlorhydria.³⁷ Patients should be advised to avoid foods high in oxalate and fat.

Primary hyperoxaluria is caused by inherited inborn errors of glyoxylate metabolism that cause overproduction of oxalate and urinary oxalate excretion above 135 to 270 mg/day.

Type 1 primary hyperoxaluria is the most common (accounting for 90% of cases) and is caused by reduced activity of hepatic peroxisomal AGT.

Type 2 is from a deficiency of glyoxylate reductase-hydroxypyruvate reductase (GRHPR).

Type 3 is from mutations in the HOGA1 gene, which codes for the liver-specific mitochondrial 4-hydroxy-2-oxoglutarate aldolase enzyme involved in degradation of hydroxyproline to pyruvate and glyoxalate.³⁸

High fluid intake to produce a urinary volume of 3 L/day reduces intratubular oxalate deposition and should be encouraged. Potassium citrate (0.15 mg/kg), oral phosphate supplements (30–40 mg/kg of orthophosphate), and magnesium oxide (500 mg/day/m²) inhibit precipitation of calcium oxalate in the urine.^39,40 Pyridoxine, a coenzyme of AGT, increases the conversion of glyoxylate to glycine instead of oxalate and is prescribed at a starting dose of 5 mg/kg (which can be titrated up to 20 mg/kg if there is no response) in patients with type 1 primary hyperoxaluria. About 50% of patients with type 1 respond successfully to pyridoxine, and a 3- to 6-month trial should be given in all patients in this category.³⁴ AGT is present only in hepatocytes, and GRHPR is found in multiple tissues; therefore, combined liver-kidney transplant is the treatment of choice in patients with type 1 primary hyperoxaluria, whereas isolated kidney transplant is recommended in patients with type 2.⁴¹

Reducing uric acid excretion

Hyperuricosuria is defined as uric acid excretion of greater than 800 mg/day in men and greater than 750 mg/day in women.

The association of hyperuricosuria with increased risk of calcium oxalate stone formation is controversial. Curhan and Taylor,¹⁸ in a cross-sectional study of 3,350 men and women, reported that there was no difference in mean 24-hour uric acid excretion in individuals with and without a history of stones.

The mechanism by which uric acid leads to calcium oxalate stones is not completely known and could be the “salting out” of calcium oxalate from the urine.⁴²

Dietary purine restriction, ie, limiting intake of nondairy animal protein to 0.8 to 1 g/kg/day, is the initial dietary intervention.¹¹ Allopurinol is the alternative approach if the patient is not compliant or if dietary restriction fails.⁴³

In a study by Ettinger et al,⁴⁴ 60 patients with hyperuricosuria and normocalciuria were randomized to receive allopurinol (100 mg three times daily) or a placebo. The allopurinol group had a rate of calculus events of 0.12 per patient per year, compared with 0.26 in the placebo group.

Increasing citrate excretion

Hypocitraturia is a well-known risk factor for the formation of kidney stones. It is usually defined as a citrate excretion of less than 320 mg/day for adults.

Citrate prevents formation of calcium crystals by binding to calcium, thereby lowering the concentration of calcium oxalate below the saturation point.⁴⁵

Diet therapy. Patients with calcium oxalate stones and hypocitraturia should be encouraged to increase their intake of fruits and vegetables, which enhances urinary citrate excretion, and to limit their intake of nondairy animal protein.¹¹

The use of citrus products in preventing stones in patients with hypocitraturia is controversial, however, and needs to be studied more.

One study⁴⁶ demonstrated that lemon juice was beneficial in hypocitraturic nephrolithiasis: 4 oz/day of lemon juice concentrate in the form of lemonade was associated with an increase in urinary citrate excretion to 346 mg/day from 142 mg/day in 11 of 12 patients who participated.

Odvina⁴⁷ compared the effects of orange juice with those of lemonade on the acid-base profile and urinary stone risk under controlled metabolic conditions in 13 volunteers. Orange juice was reported to have greater alkalinizing and citraturic effects and was associated with lower calculated calcium oxalate supersaturation compared with lemonade.

Lemonade therapy may be used as adjunctive treatment in patients who do not comply with or cannot tolerate alkali therapy. However, we advise caution about recommending citrus products, as they can increase oxalate excretion.

Pharmacotherapy includes alkali therapy. Barcelo et al⁴⁸ compared the effects of potassium citrate and placebo in 57 patients with calcium oxalate stones and hypocitraturia. Patients treated with potassium citrate had a rate of stone formation of 0.1 event per patient per year, compared with 1.1 in the placebo group.

Many forms of alkaline citrate are available. Potassium citrate is preferred over sodium citrate since the latter may increase urine calcium excretion.⁴⁹ Treatment is usually started at 30 mEq/day and is titrated to a maximal dose of 60 mEq/day for a urinary citrate excretion greater than 500 mg/day.

Common side effects are abdominal bloating and hyperkalemia (especially with renal insufficiency), and in such cases sodium-based alkali, sodium citrate, or sodium bicarbonate can be prescribed.

PREVENTING CALCIUM PHOSPHATE STONES

Risk factors for calcium phosphate stones are similar to those for calcium oxalate stones (other than hyperoxaluria), but calcium phosphate stones are formed in alkaline urine (usually urine pH > 6.0), often the result of distal renal tubular acidosis. Preventive measures are similar to those for calcium oxalate stones.

Alkali therapy should be used with caution because of its effect on urinary pH and the risk of precipitation of calcium phosphate crystals.⁵⁰ Use of potassium citrate was found to be associated with increases in both urinary citrate excretion and calcium phosphate supersaturation in hypercalciuric stone-forming rats.⁵¹ It is therefore challenging to manage patients with calcium phosphate stones and hypocitraturia. Alkali administration in this setting may diminish the formation of new stones by correcting hypocitraturia, but at the same time it may increase the likelihood of calcium phosphate stone formation by increasing the urinary pH. When the urine pH increases to above 6.5 with no significant change in urine citrate or urine calcium excretion, we recommend stopping alkali therapy.

PREVENTING URIC ACID STONES

Clinical conditions associated with uric acid stones include metabolic syndrome, diabetes mellitus, gout, chronic diarrheal illness, and conditions that increase tissue turnover and uric acid production, such as malignancies. Other risk factors for uric acid stone formation are low urine volume, low uric pH, and hyperuricosuria.

Abnormally acidic urine is the most common risk factor. Metabolic syndrome and diabetes mellitus reduce ammonia production, resulting in a lower urinary pH, which predisposes to uric acid stone formation. Chronic diarrhea also acidifies the urine by loss of bicarbonate. Similarly, in gout, the predisposing factor in uric acid stone formation is the persistently acidic urine due to impaired ammonium excretion.⁵² Uric acid precipitates to form uric acid stones in a low urinary pH even with normal excretion rates of 600 to 800 mg/day and a urinary volume of 1 to 1.5 L.⁵³

Therefore, apart from increasing fluid intake, urinary alkalization is the cornerstone of management of uric acid stones. Potassium citrate is the preferred alkali salt and is started at a dose of 30 mEq/day for a goal urinary pH of 6 to 6.5.⁴⁷

Patients with hyperuricosuria are also advised to restrict their protein intake to no more than 0.8 to 1 mg/kg/day.

If the above measures fail, patients are treated with a xanthine oxidase inhibitor, ie, allopurinol or febuxostat, even if their uric acid excretion is normal.⁵⁴

PREVENTING STRUVITE STONES

Struvite stones contain magnesium ammonium phosphate and are due to chronic upper urinary tract infection with urea-splitting bacteria such as Proteus, Klebsiella, Pseudomonas, and enterococci. Urea hydrolysis releases hydroxyl ions, resulting in alkaline urine that promotes struvite stone formation. Early detection and treatment are important, since struvite stones are associated with morbidity and rapid progression.

Medical treatment of struvite stones is usually unsuccessful, and the patient is referred to a urologist for surgical removal of the stones, the gold standard treatment.⁵⁵ Long-term use of culture-specific antibiotics to prevent new stone growth is not well studied. Medical therapy by itself is preferred in patients who refuse stone removal or cannot tolerate it. Urease inhibitors such as acetohydroxamic acid have been successful in preventing or slowing stone growth, but their use is limited by frequent side effects such as nausea, headache, rash, and thrombophlebitis.⁵⁶

CYSTINE STONES

Cystine stones occur in people with inherited defects of renal tubular and intestinal transport of cysteine and dibasic amino acids that cause excessive excretion of urinary cystine, ie, 480 to 3,600 mg/day.

Cystine is formed from two cysteine molecules linked by a disulfide bond. The solubility of cystine is pH-dependent, with increased solubility at higher urinary pH. The goal is to maintain a urinary cystine concentration below its solubility level by keeping the cystine concentration below 243 mg/L and the urine cystine supersaturation (the ratio of the urine cysteine concentration to the cysteine solubility in the same sample) less than 0.6.⁵⁷ Therapy is aimed at increasing daily urinary volume to 3 L and urine alkalization to pH above 7, in order to increase cystine solubility by 300%.⁵⁸

Overnight dehydration should be prevented, and patients should be encouraged to wake up at least once a night to void and drink additional water. Sodium restriction to 100 mmol/day (2,300 mg/day) and moderate protein restriction to 0.8 to 1 g/kg/day are associated with decreased cystine excretion, but long-term studies demonstrating their benefit in preventing cystine stones are lacking.⁵⁹

A thiol-containing drug, eg, D-penicillamine (0.5–2 g/day) or tiopronin (400–1,200 mg/day), should be added to the conservative measures if they have not been effective for 3 months or if there is history of noncompliance.⁶⁰ Thiol-containing drugs have a sulfhydryl group that reduces the disulfide bond, and they form soluble disulfide cysteine-drug complexes with greater ability to solubilize cystine in alkaline urine. They must always be used in conjunction with fluid and alkali therapy.⁶¹

Both drugs have severe and common adverse effects including leukopenia, aplastic anemia, fever, rash, arthritis, hepatotoxicity, pyridoxine deficiency, and proteinuria (membranous nephropathy). However, tiopronin seems to have a lesser incidence of side effects.⁶² Regular monitoring of complete blood cell counts, liver enzymes, and urine protein should be done.

Captopril contains a sulfhydryl group, and the captopril-cysteine disulfide is more soluble than cysteine alone. The amount of captopril that appears in the urine is low, and doses of 150 mg/day are usually required to reduce cysteine excretion, which can lead to hypotension. The efficacy of captopril in treating cystine stones is unproven, and this drug is used only if patients cannot tolerate other thiol-containing drugs.⁶³

Nephrolithiasis is common and often recurs. This review focuses on measures to prevent recurrent stone formation. Some measures apply to all patients, and some apply to specific types of stones.

COMMON AND INCREASING

According to data from the 2007–2010 National Health and Nutrition Examination Survey, the prevalence of nephrolithiasis in the United States was 10.6% in men and 7.1% in women. On average, 1 in 11 Americans will develop kidney stones at least once in their lifetime.¹

By race and sex, white men have the highest incidence of nephrolithiasis and Asian women have the lowest. It is less common before age 20 and peaks in incidence in the third and fourth decades of life.

The prevalence has steadily increased in the past few decades (Table 1),^1,2 but the reasons are not clear. The trend may be due to changes in diet and lifestyle, increasing prevalence of obesity and diabetes, migration from rural to urban areas, and global warming, with higher temperature resulting in dehydration and high urinary concentration of calcium and other stone-forming salts.³ Nephrolithiasis is now recognized as a systemic disorder associated with chronic kidney disease, bone loss and fractures, increased risk of coronary artery disease, hypertension, type 2 diabetes mellitus, and metabolic syndrome (Table 2).^4–7

Without medical treatment, the 5-year recurrence rate is high, ranging from 35% to 50% after an initial stone event.⁸ Annual medical costs of care for kidney stones in the United States exceed $4.5 billion, with additional costs from missed work. Therefore, this condition has a considerable economic and social burden, which underscores the importance of prevention.⁹

MOST STONES CONTAIN CALCIUM

About 80% of kidney stones in adults contain calcium, and calcium oxalate stones are more common than calcium phosphate stones. Uric acid and struvite stones account for 5% to 15%, and cystine, protease inhibitor, triamterene, 2,8-dihydroxyadenine (2,8-DHA) and xanthine stones each account for less than 1%.¹⁰

Stones form when the urinary concentration of stone-forming salts, which is inversely proportional to urine volume, is higher than their saturation point, which is affected by urine pH. Acidic urine (low pH) predisposes to the formation of uric acid and cystine stones, whereas alkaline urine (high pH) favors calcium phosphate stones.

INCREASED FLUID INTAKE FOR ALL

High fluid intake, enough to produce at least 2.5 L of urine per day, should be the initial therapy to prevent stone recurrence.¹¹

Borghi et al¹² randomly assigned 199 patients who had a first calcium stone to high oral fluid intake or no intervention and followed them prospectively for 5 years. The recurrence rate was 12% in the treated group and 27% in the control group. Another study, in patients who had undergone shock wave lithotripsy, found a recurrence rate of 8% in those randomized to increase fluid intake to achieve urine output greater than 2.5 L/day, compared with 56% in those assigned to no treatment.¹³

Certain beverages increase the risk of stones and should be avoided. Sugar-sweetened noncola soda and punch are associated with a 33% higher risk of kidney stones, and cola sodas are associated with a 23% higher risk.¹⁴ Prospective studies have shown that the consumption of coffee, beer, wine, and orange juice is associated with a lower likelihood of stone formation.^13,15

Table 3 is a brief summary of the dietary and pharmacologic interventions in the management of recurrent nephrolithiasis.

PREVENTING CALCIUM OXALATE STONES

Major urinary risk factors associated with calcium oxalate stones are hypercalciuria, hyperoxaluria, hyperuricosuria, hypocitraturia, and low urine volume.¹⁶ Preventing calcium stones therefore depends on reducing the urinary concentration of calcium and oxalate, increasing urinary levels of inhibitors such as citrate, and increasing urine volume.

Reducing calcium excretion

Hypercalciuria has been traditionally defined as 24-hour urinary calcium excretion greater than 300 mg/day in men, greater than 250 mg in women, or greater than 4 mg/kg in men or women.¹⁷ It is a graded risk factor, and the cut points used in published research and clinical laboratories vary substantially. Some institutions use the same value for hypercalciuria in both sexes, eg, greater than 200 mg/day.¹⁸

Excessive sodium intake is the most common cause of hypercalciuria. Systemic conditions such as primary hyperparathyroidism, sarcoidosis, and renal tubular acidosis also cause hypercalciuria but are uncommon.¹⁹ Management depends on the underlying cause and includes dietary modifications and pharmacologic therapy.

Dietary modifications have a pivotal role in the management of recurrent stones that are due to hypercalciuria.

Dietary calcium should not be restricted, since calcium reduces the excretion of urinary oxalate by decreasing intestinal absorption of oxalate. Guidelines from the American Urological Association recommend a daily calcium intake of 1,000 to 1,200 mg.^11–20 Moreover, restriction of dietary calcium to less than 800 mg/day (the current recommended daily allowance for adults) can lead to negative calcium balance and bone loss.

Sodium intake also influences hypercalciuria. Calcium is reabsorbed passively in the proximal tubule due to the concentration gradient created by active reabsorption of sodium. A high sodium intake causes volume expansion, leading to a decrease in proximal sodium and calcium reabsorption and enhancing calcium excretion. A low-sodium diet (80–100 mmol/day, or 1,800–2,300 mg/day) is recommended. This enhances proximal sodium and passive calcium absorption and leads to a decrease in calcium excretion.²¹

Dietary protein increases the acid load by production of sulfuric acid and leads to hypercalciuria by its action on bone and kidney. Animal protein has a higher content of sulfur and generates a higher acid load compared with vegetable protein and has been associated with an increased incidence of stone formation, at least in men.^20,22 Borghi et al²³ reported that the combination of restricted intake of animal protein (52 g/day), restricted salt intake (50 mmol, or 2,900 mg/day of sodium chloride), and normal calcium intake (30 mmol/day, or 1,200 mg/day) was associated with a lower incidence of stone recurrence in men with hypercalciuria compared with traditional low-calcium intake (10 mmol, or 400 mg/day). Patients should therefore be advised to avoid excessive intake of animal protein.

Increasing the dietary intake of fruits and vegetables as in the Dietary Approach to Stop Hypertension (DASH) diet is beneficial and reduces the risk of stone recurrence, mainly by increasing citrate excretion.²⁴

Pharmacologic therapy in hypercalciuria. Thiazide diuretics are the mainstay of pharmacotherapy for preventing recurrent stones in patients with idiopathic hypercalciuria. They reduce the risk of stone recurrence by about 50%, as reported in a recent meta-analysis that looked at five trials comparing thiazide diuretics with placebo.²⁵ They lower calcium excretion by causing volume depletion, thereby increasing proximal sodium and passive calcium reabsorption.

Chlorthalidone and hydrochlorothiazide are the thiazides commonly used to treat hypercalciuria. The dosage is titrated to the urinary calcium excretion, and a common mistake is to use doses that are too low. They are usually started at 25 mg/day, but often require an increase to 50 to 100 mg/day for adequate lowering of urinary calcium.

Care should be taken to avoid hypokalemia. If it occurs, it can be corrected by adding the potassium-sparing diuretic amiloride (5–10 mg/day), which increases calcium reabsorption in collecting ducts or, in patients with hypocitraturia, potassium citrate-potassium bicarbonate. (Sodium salts should be avoided, since they increase renal calcium excretion.)²⁶

Management of hypercalciuria with metabolic causes, which include primary hyper­parathyroidism and chronic acidemia. Patients who have hypercalciuria from primary hyperparathyroidism are treated with parathyroidectomy.²⁷ Chronic metabolic acidosis causes hypercalciuria by loss of bone calcium and hypocitraturia by increasing active proximal absorption of citrate. Potassium citrate or potassium bicarbonate is used to prevent stones in such patients; sodium salts should be avoided.²⁸

Reducing oxalate excretion

Hyperoxaluria has traditionally been defined as urinary oxalate excretion of more than 45 mg/day. However, the optimal cutoff point for urinary oxalate excretion is unclear, as is the optimal cutoff for hypercalciuria. The risk of stone formation has been shown to increase with oxalate excretion even above 25 mg/day, which is within the normal limit.¹⁸

Idiopathic hyperoxaluria. High dietary oxalate intake, especially when associated with low calcium intake, leads to idiopathic hyperoxaluria. However, the contribution of abnormal endogenous oxalate metabolism is uncertain. Ingested calcium binds to oxalate in the intestinal tract and reduces both the absorption of intestinal oxalate absorption and the excretion of urinary oxalate.²⁹ High dietary oxalate intake has usually been regarded as a major risk factor for kidney stones.

Taylor and Curhan,³⁰ in a prospective study, reported a mild increase in the risk of stones in the highest quintile of dietary oxalate intake compared with the lowest quintile for men (relative risk [RR] 1.22, 95% confidence interval [CI] 1.03–1.45) and older women (RR 1.21, 95% CI 1.01–1.44). They also demonstrated that eating eight or more servings of spinach per month compared with fewer than one serving per month was associated with a similar increase of stone risk in men (RR 1.30, 95% CI 1.08–1.58) and older women (RR 1.34 95% CI 1.1–1.64). In contrast, spinach and dietary oxalate intake did not increase the risk of nephrolithiasis in young women. The authors concluded that the risk associated with oxalate intake was modest, and their data did not support the contention that dietary oxalate is a major risk factor for kidney stones.

Higher oxalate intake increases urinary oxalate excretion and presumably the risk of nephrolithiasis. Limiting dietary oxalate to prevent stones is recommended if habitually high dietary intake of oxalate is identified or follow-up urine measurements show a decrease in oxalate excretion.³¹ Foods rich in oxalate include spinach, rhubarb, nuts, legumes, cocoa, okra, and chocolate.

The DASH diet, which is high in fruits and vegetables, moderate in low-fat dairy products, and low in animal protein, is an effective dietary alternative and has been associated with a lower risk of calcium oxalate stones.²⁴ Consuming fruits and vegetables increases the excretion of urinary citrate, which is an inhibitor of stone formation. Also, it has been proposed that the DASH diet contains unknown factors that reduce stone risk.

Taylor et al³² prospectively examined the relationship between the DASH diet and the incidence of kidney stones and found that the diet significantly reduced the risk of kidney stones. The relative risks of occurrence of kidney stones in participants in the highest quintile of the DASH score (a measure of adherence to the DASH diet) compared with the lowest quintile were 0.55 (95% CI 0.46–0.65) for men, 0.58 (95% CI 0.49–0.68) for older women, and 0.60 (95% CI 0.52–0.70) for younger women, which the authors characterized as “a marked decrease in kidney stone risk.”

Vitamin C intake should be restricted to 90 mg/day in patients who have a history of calcium oxalate stones. Urivetzky et al³³ found that urinary oxalate excretion increased by 6 to 13 mg/day at doses of ascorbic acid greater than 500 mg.

Pyridoxine (vitamin B₆), a coenzyme of alanine-glyoxylate aminotransferase (AGT), increases the conversion of glyoxylate to glycine instead of oxalate and is used in the treatment of type 1 primary hyperoxaluria (see below).³⁴ However, its effect in preventing stones in idiopathic hyperoxaluria is not well known, and it has not been studied in a randomized controlled trial. In a prospective study, Curhan et al³⁵ reported that high intake of pyridoxine (> 40 mg/day) was associated with a lower risk of stone formation in women, but no such benefit was found in men.

Enteric hyperoxaluria. About 90% of dietary oxalate binds to calcium in the small intestine and is excreted in the stool. The remaining 10% is absorbed in the colon and is secreted in urine. Hyperoxaluria is frequently seen with fat malabsorption from inflammatory bowel disease, short gut syndrome, and gastric bypass surgery. In these conditions, excess fat binds to dietary calcium, leading to increased absorption of free oxalate in the colon.³⁶

Treatment is directed at decreasing intestinal oxalate absorption and should include high fluid intake and oral calcium supplements. Calcium carbonate or citrate causes precipitation of oxalate in the intestinal lumen and is prescribed as 1 to 4 g in three to four divided doses, always with meals. Calcium citrate is preferred over calcium carbonate in stone-formers because of the benefit of citrate and calcium citrate’s higher solubility and greater effectiveness in the presence of achlorhydria.³⁷ Patients should be advised to avoid foods high in oxalate and fat.

Primary hyperoxaluria is caused by inherited inborn errors of glyoxylate metabolism that cause overproduction of oxalate and urinary oxalate excretion above 135 to 270 mg/day.

Type 1 primary hyperoxaluria is the most common (accounting for 90% of cases) and is caused by reduced activity of hepatic peroxisomal AGT.

Type 2 is from a deficiency of glyoxylate reductase-hydroxypyruvate reductase (GRHPR).

Type 3 is from mutations in the HOGA1 gene, which codes for the liver-specific mitochondrial 4-hydroxy-2-oxoglutarate aldolase enzyme involved in degradation of hydroxyproline to pyruvate and glyoxalate.³⁸

High fluid intake to produce a urinary volume of 3 L/day reduces intratubular oxalate deposition and should be encouraged. Potassium citrate (0.15 mg/kg), oral phosphate supplements (30–40 mg/kg of orthophosphate), and magnesium oxide (500 mg/day/m²) inhibit precipitation of calcium oxalate in the urine.^39,40 Pyridoxine, a coenzyme of AGT, increases the conversion of glyoxylate to glycine instead of oxalate and is prescribed at a starting dose of 5 mg/kg (which can be titrated up to 20 mg/kg if there is no response) in patients with type 1 primary hyperoxaluria. About 50% of patients with type 1 respond successfully to pyridoxine, and a 3- to 6-month trial should be given in all patients in this category.³⁴ AGT is present only in hepatocytes, and GRHPR is found in multiple tissues; therefore, combined liver-kidney transplant is the treatment of choice in patients with type 1 primary hyperoxaluria, whereas isolated kidney transplant is recommended in patients with type 2.⁴¹

Reducing uric acid excretion

Hyperuricosuria is defined as uric acid excretion of greater than 800 mg/day in men and greater than 750 mg/day in women.

The association of hyperuricosuria with increased risk of calcium oxalate stone formation is controversial. Curhan and Taylor,¹⁸ in a cross-sectional study of 3,350 men and women, reported that there was no difference in mean 24-hour uric acid excretion in individuals with and without a history of stones.

The mechanism by which uric acid leads to calcium oxalate stones is not completely known and could be the “salting out” of calcium oxalate from the urine.⁴²

Dietary purine restriction, ie, limiting intake of nondairy animal protein to 0.8 to 1 g/kg/day, is the initial dietary intervention.¹¹ Allopurinol is the alternative approach if the patient is not compliant or if dietary restriction fails.⁴³

In a study by Ettinger et al,⁴⁴ 60 patients with hyperuricosuria and normocalciuria were randomized to receive allopurinol (100 mg three times daily) or a placebo. The allopurinol group had a rate of calculus events of 0.12 per patient per year, compared with 0.26 in the placebo group.

Increasing citrate excretion

Hypocitraturia is a well-known risk factor for the formation of kidney stones. It is usually defined as a citrate excretion of less than 320 mg/day for adults.

Citrate prevents formation of calcium crystals by binding to calcium, thereby lowering the concentration of calcium oxalate below the saturation point.⁴⁵

Diet therapy. Patients with calcium oxalate stones and hypocitraturia should be encouraged to increase their intake of fruits and vegetables, which enhances urinary citrate excretion, and to limit their intake of nondairy animal protein.¹¹

The use of citrus products in preventing stones in patients with hypocitraturia is controversial, however, and needs to be studied more.

One study⁴⁶ demonstrated that lemon juice was beneficial in hypocitraturic nephrolithiasis: 4 oz/day of lemon juice concentrate in the form of lemonade was associated with an increase in urinary citrate excretion to 346 mg/day from 142 mg/day in 11 of 12 patients who participated.

Odvina⁴⁷ compared the effects of orange juice with those of lemonade on the acid-base profile and urinary stone risk under controlled metabolic conditions in 13 volunteers. Orange juice was reported to have greater alkalinizing and citraturic effects and was associated with lower calculated calcium oxalate supersaturation compared with lemonade.

Lemonade therapy may be used as adjunctive treatment in patients who do not comply with or cannot tolerate alkali therapy. However, we advise caution about recommending citrus products, as they can increase oxalate excretion.

Pharmacotherapy includes alkali therapy. Barcelo et al⁴⁸ compared the effects of potassium citrate and placebo in 57 patients with calcium oxalate stones and hypocitraturia. Patients treated with potassium citrate had a rate of stone formation of 0.1 event per patient per year, compared with 1.1 in the placebo group.

Many forms of alkaline citrate are available. Potassium citrate is preferred over sodium citrate since the latter may increase urine calcium excretion.⁴⁹ Treatment is usually started at 30 mEq/day and is titrated to a maximal dose of 60 mEq/day for a urinary citrate excretion greater than 500 mg/day.

Common side effects are abdominal bloating and hyperkalemia (especially with renal insufficiency), and in such cases sodium-based alkali, sodium citrate, or sodium bicarbonate can be prescribed.

PREVENTING CALCIUM PHOSPHATE STONES

Risk factors for calcium phosphate stones are similar to those for calcium oxalate stones (other than hyperoxaluria), but calcium phosphate stones are formed in alkaline urine (usually urine pH > 6.0), often the result of distal renal tubular acidosis. Preventive measures are similar to those for calcium oxalate stones.

Alkali therapy should be used with caution because of its effect on urinary pH and the risk of precipitation of calcium phosphate crystals.⁵⁰ Use of potassium citrate was found to be associated with increases in both urinary citrate excretion and calcium phosphate supersaturation in hypercalciuric stone-forming rats.⁵¹ It is therefore challenging to manage patients with calcium phosphate stones and hypocitraturia. Alkali administration in this setting may diminish the formation of new stones by correcting hypocitraturia, but at the same time it may increase the likelihood of calcium phosphate stone formation by increasing the urinary pH. When the urine pH increases to above 6.5 with no significant change in urine citrate or urine calcium excretion, we recommend stopping alkali therapy.

PREVENTING URIC ACID STONES

Clinical conditions associated with uric acid stones include metabolic syndrome, diabetes mellitus, gout, chronic diarrheal illness, and conditions that increase tissue turnover and uric acid production, such as malignancies. Other risk factors for uric acid stone formation are low urine volume, low uric pH, and hyperuricosuria.

Abnormally acidic urine is the most common risk factor. Metabolic syndrome and diabetes mellitus reduce ammonia production, resulting in a lower urinary pH, which predisposes to uric acid stone formation. Chronic diarrhea also acidifies the urine by loss of bicarbonate. Similarly, in gout, the predisposing factor in uric acid stone formation is the persistently acidic urine due to impaired ammonium excretion.⁵² Uric acid precipitates to form uric acid stones in a low urinary pH even with normal excretion rates of 600 to 800 mg/day and a urinary volume of 1 to 1.5 L.⁵³

Therefore, apart from increasing fluid intake, urinary alkalization is the cornerstone of management of uric acid stones. Potassium citrate is the preferred alkali salt and is started at a dose of 30 mEq/day for a goal urinary pH of 6 to 6.5.⁴⁷

Patients with hyperuricosuria are also advised to restrict their protein intake to no more than 0.8 to 1 mg/kg/day.

If the above measures fail, patients are treated with a xanthine oxidase inhibitor, ie, allopurinol or febuxostat, even if their uric acid excretion is normal.⁵⁴

PREVENTING STRUVITE STONES

Struvite stones contain magnesium ammonium phosphate and are due to chronic upper urinary tract infection with urea-splitting bacteria such as Proteus, Klebsiella, Pseudomonas, and enterococci. Urea hydrolysis releases hydroxyl ions, resulting in alkaline urine that promotes struvite stone formation. Early detection and treatment are important, since struvite stones are associated with morbidity and rapid progression.

Medical treatment of struvite stones is usually unsuccessful, and the patient is referred to a urologist for surgical removal of the stones, the gold standard treatment.⁵⁵ Long-term use of culture-specific antibiotics to prevent new stone growth is not well studied. Medical therapy by itself is preferred in patients who refuse stone removal or cannot tolerate it. Urease inhibitors such as acetohydroxamic acid have been successful in preventing or slowing stone growth, but their use is limited by frequent side effects such as nausea, headache, rash, and thrombophlebitis.⁵⁶

CYSTINE STONES

Cystine stones occur in people with inherited defects of renal tubular and intestinal transport of cysteine and dibasic amino acids that cause excessive excretion of urinary cystine, ie, 480 to 3,600 mg/day.

Cystine is formed from two cysteine molecules linked by a disulfide bond. The solubility of cystine is pH-dependent, with increased solubility at higher urinary pH. The goal is to maintain a urinary cystine concentration below its solubility level by keeping the cystine concentration below 243 mg/L and the urine cystine supersaturation (the ratio of the urine cysteine concentration to the cysteine solubility in the same sample) less than 0.6.⁵⁷ Therapy is aimed at increasing daily urinary volume to 3 L and urine alkalization to pH above 7, in order to increase cystine solubility by 300%.⁵⁸

Overnight dehydration should be prevented, and patients should be encouraged to wake up at least once a night to void and drink additional water. Sodium restriction to 100 mmol/day (2,300 mg/day) and moderate protein restriction to 0.8 to 1 g/kg/day are associated with decreased cystine excretion, but long-term studies demonstrating their benefit in preventing cystine stones are lacking.⁵⁹

A thiol-containing drug, eg, D-penicillamine (0.5–2 g/day) or tiopronin (400–1,200 mg/day), should be added to the conservative measures if they have not been effective for 3 months or if there is history of noncompliance.⁶⁰ Thiol-containing drugs have a sulfhydryl group that reduces the disulfide bond, and they form soluble disulfide cysteine-drug complexes with greater ability to solubilize cystine in alkaline urine. They must always be used in conjunction with fluid and alkali therapy.⁶¹

Both drugs have severe and common adverse effects including leukopenia, aplastic anemia, fever, rash, arthritis, hepatotoxicity, pyridoxine deficiency, and proteinuria (membranous nephropathy). However, tiopronin seems to have a lesser incidence of side effects.⁶² Regular monitoring of complete blood cell counts, liver enzymes, and urine protein should be done.

Captopril contains a sulfhydryl group, and the captopril-cysteine disulfide is more soluble than cysteine alone. The amount of captopril that appears in the urine is low, and doses of 150 mg/day are usually required to reduce cysteine excretion, which can lead to hypotension. The efficacy of captopril in treating cystine stones is unproven, and this drug is used only if patients cannot tolerate other thiol-containing drugs.⁶³

Computed tomography (CT) plays an important role in the diagnosis and treatment of many clinical conditions¹ involving the chest wall, mediastinum, pleura, pulmonary arteries, and lung parenchyma. The need for enhancement with intravenous (IV) contrast depends on the specific clinical indication (Table 1).

EVALUATION OF SUSPECTED CANCER

CT is commonly used to diagnose, stage, and plan treatment for lung cancer, other primary neoplastic processes involving the chest, and metastatic disease.² The need for contrast varies on a case-by-case basis, and the benefits of contrast should be weighed against the potential risks in each patient.

When the neoplasm has CT attenuation similar to that of adjacent structures (lymph nodes in the hilum, masses in the mediastinum or chest wall), IV contrast can improve identification of the lesion and delineation of its margins and the relationship with adjacent structures (eg, vascular structures) (Figure 1).

CT without contrast for screening

The diagnostic algorithm for lung cancer screening is evolving. The US Preventive Services Task Force currently recommends low-dose CT without contrast, along with appropriate patient counseling, for patients with a history of smoking and an age range as detailed in the Task Force statement.³

Follow-up of a solitary pulmonary nodule also typically does not require contrast enhancement, though some investigators have reported high sensitivity with dynamic contrast enhancement of pulmonary nodules.⁴ This represents a rare clinical application of chest CT with and without contrast.

EVALUATION OF THORACIC VASCULAR DISEASE

For the assessment of vascular disease, CT in most cases requires IV contrast to delineate the vessel lumen. Pulmonary embolic disease is the third most common cause of acute cardiovascular disease.⁵ CT pulmonary angiography is the most common way to assess for pulmonary embolic disease, as it is accurate, fast, and widely available, and can assess alternate pathologies in cases of undifferentiated chest pain. Contrast enhancement of the pulmonary arteries is key, as embolic disease is identified as abnormal filling defects within the pulmonary arteries (Figure 2).

Contrast enhancement is also used to evaluate superior vena cava syndrome. At our institution, the CT protocol includes concomitant injections in the upper-extremity veins, with imaging timed for venous phase enhancement (pulmonary venogram). In cases of suspected arteriovenous malformation, a protocol similar to that used for suspected pulmonary embolus is used (Figure 3), although in some instances, the imaging features of arteriovenous malformation may be detectable without IV contrast.

EVALUATION OF PULMONARY PARENCHYMAL DISEASE

Infection, inflammation, and edema of the lung parenchyma are usually well depicted on CT without contrast enhancement. However, contrast may be helpful if there are concerns about complications such as chest wall involvement, where contrast enhancement may help further delineate the extent of complications.

Assessment of interstitial lung disease does not require use of IV contrast; rather, a tailored protocol with thinner slices and noncontiguous expiratory images can be used to evaluate for air-trapping and dynamic airway compromise (Figure 4). Evaluation of chronic obstructive pulmonary disease also does not require IV contrast.

EVALUATION OF THE PLEURA

In pleural effusion, CT assessment for the presence, location, and extent of the effusion does not require contrast. However, contrast enhancement is used to evaluate suspected or known exudative effusions and empyema.⁶ It also aids the evaluation of metastatic or primary malignancy of the pleura, particularly in cases of occult disease, as enhancement and thickening of the pleura are of diagnostic interest.

EVALUATION OF AIRWAY DISEASE

Diseases of the large airway, such as stenosis and thickening, and diseases of the small airways, such as bronchiolitis, typically do not require contrast enhancement. At our institution, to assess dynamic airway narrowing, we use a dedicated airway protocol, including inspiratory and expiratory phases and multiplanar reformatted images.

EVALUATION OF STERNAL AND MEDIASTINAL INFECTIONS

Postoperative sternal wound infections are not uncommon and range from cellulitis to frank osteomyelitis. Mediastinitis may likewise be iatrogenic or may spread from the oropharynx. CT with contrast can help to depict infection of the chest wall or mediastinum and in some instances can also delineate the route of spread.⁷

TYPES OF IV CONTRAST MEDIA

Contrast media used in CT contain iodine, which causes increased absorption and scattering of radiation in body tissues and blood. Other contrast media, such as those used for magnetic resonance imaging or barium enemas, do not contain iodine. This absorption and scattering in turn results in higher CT attenuation values, or “enhancement” on CT images. The extent of enhancement depends on the amount and rate of contrast material administered, as well as on patient factors (eg, tissue vascularity, permeability, interstitial space) and the energy (tube voltage) of the incident x-rays.⁸

Adverse reactions

Contrast materials are generally safe; however, as with any pharmaceutical, there is the potential for adverse reactions. These reactions are relatively rare and are usually mild but occasionally can be severe.⁹ Anaphylactoid reactions have an unclear etiology but mimic allergic reactions, and they are more likely to occur in patients with a previous reaction to contrast and in patients with asthma or cardiovascular or renal disease.

Nonanaphylactoid reactions are dependent on contrast osmolality and on the volume and route of injection (unlike anaphylactoid reactions).¹⁰ Typical symptoms include warmth, metallic taste, and nausea or vomiting.

Contrast-related nephrotoxicity has been reported,¹¹ although this has been challenged more recently.¹² Suspected risk factors for this complication include advanced age, cardiovascular disease, treatment with chemotherapy, elevated serum creatinine level, dehydration, diabetes, use of nonsteroidal anti-inflammatory medications, myeloma,¹³ renal disease, and kidney transplant.

Detailed protocols for premedication and management of contrast adverse reactions are beyond the scope of this review and the reader is advised to refer to dedicated manuals.¹⁰

Acknowledgment: We are grateful for the editorial assistance of Megan M. Griffiths, scientific writer for the Imaging Institute, Cleveland Clinic.

Computed tomography (CT) plays an important role in the diagnosis and treatment of many clinical conditions¹ involving the chest wall, mediastinum, pleura, pulmonary arteries, and lung parenchyma. The need for enhancement with intravenous (IV) contrast depends on the specific clinical indication (Table 1).

EVALUATION OF SUSPECTED CANCER

CT is commonly used to diagnose, stage, and plan treatment for lung cancer, other primary neoplastic processes involving the chest, and metastatic disease.² The need for contrast varies on a case-by-case basis, and the benefits of contrast should be weighed against the potential risks in each patient.

When the neoplasm has CT attenuation similar to that of adjacent structures (lymph nodes in the hilum, masses in the mediastinum or chest wall), IV contrast can improve identification of the lesion and delineation of its margins and the relationship with adjacent structures (eg, vascular structures) (Figure 1).

CT without contrast for screening

The diagnostic algorithm for lung cancer screening is evolving. The US Preventive Services Task Force currently recommends low-dose CT without contrast, along with appropriate patient counseling, for patients with a history of smoking and an age range as detailed in the Task Force statement.³

Follow-up of a solitary pulmonary nodule also typically does not require contrast enhancement, though some investigators have reported high sensitivity with dynamic contrast enhancement of pulmonary nodules.⁴ This represents a rare clinical application of chest CT with and without contrast.

EVALUATION OF THORACIC VASCULAR DISEASE

For the assessment of vascular disease, CT in most cases requires IV contrast to delineate the vessel lumen. Pulmonary embolic disease is the third most common cause of acute cardiovascular disease.⁵ CT pulmonary angiography is the most common way to assess for pulmonary embolic disease, as it is accurate, fast, and widely available, and can assess alternate pathologies in cases of undifferentiated chest pain. Contrast enhancement of the pulmonary arteries is key, as embolic disease is identified as abnormal filling defects within the pulmonary arteries (Figure 2).

Contrast enhancement is also used to evaluate superior vena cava syndrome. At our institution, the CT protocol includes concomitant injections in the upper-extremity veins, with imaging timed for venous phase enhancement (pulmonary venogram). In cases of suspected arteriovenous malformation, a protocol similar to that used for suspected pulmonary embolus is used (Figure 3), although in some instances, the imaging features of arteriovenous malformation may be detectable without IV contrast.

EVALUATION OF PULMONARY PARENCHYMAL DISEASE

Infection, inflammation, and edema of the lung parenchyma are usually well depicted on CT without contrast enhancement. However, contrast may be helpful if there are concerns about complications such as chest wall involvement, where contrast enhancement may help further delineate the extent of complications.

Assessment of interstitial lung disease does not require use of IV contrast; rather, a tailored protocol with thinner slices and noncontiguous expiratory images can be used to evaluate for air-trapping and dynamic airway compromise (Figure 4). Evaluation of chronic obstructive pulmonary disease also does not require IV contrast.

EVALUATION OF THE PLEURA

In pleural effusion, CT assessment for the presence, location, and extent of the effusion does not require contrast. However, contrast enhancement is used to evaluate suspected or known exudative effusions and empyema.⁶ It also aids the evaluation of metastatic or primary malignancy of the pleura, particularly in cases of occult disease, as enhancement and thickening of the pleura are of diagnostic interest.

EVALUATION OF AIRWAY DISEASE

Diseases of the large airway, such as stenosis and thickening, and diseases of the small airways, such as bronchiolitis, typically do not require contrast enhancement. At our institution, to assess dynamic airway narrowing, we use a dedicated airway protocol, including inspiratory and expiratory phases and multiplanar reformatted images.

EVALUATION OF STERNAL AND MEDIASTINAL INFECTIONS

Postoperative sternal wound infections are not uncommon and range from cellulitis to frank osteomyelitis. Mediastinitis may likewise be iatrogenic or may spread from the oropharynx. CT with contrast can help to depict infection of the chest wall or mediastinum and in some instances can also delineate the route of spread.⁷

TYPES OF IV CONTRAST MEDIA

Contrast media used in CT contain iodine, which causes increased absorption and scattering of radiation in body tissues and blood. Other contrast media, such as those used for magnetic resonance imaging or barium enemas, do not contain iodine. This absorption and scattering in turn results in higher CT attenuation values, or “enhancement” on CT images. The extent of enhancement depends on the amount and rate of contrast material administered, as well as on patient factors (eg, tissue vascularity, permeability, interstitial space) and the energy (tube voltage) of the incident x-rays.⁸

Adverse reactions

Contrast materials are generally safe; however, as with any pharmaceutical, there is the potential for adverse reactions. These reactions are relatively rare and are usually mild but occasionally can be severe.⁹ Anaphylactoid reactions have an unclear etiology but mimic allergic reactions, and they are more likely to occur in patients with a previous reaction to contrast and in patients with asthma or cardiovascular or renal disease.

Nonanaphylactoid reactions are dependent on contrast osmolality and on the volume and route of injection (unlike anaphylactoid reactions).¹⁰ Typical symptoms include warmth, metallic taste, and nausea or vomiting.

Contrast-related nephrotoxicity has been reported,¹¹ although this has been challenged more recently.¹² Suspected risk factors for this complication include advanced age, cardiovascular disease, treatment with chemotherapy, elevated serum creatinine level, dehydration, diabetes, use of nonsteroidal anti-inflammatory medications, myeloma,¹³ renal disease, and kidney transplant.

Detailed protocols for premedication and management of contrast adverse reactions are beyond the scope of this review and the reader is advised to refer to dedicated manuals.¹⁰

Acknowledgment: We are grateful for the editorial assistance of Megan M. Griffiths, scientific writer for the Imaging Institute, Cleveland Clinic.

Computed tomography (CT) plays an important role in the diagnosis and treatment of many clinical conditions¹ involving the chest wall, mediastinum, pleura, pulmonary arteries, and lung parenchyma. The need for enhancement with intravenous (IV) contrast depends on the specific clinical indication (Table 1).

EVALUATION OF SUSPECTED CANCER

CT is commonly used to diagnose, stage, and plan treatment for lung cancer, other primary neoplastic processes involving the chest, and metastatic disease.² The need for contrast varies on a case-by-case basis, and the benefits of contrast should be weighed against the potential risks in each patient.

When the neoplasm has CT attenuation similar to that of adjacent structures (lymph nodes in the hilum, masses in the mediastinum or chest wall), IV contrast can improve identification of the lesion and delineation of its margins and the relationship with adjacent structures (eg, vascular structures) (Figure 1).

CT without contrast for screening

The diagnostic algorithm for lung cancer screening is evolving. The US Preventive Services Task Force currently recommends low-dose CT without contrast, along with appropriate patient counseling, for patients with a history of smoking and an age range as detailed in the Task Force statement.³

Follow-up of a solitary pulmonary nodule also typically does not require contrast enhancement, though some investigators have reported high sensitivity with dynamic contrast enhancement of pulmonary nodules.⁴ This represents a rare clinical application of chest CT with and without contrast.

EVALUATION OF THORACIC VASCULAR DISEASE

For the assessment of vascular disease, CT in most cases requires IV contrast to delineate the vessel lumen. Pulmonary embolic disease is the third most common cause of acute cardiovascular disease.⁵ CT pulmonary angiography is the most common way to assess for pulmonary embolic disease, as it is accurate, fast, and widely available, and can assess alternate pathologies in cases of undifferentiated chest pain. Contrast enhancement of the pulmonary arteries is key, as embolic disease is identified as abnormal filling defects within the pulmonary arteries (Figure 2).

Contrast enhancement is also used to evaluate superior vena cava syndrome. At our institution, the CT protocol includes concomitant injections in the upper-extremity veins, with imaging timed for venous phase enhancement (pulmonary venogram). In cases of suspected arteriovenous malformation, a protocol similar to that used for suspected pulmonary embolus is used (Figure 3), although in some instances, the imaging features of arteriovenous malformation may be detectable without IV contrast.

EVALUATION OF PULMONARY PARENCHYMAL DISEASE

Infection, inflammation, and edema of the lung parenchyma are usually well depicted on CT without contrast enhancement. However, contrast may be helpful if there are concerns about complications such as chest wall involvement, where contrast enhancement may help further delineate the extent of complications.

Assessment of interstitial lung disease does not require use of IV contrast; rather, a tailored protocol with thinner slices and noncontiguous expiratory images can be used to evaluate for air-trapping and dynamic airway compromise (Figure 4). Evaluation of chronic obstructive pulmonary disease also does not require IV contrast.

EVALUATION OF THE PLEURA

In pleural effusion, CT assessment for the presence, location, and extent of the effusion does not require contrast. However, contrast enhancement is used to evaluate suspected or known exudative effusions and empyema.⁶ It also aids the evaluation of metastatic or primary malignancy of the pleura, particularly in cases of occult disease, as enhancement and thickening of the pleura are of diagnostic interest.

EVALUATION OF AIRWAY DISEASE

Diseases of the large airway, such as stenosis and thickening, and diseases of the small airways, such as bronchiolitis, typically do not require contrast enhancement. At our institution, to assess dynamic airway narrowing, we use a dedicated airway protocol, including inspiratory and expiratory phases and multiplanar reformatted images.

EVALUATION OF STERNAL AND MEDIASTINAL INFECTIONS

Postoperative sternal wound infections are not uncommon and range from cellulitis to frank osteomyelitis. Mediastinitis may likewise be iatrogenic or may spread from the oropharynx. CT with contrast can help to depict infection of the chest wall or mediastinum and in some instances can also delineate the route of spread.⁷

TYPES OF IV CONTRAST MEDIA

Contrast media used in CT contain iodine, which causes increased absorption and scattering of radiation in body tissues and blood. Other contrast media, such as those used for magnetic resonance imaging or barium enemas, do not contain iodine. This absorption and scattering in turn results in higher CT attenuation values, or “enhancement” on CT images. The extent of enhancement depends on the amount and rate of contrast material administered, as well as on patient factors (eg, tissue vascularity, permeability, interstitial space) and the energy (tube voltage) of the incident x-rays.⁸

Adverse reactions

Contrast materials are generally safe; however, as with any pharmaceutical, there is the potential for adverse reactions. These reactions are relatively rare and are usually mild but occasionally can be severe.⁹ Anaphylactoid reactions have an unclear etiology but mimic allergic reactions, and they are more likely to occur in patients with a previous reaction to contrast and in patients with asthma or cardiovascular or renal disease.

Nonanaphylactoid reactions are dependent on contrast osmolality and on the volume and route of injection (unlike anaphylactoid reactions).¹⁰ Typical symptoms include warmth, metallic taste, and nausea or vomiting.

Contrast-related nephrotoxicity has been reported,¹¹ although this has been challenged more recently.¹² Suspected risk factors for this complication include advanced age, cardiovascular disease, treatment with chemotherapy, elevated serum creatinine level, dehydration, diabetes, use of nonsteroidal anti-inflammatory medications, myeloma,¹³ renal disease, and kidney transplant.

Detailed protocols for premedication and management of contrast adverse reactions are beyond the scope of this review and the reader is advised to refer to dedicated manuals.¹⁰

Acknowledgment: We are grateful for the editorial assistance of Megan M. Griffiths, scientific writer for the Imaging Institute, Cleveland Clinic.