Pregnant woman
Photo by Nina Matthews

A blood test developed to diagnose a rare genetic blood cell disorder, atypical hemolytic uremic syndrome (aHUS), may also aid in the diagnosis of HELLP syndrome, a life-threatening high blood pressure condition that affects 1% of all pregnant women.

The study, based on blood samples from a small number of women, suggests that aHUS has similar underlying biochemistry to HELLP, which affects hemolysis, elevates liver enzymes, and causes a low platelet count. Both conditions have over activation of the alternative pathway of complement.

At present, no diagnostic blood or biomarker test exists to diagnose HELLP, which is thought to be a severe form of preeclampsia. The condition is diagnosed only by its symptoms.

Senior study author Robert Brodsky, MD, of Johns Hopkins, and his team developed the modified Ham test to diagnose aHUS, a genetic disorder in which abnormal blood clots form in small blood vessels in the kidneys. They published that work last year in Blood.
 
The two conditions share a number of traits, such as hemolysis, elevated liver enzymes, a low platelet count, kidney dysfunction, high blood pressure, and seizures. This led the investigators to believe that the modified Ham test could also help identify women with HELLP syndrome.

"The clinical implications from an obstetric point of view are potentially huge," said lead study author Arthur Vaught, MD, also of Johns Hopkins. "If this works, we can reduce pre-term deliveries, stays in the neonatal intensive care unit, and other complications for mothers and their babies."

The team analyzed serum samples from 14 women with classic or atypical HELLP syndrome, 7 with severe preeclampsia, 11 women with normal pregnancies, and 8 healthy nonpregnant women. All pregnant women were at least 23 weeks’ gestation, the point at which HELLP symptoms start to arise.

The team evaluated patient sera using terminal product of complement activation (C5b-9). They observed that women with classic or atypical HELLP had increased complement activation compared to nonpregnant controls.

Women with classic HELLP had an average cell killing of 34.3% compared with 26% in women with atypical HELLP, 5% in women with normal pregnancies, and3.3% in women who were not pregnant.

The investigators then added eculizumab to HELLP sera to see whether the agent could inhibit complement activation. They found that mixing HELLP serum with eculizumab-containing serum significantly decreased cell killing compared with HELLP serum alone.

The kill rate in women with classic or atypical HELLP decreased from 34% to 5% with eculizumab.

Eculizumab (Soliris), manufactured by Alexion Pharmaceuticals, is a monoclonal antibody approved by the US Food and Drug Administration for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and aHUS.

Further investigation is required to confirm these findings, but thus far, the investigators believe the modified Ham assay may assist in diagnosing the HELLP syndrome and corroborate its relationship to aHUS.

The current study by Vaught et al is published in Experimental Hematology.

Pregnant woman
Photo by Nina Matthews

A blood test developed to diagnose a rare genetic blood cell disorder, atypical hemolytic uremic syndrome (aHUS), may also aid in the diagnosis of HELLP syndrome, a life-threatening high blood pressure condition that affects 1% of all pregnant women.

The study, based on blood samples from a small number of women, suggests that aHUS has similar underlying biochemistry to HELLP, which affects hemolysis, elevates liver enzymes, and causes a low platelet count. Both conditions have over activation of the alternative pathway of complement.

At present, no diagnostic blood or biomarker test exists to diagnose HELLP, which is thought to be a severe form of preeclampsia. The condition is diagnosed only by its symptoms.

Senior study author Robert Brodsky, MD, of Johns Hopkins, and his team developed the modified Ham test to diagnose aHUS, a genetic disorder in which abnormal blood clots form in small blood vessels in the kidneys. They published that work last year in Blood.
 
The two conditions share a number of traits, such as hemolysis, elevated liver enzymes, a low platelet count, kidney dysfunction, high blood pressure, and seizures. This led the investigators to believe that the modified Ham test could also help identify women with HELLP syndrome.

"The clinical implications from an obstetric point of view are potentially huge," said lead study author Arthur Vaught, MD, also of Johns Hopkins. "If this works, we can reduce pre-term deliveries, stays in the neonatal intensive care unit, and other complications for mothers and their babies."

The team analyzed serum samples from 14 women with classic or atypical HELLP syndrome, 7 with severe preeclampsia, 11 women with normal pregnancies, and 8 healthy nonpregnant women. All pregnant women were at least 23 weeks’ gestation, the point at which HELLP symptoms start to arise.

The team evaluated patient sera using terminal product of complement activation (C5b-9). They observed that women with classic or atypical HELLP had increased complement activation compared to nonpregnant controls.

Women with classic HELLP had an average cell killing of 34.3% compared with 26% in women with atypical HELLP, 5% in women with normal pregnancies, and3.3% in women who were not pregnant.

The investigators then added eculizumab to HELLP sera to see whether the agent could inhibit complement activation. They found that mixing HELLP serum with eculizumab-containing serum significantly decreased cell killing compared with HELLP serum alone.

The kill rate in women with classic or atypical HELLP decreased from 34% to 5% with eculizumab.

Eculizumab (Soliris), manufactured by Alexion Pharmaceuticals, is a monoclonal antibody approved by the US Food and Drug Administration for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and aHUS.

Further investigation is required to confirm these findings, but thus far, the investigators believe the modified Ham assay may assist in diagnosing the HELLP syndrome and corroborate its relationship to aHUS.

The current study by Vaught et al is published in Experimental Hematology.

Pregnant woman
Photo by Nina Matthews

A blood test developed to diagnose a rare genetic blood cell disorder, atypical hemolytic uremic syndrome (aHUS), may also aid in the diagnosis of HELLP syndrome, a life-threatening high blood pressure condition that affects 1% of all pregnant women.

The study, based on blood samples from a small number of women, suggests that aHUS has similar underlying biochemistry to HELLP, which affects hemolysis, elevates liver enzymes, and causes a low platelet count. Both conditions have over activation of the alternative pathway of complement.

At present, no diagnostic blood or biomarker test exists to diagnose HELLP, which is thought to be a severe form of preeclampsia. The condition is diagnosed only by its symptoms.

Senior study author Robert Brodsky, MD, of Johns Hopkins, and his team developed the modified Ham test to diagnose aHUS, a genetic disorder in which abnormal blood clots form in small blood vessels in the kidneys. They published that work last year in Blood.
 
The two conditions share a number of traits, such as hemolysis, elevated liver enzymes, a low platelet count, kidney dysfunction, high blood pressure, and seizures. This led the investigators to believe that the modified Ham test could also help identify women with HELLP syndrome.

"The clinical implications from an obstetric point of view are potentially huge," said lead study author Arthur Vaught, MD, also of Johns Hopkins. "If this works, we can reduce pre-term deliveries, stays in the neonatal intensive care unit, and other complications for mothers and their babies."

The team analyzed serum samples from 14 women with classic or atypical HELLP syndrome, 7 with severe preeclampsia, 11 women with normal pregnancies, and 8 healthy nonpregnant women. All pregnant women were at least 23 weeks’ gestation, the point at which HELLP symptoms start to arise.

The team evaluated patient sera using terminal product of complement activation (C5b-9). They observed that women with classic or atypical HELLP had increased complement activation compared to nonpregnant controls.

Women with classic HELLP had an average cell killing of 34.3% compared with 26% in women with atypical HELLP, 5% in women with normal pregnancies, and3.3% in women who were not pregnant.

The investigators then added eculizumab to HELLP sera to see whether the agent could inhibit complement activation. They found that mixing HELLP serum with eculizumab-containing serum significantly decreased cell killing compared with HELLP serum alone.

The kill rate in women with classic or atypical HELLP decreased from 34% to 5% with eculizumab.

Eculizumab (Soliris), manufactured by Alexion Pharmaceuticals, is a monoclonal antibody approved by the US Food and Drug Administration for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and aHUS.

Further investigation is required to confirm these findings, but thus far, the investigators believe the modified Ham assay may assist in diagnosing the HELLP syndrome and corroborate its relationship to aHUS.

The current study by Vaught et al is published in Experimental Hematology.

Table of Contents

• Discrimination, Dignity, and Duty
• Survival After Long-Term Residence in an Intensive Care Unit
• Disease-Modifying Therapies in Multiple Sclerosis: Overview and Treatment Considerations
• The Relationship Between Male Patients’ Antihypertensive Medication Beliefs and Erectile Function
• A Physician With Thigh Pain
• Shared Medical Appointments for Glycemic Management in Rural Veterans

Table of Contents

• Discrimination, Dignity, and Duty
• Survival After Long-Term Residence in an Intensive Care Unit
• Disease-Modifying Therapies in Multiple Sclerosis: Overview and Treatment Considerations
• The Relationship Between Male Patients’ Antihypertensive Medication Beliefs and Erectile Function
• A Physician With Thigh Pain
• Shared Medical Appointments for Glycemic Management in Rural Veterans

Table of Contents

• Discrimination, Dignity, and Duty
• Survival After Long-Term Residence in an Intensive Care Unit
• Disease-Modifying Therapies in Multiple Sclerosis: Overview and Treatment Considerations
• The Relationship Between Male Patients’ Antihypertensive Medication Beliefs and Erectile Function
• A Physician With Thigh Pain
• Shared Medical Appointments for Glycemic Management in Rural Veterans

A 12-week regimen achieved sustained viral response for 90% of patients with genotype 1 hepatitis C virus (HCV) infection and stage 4 or 5 chronic kidney disease (CKD), researchers reported in the April issue of Gastroenterology.

“The regimen is well tolerated, though ribavirin use may require a reduction or interruption to manage anemia,” said Dr. Paul Pockros at Scripps Clinic and Scripps Translational Science Institute in La Jolla, Calif., and his associates. The second phase of the study will evaluate the regimen in treatment-experienced CKD patients and those with compensated cirrhosis, they said.

©picsfive/Fotolia

The regimen contained ombitasvir, paritaprevir, ritonavir, and dasabuvir.

Between 8% and 44% of hemodialysis patients are HCV positive, and CKD is known to heighten the risk of HCV-associated cirrhosis, hepatocellular carcinoma, and liver-related death, the researchers noted. While sofosbuvir is cleared renally, ombitasvir, paritaprevir, ritonavir, and dasabuvir undergo hepatic metabolism and needed no dose adjustment in phase I studies of patients with mild, moderate, or severe renal impairment. To further investigate the safety and efficacy of these direct-acting antivirals in patients with severe kidney disease, the researchers performed a single-arm, open-label, multicenter study of 20 treatment-naive, noncirrhotic, HCV-infected adults with stage 4 CKD (estimated glomerular filtration rate, 15-30 mL/min per 1.73 m²) or stage 5 (eGFR, less than 15 mL/min per 1.73 m² or requiring hemodialysis). Patients received once-daily ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) plus dasabuvir (250 mg) for 12 weeks. The 13 patients with genotype 1a infections also received once-daily ribavirin (200 mg). Most patients were black men with stage 5 CKD, and 14 were on hemodialysis, the researchers said (Gastroenterology. 2016 Apr 16. doi: 10.1053/j.gastro.2016.02.078).

All 20 patients completed treatment, and 18 (90%) achieved sustained viral response (SVR) at posttreatment week 12 (SVR12; 95% confidence interval, 70%-97%). No patients developed hepatic decompensation, the researchers said. The most common adverse effects were anemia (45%), fatigue (35%), diarrhea (25%), and nausea (25%). Anemia developed only in patients receiving ribavirin and was more pronounced than in phase III studies of this regimen, the researchers said. Hemoglobin levels dropped an average of 1.38 plus or minus 1.54 g/dL among patients who received ribavirin, compared with 0.02 plus or minus 0.9 g/dL among patients who did not receive ribavirin. There was one case of grade 3 anemia related to incorrect dosing of ribavirin; the lowest measured hemoglobin level was 7.0 g/dL, which improved to more than 10 g/dL after stopping ribavirin and starting erythropoietin treatment. This patient also achieved SVR12. The other eight patients who developed anemia also stopped ribavirin, although three were able to resume it after their hemoglobin levels improved.

Of the two patients who did not achieve SVR12, one relapsed 4 weeks after treatment, and one died of cardiac arrest 14 days after treatment. The patient who died had a history of hypertension; his hemoglobin level was stable (9-11 g/dL) during the last 6 weeks of treatment, and was 10 g/dL at admission, suggesting that ribavirin-induced anemia did not cause the cardiac event, the investigators said.

“The results of this study are important for hepatologists, gastroenterologists, and infectious disease specialists who are accustomed to treating HCV-infected patients with DAA [direct-acting antiviral] therapy but who may not yet have seen sufficient data to initiate DAA therapy in patients with ESRD [end-stage renal disease],” the researchers concluded. “Nephrologists, who may not be accustomed to treating HCV, should also be aware that treatment options may now be available that can help prevent the end-stage sequelae of HCV. How treatment of HCV infection affects early or intermediate stages of CKD and how achievement of SVR impacts strategies for kidney transplantation in patients with ESRD require more study.”

AbbVie makes the regimen and sponsored the study. Dr. Pockros and six coinvestigators disclosed financial relationships with AbbVie and numerous other pharmaceutical companies. Seven coinvestigators reported being employed by AbbVie.

A 12-week regimen achieved sustained viral response for 90% of patients with genotype 1 hepatitis C virus (HCV) infection and stage 4 or 5 chronic kidney disease (CKD), researchers reported in the April issue of Gastroenterology.

“The regimen is well tolerated, though ribavirin use may require a reduction or interruption to manage anemia,” said Dr. Paul Pockros at Scripps Clinic and Scripps Translational Science Institute in La Jolla, Calif., and his associates. The second phase of the study will evaluate the regimen in treatment-experienced CKD patients and those with compensated cirrhosis, they said.

©picsfive/Fotolia

The regimen contained ombitasvir, paritaprevir, ritonavir, and dasabuvir.

Between 8% and 44% of hemodialysis patients are HCV positive, and CKD is known to heighten the risk of HCV-associated cirrhosis, hepatocellular carcinoma, and liver-related death, the researchers noted. While sofosbuvir is cleared renally, ombitasvir, paritaprevir, ritonavir, and dasabuvir undergo hepatic metabolism and needed no dose adjustment in phase I studies of patients with mild, moderate, or severe renal impairment. To further investigate the safety and efficacy of these direct-acting antivirals in patients with severe kidney disease, the researchers performed a single-arm, open-label, multicenter study of 20 treatment-naive, noncirrhotic, HCV-infected adults with stage 4 CKD (estimated glomerular filtration rate, 15-30 mL/min per 1.73 m²) or stage 5 (eGFR, less than 15 mL/min per 1.73 m² or requiring hemodialysis). Patients received once-daily ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) plus dasabuvir (250 mg) for 12 weeks. The 13 patients with genotype 1a infections also received once-daily ribavirin (200 mg). Most patients were black men with stage 5 CKD, and 14 were on hemodialysis, the researchers said (Gastroenterology. 2016 Apr 16. doi: 10.1053/j.gastro.2016.02.078).

All 20 patients completed treatment, and 18 (90%) achieved sustained viral response (SVR) at posttreatment week 12 (SVR12; 95% confidence interval, 70%-97%). No patients developed hepatic decompensation, the researchers said. The most common adverse effects were anemia (45%), fatigue (35%), diarrhea (25%), and nausea (25%). Anemia developed only in patients receiving ribavirin and was more pronounced than in phase III studies of this regimen, the researchers said. Hemoglobin levels dropped an average of 1.38 plus or minus 1.54 g/dL among patients who received ribavirin, compared with 0.02 plus or minus 0.9 g/dL among patients who did not receive ribavirin. There was one case of grade 3 anemia related to incorrect dosing of ribavirin; the lowest measured hemoglobin level was 7.0 g/dL, which improved to more than 10 g/dL after stopping ribavirin and starting erythropoietin treatment. This patient also achieved SVR12. The other eight patients who developed anemia also stopped ribavirin, although three were able to resume it after their hemoglobin levels improved.

Of the two patients who did not achieve SVR12, one relapsed 4 weeks after treatment, and one died of cardiac arrest 14 days after treatment. The patient who died had a history of hypertension; his hemoglobin level was stable (9-11 g/dL) during the last 6 weeks of treatment, and was 10 g/dL at admission, suggesting that ribavirin-induced anemia did not cause the cardiac event, the investigators said.

“The results of this study are important for hepatologists, gastroenterologists, and infectious disease specialists who are accustomed to treating HCV-infected patients with DAA [direct-acting antiviral] therapy but who may not yet have seen sufficient data to initiate DAA therapy in patients with ESRD [end-stage renal disease],” the researchers concluded. “Nephrologists, who may not be accustomed to treating HCV, should also be aware that treatment options may now be available that can help prevent the end-stage sequelae of HCV. How treatment of HCV infection affects early or intermediate stages of CKD and how achievement of SVR impacts strategies for kidney transplantation in patients with ESRD require more study.”

AbbVie makes the regimen and sponsored the study. Dr. Pockros and six coinvestigators disclosed financial relationships with AbbVie and numerous other pharmaceutical companies. Seven coinvestigators reported being employed by AbbVie.

A 12-week regimen achieved sustained viral response for 90% of patients with genotype 1 hepatitis C virus (HCV) infection and stage 4 or 5 chronic kidney disease (CKD), researchers reported in the April issue of Gastroenterology.

“The regimen is well tolerated, though ribavirin use may require a reduction or interruption to manage anemia,” said Dr. Paul Pockros at Scripps Clinic and Scripps Translational Science Institute in La Jolla, Calif., and his associates. The second phase of the study will evaluate the regimen in treatment-experienced CKD patients and those with compensated cirrhosis, they said.

©picsfive/Fotolia

The regimen contained ombitasvir, paritaprevir, ritonavir, and dasabuvir.

Between 8% and 44% of hemodialysis patients are HCV positive, and CKD is known to heighten the risk of HCV-associated cirrhosis, hepatocellular carcinoma, and liver-related death, the researchers noted. While sofosbuvir is cleared renally, ombitasvir, paritaprevir, ritonavir, and dasabuvir undergo hepatic metabolism and needed no dose adjustment in phase I studies of patients with mild, moderate, or severe renal impairment. To further investigate the safety and efficacy of these direct-acting antivirals in patients with severe kidney disease, the researchers performed a single-arm, open-label, multicenter study of 20 treatment-naive, noncirrhotic, HCV-infected adults with stage 4 CKD (estimated glomerular filtration rate, 15-30 mL/min per 1.73 m²) or stage 5 (eGFR, less than 15 mL/min per 1.73 m² or requiring hemodialysis). Patients received once-daily ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) plus dasabuvir (250 mg) for 12 weeks. The 13 patients with genotype 1a infections also received once-daily ribavirin (200 mg). Most patients were black men with stage 5 CKD, and 14 were on hemodialysis, the researchers said (Gastroenterology. 2016 Apr 16. doi: 10.1053/j.gastro.2016.02.078).

All 20 patients completed treatment, and 18 (90%) achieved sustained viral response (SVR) at posttreatment week 12 (SVR12; 95% confidence interval, 70%-97%). No patients developed hepatic decompensation, the researchers said. The most common adverse effects were anemia (45%), fatigue (35%), diarrhea (25%), and nausea (25%). Anemia developed only in patients receiving ribavirin and was more pronounced than in phase III studies of this regimen, the researchers said. Hemoglobin levels dropped an average of 1.38 plus or minus 1.54 g/dL among patients who received ribavirin, compared with 0.02 plus or minus 0.9 g/dL among patients who did not receive ribavirin. There was one case of grade 3 anemia related to incorrect dosing of ribavirin; the lowest measured hemoglobin level was 7.0 g/dL, which improved to more than 10 g/dL after stopping ribavirin and starting erythropoietin treatment. This patient also achieved SVR12. The other eight patients who developed anemia also stopped ribavirin, although three were able to resume it after their hemoglobin levels improved.

Of the two patients who did not achieve SVR12, one relapsed 4 weeks after treatment, and one died of cardiac arrest 14 days after treatment. The patient who died had a history of hypertension; his hemoglobin level was stable (9-11 g/dL) during the last 6 weeks of treatment, and was 10 g/dL at admission, suggesting that ribavirin-induced anemia did not cause the cardiac event, the investigators said.

“The results of this study are important for hepatologists, gastroenterologists, and infectious disease specialists who are accustomed to treating HCV-infected patients with DAA [direct-acting antiviral] therapy but who may not yet have seen sufficient data to initiate DAA therapy in patients with ESRD [end-stage renal disease],” the researchers concluded. “Nephrologists, who may not be accustomed to treating HCV, should also be aware that treatment options may now be available that can help prevent the end-stage sequelae of HCV. How treatment of HCV infection affects early or intermediate stages of CKD and how achievement of SVR impacts strategies for kidney transplantation in patients with ESRD require more study.”

AbbVie makes the regimen and sponsored the study. Dr. Pockros and six coinvestigators disclosed financial relationships with AbbVie and numerous other pharmaceutical companies. Seven coinvestigators reported being employed by AbbVie.

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.