The Journal of Family Practice

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; sblipp01@louisville.edu.

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; sblipp01@louisville.edu.

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; sblipp01@louisville.edu.

THE CASE

A 17-year-old boy presented to the emergency department (ED) with a headache, dizziness, lethargy, and weakness that he’d had for 2 weeks. The patient was taking a selective serotonin reuptake inhibitor (SSRI) for depression (sertraline 25 mg/d). He had been vomiting twice daily for the past 3 years. (Although he had been seen multiple times in urgent care clinics, he did not have regular medical care.) The boy was fatigued and had dark yellow urine. His father indicated that his son’s skin had darkened over the last 5 to 6 years and that he had been adding salt, in large quantities, to nearly all of his meals for 10 years.

The boy’s health issues were impacting his school life. He was dismissed from school often because his teachers felt he was skipping class and using the excuse of needing to urinate or vomit. He had traveled back and forth to Mexico about 2 times a year, with the last time being about 3 months before his trip to the ED.

The patient’s vitals included a temperature of 96.3º F, heart rate (HR) of 77 beats/min, respiratory rate of 16 breaths/min, and a supine blood pressure (BP) of 102/58 mm Hg. (The patient’s BP was not obtained when sitting or standing, because he felt dizzy when trying to stand or sit up and the HR monitor increased to 100 beats/min.) His weight was 106.9 pounds and height was 5 feet 8 inches. The teen was ill-appearing and somnolent. No jugular vein distention, murmurs, or gallops were noted on exam. The patient’s lips were dry and cracked, gums were darkened, and his skin was clammy to the touch. His abdomen was soft with hypoactive bowel sounds and no ascites. His extremities were non-edematous.

A chemistry panel showed a low sodium level of 99 mEq/L, a somewhat high potassium level of 5.2 mmol/L, low chloride (69 mEq/L) and CO₂ (5 mEq/L) levels, a high glucose level (124 mg/dL), and normal creatinine (0.79 mg/dL), albumin (5.2 g/dL), and thyroid stimulating hormone (2.4 mIU/L) levels. A tuberculosis (TB) test, acute hepatitis panel, human immunodeficiency test, and urine drug screen were all negative. Liver enzymes and lipase levels were normal.

The patient was admitted to the pediatric intensive care unit (PICU) on 200 mL/hr normal saline (twice the normal maintenance rate) and we took over his care.

THE DIAGNOSIS

Because of the patient’s severe hyponatremia, the differential diagnosis included heart failure, cirrhosis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), SSRI-induced SIADH, cerebral salt wasting, severe hypothyroidism, adrenal insufficiency, malignancies, ecstasy use, renal failure, low dietary solute intake, and psychogenic polydipsia.

A random cortisol test taken in the ED returned and was noted to be very low (<1 mcg/dL). This information, plus the signs of aldosterone deficiency (low sodium and elevated potassium levels) and adrenocorticotropic hormone (ACTH) excess (skin darkening), prompted us to perform a 250-mcg ACTH stimulation test. Results at 30 and 60 minutes both showed cortisol at <1 mcg/dL, which led us to suspect adrenal insufficiency. The diagnosis of autoimmune adrenalitis, or Addison’s disease, was confirmed after inpatient lab work returned with positive 21-hydroxylase antibodies and an elevated ACTH (1117 pg/mL; normal, 10-65 pg/mL).

We noted that the patient’s sodium level was gradually increasing while he was receiving the intravenous (IV) fluids. We were concerned, though, that too rapid a sodium correction would put the patient at risk for central pontine myelinolysis (CPM). So we held off on steroids until 24 hours after he was admitted to the PICU, when his sodium level reached 110 mEq/L.

DISCUSSION

The first evidence of Addison’s disease is usually an increase in plasma renin activity with low serum aldosterone.

Primary adrenal insufficiency in the developed world is commonly caused by autoimmune adrenalitis, also known as Addison’s disease. Addison’s disease is the cause of primary adrenal insufficiency in 70% to 90% of cases, with the remainder caused by TB, adrenal hemorrhage, infarction, lymphoma, cytomegalovirus, adrenoleukodystrophy, or metastatic cancer. We also considered adrenoleukodystrophy in our patient, but felt it unlikely in a 17-year-old with normal mental status and positive adrenal antibodies.

The first evidence of Addison’s disease is usually an increase in plasma renin activity with low serum aldosterone. This might explain our patient’s years of salt cravings prior to presentation. There is typically a decrease in serum cortisol response to ACTH stimulation several months to years after the onset of salt cravings. The next sign of deterioration in adrenal function is an increase in basal serum ACTH; the process concludes with a decreased basal serum cortisol level.^1-3 By the time our patient presented to the ED, his ACTH was very high, his cortisol was low, and his ACTH stimulation response was low.

Acute adrenal insufficiency crisis usually occurs after a prolonged period of nonspecific complaints due to a loss of both glucocorticoids and mineralocorticoids; by the time overt symptoms occur, 90% of the adrenal gland may be destroyed.³ Patients (such as ours) may present with symptoms such as abdominal pain, weakness, vomiting, fever, and decreased responsiveness. Hyponatremia and hyperkalemia are commonly seen at initial diagnosis. BP can be compromised in some patients due to loss of vascular tone; our patient did not present with this finding.

Treatment includes hydrocortisone and fludrocortisone for life

Initial management focuses on rehydration, maintenance of BP, cardiac monitoring, and electrolyte monitoring with a focus on slow normalization of electrolyte abnormalities. Patients should be treated with hydrocortisone (approximately 10 mg/m²/d) and fludrocortisone (usually 0.1 mg/d), and they will be maintained on this regimen for life.^1,3

During acute illness, the doses of hydrocortisone are usually tripled and given 3 times per day to address the increased cortisol needs of the stress response. Lack of stress dose steroids in the setting of illness can lead to repeat adrenal crisis events.

Patients should be taught about intramuscular (IM) hydrocortisone use (100 mg IM) for emergencies and should have medical identification. In many states, emergency medical technicians (EMTs) are now able to administer the patient’s own supply of hydrocortisone. EMTs have even begun carrying hydrocortisone in some states in response to a campaign by the CARES Foundation, a nonprofit organization dedicated to helping families and individuals affected by congenital adrenal hyperplasia.

We started our patient on 100 mg/m²/d hydrocortisone 24 hours after he was admitted to the PICU. (At that time, his sodium level was 110 mEq/L.) Forty-eight hours after admission, we started the patient on fludrocortisone for mineralocorticoid effect at 0.1 mg/d. (The patient’s sodium level was 122 mEq/L). At 72 hours after admission, the patient’s sodium level was 137 mEq/L and his mental status was normal. Normal saline was discontinued when sodium normalized. He was discharged 2 days later. He was informed he should continue these medications for life, though doses might be adjusted slightly with time.

Two weeks later, our patient’s sodium level had reached 141 mEq/L and his weight loss, depression, vomiting, and fatigue had resolved. He stopped taking his SSRI. He was still craving extra salt, but not as much, and his urine was no longer a very dark yellow.

In retrospect, starting this patient on steroids earlier may not have resulted in any more of a rapid sodium rise than that which occurred otherwise, but we believe that our concern for CPM at that time justified the delay in steroid use. We felt it was safe to delay steroids because the patient’s BP was stable and his clinical picture was rapidly improving. In most cases, however, delaying steroids is not advisable.

THE TAKEAWAY

Adrenal insufficiency can be clearly diagnosed via labs and clinical presentation, and is potentially lethal if unrecognized. The predominant manifestations of adrenal crisis are hypotension and shock, usually with hyponatremia and hyperkalemia. During stressful events or illness, patients should increase their glucocorticoid dose. If they are on hydrocortisone, instructions are usually to triple the dose, and give the medication 3 times a day. Patients require instruction beforehand on how and when to increase doses for illness so that they can handle this on their own. Patients should carry a medical identification card so that their condition is evident to anyone caring for them in the ED.

THE CASE

A 17-year-old boy presented to the emergency department (ED) with a headache, dizziness, lethargy, and weakness that he’d had for 2 weeks. The patient was taking a selective serotonin reuptake inhibitor (SSRI) for depression (sertraline 25 mg/d). He had been vomiting twice daily for the past 3 years. (Although he had been seen multiple times in urgent care clinics, he did not have regular medical care.) The boy was fatigued and had dark yellow urine. His father indicated that his son’s skin had darkened over the last 5 to 6 years and that he had been adding salt, in large quantities, to nearly all of his meals for 10 years.

The boy’s health issues were impacting his school life. He was dismissed from school often because his teachers felt he was skipping class and using the excuse of needing to urinate or vomit. He had traveled back and forth to Mexico about 2 times a year, with the last time being about 3 months before his trip to the ED.

The patient’s vitals included a temperature of 96.3º F, heart rate (HR) of 77 beats/min, respiratory rate of 16 breaths/min, and a supine blood pressure (BP) of 102/58 mm Hg. (The patient’s BP was not obtained when sitting or standing, because he felt dizzy when trying to stand or sit up and the HR monitor increased to 100 beats/min.) His weight was 106.9 pounds and height was 5 feet 8 inches. The teen was ill-appearing and somnolent. No jugular vein distention, murmurs, or gallops were noted on exam. The patient’s lips were dry and cracked, gums were darkened, and his skin was clammy to the touch. His abdomen was soft with hypoactive bowel sounds and no ascites. His extremities were non-edematous.

A chemistry panel showed a low sodium level of 99 mEq/L, a somewhat high potassium level of 5.2 mmol/L, low chloride (69 mEq/L) and CO₂ (5 mEq/L) levels, a high glucose level (124 mg/dL), and normal creatinine (0.79 mg/dL), albumin (5.2 g/dL), and thyroid stimulating hormone (2.4 mIU/L) levels. A tuberculosis (TB) test, acute hepatitis panel, human immunodeficiency test, and urine drug screen were all negative. Liver enzymes and lipase levels were normal.

The patient was admitted to the pediatric intensive care unit (PICU) on 200 mL/hr normal saline (twice the normal maintenance rate) and we took over his care.

THE DIAGNOSIS

Because of the patient’s severe hyponatremia, the differential diagnosis included heart failure, cirrhosis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), SSRI-induced SIADH, cerebral salt wasting, severe hypothyroidism, adrenal insufficiency, malignancies, ecstasy use, renal failure, low dietary solute intake, and psychogenic polydipsia.

A random cortisol test taken in the ED returned and was noted to be very low (<1 mcg/dL). This information, plus the signs of aldosterone deficiency (low sodium and elevated potassium levels) and adrenocorticotropic hormone (ACTH) excess (skin darkening), prompted us to perform a 250-mcg ACTH stimulation test. Results at 30 and 60 minutes both showed cortisol at <1 mcg/dL, which led us to suspect adrenal insufficiency. The diagnosis of autoimmune adrenalitis, or Addison’s disease, was confirmed after inpatient lab work returned with positive 21-hydroxylase antibodies and an elevated ACTH (1117 pg/mL; normal, 10-65 pg/mL).

We noted that the patient’s sodium level was gradually increasing while he was receiving the intravenous (IV) fluids. We were concerned, though, that too rapid a sodium correction would put the patient at risk for central pontine myelinolysis (CPM). So we held off on steroids until 24 hours after he was admitted to the PICU, when his sodium level reached 110 mEq/L.

DISCUSSION

The first evidence of Addison’s disease is usually an increase in plasma renin activity with low serum aldosterone.

Primary adrenal insufficiency in the developed world is commonly caused by autoimmune adrenalitis, also known as Addison’s disease. Addison’s disease is the cause of primary adrenal insufficiency in 70% to 90% of cases, with the remainder caused by TB, adrenal hemorrhage, infarction, lymphoma, cytomegalovirus, adrenoleukodystrophy, or metastatic cancer. We also considered adrenoleukodystrophy in our patient, but felt it unlikely in a 17-year-old with normal mental status and positive adrenal antibodies.

The first evidence of Addison’s disease is usually an increase in plasma renin activity with low serum aldosterone. This might explain our patient’s years of salt cravings prior to presentation. There is typically a decrease in serum cortisol response to ACTH stimulation several months to years after the onset of salt cravings. The next sign of deterioration in adrenal function is an increase in basal serum ACTH; the process concludes with a decreased basal serum cortisol level.^1-3 By the time our patient presented to the ED, his ACTH was very high, his cortisol was low, and his ACTH stimulation response was low.

Acute adrenal insufficiency crisis usually occurs after a prolonged period of nonspecific complaints due to a loss of both glucocorticoids and mineralocorticoids; by the time overt symptoms occur, 90% of the adrenal gland may be destroyed.³ Patients (such as ours) may present with symptoms such as abdominal pain, weakness, vomiting, fever, and decreased responsiveness. Hyponatremia and hyperkalemia are commonly seen at initial diagnosis. BP can be compromised in some patients due to loss of vascular tone; our patient did not present with this finding.

Treatment includes hydrocortisone and fludrocortisone for life

Initial management focuses on rehydration, maintenance of BP, cardiac monitoring, and electrolyte monitoring with a focus on slow normalization of electrolyte abnormalities. Patients should be treated with hydrocortisone (approximately 10 mg/m²/d) and fludrocortisone (usually 0.1 mg/d), and they will be maintained on this regimen for life.^1,3

During acute illness, the doses of hydrocortisone are usually tripled and given 3 times per day to address the increased cortisol needs of the stress response. Lack of stress dose steroids in the setting of illness can lead to repeat adrenal crisis events.

Patients should be taught about intramuscular (IM) hydrocortisone use (100 mg IM) for emergencies and should have medical identification. In many states, emergency medical technicians (EMTs) are now able to administer the patient’s own supply of hydrocortisone. EMTs have even begun carrying hydrocortisone in some states in response to a campaign by the CARES Foundation, a nonprofit organization dedicated to helping families and individuals affected by congenital adrenal hyperplasia.

We started our patient on 100 mg/m²/d hydrocortisone 24 hours after he was admitted to the PICU. (At that time, his sodium level was 110 mEq/L.) Forty-eight hours after admission, we started the patient on fludrocortisone for mineralocorticoid effect at 0.1 mg/d. (The patient’s sodium level was 122 mEq/L). At 72 hours after admission, the patient’s sodium level was 137 mEq/L and his mental status was normal. Normal saline was discontinued when sodium normalized. He was discharged 2 days later. He was informed he should continue these medications for life, though doses might be adjusted slightly with time.

Two weeks later, our patient’s sodium level had reached 141 mEq/L and his weight loss, depression, vomiting, and fatigue had resolved. He stopped taking his SSRI. He was still craving extra salt, but not as much, and his urine was no longer a very dark yellow.

In retrospect, starting this patient on steroids earlier may not have resulted in any more of a rapid sodium rise than that which occurred otherwise, but we believe that our concern for CPM at that time justified the delay in steroid use. We felt it was safe to delay steroids because the patient’s BP was stable and his clinical picture was rapidly improving. In most cases, however, delaying steroids is not advisable.

THE TAKEAWAY

Adrenal insufficiency can be clearly diagnosed via labs and clinical presentation, and is potentially lethal if unrecognized. The predominant manifestations of adrenal crisis are hypotension and shock, usually with hyponatremia and hyperkalemia. During stressful events or illness, patients should increase their glucocorticoid dose. If they are on hydrocortisone, instructions are usually to triple the dose, and give the medication 3 times a day. Patients require instruction beforehand on how and when to increase doses for illness so that they can handle this on their own. Patients should carry a medical identification card so that their condition is evident to anyone caring for them in the ED.

THE CASE

A 17-year-old boy presented to the emergency department (ED) with a headache, dizziness, lethargy, and weakness that he’d had for 2 weeks. The patient was taking a selective serotonin reuptake inhibitor (SSRI) for depression (sertraline 25 mg/d). He had been vomiting twice daily for the past 3 years. (Although he had been seen multiple times in urgent care clinics, he did not have regular medical care.) The boy was fatigued and had dark yellow urine. His father indicated that his son’s skin had darkened over the last 5 to 6 years and that he had been adding salt, in large quantities, to nearly all of his meals for 10 years.

The boy’s health issues were impacting his school life. He was dismissed from school often because his teachers felt he was skipping class and using the excuse of needing to urinate or vomit. He had traveled back and forth to Mexico about 2 times a year, with the last time being about 3 months before his trip to the ED.

The patient’s vitals included a temperature of 96.3º F, heart rate (HR) of 77 beats/min, respiratory rate of 16 breaths/min, and a supine blood pressure (BP) of 102/58 mm Hg. (The patient’s BP was not obtained when sitting or standing, because he felt dizzy when trying to stand or sit up and the HR monitor increased to 100 beats/min.) His weight was 106.9 pounds and height was 5 feet 8 inches. The teen was ill-appearing and somnolent. No jugular vein distention, murmurs, or gallops were noted on exam. The patient’s lips were dry and cracked, gums were darkened, and his skin was clammy to the touch. His abdomen was soft with hypoactive bowel sounds and no ascites. His extremities were non-edematous.

A chemistry panel showed a low sodium level of 99 mEq/L, a somewhat high potassium level of 5.2 mmol/L, low chloride (69 mEq/L) and CO₂ (5 mEq/L) levels, a high glucose level (124 mg/dL), and normal creatinine (0.79 mg/dL), albumin (5.2 g/dL), and thyroid stimulating hormone (2.4 mIU/L) levels. A tuberculosis (TB) test, acute hepatitis panel, human immunodeficiency test, and urine drug screen were all negative. Liver enzymes and lipase levels were normal.

The patient was admitted to the pediatric intensive care unit (PICU) on 200 mL/hr normal saline (twice the normal maintenance rate) and we took over his care.

THE DIAGNOSIS

Because of the patient’s severe hyponatremia, the differential diagnosis included heart failure, cirrhosis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), SSRI-induced SIADH, cerebral salt wasting, severe hypothyroidism, adrenal insufficiency, malignancies, ecstasy use, renal failure, low dietary solute intake, and psychogenic polydipsia.

A random cortisol test taken in the ED returned and was noted to be very low (<1 mcg/dL). This information, plus the signs of aldosterone deficiency (low sodium and elevated potassium levels) and adrenocorticotropic hormone (ACTH) excess (skin darkening), prompted us to perform a 250-mcg ACTH stimulation test. Results at 30 and 60 minutes both showed cortisol at <1 mcg/dL, which led us to suspect adrenal insufficiency. The diagnosis of autoimmune adrenalitis, or Addison’s disease, was confirmed after inpatient lab work returned with positive 21-hydroxylase antibodies and an elevated ACTH (1117 pg/mL; normal, 10-65 pg/mL).

We noted that the patient’s sodium level was gradually increasing while he was receiving the intravenous (IV) fluids. We were concerned, though, that too rapid a sodium correction would put the patient at risk for central pontine myelinolysis (CPM). So we held off on steroids until 24 hours after he was admitted to the PICU, when his sodium level reached 110 mEq/L.

DISCUSSION

The first evidence of Addison’s disease is usually an increase in plasma renin activity with low serum aldosterone.

Primary adrenal insufficiency in the developed world is commonly caused by autoimmune adrenalitis, also known as Addison’s disease. Addison’s disease is the cause of primary adrenal insufficiency in 70% to 90% of cases, with the remainder caused by TB, adrenal hemorrhage, infarction, lymphoma, cytomegalovirus, adrenoleukodystrophy, or metastatic cancer. We also considered adrenoleukodystrophy in our patient, but felt it unlikely in a 17-year-old with normal mental status and positive adrenal antibodies.

The first evidence of Addison’s disease is usually an increase in plasma renin activity with low serum aldosterone. This might explain our patient’s years of salt cravings prior to presentation. There is typically a decrease in serum cortisol response to ACTH stimulation several months to years after the onset of salt cravings. The next sign of deterioration in adrenal function is an increase in basal serum ACTH; the process concludes with a decreased basal serum cortisol level.^1-3 By the time our patient presented to the ED, his ACTH was very high, his cortisol was low, and his ACTH stimulation response was low.

Acute adrenal insufficiency crisis usually occurs after a prolonged period of nonspecific complaints due to a loss of both glucocorticoids and mineralocorticoids; by the time overt symptoms occur, 90% of the adrenal gland may be destroyed.³ Patients (such as ours) may present with symptoms such as abdominal pain, weakness, vomiting, fever, and decreased responsiveness. Hyponatremia and hyperkalemia are commonly seen at initial diagnosis. BP can be compromised in some patients due to loss of vascular tone; our patient did not present with this finding.

Treatment includes hydrocortisone and fludrocortisone for life

Initial management focuses on rehydration, maintenance of BP, cardiac monitoring, and electrolyte monitoring with a focus on slow normalization of electrolyte abnormalities. Patients should be treated with hydrocortisone (approximately 10 mg/m²/d) and fludrocortisone (usually 0.1 mg/d), and they will be maintained on this regimen for life.^1,3

During acute illness, the doses of hydrocortisone are usually tripled and given 3 times per day to address the increased cortisol needs of the stress response. Lack of stress dose steroids in the setting of illness can lead to repeat adrenal crisis events.

Patients should be taught about intramuscular (IM) hydrocortisone use (100 mg IM) for emergencies and should have medical identification. In many states, emergency medical technicians (EMTs) are now able to administer the patient’s own supply of hydrocortisone. EMTs have even begun carrying hydrocortisone in some states in response to a campaign by the CARES Foundation, a nonprofit organization dedicated to helping families and individuals affected by congenital adrenal hyperplasia.

We started our patient on 100 mg/m²/d hydrocortisone 24 hours after he was admitted to the PICU. (At that time, his sodium level was 110 mEq/L.) Forty-eight hours after admission, we started the patient on fludrocortisone for mineralocorticoid effect at 0.1 mg/d. (The patient’s sodium level was 122 mEq/L). At 72 hours after admission, the patient’s sodium level was 137 mEq/L and his mental status was normal. Normal saline was discontinued when sodium normalized. He was discharged 2 days later. He was informed he should continue these medications for life, though doses might be adjusted slightly with time.

Two weeks later, our patient’s sodium level had reached 141 mEq/L and his weight loss, depression, vomiting, and fatigue had resolved. He stopped taking his SSRI. He was still craving extra salt, but not as much, and his urine was no longer a very dark yellow.

In retrospect, starting this patient on steroids earlier may not have resulted in any more of a rapid sodium rise than that which occurred otherwise, but we believe that our concern for CPM at that time justified the delay in steroid use. We felt it was safe to delay steroids because the patient’s BP was stable and his clinical picture was rapidly improving. In most cases, however, delaying steroids is not advisable.

THE TAKEAWAY

Adrenal insufficiency can be clearly diagnosed via labs and clinical presentation, and is potentially lethal if unrecognized. The predominant manifestations of adrenal crisis are hypotension and shock, usually with hyponatremia and hyperkalemia. During stressful events or illness, patients should increase their glucocorticoid dose. If they are on hydrocortisone, instructions are usually to triple the dose, and give the medication 3 times a day. Patients require instruction beforehand on how and when to increase doses for illness so that they can handle this on their own. Patients should carry a medical identification card so that their condition is evident to anyone caring for them in the ED.

THE CASE

The mother of a 13-year-old girl brought her daughter to our family medicine clinic for follow-up after being seen in the emergency department (ED) 3 days earlier. The girl had presented to the ED with a one-day history of back, chest, and vaginal pain. She was diagnosed with a urinary tract infection and treated empirically with phenazopyridine and cephalexin pending a urine culture.

During the follow-up appointment, the patient complained of worsening vaginal pain and increased vaginal discharge, but reported resolution of her back and chest pain. She also said that a week earlier, she’d had a fever that reached 104° F and a sore throat. She denied urinary frequency/urgency, sexual activity, or sexual abuse. The result of the urine culture performed in the ED was <10,000 col/mL (normal urogenital flora).

A genitourinary (GU) exam revealed erythematous patches with small amounts of crusting at the inner labia bilaterally. The labia were also swollen and diffusely tender to palpation. The patient had a white/gray discharge, but no vesicles or papules. The physician was unable to place a speculum due to pain.

The differential diagnosis at the time included candidal vaginitis and cellulitis. Since the patient’s skin was non-erythematous and she had vaginal discharge, she was treated for presumed severe candidal vaginitis with fluconazole and clotrimazole 1% cream. (The antibiotics were stopped because the patient reported worsening symptoms after they were prescribed in the ED.) The patient was told to return to the ED if she experienced signs and symptoms such as worsening vaginal pain or discharge, fever, or chills. A repeat urine culture was performed and the results came back normal.

Worsening symptoms. Six days later, the patient returned to the ED with urinary hesitation and persistent dysuria; she was admitted for pain control. She also complained of worsening labial swelling and increased vaginal discharge despite adherence to the fluconazole and clotrimazole cream regimen, which were discontinued on admission to the ED. She continued to deny being sexually active or abused.

A GU exam showed a 1-cm shallow ulcer on the right labium and a copious amount of foul-smelling white discharge. An Ob/Gyn resident and attending physician examined the patient; their differential diagnosis at this point included herpes simplex virus (HSV), Epstein-Barr virus (EBV), gonorrhea/chlamydia, and trauma. The patient was given topical lidocaine for pain control and started on acyclovir for presumed HSV while awaiting the HSV test results. A pelvic ultrasound and laboratory work-up were ordered at this time as well.

THE DIAGNOSIS

One review found only 13 instances of genital ulceration in females attributable to Epstein-Barr virus. The exact method by which EBV causes the ulcers is unclear.

The pelvic ultrasound showed that the uterus was a normal size and that there was no gross mass or significant pelvic fluid. The patient’s right ovary measured 2.8 × 1.6 cm; the left ovary was not seen.

The patient’s laboratory work-up included an unremarkable comprehensive metabolic panel. A complete blood count was within normal limits, except for the patient’s monocyte level, which was at 12.9% (reference range: 0%-12%). The patient had a negative urinary human chorionic gonadotropin test, and was negative for HSV, chlamydia, gonorrhea, and trichomoniasis. A rapid plasma reagin test and human immunodeficiency virus antibody (1+2) tests were nonreactive. A wet prep was negative. A mononuclear spot test (monospot), however, was positive.

Results from the monospot testing took several days to return. By the time the results arrived, the patient had been transferred to a local children’s hospital for assessment in their pediatric urology department, as she was experiencing urinary hesitation and required catheterization. The diagnosis of infectious mononucleosis presenting with genital ulcer was made. EBV cultures were never obtained, but seemed to be the likely cause of the patient’s infectious mononucleosis given her clinical symptoms and lab results.

DISCUSSION

Approximately 95% of adults worldwide are infected with EBV.¹ While the infection is often asymptomatic, some patients will develop infectious mononucleosis.¹ EBV is the most common cause of infectious mononucleosis, mainly affecting teenagers and young adults (especially college students). At least 25% of teenagers and young adults who become infected with EBV will develop infectious mononucleosis.²

Typical symptoms of infectious mononucleosis include extreme fatigue, fever, sore throat, and head and body aches.² In this case, the patient did have a fever and sore throat one week prior to presentation at our clinic, but she never complained of fatigue.

The association between mononucleosis and genital ulcers is not well known,^3,4 and the exact method by which EBV causes genital ulcers is unclear.⁵ One review found that only 13 instances of genital ulceration in females attributable to EBV infection had been reported.⁵ When ulceration does occur, the majority of cases have involved young females who presented with only mild symptoms of mononucleosis.^3,6 EBV has been found to present in the cervix, which suggests direct inoculation.^3,6

Our patient remained catheterized for 2 days while in the children’s hospital. Her ulcer started to heal and she was sent home in stable condition. No additional follow-up was required and the ulcer did not recur.

THE TAKEAWAY

Include infectious mononucleosis in the differential for patients presenting with vaginal ulcers—especially those who deny sexual activity. Including testing for EBV and mononucleosis antibodies in the work-up can aid in the diagnosis. Cases such as this one are also a good reminder of the need to question young people while their parents/guardians are not in the examroom to foster an open and honest patient-physician relationship.

THE CASE

The mother of a 13-year-old girl brought her daughter to our family medicine clinic for follow-up after being seen in the emergency department (ED) 3 days earlier. The girl had presented to the ED with a one-day history of back, chest, and vaginal pain. She was diagnosed with a urinary tract infection and treated empirically with phenazopyridine and cephalexin pending a urine culture.

During the follow-up appointment, the patient complained of worsening vaginal pain and increased vaginal discharge, but reported resolution of her back and chest pain. She also said that a week earlier, she’d had a fever that reached 104° F and a sore throat. She denied urinary frequency/urgency, sexual activity, or sexual abuse. The result of the urine culture performed in the ED was <10,000 col/mL (normal urogenital flora).

A genitourinary (GU) exam revealed erythematous patches with small amounts of crusting at the inner labia bilaterally. The labia were also swollen and diffusely tender to palpation. The patient had a white/gray discharge, but no vesicles or papules. The physician was unable to place a speculum due to pain.

The differential diagnosis at the time included candidal vaginitis and cellulitis. Since the patient’s skin was non-erythematous and she had vaginal discharge, she was treated for presumed severe candidal vaginitis with fluconazole and clotrimazole 1% cream. (The antibiotics were stopped because the patient reported worsening symptoms after they were prescribed in the ED.) The patient was told to return to the ED if she experienced signs and symptoms such as worsening vaginal pain or discharge, fever, or chills. A repeat urine culture was performed and the results came back normal.

Worsening symptoms. Six days later, the patient returned to the ED with urinary hesitation and persistent dysuria; she was admitted for pain control. She also complained of worsening labial swelling and increased vaginal discharge despite adherence to the fluconazole and clotrimazole cream regimen, which were discontinued on admission to the ED. She continued to deny being sexually active or abused.

A GU exam showed a 1-cm shallow ulcer on the right labium and a copious amount of foul-smelling white discharge. An Ob/Gyn resident and attending physician examined the patient; their differential diagnosis at this point included herpes simplex virus (HSV), Epstein-Barr virus (EBV), gonorrhea/chlamydia, and trauma. The patient was given topical lidocaine for pain control and started on acyclovir for presumed HSV while awaiting the HSV test results. A pelvic ultrasound and laboratory work-up were ordered at this time as well.

THE DIAGNOSIS

One review found only 13 instances of genital ulceration in females attributable to Epstein-Barr virus. The exact method by which EBV causes the ulcers is unclear.

The pelvic ultrasound showed that the uterus was a normal size and that there was no gross mass or significant pelvic fluid. The patient’s right ovary measured 2.8 × 1.6 cm; the left ovary was not seen.

The patient’s laboratory work-up included an unremarkable comprehensive metabolic panel. A complete blood count was within normal limits, except for the patient’s monocyte level, which was at 12.9% (reference range: 0%-12%). The patient had a negative urinary human chorionic gonadotropin test, and was negative for HSV, chlamydia, gonorrhea, and trichomoniasis. A rapid plasma reagin test and human immunodeficiency virus antibody (1+2) tests were nonreactive. A wet prep was negative. A mononuclear spot test (monospot), however, was positive.

Results from the monospot testing took several days to return. By the time the results arrived, the patient had been transferred to a local children’s hospital for assessment in their pediatric urology department, as she was experiencing urinary hesitation and required catheterization. The diagnosis of infectious mononucleosis presenting with genital ulcer was made. EBV cultures were never obtained, but seemed to be the likely cause of the patient’s infectious mononucleosis given her clinical symptoms and lab results.

DISCUSSION

Approximately 95% of adults worldwide are infected with EBV.¹ While the infection is often asymptomatic, some patients will develop infectious mononucleosis.¹ EBV is the most common cause of infectious mononucleosis, mainly affecting teenagers and young adults (especially college students). At least 25% of teenagers and young adults who become infected with EBV will develop infectious mononucleosis.²

Typical symptoms of infectious mononucleosis include extreme fatigue, fever, sore throat, and head and body aches.² In this case, the patient did have a fever and sore throat one week prior to presentation at our clinic, but she never complained of fatigue.

The association between mononucleosis and genital ulcers is not well known,^3,4 and the exact method by which EBV causes genital ulcers is unclear.⁵ One review found that only 13 instances of genital ulceration in females attributable to EBV infection had been reported.⁵ When ulceration does occur, the majority of cases have involved young females who presented with only mild symptoms of mononucleosis.^3,6 EBV has been found to present in the cervix, which suggests direct inoculation.^3,6

Our patient remained catheterized for 2 days while in the children’s hospital. Her ulcer started to heal and she was sent home in stable condition. No additional follow-up was required and the ulcer did not recur.

THE TAKEAWAY

Include infectious mononucleosis in the differential for patients presenting with vaginal ulcers—especially those who deny sexual activity. Including testing for EBV and mononucleosis antibodies in the work-up can aid in the diagnosis. Cases such as this one are also a good reminder of the need to question young people while their parents/guardians are not in the examroom to foster an open and honest patient-physician relationship.

THE CASE

The mother of a 13-year-old girl brought her daughter to our family medicine clinic for follow-up after being seen in the emergency department (ED) 3 days earlier. The girl had presented to the ED with a one-day history of back, chest, and vaginal pain. She was diagnosed with a urinary tract infection and treated empirically with phenazopyridine and cephalexin pending a urine culture.

During the follow-up appointment, the patient complained of worsening vaginal pain and increased vaginal discharge, but reported resolution of her back and chest pain. She also said that a week earlier, she’d had a fever that reached 104° F and a sore throat. She denied urinary frequency/urgency, sexual activity, or sexual abuse. The result of the urine culture performed in the ED was <10,000 col/mL (normal urogenital flora).

A genitourinary (GU) exam revealed erythematous patches with small amounts of crusting at the inner labia bilaterally. The labia were also swollen and diffusely tender to palpation. The patient had a white/gray discharge, but no vesicles or papules. The physician was unable to place a speculum due to pain.

The differential diagnosis at the time included candidal vaginitis and cellulitis. Since the patient’s skin was non-erythematous and she had vaginal discharge, she was treated for presumed severe candidal vaginitis with fluconazole and clotrimazole 1% cream. (The antibiotics were stopped because the patient reported worsening symptoms after they were prescribed in the ED.) The patient was told to return to the ED if she experienced signs and symptoms such as worsening vaginal pain or discharge, fever, or chills. A repeat urine culture was performed and the results came back normal.

Worsening symptoms. Six days later, the patient returned to the ED with urinary hesitation and persistent dysuria; she was admitted for pain control. She also complained of worsening labial swelling and increased vaginal discharge despite adherence to the fluconazole and clotrimazole cream regimen, which were discontinued on admission to the ED. She continued to deny being sexually active or abused.

A GU exam showed a 1-cm shallow ulcer on the right labium and a copious amount of foul-smelling white discharge. An Ob/Gyn resident and attending physician examined the patient; their differential diagnosis at this point included herpes simplex virus (HSV), Epstein-Barr virus (EBV), gonorrhea/chlamydia, and trauma. The patient was given topical lidocaine for pain control and started on acyclovir for presumed HSV while awaiting the HSV test results. A pelvic ultrasound and laboratory work-up were ordered at this time as well.

THE DIAGNOSIS

One review found only 13 instances of genital ulceration in females attributable to Epstein-Barr virus. The exact method by which EBV causes the ulcers is unclear.

The pelvic ultrasound showed that the uterus was a normal size and that there was no gross mass or significant pelvic fluid. The patient’s right ovary measured 2.8 × 1.6 cm; the left ovary was not seen.

The patient’s laboratory work-up included an unremarkable comprehensive metabolic panel. A complete blood count was within normal limits, except for the patient’s monocyte level, which was at 12.9% (reference range: 0%-12%). The patient had a negative urinary human chorionic gonadotropin test, and was negative for HSV, chlamydia, gonorrhea, and trichomoniasis. A rapid plasma reagin test and human immunodeficiency virus antibody (1+2) tests were nonreactive. A wet prep was negative. A mononuclear spot test (monospot), however, was positive.

Results from the monospot testing took several days to return. By the time the results arrived, the patient had been transferred to a local children’s hospital for assessment in their pediatric urology department, as she was experiencing urinary hesitation and required catheterization. The diagnosis of infectious mononucleosis presenting with genital ulcer was made. EBV cultures were never obtained, but seemed to be the likely cause of the patient’s infectious mononucleosis given her clinical symptoms and lab results.

DISCUSSION

Approximately 95% of adults worldwide are infected with EBV.¹ While the infection is often asymptomatic, some patients will develop infectious mononucleosis.¹ EBV is the most common cause of infectious mononucleosis, mainly affecting teenagers and young adults (especially college students). At least 25% of teenagers and young adults who become infected with EBV will develop infectious mononucleosis.²

Typical symptoms of infectious mononucleosis include extreme fatigue, fever, sore throat, and head and body aches.² In this case, the patient did have a fever and sore throat one week prior to presentation at our clinic, but she never complained of fatigue.

The association between mononucleosis and genital ulcers is not well known,^3,4 and the exact method by which EBV causes genital ulcers is unclear.⁵ One review found that only 13 instances of genital ulceration in females attributable to EBV infection had been reported.⁵ When ulceration does occur, the majority of cases have involved young females who presented with only mild symptoms of mononucleosis.^3,6 EBV has been found to present in the cervix, which suggests direct inoculation.^3,6

Our patient remained catheterized for 2 days while in the children’s hospital. Her ulcer started to heal and she was sent home in stable condition. No additional follow-up was required and the ulcer did not recur.

THE TAKEAWAY

Include infectious mononucleosis in the differential for patients presenting with vaginal ulcers—especially those who deny sexual activity. Including testing for EBV and mononucleosis antibodies in the work-up can aid in the diagnosis. Cases such as this one are also a good reminder of the need to question young people while their parents/guardians are not in the examroom to foster an open and honest patient-physician relationship.

A 25-year-old G2P1 mother gave birth to a boy at 40 and 6/7 weeks by vaginal delivery. Labor was induced because of oligohydramnios complicated by chorioamnionitis. The mother was treated with vancomycin and gentamicin. Prenatal lab work and delivery were otherwise unremarkable.

The delivering physician (CG) noted that the neonate had numerous brown, red, and black plaques distributed over his abdomen, lower back, groin, and thighs (FIGURE). Some plaques were hypertrichotic and other areas, apart from the plaques, were thinly desquamated. Apgar scores were 8 and 9 and the remainder of the exam, including the neurologic exam, was normal. The Dermatology Service (JK) was consulted.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Giant congenital nevus

Congenital melanocytic nevi (CMN) are pigmented lesions that are present at birth and created by the abnormal migration of neural crest cells during embryogenesis.¹ Nevi are categorized by size as small (<1.5 cm), medium (1.5-20 cm), large (>20 cm), and giant (>40 cm).² Congenital nevi tend to start out flat, with uniform pigmentation, but can become more variegated in texture and color as normal growth and development continue. Giant congenital nevi are likely to thicken, darken, and enlarge as the patient grows. Some nevi may develop very coarse or dark hair.

CMN can cover any part of the body and occur independent of skin color and other ethnic factors.³ Giant congenital nevi are rare, with an incidence of approximately one in 50,000 live births and with males and females equally affected.^3,4 The condition is diagnosed at birth, based on the appearance of the lesions.

The differential diagnosis for CMN includes café au lait macules, blue-gray spots (aka Mongolian spots), nevus of Ota, nevus spilus, and vascular malformations (TABLE).⁵ CMN may present in almost any location and may be brown, black, pink, or purple in color. Café au lait macules, blue-gray spots, nevus of Ota, nevus spilus, and vascular malformations have individual location and color characteristics that set them apart clinically.

Monitor patients for melanoma, CNS complications

Patients with CMN are at increased risk of neurocutaneous melanosis (NCM) and cutaneous melanoma.

Neurocutaneous melanosis, a complication of giant congenital nevi, is a melanocyte proliferation in the central nervous system (CNS). Between 6% and 11% of patients with giant congenital nevi develop symptomatic NCM in childhood. Thus, any CNS symptoms should be fully evaluated.^4,6 NCM can result in seizures, cranial nerve palsy, hydrocephalus, and leptomeningeal melanoma.

Besides giant congenital nevi, risk factors for NCM include male sex, large numbers of satellite nevi, and the presence of nevi over the posterior midline or head and neck.⁷ The prognosis is poor for patients who develop neurologic symptoms. NCM is associated with other malignancies, including rhadomyosarcoma, liposarcoma, and malignant peripheral nerve sheath tumors.⁴

By age 10, up to 8% of patients with giant congenital nevi will develop melanoma within the nevi.

Magnetic resonance imaging (MRI) is helpful to exclude NCM. Ideally, an MRI should be ordered before 4 months of age, at which time myelination begins to make the identification of melanin deposits in the CNS more challenging.⁷ Not all patients with imaging findings that are consistent with NCM will develop symptoms.⁸

Melanoma. By age 10, up to 8% of patients with giant congenital nevi will develop melanoma within the nevi; most of these cases occur during the first 2 years of life.^7,9 Patients with NCM are at even greater risk: their rate of malignant melanoma is between 40% and 60%.⁶ As a result, patients should be monitored closely for any signs of the disease. Total body photography, serial clinical photos, and patient self-exam are helpful to detect changes and de novo lesions. New lesions or ulcerations superimposed on existing nevi may indicate malignancy.⁷ Sun protection is critical to reduce the risk of melanogenesis.

Should patients pursue surgery? It’s debatable

For children with congenital nevi and other skin conditions, the American Academy of Dermatology offers summer camps across the country.

Options for patients with large and giant CMN include early curettage (prior to 2 weeks of life), local excision (often with tissue expansion), dermabrasion, and laser therapy.² There is considerable debate about surgery. Advocates of surgery cite psychosocial relief as a major treatment benefit and speculate about prevention of melanoma. Opponents worry that excessive surgical intervention may cause melanogenesis in a scar or deep in an area of treatment. And, while smaller congenital nevi are easier to surgically remove, they have a low associated risk of developing melanoma and are typically monitored clinically.

Children with congenital nevi will need support

Several nonprofit organizations offer resources for children with congenital nevi and their families. Nevus Outreach (www.nevus.org) is an organization devoted to improving awareness and providing support for people with CMN and NCM. The group maintains a registry of patients with large nevi in an effort to help researchers improve treatment and identify a cure.

For children with congenital nevi and other skin conditions, the American Academy of Dermatology offers its “Camp Discovery” at locations across the country (https://www.aad.org/public/kids/camp-discovery). Camp Discovery provides full scholarships and includes transportation to each of the individual camps for attendees.

Our patient underwent an MRI on his fifth day of life. The results were normal and he hadn’t developed any neurologic symptoms at 4 months of age. The child sees his family physician for routine well-child visits and a dermatologist annually. The dermatologist is carefully monitoring the nevi, which continue to grow.

CORRESPONDENCE
Jonathan Karnes, MD, 6 East Chestnut Street, Suite 340, Augusta, ME 04330; jonathan.karnes@mainegeneral.org.

A 25-year-old G2P1 mother gave birth to a boy at 40 and 6/7 weeks by vaginal delivery. Labor was induced because of oligohydramnios complicated by chorioamnionitis. The mother was treated with vancomycin and gentamicin. Prenatal lab work and delivery were otherwise unremarkable.

The delivering physician (CG) noted that the neonate had numerous brown, red, and black plaques distributed over his abdomen, lower back, groin, and thighs (FIGURE). Some plaques were hypertrichotic and other areas, apart from the plaques, were thinly desquamated. Apgar scores were 8 and 9 and the remainder of the exam, including the neurologic exam, was normal. The Dermatology Service (JK) was consulted.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Giant congenital nevus

Congenital melanocytic nevi (CMN) are pigmented lesions that are present at birth and created by the abnormal migration of neural crest cells during embryogenesis.¹ Nevi are categorized by size as small (<1.5 cm), medium (1.5-20 cm), large (>20 cm), and giant (>40 cm).² Congenital nevi tend to start out flat, with uniform pigmentation, but can become more variegated in texture and color as normal growth and development continue. Giant congenital nevi are likely to thicken, darken, and enlarge as the patient grows. Some nevi may develop very coarse or dark hair.

CMN can cover any part of the body and occur independent of skin color and other ethnic factors.³ Giant congenital nevi are rare, with an incidence of approximately one in 50,000 live births and with males and females equally affected.^3,4 The condition is diagnosed at birth, based on the appearance of the lesions.

The differential diagnosis for CMN includes café au lait macules, blue-gray spots (aka Mongolian spots), nevus of Ota, nevus spilus, and vascular malformations (TABLE).⁵ CMN may present in almost any location and may be brown, black, pink, or purple in color. Café au lait macules, blue-gray spots, nevus of Ota, nevus spilus, and vascular malformations have individual location and color characteristics that set them apart clinically.

Monitor patients for melanoma, CNS complications

Patients with CMN are at increased risk of neurocutaneous melanosis (NCM) and cutaneous melanoma.

Neurocutaneous melanosis, a complication of giant congenital nevi, is a melanocyte proliferation in the central nervous system (CNS). Between 6% and 11% of patients with giant congenital nevi develop symptomatic NCM in childhood. Thus, any CNS symptoms should be fully evaluated.^4,6 NCM can result in seizures, cranial nerve palsy, hydrocephalus, and leptomeningeal melanoma.

Besides giant congenital nevi, risk factors for NCM include male sex, large numbers of satellite nevi, and the presence of nevi over the posterior midline or head and neck.⁷ The prognosis is poor for patients who develop neurologic symptoms. NCM is associated with other malignancies, including rhadomyosarcoma, liposarcoma, and malignant peripheral nerve sheath tumors.⁴

By age 10, up to 8% of patients with giant congenital nevi will develop melanoma within the nevi.

Magnetic resonance imaging (MRI) is helpful to exclude NCM. Ideally, an MRI should be ordered before 4 months of age, at which time myelination begins to make the identification of melanin deposits in the CNS more challenging.⁷ Not all patients with imaging findings that are consistent with NCM will develop symptoms.⁸

Melanoma. By age 10, up to 8% of patients with giant congenital nevi will develop melanoma within the nevi; most of these cases occur during the first 2 years of life.^7,9 Patients with NCM are at even greater risk: their rate of malignant melanoma is between 40% and 60%.⁶ As a result, patients should be monitored closely for any signs of the disease. Total body photography, serial clinical photos, and patient self-exam are helpful to detect changes and de novo lesions. New lesions or ulcerations superimposed on existing nevi may indicate malignancy.⁷ Sun protection is critical to reduce the risk of melanogenesis.

Should patients pursue surgery? It’s debatable

For children with congenital nevi and other skin conditions, the American Academy of Dermatology offers summer camps across the country.

Options for patients with large and giant CMN include early curettage (prior to 2 weeks of life), local excision (often with tissue expansion), dermabrasion, and laser therapy.² There is considerable debate about surgery. Advocates of surgery cite psychosocial relief as a major treatment benefit and speculate about prevention of melanoma. Opponents worry that excessive surgical intervention may cause melanogenesis in a scar or deep in an area of treatment. And, while smaller congenital nevi are easier to surgically remove, they have a low associated risk of developing melanoma and are typically monitored clinically.

Children with congenital nevi will need support

Several nonprofit organizations offer resources for children with congenital nevi and their families. Nevus Outreach (www.nevus.org) is an organization devoted to improving awareness and providing support for people with CMN and NCM. The group maintains a registry of patients with large nevi in an effort to help researchers improve treatment and identify a cure.

For children with congenital nevi and other skin conditions, the American Academy of Dermatology offers its “Camp Discovery” at locations across the country (https://www.aad.org/public/kids/camp-discovery). Camp Discovery provides full scholarships and includes transportation to each of the individual camps for attendees.

Our patient underwent an MRI on his fifth day of life. The results were normal and he hadn’t developed any neurologic symptoms at 4 months of age. The child sees his family physician for routine well-child visits and a dermatologist annually. The dermatologist is carefully monitoring the nevi, which continue to grow.

CORRESPONDENCE
Jonathan Karnes, MD, 6 East Chestnut Street, Suite 340, Augusta, ME 04330; jonathan.karnes@mainegeneral.org.

A 25-year-old G2P1 mother gave birth to a boy at 40 and 6/7 weeks by vaginal delivery. Labor was induced because of oligohydramnios complicated by chorioamnionitis. The mother was treated with vancomycin and gentamicin. Prenatal lab work and delivery were otherwise unremarkable.

The delivering physician (CG) noted that the neonate had numerous brown, red, and black plaques distributed over his abdomen, lower back, groin, and thighs (FIGURE). Some plaques were hypertrichotic and other areas, apart from the plaques, were thinly desquamated. Apgar scores were 8 and 9 and the remainder of the exam, including the neurologic exam, was normal. The Dermatology Service (JK) was consulted.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Giant congenital nevus

Congenital melanocytic nevi (CMN) are pigmented lesions that are present at birth and created by the abnormal migration of neural crest cells during embryogenesis.¹ Nevi are categorized by size as small (<1.5 cm), medium (1.5-20 cm), large (>20 cm), and giant (>40 cm).² Congenital nevi tend to start out flat, with uniform pigmentation, but can become more variegated in texture and color as normal growth and development continue. Giant congenital nevi are likely to thicken, darken, and enlarge as the patient grows. Some nevi may develop very coarse or dark hair.

CMN can cover any part of the body and occur independent of skin color and other ethnic factors.³ Giant congenital nevi are rare, with an incidence of approximately one in 50,000 live births and with males and females equally affected.^3,4 The condition is diagnosed at birth, based on the appearance of the lesions.

The differential diagnosis for CMN includes café au lait macules, blue-gray spots (aka Mongolian spots), nevus of Ota, nevus spilus, and vascular malformations (TABLE).⁵ CMN may present in almost any location and may be brown, black, pink, or purple in color. Café au lait macules, blue-gray spots, nevus of Ota, nevus spilus, and vascular malformations have individual location and color characteristics that set them apart clinically.

Monitor patients for melanoma, CNS complications

Patients with CMN are at increased risk of neurocutaneous melanosis (NCM) and cutaneous melanoma.

Neurocutaneous melanosis, a complication of giant congenital nevi, is a melanocyte proliferation in the central nervous system (CNS). Between 6% and 11% of patients with giant congenital nevi develop symptomatic NCM in childhood. Thus, any CNS symptoms should be fully evaluated.^4,6 NCM can result in seizures, cranial nerve palsy, hydrocephalus, and leptomeningeal melanoma.

Besides giant congenital nevi, risk factors for NCM include male sex, large numbers of satellite nevi, and the presence of nevi over the posterior midline or head and neck.⁷ The prognosis is poor for patients who develop neurologic symptoms. NCM is associated with other malignancies, including rhadomyosarcoma, liposarcoma, and malignant peripheral nerve sheath tumors.⁴

By age 10, up to 8% of patients with giant congenital nevi will develop melanoma within the nevi.

Magnetic resonance imaging (MRI) is helpful to exclude NCM. Ideally, an MRI should be ordered before 4 months of age, at which time myelination begins to make the identification of melanin deposits in the CNS more challenging.⁷ Not all patients with imaging findings that are consistent with NCM will develop symptoms.⁸

Melanoma. By age 10, up to 8% of patients with giant congenital nevi will develop melanoma within the nevi; most of these cases occur during the first 2 years of life.^7,9 Patients with NCM are at even greater risk: their rate of malignant melanoma is between 40% and 60%.⁶ As a result, patients should be monitored closely for any signs of the disease. Total body photography, serial clinical photos, and patient self-exam are helpful to detect changes and de novo lesions. New lesions or ulcerations superimposed on existing nevi may indicate malignancy.⁷ Sun protection is critical to reduce the risk of melanogenesis.

Should patients pursue surgery? It’s debatable

For children with congenital nevi and other skin conditions, the American Academy of Dermatology offers summer camps across the country.

Options for patients with large and giant CMN include early curettage (prior to 2 weeks of life), local excision (often with tissue expansion), dermabrasion, and laser therapy.² There is considerable debate about surgery. Advocates of surgery cite psychosocial relief as a major treatment benefit and speculate about prevention of melanoma. Opponents worry that excessive surgical intervention may cause melanogenesis in a scar or deep in an area of treatment. And, while smaller congenital nevi are easier to surgically remove, they have a low associated risk of developing melanoma and are typically monitored clinically.

Children with congenital nevi will need support

Several nonprofit organizations offer resources for children with congenital nevi and their families. Nevus Outreach (www.nevus.org) is an organization devoted to improving awareness and providing support for people with CMN and NCM. The group maintains a registry of patients with large nevi in an effort to help researchers improve treatment and identify a cure.

For children with congenital nevi and other skin conditions, the American Academy of Dermatology offers its “Camp Discovery” at locations across the country (https://www.aad.org/public/kids/camp-discovery). Camp Discovery provides full scholarships and includes transportation to each of the individual camps for attendees.

Our patient underwent an MRI on his fifth day of life. The results were normal and he hadn’t developed any neurologic symptoms at 4 months of age. The child sees his family physician for routine well-child visits and a dermatologist annually. The dermatologist is carefully monitoring the nevi, which continue to grow.

CORRESPONDENCE
Jonathan Karnes, MD, 6 East Chestnut Street, Suite 340, Augusta, ME 04330; jonathan.karnes@mainegeneral.org.

It’s been about 2 years since I had my first e-cigarette discussion with a patient. He was a smoker in his 30s and, since we routinely screen for tobacco use in our practice, I asked him if he was interested in quitting. He said he was cutting down by using e-cigarettes, but had not yet stopped smoking.

According to the 2 articles on e-cigarettes in this issue—one original research study about the prevalence of e-cigarette use in rural Illinois and one review of the safety of e-cigarettes—my experience with this patient is typical of e-cigarette users. Many are “dual users” who turn to e-cigarettes to try to cut down on their tobacco use.

As these 2 articles discuss, we still have a great deal to learn about the potential harms and benefits of e-cigarettes. What chemicals are people taking into their bodies and how dangerous are they? And even if they pose health risks, do e-cigarettes have value as smoking cessation aids if they are less harmful than tobacco?

One could simply take a “just say No” approach, as does my wife who says, “Any chemical you inhale into your lungs can’t be good for you!” Or, one can assume the more moderate lesser-of-two-evils stance of the British health system, which posits that there may be some benefit to e-cigarettes if they help people cut down or stop using tobacco products.

Are e-cigarettes a "gateway" to the use of tobacco and other substances of abuse? Or do they represent an effective way to quit smoking?

In writing this editorial, I conducted a quick literature search that yielded only 5 legitimate randomized trials of e-cigarettes to reduce or eliminate tobacco use, and the results were underwhelming. At best, e-cigarettes appear to be as effective as other forms of nicotine replacement, such as patches, which do not have chemical additives.

Fortunately, researchers are taking e-cigarettes seriously, and research is ongoing. Using the search term “e-cigarette” yielded 2058 references, indicating a respectable amount of e-cigarette research conducted over the past 6 years. Most of the research so far has been about the chemical constituents of the vapor people inhale or about use patterns. There is still a lack of definitive research on whether e-cigarettes are an effective smoking cessation method or a “gateway” to the use of tobacco and other substances of abuse.

Or perhaps they are both.

Hopefully, in 5 years we will know a great deal more, but until we do, I am happy to see that the US Food and Drug Administration has decided to regulate e-cigarettes like tobacco.

It’s been about 2 years since I had my first e-cigarette discussion with a patient. He was a smoker in his 30s and, since we routinely screen for tobacco use in our practice, I asked him if he was interested in quitting. He said he was cutting down by using e-cigarettes, but had not yet stopped smoking.

According to the 2 articles on e-cigarettes in this issue—one original research study about the prevalence of e-cigarette use in rural Illinois and one review of the safety of e-cigarettes—my experience with this patient is typical of e-cigarette users. Many are “dual users” who turn to e-cigarettes to try to cut down on their tobacco use.

As these 2 articles discuss, we still have a great deal to learn about the potential harms and benefits of e-cigarettes. What chemicals are people taking into their bodies and how dangerous are they? And even if they pose health risks, do e-cigarettes have value as smoking cessation aids if they are less harmful than tobacco?

One could simply take a “just say No” approach, as does my wife who says, “Any chemical you inhale into your lungs can’t be good for you!” Or, one can assume the more moderate lesser-of-two-evils stance of the British health system, which posits that there may be some benefit to e-cigarettes if they help people cut down or stop using tobacco products.

Are e-cigarettes a "gateway" to the use of tobacco and other substances of abuse? Or do they represent an effective way to quit smoking?

In writing this editorial, I conducted a quick literature search that yielded only 5 legitimate randomized trials of e-cigarettes to reduce or eliminate tobacco use, and the results were underwhelming. At best, e-cigarettes appear to be as effective as other forms of nicotine replacement, such as patches, which do not have chemical additives.

Fortunately, researchers are taking e-cigarettes seriously, and research is ongoing. Using the search term “e-cigarette” yielded 2058 references, indicating a respectable amount of e-cigarette research conducted over the past 6 years. Most of the research so far has been about the chemical constituents of the vapor people inhale or about use patterns. There is still a lack of definitive research on whether e-cigarettes are an effective smoking cessation method or a “gateway” to the use of tobacco and other substances of abuse.

Or perhaps they are both.

Hopefully, in 5 years we will know a great deal more, but until we do, I am happy to see that the US Food and Drug Administration has decided to regulate e-cigarettes like tobacco.

It’s been about 2 years since I had my first e-cigarette discussion with a patient. He was a smoker in his 30s and, since we routinely screen for tobacco use in our practice, I asked him if he was interested in quitting. He said he was cutting down by using e-cigarettes, but had not yet stopped smoking.

According to the 2 articles on e-cigarettes in this issue—one original research study about the prevalence of e-cigarette use in rural Illinois and one review of the safety of e-cigarettes—my experience with this patient is typical of e-cigarette users. Many are “dual users” who turn to e-cigarettes to try to cut down on their tobacco use.

As these 2 articles discuss, we still have a great deal to learn about the potential harms and benefits of e-cigarettes. What chemicals are people taking into their bodies and how dangerous are they? And even if they pose health risks, do e-cigarettes have value as smoking cessation aids if they are less harmful than tobacco?

One could simply take a “just say No” approach, as does my wife who says, “Any chemical you inhale into your lungs can’t be good for you!” Or, one can assume the more moderate lesser-of-two-evils stance of the British health system, which posits that there may be some benefit to e-cigarettes if they help people cut down or stop using tobacco products.

Are e-cigarettes a "gateway" to the use of tobacco and other substances of abuse? Or do they represent an effective way to quit smoking?

In writing this editorial, I conducted a quick literature search that yielded only 5 legitimate randomized trials of e-cigarettes to reduce or eliminate tobacco use, and the results were underwhelming. At best, e-cigarettes appear to be as effective as other forms of nicotine replacement, such as patches, which do not have chemical additives.

Fortunately, researchers are taking e-cigarettes seriously, and research is ongoing. Using the search term “e-cigarette” yielded 2058 references, indicating a respectable amount of e-cigarette research conducted over the past 6 years. Most of the research so far has been about the chemical constituents of the vapor people inhale or about use patterns. There is still a lack of definitive research on whether e-cigarettes are an effective smoking cessation method or a “gateway” to the use of tobacco and other substances of abuse.

Or perhaps they are both.

Hopefully, in 5 years we will know a great deal more, but until we do, I am happy to see that the US Food and Drug Administration has decided to regulate e-cigarettes like tobacco.