Adults with irritable bowel syndrome (IBS) who underwent psychotherapy improved more than about 75% of controls, and the effect “remained significant and medium in magnitude” for at least 6-12 months, according to a meta-analysis of 41 randomized, controlled trials reported in the July issue of Clinical Gastroenterology and Hepatology.

The finding “is particularly noteworthy because of the typically recurrent, persistent nature of IBS symptoms,” said Kelsey Laird, a doctoral student of clinical psychology at Vanderbilt University in Nashville, Tenn., together with her associates there. “Future research is needed to compare the longevity of treatment effects for psychotherapy with pharmacologic therapies, such as antidepressants,” they added. “Although it is beyond the scope of this review, it is also important to consider the mechanisms by which psychotherapies improve GI symptoms and to determine the ‘active ingredients’ responsible for this effect.”

©MacXever/Thinkstock

Up to 16% of individuals in the United States have IBS, and treating it costs anywhere from $950 million to $1.35 billion per year, the researchers noted. Other meta-analyses found psychotherapy about as effective as antidepressants for treating IBS-related GI symptoms over the short term, but its long-term efficacy was unknown, they added. Therefore, they searched PubMed, PsycINFO, Science Direct, and ProQuest through Aug. 15, 2015, identifying randomized controlled trials of psychological therapy and active or nonactive comparators. Psychotherapy included not only traditional psychodynamic and cognitive-behavioral therapies, but also mind-body approaches, such as relaxation training, biofeedback, and yoga, “which can be conceptualized as mindful movement,” Ms. Laird and her associates said. Comparators included support groups, education, sham treatments for hypnosis or biofeedback, online discussion forums, enhanced medical care, treatment as usual, symptom monitoring, and being wait-listed for psychological treatment (Clin Gastroenterol Hepatol. 2016 Jan 21. doi: 10.1016/j.cgh.2015.11.020). The 41 trials included 2,290 patients, comprising 1,183 assigned to the psychological modalities and 1,107 assigned to the various comparators. Taken together, the psychological modalities were associated with greater improvements in GI symptoms immediately after treatment, as compared with the grouped comparators. The Cohen’s d value was 0.69 (95% confidence interval, 0.52-0.86; P less than .001), indicating a medium effect size, the researchers said. Moreover, Cohen’s d values were 0.76 and 0.73, respectively, at short-term follow-up (1-6 months) and long-term follow-up (6-12 months). “On average, individuals who received psychotherapy had a greater reduction in GI symptoms after treatment than 75% of individuals assigned to a control condition,” the researchers concluded.

Effect sizes were similar among cognitive, cognitive-behavioral, and relaxation and hypnosis interventions, and between interventions delivered online and in person, the investigators also reported. Furthermore, longer durations or sessions of psychotherapy did not appear to further improve symptoms.

Study limitations included substantial variability between trials, and the fact that none of the 41 trials could be seen as having a low risk of bias in every domain assessed, the investigators said. “This was partially a result of the difficulty in blinding participants in psychological trials,” they noted. “However, even after excluding this domain, only nine trials were rated as low risk of bias in all remaining domains. Future studies should follow the CONSORT guidelines for [randomized controlled trials], use [intention-to-treat] designs, use active control conditions to control for nonspecific treatment effects, and assess treatment credibility and expectancy.”

The authors reported no funding sources and had no disclosures.

Adults with irritable bowel syndrome (IBS) who underwent psychotherapy improved more than about 75% of controls, and the effect “remained significant and medium in magnitude” for at least 6-12 months, according to a meta-analysis of 41 randomized, controlled trials reported in the July issue of Clinical Gastroenterology and Hepatology.

The finding “is particularly noteworthy because of the typically recurrent, persistent nature of IBS symptoms,” said Kelsey Laird, a doctoral student of clinical psychology at Vanderbilt University in Nashville, Tenn., together with her associates there. “Future research is needed to compare the longevity of treatment effects for psychotherapy with pharmacologic therapies, such as antidepressants,” they added. “Although it is beyond the scope of this review, it is also important to consider the mechanisms by which psychotherapies improve GI symptoms and to determine the ‘active ingredients’ responsible for this effect.”

©MacXever/Thinkstock

Up to 16% of individuals in the United States have IBS, and treating it costs anywhere from $950 million to $1.35 billion per year, the researchers noted. Other meta-analyses found psychotherapy about as effective as antidepressants for treating IBS-related GI symptoms over the short term, but its long-term efficacy was unknown, they added. Therefore, they searched PubMed, PsycINFO, Science Direct, and ProQuest through Aug. 15, 2015, identifying randomized controlled trials of psychological therapy and active or nonactive comparators. Psychotherapy included not only traditional psychodynamic and cognitive-behavioral therapies, but also mind-body approaches, such as relaxation training, biofeedback, and yoga, “which can be conceptualized as mindful movement,” Ms. Laird and her associates said. Comparators included support groups, education, sham treatments for hypnosis or biofeedback, online discussion forums, enhanced medical care, treatment as usual, symptom monitoring, and being wait-listed for psychological treatment (Clin Gastroenterol Hepatol. 2016 Jan 21. doi: 10.1016/j.cgh.2015.11.020). The 41 trials included 2,290 patients, comprising 1,183 assigned to the psychological modalities and 1,107 assigned to the various comparators. Taken together, the psychological modalities were associated with greater improvements in GI symptoms immediately after treatment, as compared with the grouped comparators. The Cohen’s d value was 0.69 (95% confidence interval, 0.52-0.86; P less than .001), indicating a medium effect size, the researchers said. Moreover, Cohen’s d values were 0.76 and 0.73, respectively, at short-term follow-up (1-6 months) and long-term follow-up (6-12 months). “On average, individuals who received psychotherapy had a greater reduction in GI symptoms after treatment than 75% of individuals assigned to a control condition,” the researchers concluded.

Effect sizes were similar among cognitive, cognitive-behavioral, and relaxation and hypnosis interventions, and between interventions delivered online and in person, the investigators also reported. Furthermore, longer durations or sessions of psychotherapy did not appear to further improve symptoms.

Study limitations included substantial variability between trials, and the fact that none of the 41 trials could be seen as having a low risk of bias in every domain assessed, the investigators said. “This was partially a result of the difficulty in blinding participants in psychological trials,” they noted. “However, even after excluding this domain, only nine trials were rated as low risk of bias in all remaining domains. Future studies should follow the CONSORT guidelines for [randomized controlled trials], use [intention-to-treat] designs, use active control conditions to control for nonspecific treatment effects, and assess treatment credibility and expectancy.”

The authors reported no funding sources and had no disclosures.

Adults with irritable bowel syndrome (IBS) who underwent psychotherapy improved more than about 75% of controls, and the effect “remained significant and medium in magnitude” for at least 6-12 months, according to a meta-analysis of 41 randomized, controlled trials reported in the July issue of Clinical Gastroenterology and Hepatology.

The finding “is particularly noteworthy because of the typically recurrent, persistent nature of IBS symptoms,” said Kelsey Laird, a doctoral student of clinical psychology at Vanderbilt University in Nashville, Tenn., together with her associates there. “Future research is needed to compare the longevity of treatment effects for psychotherapy with pharmacologic therapies, such as antidepressants,” they added. “Although it is beyond the scope of this review, it is also important to consider the mechanisms by which psychotherapies improve GI symptoms and to determine the ‘active ingredients’ responsible for this effect.”

©MacXever/Thinkstock

Up to 16% of individuals in the United States have IBS, and treating it costs anywhere from $950 million to $1.35 billion per year, the researchers noted. Other meta-analyses found psychotherapy about as effective as antidepressants for treating IBS-related GI symptoms over the short term, but its long-term efficacy was unknown, they added. Therefore, they searched PubMed, PsycINFO, Science Direct, and ProQuest through Aug. 15, 2015, identifying randomized controlled trials of psychological therapy and active or nonactive comparators. Psychotherapy included not only traditional psychodynamic and cognitive-behavioral therapies, but also mind-body approaches, such as relaxation training, biofeedback, and yoga, “which can be conceptualized as mindful movement,” Ms. Laird and her associates said. Comparators included support groups, education, sham treatments for hypnosis or biofeedback, online discussion forums, enhanced medical care, treatment as usual, symptom monitoring, and being wait-listed for psychological treatment (Clin Gastroenterol Hepatol. 2016 Jan 21. doi: 10.1016/j.cgh.2015.11.020). The 41 trials included 2,290 patients, comprising 1,183 assigned to the psychological modalities and 1,107 assigned to the various comparators. Taken together, the psychological modalities were associated with greater improvements in GI symptoms immediately after treatment, as compared with the grouped comparators. The Cohen’s d value was 0.69 (95% confidence interval, 0.52-0.86; P less than .001), indicating a medium effect size, the researchers said. Moreover, Cohen’s d values were 0.76 and 0.73, respectively, at short-term follow-up (1-6 months) and long-term follow-up (6-12 months). “On average, individuals who received psychotherapy had a greater reduction in GI symptoms after treatment than 75% of individuals assigned to a control condition,” the researchers concluded.

Effect sizes were similar among cognitive, cognitive-behavioral, and relaxation and hypnosis interventions, and between interventions delivered online and in person, the investigators also reported. Furthermore, longer durations or sessions of psychotherapy did not appear to further improve symptoms.

Study limitations included substantial variability between trials, and the fact that none of the 41 trials could be seen as having a low risk of bias in every domain assessed, the investigators said. “This was partially a result of the difficulty in blinding participants in psychological trials,” they noted. “However, even after excluding this domain, only nine trials were rated as low risk of bias in all remaining domains. Future studies should follow the CONSORT guidelines for [randomized controlled trials], use [intention-to-treat] designs, use active control conditions to control for nonspecific treatment effects, and assess treatment credibility and expectancy.”

The authors reported no funding sources and had no disclosures.

Integrins that bind arginine-glycine-aspartic acid (RGD) activated stellate cells in the pancreas, inducing pancreatic fibrogenesis in mice, researchers reported in the July issue of Cellular and Molecular Gastroenterology and Hepatology.

“Small-molecule antagonists of this interaction might be developed for the treatment of pancreatic fibrotic diseases,” wrote Dr. Barbara Ulmasov and her associates at Saint Louis University.

Cytokine transforming growth factor beta, or TGFB, plays a “central” role in the activation of pancreatic stellate cells and the promotion of fibrogenesis, both in the pancreas and in other organs, the investigators noted. Because latent TGFB is “abundantly present” in the pancreas and most other tissues, it might be more important to control the activation of TGFB than its expression, they added. Studies of other organs have shown that TGFB is activated when integrins of the av family bind the RGD sequence, but no one had determined whether this was true for pancreatic fibrogenesis, Dr. Ulmasov and her associates asserted (Cell Mol Gastroenterol Hepatol. 2016 Mar 16. doi: 10.1016/j.jcmgh.2016.03.004).

Therefore, they repeatedly injected female C57BL/6 mice with cerulein to induce pancreatic fibrogenesis, and gave a group of control mice sterile saline instead. The mice then received continuous infusions of a small molecule called CWHM-12, which is an antagonist of RGD-integrin that is known to prevent both pulmonary and hepatic fibrosis in mice. After euthanizing the mice, the researchers measured pancreatic parenchymal atrophy, fibrosis, and activation of pancreatic stellate cells. They also studied TGFB activation in an established line of pancreatic stellate cells from rats.

Pancreatic stellate cells expressed messenger RNAs encoding RGD-binding integrins, the investigators found. The mice that received cerulein had higher levels of these integrins than the mice that received saline, and the cerulein group also had more disrupted acinar cell architecture, tubular complexes, and infiltrations of inflammatory cells. Mice that received prophylactic CWHM-12 had only somewhat less acinar cell loss and atrophy than the control mice, and had similar levels of inflammatory cell infiltration, but had “dramatically” lower levels of pancreatic fibrosis, the researchers said. Even if mice received CWHM-12 several days after starting cerulein, they still had less fibrosis and activation of TGFB than if they received saline, they noted.

The established line of pancreatic stellate cells “could robustly activate endogenously produced TGFB,” the investigators also reported. Furthermore, CWHM-12 “potently blocked TGFB activation,” unlike the control compound. Taken together, the findings illustrate the “critical role of RGD-binding integrins in chronic pancreatitis, and the promising potential to arrest or possibly even reverse pancreatic fibrosis using a pharmacologic approach to inhibiting integrin-mediated TGFB activation,” the researchers concluded.

The National Pancreas Foundation and the Frank R. Burton Memorial Fund supported the study. Dr. Ulmasov had no disclosures. Three coinvestigators reported being consultants and/or holding equity in Integrin Therapeutics, Nimbus Therapeutics, Bristol-Myers Squibb, Janssen, Mitsubishi Tanabe, Conatus, and Scholar Rock.

Integrins that bind arginine-glycine-aspartic acid (RGD) activated stellate cells in the pancreas, inducing pancreatic fibrogenesis in mice, researchers reported in the July issue of Cellular and Molecular Gastroenterology and Hepatology.

“Small-molecule antagonists of this interaction might be developed for the treatment of pancreatic fibrotic diseases,” wrote Dr. Barbara Ulmasov and her associates at Saint Louis University.

Cytokine transforming growth factor beta, or TGFB, plays a “central” role in the activation of pancreatic stellate cells and the promotion of fibrogenesis, both in the pancreas and in other organs, the investigators noted. Because latent TGFB is “abundantly present” in the pancreas and most other tissues, it might be more important to control the activation of TGFB than its expression, they added. Studies of other organs have shown that TGFB is activated when integrins of the av family bind the RGD sequence, but no one had determined whether this was true for pancreatic fibrogenesis, Dr. Ulmasov and her associates asserted (Cell Mol Gastroenterol Hepatol. 2016 Mar 16. doi: 10.1016/j.jcmgh.2016.03.004).

Therefore, they repeatedly injected female C57BL/6 mice with cerulein to induce pancreatic fibrogenesis, and gave a group of control mice sterile saline instead. The mice then received continuous infusions of a small molecule called CWHM-12, which is an antagonist of RGD-integrin that is known to prevent both pulmonary and hepatic fibrosis in mice. After euthanizing the mice, the researchers measured pancreatic parenchymal atrophy, fibrosis, and activation of pancreatic stellate cells. They also studied TGFB activation in an established line of pancreatic stellate cells from rats.

Pancreatic stellate cells expressed messenger RNAs encoding RGD-binding integrins, the investigators found. The mice that received cerulein had higher levels of these integrins than the mice that received saline, and the cerulein group also had more disrupted acinar cell architecture, tubular complexes, and infiltrations of inflammatory cells. Mice that received prophylactic CWHM-12 had only somewhat less acinar cell loss and atrophy than the control mice, and had similar levels of inflammatory cell infiltration, but had “dramatically” lower levels of pancreatic fibrosis, the researchers said. Even if mice received CWHM-12 several days after starting cerulein, they still had less fibrosis and activation of TGFB than if they received saline, they noted.

The established line of pancreatic stellate cells “could robustly activate endogenously produced TGFB,” the investigators also reported. Furthermore, CWHM-12 “potently blocked TGFB activation,” unlike the control compound. Taken together, the findings illustrate the “critical role of RGD-binding integrins in chronic pancreatitis, and the promising potential to arrest or possibly even reverse pancreatic fibrosis using a pharmacologic approach to inhibiting integrin-mediated TGFB activation,” the researchers concluded.

The National Pancreas Foundation and the Frank R. Burton Memorial Fund supported the study. Dr. Ulmasov had no disclosures. Three coinvestigators reported being consultants and/or holding equity in Integrin Therapeutics, Nimbus Therapeutics, Bristol-Myers Squibb, Janssen, Mitsubishi Tanabe, Conatus, and Scholar Rock.

Integrins that bind arginine-glycine-aspartic acid (RGD) activated stellate cells in the pancreas, inducing pancreatic fibrogenesis in mice, researchers reported in the July issue of Cellular and Molecular Gastroenterology and Hepatology.

“Small-molecule antagonists of this interaction might be developed for the treatment of pancreatic fibrotic diseases,” wrote Dr. Barbara Ulmasov and her associates at Saint Louis University.

Cytokine transforming growth factor beta, or TGFB, plays a “central” role in the activation of pancreatic stellate cells and the promotion of fibrogenesis, both in the pancreas and in other organs, the investigators noted. Because latent TGFB is “abundantly present” in the pancreas and most other tissues, it might be more important to control the activation of TGFB than its expression, they added. Studies of other organs have shown that TGFB is activated when integrins of the av family bind the RGD sequence, but no one had determined whether this was true for pancreatic fibrogenesis, Dr. Ulmasov and her associates asserted (Cell Mol Gastroenterol Hepatol. 2016 Mar 16. doi: 10.1016/j.jcmgh.2016.03.004).

Therefore, they repeatedly injected female C57BL/6 mice with cerulein to induce pancreatic fibrogenesis, and gave a group of control mice sterile saline instead. The mice then received continuous infusions of a small molecule called CWHM-12, which is an antagonist of RGD-integrin that is known to prevent both pulmonary and hepatic fibrosis in mice. After euthanizing the mice, the researchers measured pancreatic parenchymal atrophy, fibrosis, and activation of pancreatic stellate cells. They also studied TGFB activation in an established line of pancreatic stellate cells from rats.

Pancreatic stellate cells expressed messenger RNAs encoding RGD-binding integrins, the investigators found. The mice that received cerulein had higher levels of these integrins than the mice that received saline, and the cerulein group also had more disrupted acinar cell architecture, tubular complexes, and infiltrations of inflammatory cells. Mice that received prophylactic CWHM-12 had only somewhat less acinar cell loss and atrophy than the control mice, and had similar levels of inflammatory cell infiltration, but had “dramatically” lower levels of pancreatic fibrosis, the researchers said. Even if mice received CWHM-12 several days after starting cerulein, they still had less fibrosis and activation of TGFB than if they received saline, they noted.

The established line of pancreatic stellate cells “could robustly activate endogenously produced TGFB,” the investigators also reported. Furthermore, CWHM-12 “potently blocked TGFB activation,” unlike the control compound. Taken together, the findings illustrate the “critical role of RGD-binding integrins in chronic pancreatitis, and the promising potential to arrest or possibly even reverse pancreatic fibrosis using a pharmacologic approach to inhibiting integrin-mediated TGFB activation,” the researchers concluded.

The National Pancreas Foundation and the Frank R. Burton Memorial Fund supported the study. Dr. Ulmasov had no disclosures. Three coinvestigators reported being consultants and/or holding equity in Integrin Therapeutics, Nimbus Therapeutics, Bristol-Myers Squibb, Janssen, Mitsubishi Tanabe, Conatus, and Scholar Rock.

Among patients with hepatitis C virus infection who were in compensated cirrhosis, sustained viral response was associated with significantly lower rates of liver decompensation, hepatocellular carcinoma, and liver-related death, even in the presence of clinically meaningful portal hypertension.

But patients in stage 2 cirrhosis were more likely than were stage 1 patients to develop liver decompensation and to die of hepatocellular carcinoma, regardless of SVR, said Dr. Vito Di Marco and his associates at the University of Palermo, Italy. “The available evidence, including our own, suggests that it is opportune to treat HCV as early as possible, in order to reduce progression to stages of cirrhosis in which a viral cure may be less likely lead to ultimate achievement of a major benefit,” they wrote. The report is in the July issue of Gastroenterology.

Clinically significant portal hypertension causes esophageal varices, a “landmark” indicator of stage 2 cirrhosis, the researchers noted. To parse the effects of SVR by cirrhosis stage, they followed all 444 HCV patients with compensated cirrhosis who were treated with pegylated interferon a2b and ribavirin at their tertiary liver centers between 2001 and 2009 (Gastroenterology 2016 March 31. doi: 10.1053/j.gastro.2016.03.036).

The cohort included 218 patients without esophageal varices (that is, patients in stage 1 cirrhosis) and 226 patients with esophageal varices (stage 2 cirrhosis), the researchers said. The groups were demographically similar at baseline, and had similar body mass indices and rates of comorbidities. Rates of SVR were 31% for patients in stage 1 cirrhosis and 18% for patients in stage 2 cirrhosis (P = .003).

Among stage 1 patients, achieving SVR was associated with a lower risk of liver decompensation (0% versus 7%; P = .009), a lower annual rate of hepatocellular carcinoma (0.7% versus 2.9%; P = .002), and a lower risk of liver-related death (3% versus 12%; P = .03). Stage 1 cirrhosis patients also were about 75% less likely to develop esophageal varices if they achieved SVR than if they did not (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.11 to 0.48; P less than .001).

Eradicating HCV infection also was associated with better clinical outcomes among patients in stage 2 cirrhosis, according to the investigators. For example, those who achieved SVR had a 0.9% annual rate of hepatocellular carcinoma, compared with 3.6% for those who did not (P = .002). And only 2% of stage 2 patients who achieved SVR died from hepatocellular carcinoma, compared to 18% of those who did not (P = .003).

But regardless of SVR, patients with stage 2 cirrhosis were nearly three times more likely to develop liver compensation (HR, 2.8; 95% CI, 1.73 to 4.59) and about 1.75 times more likely to die of liver-related causes (HR, 1.77; 95% CI, 1.12 to 2.80) compared with patients in stage 1 cirrhosis, the investigators emphasized. Also, achieving SVR did not prevent stage 2 patients from developing more esophageal varices (HR, 1.58; 95% CI, 0.33 to 1.03).

The researchers acknowledged several study limitations. “We have performed many comparisons with respect to multiple endpoints, which could have increased the likelihood of inference errors that can result from multiple comparisons,” they wrote. “Furthermore, we cannot exclude the lack of power as an explanation for some of our results.” In addition, pegylated interferon–based therapies have low rates of SVR, and the study was limited to patients who could tolerate the regimen, they added. Nonetheless, the results indicate that eradicating HCV is clinically beneficial even in advanced compensated cirrhosis, but that early treatment helps maximize these outcomes, they concluded. “Pegylated interferon–free direct-acting antiviral combo regimens will ultimately increase the rate of virological cure to almost universal effectiveness,” they added. “It remains to be assessed whether the effectiveness of these new regimens will be automatically translated into a universal clinical benefit.”

The Italian Ministry of Health funded the study. The investigators had no disclosures.

Among patients with hepatitis C virus infection who were in compensated cirrhosis, sustained viral response was associated with significantly lower rates of liver decompensation, hepatocellular carcinoma, and liver-related death, even in the presence of clinically meaningful portal hypertension.

But patients in stage 2 cirrhosis were more likely than were stage 1 patients to develop liver decompensation and to die of hepatocellular carcinoma, regardless of SVR, said Dr. Vito Di Marco and his associates at the University of Palermo, Italy. “The available evidence, including our own, suggests that it is opportune to treat HCV as early as possible, in order to reduce progression to stages of cirrhosis in which a viral cure may be less likely lead to ultimate achievement of a major benefit,” they wrote. The report is in the July issue of Gastroenterology.

Clinically significant portal hypertension causes esophageal varices, a “landmark” indicator of stage 2 cirrhosis, the researchers noted. To parse the effects of SVR by cirrhosis stage, they followed all 444 HCV patients with compensated cirrhosis who were treated with pegylated interferon a2b and ribavirin at their tertiary liver centers between 2001 and 2009 (Gastroenterology 2016 March 31. doi: 10.1053/j.gastro.2016.03.036).

The cohort included 218 patients without esophageal varices (that is, patients in stage 1 cirrhosis) and 226 patients with esophageal varices (stage 2 cirrhosis), the researchers said. The groups were demographically similar at baseline, and had similar body mass indices and rates of comorbidities. Rates of SVR were 31% for patients in stage 1 cirrhosis and 18% for patients in stage 2 cirrhosis (P = .003).

Among stage 1 patients, achieving SVR was associated with a lower risk of liver decompensation (0% versus 7%; P = .009), a lower annual rate of hepatocellular carcinoma (0.7% versus 2.9%; P = .002), and a lower risk of liver-related death (3% versus 12%; P = .03). Stage 1 cirrhosis patients also were about 75% less likely to develop esophageal varices if they achieved SVR than if they did not (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.11 to 0.48; P less than .001).

Eradicating HCV infection also was associated with better clinical outcomes among patients in stage 2 cirrhosis, according to the investigators. For example, those who achieved SVR had a 0.9% annual rate of hepatocellular carcinoma, compared with 3.6% for those who did not (P = .002). And only 2% of stage 2 patients who achieved SVR died from hepatocellular carcinoma, compared to 18% of those who did not (P = .003).

But regardless of SVR, patients with stage 2 cirrhosis were nearly three times more likely to develop liver compensation (HR, 2.8; 95% CI, 1.73 to 4.59) and about 1.75 times more likely to die of liver-related causes (HR, 1.77; 95% CI, 1.12 to 2.80) compared with patients in stage 1 cirrhosis, the investigators emphasized. Also, achieving SVR did not prevent stage 2 patients from developing more esophageal varices (HR, 1.58; 95% CI, 0.33 to 1.03).

The researchers acknowledged several study limitations. “We have performed many comparisons with respect to multiple endpoints, which could have increased the likelihood of inference errors that can result from multiple comparisons,” they wrote. “Furthermore, we cannot exclude the lack of power as an explanation for some of our results.” In addition, pegylated interferon–based therapies have low rates of SVR, and the study was limited to patients who could tolerate the regimen, they added. Nonetheless, the results indicate that eradicating HCV is clinically beneficial even in advanced compensated cirrhosis, but that early treatment helps maximize these outcomes, they concluded. “Pegylated interferon–free direct-acting antiviral combo regimens will ultimately increase the rate of virological cure to almost universal effectiveness,” they added. “It remains to be assessed whether the effectiveness of these new regimens will be automatically translated into a universal clinical benefit.”

The Italian Ministry of Health funded the study. The investigators had no disclosures.

Among patients with hepatitis C virus infection who were in compensated cirrhosis, sustained viral response was associated with significantly lower rates of liver decompensation, hepatocellular carcinoma, and liver-related death, even in the presence of clinically meaningful portal hypertension.

But patients in stage 2 cirrhosis were more likely than were stage 1 patients to develop liver decompensation and to die of hepatocellular carcinoma, regardless of SVR, said Dr. Vito Di Marco and his associates at the University of Palermo, Italy. “The available evidence, including our own, suggests that it is opportune to treat HCV as early as possible, in order to reduce progression to stages of cirrhosis in which a viral cure may be less likely lead to ultimate achievement of a major benefit,” they wrote. The report is in the July issue of Gastroenterology.

Clinically significant portal hypertension causes esophageal varices, a “landmark” indicator of stage 2 cirrhosis, the researchers noted. To parse the effects of SVR by cirrhosis stage, they followed all 444 HCV patients with compensated cirrhosis who were treated with pegylated interferon a2b and ribavirin at their tertiary liver centers between 2001 and 2009 (Gastroenterology 2016 March 31. doi: 10.1053/j.gastro.2016.03.036).

The cohort included 218 patients without esophageal varices (that is, patients in stage 1 cirrhosis) and 226 patients with esophageal varices (stage 2 cirrhosis), the researchers said. The groups were demographically similar at baseline, and had similar body mass indices and rates of comorbidities. Rates of SVR were 31% for patients in stage 1 cirrhosis and 18% for patients in stage 2 cirrhosis (P = .003).

Among stage 1 patients, achieving SVR was associated with a lower risk of liver decompensation (0% versus 7%; P = .009), a lower annual rate of hepatocellular carcinoma (0.7% versus 2.9%; P = .002), and a lower risk of liver-related death (3% versus 12%; P = .03). Stage 1 cirrhosis patients also were about 75% less likely to develop esophageal varices if they achieved SVR than if they did not (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.11 to 0.48; P less than .001).

Eradicating HCV infection also was associated with better clinical outcomes among patients in stage 2 cirrhosis, according to the investigators. For example, those who achieved SVR had a 0.9% annual rate of hepatocellular carcinoma, compared with 3.6% for those who did not (P = .002). And only 2% of stage 2 patients who achieved SVR died from hepatocellular carcinoma, compared to 18% of those who did not (P = .003).

But regardless of SVR, patients with stage 2 cirrhosis were nearly three times more likely to develop liver compensation (HR, 2.8; 95% CI, 1.73 to 4.59) and about 1.75 times more likely to die of liver-related causes (HR, 1.77; 95% CI, 1.12 to 2.80) compared with patients in stage 1 cirrhosis, the investigators emphasized. Also, achieving SVR did not prevent stage 2 patients from developing more esophageal varices (HR, 1.58; 95% CI, 0.33 to 1.03).

The researchers acknowledged several study limitations. “We have performed many comparisons with respect to multiple endpoints, which could have increased the likelihood of inference errors that can result from multiple comparisons,” they wrote. “Furthermore, we cannot exclude the lack of power as an explanation for some of our results.” In addition, pegylated interferon–based therapies have low rates of SVR, and the study was limited to patients who could tolerate the regimen, they added. Nonetheless, the results indicate that eradicating HCV is clinically beneficial even in advanced compensated cirrhosis, but that early treatment helps maximize these outcomes, they concluded. “Pegylated interferon–free direct-acting antiviral combo regimens will ultimately increase the rate of virological cure to almost universal effectiveness,” they added. “It remains to be assessed whether the effectiveness of these new regimens will be automatically translated into a universal clinical benefit.”

The Italian Ministry of Health funded the study. The investigators had no disclosures.

Among patients with immune-mediated diseases and a history of malignancy, cancer recurrence rates were similar regardless of whether they received tumor necrosis factor inhibitors, traditional immunosuppressants, or no immunosuppression, according to a meta-analysis of 16 cohort and case-control studies.

“However, there is a need for larger studies to prospectively monitor for cancer recurrence and new malignancies in this population to better inform our practice,” wrote Dr. Edward Shelton of Massachusetts General Hospital in Boston, and his associates. The report is in the July issue of Gastroenterology.

Patients with immune-mediated diseases often have a history of malignancy, raising questions about the effects of therapies that target the immune system, the researchers noted. However, relevant studies have been “small with few events, preventing robust estimates of risk,” they said. They searched Medline, Embase, and conference proceedings through April 2015 for studies of the risk of primary or recurrent cancer among patients with a history of malignancy who were exposed to thiopurines, methotrexate, or anti-TNF agents, or no immunosuppression. Among the 16 studies meeting these criteria, seven included patients with rheumatoid arthritis, seven included patients with inflammatory bowel disease, one included both diseases, and one included patients with psoriasis. Twelve were cohort studies, one was a case-control study, and three were case series. The resulting meta-analysis comprised 11,702 patients who contributed a total of 31,258 person-years of follow-up (Gastroenterology 2016 May 13. doi: 10.1053/j.gastro.2016.03.037).

Rates of cancer recurrence were statistically similar among patients who received no immunosuppression, anti-TNF therapy, traditional immune modulators, or combination regimens (P greater than .1 for differences among groups). Numerically, however, the risk of recurrent cancer was highest with combination immunotherapy (54.5 cases per 1,000 person-years of follow-up), compared with 37.5 cases per 1,000 person-years for patients who did not receive immunosuppressive treatment, 36.2 cases per 1,000 person-years for patients who received traditional immunomodulator monotherapy, and 33.8 cases per 1,000 person-years for patients who received anti-TNF agents. Analyses of subgroups of patients with new or recurrent cancers, or various types of therapies, and of specific immune-mediated diseases yielded “similar results, with no increase in risk,” said the researchers. Furthermore, rates of cancer recurrence did not statistically differ depending on whether patients started immunosuppression less than or more than 6 years after their index cancer (P = .43).

“Treatment decisions after a cancer diagnosis are complex, and must take into account the natural history of cancer, histologic type and stage, time from diagnosis, and course of underlying chronic inflammatory disease,” the researchers noted. “Our findings suggest that anti-TNF therapy, conventional immunosuppressant therapy, or combination immunosuppression are not associated with an increased risk of cancer recurrence in this population.”

The researchers cited several limitations. Notably, three of the studies included only 20 patients, and the studies included variable index cancers and methods for detecting recurrent cancers. “It also is possible, and likely, that patients who were at high risk for recurrence were not recommenced on immunosuppression, and consequently our findings may be more applicable to a population in which the patient and physicians were comfortable with re-initiation of therapy,” they said.

The National Institutes of Health supported several of the study investigators. Dr. Shelton had no disclosures. Five coinvestigators disclosed relationships with a number of pharmaceutical companies.

Among patients with immune-mediated diseases and a history of malignancy, cancer recurrence rates were similar regardless of whether they received tumor necrosis factor inhibitors, traditional immunosuppressants, or no immunosuppression, according to a meta-analysis of 16 cohort and case-control studies.

“However, there is a need for larger studies to prospectively monitor for cancer recurrence and new malignancies in this population to better inform our practice,” wrote Dr. Edward Shelton of Massachusetts General Hospital in Boston, and his associates. The report is in the July issue of Gastroenterology.

Patients with immune-mediated diseases often have a history of malignancy, raising questions about the effects of therapies that target the immune system, the researchers noted. However, relevant studies have been “small with few events, preventing robust estimates of risk,” they said. They searched Medline, Embase, and conference proceedings through April 2015 for studies of the risk of primary or recurrent cancer among patients with a history of malignancy who were exposed to thiopurines, methotrexate, or anti-TNF agents, or no immunosuppression. Among the 16 studies meeting these criteria, seven included patients with rheumatoid arthritis, seven included patients with inflammatory bowel disease, one included both diseases, and one included patients with psoriasis. Twelve were cohort studies, one was a case-control study, and three were case series. The resulting meta-analysis comprised 11,702 patients who contributed a total of 31,258 person-years of follow-up (Gastroenterology 2016 May 13. doi: 10.1053/j.gastro.2016.03.037).

Rates of cancer recurrence were statistically similar among patients who received no immunosuppression, anti-TNF therapy, traditional immune modulators, or combination regimens (P greater than .1 for differences among groups). Numerically, however, the risk of recurrent cancer was highest with combination immunotherapy (54.5 cases per 1,000 person-years of follow-up), compared with 37.5 cases per 1,000 person-years for patients who did not receive immunosuppressive treatment, 36.2 cases per 1,000 person-years for patients who received traditional immunomodulator monotherapy, and 33.8 cases per 1,000 person-years for patients who received anti-TNF agents. Analyses of subgroups of patients with new or recurrent cancers, or various types of therapies, and of specific immune-mediated diseases yielded “similar results, with no increase in risk,” said the researchers. Furthermore, rates of cancer recurrence did not statistically differ depending on whether patients started immunosuppression less than or more than 6 years after their index cancer (P = .43).

“Treatment decisions after a cancer diagnosis are complex, and must take into account the natural history of cancer, histologic type and stage, time from diagnosis, and course of underlying chronic inflammatory disease,” the researchers noted. “Our findings suggest that anti-TNF therapy, conventional immunosuppressant therapy, or combination immunosuppression are not associated with an increased risk of cancer recurrence in this population.”

The researchers cited several limitations. Notably, three of the studies included only 20 patients, and the studies included variable index cancers and methods for detecting recurrent cancers. “It also is possible, and likely, that patients who were at high risk for recurrence were not recommenced on immunosuppression, and consequently our findings may be more applicable to a population in which the patient and physicians were comfortable with re-initiation of therapy,” they said.

The National Institutes of Health supported several of the study investigators. Dr. Shelton had no disclosures. Five coinvestigators disclosed relationships with a number of pharmaceutical companies.

Among patients with immune-mediated diseases and a history of malignancy, cancer recurrence rates were similar regardless of whether they received tumor necrosis factor inhibitors, traditional immunosuppressants, or no immunosuppression, according to a meta-analysis of 16 cohort and case-control studies.

“However, there is a need for larger studies to prospectively monitor for cancer recurrence and new malignancies in this population to better inform our practice,” wrote Dr. Edward Shelton of Massachusetts General Hospital in Boston, and his associates. The report is in the July issue of Gastroenterology.

Patients with immune-mediated diseases often have a history of malignancy, raising questions about the effects of therapies that target the immune system, the researchers noted. However, relevant studies have been “small with few events, preventing robust estimates of risk,” they said. They searched Medline, Embase, and conference proceedings through April 2015 for studies of the risk of primary or recurrent cancer among patients with a history of malignancy who were exposed to thiopurines, methotrexate, or anti-TNF agents, or no immunosuppression. Among the 16 studies meeting these criteria, seven included patients with rheumatoid arthritis, seven included patients with inflammatory bowel disease, one included both diseases, and one included patients with psoriasis. Twelve were cohort studies, one was a case-control study, and three were case series. The resulting meta-analysis comprised 11,702 patients who contributed a total of 31,258 person-years of follow-up (Gastroenterology 2016 May 13. doi: 10.1053/j.gastro.2016.03.037).

Rates of cancer recurrence were statistically similar among patients who received no immunosuppression, anti-TNF therapy, traditional immune modulators, or combination regimens (P greater than .1 for differences among groups). Numerically, however, the risk of recurrent cancer was highest with combination immunotherapy (54.5 cases per 1,000 person-years of follow-up), compared with 37.5 cases per 1,000 person-years for patients who did not receive immunosuppressive treatment, 36.2 cases per 1,000 person-years for patients who received traditional immunomodulator monotherapy, and 33.8 cases per 1,000 person-years for patients who received anti-TNF agents. Analyses of subgroups of patients with new or recurrent cancers, or various types of therapies, and of specific immune-mediated diseases yielded “similar results, with no increase in risk,” said the researchers. Furthermore, rates of cancer recurrence did not statistically differ depending on whether patients started immunosuppression less than or more than 6 years after their index cancer (P = .43).

“Treatment decisions after a cancer diagnosis are complex, and must take into account the natural history of cancer, histologic type and stage, time from diagnosis, and course of underlying chronic inflammatory disease,” the researchers noted. “Our findings suggest that anti-TNF therapy, conventional immunosuppressant therapy, or combination immunosuppression are not associated with an increased risk of cancer recurrence in this population.”

The researchers cited several limitations. Notably, three of the studies included only 20 patients, and the studies included variable index cancers and methods for detecting recurrent cancers. “It also is possible, and likely, that patients who were at high risk for recurrence were not recommenced on immunosuppression, and consequently our findings may be more applicable to a population in which the patient and physicians were comfortable with re-initiation of therapy,” they said.

The National Institutes of Health supported several of the study investigators. Dr. Shelton had no disclosures. Five coinvestigators disclosed relationships with a number of pharmaceutical companies.

Adults with irritable bowel syndrome (IBS) who underwent psychotherapy improved more than about 75% of controls, and the effect “remained significant and medium in magnitude” for at least 6-12 months, according to a meta-analysis of 41 randomized, controlled trials reported in the July issue of Clinical Gastroenterology and Hepatology.

The finding “is particularly noteworthy because of the typically recurrent, persistent nature of IBS symptoms,” said Kelsey Laird, a doctoral student of clinical psychology at Vanderbilt University in Nashville, Tenn., together with her associates there. “Future research is needed to compare the longevity of treatment effects for psychotherapy with pharmacologic therapies, such as antidepressants,” they added. “Although it is beyond the scope of this review, it is also important to consider the mechanisms by which psychotherapies improve GI symptoms and to determine the ‘active ingredients’ responsible for this effect.”

©MacXever/Thinkstock

Up to 16% of individuals in the United States have IBS, and treating it costs anywhere from $950 million to $1.35 billion per year, the researchers noted. Other meta-analyses found psychotherapy about as effective as antidepressants for treating IBS-related GI symptoms over the short term, but its long-term efficacy was unknown, they added. Therefore, they searched PubMed, PsycINFO, Science Direct, and ProQuest through Aug. 15, 2015, identifying randomized controlled trials of psychological therapy and active or nonactive comparators. Psychotherapy included not only traditional psychodynamic and cognitive-behavioral therapies, but also mind-body approaches, such as relaxation training, biofeedback, and yoga, “which can be conceptualized as mindful movement,” Ms. Laird and her associates said. Comparators included support groups, education, sham treatments for hypnosis or biofeedback, online discussion forums, enhanced medical care, treatment as usual, symptom monitoring, and being wait-listed for psychological treatment (Clin Gastroenterol Hepatol. 2016 Jan 21. doi: 10.1016/j.cgh.2015.11.020). The 41 trials included 2,290 patients, comprising 1,183 assigned to the psychological modalities and 1,107 assigned to the various comparators. Taken together, the psychological modalities were associated with greater improvements in GI symptoms immediately after treatment, as compared with the grouped comparators. The Cohen’s d value was 0.69 (95% confidence interval, 0.52-0.86; P less than .001), indicating a medium effect size, the researchers said. Moreover, Cohen’s d values were 0.76 and 0.73, respectively, at short-term follow-up (1-6 months) and long-term follow-up (6-12 months). “On average, individuals who received psychotherapy had a greater reduction in GI symptoms after treatment than 75% of individuals assigned to a control condition,” the researchers concluded.

Effect sizes were similar among cognitive, cognitive-behavioral, and relaxation and hypnosis interventions, and between interventions delivered online and in person, the investigators also reported. Furthermore, longer durations or sessions of psychotherapy did not appear to further improve symptoms.

Study limitations included substantial variability between trials, and the fact that none of the 41 trials could be seen as having a low risk of bias in every domain assessed, the investigators said. “This was partially a result of the difficulty in blinding participants in psychological trials,” they noted. “However, even after excluding this domain, only nine trials were rated as low risk of bias in all remaining domains. Future studies should follow the CONSORT guidelines for [randomized controlled trials], use [intention-to-treat] designs, use active control conditions to control for nonspecific treatment effects, and assess treatment credibility and expectancy.”

The authors reported no funding sources and had no disclosures.

Adults with irritable bowel syndrome (IBS) who underwent psychotherapy improved more than about 75% of controls, and the effect “remained significant and medium in magnitude” for at least 6-12 months, according to a meta-analysis of 41 randomized, controlled trials reported in the July issue of Clinical Gastroenterology and Hepatology.

The finding “is particularly noteworthy because of the typically recurrent, persistent nature of IBS symptoms,” said Kelsey Laird, a doctoral student of clinical psychology at Vanderbilt University in Nashville, Tenn., together with her associates there. “Future research is needed to compare the longevity of treatment effects for psychotherapy with pharmacologic therapies, such as antidepressants,” they added. “Although it is beyond the scope of this review, it is also important to consider the mechanisms by which psychotherapies improve GI symptoms and to determine the ‘active ingredients’ responsible for this effect.”

©MacXever/Thinkstock

Up to 16% of individuals in the United States have IBS, and treating it costs anywhere from $950 million to $1.35 billion per year, the researchers noted. Other meta-analyses found psychotherapy about as effective as antidepressants for treating IBS-related GI symptoms over the short term, but its long-term efficacy was unknown, they added. Therefore, they searched PubMed, PsycINFO, Science Direct, and ProQuest through Aug. 15, 2015, identifying randomized controlled trials of psychological therapy and active or nonactive comparators. Psychotherapy included not only traditional psychodynamic and cognitive-behavioral therapies, but also mind-body approaches, such as relaxation training, biofeedback, and yoga, “which can be conceptualized as mindful movement,” Ms. Laird and her associates said. Comparators included support groups, education, sham treatments for hypnosis or biofeedback, online discussion forums, enhanced medical care, treatment as usual, symptom monitoring, and being wait-listed for psychological treatment (Clin Gastroenterol Hepatol. 2016 Jan 21. doi: 10.1016/j.cgh.2015.11.020). The 41 trials included 2,290 patients, comprising 1,183 assigned to the psychological modalities and 1,107 assigned to the various comparators. Taken together, the psychological modalities were associated with greater improvements in GI symptoms immediately after treatment, as compared with the grouped comparators. The Cohen’s d value was 0.69 (95% confidence interval, 0.52-0.86; P less than .001), indicating a medium effect size, the researchers said. Moreover, Cohen’s d values were 0.76 and 0.73, respectively, at short-term follow-up (1-6 months) and long-term follow-up (6-12 months). “On average, individuals who received psychotherapy had a greater reduction in GI symptoms after treatment than 75% of individuals assigned to a control condition,” the researchers concluded.

Effect sizes were similar among cognitive, cognitive-behavioral, and relaxation and hypnosis interventions, and between interventions delivered online and in person, the investigators also reported. Furthermore, longer durations or sessions of psychotherapy did not appear to further improve symptoms.

Study limitations included substantial variability between trials, and the fact that none of the 41 trials could be seen as having a low risk of bias in every domain assessed, the investigators said. “This was partially a result of the difficulty in blinding participants in psychological trials,” they noted. “However, even after excluding this domain, only nine trials were rated as low risk of bias in all remaining domains. Future studies should follow the CONSORT guidelines for [randomized controlled trials], use [intention-to-treat] designs, use active control conditions to control for nonspecific treatment effects, and assess treatment credibility and expectancy.”

The authors reported no funding sources and had no disclosures.

Adults with irritable bowel syndrome (IBS) who underwent psychotherapy improved more than about 75% of controls, and the effect “remained significant and medium in magnitude” for at least 6-12 months, according to a meta-analysis of 41 randomized, controlled trials reported in the July issue of Clinical Gastroenterology and Hepatology.

The finding “is particularly noteworthy because of the typically recurrent, persistent nature of IBS symptoms,” said Kelsey Laird, a doctoral student of clinical psychology at Vanderbilt University in Nashville, Tenn., together with her associates there. “Future research is needed to compare the longevity of treatment effects for psychotherapy with pharmacologic therapies, such as antidepressants,” they added. “Although it is beyond the scope of this review, it is also important to consider the mechanisms by which psychotherapies improve GI symptoms and to determine the ‘active ingredients’ responsible for this effect.”

©MacXever/Thinkstock

Up to 16% of individuals in the United States have IBS, and treating it costs anywhere from $950 million to $1.35 billion per year, the researchers noted. Other meta-analyses found psychotherapy about as effective as antidepressants for treating IBS-related GI symptoms over the short term, but its long-term efficacy was unknown, they added. Therefore, they searched PubMed, PsycINFO, Science Direct, and ProQuest through Aug. 15, 2015, identifying randomized controlled trials of psychological therapy and active or nonactive comparators. Psychotherapy included not only traditional psychodynamic and cognitive-behavioral therapies, but also mind-body approaches, such as relaxation training, biofeedback, and yoga, “which can be conceptualized as mindful movement,” Ms. Laird and her associates said. Comparators included support groups, education, sham treatments for hypnosis or biofeedback, online discussion forums, enhanced medical care, treatment as usual, symptom monitoring, and being wait-listed for psychological treatment (Clin Gastroenterol Hepatol. 2016 Jan 21. doi: 10.1016/j.cgh.2015.11.020). The 41 trials included 2,290 patients, comprising 1,183 assigned to the psychological modalities and 1,107 assigned to the various comparators. Taken together, the psychological modalities were associated with greater improvements in GI symptoms immediately after treatment, as compared with the grouped comparators. The Cohen’s d value was 0.69 (95% confidence interval, 0.52-0.86; P less than .001), indicating a medium effect size, the researchers said. Moreover, Cohen’s d values were 0.76 and 0.73, respectively, at short-term follow-up (1-6 months) and long-term follow-up (6-12 months). “On average, individuals who received psychotherapy had a greater reduction in GI symptoms after treatment than 75% of individuals assigned to a control condition,” the researchers concluded.

Effect sizes were similar among cognitive, cognitive-behavioral, and relaxation and hypnosis interventions, and between interventions delivered online and in person, the investigators also reported. Furthermore, longer durations or sessions of psychotherapy did not appear to further improve symptoms.

Study limitations included substantial variability between trials, and the fact that none of the 41 trials could be seen as having a low risk of bias in every domain assessed, the investigators said. “This was partially a result of the difficulty in blinding participants in psychological trials,” they noted. “However, even after excluding this domain, only nine trials were rated as low risk of bias in all remaining domains. Future studies should follow the CONSORT guidelines for [randomized controlled trials], use [intention-to-treat] designs, use active control conditions to control for nonspecific treatment effects, and assess treatment credibility and expectancy.”

The authors reported no funding sources and had no disclosures.

State Medicaid programs denied nearly half of requests to cover direct-acting antiviral drugs for patients with chronic hepatitis C virus (HCV) infection, according to a prospective study of beneficiaries in Delaware, Maryland, New Jersey, and Pennsylvania reported in the July issue of Clinical Gastroenterology and Hepatology.

In contrast, only 5% of Medicare patients and 10% of privately insured patients were denied coverage, said Dr. Vincent Lo Re III of the University of Pennsylvania, Philadelphia, together with his associates. “Notably, nearly one-quarter of Medicaid recipients with cirrhosis experienced treatment denial. Medicaid patients from these states also experienced a longer time to prescription fill than those with Medicare or commercial insurance,” the researchers said.

©roxanabalint/Thinkstock

Their study included 2,321 HCV patients prescribed a direct-acting antiviral regimen between November 1, 2014 and April 30, 2015. All prescriptions were submitted to a specialty pharmacy that serves HCV patients in Maryland, Pennsylvania, Delaware, and New Jersey, the investigators noted. They focused on “absolute denial,” meaning that the prescription was never filled because the insurer denied coverage, regardless of appeals. “Data are lacking on the incidence of absolute denial of direct-acting antiviral prescriptions and factors associated with this outcome,” the investigators said. “These data are important because absolute denial of HCV treatment by insurers might have adverse outcomes on patients and could harm patient-provider relationships” (Clin Gastroenterol Hepatol. 2016 Apr 5. doi: 10.1016/j.cgh.2016.03.040).

Source: American Gastroenterological Association

A total of 1,023 study patients were privately insured, 795 were enrolled in Medicare, and 503 were Medicaid patients, according to the researchers. In all, 377 patients (16%) received absolute denials, most often because of “insufficient information to assess medical need” (36% of denials) and “lack of medical necessity” (35%). Medicaid patients faced an absolute denial rate of 46% – significantly higher than rates for private insurers (10.5%) or Medicare (5%; P less than .001 for both comparisons). After adjusting for potential confounders, Medicaid patients were more than four times as likely to be denied coverage for direct-acting antivirals, compared with privately insured patients (relative risk, 4.1; 95% confidence interval, 3.4-5.1). Delaware’s Medicaid program had the highest rate of absolute denial (57%), followed by Pennsylvania (48%), Maryland (47%), and New Jersey (37%).

Medicaid programs even refused to cover direct-acting antiviral prescriptions for 25% of patients who had cirrhosis, compared with absolute denial rates of only 1% for Medicare and 3% of private insurers (P less than .001 for both comparisons), according to the researchers. The implications of these denials “remain unknown,” but lack of treatment increases the risk of end-stage liver disease, hepatocellular carcinoma, extrahepatic disease, HCV transmission, and “anxiety and stress about HCV disease progression, [which can] provoke distrust among patients of the health care system and their providers,” they added. “Clinicians then are challenged to explain the denial, and important opportunities for patient engagement, education, and cure could be irrevocably lost.”

Medicaid programs also initially denied about 25% of prescriptions before eventually approving them, despite the fact that “patients had complete prior authorization requests that should have contained the materials needed to justify approval,” said the investigators. Furthermore, denial letters usually did not specify the information that was needed, “making it difficult [for clinicians] to appeal the decision.” In contrast, only about 8% of privately insured patients and 13% of Medicare enrollees were initially denied coverage.

Prescriptions as a whole were more likely to be filled in the last 3 months of the study than earlier, perhaps because insurers are starting to relax their reimbursement criteria, said the investigators. Indeed, in October 2015, the American Association for the Study of Liver Diseases and the Infectious Disease Society of America stopped triaging groups of patients for direct-acting antiviral therapy, they noted.

The research was supported by the Penn Center for AIDS Research, which is funded by the National Institutes of Health. Dr. Lo Re received investigator-initiated research support from AstraZeneca. Five coinvestigators reported relationships with a number of pharmaceutical companies. Four coinvestigators reported employment by the study site, Burman’s Specialty Pharmacy. The other four coauthors had no disclosures.

State Medicaid programs denied nearly half of requests to cover direct-acting antiviral drugs for patients with chronic hepatitis C virus (HCV) infection, according to a prospective study of beneficiaries in Delaware, Maryland, New Jersey, and Pennsylvania reported in the July issue of Clinical Gastroenterology and Hepatology.

In contrast, only 5% of Medicare patients and 10% of privately insured patients were denied coverage, said Dr. Vincent Lo Re III of the University of Pennsylvania, Philadelphia, together with his associates. “Notably, nearly one-quarter of Medicaid recipients with cirrhosis experienced treatment denial. Medicaid patients from these states also experienced a longer time to prescription fill than those with Medicare or commercial insurance,” the researchers said.

©roxanabalint/Thinkstock

Their study included 2,321 HCV patients prescribed a direct-acting antiviral regimen between November 1, 2014 and April 30, 2015. All prescriptions were submitted to a specialty pharmacy that serves HCV patients in Maryland, Pennsylvania, Delaware, and New Jersey, the investigators noted. They focused on “absolute denial,” meaning that the prescription was never filled because the insurer denied coverage, regardless of appeals. “Data are lacking on the incidence of absolute denial of direct-acting antiviral prescriptions and factors associated with this outcome,” the investigators said. “These data are important because absolute denial of HCV treatment by insurers might have adverse outcomes on patients and could harm patient-provider relationships” (Clin Gastroenterol Hepatol. 2016 Apr 5. doi: 10.1016/j.cgh.2016.03.040).

Source: American Gastroenterological Association

A total of 1,023 study patients were privately insured, 795 were enrolled in Medicare, and 503 were Medicaid patients, according to the researchers. In all, 377 patients (16%) received absolute denials, most often because of “insufficient information to assess medical need” (36% of denials) and “lack of medical necessity” (35%). Medicaid patients faced an absolute denial rate of 46% – significantly higher than rates for private insurers (10.5%) or Medicare (5%; P less than .001 for both comparisons). After adjusting for potential confounders, Medicaid patients were more than four times as likely to be denied coverage for direct-acting antivirals, compared with privately insured patients (relative risk, 4.1; 95% confidence interval, 3.4-5.1). Delaware’s Medicaid program had the highest rate of absolute denial (57%), followed by Pennsylvania (48%), Maryland (47%), and New Jersey (37%).

Medicaid programs even refused to cover direct-acting antiviral prescriptions for 25% of patients who had cirrhosis, compared with absolute denial rates of only 1% for Medicare and 3% of private insurers (P less than .001 for both comparisons), according to the researchers. The implications of these denials “remain unknown,” but lack of treatment increases the risk of end-stage liver disease, hepatocellular carcinoma, extrahepatic disease, HCV transmission, and “anxiety and stress about HCV disease progression, [which can] provoke distrust among patients of the health care system and their providers,” they added. “Clinicians then are challenged to explain the denial, and important opportunities for patient engagement, education, and cure could be irrevocably lost.”

Medicaid programs also initially denied about 25% of prescriptions before eventually approving them, despite the fact that “patients had complete prior authorization requests that should have contained the materials needed to justify approval,” said the investigators. Furthermore, denial letters usually did not specify the information that was needed, “making it difficult [for clinicians] to appeal the decision.” In contrast, only about 8% of privately insured patients and 13% of Medicare enrollees were initially denied coverage.

Prescriptions as a whole were more likely to be filled in the last 3 months of the study than earlier, perhaps because insurers are starting to relax their reimbursement criteria, said the investigators. Indeed, in October 2015, the American Association for the Study of Liver Diseases and the Infectious Disease Society of America stopped triaging groups of patients for direct-acting antiviral therapy, they noted.

The research was supported by the Penn Center for AIDS Research, which is funded by the National Institutes of Health. Dr. Lo Re received investigator-initiated research support from AstraZeneca. Five coinvestigators reported relationships with a number of pharmaceutical companies. Four coinvestigators reported employment by the study site, Burman’s Specialty Pharmacy. The other four coauthors had no disclosures.

State Medicaid programs denied nearly half of requests to cover direct-acting antiviral drugs for patients with chronic hepatitis C virus (HCV) infection, according to a prospective study of beneficiaries in Delaware, Maryland, New Jersey, and Pennsylvania reported in the July issue of Clinical Gastroenterology and Hepatology.

In contrast, only 5% of Medicare patients and 10% of privately insured patients were denied coverage, said Dr. Vincent Lo Re III of the University of Pennsylvania, Philadelphia, together with his associates. “Notably, nearly one-quarter of Medicaid recipients with cirrhosis experienced treatment denial. Medicaid patients from these states also experienced a longer time to prescription fill than those with Medicare or commercial insurance,” the researchers said.

©roxanabalint/Thinkstock

Their study included 2,321 HCV patients prescribed a direct-acting antiviral regimen between November 1, 2014 and April 30, 2015. All prescriptions were submitted to a specialty pharmacy that serves HCV patients in Maryland, Pennsylvania, Delaware, and New Jersey, the investigators noted. They focused on “absolute denial,” meaning that the prescription was never filled because the insurer denied coverage, regardless of appeals. “Data are lacking on the incidence of absolute denial of direct-acting antiviral prescriptions and factors associated with this outcome,” the investigators said. “These data are important because absolute denial of HCV treatment by insurers might have adverse outcomes on patients and could harm patient-provider relationships” (Clin Gastroenterol Hepatol. 2016 Apr 5. doi: 10.1016/j.cgh.2016.03.040).

Source: American Gastroenterological Association

A total of 1,023 study patients were privately insured, 795 were enrolled in Medicare, and 503 were Medicaid patients, according to the researchers. In all, 377 patients (16%) received absolute denials, most often because of “insufficient information to assess medical need” (36% of denials) and “lack of medical necessity” (35%). Medicaid patients faced an absolute denial rate of 46% – significantly higher than rates for private insurers (10.5%) or Medicare (5%; P less than .001 for both comparisons). After adjusting for potential confounders, Medicaid patients were more than four times as likely to be denied coverage for direct-acting antivirals, compared with privately insured patients (relative risk, 4.1; 95% confidence interval, 3.4-5.1). Delaware’s Medicaid program had the highest rate of absolute denial (57%), followed by Pennsylvania (48%), Maryland (47%), and New Jersey (37%).

Medicaid programs even refused to cover direct-acting antiviral prescriptions for 25% of patients who had cirrhosis, compared with absolute denial rates of only 1% for Medicare and 3% of private insurers (P less than .001 for both comparisons), according to the researchers. The implications of these denials “remain unknown,” but lack of treatment increases the risk of end-stage liver disease, hepatocellular carcinoma, extrahepatic disease, HCV transmission, and “anxiety and stress about HCV disease progression, [which can] provoke distrust among patients of the health care system and their providers,” they added. “Clinicians then are challenged to explain the denial, and important opportunities for patient engagement, education, and cure could be irrevocably lost.”

Medicaid programs also initially denied about 25% of prescriptions before eventually approving them, despite the fact that “patients had complete prior authorization requests that should have contained the materials needed to justify approval,” said the investigators. Furthermore, denial letters usually did not specify the information that was needed, “making it difficult [for clinicians] to appeal the decision.” In contrast, only about 8% of privately insured patients and 13% of Medicare enrollees were initially denied coverage.

Prescriptions as a whole were more likely to be filled in the last 3 months of the study than earlier, perhaps because insurers are starting to relax their reimbursement criteria, said the investigators. Indeed, in October 2015, the American Association for the Study of Liver Diseases and the Infectious Disease Society of America stopped triaging groups of patients for direct-acting antiviral therapy, they noted.

The research was supported by the Penn Center for AIDS Research, which is funded by the National Institutes of Health. Dr. Lo Re received investigator-initiated research support from AstraZeneca. Five coinvestigators reported relationships with a number of pharmaceutical companies. Four coinvestigators reported employment by the study site, Burman’s Specialty Pharmacy. The other four coauthors had no disclosures.

According to the Surveillance, Epidemiology, and End Results database, 5-year overall survival rates have improved for nearly all tumor types during the past 40 years.¹ This has been accomplished with better treatment and earlier detection of the most common cancers, as well as the uncommon but highly curable tumor types.

Primary care physicians play a vital role in detecting cancers at earlier stages and synthesizing information from a patient’s presentation, vital signs, physical examination, and results of laboratory and radiographic testing. Yet cancers can be easily overlooked, and highly curable cancers such as Hodgkin lymphoma and testicular cancer, with 5-year survival rates above 85%, can have unusual presentations. Aside from the obvious health consequences, missed cancer diagnoses are often the subject of malpractice suits.

This paper reviews cancers that are easily missed and provides clinically relevant pearls from an oncologic perspective for primary care physicians, who are generally the first point of contact for patients.

BREAST CANCER DETECTION AND SCREENING

Breast cancer is the second most common cause of cancer death in US women and the most common cause of death in US women ages 20 to 59 (Table 1).^2–4

Screening mammography has had a significant impact on early detection rates, and this has translated into a 20% to 30% decrease in the breast cancer mortality rate.^5,6 But despite national screening guidelines, up to 15% of cases are diagnosed on the basis of a palpable breast mass not detected on mammography, and 30% are diagnosed with a breast mass during the interval between mammograms.^5,6 Moreover, delay in breast cancer diagnosis is one of the most common reasons for malpractice suits.^7,8

Warning signs

Breast cancer can present clinically as a single, dominant, indurated mass with irregular borders. The mass can have associated ecchymosis, erythema, nipple discharge, nipple retraction, and nipple eczema.^9,10 Pay close attention to any history of breast trauma, pain, signs or symptoms suggestive of local infection, and the lesion’s relationship to the patient’s menstrual cycle. Locally advanced disease typically presents with axillary adenopathy, as well as skin findings such as erythema, thickening, and dimpling.

Initial imaging workup for a breast mass

Women presenting with a breast mass should undergo breast imaging, followed by core needle biopsy of any suspicious abnormality. Depending on the clinical breast examination and the interpretation of the mammogram, as reported as a Breast Imaging Reporting and Data System (BIRADS) score, ultrasonography, magnetic resonance imaging, or biopsy may be the next course of action. Ultrasonography is recommended in evaluating masses in women who are under age 30 (who are more likely to have dense breasts that make standard mammography difficult to interpret) or who are pregnant (because it does not involve radiation).

For patients with a borderline or indeterminate clinical examination (eg, asymmetric skin-thickening or discoloration, nipple discharge or inversion, nodularity, finding on imaging [ie, BIRADS 3 lesion]), closer follow-up with repeat or additional imaging or biopsy, or both, is strongly recommended.

Screening recommendations vary

The age at which to start breast cancer screening has been a matter of debate in recent years, and different organizations have different recommendations (Table 2).^11–13 According to the American Cancer Society (ACS), women should begin screening mammography at age 45 and should continue it indefinitely as long as they are in good health.¹¹ This guideline is in line with those of the National Comprehensive Cancer Network (NCCN)¹² but differs from those of the US Preventive Services Task Force (USPSTF).¹³

One reason for the controversy is that although starting screening at a younger age may allow for earlier detection, it also leads to overdiagnosis and to unnecessary tests and procedures. However, the NCCN noted limitations in studies looking at the overdiagnosis of breast cancer, including their use of incidence data from the 1970s, which not only underestimated the annual incidence of breast cancer in the United States, but also neglected to differentiate invasive cancer from ductal carcinoma in situ.¹² Additionally, by detecting breast cancer lesions 2 years before they are discovered by clinical breast examination, mammography has been found to reduce the mortality rate from breast cancer.¹⁴

The frequency of mammography should be individualized and should involve not only an assessment of the patient’s risk factors (eg, age, family history, genetic predisposition, history of precancerous lesions, history of radiation exposure) but also a discussion of the benefits, limitations, and potential harms of screening. Both the ACS and the NCCN recommend yearly mammography for women ages 45 to 54. For those age 55 and older, the ACS recommends screening mammography every 2 years until the patient’s life expectancy is less than 10 years, whereas the NCCN recommends yearly screening mammography indefinitely. Meanwhile, the USPSTF recommends mammograms every 2 years for women ages 50 to 74.

Pearls

• Pay close attention to a history of breast trauma, pain, and signs of infection.
• Consider ultrasonography for women under age 30, who are more likely to have dense breasts.

COLORECTAL CANCER

With an estimated annual incidence of 132,700 cases diagnosed in the United States in 2015, colorectal cancer is the third most common cancer.

National guidelines that recommend colonoscopy (starting at age 50 for people at standard risk) have had a significant impact on early detection rates and have translated into a significant decrease in mortality rates.^2,15,16 However, a missed diagnosis of colorectal cancer is one of the most common reasons for malpractice suits, typically because the patient was not referred for colonoscopy according to national guidelines.^17–19

Symptoms depend on tumor location

In symptomatic cases, clinical manifestations differ depending on tumor location.

Left-sided tumors can present with hematochezia, colicky abdominal pain, and a change in bowel habits. And because the descending (left) colon has a smaller lumen than the right and tumors typically are annular in shape, left-sided cancers may present with abdominal distention with or without bowel obstruction or nausea and vomiting.

Right-sided tumors typically present with iron deficiency anemia from unrecognized blood loss.

Tumors near the rectum can cause tenesmus, rectal pain, and diminished caliber of stools.

In the United States, 20% of colorectal cancer patients have distant metastases at the time of diagnosis, and the most common sites are the lymph nodes, liver, lungs, and peritoneum.¹⁷

Uncommon presentations of colorectal cancer include pneumaturia, fecaluria or recurrent urinary tract infection from a fistula, bacteremia with Streptococcus bovis or Clostridium septicum, and intra-abdominal abscess from a localized bowel perforation.^20,21

Initial workup

Once cancer is suspected, colonoscopy is the most accurate and versatile diagnostic test. It not only permits localization and biopsy of lesions throughout the large bowel, but also detects synchronous neoplasms and permits removal of polyps. Computed tomographic (CT) colonography is an alternative if colonoscopy is contraindicated, but it can only detect larger (ie, > 6-mm) tumors.²²

According to the ACS,²³ men and women at average risk should undergo colorectal cancer screening beginning at age 50. ACS screening recommendations for polyps and colorectal cancer include flexible sigmoidoscopy every 5 years, colonoscopy every 10 years, double-contrast barium enema every 5 years, or CT colonography every 5 years. Tests that detect cancer but not polyps include guaiac-based fecal occult blood test (every year), fecal immunochemical test (every year), stool DNA test (every 3 years). These recommendations are fairly consistent with those of the NCCN¹² and USPSTF²⁴ (Table 3).^12,23,24

Pearls

• Uncommon presentations include urinary tract problems and intra-abdominal abscess.
• CT colonography can only detect larger tumors.

PROSTATE CANCER

With an estimated 220,800 cases and 27,540 deaths in 2015, prostate cancer is the most common cancer and the second most common cause of cancer-related death in US men.² Widespread use of serum prostate-specific antigen (PSA) testing has increased the rate of detection of prostate cancer.

Signs and symptoms

Most men with early-stage prostate cancer have no symptoms directly attributable to the disease.

Obstructive symptoms such as hesitancy, decreased stream, retention, and nocturia are common but are usually related to concomitant benign prostatic hypertrophy. As in prostatitis, patients with prostate cancer may present with irritative symptoms such as urinary frequency, dysuria, and urgency.

Patients who present with locally advanced prostate cancer may have symptoms secondary to local invasion, such as hematuria, hematospermia, and new-onset erectile dysfunction.

Prostate cancer usually metastasizes to bone, most commonly to the vertebrae and sternum, and the associated pain can be acute or insidious.

Diagnosis

Prostate cancer is most often diagnosed after biopsy prompted by an elevated PSA level or an abnormal digital rectal examination. The most common abnormal laboratory findings in patients with metastatic prostate cancer are an elevated serum PSA level (typically > 10 ng/mL), an elevated serum alkaline phosphatase level, and anemia, which are all proportional to the extent of bone involvement.

Screening is still controversial

There has been considerable controversy in recent years with regard to PSA screening because of the lack of significant benefit and the potential for harm to the patient, with an overdiagnosis rate ranging from 23% to 42%.²⁵

According to the ACS,²⁶ certain groups of men should make an informed decision with their physician about whether to undergo screening: men over age 50 at average risk of prostate cancer and with at least a 10-year life expectancy, men over age 45 at high risk, and men over age 40 at an even higher risk. These ACS guidelines are consistent with those of the NCCN¹² but differ from those of the USPSTF²⁷ (Table 4).^12,26,27

The patient should fully understand the risks and benefits of prostate cancer screening, as well as why it is controversial: ie, while the lifetime risk of being diagnosed with prostate cancer has increased, the lifetime risk of dying from it has remained the same after the advent of PSA testing.

Adverse effects of biopsy and treatment

Prostate biopsy is associated with infectious and bleeding complications, in addition to anxiety and physical discomfort.²⁸ Treatment-related adverse effects include urinary incontinence, sexual dysfunction, and bowel problems.

Could these potential harms be overstated and the benefit be greater than currently thought? The NCCN¹² noted that some of the landmark prostate cancer screening studies found a potential benefit in screening high-risk patients such as black men. Moreover, the studies used the sextant prostate biopsy technique, whereas now the extended core biopsy technique is the standard of care. And the studies may have underestimated the benefit of screening because the trial patients were relatively old (age 60) when their first PSA measurement was done, they were screened at long intervals (every 4 years), and the treatment options available at the time were not as good as those available today.¹²

Pearls

• Laboratory findings in metastatic prostate cancer are proportional to the extent of bone involvement.
• Most men with early-stage prostate cancer have no symptoms attributable to the disease.

LUNG CANCER

Lung cancer is the second most common type of cancer in men and women but has the highest mortality rate. In the United States, in 2015, an estimated 221,200 new cases of lung cancer and 158,040 deaths were expected.² Lung cancer deaths have begun to decline in both men and women, and this is due to the decline in smoking. The impact of lung cancer screening may not be seen for another 5 to 10 years.²⁹

A wide range of symptoms, presentations

Many patients with squamous cell carcinoma and small-cell lung carcinoma present with symptoms related to tumor involvement of the central airways,³⁰ including cough, hemoptysis, and postobstructive pneumonia. Partial obstruction of a bronchus may cause localized wheezing, heard by the patient or by the clinician on auscultation, whereas obstruction of larger airways can cause stridor.

Patients with advanced disease present with dull, aching, persistent chest pain from mediastinal, pleural, or chest wall extension, dyspnea from lymphangitic tumor spread, tumor emboli, pneumothorax, pleural effusion, or pericardial effusion with tamponade. Less commonly, patients may present with unilateral paralysis of the diaphragm from phrenic nerve damage or with hoarseness from recurrent laryngeal nerve compression.³¹

Bronchorrhea—production of large volumes of thin, mucoid secretions resulting in cough—may be a feature of bronchoalveolar cell carcinoma, a rare subtype of non-small-cell lung carcinoma.

Patients uncommonly present with superior vena cava syndrome, an oncologic emergency that most often causes facial and arm swelling, dyspnea, cough, and headache.

Non-small-cell lung carcinoma arising in the superior sulcus may in rare cases cause Pancoast syndrome (manifested by shoulder pain and atrophy of the hand muscles from brachial plexus involvement), Horner syndrome (manifested by ptosis, miosis, and anhidrosis), or rib destruction.

If metastasis occurs, lung cancer commonly metastasizes to the liver and adrenal glands. At the time of diagnosis, 20% to 30% of patients with small-cell lung carcinoma have symptoms of central nervous system metastasis.

The screening controversy

Lung cancer screening is controversial because previous large studies have failed to show a clinical benefit (ie, improved survival rates) of CT screening in smokers. However, based on the results of a later large randomized trial,³² the ACS³³ now recommends that patients ages 55 to 74 who are in fairly good health, have at least a 30-pack-year smoking history, and are currently smoking or have quit smoking within the last 15 years should discuss with their physician the benefits, limitations, and potential harms of lung cancer screening. These recommendations are similar to those of the NCCN^12,34 and USPSTF³⁵ (Table 5).^12,33–35 The ACS guidelines also emphasize that screening should be done only at facilities with extensive experience with low-dose CT.

Follow-up evaluation

If imaging detects a lung nodule, its size and consistency are crucial in determining the course of action.³³ If an endobronchial growth or solid nodule larger than 8 mm is discovered, the primary care physician should consider ordering either a repeat low-dose CT scan after 1 month or a positron-emission tomography CT scan.³⁴ The diagnosis should be confirmed by biopsy or by surgical removal of the nodule if localized and accessible, with sites of metastasis typically taking priority.

Pearl

• At diagnosis, 20% to 30% of patients with small-cell lung cancer have symptoms of central nervous system metastasis.

HIGHLY CURABLE CANCERS WITH UNUSUAL PRESENTATIONS

Hodgkin lymphoma

With 9,190 new cases in the United States annually and a 5-year overall survival rate over 85%, Hodgkin lymphoma is one of the least common but most curable cancers.^1,2 In the United States, there are two diagnostic peaks, one around age 20 and one around age 65.³⁶ In patients with human immunodeficiency virus infection, the rate is 15 to 30 times higher than in the general population, regardless of disease status or compliance with highly active retroviral therapy.³⁷

Hodgkin lymphoma typically presents as a nontender painless mass with rubbery consistency. The involved lymph node is typically cervical or supraclavicular. Although not detectable on physical examination, enlarged mediastinal nodes and retroperitoneal nodes are often present. Less commonly, patients may present with enlarged axillary and inguinal nodes.³⁸

A second common presentation is the discovery of a mediastinal mass on routine chest radiography. A large percentage of patients present with at least one systemic symptom, which may include fever, night sweats, and unintentional weight loss. Generalized pruritus occurs early in the disease course in 10% to 15% of patients and is occasionally severe enough to cause intense scratching and excoriations.

A more unusual presentation of Hodgkin lymphoma is severe pain at areas of involvement after alcohol ingestion.

Most patients present with overt disease, but the presenting symptoms and signs may be relatively nonspecific and subtle and more consistent with an infectious process.

Hodgkin disease has a variable tempo, but overt symptoms typically occur after several months rather than years. As a general rule, it starts at a single site within the lymphatic system, usually a lymph node, and then spreads to adjacent nodes via lymphatic channels before disseminating to distant nonadjacent sites and organs. With this in mind, it is unusual to have bilateral axillary involvement without disease in the lower neck, and extremely unusual to have hepatic or bone marrow infiltration without disease in the spleen.

The diagnosis is established by whole lymph node tissue biopsy. Due to the high rate of inflammation in the area, inguinal nodes should not be biopsied if other equally suspicious peripheral nodes are present elsewhere. When the diagnosis of Hodgkin lymphoma is made from biopsy of an extranodal site, such as the stomach, spleen, Waldeyer ring, central nervous system, lung, bone, or skin, lymph node biopsy is also desirable for diagnostic confirmation.

Testicular cancer

Although accounting for only about 1% of all cancers in men, testicular cancer is the most common solid tumor affecting males between ages 15 and 35.^1,2 With a 5-year survival rate of over 95%, testicular cancer is also one of the most curable cancers.

Testicular tumors usually present as a painless nodule or swelling of one testicle. Uncommonly, patients have metastatic disease at diagnosis, with the most common sites being lymph nodes, lung, bone, and the brain. Gynecomastia, associated with the production of human chorionic gonadotropin, occurs in about 5% of men with testicular germ cell tumors and 20% to 30% of men with Leydig cell tumors.³⁹ Rarely, patients may present with paraneoplastic hyperthyroidism, which is secondary to thyroid-stimulating hormone and human chorionic gonadotropin sharing a common homologous alpha and beta subunit.⁴⁰

Prompt diagnosis and treatment of testicular cancer provides the best opportunity for cure. Therefore, any testicular mass, even a painful scrotal lesion, should be evaluated as if it is testicular cancer until it is proven otherwise. The diagnostic evaluation of suspected testicular cancer includes scrotal ultrasonography. Radiographic testing, as deemed clinically necessary by the consulting urologist and medical oncologist, may include chest radiography, CT (chest, abdomen, pelvis), brain magnetic resonance imaging, or bone scan.

The primary care laboratory evaluation should include a complete metabolic profile and measurements of lactate dehydrogenase and serum tumor markers such as alpha fetoprotein and human chorionic gonadotropin. In nonseminomatous germ cell tumors, alpha fetoprotein or human chorionic gonadotropin, or both, can be elevated in 80% to 85% of patients. However, in seminoma, alpha fetoprotein is never elevated, and the serum human chorionic gonadotropin is elevated in only 20% to 25% of patients.⁴¹

Patients with a suspicious testicular mass should be referred promptly to a urologist for consideration of radical inguinal orchiectomy and, in some cases, retroperitoneal lymph node dissection. Testicular biopsy is not part of the evaluation as it may result in tumor seeding into the scrotal sac or metastatic spread of tumor to the inguinal nodes. Inguinal biopsy of the contralateral testis is considered if ultrasonography raises suspicion of an intratesticular abnormality, cryptorchid testis, or marked testicular atrophy. Discussing sperm banking with the patient is part of the diagnostic workup, as cumulative cisplatin doses greater than 400 mg/m² can result in permanent infertility in 50% of men.⁴²

Pearls

• In Hodgkin lymphoma, bilateral axillary involvement without disease in the lower neck is unusual.
• Discussing sperm banking is part of the diagnostic workup for testicular cancer.

According to the Surveillance, Epidemiology, and End Results database, 5-year overall survival rates have improved for nearly all tumor types during the past 40 years.¹ This has been accomplished with better treatment and earlier detection of the most common cancers, as well as the uncommon but highly curable tumor types.

Primary care physicians play a vital role in detecting cancers at earlier stages and synthesizing information from a patient’s presentation, vital signs, physical examination, and results of laboratory and radiographic testing. Yet cancers can be easily overlooked, and highly curable cancers such as Hodgkin lymphoma and testicular cancer, with 5-year survival rates above 85%, can have unusual presentations. Aside from the obvious health consequences, missed cancer diagnoses are often the subject of malpractice suits.

This paper reviews cancers that are easily missed and provides clinically relevant pearls from an oncologic perspective for primary care physicians, who are generally the first point of contact for patients.

BREAST CANCER DETECTION AND SCREENING

Breast cancer is the second most common cause of cancer death in US women and the most common cause of death in US women ages 20 to 59 (Table 1).^2–4

Screening mammography has had a significant impact on early detection rates, and this has translated into a 20% to 30% decrease in the breast cancer mortality rate.^5,6 But despite national screening guidelines, up to 15% of cases are diagnosed on the basis of a palpable breast mass not detected on mammography, and 30% are diagnosed with a breast mass during the interval between mammograms.^5,6 Moreover, delay in breast cancer diagnosis is one of the most common reasons for malpractice suits.^7,8

Warning signs

Breast cancer can present clinically as a single, dominant, indurated mass with irregular borders. The mass can have associated ecchymosis, erythema, nipple discharge, nipple retraction, and nipple eczema.^9,10 Pay close attention to any history of breast trauma, pain, signs or symptoms suggestive of local infection, and the lesion’s relationship to the patient’s menstrual cycle. Locally advanced disease typically presents with axillary adenopathy, as well as skin findings such as erythema, thickening, and dimpling.

Initial imaging workup for a breast mass

Women presenting with a breast mass should undergo breast imaging, followed by core needle biopsy of any suspicious abnormality. Depending on the clinical breast examination and the interpretation of the mammogram, as reported as a Breast Imaging Reporting and Data System (BIRADS) score, ultrasonography, magnetic resonance imaging, or biopsy may be the next course of action. Ultrasonography is recommended in evaluating masses in women who are under age 30 (who are more likely to have dense breasts that make standard mammography difficult to interpret) or who are pregnant (because it does not involve radiation).

For patients with a borderline or indeterminate clinical examination (eg, asymmetric skin-thickening or discoloration, nipple discharge or inversion, nodularity, finding on imaging [ie, BIRADS 3 lesion]), closer follow-up with repeat or additional imaging or biopsy, or both, is strongly recommended.

Screening recommendations vary

The age at which to start breast cancer screening has been a matter of debate in recent years, and different organizations have different recommendations (Table 2).^11–13 According to the American Cancer Society (ACS), women should begin screening mammography at age 45 and should continue it indefinitely as long as they are in good health.¹¹ This guideline is in line with those of the National Comprehensive Cancer Network (NCCN)¹² but differs from those of the US Preventive Services Task Force (USPSTF).¹³

One reason for the controversy is that although starting screening at a younger age may allow for earlier detection, it also leads to overdiagnosis and to unnecessary tests and procedures. However, the NCCN noted limitations in studies looking at the overdiagnosis of breast cancer, including their use of incidence data from the 1970s, which not only underestimated the annual incidence of breast cancer in the United States, but also neglected to differentiate invasive cancer from ductal carcinoma in situ.¹² Additionally, by detecting breast cancer lesions 2 years before they are discovered by clinical breast examination, mammography has been found to reduce the mortality rate from breast cancer.¹⁴

The frequency of mammography should be individualized and should involve not only an assessment of the patient’s risk factors (eg, age, family history, genetic predisposition, history of precancerous lesions, history of radiation exposure) but also a discussion of the benefits, limitations, and potential harms of screening. Both the ACS and the NCCN recommend yearly mammography for women ages 45 to 54. For those age 55 and older, the ACS recommends screening mammography every 2 years until the patient’s life expectancy is less than 10 years, whereas the NCCN recommends yearly screening mammography indefinitely. Meanwhile, the USPSTF recommends mammograms every 2 years for women ages 50 to 74.

Pearls

• Pay close attention to a history of breast trauma, pain, and signs of infection.
• Consider ultrasonography for women under age 30, who are more likely to have dense breasts.

COLORECTAL CANCER

With an estimated annual incidence of 132,700 cases diagnosed in the United States in 2015, colorectal cancer is the third most common cancer.

National guidelines that recommend colonoscopy (starting at age 50 for people at standard risk) have had a significant impact on early detection rates and have translated into a significant decrease in mortality rates.^2,15,16 However, a missed diagnosis of colorectal cancer is one of the most common reasons for malpractice suits, typically because the patient was not referred for colonoscopy according to national guidelines.^17–19

Symptoms depend on tumor location

In symptomatic cases, clinical manifestations differ depending on tumor location.

Left-sided tumors can present with hematochezia, colicky abdominal pain, and a change in bowel habits. And because the descending (left) colon has a smaller lumen than the right and tumors typically are annular in shape, left-sided cancers may present with abdominal distention with or without bowel obstruction or nausea and vomiting.

Right-sided tumors typically present with iron deficiency anemia from unrecognized blood loss.

Tumors near the rectum can cause tenesmus, rectal pain, and diminished caliber of stools.

In the United States, 20% of colorectal cancer patients have distant metastases at the time of diagnosis, and the most common sites are the lymph nodes, liver, lungs, and peritoneum.¹⁷

Uncommon presentations of colorectal cancer include pneumaturia, fecaluria or recurrent urinary tract infection from a fistula, bacteremia with Streptococcus bovis or Clostridium septicum, and intra-abdominal abscess from a localized bowel perforation.^20,21

Initial workup

Once cancer is suspected, colonoscopy is the most accurate and versatile diagnostic test. It not only permits localization and biopsy of lesions throughout the large bowel, but also detects synchronous neoplasms and permits removal of polyps. Computed tomographic (CT) colonography is an alternative if colonoscopy is contraindicated, but it can only detect larger (ie, > 6-mm) tumors.²²

According to the ACS,²³ men and women at average risk should undergo colorectal cancer screening beginning at age 50. ACS screening recommendations for polyps and colorectal cancer include flexible sigmoidoscopy every 5 years, colonoscopy every 10 years, double-contrast barium enema every 5 years, or CT colonography every 5 years. Tests that detect cancer but not polyps include guaiac-based fecal occult blood test (every year), fecal immunochemical test (every year), stool DNA test (every 3 years). These recommendations are fairly consistent with those of the NCCN¹² and USPSTF²⁴ (Table 3).^12,23,24

Pearls

• Uncommon presentations include urinary tract problems and intra-abdominal abscess.
• CT colonography can only detect larger tumors.

PROSTATE CANCER

With an estimated 220,800 cases and 27,540 deaths in 2015, prostate cancer is the most common cancer and the second most common cause of cancer-related death in US men.² Widespread use of serum prostate-specific antigen (PSA) testing has increased the rate of detection of prostate cancer.

Signs and symptoms

Most men with early-stage prostate cancer have no symptoms directly attributable to the disease.

Obstructive symptoms such as hesitancy, decreased stream, retention, and nocturia are common but are usually related to concomitant benign prostatic hypertrophy. As in prostatitis, patients with prostate cancer may present with irritative symptoms such as urinary frequency, dysuria, and urgency.

Patients who present with locally advanced prostate cancer may have symptoms secondary to local invasion, such as hematuria, hematospermia, and new-onset erectile dysfunction.

Prostate cancer usually metastasizes to bone, most commonly to the vertebrae and sternum, and the associated pain can be acute or insidious.

Diagnosis

Prostate cancer is most often diagnosed after biopsy prompted by an elevated PSA level or an abnormal digital rectal examination. The most common abnormal laboratory findings in patients with metastatic prostate cancer are an elevated serum PSA level (typically > 10 ng/mL), an elevated serum alkaline phosphatase level, and anemia, which are all proportional to the extent of bone involvement.

Screening is still controversial

There has been considerable controversy in recent years with regard to PSA screening because of the lack of significant benefit and the potential for harm to the patient, with an overdiagnosis rate ranging from 23% to 42%.²⁵

According to the ACS,²⁶ certain groups of men should make an informed decision with their physician about whether to undergo screening: men over age 50 at average risk of prostate cancer and with at least a 10-year life expectancy, men over age 45 at high risk, and men over age 40 at an even higher risk. These ACS guidelines are consistent with those of the NCCN¹² but differ from those of the USPSTF²⁷ (Table 4).^12,26,27

The patient should fully understand the risks and benefits of prostate cancer screening, as well as why it is controversial: ie, while the lifetime risk of being diagnosed with prostate cancer has increased, the lifetime risk of dying from it has remained the same after the advent of PSA testing.

Adverse effects of biopsy and treatment

Prostate biopsy is associated with infectious and bleeding complications, in addition to anxiety and physical discomfort.²⁸ Treatment-related adverse effects include urinary incontinence, sexual dysfunction, and bowel problems.

Could these potential harms be overstated and the benefit be greater than currently thought? The NCCN¹² noted that some of the landmark prostate cancer screening studies found a potential benefit in screening high-risk patients such as black men. Moreover, the studies used the sextant prostate biopsy technique, whereas now the extended core biopsy technique is the standard of care. And the studies may have underestimated the benefit of screening because the trial patients were relatively old (age 60) when their first PSA measurement was done, they were screened at long intervals (every 4 years), and the treatment options available at the time were not as good as those available today.¹²

Pearls

• Laboratory findings in metastatic prostate cancer are proportional to the extent of bone involvement.
• Most men with early-stage prostate cancer have no symptoms attributable to the disease.

LUNG CANCER

Lung cancer is the second most common type of cancer in men and women but has the highest mortality rate. In the United States, in 2015, an estimated 221,200 new cases of lung cancer and 158,040 deaths were expected.² Lung cancer deaths have begun to decline in both men and women, and this is due to the decline in smoking. The impact of lung cancer screening may not be seen for another 5 to 10 years.²⁹

A wide range of symptoms, presentations

Many patients with squamous cell carcinoma and small-cell lung carcinoma present with symptoms related to tumor involvement of the central airways,³⁰ including cough, hemoptysis, and postobstructive pneumonia. Partial obstruction of a bronchus may cause localized wheezing, heard by the patient or by the clinician on auscultation, whereas obstruction of larger airways can cause stridor.

Patients with advanced disease present with dull, aching, persistent chest pain from mediastinal, pleural, or chest wall extension, dyspnea from lymphangitic tumor spread, tumor emboli, pneumothorax, pleural effusion, or pericardial effusion with tamponade. Less commonly, patients may present with unilateral paralysis of the diaphragm from phrenic nerve damage or with hoarseness from recurrent laryngeal nerve compression.³¹

Bronchorrhea—production of large volumes of thin, mucoid secretions resulting in cough—may be a feature of bronchoalveolar cell carcinoma, a rare subtype of non-small-cell lung carcinoma.

Patients uncommonly present with superior vena cava syndrome, an oncologic emergency that most often causes facial and arm swelling, dyspnea, cough, and headache.

Non-small-cell lung carcinoma arising in the superior sulcus may in rare cases cause Pancoast syndrome (manifested by shoulder pain and atrophy of the hand muscles from brachial plexus involvement), Horner syndrome (manifested by ptosis, miosis, and anhidrosis), or rib destruction.

If metastasis occurs, lung cancer commonly metastasizes to the liver and adrenal glands. At the time of diagnosis, 20% to 30% of patients with small-cell lung carcinoma have symptoms of central nervous system metastasis.

The screening controversy

Lung cancer screening is controversial because previous large studies have failed to show a clinical benefit (ie, improved survival rates) of CT screening in smokers. However, based on the results of a later large randomized trial,³² the ACS³³ now recommends that patients ages 55 to 74 who are in fairly good health, have at least a 30-pack-year smoking history, and are currently smoking or have quit smoking within the last 15 years should discuss with their physician the benefits, limitations, and potential harms of lung cancer screening. These recommendations are similar to those of the NCCN^12,34 and USPSTF³⁵ (Table 5).^12,33–35 The ACS guidelines also emphasize that screening should be done only at facilities with extensive experience with low-dose CT.

Follow-up evaluation

If imaging detects a lung nodule, its size and consistency are crucial in determining the course of action.³³ If an endobronchial growth or solid nodule larger than 8 mm is discovered, the primary care physician should consider ordering either a repeat low-dose CT scan after 1 month or a positron-emission tomography CT scan.³⁴ The diagnosis should be confirmed by biopsy or by surgical removal of the nodule if localized and accessible, with sites of metastasis typically taking priority.

Pearl

• At diagnosis, 20% to 30% of patients with small-cell lung cancer have symptoms of central nervous system metastasis.

HIGHLY CURABLE CANCERS WITH UNUSUAL PRESENTATIONS

Hodgkin lymphoma

With 9,190 new cases in the United States annually and a 5-year overall survival rate over 85%, Hodgkin lymphoma is one of the least common but most curable cancers.^1,2 In the United States, there are two diagnostic peaks, one around age 20 and one around age 65.³⁶ In patients with human immunodeficiency virus infection, the rate is 15 to 30 times higher than in the general population, regardless of disease status or compliance with highly active retroviral therapy.³⁷

Hodgkin lymphoma typically presents as a nontender painless mass with rubbery consistency. The involved lymph node is typically cervical or supraclavicular. Although not detectable on physical examination, enlarged mediastinal nodes and retroperitoneal nodes are often present. Less commonly, patients may present with enlarged axillary and inguinal nodes.³⁸

A second common presentation is the discovery of a mediastinal mass on routine chest radiography. A large percentage of patients present with at least one systemic symptom, which may include fever, night sweats, and unintentional weight loss. Generalized pruritus occurs early in the disease course in 10% to 15% of patients and is occasionally severe enough to cause intense scratching and excoriations.

A more unusual presentation of Hodgkin lymphoma is severe pain at areas of involvement after alcohol ingestion.

Most patients present with overt disease, but the presenting symptoms and signs may be relatively nonspecific and subtle and more consistent with an infectious process.

Hodgkin disease has a variable tempo, but overt symptoms typically occur after several months rather than years. As a general rule, it starts at a single site within the lymphatic system, usually a lymph node, and then spreads to adjacent nodes via lymphatic channels before disseminating to distant nonadjacent sites and organs. With this in mind, it is unusual to have bilateral axillary involvement without disease in the lower neck, and extremely unusual to have hepatic or bone marrow infiltration without disease in the spleen.

The diagnosis is established by whole lymph node tissue biopsy. Due to the high rate of inflammation in the area, inguinal nodes should not be biopsied if other equally suspicious peripheral nodes are present elsewhere. When the diagnosis of Hodgkin lymphoma is made from biopsy of an extranodal site, such as the stomach, spleen, Waldeyer ring, central nervous system, lung, bone, or skin, lymph node biopsy is also desirable for diagnostic confirmation.

Testicular cancer

Although accounting for only about 1% of all cancers in men, testicular cancer is the most common solid tumor affecting males between ages 15 and 35.^1,2 With a 5-year survival rate of over 95%, testicular cancer is also one of the most curable cancers.

Testicular tumors usually present as a painless nodule or swelling of one testicle. Uncommonly, patients have metastatic disease at diagnosis, with the most common sites being lymph nodes, lung, bone, and the brain. Gynecomastia, associated with the production of human chorionic gonadotropin, occurs in about 5% of men with testicular germ cell tumors and 20% to 30% of men with Leydig cell tumors.³⁹ Rarely, patients may present with paraneoplastic hyperthyroidism, which is secondary to thyroid-stimulating hormone and human chorionic gonadotropin sharing a common homologous alpha and beta subunit.⁴⁰

Prompt diagnosis and treatment of testicular cancer provides the best opportunity for cure. Therefore, any testicular mass, even a painful scrotal lesion, should be evaluated as if it is testicular cancer until it is proven otherwise. The diagnostic evaluation of suspected testicular cancer includes scrotal ultrasonography. Radiographic testing, as deemed clinically necessary by the consulting urologist and medical oncologist, may include chest radiography, CT (chest, abdomen, pelvis), brain magnetic resonance imaging, or bone scan.

The primary care laboratory evaluation should include a complete metabolic profile and measurements of lactate dehydrogenase and serum tumor markers such as alpha fetoprotein and human chorionic gonadotropin. In nonseminomatous germ cell tumors, alpha fetoprotein or human chorionic gonadotropin, or both, can be elevated in 80% to 85% of patients. However, in seminoma, alpha fetoprotein is never elevated, and the serum human chorionic gonadotropin is elevated in only 20% to 25% of patients.⁴¹

Patients with a suspicious testicular mass should be referred promptly to a urologist for consideration of radical inguinal orchiectomy and, in some cases, retroperitoneal lymph node dissection. Testicular biopsy is not part of the evaluation as it may result in tumor seeding into the scrotal sac or metastatic spread of tumor to the inguinal nodes. Inguinal biopsy of the contralateral testis is considered if ultrasonography raises suspicion of an intratesticular abnormality, cryptorchid testis, or marked testicular atrophy. Discussing sperm banking with the patient is part of the diagnostic workup, as cumulative cisplatin doses greater than 400 mg/m² can result in permanent infertility in 50% of men.⁴²

Pearls

• In Hodgkin lymphoma, bilateral axillary involvement without disease in the lower neck is unusual.
• Discussing sperm banking is part of the diagnostic workup for testicular cancer.

According to the Surveillance, Epidemiology, and End Results database, 5-year overall survival rates have improved for nearly all tumor types during the past 40 years.¹ This has been accomplished with better treatment and earlier detection of the most common cancers, as well as the uncommon but highly curable tumor types.

Primary care physicians play a vital role in detecting cancers at earlier stages and synthesizing information from a patient’s presentation, vital signs, physical examination, and results of laboratory and radiographic testing. Yet cancers can be easily overlooked, and highly curable cancers such as Hodgkin lymphoma and testicular cancer, with 5-year survival rates above 85%, can have unusual presentations. Aside from the obvious health consequences, missed cancer diagnoses are often the subject of malpractice suits.

This paper reviews cancers that are easily missed and provides clinically relevant pearls from an oncologic perspective for primary care physicians, who are generally the first point of contact for patients.

BREAST CANCER DETECTION AND SCREENING

Breast cancer is the second most common cause of cancer death in US women and the most common cause of death in US women ages 20 to 59 (Table 1).^2–4

Screening mammography has had a significant impact on early detection rates, and this has translated into a 20% to 30% decrease in the breast cancer mortality rate.^5,6 But despite national screening guidelines, up to 15% of cases are diagnosed on the basis of a palpable breast mass not detected on mammography, and 30% are diagnosed with a breast mass during the interval between mammograms.^5,6 Moreover, delay in breast cancer diagnosis is one of the most common reasons for malpractice suits.^7,8

Warning signs

Breast cancer can present clinically as a single, dominant, indurated mass with irregular borders. The mass can have associated ecchymosis, erythema, nipple discharge, nipple retraction, and nipple eczema.^9,10 Pay close attention to any history of breast trauma, pain, signs or symptoms suggestive of local infection, and the lesion’s relationship to the patient’s menstrual cycle. Locally advanced disease typically presents with axillary adenopathy, as well as skin findings such as erythema, thickening, and dimpling.

Initial imaging workup for a breast mass

Women presenting with a breast mass should undergo breast imaging, followed by core needle biopsy of any suspicious abnormality. Depending on the clinical breast examination and the interpretation of the mammogram, as reported as a Breast Imaging Reporting and Data System (BIRADS) score, ultrasonography, magnetic resonance imaging, or biopsy may be the next course of action. Ultrasonography is recommended in evaluating masses in women who are under age 30 (who are more likely to have dense breasts that make standard mammography difficult to interpret) or who are pregnant (because it does not involve radiation).

For patients with a borderline or indeterminate clinical examination (eg, asymmetric skin-thickening or discoloration, nipple discharge or inversion, nodularity, finding on imaging [ie, BIRADS 3 lesion]), closer follow-up with repeat or additional imaging or biopsy, or both, is strongly recommended.

Screening recommendations vary

The age at which to start breast cancer screening has been a matter of debate in recent years, and different organizations have different recommendations (Table 2).^11–13 According to the American Cancer Society (ACS), women should begin screening mammography at age 45 and should continue it indefinitely as long as they are in good health.¹¹ This guideline is in line with those of the National Comprehensive Cancer Network (NCCN)¹² but differs from those of the US Preventive Services Task Force (USPSTF).¹³

One reason for the controversy is that although starting screening at a younger age may allow for earlier detection, it also leads to overdiagnosis and to unnecessary tests and procedures. However, the NCCN noted limitations in studies looking at the overdiagnosis of breast cancer, including their use of incidence data from the 1970s, which not only underestimated the annual incidence of breast cancer in the United States, but also neglected to differentiate invasive cancer from ductal carcinoma in situ.¹² Additionally, by detecting breast cancer lesions 2 years before they are discovered by clinical breast examination, mammography has been found to reduce the mortality rate from breast cancer.¹⁴

The frequency of mammography should be individualized and should involve not only an assessment of the patient’s risk factors (eg, age, family history, genetic predisposition, history of precancerous lesions, history of radiation exposure) but also a discussion of the benefits, limitations, and potential harms of screening. Both the ACS and the NCCN recommend yearly mammography for women ages 45 to 54. For those age 55 and older, the ACS recommends screening mammography every 2 years until the patient’s life expectancy is less than 10 years, whereas the NCCN recommends yearly screening mammography indefinitely. Meanwhile, the USPSTF recommends mammograms every 2 years for women ages 50 to 74.

Pearls

• Pay close attention to a history of breast trauma, pain, and signs of infection.
• Consider ultrasonography for women under age 30, who are more likely to have dense breasts.

COLORECTAL CANCER

With an estimated annual incidence of 132,700 cases diagnosed in the United States in 2015, colorectal cancer is the third most common cancer.

National guidelines that recommend colonoscopy (starting at age 50 for people at standard risk) have had a significant impact on early detection rates and have translated into a significant decrease in mortality rates.^2,15,16 However, a missed diagnosis of colorectal cancer is one of the most common reasons for malpractice suits, typically because the patient was not referred for colonoscopy according to national guidelines.^17–19

Symptoms depend on tumor location

In symptomatic cases, clinical manifestations differ depending on tumor location.

Left-sided tumors can present with hematochezia, colicky abdominal pain, and a change in bowel habits. And because the descending (left) colon has a smaller lumen than the right and tumors typically are annular in shape, left-sided cancers may present with abdominal distention with or without bowel obstruction or nausea and vomiting.

Right-sided tumors typically present with iron deficiency anemia from unrecognized blood loss.

Tumors near the rectum can cause tenesmus, rectal pain, and diminished caliber of stools.

In the United States, 20% of colorectal cancer patients have distant metastases at the time of diagnosis, and the most common sites are the lymph nodes, liver, lungs, and peritoneum.¹⁷

Uncommon presentations of colorectal cancer include pneumaturia, fecaluria or recurrent urinary tract infection from a fistula, bacteremia with Streptococcus bovis or Clostridium septicum, and intra-abdominal abscess from a localized bowel perforation.^20,21

Initial workup

Once cancer is suspected, colonoscopy is the most accurate and versatile diagnostic test. It not only permits localization and biopsy of lesions throughout the large bowel, but also detects synchronous neoplasms and permits removal of polyps. Computed tomographic (CT) colonography is an alternative if colonoscopy is contraindicated, but it can only detect larger (ie, > 6-mm) tumors.²²

According to the ACS,²³ men and women at average risk should undergo colorectal cancer screening beginning at age 50. ACS screening recommendations for polyps and colorectal cancer include flexible sigmoidoscopy every 5 years, colonoscopy every 10 years, double-contrast barium enema every 5 years, or CT colonography every 5 years. Tests that detect cancer but not polyps include guaiac-based fecal occult blood test (every year), fecal immunochemical test (every year), stool DNA test (every 3 years). These recommendations are fairly consistent with those of the NCCN¹² and USPSTF²⁴ (Table 3).^12,23,24

Pearls

• Uncommon presentations include urinary tract problems and intra-abdominal abscess.
• CT colonography can only detect larger tumors.

PROSTATE CANCER

With an estimated 220,800 cases and 27,540 deaths in 2015, prostate cancer is the most common cancer and the second most common cause of cancer-related death in US men.² Widespread use of serum prostate-specific antigen (PSA) testing has increased the rate of detection of prostate cancer.

Signs and symptoms

Most men with early-stage prostate cancer have no symptoms directly attributable to the disease.

Obstructive symptoms such as hesitancy, decreased stream, retention, and nocturia are common but are usually related to concomitant benign prostatic hypertrophy. As in prostatitis, patients with prostate cancer may present with irritative symptoms such as urinary frequency, dysuria, and urgency.

Patients who present with locally advanced prostate cancer may have symptoms secondary to local invasion, such as hematuria, hematospermia, and new-onset erectile dysfunction.

Prostate cancer usually metastasizes to bone, most commonly to the vertebrae and sternum, and the associated pain can be acute or insidious.

Diagnosis

Prostate cancer is most often diagnosed after biopsy prompted by an elevated PSA level or an abnormal digital rectal examination. The most common abnormal laboratory findings in patients with metastatic prostate cancer are an elevated serum PSA level (typically > 10 ng/mL), an elevated serum alkaline phosphatase level, and anemia, which are all proportional to the extent of bone involvement.

Screening is still controversial

There has been considerable controversy in recent years with regard to PSA screening because of the lack of significant benefit and the potential for harm to the patient, with an overdiagnosis rate ranging from 23% to 42%.²⁵

According to the ACS,²⁶ certain groups of men should make an informed decision with their physician about whether to undergo screening: men over age 50 at average risk of prostate cancer and with at least a 10-year life expectancy, men over age 45 at high risk, and men over age 40 at an even higher risk. These ACS guidelines are consistent with those of the NCCN¹² but differ from those of the USPSTF²⁷ (Table 4).^12,26,27

The patient should fully understand the risks and benefits of prostate cancer screening, as well as why it is controversial: ie, while the lifetime risk of being diagnosed with prostate cancer has increased, the lifetime risk of dying from it has remained the same after the advent of PSA testing.

Adverse effects of biopsy and treatment

Prostate biopsy is associated with infectious and bleeding complications, in addition to anxiety and physical discomfort.²⁸ Treatment-related adverse effects include urinary incontinence, sexual dysfunction, and bowel problems.

Could these potential harms be overstated and the benefit be greater than currently thought? The NCCN¹² noted that some of the landmark prostate cancer screening studies found a potential benefit in screening high-risk patients such as black men. Moreover, the studies used the sextant prostate biopsy technique, whereas now the extended core biopsy technique is the standard of care. And the studies may have underestimated the benefit of screening because the trial patients were relatively old (age 60) when their first PSA measurement was done, they were screened at long intervals (every 4 years), and the treatment options available at the time were not as good as those available today.¹²

Pearls

• Laboratory findings in metastatic prostate cancer are proportional to the extent of bone involvement.
• Most men with early-stage prostate cancer have no symptoms attributable to the disease.

LUNG CANCER

Lung cancer is the second most common type of cancer in men and women but has the highest mortality rate. In the United States, in 2015, an estimated 221,200 new cases of lung cancer and 158,040 deaths were expected.² Lung cancer deaths have begun to decline in both men and women, and this is due to the decline in smoking. The impact of lung cancer screening may not be seen for another 5 to 10 years.²⁹

A wide range of symptoms, presentations

Many patients with squamous cell carcinoma and small-cell lung carcinoma present with symptoms related to tumor involvement of the central airways,³⁰ including cough, hemoptysis, and postobstructive pneumonia. Partial obstruction of a bronchus may cause localized wheezing, heard by the patient or by the clinician on auscultation, whereas obstruction of larger airways can cause stridor.

Patients with advanced disease present with dull, aching, persistent chest pain from mediastinal, pleural, or chest wall extension, dyspnea from lymphangitic tumor spread, tumor emboli, pneumothorax, pleural effusion, or pericardial effusion with tamponade. Less commonly, patients may present with unilateral paralysis of the diaphragm from phrenic nerve damage or with hoarseness from recurrent laryngeal nerve compression.³¹

Bronchorrhea—production of large volumes of thin, mucoid secretions resulting in cough—may be a feature of bronchoalveolar cell carcinoma, a rare subtype of non-small-cell lung carcinoma.

Patients uncommonly present with superior vena cava syndrome, an oncologic emergency that most often causes facial and arm swelling, dyspnea, cough, and headache.

Non-small-cell lung carcinoma arising in the superior sulcus may in rare cases cause Pancoast syndrome (manifested by shoulder pain and atrophy of the hand muscles from brachial plexus involvement), Horner syndrome (manifested by ptosis, miosis, and anhidrosis), or rib destruction.

If metastasis occurs, lung cancer commonly metastasizes to the liver and adrenal glands. At the time of diagnosis, 20% to 30% of patients with small-cell lung carcinoma have symptoms of central nervous system metastasis.

The screening controversy

Lung cancer screening is controversial because previous large studies have failed to show a clinical benefit (ie, improved survival rates) of CT screening in smokers. However, based on the results of a later large randomized trial,³² the ACS³³ now recommends that patients ages 55 to 74 who are in fairly good health, have at least a 30-pack-year smoking history, and are currently smoking or have quit smoking within the last 15 years should discuss with their physician the benefits, limitations, and potential harms of lung cancer screening. These recommendations are similar to those of the NCCN^12,34 and USPSTF³⁵ (Table 5).^12,33–35 The ACS guidelines also emphasize that screening should be done only at facilities with extensive experience with low-dose CT.

Follow-up evaluation

If imaging detects a lung nodule, its size and consistency are crucial in determining the course of action.³³ If an endobronchial growth or solid nodule larger than 8 mm is discovered, the primary care physician should consider ordering either a repeat low-dose CT scan after 1 month or a positron-emission tomography CT scan.³⁴ The diagnosis should be confirmed by biopsy or by surgical removal of the nodule if localized and accessible, with sites of metastasis typically taking priority.

Pearl

• At diagnosis, 20% to 30% of patients with small-cell lung cancer have symptoms of central nervous system metastasis.

HIGHLY CURABLE CANCERS WITH UNUSUAL PRESENTATIONS

Hodgkin lymphoma

With 9,190 new cases in the United States annually and a 5-year overall survival rate over 85%, Hodgkin lymphoma is one of the least common but most curable cancers.^1,2 In the United States, there are two diagnostic peaks, one around age 20 and one around age 65.³⁶ In patients with human immunodeficiency virus infection, the rate is 15 to 30 times higher than in the general population, regardless of disease status or compliance with highly active retroviral therapy.³⁷

Hodgkin lymphoma typically presents as a nontender painless mass with rubbery consistency. The involved lymph node is typically cervical or supraclavicular. Although not detectable on physical examination, enlarged mediastinal nodes and retroperitoneal nodes are often present. Less commonly, patients may present with enlarged axillary and inguinal nodes.³⁸

A second common presentation is the discovery of a mediastinal mass on routine chest radiography. A large percentage of patients present with at least one systemic symptom, which may include fever, night sweats, and unintentional weight loss. Generalized pruritus occurs early in the disease course in 10% to 15% of patients and is occasionally severe enough to cause intense scratching and excoriations.

A more unusual presentation of Hodgkin lymphoma is severe pain at areas of involvement after alcohol ingestion.

Most patients present with overt disease, but the presenting symptoms and signs may be relatively nonspecific and subtle and more consistent with an infectious process.

Hodgkin disease has a variable tempo, but overt symptoms typically occur after several months rather than years. As a general rule, it starts at a single site within the lymphatic system, usually a lymph node, and then spreads to adjacent nodes via lymphatic channels before disseminating to distant nonadjacent sites and organs. With this in mind, it is unusual to have bilateral axillary involvement without disease in the lower neck, and extremely unusual to have hepatic or bone marrow infiltration without disease in the spleen.

The diagnosis is established by whole lymph node tissue biopsy. Due to the high rate of inflammation in the area, inguinal nodes should not be biopsied if other equally suspicious peripheral nodes are present elsewhere. When the diagnosis of Hodgkin lymphoma is made from biopsy of an extranodal site, such as the stomach, spleen, Waldeyer ring, central nervous system, lung, bone, or skin, lymph node biopsy is also desirable for diagnostic confirmation.

Testicular cancer

Although accounting for only about 1% of all cancers in men, testicular cancer is the most common solid tumor affecting males between ages 15 and 35.^1,2 With a 5-year survival rate of over 95%, testicular cancer is also one of the most curable cancers.

Testicular tumors usually present as a painless nodule or swelling of one testicle. Uncommonly, patients have metastatic disease at diagnosis, with the most common sites being lymph nodes, lung, bone, and the brain. Gynecomastia, associated with the production of human chorionic gonadotropin, occurs in about 5% of men with testicular germ cell tumors and 20% to 30% of men with Leydig cell tumors.³⁹ Rarely, patients may present with paraneoplastic hyperthyroidism, which is secondary to thyroid-stimulating hormone and human chorionic gonadotropin sharing a common homologous alpha and beta subunit.⁴⁰

Prompt diagnosis and treatment of testicular cancer provides the best opportunity for cure. Therefore, any testicular mass, even a painful scrotal lesion, should be evaluated as if it is testicular cancer until it is proven otherwise. The diagnostic evaluation of suspected testicular cancer includes scrotal ultrasonography. Radiographic testing, as deemed clinically necessary by the consulting urologist and medical oncologist, may include chest radiography, CT (chest, abdomen, pelvis), brain magnetic resonance imaging, or bone scan.

The primary care laboratory evaluation should include a complete metabolic profile and measurements of lactate dehydrogenase and serum tumor markers such as alpha fetoprotein and human chorionic gonadotropin. In nonseminomatous germ cell tumors, alpha fetoprotein or human chorionic gonadotropin, or both, can be elevated in 80% to 85% of patients. However, in seminoma, alpha fetoprotein is never elevated, and the serum human chorionic gonadotropin is elevated in only 20% to 25% of patients.⁴¹

Patients with a suspicious testicular mass should be referred promptly to a urologist for consideration of radical inguinal orchiectomy and, in some cases, retroperitoneal lymph node dissection. Testicular biopsy is not part of the evaluation as it may result in tumor seeding into the scrotal sac or metastatic spread of tumor to the inguinal nodes. Inguinal biopsy of the contralateral testis is considered if ultrasonography raises suspicion of an intratesticular abnormality, cryptorchid testis, or marked testicular atrophy. Discussing sperm banking with the patient is part of the diagnostic workup, as cumulative cisplatin doses greater than 400 mg/m² can result in permanent infertility in 50% of men.⁴²

Pearls

• In Hodgkin lymphoma, bilateral axillary involvement without disease in the lower neck is unusual.
• Discussing sperm banking is part of the diagnostic workup for testicular cancer.

Doctor, my heart ______.” Fill in the blank with: skips, flip-flops, hiccups, stops, beats in my throat or chest, or any of the various ways patients describe palpitations. One cannot practice clinical medicine and not see patients with some variation of this chief complaint.^1–3 Not every patient who complains of palpitations will be found to have premature ventricular contractions (PVCs), but PVCs are often part of the clinical problem.

This review focuses on the initial evaluation and management of PVCs in the primary care setting (Figure 1). It is not intended to be a comprehensive review of the pathophysiology, electrophysiology, or localization and ablation of PVCs. We will discuss approaches to the initial therapy of symptomatic PVCs. We will not discuss catheter-based therapy in detail except for which patients might benefit from referral to a clinical cardiac electrophysiologist.

Findings that should prompt consideration for referral to a specialist (“red flags”) are summarized at the end of each section. The type of specialist depends to a degree on the cardiology practice available to the referring physician. In our practice, such patients are typically seen by an electrophysiologist. In other practices, a general cardiologist might see such patients initially.

INITIAL EVALUATION

A primary concern of any patient presenting with a new symptom is whether the symptom is a marker of serious risk to health or life. In a patient with palpitations, the answer depends in large part on whether he or she has underlying structural heart disease—and that is the focus of the initial evaluation.

History: Information to ascertain

• When did the patient first notice the palpitations?
• Had there been any significant life events, either illness or emotional stress, at the time the palpitations began?
• Does the patient have a known history of heart disease (myocardial infarction, heart surgery, valvular heart disease, heart failure)?
• What medications is the patient taking?
• Does the patient take any dietary or health supplements? Ask specifically about any supplements taken to help with weight loss or increase energy levels. Almost all of them contain caffeine or other “natural” sympathomimetic agents. Also ask specifically about illicit drug use. If the patient is accompanied by a parent or partner, this question can be challenging.
• When do the palpitations occur? At random? At rest? With exercise? Time of day? In relation to the menstrual cycle? (More about this later.)
• Does anything make the palpitations better? If they occur at rest, does activity make them better or worse?
• Are there symptoms of heart failure, such as dyspnea on exertion, early fatigue, decline in exercise or exertional capacity, orthopnea, or paroxysmal nocturnal dyspnea?
• Are there symptoms suggesting cardiac ischemia, such as substernal chest pain or discomfort, chest pain or discomfort brought on by or made worse by exertion, or chest pain relieved with rest or sublingual nitroglycerin?
• Have the palpitations ever been associated with syncope? Keep in mind that syncope is transient loss of consciousness that spontaneously resolves with no features to suggest seizures.⁴ Thus, a patient who reports he or she “blacks out” with the palpitations but never falls or slumps has not had loss of consciousness and therefore has not had syncope.⁵
• Is there any history of unexplained death in the family, especially in younger people? Is there a history of unexplained accidental death in young family members?

Red flags obtained from the history

• Syncope related to palpitations
• Palpitations triggered by activity or exertion
• Known significant heart disease, congenital heart disease, or history of heart surgery
• Family history of premature unexplained sudden death in a first-degree relative.

Physical examination

The physical examination should focus on detecting any signs of underlying heart or vascular disease, eg:

• Significant murmurs
• Abnormal S3 or S4
• Displaced and diffuse point of maximal impulse or precordial heave
• Signs of right or left heart failure, or both, eg, peripheral edema, elevation of jugular venous pulse, rales, S3, S4.

Electrocardiography

We consider 12-lead electrocardiography (ECG) a part of the initial examination and assessment, not an ancillary test. One cannot evaluate a patient’s complaint of palpitations without ECG. Ideally, ECG should include a long 12-lead rhythm strip. The clinician should look for any evidence of underlying structural heart disease, eg:

• Pathologic Q waves
• Long QT interval
• ST-segment elevation in leads V₁ and V₂ consistent with a Brugada pattern
• Epsilon waves (seen in right ventricular arrhythmogenic cardiomyopathy).

Examples of the above can be found at sites such as ecgpedia.org.

Red flags in the physical examination and ECG

Any of the above findings on physical examination or ECG should prompt consideration of early referral, even though we have yet to establish that the palpitations are due to PVCs. Early consultation is suggested not for treatment of the palpitations but for further evaluation of structural heart disease.

Assuming the history, physical examination, and electrocardiography do not demonstrate any reasons for early cardiology or electrophysiology consultation, what’s next?

FURTHER EVALUATION: EXTENDED MONITORING

With luck, the patient’s typical palpitations will occur during ECG, in which case the palpitations can reasonably be attributed to PVCs. If not, monitoring is required to establish the cause of the patient’s symptoms.

The type of monitoring to order depends on the frequency of the palpitations. If the patient reports several episodes per day, then a 24- or 48-hour Holter monitor should both allow for a diagnosis and document the PVC burden (ie, the percent of the patient’s heartbeats that are PVCs), or the burden of whatever is the cause of the patient’s palpitations.

If the palpitations are less frequent, a 14-to-30-day monitor should be considered. A standard event recorder can confirm that the palpitations are due to PVCs but does not tell you the PVC burden. For that, a system capable of mobile outpatient cardiac telemetry is needed. Several such systems are commercially available.

A Holter monitor or other monitoring system is useful in determining whether the PVCs are unifocal (all look the same) or multifocal (have more than one morphology) and whether, in addition to PVCs, the patient has nonsustained ventricular tachycardia or sustained ventricular tachycardia (by definition lasting longer than 30 seconds or associated with symptoms of hemodynamic compromise such as near-syncope). Even if the patient has nonsustained ventricular tachycardia, if the heart is structurally normal the prognosis remains excellent.

Given the importance of knowing whether the patient has structural heart disease, we have a low threshold for ordering echocardiography, especially if nonsustained ventricular tachycardia has been documented. The finding of significant systolic dysfunction on echocardiography should prompt a cardiology consultation even if the physical examination is normal. In patients who have a high PVC burden, echocardiography is used to monitor for arrhythmia-induced cardiomyopathy.⁶

If the patient’s symptoms occur with activity, an exercise study can be helpful. It is important to either supervise the study oneself or, at the least, alert the exercise laboratory staff that the study is being performed to evaluate for exercise-induced arrhythmias. If the exercise study induces sustained ventricular tachycardia, the patient is almost invariably admitted to the hospital and inpatient consultation with an electrophysiologist is obtained.

Red flags on extended monitoring

• Multifocal PVCs or nonsustained ventricular tachycardia
• Polymorphic nonsustained ventricular tachycardia
• Sustained ventricular tachycardia; this still may be idiopathic and have a benign prognosis but generally should prompt referral.

If at this point no red flags have been uncovered, monitoring has established the patient’s symptoms are due to PVCs, and our examination and ancillary testing have established the patient has a structurally normal heart, what is the next step?

IDIOPATHIC PVCs

PVCs in a patient with a structurally normal heart are called “idiopathic.” Often, these patients will also be found to have nonsustained ventricular tachycardia, and may also be classified as having “idiopathic ventricular tachycardia.” Regardless of whether the patient has PVCs, nonsustained ventricular tachycardia, or both, the management approach is the same.

Roughly 60% to 80% of idiopathic PVCs originate from the right ventricle, in particular the right ventricular outflow tract.⁷ Patients with outflow tract PVCs typically present between the ages of 30 and 50 but range from adolescents to elders. More women than men are affected.

Outflow tract PVCs often occur only, or at much greater frequency, within a range of heart rates.⁸ Individual patients may have different ranges of heart rates at which their PVCs are more frequent. Patients may complain that their palpitations are more frequent at rest, early in exercise, at a peak of exercise, or early in recovery from exercise. It is not unusual for patients with outflow tract PVCs to report that activity reduces the frequency of their palpitations. Women might note an increase in their symptoms during menstruation.⁹ It is not clear, however, that this perceived increase in palpitations is in fact due to an increase in the number of PVCs.¹⁰

If the patient’s PVCs have not been captured on 12-lead ECG (ie, if it is not seen in all 12 leads), 12-lead Holter monitoring, if available, can be helpful. Examination of the morphology of the PVC on 12-lead ECG is extremely helpful. Outflow tract PVCs are the most common cause of idiopathic PVCs and nonsustained ventricular tachycardia and are easily recognizable with 12-lead ECG.

ECG points to the origin of the PVCs

A PVC arising on the right side of the heart will activate the right ventricle first and then the left ventricle. This is analogous to the sequence of ventricular activation in a patient with left bundle-branch block. Not surprisingly, on ECG a right-sided PVC looks similar to the QRS complex seen in left bundle-branch block—similar, but not identical.

When describing PVCs or the morphology of nonsustained ventricular tachycardia,  the terms “left bundle-branch block pattern” and “right bundle-branch block pattern” refer to lead V₁. If the PVC is negative (or mostly negative) in V₁, the PVC has a left bundle-branch block pattern. A PVC that is positive in V₁ is said to have a right bundle-branch block pattern and by implication arises from the left side of the heart.

A PVC originating from the top of the heart will move from top to bottom. The electrical axis of the PVC will be directed inferiorly. This means the PVC will be strongly positive in the inferior leads, ie, II, aVF, and III.

The electrocardiogram shown in Figure 2 demonstrates the typical appearance of a right ventricular outflow tract PVC.

If the PVC arises from the left ventricular outflow tract, the axis will still be inferiorly directed. However, the further to the left the origin of the PVC, the earlier the precordial transition will occur (the point at which the PVC is more positive than negative in the precordial leads). A PVC origin far enough to the left will result in a right bundle-branch block pattern PVC.

Not all idiopathic PVCs arise from the outflow tracts. A right bundle branch block pattern PVC does not imply the presence of underlying structural heart disease. PVCs may arise from both the tricuspid and mitral valve annuli, the left ventricular fascicles, or from the epicardium.

Multiple methods have been proposed to locate the origin of the PVC. For example, Park et al reviewed the use of surface ECG in locating the site of origin of ventricular tachycardia.¹¹ All such algorithms should be applied with care, and with awareness of the caveats associated with their use.

Arrhythmogenic right ventricular cardiomyopathy is not benign

Arrhythmogenic right ventricular cardiomyopathy may give rise to PVCs or nonsustained ventricular tachycardia with morphologies similar to those of right ventricular outflow tract PVCs and ventricular tachycardia. The ventricular tachycardia complicating arrhythmogenic cardiomyopathy is, like PVCs arising from the right ventricular outflow tract, commonly associated with exercise or activity.

Unlike right ventricular outflow tract tachycardia, ventricular tachycardia related to arrhythmogenic cardiomyopathy is not benign.¹² Distinguishing right ventricular outflow tract tachycardia from tachycardia secondary to arrhythmogenic cardiomyopathy is therefore critical.

Good-quality ECG demonstrating normal right ventricular size and function is reassuring, and if echocardiography is not conclusive, cardiovascular magnetic resonance imaging may provide additional diagnostic and prognostic data, especially when arrhythmogenic cardiomyopathy, cardiac sarcoidosis, or cardiac amyloidosis is suspected.⁶

Recently, magnetic resonance imaging has been used most for infiltrative diseases as the imaging modality of choice due to its superior tissue characterization and noninvasive morphological and functional evaluation. Magnetic resonance imaging findings in patients with arrhythmogenic cardiomyopathy correlate well with those of endomyocardial biopsy, angiography, and echocardiography  and have been associated with incremental arrhythmic risk in the setting of electrical abnormalities. The increasing use of magnetic resonance imaging is leading to the recognition that left ventricular involvement (left-dominant arrhythmogenic right ventricular cardiomyopathy) is more common than previously recognized, with some suggesting that arrhythmogenic right ventricular cardiomyopathy should be simply called “arrhythmogenic cardiomyopathy.”

Although endomyocardial biopsy can establish the diagnosis of arrhythmogenic right ventricular cardiomyopathy, it is rarely performed because it has a high false-negative rate owing to the patchy, epicardial nature of this disorder.¹³

Red flags for cardiomyopathy

• Multifocal PVCs, or nonsustained ventricular tachycardia of more than one morphology on monitoring
• Syncope associated with active exercise
• Abnormal imaging findings that are consistent with arrhythmogenic right ventricular cardiomyopathy, cardiac sarcoidosis, or amyloidosis.

WHEN TO TREAT IDIOPATHIC PVCs

In our practice we explain to patients that there are two primary indications for treating idiopathic PVCs: (1) to relieve symptoms or (2) in asymptomatic patients with presumed arrhythmia-induced cardiomyopathy, to try to reverse the cardiomyopathy by eliminating the PVCs.

Some patients report severe symptoms due to their PVCs. Other patients appear to have no symptoms whatsoever, while still others are not overly bothered by the PVCs but are concerned that they may indicate they are at increased risk of cardiac events. In this last group, an evaluation such as outlined above that discloses no evidence of structural heart disease and reassurance by the physician may be all the treatment needed.

Even if they have no symptoms or only minimal symptoms, patients with a high PVC burden require follow-up because of the association between frequent PVCs and arrhythmia-induced cardiomyopathy.^14,15 What constitutes a “high” PVC burden remains a matter of debate. Left ventricular dysfunction has generally been reported at PVC burdens above 15% to 25% of the total cardiac beats, though this percentage can be as low as 10%.¹⁴

Eliminating the high burden of PVCs in patients with left ventricular dysfunction may significantly improve left ventricular systolic function.¹⁵ It is likely, however, that more than PVC burden alone contributes to the development of the cardiomyopathy.¹⁴

Given these complexities, it is reasonable to request an electrophysiology consultation for patients who have more than rare PVCs. What is rare? There is no defined standard, but a PVC burden less than 1% is reasonable.

Treatment of the PVCs may be indicated in patients with systolic heart failure receiving cardiac resynchronization therapy, ie, a biventricular pacemaker. For cardiac resynchronization therapy to be clinically beneficial, close to 100% of heartbeats need to be paced, and frequent PVCs, even at a burden less than 10%, may undermine its effectiveness.¹⁶

HOW TO INTERVENE?

Beta-blockers and nondihydropyridine calcium channel blockers have both been used to treat symptomatic PVCs. If the patient is found to have systolic dysfunction as part of the evaluation, a beta-blocker is indicated, irrespective of any desire to treat the PVCs. Beta-blockers and calcium channel blockers both have low adverse effect profiles. They are available in once-a-day formulations and are inexpensive. Their efficacy is variable. The use of these medications is well within the purview of the primary care physician.

Selective beta-blockers are the first choice in treatment, and metoprolol is commonly used in clinical practice. We start with a low dose and increase it based on symptom relief.

As noted, only nondihydropyridine calcium channel blockers should be used for treatment of PVCs. As with beta-blockers, we start at a low dose and increase as needed based on the response to therapy.

Antiarrhythymic drugs are classified according to the Vaughan-Williams system. The ones most frequently used for PVCs are the class Ic drugs propafenone and flecainide and the class III drugs  sotalol, amiodarone, and dofetalide. However, in our experience, if first-line agents (ie, beta-blockers and nondihydropyridine calcium channel blockers) are unsuccessful in controlling the patient’s symptoms, most primary care physicians are uncomfortable prescribing class Ic and class III drugs. Failure of a beta-blocker, a calcium channel blocker, or both often results in referral to a cardiologist or electrophysiologist.

The consultation should include a careful discussion with the patient regarding the risk of treatment with a type I or a type III drug vs catheter ablation. Treatment with class I or class III antiarrhythmic drugs always entails a small risk of proarrhythmia. The choice between drug therapy or ablation therapy is highly individualized. However, if elimination of the PVCs is of paramount importance, such as in cases of arrhythmia-induced cardiomyopathy, ablation therapy is more effective at eliminating the PVCs, although at the cost of an invasive procedure. Fortunately, the risk of complications with ablation therapy is quite low.

No drugs are approved by the US Food and Drug Administration for treating PVCs or nonsustained ventricular tachycardia. The drugs that do have an indication for treatment of ventricular arrhythmias are labeled as being indicated for “sustained” or “life-threatening” ventricular arrhythmias. The use of drugs for the treatment of PVCs or nonsustained ventricular tachycardia represents off-label usage.

Referral to discuss catheter ablation of the PVCs⁶ should be considered for patients who:

• Have undergone unsuccessful attempts at drug therapy for either symptoms or PVC-related cardiomyopathy
• Refuse drug therapy but have severe symptoms, or
• Do not respond to cardiac resynchronization therapy due to suboptimal pacing due to PVCs.

Doctor, my heart ______.” Fill in the blank with: skips, flip-flops, hiccups, stops, beats in my throat or chest, or any of the various ways patients describe palpitations. One cannot practice clinical medicine and not see patients with some variation of this chief complaint.^1–3 Not every patient who complains of palpitations will be found to have premature ventricular contractions (PVCs), but PVCs are often part of the clinical problem.

This review focuses on the initial evaluation and management of PVCs in the primary care setting (Figure 1). It is not intended to be a comprehensive review of the pathophysiology, electrophysiology, or localization and ablation of PVCs. We will discuss approaches to the initial therapy of symptomatic PVCs. We will not discuss catheter-based therapy in detail except for which patients might benefit from referral to a clinical cardiac electrophysiologist.

Findings that should prompt consideration for referral to a specialist (“red flags”) are summarized at the end of each section. The type of specialist depends to a degree on the cardiology practice available to the referring physician. In our practice, such patients are typically seen by an electrophysiologist. In other practices, a general cardiologist might see such patients initially.

INITIAL EVALUATION

A primary concern of any patient presenting with a new symptom is whether the symptom is a marker of serious risk to health or life. In a patient with palpitations, the answer depends in large part on whether he or she has underlying structural heart disease—and that is the focus of the initial evaluation.

History: Information to ascertain

• When did the patient first notice the palpitations?
• Had there been any significant life events, either illness or emotional stress, at the time the palpitations began?
• Does the patient have a known history of heart disease (myocardial infarction, heart surgery, valvular heart disease, heart failure)?
• What medications is the patient taking?
• Does the patient take any dietary or health supplements? Ask specifically about any supplements taken to help with weight loss or increase energy levels. Almost all of them contain caffeine or other “natural” sympathomimetic agents. Also ask specifically about illicit drug use. If the patient is accompanied by a parent or partner, this question can be challenging.
• When do the palpitations occur? At random? At rest? With exercise? Time of day? In relation to the menstrual cycle? (More about this later.)
• Does anything make the palpitations better? If they occur at rest, does activity make them better or worse?
• Are there symptoms of heart failure, such as dyspnea on exertion, early fatigue, decline in exercise or exertional capacity, orthopnea, or paroxysmal nocturnal dyspnea?
• Are there symptoms suggesting cardiac ischemia, such as substernal chest pain or discomfort, chest pain or discomfort brought on by or made worse by exertion, or chest pain relieved with rest or sublingual nitroglycerin?
• Have the palpitations ever been associated with syncope? Keep in mind that syncope is transient loss of consciousness that spontaneously resolves with no features to suggest seizures.⁴ Thus, a patient who reports he or she “blacks out” with the palpitations but never falls or slumps has not had loss of consciousness and therefore has not had syncope.⁵
• Is there any history of unexplained death in the family, especially in younger people? Is there a history of unexplained accidental death in young family members?

Red flags obtained from the history

• Syncope related to palpitations
• Palpitations triggered by activity or exertion
• Known significant heart disease, congenital heart disease, or history of heart surgery
• Family history of premature unexplained sudden death in a first-degree relative.

Physical examination

The physical examination should focus on detecting any signs of underlying heart or vascular disease, eg:

• Significant murmurs
• Abnormal S3 or S4
• Displaced and diffuse point of maximal impulse or precordial heave
• Signs of right or left heart failure, or both, eg, peripheral edema, elevation of jugular venous pulse, rales, S3, S4.

Electrocardiography

We consider 12-lead electrocardiography (ECG) a part of the initial examination and assessment, not an ancillary test. One cannot evaluate a patient’s complaint of palpitations without ECG. Ideally, ECG should include a long 12-lead rhythm strip. The clinician should look for any evidence of underlying structural heart disease, eg:

• Pathologic Q waves
• Long QT interval
• ST-segment elevation in leads V₁ and V₂ consistent with a Brugada pattern
• Epsilon waves (seen in right ventricular arrhythmogenic cardiomyopathy).

Examples of the above can be found at sites such as ecgpedia.org.

Red flags in the physical examination and ECG

Any of the above findings on physical examination or ECG should prompt consideration of early referral, even though we have yet to establish that the palpitations are due to PVCs. Early consultation is suggested not for treatment of the palpitations but for further evaluation of structural heart disease.

Assuming the history, physical examination, and electrocardiography do not demonstrate any reasons for early cardiology or electrophysiology consultation, what’s next?

FURTHER EVALUATION: EXTENDED MONITORING

With luck, the patient’s typical palpitations will occur during ECG, in which case the palpitations can reasonably be attributed to PVCs. If not, monitoring is required to establish the cause of the patient’s symptoms.

The type of monitoring to order depends on the frequency of the palpitations. If the patient reports several episodes per day, then a 24- or 48-hour Holter monitor should both allow for a diagnosis and document the PVC burden (ie, the percent of the patient’s heartbeats that are PVCs), or the burden of whatever is the cause of the patient’s palpitations.

If the palpitations are less frequent, a 14-to-30-day monitor should be considered. A standard event recorder can confirm that the palpitations are due to PVCs but does not tell you the PVC burden. For that, a system capable of mobile outpatient cardiac telemetry is needed. Several such systems are commercially available.

A Holter monitor or other monitoring system is useful in determining whether the PVCs are unifocal (all look the same) or multifocal (have more than one morphology) and whether, in addition to PVCs, the patient has nonsustained ventricular tachycardia or sustained ventricular tachycardia (by definition lasting longer than 30 seconds or associated with symptoms of hemodynamic compromise such as near-syncope). Even if the patient has nonsustained ventricular tachycardia, if the heart is structurally normal the prognosis remains excellent.

Given the importance of knowing whether the patient has structural heart disease, we have a low threshold for ordering echocardiography, especially if nonsustained ventricular tachycardia has been documented. The finding of significant systolic dysfunction on echocardiography should prompt a cardiology consultation even if the physical examination is normal. In patients who have a high PVC burden, echocardiography is used to monitor for arrhythmia-induced cardiomyopathy.⁶

If the patient’s symptoms occur with activity, an exercise study can be helpful. It is important to either supervise the study oneself or, at the least, alert the exercise laboratory staff that the study is being performed to evaluate for exercise-induced arrhythmias. If the exercise study induces sustained ventricular tachycardia, the patient is almost invariably admitted to the hospital and inpatient consultation with an electrophysiologist is obtained.

Red flags on extended monitoring

• Multifocal PVCs or nonsustained ventricular tachycardia
• Polymorphic nonsustained ventricular tachycardia
• Sustained ventricular tachycardia; this still may be idiopathic and have a benign prognosis but generally should prompt referral.

If at this point no red flags have been uncovered, monitoring has established the patient’s symptoms are due to PVCs, and our examination and ancillary testing have established the patient has a structurally normal heart, what is the next step?

IDIOPATHIC PVCs

PVCs in a patient with a structurally normal heart are called “idiopathic.” Often, these patients will also be found to have nonsustained ventricular tachycardia, and may also be classified as having “idiopathic ventricular tachycardia.” Regardless of whether the patient has PVCs, nonsustained ventricular tachycardia, or both, the management approach is the same.

Roughly 60% to 80% of idiopathic PVCs originate from the right ventricle, in particular the right ventricular outflow tract.⁷ Patients with outflow tract PVCs typically present between the ages of 30 and 50 but range from adolescents to elders. More women than men are affected.

Outflow tract PVCs often occur only, or at much greater frequency, within a range of heart rates.⁸ Individual patients may have different ranges of heart rates at which their PVCs are more frequent. Patients may complain that their palpitations are more frequent at rest, early in exercise, at a peak of exercise, or early in recovery from exercise. It is not unusual for patients with outflow tract PVCs to report that activity reduces the frequency of their palpitations. Women might note an increase in their symptoms during menstruation.⁹ It is not clear, however, that this perceived increase in palpitations is in fact due to an increase in the number of PVCs.¹⁰

If the patient’s PVCs have not been captured on 12-lead ECG (ie, if it is not seen in all 12 leads), 12-lead Holter monitoring, if available, can be helpful. Examination of the morphology of the PVC on 12-lead ECG is extremely helpful. Outflow tract PVCs are the most common cause of idiopathic PVCs and nonsustained ventricular tachycardia and are easily recognizable with 12-lead ECG.

ECG points to the origin of the PVCs

A PVC arising on the right side of the heart will activate the right ventricle first and then the left ventricle. This is analogous to the sequence of ventricular activation in a patient with left bundle-branch block. Not surprisingly, on ECG a right-sided PVC looks similar to the QRS complex seen in left bundle-branch block—similar, but not identical.

When describing PVCs or the morphology of nonsustained ventricular tachycardia,  the terms “left bundle-branch block pattern” and “right bundle-branch block pattern” refer to lead V₁. If the PVC is negative (or mostly negative) in V₁, the PVC has a left bundle-branch block pattern. A PVC that is positive in V₁ is said to have a right bundle-branch block pattern and by implication arises from the left side of the heart.

A PVC originating from the top of the heart will move from top to bottom. The electrical axis of the PVC will be directed inferiorly. This means the PVC will be strongly positive in the inferior leads, ie, II, aVF, and III.

The electrocardiogram shown in Figure 2 demonstrates the typical appearance of a right ventricular outflow tract PVC.

If the PVC arises from the left ventricular outflow tract, the axis will still be inferiorly directed. However, the further to the left the origin of the PVC, the earlier the precordial transition will occur (the point at which the PVC is more positive than negative in the precordial leads). A PVC origin far enough to the left will result in a right bundle-branch block pattern PVC.

Not all idiopathic PVCs arise from the outflow tracts. A right bundle branch block pattern PVC does not imply the presence of underlying structural heart disease. PVCs may arise from both the tricuspid and mitral valve annuli, the left ventricular fascicles, or from the epicardium.

Multiple methods have been proposed to locate the origin of the PVC. For example, Park et al reviewed the use of surface ECG in locating the site of origin of ventricular tachycardia.¹¹ All such algorithms should be applied with care, and with awareness of the caveats associated with their use.

Arrhythmogenic right ventricular cardiomyopathy is not benign

Arrhythmogenic right ventricular cardiomyopathy may give rise to PVCs or nonsustained ventricular tachycardia with morphologies similar to those of right ventricular outflow tract PVCs and ventricular tachycardia. The ventricular tachycardia complicating arrhythmogenic cardiomyopathy is, like PVCs arising from the right ventricular outflow tract, commonly associated with exercise or activity.

Unlike right ventricular outflow tract tachycardia, ventricular tachycardia related to arrhythmogenic cardiomyopathy is not benign.¹² Distinguishing right ventricular outflow tract tachycardia from tachycardia secondary to arrhythmogenic cardiomyopathy is therefore critical.

Good-quality ECG demonstrating normal right ventricular size and function is reassuring, and if echocardiography is not conclusive, cardiovascular magnetic resonance imaging may provide additional diagnostic and prognostic data, especially when arrhythmogenic cardiomyopathy, cardiac sarcoidosis, or cardiac amyloidosis is suspected.⁶

Recently, magnetic resonance imaging has been used most for infiltrative diseases as the imaging modality of choice due to its superior tissue characterization and noninvasive morphological and functional evaluation. Magnetic resonance imaging findings in patients with arrhythmogenic cardiomyopathy correlate well with those of endomyocardial biopsy, angiography, and echocardiography  and have been associated with incremental arrhythmic risk in the setting of electrical abnormalities. The increasing use of magnetic resonance imaging is leading to the recognition that left ventricular involvement (left-dominant arrhythmogenic right ventricular cardiomyopathy) is more common than previously recognized, with some suggesting that arrhythmogenic right ventricular cardiomyopathy should be simply called “arrhythmogenic cardiomyopathy.”

Although endomyocardial biopsy can establish the diagnosis of arrhythmogenic right ventricular cardiomyopathy, it is rarely performed because it has a high false-negative rate owing to the patchy, epicardial nature of this disorder.¹³

Red flags for cardiomyopathy

• Multifocal PVCs, or nonsustained ventricular tachycardia of more than one morphology on monitoring
• Syncope associated with active exercise
• Abnormal imaging findings that are consistent with arrhythmogenic right ventricular cardiomyopathy, cardiac sarcoidosis, or amyloidosis.

WHEN TO TREAT IDIOPATHIC PVCs

In our practice we explain to patients that there are two primary indications for treating idiopathic PVCs: (1) to relieve symptoms or (2) in asymptomatic patients with presumed arrhythmia-induced cardiomyopathy, to try to reverse the cardiomyopathy by eliminating the PVCs.

Some patients report severe symptoms due to their PVCs. Other patients appear to have no symptoms whatsoever, while still others are not overly bothered by the PVCs but are concerned that they may indicate they are at increased risk of cardiac events. In this last group, an evaluation such as outlined above that discloses no evidence of structural heart disease and reassurance by the physician may be all the treatment needed.

Even if they have no symptoms or only minimal symptoms, patients with a high PVC burden require follow-up because of the association between frequent PVCs and arrhythmia-induced cardiomyopathy.^14,15 What constitutes a “high” PVC burden remains a matter of debate. Left ventricular dysfunction has generally been reported at PVC burdens above 15% to 25% of the total cardiac beats, though this percentage can be as low as 10%.¹⁴

Eliminating the high burden of PVCs in patients with left ventricular dysfunction may significantly improve left ventricular systolic function.¹⁵ It is likely, however, that more than PVC burden alone contributes to the development of the cardiomyopathy.¹⁴

Given these complexities, it is reasonable to request an electrophysiology consultation for patients who have more than rare PVCs. What is rare? There is no defined standard, but a PVC burden less than 1% is reasonable.

Treatment of the PVCs may be indicated in patients with systolic heart failure receiving cardiac resynchronization therapy, ie, a biventricular pacemaker. For cardiac resynchronization therapy to be clinically beneficial, close to 100% of heartbeats need to be paced, and frequent PVCs, even at a burden less than 10%, may undermine its effectiveness.¹⁶

HOW TO INTERVENE?

Beta-blockers and nondihydropyridine calcium channel blockers have both been used to treat symptomatic PVCs. If the patient is found to have systolic dysfunction as part of the evaluation, a beta-blocker is indicated, irrespective of any desire to treat the PVCs. Beta-blockers and calcium channel blockers both have low adverse effect profiles. They are available in once-a-day formulations and are inexpensive. Their efficacy is variable. The use of these medications is well within the purview of the primary care physician.

Selective beta-blockers are the first choice in treatment, and metoprolol is commonly used in clinical practice. We start with a low dose and increase it based on symptom relief.

As noted, only nondihydropyridine calcium channel blockers should be used for treatment of PVCs. As with beta-blockers, we start at a low dose and increase as needed based on the response to therapy.

Antiarrhythymic drugs are classified according to the Vaughan-Williams system. The ones most frequently used for PVCs are the class Ic drugs propafenone and flecainide and the class III drugs  sotalol, amiodarone, and dofetalide. However, in our experience, if first-line agents (ie, beta-blockers and nondihydropyridine calcium channel blockers) are unsuccessful in controlling the patient’s symptoms, most primary care physicians are uncomfortable prescribing class Ic and class III drugs. Failure of a beta-blocker, a calcium channel blocker, or both often results in referral to a cardiologist or electrophysiologist.

The consultation should include a careful discussion with the patient regarding the risk of treatment with a type I or a type III drug vs catheter ablation. Treatment with class I or class III antiarrhythmic drugs always entails a small risk of proarrhythmia. The choice between drug therapy or ablation therapy is highly individualized. However, if elimination of the PVCs is of paramount importance, such as in cases of arrhythmia-induced cardiomyopathy, ablation therapy is more effective at eliminating the PVCs, although at the cost of an invasive procedure. Fortunately, the risk of complications with ablation therapy is quite low.

No drugs are approved by the US Food and Drug Administration for treating PVCs or nonsustained ventricular tachycardia. The drugs that do have an indication for treatment of ventricular arrhythmias are labeled as being indicated for “sustained” or “life-threatening” ventricular arrhythmias. The use of drugs for the treatment of PVCs or nonsustained ventricular tachycardia represents off-label usage.

Referral to discuss catheter ablation of the PVCs⁶ should be considered for patients who:

• Have undergone unsuccessful attempts at drug therapy for either symptoms or PVC-related cardiomyopathy
• Refuse drug therapy but have severe symptoms, or
• Do not respond to cardiac resynchronization therapy due to suboptimal pacing due to PVCs.

Doctor, my heart ______.” Fill in the blank with: skips, flip-flops, hiccups, stops, beats in my throat or chest, or any of the various ways patients describe palpitations. One cannot practice clinical medicine and not see patients with some variation of this chief complaint.^1–3 Not every patient who complains of palpitations will be found to have premature ventricular contractions (PVCs), but PVCs are often part of the clinical problem.

This review focuses on the initial evaluation and management of PVCs in the primary care setting (Figure 1). It is not intended to be a comprehensive review of the pathophysiology, electrophysiology, or localization and ablation of PVCs. We will discuss approaches to the initial therapy of symptomatic PVCs. We will not discuss catheter-based therapy in detail except for which patients might benefit from referral to a clinical cardiac electrophysiologist.

Findings that should prompt consideration for referral to a specialist (“red flags”) are summarized at the end of each section. The type of specialist depends to a degree on the cardiology practice available to the referring physician. In our practice, such patients are typically seen by an electrophysiologist. In other practices, a general cardiologist might see such patients initially.

INITIAL EVALUATION

A primary concern of any patient presenting with a new symptom is whether the symptom is a marker of serious risk to health or life. In a patient with palpitations, the answer depends in large part on whether he or she has underlying structural heart disease—and that is the focus of the initial evaluation.

History: Information to ascertain

• When did the patient first notice the palpitations?
• Had there been any significant life events, either illness or emotional stress, at the time the palpitations began?
• Does the patient have a known history of heart disease (myocardial infarction, heart surgery, valvular heart disease, heart failure)?
• What medications is the patient taking?
• Does the patient take any dietary or health supplements? Ask specifically about any supplements taken to help with weight loss or increase energy levels. Almost all of them contain caffeine or other “natural” sympathomimetic agents. Also ask specifically about illicit drug use. If the patient is accompanied by a parent or partner, this question can be challenging.
• When do the palpitations occur? At random? At rest? With exercise? Time of day? In relation to the menstrual cycle? (More about this later.)
• Does anything make the palpitations better? If they occur at rest, does activity make them better or worse?
• Are there symptoms of heart failure, such as dyspnea on exertion, early fatigue, decline in exercise or exertional capacity, orthopnea, or paroxysmal nocturnal dyspnea?
• Are there symptoms suggesting cardiac ischemia, such as substernal chest pain or discomfort, chest pain or discomfort brought on by or made worse by exertion, or chest pain relieved with rest or sublingual nitroglycerin?
• Have the palpitations ever been associated with syncope? Keep in mind that syncope is transient loss of consciousness that spontaneously resolves with no features to suggest seizures.⁴ Thus, a patient who reports he or she “blacks out” with the palpitations but never falls or slumps has not had loss of consciousness and therefore has not had syncope.⁵
• Is there any history of unexplained death in the family, especially in younger people? Is there a history of unexplained accidental death in young family members?

Red flags obtained from the history

• Syncope related to palpitations
• Palpitations triggered by activity or exertion
• Known significant heart disease, congenital heart disease, or history of heart surgery
• Family history of premature unexplained sudden death in a first-degree relative.

Physical examination

The physical examination should focus on detecting any signs of underlying heart or vascular disease, eg:

• Significant murmurs
• Abnormal S3 or S4
• Displaced and diffuse point of maximal impulse or precordial heave
• Signs of right or left heart failure, or both, eg, peripheral edema, elevation of jugular venous pulse, rales, S3, S4.

Electrocardiography

We consider 12-lead electrocardiography (ECG) a part of the initial examination and assessment, not an ancillary test. One cannot evaluate a patient’s complaint of palpitations without ECG. Ideally, ECG should include a long 12-lead rhythm strip. The clinician should look for any evidence of underlying structural heart disease, eg:

• Pathologic Q waves
• Long QT interval
• ST-segment elevation in leads V₁ and V₂ consistent with a Brugada pattern
• Epsilon waves (seen in right ventricular arrhythmogenic cardiomyopathy).

Examples of the above can be found at sites such as ecgpedia.org.

Red flags in the physical examination and ECG

Any of the above findings on physical examination or ECG should prompt consideration of early referral, even though we have yet to establish that the palpitations are due to PVCs. Early consultation is suggested not for treatment of the palpitations but for further evaluation of structural heart disease.

Assuming the history, physical examination, and electrocardiography do not demonstrate any reasons for early cardiology or electrophysiology consultation, what’s next?

FURTHER EVALUATION: EXTENDED MONITORING

With luck, the patient’s typical palpitations will occur during ECG, in which case the palpitations can reasonably be attributed to PVCs. If not, monitoring is required to establish the cause of the patient’s symptoms.

The type of monitoring to order depends on the frequency of the palpitations. If the patient reports several episodes per day, then a 24- or 48-hour Holter monitor should both allow for a diagnosis and document the PVC burden (ie, the percent of the patient’s heartbeats that are PVCs), or the burden of whatever is the cause of the patient’s palpitations.

If the palpitations are less frequent, a 14-to-30-day monitor should be considered. A standard event recorder can confirm that the palpitations are due to PVCs but does not tell you the PVC burden. For that, a system capable of mobile outpatient cardiac telemetry is needed. Several such systems are commercially available.

A Holter monitor or other monitoring system is useful in determining whether the PVCs are unifocal (all look the same) or multifocal (have more than one morphology) and whether, in addition to PVCs, the patient has nonsustained ventricular tachycardia or sustained ventricular tachycardia (by definition lasting longer than 30 seconds or associated with symptoms of hemodynamic compromise such as near-syncope). Even if the patient has nonsustained ventricular tachycardia, if the heart is structurally normal the prognosis remains excellent.

Given the importance of knowing whether the patient has structural heart disease, we have a low threshold for ordering echocardiography, especially if nonsustained ventricular tachycardia has been documented. The finding of significant systolic dysfunction on echocardiography should prompt a cardiology consultation even if the physical examination is normal. In patients who have a high PVC burden, echocardiography is used to monitor for arrhythmia-induced cardiomyopathy.⁶

If the patient’s symptoms occur with activity, an exercise study can be helpful. It is important to either supervise the study oneself or, at the least, alert the exercise laboratory staff that the study is being performed to evaluate for exercise-induced arrhythmias. If the exercise study induces sustained ventricular tachycardia, the patient is almost invariably admitted to the hospital and inpatient consultation with an electrophysiologist is obtained.

Red flags on extended monitoring

• Multifocal PVCs or nonsustained ventricular tachycardia
• Polymorphic nonsustained ventricular tachycardia
• Sustained ventricular tachycardia; this still may be idiopathic and have a benign prognosis but generally should prompt referral.

If at this point no red flags have been uncovered, monitoring has established the patient’s symptoms are due to PVCs, and our examination and ancillary testing have established the patient has a structurally normal heart, what is the next step?

IDIOPATHIC PVCs

PVCs in a patient with a structurally normal heart are called “idiopathic.” Often, these patients will also be found to have nonsustained ventricular tachycardia, and may also be classified as having “idiopathic ventricular tachycardia.” Regardless of whether the patient has PVCs, nonsustained ventricular tachycardia, or both, the management approach is the same.

Roughly 60% to 80% of idiopathic PVCs originate from the right ventricle, in particular the right ventricular outflow tract.⁷ Patients with outflow tract PVCs typically present between the ages of 30 and 50 but range from adolescents to elders. More women than men are affected.

Outflow tract PVCs often occur only, or at much greater frequency, within a range of heart rates.⁸ Individual patients may have different ranges of heart rates at which their PVCs are more frequent. Patients may complain that their palpitations are more frequent at rest, early in exercise, at a peak of exercise, or early in recovery from exercise. It is not unusual for patients with outflow tract PVCs to report that activity reduces the frequency of their palpitations. Women might note an increase in their symptoms during menstruation.⁹ It is not clear, however, that this perceived increase in palpitations is in fact due to an increase in the number of PVCs.¹⁰

If the patient’s PVCs have not been captured on 12-lead ECG (ie, if it is not seen in all 12 leads), 12-lead Holter monitoring, if available, can be helpful. Examination of the morphology of the PVC on 12-lead ECG is extremely helpful. Outflow tract PVCs are the most common cause of idiopathic PVCs and nonsustained ventricular tachycardia and are easily recognizable with 12-lead ECG.

ECG points to the origin of the PVCs

A PVC arising on the right side of the heart will activate the right ventricle first and then the left ventricle. This is analogous to the sequence of ventricular activation in a patient with left bundle-branch block. Not surprisingly, on ECG a right-sided PVC looks similar to the QRS complex seen in left bundle-branch block—similar, but not identical.

When describing PVCs or the morphology of nonsustained ventricular tachycardia,  the terms “left bundle-branch block pattern” and “right bundle-branch block pattern” refer to lead V₁. If the PVC is negative (or mostly negative) in V₁, the PVC has a left bundle-branch block pattern. A PVC that is positive in V₁ is said to have a right bundle-branch block pattern and by implication arises from the left side of the heart.

A PVC originating from the top of the heart will move from top to bottom. The electrical axis of the PVC will be directed inferiorly. This means the PVC will be strongly positive in the inferior leads, ie, II, aVF, and III.

The electrocardiogram shown in Figure 2 demonstrates the typical appearance of a right ventricular outflow tract PVC.

If the PVC arises from the left ventricular outflow tract, the axis will still be inferiorly directed. However, the further to the left the origin of the PVC, the earlier the precordial transition will occur (the point at which the PVC is more positive than negative in the precordial leads). A PVC origin far enough to the left will result in a right bundle-branch block pattern PVC.

Not all idiopathic PVCs arise from the outflow tracts. A right bundle branch block pattern PVC does not imply the presence of underlying structural heart disease. PVCs may arise from both the tricuspid and mitral valve annuli, the left ventricular fascicles, or from the epicardium.

Multiple methods have been proposed to locate the origin of the PVC. For example, Park et al reviewed the use of surface ECG in locating the site of origin of ventricular tachycardia.¹¹ All such algorithms should be applied with care, and with awareness of the caveats associated with their use.

Arrhythmogenic right ventricular cardiomyopathy is not benign

Arrhythmogenic right ventricular cardiomyopathy may give rise to PVCs or nonsustained ventricular tachycardia with morphologies similar to those of right ventricular outflow tract PVCs and ventricular tachycardia. The ventricular tachycardia complicating arrhythmogenic cardiomyopathy is, like PVCs arising from the right ventricular outflow tract, commonly associated with exercise or activity.

Unlike right ventricular outflow tract tachycardia, ventricular tachycardia related to arrhythmogenic cardiomyopathy is not benign.¹² Distinguishing right ventricular outflow tract tachycardia from tachycardia secondary to arrhythmogenic cardiomyopathy is therefore critical.

Good-quality ECG demonstrating normal right ventricular size and function is reassuring, and if echocardiography is not conclusive, cardiovascular magnetic resonance imaging may provide additional diagnostic and prognostic data, especially when arrhythmogenic cardiomyopathy, cardiac sarcoidosis, or cardiac amyloidosis is suspected.⁶

Recently, magnetic resonance imaging has been used most for infiltrative diseases as the imaging modality of choice due to its superior tissue characterization and noninvasive morphological and functional evaluation. Magnetic resonance imaging findings in patients with arrhythmogenic cardiomyopathy correlate well with those of endomyocardial biopsy, angiography, and echocardiography  and have been associated with incremental arrhythmic risk in the setting of electrical abnormalities. The increasing use of magnetic resonance imaging is leading to the recognition that left ventricular involvement (left-dominant arrhythmogenic right ventricular cardiomyopathy) is more common than previously recognized, with some suggesting that arrhythmogenic right ventricular cardiomyopathy should be simply called “arrhythmogenic cardiomyopathy.”

Although endomyocardial biopsy can establish the diagnosis of arrhythmogenic right ventricular cardiomyopathy, it is rarely performed because it has a high false-negative rate owing to the patchy, epicardial nature of this disorder.¹³

Red flags for cardiomyopathy

• Multifocal PVCs, or nonsustained ventricular tachycardia of more than one morphology on monitoring
• Syncope associated with active exercise
• Abnormal imaging findings that are consistent with arrhythmogenic right ventricular cardiomyopathy, cardiac sarcoidosis, or amyloidosis.

WHEN TO TREAT IDIOPATHIC PVCs

In our practice we explain to patients that there are two primary indications for treating idiopathic PVCs: (1) to relieve symptoms or (2) in asymptomatic patients with presumed arrhythmia-induced cardiomyopathy, to try to reverse the cardiomyopathy by eliminating the PVCs.

Some patients report severe symptoms due to their PVCs. Other patients appear to have no symptoms whatsoever, while still others are not overly bothered by the PVCs but are concerned that they may indicate they are at increased risk of cardiac events. In this last group, an evaluation such as outlined above that discloses no evidence of structural heart disease and reassurance by the physician may be all the treatment needed.

Even if they have no symptoms or only minimal symptoms, patients with a high PVC burden require follow-up because of the association between frequent PVCs and arrhythmia-induced cardiomyopathy.^14,15 What constitutes a “high” PVC burden remains a matter of debate. Left ventricular dysfunction has generally been reported at PVC burdens above 15% to 25% of the total cardiac beats, though this percentage can be as low as 10%.¹⁴

Eliminating the high burden of PVCs in patients with left ventricular dysfunction may significantly improve left ventricular systolic function.¹⁵ It is likely, however, that more than PVC burden alone contributes to the development of the cardiomyopathy.¹⁴

Given these complexities, it is reasonable to request an electrophysiology consultation for patients who have more than rare PVCs. What is rare? There is no defined standard, but a PVC burden less than 1% is reasonable.

Treatment of the PVCs may be indicated in patients with systolic heart failure receiving cardiac resynchronization therapy, ie, a biventricular pacemaker. For cardiac resynchronization therapy to be clinically beneficial, close to 100% of heartbeats need to be paced, and frequent PVCs, even at a burden less than 10%, may undermine its effectiveness.¹⁶

HOW TO INTERVENE?

Beta-blockers and nondihydropyridine calcium channel blockers have both been used to treat symptomatic PVCs. If the patient is found to have systolic dysfunction as part of the evaluation, a beta-blocker is indicated, irrespective of any desire to treat the PVCs. Beta-blockers and calcium channel blockers both have low adverse effect profiles. They are available in once-a-day formulations and are inexpensive. Their efficacy is variable. The use of these medications is well within the purview of the primary care physician.

Selective beta-blockers are the first choice in treatment, and metoprolol is commonly used in clinical practice. We start with a low dose and increase it based on symptom relief.

As noted, only nondihydropyridine calcium channel blockers should be used for treatment of PVCs. As with beta-blockers, we start at a low dose and increase as needed based on the response to therapy.

Antiarrhythymic drugs are classified according to the Vaughan-Williams system. The ones most frequently used for PVCs are the class Ic drugs propafenone and flecainide and the class III drugs  sotalol, amiodarone, and dofetalide. However, in our experience, if first-line agents (ie, beta-blockers and nondihydropyridine calcium channel blockers) are unsuccessful in controlling the patient’s symptoms, most primary care physicians are uncomfortable prescribing class Ic and class III drugs. Failure of a beta-blocker, a calcium channel blocker, or both often results in referral to a cardiologist or electrophysiologist.

The consultation should include a careful discussion with the patient regarding the risk of treatment with a type I or a type III drug vs catheter ablation. Treatment with class I or class III antiarrhythmic drugs always entails a small risk of proarrhythmia. The choice between drug therapy or ablation therapy is highly individualized. However, if elimination of the PVCs is of paramount importance, such as in cases of arrhythmia-induced cardiomyopathy, ablation therapy is more effective at eliminating the PVCs, although at the cost of an invasive procedure. Fortunately, the risk of complications with ablation therapy is quite low.

No drugs are approved by the US Food and Drug Administration for treating PVCs or nonsustained ventricular tachycardia. The drugs that do have an indication for treatment of ventricular arrhythmias are labeled as being indicated for “sustained” or “life-threatening” ventricular arrhythmias. The use of drugs for the treatment of PVCs or nonsustained ventricular tachycardia represents off-label usage.

Referral to discuss catheter ablation of the PVCs⁶ should be considered for patients who:

• Have undergone unsuccessful attempts at drug therapy for either symptoms or PVC-related cardiomyopathy
• Refuse drug therapy but have severe symptoms, or
• Do not respond to cardiac resynchronization therapy due to suboptimal pacing due to PVCs.

Until the advent of the electronic medical record (EMR), patient charts were filled with handwritten notes documenting visits to the office and read in linear fashion, starting with the patient’s perspective of the problem, then the objective findings of the physical examination, supporting objective data, and finally, the physician’s assessment and treatment plan.

The reliable subjective, objective, assessment, plan (SOAP) approach to notes first advocated by Lawrence Weed in the 1960s did a remarkable job of conveying the physician’s thought process, supporting data, and conclusions.^1,2 The notes were brief by necessity, as the physician did not want to spend time writing extraneous information.

In the age of the EMR, large quantities of data are included in the patient notes that have no connection to or do not clearly convey the physician’s thought process. In 2013, 78% of office-based physicians were using EMRs, an increase from 18% in 2001 and an adoption rate accelerated by federal government policies.^3,4 But many physicians still do not feel competent reading or writing notes in an EMR and still prefer to read succinct narrative notes.⁵

This problem is not unique to seasoned physicians. Medical students are also failing to learn how to appropriately document office visits in the EMR, as 52% of medical schools prohibit them from writing in patient charts.⁶

As a result, we believed that a reassessment of Dr. Weed’s problem-oriented approach to the medical record was required to streamline the EMR and facilitate the way information is conveyed between providers of the patient’s care. Too often, large quantities of laboratory, radiographic, and pathology results are dumped into the record, burying pertinent information about the physician’s thought process, assessment, and evaluation and treatment plan and making it difficult to quickly and efficiently determine the plan.

We recently adopted an approach to office notes that is a modification of the SOAP note. While physicians often gather subjective, objective, and laboratory information to deductively formulate a diagnosis, it is not necessary to document it in the traditional deductive format in the EMR when the information is readily accessible in other areas of the record. Furthermore, a deductive format in the modern EMR produces excessively lengthy notes that require pages of screen scrolling to find the key elements required for effective patient care. This is time-consuming and is a daily obstruction to patient care.

The format that we have been using for almost 10 years still allows the physician to adhere to the problem-oriented medical note philosophy. We call it the CAPS note, which stands for concern, assessment, plan, and supporting data. This approach allows others involved in the patient’s care to efficiently extract critical components (assessment and plan for a specifically stated problem) while still allowing the inclusion of supporting data for reference and for coding and billing.

The structure of the CAPS note is:

• Concern: The primary purpose of the patient’s visit, including the history of the present illness, as conveyed by the patient, and the current status of the concern.
• Assessment: A succinct definition of the patient’s concern along with an accompanying medical diagnosis.
• Plan: The clinician’s immediate and long-term intentions for addressing the patient’s concern or condition.
• Supporting objective and subjective information: All supporting objective data, starting with the physical examination, then the results of laboratory and radiographic tests, and any other information that contributed to the clinician’s medical reasoning. Then, subjective information is included, such as the patient’s past medical, surgical, family, and social histories; current medications; allergies; and a comprehensive review of systems.

This structure keeps the most important information at the top when the encounter is opened on the computer screen and eliminates the need for unnecessary scrolling and searching, not to mention frustration and delays in patient care. Other less pertinent information appears toward the bottom of the record.

THE APSO NOTE VS THE SOAP NOTE

Frustration over the difficulty of finding the most pertinent information in the EMR—the assessment and the plan—has led others to propose a rearrangement of the traditional SOAP note. The APSO (assessment, plan, subjective, objective) note^7,8 was created for inpatient daily progress notes, a situation in which the patient’s concern is unlikely to change dramatically on a daily basis and was not intended for use in outpatient clinics.⁸ While the APSO format does allow colleagues rapid access to the physician’s assessment and plan, it abandons the patient-centered approach of Dr. Weed’s problem-oriented medical record in that it makes it more difficult to find why the patient initially sought care, how long the patient has had the problem, or if there were prior attempts to treat it. These critical details are buried in the bowels of the note.

The advantage of the CAPS note (Table 1) is that it retains the patient-centered, problem-oriented spirit of the SOAP format, while moving potentially supportive yet distracting data fields to later in the note. Thus it is applicable to inpatient and outpatient settings.

In the inpatient setting, the fields remain in the same order, but the chief complaint is often the admitting diagnosis or surgical procedure, followed by a quick line on the interval history. The assessment and plan can then follow in much the same way as it would in the outpatient setting, and below that are the patient’s daily laboratory results, radiographic studies, physical examination findings, and any other relevant supporting data. This format allows rapid access to critical information needed by either consultants or cross-covering practitioners who primarily want to know why the patient was admitted, the status, and the primary team’s plan.

ANY TEMPLATE HAS LIMITATIONS

Any standardized template for progress notes in the EMR has limitations. The CAPS format would be easier for a hospital-based physician, who typically addresses one or a small number of concerns, than for an office-based general practitioner who may have to address a multitude of comorbidities in a single visit.

Also, different physicians use the EMR differently. For example, a survey of 1,088 physicians found that 60% of primary care physicians used templates (60%) vs only 34% of specialists, and that 38% of specialists relied mainly on dictation.⁹

The CAPS approach to the office visit note offers a blend of a template and free text, either typed or dictated, while keeping a structured format that permits others participating in the patient’s care to easily extract desired information. The template can easily be brought up in the patient’s chart, then by either typing or using voice-recognition software, the patient’s chief complaint, history of the present illness, assessment, and plan can be easily completed.

The CAPS format should continue to allow notes to fulfill medicolegal and billing obligations, but without cluttering true clinical reasoning. As more institutions adopt an open-notes policy, permitting patients to freely browse their own medical records, patients will benefit from a clearly structured clinical note that focuses on their problem and the practitioner’s solution. This provides patients a sense of validation and reassurance that the note starts with their concern and history, followed by the practitioner’s assessment and plan, so they can easily affirm that they were accurately heard and can identify the diagnosis given to them by the medical practitioner and the plan moving forward.

Since a return to succinct, albeit often illegible, handwritten clinic notes is impossible, our proposed method of documenting a clinic visit embraces the EMR with a concise yet comprehensive clinic note.

Until the advent of the electronic medical record (EMR), patient charts were filled with handwritten notes documenting visits to the office and read in linear fashion, starting with the patient’s perspective of the problem, then the objective findings of the physical examination, supporting objective data, and finally, the physician’s assessment and treatment plan.

The reliable subjective, objective, assessment, plan (SOAP) approach to notes first advocated by Lawrence Weed in the 1960s did a remarkable job of conveying the physician’s thought process, supporting data, and conclusions.^1,2 The notes were brief by necessity, as the physician did not want to spend time writing extraneous information.

In the age of the EMR, large quantities of data are included in the patient notes that have no connection to or do not clearly convey the physician’s thought process. In 2013, 78% of office-based physicians were using EMRs, an increase from 18% in 2001 and an adoption rate accelerated by federal government policies.^3,4 But many physicians still do not feel competent reading or writing notes in an EMR and still prefer to read succinct narrative notes.⁵

This problem is not unique to seasoned physicians. Medical students are also failing to learn how to appropriately document office visits in the EMR, as 52% of medical schools prohibit them from writing in patient charts.⁶

As a result, we believed that a reassessment of Dr. Weed’s problem-oriented approach to the medical record was required to streamline the EMR and facilitate the way information is conveyed between providers of the patient’s care. Too often, large quantities of laboratory, radiographic, and pathology results are dumped into the record, burying pertinent information about the physician’s thought process, assessment, and evaluation and treatment plan and making it difficult to quickly and efficiently determine the plan.

We recently adopted an approach to office notes that is a modification of the SOAP note. While physicians often gather subjective, objective, and laboratory information to deductively formulate a diagnosis, it is not necessary to document it in the traditional deductive format in the EMR when the information is readily accessible in other areas of the record. Furthermore, a deductive format in the modern EMR produces excessively lengthy notes that require pages of screen scrolling to find the key elements required for effective patient care. This is time-consuming and is a daily obstruction to patient care.

The format that we have been using for almost 10 years still allows the physician to adhere to the problem-oriented medical note philosophy. We call it the CAPS note, which stands for concern, assessment, plan, and supporting data. This approach allows others involved in the patient’s care to efficiently extract critical components (assessment and plan for a specifically stated problem) while still allowing the inclusion of supporting data for reference and for coding and billing.

The structure of the CAPS note is:

• Concern: The primary purpose of the patient’s visit, including the history of the present illness, as conveyed by the patient, and the current status of the concern.
• Assessment: A succinct definition of the patient’s concern along with an accompanying medical diagnosis.
• Plan: The clinician’s immediate and long-term intentions for addressing the patient’s concern or condition.
• Supporting objective and subjective information: All supporting objective data, starting with the physical examination, then the results of laboratory and radiographic tests, and any other information that contributed to the clinician’s medical reasoning. Then, subjective information is included, such as the patient’s past medical, surgical, family, and social histories; current medications; allergies; and a comprehensive review of systems.

This structure keeps the most important information at the top when the encounter is opened on the computer screen and eliminates the need for unnecessary scrolling and searching, not to mention frustration and delays in patient care. Other less pertinent information appears toward the bottom of the record.

THE APSO NOTE VS THE SOAP NOTE

Frustration over the difficulty of finding the most pertinent information in the EMR—the assessment and the plan—has led others to propose a rearrangement of the traditional SOAP note. The APSO (assessment, plan, subjective, objective) note^7,8 was created for inpatient daily progress notes, a situation in which the patient’s concern is unlikely to change dramatically on a daily basis and was not intended for use in outpatient clinics.⁸ While the APSO format does allow colleagues rapid access to the physician’s assessment and plan, it abandons the patient-centered approach of Dr. Weed’s problem-oriented medical record in that it makes it more difficult to find why the patient initially sought care, how long the patient has had the problem, or if there were prior attempts to treat it. These critical details are buried in the bowels of the note.

The advantage of the CAPS note (Table 1) is that it retains the patient-centered, problem-oriented spirit of the SOAP format, while moving potentially supportive yet distracting data fields to later in the note. Thus it is applicable to inpatient and outpatient settings.

In the inpatient setting, the fields remain in the same order, but the chief complaint is often the admitting diagnosis or surgical procedure, followed by a quick line on the interval history. The assessment and plan can then follow in much the same way as it would in the outpatient setting, and below that are the patient’s daily laboratory results, radiographic studies, physical examination findings, and any other relevant supporting data. This format allows rapid access to critical information needed by either consultants or cross-covering practitioners who primarily want to know why the patient was admitted, the status, and the primary team’s plan.

ANY TEMPLATE HAS LIMITATIONS

Any standardized template for progress notes in the EMR has limitations. The CAPS format would be easier for a hospital-based physician, who typically addresses one or a small number of concerns, than for an office-based general practitioner who may have to address a multitude of comorbidities in a single visit.

Also, different physicians use the EMR differently. For example, a survey of 1,088 physicians found that 60% of primary care physicians used templates (60%) vs only 34% of specialists, and that 38% of specialists relied mainly on dictation.⁹

The CAPS approach to the office visit note offers a blend of a template and free text, either typed or dictated, while keeping a structured format that permits others participating in the patient’s care to easily extract desired information. The template can easily be brought up in the patient’s chart, then by either typing or using voice-recognition software, the patient’s chief complaint, history of the present illness, assessment, and plan can be easily completed.

The CAPS format should continue to allow notes to fulfill medicolegal and billing obligations, but without cluttering true clinical reasoning. As more institutions adopt an open-notes policy, permitting patients to freely browse their own medical records, patients will benefit from a clearly structured clinical note that focuses on their problem and the practitioner’s solution. This provides patients a sense of validation and reassurance that the note starts with their concern and history, followed by the practitioner’s assessment and plan, so they can easily affirm that they were accurately heard and can identify the diagnosis given to them by the medical practitioner and the plan moving forward.

Since a return to succinct, albeit often illegible, handwritten clinic notes is impossible, our proposed method of documenting a clinic visit embraces the EMR with a concise yet comprehensive clinic note.

Until the advent of the electronic medical record (EMR), patient charts were filled with handwritten notes documenting visits to the office and read in linear fashion, starting with the patient’s perspective of the problem, then the objective findings of the physical examination, supporting objective data, and finally, the physician’s assessment and treatment plan.

The reliable subjective, objective, assessment, plan (SOAP) approach to notes first advocated by Lawrence Weed in the 1960s did a remarkable job of conveying the physician’s thought process, supporting data, and conclusions.^1,2 The notes were brief by necessity, as the physician did not want to spend time writing extraneous information.

In the age of the EMR, large quantities of data are included in the patient notes that have no connection to or do not clearly convey the physician’s thought process. In 2013, 78% of office-based physicians were using EMRs, an increase from 18% in 2001 and an adoption rate accelerated by federal government policies.^3,4 But many physicians still do not feel competent reading or writing notes in an EMR and still prefer to read succinct narrative notes.⁵

This problem is not unique to seasoned physicians. Medical students are also failing to learn how to appropriately document office visits in the EMR, as 52% of medical schools prohibit them from writing in patient charts.⁶

As a result, we believed that a reassessment of Dr. Weed’s problem-oriented approach to the medical record was required to streamline the EMR and facilitate the way information is conveyed between providers of the patient’s care. Too often, large quantities of laboratory, radiographic, and pathology results are dumped into the record, burying pertinent information about the physician’s thought process, assessment, and evaluation and treatment plan and making it difficult to quickly and efficiently determine the plan.

We recently adopted an approach to office notes that is a modification of the SOAP note. While physicians often gather subjective, objective, and laboratory information to deductively formulate a diagnosis, it is not necessary to document it in the traditional deductive format in the EMR when the information is readily accessible in other areas of the record. Furthermore, a deductive format in the modern EMR produces excessively lengthy notes that require pages of screen scrolling to find the key elements required for effective patient care. This is time-consuming and is a daily obstruction to patient care.

The format that we have been using for almost 10 years still allows the physician to adhere to the problem-oriented medical note philosophy. We call it the CAPS note, which stands for concern, assessment, plan, and supporting data. This approach allows others involved in the patient’s care to efficiently extract critical components (assessment and plan for a specifically stated problem) while still allowing the inclusion of supporting data for reference and for coding and billing.

The structure of the CAPS note is:

• Concern: The primary purpose of the patient’s visit, including the history of the present illness, as conveyed by the patient, and the current status of the concern.
• Assessment: A succinct definition of the patient’s concern along with an accompanying medical diagnosis.
• Plan: The clinician’s immediate and long-term intentions for addressing the patient’s concern or condition.
• Supporting objective and subjective information: All supporting objective data, starting with the physical examination, then the results of laboratory and radiographic tests, and any other information that contributed to the clinician’s medical reasoning. Then, subjective information is included, such as the patient’s past medical, surgical, family, and social histories; current medications; allergies; and a comprehensive review of systems.

This structure keeps the most important information at the top when the encounter is opened on the computer screen and eliminates the need for unnecessary scrolling and searching, not to mention frustration and delays in patient care. Other less pertinent information appears toward the bottom of the record.

THE APSO NOTE VS THE SOAP NOTE

Frustration over the difficulty of finding the most pertinent information in the EMR—the assessment and the plan—has led others to propose a rearrangement of the traditional SOAP note. The APSO (assessment, plan, subjective, objective) note^7,8 was created for inpatient daily progress notes, a situation in which the patient’s concern is unlikely to change dramatically on a daily basis and was not intended for use in outpatient clinics.⁸ While the APSO format does allow colleagues rapid access to the physician’s assessment and plan, it abandons the patient-centered approach of Dr. Weed’s problem-oriented medical record in that it makes it more difficult to find why the patient initially sought care, how long the patient has had the problem, or if there were prior attempts to treat it. These critical details are buried in the bowels of the note.

The advantage of the CAPS note (Table 1) is that it retains the patient-centered, problem-oriented spirit of the SOAP format, while moving potentially supportive yet distracting data fields to later in the note. Thus it is applicable to inpatient and outpatient settings.

In the inpatient setting, the fields remain in the same order, but the chief complaint is often the admitting diagnosis or surgical procedure, followed by a quick line on the interval history. The assessment and plan can then follow in much the same way as it would in the outpatient setting, and below that are the patient’s daily laboratory results, radiographic studies, physical examination findings, and any other relevant supporting data. This format allows rapid access to critical information needed by either consultants or cross-covering practitioners who primarily want to know why the patient was admitted, the status, and the primary team’s plan.

ANY TEMPLATE HAS LIMITATIONS

Any standardized template for progress notes in the EMR has limitations. The CAPS format would be easier for a hospital-based physician, who typically addresses one or a small number of concerns, than for an office-based general practitioner who may have to address a multitude of comorbidities in a single visit.

Also, different physicians use the EMR differently. For example, a survey of 1,088 physicians found that 60% of primary care physicians used templates (60%) vs only 34% of specialists, and that 38% of specialists relied mainly on dictation.⁹

The CAPS approach to the office visit note offers a blend of a template and free text, either typed or dictated, while keeping a structured format that permits others participating in the patient’s care to easily extract desired information. The template can easily be brought up in the patient’s chart, then by either typing or using voice-recognition software, the patient’s chief complaint, history of the present illness, assessment, and plan can be easily completed.

The CAPS format should continue to allow notes to fulfill medicolegal and billing obligations, but without cluttering true clinical reasoning. As more institutions adopt an open-notes policy, permitting patients to freely browse their own medical records, patients will benefit from a clearly structured clinical note that focuses on their problem and the practitioner’s solution. This provides patients a sense of validation and reassurance that the note starts with their concern and history, followed by the practitioner’s assessment and plan, so they can easily affirm that they were accurately heard and can identify the diagnosis given to them by the medical practitioner and the plan moving forward.

Since a return to succinct, albeit often illegible, handwritten clinic notes is impossible, our proposed method of documenting a clinic visit embraces the EMR with a concise yet comprehensive clinic note.

Alpha-1 antitrypsin deficiency is a common but underrecognized genetic condition that increases the risk of chronic obstructive pulmonary disease (COPD) and liver disease. Primary care providers can play a critical role in detecting it and managing patients who have it.

RECOGNIZED CASES ARE THE TIP OF THE ICEBERG

First described in 1963,¹ alpha-1 antitrypsin deficiency is estimated to affect 100,000 Americans, fewer than 15,000 of whom have received a clinical diagnosis. As further evidence of its underrecognition,^2–7 many patients experience long delays between their first symptoms and the diagnosis. Early studies indicated that the average diagnostic delay was 7.2 years,4 and the latest studies, as recent as 2013, indicate a similar diagnostic delay.⁷

Furthermore, many patients see multiple healthcare providers before receiving the correct diagnosis. A 1994 survey by this author⁴ found that 43.7% of patients who had severe deficiency of alpha-1 antitrypsin saw at least three physicians before the correct diagnosis was made.

Why is the disease underrecognized?

Several reasons may account for underrecognition of this disease. Many clinicians—including, unfortunately, many pulmonologists—do not know much about it,^7,8 do not adhere to clinical guidelines,^9,10 or harbor the misperception that there is no therapy available and, therefore, no compelling reason to make a diagnosis.⁷

Regarding inadequate knowledge, in a study by Taliercio, Chatburn, and this author,⁸ internal medicine residents scored only 63% correct on a 10-question quiz on diagnostic features of alpha-1 antitrypsin deficiency. There was no evidence of a training effect—senior residents scored no higher than interns.

Similarly, when Greulich et al⁷ surveyed German and Italian internists, general practitioners, and pulmonologists, one-fourth to one-half of them (depending on specialty and country) stated that they knew either very little or nothing at all about alpha-1 antitrypsin deficiency. In addition, 7% to 8% agreed with the statement, “There is no treatment available for this disease.”⁷

Nonadoption of clinical guidelines has been widely recognized in medicine and is evident in the failure to implement various recommended practices,^9,10 such as low-stretch ventilation for acute respiratory distress syndrome and prophylaxis against deep vein thrombosis.

Finding the rest of the iceberg

Efforts to enhance compliance with guidelines on testing for alpha-1 antitrypsin deficiency have included using the electronic medical record to prompt physicians to test appropriate candidates.^11–13

Jain et al¹³ examined the effect of installing such a prompting system to remind physicians to test for alpha-1 antitrypsin deficiency in patients with airflow obstruction that does not reverse with a bronchodilator—a recognized indication for testing for this disease according to standards endorsed by the American Thoracic Society and European Respiratory Society.¹⁴ At baseline, only 4.7% of appropriate candidates were being tested; after a prompt was installed in the electronic medical record, the rate rose to 15.1%, still a minority of candidates.

Another strategy is to empower respiratory therapists who perform pulmonary function tests to invite patients to be tested if their pulmonary function tests show postbronchodilator airflow obstruction. Rahaghi et al¹⁵ showed that using this strategy, 20 (0.63%) of 3,152 patients who were found to have fixed airflow obstruction when they underwent pulmonary function testing were newly diagnosed with severe deficiency of alpha-1 antitrypsin. Other targeted detection studies in patients with COPD estimated the prevalence of alpha-1 antitrypsin deficiency at up to 12%.³

PHYSIOLOGY AND PATHOPHYSIOLOGY OF ALPHA-1 ANTITRYPSIN DEFICIENCY

Alpha-1 antitrypsin is a single-chain, 394-amino acid glycoprotein with three carbohydrate side chains found at asparagine residues along the primary structure.¹⁶

A major physiologic function of this molecule is to bind neutrophil elastase, which it does avidly. In a “mousetrap-like” mechanism,¹⁶ an active site on the alpha-1 antitrypsin molecule captures the neutrophil elastase and is cleaved, releasing steric energy in the molecule, catapulting the neutrophil elastase to the opposite side of the alpha-1 antitrypsin molecule, and inactivating it (Figure 1).

MM is normal, ZZ is not

Alpha-1 antitrypsin deficiency is inherited as an autosomal-codominant condition.¹⁷

The SERPINA1 gene, which codes for alpha-1 antitrypsin, is located on the long arm of the 14th chromosome, and more than 150 alleles of this gene have been identified to date. The normal allele is denoted M, and the allele most commonly associated with severe deficiency is denoted Z. People who are homozygous for the M allele (ie, normal) are called PI*MM (PI stands for “protease inhibitor”), and those who are homozygous for the Z allele are PI*ZZ. More than 90% of patients with severe alpha-1 antitrypsin deficiency are PI*ZZ.¹⁸

The Z allele has a single amino acid substitution (glutamic acid-to-lysine at position 342), which results in abnormal folding and formation of polymers of the Z molecule within hepatocytes.^19,20 These polymers are recognized on liver biopsy as periodic acid-Schiff diastase-resistant eosinophilic inclusion bodies on histologic staining (Figure 2).

With alpha-1 antitrypsin trapped as Z-molecule polymers in the liver, the amount in the bloodstream falls, and there is a consequent decrease in the amount available in the lung to oppose the proteolytic burden of neutrophil elastase, especially in people who smoke or work in dusty environments.²¹

Tan et al²² have shown that some of the polymerized Z protein can escape the liver and circulate in the blood and that alveolar macrophages may also produce Z polymers. These Z polymers are chemotactic for neutrophils,²³ so that their presence in the lung fuels the inflammatory cascade by recruiting more neutrophils to the lung, thereby increasing the proteolytic burden to the lung and increasing the risk of emphysema. Z monomers that do circulate can bind neutrophil elastase, but their binding avidity to neutrophil elastase is substantially lower than that of M-type alpha-1 antitrypsin.

CLINICAL MANIFESTATIONS

Alpha-1 antitrypsin deficiency of the PI*ZZ type is associated with two major clinical manifestations:

• Emphysema, resulting from the loss of proteolytic protection of the lung by alpha-1 antitrypsin (a toxic loss of function), and
• Liver diseases such as cirrhosis and chronic hepatitis, which result from abnormal accumulation of alpha-1 antitrypsin within hepatocytes (a toxic gain of function), and hepatoma.¹⁷

Other clinical manifestations of PI*ZZ alpha-1 antitrypsin deficiency include panniculitis and an association with cytoplasmic antineutrophil cytoplasmic antibody-positive vasculitis.¹⁷

Some uncertainty exists regarding the risk associated with the PI*MZ heterozygous state because there has been no systematic longitudinal study of people with this genotype. However, the weight of available experience suggests that PI*MZ individuals who have never smoked are not at increased risk of developing emphysema.²⁴

Findings from a national registry: PI*ZZ COPD resembles ‘usual’ COPD

Distinguishing patients with alpha-1 antitrypsin deficiency from those with “usual” COPD (ie, without alpha-1 antitrypsin deficiency) can be difficult, as shown in data from the National Heart, Lung, and Blood Institute’s   Alpha-1 Antitrypsin Deficiency Registry study.¹⁸ This multicenter, longitudinal, observational study contains the largest well-characterized cohort with severe deficiency of alpha-1 antitrypsin (PI*ZZ, PI*ZNull, etc), with 1,129 patients. 

Pulmonary function test results were consistent with emphysema in most of the patients in the registry. Mean postbronchodilator pulmonary function values (± standard error of the mean) were:

• Forced expiratory volume in 1 second (FEV₁) 46.7% of predicted (± 30%)
• Ratio of FEV₁ to forced vital capacity 42.9% (± 20.4% )
• Mean diffusing capacity for carbon monoxide 50.3% of predicted (± 22.5%).

Like many patients with usual COPD, 60% of the registry patients demonstrated a component of airway reactivity, with significant reversal of airflow obstruction over three spirometries after receiving a dose of an inhaled bronchodilator (characterized by a 12% and 200-mL postbronchodilator rise in FEV₁). Moreover, 78 patients had normal lung function.

Symptoms also resembled those in patients with usual emphysema, chronic bronchitis, or both. On enrollment in the registry, 83.9% of the patients had shortness of breath on exertion, 75.5% had wheezing with upper respiratory infections, 65.3% had wheezing without upper respiratory infection, 67.6% had recent debilitating chest illness, 42.4% had “usual” cough, and 49.6% had annual cough and phlegm episodes.

Imaging findings. Although the classic teaching is that emphysema due to alpha-1 antitrypsin deficiency produces lower-lobe hyperlucency on plain films, relying on this sign would lead to underrecognition, as 36% of PI*ZZ patients have apical-predominant emphysema on chest computed tomography,²⁴ which resembles the usual centriacinar emphysema pattern. Figure 3 shows axial computed tomographic scans through the apices and the bases of the lungs of a patient with alpha-1 antitrypsin deficiency.  

In view of these difficulties, guidelines from the American Thoracic Society and European Respiratory Society¹⁴ endorse testing for alpha-1 antitrypsin deficiency in all adults who have symptoms and fixed airflow obstruction (Table 1).

CONSEQUENCES OF ALPHA-1 ANTITRYPSIN DEFICIENCY

Two large screening studies^2,3,25,26 followed people who were identified at birth as having alpha-1 antitrypsin deficiency to examine the natural course of the disease.

The larger of the two studies²⁷ tested 200,000 Swedish newborns. Follow-up of this cohort to age 35 indicated that 35-year-old never-smoking PI*ZZ individuals have normal lung function and no excess emphysema on computed tomography compared with normal peers matched for age and sex.²⁷ In contrast, the few PI*ZZ ever-smokers demonstrated a lower level of transfer factor and significantly more emphysema on computed tomography than normal (PI*MM) never-smokers.

Faster decline in lung function

Data from the National Heart, Lung, and Blood Institute registry indicate that, on average, people with severe alpha-1 antitrypsin deficiency lose lung function faster than people without the disease.²⁸ Specifically, in never-smokers in the registry, the average rate of FEV₁ decline was 67 mL/year, and among ex-smokers, it was 54 mL/year. Both of these values exceed the general age-related rate of FEV₁ decline of approximately 20 to 25 mL/year in never-smoking, normal adults. Among current smokers in the registry with severe alpha-1 antitrypsin deficiency, the rate of FEV₁ decline was 109 mL/year.

Rates of FEV₁ decline over time vary among groups with differing degrees of airflow obstruction. For example, PI*ZZ patients with moderate COPD (stage II of the four-stage Global Initiative for Chronic Obstructive Lung Disease classification system) lose lung function faster than patients with either milder or more severe degrees of airflow obstruction.²⁹

As with COPD in general, exacerbations of COPD in people with severe deficiency of alpha-1 antitrypsin are associated with worsened clinical status. In one series,³⁰ 54% of 265 PI*ZZ patients experienced an exacerbation in the first year of follow-up, and 18% experienced at least three. Such exacerbations occurred in December and January in 32% of these individuals, likely due to a viral precipitant.

Increased mortality

Severe deficiency of alpha-1 antitrypsin is associated not only with severe morbidity but also death. In the national registry, the overall rate of death was 18.6% at 5 years of follow-up, or approximately 3% per year.²⁸

A low FEV₁ at entry was a bad sign. Patients entering the registry with FEV₁ values below 15% of predicted had a 36% mortality rate at 3 years, compared with 2.6% in those whose baseline FEV₁ exceeded 50% of predicted.

Underlying causes of death in registry participants included emphysema (accounting for 72% of deaths) and cirrhosis (10%),³¹ which were the only causes of death more frequent than in age- and sex-matched controls. In a series of never-smokers who had PI*ZZ alpha-1 antitrypsin deficiency,³² death was less frequently attributed to emphysema than in the national registry (46%) and more often attributed to cirrhosis (28%), indicating that never-smokers may more frequently escape the ravages of emphysema but experience a higher rate of developing cirrhosis later in life.³³

DIAGNOSING ALPHA-1 ANTITRYPSIN DEFICIENCY

Available blood tests for alpha-1 antitrypsin deficiency include:

The serum alpha-1 antitrypsin level, most often done by nephelometry. Normal serum levels generally range from 100 to 220 mg/dL.

Phenotyping, usually performed by isoelectric focusing, which can identify different band patterns associated with different alleles.

Genotyping involves determining which alpha-1 antitrypsin alleles are present, most often using polymerase chain reaction testing targeting the S and Z alleles and occasionally set up to detect less common alleles such as F and I.¹⁷

Gene sequencing is occasionally necessary to achieve an accurate, definitive  diagnosis.

Free, confidential testing is available

Clinical testing most often involves checking both a serum level and a phenotype or genotype. Such tests are often available in hospital laboratories and commercial laboratories, with testing also facilitated by the availability of free testing kits from several manufacturers of drugs for alpha-1 antitrypsin deficiency.

The Alpha-1 Foundation (www.alpha1.org)³⁴ also offers a free, home-based confidential testing kit through a research protocol at the Medical University of South Carolina ([email protected]) called the Alpha-1 Coded Testing (ACT) study. Patients can receive a kit and lancet at home, submit the dried blood-spot specimen, and receive in the mail a confidential serum level and genotype.

The availability of such home-based confidential testing allows patients to seek testing without a physician’s order and makes it easier for facilitated allied health providers, such as respiratory therapists, to recommend testing in appropriate clinical circumstances.¹⁵

TREATMENT OF ALPHA-1 ANTITRYPSIN DEFICIENCY

The treatment of patients with severe deficiency of alpha-1 antitrypsin and emphysema generally resembles that of patients with usual COPD. Specifically, smoking cessation, bronchodilators, occasionally inhaled steroids, supplemental oxygen, preventive vaccinations, and pulmonary rehabilitation are indicated as per usual clinical assessment.

Lung volume reduction surgery, which is beneficial in appropriate subsets of COPD patients, is generally less effective in those with severe alpha-1 antitrypsin deficiency,³⁵ specifically because the magnitude of FEV₁ increase and the duration of such a rise are lower than in usual COPD patients.

Augmentation therapy

Specific therapy for alpha-1 antitrypsin deficiency currently involves weekly intravenous infusions of purified, pooled human-plasma-derived alpha-1 antitrypsin, so-called augmentation therapy. Four drugs have been approved for use in the United States:

• Prolastin-C (Grifols, Barcelona, Spain)
• Aralast NP (Baxalta, Bonneckborn, IL)
• Zemaira (CSL Behring, King of Prussia, PA)
• Glassia (Baxalta, Bonneckborn, IL, and Kamada, Ness Ziona, Israel).

All of these were approved for use in the United States on the basis of biochemical efficacy. Specifically, infusion of these drugs has been shown to raise serum levels above a protective threshold value (generally considered 57 mg/dL, the value below which the risk of developing emphysema increases beyond normal).

Randomized controlled trials^36,37 have addressed the efficacy of intravenous augmentation therapy, and although no single trial has been definitive, the weight of evidence shows that augmentation therapy can slow the progression of emphysema. For example, in a study by Dirksen et al,³⁷ augmentation therapy was associated with a slower progression of emphysema as assessed by the rate of loss of lung density on computed tomography.

On the basis of the available evidence, the American Thoracic Society and European Respiratory Society¹⁴ have recommended augmentation therapy in individuals with “established airflow obstruction from alpha-1 antitrypsin deficiency.”¹⁴ Their guidelines go on to say that the evidence that augmentation therapy is beneficial “is stronger for individuals with moderate airflow obstruction (eg, FEV₁ 35%–60% of predicted) than for those with severe airflow obstruction. Augmentation therapy is not currently recommended for individuals without emphysema.”

The guidelines recognize that although augmentation therapy does not satisfy the usual criteria for cost-effectiveness (< $50,000 per quality-adjusted life year) due to its high cost (approximately $100,000 per year if paid for out of pocket),³⁸ it is recommended for appropriate candidates because it is the only available specific therapy for severe deficiency of alpha-1 antitrypsin.

Novel therapies

In addition to current treatment approaches of augmentation therapy, a number of novel treatment strategies are being investigated, several of which hold much promise.

Gene therapy, using adeno-associated virus to transfect the normal human gene into individuals with severe deficiency of alpha-1 antitrypsin, has been undertaken and is currently under study. In addition, a variety of approaches to interdict production of abnormal Z protein from the liver are being examined, as well as inhaled hyaluronic acid to protect the lung.

Alpha-1 antitrypsin deficiency is a common but underrecognized genetic condition that increases the risk of chronic obstructive pulmonary disease (COPD) and liver disease. Primary care providers can play a critical role in detecting it and managing patients who have it.

RECOGNIZED CASES ARE THE TIP OF THE ICEBERG

First described in 1963,¹ alpha-1 antitrypsin deficiency is estimated to affect 100,000 Americans, fewer than 15,000 of whom have received a clinical diagnosis. As further evidence of its underrecognition,^2–7 many patients experience long delays between their first symptoms and the diagnosis. Early studies indicated that the average diagnostic delay was 7.2 years,4 and the latest studies, as recent as 2013, indicate a similar diagnostic delay.⁷

Furthermore, many patients see multiple healthcare providers before receiving the correct diagnosis. A 1994 survey by this author⁴ found that 43.7% of patients who had severe deficiency of alpha-1 antitrypsin saw at least three physicians before the correct diagnosis was made.

Why is the disease underrecognized?

Several reasons may account for underrecognition of this disease. Many clinicians—including, unfortunately, many pulmonologists—do not know much about it,^7,8 do not adhere to clinical guidelines,^9,10 or harbor the misperception that there is no therapy available and, therefore, no compelling reason to make a diagnosis.⁷

Regarding inadequate knowledge, in a study by Taliercio, Chatburn, and this author,⁸ internal medicine residents scored only 63% correct on a 10-question quiz on diagnostic features of alpha-1 antitrypsin deficiency. There was no evidence of a training effect—senior residents scored no higher than interns.

Similarly, when Greulich et al⁷ surveyed German and Italian internists, general practitioners, and pulmonologists, one-fourth to one-half of them (depending on specialty and country) stated that they knew either very little or nothing at all about alpha-1 antitrypsin deficiency. In addition, 7% to 8% agreed with the statement, “There is no treatment available for this disease.”⁷

Nonadoption of clinical guidelines has been widely recognized in medicine and is evident in the failure to implement various recommended practices,^9,10 such as low-stretch ventilation for acute respiratory distress syndrome and prophylaxis against deep vein thrombosis.

Finding the rest of the iceberg

Efforts to enhance compliance with guidelines on testing for alpha-1 antitrypsin deficiency have included using the electronic medical record to prompt physicians to test appropriate candidates.^11–13

Jain et al¹³ examined the effect of installing such a prompting system to remind physicians to test for alpha-1 antitrypsin deficiency in patients with airflow obstruction that does not reverse with a bronchodilator—a recognized indication for testing for this disease according to standards endorsed by the American Thoracic Society and European Respiratory Society.¹⁴ At baseline, only 4.7% of appropriate candidates were being tested; after a prompt was installed in the electronic medical record, the rate rose to 15.1%, still a minority of candidates.

Another strategy is to empower respiratory therapists who perform pulmonary function tests to invite patients to be tested if their pulmonary function tests show postbronchodilator airflow obstruction. Rahaghi et al¹⁵ showed that using this strategy, 20 (0.63%) of 3,152 patients who were found to have fixed airflow obstruction when they underwent pulmonary function testing were newly diagnosed with severe deficiency of alpha-1 antitrypsin. Other targeted detection studies in patients with COPD estimated the prevalence of alpha-1 antitrypsin deficiency at up to 12%.³

PHYSIOLOGY AND PATHOPHYSIOLOGY OF ALPHA-1 ANTITRYPSIN DEFICIENCY

Alpha-1 antitrypsin is a single-chain, 394-amino acid glycoprotein with three carbohydrate side chains found at asparagine residues along the primary structure.¹⁶

A major physiologic function of this molecule is to bind neutrophil elastase, which it does avidly. In a “mousetrap-like” mechanism,¹⁶ an active site on the alpha-1 antitrypsin molecule captures the neutrophil elastase and is cleaved, releasing steric energy in the molecule, catapulting the neutrophil elastase to the opposite side of the alpha-1 antitrypsin molecule, and inactivating it (Figure 1).

MM is normal, ZZ is not

Alpha-1 antitrypsin deficiency is inherited as an autosomal-codominant condition.¹⁷

The SERPINA1 gene, which codes for alpha-1 antitrypsin, is located on the long arm of the 14th chromosome, and more than 150 alleles of this gene have been identified to date. The normal allele is denoted M, and the allele most commonly associated with severe deficiency is denoted Z. People who are homozygous for the M allele (ie, normal) are called PI*MM (PI stands for “protease inhibitor”), and those who are homozygous for the Z allele are PI*ZZ. More than 90% of patients with severe alpha-1 antitrypsin deficiency are PI*ZZ.¹⁸

The Z allele has a single amino acid substitution (glutamic acid-to-lysine at position 342), which results in abnormal folding and formation of polymers of the Z molecule within hepatocytes.^19,20 These polymers are recognized on liver biopsy as periodic acid-Schiff diastase-resistant eosinophilic inclusion bodies on histologic staining (Figure 2).

With alpha-1 antitrypsin trapped as Z-molecule polymers in the liver, the amount in the bloodstream falls, and there is a consequent decrease in the amount available in the lung to oppose the proteolytic burden of neutrophil elastase, especially in people who smoke or work in dusty environments.²¹

Tan et al²² have shown that some of the polymerized Z protein can escape the liver and circulate in the blood and that alveolar macrophages may also produce Z polymers. These Z polymers are chemotactic for neutrophils,²³ so that their presence in the lung fuels the inflammatory cascade by recruiting more neutrophils to the lung, thereby increasing the proteolytic burden to the lung and increasing the risk of emphysema. Z monomers that do circulate can bind neutrophil elastase, but their binding avidity to neutrophil elastase is substantially lower than that of M-type alpha-1 antitrypsin.

CLINICAL MANIFESTATIONS

Alpha-1 antitrypsin deficiency of the PI*ZZ type is associated with two major clinical manifestations:

• Emphysema, resulting from the loss of proteolytic protection of the lung by alpha-1 antitrypsin (a toxic loss of function), and
• Liver diseases such as cirrhosis and chronic hepatitis, which result from abnormal accumulation of alpha-1 antitrypsin within hepatocytes (a toxic gain of function), and hepatoma.¹⁷

Other clinical manifestations of PI*ZZ alpha-1 antitrypsin deficiency include panniculitis and an association with cytoplasmic antineutrophil cytoplasmic antibody-positive vasculitis.¹⁷

Some uncertainty exists regarding the risk associated with the PI*MZ heterozygous state because there has been no systematic longitudinal study of people with this genotype. However, the weight of available experience suggests that PI*MZ individuals who have never smoked are not at increased risk of developing emphysema.²⁴

Findings from a national registry: PI*ZZ COPD resembles ‘usual’ COPD

Distinguishing patients with alpha-1 antitrypsin deficiency from those with “usual” COPD (ie, without alpha-1 antitrypsin deficiency) can be difficult, as shown in data from the National Heart, Lung, and Blood Institute’s   Alpha-1 Antitrypsin Deficiency Registry study.¹⁸ This multicenter, longitudinal, observational study contains the largest well-characterized cohort with severe deficiency of alpha-1 antitrypsin (PI*ZZ, PI*ZNull, etc), with 1,129 patients. 

Pulmonary function test results were consistent with emphysema in most of the patients in the registry. Mean postbronchodilator pulmonary function values (± standard error of the mean) were:

• Forced expiratory volume in 1 second (FEV₁) 46.7% of predicted (± 30%)
• Ratio of FEV₁ to forced vital capacity 42.9% (± 20.4% )
• Mean diffusing capacity for carbon monoxide 50.3% of predicted (± 22.5%).

Like many patients with usual COPD, 60% of the registry patients demonstrated a component of airway reactivity, with significant reversal of airflow obstruction over three spirometries after receiving a dose of an inhaled bronchodilator (characterized by a 12% and 200-mL postbronchodilator rise in FEV₁). Moreover, 78 patients had normal lung function.

Symptoms also resembled those in patients with usual emphysema, chronic bronchitis, or both. On enrollment in the registry, 83.9% of the patients had shortness of breath on exertion, 75.5% had wheezing with upper respiratory infections, 65.3% had wheezing without upper respiratory infection, 67.6% had recent debilitating chest illness, 42.4% had “usual” cough, and 49.6% had annual cough and phlegm episodes.

Imaging findings. Although the classic teaching is that emphysema due to alpha-1 antitrypsin deficiency produces lower-lobe hyperlucency on plain films, relying on this sign would lead to underrecognition, as 36% of PI*ZZ patients have apical-predominant emphysema on chest computed tomography,²⁴ which resembles the usual centriacinar emphysema pattern. Figure 3 shows axial computed tomographic scans through the apices and the bases of the lungs of a patient with alpha-1 antitrypsin deficiency.  

In view of these difficulties, guidelines from the American Thoracic Society and European Respiratory Society¹⁴ endorse testing for alpha-1 antitrypsin deficiency in all adults who have symptoms and fixed airflow obstruction (Table 1).

CONSEQUENCES OF ALPHA-1 ANTITRYPSIN DEFICIENCY

Two large screening studies^2,3,25,26 followed people who were identified at birth as having alpha-1 antitrypsin deficiency to examine the natural course of the disease.

The larger of the two studies²⁷ tested 200,000 Swedish newborns. Follow-up of this cohort to age 35 indicated that 35-year-old never-smoking PI*ZZ individuals have normal lung function and no excess emphysema on computed tomography compared with normal peers matched for age and sex.²⁷ In contrast, the few PI*ZZ ever-smokers demonstrated a lower level of transfer factor and significantly more emphysema on computed tomography than normal (PI*MM) never-smokers.

Faster decline in lung function

Data from the National Heart, Lung, and Blood Institute registry indicate that, on average, people with severe alpha-1 antitrypsin deficiency lose lung function faster than people without the disease.²⁸ Specifically, in never-smokers in the registry, the average rate of FEV₁ decline was 67 mL/year, and among ex-smokers, it was 54 mL/year. Both of these values exceed the general age-related rate of FEV₁ decline of approximately 20 to 25 mL/year in never-smoking, normal adults. Among current smokers in the registry with severe alpha-1 antitrypsin deficiency, the rate of FEV₁ decline was 109 mL/year.

Rates of FEV₁ decline over time vary among groups with differing degrees of airflow obstruction. For example, PI*ZZ patients with moderate COPD (stage II of the four-stage Global Initiative for Chronic Obstructive Lung Disease classification system) lose lung function faster than patients with either milder or more severe degrees of airflow obstruction.²⁹

As with COPD in general, exacerbations of COPD in people with severe deficiency of alpha-1 antitrypsin are associated with worsened clinical status. In one series,³⁰ 54% of 265 PI*ZZ patients experienced an exacerbation in the first year of follow-up, and 18% experienced at least three. Such exacerbations occurred in December and January in 32% of these individuals, likely due to a viral precipitant.

Increased mortality

Severe deficiency of alpha-1 antitrypsin is associated not only with severe morbidity but also death. In the national registry, the overall rate of death was 18.6% at 5 years of follow-up, or approximately 3% per year.²⁸

A low FEV₁ at entry was a bad sign. Patients entering the registry with FEV₁ values below 15% of predicted had a 36% mortality rate at 3 years, compared with 2.6% in those whose baseline FEV₁ exceeded 50% of predicted.

Underlying causes of death in registry participants included emphysema (accounting for 72% of deaths) and cirrhosis (10%),³¹ which were the only causes of death more frequent than in age- and sex-matched controls. In a series of never-smokers who had PI*ZZ alpha-1 antitrypsin deficiency,³² death was less frequently attributed to emphysema than in the national registry (46%) and more often attributed to cirrhosis (28%), indicating that never-smokers may more frequently escape the ravages of emphysema but experience a higher rate of developing cirrhosis later in life.³³

DIAGNOSING ALPHA-1 ANTITRYPSIN DEFICIENCY

Available blood tests for alpha-1 antitrypsin deficiency include:

The serum alpha-1 antitrypsin level, most often done by nephelometry. Normal serum levels generally range from 100 to 220 mg/dL.

Phenotyping, usually performed by isoelectric focusing, which can identify different band patterns associated with different alleles.

Genotyping involves determining which alpha-1 antitrypsin alleles are present, most often using polymerase chain reaction testing targeting the S and Z alleles and occasionally set up to detect less common alleles such as F and I.¹⁷

Gene sequencing is occasionally necessary to achieve an accurate, definitive  diagnosis.

Free, confidential testing is available

Clinical testing most often involves checking both a serum level and a phenotype or genotype. Such tests are often available in hospital laboratories and commercial laboratories, with testing also facilitated by the availability of free testing kits from several manufacturers of drugs for alpha-1 antitrypsin deficiency.

The Alpha-1 Foundation (www.alpha1.org)³⁴ also offers a free, home-based confidential testing kit through a research protocol at the Medical University of South Carolina ([email protected]) called the Alpha-1 Coded Testing (ACT) study. Patients can receive a kit and lancet at home, submit the dried blood-spot specimen, and receive in the mail a confidential serum level and genotype.

The availability of such home-based confidential testing allows patients to seek testing without a physician’s order and makes it easier for facilitated allied health providers, such as respiratory therapists, to recommend testing in appropriate clinical circumstances.¹⁵

TREATMENT OF ALPHA-1 ANTITRYPSIN DEFICIENCY

The treatment of patients with severe deficiency of alpha-1 antitrypsin and emphysema generally resembles that of patients with usual COPD. Specifically, smoking cessation, bronchodilators, occasionally inhaled steroids, supplemental oxygen, preventive vaccinations, and pulmonary rehabilitation are indicated as per usual clinical assessment.

Lung volume reduction surgery, which is beneficial in appropriate subsets of COPD patients, is generally less effective in those with severe alpha-1 antitrypsin deficiency,³⁵ specifically because the magnitude of FEV₁ increase and the duration of such a rise are lower than in usual COPD patients.

Augmentation therapy

Specific therapy for alpha-1 antitrypsin deficiency currently involves weekly intravenous infusions of purified, pooled human-plasma-derived alpha-1 antitrypsin, so-called augmentation therapy. Four drugs have been approved for use in the United States:

• Prolastin-C (Grifols, Barcelona, Spain)
• Aralast NP (Baxalta, Bonneckborn, IL)
• Zemaira (CSL Behring, King of Prussia, PA)
• Glassia (Baxalta, Bonneckborn, IL, and Kamada, Ness Ziona, Israel).

All of these were approved for use in the United States on the basis of biochemical efficacy. Specifically, infusion of these drugs has been shown to raise serum levels above a protective threshold value (generally considered 57 mg/dL, the value below which the risk of developing emphysema increases beyond normal).

Randomized controlled trials^36,37 have addressed the efficacy of intravenous augmentation therapy, and although no single trial has been definitive, the weight of evidence shows that augmentation therapy can slow the progression of emphysema. For example, in a study by Dirksen et al,³⁷ augmentation therapy was associated with a slower progression of emphysema as assessed by the rate of loss of lung density on computed tomography.

On the basis of the available evidence, the American Thoracic Society and European Respiratory Society¹⁴ have recommended augmentation therapy in individuals with “established airflow obstruction from alpha-1 antitrypsin deficiency.”¹⁴ Their guidelines go on to say that the evidence that augmentation therapy is beneficial “is stronger for individuals with moderate airflow obstruction (eg, FEV₁ 35%–60% of predicted) than for those with severe airflow obstruction. Augmentation therapy is not currently recommended for individuals without emphysema.”

The guidelines recognize that although augmentation therapy does not satisfy the usual criteria for cost-effectiveness (< $50,000 per quality-adjusted life year) due to its high cost (approximately $100,000 per year if paid for out of pocket),³⁸ it is recommended for appropriate candidates because it is the only available specific therapy for severe deficiency of alpha-1 antitrypsin.

Novel therapies

In addition to current treatment approaches of augmentation therapy, a number of novel treatment strategies are being investigated, several of which hold much promise.

Gene therapy, using adeno-associated virus to transfect the normal human gene into individuals with severe deficiency of alpha-1 antitrypsin, has been undertaken and is currently under study. In addition, a variety of approaches to interdict production of abnormal Z protein from the liver are being examined, as well as inhaled hyaluronic acid to protect the lung.

Alpha-1 antitrypsin deficiency is a common but underrecognized genetic condition that increases the risk of chronic obstructive pulmonary disease (COPD) and liver disease. Primary care providers can play a critical role in detecting it and managing patients who have it.

RECOGNIZED CASES ARE THE TIP OF THE ICEBERG

First described in 1963,¹ alpha-1 antitrypsin deficiency is estimated to affect 100,000 Americans, fewer than 15,000 of whom have received a clinical diagnosis. As further evidence of its underrecognition,^2–7 many patients experience long delays between their first symptoms and the diagnosis. Early studies indicated that the average diagnostic delay was 7.2 years,4 and the latest studies, as recent as 2013, indicate a similar diagnostic delay.⁷

Furthermore, many patients see multiple healthcare providers before receiving the correct diagnosis. A 1994 survey by this author⁴ found that 43.7% of patients who had severe deficiency of alpha-1 antitrypsin saw at least three physicians before the correct diagnosis was made.

Why is the disease underrecognized?

Several reasons may account for underrecognition of this disease. Many clinicians—including, unfortunately, many pulmonologists—do not know much about it,^7,8 do not adhere to clinical guidelines,^9,10 or harbor the misperception that there is no therapy available and, therefore, no compelling reason to make a diagnosis.⁷

Regarding inadequate knowledge, in a study by Taliercio, Chatburn, and this author,⁸ internal medicine residents scored only 63% correct on a 10-question quiz on diagnostic features of alpha-1 antitrypsin deficiency. There was no evidence of a training effect—senior residents scored no higher than interns.

Similarly, when Greulich et al⁷ surveyed German and Italian internists, general practitioners, and pulmonologists, one-fourth to one-half of them (depending on specialty and country) stated that they knew either very little or nothing at all about alpha-1 antitrypsin deficiency. In addition, 7% to 8% agreed with the statement, “There is no treatment available for this disease.”⁷

Nonadoption of clinical guidelines has been widely recognized in medicine and is evident in the failure to implement various recommended practices,^9,10 such as low-stretch ventilation for acute respiratory distress syndrome and prophylaxis against deep vein thrombosis.

Finding the rest of the iceberg

Efforts to enhance compliance with guidelines on testing for alpha-1 antitrypsin deficiency have included using the electronic medical record to prompt physicians to test appropriate candidates.^11–13

Jain et al¹³ examined the effect of installing such a prompting system to remind physicians to test for alpha-1 antitrypsin deficiency in patients with airflow obstruction that does not reverse with a bronchodilator—a recognized indication for testing for this disease according to standards endorsed by the American Thoracic Society and European Respiratory Society.¹⁴ At baseline, only 4.7% of appropriate candidates were being tested; after a prompt was installed in the electronic medical record, the rate rose to 15.1%, still a minority of candidates.

Another strategy is to empower respiratory therapists who perform pulmonary function tests to invite patients to be tested if their pulmonary function tests show postbronchodilator airflow obstruction. Rahaghi et al¹⁵ showed that using this strategy, 20 (0.63%) of 3,152 patients who were found to have fixed airflow obstruction when they underwent pulmonary function testing were newly diagnosed with severe deficiency of alpha-1 antitrypsin. Other targeted detection studies in patients with COPD estimated the prevalence of alpha-1 antitrypsin deficiency at up to 12%.³

PHYSIOLOGY AND PATHOPHYSIOLOGY OF ALPHA-1 ANTITRYPSIN DEFICIENCY

Alpha-1 antitrypsin is a single-chain, 394-amino acid glycoprotein with three carbohydrate side chains found at asparagine residues along the primary structure.¹⁶

A major physiologic function of this molecule is to bind neutrophil elastase, which it does avidly. In a “mousetrap-like” mechanism,¹⁶ an active site on the alpha-1 antitrypsin molecule captures the neutrophil elastase and is cleaved, releasing steric energy in the molecule, catapulting the neutrophil elastase to the opposite side of the alpha-1 antitrypsin molecule, and inactivating it (Figure 1).

MM is normal, ZZ is not

Alpha-1 antitrypsin deficiency is inherited as an autosomal-codominant condition.¹⁷

The SERPINA1 gene, which codes for alpha-1 antitrypsin, is located on the long arm of the 14th chromosome, and more than 150 alleles of this gene have been identified to date. The normal allele is denoted M, and the allele most commonly associated with severe deficiency is denoted Z. People who are homozygous for the M allele (ie, normal) are called PI*MM (PI stands for “protease inhibitor”), and those who are homozygous for the Z allele are PI*ZZ. More than 90% of patients with severe alpha-1 antitrypsin deficiency are PI*ZZ.¹⁸

The Z allele has a single amino acid substitution (glutamic acid-to-lysine at position 342), which results in abnormal folding and formation of polymers of the Z molecule within hepatocytes.^19,20 These polymers are recognized on liver biopsy as periodic acid-Schiff diastase-resistant eosinophilic inclusion bodies on histologic staining (Figure 2).

With alpha-1 antitrypsin trapped as Z-molecule polymers in the liver, the amount in the bloodstream falls, and there is a consequent decrease in the amount available in the lung to oppose the proteolytic burden of neutrophil elastase, especially in people who smoke or work in dusty environments.²¹

Tan et al²² have shown that some of the polymerized Z protein can escape the liver and circulate in the blood and that alveolar macrophages may also produce Z polymers. These Z polymers are chemotactic for neutrophils,²³ so that their presence in the lung fuels the inflammatory cascade by recruiting more neutrophils to the lung, thereby increasing the proteolytic burden to the lung and increasing the risk of emphysema. Z monomers that do circulate can bind neutrophil elastase, but their binding avidity to neutrophil elastase is substantially lower than that of M-type alpha-1 antitrypsin.

CLINICAL MANIFESTATIONS

Alpha-1 antitrypsin deficiency of the PI*ZZ type is associated with two major clinical manifestations:

• Emphysema, resulting from the loss of proteolytic protection of the lung by alpha-1 antitrypsin (a toxic loss of function), and
• Liver diseases such as cirrhosis and chronic hepatitis, which result from abnormal accumulation of alpha-1 antitrypsin within hepatocytes (a toxic gain of function), and hepatoma.¹⁷

Other clinical manifestations of PI*ZZ alpha-1 antitrypsin deficiency include panniculitis and an association with cytoplasmic antineutrophil cytoplasmic antibody-positive vasculitis.¹⁷

Some uncertainty exists regarding the risk associated with the PI*MZ heterozygous state because there has been no systematic longitudinal study of people with this genotype. However, the weight of available experience suggests that PI*MZ individuals who have never smoked are not at increased risk of developing emphysema.²⁴

Findings from a national registry: PI*ZZ COPD resembles ‘usual’ COPD

Distinguishing patients with alpha-1 antitrypsin deficiency from those with “usual” COPD (ie, without alpha-1 antitrypsin deficiency) can be difficult, as shown in data from the National Heart, Lung, and Blood Institute’s   Alpha-1 Antitrypsin Deficiency Registry study.¹⁸ This multicenter, longitudinal, observational study contains the largest well-characterized cohort with severe deficiency of alpha-1 antitrypsin (PI*ZZ, PI*ZNull, etc), with 1,129 patients. 

Pulmonary function test results were consistent with emphysema in most of the patients in the registry. Mean postbronchodilator pulmonary function values (± standard error of the mean) were:

• Forced expiratory volume in 1 second (FEV₁) 46.7% of predicted (± 30%)
• Ratio of FEV₁ to forced vital capacity 42.9% (± 20.4% )
• Mean diffusing capacity for carbon monoxide 50.3% of predicted (± 22.5%).

Like many patients with usual COPD, 60% of the registry patients demonstrated a component of airway reactivity, with significant reversal of airflow obstruction over three spirometries after receiving a dose of an inhaled bronchodilator (characterized by a 12% and 200-mL postbronchodilator rise in FEV₁). Moreover, 78 patients had normal lung function.

Symptoms also resembled those in patients with usual emphysema, chronic bronchitis, or both. On enrollment in the registry, 83.9% of the patients had shortness of breath on exertion, 75.5% had wheezing with upper respiratory infections, 65.3% had wheezing without upper respiratory infection, 67.6% had recent debilitating chest illness, 42.4% had “usual” cough, and 49.6% had annual cough and phlegm episodes.

Imaging findings. Although the classic teaching is that emphysema due to alpha-1 antitrypsin deficiency produces lower-lobe hyperlucency on plain films, relying on this sign would lead to underrecognition, as 36% of PI*ZZ patients have apical-predominant emphysema on chest computed tomography,²⁴ which resembles the usual centriacinar emphysema pattern. Figure 3 shows axial computed tomographic scans through the apices and the bases of the lungs of a patient with alpha-1 antitrypsin deficiency.  

In view of these difficulties, guidelines from the American Thoracic Society and European Respiratory Society¹⁴ endorse testing for alpha-1 antitrypsin deficiency in all adults who have symptoms and fixed airflow obstruction (Table 1).

CONSEQUENCES OF ALPHA-1 ANTITRYPSIN DEFICIENCY

Two large screening studies^2,3,25,26 followed people who were identified at birth as having alpha-1 antitrypsin deficiency to examine the natural course of the disease.

The larger of the two studies²⁷ tested 200,000 Swedish newborns. Follow-up of this cohort to age 35 indicated that 35-year-old never-smoking PI*ZZ individuals have normal lung function and no excess emphysema on computed tomography compared with normal peers matched for age and sex.²⁷ In contrast, the few PI*ZZ ever-smokers demonstrated a lower level of transfer factor and significantly more emphysema on computed tomography than normal (PI*MM) never-smokers.

Faster decline in lung function

Data from the National Heart, Lung, and Blood Institute registry indicate that, on average, people with severe alpha-1 antitrypsin deficiency lose lung function faster than people without the disease.²⁸ Specifically, in never-smokers in the registry, the average rate of FEV₁ decline was 67 mL/year, and among ex-smokers, it was 54 mL/year. Both of these values exceed the general age-related rate of FEV₁ decline of approximately 20 to 25 mL/year in never-smoking, normal adults. Among current smokers in the registry with severe alpha-1 antitrypsin deficiency, the rate of FEV₁ decline was 109 mL/year.

Rates of FEV₁ decline over time vary among groups with differing degrees of airflow obstruction. For example, PI*ZZ patients with moderate COPD (stage II of the four-stage Global Initiative for Chronic Obstructive Lung Disease classification system) lose lung function faster than patients with either milder or more severe degrees of airflow obstruction.²⁹

As with COPD in general, exacerbations of COPD in people with severe deficiency of alpha-1 antitrypsin are associated with worsened clinical status. In one series,³⁰ 54% of 265 PI*ZZ patients experienced an exacerbation in the first year of follow-up, and 18% experienced at least three. Such exacerbations occurred in December and January in 32% of these individuals, likely due to a viral precipitant.

Increased mortality

Severe deficiency of alpha-1 antitrypsin is associated not only with severe morbidity but also death. In the national registry, the overall rate of death was 18.6% at 5 years of follow-up, or approximately 3% per year.²⁸

A low FEV₁ at entry was a bad sign. Patients entering the registry with FEV₁ values below 15% of predicted had a 36% mortality rate at 3 years, compared with 2.6% in those whose baseline FEV₁ exceeded 50% of predicted.

Underlying causes of death in registry participants included emphysema (accounting for 72% of deaths) and cirrhosis (10%),³¹ which were the only causes of death more frequent than in age- and sex-matched controls. In a series of never-smokers who had PI*ZZ alpha-1 antitrypsin deficiency,³² death was less frequently attributed to emphysema than in the national registry (46%) and more often attributed to cirrhosis (28%), indicating that never-smokers may more frequently escape the ravages of emphysema but experience a higher rate of developing cirrhosis later in life.³³

DIAGNOSING ALPHA-1 ANTITRYPSIN DEFICIENCY

Available blood tests for alpha-1 antitrypsin deficiency include:

The serum alpha-1 antitrypsin level, most often done by nephelometry. Normal serum levels generally range from 100 to 220 mg/dL.

Phenotyping, usually performed by isoelectric focusing, which can identify different band patterns associated with different alleles.

Genotyping involves determining which alpha-1 antitrypsin alleles are present, most often using polymerase chain reaction testing targeting the S and Z alleles and occasionally set up to detect less common alleles such as F and I.¹⁷

Gene sequencing is occasionally necessary to achieve an accurate, definitive  diagnosis.

Free, confidential testing is available

Clinical testing most often involves checking both a serum level and a phenotype or genotype. Such tests are often available in hospital laboratories and commercial laboratories, with testing also facilitated by the availability of free testing kits from several manufacturers of drugs for alpha-1 antitrypsin deficiency.

The Alpha-1 Foundation (www.alpha1.org)³⁴ also offers a free, home-based confidential testing kit through a research protocol at the Medical University of South Carolina ([email protected]) called the Alpha-1 Coded Testing (ACT) study. Patients can receive a kit and lancet at home, submit the dried blood-spot specimen, and receive in the mail a confidential serum level and genotype.

The availability of such home-based confidential testing allows patients to seek testing without a physician’s order and makes it easier for facilitated allied health providers, such as respiratory therapists, to recommend testing in appropriate clinical circumstances.¹⁵

TREATMENT OF ALPHA-1 ANTITRYPSIN DEFICIENCY

The treatment of patients with severe deficiency of alpha-1 antitrypsin and emphysema generally resembles that of patients with usual COPD. Specifically, smoking cessation, bronchodilators, occasionally inhaled steroids, supplemental oxygen, preventive vaccinations, and pulmonary rehabilitation are indicated as per usual clinical assessment.

Lung volume reduction surgery, which is beneficial in appropriate subsets of COPD patients, is generally less effective in those with severe alpha-1 antitrypsin deficiency,³⁵ specifically because the magnitude of FEV₁ increase and the duration of such a rise are lower than in usual COPD patients.

Augmentation therapy

Specific therapy for alpha-1 antitrypsin deficiency currently involves weekly intravenous infusions of purified, pooled human-plasma-derived alpha-1 antitrypsin, so-called augmentation therapy. Four drugs have been approved for use in the United States:

• Prolastin-C (Grifols, Barcelona, Spain)
• Aralast NP (Baxalta, Bonneckborn, IL)
• Zemaira (CSL Behring, King of Prussia, PA)
• Glassia (Baxalta, Bonneckborn, IL, and Kamada, Ness Ziona, Israel).

All of these were approved for use in the United States on the basis of biochemical efficacy. Specifically, infusion of these drugs has been shown to raise serum levels above a protective threshold value (generally considered 57 mg/dL, the value below which the risk of developing emphysema increases beyond normal).

Randomized controlled trials^36,37 have addressed the efficacy of intravenous augmentation therapy, and although no single trial has been definitive, the weight of evidence shows that augmentation therapy can slow the progression of emphysema. For example, in a study by Dirksen et al,³⁷ augmentation therapy was associated with a slower progression of emphysema as assessed by the rate of loss of lung density on computed tomography.

On the basis of the available evidence, the American Thoracic Society and European Respiratory Society¹⁴ have recommended augmentation therapy in individuals with “established airflow obstruction from alpha-1 antitrypsin deficiency.”¹⁴ Their guidelines go on to say that the evidence that augmentation therapy is beneficial “is stronger for individuals with moderate airflow obstruction (eg, FEV₁ 35%–60% of predicted) than for those with severe airflow obstruction. Augmentation therapy is not currently recommended for individuals without emphysema.”

The guidelines recognize that although augmentation therapy does not satisfy the usual criteria for cost-effectiveness (< $50,000 per quality-adjusted life year) due to its high cost (approximately $100,000 per year if paid for out of pocket),³⁸ it is recommended for appropriate candidates because it is the only available specific therapy for severe deficiency of alpha-1 antitrypsin.

Novel therapies

In addition to current treatment approaches of augmentation therapy, a number of novel treatment strategies are being investigated, several of which hold much promise.

Gene therapy, using adeno-associated virus to transfect the normal human gene into individuals with severe deficiency of alpha-1 antitrypsin, has been undertaken and is currently under study. In addition, a variety of approaches to interdict production of abnormal Z protein from the liver are being examined, as well as inhaled hyaluronic acid to protect the lung.