Champion…. You ARE A CHAMPION for your patients, and as a CHEST Foundation supporter, you are a Champion for Lung Health! These words are now staples in our foundation mission. To champion lung health through clinical research and community service grants, patient education, and community service, the impact your support can have is quite profound. You are a part of an elite group to be called “champions,” and you should be celebrated for all the ways that you have championed lung health in 2017.

• YOU funded more than a half-million dollars in community service grants awarded to the next generation of CHEST leaders.
• YOU educated MILLIONS by supporting nationwide disease awareness campaigns for COPD, asthma, sarcoidosis, and lung cancer.
• YOU brought the Lung Health Experience to communities where over 1,000 people received COPD and asthma education, as well as spirometry screening.
• YOU created awareness in rare disease spaces and raised crucial support by partnering with family foundations, such as the Irv Family Foundation.
• The reach of these activities in 2017 has been astounding, and YOU, as a champion for lung health, have generated a great impact on the chest medicine community and the patients we serve.
• Now, the CHEST Foundation asks YOU to join us and support our efforts for 2018 by giving to the CHEST Foundation Annual Fund today. We ask you to help:
• Meet our fundraising goal of $700,000 for new clinical research and community service grants.
• Support NEW lung health disease awareness campaigns.
• Expand family foundation partnerships to create NEW patient resources.
• Provide NEW e-learning modules to aide patients and caregivers in managing health.

Your support today makes possible tomorrow’s advances in lung health and chest medicine. YOU believe in patient outcomes and, for that commitment, we graciously thank you. YOU save lives by supporting clinical research, patient education, and community service.

Be THE Champion for Lung Health that patients and families count on, and make an impact today. YOU can be a champion and DONATE today through a new gift to the CHEST Foundation. We cannot meet our goals for the health professionals, patients, families, and caregivers we serve without you.

Thank you for your essential continued support!

Champion…. You ARE A CHAMPION for your patients, and as a CHEST Foundation supporter, you are a Champion for Lung Health! These words are now staples in our foundation mission. To champion lung health through clinical research and community service grants, patient education, and community service, the impact your support can have is quite profound. You are a part of an elite group to be called “champions,” and you should be celebrated for all the ways that you have championed lung health in 2017.

• YOU funded more than a half-million dollars in community service grants awarded to the next generation of CHEST leaders.
• YOU educated MILLIONS by supporting nationwide disease awareness campaigns for COPD, asthma, sarcoidosis, and lung cancer.
• YOU brought the Lung Health Experience to communities where over 1,000 people received COPD and asthma education, as well as spirometry screening.
• YOU created awareness in rare disease spaces and raised crucial support by partnering with family foundations, such as the Irv Family Foundation.
• The reach of these activities in 2017 has been astounding, and YOU, as a champion for lung health, have generated a great impact on the chest medicine community and the patients we serve.
• Now, the CHEST Foundation asks YOU to join us and support our efforts for 2018 by giving to the CHEST Foundation Annual Fund today. We ask you to help:
• Meet our fundraising goal of $700,000 for new clinical research and community service grants.
• Support NEW lung health disease awareness campaigns.
• Expand family foundation partnerships to create NEW patient resources.
• Provide NEW e-learning modules to aide patients and caregivers in managing health.

Your support today makes possible tomorrow’s advances in lung health and chest medicine. YOU believe in patient outcomes and, for that commitment, we graciously thank you. YOU save lives by supporting clinical research, patient education, and community service.

Be THE Champion for Lung Health that patients and families count on, and make an impact today. YOU can be a champion and DONATE today through a new gift to the CHEST Foundation. We cannot meet our goals for the health professionals, patients, families, and caregivers we serve without you.

Thank you for your essential continued support!

Champion…. You ARE A CHAMPION for your patients, and as a CHEST Foundation supporter, you are a Champion for Lung Health! These words are now staples in our foundation mission. To champion lung health through clinical research and community service grants, patient education, and community service, the impact your support can have is quite profound. You are a part of an elite group to be called “champions,” and you should be celebrated for all the ways that you have championed lung health in 2017.

• YOU funded more than a half-million dollars in community service grants awarded to the next generation of CHEST leaders.
• YOU educated MILLIONS by supporting nationwide disease awareness campaigns for COPD, asthma, sarcoidosis, and lung cancer.
• YOU brought the Lung Health Experience to communities where over 1,000 people received COPD and asthma education, as well as spirometry screening.
• YOU created awareness in rare disease spaces and raised crucial support by partnering with family foundations, such as the Irv Family Foundation.
• The reach of these activities in 2017 has been astounding, and YOU, as a champion for lung health, have generated a great impact on the chest medicine community and the patients we serve.
• Now, the CHEST Foundation asks YOU to join us and support our efforts for 2018 by giving to the CHEST Foundation Annual Fund today. We ask you to help:
• Meet our fundraising goal of $700,000 for new clinical research and community service grants.
• Support NEW lung health disease awareness campaigns.
• Expand family foundation partnerships to create NEW patient resources.
• Provide NEW e-learning modules to aide patients and caregivers in managing health.

Your support today makes possible tomorrow’s advances in lung health and chest medicine. YOU believe in patient outcomes and, for that commitment, we graciously thank you. YOU save lives by supporting clinical research, patient education, and community service.

Be THE Champion for Lung Health that patients and families count on, and make an impact today. YOU can be a champion and DONATE today through a new gift to the CHEST Foundation. We cannot meet our goals for the health professionals, patients, families, and caregivers we serve without you.

Thank you for your essential continued support!

Treatment of fibrotic interstitial lung disease (ILD) is often dissatisfying to clinicians and patients. Despite significant advances in the field, particularly the validation of the efficacy of the antifibrotic drugs nintedanib (Richeldi L, et al. N Engl J Med. 2014;370[22]:2071) and pirfenidone (King TE Jr, et al. N Engl J Med. 2014;370[(22]:2083) in slowing the progression of idiopathic pulmonary fibrosis (IPF), we are still left with a paucity of therapeutic options to modulate the course of disease and improve functional outcomes. Given the difficulties in addressing the progression of parenchymal fibrosis, the pulmonary community has looked for alternative ways to approach treatment of ILD. One potential therapeutic inroad that has garnered substantial interest is the treatment of concurrent pulmonary hypertension (PH) or group 3 PH (Seeger W, et al. J Am Coll Cardiol. 2013;62 (25 Suppl):D109).

Group 3 PH – The rationale to treat

Group 3 PH has an indisputable association with adverse outcomes, including decreased functional status, increased need for supplemental oxygen, and decreased survival (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4.2017;67-84). In fact, PH is such a powerful predictor of survival in fibrotic ILD, the International Society of Heart and Lung Transplant (ISHLT) guidelines on candidate selection for lung transplantation cite development of PH as an indication for transplant listing (Weill D, et al. J Heart Lung Transplant. 2015;34:1). When one considers the strong association between group 3 PH and adverse outcomes, the numerous pulmonary vasodilator agents available to treat pulmonary arterial hypertension (PAH), and the success achieved in treating PAH, it is easy to see why group 3 PH is such a tempting therapeutic target.

Previous studies of pulmonary vasodilator therapy for group 3 PH

Over 20 studies assessing the effectiveness of pulmonary vasodilator therapy in ILD have been published (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4. 2017;67) The majority was small and unblinded with inherent limitations. To date, no randomized controlled trial (RCT) of therapy for group 3 PH has demonstrated efficacy. Several studies amongst the RCTs deserve highlighting. The most encouraging RCT of therapy for group 3 PH was STEP-IPF. This study compared sildenafil with placebo in 180 patients with advanced IPF. Though the study failed to demonstrate a difference in the primary endpoint of ≥ 20% increase in 6-minute walk test (6MWT) distance, it did show improvement in several secondary endpoints, including arterial oxygen saturation and quality of life measures (Zisman DA, et al. N Engl J Med. 2010;363[7]:620).

The BUILD-3 study compared bosentan with placebo in 617 patients with IPF. Enrolled patients were not required to have PH. While bosentan was well tolerated, it failed to improve the primary endpoint of time to disease progression or death or secondary endpoints regarding quality of life or dyspnea (King TE Jr, et al. Am J Respir Crit Care Med. 2011; 184[1]:92). A smaller study comparing bosentan with placebo in 60 patients with fibrotic ILD with right-sided heart catheterization (RHC) confirmed PH failed to demonstrate any difference in pulmonary vascular hemodynamics, functional status, or symptoms (Corte TJ, et al. Am J Respir Crit Care Med. 2014;190[2]:208). Studies of the newer endothelin receptor antagonists, macitentan (Raghu, et al. Eur Respir J. 2013;42[6]:1622) and ambrisentan (Raghu, et al. Ann Int Med. 2013;158[9]:641), were conducted and failed to demonstrate improvements in outcomes, as well. Overall, the results of the available RCTs of pulmonary vasodilator therapy in group 3 PH have been disappointing, failing to conclusively improve the primary outcome in any of the studies performed.
 

Hot off the presses – RISE-IIP

The latest letdown in group 3 PH is “Riociguat for the Treatment of Pulmonary Hypertension in Idiopathic Interstitial Pneumonia (RISE-IIP). The results of the study were recently presented at the European Respiratory Society meeting in Milan, Italy, by my colleague from Inova Fairfax Hospital (Falls Church, VA), Dr. Steven Nathan. Riociguat is a soluble guanylate cyclase stimulator approved for use in PAH and chronic thromboembolic pulmonary hypertension. The rationale for the study was that riociguat would improve pulmonary hemodynamics leading to improved functional status. Additionally, several preclinical models have demonstrated antifibrotic effects of the drug (Geschka S, et al. PLoS One. 2011;6:e21853). Justification for the study was also bolstered by promising results from a pilot study conducted in 22 patients with RHC-confirmed PH with a mean pulmonary artery pressure (mPAP) > 30 and fibrotic lung disease. In this study, patients treated with riociguat had improved pulmonary vascular resistance, cardiac output, and 6MWT distance.

To be included in RISE-IIP, patients were required to have an idiopathic interstitial pneumonia, PH confirmed by RHC with a mPAP ≥ 25 mm Hg, World Health Organization Functional Class 2-4 symptoms, and a forced vital capacity (FVC) ≥ 45% predicted. Pertinent exclusion criteria included significant left-sided heart disease and extent of emphysema greater than fibrosis on HRCT. Patients with connective tissue disease, chronic hypersensitivity pneumonitis, occupational lung disease, and sarcoidosis were ineligible to participate. The placebo-controlled portion of the study lasted 26 weeks then crossed into an open label extension trial.

The study enrolled 147 total patients, with 73 receiving riociguat and 74 in the placebo arm. There was no significant improvement in the primary outcome of change in 6MWT distance or the secondary combined endpoint assessing clinical worsening. The study was terminated early for safety due to an increased number of deaths and adverse events in the treatment group. During the blinded phase of the study, eight deaths (11%) occurred in the riociguat arm as compared with three deaths (4%) in the placebo arm. Seventy patients entered the open label extension phase of the trial, and 9 of these patients died. Eight of these deaths occurred in the patients previously receiving placebo who were switched to riociguat. The authors of the study found no conclusive potential etiology to explain the increased mortality seen.
 

RISE’ing from the ashes – Where do we go from here?

So, what should we take away from the negative results of the RISE-IIP trial? Some may argue that treatment of group 3 PH is a flawed premise and should be abandoned. Perhaps development of group 3 PH is an adaptive response to worsening fibrotic lung disease, and treatment of the PH is unlikely to alter outcomes and introduces the possibility of harm through worsening hypoxemia due to increased ventilation/perfusion mismatch with nonselective pulmonary vasodilation. I suspect the truth is somewhat more nuanced. I believe there is a select population with severe or “out-of-proportion” PH that may still benefit from vasodilator therapy. Trials targeting patients with a higher mPAP or low cardiac index could test this hypothesis but will be difficult to enroll. Another possibility is that our mechanism of drug delivery in prior trials has been suboptimal. Inhaled pulmonary vasodilator therapy should minimize the risk of worsening ventilation/perfusion mismatch. An RCT assessing the response to inhaled treprostinil in group 3 PH (NCT02630316) is currently enrolling at 96 centers across the United States. Until data supporting positive effects from treating group 3 PH emerge, I would recommend against off-label treatment and encourage referral to clinical trials. Given the potential for harm, riociguat should be avoided in group 3 PH. If off-label therapy is being entertained in a patient with severe PH that is out of proportion to the extent of fibrotic lung disease, it should be initiated cautiously at a center experienced in treating PH. Finally, clinicians should refer appropriate candidates with ILD and group 3 PH for lung transplantation evaluation.

The great inventor Thomas Edison is credited with saying “I have not failed. I’ve just found 10,000 ways that won’t work.” While disappointing, negative studies are to be expected as we search for improved therapies for our patients. It’s essential that we reflect upon these studies, so we can improve future trial design.

Treatment of fibrotic interstitial lung disease (ILD) is often dissatisfying to clinicians and patients. Despite significant advances in the field, particularly the validation of the efficacy of the antifibrotic drugs nintedanib (Richeldi L, et al. N Engl J Med. 2014;370[22]:2071) and pirfenidone (King TE Jr, et al. N Engl J Med. 2014;370[(22]:2083) in slowing the progression of idiopathic pulmonary fibrosis (IPF), we are still left with a paucity of therapeutic options to modulate the course of disease and improve functional outcomes. Given the difficulties in addressing the progression of parenchymal fibrosis, the pulmonary community has looked for alternative ways to approach treatment of ILD. One potential therapeutic inroad that has garnered substantial interest is the treatment of concurrent pulmonary hypertension (PH) or group 3 PH (Seeger W, et al. J Am Coll Cardiol. 2013;62 (25 Suppl):D109).

Group 3 PH – The rationale to treat

Group 3 PH has an indisputable association with adverse outcomes, including decreased functional status, increased need for supplemental oxygen, and decreased survival (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4.2017;67-84). In fact, PH is such a powerful predictor of survival in fibrotic ILD, the International Society of Heart and Lung Transplant (ISHLT) guidelines on candidate selection for lung transplantation cite development of PH as an indication for transplant listing (Weill D, et al. J Heart Lung Transplant. 2015;34:1). When one considers the strong association between group 3 PH and adverse outcomes, the numerous pulmonary vasodilator agents available to treat pulmonary arterial hypertension (PAH), and the success achieved in treating PAH, it is easy to see why group 3 PH is such a tempting therapeutic target.

Previous studies of pulmonary vasodilator therapy for group 3 PH

Over 20 studies assessing the effectiveness of pulmonary vasodilator therapy in ILD have been published (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4. 2017;67) The majority was small and unblinded with inherent limitations. To date, no randomized controlled trial (RCT) of therapy for group 3 PH has demonstrated efficacy. Several studies amongst the RCTs deserve highlighting. The most encouraging RCT of therapy for group 3 PH was STEP-IPF. This study compared sildenafil with placebo in 180 patients with advanced IPF. Though the study failed to demonstrate a difference in the primary endpoint of ≥ 20% increase in 6-minute walk test (6MWT) distance, it did show improvement in several secondary endpoints, including arterial oxygen saturation and quality of life measures (Zisman DA, et al. N Engl J Med. 2010;363[7]:620).

The BUILD-3 study compared bosentan with placebo in 617 patients with IPF. Enrolled patients were not required to have PH. While bosentan was well tolerated, it failed to improve the primary endpoint of time to disease progression or death or secondary endpoints regarding quality of life or dyspnea (King TE Jr, et al. Am J Respir Crit Care Med. 2011; 184[1]:92). A smaller study comparing bosentan with placebo in 60 patients with fibrotic ILD with right-sided heart catheterization (RHC) confirmed PH failed to demonstrate any difference in pulmonary vascular hemodynamics, functional status, or symptoms (Corte TJ, et al. Am J Respir Crit Care Med. 2014;190[2]:208). Studies of the newer endothelin receptor antagonists, macitentan (Raghu, et al. Eur Respir J. 2013;42[6]:1622) and ambrisentan (Raghu, et al. Ann Int Med. 2013;158[9]:641), were conducted and failed to demonstrate improvements in outcomes, as well. Overall, the results of the available RCTs of pulmonary vasodilator therapy in group 3 PH have been disappointing, failing to conclusively improve the primary outcome in any of the studies performed.
 

Hot off the presses – RISE-IIP

The latest letdown in group 3 PH is “Riociguat for the Treatment of Pulmonary Hypertension in Idiopathic Interstitial Pneumonia (RISE-IIP). The results of the study were recently presented at the European Respiratory Society meeting in Milan, Italy, by my colleague from Inova Fairfax Hospital (Falls Church, VA), Dr. Steven Nathan. Riociguat is a soluble guanylate cyclase stimulator approved for use in PAH and chronic thromboembolic pulmonary hypertension. The rationale for the study was that riociguat would improve pulmonary hemodynamics leading to improved functional status. Additionally, several preclinical models have demonstrated antifibrotic effects of the drug (Geschka S, et al. PLoS One. 2011;6:e21853). Justification for the study was also bolstered by promising results from a pilot study conducted in 22 patients with RHC-confirmed PH with a mean pulmonary artery pressure (mPAP) > 30 and fibrotic lung disease. In this study, patients treated with riociguat had improved pulmonary vascular resistance, cardiac output, and 6MWT distance.

To be included in RISE-IIP, patients were required to have an idiopathic interstitial pneumonia, PH confirmed by RHC with a mPAP ≥ 25 mm Hg, World Health Organization Functional Class 2-4 symptoms, and a forced vital capacity (FVC) ≥ 45% predicted. Pertinent exclusion criteria included significant left-sided heart disease and extent of emphysema greater than fibrosis on HRCT. Patients with connective tissue disease, chronic hypersensitivity pneumonitis, occupational lung disease, and sarcoidosis were ineligible to participate. The placebo-controlled portion of the study lasted 26 weeks then crossed into an open label extension trial.

The study enrolled 147 total patients, with 73 receiving riociguat and 74 in the placebo arm. There was no significant improvement in the primary outcome of change in 6MWT distance or the secondary combined endpoint assessing clinical worsening. The study was terminated early for safety due to an increased number of deaths and adverse events in the treatment group. During the blinded phase of the study, eight deaths (11%) occurred in the riociguat arm as compared with three deaths (4%) in the placebo arm. Seventy patients entered the open label extension phase of the trial, and 9 of these patients died. Eight of these deaths occurred in the patients previously receiving placebo who were switched to riociguat. The authors of the study found no conclusive potential etiology to explain the increased mortality seen.
 

RISE’ing from the ashes – Where do we go from here?

So, what should we take away from the negative results of the RISE-IIP trial? Some may argue that treatment of group 3 PH is a flawed premise and should be abandoned. Perhaps development of group 3 PH is an adaptive response to worsening fibrotic lung disease, and treatment of the PH is unlikely to alter outcomes and introduces the possibility of harm through worsening hypoxemia due to increased ventilation/perfusion mismatch with nonselective pulmonary vasodilation. I suspect the truth is somewhat more nuanced. I believe there is a select population with severe or “out-of-proportion” PH that may still benefit from vasodilator therapy. Trials targeting patients with a higher mPAP or low cardiac index could test this hypothesis but will be difficult to enroll. Another possibility is that our mechanism of drug delivery in prior trials has been suboptimal. Inhaled pulmonary vasodilator therapy should minimize the risk of worsening ventilation/perfusion mismatch. An RCT assessing the response to inhaled treprostinil in group 3 PH (NCT02630316) is currently enrolling at 96 centers across the United States. Until data supporting positive effects from treating group 3 PH emerge, I would recommend against off-label treatment and encourage referral to clinical trials. Given the potential for harm, riociguat should be avoided in group 3 PH. If off-label therapy is being entertained in a patient with severe PH that is out of proportion to the extent of fibrotic lung disease, it should be initiated cautiously at a center experienced in treating PH. Finally, clinicians should refer appropriate candidates with ILD and group 3 PH for lung transplantation evaluation.

The great inventor Thomas Edison is credited with saying “I have not failed. I’ve just found 10,000 ways that won’t work.” While disappointing, negative studies are to be expected as we search for improved therapies for our patients. It’s essential that we reflect upon these studies, so we can improve future trial design.

Treatment of fibrotic interstitial lung disease (ILD) is often dissatisfying to clinicians and patients. Despite significant advances in the field, particularly the validation of the efficacy of the antifibrotic drugs nintedanib (Richeldi L, et al. N Engl J Med. 2014;370[22]:2071) and pirfenidone (King TE Jr, et al. N Engl J Med. 2014;370[(22]:2083) in slowing the progression of idiopathic pulmonary fibrosis (IPF), we are still left with a paucity of therapeutic options to modulate the course of disease and improve functional outcomes. Given the difficulties in addressing the progression of parenchymal fibrosis, the pulmonary community has looked for alternative ways to approach treatment of ILD. One potential therapeutic inroad that has garnered substantial interest is the treatment of concurrent pulmonary hypertension (PH) or group 3 PH (Seeger W, et al. J Am Coll Cardiol. 2013;62 (25 Suppl):D109).

Group 3 PH – The rationale to treat

Group 3 PH has an indisputable association with adverse outcomes, including decreased functional status, increased need for supplemental oxygen, and decreased survival (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4.2017;67-84). In fact, PH is such a powerful predictor of survival in fibrotic ILD, the International Society of Heart and Lung Transplant (ISHLT) guidelines on candidate selection for lung transplantation cite development of PH as an indication for transplant listing (Weill D, et al. J Heart Lung Transplant. 2015;34:1). When one considers the strong association between group 3 PH and adverse outcomes, the numerous pulmonary vasodilator agents available to treat pulmonary arterial hypertension (PAH), and the success achieved in treating PAH, it is easy to see why group 3 PH is such a tempting therapeutic target.

Previous studies of pulmonary vasodilator therapy for group 3 PH

Over 20 studies assessing the effectiveness of pulmonary vasodilator therapy in ILD have been published (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4. 2017;67) The majority was small and unblinded with inherent limitations. To date, no randomized controlled trial (RCT) of therapy for group 3 PH has demonstrated efficacy. Several studies amongst the RCTs deserve highlighting. The most encouraging RCT of therapy for group 3 PH was STEP-IPF. This study compared sildenafil with placebo in 180 patients with advanced IPF. Though the study failed to demonstrate a difference in the primary endpoint of ≥ 20% increase in 6-minute walk test (6MWT) distance, it did show improvement in several secondary endpoints, including arterial oxygen saturation and quality of life measures (Zisman DA, et al. N Engl J Med. 2010;363[7]:620).

The BUILD-3 study compared bosentan with placebo in 617 patients with IPF. Enrolled patients were not required to have PH. While bosentan was well tolerated, it failed to improve the primary endpoint of time to disease progression or death or secondary endpoints regarding quality of life or dyspnea (King TE Jr, et al. Am J Respir Crit Care Med. 2011; 184[1]:92). A smaller study comparing bosentan with placebo in 60 patients with fibrotic ILD with right-sided heart catheterization (RHC) confirmed PH failed to demonstrate any difference in pulmonary vascular hemodynamics, functional status, or symptoms (Corte TJ, et al. Am J Respir Crit Care Med. 2014;190[2]:208). Studies of the newer endothelin receptor antagonists, macitentan (Raghu, et al. Eur Respir J. 2013;42[6]:1622) and ambrisentan (Raghu, et al. Ann Int Med. 2013;158[9]:641), were conducted and failed to demonstrate improvements in outcomes, as well. Overall, the results of the available RCTs of pulmonary vasodilator therapy in group 3 PH have been disappointing, failing to conclusively improve the primary outcome in any of the studies performed.
 

Hot off the presses – RISE-IIP

The latest letdown in group 3 PH is “Riociguat for the Treatment of Pulmonary Hypertension in Idiopathic Interstitial Pneumonia (RISE-IIP). The results of the study were recently presented at the European Respiratory Society meeting in Milan, Italy, by my colleague from Inova Fairfax Hospital (Falls Church, VA), Dr. Steven Nathan. Riociguat is a soluble guanylate cyclase stimulator approved for use in PAH and chronic thromboembolic pulmonary hypertension. The rationale for the study was that riociguat would improve pulmonary hemodynamics leading to improved functional status. Additionally, several preclinical models have demonstrated antifibrotic effects of the drug (Geschka S, et al. PLoS One. 2011;6:e21853). Justification for the study was also bolstered by promising results from a pilot study conducted in 22 patients with RHC-confirmed PH with a mean pulmonary artery pressure (mPAP) > 30 and fibrotic lung disease. In this study, patients treated with riociguat had improved pulmonary vascular resistance, cardiac output, and 6MWT distance.

To be included in RISE-IIP, patients were required to have an idiopathic interstitial pneumonia, PH confirmed by RHC with a mPAP ≥ 25 mm Hg, World Health Organization Functional Class 2-4 symptoms, and a forced vital capacity (FVC) ≥ 45% predicted. Pertinent exclusion criteria included significant left-sided heart disease and extent of emphysema greater than fibrosis on HRCT. Patients with connective tissue disease, chronic hypersensitivity pneumonitis, occupational lung disease, and sarcoidosis were ineligible to participate. The placebo-controlled portion of the study lasted 26 weeks then crossed into an open label extension trial.

The study enrolled 147 total patients, with 73 receiving riociguat and 74 in the placebo arm. There was no significant improvement in the primary outcome of change in 6MWT distance or the secondary combined endpoint assessing clinical worsening. The study was terminated early for safety due to an increased number of deaths and adverse events in the treatment group. During the blinded phase of the study, eight deaths (11%) occurred in the riociguat arm as compared with three deaths (4%) in the placebo arm. Seventy patients entered the open label extension phase of the trial, and 9 of these patients died. Eight of these deaths occurred in the patients previously receiving placebo who were switched to riociguat. The authors of the study found no conclusive potential etiology to explain the increased mortality seen.
 

RISE’ing from the ashes – Where do we go from here?

So, what should we take away from the negative results of the RISE-IIP trial? Some may argue that treatment of group 3 PH is a flawed premise and should be abandoned. Perhaps development of group 3 PH is an adaptive response to worsening fibrotic lung disease, and treatment of the PH is unlikely to alter outcomes and introduces the possibility of harm through worsening hypoxemia due to increased ventilation/perfusion mismatch with nonselective pulmonary vasodilation. I suspect the truth is somewhat more nuanced. I believe there is a select population with severe or “out-of-proportion” PH that may still benefit from vasodilator therapy. Trials targeting patients with a higher mPAP or low cardiac index could test this hypothesis but will be difficult to enroll. Another possibility is that our mechanism of drug delivery in prior trials has been suboptimal. Inhaled pulmonary vasodilator therapy should minimize the risk of worsening ventilation/perfusion mismatch. An RCT assessing the response to inhaled treprostinil in group 3 PH (NCT02630316) is currently enrolling at 96 centers across the United States. Until data supporting positive effects from treating group 3 PH emerge, I would recommend against off-label treatment and encourage referral to clinical trials. Given the potential for harm, riociguat should be avoided in group 3 PH. If off-label therapy is being entertained in a patient with severe PH that is out of proportion to the extent of fibrotic lung disease, it should be initiated cautiously at a center experienced in treating PH. Finally, clinicians should refer appropriate candidates with ILD and group 3 PH for lung transplantation evaluation.

The great inventor Thomas Edison is credited with saying “I have not failed. I’ve just found 10,000 ways that won’t work.” While disappointing, negative studies are to be expected as we search for improved therapies for our patients. It’s essential that we reflect upon these studies, so we can improve future trial design.

The American Board of Internal Medicine is extending its “no consequence” Knowledge Check-In attempt to all subspecialties.

ABIM previously announced that, beginning in 2018, physicians taking the Knowledge Check-In in 2018 would get another chance to take it in 2 years if they were unsuccessful, even if they were due to pass the maintenance of certification (MOC) exam later that year. In 2018, Knowledge Check-Ins will be offered in internal medicine and nephrology.

“Based on feedback ABIM has received from the physician community, we are happy to let you know that we are extending this policy to include all other internal medicine subspecialties in the future,” ABIM said in a Dec. 4 announcement on its website. “This means that if a physician takes the Knowledge Check-In in the first year it is offered in their subspecialty and is unsuccessful, they will get at least one additional opportunity to take and pass it 2 years later.”

The Knowledge Check-In is an alternative to the traditional MOC process, and is administered every 2 years rather than the standard decade between MOC exams. ABIM noted that a single failure on a Knowledge Check-In will not result in a status change to a physician’s certification status.

Separately, ABIM also announced that it will continue to make practice assessment activities (part IV of the MOC program) a part of the portfolio of options that can be used to satisfy MOC requirements.

“Our intent is to support physicians completing MOC activities that are most meaningful to their practice, including those that enhance and improve medical knowledge, as well as many existing quality improvement activities, and those that blend both,” ABIM said in its announcement.

[email protected]

The American Board of Internal Medicine is extending its “no consequence” Knowledge Check-In attempt to all subspecialties.

ABIM previously announced that, beginning in 2018, physicians taking the Knowledge Check-In in 2018 would get another chance to take it in 2 years if they were unsuccessful, even if they were due to pass the maintenance of certification (MOC) exam later that year. In 2018, Knowledge Check-Ins will be offered in internal medicine and nephrology.

“Based on feedback ABIM has received from the physician community, we are happy to let you know that we are extending this policy to include all other internal medicine subspecialties in the future,” ABIM said in a Dec. 4 announcement on its website. “This means that if a physician takes the Knowledge Check-In in the first year it is offered in their subspecialty and is unsuccessful, they will get at least one additional opportunity to take and pass it 2 years later.”

The Knowledge Check-In is an alternative to the traditional MOC process, and is administered every 2 years rather than the standard decade between MOC exams. ABIM noted that a single failure on a Knowledge Check-In will not result in a status change to a physician’s certification status.

Separately, ABIM also announced that it will continue to make practice assessment activities (part IV of the MOC program) a part of the portfolio of options that can be used to satisfy MOC requirements.

“Our intent is to support physicians completing MOC activities that are most meaningful to their practice, including those that enhance and improve medical knowledge, as well as many existing quality improvement activities, and those that blend both,” ABIM said in its announcement.

[email protected]

The American Board of Internal Medicine is extending its “no consequence” Knowledge Check-In attempt to all subspecialties.

ABIM previously announced that, beginning in 2018, physicians taking the Knowledge Check-In in 2018 would get another chance to take it in 2 years if they were unsuccessful, even if they were due to pass the maintenance of certification (MOC) exam later that year. In 2018, Knowledge Check-Ins will be offered in internal medicine and nephrology.

“Based on feedback ABIM has received from the physician community, we are happy to let you know that we are extending this policy to include all other internal medicine subspecialties in the future,” ABIM said in a Dec. 4 announcement on its website. “This means that if a physician takes the Knowledge Check-In in the first year it is offered in their subspecialty and is unsuccessful, they will get at least one additional opportunity to take and pass it 2 years later.”

The Knowledge Check-In is an alternative to the traditional MOC process, and is administered every 2 years rather than the standard decade between MOC exams. ABIM noted that a single failure on a Knowledge Check-In will not result in a status change to a physician’s certification status.

Separately, ABIM also announced that it will continue to make practice assessment activities (part IV of the MOC program) a part of the portfolio of options that can be used to satisfy MOC requirements.

“Our intent is to support physicians completing MOC activities that are most meaningful to their practice, including those that enhance and improve medical knowledge, as well as many existing quality improvement activities, and those that blend both,” ABIM said in its announcement.

[email protected]

LOS ANGELES – Growing evidence from basic science and preclinical studies demonstrates that insulin plays a key role in brain synaptic function viability, vascular function, amyloid/tau regulation, and cerebral glucose metabolism.

In addition, brain insulin resistance in Alzheimer’s disease (AD) is associated with increased cerebral hyperglycemia, reduced cerebral glucose utilization, reduced blood flow, and reduced accumulation of amyloid and tau.

Doug Brunk/Frontline Medical News

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LOS ANGELES – Growing evidence from basic science and preclinical studies demonstrates that insulin plays a key role in brain synaptic function viability, vascular function, amyloid/tau regulation, and cerebral glucose metabolism.

In addition, brain insulin resistance in Alzheimer’s disease (AD) is associated with increased cerebral hyperglycemia, reduced cerebral glucose utilization, reduced blood flow, and reduced accumulation of amyloid and tau.

Doug Brunk/Frontline Medical News

[email protected]

LOS ANGELES – Growing evidence from basic science and preclinical studies demonstrates that insulin plays a key role in brain synaptic function viability, vascular function, amyloid/tau regulation, and cerebral glucose metabolism.

In addition, brain insulin resistance in Alzheimer’s disease (AD) is associated with increased cerebral hyperglycemia, reduced cerebral glucose utilization, reduced blood flow, and reduced accumulation of amyloid and tau.

Doug Brunk/Frontline Medical News

[email protected]

On May 5, 2017, the Food and Drug Administration approved edaravone (Radicava) for the treatment of patients with amyotrophic lateral sclerosis (ALS). Developed by Mitsubishi Tanabe Pharma Corporation, edaravone is the first FDA-approved treatment for ALS since the approval of riluzole (Rilutek) in 1995. Edaravone was originally developed as an acute stroke treatment and then later studied in two separate trials in Japan to assess its efficacy in treating ALS.

Ms. Chang is a research intern, and Dr. Ross is a professor of neurology and director of the ALS Clinic, at Mayo Clinic Arizona in Scottsdale. Dr. Ross reported serving as the Mayo Clinic Arizona site primary investigator for the ALS investigational drug NP001.

On May 5, 2017, the Food and Drug Administration approved edaravone (Radicava) for the treatment of patients with amyotrophic lateral sclerosis (ALS). Developed by Mitsubishi Tanabe Pharma Corporation, edaravone is the first FDA-approved treatment for ALS since the approval of riluzole (Rilutek) in 1995. Edaravone was originally developed as an acute stroke treatment and then later studied in two separate trials in Japan to assess its efficacy in treating ALS.

Ms. Chang is a research intern, and Dr. Ross is a professor of neurology and director of the ALS Clinic, at Mayo Clinic Arizona in Scottsdale. Dr. Ross reported serving as the Mayo Clinic Arizona site primary investigator for the ALS investigational drug NP001.

On May 5, 2017, the Food and Drug Administration approved edaravone (Radicava) for the treatment of patients with amyotrophic lateral sclerosis (ALS). Developed by Mitsubishi Tanabe Pharma Corporation, edaravone is the first FDA-approved treatment for ALS since the approval of riluzole (Rilutek) in 1995. Edaravone was originally developed as an acute stroke treatment and then later studied in two separate trials in Japan to assess its efficacy in treating ALS.

Ms. Chang is a research intern, and Dr. Ross is a professor of neurology and director of the ALS Clinic, at Mayo Clinic Arizona in Scottsdale. Dr. Ross reported serving as the Mayo Clinic Arizona site primary investigator for the ALS investigational drug NP001.

SAN DIEGO – Surgical residents spend a large part of every working day in front of a computer screen, with first-year residents saying they spend an average of more than 13 hours a day on electronic medical records (EMRs).

“Residents are spending a lot of time sitting at a computer, and residents seem to be in agreement that this is time they could potentially be spending learning how to operate and care for patients, which is one of the fundamental purposes of residency training,” study lead author Edward S. Shipper III, MD, a PGY-3 general surgery resident at UT Health-San Antonio, said in an interview after he presented the study findings at the annual clinical congress of the American College of Surgeons.

SAN DIEGO – Surgical residents spend a large part of every working day in front of a computer screen, with first-year residents saying they spend an average of more than 13 hours a day on electronic medical records (EMRs).

“Residents are spending a lot of time sitting at a computer, and residents seem to be in agreement that this is time they could potentially be spending learning how to operate and care for patients, which is one of the fundamental purposes of residency training,” study lead author Edward S. Shipper III, MD, a PGY-3 general surgery resident at UT Health-San Antonio, said in an interview after he presented the study findings at the annual clinical congress of the American College of Surgeons.

SAN DIEGO – Surgical residents spend a large part of every working day in front of a computer screen, with first-year residents saying they spend an average of more than 13 hours a day on electronic medical records (EMRs).

“Residents are spending a lot of time sitting at a computer, and residents seem to be in agreement that this is time they could potentially be spending learning how to operate and care for patients, which is one of the fundamental purposes of residency training,” study lead author Edward S. Shipper III, MD, a PGY-3 general surgery resident at UT Health-San Antonio, said in an interview after he presented the study findings at the annual clinical congress of the American College of Surgeons.

The Food and Drug Administration has granted breakthrough therapy designation to bb2121, a chimeric antigen receptor T-cell (CAR T) therapy that targets b-cell maturation antigen (BCMA) in patients with relapsed/refractory multiple myeloma.

The therapy, being developed jointly by Celgene and bluebird bio, will be given expedited review by the FDA under the program. Meanwhile, European drug officials have granted it Priority Medicines eligibility, which also provides accelerated review.

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The Food and Drug Administration has granted breakthrough therapy designation to bb2121, a chimeric antigen receptor T-cell (CAR T) therapy that targets b-cell maturation antigen (BCMA) in patients with relapsed/refractory multiple myeloma.

The therapy, being developed jointly by Celgene and bluebird bio, will be given expedited review by the FDA under the program. Meanwhile, European drug officials have granted it Priority Medicines eligibility, which also provides accelerated review.

[email protected]

The Food and Drug Administration has granted breakthrough therapy designation to bb2121, a chimeric antigen receptor T-cell (CAR T) therapy that targets b-cell maturation antigen (BCMA) in patients with relapsed/refractory multiple myeloma.

The therapy, being developed jointly by Celgene and bluebird bio, will be given expedited review by the FDA under the program. Meanwhile, European drug officials have granted it Priority Medicines eligibility, which also provides accelerated review.

[email protected]

Primary biliary cholangitis patients who had concomitant nonalcoholic fatty liver disease (NAFLD) experienced no worse disease progression than patients who had PBC alone, according to Gerald Yosel Minuk, MD, and his associates.

At baseline, the 168 patients in the PBC-only group had higher serum alkaline phosphatase and gamma-glutamyl transferase values than the 68 patients in the NAFLD/PBC group, as well as having higher FIB-4 scores. The percentage of patients with aspartate aminotransferase/platelet ratio indexes (APRI) greater than 1.5 was slightly higher in the PBC-only group, but the difference was not significant.

After follow-up periods averaging 6.7 years in the PBC-only group and 6.4 years in the NAFLD/PBC group, yearly increases in FIB-4 and prevalence of APRI greater than 1.5 were greater in the PBC-only group, though the difference did not reach significance. PBC-only patients were more likely to have developed radiologic evidence of cirrhosis during the follow-up period (42% vs. 19%, P less than .001).

“Were the results of the present study to be confirmed by others, the question arises as to why NAFLD does not adversely and may favorably impact on PBC. Here, it is tempting to speculate that because PBC livers are associated with a paucity of immunosuppressive regulator T cells (Tregs) whereas in NAFLD, Tregs are recruited to the liver in increased numbers, a restoration of the immune balance in PBC livers might explain these findings,” the investigators noted.

Find the full study in Liver International (doi: 10.1111/liv.13644).

[email protected]

Primary biliary cholangitis patients who had concomitant nonalcoholic fatty liver disease (NAFLD) experienced no worse disease progression than patients who had PBC alone, according to Gerald Yosel Minuk, MD, and his associates.

At baseline, the 168 patients in the PBC-only group had higher serum alkaline phosphatase and gamma-glutamyl transferase values than the 68 patients in the NAFLD/PBC group, as well as having higher FIB-4 scores. The percentage of patients with aspartate aminotransferase/platelet ratio indexes (APRI) greater than 1.5 was slightly higher in the PBC-only group, but the difference was not significant.

After follow-up periods averaging 6.7 years in the PBC-only group and 6.4 years in the NAFLD/PBC group, yearly increases in FIB-4 and prevalence of APRI greater than 1.5 were greater in the PBC-only group, though the difference did not reach significance. PBC-only patients were more likely to have developed radiologic evidence of cirrhosis during the follow-up period (42% vs. 19%, P less than .001).

“Were the results of the present study to be confirmed by others, the question arises as to why NAFLD does not adversely and may favorably impact on PBC. Here, it is tempting to speculate that because PBC livers are associated with a paucity of immunosuppressive regulator T cells (Tregs) whereas in NAFLD, Tregs are recruited to the liver in increased numbers, a restoration of the immune balance in PBC livers might explain these findings,” the investigators noted.

Find the full study in Liver International (doi: 10.1111/liv.13644).

[email protected]

Primary biliary cholangitis patients who had concomitant nonalcoholic fatty liver disease (NAFLD) experienced no worse disease progression than patients who had PBC alone, according to Gerald Yosel Minuk, MD, and his associates.

At baseline, the 168 patients in the PBC-only group had higher serum alkaline phosphatase and gamma-glutamyl transferase values than the 68 patients in the NAFLD/PBC group, as well as having higher FIB-4 scores. The percentage of patients with aspartate aminotransferase/platelet ratio indexes (APRI) greater than 1.5 was slightly higher in the PBC-only group, but the difference was not significant.

After follow-up periods averaging 6.7 years in the PBC-only group and 6.4 years in the NAFLD/PBC group, yearly increases in FIB-4 and prevalence of APRI greater than 1.5 were greater in the PBC-only group, though the difference did not reach significance. PBC-only patients were more likely to have developed radiologic evidence of cirrhosis during the follow-up period (42% vs. 19%, P less than .001).

“Were the results of the present study to be confirmed by others, the question arises as to why NAFLD does not adversely and may favorably impact on PBC. Here, it is tempting to speculate that because PBC livers are associated with a paucity of immunosuppressive regulator T cells (Tregs) whereas in NAFLD, Tregs are recruited to the liver in increased numbers, a restoration of the immune balance in PBC livers might explain these findings,” the investigators noted.

Find the full study in Liver International (doi: 10.1111/liv.13644).

[email protected]

The sweeping tax bill passed in the Senate could have a dramatic effect on Medicare physician pay, unless Congress waives its own pay-as-you-go rules requiring that any spending increases be offset by other spending cuts.

At issue is the Senate bill’s repeal of the Affordable Care Act requirement that every individual have health insurance – the individual mandate.

franckreporter/Thinkstock

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The sweeping tax bill passed in the Senate could have a dramatic effect on Medicare physician pay, unless Congress waives its own pay-as-you-go rules requiring that any spending increases be offset by other spending cuts.

At issue is the Senate bill’s repeal of the Affordable Care Act requirement that every individual have health insurance – the individual mandate.

franckreporter/Thinkstock

[email protected]

The sweeping tax bill passed in the Senate could have a dramatic effect on Medicare physician pay, unless Congress waives its own pay-as-you-go rules requiring that any spending increases be offset by other spending cuts.

At issue is the Senate bill’s repeal of the Affordable Care Act requirement that every individual have health insurance – the individual mandate.

franckreporter/Thinkstock

[email protected]

A 32-year-old woman presented to the emergency department (ED) with 3 months of abdominal pain and 1 week of vomiting.

The differential diagnosis of abdominal pain is broad. This presentation could be caused by disorders of the gastrointestinal (GI), gynecologic, urinary, or, less likely, the neuromuscular systems. The presence of vomiting supports a GI cause. Pregnancy should be excluded in any woman of childbearing age presenting with abdominal pain.

Characteristics of the pain, including location, temporal characteristics, severity, and aggravating and alleviating factors, can narrow the differential diagnosis. The past medical history, including prior surgeries, menstrual, and obstetric history, is also critical.

Approximately 3 months prior to presentation, she reported a tick bite that had evolved into a circumferential targetoid rash. Her primary care provider performed serologic testing for Lyme disease, which was negative, and prescribed doxycycline, which she stopped after a week because of nausea and diffuse, achy, and constant abdominal pain. After initial improvement, symptoms recurred a week prior to presentation. The nausea was now associated with intractable vomiting and anorexia. She denied hematemesis or coffee ground emesis. Her abdominal pain intensified and radiated to her back. She lost 10 pounds over the past week. She denied headache, constipation, diarrhea, blood per rectum, melena, dysuria, vaginal discharge, or rash. She reported chills and temperatures up to 37.8 ° C at home.

She had a history of migraine headaches for which she took ibuprofen occasionally but took no other prescription or over-the-counter medications. She had never smoked, consumed 2 alcoholic beverages a month, and denied illicit drug use. She lived with her boyfriend on a farm in Indiana where she raised chickens, rabbits, and ducks.

The patient dates the onset of nausea and abdominal pain to a course of doxycycline, presumably prescribed for early Lyme disease, which was stopped after only 1 week. GI side effects, including nausea, vomiting, and upper abdominal pain, are common with doxycycline and may account for the early symptoms. However, these symptoms typically resolve promptly with drug discontinuation. Doxycycline may rarely cause esophageal and gastric ulcers, which could explain her symptoms.

Fewer than half of patients with erythema migrans caused by Lyme disease are seropositive at presentation, as there has been insufficient time for antibodies to develop. Lyme disease typically affects the skin, joints, heart, and nervous system and only rarely affects the GI tract. Acute Lyme disease can cause intestinal pseudoobstruction, splenomegaly, and mild hepatitis. Although Lyme disease is unlikely to be the cause of the current symptoms, serologic testing should be repeated and should be positive if the patient now has early disseminated disease.

Patients with Lyme disease are occasionally coinfected with a second organism. Ixodes scapularis, the tick that transmits Lyme disease in the Northeast and Midwest, can be coinfected with Babesia microti, a red cell parasite. Babesiosis can persist for months and presents with fever, malaise, and many other nonspecific symptoms, including some that this patient has: anorexia, weight loss, abdominal pain, and vomiting.

The history of migraine and intractable vomiting suggests the possibility of cyclic vomiting syndrome. This syndrome is characterized by episodic bouts of vomiting lasting from hours to as long as a week. The vomiting is often accompanied by abdominal pain and occasionally headaches. Episodes are separated by asymptomatic periods that may last months. Cyclic vomiting syndrome can occur at any age but is more common in children, those with a personal or family history of migraines, and heavy users of cannabis. At least 3 stereotypical episodes are required to make the diagnosis, so a history of prior similar symptoms should be explored.

The differential diagnosis of abdominal pain and vomiting should stay broad until a comprehensive physical exam and initial laboratory tests are performed. Volume status should be assessed by estimating jugular venous pressure and by obtaining supine and standing blood pressure measurements. The abdomen should be examined carefully, and the presence or absence of hepatomegaly, splenomegaly, masses, and ascites should be specifically noted. The presence of bradycardia, oligoarticular arthritis, or neuropathy could provide supporting evidence for Lyme disease. Pregnancy is less likely given the diffuse and persistent nature of the pain but should still be excluded.

On physical examination, she was distressed, writhing on the bed, and appearing comfortable only on her side with her knees flexed. Her temperature was 36.5 ° C, heart rate 83 beats per minute, respiratory rate 18 breaths per minute, blood pressure 143/77 mmHg, and oxygen saturation 94% while breathing ambient air. Her abdomen was diffusely tender, most markedly in the epigastrium. Abdominal rigidity, rebound tenderness, and costovertebral tenderness were absent. There was no rash; the previously reported targetoid skin lesion was no longer present. The remainder of the exam was normal.

Laboratory evaluation showed a white count of 7900/mm3, hemoglobin 14.3 gm/dL with normocytic indices, and a platelet count of 175,000/mm3. Sodium was 130 mmol/L, potassium was 3.1 mmol/L, bicarbonate 26 mmol/L, blood urea nitrogen 15 mg/dL, creatinine 0.6 mg/dL, and glucose 92 mg/dL. Serum calcium, aspartate aminotransferase, alanine aminotransferase, bilirubin, and lipase were normal. A urine pregnancy test was negative. Urine analysis was negative for nitrites and leukocyte esterase. Abdominal and pelvic computed tomography (CT) scan with intravenous (IV) contrast performed 3 days prior at an outside ED revealed a 3.4 centimeter left ovarian cyst. A subsequent transvaginal ultrasound was negative for cyst torsion and confirmed appropriate placement of an intrauterine device.

The absence of abdominal rigidity and rebound tenderness does not exclude peritonitis. A normal white blood cell count also does not reliably exclude serious intraabdominal pathology. However, the CT scan argues strongly against many common causes of abdominal pain, including appendicitis, diverticulitis, perforated ulcer, intestinal obstruction, and malignancy, assuming the symptoms have not changed since it was performed.

The patient’s laboratory studies argue against biliary obstruction, pancreatitis, pregnancy, hypercalcemia, and ongoing urinary tract infection. Patients with functional gallbladder disorders may have normal laboratory and CT findings but typically have recurrent, biliary-colic-type pain. The low serum potassium, a high blood urea nitrogen to creatinine ratio, and a low serum sodium reflect her significant vomiting. The hyponatremia is consistent with the appropriate release of antidiuretic hormone (ADH) in the setting of volume depletion. She should receive isotonic fluids plus potassium in addition to symptomatic treatment of pain and nausea. Given the severity and duration of symptoms, an esophagogastroduodenoscopy (EGD) should be performed to exclude GI mucosal disease, including peptic ulcer disease and gastritis, which may not be evident on the CT scan.

Additional diagnoses should be considered at this point. This patient has exposure to chickens, ducks, rabbits, and ticks as well as reported chills and mild temperature elevation at home. Tularemia, which can be transmitted by tick bites or exposure to infected rabbits, can cause a prolonged illness. Some patients have abdominal pain, anorexia, nausea, and weight loss, although fever is usually more prominent. Tularemia is uncommon and most frequently seen in the south-central part of the United States but has been reported throughout the country. She should be queried regarding additional exposures, including well water to assess her risk for Campylobacter infection.

Opiate withdrawal can present with pain and vomiting, but she reports no opiate use and lacks other findings such pupillary dilation or piloerection. Given the prevalence of opiate abuse, however, a toxicology screen should be performed. Hypercalcemia and diabetic ketoacidosis as metabolic causes of abdominal pain have been ruled out by her laboratory values. If no other cause is identified, other metabolic etiologies like Addison disease, familial Mediterranean fever, or porphyria should be considered.

Cyclic vomiting syndrome should still be on the differential. It is a diagnosis of exclusion requiring a history of recurrent, stereotypical episodes, which should be explicitly explored.

The patient was admitted to a medical unit by the hospitalist service and received IV normal saline, parenteral potassium, and IV pantoprazole. She underwent an EGD that revealed minor erosions in the antrum of the stomach. Biopsies were obtained.

Seven hours after the endoscopy, the patient had a brief period of confusion followed by a generalized tonic-clonic seizure lasting 1 minute. A head CT without contrast was negative for any focal abnormality. Repeat laboratory evaluation revealed that serum sodium was 125 mmol/L, and serum glucose was 113 mg/dL. She was transferred to the progressive care unit and received IV levetiracetam.

The endoscopy excluded structural abnormalities of the stomach and duodenum. The patient now has an additional problem, seizure, which needs to be incorporated in the diagnostic reasoning.

Seizures can be caused by the rapid development of severe hyponatremia, with serum sodium levels usually less than 120 mmol/L. Seizures caused by hyponatremia are typically preceded by headache and lethargy, as the intracellular movement of excess water causes cerebral edema. Hyponatremia is unlikely to be the cause of her seizure but should nevertheless be evaluated with a urine sodium concentration and serum and urine osmolality. If she is euvolemic, the IV fluids should be stopped and her free water intake should be restricted to avoid worsening the hyponatremia, as it is potentially caused by the syndrome of inappropriate ADH (SIADH).

There are many other possible causes for new onset seizures in adults, including brain tumor, head trauma, alcohol withdrawal, medications, and central nervous system infection, including Lyme disease. Lyme serologies should be repeated.

In this patient, it is likely that the seizure is a manifestation of the same illness that is causing her vomiting and abdominal pain. Seizure is not a feature of cyclic vomiting syndrome in adults. It is also not a feature of tularemia, adrenal insufficiency, or opioid withdrawal.

Acute intermittent porphyria (AIP) can cause both abdominal and neurologic problems. Hyponatremia is common during acute attacks, caused by either the inappropriate release of ADH or the appropriate release of the hormone if there is fluid loss. AIP is a rare diagnosis but could explain the uncommon combination of abdominal pain, vomiting, seizure, and hyponatremia. A spot urine porphobilinogen test should be sent to assess for AIP.

Additional laboratory studies were sent. Serum osmolality was 269 mosm/kg with a corresponding urine osmolality of 699 mosm/kg. A random urine sodium was 145 mEq/L. Thyroid stimulating hormone and cosyntropin stimulating testing were normal. IgM and IgG antibodies to Borrelia burgdorferi were negative. Urine porphobilinogen was sent. An electroencephalogram did not reveal epileptiform discharges. Magnetic resonance imaging (MRI) of the brain was significant for T2/FLAIR hyperintensity in the cortex and subcortical white matter of the occipital lobes bilaterally. Hypertonic saline and fluid restriction were initiated.

The patient’s labs are consistent with SIADH. Excessive ADH release because of volume depletion and consequent hyponatremia should have improved rapidly with the administration of saline. The high urine sodium suggests that she is now volume replete, while the high urine osmolality is consistent with the presence of excessive ADH in the absence of appropriate stimuli. In the context of normal thyroid and adrenal function, the hyponatremia is likely due to the SIADH.

Negative serologic testing for Lyme disease, 3 months after the onset of rash, excludes this diagnosis.

The MRI findings are consistent with posterior reversible encephalopathy syndrome (PRES), a clinicoradiographic syndrome of headache, altered mental status, seizure, and/or vision loss with associated white matter abnormalities of the posterior cerebral hemispheres. PRES has been reported with AIP as well as other disorders, most commonly hypertensive encephalopathy, eclampsia, and immunosuppressive drug use.

The patient’s sodium improved with fluid restriction and the administration of hypertonic saline. There was no recurrence of seizure activity. Amlodipine was initiated for blood pressure readings as high as 156/106 mmHg. A hepatobiliary scan revealed a gallbladder ejection fraction of 13%. Biopsies from her endoscopy revealed nonspecific inflammation without the presence of Helicobacter pylori. The patient was discharged home 7 days after admission after stabilization of serum sodium, improvement in her abdominal pain, and tolerance of oral intake. A plan was made for outpatient cholecystectomy.

Many causes of abdominal pain have been excluded and the remaining diagnostic possibility, porphyria, is rare. The clinicians have revisited their differential and considered other causes of abdominal pain, including functional gallbladder disorders. However, chronic cholecystitis (or functional gallbladder disorder) is not this patient’s primary problem. The diffuse, severe, and constant abdominal pain prior to admission is not typical of biliary pain, and many medical conditions and drugs, including amlodipine, can lead to a positive hepatobiliary scan. Chronic cholecystitis would not explain her seizure.

AIP remains at the top of the differential for this young woman. A urine porphobilinogen has been sent and must be followed up prior to any further workup or surgery.

One week after discharge, the patient’s urine porphobilinogen resulted at 172.8 mCmol/ (upper limits of normal 8.8). Sequencing analysis for genes coding the enzymes involved in the synthetic pathway for heme were sent. Hydroxymethylbilane synthase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase mutation assays were all normal. Despite the normal genetic assays, the diagnosis of AIP was made on the basis of the clinical presentation and elevated urine porphobilinogen. The patient was referred to a hematologist and initiated on oral glucose supplements and hematin infusions.

Although abdominal pain has a broad differential, the combination of abdominal pain and neurologic or psychiatric symptoms should suggest the possibility of porphyria, especially if symptoms are recurrent or unexplained. The porphyrias are a group of disorders caused by defects in the synthetic pathway of heme, leading to an overproduction and accumulation of precursors. Heme is a component of multiple proteins, including hemoglobin, myoglobin, and the cytochrome P450 enzymes. Although it is synthesized in all tissues, the bone marrow and liver are the organs most actively involved. The porphyrias can be classified according to the primary site of the overproduction and accumulation of heme precursors (liver vs bone marrow). Although there is overlap between the 2 groups, hepatic porphyrias often present with acute neurovisceral symptoms, while the erythropoietic porphyrias often cause cutaneous photosensitivity.¹

AIP is the most common hepatic porphyria with a prevalence of 1 in 20,000 in Caucasians of Western European descent.¹ AIP is caused by a defect in the gene that encodes porphobilinogen deaminase, leading to the accumulation of porphobilinogen.¹ The cardinal manifestation is an acute porphyric attack. While the precise mechanisms underlying the symptoms are unknown, the accumulating metabolites may be directly neurotoxic.² Attacks are precipitated by factors that induce heme synthesis, including caloric restriction, alcohol, and certain medications, particularly those that upregulate cyP450. The most commonly implicated drugs are anesthetics, antiepileptics, sulfonamides, rifampin, and estrogen and progesterone. Attacks can also be precipitated by changes in endogenous sex hormone levels, like the increase in progesterone seen in the luteal phase of the menstrual cycle, which may account for the higher incidence of symptomatic attacks in women.³

Acute attacks of AIP may have a wide variety of presentations; the disease was referred to as the “little imitator” in the early 20th century.⁴ The most common symptom is acute, severe abdominal pain, which may mimic an acute abdomen. Because the pain is neuropathic rather than inflammatory, abdominal tenderness, rebound, fever, and leukocytosis are usually absent, as they were in this patient. Abdominal pain is often accompanied by neuropsychiatric symptoms, including sensory and motor neuropathy, anxiety, hallucinations, delirium, and altered level of consciousness. Seizure occurs in 20% of cases. Involvement of the autonomic nervous system causes tachycardia and new onset hypertension in the majority of patients as well as restlessness and tremor. Hyponatremia, mediated by the syndrome of inappropriate ADH secretion, occurs in nearly a third of patients.^5,6 MRI findings consistent with PRES have also been described in AIP.⁷

The diagnosis of AIP is often delayed; diagnosis later in the disease course is associated with a poorer prognosis.⁸ Reported intervals between presentation and diagnosis range from several months to as long as 20 years.⁹ Associating the use of medications, caloric restriction, or the menstrual cycle with the exacerbation of symptoms or darkening of urine can help prompt an earlier diagnosis.⁶

AIP can be diagnosed by detecting a greater than 5-fold elevation of urinary porphobilinogen excretion in conjunction with the typical symptoms of an acute attack.⁵ Renal dysfunction causes urinary excretion of PBG to fall and serum levels to rise.¹⁰ Serum PBG levels should therefore be sent when AIP is suspected in the setting of renal dysfunction. The primary role of genetic testing in a patient who has AIP confirmed clinically and biochemically is to assist in genetic counseling and to identify asymptomatic family members.¹¹ Genetic testing is not required to confirm the diagnosis and does not help prognosticate. It is unusual that a mutation was not detected in this case, as the current sensitivity of genetic testing is 97% to 100%.¹¹

There are 4 principles of management of an acute porphyric attack. First, any precipitating factors such as medications should be stopped. Second, abdominal pain should be treated appropriately with opioids, if necessary. Third, if autonomic dysfunction is present, beta-blockers or clonidine should be given to treat hypertension.⁵ Finally, glucose and/or hemin should be administered to downregulate aminolevulinic acid (ALA) synthase by negative feedback. Downregulation of ALA synthase decreases the accumulation of the neurotoxic porphyrin precursors ALA and PBG.5 For patients with mild symptoms, glucose alone (300-500 g/d) may be enough to abort the attack.¹² This can be achieved via a high-carbohydrate diet in those able to tolerate oral intake or via continuous infusions of dextrose containing fluids.⁵ For more severe attacks with associated polyneuropathy, respiratory muscle weakness, or seizures, or for attacks that are not resolving, heme preparations dosed at 3 to 4 mg/kg/d for 3 to 4 days are indicated.⁵

The recent diagnosis of acute Lyme disease was a distractor in this presentation. In Lyme endemic areas, patients with erythema migrans are treated based on the clinical presentation rather than serologic testing.¹³ Although this patient took only 1 week of doxycycline, testing during this hospitalization showed that she had either been cured early or had not had Lyme disease in the first place. There is no known association between Lyme disease and the porphyrias, and doxycycline is not a common precipitant of AIP attacks.¹⁴ However, the GI side effects of doxycycline may have decreased caloric intake and ultimately provoked the patient’s first attack of AIP. The clinicians in this case appropriately avoided the “target” but hit the mark by correctly diagnosing AIP.

• Consider AIP in patients with unexplained abdominal pain, especially when accompanied by neuropsychiatric symptoms and autonomic lability.
• Diagnose AIP by sending a urine PBG during a suspected acute attack.
• Treat AIP acutely by removing precipitants, treating abdominal pain, and initiating dextrose-containing fluids and hemin infusions to downregulate ALA synthase.

The authors thank the patient who enthusiastically supported the writing of this report.

Disclosure

Warren Gavin, MD has disclosed participation in expert testimony. The authors have no financial or other conflicts of interest to disclose.

A 32-year-old woman presented to the emergency department (ED) with 3 months of abdominal pain and 1 week of vomiting.

The differential diagnosis of abdominal pain is broad. This presentation could be caused by disorders of the gastrointestinal (GI), gynecologic, urinary, or, less likely, the neuromuscular systems. The presence of vomiting supports a GI cause. Pregnancy should be excluded in any woman of childbearing age presenting with abdominal pain.

Characteristics of the pain, including location, temporal characteristics, severity, and aggravating and alleviating factors, can narrow the differential diagnosis. The past medical history, including prior surgeries, menstrual, and obstetric history, is also critical.

Approximately 3 months prior to presentation, she reported a tick bite that had evolved into a circumferential targetoid rash. Her primary care provider performed serologic testing for Lyme disease, which was negative, and prescribed doxycycline, which she stopped after a week because of nausea and diffuse, achy, and constant abdominal pain. After initial improvement, symptoms recurred a week prior to presentation. The nausea was now associated with intractable vomiting and anorexia. She denied hematemesis or coffee ground emesis. Her abdominal pain intensified and radiated to her back. She lost 10 pounds over the past week. She denied headache, constipation, diarrhea, blood per rectum, melena, dysuria, vaginal discharge, or rash. She reported chills and temperatures up to 37.8 ° C at home.

She had a history of migraine headaches for which she took ibuprofen occasionally but took no other prescription or over-the-counter medications. She had never smoked, consumed 2 alcoholic beverages a month, and denied illicit drug use. She lived with her boyfriend on a farm in Indiana where she raised chickens, rabbits, and ducks.

The patient dates the onset of nausea and abdominal pain to a course of doxycycline, presumably prescribed for early Lyme disease, which was stopped after only 1 week. GI side effects, including nausea, vomiting, and upper abdominal pain, are common with doxycycline and may account for the early symptoms. However, these symptoms typically resolve promptly with drug discontinuation. Doxycycline may rarely cause esophageal and gastric ulcers, which could explain her symptoms.

Fewer than half of patients with erythema migrans caused by Lyme disease are seropositive at presentation, as there has been insufficient time for antibodies to develop. Lyme disease typically affects the skin, joints, heart, and nervous system and only rarely affects the GI tract. Acute Lyme disease can cause intestinal pseudoobstruction, splenomegaly, and mild hepatitis. Although Lyme disease is unlikely to be the cause of the current symptoms, serologic testing should be repeated and should be positive if the patient now has early disseminated disease.

Patients with Lyme disease are occasionally coinfected with a second organism. Ixodes scapularis, the tick that transmits Lyme disease in the Northeast and Midwest, can be coinfected with Babesia microti, a red cell parasite. Babesiosis can persist for months and presents with fever, malaise, and many other nonspecific symptoms, including some that this patient has: anorexia, weight loss, abdominal pain, and vomiting.

The history of migraine and intractable vomiting suggests the possibility of cyclic vomiting syndrome. This syndrome is characterized by episodic bouts of vomiting lasting from hours to as long as a week. The vomiting is often accompanied by abdominal pain and occasionally headaches. Episodes are separated by asymptomatic periods that may last months. Cyclic vomiting syndrome can occur at any age but is more common in children, those with a personal or family history of migraines, and heavy users of cannabis. At least 3 stereotypical episodes are required to make the diagnosis, so a history of prior similar symptoms should be explored.

The differential diagnosis of abdominal pain and vomiting should stay broad until a comprehensive physical exam and initial laboratory tests are performed. Volume status should be assessed by estimating jugular venous pressure and by obtaining supine and standing blood pressure measurements. The abdomen should be examined carefully, and the presence or absence of hepatomegaly, splenomegaly, masses, and ascites should be specifically noted. The presence of bradycardia, oligoarticular arthritis, or neuropathy could provide supporting evidence for Lyme disease. Pregnancy is less likely given the diffuse and persistent nature of the pain but should still be excluded.

On physical examination, she was distressed, writhing on the bed, and appearing comfortable only on her side with her knees flexed. Her temperature was 36.5 ° C, heart rate 83 beats per minute, respiratory rate 18 breaths per minute, blood pressure 143/77 mmHg, and oxygen saturation 94% while breathing ambient air. Her abdomen was diffusely tender, most markedly in the epigastrium. Abdominal rigidity, rebound tenderness, and costovertebral tenderness were absent. There was no rash; the previously reported targetoid skin lesion was no longer present. The remainder of the exam was normal.

Laboratory evaluation showed a white count of 7900/mm3, hemoglobin 14.3 gm/dL with normocytic indices, and a platelet count of 175,000/mm3. Sodium was 130 mmol/L, potassium was 3.1 mmol/L, bicarbonate 26 mmol/L, blood urea nitrogen 15 mg/dL, creatinine 0.6 mg/dL, and glucose 92 mg/dL. Serum calcium, aspartate aminotransferase, alanine aminotransferase, bilirubin, and lipase were normal. A urine pregnancy test was negative. Urine analysis was negative for nitrites and leukocyte esterase. Abdominal and pelvic computed tomography (CT) scan with intravenous (IV) contrast performed 3 days prior at an outside ED revealed a 3.4 centimeter left ovarian cyst. A subsequent transvaginal ultrasound was negative for cyst torsion and confirmed appropriate placement of an intrauterine device.

The absence of abdominal rigidity and rebound tenderness does not exclude peritonitis. A normal white blood cell count also does not reliably exclude serious intraabdominal pathology. However, the CT scan argues strongly against many common causes of abdominal pain, including appendicitis, diverticulitis, perforated ulcer, intestinal obstruction, and malignancy, assuming the symptoms have not changed since it was performed.

The patient’s laboratory studies argue against biliary obstruction, pancreatitis, pregnancy, hypercalcemia, and ongoing urinary tract infection. Patients with functional gallbladder disorders may have normal laboratory and CT findings but typically have recurrent, biliary-colic-type pain. The low serum potassium, a high blood urea nitrogen to creatinine ratio, and a low serum sodium reflect her significant vomiting. The hyponatremia is consistent with the appropriate release of antidiuretic hormone (ADH) in the setting of volume depletion. She should receive isotonic fluids plus potassium in addition to symptomatic treatment of pain and nausea. Given the severity and duration of symptoms, an esophagogastroduodenoscopy (EGD) should be performed to exclude GI mucosal disease, including peptic ulcer disease and gastritis, which may not be evident on the CT scan.

Additional diagnoses should be considered at this point. This patient has exposure to chickens, ducks, rabbits, and ticks as well as reported chills and mild temperature elevation at home. Tularemia, which can be transmitted by tick bites or exposure to infected rabbits, can cause a prolonged illness. Some patients have abdominal pain, anorexia, nausea, and weight loss, although fever is usually more prominent. Tularemia is uncommon and most frequently seen in the south-central part of the United States but has been reported throughout the country. She should be queried regarding additional exposures, including well water to assess her risk for Campylobacter infection.

Opiate withdrawal can present with pain and vomiting, but she reports no opiate use and lacks other findings such pupillary dilation or piloerection. Given the prevalence of opiate abuse, however, a toxicology screen should be performed. Hypercalcemia and diabetic ketoacidosis as metabolic causes of abdominal pain have been ruled out by her laboratory values. If no other cause is identified, other metabolic etiologies like Addison disease, familial Mediterranean fever, or porphyria should be considered.

Cyclic vomiting syndrome should still be on the differential. It is a diagnosis of exclusion requiring a history of recurrent, stereotypical episodes, which should be explicitly explored.

The patient was admitted to a medical unit by the hospitalist service and received IV normal saline, parenteral potassium, and IV pantoprazole. She underwent an EGD that revealed minor erosions in the antrum of the stomach. Biopsies were obtained.

Seven hours after the endoscopy, the patient had a brief period of confusion followed by a generalized tonic-clonic seizure lasting 1 minute. A head CT without contrast was negative for any focal abnormality. Repeat laboratory evaluation revealed that serum sodium was 125 mmol/L, and serum glucose was 113 mg/dL. She was transferred to the progressive care unit and received IV levetiracetam.

The endoscopy excluded structural abnormalities of the stomach and duodenum. The patient now has an additional problem, seizure, which needs to be incorporated in the diagnostic reasoning.

Seizures can be caused by the rapid development of severe hyponatremia, with serum sodium levels usually less than 120 mmol/L. Seizures caused by hyponatremia are typically preceded by headache and lethargy, as the intracellular movement of excess water causes cerebral edema. Hyponatremia is unlikely to be the cause of her seizure but should nevertheless be evaluated with a urine sodium concentration and serum and urine osmolality. If she is euvolemic, the IV fluids should be stopped and her free water intake should be restricted to avoid worsening the hyponatremia, as it is potentially caused by the syndrome of inappropriate ADH (SIADH).

There are many other possible causes for new onset seizures in adults, including brain tumor, head trauma, alcohol withdrawal, medications, and central nervous system infection, including Lyme disease. Lyme serologies should be repeated.

In this patient, it is likely that the seizure is a manifestation of the same illness that is causing her vomiting and abdominal pain. Seizure is not a feature of cyclic vomiting syndrome in adults. It is also not a feature of tularemia, adrenal insufficiency, or opioid withdrawal.

Acute intermittent porphyria (AIP) can cause both abdominal and neurologic problems. Hyponatremia is common during acute attacks, caused by either the inappropriate release of ADH or the appropriate release of the hormone if there is fluid loss. AIP is a rare diagnosis but could explain the uncommon combination of abdominal pain, vomiting, seizure, and hyponatremia. A spot urine porphobilinogen test should be sent to assess for AIP.

Additional laboratory studies were sent. Serum osmolality was 269 mosm/kg with a corresponding urine osmolality of 699 mosm/kg. A random urine sodium was 145 mEq/L. Thyroid stimulating hormone and cosyntropin stimulating testing were normal. IgM and IgG antibodies to Borrelia burgdorferi were negative. Urine porphobilinogen was sent. An electroencephalogram did not reveal epileptiform discharges. Magnetic resonance imaging (MRI) of the brain was significant for T2/FLAIR hyperintensity in the cortex and subcortical white matter of the occipital lobes bilaterally. Hypertonic saline and fluid restriction were initiated.

The patient’s labs are consistent with SIADH. Excessive ADH release because of volume depletion and consequent hyponatremia should have improved rapidly with the administration of saline. The high urine sodium suggests that she is now volume replete, while the high urine osmolality is consistent with the presence of excessive ADH in the absence of appropriate stimuli. In the context of normal thyroid and adrenal function, the hyponatremia is likely due to the SIADH.

Negative serologic testing for Lyme disease, 3 months after the onset of rash, excludes this diagnosis.

The MRI findings are consistent with posterior reversible encephalopathy syndrome (PRES), a clinicoradiographic syndrome of headache, altered mental status, seizure, and/or vision loss with associated white matter abnormalities of the posterior cerebral hemispheres. PRES has been reported with AIP as well as other disorders, most commonly hypertensive encephalopathy, eclampsia, and immunosuppressive drug use.

The patient’s sodium improved with fluid restriction and the administration of hypertonic saline. There was no recurrence of seizure activity. Amlodipine was initiated for blood pressure readings as high as 156/106 mmHg. A hepatobiliary scan revealed a gallbladder ejection fraction of 13%. Biopsies from her endoscopy revealed nonspecific inflammation without the presence of Helicobacter pylori. The patient was discharged home 7 days after admission after stabilization of serum sodium, improvement in her abdominal pain, and tolerance of oral intake. A plan was made for outpatient cholecystectomy.

Many causes of abdominal pain have been excluded and the remaining diagnostic possibility, porphyria, is rare. The clinicians have revisited their differential and considered other causes of abdominal pain, including functional gallbladder disorders. However, chronic cholecystitis (or functional gallbladder disorder) is not this patient’s primary problem. The diffuse, severe, and constant abdominal pain prior to admission is not typical of biliary pain, and many medical conditions and drugs, including amlodipine, can lead to a positive hepatobiliary scan. Chronic cholecystitis would not explain her seizure.

AIP remains at the top of the differential for this young woman. A urine porphobilinogen has been sent and must be followed up prior to any further workup or surgery.

One week after discharge, the patient’s urine porphobilinogen resulted at 172.8 mCmol/ (upper limits of normal 8.8). Sequencing analysis for genes coding the enzymes involved in the synthetic pathway for heme were sent. Hydroxymethylbilane synthase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase mutation assays were all normal. Despite the normal genetic assays, the diagnosis of AIP was made on the basis of the clinical presentation and elevated urine porphobilinogen. The patient was referred to a hematologist and initiated on oral glucose supplements and hematin infusions.

Although abdominal pain has a broad differential, the combination of abdominal pain and neurologic or psychiatric symptoms should suggest the possibility of porphyria, especially if symptoms are recurrent or unexplained. The porphyrias are a group of disorders caused by defects in the synthetic pathway of heme, leading to an overproduction and accumulation of precursors. Heme is a component of multiple proteins, including hemoglobin, myoglobin, and the cytochrome P450 enzymes. Although it is synthesized in all tissues, the bone marrow and liver are the organs most actively involved. The porphyrias can be classified according to the primary site of the overproduction and accumulation of heme precursors (liver vs bone marrow). Although there is overlap between the 2 groups, hepatic porphyrias often present with acute neurovisceral symptoms, while the erythropoietic porphyrias often cause cutaneous photosensitivity.¹

AIP is the most common hepatic porphyria with a prevalence of 1 in 20,000 in Caucasians of Western European descent.¹ AIP is caused by a defect in the gene that encodes porphobilinogen deaminase, leading to the accumulation of porphobilinogen.¹ The cardinal manifestation is an acute porphyric attack. While the precise mechanisms underlying the symptoms are unknown, the accumulating metabolites may be directly neurotoxic.² Attacks are precipitated by factors that induce heme synthesis, including caloric restriction, alcohol, and certain medications, particularly those that upregulate cyP450. The most commonly implicated drugs are anesthetics, antiepileptics, sulfonamides, rifampin, and estrogen and progesterone. Attacks can also be precipitated by changes in endogenous sex hormone levels, like the increase in progesterone seen in the luteal phase of the menstrual cycle, which may account for the higher incidence of symptomatic attacks in women.³

Acute attacks of AIP may have a wide variety of presentations; the disease was referred to as the “little imitator” in the early 20th century.⁴ The most common symptom is acute, severe abdominal pain, which may mimic an acute abdomen. Because the pain is neuropathic rather than inflammatory, abdominal tenderness, rebound, fever, and leukocytosis are usually absent, as they were in this patient. Abdominal pain is often accompanied by neuropsychiatric symptoms, including sensory and motor neuropathy, anxiety, hallucinations, delirium, and altered level of consciousness. Seizure occurs in 20% of cases. Involvement of the autonomic nervous system causes tachycardia and new onset hypertension in the majority of patients as well as restlessness and tremor. Hyponatremia, mediated by the syndrome of inappropriate ADH secretion, occurs in nearly a third of patients.^5,6 MRI findings consistent with PRES have also been described in AIP.⁷

The diagnosis of AIP is often delayed; diagnosis later in the disease course is associated with a poorer prognosis.⁸ Reported intervals between presentation and diagnosis range from several months to as long as 20 years.⁹ Associating the use of medications, caloric restriction, or the menstrual cycle with the exacerbation of symptoms or darkening of urine can help prompt an earlier diagnosis.⁶

AIP can be diagnosed by detecting a greater than 5-fold elevation of urinary porphobilinogen excretion in conjunction with the typical symptoms of an acute attack.⁵ Renal dysfunction causes urinary excretion of PBG to fall and serum levels to rise.¹⁰ Serum PBG levels should therefore be sent when AIP is suspected in the setting of renal dysfunction. The primary role of genetic testing in a patient who has AIP confirmed clinically and biochemically is to assist in genetic counseling and to identify asymptomatic family members.¹¹ Genetic testing is not required to confirm the diagnosis and does not help prognosticate. It is unusual that a mutation was not detected in this case, as the current sensitivity of genetic testing is 97% to 100%.¹¹

There are 4 principles of management of an acute porphyric attack. First, any precipitating factors such as medications should be stopped. Second, abdominal pain should be treated appropriately with opioids, if necessary. Third, if autonomic dysfunction is present, beta-blockers or clonidine should be given to treat hypertension.⁵ Finally, glucose and/or hemin should be administered to downregulate aminolevulinic acid (ALA) synthase by negative feedback. Downregulation of ALA synthase decreases the accumulation of the neurotoxic porphyrin precursors ALA and PBG.5 For patients with mild symptoms, glucose alone (300-500 g/d) may be enough to abort the attack.¹² This can be achieved via a high-carbohydrate diet in those able to tolerate oral intake or via continuous infusions of dextrose containing fluids.⁵ For more severe attacks with associated polyneuropathy, respiratory muscle weakness, or seizures, or for attacks that are not resolving, heme preparations dosed at 3 to 4 mg/kg/d for 3 to 4 days are indicated.⁵

The recent diagnosis of acute Lyme disease was a distractor in this presentation. In Lyme endemic areas, patients with erythema migrans are treated based on the clinical presentation rather than serologic testing.¹³ Although this patient took only 1 week of doxycycline, testing during this hospitalization showed that she had either been cured early or had not had Lyme disease in the first place. There is no known association between Lyme disease and the porphyrias, and doxycycline is not a common precipitant of AIP attacks.¹⁴ However, the GI side effects of doxycycline may have decreased caloric intake and ultimately provoked the patient’s first attack of AIP. The clinicians in this case appropriately avoided the “target” but hit the mark by correctly diagnosing AIP.

• Consider AIP in patients with unexplained abdominal pain, especially when accompanied by neuropsychiatric symptoms and autonomic lability.
• Diagnose AIP by sending a urine PBG during a suspected acute attack.
• Treat AIP acutely by removing precipitants, treating abdominal pain, and initiating dextrose-containing fluids and hemin infusions to downregulate ALA synthase.

The authors thank the patient who enthusiastically supported the writing of this report.

Disclosure

Warren Gavin, MD has disclosed participation in expert testimony. The authors have no financial or other conflicts of interest to disclose.

A 32-year-old woman presented to the emergency department (ED) with 3 months of abdominal pain and 1 week of vomiting.

The differential diagnosis of abdominal pain is broad. This presentation could be caused by disorders of the gastrointestinal (GI), gynecologic, urinary, or, less likely, the neuromuscular systems. The presence of vomiting supports a GI cause. Pregnancy should be excluded in any woman of childbearing age presenting with abdominal pain.

Characteristics of the pain, including location, temporal characteristics, severity, and aggravating and alleviating factors, can narrow the differential diagnosis. The past medical history, including prior surgeries, menstrual, and obstetric history, is also critical.

Approximately 3 months prior to presentation, she reported a tick bite that had evolved into a circumferential targetoid rash. Her primary care provider performed serologic testing for Lyme disease, which was negative, and prescribed doxycycline, which she stopped after a week because of nausea and diffuse, achy, and constant abdominal pain. After initial improvement, symptoms recurred a week prior to presentation. The nausea was now associated with intractable vomiting and anorexia. She denied hematemesis or coffee ground emesis. Her abdominal pain intensified and radiated to her back. She lost 10 pounds over the past week. She denied headache, constipation, diarrhea, blood per rectum, melena, dysuria, vaginal discharge, or rash. She reported chills and temperatures up to 37.8 ° C at home.

She had a history of migraine headaches for which she took ibuprofen occasionally but took no other prescription or over-the-counter medications. She had never smoked, consumed 2 alcoholic beverages a month, and denied illicit drug use. She lived with her boyfriend on a farm in Indiana where she raised chickens, rabbits, and ducks.

The patient dates the onset of nausea and abdominal pain to a course of doxycycline, presumably prescribed for early Lyme disease, which was stopped after only 1 week. GI side effects, including nausea, vomiting, and upper abdominal pain, are common with doxycycline and may account for the early symptoms. However, these symptoms typically resolve promptly with drug discontinuation. Doxycycline may rarely cause esophageal and gastric ulcers, which could explain her symptoms.

Fewer than half of patients with erythema migrans caused by Lyme disease are seropositive at presentation, as there has been insufficient time for antibodies to develop. Lyme disease typically affects the skin, joints, heart, and nervous system and only rarely affects the GI tract. Acute Lyme disease can cause intestinal pseudoobstruction, splenomegaly, and mild hepatitis. Although Lyme disease is unlikely to be the cause of the current symptoms, serologic testing should be repeated and should be positive if the patient now has early disseminated disease.

Patients with Lyme disease are occasionally coinfected with a second organism. Ixodes scapularis, the tick that transmits Lyme disease in the Northeast and Midwest, can be coinfected with Babesia microti, a red cell parasite. Babesiosis can persist for months and presents with fever, malaise, and many other nonspecific symptoms, including some that this patient has: anorexia, weight loss, abdominal pain, and vomiting.

The history of migraine and intractable vomiting suggests the possibility of cyclic vomiting syndrome. This syndrome is characterized by episodic bouts of vomiting lasting from hours to as long as a week. The vomiting is often accompanied by abdominal pain and occasionally headaches. Episodes are separated by asymptomatic periods that may last months. Cyclic vomiting syndrome can occur at any age but is more common in children, those with a personal or family history of migraines, and heavy users of cannabis. At least 3 stereotypical episodes are required to make the diagnosis, so a history of prior similar symptoms should be explored.

The differential diagnosis of abdominal pain and vomiting should stay broad until a comprehensive physical exam and initial laboratory tests are performed. Volume status should be assessed by estimating jugular venous pressure and by obtaining supine and standing blood pressure measurements. The abdomen should be examined carefully, and the presence or absence of hepatomegaly, splenomegaly, masses, and ascites should be specifically noted. The presence of bradycardia, oligoarticular arthritis, or neuropathy could provide supporting evidence for Lyme disease. Pregnancy is less likely given the diffuse and persistent nature of the pain but should still be excluded.

On physical examination, she was distressed, writhing on the bed, and appearing comfortable only on her side with her knees flexed. Her temperature was 36.5 ° C, heart rate 83 beats per minute, respiratory rate 18 breaths per minute, blood pressure 143/77 mmHg, and oxygen saturation 94% while breathing ambient air. Her abdomen was diffusely tender, most markedly in the epigastrium. Abdominal rigidity, rebound tenderness, and costovertebral tenderness were absent. There was no rash; the previously reported targetoid skin lesion was no longer present. The remainder of the exam was normal.

Laboratory evaluation showed a white count of 7900/mm3, hemoglobin 14.3 gm/dL with normocytic indices, and a platelet count of 175,000/mm3. Sodium was 130 mmol/L, potassium was 3.1 mmol/L, bicarbonate 26 mmol/L, blood urea nitrogen 15 mg/dL, creatinine 0.6 mg/dL, and glucose 92 mg/dL. Serum calcium, aspartate aminotransferase, alanine aminotransferase, bilirubin, and lipase were normal. A urine pregnancy test was negative. Urine analysis was negative for nitrites and leukocyte esterase. Abdominal and pelvic computed tomography (CT) scan with intravenous (IV) contrast performed 3 days prior at an outside ED revealed a 3.4 centimeter left ovarian cyst. A subsequent transvaginal ultrasound was negative for cyst torsion and confirmed appropriate placement of an intrauterine device.

The absence of abdominal rigidity and rebound tenderness does not exclude peritonitis. A normal white blood cell count also does not reliably exclude serious intraabdominal pathology. However, the CT scan argues strongly against many common causes of abdominal pain, including appendicitis, diverticulitis, perforated ulcer, intestinal obstruction, and malignancy, assuming the symptoms have not changed since it was performed.

The patient’s laboratory studies argue against biliary obstruction, pancreatitis, pregnancy, hypercalcemia, and ongoing urinary tract infection. Patients with functional gallbladder disorders may have normal laboratory and CT findings but typically have recurrent, biliary-colic-type pain. The low serum potassium, a high blood urea nitrogen to creatinine ratio, and a low serum sodium reflect her significant vomiting. The hyponatremia is consistent with the appropriate release of antidiuretic hormone (ADH) in the setting of volume depletion. She should receive isotonic fluids plus potassium in addition to symptomatic treatment of pain and nausea. Given the severity and duration of symptoms, an esophagogastroduodenoscopy (EGD) should be performed to exclude GI mucosal disease, including peptic ulcer disease and gastritis, which may not be evident on the CT scan.

Additional diagnoses should be considered at this point. This patient has exposure to chickens, ducks, rabbits, and ticks as well as reported chills and mild temperature elevation at home. Tularemia, which can be transmitted by tick bites or exposure to infected rabbits, can cause a prolonged illness. Some patients have abdominal pain, anorexia, nausea, and weight loss, although fever is usually more prominent. Tularemia is uncommon and most frequently seen in the south-central part of the United States but has been reported throughout the country. She should be queried regarding additional exposures, including well water to assess her risk for Campylobacter infection.

Opiate withdrawal can present with pain and vomiting, but she reports no opiate use and lacks other findings such pupillary dilation or piloerection. Given the prevalence of opiate abuse, however, a toxicology screen should be performed. Hypercalcemia and diabetic ketoacidosis as metabolic causes of abdominal pain have been ruled out by her laboratory values. If no other cause is identified, other metabolic etiologies like Addison disease, familial Mediterranean fever, or porphyria should be considered.

Cyclic vomiting syndrome should still be on the differential. It is a diagnosis of exclusion requiring a history of recurrent, stereotypical episodes, which should be explicitly explored.

The patient was admitted to a medical unit by the hospitalist service and received IV normal saline, parenteral potassium, and IV pantoprazole. She underwent an EGD that revealed minor erosions in the antrum of the stomach. Biopsies were obtained.

Seven hours after the endoscopy, the patient had a brief period of confusion followed by a generalized tonic-clonic seizure lasting 1 minute. A head CT without contrast was negative for any focal abnormality. Repeat laboratory evaluation revealed that serum sodium was 125 mmol/L, and serum glucose was 113 mg/dL. She was transferred to the progressive care unit and received IV levetiracetam.

The endoscopy excluded structural abnormalities of the stomach and duodenum. The patient now has an additional problem, seizure, which needs to be incorporated in the diagnostic reasoning.

Seizures can be caused by the rapid development of severe hyponatremia, with serum sodium levels usually less than 120 mmol/L. Seizures caused by hyponatremia are typically preceded by headache and lethargy, as the intracellular movement of excess water causes cerebral edema. Hyponatremia is unlikely to be the cause of her seizure but should nevertheless be evaluated with a urine sodium concentration and serum and urine osmolality. If she is euvolemic, the IV fluids should be stopped and her free water intake should be restricted to avoid worsening the hyponatremia, as it is potentially caused by the syndrome of inappropriate ADH (SIADH).

There are many other possible causes for new onset seizures in adults, including brain tumor, head trauma, alcohol withdrawal, medications, and central nervous system infection, including Lyme disease. Lyme serologies should be repeated.

In this patient, it is likely that the seizure is a manifestation of the same illness that is causing her vomiting and abdominal pain. Seizure is not a feature of cyclic vomiting syndrome in adults. It is also not a feature of tularemia, adrenal insufficiency, or opioid withdrawal.

Acute intermittent porphyria (AIP) can cause both abdominal and neurologic problems. Hyponatremia is common during acute attacks, caused by either the inappropriate release of ADH or the appropriate release of the hormone if there is fluid loss. AIP is a rare diagnosis but could explain the uncommon combination of abdominal pain, vomiting, seizure, and hyponatremia. A spot urine porphobilinogen test should be sent to assess for AIP.

Additional laboratory studies were sent. Serum osmolality was 269 mosm/kg with a corresponding urine osmolality of 699 mosm/kg. A random urine sodium was 145 mEq/L. Thyroid stimulating hormone and cosyntropin stimulating testing were normal. IgM and IgG antibodies to Borrelia burgdorferi were negative. Urine porphobilinogen was sent. An electroencephalogram did not reveal epileptiform discharges. Magnetic resonance imaging (MRI) of the brain was significant for T2/FLAIR hyperintensity in the cortex and subcortical white matter of the occipital lobes bilaterally. Hypertonic saline and fluid restriction were initiated.

The patient’s labs are consistent with SIADH. Excessive ADH release because of volume depletion and consequent hyponatremia should have improved rapidly with the administration of saline. The high urine sodium suggests that she is now volume replete, while the high urine osmolality is consistent with the presence of excessive ADH in the absence of appropriate stimuli. In the context of normal thyroid and adrenal function, the hyponatremia is likely due to the SIADH.

Negative serologic testing for Lyme disease, 3 months after the onset of rash, excludes this diagnosis.

The MRI findings are consistent with posterior reversible encephalopathy syndrome (PRES), a clinicoradiographic syndrome of headache, altered mental status, seizure, and/or vision loss with associated white matter abnormalities of the posterior cerebral hemispheres. PRES has been reported with AIP as well as other disorders, most commonly hypertensive encephalopathy, eclampsia, and immunosuppressive drug use.

The patient’s sodium improved with fluid restriction and the administration of hypertonic saline. There was no recurrence of seizure activity. Amlodipine was initiated for blood pressure readings as high as 156/106 mmHg. A hepatobiliary scan revealed a gallbladder ejection fraction of 13%. Biopsies from her endoscopy revealed nonspecific inflammation without the presence of Helicobacter pylori. The patient was discharged home 7 days after admission after stabilization of serum sodium, improvement in her abdominal pain, and tolerance of oral intake. A plan was made for outpatient cholecystectomy.

Many causes of abdominal pain have been excluded and the remaining diagnostic possibility, porphyria, is rare. The clinicians have revisited their differential and considered other causes of abdominal pain, including functional gallbladder disorders. However, chronic cholecystitis (or functional gallbladder disorder) is not this patient’s primary problem. The diffuse, severe, and constant abdominal pain prior to admission is not typical of biliary pain, and many medical conditions and drugs, including amlodipine, can lead to a positive hepatobiliary scan. Chronic cholecystitis would not explain her seizure.

AIP remains at the top of the differential for this young woman. A urine porphobilinogen has been sent and must be followed up prior to any further workup or surgery.

One week after discharge, the patient’s urine porphobilinogen resulted at 172.8 mCmol/ (upper limits of normal 8.8). Sequencing analysis for genes coding the enzymes involved in the synthetic pathway for heme were sent. Hydroxymethylbilane synthase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase mutation assays were all normal. Despite the normal genetic assays, the diagnosis of AIP was made on the basis of the clinical presentation and elevated urine porphobilinogen. The patient was referred to a hematologist and initiated on oral glucose supplements and hematin infusions.

Although abdominal pain has a broad differential, the combination of abdominal pain and neurologic or psychiatric symptoms should suggest the possibility of porphyria, especially if symptoms are recurrent or unexplained. The porphyrias are a group of disorders caused by defects in the synthetic pathway of heme, leading to an overproduction and accumulation of precursors. Heme is a component of multiple proteins, including hemoglobin, myoglobin, and the cytochrome P450 enzymes. Although it is synthesized in all tissues, the bone marrow and liver are the organs most actively involved. The porphyrias can be classified according to the primary site of the overproduction and accumulation of heme precursors (liver vs bone marrow). Although there is overlap between the 2 groups, hepatic porphyrias often present with acute neurovisceral symptoms, while the erythropoietic porphyrias often cause cutaneous photosensitivity.¹

AIP is the most common hepatic porphyria with a prevalence of 1 in 20,000 in Caucasians of Western European descent.¹ AIP is caused by a defect in the gene that encodes porphobilinogen deaminase, leading to the accumulation of porphobilinogen.¹ The cardinal manifestation is an acute porphyric attack. While the precise mechanisms underlying the symptoms are unknown, the accumulating metabolites may be directly neurotoxic.² Attacks are precipitated by factors that induce heme synthesis, including caloric restriction, alcohol, and certain medications, particularly those that upregulate cyP450. The most commonly implicated drugs are anesthetics, antiepileptics, sulfonamides, rifampin, and estrogen and progesterone. Attacks can also be precipitated by changes in endogenous sex hormone levels, like the increase in progesterone seen in the luteal phase of the menstrual cycle, which may account for the higher incidence of symptomatic attacks in women.³

Acute attacks of AIP may have a wide variety of presentations; the disease was referred to as the “little imitator” in the early 20th century.⁴ The most common symptom is acute, severe abdominal pain, which may mimic an acute abdomen. Because the pain is neuropathic rather than inflammatory, abdominal tenderness, rebound, fever, and leukocytosis are usually absent, as they were in this patient. Abdominal pain is often accompanied by neuropsychiatric symptoms, including sensory and motor neuropathy, anxiety, hallucinations, delirium, and altered level of consciousness. Seizure occurs in 20% of cases. Involvement of the autonomic nervous system causes tachycardia and new onset hypertension in the majority of patients as well as restlessness and tremor. Hyponatremia, mediated by the syndrome of inappropriate ADH secretion, occurs in nearly a third of patients.^5,6 MRI findings consistent with PRES have also been described in AIP.⁷

The diagnosis of AIP is often delayed; diagnosis later in the disease course is associated with a poorer prognosis.⁸ Reported intervals between presentation and diagnosis range from several months to as long as 20 years.⁹ Associating the use of medications, caloric restriction, or the menstrual cycle with the exacerbation of symptoms or darkening of urine can help prompt an earlier diagnosis.⁶

AIP can be diagnosed by detecting a greater than 5-fold elevation of urinary porphobilinogen excretion in conjunction with the typical symptoms of an acute attack.⁵ Renal dysfunction causes urinary excretion of PBG to fall and serum levels to rise.¹⁰ Serum PBG levels should therefore be sent when AIP is suspected in the setting of renal dysfunction. The primary role of genetic testing in a patient who has AIP confirmed clinically and biochemically is to assist in genetic counseling and to identify asymptomatic family members.¹¹ Genetic testing is not required to confirm the diagnosis and does not help prognosticate. It is unusual that a mutation was not detected in this case, as the current sensitivity of genetic testing is 97% to 100%.¹¹

There are 4 principles of management of an acute porphyric attack. First, any precipitating factors such as medications should be stopped. Second, abdominal pain should be treated appropriately with opioids, if necessary. Third, if autonomic dysfunction is present, beta-blockers or clonidine should be given to treat hypertension.⁵ Finally, glucose and/or hemin should be administered to downregulate aminolevulinic acid (ALA) synthase by negative feedback. Downregulation of ALA synthase decreases the accumulation of the neurotoxic porphyrin precursors ALA and PBG.5 For patients with mild symptoms, glucose alone (300-500 g/d) may be enough to abort the attack.¹² This can be achieved via a high-carbohydrate diet in those able to tolerate oral intake or via continuous infusions of dextrose containing fluids.⁵ For more severe attacks with associated polyneuropathy, respiratory muscle weakness, or seizures, or for attacks that are not resolving, heme preparations dosed at 3 to 4 mg/kg/d for 3 to 4 days are indicated.⁵

The recent diagnosis of acute Lyme disease was a distractor in this presentation. In Lyme endemic areas, patients with erythema migrans are treated based on the clinical presentation rather than serologic testing.¹³ Although this patient took only 1 week of doxycycline, testing during this hospitalization showed that she had either been cured early or had not had Lyme disease in the first place. There is no known association between Lyme disease and the porphyrias, and doxycycline is not a common precipitant of AIP attacks.¹⁴ However, the GI side effects of doxycycline may have decreased caloric intake and ultimately provoked the patient’s first attack of AIP. The clinicians in this case appropriately avoided the “target” but hit the mark by correctly diagnosing AIP.

• Consider AIP in patients with unexplained abdominal pain, especially when accompanied by neuropsychiatric symptoms and autonomic lability.
• Diagnose AIP by sending a urine PBG during a suspected acute attack.
• Treat AIP acutely by removing precipitants, treating abdominal pain, and initiating dextrose-containing fluids and hemin infusions to downregulate ALA synthase.

The authors thank the patient who enthusiastically supported the writing of this report.

Disclosure

Warren Gavin, MD has disclosed participation in expert testimony. The authors have no financial or other conflicts of interest to disclose.