In Focus

 

While constipation is one of the most common symptoms managed by practicing gastroenterologists, it can also be among the most challenging. As a presenting complaint, constipation manifests with widely varying degrees of severity and may be seen in all age groups, ethnicities, and socioeconomic backgrounds. Its implications can include chronic and serious functional impairment as well as protracted and often excessive health care utilization. A growing number of pharmacologic and nonpharmacologic interventions have become available and proven to be effective when appropriately deployed. As such, health care providers and particularly gastroenterologists should strive to develop logical and efficient strategies for addressing this common disorder.

Clinical importance

While there are a variety of etiologies for constipation (Table 1), a large proportion of chronic cases fall within the framework of functional gastrointestinal disorders, a category with a substantial burden of disease across the population. Prevalence estimates vary, but constipation likely affects between 12% and 20% of the North American population.¹ Research has demonstrated significant health care expenditures associated with chronic constipation management; U.S. estimates suggest direct costs on the order of hundreds of millions of dollars per year, roughly half of which are attributable to inpatient care.² The financial burden of constipation also includes indirect costs associated with absenteeism as well as the risks of hospitalization and invasive procedures.³

Physical and emotional complications can be likewise significant and affect all age groups, from newborns to patients in the last days of life. Hirschsprung’s disease, for example, can lead to life-threatening sequelae in infancy, such as spontaneous perforation or enterocolitis, or more prolonged functional impairments when it remains undiagnosed. Severe constipation in childhood can lead to encopresis, translating in turn into ostracism and impaired social functioning. Fecal incontinence associated with overflow diarrhea is common and debilitating, particularly in the elderly population.
 

 

The potential mechanical complications of constipation lead to its overlap with a variety of other gastrointestinal complaints. For example, the difficulties of passing inspissated stool can provoke lower gastrointestinal bleeding from irritated hemorrhoids, anal fissures, stercoral ulcers, or prolapsed rectal tissue. Retained stool can also lead to upper gastrointestinal symptoms such as postprandial bloating or early satiety.⁴ Delayed fecal discharge can promote an increase in fermentative microbiota, associated in turn with the production of short-chain fatty acids, methane, and other gaseous byproducts.

The initial assessment

History

Taking an appropriate history is an essential step toward achieving a successful outcome. Presenting concerns related to constipation can range from hard, infrequent, or small-volume stools; abdominal or rectal pain associated with the process of elimination; and bloating, nausea, or early satiety. A sound diagnosis requires a keen understanding of what patients mean when they indicate that they are constipated, an accurate assessment of its impact on quality of life, and a careful inventory of potentially associated complications.

It is critical to define the duration of the problem. Not infrequently, patients will focus on recent events while failing to reveal that altered bowel habits or other functional symptoms have been problematic for years. Reminding the patients to “begin at the beginning” can aid enormously in contextualizing their complaints. Individuals with longstanding symptoms and previously negative evaluations are much less likely to present with a new organic disease than are those in whom symptoms have truly arisen de novo.

The presence or absence of alarm symptoms such as weight loss or anemia certainly merit specific investigation. An inventory of medications that might predispose to constipation (e.g., opiates, calcium channel blockers, loop diuretics, and anticholinergic agents) is likewise prudent. A history salient for multiple, prolonged, or complicated vaginal deliveries or other perineal trauma would also be relevant to the risk of underlying pelvic floor disorder.
 

Defining constipation by frequency of bowel eliminations alone has proved inaccurate at predicting actual severity. This is in part because the bowel movement frequency varies widely in healthy individuals (anywhere from thrice daily to once every 3 days) and in part because the primary indicator of effective evacuation is not frequency but volume – a much more difficult quantity for patients to gauge.⁵ The Bristol Stool Scale is a simple, standardized tool that more accurately evaluates the presence or absence of colonic dysfunction. For example, patients passing Type 1-2 (hard or lumpy) stools often have an element of constipation that needs to be addressed.⁶ However, the interpretation of stool consistency assessments is still aided by awareness of both frequency and volume. A patient passing multiple small-volume Type 6-7 (loose or watery) stools may be the most constipated, presenting with overflow or paradoxical diarrhea attributable to fecal impaction.

 

Physical examination

An expert physical exam is another essential aspect of the initial assessment. Alarm features can be elicited in this context as well via signs of pallor, weight loss, blood in the stool, physical abuse, or advanced psychological distress. Attention should also be paid to signs of a systemic disorder that might be associated with gastrointestinal dysmotility including previously unrecognized signs of Raynaud’s syndrome, sclerodactyly, amyloidosis, surgical scars, and joint hypermobility.^7,8 Abdominal bloating, a frequently vague symptomatic complaint, can be correlated with the presence or absence of distention as perceived by the patient and/or the examiner.⁹

Any initial evaluation of constipation should also include a detailed digital rectal exam. A complete examination should include a careful visual assessment of the perianal region for external lesions and of the degree and directional appropriateness of pelvic floor excursion (perineal elevation and descent) during squeeze and simulated defecation maneuvers, respectively. Digital examination should include palpation for the presence or absence of pain as well as stool, blood, or masses in the rectal vault, as well as an assessment of sphincter tone at baseline, with squeeze, and with simulated defecation. Rectal pressure generation with the latter maneuver can also be qualitatively assessed. Research has suggested moderate agreement between the digital rectal examination and formal manometric evaluation in diagnosing dyssynergic defecation, underscoring the former’s utility in guiding initial management decisions.¹⁰

Testing

It is reasonable to exclude metabolic, inflammatory, or other secondary etiologies of constipation in patients in whom history or examination raises suspicion. Likewise, colonoscopy should be considered in patients with alarm features or who are due for age-appropriate screening. That said, in the absence of risk factors or ancillary signs and symptoms, a detailed diagnostic work-up is often unnecessary. The AGA’s Medical Position Statement on Constipation recommends a complete blood count as the only test to be ordered on a standard basis in the work-up of constipation.¹¹

In patients new to one’s practice, the diligent retrieval of prior records is one of the most efficient ways to avoid wasting health care resources. Locating an old abdominal radiograph that demonstrates extensive retained stool can not only secure the diagnosis for vague symptomatic complaints but also obviate the need for more extensive testing. One should instead consider how symptom duration and the associated changes in objectives measures such as weight and laboratory parameters can be used to justify or refute the need for repeating costly or invasive studies.

It is important to consider the potential contribution of defecatory dyssynergy to chronic constipation early in a patient’s presentation, and to return to this possibility in the future if initial therapeutic interventions are unsuccessful. An abnormal qualitative assessment on digital rectal examination should trigger a more formal characterization of the patient’s defecatory mechanics via anorectal manometry (ARM) and balloon expulsion testing (BET). Likewise, a lack of response to initial pharmacotherapy should prompt suspicion for outlet dysfunction, which can be queried with functional testing even if a rectal examination is qualitatively unrevealing.

Initial approach to the chronically constipated patient

The aforementioned AGA Medical Position Statement provides a helpful algorithm regarding the diagnostic approach to constipation (Figure 1). In the absence of concern for secondary etiologies of constipation, an initial therapeutic trial of dietary, lifestyle, and medication-based intervention is reasonable for mild symptoms. Patients should be encouraged to strive for 25-30 grams of dietary fiber intake per day. For patients unable to reach this goal via high-fiber foods alone, psyllium husk is a popular supplement, but it should be initiated at modest doses to mitigate the risk of bloating. Fiber may be supplemented with the use of osmotic laxatives (e.g., polyethylene glycol) with instructions that the initial dose may be modified as needed to optimal effectiveness. Selective response to rectal therapies (e.g., bisacodyl or glycerin suppositories) over osmotic laxatives may also suggest utility in early queries of outlet dysfunction.

An abdominal radiograph can be helpful not only to diagnose constipation but also to assess the stool burden present at the time of beginning treatment. For patients presenting with a significant degree of fecal loading, an initial bowel cleanse with four liters of osmotically balanced polyethylene glycol can be a useful means of eliminating background fecal impactions that might have mitigated the effectiveness of initial therapies in the past or that might reduce the effectiveness of daily laxative therapy moving forward.

Patients with a diagnosis of defecatory dyssynergy made via ARM/BET should be referred to pelvic floor physical therapy with biofeedback. Recognizing that courses of therapy are highly individualized in practice, randomized controlled trials suggest symptom improvement in 70%-80% of patients, with the majority also demonstrating maintenance of response.¹² Biofeedback appears to be an essential component of this modality based on meta-analysis data and should be requested specifically by the referring provider.¹³

 

Pharmacologic agents

For those patients with more severe initial presentations or whose symptoms persist despite initial medical management, there are several pharmacologic agents that may be considered on a prescription basis (Table 2). Linaclotide, a minimally absorbed guanylate cyclase agonist, is approved by the Food and Drug Administration for patients with irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). Improvements in constipation tend to occur over a slightly shorter timeline than in abdominal pain, though both have been demonstrated in comparison to placebo.^14,15 Plecanatide, a newer agent with a similar mechanism of action, has demonstrated improvements in bowel movement frequency and was recently approved for CIC.¹⁶ Lubiprostone, a chloride channel agonist, has demonstrated benefit for IBS-C and CIC as well, though its side effect profile is more varied, including dose-related nausea in up to 30% of patients.¹⁷

For patients with opioid-induced constipation who cannot wean from the opioid medications, the peripheral acting mu-opioid receptor antagonists may be quite helpful. These include injectable as well as oral formulations (e.g., methylnaltrexone and naloxegol, respectively) with additional agents under active investigation in particular clinical subsets (e.g., naldemedine for patients with cancer-related pain).^18,19 Prucalopride, a selective serotonin receptor agonist, has also demonstrated benefit for constipation; it is available abroad but not yet approved for use in the United States.²⁰ Prucalopride shares its primary mechanism of action (selective agonism of the 5HT4 serotonin receptor) with cisapride, a previously quite popular gastrointestinal motility agent that was subsequently withdrawn from the U.S. market because of arrhythmia risk.²¹ This risk is likely attributable to cisapride’s dual binding affinity for potassium channels, a feature that prucalopride does not share; as such, cardiotoxicity is not an active concern with the latter agent.²²

Still other pharmacologic agents with novel mechanisms of action are currently under investigation. Tenapanor, an inhibitor of a particular sodium/potassium exchanger in the gut lumen, mitigates intestinal sodium absorption, which increases fluid volume and transit. A recent phase 2 study demonstrated significantly increased stool frequency relative to placebo in patients with IBS-C.²³ Elobixibat, an ileal bile acid transport inhibitor, promotes colonic retention of bile acids and, in placebo-controlled studies, has led to accelerated colonic transit and an increased number of spontaneous bowel movements in patients with CIC.²⁴

Persistent constipation

In cases of refractory constipation (in practical terms, symptoms that persist despite trials of escalating medical therapy over at least 6 weeks), it is worth revisiting the question of etiology. Querying defecatory dyssynergy via ARM/BET, if not pursued prior to trials of newer pharmacologic agents, should certainly be explored in the event that such trials fail. Inconclusive results of ARM and BET testing, or BET abnormalities that persist despite a course of physical therapy with biofeedback, may raise suspicion for pelvic organ prolapse, which may be formally evaluated with defecography. Additional testing for metabolic or structural predispositions toward constipation may also be reasonable at this juncture.

Formal colonic transit testing via radio-opaque markers, scintigraphy, or the wireless motility capsule is often inaccurate in the setting of dyssynergic defecation and should be pursued only after this entity has been excluded or successfully treated.²⁵ While there are not many practical distinctions at present in the therapeutic management of slow-transit versus normal-transit constipation, the use of novel medications with an explicitly prokinetic mechanism of action may be reasonable to consider in the setting of a document delay in colonic transit. Such delays can also help justify further specialized diagnostic testing (e.g., colonic manometry), and, in rare refractory cases, surgical intervention.

Consideration of colectomy should be reserved for highly selected patients with delayed colonic transit, normal defecatory mechanics, and the absence of potentially explanatory background conditions (e.g., connective tissue disease). Clear evidence of an underlying colonic myopathy or neuropathy may militate in favor of a more targeted surgical intervention (e.g., subtotal colectomy) or guide one’s clinical evaluation toward alternative systemic diagnoses. A diverting loop ileostomy with interval assessment of symptoms may be useful to clarify the potential benefits of colectomy while preserving the option of operative reversal. Proximal transit delays should be definitively excluded before pursuing colonic resections given evidence that multisegment transit delays portend significantly worse postoperative outcomes.²⁶

Conclusion

Constipation is a common, sometimes confusing presenting complaint and the variety of established and emergent options for diagnosis and therapy can lend themselves to haphazard application. Patients and providers both are well served by a clinical approach, rooted in a comprehensive history and examination, that begins to organize these options in thoughtful sequence.



Dr. Ahuja is assistant professor of clinical medicine, division of gastroenterology; Dr. Reynolds is professor of clinical medicine, and director of the program in neurogastroenterology and motility, division of gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

 

References

1. Higgins P.D., Johanson J.F. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol. 2004 Apr;99(4):750-9. PubMed PMID: 15089911.

2. Martin B.C., Barghout V., Cerulli A. Direct medical costs of constipation in the United States. Manage Care Interface. 2006 Dec;19(12):43-9. PubMed PMID: 17274481.

3. Sun S.X., Dibonaventura M., Purayidathil F.W., et al. Impact of chronic constipation on health-related quality of life, work productivity, and healthcare resource use: an analysis of the National Health and Wellness Survey. Dig Dis Sc. 2011 Sep;56(9):2688-95. PubMed PMID: 21380761.

4. Heidelbaugh J.J., Stelwagon M., Miller S.A., et al. The spectrum of constipation-predominant irritable bowel syndrome and chronic idiopathic constipation: US survey assessing symptoms, care seeking, and disease burden. Am J Gastroenterol. 2015 Apr;110(4):580-7.

5. Mitsuhashi S., Ballou S., Jiang Z.G., et al. Characterizing normal bowel frequency and consistency in a representative sample of adults in the United States (NHANES). Am J Gastroenterol. 2017 Aug 01. PubMed PMID: 28762379.

6. Saad R.J., Rao S.S., Koch K.L., et al. Do stool form and frequency correlate with whole-gut and colonic transit? Results from a multicenter study in constipated individuals and healthy controls. Am J Gastroenterol. 2010 Feb;105(2):403-11. PubMed PMID: 19888202.

7. Castori M., Morlino S., Pascolini G., et al. Gastrointestinal and nutritional issues in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. American Journal of Medical Genetics Part C, Semin Med Genet. 2015 Mar;169C(1):54-75. PubMed PMID: 25821092.

8. Nagaraja V., McMahan Z.H., Getzug T., Khanna D. Management of gastrointestinal involvement in scleroderma. Curr Treatm Opt Rheumatol. 2015 Mar 01;1(1):82-105. PubMed PMID: 26005632. Pubmed Central PMCID: 4437639.

9. Malagelada J.R., Accarino A., Azpiroz F. Bloating and abdominal distension: Old misconceptions and current knowledge. Am J Gastroenterol. 2017 Aug;112(8):1221-31. PubMed PMID: 28508867.

10. Soh J.S., Lee H.J., Jung K.W., et al. The diagnostic value of a digital rectal examination compared with high-resolution anorectal manometry in patients with chronic constipation and fecal incontinence. Am J Gastroenterol. 2015 Aug;110(8):1197-204. PubMed PMID: 26032152.

11. American Gastroenterological Association, Bharucha A.E., Dorn S.D., Lembo A., Pressman A. American Gastroenterological Association medical position statement on constipation. Gastroenterology. 2013 Jan;144(1):211-7. PubMed PMID: 23261064.

12. Skardoon G.R., Khera A.J., Emmanuel A.V., Burgell R.E. Review article: dyssynergic defaecation and biofeedback therapy in the pathophysiology and management of functional constipation. Aliment Pharmacol Therapeut. 2017 Aug;46(4):410-23. PubMed PMID: 28660663.

13. Koh C.E., Young C.J., Young J.M., Solomon M.J. Systematic review of randomized controlled trials of the effectiveness of biofeedback for pelvic floor dysfunction. Br J Surg. 2008 Sep;95(9):1079-87. PubMed PMID: 18655219.

14. Rao S., Lembo A.J., Shiff S.J., et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012 Nov;107(11):1714-24; quiz p 25. PubMed PMID: 22986440. Pubmed Central PMCID: 3504311.

15. Lacy B.E., Schey R., Shiff S.J., et al. Linaclotide in chronic idiopathic constipation patients with moderate to severe abdominal bloating: A randomized, controlled trial. PloS One. 2015;10(7):e0134349. PubMed PMID: 26222318. Pubmed Central PMCID: 4519259.

16. Miner P.B., Jr., Koltun W.D., Wiener G.J., et al. A randomized phase III clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation. Am J Gastroenterol. 2017 Apr;112(4):613-21. PubMed PMID: 28169285. Pubmed Central PMCID: 5415706.

17. Johanson J.F., Drossman D.A., Panas R., Wahle A., Ueno R. Clinical trial: phase 2 study of lubiprostone for irritable bowel syndrome with constipation. Aliment Pharmacol Therapeut. 2008 Apr;27(8):685-96. PubMed PMID: 18248656.

18. Chey W.D., Webster L., Sostek M., Lappalainen J., Barker P.N., Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med. 2014 Jun 19;370(25):2387-96. PubMed PMID: 24896818.

19. Katakami N., Oda K., Tauchi K., et al. Phase IIb, randomized, double-blind, placebo-controlled study of naldemedine for the treatment of opioid-induced constipation in patients with cancer. J Clin Oncol. 2017 Jun 10;35(17):1921-8. PubMed PMID: 28445097.

20. Sajid M.S., Hebbar M., Baig M.K., Li A., Philipose Z. Use of prucalopride for chronic constipation: A systematic review and meta-analysis of published randomized, controlled trials. J Neurogastroenterol Motil. 2016 Jul 30;22(3):412-22. PubMed PMID: 27127190. Pubmed Central PMCID: 4930296.

21. Quigley E.M. Cisapride: What can we learn from the rise and fall of a prokinetic? J Dig Dis. 2011 Jun;12(3):147-56. PubMed PMID: 21615867.

22. Conlon K., De Maeyer J.H., Bruce C., et al. Nonclinical cardiovascular studies of prucalopride, a highly selective 5-hydroxytryptamine 4 receptor agonist. J Pharmacol Exp Therapeut. 2017 Nov; doi: 10.1124/jpet.117.244079 [epub ahead of print].

23. Chey W.D., Lembo A.J., Rosenbaum D.P. Tenapanor treatment of patients with constipation-predominant irritable bowel syndrome: a phase 2, randomized, placebo-controlled efficacy and safety trial. Am J Gastroenterol. 2017;112:763-74.

24. Simren M., Bajor A., Gillberg P-G, Rudling M., Abrahamsson H. Randomised clinical trial: the ileal bile acid transporter inhibitor A3309 vs. placebo in patients with chronic idiopathic constipation – a double-blind study. Aliment Pharmacol Ther. 2011 Jul;34(1):41-50.

25. Zarate N., Knowles C.H., Newell M., et al. In patients with slow transit constipation, the pattern of colonic transit delay does not differentiate between those with and without impaired rectal evacuation. Am J Gastroenterol. 2008 Feb;103(2):427-34. PubMed PMID: 18070233.

26. Redmond J.M., Smith G.W., Barofsky I., et al. Physiological tests to predict long-term outcome of total abdominal colectomy for intractable constipation. Am J Gastroenterol. 1995 May;90(5):748-53. PubMed PMID: 7733081.

 

While constipation is one of the most common symptoms managed by practicing gastroenterologists, it can also be among the most challenging. As a presenting complaint, constipation manifests with widely varying degrees of severity and may be seen in all age groups, ethnicities, and socioeconomic backgrounds. Its implications can include chronic and serious functional impairment as well as protracted and often excessive health care utilization. A growing number of pharmacologic and nonpharmacologic interventions have become available and proven to be effective when appropriately deployed. As such, health care providers and particularly gastroenterologists should strive to develop logical and efficient strategies for addressing this common disorder.

Clinical importance

While there are a variety of etiologies for constipation (Table 1), a large proportion of chronic cases fall within the framework of functional gastrointestinal disorders, a category with a substantial burden of disease across the population. Prevalence estimates vary, but constipation likely affects between 12% and 20% of the North American population.¹ Research has demonstrated significant health care expenditures associated with chronic constipation management; U.S. estimates suggest direct costs on the order of hundreds of millions of dollars per year, roughly half of which are attributable to inpatient care.² The financial burden of constipation also includes indirect costs associated with absenteeism as well as the risks of hospitalization and invasive procedures.³

Physical and emotional complications can be likewise significant and affect all age groups, from newborns to patients in the last days of life. Hirschsprung’s disease, for example, can lead to life-threatening sequelae in infancy, such as spontaneous perforation or enterocolitis, or more prolonged functional impairments when it remains undiagnosed. Severe constipation in childhood can lead to encopresis, translating in turn into ostracism and impaired social functioning. Fecal incontinence associated with overflow diarrhea is common and debilitating, particularly in the elderly population.
 

 

The potential mechanical complications of constipation lead to its overlap with a variety of other gastrointestinal complaints. For example, the difficulties of passing inspissated stool can provoke lower gastrointestinal bleeding from irritated hemorrhoids, anal fissures, stercoral ulcers, or prolapsed rectal tissue. Retained stool can also lead to upper gastrointestinal symptoms such as postprandial bloating or early satiety.⁴ Delayed fecal discharge can promote an increase in fermentative microbiota, associated in turn with the production of short-chain fatty acids, methane, and other gaseous byproducts.

The initial assessment

History

Taking an appropriate history is an essential step toward achieving a successful outcome. Presenting concerns related to constipation can range from hard, infrequent, or small-volume stools; abdominal or rectal pain associated with the process of elimination; and bloating, nausea, or early satiety. A sound diagnosis requires a keen understanding of what patients mean when they indicate that they are constipated, an accurate assessment of its impact on quality of life, and a careful inventory of potentially associated complications.

It is critical to define the duration of the problem. Not infrequently, patients will focus on recent events while failing to reveal that altered bowel habits or other functional symptoms have been problematic for years. Reminding the patients to “begin at the beginning” can aid enormously in contextualizing their complaints. Individuals with longstanding symptoms and previously negative evaluations are much less likely to present with a new organic disease than are those in whom symptoms have truly arisen de novo.

The presence or absence of alarm symptoms such as weight loss or anemia certainly merit specific investigation. An inventory of medications that might predispose to constipation (e.g., opiates, calcium channel blockers, loop diuretics, and anticholinergic agents) is likewise prudent. A history salient for multiple, prolonged, or complicated vaginal deliveries or other perineal trauma would also be relevant to the risk of underlying pelvic floor disorder.
 

Defining constipation by frequency of bowel eliminations alone has proved inaccurate at predicting actual severity. This is in part because the bowel movement frequency varies widely in healthy individuals (anywhere from thrice daily to once every 3 days) and in part because the primary indicator of effective evacuation is not frequency but volume – a much more difficult quantity for patients to gauge.⁵ The Bristol Stool Scale is a simple, standardized tool that more accurately evaluates the presence or absence of colonic dysfunction. For example, patients passing Type 1-2 (hard or lumpy) stools often have an element of constipation that needs to be addressed.⁶ However, the interpretation of stool consistency assessments is still aided by awareness of both frequency and volume. A patient passing multiple small-volume Type 6-7 (loose or watery) stools may be the most constipated, presenting with overflow or paradoxical diarrhea attributable to fecal impaction.

 

Physical examination

An expert physical exam is another essential aspect of the initial assessment. Alarm features can be elicited in this context as well via signs of pallor, weight loss, blood in the stool, physical abuse, or advanced psychological distress. Attention should also be paid to signs of a systemic disorder that might be associated with gastrointestinal dysmotility including previously unrecognized signs of Raynaud’s syndrome, sclerodactyly, amyloidosis, surgical scars, and joint hypermobility.^7,8 Abdominal bloating, a frequently vague symptomatic complaint, can be correlated with the presence or absence of distention as perceived by the patient and/or the examiner.⁹

Any initial evaluation of constipation should also include a detailed digital rectal exam. A complete examination should include a careful visual assessment of the perianal region for external lesions and of the degree and directional appropriateness of pelvic floor excursion (perineal elevation and descent) during squeeze and simulated defecation maneuvers, respectively. Digital examination should include palpation for the presence or absence of pain as well as stool, blood, or masses in the rectal vault, as well as an assessment of sphincter tone at baseline, with squeeze, and with simulated defecation. Rectal pressure generation with the latter maneuver can also be qualitatively assessed. Research has suggested moderate agreement between the digital rectal examination and formal manometric evaluation in diagnosing dyssynergic defecation, underscoring the former’s utility in guiding initial management decisions.¹⁰

Testing

It is reasonable to exclude metabolic, inflammatory, or other secondary etiologies of constipation in patients in whom history or examination raises suspicion. Likewise, colonoscopy should be considered in patients with alarm features or who are due for age-appropriate screening. That said, in the absence of risk factors or ancillary signs and symptoms, a detailed diagnostic work-up is often unnecessary. The AGA’s Medical Position Statement on Constipation recommends a complete blood count as the only test to be ordered on a standard basis in the work-up of constipation.¹¹

In patients new to one’s practice, the diligent retrieval of prior records is one of the most efficient ways to avoid wasting health care resources. Locating an old abdominal radiograph that demonstrates extensive retained stool can not only secure the diagnosis for vague symptomatic complaints but also obviate the need for more extensive testing. One should instead consider how symptom duration and the associated changes in objectives measures such as weight and laboratory parameters can be used to justify or refute the need for repeating costly or invasive studies.

It is important to consider the potential contribution of defecatory dyssynergy to chronic constipation early in a patient’s presentation, and to return to this possibility in the future if initial therapeutic interventions are unsuccessful. An abnormal qualitative assessment on digital rectal examination should trigger a more formal characterization of the patient’s defecatory mechanics via anorectal manometry (ARM) and balloon expulsion testing (BET). Likewise, a lack of response to initial pharmacotherapy should prompt suspicion for outlet dysfunction, which can be queried with functional testing even if a rectal examination is qualitatively unrevealing.

Initial approach to the chronically constipated patient

The aforementioned AGA Medical Position Statement provides a helpful algorithm regarding the diagnostic approach to constipation (Figure 1). In the absence of concern for secondary etiologies of constipation, an initial therapeutic trial of dietary, lifestyle, and medication-based intervention is reasonable for mild symptoms. Patients should be encouraged to strive for 25-30 grams of dietary fiber intake per day. For patients unable to reach this goal via high-fiber foods alone, psyllium husk is a popular supplement, but it should be initiated at modest doses to mitigate the risk of bloating. Fiber may be supplemented with the use of osmotic laxatives (e.g., polyethylene glycol) with instructions that the initial dose may be modified as needed to optimal effectiveness. Selective response to rectal therapies (e.g., bisacodyl or glycerin suppositories) over osmotic laxatives may also suggest utility in early queries of outlet dysfunction.

An abdominal radiograph can be helpful not only to diagnose constipation but also to assess the stool burden present at the time of beginning treatment. For patients presenting with a significant degree of fecal loading, an initial bowel cleanse with four liters of osmotically balanced polyethylene glycol can be a useful means of eliminating background fecal impactions that might have mitigated the effectiveness of initial therapies in the past or that might reduce the effectiveness of daily laxative therapy moving forward.

Patients with a diagnosis of defecatory dyssynergy made via ARM/BET should be referred to pelvic floor physical therapy with biofeedback. Recognizing that courses of therapy are highly individualized in practice, randomized controlled trials suggest symptom improvement in 70%-80% of patients, with the majority also demonstrating maintenance of response.¹² Biofeedback appears to be an essential component of this modality based on meta-analysis data and should be requested specifically by the referring provider.¹³

 

Pharmacologic agents

For those patients with more severe initial presentations or whose symptoms persist despite initial medical management, there are several pharmacologic agents that may be considered on a prescription basis (Table 2). Linaclotide, a minimally absorbed guanylate cyclase agonist, is approved by the Food and Drug Administration for patients with irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). Improvements in constipation tend to occur over a slightly shorter timeline than in abdominal pain, though both have been demonstrated in comparison to placebo.^14,15 Plecanatide, a newer agent with a similar mechanism of action, has demonstrated improvements in bowel movement frequency and was recently approved for CIC.¹⁶ Lubiprostone, a chloride channel agonist, has demonstrated benefit for IBS-C and CIC as well, though its side effect profile is more varied, including dose-related nausea in up to 30% of patients.¹⁷

For patients with opioid-induced constipation who cannot wean from the opioid medications, the peripheral acting mu-opioid receptor antagonists may be quite helpful. These include injectable as well as oral formulations (e.g., methylnaltrexone and naloxegol, respectively) with additional agents under active investigation in particular clinical subsets (e.g., naldemedine for patients with cancer-related pain).^18,19 Prucalopride, a selective serotonin receptor agonist, has also demonstrated benefit for constipation; it is available abroad but not yet approved for use in the United States.²⁰ Prucalopride shares its primary mechanism of action (selective agonism of the 5HT4 serotonin receptor) with cisapride, a previously quite popular gastrointestinal motility agent that was subsequently withdrawn from the U.S. market because of arrhythmia risk.²¹ This risk is likely attributable to cisapride’s dual binding affinity for potassium channels, a feature that prucalopride does not share; as such, cardiotoxicity is not an active concern with the latter agent.²²

Still other pharmacologic agents with novel mechanisms of action are currently under investigation. Tenapanor, an inhibitor of a particular sodium/potassium exchanger in the gut lumen, mitigates intestinal sodium absorption, which increases fluid volume and transit. A recent phase 2 study demonstrated significantly increased stool frequency relative to placebo in patients with IBS-C.²³ Elobixibat, an ileal bile acid transport inhibitor, promotes colonic retention of bile acids and, in placebo-controlled studies, has led to accelerated colonic transit and an increased number of spontaneous bowel movements in patients with CIC.²⁴

Persistent constipation

In cases of refractory constipation (in practical terms, symptoms that persist despite trials of escalating medical therapy over at least 6 weeks), it is worth revisiting the question of etiology. Querying defecatory dyssynergy via ARM/BET, if not pursued prior to trials of newer pharmacologic agents, should certainly be explored in the event that such trials fail. Inconclusive results of ARM and BET testing, or BET abnormalities that persist despite a course of physical therapy with biofeedback, may raise suspicion for pelvic organ prolapse, which may be formally evaluated with defecography. Additional testing for metabolic or structural predispositions toward constipation may also be reasonable at this juncture.

Formal colonic transit testing via radio-opaque markers, scintigraphy, or the wireless motility capsule is often inaccurate in the setting of dyssynergic defecation and should be pursued only after this entity has been excluded or successfully treated.²⁵ While there are not many practical distinctions at present in the therapeutic management of slow-transit versus normal-transit constipation, the use of novel medications with an explicitly prokinetic mechanism of action may be reasonable to consider in the setting of a document delay in colonic transit. Such delays can also help justify further specialized diagnostic testing (e.g., colonic manometry), and, in rare refractory cases, surgical intervention.

Consideration of colectomy should be reserved for highly selected patients with delayed colonic transit, normal defecatory mechanics, and the absence of potentially explanatory background conditions (e.g., connective tissue disease). Clear evidence of an underlying colonic myopathy or neuropathy may militate in favor of a more targeted surgical intervention (e.g., subtotal colectomy) or guide one’s clinical evaluation toward alternative systemic diagnoses. A diverting loop ileostomy with interval assessment of symptoms may be useful to clarify the potential benefits of colectomy while preserving the option of operative reversal. Proximal transit delays should be definitively excluded before pursuing colonic resections given evidence that multisegment transit delays portend significantly worse postoperative outcomes.²⁶

Conclusion

Constipation is a common, sometimes confusing presenting complaint and the variety of established and emergent options for diagnosis and therapy can lend themselves to haphazard application. Patients and providers both are well served by a clinical approach, rooted in a comprehensive history and examination, that begins to organize these options in thoughtful sequence.



Dr. Ahuja is assistant professor of clinical medicine, division of gastroenterology; Dr. Reynolds is professor of clinical medicine, and director of the program in neurogastroenterology and motility, division of gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

 

References

1. Higgins P.D., Johanson J.F. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol. 2004 Apr;99(4):750-9. PubMed PMID: 15089911.

2. Martin B.C., Barghout V., Cerulli A. Direct medical costs of constipation in the United States. Manage Care Interface. 2006 Dec;19(12):43-9. PubMed PMID: 17274481.

3. Sun S.X., Dibonaventura M., Purayidathil F.W., et al. Impact of chronic constipation on health-related quality of life, work productivity, and healthcare resource use: an analysis of the National Health and Wellness Survey. Dig Dis Sc. 2011 Sep;56(9):2688-95. PubMed PMID: 21380761.

4. Heidelbaugh J.J., Stelwagon M., Miller S.A., et al. The spectrum of constipation-predominant irritable bowel syndrome and chronic idiopathic constipation: US survey assessing symptoms, care seeking, and disease burden. Am J Gastroenterol. 2015 Apr;110(4):580-7.

5. Mitsuhashi S., Ballou S., Jiang Z.G., et al. Characterizing normal bowel frequency and consistency in a representative sample of adults in the United States (NHANES). Am J Gastroenterol. 2017 Aug 01. PubMed PMID: 28762379.

6. Saad R.J., Rao S.S., Koch K.L., et al. Do stool form and frequency correlate with whole-gut and colonic transit? Results from a multicenter study in constipated individuals and healthy controls. Am J Gastroenterol. 2010 Feb;105(2):403-11. PubMed PMID: 19888202.

7. Castori M., Morlino S., Pascolini G., et al. Gastrointestinal and nutritional issues in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. American Journal of Medical Genetics Part C, Semin Med Genet. 2015 Mar;169C(1):54-75. PubMed PMID: 25821092.

8. Nagaraja V., McMahan Z.H., Getzug T., Khanna D. Management of gastrointestinal involvement in scleroderma. Curr Treatm Opt Rheumatol. 2015 Mar 01;1(1):82-105. PubMed PMID: 26005632. Pubmed Central PMCID: 4437639.

9. Malagelada J.R., Accarino A., Azpiroz F. Bloating and abdominal distension: Old misconceptions and current knowledge. Am J Gastroenterol. 2017 Aug;112(8):1221-31. PubMed PMID: 28508867.

10. Soh J.S., Lee H.J., Jung K.W., et al. The diagnostic value of a digital rectal examination compared with high-resolution anorectal manometry in patients with chronic constipation and fecal incontinence. Am J Gastroenterol. 2015 Aug;110(8):1197-204. PubMed PMID: 26032152.

11. American Gastroenterological Association, Bharucha A.E., Dorn S.D., Lembo A., Pressman A. American Gastroenterological Association medical position statement on constipation. Gastroenterology. 2013 Jan;144(1):211-7. PubMed PMID: 23261064.

12. Skardoon G.R., Khera A.J., Emmanuel A.V., Burgell R.E. Review article: dyssynergic defaecation and biofeedback therapy in the pathophysiology and management of functional constipation. Aliment Pharmacol Therapeut. 2017 Aug;46(4):410-23. PubMed PMID: 28660663.

13. Koh C.E., Young C.J., Young J.M., Solomon M.J. Systematic review of randomized controlled trials of the effectiveness of biofeedback for pelvic floor dysfunction. Br J Surg. 2008 Sep;95(9):1079-87. PubMed PMID: 18655219.

14. Rao S., Lembo A.J., Shiff S.J., et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012 Nov;107(11):1714-24; quiz p 25. PubMed PMID: 22986440. Pubmed Central PMCID: 3504311.

15. Lacy B.E., Schey R., Shiff S.J., et al. Linaclotide in chronic idiopathic constipation patients with moderate to severe abdominal bloating: A randomized, controlled trial. PloS One. 2015;10(7):e0134349. PubMed PMID: 26222318. Pubmed Central PMCID: 4519259.

16. Miner P.B., Jr., Koltun W.D., Wiener G.J., et al. A randomized phase III clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation. Am J Gastroenterol. 2017 Apr;112(4):613-21. PubMed PMID: 28169285. Pubmed Central PMCID: 5415706.

17. Johanson J.F., Drossman D.A., Panas R., Wahle A., Ueno R. Clinical trial: phase 2 study of lubiprostone for irritable bowel syndrome with constipation. Aliment Pharmacol Therapeut. 2008 Apr;27(8):685-96. PubMed PMID: 18248656.

18. Chey W.D., Webster L., Sostek M., Lappalainen J., Barker P.N., Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med. 2014 Jun 19;370(25):2387-96. PubMed PMID: 24896818.

19. Katakami N., Oda K., Tauchi K., et al. Phase IIb, randomized, double-blind, placebo-controlled study of naldemedine for the treatment of opioid-induced constipation in patients with cancer. J Clin Oncol. 2017 Jun 10;35(17):1921-8. PubMed PMID: 28445097.

20. Sajid M.S., Hebbar M., Baig M.K., Li A., Philipose Z. Use of prucalopride for chronic constipation: A systematic review and meta-analysis of published randomized, controlled trials. J Neurogastroenterol Motil. 2016 Jul 30;22(3):412-22. PubMed PMID: 27127190. Pubmed Central PMCID: 4930296.

21. Quigley E.M. Cisapride: What can we learn from the rise and fall of a prokinetic? J Dig Dis. 2011 Jun;12(3):147-56. PubMed PMID: 21615867.

22. Conlon K., De Maeyer J.H., Bruce C., et al. Nonclinical cardiovascular studies of prucalopride, a highly selective 5-hydroxytryptamine 4 receptor agonist. J Pharmacol Exp Therapeut. 2017 Nov; doi: 10.1124/jpet.117.244079 [epub ahead of print].

23. Chey W.D., Lembo A.J., Rosenbaum D.P. Tenapanor treatment of patients with constipation-predominant irritable bowel syndrome: a phase 2, randomized, placebo-controlled efficacy and safety trial. Am J Gastroenterol. 2017;112:763-74.

24. Simren M., Bajor A., Gillberg P-G, Rudling M., Abrahamsson H. Randomised clinical trial: the ileal bile acid transporter inhibitor A3309 vs. placebo in patients with chronic idiopathic constipation – a double-blind study. Aliment Pharmacol Ther. 2011 Jul;34(1):41-50.

25. Zarate N., Knowles C.H., Newell M., et al. In patients with slow transit constipation, the pattern of colonic transit delay does not differentiate between those with and without impaired rectal evacuation. Am J Gastroenterol. 2008 Feb;103(2):427-34. PubMed PMID: 18070233.

26. Redmond J.M., Smith G.W., Barofsky I., et al. Physiological tests to predict long-term outcome of total abdominal colectomy for intractable constipation. Am J Gastroenterol. 1995 May;90(5):748-53. PubMed PMID: 7733081.

 

While constipation is one of the most common symptoms managed by practicing gastroenterologists, it can also be among the most challenging. As a presenting complaint, constipation manifests with widely varying degrees of severity and may be seen in all age groups, ethnicities, and socioeconomic backgrounds. Its implications can include chronic and serious functional impairment as well as protracted and often excessive health care utilization. A growing number of pharmacologic and nonpharmacologic interventions have become available and proven to be effective when appropriately deployed. As such, health care providers and particularly gastroenterologists should strive to develop logical and efficient strategies for addressing this common disorder.

Clinical importance

While there are a variety of etiologies for constipation (Table 1), a large proportion of chronic cases fall within the framework of functional gastrointestinal disorders, a category with a substantial burden of disease across the population. Prevalence estimates vary, but constipation likely affects between 12% and 20% of the North American population.¹ Research has demonstrated significant health care expenditures associated with chronic constipation management; U.S. estimates suggest direct costs on the order of hundreds of millions of dollars per year, roughly half of which are attributable to inpatient care.² The financial burden of constipation also includes indirect costs associated with absenteeism as well as the risks of hospitalization and invasive procedures.³

Physical and emotional complications can be likewise significant and affect all age groups, from newborns to patients in the last days of life. Hirschsprung’s disease, for example, can lead to life-threatening sequelae in infancy, such as spontaneous perforation or enterocolitis, or more prolonged functional impairments when it remains undiagnosed. Severe constipation in childhood can lead to encopresis, translating in turn into ostracism and impaired social functioning. Fecal incontinence associated with overflow diarrhea is common and debilitating, particularly in the elderly population.
 

 

The potential mechanical complications of constipation lead to its overlap with a variety of other gastrointestinal complaints. For example, the difficulties of passing inspissated stool can provoke lower gastrointestinal bleeding from irritated hemorrhoids, anal fissures, stercoral ulcers, or prolapsed rectal tissue. Retained stool can also lead to upper gastrointestinal symptoms such as postprandial bloating or early satiety.⁴ Delayed fecal discharge can promote an increase in fermentative microbiota, associated in turn with the production of short-chain fatty acids, methane, and other gaseous byproducts.

The initial assessment

History

Taking an appropriate history is an essential step toward achieving a successful outcome. Presenting concerns related to constipation can range from hard, infrequent, or small-volume stools; abdominal or rectal pain associated with the process of elimination; and bloating, nausea, or early satiety. A sound diagnosis requires a keen understanding of what patients mean when they indicate that they are constipated, an accurate assessment of its impact on quality of life, and a careful inventory of potentially associated complications.

It is critical to define the duration of the problem. Not infrequently, patients will focus on recent events while failing to reveal that altered bowel habits or other functional symptoms have been problematic for years. Reminding the patients to “begin at the beginning” can aid enormously in contextualizing their complaints. Individuals with longstanding symptoms and previously negative evaluations are much less likely to present with a new organic disease than are those in whom symptoms have truly arisen de novo.

The presence or absence of alarm symptoms such as weight loss or anemia certainly merit specific investigation. An inventory of medications that might predispose to constipation (e.g., opiates, calcium channel blockers, loop diuretics, and anticholinergic agents) is likewise prudent. A history salient for multiple, prolonged, or complicated vaginal deliveries or other perineal trauma would also be relevant to the risk of underlying pelvic floor disorder.
 

Defining constipation by frequency of bowel eliminations alone has proved inaccurate at predicting actual severity. This is in part because the bowel movement frequency varies widely in healthy individuals (anywhere from thrice daily to once every 3 days) and in part because the primary indicator of effective evacuation is not frequency but volume – a much more difficult quantity for patients to gauge.⁵ The Bristol Stool Scale is a simple, standardized tool that more accurately evaluates the presence or absence of colonic dysfunction. For example, patients passing Type 1-2 (hard or lumpy) stools often have an element of constipation that needs to be addressed.⁶ However, the interpretation of stool consistency assessments is still aided by awareness of both frequency and volume. A patient passing multiple small-volume Type 6-7 (loose or watery) stools may be the most constipated, presenting with overflow or paradoxical diarrhea attributable to fecal impaction.

 

Physical examination

An expert physical exam is another essential aspect of the initial assessment. Alarm features can be elicited in this context as well via signs of pallor, weight loss, blood in the stool, physical abuse, or advanced psychological distress. Attention should also be paid to signs of a systemic disorder that might be associated with gastrointestinal dysmotility including previously unrecognized signs of Raynaud’s syndrome, sclerodactyly, amyloidosis, surgical scars, and joint hypermobility.^7,8 Abdominal bloating, a frequently vague symptomatic complaint, can be correlated with the presence or absence of distention as perceived by the patient and/or the examiner.⁹

Any initial evaluation of constipation should also include a detailed digital rectal exam. A complete examination should include a careful visual assessment of the perianal region for external lesions and of the degree and directional appropriateness of pelvic floor excursion (perineal elevation and descent) during squeeze and simulated defecation maneuvers, respectively. Digital examination should include palpation for the presence or absence of pain as well as stool, blood, or masses in the rectal vault, as well as an assessment of sphincter tone at baseline, with squeeze, and with simulated defecation. Rectal pressure generation with the latter maneuver can also be qualitatively assessed. Research has suggested moderate agreement between the digital rectal examination and formal manometric evaluation in diagnosing dyssynergic defecation, underscoring the former’s utility in guiding initial management decisions.¹⁰

Testing

It is reasonable to exclude metabolic, inflammatory, or other secondary etiologies of constipation in patients in whom history or examination raises suspicion. Likewise, colonoscopy should be considered in patients with alarm features or who are due for age-appropriate screening. That said, in the absence of risk factors or ancillary signs and symptoms, a detailed diagnostic work-up is often unnecessary. The AGA’s Medical Position Statement on Constipation recommends a complete blood count as the only test to be ordered on a standard basis in the work-up of constipation.¹¹

In patients new to one’s practice, the diligent retrieval of prior records is one of the most efficient ways to avoid wasting health care resources. Locating an old abdominal radiograph that demonstrates extensive retained stool can not only secure the diagnosis for vague symptomatic complaints but also obviate the need for more extensive testing. One should instead consider how symptom duration and the associated changes in objectives measures such as weight and laboratory parameters can be used to justify or refute the need for repeating costly or invasive studies.

It is important to consider the potential contribution of defecatory dyssynergy to chronic constipation early in a patient’s presentation, and to return to this possibility in the future if initial therapeutic interventions are unsuccessful. An abnormal qualitative assessment on digital rectal examination should trigger a more formal characterization of the patient’s defecatory mechanics via anorectal manometry (ARM) and balloon expulsion testing (BET). Likewise, a lack of response to initial pharmacotherapy should prompt suspicion for outlet dysfunction, which can be queried with functional testing even if a rectal examination is qualitatively unrevealing.

Initial approach to the chronically constipated patient

The aforementioned AGA Medical Position Statement provides a helpful algorithm regarding the diagnostic approach to constipation (Figure 1). In the absence of concern for secondary etiologies of constipation, an initial therapeutic trial of dietary, lifestyle, and medication-based intervention is reasonable for mild symptoms. Patients should be encouraged to strive for 25-30 grams of dietary fiber intake per day. For patients unable to reach this goal via high-fiber foods alone, psyllium husk is a popular supplement, but it should be initiated at modest doses to mitigate the risk of bloating. Fiber may be supplemented with the use of osmotic laxatives (e.g., polyethylene glycol) with instructions that the initial dose may be modified as needed to optimal effectiveness. Selective response to rectal therapies (e.g., bisacodyl or glycerin suppositories) over osmotic laxatives may also suggest utility in early queries of outlet dysfunction.

An abdominal radiograph can be helpful not only to diagnose constipation but also to assess the stool burden present at the time of beginning treatment. For patients presenting with a significant degree of fecal loading, an initial bowel cleanse with four liters of osmotically balanced polyethylene glycol can be a useful means of eliminating background fecal impactions that might have mitigated the effectiveness of initial therapies in the past or that might reduce the effectiveness of daily laxative therapy moving forward.

Patients with a diagnosis of defecatory dyssynergy made via ARM/BET should be referred to pelvic floor physical therapy with biofeedback. Recognizing that courses of therapy are highly individualized in practice, randomized controlled trials suggest symptom improvement in 70%-80% of patients, with the majority also demonstrating maintenance of response.¹² Biofeedback appears to be an essential component of this modality based on meta-analysis data and should be requested specifically by the referring provider.¹³

 

Pharmacologic agents

For those patients with more severe initial presentations or whose symptoms persist despite initial medical management, there are several pharmacologic agents that may be considered on a prescription basis (Table 2). Linaclotide, a minimally absorbed guanylate cyclase agonist, is approved by the Food and Drug Administration for patients with irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). Improvements in constipation tend to occur over a slightly shorter timeline than in abdominal pain, though both have been demonstrated in comparison to placebo.^14,15 Plecanatide, a newer agent with a similar mechanism of action, has demonstrated improvements in bowel movement frequency and was recently approved for CIC.¹⁶ Lubiprostone, a chloride channel agonist, has demonstrated benefit for IBS-C and CIC as well, though its side effect profile is more varied, including dose-related nausea in up to 30% of patients.¹⁷

For patients with opioid-induced constipation who cannot wean from the opioid medications, the peripheral acting mu-opioid receptor antagonists may be quite helpful. These include injectable as well as oral formulations (e.g., methylnaltrexone and naloxegol, respectively) with additional agents under active investigation in particular clinical subsets (e.g., naldemedine for patients with cancer-related pain).^18,19 Prucalopride, a selective serotonin receptor agonist, has also demonstrated benefit for constipation; it is available abroad but not yet approved for use in the United States.²⁰ Prucalopride shares its primary mechanism of action (selective agonism of the 5HT4 serotonin receptor) with cisapride, a previously quite popular gastrointestinal motility agent that was subsequently withdrawn from the U.S. market because of arrhythmia risk.²¹ This risk is likely attributable to cisapride’s dual binding affinity for potassium channels, a feature that prucalopride does not share; as such, cardiotoxicity is not an active concern with the latter agent.²²

Still other pharmacologic agents with novel mechanisms of action are currently under investigation. Tenapanor, an inhibitor of a particular sodium/potassium exchanger in the gut lumen, mitigates intestinal sodium absorption, which increases fluid volume and transit. A recent phase 2 study demonstrated significantly increased stool frequency relative to placebo in patients with IBS-C.²³ Elobixibat, an ileal bile acid transport inhibitor, promotes colonic retention of bile acids and, in placebo-controlled studies, has led to accelerated colonic transit and an increased number of spontaneous bowel movements in patients with CIC.²⁴

Persistent constipation

In cases of refractory constipation (in practical terms, symptoms that persist despite trials of escalating medical therapy over at least 6 weeks), it is worth revisiting the question of etiology. Querying defecatory dyssynergy via ARM/BET, if not pursued prior to trials of newer pharmacologic agents, should certainly be explored in the event that such trials fail. Inconclusive results of ARM and BET testing, or BET abnormalities that persist despite a course of physical therapy with biofeedback, may raise suspicion for pelvic organ prolapse, which may be formally evaluated with defecography. Additional testing for metabolic or structural predispositions toward constipation may also be reasonable at this juncture.

Formal colonic transit testing via radio-opaque markers, scintigraphy, or the wireless motility capsule is often inaccurate in the setting of dyssynergic defecation and should be pursued only after this entity has been excluded or successfully treated.²⁵ While there are not many practical distinctions at present in the therapeutic management of slow-transit versus normal-transit constipation, the use of novel medications with an explicitly prokinetic mechanism of action may be reasonable to consider in the setting of a document delay in colonic transit. Such delays can also help justify further specialized diagnostic testing (e.g., colonic manometry), and, in rare refractory cases, surgical intervention.

Consideration of colectomy should be reserved for highly selected patients with delayed colonic transit, normal defecatory mechanics, and the absence of potentially explanatory background conditions (e.g., connective tissue disease). Clear evidence of an underlying colonic myopathy or neuropathy may militate in favor of a more targeted surgical intervention (e.g., subtotal colectomy) or guide one’s clinical evaluation toward alternative systemic diagnoses. A diverting loop ileostomy with interval assessment of symptoms may be useful to clarify the potential benefits of colectomy while preserving the option of operative reversal. Proximal transit delays should be definitively excluded before pursuing colonic resections given evidence that multisegment transit delays portend significantly worse postoperative outcomes.²⁶

Conclusion

Constipation is a common, sometimes confusing presenting complaint and the variety of established and emergent options for diagnosis and therapy can lend themselves to haphazard application. Patients and providers both are well served by a clinical approach, rooted in a comprehensive history and examination, that begins to organize these options in thoughtful sequence.



Dr. Ahuja is assistant professor of clinical medicine, division of gastroenterology; Dr. Reynolds is professor of clinical medicine, and director of the program in neurogastroenterology and motility, division of gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

 

References

1. Higgins P.D., Johanson J.F. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol. 2004 Apr;99(4):750-9. PubMed PMID: 15089911.

2. Martin B.C., Barghout V., Cerulli A. Direct medical costs of constipation in the United States. Manage Care Interface. 2006 Dec;19(12):43-9. PubMed PMID: 17274481.

3. Sun S.X., Dibonaventura M., Purayidathil F.W., et al. Impact of chronic constipation on health-related quality of life, work productivity, and healthcare resource use: an analysis of the National Health and Wellness Survey. Dig Dis Sc. 2011 Sep;56(9):2688-95. PubMed PMID: 21380761.

4. Heidelbaugh J.J., Stelwagon M., Miller S.A., et al. The spectrum of constipation-predominant irritable bowel syndrome and chronic idiopathic constipation: US survey assessing symptoms, care seeking, and disease burden. Am J Gastroenterol. 2015 Apr;110(4):580-7.

5. Mitsuhashi S., Ballou S., Jiang Z.G., et al. Characterizing normal bowel frequency and consistency in a representative sample of adults in the United States (NHANES). Am J Gastroenterol. 2017 Aug 01. PubMed PMID: 28762379.

6. Saad R.J., Rao S.S., Koch K.L., et al. Do stool form and frequency correlate with whole-gut and colonic transit? Results from a multicenter study in constipated individuals and healthy controls. Am J Gastroenterol. 2010 Feb;105(2):403-11. PubMed PMID: 19888202.

7. Castori M., Morlino S., Pascolini G., et al. Gastrointestinal and nutritional issues in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. American Journal of Medical Genetics Part C, Semin Med Genet. 2015 Mar;169C(1):54-75. PubMed PMID: 25821092.

8. Nagaraja V., McMahan Z.H., Getzug T., Khanna D. Management of gastrointestinal involvement in scleroderma. Curr Treatm Opt Rheumatol. 2015 Mar 01;1(1):82-105. PubMed PMID: 26005632. Pubmed Central PMCID: 4437639.

9. Malagelada J.R., Accarino A., Azpiroz F. Bloating and abdominal distension: Old misconceptions and current knowledge. Am J Gastroenterol. 2017 Aug;112(8):1221-31. PubMed PMID: 28508867.

10. Soh J.S., Lee H.J., Jung K.W., et al. The diagnostic value of a digital rectal examination compared with high-resolution anorectal manometry in patients with chronic constipation and fecal incontinence. Am J Gastroenterol. 2015 Aug;110(8):1197-204. PubMed PMID: 26032152.

11. American Gastroenterological Association, Bharucha A.E., Dorn S.D., Lembo A., Pressman A. American Gastroenterological Association medical position statement on constipation. Gastroenterology. 2013 Jan;144(1):211-7. PubMed PMID: 23261064.

12. Skardoon G.R., Khera A.J., Emmanuel A.V., Burgell R.E. Review article: dyssynergic defaecation and biofeedback therapy in the pathophysiology and management of functional constipation. Aliment Pharmacol Therapeut. 2017 Aug;46(4):410-23. PubMed PMID: 28660663.

13. Koh C.E., Young C.J., Young J.M., Solomon M.J. Systematic review of randomized controlled trials of the effectiveness of biofeedback for pelvic floor dysfunction. Br J Surg. 2008 Sep;95(9):1079-87. PubMed PMID: 18655219.

14. Rao S., Lembo A.J., Shiff S.J., et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012 Nov;107(11):1714-24; quiz p 25. PubMed PMID: 22986440. Pubmed Central PMCID: 3504311.

15. Lacy B.E., Schey R., Shiff S.J., et al. Linaclotide in chronic idiopathic constipation patients with moderate to severe abdominal bloating: A randomized, controlled trial. PloS One. 2015;10(7):e0134349. PubMed PMID: 26222318. Pubmed Central PMCID: 4519259.

16. Miner P.B., Jr., Koltun W.D., Wiener G.J., et al. A randomized phase III clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation. Am J Gastroenterol. 2017 Apr;112(4):613-21. PubMed PMID: 28169285. Pubmed Central PMCID: 5415706.

17. Johanson J.F., Drossman D.A., Panas R., Wahle A., Ueno R. Clinical trial: phase 2 study of lubiprostone for irritable bowel syndrome with constipation. Aliment Pharmacol Therapeut. 2008 Apr;27(8):685-96. PubMed PMID: 18248656.

18. Chey W.D., Webster L., Sostek M., Lappalainen J., Barker P.N., Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med. 2014 Jun 19;370(25):2387-96. PubMed PMID: 24896818.

19. Katakami N., Oda K., Tauchi K., et al. Phase IIb, randomized, double-blind, placebo-controlled study of naldemedine for the treatment of opioid-induced constipation in patients with cancer. J Clin Oncol. 2017 Jun 10;35(17):1921-8. PubMed PMID: 28445097.

20. Sajid M.S., Hebbar M., Baig M.K., Li A., Philipose Z. Use of prucalopride for chronic constipation: A systematic review and meta-analysis of published randomized, controlled trials. J Neurogastroenterol Motil. 2016 Jul 30;22(3):412-22. PubMed PMID: 27127190. Pubmed Central PMCID: 4930296.

21. Quigley E.M. Cisapride: What can we learn from the rise and fall of a prokinetic? J Dig Dis. 2011 Jun;12(3):147-56. PubMed PMID: 21615867.

22. Conlon K., De Maeyer J.H., Bruce C., et al. Nonclinical cardiovascular studies of prucalopride, a highly selective 5-hydroxytryptamine 4 receptor agonist. J Pharmacol Exp Therapeut. 2017 Nov; doi: 10.1124/jpet.117.244079 [epub ahead of print].

23. Chey W.D., Lembo A.J., Rosenbaum D.P. Tenapanor treatment of patients with constipation-predominant irritable bowel syndrome: a phase 2, randomized, placebo-controlled efficacy and safety trial. Am J Gastroenterol. 2017;112:763-74.

24. Simren M., Bajor A., Gillberg P-G, Rudling M., Abrahamsson H. Randomised clinical trial: the ileal bile acid transporter inhibitor A3309 vs. placebo in patients with chronic idiopathic constipation – a double-blind study. Aliment Pharmacol Ther. 2011 Jul;34(1):41-50.

25. Zarate N., Knowles C.H., Newell M., et al. In patients with slow transit constipation, the pattern of colonic transit delay does not differentiate between those with and without impaired rectal evacuation. Am J Gastroenterol. 2008 Feb;103(2):427-34. PubMed PMID: 18070233.

26. Redmond J.M., Smith G.W., Barofsky I., et al. Physiological tests to predict long-term outcome of total abdominal colectomy for intractable constipation. Am J Gastroenterol. 1995 May;90(5):748-53. PubMed PMID: 7733081.

 

Introduction

Direct visualization of the biliary ductal system is quickly gaining importance among gastroenterologists. Since the inception of cholangioscopy in the 1970s, the technology has progressed, allowing for ease of use, better visualization, and a growing number of indications. Conventional endoscopic retrograde cholangiopancreatography (ERCP) is successful for removal of bile duct stones (with success rates over 90%);¹ however, its use in the evaluation of potential biliary neoplasia has been somewhat disappointing. The diagnostic yield of ERCP-guided biliary brushings can range from 30% to 40%.^2-4 An alternative to ERCP-guided biliary brushings for biliary strictures is endoscopic ultrasound (EUS)-directed fine needle aspiration (FNA), but the reported sensitivity remains poor, ranging from 43% to 77% with negative predictive values of less than 30%.^5-7 These results leave much to be desired for diagnostic yield.

The newest method of evaluating pancreaticobiliary pathology is with direct visualization using cholangioscopy. The advantages of this modality include the ability to obtain direct visualization as well as targeted biopsies of suspicious lesions. The first fiberoptic cholangioscope was introduced in 1965 and the first use of peroral cholangioscopy was reported in in the mid 1970s.^8,9 Early models were limited by their delicacy, relative immmobility, lack of dedicated irrigation channel, and need for two endoscopists using a “mother baby” design. Fiberoptic single-operator cholangiopancreatoscopy (FSOCP) was first introduced in 2006 by Boston Scientific (Marlborough, MA).¹⁰ It was designed to address the previously stated shortcomings of the first-generation cholangioscopy devices. Since its introduction, it has gained worldwide popularity in the diagnosis and management of pancreaticobiliary pathology and complex biliary stones.

The initial model employed a reusable fiber optic optical probe, a disposable cholangioscope access and delivery catheter, and disposable small-caliber biopsy forceps. The components can be introduced through a duodenoscope that has a minimum working channel diameter of 3.4 mm. The original FSOCP catheter is attached to the duodenoscope by a silastic belt just below the operating channel, allowing for single operator use. The access and delivery catheter has an outer diameter of 10 F and three separate ports: an optical port, two dedicated 0.6-mm irrigation channels, and a 1.2-mm accessory channel that accepts various accessories including the small-caliber biopsy forceps, electrohydraulic lithotripsy (EHL) fibers, or a holmium laser probe. The catheter has fourway tip deflection. The fiberoptic probe does have limitations, including its limited field of view, fragility of the fiber, and need for adjustment of the lens focus. Because of these limitations, a digital single-operator cholangioscope (DSOCP) was developed and introduced in 2014 (Boston Scientific, Marlborough, MA). In the DSOCP system, the light is generated by two independent light-emitting diodes and a complementary metal-oxide semiconductor digital camera chip. Improvements included a wider 120-degree field of view, dedicated irrigation and aspiration channels/connections, suction channel, and redesigned accessory channel. The cholangioscope is entirely disposable. The processor receives video signals from the catheter, processes the signals and outputs video images to an attached monitor. The newer digital-based platform has shown promising results, including higher diagnostic yield and shorter ERCP completion time when compared with similarly performed procedures using the fiberoptic-based platform.¹¹

Clinical indications

Direct visualization and biopsy of indeterminate biliary strictures has resulted in greatly improved diagnostic accuracy and collection of adequate tissue (Figures. 1,2). In a recent systematic review, the pooled sensitivity and specificity of cholangioscopy-guided biopsies in the diagnosis of malignant biliary strictures was 61% (95% confidence interval, 55%-65%) and 98% (95% CI, 96%-99%), respectively. Direct comparison of small-caliber direct biopsies with standard brushings and biopsies showed small-caliber direct biopsies having a sensitivity of 76.5% versus 5.8% and 29% with standard brushes and biopsies, respectively.¹² The pooled sensitivity and specificity of six studies using cholangioscopy with targeted biopsies in the diagnosis of cholangiocarcinoma was 66.2% and 97.0%, respectively.¹² Studies have shown that small-caliber forceps obtains tissue adequate for pathologic evaluation in 82%-97% of biopsy samples retrieved.^13-17 Three prospective trials have evaluated the diagnostic accuracy of small-caliber forceps for indeterminate biliary lesions. The accuracy ranged from 72% to 85% with a sensitivity of 49%-82%, specificity of 82%-100%, positive predictive value of 100%, and negative predictive value of 69%-100%.^15-17 The improved diagnostic accuracy of cholangioscopy for indeterminate biliary strictures stems from its direct visualization ability. Traditional sampling techniques (cytology brushings and fluoroscopically guided biopsies) are plagued by low sensitivity and negative predictive value caused by a relatively high false-positive rate.

DSOCP appears to have improved accuracy over fiberoptic equipment. In a recent multicenter observational study in patients undergoing digital cholangioscopy, the guided biopsies resulted in adequate tissue for histologic evaluation in 98% of patients. In addition, the sensitivity and specificity of digital cholangioscope-guided biopsies for diagnosis of malignancy was 85% and 100%, respectively.¹¹

Dr. Sonnier, Dr. Mizrahi, and Dr. Pleskow

Conventional ERCP is successful in most cases of biliary stone extraction but, in 5%-10% of cases, stones can be difficult to remove because of size, location above strictures, or adherence to the bile duct wall¹⁸ (Figure 3). In addition, lithotripsy with standard fluoroscopic guidance can cause stone fragments to get lost. In one study, 29% of ERCP-lost gallstones were diagnosed by post-hoc cholangioscopy.¹⁹ A number of studies have documented a high success rate of FSOCP- or DSOCP-guided lithotripsy, ranging from 90% to 100% (13,14,16,20,21). In addition cholangioscopy can circumvent the need for mechanical lithotripsy. EHL is used for the majority of cases, but use of a holium laser has also been described.^20,21 The dedicated irrigation channels on the FSOCP/DSOCP system give the ability to continuously fill the biliary system with fluid, which is required for EHL (Figures 4,5).

Dr. Sonnier, Dr. Mizrahi, and Dr. Pleskow

Diagnostic pancreatoscopy has advantages in the diagnosis and future management of malignancies and intraductal papillary mucinous neoplasms (IPMNs). In addition, pancreatic duct stones can easily be managed with digital pancreatoscopy and lithotripsy (EHL or laser lithotripsy). A study that included 115 patients that were followed for at least 2 years showed that pancreatoscopy was able to diagnose 63% of pancreatic cancers, 80% of benign strictures, and 95% of intraductal papillary mucinous neoplasms based on visual appearances. The authors were able to discern neoplasia based on visual findings, including coarse or granular mucosa, protrusion, papillary tumor, and tumor vessel.²² In a similar study, patients with confirmed intraductal papilliary mucinous neoplasms (IPMN) underwent peroral pancreatoscopy and/or intraductal ultrasound preoperatively. The detected protruding lesions were classified into five groups: granular mucosa, fish-egg with or without vascular images, villous type, and vegetative type. The diagnostic accuracy of peroral pancreatoscopy in differentiating benign IPMN from malignant ones was 88% with a sensitivity and specificity of 100% and 71% in the main duct type, respectively, and sensitivities and specificities of 43% and 100% of branch type, respectively.²³

DSOCP also has therapeutic implications for other pancreatic diseases. Pancreatic duct obstruction can be caused by stones and strictures. A large multicenter study of 1,000 patients with chronic pancreatitis revealed obstruction of the main pancreatic duct (MPD) in 50%; with 32% being caused by strictures and stones, while 18% were due solely to stones.²⁴ Currently accepted treatments for pancreaticolithiasis include extracorporeal shock wave lithotripsy, ERCP with stone clearance, and stenting or surgery (pancreaticojejunostomy) but these techniques have limitations and can incur morbidity.

DSOCP has recently been evaluated as an alternative technique in treating MPD stones. In a recent study, Bekkali et al reviewed their 3-year experience of digital pancreatoscopy and EHL for pancreatic duct stones. Of the pancreatoscopy procedures performed, 7% were for pancreatic stones. All the patients had painful chronic pancreatitis, radiographic evidence of a dilated pancreatic duct, and MPD stone disease. Stone fragmentation and pancreatic duct decompression were achieved in 83% without complications. Two patients required two EHL procedures to achieve clearance. In the single patient with failed clearance, pancreatoscopy revealed the stone to be in adjacent parenchyma and not in the pancreatic duct. All patients with successful pancreatoscopy and EHL had pain relief and marked improvement during follow up.²⁵

Other less common diagnostic indications for DSOCP include evaluation of cystic lesions of the biliary tract, verifying clearance of bile duct stones, bile duct ischemia evaluation after liver transplantation, hemobilia evaluation, removal of a bile duct foreign body, and evaluation of bile duct involvement in the presence of an ampullary adenoma.^{3,14,15,20,26,27}

 

Risks and complications

In general, complications from cholangioscopy systems are similar to traditional ERCP. These complications can range from relatively mild to potentially life-threatening sequelae including: cholangitis, bacteremia, abdominal pain, pancreatitis, hypotension, nausea, liver abscesses, radiculopathy, bile duct drilling (from the guide-wire), clinically insignificant amylase and lipase elevation, and systemic inflammatory response syndrome.²⁴ A large retrospective study evaluated whether ERCP with cholangiopancreatoscopy was associated with higher rates of complication than ERCP alone. A total of 4,214 ERCPs were included, of which 402 ERCPs with cholangiopancreatoscopy were analyzed. Adverse event rates for the ERCP alone group and ERCP with cholangiopancreatoscopy were 2.9% and 7.0%, respectively, with an odds ratio of 2.5. This study revealed a significantly higher rate of cholangitis, which the authors proposed was due to the saline irrigation needed for visualization during the procedure.²⁸ Duodenal perforation appears to be rare and was treated conservatively.^14,29

Conclusions

Direct visualization of the biliary and pancreatic ductal system with fiber-optic and now digital-based platforms have greatly expanded the diagnostic and therapeutic capabilities available to gastroenterologists in the diagnosis and management of biliary and pancreatic disorders. The digital single-operator cholangiopancreatascope system offers greater diagnostic yield of pancreaticobiliary disorders over conventional diagnostic sampling techniques. In addition, direct visualization has expanded our therapeutic ability in complex stone disease allowing laser-based therapies that are not available with traditional fluoroscopic based techniques. Cholangiopancreatoscopic techniques and indications are rapidly expanding and will continue to expand the diagnostic and therapeutic armamentarium available to gastroenterologists.

Dr. Sonnier is a general gastroenterology fellow, division of gastroenterology, University of South Alabama. Dr. Mizrahi is director of advanced endoscopy, division of gastroenterology, University of South Alabama. Dr. Pleskow, is clinical chief, department of gastroenterology, Beth Israel Deaconess Medical Center, and associate professor of medicine, Harvard Medical School, Boston. Dr. Sonnier and Dr. Mizrahi have no conflicts of interest. Dr. Pleskow serves as a consultant to Boston Scientific.

References

1. Cohen S., et al. Gastrointest Endosc. 2002;56:803–9

2. Lee J.G., et al. Am J Gastroenterol. 1995;90:722-6.

3. De Bellis M., et al. Gastrointest Endosc. 2003;58:176-82

4. Fritcher E.G., et al. Gastroenterology. 2009;136:2180-6.

5. Rosch T., et al. Gastrointest Endosc. 2004;60:390-6.

6. Byrne M.F., et al. Endoscopy. 2004;36:715-9.

7. DeWitt J., et al. Gastrointest Endosc. 2006;64:325-33.

8. Rosch W., Endoscopy. 1976;8:172-5.

9. Takekoshi T., Takagi K. Gastrointest Endosc. 1975;17:678-83.

10. Chen Y.K. Gastrointest Endosc 2007;65:303-11.

11. Navaneethan U., et al. Gastrointest Endosc 2016;84:649-55.

12. Navaneethan U., et al. Gastrointest Endosc 2015;82: 608-14.

13. Chen Y.K., Pleskow DK. Gastrointest Endosc. 2007;65:832-41.

14. Draganov P.V., et al. Gastrointest Endosc. 2011;73:971-9.

15. Ramchandani M., et al. Gastrointest Endosc. 2011;74:511-9.

16. Chen Y.K., et al. Gastrointest Endosc. 2011;74:805-14.

17. Draganov P.V., et al. Gastrointest Endosc. 2012;75:347-53.

18. Classen M., et al. Endoscopy 1988;20:21-6.

19. Parsi M.A., et al. Gastrointest Endosc 2008;67:AB102.

20. Fishman D.S., et al. World J Gastroenterol. 2009;15:1353-8.

21. Maydeo A., et al. Gastrointest Endosc. 2011;74:1308-14.

22. Yamao K., et al. Gastrointest Endosc 2003;57:205-9.

23. Hara T., et al. Gastroenterology 2002;122:34-43.

24. Rösch T., et al. Endoscopy. 2002;34:765–71.

25. Bekkali N.L., et al. Pancreas. 2017;46:528-30.

26. Adwan H., et al. Dig Endosc. 2011;23:199-200.

27. Ransibrahmanakul K., et al. Clin Gastroenterol Hepatol. 2010;8:e9.

28. Pereira P., et al. J Gastrointestin Liver Dis, June 2017;Vol. 26(No 2):165-70.

29. Kawakubo K., et al. Endoscopy 2011;43:E241-2.

 

Introduction

Direct visualization of the biliary ductal system is quickly gaining importance among gastroenterologists. Since the inception of cholangioscopy in the 1970s, the technology has progressed, allowing for ease of use, better visualization, and a growing number of indications. Conventional endoscopic retrograde cholangiopancreatography (ERCP) is successful for removal of bile duct stones (with success rates over 90%);¹ however, its use in the evaluation of potential biliary neoplasia has been somewhat disappointing. The diagnostic yield of ERCP-guided biliary brushings can range from 30% to 40%.^2-4 An alternative to ERCP-guided biliary brushings for biliary strictures is endoscopic ultrasound (EUS)-directed fine needle aspiration (FNA), but the reported sensitivity remains poor, ranging from 43% to 77% with negative predictive values of less than 30%.^5-7 These results leave much to be desired for diagnostic yield.

The newest method of evaluating pancreaticobiliary pathology is with direct visualization using cholangioscopy. The advantages of this modality include the ability to obtain direct visualization as well as targeted biopsies of suspicious lesions. The first fiberoptic cholangioscope was introduced in 1965 and the first use of peroral cholangioscopy was reported in in the mid 1970s.^8,9 Early models were limited by their delicacy, relative immmobility, lack of dedicated irrigation channel, and need for two endoscopists using a “mother baby” design. Fiberoptic single-operator cholangiopancreatoscopy (FSOCP) was first introduced in 2006 by Boston Scientific (Marlborough, MA).¹⁰ It was designed to address the previously stated shortcomings of the first-generation cholangioscopy devices. Since its introduction, it has gained worldwide popularity in the diagnosis and management of pancreaticobiliary pathology and complex biliary stones.

The initial model employed a reusable fiber optic optical probe, a disposable cholangioscope access and delivery catheter, and disposable small-caliber biopsy forceps. The components can be introduced through a duodenoscope that has a minimum working channel diameter of 3.4 mm. The original FSOCP catheter is attached to the duodenoscope by a silastic belt just below the operating channel, allowing for single operator use. The access and delivery catheter has an outer diameter of 10 F and three separate ports: an optical port, two dedicated 0.6-mm irrigation channels, and a 1.2-mm accessory channel that accepts various accessories including the small-caliber biopsy forceps, electrohydraulic lithotripsy (EHL) fibers, or a holmium laser probe. The catheter has fourway tip deflection. The fiberoptic probe does have limitations, including its limited field of view, fragility of the fiber, and need for adjustment of the lens focus. Because of these limitations, a digital single-operator cholangioscope (DSOCP) was developed and introduced in 2014 (Boston Scientific, Marlborough, MA). In the DSOCP system, the light is generated by two independent light-emitting diodes and a complementary metal-oxide semiconductor digital camera chip. Improvements included a wider 120-degree field of view, dedicated irrigation and aspiration channels/connections, suction channel, and redesigned accessory channel. The cholangioscope is entirely disposable. The processor receives video signals from the catheter, processes the signals and outputs video images to an attached monitor. The newer digital-based platform has shown promising results, including higher diagnostic yield and shorter ERCP completion time when compared with similarly performed procedures using the fiberoptic-based platform.¹¹

Clinical indications

Direct visualization and biopsy of indeterminate biliary strictures has resulted in greatly improved diagnostic accuracy and collection of adequate tissue (Figures. 1,2). In a recent systematic review, the pooled sensitivity and specificity of cholangioscopy-guided biopsies in the diagnosis of malignant biliary strictures was 61% (95% confidence interval, 55%-65%) and 98% (95% CI, 96%-99%), respectively. Direct comparison of small-caliber direct biopsies with standard brushings and biopsies showed small-caliber direct biopsies having a sensitivity of 76.5% versus 5.8% and 29% with standard brushes and biopsies, respectively.¹² The pooled sensitivity and specificity of six studies using cholangioscopy with targeted biopsies in the diagnosis of cholangiocarcinoma was 66.2% and 97.0%, respectively.¹² Studies have shown that small-caliber forceps obtains tissue adequate for pathologic evaluation in 82%-97% of biopsy samples retrieved.^13-17 Three prospective trials have evaluated the diagnostic accuracy of small-caliber forceps for indeterminate biliary lesions. The accuracy ranged from 72% to 85% with a sensitivity of 49%-82%, specificity of 82%-100%, positive predictive value of 100%, and negative predictive value of 69%-100%.^15-17 The improved diagnostic accuracy of cholangioscopy for indeterminate biliary strictures stems from its direct visualization ability. Traditional sampling techniques (cytology brushings and fluoroscopically guided biopsies) are plagued by low sensitivity and negative predictive value caused by a relatively high false-positive rate.

DSOCP appears to have improved accuracy over fiberoptic equipment. In a recent multicenter observational study in patients undergoing digital cholangioscopy, the guided biopsies resulted in adequate tissue for histologic evaluation in 98% of patients. In addition, the sensitivity and specificity of digital cholangioscope-guided biopsies for diagnosis of malignancy was 85% and 100%, respectively.¹¹

Dr. Sonnier, Dr. Mizrahi, and Dr. Pleskow

Conventional ERCP is successful in most cases of biliary stone extraction but, in 5%-10% of cases, stones can be difficult to remove because of size, location above strictures, or adherence to the bile duct wall¹⁸ (Figure 3). In addition, lithotripsy with standard fluoroscopic guidance can cause stone fragments to get lost. In one study, 29% of ERCP-lost gallstones were diagnosed by post-hoc cholangioscopy.¹⁹ A number of studies have documented a high success rate of FSOCP- or DSOCP-guided lithotripsy, ranging from 90% to 100% (13,14,16,20,21). In addition cholangioscopy can circumvent the need for mechanical lithotripsy. EHL is used for the majority of cases, but use of a holium laser has also been described.^20,21 The dedicated irrigation channels on the FSOCP/DSOCP system give the ability to continuously fill the biliary system with fluid, which is required for EHL (Figures 4,5).

Dr. Sonnier, Dr. Mizrahi, and Dr. Pleskow

Diagnostic pancreatoscopy has advantages in the diagnosis and future management of malignancies and intraductal papillary mucinous neoplasms (IPMNs). In addition, pancreatic duct stones can easily be managed with digital pancreatoscopy and lithotripsy (EHL or laser lithotripsy). A study that included 115 patients that were followed for at least 2 years showed that pancreatoscopy was able to diagnose 63% of pancreatic cancers, 80% of benign strictures, and 95% of intraductal papillary mucinous neoplasms based on visual appearances. The authors were able to discern neoplasia based on visual findings, including coarse or granular mucosa, protrusion, papillary tumor, and tumor vessel.²² In a similar study, patients with confirmed intraductal papilliary mucinous neoplasms (IPMN) underwent peroral pancreatoscopy and/or intraductal ultrasound preoperatively. The detected protruding lesions were classified into five groups: granular mucosa, fish-egg with or without vascular images, villous type, and vegetative type. The diagnostic accuracy of peroral pancreatoscopy in differentiating benign IPMN from malignant ones was 88% with a sensitivity and specificity of 100% and 71% in the main duct type, respectively, and sensitivities and specificities of 43% and 100% of branch type, respectively.²³

DSOCP also has therapeutic implications for other pancreatic diseases. Pancreatic duct obstruction can be caused by stones and strictures. A large multicenter study of 1,000 patients with chronic pancreatitis revealed obstruction of the main pancreatic duct (MPD) in 50%; with 32% being caused by strictures and stones, while 18% were due solely to stones.²⁴ Currently accepted treatments for pancreaticolithiasis include extracorporeal shock wave lithotripsy, ERCP with stone clearance, and stenting or surgery (pancreaticojejunostomy) but these techniques have limitations and can incur morbidity.

DSOCP has recently been evaluated as an alternative technique in treating MPD stones. In a recent study, Bekkali et al reviewed their 3-year experience of digital pancreatoscopy and EHL for pancreatic duct stones. Of the pancreatoscopy procedures performed, 7% were for pancreatic stones. All the patients had painful chronic pancreatitis, radiographic evidence of a dilated pancreatic duct, and MPD stone disease. Stone fragmentation and pancreatic duct decompression were achieved in 83% without complications. Two patients required two EHL procedures to achieve clearance. In the single patient with failed clearance, pancreatoscopy revealed the stone to be in adjacent parenchyma and not in the pancreatic duct. All patients with successful pancreatoscopy and EHL had pain relief and marked improvement during follow up.²⁵

Other less common diagnostic indications for DSOCP include evaluation of cystic lesions of the biliary tract, verifying clearance of bile duct stones, bile duct ischemia evaluation after liver transplantation, hemobilia evaluation, removal of a bile duct foreign body, and evaluation of bile duct involvement in the presence of an ampullary adenoma.^{3,14,15,20,26,27}

 

Risks and complications

In general, complications from cholangioscopy systems are similar to traditional ERCP. These complications can range from relatively mild to potentially life-threatening sequelae including: cholangitis, bacteremia, abdominal pain, pancreatitis, hypotension, nausea, liver abscesses, radiculopathy, bile duct drilling (from the guide-wire), clinically insignificant amylase and lipase elevation, and systemic inflammatory response syndrome.²⁴ A large retrospective study evaluated whether ERCP with cholangiopancreatoscopy was associated with higher rates of complication than ERCP alone. A total of 4,214 ERCPs were included, of which 402 ERCPs with cholangiopancreatoscopy were analyzed. Adverse event rates for the ERCP alone group and ERCP with cholangiopancreatoscopy were 2.9% and 7.0%, respectively, with an odds ratio of 2.5. This study revealed a significantly higher rate of cholangitis, which the authors proposed was due to the saline irrigation needed for visualization during the procedure.²⁸ Duodenal perforation appears to be rare and was treated conservatively.^14,29

Conclusions

Direct visualization of the biliary and pancreatic ductal system with fiber-optic and now digital-based platforms have greatly expanded the diagnostic and therapeutic capabilities available to gastroenterologists in the diagnosis and management of biliary and pancreatic disorders. The digital single-operator cholangiopancreatascope system offers greater diagnostic yield of pancreaticobiliary disorders over conventional diagnostic sampling techniques. In addition, direct visualization has expanded our therapeutic ability in complex stone disease allowing laser-based therapies that are not available with traditional fluoroscopic based techniques. Cholangiopancreatoscopic techniques and indications are rapidly expanding and will continue to expand the diagnostic and therapeutic armamentarium available to gastroenterologists.

Dr. Sonnier is a general gastroenterology fellow, division of gastroenterology, University of South Alabama. Dr. Mizrahi is director of advanced endoscopy, division of gastroenterology, University of South Alabama. Dr. Pleskow, is clinical chief, department of gastroenterology, Beth Israel Deaconess Medical Center, and associate professor of medicine, Harvard Medical School, Boston. Dr. Sonnier and Dr. Mizrahi have no conflicts of interest. Dr. Pleskow serves as a consultant to Boston Scientific.

References

1. Cohen S., et al. Gastrointest Endosc. 2002;56:803–9

2. Lee J.G., et al. Am J Gastroenterol. 1995;90:722-6.

3. De Bellis M., et al. Gastrointest Endosc. 2003;58:176-82

4. Fritcher E.G., et al. Gastroenterology. 2009;136:2180-6.

5. Rosch T., et al. Gastrointest Endosc. 2004;60:390-6.

6. Byrne M.F., et al. Endoscopy. 2004;36:715-9.

7. DeWitt J., et al. Gastrointest Endosc. 2006;64:325-33.

8. Rosch W., Endoscopy. 1976;8:172-5.

9. Takekoshi T., Takagi K. Gastrointest Endosc. 1975;17:678-83.

10. Chen Y.K. Gastrointest Endosc 2007;65:303-11.

11. Navaneethan U., et al. Gastrointest Endosc 2016;84:649-55.

12. Navaneethan U., et al. Gastrointest Endosc 2015;82: 608-14.

13. Chen Y.K., Pleskow DK. Gastrointest Endosc. 2007;65:832-41.

14. Draganov P.V., et al. Gastrointest Endosc. 2011;73:971-9.

15. Ramchandani M., et al. Gastrointest Endosc. 2011;74:511-9.

16. Chen Y.K., et al. Gastrointest Endosc. 2011;74:805-14.

17. Draganov P.V., et al. Gastrointest Endosc. 2012;75:347-53.

18. Classen M., et al. Endoscopy 1988;20:21-6.

19. Parsi M.A., et al. Gastrointest Endosc 2008;67:AB102.

20. Fishman D.S., et al. World J Gastroenterol. 2009;15:1353-8.

21. Maydeo A., et al. Gastrointest Endosc. 2011;74:1308-14.

22. Yamao K., et al. Gastrointest Endosc 2003;57:205-9.

23. Hara T., et al. Gastroenterology 2002;122:34-43.

24. Rösch T., et al. Endoscopy. 2002;34:765–71.

25. Bekkali N.L., et al. Pancreas. 2017;46:528-30.

26. Adwan H., et al. Dig Endosc. 2011;23:199-200.

27. Ransibrahmanakul K., et al. Clin Gastroenterol Hepatol. 2010;8:e9.

28. Pereira P., et al. J Gastrointestin Liver Dis, June 2017;Vol. 26(No 2):165-70.

29. Kawakubo K., et al. Endoscopy 2011;43:E241-2.

 

Introduction

Direct visualization of the biliary ductal system is quickly gaining importance among gastroenterologists. Since the inception of cholangioscopy in the 1970s, the technology has progressed, allowing for ease of use, better visualization, and a growing number of indications. Conventional endoscopic retrograde cholangiopancreatography (ERCP) is successful for removal of bile duct stones (with success rates over 90%);¹ however, its use in the evaluation of potential biliary neoplasia has been somewhat disappointing. The diagnostic yield of ERCP-guided biliary brushings can range from 30% to 40%.^2-4 An alternative to ERCP-guided biliary brushings for biliary strictures is endoscopic ultrasound (EUS)-directed fine needle aspiration (FNA), but the reported sensitivity remains poor, ranging from 43% to 77% with negative predictive values of less than 30%.^5-7 These results leave much to be desired for diagnostic yield.

The newest method of evaluating pancreaticobiliary pathology is with direct visualization using cholangioscopy. The advantages of this modality include the ability to obtain direct visualization as well as targeted biopsies of suspicious lesions. The first fiberoptic cholangioscope was introduced in 1965 and the first use of peroral cholangioscopy was reported in in the mid 1970s.^8,9 Early models were limited by their delicacy, relative immmobility, lack of dedicated irrigation channel, and need for two endoscopists using a “mother baby” design. Fiberoptic single-operator cholangiopancreatoscopy (FSOCP) was first introduced in 2006 by Boston Scientific (Marlborough, MA).¹⁰ It was designed to address the previously stated shortcomings of the first-generation cholangioscopy devices. Since its introduction, it has gained worldwide popularity in the diagnosis and management of pancreaticobiliary pathology and complex biliary stones.

The initial model employed a reusable fiber optic optical probe, a disposable cholangioscope access and delivery catheter, and disposable small-caliber biopsy forceps. The components can be introduced through a duodenoscope that has a minimum working channel diameter of 3.4 mm. The original FSOCP catheter is attached to the duodenoscope by a silastic belt just below the operating channel, allowing for single operator use. The access and delivery catheter has an outer diameter of 10 F and three separate ports: an optical port, two dedicated 0.6-mm irrigation channels, and a 1.2-mm accessory channel that accepts various accessories including the small-caliber biopsy forceps, electrohydraulic lithotripsy (EHL) fibers, or a holmium laser probe. The catheter has fourway tip deflection. The fiberoptic probe does have limitations, including its limited field of view, fragility of the fiber, and need for adjustment of the lens focus. Because of these limitations, a digital single-operator cholangioscope (DSOCP) was developed and introduced in 2014 (Boston Scientific, Marlborough, MA). In the DSOCP system, the light is generated by two independent light-emitting diodes and a complementary metal-oxide semiconductor digital camera chip. Improvements included a wider 120-degree field of view, dedicated irrigation and aspiration channels/connections, suction channel, and redesigned accessory channel. The cholangioscope is entirely disposable. The processor receives video signals from the catheter, processes the signals and outputs video images to an attached monitor. The newer digital-based platform has shown promising results, including higher diagnostic yield and shorter ERCP completion time when compared with similarly performed procedures using the fiberoptic-based platform.¹¹

Clinical indications

Direct visualization and biopsy of indeterminate biliary strictures has resulted in greatly improved diagnostic accuracy and collection of adequate tissue (Figures. 1,2). In a recent systematic review, the pooled sensitivity and specificity of cholangioscopy-guided biopsies in the diagnosis of malignant biliary strictures was 61% (95% confidence interval, 55%-65%) and 98% (95% CI, 96%-99%), respectively. Direct comparison of small-caliber direct biopsies with standard brushings and biopsies showed small-caliber direct biopsies having a sensitivity of 76.5% versus 5.8% and 29% with standard brushes and biopsies, respectively.¹² The pooled sensitivity and specificity of six studies using cholangioscopy with targeted biopsies in the diagnosis of cholangiocarcinoma was 66.2% and 97.0%, respectively.¹² Studies have shown that small-caliber forceps obtains tissue adequate for pathologic evaluation in 82%-97% of biopsy samples retrieved.^13-17 Three prospective trials have evaluated the diagnostic accuracy of small-caliber forceps for indeterminate biliary lesions. The accuracy ranged from 72% to 85% with a sensitivity of 49%-82%, specificity of 82%-100%, positive predictive value of 100%, and negative predictive value of 69%-100%.^15-17 The improved diagnostic accuracy of cholangioscopy for indeterminate biliary strictures stems from its direct visualization ability. Traditional sampling techniques (cytology brushings and fluoroscopically guided biopsies) are plagued by low sensitivity and negative predictive value caused by a relatively high false-positive rate.

DSOCP appears to have improved accuracy over fiberoptic equipment. In a recent multicenter observational study in patients undergoing digital cholangioscopy, the guided biopsies resulted in adequate tissue for histologic evaluation in 98% of patients. In addition, the sensitivity and specificity of digital cholangioscope-guided biopsies for diagnosis of malignancy was 85% and 100%, respectively.¹¹

Dr. Sonnier, Dr. Mizrahi, and Dr. Pleskow

Conventional ERCP is successful in most cases of biliary stone extraction but, in 5%-10% of cases, stones can be difficult to remove because of size, location above strictures, or adherence to the bile duct wall¹⁸ (Figure 3). In addition, lithotripsy with standard fluoroscopic guidance can cause stone fragments to get lost. In one study, 29% of ERCP-lost gallstones were diagnosed by post-hoc cholangioscopy.¹⁹ A number of studies have documented a high success rate of FSOCP- or DSOCP-guided lithotripsy, ranging from 90% to 100% (13,14,16,20,21). In addition cholangioscopy can circumvent the need for mechanical lithotripsy. EHL is used for the majority of cases, but use of a holium laser has also been described.^20,21 The dedicated irrigation channels on the FSOCP/DSOCP system give the ability to continuously fill the biliary system with fluid, which is required for EHL (Figures 4,5).

Dr. Sonnier, Dr. Mizrahi, and Dr. Pleskow

Diagnostic pancreatoscopy has advantages in the diagnosis and future management of malignancies and intraductal papillary mucinous neoplasms (IPMNs). In addition, pancreatic duct stones can easily be managed with digital pancreatoscopy and lithotripsy (EHL or laser lithotripsy). A study that included 115 patients that were followed for at least 2 years showed that pancreatoscopy was able to diagnose 63% of pancreatic cancers, 80% of benign strictures, and 95% of intraductal papillary mucinous neoplasms based on visual appearances. The authors were able to discern neoplasia based on visual findings, including coarse or granular mucosa, protrusion, papillary tumor, and tumor vessel.²² In a similar study, patients with confirmed intraductal papilliary mucinous neoplasms (IPMN) underwent peroral pancreatoscopy and/or intraductal ultrasound preoperatively. The detected protruding lesions were classified into five groups: granular mucosa, fish-egg with or without vascular images, villous type, and vegetative type. The diagnostic accuracy of peroral pancreatoscopy in differentiating benign IPMN from malignant ones was 88% with a sensitivity and specificity of 100% and 71% in the main duct type, respectively, and sensitivities and specificities of 43% and 100% of branch type, respectively.²³

DSOCP also has therapeutic implications for other pancreatic diseases. Pancreatic duct obstruction can be caused by stones and strictures. A large multicenter study of 1,000 patients with chronic pancreatitis revealed obstruction of the main pancreatic duct (MPD) in 50%; with 32% being caused by strictures and stones, while 18% were due solely to stones.²⁴ Currently accepted treatments for pancreaticolithiasis include extracorporeal shock wave lithotripsy, ERCP with stone clearance, and stenting or surgery (pancreaticojejunostomy) but these techniques have limitations and can incur morbidity.

DSOCP has recently been evaluated as an alternative technique in treating MPD stones. In a recent study, Bekkali et al reviewed their 3-year experience of digital pancreatoscopy and EHL for pancreatic duct stones. Of the pancreatoscopy procedures performed, 7% were for pancreatic stones. All the patients had painful chronic pancreatitis, radiographic evidence of a dilated pancreatic duct, and MPD stone disease. Stone fragmentation and pancreatic duct decompression were achieved in 83% without complications. Two patients required two EHL procedures to achieve clearance. In the single patient with failed clearance, pancreatoscopy revealed the stone to be in adjacent parenchyma and not in the pancreatic duct. All patients with successful pancreatoscopy and EHL had pain relief and marked improvement during follow up.²⁵

Other less common diagnostic indications for DSOCP include evaluation of cystic lesions of the biliary tract, verifying clearance of bile duct stones, bile duct ischemia evaluation after liver transplantation, hemobilia evaluation, removal of a bile duct foreign body, and evaluation of bile duct involvement in the presence of an ampullary adenoma.^{3,14,15,20,26,27}

 

Risks and complications

In general, complications from cholangioscopy systems are similar to traditional ERCP. These complications can range from relatively mild to potentially life-threatening sequelae including: cholangitis, bacteremia, abdominal pain, pancreatitis, hypotension, nausea, liver abscesses, radiculopathy, bile duct drilling (from the guide-wire), clinically insignificant amylase and lipase elevation, and systemic inflammatory response syndrome.²⁴ A large retrospective study evaluated whether ERCP with cholangiopancreatoscopy was associated with higher rates of complication than ERCP alone. A total of 4,214 ERCPs were included, of which 402 ERCPs with cholangiopancreatoscopy were analyzed. Adverse event rates for the ERCP alone group and ERCP with cholangiopancreatoscopy were 2.9% and 7.0%, respectively, with an odds ratio of 2.5. This study revealed a significantly higher rate of cholangitis, which the authors proposed was due to the saline irrigation needed for visualization during the procedure.²⁸ Duodenal perforation appears to be rare and was treated conservatively.^14,29

Conclusions

Direct visualization of the biliary and pancreatic ductal system with fiber-optic and now digital-based platforms have greatly expanded the diagnostic and therapeutic capabilities available to gastroenterologists in the diagnosis and management of biliary and pancreatic disorders. The digital single-operator cholangiopancreatascope system offers greater diagnostic yield of pancreaticobiliary disorders over conventional diagnostic sampling techniques. In addition, direct visualization has expanded our therapeutic ability in complex stone disease allowing laser-based therapies that are not available with traditional fluoroscopic based techniques. Cholangiopancreatoscopic techniques and indications are rapidly expanding and will continue to expand the diagnostic and therapeutic armamentarium available to gastroenterologists.

Dr. Sonnier is a general gastroenterology fellow, division of gastroenterology, University of South Alabama. Dr. Mizrahi is director of advanced endoscopy, division of gastroenterology, University of South Alabama. Dr. Pleskow, is clinical chief, department of gastroenterology, Beth Israel Deaconess Medical Center, and associate professor of medicine, Harvard Medical School, Boston. Dr. Sonnier and Dr. Mizrahi have no conflicts of interest. Dr. Pleskow serves as a consultant to Boston Scientific.

References

1. Cohen S., et al. Gastrointest Endosc. 2002;56:803–9

2. Lee J.G., et al. Am J Gastroenterol. 1995;90:722-6.

3. De Bellis M., et al. Gastrointest Endosc. 2003;58:176-82

4. Fritcher E.G., et al. Gastroenterology. 2009;136:2180-6.

5. Rosch T., et al. Gastrointest Endosc. 2004;60:390-6.

6. Byrne M.F., et al. Endoscopy. 2004;36:715-9.

7. DeWitt J., et al. Gastrointest Endosc. 2006;64:325-33.

8. Rosch W., Endoscopy. 1976;8:172-5.

9. Takekoshi T., Takagi K. Gastrointest Endosc. 1975;17:678-83.

10. Chen Y.K. Gastrointest Endosc 2007;65:303-11.

11. Navaneethan U., et al. Gastrointest Endosc 2016;84:649-55.

12. Navaneethan U., et al. Gastrointest Endosc 2015;82: 608-14.

13. Chen Y.K., Pleskow DK. Gastrointest Endosc. 2007;65:832-41.

14. Draganov P.V., et al. Gastrointest Endosc. 2011;73:971-9.

15. Ramchandani M., et al. Gastrointest Endosc. 2011;74:511-9.

16. Chen Y.K., et al. Gastrointest Endosc. 2011;74:805-14.

17. Draganov P.V., et al. Gastrointest Endosc. 2012;75:347-53.

18. Classen M., et al. Endoscopy 1988;20:21-6.

19. Parsi M.A., et al. Gastrointest Endosc 2008;67:AB102.

20. Fishman D.S., et al. World J Gastroenterol. 2009;15:1353-8.

21. Maydeo A., et al. Gastrointest Endosc. 2011;74:1308-14.

22. Yamao K., et al. Gastrointest Endosc 2003;57:205-9.

23. Hara T., et al. Gastroenterology 2002;122:34-43.

24. Rösch T., et al. Endoscopy. 2002;34:765–71.

25. Bekkali N.L., et al. Pancreas. 2017;46:528-30.

26. Adwan H., et al. Dig Endosc. 2011;23:199-200.

27. Ransibrahmanakul K., et al. Clin Gastroenterol Hepatol. 2010;8:e9.

28. Pereira P., et al. J Gastrointestin Liver Dis, June 2017;Vol. 26(No 2):165-70.

29. Kawakubo K., et al. Endoscopy 2011;43:E241-2.

 

Introduction

Chronic esophageal symptoms attributed to gastroesophageal reflux disease (GERD) are common presenting symptoms in gastroenterology, leading to high healthcare costs and adverse quality of life globally.^1,2 The clinical diagnosis of GERD hinges on the presence of “troublesome” compatible typical symptoms (heartburn, acid regurgitation) or evidence of mucosal injury on endoscopy (esophagitis, Barrett’s esophagus, peptic stricture).³ With the growing availability of proton pump inhibitors (PPIs), patients and clinicians often utilize an empiric therapeutic trial of PPI as an initial test, with symptom improvement in the absence of alarm symptoms indicating a high likelihood of GERD.⁴ A meta-analysis of studies that used objective measures of GERD (in this case, 24-hour pH monitoring) showed that the “PPI test” has a sensitivity of 78%, but a specificity of only 54%, as a diagnostic approach to GERD symptoms.⁵ Apart from noncardiac chest pain, the diagnostic yield is even lower for atypical and extra-esophageal symptoms such as cough or laryngeal symptoms.⁶

Therefore, when symptoms persist despite seemingly adequate PPI therapy, esophageal investigation may start with endoscopy but continues with ambulatory reflux and motility testing.⁷ At endoscopy, exclusion of eosinophilic esophagitis with esophageal biopsies represents an important component of initial evaluation when symptoms are refractory to PPIs.⁸ Further, the more atypical the presentation, the greater the need for esophageal testing prior to long-term PPI therapy. Esophageal function testing is also indicated when confirmation of GERD is needed prior to surgical or endoscopic reflux procedures.
 

The “nuts and bolts” of reflux testing

Ambulatory reflux testing assesses esophageal reflux burden and symptom-reflux association (SRA). Individual reflux events are identified as either a drop in esophageal pH to less than 4 (acid reflux events), or a sharp decrease in esophageal impedance measurements in a retrograde fashion (impedance-detected reflux events), with subsequent recovery to the baseline in each instance. Ambulatory reflux testing affords insight into three areas: 1) measurement of esophageal acid exposure time (AET); the cumulative time duration when distal esophageal pH is less than 4 at the recording site, reported as a percentage of the recording period; 2) measurement of the number of reflux events both acidic (from pH monitoring) and weakly acidic/alkaline (from impedance monitoring); and 3) quantitative evaluation of the association between reported symptom episodes and reflux events.

The three available modalities of ambulatory reflux monitoring consist of catheter-based pH, wireless pH, and combined catheter-based pH-impedance monitoring. Catheter-based pH monitoring, introduced in the 1970s, requires transnasal catheter placement and typically records for 24 hours before catheter removal. The catheter is positioned with the distal pH sensor 5 cm proximal to the upper margin of the manometrically identified lower esophageal sphincter (LES). New guidelines suggest AET less than 4% is reliably normal, while AET greater than 6% is pathologic; values in between are considered borderline and require alternate evidence for GERD, such as endoscopic findings.⁷ Wireless pH probes are placed 6 cm proximal to the squamocolumnar junction at endoscopy and communicate with a pager-sized receiver worn by the patient.⁹ Patient comfort is not compromised, with less restriction of typical patient activities compared to catheter-based testing, facilitating longer recording periods of 48-96 hours, which can overcome day-to-day variations in esophageal reflux burden.⁷ With catheter-based pH-impedance monitoring, multiple pairs of impedance sensors measure the resistance to flow of a tiny electrical current between sensors. Since resistance to flow (that is, impedance) is low in the presence of a bolus or refluxate in the esophageal lumen, the impedance tracing drops during reflux events in a retrograde fashion across the esophageal impedance sensor pairs, regardless of the acidity of the reflux (Figure 1).¹⁰ Combined pH-impedance testing thus detects refluxate in the esophagus regardless of pH, improving the sensitivity of detection of reflux events over pH testing alone, thereby promoting greater yield of SRA. However, there remains wide inter-observer variation on the designation of impedance reflux events.¹¹

The two most commonly utilized SRA metrics are the symptom index (SI) and symptom-association probability (SAP). Individual symptom episodes are designated as related to preceding reflux events if they occur within 2 minutes of the reflux events. The SI represents the simple ratio of the number of reflux-related symptoms to the total number of symptom episodes reported during the ambulatory reflux study, with values above 50% designated as positive.¹² For calculation of the SAP, the ambulatory reflux study is divided into 2-minute intervals. For each interval, the presence or absence of a reflux event and a symptom episode is assessed; the final counts are tabulated on a 2 x 2 table, and a Fisher exact test is applied to generate a “P” value. The SAP is positive if P is less than 0.05, corresponding to an SAP of greater than 95%, or a less than 5% chance that the observed association between symptoms and reflux events occurred by chance.¹³ The SAP can also be calculated post-hoc with data typically extracted during a pH study, using statistical modeling; termed the Ghillebert Probability Estimate,¹⁴ this corresponds well with the former method of SAP calculation.¹⁵

The SI and SAP can be calculated individually for acid-detected reflux events and for impedance-detected reflux events. Since reflux events are better detected with impedance, combined pH-impedance testing increases the yield of detecting positive SRA, especially when performed off PPI therapy.^16,17 Because these indices are heavily reliant on patient reporting of symptom episodes, SRA can be overinterpreted;¹⁸ positive associations are more clinically useful than negative results in the evaluation of symptoms attributed to GERD.¹⁹ Despite these concerns, the two most consistent predictors of symptomatic outcome with antireflux therapy on pH-impedance testing are abnormal AET and positive SAP with impedance-detected reflux events.¹⁷

Copyright Elsevier/AGA

Along with reflux testing, an esophageal high-resolution manometry (HRM) study is typically performed to establish the location of the LES for placement of reflux catheters. Beyond this primary indication, HRM serves the important role of excluding significant esophageal motor disorders in these patients, particularly achalasia spectrum disorders.²⁰ Despite a diametrically opposite pathophysiology compared to GERD, achalasia can present with retrosternal discomfort (often interpreted as heartburn) and esophageal regurgitation (potentially interpreted as acid regurgitation).²¹ Therefore, achalasia spectrum disorders can be mistaken for GERD and managed with acid suppression, thereby contributing to the pool of symptomatic patients refractory to PPI therapy. HRM has high accuracy and specificity for the diagnosis of achalasia and other major esophageal motor disorders.²² Other foregut disorders diagnosed using HRM (typically combined HRM and impedance, or HRiM) include rumination and supragastric belching. The exclusion of a major esophageal motor disorder is also a requirement for the diagnosis of a functional esophageal disorder, where esophageal reflux testing is normal.²³

 

Testing on or off PPI?

For symptoms attributable to GERD that persist despite properly administered PPI therapy, the 2013 American College of Gastroenterology guidelines suggest upper endoscopy with esophageal biopsies for typical symptoms and appropriate referrals for atypical symptoms.²⁴ However, if these evaluations are unremarkable, reflux monitoring is recommended, with PPI status for testing guided by the pre-test probability of GERD: with a low pre-test probability of GERD, reflux testing is best performed off PPI with either pH or combined pH-impedance testing. In contrast, with a high pre-test probability of GERD, testing is best performed on PPI with combined pH-impedance testing. A similar concept is proposed in the Rome IV approach (Figure 2)²³ and on GERD consensus guidelines:⁷ when heartburn or chest pain persists despite PPI therapy and endoscopy and esophageal biopsies are normal, evidence for GERD (past esophagitis, Barrett’s esophagus, peptic stricture, or prior positive reflux testing) prompts pH-impedance monitoring on PPI therapy (i.e., proven GERD). Those without this evidence for proven GERD (i.e., unproven GERD) are best tested off PPI, and the test utilized can be either pH alone or combined pH-impedance.

GERD phenotypes and management

The presence or absence of the two core metrics on ambulatory reflux monitoring – abnormal AET and positive SRA – can stratify symptomatic GERD patients into phenotypes that predict symptomatic improvement with antireflux therapy and guide management of symptoms (Figure 3).^25,26 The presence of both abnormal AET and positive SRA suggests “strong” evidence for GERD, for which symptom improvement is likely with maximization of antireflux therapy, which can include BID PPI, baclofen (to decrease transient LES relaxations), alginates (such as Gaviscon), and consideration of endosopic or surgical antireflux procedures such as fundoplication or magnetic sphincter augmentation. Abnormal AET but negative SRA is regarded as “good” evidence for GERD, for which similar antireflux therapies can be advocated. Normal AET but positive SRA is designated as “reflux hypersensitivity,”²³ with increasing proportions of patients meeting this phenotype when tested with combined pH-impedance and off PPI therapy.²⁷ Both normal AET and negative SRA suggest equivocal evidence for GERD and the likely presence of a functional esophageal disorder, such as functional heartburn.²³ For reflux hypersensitivity and especially functional esophageal disorders, antireflux therapy is unlikely to be as effective and management can include pharmacologic neuromodulation (such as tricyclic antidepressants administered at bedtime) as well as adjunctive nonpharmacologic approaches (such as stress reduction, relaxation, hypnosis, or cognitive-behavioral therapy).

The future of reflux diagnostics

Reflux testing, especially 24-hour catheter-based monitoring, offers cross-sectional assessment of reflux burden and does not take day-to-day variations in reflux exposure into account in a disease characterized by chronic symptoms and long-term management implications. This shortcoming has prompted interest in novel reflux diagnostics that may afford further insight into longitudinal reflux exposure. Baseline mucosal impedance, which can be gleaned from pH-impedance tracings during nocturnal resting periods²⁸ or by using prototype devices at endoscopy,²⁹ can segregate erosive and nonerosive GERD from controls and may serve as a surrogate marker for reflux-induced mucosal changes and esophageal mucosal integrity.^29-32 Postreflux swallow-induced peristaltic wave index, or the frequencies with which reflux events are followed by clearing esophageal peristaltic waves, represents another novel reflux metric extracted from pH-impedance tracings that may be a marker of refluxate clearance and resolution of esophageal mucosal acidification.³³ Finally, there has been revived interest in the value of dilated intercellular spaces on electron microscopy to assess esophageal mucosal integrity to provide evidence of longitudinal – rather than cross-sectional – reflux exposure.³⁴

Conclusions

For esophageal symptoms potentially attributable to GERD that persist despite optimized PPI therapy, esophageal testing should be undertaken, starting with endoscopy and biopsies and proceeding to ambulatory reflux monitoring with HRM. The decisions between pH testing alone versus combined pH-impedance monitoring, and between testing on or off PPI therapy, can be guided either by the pre-test probability of GERD or whether GERD has been proven or unproven in prior evaluations (Figure 2). Elevated AET and positive SRA with impedance-detected reflux events can predict the likelihood of successful management outcomes from antireflux therapy. These two core metrics can be utilized to phenotype GERD and guide management approaches for persisting symptoms (Figure 3). Novel impedance metrics (baseline mucosal impedance, postreflux swallow-induced peristaltic wave index) and markers for esophageal mucosal damage continue to be studied as potential markers for evidence of longitudinal reflux exposure.

Dr. Patel is assistant professor of medicine, division of gastroenterology, Duke University School of Medicine and the Durham Veterans Affairs Medical Center, Durham, N.C. Dr. Gyawali is professor of medicine, division of gastroenterology, Washington University School of Medicine, St. Louis, Mo.

 

References

1. Shaheen N.J., et al. Am J Gastroenterol. 2006;101:2128-38.

2. Patel A., Gyawali C.P.. Switzerland: Springer International, 2016.

3. Vakil N., et al. Am J Gastroenterol. 2006;101:1900-20; quiz 1943.

4. Fass R., et al. Arch Intern Med. 1999;159:2161-8.

5. Numans M.E., et al. Ann Intern Med. 2004;140:518-27.

6. Shaheen N.J., et al. Aliment Pharmacol Ther. 2011;33:225-34.

7. Roman S., et al. Neurogastroenterol Motil Mar 31. doi: 10.1111/nmo.13067. [Epub ahead of print] 2017.

8. Dellon E.S., et al. Am J Gastroenterol. 2013;108:679-92; quiz 693.

9. Pandolfino JE, Vela MF. Gastrointest Endosc. 2009;69:917-30, 930 e1.

10. Shay S., et al. Am J Gastroenterol. 2004;99:1037-43.

11. Zerbib F., et al. Clin Gastroenterol Hepatol. 2013;11:366-72.

12. Wiener G.J., et al. Am J Gastroenterol 1988;83:358-61.

13. Weusten B.L., et al. Gastroenterology. 1994;107:1741-5.

14. Ghillebert G., et al. Gut 1990;31:738-44.

15. Kushnir V.M., et al. Aliment Pharmacol Ther. 2012;35(9):1080-7.

16. Bredenoord A.J., et al. Am J Gastroenterol. 2006;101:453-9.

17. Patel A., et al. Clin Gastroenterol Hepatol. 2015;13:884-91.

18. Slaughter J.C., et al. Clin Gastroenterol Hepatol. 2011;9:868-74.

19. Kavitt R.T., et al. Am J Gastroenterol. 2012;107:1826-32.

20. Kahrilas P.J., et al. Gastroenterology 2008;135:1383-91, 1391 e1-5.

21. Kessing B.F., et al. Clin Gastroenterol Hepatol. 2011;9:1020-4.

22. Kahrilas P.J., et al. Neurogastroenterol Motil. 2015;27:160-74.

23. Aziz A, et al. Esophageal disorders. Gastroenterology 2016;150:1368-79.

24. Katz P.O., et al. Am J Gastroenterol. 2013;108:308-28; quiz 329.

25. Boeckxstaens G., et al. Gut 2014;63:1185-93.

26. Patel A., et al. Neurogastroenterol Motil. 2016;28:513-21.

27. Patel A., et al. Neurogastroenterol Motil. 2016;28:1382-90.

28. Martinucci I., et al. Neurogastroenterol Motil. 2014;26:546-55.

29. Ates F., et al. Gastroenterology 2015;148:334-43.

30. Kessing B.F., et al. Am J Gastroenterol. 2011;106:2093-7.

31. Patel A., et al. Aliment Pharmacol Ther. 2016;44:890-8.

32. Frazzoni M., et al. Neurogastroenterol Motil. 2016.

33. Frazzoni M., et al. Neurogastroenterol Motil. 2013;25:399-406, e295.

34. Vela M.F., et al. Am J Gastroenterol. 2011;106:844-50.
 

 

Introduction

Chronic esophageal symptoms attributed to gastroesophageal reflux disease (GERD) are common presenting symptoms in gastroenterology, leading to high healthcare costs and adverse quality of life globally.^1,2 The clinical diagnosis of GERD hinges on the presence of “troublesome” compatible typical symptoms (heartburn, acid regurgitation) or evidence of mucosal injury on endoscopy (esophagitis, Barrett’s esophagus, peptic stricture).³ With the growing availability of proton pump inhibitors (PPIs), patients and clinicians often utilize an empiric therapeutic trial of PPI as an initial test, with symptom improvement in the absence of alarm symptoms indicating a high likelihood of GERD.⁴ A meta-analysis of studies that used objective measures of GERD (in this case, 24-hour pH monitoring) showed that the “PPI test” has a sensitivity of 78%, but a specificity of only 54%, as a diagnostic approach to GERD symptoms.⁵ Apart from noncardiac chest pain, the diagnostic yield is even lower for atypical and extra-esophageal symptoms such as cough or laryngeal symptoms.⁶

Therefore, when symptoms persist despite seemingly adequate PPI therapy, esophageal investigation may start with endoscopy but continues with ambulatory reflux and motility testing.⁷ At endoscopy, exclusion of eosinophilic esophagitis with esophageal biopsies represents an important component of initial evaluation when symptoms are refractory to PPIs.⁸ Further, the more atypical the presentation, the greater the need for esophageal testing prior to long-term PPI therapy. Esophageal function testing is also indicated when confirmation of GERD is needed prior to surgical or endoscopic reflux procedures.
 

The “nuts and bolts” of reflux testing

Ambulatory reflux testing assesses esophageal reflux burden and symptom-reflux association (SRA). Individual reflux events are identified as either a drop in esophageal pH to less than 4 (acid reflux events), or a sharp decrease in esophageal impedance measurements in a retrograde fashion (impedance-detected reflux events), with subsequent recovery to the baseline in each instance. Ambulatory reflux testing affords insight into three areas: 1) measurement of esophageal acid exposure time (AET); the cumulative time duration when distal esophageal pH is less than 4 at the recording site, reported as a percentage of the recording period; 2) measurement of the number of reflux events both acidic (from pH monitoring) and weakly acidic/alkaline (from impedance monitoring); and 3) quantitative evaluation of the association between reported symptom episodes and reflux events.

The three available modalities of ambulatory reflux monitoring consist of catheter-based pH, wireless pH, and combined catheter-based pH-impedance monitoring. Catheter-based pH monitoring, introduced in the 1970s, requires transnasal catheter placement and typically records for 24 hours before catheter removal. The catheter is positioned with the distal pH sensor 5 cm proximal to the upper margin of the manometrically identified lower esophageal sphincter (LES). New guidelines suggest AET less than 4% is reliably normal, while AET greater than 6% is pathologic; values in between are considered borderline and require alternate evidence for GERD, such as endoscopic findings.⁷ Wireless pH probes are placed 6 cm proximal to the squamocolumnar junction at endoscopy and communicate with a pager-sized receiver worn by the patient.⁹ Patient comfort is not compromised, with less restriction of typical patient activities compared to catheter-based testing, facilitating longer recording periods of 48-96 hours, which can overcome day-to-day variations in esophageal reflux burden.⁷ With catheter-based pH-impedance monitoring, multiple pairs of impedance sensors measure the resistance to flow of a tiny electrical current between sensors. Since resistance to flow (that is, impedance) is low in the presence of a bolus or refluxate in the esophageal lumen, the impedance tracing drops during reflux events in a retrograde fashion across the esophageal impedance sensor pairs, regardless of the acidity of the reflux (Figure 1).¹⁰ Combined pH-impedance testing thus detects refluxate in the esophagus regardless of pH, improving the sensitivity of detection of reflux events over pH testing alone, thereby promoting greater yield of SRA. However, there remains wide inter-observer variation on the designation of impedance reflux events.¹¹

The two most commonly utilized SRA metrics are the symptom index (SI) and symptom-association probability (SAP). Individual symptom episodes are designated as related to preceding reflux events if they occur within 2 minutes of the reflux events. The SI represents the simple ratio of the number of reflux-related symptoms to the total number of symptom episodes reported during the ambulatory reflux study, with values above 50% designated as positive.¹² For calculation of the SAP, the ambulatory reflux study is divided into 2-minute intervals. For each interval, the presence or absence of a reflux event and a symptom episode is assessed; the final counts are tabulated on a 2 x 2 table, and a Fisher exact test is applied to generate a “P” value. The SAP is positive if P is less than 0.05, corresponding to an SAP of greater than 95%, or a less than 5% chance that the observed association between symptoms and reflux events occurred by chance.¹³ The SAP can also be calculated post-hoc with data typically extracted during a pH study, using statistical modeling; termed the Ghillebert Probability Estimate,¹⁴ this corresponds well with the former method of SAP calculation.¹⁵

The SI and SAP can be calculated individually for acid-detected reflux events and for impedance-detected reflux events. Since reflux events are better detected with impedance, combined pH-impedance testing increases the yield of detecting positive SRA, especially when performed off PPI therapy.^16,17 Because these indices are heavily reliant on patient reporting of symptom episodes, SRA can be overinterpreted;¹⁸ positive associations are more clinically useful than negative results in the evaluation of symptoms attributed to GERD.¹⁹ Despite these concerns, the two most consistent predictors of symptomatic outcome with antireflux therapy on pH-impedance testing are abnormal AET and positive SAP with impedance-detected reflux events.¹⁷

Copyright Elsevier/AGA

Along with reflux testing, an esophageal high-resolution manometry (HRM) study is typically performed to establish the location of the LES for placement of reflux catheters. Beyond this primary indication, HRM serves the important role of excluding significant esophageal motor disorders in these patients, particularly achalasia spectrum disorders.²⁰ Despite a diametrically opposite pathophysiology compared to GERD, achalasia can present with retrosternal discomfort (often interpreted as heartburn) and esophageal regurgitation (potentially interpreted as acid regurgitation).²¹ Therefore, achalasia spectrum disorders can be mistaken for GERD and managed with acid suppression, thereby contributing to the pool of symptomatic patients refractory to PPI therapy. HRM has high accuracy and specificity for the diagnosis of achalasia and other major esophageal motor disorders.²² Other foregut disorders diagnosed using HRM (typically combined HRM and impedance, or HRiM) include rumination and supragastric belching. The exclusion of a major esophageal motor disorder is also a requirement for the diagnosis of a functional esophageal disorder, where esophageal reflux testing is normal.²³

 

Testing on or off PPI?

For symptoms attributable to GERD that persist despite properly administered PPI therapy, the 2013 American College of Gastroenterology guidelines suggest upper endoscopy with esophageal biopsies for typical symptoms and appropriate referrals for atypical symptoms.²⁴ However, if these evaluations are unremarkable, reflux monitoring is recommended, with PPI status for testing guided by the pre-test probability of GERD: with a low pre-test probability of GERD, reflux testing is best performed off PPI with either pH or combined pH-impedance testing. In contrast, with a high pre-test probability of GERD, testing is best performed on PPI with combined pH-impedance testing. A similar concept is proposed in the Rome IV approach (Figure 2)²³ and on GERD consensus guidelines:⁷ when heartburn or chest pain persists despite PPI therapy and endoscopy and esophageal biopsies are normal, evidence for GERD (past esophagitis, Barrett’s esophagus, peptic stricture, or prior positive reflux testing) prompts pH-impedance monitoring on PPI therapy (i.e., proven GERD). Those without this evidence for proven GERD (i.e., unproven GERD) are best tested off PPI, and the test utilized can be either pH alone or combined pH-impedance.

GERD phenotypes and management

The presence or absence of the two core metrics on ambulatory reflux monitoring – abnormal AET and positive SRA – can stratify symptomatic GERD patients into phenotypes that predict symptomatic improvement with antireflux therapy and guide management of symptoms (Figure 3).^25,26 The presence of both abnormal AET and positive SRA suggests “strong” evidence for GERD, for which symptom improvement is likely with maximization of antireflux therapy, which can include BID PPI, baclofen (to decrease transient LES relaxations), alginates (such as Gaviscon), and consideration of endosopic or surgical antireflux procedures such as fundoplication or magnetic sphincter augmentation. Abnormal AET but negative SRA is regarded as “good” evidence for GERD, for which similar antireflux therapies can be advocated. Normal AET but positive SRA is designated as “reflux hypersensitivity,”²³ with increasing proportions of patients meeting this phenotype when tested with combined pH-impedance and off PPI therapy.²⁷ Both normal AET and negative SRA suggest equivocal evidence for GERD and the likely presence of a functional esophageal disorder, such as functional heartburn.²³ For reflux hypersensitivity and especially functional esophageal disorders, antireflux therapy is unlikely to be as effective and management can include pharmacologic neuromodulation (such as tricyclic antidepressants administered at bedtime) as well as adjunctive nonpharmacologic approaches (such as stress reduction, relaxation, hypnosis, or cognitive-behavioral therapy).

The future of reflux diagnostics

Reflux testing, especially 24-hour catheter-based monitoring, offers cross-sectional assessment of reflux burden and does not take day-to-day variations in reflux exposure into account in a disease characterized by chronic symptoms and long-term management implications. This shortcoming has prompted interest in novel reflux diagnostics that may afford further insight into longitudinal reflux exposure. Baseline mucosal impedance, which can be gleaned from pH-impedance tracings during nocturnal resting periods²⁸ or by using prototype devices at endoscopy,²⁹ can segregate erosive and nonerosive GERD from controls and may serve as a surrogate marker for reflux-induced mucosal changes and esophageal mucosal integrity.^29-32 Postreflux swallow-induced peristaltic wave index, or the frequencies with which reflux events are followed by clearing esophageal peristaltic waves, represents another novel reflux metric extracted from pH-impedance tracings that may be a marker of refluxate clearance and resolution of esophageal mucosal acidification.³³ Finally, there has been revived interest in the value of dilated intercellular spaces on electron microscopy to assess esophageal mucosal integrity to provide evidence of longitudinal – rather than cross-sectional – reflux exposure.³⁴

Conclusions

For esophageal symptoms potentially attributable to GERD that persist despite optimized PPI therapy, esophageal testing should be undertaken, starting with endoscopy and biopsies and proceeding to ambulatory reflux monitoring with HRM. The decisions between pH testing alone versus combined pH-impedance monitoring, and between testing on or off PPI therapy, can be guided either by the pre-test probability of GERD or whether GERD has been proven or unproven in prior evaluations (Figure 2). Elevated AET and positive SRA with impedance-detected reflux events can predict the likelihood of successful management outcomes from antireflux therapy. These two core metrics can be utilized to phenotype GERD and guide management approaches for persisting symptoms (Figure 3). Novel impedance metrics (baseline mucosal impedance, postreflux swallow-induced peristaltic wave index) and markers for esophageal mucosal damage continue to be studied as potential markers for evidence of longitudinal reflux exposure.

Dr. Patel is assistant professor of medicine, division of gastroenterology, Duke University School of Medicine and the Durham Veterans Affairs Medical Center, Durham, N.C. Dr. Gyawali is professor of medicine, division of gastroenterology, Washington University School of Medicine, St. Louis, Mo.

 

References

1. Shaheen N.J., et al. Am J Gastroenterol. 2006;101:2128-38.

2. Patel A., Gyawali C.P.. Switzerland: Springer International, 2016.

3. Vakil N., et al. Am J Gastroenterol. 2006;101:1900-20; quiz 1943.

4. Fass R., et al. Arch Intern Med. 1999;159:2161-8.

5. Numans M.E., et al. Ann Intern Med. 2004;140:518-27.

6. Shaheen N.J., et al. Aliment Pharmacol Ther. 2011;33:225-34.

7. Roman S., et al. Neurogastroenterol Motil Mar 31. doi: 10.1111/nmo.13067. [Epub ahead of print] 2017.

8. Dellon E.S., et al. Am J Gastroenterol. 2013;108:679-92; quiz 693.

9. Pandolfino JE, Vela MF. Gastrointest Endosc. 2009;69:917-30, 930 e1.

10. Shay S., et al. Am J Gastroenterol. 2004;99:1037-43.

11. Zerbib F., et al. Clin Gastroenterol Hepatol. 2013;11:366-72.

12. Wiener G.J., et al. Am J Gastroenterol 1988;83:358-61.

13. Weusten B.L., et al. Gastroenterology. 1994;107:1741-5.

14. Ghillebert G., et al. Gut 1990;31:738-44.

15. Kushnir V.M., et al. Aliment Pharmacol Ther. 2012;35(9):1080-7.

16. Bredenoord A.J., et al. Am J Gastroenterol. 2006;101:453-9.

17. Patel A., et al. Clin Gastroenterol Hepatol. 2015;13:884-91.

18. Slaughter J.C., et al. Clin Gastroenterol Hepatol. 2011;9:868-74.

19. Kavitt R.T., et al. Am J Gastroenterol. 2012;107:1826-32.

20. Kahrilas P.J., et al. Gastroenterology 2008;135:1383-91, 1391 e1-5.

21. Kessing B.F., et al. Clin Gastroenterol Hepatol. 2011;9:1020-4.

22. Kahrilas P.J., et al. Neurogastroenterol Motil. 2015;27:160-74.

23. Aziz A, et al. Esophageal disorders. Gastroenterology 2016;150:1368-79.

24. Katz P.O., et al. Am J Gastroenterol. 2013;108:308-28; quiz 329.

25. Boeckxstaens G., et al. Gut 2014;63:1185-93.

26. Patel A., et al. Neurogastroenterol Motil. 2016;28:513-21.

27. Patel A., et al. Neurogastroenterol Motil. 2016;28:1382-90.

28. Martinucci I., et al. Neurogastroenterol Motil. 2014;26:546-55.

29. Ates F., et al. Gastroenterology 2015;148:334-43.

30. Kessing B.F., et al. Am J Gastroenterol. 2011;106:2093-7.

31. Patel A., et al. Aliment Pharmacol Ther. 2016;44:890-8.

32. Frazzoni M., et al. Neurogastroenterol Motil. 2016.

33. Frazzoni M., et al. Neurogastroenterol Motil. 2013;25:399-406, e295.

34. Vela M.F., et al. Am J Gastroenterol. 2011;106:844-50.
 

 

Introduction

Chronic esophageal symptoms attributed to gastroesophageal reflux disease (GERD) are common presenting symptoms in gastroenterology, leading to high healthcare costs and adverse quality of life globally.^1,2 The clinical diagnosis of GERD hinges on the presence of “troublesome” compatible typical symptoms (heartburn, acid regurgitation) or evidence of mucosal injury on endoscopy (esophagitis, Barrett’s esophagus, peptic stricture).³ With the growing availability of proton pump inhibitors (PPIs), patients and clinicians often utilize an empiric therapeutic trial of PPI as an initial test, with symptom improvement in the absence of alarm symptoms indicating a high likelihood of GERD.⁴ A meta-analysis of studies that used objective measures of GERD (in this case, 24-hour pH monitoring) showed that the “PPI test” has a sensitivity of 78%, but a specificity of only 54%, as a diagnostic approach to GERD symptoms.⁵ Apart from noncardiac chest pain, the diagnostic yield is even lower for atypical and extra-esophageal symptoms such as cough or laryngeal symptoms.⁶

Therefore, when symptoms persist despite seemingly adequate PPI therapy, esophageal investigation may start with endoscopy but continues with ambulatory reflux and motility testing.⁷ At endoscopy, exclusion of eosinophilic esophagitis with esophageal biopsies represents an important component of initial evaluation when symptoms are refractory to PPIs.⁸ Further, the more atypical the presentation, the greater the need for esophageal testing prior to long-term PPI therapy. Esophageal function testing is also indicated when confirmation of GERD is needed prior to surgical or endoscopic reflux procedures.
 

The “nuts and bolts” of reflux testing

Ambulatory reflux testing assesses esophageal reflux burden and symptom-reflux association (SRA). Individual reflux events are identified as either a drop in esophageal pH to less than 4 (acid reflux events), or a sharp decrease in esophageal impedance measurements in a retrograde fashion (impedance-detected reflux events), with subsequent recovery to the baseline in each instance. Ambulatory reflux testing affords insight into three areas: 1) measurement of esophageal acid exposure time (AET); the cumulative time duration when distal esophageal pH is less than 4 at the recording site, reported as a percentage of the recording period; 2) measurement of the number of reflux events both acidic (from pH monitoring) and weakly acidic/alkaline (from impedance monitoring); and 3) quantitative evaluation of the association between reported symptom episodes and reflux events.

The three available modalities of ambulatory reflux monitoring consist of catheter-based pH, wireless pH, and combined catheter-based pH-impedance monitoring. Catheter-based pH monitoring, introduced in the 1970s, requires transnasal catheter placement and typically records for 24 hours before catheter removal. The catheter is positioned with the distal pH sensor 5 cm proximal to the upper margin of the manometrically identified lower esophageal sphincter (LES). New guidelines suggest AET less than 4% is reliably normal, while AET greater than 6% is pathologic; values in between are considered borderline and require alternate evidence for GERD, such as endoscopic findings.⁷ Wireless pH probes are placed 6 cm proximal to the squamocolumnar junction at endoscopy and communicate with a pager-sized receiver worn by the patient.⁹ Patient comfort is not compromised, with less restriction of typical patient activities compared to catheter-based testing, facilitating longer recording periods of 48-96 hours, which can overcome day-to-day variations in esophageal reflux burden.⁷ With catheter-based pH-impedance monitoring, multiple pairs of impedance sensors measure the resistance to flow of a tiny electrical current between sensors. Since resistance to flow (that is, impedance) is low in the presence of a bolus or refluxate in the esophageal lumen, the impedance tracing drops during reflux events in a retrograde fashion across the esophageal impedance sensor pairs, regardless of the acidity of the reflux (Figure 1).¹⁰ Combined pH-impedance testing thus detects refluxate in the esophagus regardless of pH, improving the sensitivity of detection of reflux events over pH testing alone, thereby promoting greater yield of SRA. However, there remains wide inter-observer variation on the designation of impedance reflux events.¹¹

The two most commonly utilized SRA metrics are the symptom index (SI) and symptom-association probability (SAP). Individual symptom episodes are designated as related to preceding reflux events if they occur within 2 minutes of the reflux events. The SI represents the simple ratio of the number of reflux-related symptoms to the total number of symptom episodes reported during the ambulatory reflux study, with values above 50% designated as positive.¹² For calculation of the SAP, the ambulatory reflux study is divided into 2-minute intervals. For each interval, the presence or absence of a reflux event and a symptom episode is assessed; the final counts are tabulated on a 2 x 2 table, and a Fisher exact test is applied to generate a “P” value. The SAP is positive if P is less than 0.05, corresponding to an SAP of greater than 95%, or a less than 5% chance that the observed association between symptoms and reflux events occurred by chance.¹³ The SAP can also be calculated post-hoc with data typically extracted during a pH study, using statistical modeling; termed the Ghillebert Probability Estimate,¹⁴ this corresponds well with the former method of SAP calculation.¹⁵

The SI and SAP can be calculated individually for acid-detected reflux events and for impedance-detected reflux events. Since reflux events are better detected with impedance, combined pH-impedance testing increases the yield of detecting positive SRA, especially when performed off PPI therapy.^16,17 Because these indices are heavily reliant on patient reporting of symptom episodes, SRA can be overinterpreted;¹⁸ positive associations are more clinically useful than negative results in the evaluation of symptoms attributed to GERD.¹⁹ Despite these concerns, the two most consistent predictors of symptomatic outcome with antireflux therapy on pH-impedance testing are abnormal AET and positive SAP with impedance-detected reflux events.¹⁷

Copyright Elsevier/AGA

Along with reflux testing, an esophageal high-resolution manometry (HRM) study is typically performed to establish the location of the LES for placement of reflux catheters. Beyond this primary indication, HRM serves the important role of excluding significant esophageal motor disorders in these patients, particularly achalasia spectrum disorders.²⁰ Despite a diametrically opposite pathophysiology compared to GERD, achalasia can present with retrosternal discomfort (often interpreted as heartburn) and esophageal regurgitation (potentially interpreted as acid regurgitation).²¹ Therefore, achalasia spectrum disorders can be mistaken for GERD and managed with acid suppression, thereby contributing to the pool of symptomatic patients refractory to PPI therapy. HRM has high accuracy and specificity for the diagnosis of achalasia and other major esophageal motor disorders.²² Other foregut disorders diagnosed using HRM (typically combined HRM and impedance, or HRiM) include rumination and supragastric belching. The exclusion of a major esophageal motor disorder is also a requirement for the diagnosis of a functional esophageal disorder, where esophageal reflux testing is normal.²³

 

Testing on or off PPI?

For symptoms attributable to GERD that persist despite properly administered PPI therapy, the 2013 American College of Gastroenterology guidelines suggest upper endoscopy with esophageal biopsies for typical symptoms and appropriate referrals for atypical symptoms.²⁴ However, if these evaluations are unremarkable, reflux monitoring is recommended, with PPI status for testing guided by the pre-test probability of GERD: with a low pre-test probability of GERD, reflux testing is best performed off PPI with either pH or combined pH-impedance testing. In contrast, with a high pre-test probability of GERD, testing is best performed on PPI with combined pH-impedance testing. A similar concept is proposed in the Rome IV approach (Figure 2)²³ and on GERD consensus guidelines:⁷ when heartburn or chest pain persists despite PPI therapy and endoscopy and esophageal biopsies are normal, evidence for GERD (past esophagitis, Barrett’s esophagus, peptic stricture, or prior positive reflux testing) prompts pH-impedance monitoring on PPI therapy (i.e., proven GERD). Those without this evidence for proven GERD (i.e., unproven GERD) are best tested off PPI, and the test utilized can be either pH alone or combined pH-impedance.

GERD phenotypes and management

The presence or absence of the two core metrics on ambulatory reflux monitoring – abnormal AET and positive SRA – can stratify symptomatic GERD patients into phenotypes that predict symptomatic improvement with antireflux therapy and guide management of symptoms (Figure 3).^25,26 The presence of both abnormal AET and positive SRA suggests “strong” evidence for GERD, for which symptom improvement is likely with maximization of antireflux therapy, which can include BID PPI, baclofen (to decrease transient LES relaxations), alginates (such as Gaviscon), and consideration of endosopic or surgical antireflux procedures such as fundoplication or magnetic sphincter augmentation. Abnormal AET but negative SRA is regarded as “good” evidence for GERD, for which similar antireflux therapies can be advocated. Normal AET but positive SRA is designated as “reflux hypersensitivity,”²³ with increasing proportions of patients meeting this phenotype when tested with combined pH-impedance and off PPI therapy.²⁷ Both normal AET and negative SRA suggest equivocal evidence for GERD and the likely presence of a functional esophageal disorder, such as functional heartburn.²³ For reflux hypersensitivity and especially functional esophageal disorders, antireflux therapy is unlikely to be as effective and management can include pharmacologic neuromodulation (such as tricyclic antidepressants administered at bedtime) as well as adjunctive nonpharmacologic approaches (such as stress reduction, relaxation, hypnosis, or cognitive-behavioral therapy).

The future of reflux diagnostics

Reflux testing, especially 24-hour catheter-based monitoring, offers cross-sectional assessment of reflux burden and does not take day-to-day variations in reflux exposure into account in a disease characterized by chronic symptoms and long-term management implications. This shortcoming has prompted interest in novel reflux diagnostics that may afford further insight into longitudinal reflux exposure. Baseline mucosal impedance, which can be gleaned from pH-impedance tracings during nocturnal resting periods²⁸ or by using prototype devices at endoscopy,²⁹ can segregate erosive and nonerosive GERD from controls and may serve as a surrogate marker for reflux-induced mucosal changes and esophageal mucosal integrity.^29-32 Postreflux swallow-induced peristaltic wave index, or the frequencies with which reflux events are followed by clearing esophageal peristaltic waves, represents another novel reflux metric extracted from pH-impedance tracings that may be a marker of refluxate clearance and resolution of esophageal mucosal acidification.³³ Finally, there has been revived interest in the value of dilated intercellular spaces on electron microscopy to assess esophageal mucosal integrity to provide evidence of longitudinal – rather than cross-sectional – reflux exposure.³⁴

Conclusions

For esophageal symptoms potentially attributable to GERD that persist despite optimized PPI therapy, esophageal testing should be undertaken, starting with endoscopy and biopsies and proceeding to ambulatory reflux monitoring with HRM. The decisions between pH testing alone versus combined pH-impedance monitoring, and between testing on or off PPI therapy, can be guided either by the pre-test probability of GERD or whether GERD has been proven or unproven in prior evaluations (Figure 2). Elevated AET and positive SRA with impedance-detected reflux events can predict the likelihood of successful management outcomes from antireflux therapy. These two core metrics can be utilized to phenotype GERD and guide management approaches for persisting symptoms (Figure 3). Novel impedance metrics (baseline mucosal impedance, postreflux swallow-induced peristaltic wave index) and markers for esophageal mucosal damage continue to be studied as potential markers for evidence of longitudinal reflux exposure.

Dr. Patel is assistant professor of medicine, division of gastroenterology, Duke University School of Medicine and the Durham Veterans Affairs Medical Center, Durham, N.C. Dr. Gyawali is professor of medicine, division of gastroenterology, Washington University School of Medicine, St. Louis, Mo.

 

References

1. Shaheen N.J., et al. Am J Gastroenterol. 2006;101:2128-38.

2. Patel A., Gyawali C.P.. Switzerland: Springer International, 2016.

3. Vakil N., et al. Am J Gastroenterol. 2006;101:1900-20; quiz 1943.

4. Fass R., et al. Arch Intern Med. 1999;159:2161-8.

5. Numans M.E., et al. Ann Intern Med. 2004;140:518-27.

6. Shaheen N.J., et al. Aliment Pharmacol Ther. 2011;33:225-34.

7. Roman S., et al. Neurogastroenterol Motil Mar 31. doi: 10.1111/nmo.13067. [Epub ahead of print] 2017.

8. Dellon E.S., et al. Am J Gastroenterol. 2013;108:679-92; quiz 693.

9. Pandolfino JE, Vela MF. Gastrointest Endosc. 2009;69:917-30, 930 e1.

10. Shay S., et al. Am J Gastroenterol. 2004;99:1037-43.

11. Zerbib F., et al. Clin Gastroenterol Hepatol. 2013;11:366-72.

12. Wiener G.J., et al. Am J Gastroenterol 1988;83:358-61.

13. Weusten B.L., et al. Gastroenterology. 1994;107:1741-5.

14. Ghillebert G., et al. Gut 1990;31:738-44.

15. Kushnir V.M., et al. Aliment Pharmacol Ther. 2012;35(9):1080-7.

16. Bredenoord A.J., et al. Am J Gastroenterol. 2006;101:453-9.

17. Patel A., et al. Clin Gastroenterol Hepatol. 2015;13:884-91.

18. Slaughter J.C., et al. Clin Gastroenterol Hepatol. 2011;9:868-74.

19. Kavitt R.T., et al. Am J Gastroenterol. 2012;107:1826-32.

20. Kahrilas P.J., et al. Gastroenterology 2008;135:1383-91, 1391 e1-5.

21. Kessing B.F., et al. Clin Gastroenterol Hepatol. 2011;9:1020-4.

22. Kahrilas P.J., et al. Neurogastroenterol Motil. 2015;27:160-74.

23. Aziz A, et al. Esophageal disorders. Gastroenterology 2016;150:1368-79.

24. Katz P.O., et al. Am J Gastroenterol. 2013;108:308-28; quiz 329.

25. Boeckxstaens G., et al. Gut 2014;63:1185-93.

26. Patel A., et al. Neurogastroenterol Motil. 2016;28:513-21.

27. Patel A., et al. Neurogastroenterol Motil. 2016;28:1382-90.

28. Martinucci I., et al. Neurogastroenterol Motil. 2014;26:546-55.

29. Ates F., et al. Gastroenterology 2015;148:334-43.

30. Kessing B.F., et al. Am J Gastroenterol. 2011;106:2093-7.

31. Patel A., et al. Aliment Pharmacol Ther. 2016;44:890-8.

32. Frazzoni M., et al. Neurogastroenterol Motil. 2016.

33. Frazzoni M., et al. Neurogastroenterol Motil. 2013;25:399-406, e295.

34. Vela M.F., et al. Am J Gastroenterol. 2011;106:844-50.
 

 

Inflammatory bowel disease (IBD) consists of two chronic inflammatory diseases, Crohn’s disease (CD) and ulcerative colitis (UC), as well as a small category of patients (~10%) who have atypical features called IBD-unclassified (IBD-U) or indeterminate colitis. The prevalence of IBD ranges from 0.3% to 0.5% overall in North America and Europe.¹ In North America, the incidences of CD and UC are estimated to be 3.1 to 14.6 per 100,000 person-years and 2.2 to 14.3 cases per 100,000 person-years, respectively; similar rates are seen in Europe.² However, incidences up to 19.2 and 20.2 per 100,000 for UC and CD, respectively, have been reported in Canada.3^,4 The incidences of both UC and CD are increasing over time in Western countries and in rapidly industrializing countries throughout Asia and South America.^5-8

With the increased incidence and advances in the treatment of IBD, many more patients are being treated with corticosteroids, immunomodulators, and biologics. Over time, there has also evolved an understanding of the importance of health maintenance in IBD patients, especially since patients with IBD receive fewer recommended preventive health services than general medical patients even though the use of immunosuppression is an argument for more attention to these issues.⁹ Gastroenterologists may see patients more frequently than their primary care provider (PCP) or PCPs may be unaware of the specific needs of IBD patients. Therefore, it is important that gastroenterologists are knowledgeable about the health maintenance recommendations that can be made to patients and to communicate these to PCPs. Recent society guidelines endorse the importance of this aspect of our practice.¹⁰ The discussion below highlights health maintenance issues that should be fundamental aspects of our IBD practices, however it does not address colon cancer screening and surveillance since these are beyond the scope of this article.
 

Influenza vaccine and pneumococcal vaccine

Influenza A and B outbreaks are commonly seen during the fall and early spring and risk factors for pneumonia and hospitalization include older age, chronic medical conditions, and immunosuppression. The CDC now recommend annual influenza vaccination for all individuals older than six months. For patients on immunosuppression, the vaccine administered should be the inactivated vaccine, as live attenuated vaccines should not be administered to these patients.

Copyright Shawn Rocco

Patients with IBD are also at an increased risk of bacterial pneumonia, the most common etiology of which is pneumococcal pneumonia.¹¹ The Advisory Committee on Immunization Practices (ACIP) recommends that patients on immunosuppression receive a one-time dose of the pneumococcal conjugate vaccine PCV13, followed by a dose of the pneumococcal polysaccharide vaccine PPSV23 one year later (eight weeks at the earliest). A second dose of PPSV23 should be given five years later and a third dose after 65 years of age.

In IBD patients, the influenza and pneumococcal vaccines are both well tolerated without an increased rate of adverse effects over the general population and without an increased risk of IBD flares after vaccination.¹² A common question for patients on biologic therapy is whether the vaccine should be timed at a specific point in the dose cycle. For infliximab, and likely other biologics, the timing does not change the vaccine immunogenicity and patients should be given these vaccines regardless of where they are in the cycle of administration of their biologic.¹³ In addition, there is significant response to influenza and pneumococcal vaccines in patients on combination therapy with immunomodulators and anti-TNFs and concerns about a lack of response to vaccines should not discourage vaccination since benefits are still acquired by patients even if immunogenicity is somewhat decreased.^14,15

Other vaccinations

In addition to the influenza and pneumococcal vaccines, adult and pediatric patients with IBD should follow the ACIP recommendations for tetanus, diphtheria, pertussis (Tdap), Td boosters, hepatitis A, hepatitis B, human papilloma virus (HPV), and meningococcal vaccinations.^16,17

Live vaccines including measles mumps rubella (MMR), varicella, and zoster vaccines are in general contraindicated in immunosuppressed patients on corticosteroids, azathioprine/6-mercaptopurine, methotrexate, anti-TNF, and anti-integrin biologics. An inactive varicella-zoster vaccine will likely be available in the near future and may obviate the need for the live vaccine, which is an important development given the increased risk of zoster in patients with IBD on immunosuppression.¹⁸

Osteoporosis screening

Copyright Shawn Rocco

Both men and women with IBD have an elevated risk of osteoporosis and osteopenia as well as elevated fracture risk.¹⁹ This is related to frequent chronic corticosteroid use, chronic inflammation (high disease activity), women with low BMI, smoking, older age (women > 65, men >70), terminal ileal disease or resection in patients with CD, and proctocolectomy and ileal pouch-anal anastomosis in patients with UC. The recommendations are to obtain baseline bone density evaluation only in patients with risk factors, including young patients since osteopenia can be present at a young age. If If osteopenia is noted, then calcium (1000-1200mg daily) and vitamin D (1000-4000IU daily) supplementation can be associated with improvement in osteopenia.²⁰ If osteoporosis is noted, patients should be referred to rheumatology or endocrinology for evaluation for bisphosphonate therapy which is also associated with improved outcomes.²¹ Bone density testing should be repeated every two years in patients with osteoporosis on treatment and less frequently when there is improvement.²² Given the association of bone metabolism disorders with smoking, this is one more reason to encourage our patients to quit.

 

Skin cancer screening

Multiple studies have demonstrated that immunosuppression, especially with methotrexate and azathioprine/6-mercaptopurine (6MP) is a risk factor for the development of initial and recurrent non-melanoma skin cancer (NMSC) in IBD patients, the data for biologics are less definitive.^23-25 In addition, biologics are associated with increased risk of melanoma in IBD.²⁶ The elevated risk of skin cancer begins in the first year of treatment with thiopurines and may continue after discontinuation. On the basis of this data, screening for melanoma and NMSC is recommended in IBD patients on immunosuppression. Especially for patients on thiopurines it is reasonable for the initial dermatologist visit to occur in the first year of treatment and thereafter with at least annual visits for a full body skin examination. In addition, it is reasonable to recommend regular sunscreen use and protective clothing such as hats.

Cervical cancer screening

A recent meta-analysis shows that women with IBD on immunosuppression have an increased risk of cervical high grade dysplasia and cervical cancer.²⁷ HPV is the major risk factor for cervical cancer and is necessary for its development. The current American College of Gynecology guidelines for women on immunosuppression are to start cervical cancer screening at 21 and annual screening thereafter with Pap and HPV testing.²⁸

Smoking

Smoking has well known associations with poor outcomes in the general population such as increased risk of lung and pancreatic cancers, as well as high risk of cardiovascular disease. In addition, smoking has risks specific to IBD. In CD, smoking is associated with increased disease activity, increased risk of post-operative recurrence, and increased severity of disease.²⁹ Smoking cessation is associated with improved long-term disease outcomes and less risk.³⁰ Making it a point to regularly discuss smoking cessation and partnering with PCPs to offer evidence-based quitting aids may be one of our most significant and beneficial interventions.

Depression and anxiety

Several studies have shown high levels of depression and anxiety in IBD patients and higher levels of depression are associated with increased symptoms, clinical recurrence, poor quality of life and decreased social support.^31-33 A recent systematic review of several studies suggested that antidepressants use in IBD patients benefits their mental health and may improve their clinical course as well.³⁴ As such, screening for depression and anxiety regularly and either offering treatment or referral to psychiatrists and psychologists for further management is recommended.¹⁰

Conclusion

Patients with IBD frequently develop long-term relationships with their gastroenterologists due to their lifelong chronic disease. It is therefore incumbent on us to be attentive to issues related to IBD patients’ preventive care and collaborate with PCPs to coordinate care for our patients since many of these interventions have both short-term and long-term benefits.

Dr. Chachu is assistant professor and gastroenterologist at Duke University, Durham, N.C.

References

1. Kaplan GG, Ng SC. Understanding and Preventing the Global Increase of Inflammatory Bowel Disease. Gastroenterology. 2017;152(2):313-21.e2.

2. Loftus EV, Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004;126(6):1504-17.

3. Bernstein CN, Wajda A, Svenson LW, et al. The Epidemiology of Inflammatory Bowel Disease in Canada: A Population-Based Study. The American journal of gastroenterology. 2006;101(7):1559-68.

4. Lowe AM, Roy PO, M BP, et al. Epidemiology of Crohn’s disease in Quebec, Canada. Inflammatory bowel diseases. 2009;15(3):429-35.

5. Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2007;5(12):1424-9.

6. Kappelman MD, Moore KR, Allen JK, et al. Recent trends in the prevalence of Crohn’s disease and ulcerative colitis in a commercially insured US population. Digestive diseases and sciences. 2013;58(2):519-25.

7. Ng SC, Kaplan G, Banerjee R, et al. 78 Incidence and Phenotype of Inflammatory Bowel Disease From 13 Countries in Asia-Pacific: Results From the Asia-Pacific Crohn’s and Colitis Epidemiologic Study 2011-2013. Gastroenterology.150(4):S21.

8. Parente JML, Coy CSR, Campelo V, et al. Inflammatory bowel disease in an underdeveloped region of Northeastern Brazil. World Journal of Gastroenterology : WJG. 2015;21(4):1197-206.

9. Selby L, Kane S, Wilson J, et al. Receipt of preventive health services by IBD patients is significantly lower than by primary care patients. Inflammatory bowel diseases. 2008;14(2):253-8.

10. Farraye FA, Melmed GY, Lichtenstein GR, et al. ACG Clinical Guideline: Preventive Care in Inflammatory Bowel Disease. The American journal of gastroenterology. 2017;112(2):241-58.

11. Long MD, Martin C, Sandler RS, et al. Increased risk of pneumonia among patients with inflammatory bowel disease. The American journal of gastroenterology. 2013;108(2):240-8.

12. Rahier JF, Papay P, Salleron J, et al. H1N1 vaccines in a large observational cohort of patients with inflammatory bowel disease treated with immunomodulators and biological therapy. Gut. 2011;60(4):456-62.

13. deBruyn J, Fonseca K, Ghosh S, et al. Immunogenicity of Influenza Vaccine for Patients with Inflammatory Bowel Disease on Maintenance Infliximab Therapy: A Randomized Trial. Inflammatory bowel diseases. 2016;22(3):638-47.

14. Brezinschek HP, Hofstaetter T, Leeb BF, et al. Immunization of patients with rheumatoid arthritis with antitumor necrosis factor alpha therapy and methotrexate. Current opinion in rheumatology. 2008;20(3):295-9.

15. Kaine JL, Kivitz AJ, Birbara C, et al. Immune responses following administration of influenza and pneumococcal vaccines to patients with rheumatoid arthritis receiving adalimumab. J Rheumatol. 2007;34(2):272-9.

16. Kim DK, Riley LE, Harriman KH, et al. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older - United States, 2017. MMWR Morbidity and mortality weekly report. 2017;66(5):136-8.

17. Robinson CL, Romero JR, Kempe A, et al. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Children and Adolescents Aged 18 Years or Younger - United States, 2017. MMWR Morbidity and mortality weekly report. 2017;66(5):134-5.

18. Cullen G, Baden RP, Cheifetz AS. Varicella zoster virus infection in inflammatory bowel disease. Inflammatory bowel diseases. 2012;18(12):2392-403.

19. Card T, West J, Hubbard R, et al. Hip fractures in patients with inflammatory bowel disease and their relationship to corticosteroid use: a population based cohort study. Gut. 2004;53(2):251-5.

20. Casals-Seoane F, Chaparro M, Mate J, et al. Clinical Course of Bone Metabolism Disorders in Patients with Inflammatory Bowel Disease: A 5-Year Prospective Study. Inflammatory bowel diseases. 2016;22(8):1929-36.

21. Melek J, Sakuraba A. Efficacy and safety of medical therapy for low bone mineral density in patients with inflammatory bowel disease: a meta-analysis and systematic review. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2014;12(1):32-44.e5.

22. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Osteoporosis International. 2014;25(10):2359-81.

23. Peyrin-Biroulet L, Khosrotehrani K, Carrat F, et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology. 2011;141(5):1621-28.e1-5.

24. Long MD, Herfarth HH, Pipkin CA, et al. Increased risk for non-melanoma skin cancer in patients with inflammatory bowel disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2010;8(3):268-74.

25. Scott FI, Mamtani R, Brensinger CM, et al. Risk of Nonmelanoma Skin Cancer Associated With the Use of Immunosuppressant and Biologic Agents in Patients With a History of Autoimmune Disease and Nonmelanoma Skin Cancer. JAMA dermatology. 2016;152(2):164-72.

26. Long MD, Martin CF, Pipkin CA, et al. Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology. 2012;143(2):390-9.e1.

27. Allegretti JR, Barnes EL, Cameron A. Are patients with inflammatory bowel disease on chronic immunosuppressive therapy at increased risk of cervical high-grade dysplasia/cancer? A meta-analysis. Inflammatory bowel diseases. 2015;21(5):1089-97.

28. Practice Bulletin No. 168: Cervical Cancer Screening and Prevention. Obstetrics and gynecology. 2016;128(4):e111-30.

29. Ryan WR, Allan RN, Yamamoto T, et al. Crohn’s disease patients who quit smoking have a reduced risk of reoperation for recurrence. American journal of surgery. 2004;187(2):219-25.

30. Cosnes J, Beaugerie L, Carbonnel F, et al. Smoking cessation and the course of Crohn’s disease: an intervention study. Gastroenterology. 2001;120(5):1093-9.

31. Fuller-Thomson E, Sulman J. Depression and inflammatory bowel disease: findings from two nationally representative Canadian surveys. Inflammatory bowel diseases. 2006;12(8):697-707.

32. Walker EA, Gelfand MD, Gelfand AN, et al. The relationship of current psychiatric disorder to functional disability and distress in patients with inflammatory bowel disease. General hospital psychiatry. 1996;18(4):220-9.

33. Mikocka-Walus A, Pittet V, Rossel J-B, et al. Symptoms of Depression and Anxiety Are Independently Associated With Clinical Recurrence of Inflammatory Bowel Disease. Clinical Gastroenterology and Hepatology.14(6):829-35.e1.

34. Macer BJD, Prady SL, Mikocka-Walus A. Antidepressants in Inflammatory Bowel Disease: A Systematic Review. Inflammatory bowel diseases. 2017;23(4):534-50.

 

Inflammatory bowel disease (IBD) consists of two chronic inflammatory diseases, Crohn’s disease (CD) and ulcerative colitis (UC), as well as a small category of patients (~10%) who have atypical features called IBD-unclassified (IBD-U) or indeterminate colitis. The prevalence of IBD ranges from 0.3% to 0.5% overall in North America and Europe.¹ In North America, the incidences of CD and UC are estimated to be 3.1 to 14.6 per 100,000 person-years and 2.2 to 14.3 cases per 100,000 person-years, respectively; similar rates are seen in Europe.² However, incidences up to 19.2 and 20.2 per 100,000 for UC and CD, respectively, have been reported in Canada.3^,4 The incidences of both UC and CD are increasing over time in Western countries and in rapidly industrializing countries throughout Asia and South America.^5-8

With the increased incidence and advances in the treatment of IBD, many more patients are being treated with corticosteroids, immunomodulators, and biologics. Over time, there has also evolved an understanding of the importance of health maintenance in IBD patients, especially since patients with IBD receive fewer recommended preventive health services than general medical patients even though the use of immunosuppression is an argument for more attention to these issues.⁹ Gastroenterologists may see patients more frequently than their primary care provider (PCP) or PCPs may be unaware of the specific needs of IBD patients. Therefore, it is important that gastroenterologists are knowledgeable about the health maintenance recommendations that can be made to patients and to communicate these to PCPs. Recent society guidelines endorse the importance of this aspect of our practice.¹⁰ The discussion below highlights health maintenance issues that should be fundamental aspects of our IBD practices, however it does not address colon cancer screening and surveillance since these are beyond the scope of this article.
 

Influenza vaccine and pneumococcal vaccine

Influenza A and B outbreaks are commonly seen during the fall and early spring and risk factors for pneumonia and hospitalization include older age, chronic medical conditions, and immunosuppression. The CDC now recommend annual influenza vaccination for all individuals older than six months. For patients on immunosuppression, the vaccine administered should be the inactivated vaccine, as live attenuated vaccines should not be administered to these patients.

Copyright Shawn Rocco

Patients with IBD are also at an increased risk of bacterial pneumonia, the most common etiology of which is pneumococcal pneumonia.¹¹ The Advisory Committee on Immunization Practices (ACIP) recommends that patients on immunosuppression receive a one-time dose of the pneumococcal conjugate vaccine PCV13, followed by a dose of the pneumococcal polysaccharide vaccine PPSV23 one year later (eight weeks at the earliest). A second dose of PPSV23 should be given five years later and a third dose after 65 years of age.

In IBD patients, the influenza and pneumococcal vaccines are both well tolerated without an increased rate of adverse effects over the general population and without an increased risk of IBD flares after vaccination.¹² A common question for patients on biologic therapy is whether the vaccine should be timed at a specific point in the dose cycle. For infliximab, and likely other biologics, the timing does not change the vaccine immunogenicity and patients should be given these vaccines regardless of where they are in the cycle of administration of their biologic.¹³ In addition, there is significant response to influenza and pneumococcal vaccines in patients on combination therapy with immunomodulators and anti-TNFs and concerns about a lack of response to vaccines should not discourage vaccination since benefits are still acquired by patients even if immunogenicity is somewhat decreased.^14,15

Other vaccinations

In addition to the influenza and pneumococcal vaccines, adult and pediatric patients with IBD should follow the ACIP recommendations for tetanus, diphtheria, pertussis (Tdap), Td boosters, hepatitis A, hepatitis B, human papilloma virus (HPV), and meningococcal vaccinations.^16,17

Live vaccines including measles mumps rubella (MMR), varicella, and zoster vaccines are in general contraindicated in immunosuppressed patients on corticosteroids, azathioprine/6-mercaptopurine, methotrexate, anti-TNF, and anti-integrin biologics. An inactive varicella-zoster vaccine will likely be available in the near future and may obviate the need for the live vaccine, which is an important development given the increased risk of zoster in patients with IBD on immunosuppression.¹⁸

Osteoporosis screening

Copyright Shawn Rocco

Both men and women with IBD have an elevated risk of osteoporosis and osteopenia as well as elevated fracture risk.¹⁹ This is related to frequent chronic corticosteroid use, chronic inflammation (high disease activity), women with low BMI, smoking, older age (women > 65, men >70), terminal ileal disease or resection in patients with CD, and proctocolectomy and ileal pouch-anal anastomosis in patients with UC. The recommendations are to obtain baseline bone density evaluation only in patients with risk factors, including young patients since osteopenia can be present at a young age. If If osteopenia is noted, then calcium (1000-1200mg daily) and vitamin D (1000-4000IU daily) supplementation can be associated with improvement in osteopenia.²⁰ If osteoporosis is noted, patients should be referred to rheumatology or endocrinology for evaluation for bisphosphonate therapy which is also associated with improved outcomes.²¹ Bone density testing should be repeated every two years in patients with osteoporosis on treatment and less frequently when there is improvement.²² Given the association of bone metabolism disorders with smoking, this is one more reason to encourage our patients to quit.

 

Skin cancer screening

Multiple studies have demonstrated that immunosuppression, especially with methotrexate and azathioprine/6-mercaptopurine (6MP) is a risk factor for the development of initial and recurrent non-melanoma skin cancer (NMSC) in IBD patients, the data for biologics are less definitive.^23-25 In addition, biologics are associated with increased risk of melanoma in IBD.²⁶ The elevated risk of skin cancer begins in the first year of treatment with thiopurines and may continue after discontinuation. On the basis of this data, screening for melanoma and NMSC is recommended in IBD patients on immunosuppression. Especially for patients on thiopurines it is reasonable for the initial dermatologist visit to occur in the first year of treatment and thereafter with at least annual visits for a full body skin examination. In addition, it is reasonable to recommend regular sunscreen use and protective clothing such as hats.

Cervical cancer screening

A recent meta-analysis shows that women with IBD on immunosuppression have an increased risk of cervical high grade dysplasia and cervical cancer.²⁷ HPV is the major risk factor for cervical cancer and is necessary for its development. The current American College of Gynecology guidelines for women on immunosuppression are to start cervical cancer screening at 21 and annual screening thereafter with Pap and HPV testing.²⁸

Smoking

Smoking has well known associations with poor outcomes in the general population such as increased risk of lung and pancreatic cancers, as well as high risk of cardiovascular disease. In addition, smoking has risks specific to IBD. In CD, smoking is associated with increased disease activity, increased risk of post-operative recurrence, and increased severity of disease.²⁹ Smoking cessation is associated with improved long-term disease outcomes and less risk.³⁰ Making it a point to regularly discuss smoking cessation and partnering with PCPs to offer evidence-based quitting aids may be one of our most significant and beneficial interventions.

Depression and anxiety

Several studies have shown high levels of depression and anxiety in IBD patients and higher levels of depression are associated with increased symptoms, clinical recurrence, poor quality of life and decreased social support.^31-33 A recent systematic review of several studies suggested that antidepressants use in IBD patients benefits their mental health and may improve their clinical course as well.³⁴ As such, screening for depression and anxiety regularly and either offering treatment or referral to psychiatrists and psychologists for further management is recommended.¹⁰

Conclusion

Patients with IBD frequently develop long-term relationships with their gastroenterologists due to their lifelong chronic disease. It is therefore incumbent on us to be attentive to issues related to IBD patients’ preventive care and collaborate with PCPs to coordinate care for our patients since many of these interventions have both short-term and long-term benefits.

Dr. Chachu is assistant professor and gastroenterologist at Duke University, Durham, N.C.

References

1. Kaplan GG, Ng SC. Understanding and Preventing the Global Increase of Inflammatory Bowel Disease. Gastroenterology. 2017;152(2):313-21.e2.

2. Loftus EV, Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004;126(6):1504-17.

3. Bernstein CN, Wajda A, Svenson LW, et al. The Epidemiology of Inflammatory Bowel Disease in Canada: A Population-Based Study. The American journal of gastroenterology. 2006;101(7):1559-68.

4. Lowe AM, Roy PO, M BP, et al. Epidemiology of Crohn’s disease in Quebec, Canada. Inflammatory bowel diseases. 2009;15(3):429-35.

5. Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2007;5(12):1424-9.

6. Kappelman MD, Moore KR, Allen JK, et al. Recent trends in the prevalence of Crohn’s disease and ulcerative colitis in a commercially insured US population. Digestive diseases and sciences. 2013;58(2):519-25.

7. Ng SC, Kaplan G, Banerjee R, et al. 78 Incidence and Phenotype of Inflammatory Bowel Disease From 13 Countries in Asia-Pacific: Results From the Asia-Pacific Crohn’s and Colitis Epidemiologic Study 2011-2013. Gastroenterology.150(4):S21.

8. Parente JML, Coy CSR, Campelo V, et al. Inflammatory bowel disease in an underdeveloped region of Northeastern Brazil. World Journal of Gastroenterology : WJG. 2015;21(4):1197-206.

9. Selby L, Kane S, Wilson J, et al. Receipt of preventive health services by IBD patients is significantly lower than by primary care patients. Inflammatory bowel diseases. 2008;14(2):253-8.

10. Farraye FA, Melmed GY, Lichtenstein GR, et al. ACG Clinical Guideline: Preventive Care in Inflammatory Bowel Disease. The American journal of gastroenterology. 2017;112(2):241-58.

11. Long MD, Martin C, Sandler RS, et al. Increased risk of pneumonia among patients with inflammatory bowel disease. The American journal of gastroenterology. 2013;108(2):240-8.

12. Rahier JF, Papay P, Salleron J, et al. H1N1 vaccines in a large observational cohort of patients with inflammatory bowel disease treated with immunomodulators and biological therapy. Gut. 2011;60(4):456-62.

13. deBruyn J, Fonseca K, Ghosh S, et al. Immunogenicity of Influenza Vaccine for Patients with Inflammatory Bowel Disease on Maintenance Infliximab Therapy: A Randomized Trial. Inflammatory bowel diseases. 2016;22(3):638-47.

14. Brezinschek HP, Hofstaetter T, Leeb BF, et al. Immunization of patients with rheumatoid arthritis with antitumor necrosis factor alpha therapy and methotrexate. Current opinion in rheumatology. 2008;20(3):295-9.

15. Kaine JL, Kivitz AJ, Birbara C, et al. Immune responses following administration of influenza and pneumococcal vaccines to patients with rheumatoid arthritis receiving adalimumab. J Rheumatol. 2007;34(2):272-9.

16. Kim DK, Riley LE, Harriman KH, et al. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older - United States, 2017. MMWR Morbidity and mortality weekly report. 2017;66(5):136-8.

17. Robinson CL, Romero JR, Kempe A, et al. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Children and Adolescents Aged 18 Years or Younger - United States, 2017. MMWR Morbidity and mortality weekly report. 2017;66(5):134-5.

18. Cullen G, Baden RP, Cheifetz AS. Varicella zoster virus infection in inflammatory bowel disease. Inflammatory bowel diseases. 2012;18(12):2392-403.

19. Card T, West J, Hubbard R, et al. Hip fractures in patients with inflammatory bowel disease and their relationship to corticosteroid use: a population based cohort study. Gut. 2004;53(2):251-5.

20. Casals-Seoane F, Chaparro M, Mate J, et al. Clinical Course of Bone Metabolism Disorders in Patients with Inflammatory Bowel Disease: A 5-Year Prospective Study. Inflammatory bowel diseases. 2016;22(8):1929-36.

21. Melek J, Sakuraba A. Efficacy and safety of medical therapy for low bone mineral density in patients with inflammatory bowel disease: a meta-analysis and systematic review. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2014;12(1):32-44.e5.

22. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Osteoporosis International. 2014;25(10):2359-81.

23. Peyrin-Biroulet L, Khosrotehrani K, Carrat F, et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology. 2011;141(5):1621-28.e1-5.

24. Long MD, Herfarth HH, Pipkin CA, et al. Increased risk for non-melanoma skin cancer in patients with inflammatory bowel disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2010;8(3):268-74.

25. Scott FI, Mamtani R, Brensinger CM, et al. Risk of Nonmelanoma Skin Cancer Associated With the Use of Immunosuppressant and Biologic Agents in Patients With a History of Autoimmune Disease and Nonmelanoma Skin Cancer. JAMA dermatology. 2016;152(2):164-72.

26. Long MD, Martin CF, Pipkin CA, et al. Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology. 2012;143(2):390-9.e1.

27. Allegretti JR, Barnes EL, Cameron A. Are patients with inflammatory bowel disease on chronic immunosuppressive therapy at increased risk of cervical high-grade dysplasia/cancer? A meta-analysis. Inflammatory bowel diseases. 2015;21(5):1089-97.

28. Practice Bulletin No. 168: Cervical Cancer Screening and Prevention. Obstetrics and gynecology. 2016;128(4):e111-30.

29. Ryan WR, Allan RN, Yamamoto T, et al. Crohn’s disease patients who quit smoking have a reduced risk of reoperation for recurrence. American journal of surgery. 2004;187(2):219-25.

30. Cosnes J, Beaugerie L, Carbonnel F, et al. Smoking cessation and the course of Crohn’s disease: an intervention study. Gastroenterology. 2001;120(5):1093-9.

31. Fuller-Thomson E, Sulman J. Depression and inflammatory bowel disease: findings from two nationally representative Canadian surveys. Inflammatory bowel diseases. 2006;12(8):697-707.

32. Walker EA, Gelfand MD, Gelfand AN, et al. The relationship of current psychiatric disorder to functional disability and distress in patients with inflammatory bowel disease. General hospital psychiatry. 1996;18(4):220-9.

33. Mikocka-Walus A, Pittet V, Rossel J-B, et al. Symptoms of Depression and Anxiety Are Independently Associated With Clinical Recurrence of Inflammatory Bowel Disease. Clinical Gastroenterology and Hepatology.14(6):829-35.e1.

34. Macer BJD, Prady SL, Mikocka-Walus A. Antidepressants in Inflammatory Bowel Disease: A Systematic Review. Inflammatory bowel diseases. 2017;23(4):534-50.

 

Inflammatory bowel disease (IBD) consists of two chronic inflammatory diseases, Crohn’s disease (CD) and ulcerative colitis (UC), as well as a small category of patients (~10%) who have atypical features called IBD-unclassified (IBD-U) or indeterminate colitis. The prevalence of IBD ranges from 0.3% to 0.5% overall in North America and Europe.¹ In North America, the incidences of CD and UC are estimated to be 3.1 to 14.6 per 100,000 person-years and 2.2 to 14.3 cases per 100,000 person-years, respectively; similar rates are seen in Europe.² However, incidences up to 19.2 and 20.2 per 100,000 for UC and CD, respectively, have been reported in Canada.3^,4 The incidences of both UC and CD are increasing over time in Western countries and in rapidly industrializing countries throughout Asia and South America.^5-8

With the increased incidence and advances in the treatment of IBD, many more patients are being treated with corticosteroids, immunomodulators, and biologics. Over time, there has also evolved an understanding of the importance of health maintenance in IBD patients, especially since patients with IBD receive fewer recommended preventive health services than general medical patients even though the use of immunosuppression is an argument for more attention to these issues.⁹ Gastroenterologists may see patients more frequently than their primary care provider (PCP) or PCPs may be unaware of the specific needs of IBD patients. Therefore, it is important that gastroenterologists are knowledgeable about the health maintenance recommendations that can be made to patients and to communicate these to PCPs. Recent society guidelines endorse the importance of this aspect of our practice.¹⁰ The discussion below highlights health maintenance issues that should be fundamental aspects of our IBD practices, however it does not address colon cancer screening and surveillance since these are beyond the scope of this article.
 

Influenza vaccine and pneumococcal vaccine

Influenza A and B outbreaks are commonly seen during the fall and early spring and risk factors for pneumonia and hospitalization include older age, chronic medical conditions, and immunosuppression. The CDC now recommend annual influenza vaccination for all individuals older than six months. For patients on immunosuppression, the vaccine administered should be the inactivated vaccine, as live attenuated vaccines should not be administered to these patients.

Copyright Shawn Rocco

Patients with IBD are also at an increased risk of bacterial pneumonia, the most common etiology of which is pneumococcal pneumonia.¹¹ The Advisory Committee on Immunization Practices (ACIP) recommends that patients on immunosuppression receive a one-time dose of the pneumococcal conjugate vaccine PCV13, followed by a dose of the pneumococcal polysaccharide vaccine PPSV23 one year later (eight weeks at the earliest). A second dose of PPSV23 should be given five years later and a third dose after 65 years of age.

In IBD patients, the influenza and pneumococcal vaccines are both well tolerated without an increased rate of adverse effects over the general population and without an increased risk of IBD flares after vaccination.¹² A common question for patients on biologic therapy is whether the vaccine should be timed at a specific point in the dose cycle. For infliximab, and likely other biologics, the timing does not change the vaccine immunogenicity and patients should be given these vaccines regardless of where they are in the cycle of administration of their biologic.¹³ In addition, there is significant response to influenza and pneumococcal vaccines in patients on combination therapy with immunomodulators and anti-TNFs and concerns about a lack of response to vaccines should not discourage vaccination since benefits are still acquired by patients even if immunogenicity is somewhat decreased.^14,15

Other vaccinations

In addition to the influenza and pneumococcal vaccines, adult and pediatric patients with IBD should follow the ACIP recommendations for tetanus, diphtheria, pertussis (Tdap), Td boosters, hepatitis A, hepatitis B, human papilloma virus (HPV), and meningococcal vaccinations.^16,17

Live vaccines including measles mumps rubella (MMR), varicella, and zoster vaccines are in general contraindicated in immunosuppressed patients on corticosteroids, azathioprine/6-mercaptopurine, methotrexate, anti-TNF, and anti-integrin biologics. An inactive varicella-zoster vaccine will likely be available in the near future and may obviate the need for the live vaccine, which is an important development given the increased risk of zoster in patients with IBD on immunosuppression.¹⁸

Osteoporosis screening

Copyright Shawn Rocco

Both men and women with IBD have an elevated risk of osteoporosis and osteopenia as well as elevated fracture risk.¹⁹ This is related to frequent chronic corticosteroid use, chronic inflammation (high disease activity), women with low BMI, smoking, older age (women > 65, men >70), terminal ileal disease or resection in patients with CD, and proctocolectomy and ileal pouch-anal anastomosis in patients with UC. The recommendations are to obtain baseline bone density evaluation only in patients with risk factors, including young patients since osteopenia can be present at a young age. If If osteopenia is noted, then calcium (1000-1200mg daily) and vitamin D (1000-4000IU daily) supplementation can be associated with improvement in osteopenia.²⁰ If osteoporosis is noted, patients should be referred to rheumatology or endocrinology for evaluation for bisphosphonate therapy which is also associated with improved outcomes.²¹ Bone density testing should be repeated every two years in patients with osteoporosis on treatment and less frequently when there is improvement.²² Given the association of bone metabolism disorders with smoking, this is one more reason to encourage our patients to quit.

 

Skin cancer screening

Multiple studies have demonstrated that immunosuppression, especially with methotrexate and azathioprine/6-mercaptopurine (6MP) is a risk factor for the development of initial and recurrent non-melanoma skin cancer (NMSC) in IBD patients, the data for biologics are less definitive.^23-25 In addition, biologics are associated with increased risk of melanoma in IBD.²⁶ The elevated risk of skin cancer begins in the first year of treatment with thiopurines and may continue after discontinuation. On the basis of this data, screening for melanoma and NMSC is recommended in IBD patients on immunosuppression. Especially for patients on thiopurines it is reasonable for the initial dermatologist visit to occur in the first year of treatment and thereafter with at least annual visits for a full body skin examination. In addition, it is reasonable to recommend regular sunscreen use and protective clothing such as hats.

Cervical cancer screening

A recent meta-analysis shows that women with IBD on immunosuppression have an increased risk of cervical high grade dysplasia and cervical cancer.²⁷ HPV is the major risk factor for cervical cancer and is necessary for its development. The current American College of Gynecology guidelines for women on immunosuppression are to start cervical cancer screening at 21 and annual screening thereafter with Pap and HPV testing.²⁸

Smoking

Smoking has well known associations with poor outcomes in the general population such as increased risk of lung and pancreatic cancers, as well as high risk of cardiovascular disease. In addition, smoking has risks specific to IBD. In CD, smoking is associated with increased disease activity, increased risk of post-operative recurrence, and increased severity of disease.²⁹ Smoking cessation is associated with improved long-term disease outcomes and less risk.³⁰ Making it a point to regularly discuss smoking cessation and partnering with PCPs to offer evidence-based quitting aids may be one of our most significant and beneficial interventions.

Depression and anxiety

Several studies have shown high levels of depression and anxiety in IBD patients and higher levels of depression are associated with increased symptoms, clinical recurrence, poor quality of life and decreased social support.^31-33 A recent systematic review of several studies suggested that antidepressants use in IBD patients benefits their mental health and may improve their clinical course as well.³⁴ As such, screening for depression and anxiety regularly and either offering treatment or referral to psychiatrists and psychologists for further management is recommended.¹⁰

Conclusion

Patients with IBD frequently develop long-term relationships with their gastroenterologists due to their lifelong chronic disease. It is therefore incumbent on us to be attentive to issues related to IBD patients’ preventive care and collaborate with PCPs to coordinate care for our patients since many of these interventions have both short-term and long-term benefits.

Dr. Chachu is assistant professor and gastroenterologist at Duke University, Durham, N.C.

References

1. Kaplan GG, Ng SC. Understanding and Preventing the Global Increase of Inflammatory Bowel Disease. Gastroenterology. 2017;152(2):313-21.e2.

2. Loftus EV, Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004;126(6):1504-17.

3. Bernstein CN, Wajda A, Svenson LW, et al. The Epidemiology of Inflammatory Bowel Disease in Canada: A Population-Based Study. The American journal of gastroenterology. 2006;101(7):1559-68.

4. Lowe AM, Roy PO, M BP, et al. Epidemiology of Crohn’s disease in Quebec, Canada. Inflammatory bowel diseases. 2009;15(3):429-35.

5. Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2007;5(12):1424-9.

6. Kappelman MD, Moore KR, Allen JK, et al. Recent trends in the prevalence of Crohn’s disease and ulcerative colitis in a commercially insured US population. Digestive diseases and sciences. 2013;58(2):519-25.

7. Ng SC, Kaplan G, Banerjee R, et al. 78 Incidence and Phenotype of Inflammatory Bowel Disease From 13 Countries in Asia-Pacific: Results From the Asia-Pacific Crohn’s and Colitis Epidemiologic Study 2011-2013. Gastroenterology.150(4):S21.

8. Parente JML, Coy CSR, Campelo V, et al. Inflammatory bowel disease in an underdeveloped region of Northeastern Brazil. World Journal of Gastroenterology : WJG. 2015;21(4):1197-206.

9. Selby L, Kane S, Wilson J, et al. Receipt of preventive health services by IBD patients is significantly lower than by primary care patients. Inflammatory bowel diseases. 2008;14(2):253-8.

10. Farraye FA, Melmed GY, Lichtenstein GR, et al. ACG Clinical Guideline: Preventive Care in Inflammatory Bowel Disease. The American journal of gastroenterology. 2017;112(2):241-58.

11. Long MD, Martin C, Sandler RS, et al. Increased risk of pneumonia among patients with inflammatory bowel disease. The American journal of gastroenterology. 2013;108(2):240-8.

12. Rahier JF, Papay P, Salleron J, et al. H1N1 vaccines in a large observational cohort of patients with inflammatory bowel disease treated with immunomodulators and biological therapy. Gut. 2011;60(4):456-62.

13. deBruyn J, Fonseca K, Ghosh S, et al. Immunogenicity of Influenza Vaccine for Patients with Inflammatory Bowel Disease on Maintenance Infliximab Therapy: A Randomized Trial. Inflammatory bowel diseases. 2016;22(3):638-47.

14. Brezinschek HP, Hofstaetter T, Leeb BF, et al. Immunization of patients with rheumatoid arthritis with antitumor necrosis factor alpha therapy and methotrexate. Current opinion in rheumatology. 2008;20(3):295-9.

15. Kaine JL, Kivitz AJ, Birbara C, et al. Immune responses following administration of influenza and pneumococcal vaccines to patients with rheumatoid arthritis receiving adalimumab. J Rheumatol. 2007;34(2):272-9.

16. Kim DK, Riley LE, Harriman KH, et al. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older - United States, 2017. MMWR Morbidity and mortality weekly report. 2017;66(5):136-8.

17. Robinson CL, Romero JR, Kempe A, et al. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Children and Adolescents Aged 18 Years or Younger - United States, 2017. MMWR Morbidity and mortality weekly report. 2017;66(5):134-5.

18. Cullen G, Baden RP, Cheifetz AS. Varicella zoster virus infection in inflammatory bowel disease. Inflammatory bowel diseases. 2012;18(12):2392-403.

19. Card T, West J, Hubbard R, et al. Hip fractures in patients with inflammatory bowel disease and their relationship to corticosteroid use: a population based cohort study. Gut. 2004;53(2):251-5.

20. Casals-Seoane F, Chaparro M, Mate J, et al. Clinical Course of Bone Metabolism Disorders in Patients with Inflammatory Bowel Disease: A 5-Year Prospective Study. Inflammatory bowel diseases. 2016;22(8):1929-36.

21. Melek J, Sakuraba A. Efficacy and safety of medical therapy for low bone mineral density in patients with inflammatory bowel disease: a meta-analysis and systematic review. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2014;12(1):32-44.e5.

22. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Osteoporosis International. 2014;25(10):2359-81.

23. Peyrin-Biroulet L, Khosrotehrani K, Carrat F, et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology. 2011;141(5):1621-28.e1-5.

24. Long MD, Herfarth HH, Pipkin CA, et al. Increased risk for non-melanoma skin cancer in patients with inflammatory bowel disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2010;8(3):268-74.

25. Scott FI, Mamtani R, Brensinger CM, et al. Risk of Nonmelanoma Skin Cancer Associated With the Use of Immunosuppressant and Biologic Agents in Patients With a History of Autoimmune Disease and Nonmelanoma Skin Cancer. JAMA dermatology. 2016;152(2):164-72.

26. Long MD, Martin CF, Pipkin CA, et al. Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology. 2012;143(2):390-9.e1.

27. Allegretti JR, Barnes EL, Cameron A. Are patients with inflammatory bowel disease on chronic immunosuppressive therapy at increased risk of cervical high-grade dysplasia/cancer? A meta-analysis. Inflammatory bowel diseases. 2015;21(5):1089-97.

28. Practice Bulletin No. 168: Cervical Cancer Screening and Prevention. Obstetrics and gynecology. 2016;128(4):e111-30.

29. Ryan WR, Allan RN, Yamamoto T, et al. Crohn’s disease patients who quit smoking have a reduced risk of reoperation for recurrence. American journal of surgery. 2004;187(2):219-25.

30. Cosnes J, Beaugerie L, Carbonnel F, et al. Smoking cessation and the course of Crohn’s disease: an intervention study. Gastroenterology. 2001;120(5):1093-9.

31. Fuller-Thomson E, Sulman J. Depression and inflammatory bowel disease: findings from two nationally representative Canadian surveys. Inflammatory bowel diseases. 2006;12(8):697-707.

32. Walker EA, Gelfand MD, Gelfand AN, et al. The relationship of current psychiatric disorder to functional disability and distress in patients with inflammatory bowel disease. General hospital psychiatry. 1996;18(4):220-9.

33. Mikocka-Walus A, Pittet V, Rossel J-B, et al. Symptoms of Depression and Anxiety Are Independently Associated With Clinical Recurrence of Inflammatory Bowel Disease. Clinical Gastroenterology and Hepatology.14(6):829-35.e1.

34. Macer BJD, Prady SL, Mikocka-Walus A. Antidepressants in Inflammatory Bowel Disease: A Systematic Review. Inflammatory bowel diseases. 2017;23(4):534-50.

 

Historical perspective

The term “pancreas” derives its name from the Greek words pan (all) and kreas (flesh). Understanding pancreas physiology was first attempted in the 17th century by Regnier de Graaf^1. Giovanni Morgagni is credited with the first description of the syndrome of acute pancreatitis (AP) in 1761². Reginald Huber Fitz proposed the first classification of AP into hemorrhagic, gangrenous, and suppurative types in 1889³. The distinction of acute from chronic pancreatitis was not well described until the middle of the 20th century when Mandred W. Comfort gave a detailed account of chronic relapsing pancreatitis in 1946⁴.

AP is the one of the most common gastrointestinal disorders requiring hospitalization, accounting for roughly 270,000 admissions annually in the U.S., which translates into a $2.6 billion annual health care expenditure.
 

Diagnosis and classification of severity

The diagnosis of AP is based on the presence of two of the three following criteria: typical abdominal pain (severe, upper abdominal pain frequently radiating to the back), serum amylase and/or lipase levels greater than 3 times the upper limit of normal, and/or characteristic imaging findings.

The original 1992 Atlanta classification provided the first blueprint to standardize how severity of AP was defined⁵. Over the years, better understanding of AP pathophysiology and its complications led to a greater focus on local and systemic determinants of severity⁶ and eventually the Revised Atlanta Classification (RAC) in 2013 (Table 1).
 

Management of acute pancreatitis

Prevention

As with any disorder, management starts with prevention. Primary prevention of AP has only been well studied in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). Post-ERCP pancreatitis (PEP) is the most common and arguably the most dreaded complication of ERCP with reported incidence of approximately 10%⁷. Several medications and endoscopic interventions have been assessed for the prevention of PEP. Of these, placement of prophylactic pancreatic duct stents^8,9 and administration of rectal nonsteroidal anti-inflammatory drugs, especially indomethacin, have shown significant benefit in reducing risk for PEP^10,11. It is unclear at this point whether rectal indomethacin alone (without pancreatic duct stenting) is sufficient in patients at high risk for PEP. The SVI (Stent Vs. Indomethacin) trial¹², an ongoing multicenter randomized controlled trial, aims to answer this specific question.

Determination of etiology

The most common causes of AP are gallstones and alcohol, accounting for more than two-thirds of all cases¹³. Other etiologies include hypertriglyceridemia, ERCP, drugs induced, familial/hereditary, and post-traumatic. Initial work up includes a thorough history to quantify alcohol consumption and assess for recently started medications, measurement of liver injury tests¹⁴ and triglyceride levels, and performance of a transabdominal ultrasound to evaluate for biliary dilation, chole- and choledocholithiasis¹⁵.

Assessment of disease severity

There is a plethora of scoring systems developed to predict AP severity and outcomes at presentation and/or within the first 24 hours. These include the Ranson’s criteria described in 1974, the APACHE-II (Acute Physiology and Chronic Health Evaluation II), BISAP (Bedside Index of Severity in Acute Pancreatitis) scores, and others. They all have similar, but only modest, accuracy^16,17. Experts recommend¹⁸ that the Systemic Inflammatory Response Syndrome (SIRS) may be the most useful score in daily clinical practice, given that all of its four parameters are readily available (temperature, heart rate, respiratory rate, and white blood cell count) and the score is easy to calculate. Recent studies suggest that admission hematocrit and rise in blood urea nitrogen (BUN) at 24 hours are as accurate as more complex scoring systems in predicting severe disease¹⁹.

 

Fluid resuscitation

Despite extensive research and trials using medications such as ulinastatin, octreotide, pentoxifylline, gabexate, N-acetyl cysteine, steroids, IL-10, and antibiotics²⁰, no pharmacologic agent has been shown to significantly alter the clinical course/outcomes of AP.

Adequate intravenous hydration remains the cornerstone of early management in AP²¹. Studies have demonstrated that increased intestinal permeability, secondary to reduced intestinal capillary microcirculation, leads to bacterial translocation and development of SIRS²². Intestinal microcirculation does not become as readily impaired, and there is a certain “latency” to its onset, from the insult that triggers pancreatitis. This gives rise to the concept of a “golden window” of 12-24 hours from the insult to potentially reverse such changes and prevent organ dysfunction. It has been shown that patients who are adequately resuscitated with intravenous fluids have lower risk for local and systemic complications²³.

What remains debatable is the amount and type of fluid administered. Lactated Ringers (LR) is likely the optimal solution, based on a small prospective randomized-controlled study showing that administration of LR reduced SIRS compared with saline²⁴. Endpoints to guide adequacy of fluid resuscitation in the first 24-48 hours include measurement of urine output (at least 0.5 mL/kg per hour)²⁵, decrease in hematocrit²⁶ and BUN levels²⁷.

 

 

Selecting level of care and ICU management

Patients with predicted severe AP or those with persistent SIRS despite initial fluid resuscitation should be managed in a closely monitored unit, ideally an ICU. Patients with impending respiratory failure require mechanical ventilation, renal failure complicated by metabolic acidosis and/or hyperkalemia requires hemodialysis, and cardiovascular shock requires the initiation of vasopressors and continuous monitoring of blood pressure via an arterial line. A special entity that requires ICU level care is hypertriglyceridemia (HTG)-induced severe AP. HTG should be considered as the etiology of AP in certain clinical scenarios²⁸: previous history of HTG, poorly controlled diabetes mellitus, history of significant alcohol use, third trimester of pregnancy, and use of certain medications associated with HTG such as oral estrogens, tamoxifen, and propofol. Levels of triglyceride greater than 1000 mg/dL strongly point toward HTG being the etiology.

Plasmapheresis, which filters and removes triglycerides from plasma, has been reported as an efficient treatment in such patients based on case series^29,30. At this time its use may only be justified in patients with predicted severe AP from HTG, preferably within the first 24 hours of presentation.


Urgent ERCP

Urgent ERCP (within 24-48 hours of admission) in patients with biliary AP is indicated³¹ when there is strong clinical suspicion for concomitant cholangitis and/or evidence of ongoing biliary obstruction (secondary to choledocholithiasis) on imaging. Currently, predicted severe AP of biliary etiology does not constitute an indication of urgent ERCP in the absence of the above parameters³².

 

Nutrition

Recovery of the gut function is often delayed for several days or weeks in patients with severe AP. Studies have shown that prolonged fasting in such circumstances leads to malnutrition and worse prognosis^33,34. Enteral nutrition via a nasogastric (NG) or nasojejunal (NJ) tube is the preferred route of nutritional support, as it is associated with lower risk of infection, multi-organ failure, and mortality when compared to total parenteral nutrition³³.

The question of whether NJ feeding offers any additional advantages over NG feeding has not been clearly answered with a recent randomized trial showing NG feeds not to be inferior to NJ feeds³⁵. In regards to the timing of initiation of enteral nutrition, early nasoenteric feeding within 24 hours from presentation was found not to be superior compared to on-demand feeding in patients with predicted severe AP³⁶.


Strategies to decrease risk of recurrent attacks

The etiology of AP can be determined in the majority of patients. In many instances, recurrence can be prevented, i.e., in biliary or alcoholic etiologies. In patients with mild biliary AP, evidence supports³⁷ the performance of cholecystectomy during the index admission. In cases of severe biliary AP complicated by pancreatic necrosis and/or peripancreatic fluid collections, cholecystectomy should be delayed for a few weeks until the collections regress or mature³⁸. In poor surgical candidates, ERCP with biliary sphincterotomy offers an alternative, but less effective, means of reducing the risk of recurrent attacks in patients with biliary AP³⁹. In subjects with first AP attack of alcoholic etiology, counseling focusing on alcohol cessation has shown to reduce risk of recurrences⁴⁰. Similarly, appropriate plans to treat and follow-up underlying metabolic etiologies (hypercalcemia and HTG) should be preferably instituted prior to the patients’ discharge.

 

 

Management of peripancreatic fluid collections

Patients with AP frequently develop peripancreatic fluid collections (PFCs). Based on the revised Atlanta classification, those are categorized into four types (Table 2, Figures 1-4).

The majority of acute PFCs in patients without evidence of pancreatic necrosis regress within a few weeks and thus intervention is not indicated early in the disease course. Current literature supports delaying the drainage/debridement of such collections for several weeks. The mortality from interventions decreases as the time to intervention from onset of symptoms increases⁴¹. Delaying intervention gives more time for recovery from systemic complications and allows the encapsulating wall and contents to organize further.

It is only the mature PFCs, which are symptomatic resulting in abdominal pain, nausea, early satiety, gastric outlet obstruction, failure to thrive, and/or biliary obstruction, that need to be drained/debrided⁴². Minimally invasive approaches have shown to result in better outcomes when compared to open laparotomy. Minimally invasive approaches include placement of percutaneous drainage catheters by interventional radiology (retroperitoneal approach preferred when feasible), endoscopic drainage/debridement, laparoscopy, and retroperitoneal necrosectomy following a step-up approach⁴³.

 

While surgery is still an option for patients with symptomatic mature PFCs, endoscopic ultrasound-guided drainage in expert hands has been shown to be cost effective, with shorter hospital stay and even decreased risk of cyst recurrence compared with surgical cyst-gastrostomy creation⁴⁴. Ultrasound or computed tomography-guided drainage of such collections with a percutaneous catheter is an equally efficacious option when compared to the endoscopic approach. However, patients undergoing endotherapy require fewer procedures and imaging studies and shorter length of stay⁴⁵ when compared with radiological interventions.

 

Management of pancreatic necrosis

Although this topic has generated much debate, the majority of available evidence shows no clinical benefit from using prophylactic antibiotics to prevent infection in pancreatic necrosis⁴⁶.

Infectious complications are the major cause of late mortality in AP. The predominant source is bacterial translocation from the GI tract^47,48. Infected pancreatic necrosis should be suspected in patients with imaging evidence of pancreatic or extrapancreatic necrosis, who have a sudden deterioration in clinical status, typically 2-3 weeks after onset of symptoms or if gas bubbles are seen within a necrotic collection (Figure 2). When infected pancreatic necrosis is suspected or established, antibiotics such as carbapenems, fluoroquinolones, metronidazole, and cephalosporin should be started, which have better penetrance into ischemic pancreatic tissue. CT guided aspiration has lost much of its utility, since there has been a paradigm shift to delaying drainage of infected (suspected or established) pancreatic necrosis. A negative or positive CT aspirate does not dictate timing of intervention and is only recommended if a fungal or drug resistant infection is suspected¹⁵. As mentioned above, when debridement of an infected necroma is contemplated, the two guiding principles are to delay drainage and use minimally invasive approaches.

Vascular complications

Vascular complications such as splanchnic vein thrombosis can occur in up to a quarter of AP patients⁴⁹. Anticoagulation is not usually indicated unless thrombosis is extensive and causes bowel ischemia. Arterial pseudoaneurysms are rare but life threatening complications of AP. They typically require interventional radiology guided coil embolization to prevent massive bleeding⁵⁰.

Abdominal compartment syndrome

Abdominal compartment syndrome is an end result of third spacing of fluid into the abdominal cavity secondary to inflammation and fluid resuscitation in severe pancreatitis. Abdominal pressure in patients can be monitored by measuring bladder pressures. Intra-abdominal hypertension is defined as a sustained pressure greater than 12 mm Hg, while abdominal compartment syndrome is defined as sustained intra-abdominal pressure greater than 20 mm Hg with new organ failure⁵¹. Intra-abdominal hypertension (IAH) is present in up to 75% of patients with severe AP. While all conservative measures to prevent development or worsening of IAH should be implemented (adequate sedation, decompression of bowel in patients with ileus, etc.), current guidelines do not recommend aggressive interventions to treat it. On the other hand, abdominal compartment syndrome is a life-threatening complication that requires urgent intervention to decrease intra-abdominal pressure, such as percutaneous drain placement or surgical fasciotomy^52,53.

Conclusion

The key principles in the management of acute pancreatitis are aggressive hydration and preventing development of end organ failure. In the last two decades there has been a paradigm shift in the guidelines for management of peripancreatic fluid collections and pancreatic necrosis. When feasible, drainage of these collections should be delayed and be performed using minimally invasive interventions. There is still an urgent need for developing and testing disease-specific treatments targeting control of the inflammatory response in the early phase of acute pancreatitis and prevention of development of severe disease with end-organ dysfunction.

Dr. Gulati is a gastroenterology and hepatology fellow at Allegheny Health Network, Pittsburgh, and Dr. Papachristou is professor of medicine, University of Pittsburgh School of Medicine, Pittsburgh.

References

1. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, Chapter 55, 923-33.

2. Morgagni G.B. [Fie Books on the Seats and Causes of Diseases as Discovered by the Anatomist]. Venice, Italy: Typographia Remondiniana;1761.

3. Fitz R.H. Boston Med Surg J. 1889;120:181-8.

4. Comfort M., Gambill E., Baggesnstoss A. Gastroenterology. 1946;6:238-76.

5. Bollen T.L., van Santvoort H.C., Besselink M.G., et al. Br J Surg. 2008;95:6–21.

6. Dellinger E.P., Forsmark C.E., Layer P., et al. Ann Surg. 2012 Dec;256[6]:875-80.

7. Kochar B., Akshintala V.S., Afghani E., et al. Gastrointest Endosc. 2015 Jan;81[1]:143-9.

8. Choudhary A., Bechtold M.L., Arif M., et al. Gastrointest Endosc. 2011 Feb;73[2]:275-82.

9. Shi Q.Q., Ning X.Y., Zhan L.L., Tang G.D., Lv X.P. World J Gastroenterol. 2014 Jun 14;20[22]:7040-8.

10. Elmunzer B.J., Waljee A.K., Elta G.H., Taylor J.R., Fehmi S.M., Higgins P.D. Gut. 2008 Sep;57[9]:1262-7.

11. Sethi S., Sethi N., Wadhwa V., Garud S., Brown A. Pancreas. 2014 Mar;43[2]:190-7. 
12. Elmunzer B.J., Serrano J., Chak A., et al. Trials. 2016 Mar 3;17[1]:120.

13. Lowenfels A.B., Maisonneuve P., Sullivan T. Curr Gastroenterol Rep. 2009;11:97-103.

14. Agarwal N., Pitchumoni C.S., Sivaprasad A.V. Am J Gastroenterol. 1990;85:356-66.

15. Tenner S., Baillie J., DeWitt J. Vege S.S. Am J Gastroenterol. 2013;108:1400-15.

16. Papachristou G.I., Muddana V., Yadav D., et al. Am J Gastroenterol. 2010;105:435-41.

17. Mounzer R., et al. Gastroenterology 2012;142:1476-82.

18. Working Group IAP/APA Acute Pancreatitis Guidelines. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

19. Koutroumpakis E., Wu B.U., Bakker O.J., et al. Am J Gastroenterol. 2015 Dec;110[12]:1707-16.

20. Bang U.C., Semb S., Nojgaard C., Bendtsen F. World J Gastroenterol. 2008 May 21;14[19]:2968-76.

21. Warndorf M.G., Kurtzman J.T., Bartel M.J., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:705-9.

22. Hotz H.G., Foitzik T., Rohweder J., et al. J Gastrointest Surg. 1998 Nov-Dec;2[6]:518-25.

23. Brown A., Baillargeon J.D., Hughes M.D., et al. Pancreatology 2002;2:104-7.

24. Wu B.U., Hwang J.Q., Gardner T.H., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:710-7.

25. Forsmark C.E., Baillie J., AGA Institute Clinical Practice and Economics Committee, AGA Institute Governing Board. Gastroenterology. 2007 May;132[5]:2022-44.

26. Lankisch P.G., Mahlke R., Blum T., et al. Am J Gastroenterol. 2001;96:2081-5.

27. Wu B.U., Johannes R.S., Sun X., et al. Gastroenterology 2009;137:129-35.

28. Scherer J., Singh V.P., Pitchumoni C.S., Yadav D. J Clin Gastroenterol. 2014 Mar;48[3]:195-203.

29. Gubensek J., Buturovic-Ponikvar J., Romozi K., Ponikvar R. PLoS One. 2014 Jul 21;9[7]:e102748.

30. Chen J.H., Yeh J.H., Lai H.W., Liao C.S. World J Gastroenterol. 2004 Aug 1;10[15]:2272-4.

31. Tse F., Yuan Y. Cochrane Database Syst Rev. 2012 May 16;[5]:CD009779.

32. Folsch U.R., Nitsche R., Ludtke R., et al. N Engl J Med. 1997;336:237-42.

33. Al-Omran M., Albalawi Z.H., Tashkandi M.F., Al-Ansary L.A. Cochrane Database Syst Rev. 2010 Jan 20;[1]:CD002837.

 

34. Li J.Y., Yu T., Chen G.C., et al. PLoS One. 2013;8[6]:e64926.

35. Singh N., Sharma B., Sharma M., et al. Pancreas. 2012 Jan;41[1]:153-9.

36. Bakker O.J., van Brunschot S., van Santvoort H.C., et al. N Engl J Med. 2014 Nov 20;371[21]:1983-93.

37. Van Baal M.C., Besselink M.G., Bakker O.J., et al. Ann Surg. 2012;255:860–6.

38. Nealon W.H., Bawduniak J., Walser E.M. Ann Surg. 2004 Jun;239[6]:741-9.

39. Sanjay P., Yeeting S., Whigham C., Judson H., Polignano F.M., Tait I.S. Surg Endosc. 2008 Aug;22[8]:1832-7.

40. Nordback I., Pelli H., Lappalainen-Lehto R., Järvinen S., Räty S., Sand J. Gastroenterology. 2009 Mar;136[3]:848-55.

41. Besselink M.G., Verwer T.J., Schoenmaeckers E.J., et al. Arch Surg. 2007;142:1194-201.

42. Besselink M., van Santvoort H., Freeman M. et al. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

43. Hjalmar C., van Santvoort, H., Besselink M.G., et al. N Engl J Med. 2010;362:1491-502.

44. Varadarajulu S., Bang J.Y., Sutton B.S., et al. Gastroenterology. 2013;145:583-90.e1.

45. Akshintala V.S., Saxena P., Zaheer A., et al. Gastrointest Endosc. 2014 Jun;79[6]:921-8.

46. Jiang K, Huang W, Yang XN., et al. World J Gastroenterol. 2012;18:279–84.

47. Dervenis C., Smailis D., Hatzitheoklitos E. J Hepatobiliary Pancreat Surg. 2003;10[6]:415Y418.

48. Gloor B., Muller C.A., Worni M., et al. Arch Surg. 2001;136[5]:592Y596.

49. Nadkarni N.A., Khanna S., Vege S.S. Pancreas. 2013 Aug;42[6]:924-31.

50. Marshall G.T., Howell D.A., Hansen B.L., Amberson S.M., Abourjaily G.S., Bredenberg C.E. Arch Surg. 1996 Mar;131[3]:278-83.

51. Malbrain M.L., Cheatham M.L., Kirkpatrick A., et al. Intensive Care Med. 2006 Nov;32[11]:1722-32.

52. De Waele J.J. Leppaniemi A.K. World J Surg. 2009;33:1128-33.

53. Kirkpatrick A.W., Roberts D.J., De W.J., et al. Intensive Care Med. 2013 Jul;39[7]1190-206.
 

 

Historical perspective

The term “pancreas” derives its name from the Greek words pan (all) and kreas (flesh). Understanding pancreas physiology was first attempted in the 17th century by Regnier de Graaf^1. Giovanni Morgagni is credited with the first description of the syndrome of acute pancreatitis (AP) in 1761². Reginald Huber Fitz proposed the first classification of AP into hemorrhagic, gangrenous, and suppurative types in 1889³. The distinction of acute from chronic pancreatitis was not well described until the middle of the 20th century when Mandred W. Comfort gave a detailed account of chronic relapsing pancreatitis in 1946⁴.

AP is the one of the most common gastrointestinal disorders requiring hospitalization, accounting for roughly 270,000 admissions annually in the U.S., which translates into a $2.6 billion annual health care expenditure.
 

Diagnosis and classification of severity

The diagnosis of AP is based on the presence of two of the three following criteria: typical abdominal pain (severe, upper abdominal pain frequently radiating to the back), serum amylase and/or lipase levels greater than 3 times the upper limit of normal, and/or characteristic imaging findings.

The original 1992 Atlanta classification provided the first blueprint to standardize how severity of AP was defined⁵. Over the years, better understanding of AP pathophysiology and its complications led to a greater focus on local and systemic determinants of severity⁶ and eventually the Revised Atlanta Classification (RAC) in 2013 (Table 1).
 

Management of acute pancreatitis

Prevention

As with any disorder, management starts with prevention. Primary prevention of AP has only been well studied in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). Post-ERCP pancreatitis (PEP) is the most common and arguably the most dreaded complication of ERCP with reported incidence of approximately 10%⁷. Several medications and endoscopic interventions have been assessed for the prevention of PEP. Of these, placement of prophylactic pancreatic duct stents^8,9 and administration of rectal nonsteroidal anti-inflammatory drugs, especially indomethacin, have shown significant benefit in reducing risk for PEP^10,11. It is unclear at this point whether rectal indomethacin alone (without pancreatic duct stenting) is sufficient in patients at high risk for PEP. The SVI (Stent Vs. Indomethacin) trial¹², an ongoing multicenter randomized controlled trial, aims to answer this specific question.

Determination of etiology

The most common causes of AP are gallstones and alcohol, accounting for more than two-thirds of all cases¹³. Other etiologies include hypertriglyceridemia, ERCP, drugs induced, familial/hereditary, and post-traumatic. Initial work up includes a thorough history to quantify alcohol consumption and assess for recently started medications, measurement of liver injury tests¹⁴ and triglyceride levels, and performance of a transabdominal ultrasound to evaluate for biliary dilation, chole- and choledocholithiasis¹⁵.

Assessment of disease severity

There is a plethora of scoring systems developed to predict AP severity and outcomes at presentation and/or within the first 24 hours. These include the Ranson’s criteria described in 1974, the APACHE-II (Acute Physiology and Chronic Health Evaluation II), BISAP (Bedside Index of Severity in Acute Pancreatitis) scores, and others. They all have similar, but only modest, accuracy^16,17. Experts recommend¹⁸ that the Systemic Inflammatory Response Syndrome (SIRS) may be the most useful score in daily clinical practice, given that all of its four parameters are readily available (temperature, heart rate, respiratory rate, and white blood cell count) and the score is easy to calculate. Recent studies suggest that admission hematocrit and rise in blood urea nitrogen (BUN) at 24 hours are as accurate as more complex scoring systems in predicting severe disease¹⁹.

 

Fluid resuscitation

Despite extensive research and trials using medications such as ulinastatin, octreotide, pentoxifylline, gabexate, N-acetyl cysteine, steroids, IL-10, and antibiotics²⁰, no pharmacologic agent has been shown to significantly alter the clinical course/outcomes of AP.

Adequate intravenous hydration remains the cornerstone of early management in AP²¹. Studies have demonstrated that increased intestinal permeability, secondary to reduced intestinal capillary microcirculation, leads to bacterial translocation and development of SIRS²². Intestinal microcirculation does not become as readily impaired, and there is a certain “latency” to its onset, from the insult that triggers pancreatitis. This gives rise to the concept of a “golden window” of 12-24 hours from the insult to potentially reverse such changes and prevent organ dysfunction. It has been shown that patients who are adequately resuscitated with intravenous fluids have lower risk for local and systemic complications²³.

What remains debatable is the amount and type of fluid administered. Lactated Ringers (LR) is likely the optimal solution, based on a small prospective randomized-controlled study showing that administration of LR reduced SIRS compared with saline²⁴. Endpoints to guide adequacy of fluid resuscitation in the first 24-48 hours include measurement of urine output (at least 0.5 mL/kg per hour)²⁵, decrease in hematocrit²⁶ and BUN levels²⁷.

 

 

Selecting level of care and ICU management

Patients with predicted severe AP or those with persistent SIRS despite initial fluid resuscitation should be managed in a closely monitored unit, ideally an ICU. Patients with impending respiratory failure require mechanical ventilation, renal failure complicated by metabolic acidosis and/or hyperkalemia requires hemodialysis, and cardiovascular shock requires the initiation of vasopressors and continuous monitoring of blood pressure via an arterial line. A special entity that requires ICU level care is hypertriglyceridemia (HTG)-induced severe AP. HTG should be considered as the etiology of AP in certain clinical scenarios²⁸: previous history of HTG, poorly controlled diabetes mellitus, history of significant alcohol use, third trimester of pregnancy, and use of certain medications associated with HTG such as oral estrogens, tamoxifen, and propofol. Levels of triglyceride greater than 1000 mg/dL strongly point toward HTG being the etiology.

Plasmapheresis, which filters and removes triglycerides from plasma, has been reported as an efficient treatment in such patients based on case series^29,30. At this time its use may only be justified in patients with predicted severe AP from HTG, preferably within the first 24 hours of presentation.


Urgent ERCP

Urgent ERCP (within 24-48 hours of admission) in patients with biliary AP is indicated³¹ when there is strong clinical suspicion for concomitant cholangitis and/or evidence of ongoing biliary obstruction (secondary to choledocholithiasis) on imaging. Currently, predicted severe AP of biliary etiology does not constitute an indication of urgent ERCP in the absence of the above parameters³².

 

Nutrition

Recovery of the gut function is often delayed for several days or weeks in patients with severe AP. Studies have shown that prolonged fasting in such circumstances leads to malnutrition and worse prognosis^33,34. Enteral nutrition via a nasogastric (NG) or nasojejunal (NJ) tube is the preferred route of nutritional support, as it is associated with lower risk of infection, multi-organ failure, and mortality when compared to total parenteral nutrition³³.

The question of whether NJ feeding offers any additional advantages over NG feeding has not been clearly answered with a recent randomized trial showing NG feeds not to be inferior to NJ feeds³⁵. In regards to the timing of initiation of enteral nutrition, early nasoenteric feeding within 24 hours from presentation was found not to be superior compared to on-demand feeding in patients with predicted severe AP³⁶.


Strategies to decrease risk of recurrent attacks

The etiology of AP can be determined in the majority of patients. In many instances, recurrence can be prevented, i.e., in biliary or alcoholic etiologies. In patients with mild biliary AP, evidence supports³⁷ the performance of cholecystectomy during the index admission. In cases of severe biliary AP complicated by pancreatic necrosis and/or peripancreatic fluid collections, cholecystectomy should be delayed for a few weeks until the collections regress or mature³⁸. In poor surgical candidates, ERCP with biliary sphincterotomy offers an alternative, but less effective, means of reducing the risk of recurrent attacks in patients with biliary AP³⁹. In subjects with first AP attack of alcoholic etiology, counseling focusing on alcohol cessation has shown to reduce risk of recurrences⁴⁰. Similarly, appropriate plans to treat and follow-up underlying metabolic etiologies (hypercalcemia and HTG) should be preferably instituted prior to the patients’ discharge.

 

 

Management of peripancreatic fluid collections

Patients with AP frequently develop peripancreatic fluid collections (PFCs). Based on the revised Atlanta classification, those are categorized into four types (Table 2, Figures 1-4).

The majority of acute PFCs in patients without evidence of pancreatic necrosis regress within a few weeks and thus intervention is not indicated early in the disease course. Current literature supports delaying the drainage/debridement of such collections for several weeks. The mortality from interventions decreases as the time to intervention from onset of symptoms increases⁴¹. Delaying intervention gives more time for recovery from systemic complications and allows the encapsulating wall and contents to organize further.

It is only the mature PFCs, which are symptomatic resulting in abdominal pain, nausea, early satiety, gastric outlet obstruction, failure to thrive, and/or biliary obstruction, that need to be drained/debrided⁴². Minimally invasive approaches have shown to result in better outcomes when compared to open laparotomy. Minimally invasive approaches include placement of percutaneous drainage catheters by interventional radiology (retroperitoneal approach preferred when feasible), endoscopic drainage/debridement, laparoscopy, and retroperitoneal necrosectomy following a step-up approach⁴³.

 

While surgery is still an option for patients with symptomatic mature PFCs, endoscopic ultrasound-guided drainage in expert hands has been shown to be cost effective, with shorter hospital stay and even decreased risk of cyst recurrence compared with surgical cyst-gastrostomy creation⁴⁴. Ultrasound or computed tomography-guided drainage of such collections with a percutaneous catheter is an equally efficacious option when compared to the endoscopic approach. However, patients undergoing endotherapy require fewer procedures and imaging studies and shorter length of stay⁴⁵ when compared with radiological interventions.

 

Management of pancreatic necrosis

Although this topic has generated much debate, the majority of available evidence shows no clinical benefit from using prophylactic antibiotics to prevent infection in pancreatic necrosis⁴⁶.

Infectious complications are the major cause of late mortality in AP. The predominant source is bacterial translocation from the GI tract^47,48. Infected pancreatic necrosis should be suspected in patients with imaging evidence of pancreatic or extrapancreatic necrosis, who have a sudden deterioration in clinical status, typically 2-3 weeks after onset of symptoms or if gas bubbles are seen within a necrotic collection (Figure 2). When infected pancreatic necrosis is suspected or established, antibiotics such as carbapenems, fluoroquinolones, metronidazole, and cephalosporin should be started, which have better penetrance into ischemic pancreatic tissue. CT guided aspiration has lost much of its utility, since there has been a paradigm shift to delaying drainage of infected (suspected or established) pancreatic necrosis. A negative or positive CT aspirate does not dictate timing of intervention and is only recommended if a fungal or drug resistant infection is suspected¹⁵. As mentioned above, when debridement of an infected necroma is contemplated, the two guiding principles are to delay drainage and use minimally invasive approaches.

Vascular complications

Vascular complications such as splanchnic vein thrombosis can occur in up to a quarter of AP patients⁴⁹. Anticoagulation is not usually indicated unless thrombosis is extensive and causes bowel ischemia. Arterial pseudoaneurysms are rare but life threatening complications of AP. They typically require interventional radiology guided coil embolization to prevent massive bleeding⁵⁰.

Abdominal compartment syndrome

Abdominal compartment syndrome is an end result of third spacing of fluid into the abdominal cavity secondary to inflammation and fluid resuscitation in severe pancreatitis. Abdominal pressure in patients can be monitored by measuring bladder pressures. Intra-abdominal hypertension is defined as a sustained pressure greater than 12 mm Hg, while abdominal compartment syndrome is defined as sustained intra-abdominal pressure greater than 20 mm Hg with new organ failure⁵¹. Intra-abdominal hypertension (IAH) is present in up to 75% of patients with severe AP. While all conservative measures to prevent development or worsening of IAH should be implemented (adequate sedation, decompression of bowel in patients with ileus, etc.), current guidelines do not recommend aggressive interventions to treat it. On the other hand, abdominal compartment syndrome is a life-threatening complication that requires urgent intervention to decrease intra-abdominal pressure, such as percutaneous drain placement or surgical fasciotomy^52,53.

Conclusion

The key principles in the management of acute pancreatitis are aggressive hydration and preventing development of end organ failure. In the last two decades there has been a paradigm shift in the guidelines for management of peripancreatic fluid collections and pancreatic necrosis. When feasible, drainage of these collections should be delayed and be performed using minimally invasive interventions. There is still an urgent need for developing and testing disease-specific treatments targeting control of the inflammatory response in the early phase of acute pancreatitis and prevention of development of severe disease with end-organ dysfunction.

Dr. Gulati is a gastroenterology and hepatology fellow at Allegheny Health Network, Pittsburgh, and Dr. Papachristou is professor of medicine, University of Pittsburgh School of Medicine, Pittsburgh.

References

1. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, Chapter 55, 923-33.

2. Morgagni G.B. [Fie Books on the Seats and Causes of Diseases as Discovered by the Anatomist]. Venice, Italy: Typographia Remondiniana;1761.

3. Fitz R.H. Boston Med Surg J. 1889;120:181-8.

4. Comfort M., Gambill E., Baggesnstoss A. Gastroenterology. 1946;6:238-76.

5. Bollen T.L., van Santvoort H.C., Besselink M.G., et al. Br J Surg. 2008;95:6–21.

6. Dellinger E.P., Forsmark C.E., Layer P., et al. Ann Surg. 2012 Dec;256[6]:875-80.

7. Kochar B., Akshintala V.S., Afghani E., et al. Gastrointest Endosc. 2015 Jan;81[1]:143-9.

8. Choudhary A., Bechtold M.L., Arif M., et al. Gastrointest Endosc. 2011 Feb;73[2]:275-82.

9. Shi Q.Q., Ning X.Y., Zhan L.L., Tang G.D., Lv X.P. World J Gastroenterol. 2014 Jun 14;20[22]:7040-8.

10. Elmunzer B.J., Waljee A.K., Elta G.H., Taylor J.R., Fehmi S.M., Higgins P.D. Gut. 2008 Sep;57[9]:1262-7.

11. Sethi S., Sethi N., Wadhwa V., Garud S., Brown A. Pancreas. 2014 Mar;43[2]:190-7. 
12. Elmunzer B.J., Serrano J., Chak A., et al. Trials. 2016 Mar 3;17[1]:120.

13. Lowenfels A.B., Maisonneuve P., Sullivan T. Curr Gastroenterol Rep. 2009;11:97-103.

14. Agarwal N., Pitchumoni C.S., Sivaprasad A.V. Am J Gastroenterol. 1990;85:356-66.

15. Tenner S., Baillie J., DeWitt J. Vege S.S. Am J Gastroenterol. 2013;108:1400-15.

16. Papachristou G.I., Muddana V., Yadav D., et al. Am J Gastroenterol. 2010;105:435-41.

17. Mounzer R., et al. Gastroenterology 2012;142:1476-82.

18. Working Group IAP/APA Acute Pancreatitis Guidelines. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

19. Koutroumpakis E., Wu B.U., Bakker O.J., et al. Am J Gastroenterol. 2015 Dec;110[12]:1707-16.

20. Bang U.C., Semb S., Nojgaard C., Bendtsen F. World J Gastroenterol. 2008 May 21;14[19]:2968-76.

21. Warndorf M.G., Kurtzman J.T., Bartel M.J., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:705-9.

22. Hotz H.G., Foitzik T., Rohweder J., et al. J Gastrointest Surg. 1998 Nov-Dec;2[6]:518-25.

23. Brown A., Baillargeon J.D., Hughes M.D., et al. Pancreatology 2002;2:104-7.

24. Wu B.U., Hwang J.Q., Gardner T.H., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:710-7.

25. Forsmark C.E., Baillie J., AGA Institute Clinical Practice and Economics Committee, AGA Institute Governing Board. Gastroenterology. 2007 May;132[5]:2022-44.

26. Lankisch P.G., Mahlke R., Blum T., et al. Am J Gastroenterol. 2001;96:2081-5.

27. Wu B.U., Johannes R.S., Sun X., et al. Gastroenterology 2009;137:129-35.

28. Scherer J., Singh V.P., Pitchumoni C.S., Yadav D. J Clin Gastroenterol. 2014 Mar;48[3]:195-203.

29. Gubensek J., Buturovic-Ponikvar J., Romozi K., Ponikvar R. PLoS One. 2014 Jul 21;9[7]:e102748.

30. Chen J.H., Yeh J.H., Lai H.W., Liao C.S. World J Gastroenterol. 2004 Aug 1;10[15]:2272-4.

31. Tse F., Yuan Y. Cochrane Database Syst Rev. 2012 May 16;[5]:CD009779.

32. Folsch U.R., Nitsche R., Ludtke R., et al. N Engl J Med. 1997;336:237-42.

33. Al-Omran M., Albalawi Z.H., Tashkandi M.F., Al-Ansary L.A. Cochrane Database Syst Rev. 2010 Jan 20;[1]:CD002837.

 

34. Li J.Y., Yu T., Chen G.C., et al. PLoS One. 2013;8[6]:e64926.

35. Singh N., Sharma B., Sharma M., et al. Pancreas. 2012 Jan;41[1]:153-9.

36. Bakker O.J., van Brunschot S., van Santvoort H.C., et al. N Engl J Med. 2014 Nov 20;371[21]:1983-93.

37. Van Baal M.C., Besselink M.G., Bakker O.J., et al. Ann Surg. 2012;255:860–6.

38. Nealon W.H., Bawduniak J., Walser E.M. Ann Surg. 2004 Jun;239[6]:741-9.

39. Sanjay P., Yeeting S., Whigham C., Judson H., Polignano F.M., Tait I.S. Surg Endosc. 2008 Aug;22[8]:1832-7.

40. Nordback I., Pelli H., Lappalainen-Lehto R., Järvinen S., Räty S., Sand J. Gastroenterology. 2009 Mar;136[3]:848-55.

41. Besselink M.G., Verwer T.J., Schoenmaeckers E.J., et al. Arch Surg. 2007;142:1194-201.

42. Besselink M., van Santvoort H., Freeman M. et al. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

43. Hjalmar C., van Santvoort, H., Besselink M.G., et al. N Engl J Med. 2010;362:1491-502.

44. Varadarajulu S., Bang J.Y., Sutton B.S., et al. Gastroenterology. 2013;145:583-90.e1.

45. Akshintala V.S., Saxena P., Zaheer A., et al. Gastrointest Endosc. 2014 Jun;79[6]:921-8.

46. Jiang K, Huang W, Yang XN., et al. World J Gastroenterol. 2012;18:279–84.

47. Dervenis C., Smailis D., Hatzitheoklitos E. J Hepatobiliary Pancreat Surg. 2003;10[6]:415Y418.

48. Gloor B., Muller C.A., Worni M., et al. Arch Surg. 2001;136[5]:592Y596.

49. Nadkarni N.A., Khanna S., Vege S.S. Pancreas. 2013 Aug;42[6]:924-31.

50. Marshall G.T., Howell D.A., Hansen B.L., Amberson S.M., Abourjaily G.S., Bredenberg C.E. Arch Surg. 1996 Mar;131[3]:278-83.

51. Malbrain M.L., Cheatham M.L., Kirkpatrick A., et al. Intensive Care Med. 2006 Nov;32[11]:1722-32.

52. De Waele J.J. Leppaniemi A.K. World J Surg. 2009;33:1128-33.

53. Kirkpatrick A.W., Roberts D.J., De W.J., et al. Intensive Care Med. 2013 Jul;39[7]1190-206.
 

 

Historical perspective

The term “pancreas” derives its name from the Greek words pan (all) and kreas (flesh). Understanding pancreas physiology was first attempted in the 17th century by Regnier de Graaf^1. Giovanni Morgagni is credited with the first description of the syndrome of acute pancreatitis (AP) in 1761². Reginald Huber Fitz proposed the first classification of AP into hemorrhagic, gangrenous, and suppurative types in 1889³. The distinction of acute from chronic pancreatitis was not well described until the middle of the 20th century when Mandred W. Comfort gave a detailed account of chronic relapsing pancreatitis in 1946⁴.

AP is the one of the most common gastrointestinal disorders requiring hospitalization, accounting for roughly 270,000 admissions annually in the U.S., which translates into a $2.6 billion annual health care expenditure.
 

Diagnosis and classification of severity

The diagnosis of AP is based on the presence of two of the three following criteria: typical abdominal pain (severe, upper abdominal pain frequently radiating to the back), serum amylase and/or lipase levels greater than 3 times the upper limit of normal, and/or characteristic imaging findings.

The original 1992 Atlanta classification provided the first blueprint to standardize how severity of AP was defined⁵. Over the years, better understanding of AP pathophysiology and its complications led to a greater focus on local and systemic determinants of severity⁶ and eventually the Revised Atlanta Classification (RAC) in 2013 (Table 1).
 

Management of acute pancreatitis

Prevention

As with any disorder, management starts with prevention. Primary prevention of AP has only been well studied in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). Post-ERCP pancreatitis (PEP) is the most common and arguably the most dreaded complication of ERCP with reported incidence of approximately 10%⁷. Several medications and endoscopic interventions have been assessed for the prevention of PEP. Of these, placement of prophylactic pancreatic duct stents^8,9 and administration of rectal nonsteroidal anti-inflammatory drugs, especially indomethacin, have shown significant benefit in reducing risk for PEP^10,11. It is unclear at this point whether rectal indomethacin alone (without pancreatic duct stenting) is sufficient in patients at high risk for PEP. The SVI (Stent Vs. Indomethacin) trial¹², an ongoing multicenter randomized controlled trial, aims to answer this specific question.

Determination of etiology

The most common causes of AP are gallstones and alcohol, accounting for more than two-thirds of all cases¹³. Other etiologies include hypertriglyceridemia, ERCP, drugs induced, familial/hereditary, and post-traumatic. Initial work up includes a thorough history to quantify alcohol consumption and assess for recently started medications, measurement of liver injury tests¹⁴ and triglyceride levels, and performance of a transabdominal ultrasound to evaluate for biliary dilation, chole- and choledocholithiasis¹⁵.

Assessment of disease severity

There is a plethora of scoring systems developed to predict AP severity and outcomes at presentation and/or within the first 24 hours. These include the Ranson’s criteria described in 1974, the APACHE-II (Acute Physiology and Chronic Health Evaluation II), BISAP (Bedside Index of Severity in Acute Pancreatitis) scores, and others. They all have similar, but only modest, accuracy^16,17. Experts recommend¹⁸ that the Systemic Inflammatory Response Syndrome (SIRS) may be the most useful score in daily clinical practice, given that all of its four parameters are readily available (temperature, heart rate, respiratory rate, and white blood cell count) and the score is easy to calculate. Recent studies suggest that admission hematocrit and rise in blood urea nitrogen (BUN) at 24 hours are as accurate as more complex scoring systems in predicting severe disease¹⁹.

 

Fluid resuscitation

Despite extensive research and trials using medications such as ulinastatin, octreotide, pentoxifylline, gabexate, N-acetyl cysteine, steroids, IL-10, and antibiotics²⁰, no pharmacologic agent has been shown to significantly alter the clinical course/outcomes of AP.

Adequate intravenous hydration remains the cornerstone of early management in AP²¹. Studies have demonstrated that increased intestinal permeability, secondary to reduced intestinal capillary microcirculation, leads to bacterial translocation and development of SIRS²². Intestinal microcirculation does not become as readily impaired, and there is a certain “latency” to its onset, from the insult that triggers pancreatitis. This gives rise to the concept of a “golden window” of 12-24 hours from the insult to potentially reverse such changes and prevent organ dysfunction. It has been shown that patients who are adequately resuscitated with intravenous fluids have lower risk for local and systemic complications²³.

What remains debatable is the amount and type of fluid administered. Lactated Ringers (LR) is likely the optimal solution, based on a small prospective randomized-controlled study showing that administration of LR reduced SIRS compared with saline²⁴. Endpoints to guide adequacy of fluid resuscitation in the first 24-48 hours include measurement of urine output (at least 0.5 mL/kg per hour)²⁵, decrease in hematocrit²⁶ and BUN levels²⁷.

 

 

Selecting level of care and ICU management

Patients with predicted severe AP or those with persistent SIRS despite initial fluid resuscitation should be managed in a closely monitored unit, ideally an ICU. Patients with impending respiratory failure require mechanical ventilation, renal failure complicated by metabolic acidosis and/or hyperkalemia requires hemodialysis, and cardiovascular shock requires the initiation of vasopressors and continuous monitoring of blood pressure via an arterial line. A special entity that requires ICU level care is hypertriglyceridemia (HTG)-induced severe AP. HTG should be considered as the etiology of AP in certain clinical scenarios²⁸: previous history of HTG, poorly controlled diabetes mellitus, history of significant alcohol use, third trimester of pregnancy, and use of certain medications associated with HTG such as oral estrogens, tamoxifen, and propofol. Levels of triglyceride greater than 1000 mg/dL strongly point toward HTG being the etiology.

Plasmapheresis, which filters and removes triglycerides from plasma, has been reported as an efficient treatment in such patients based on case series^29,30. At this time its use may only be justified in patients with predicted severe AP from HTG, preferably within the first 24 hours of presentation.


Urgent ERCP

Urgent ERCP (within 24-48 hours of admission) in patients with biliary AP is indicated³¹ when there is strong clinical suspicion for concomitant cholangitis and/or evidence of ongoing biliary obstruction (secondary to choledocholithiasis) on imaging. Currently, predicted severe AP of biliary etiology does not constitute an indication of urgent ERCP in the absence of the above parameters³².

 

Nutrition

Recovery of the gut function is often delayed for several days or weeks in patients with severe AP. Studies have shown that prolonged fasting in such circumstances leads to malnutrition and worse prognosis^33,34. Enteral nutrition via a nasogastric (NG) or nasojejunal (NJ) tube is the preferred route of nutritional support, as it is associated with lower risk of infection, multi-organ failure, and mortality when compared to total parenteral nutrition³³.

The question of whether NJ feeding offers any additional advantages over NG feeding has not been clearly answered with a recent randomized trial showing NG feeds not to be inferior to NJ feeds³⁵. In regards to the timing of initiation of enteral nutrition, early nasoenteric feeding within 24 hours from presentation was found not to be superior compared to on-demand feeding in patients with predicted severe AP³⁶.


Strategies to decrease risk of recurrent attacks

The etiology of AP can be determined in the majority of patients. In many instances, recurrence can be prevented, i.e., in biliary or alcoholic etiologies. In patients with mild biliary AP, evidence supports³⁷ the performance of cholecystectomy during the index admission. In cases of severe biliary AP complicated by pancreatic necrosis and/or peripancreatic fluid collections, cholecystectomy should be delayed for a few weeks until the collections regress or mature³⁸. In poor surgical candidates, ERCP with biliary sphincterotomy offers an alternative, but less effective, means of reducing the risk of recurrent attacks in patients with biliary AP³⁹. In subjects with first AP attack of alcoholic etiology, counseling focusing on alcohol cessation has shown to reduce risk of recurrences⁴⁰. Similarly, appropriate plans to treat and follow-up underlying metabolic etiologies (hypercalcemia and HTG) should be preferably instituted prior to the patients’ discharge.

 

 

Management of peripancreatic fluid collections

Patients with AP frequently develop peripancreatic fluid collections (PFCs). Based on the revised Atlanta classification, those are categorized into four types (Table 2, Figures 1-4).

The majority of acute PFCs in patients without evidence of pancreatic necrosis regress within a few weeks and thus intervention is not indicated early in the disease course. Current literature supports delaying the drainage/debridement of such collections for several weeks. The mortality from interventions decreases as the time to intervention from onset of symptoms increases⁴¹. Delaying intervention gives more time for recovery from systemic complications and allows the encapsulating wall and contents to organize further.

It is only the mature PFCs, which are symptomatic resulting in abdominal pain, nausea, early satiety, gastric outlet obstruction, failure to thrive, and/or biliary obstruction, that need to be drained/debrided⁴². Minimally invasive approaches have shown to result in better outcomes when compared to open laparotomy. Minimally invasive approaches include placement of percutaneous drainage catheters by interventional radiology (retroperitoneal approach preferred when feasible), endoscopic drainage/debridement, laparoscopy, and retroperitoneal necrosectomy following a step-up approach⁴³.

 

While surgery is still an option for patients with symptomatic mature PFCs, endoscopic ultrasound-guided drainage in expert hands has been shown to be cost effective, with shorter hospital stay and even decreased risk of cyst recurrence compared with surgical cyst-gastrostomy creation⁴⁴. Ultrasound or computed tomography-guided drainage of such collections with a percutaneous catheter is an equally efficacious option when compared to the endoscopic approach. However, patients undergoing endotherapy require fewer procedures and imaging studies and shorter length of stay⁴⁵ when compared with radiological interventions.

 

Management of pancreatic necrosis

Although this topic has generated much debate, the majority of available evidence shows no clinical benefit from using prophylactic antibiotics to prevent infection in pancreatic necrosis⁴⁶.

Infectious complications are the major cause of late mortality in AP. The predominant source is bacterial translocation from the GI tract^47,48. Infected pancreatic necrosis should be suspected in patients with imaging evidence of pancreatic or extrapancreatic necrosis, who have a sudden deterioration in clinical status, typically 2-3 weeks after onset of symptoms or if gas bubbles are seen within a necrotic collection (Figure 2). When infected pancreatic necrosis is suspected or established, antibiotics such as carbapenems, fluoroquinolones, metronidazole, and cephalosporin should be started, which have better penetrance into ischemic pancreatic tissue. CT guided aspiration has lost much of its utility, since there has been a paradigm shift to delaying drainage of infected (suspected or established) pancreatic necrosis. A negative or positive CT aspirate does not dictate timing of intervention and is only recommended if a fungal or drug resistant infection is suspected¹⁵. As mentioned above, when debridement of an infected necroma is contemplated, the two guiding principles are to delay drainage and use minimally invasive approaches.

Vascular complications

Vascular complications such as splanchnic vein thrombosis can occur in up to a quarter of AP patients⁴⁹. Anticoagulation is not usually indicated unless thrombosis is extensive and causes bowel ischemia. Arterial pseudoaneurysms are rare but life threatening complications of AP. They typically require interventional radiology guided coil embolization to prevent massive bleeding⁵⁰.

Abdominal compartment syndrome

Abdominal compartment syndrome is an end result of third spacing of fluid into the abdominal cavity secondary to inflammation and fluid resuscitation in severe pancreatitis. Abdominal pressure in patients can be monitored by measuring bladder pressures. Intra-abdominal hypertension is defined as a sustained pressure greater than 12 mm Hg, while abdominal compartment syndrome is defined as sustained intra-abdominal pressure greater than 20 mm Hg with new organ failure⁵¹. Intra-abdominal hypertension (IAH) is present in up to 75% of patients with severe AP. While all conservative measures to prevent development or worsening of IAH should be implemented (adequate sedation, decompression of bowel in patients with ileus, etc.), current guidelines do not recommend aggressive interventions to treat it. On the other hand, abdominal compartment syndrome is a life-threatening complication that requires urgent intervention to decrease intra-abdominal pressure, such as percutaneous drain placement or surgical fasciotomy^52,53.

Conclusion

The key principles in the management of acute pancreatitis are aggressive hydration and preventing development of end organ failure. In the last two decades there has been a paradigm shift in the guidelines for management of peripancreatic fluid collections and pancreatic necrosis. When feasible, drainage of these collections should be delayed and be performed using minimally invasive interventions. There is still an urgent need for developing and testing disease-specific treatments targeting control of the inflammatory response in the early phase of acute pancreatitis and prevention of development of severe disease with end-organ dysfunction.

Dr. Gulati is a gastroenterology and hepatology fellow at Allegheny Health Network, Pittsburgh, and Dr. Papachristou is professor of medicine, University of Pittsburgh School of Medicine, Pittsburgh.

References

1. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, Chapter 55, 923-33.

2. Morgagni G.B. [Fie Books on the Seats and Causes of Diseases as Discovered by the Anatomist]. Venice, Italy: Typographia Remondiniana;1761.

3. Fitz R.H. Boston Med Surg J. 1889;120:181-8.

4. Comfort M., Gambill E., Baggesnstoss A. Gastroenterology. 1946;6:238-76.

5. Bollen T.L., van Santvoort H.C., Besselink M.G., et al. Br J Surg. 2008;95:6–21.

6. Dellinger E.P., Forsmark C.E., Layer P., et al. Ann Surg. 2012 Dec;256[6]:875-80.

7. Kochar B., Akshintala V.S., Afghani E., et al. Gastrointest Endosc. 2015 Jan;81[1]:143-9.

8. Choudhary A., Bechtold M.L., Arif M., et al. Gastrointest Endosc. 2011 Feb;73[2]:275-82.

9. Shi Q.Q., Ning X.Y., Zhan L.L., Tang G.D., Lv X.P. World J Gastroenterol. 2014 Jun 14;20[22]:7040-8.

10. Elmunzer B.J., Waljee A.K., Elta G.H., Taylor J.R., Fehmi S.M., Higgins P.D. Gut. 2008 Sep;57[9]:1262-7.

11. Sethi S., Sethi N., Wadhwa V., Garud S., Brown A. Pancreas. 2014 Mar;43[2]:190-7. 
12. Elmunzer B.J., Serrano J., Chak A., et al. Trials. 2016 Mar 3;17[1]:120.

13. Lowenfels A.B., Maisonneuve P., Sullivan T. Curr Gastroenterol Rep. 2009;11:97-103.

14. Agarwal N., Pitchumoni C.S., Sivaprasad A.V. Am J Gastroenterol. 1990;85:356-66.

15. Tenner S., Baillie J., DeWitt J. Vege S.S. Am J Gastroenterol. 2013;108:1400-15.

16. Papachristou G.I., Muddana V., Yadav D., et al. Am J Gastroenterol. 2010;105:435-41.

17. Mounzer R., et al. Gastroenterology 2012;142:1476-82.

18. Working Group IAP/APA Acute Pancreatitis Guidelines. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

19. Koutroumpakis E., Wu B.U., Bakker O.J., et al. Am J Gastroenterol. 2015 Dec;110[12]:1707-16.

20. Bang U.C., Semb S., Nojgaard C., Bendtsen F. World J Gastroenterol. 2008 May 21;14[19]:2968-76.

21. Warndorf M.G., Kurtzman J.T., Bartel M.J., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:705-9.

22. Hotz H.G., Foitzik T., Rohweder J., et al. J Gastrointest Surg. 1998 Nov-Dec;2[6]:518-25.

23. Brown A., Baillargeon J.D., Hughes M.D., et al. Pancreatology 2002;2:104-7.

24. Wu B.U., Hwang J.Q., Gardner T.H., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:710-7.

25. Forsmark C.E., Baillie J., AGA Institute Clinical Practice and Economics Committee, AGA Institute Governing Board. Gastroenterology. 2007 May;132[5]:2022-44.

26. Lankisch P.G., Mahlke R., Blum T., et al. Am J Gastroenterol. 2001;96:2081-5.

27. Wu B.U., Johannes R.S., Sun X., et al. Gastroenterology 2009;137:129-35.

28. Scherer J., Singh V.P., Pitchumoni C.S., Yadav D. J Clin Gastroenterol. 2014 Mar;48[3]:195-203.

29. Gubensek J., Buturovic-Ponikvar J., Romozi K., Ponikvar R. PLoS One. 2014 Jul 21;9[7]:e102748.

30. Chen J.H., Yeh J.H., Lai H.W., Liao C.S. World J Gastroenterol. 2004 Aug 1;10[15]:2272-4.

31. Tse F., Yuan Y. Cochrane Database Syst Rev. 2012 May 16;[5]:CD009779.

32. Folsch U.R., Nitsche R., Ludtke R., et al. N Engl J Med. 1997;336:237-42.

33. Al-Omran M., Albalawi Z.H., Tashkandi M.F., Al-Ansary L.A. Cochrane Database Syst Rev. 2010 Jan 20;[1]:CD002837.

 

34. Li J.Y., Yu T., Chen G.C., et al. PLoS One. 2013;8[6]:e64926.

35. Singh N., Sharma B., Sharma M., et al. Pancreas. 2012 Jan;41[1]:153-9.

36. Bakker O.J., van Brunschot S., van Santvoort H.C., et al. N Engl J Med. 2014 Nov 20;371[21]:1983-93.

37. Van Baal M.C., Besselink M.G., Bakker O.J., et al. Ann Surg. 2012;255:860–6.

38. Nealon W.H., Bawduniak J., Walser E.M. Ann Surg. 2004 Jun;239[6]:741-9.

39. Sanjay P., Yeeting S., Whigham C., Judson H., Polignano F.M., Tait I.S. Surg Endosc. 2008 Aug;22[8]:1832-7.

40. Nordback I., Pelli H., Lappalainen-Lehto R., Järvinen S., Räty S., Sand J. Gastroenterology. 2009 Mar;136[3]:848-55.

41. Besselink M.G., Verwer T.J., Schoenmaeckers E.J., et al. Arch Surg. 2007;142:1194-201.

42. Besselink M., van Santvoort H., Freeman M. et al. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

43. Hjalmar C., van Santvoort, H., Besselink M.G., et al. N Engl J Med. 2010;362:1491-502.

44. Varadarajulu S., Bang J.Y., Sutton B.S., et al. Gastroenterology. 2013;145:583-90.e1.

45. Akshintala V.S., Saxena P., Zaheer A., et al. Gastrointest Endosc. 2014 Jun;79[6]:921-8.

46. Jiang K, Huang W, Yang XN., et al. World J Gastroenterol. 2012;18:279–84.

47. Dervenis C., Smailis D., Hatzitheoklitos E. J Hepatobiliary Pancreat Surg. 2003;10[6]:415Y418.

48. Gloor B., Muller C.A., Worni M., et al. Arch Surg. 2001;136[5]:592Y596.

49. Nadkarni N.A., Khanna S., Vege S.S. Pancreas. 2013 Aug;42[6]:924-31.

50. Marshall G.T., Howell D.A., Hansen B.L., Amberson S.M., Abourjaily G.S., Bredenberg C.E. Arch Surg. 1996 Mar;131[3]:278-83.

51. Malbrain M.L., Cheatham M.L., Kirkpatrick A., et al. Intensive Care Med. 2006 Nov;32[11]:1722-32.

52. De Waele J.J. Leppaniemi A.K. World J Surg. 2009;33:1128-33.

53. Kirkpatrick A.W., Roberts D.J., De W.J., et al. Intensive Care Med. 2013 Jul;39[7]1190-206.