Page 72 – Practical Gastro

Sameer Lapsia,Anupama Chawla,Juan Carlos Bucobo,Rupinder Gill

Sameer Lapsia, M.D., Clinical Fellow in Pediatric Gastroenterology. Anupama Chawla, M.D., Chief, Division of Pediatric Gastroenterology. Juan Carlos Bucobo, M.D., Assistant Professor of Medicine/ Gastroenterology. Rupinder Gill, M.D., Assistant Professor of Pediatric Gastroenterology. SUNY at Stony Brook, Health Science Center, Stony Brook, NY

CASE PRESENTATION

An otherwise healthy 14 year-old obese male presented after suffering second- and third- degree burns to over 40% of his body surface area including his face, arms and chest while attempting to light a tiki torch. His hospital course was complicated by acute respiratory distress syndrome, acute kidney injury and sepsis.

Due to an anoxic brain injury resulting in disturbed oral-motor function, the patient had a percutaneous gastrostomy tube (G-tube) placed to provide enteral feeding. Despite radiographic studies showing patency of the G-tube he began to have episodes of non-bilious vomiting after feeds. An upper gastrointestinal (UGI) series as well as a computed tomography (CT) scan of his abdomen showed no signs of obstruction or dilated loops of bowel. After a successful trial with nasojejunostomy (NJ) tube feeds, a gastrojejunostomy (GJ) tube was placed endoscopically to provide post- pyloric feeds. At that time, no mucosal abnormalities of the duodenum or proximal jejunum were appreciated.

Approximately 6 weeks later, he again presented with intermittent emesis, now occasionally bilious. An UGI series showed the tip of the jejunostomy tube had migrated back into the stomach. No obstructive bowel gas pattern was noted. Repeat endoscopy to reposition the jejunal portion of the GJ tube was performed. A 2.5 cm semi-pedunculated salmon-red colored polyp was noted in the distal duodenum/proximal jejunum (Figure 1) causing partial obstruction of the lumen. Biopsies revealed heterotopic gastric tissue with predominantly antral type gastric mucosa and occasional oxyntic cells (Figure 2). A distinct zone of demarcation was present between the heterotopic gastric mucosa and normal intestinal mucosa. There was no evidence of metaplasia, dysplasia or malignancy.

Due to the patient’s recurrent episodes of emesis, a repeat esophagogastroduodenoscopy was performed and the polyp was removed using snare cauterization. After polyp removal, the patient slowly started to tolerate feeds and was transferred to a long-term care facility.

Discussion

Heterotopic gastric mucosa (HGM) was first reported in the literature in 1912 by Poindecker. Since then there have been numerous articles describing its occurrence.¹ HGM is most commonly found along the gastrointestinal tract, but has been reported in extraintestinal sites such as the umbilicus, bronchi, spinal column, urinary bladder, gall bladder, biliary tree and scrotum.^2,3 Composed of ectopic gastric tissue, its presence distal to the ligament of Treitz is rare except in Meckel’s diverticulum and intestinal duplication.⁴ HGM has a male predominance and is usually an incidental finding. However, it can present with symptoms of vomiting secondary to obstruction or intussusception. Although rare, anemia, gastrointestinal (GI) bleeding and perforation have also been reported secondary to ulceration from the ectopic gastric mucosa.^2,5-6

In the small intestine, heterotopic gastric mucosa can clinically resemble a polyp, ulcer, adenomas, angiomas, lipomas, lymphomas or carcinoma. The frequency of HGM is 0.5-2% in the duodenum and in this portion of the GI tract it often appears as a nodular mass.^2,4 In the small intestine, the size of these masses can range from 1.0 cm-2.5 cm.⁷ There are two types of heterotopic gastric mucosa: congenital and acquired. As our patient previously had numerous UGI series, a CT scan, as well as an initial endoscopy for GJ tube placement, which did not show any evidence of a lesion, he most likely had acquired heterotopic gastric mucosa. This signifies replacement of his native small intestinal mucosa by gastric epithelial tissue, which has been described in adult patients after gastrojejunostomy. It is suspected that HGM occurs due to infiltration of mucosa through defects in the muscularis mucosa by repeated erosion.⁸ It has also been described in patients with inflammatory bowel disease, intestinal tuberculosis, celiac disease, intestinal cancers and post-irradiation enteritis.² These lesions are almost always incidental findings and little data exists on their rate of growth, though they may grow briskly.⁸

The pathology of the lesion in our patient showed only pyloric type of mucosa with rare oxyntic cells characteristic of an acquired heterotopic gastric mucosa. Most jejunal lesions are polypoid in shape as seen in our patient.² Additionally, congenital HGM is rare distal to the ligament of Treitz and includes a mixture of both fundic and pyloric-type of epithelium without any associated conditions that can cause inflammatory changes. Histopathology remains the gold standard for diagnosis of these lesions.

To avoid complications from HGM, endoscopic resection is suggested. For large masses, a surgical approach with excision followed by anastomosis to reestablish intestinal continuity may be necessary. In addition to the complications of having ectopic gastric tissue, adenocarcinomas and adenomas may rarely stem from these lesions.⁹

Our patient had occasional episodes of bilious emesis that improved after the mass was resected. We hypothesize two possible mechanisms for the patient’s symptoms: a) the size of the HGM causing partial obstruction and resulting in intermittent episodes of vomiting and/or b) the lesion acting as a lead point causing intermittent small bowel-to-small bowel intussusception.

CONCLUSION

To our knowledge, heterotopic gastric mucosa appearing after gastrojejunostomy placement and causing intermittent obstruction in a pediatric patient has not been described in the literature.

Although there are many causes of emesis after GJ tube placement, this case illustrates the importance of repeat endoscopy to evaluate for rare acquired anatomic causes like heterotopic gastric mucosa, especially if contrast studies do not yield a diagnosis.

A SPECIAL ARTICLE

Effectiveness of a Personal and Family History Questionnaire When Assessing Colorectal Cancer Risk

Seper Dezfoli,

Thomas J. McGarrity,

S. Devi Rampertab

Background: Few studies have evaluated whether a personal and family history questionnaire (PFHQ) administered at the initial patient encounter improves the provider’s ability to appropriately risk stratify patients for colorectal cancer (CRC) screening. The objective of this study was to determine if a PFHQ completed by the patient prior to the initial encounter improved the provider’s ability to extract pertinent information relating to CRC risk.

Methods: This was a prospective intervention study conducted in the adult outpatient gastroenterology clinic at Penn State Hershey Medical Center. A PFHQ was created based on expert opinion and current screening guidelines. 199 patients evaluated as new encounters between February 2009 and June 2009 completed the questionnaire. We also retrospectively evaluated 186 randomly chosen charts of new patient encounters that had not utilized a questionnaire. A point system was created to score all charts in both the retrospective (without the questionnaire) group as well as the prospective group (with the questionnaire) based on quantity and quality of information documented in the consultation reports relating to CRC risk. Results between the two groups were compared using Wilcoxon Rank Sum test.

Results: Both patient and family history scores were significantly lower in the prospective study group that completed the questionnaire (p=0.05, p<0.01, respectively) when compared to the group that did not utilize a questionnaire. Composite scores (personal & family history) were significantly lower in the study group that completed the questionnaire (p=0.01).

Conclusion: Our study demonstrated that clinician-led history taking was superior to a questionnaire in obtaining quality history that can be used to appropriately risk stratify patients for CRC screening.

Seper Dezfoli, M.D.¹ Thomas J. McGarrity, M.D.² S. Devi Rampertab, M.D.³ ¹Department of Gastroenterology, Medstar Washington Hospital Center, Washington, DC ²Division of Gastroenterology and Hepatology, Penn State Medical Center, Hershey, PA ³Division of Gastroenterology and Hepatology, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ

INTRODUCTION

Colorectal cancer (CRC) remains the third leading cause of cancer in the United States in both men and women. It is also the third leading cause of cancer-related deaths.^1,2 Evidence supports that mortality from CRC is reduced by screening asymptomatic persons.^3-8 Patients who gain the most benefit from current screening modalities are those at increased risk for developing CRC. Thus, it becomes essential to appropriately identify these individuals and refer them for screening measures accordingly.^9-13 Obtaining a personal and family history helps identify risk factors for development of sporadic cancers and potentially identify single-gene disorders such as Hereditary Non-Polyposis Colorectal Cancer (HNPCC).

Questionnaires have been utilized to assist in gathering this type of detailed history. Several modalities have been developed, including paper-based and web- based questionnaires.¹⁴ In fact, Qureshi and colleagues state in their review on family history collection in primary care that it may be logical to have a “disease- specific risk assessment tool, rather than a stand-alone tool,” so that the history can be assessed in the context of disease-specific guidelines, such as CRC screening guidelines.¹⁵ However, little is known about the clinical utility of these tools.

Few studies have attempted to ascertain whether a personal and family history questionnaire (PFHQ) enriches the ability to appropriately risk stratify patients for CRC. The objective of this study was to evaluate if a PFHQ completed by the patient prior to the initial encounter enhances a provider’s ability to extract pertinent information related to CRC risk.

METHODS
Design and Setting

This was a prospective intervention study that was conducted in the Gastroenterology adult outpatient clinic at the Milton S. Hershey Medical Center in Hershey, Pennsylvania. This institution is a large, academic referral medical center. The study was approved by the departmental scientific review committee and by the institutional review board.

A retrospective review of two hundred randomly chosen charts of patients seen as new consultations between July 2008 and November 2008, herein referred to as the “control group”, was conducted to measure outcome parameters prior to intervention. Of these, fourteen charts were excluded due to incomplete charting. The consultation reports for all the charts were evaluated for information relating to CRC risk. This allowed the investigators to establish a baseline indicator of clinicians’ ability to elicit details pertinent to determining CRC risk.

The prospective portion of the study involved patients evaluated as an initial consultation at the Gastroenterology outpatient clinic between February 2009 and June 2009 (herein referred to as the “intervention group”). One hundred ninety-nine patients were recruited for the study. Subjects were approached and consented at time of check-in. Consented participants were asked to complete a PFHQ before their physician encounter. Completed questionnaires were attached to the patient’s chart and given to the practitioners to use at their discretion. Practitioners included attending physicians, gastroenterology fellows and physician assistants. The primary investigator of this study was excluded.

A point system was created as a surrogate marker to measure the amount of useful information gathered and documented from the PFHQ. Only information that could potentially risk stratify a patient’s CRC risk was included. All charts in both the control group (without the questionnaire) as well as the intervention group (with the questionnaire) were scored based on quantity and quality of information documented in the consultation reports relating to CRC risk. We compared the results between the two groups using Wilcoxon Rank Sum test.

Development of the Questionnaire

Content of the questionnaire was solely determined by the most current CRC screening guidelines set forth in 2008 by the American Cancer Society and American Gastroenterological Association.16 The first section gathered information regarding personal history. Questions in this section surrounded a personal history of polyps, including histology, CRC, inflammatory bowel disease (IBD), and suspected diagnosis of HNPCC or familial adenomatous polyposis (FAP)

With regard to a history of polyps, the number identified and histology are important determinants of risk. In addition to pathologic terms such as “hyperplastic” and “villous”, layman terms such as “benign” and “pre-cancer” were included as an approach to increase user recall. The final question in this section was aimed to identify patients at risk for hereditary syndromes as it addressed the presence of extra-colonic tumors associated with HNPCC and FAP.

The second section of the questionnaire gathered information regarding family history. It was divided into two subsections: first-degree and second-degree relatives. Patients were asked about family history of CRC, polyps, and any extra-colonic cancers. Histology of polyps (e.g. hyperplastic versus adenomatous) is an important determinant of risk. A majority of patients are unaware of polyp histology, especially with regard to family members. Thus we incorporated time-lines as a way to extrapolate pathology of family members who may have had polyps. For example, if a patient marked that his or her father has had polyps, he or she was asked, “When were they asked to return for testing?” A response of “0-5 years” implied the patient’s father had a pre-malignant polyp whereas a response of “10 years” implied normal tissue or polyps with benign histology (i.e. hyperplastic)

Validity of the questionnaire was determined through discussion with gastroenterologists with expertise in CRC, screening guidelines, and survey design.

Development of Point-System

A novel point system was created by the investigators to assign points to pertinent information recorded in the initial consultation reports for both the retrospective charts as well as the prospective charts, which utilized the questionnaire (Table 1). Pertinent information was defined as any information that could potentially be useful in determining a patient’s risk for development of CRC in the context of current screening guidelines. That is, any piece of information that could be cross referenced with current screening CRC guidelines and lead to a decision regarding patient risk: average risk versus increased risk.

Specific information (i.e. personal history of polyps) received a full point. General information that could be helpful, but not necessarily help a practitioner risk- stratify a patient in the context of CRC (e.g. “personal history of cancer” versus “personal history of colorectal cancer”) received 0.5 points.

Qualifying statements with regard to age of onset, family relationship, histology, etc. received an additional 0.5 points each. Non-cancer history with the exception of IBD received zero points, as this information does not help risk stratify patients with regard to CRC. As there is no finite amount of information that can potentially help stratify an individual’s risk, there was no set maximum point value or range.

Thirty randomly chosen patient charts were reviewed prior to the study to obtain a general overview of practitioner language and to gain experience in applying the point system. An independent third-party also reviewed the charts and was asked to apply the point system to each chart. There was no significant difference in the average score given to the pre-study charts between the investigators and the third-party.

RESULTS

The retrospective arm of the study (control group) was comprised of 186 patients whose initial consultation reports were reviewed and scored. One hundred ninety- nine patients participated in the prospective arm of the study (intervention group) by completing the questionnaire. The demographics of the two groups are shown in Table 2. There was no significant difference in age or gender between the two study groups.

Patient and family history scores were analyzed across both groups with the non-parametric Wilcoxon rank sum test, as data were not found to follow a normal distribution as determined by the Kolmogorov-Smirnov test.

Patient history and family history scores are outlined in Table 3. Mean scores were compared. Both patient and family history scores were significantly lower in the intervention group, the prospective study group that completed the questionnaire (p=0.5 and plt;0.01, respectively). Composite scores (sum of personal and family history scores) were also significantly lower in the intervention group (p=0.01).

DISCUSSION

This study evaluated the impact a PFHQ has on the ability of a provider to extract pertinent information related to CRC risk stratification, and demonstrated two important findings. First, implementation of a PFHQ did not enhance the ability to extract information that could potentially help stratify a patient’s risk of developing CRC. Second, using a PFHQ led to significantly lower rates of documentation related to CRC risk-stratification. That is, practitioners extracted and documented more pertinent information that could potentially risk stratify a patient in the control group, the group that did not utilize the questionnaire.

Although many primary care physicians recognize the importance of gathering a family history, studies suggest that most lack the history-taking skills required to risk stratify patients appropriately while also implementing current guidelines.^17-23 One study revealed that only 50% of primary care physicians updated family histories during routine or annual examinations and only 28% routinely obtained history information beyond first-degree relatives; less than half of practitioners inquired about specific cancer types.¹⁷ A recent study surveying 285 primary-case based physicians in Germany, found that less than 75% of physicians routinely inquired about family history. Seventeen percent of the physicians utilized a standardized assessment tool to gather information, only 35% of which stating they routinely update it.²⁴ Furthermore, although several questionnaires have been formally evaluated, only a few claim to have been clinically validated.²⁵ The questionnaire in our study was created to extract information that can be cross referenced with current CRC screening guidelines and that can be used easily by clinicians. By using a standard questionnaire, we hoped to eliminate the variation between practitioner assessments of risk that results from unawareness of current guidelines.

One systematic review reporting the use and outcome of questionnaires identified only four studies that aimed to validate their questionnaire against a reference standard.²⁶ In all cases, the reference standard was a genetic interview conducted by a trained geneticist. Although geneticists do gather patient histories, typical encounters involve a clinician gathering personal and family history from a patient. Thus, the outcomes of these studies cannot be practically applied to common practice. A recent outcomes study by Vogel and co- workers evaluated the rate at which patients were referred for genetic counseling based on information gathered from a self-administered questionnaire versus a review of the patient’s electronic medical record.27 Similar to other previous studies, results were compared to a structured, genetic interview. The authors did conclude that the questionnaire led to a higher capture rates than a review of the medical record, however the study did not include physician-led interviews. In fact, no study has aimed to determine whether a questionnaire is superior to physician-led history-taking in the assessment of colorectal cancer risk in patients being seen in an outpatient setting. We provide a novel study that aimed to assess if a questionnaire is superior to physician-led history. In our study, significantly less information was extracted from patients when a questionnaire was utilized with respect to personal and family history

Lack of time is the most notable barrier to obtaining personal and family history. As questionnaires are meant to be a time-saving tool, we hypothesize that practitioners do not repeat questions pertaining to history when the patient has completed a questionnaire. The questionnaire is only as valuable as the practitioner who reads it. It must be read, and pertinent positive and negative information should be documented in the patient’s chart. This, in turn, would then lead to proper assignment of the patient into the “high risk for CRC” category and appropriate screening could then be recommended and implemented.

Our study provides a novel examination of current practices in a large outpatient gastroenterology clinic. It also examines the behavior and documentation patterns of gastroenterologists when implementing a questionnaire as compared to practices when such a tool is not utilized. Clinicians may be more inclined to remember information they asked themselves rather than information visualized on a questionnaire.

Clinician-led history taking was superior to questionnaires in obtaining quality history that can be used to appropriately risk stratify patients. This suggests that practitioners may neglect to elicit important details in the history pertaining to establishing CRC risk when a questionnaire is available. Therefore, although current studies show that physicians have suboptimal rates of assessing personal and family history, implementation of a questionnaire may be even more detrimental and possible even impede the process of gathering information. Thus, we do not recommend the implementation of questionnaires for the use to history-taking, especially in the context of CRC risk assessment.

There are limitations to this study. The questionnaire created by the study investigators was not validated. However, its content was derived from the most current CRC screening guidelines set forth by the American Cancer Society and America Gastroenterological Association in 2008. Moreover, investigators collaborated with experts in CRC screening guidelines when developing the questionnaire. Second, the point system used to analyze the primary outcome was developed and implemented by the study investigators, thus leading to potential bias. However, a subset of randomly chosen charts was analyzed by a third- party and there was no significant difference in the points assigned by investigators and the third-party analyst. Lastly, there were significant differences in the type of provider (e.g. attending versus fellow trainee) conducting the patient interviews between the two groups, which could play a confounding factor. Interestingly however, it was the intervention group, the group evaluated by significantly more attending Gastroenterologists, that scored significantly lower. Thus it appears that less formal training did not influence the negative result.

CONCLUSION

Clinician-led history-taking was superior to the utilization of a questionnaire as clinicians documented significantly lower rates of information regarding CRC risk when the questionnaire was utilized. This suggests that clinicians may rely too heavily on information- gathering tools such as questionnaires, and that implementation of a questionnaire may negatively impact information gathering and risk stratification.

Questionnaires should not be used as a sole tool to gather personal and family history in the context of CRC risk unless the practitioner actually has time to review, interpret and document what is stated on the questionnaire.

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #139

Short Bowel Syndrome in Adults – Part 4A A Guide to Front Line Drugs Used in the Treatment of Short Bowel Syndrome

Lingtak-Neander Chan,

John K. DiBaise,

Carol Rees Parrish

In patients with short bowel syndrome (SBS), malabsorption of drugs is an important consideration, particularly if the expected clinical response to a medication is not attained. Factors include length, location and health of the remaining bowel, the form of the medication administered and the site of action of the drug. Part 4A & B of this 5-part series will focus on conventional pharmacological agents used in the treatment of SBS.

A 64-year-old woman is hospitalized with hypotension, chronic diarrhea (6-10 per day over the past 4 weeks), fatigue and general malaise. Seven weeks ago, she was hospitalized with acute abdominal pain and severe nausea. Further work-up revealed acute mesenteric infarction due to a superior mesenteric artery thrombus and she underwent extensive resection of the ischemic bowel leaving her with about 100 cm of small bowel from the ligament of Treitz anastomosed to the proximal transverse colon. She was discharged from the hospital 2 weeks later on home parenteral nutrition (PN). Her weight is down 6 kg since hospital discharge 5 weeks ago. In addition to PN, she also takes loperamide 2 mg TID as needed (she has not been using it because “it doesn’t help”), cholestyramine 4 g BID, mirtazapine 15 mg daily, levothyroxine 0.075 mg daily and oral glutamine 30 g daily. Famotidine, 40 mg, has been added to her PN. Stool output, which is watery and without blood, ranges from 2500 to 3000 mL daily. She is not eating much as she is so depressed and uncomfortable and “it just comes right out anyway”; she is afraid to leave her house for fear of “having an accident.” Part 4A & B of this 5-part series on SBS will focus on conventional pharmacological agents used in the treatment of short bowel syndrome that will allow you to help this woman control her diarrhea and improve her quality of life.

Lingtak-Neander Chan, PharmD, BCNSP, Associate Professor of Pharmacy and Nutritional Sciences, University of Washington, Seattle, WA. John K. DiBaise, MD, Professor of Medicine, Mayo Clinic, Scottsdale, AZ. Carol Rees Parrish MS, RD, Nutrition Support Specialist, University of Virginia Health System Digestive Health Center of Excellence, Charlottesville, VA

INTRODUCTION

The intestine is a vital organ for the absorption of nutrients, fluids, and drugs. In patients with short bowel syndrome (SBS), malabsorption of drugs is an important consideration, particularly if the expected clinical response to a medication is not attained. In assessing the cause of lack of clinical response, a number of factors should be considered (Table 1).¹ The extent of a patient’s malabsorptive potential will depend on the length, location and health of the remaining bowel, the form of the medication administered and, in some cases, the site of action of the drug.² Although the proximal small bowel is the primary site of drug absorption, many drugs can be sufficiently absorbed along the entire length of small intestine. There is even strong evidence that some drugs can be efficiently absorbed in the colon.^3-6 The solution in response to a lack of clinical response of a drug will vary and may include escalating the dose, changing to a different dosing schedule or frequency, and/or changing to a different drug formulation (e.g., crushed tablet, capsule, liquid) or route of administration (e.g., intravenous, subcutaneous, transdermal).

Understanding the Implications of Drug Formulations

Medications in solid dosage forms, such as a tablet, need to undergo disintegration and dissolution before absorption can take place. Disintegration, whereby the tablet is broken down into small particles, takes place efficiently in the stomach in the presence of gastric acid along with the help of the churning and grinding action of the distal stomach. Dissolution is the process by which the active ingredient is dissolved into a liquid medium7 and is the final process to allow the active ingredient to be absorbed in the small intestine. Dissolution may take place in the stomach, the duodenum or the proximal jejunum. The dissolution rate is specific to the active ingredient and is pH-dependent. Regular tablets, capsules, and caplets undergo a similar process of disintegration and dissolution. Delayed-release tablets and enteric-coated tablets are formulated with a chemical coating to delay disintegration and dissolution until the tablet has passed through the stomach to prevent the active ingredient from being destroyed or inactivated by gastric secretions or where it may irritate the gastric mucosa.⁷ Time-release formulations, such as extended-release or controlled-release tablets are formulated to make the active ingredient(s) available for absorption over an extended period of time following ingestion, especially in the small intestine.^8,9

Based on these principles, impaired disintegration and dissolution of a regular tablet can occur in the setting of gastric, duodenal or proximal jejunal resection or achlorhydria, and may result in decreased oral drug absorption (i.e., bioavailability). Fortunately, SBS patients rarely have had resections of the upper gut. In these patients, improved absorption of medication can be achieved by using liquid dosage forms, such as oral solutions or suspensions (be watchful for sugar alcohols such as sorbitol and xylitol that can exacerbate diarrhea), or crushed tablets. In patients with only partial resection of the jejunum or proximal ileum, although the rate of drug absorption may be altered, the overall extent of drug absorption appears to be preserved.^10-13

Drug malabsorption is more likely in patients with extensive resection of the distal jejunum and ileum, especially with the loss of the terminal ileum and ileocecal valve,^2,12 the most common area resected in SBS patients. In these patients, if the desired clinical responses cannot be achieved by orally administered medications, use of an alternate route of drug administration such as the use of transdermal patches, subcutaneous injections or even intravenous administrations should be considered. In patients with extensive GI tract resection, sustained- release or extended-release products should generally be avoided, as the extent of drug absorption can be erratic or severely impaired.

Assessment of Drug Response

When evaluating suboptimal clinical responses to medications in SBS, a clinician should evaluate factors related to the patient and the specific medication involved. Table 2 outlines a process to aid clinicians in critically assessing the potential cause(s) of inadequate drug response.

Management of GI Hypersecretion and Chronic Diarrhea in SBS

The most commonly used medications in the SBS patient, particularly during the period of greatest intestinal adaptation, are antisecretory and antimotility agents. They are frequently necessary to control gastric hypersecretion and chronic diarrhea. Antimotility agents will be discussed in Part 4B of this series.

Gastric Hypersecretion

The link between gastric acid hypersecretion after resection of a large segment of small intestine has been known for decades and has been attributed to the development of parietal cell hyperplasia and hypergastrinemia. This process generally lasts up to 12 months after a single massive resection with more than 50% of the small intestine removed.^14,15 If additional resections are performed, the duration of gastric hypersecretion may be more prolonged. Hypersecretion results in an increase in fluid volume entering the small bowel contributing to diarrhea; it also lowers the pH of the proximal small intestine and may result in peptic injury and inactivation of pancreatic digestive enzymes further aggravating fat maldigestion.^16,17 Fortunately, with the availability of potent and safe acid reducing drugs, gastric hypersecretion in most patients can be effectively managed using histamine-2 receptor blockers (h3RB) and proton pump inhibitors (PPI). Table 3 summarizes the established regimens for different antisecretory drugs and their monitoring parameters.

Histamine-2 Receptor Blockers

h3RBs are a good choice as initial empirical therapy for gastric acid hypersecretion, on-demand symptom/ acid control, or for the management of breakthrough acid hypersecretion. h3RBs demonstrate a dose- dependent effect in reducing gastric acid secretion.¹⁸ They are generally safe and are the only systemic drugs with an immediate onset of action in reducing gastric acid secretion. Clinical effect can be detected within 1 hour after drug administration.^19,20 These drugs are available as oral and intravenous formulations. The intravenous formulations are also compatible with most parenteral nutrition (PN) solutions, making them a very accommodating therapeutic option for patients as initial therapy after intestinal surgery. Nevertheless, the long-term effectiveness of h3RBs is limited by their relatively modest efficacy and the development of tolerance over time despite dose-escalation.

Proton Pump Inhibitors

PPIs are the most potent agents in the management of diseases requiring the reduction of gastric acid secretion and are the primary drugs used as maintenance therapy for gastric hypersecretion. PPIs are most effective when proton pumps are active, such as during meal time under normal physiology. Therefore, the best time to administer these drugs is shortly before meal time.^21,22 Maximal inhibition of acid secretion will require at least 3 to 5 days of continued therapy.^23,24 In patients with SBS, especially those receiving nutrients exclusively by PN, it is less clear how to maximize the efficacy of PPIs. Additionally, up to 30% of the patients may not show adequate clinical response to PPIs.^25,26 Poor response may be due to altered pharmacogenetics, non-adherence to therapy, and/or other physiological causes.^26-28 Therefore, PPIs may not be the best therapeutic agent for all patients.

All oral PPI products are formulated with an enteric- coating (either on the outer shell of the tablet or the cover of the granules inside the capsule) to protect the drugs from acid-mediated deactivation. Some products have additional extended-release characteristics in order to extend the duration of time the active drug is present in the body. Because PPIs are absorbed in the small intestine,²⁴ in patients with SBS, their oral bioavailability may be limited. It is unclear whether the drug is absorbed adequately in the colon. In general, the clinical efficacy of the different commercially available PPIs is considered comparable.

If there is a lack of clinical response to antisecretory therapy with an oral PPI in the early postoperative period, it is reasonable to consider a trial of IV PPI as oral drug absorption may be compromised immediately after resection of small intestine. Limited data suggest that IV PPI should be started with either a twice daily bolus regimen or as a continuous infusion. A patient can be characterized as having a positive response if clinical symptoms improve (significant decrease in stool/ostomy volume) within 5 days of the initiation of IV PPI.

With proper monitoring, PPIs are safe and effective and should be considered an integral treatment for gastric hypersecretion. In the SBS patient, a PPI should be started as soon as possible after small intestinal surgery and can generally be initiated orally for most patients. For all PPIs, it will take about one week for a clinically significant response to be seen. Since h3RBs provide a more immediate clinical response, it is not unreasonable to have concurrent treatment with a PPI and an h3RB during the initial treatment period.

Clonidine

Clonidine is a centrally acting a2-adrenergic receptor agonist approved by the Food and Drug Administration for the treatment of hypertension. The GI-related side effects of clonidine include dry mouth and constipation. The exact mechanism of clonidine in reducing gastric hypersecretion is unclear, although clonidine has been shown to reduce diarrhea in patients with proximal jejunostomy and those with diabetic diarrhea. Clonidine decreases fecal water and sodium losses and prolongs intestinal transit time in patients with chronic diarrhea.^29-33 As an antisecretory drug, clonidine can be administered orally as a tablet or as a transdermal patch, a potentially advantageous option for the patient with SBS where there may be unreliable oral absorption. The effective doses are between 0.1 to 0.4 mg per day.^29,30,32 The patch only needs to be replaced weekly.³⁴ One of the most serious side effects of clonidine is hypotension, which may be exacerbated by dehydration from chronic diarrhea, seriously limiting its use in SBS. Therefore, the dose of clonidine should be started cautiously and slowly titrated up. Patients should also be advised to remove the transdermal patch before undergoing a magnetic resonance imaging procedure as burn injuries have been reported.^34,35

Octreotide

Octreotide is a synthetic analog of somatostatin. Somatostatin decreases endocrine and exocrine secretion and blood flow, reduces gallbladder contraction, slows down GI motility and inhibits secretion of most GI hormones. Inhibition of gastrin release is likely the primary mechanism for octreotide’s benefit in the treatment of gastric hypersecretion. Octreotide is available in only two parenteral forms – octreotide acetate injectable solution, which is intended for intravenous or subcutaneous injection; and octreotide acetate injectable suspension (or LAR depot), which should only be administered as an intramuscular injection. Octreotide solution is physically compatible with most PN solutions providing additional flexibility for drug administration. When starting octreotide therapy, the injectable solution should be initiated first to allow dose titration and determination of the optimal dose based upon the clinical response. Once efficacy is established, the regimen can be converted to the injectable suspension to allow less frequent dosing. Although the use of octreotide in various types of diarrhea has been reported, its effectiveness in reducing gastric hypersecretion is highly variable and unpredictable.³⁶

The typical starting dose for octreotide is 50 or 100 mcg subcutaneously TID. The dose can be titrated up every 3 to 4 days based upon clinical response; most patients will require a total daily dose between 200 to 300 mcg to attain a clinical response.^37,38 Octreotide is not the primary therapeutic agent for acute control of GI hypersecretion given its cost, subcutaneous administration, and since it generally takes 5 to 7 days to see a clinically significant response. Importantly, in SBS, since octreotide inhibits the release and function of most GI hormones, it can negatively affect intestinal adaptation. See Table 3 for a summary of the antisecretory agents and Table 4 for potential adverse reactions.

Other Pharmacotherapies Sometimes Considered in the Treatment of SBS
Bile Acid Binders

Resection of > 100 cm of terminal ileum affects the reabsorption of bile acids into the enterohepatic circulation, hence, reducing bile acid production. Since 95% of bile salts are recirculated, the reduced bile acid absorption eventually exceeds the ability of the liver to synthesize adequate replacement. This decreased bile acid pool results in impaired micelle formation and fat digestion, and manifests clinically as steatorrhea and fat soluble vitamin deficiencies. As such, the use of bile acid sequestrants may actually worsen steatorrhea and fat-soluble vitamin losses in the SBS patient and should generally be avoided, or at most reserved for those with a colon who fail other front line agents.³⁹ The entry of bile acids into the colon also enhances water secretion and accelerated colonic motility (due to the caustic nature of bile salts on colonic mucosa), affecting the colonocytes ability to reabsorb salt and water. Although an attempt to improve the depleted bile acid pool using bile acid supplements would seem worthwhile in order to improve fat maldigestion, there are no suitable bile acids readily available that will not also aggravate stool losses. See Table 5 for the doses and monitoring parameters of different bile acid sequestrants.

Pancreatic Enzymes

SBS patients with extensive proximal small bowel resections may lose sites of secretin and cholecystokinin- pancreozymin synthesis and develop decreased pancreatic and biliary secretions;⁴⁰ fortunately, most SBS patients have extensive distal small bowel resections and demonstrate normal pancreatic enzyme and bilirubin secretion. Pancreatic function is reduced in patients on PN only when there is no concomitant enteral/oral diet and, potentially, during the hypersecretory period if no antisecretory medications are being used. Although there may be concern about a mismatch of the timing of the mixing of ingested nutrients with pancreatic enzymes due to the alterations in anatomy and small bowel transit, evidence supporting the usefulness of pancreatic enzyme supplementation in SBS is lacking (and they add yet even more to that “total pill count”).

Antimicrobials

Small intestinal bacterial overgrowth (SIBO) is common in SBS patients.⁴¹ The combination of bowel dilatation and altered transit frequently seen in SBS, together with medications commonly used in these patients (e.g., acid suppressants and antimotility agents) is thought to facilitate the development of SIBO. Excess bacteria in the small bowel can:

Induce inflammatory and atrophic changes in the gut impairing absorption
Deconjugate bile acids resulting in fat maldigestion
Consume vitamin B12 leading to deficiency
Cause a number of gas-related symptoms
Aggravate diarrhea leading to a reduction in oral intake

A number of limitations of the tests used to diagnose SIBO (i.e., small bowel aspirate with quantitative bacterial culture and hydrogen breath testing most commonly used), make securing the diagnosis of SIBO in SBS challenging. Because of the test limitations and the increased risk of SIBO in this patient population, empiric treatment is often provided. Antimicrobial treatment is generally prescribed; a variety of oral broad- spectrum antibiotics can be used (Table 6) with success being judged on improvement in symptoms, reduction in stool output and/or weight gain. The continuous use of low-dose antibiotics in SBS may be necessary in some patients. To reduce the risk of antibiotic resistance, periodic rotation of 3 or 4 antibiotics is advised.

Probiotics

While high-quality evidence supporting the use of prebiotic, probiotic and synbiotic agents in SIBO is lacking in adults, there is emerging evidence from both preclinical studies and reports in the pediatric SBS population of their benefit.⁴² It is also important to remember that probiotics are regulated as dietary supplements in the U.S. and therefore product purity and safety cannot be guaranteed. Until clear evidence is available, probiotic use cannot be recommended at this time.

Glutamine

Glutamine, a ‘conditionally essential’ amino acid, is a primary energy source for the enterocyte. Its use in SBS was popularized by a series of retrospective, open-label studies and a prospective randomized, controlled clinical trial when used in combination with human growth hormone and an optimized diet.^43,44 Nevertheless, when glutamine alone was added to an ORS provided to adult SBS patients with an end- jejunostomy, no benefit was seen in terms of fluid or sodium absorption.⁴⁵ Furthermore, in a randomized, controlled, crossover study involving eight adult SBS patients, glutamine resulted in no difference in small bowel morphology, transit time, D-xylose absorption or stool output.⁴⁶

SUMMARY

Treatment of short bowel syndrome requires aggressive use of several different pharmacological agents. To maximize their efficacy, it is important for clinicians to give thought to the site of absorption, formulation, frequency, timing of each drug and individual patient’s response to therapy. Setting and monitoring endpoints for each intervention (i.e., how long you will give each intervention time to achieve efficacy or not), is crucial in the care of the SBS population. In addition, cost considerations and availability to the patient depending on where they obtain their medications are important in order to improve medication adherence. Finally, remember that there are only 24 hours in a day, one-third or more of which is spent sleeping. It is important to periodically do a “Total Pill Count,” as not only do the prescription medications, over-the counter medications, and vitamin/mineral supplements add up (and can be quite overwhelming), the osmotic contributions of these agents, as well as the sheer volume of fluid needed to take them, can contribute to yet even more stool or ostomy output.

INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #92

The Current State of the Inflammatory Bowel Disease Drug Pipeline: A Promising Time

Jason R. Goldsmith,

Peter D.R. Higgins

The pipeline for IBD therapies has exploded in recent years, as advances in our understanding of the pathogenesis of IBD have led to new therapeutic targets. This includes multiple new mechanisms of action, ranging from biologic-based immunosuppression to mucosal barrier repair. This article reviews the promising mechanisms of action and specific agents currently in clinical trials for IBD.

Jason R. Goldsmith MD, PhD¹ Peter D.R. Higgins MD, PhD, MSc² ¹Department of Medicine, ²Department of Gastroenterology, University of Michigan, Ann Arbor, MI

BACKGROUND

In recent years, basic and translational science research into the pathogenesis of inflammatory bowel diseases (IBD) have resulted in a boom of new therapeutics for IBD. This started with the anti-TNF therapies, but has significantly broadened since. This article reviews the current state of the IBD drug pipeline (Figure 1). In this pipeline, several broad mechanisms of action (MOA) show significant promise, with multiple drugs in the pipeline, with many in late phase trials and one recent FDA approval. These MOAs include anti-adhesion therapies, anti-IL12/23 therapies, and Janus kinase (JAK) inhibitors. Other MOAs are less developed, but show promise as novel mechanisms. This includes therapies that directly modulate the immune response, therapies that alter the microbiome, and therapies that enhance/repair the intestinal barrier, as well as a new appreciation of the anti-inflammatory properties of several natural products.

Anti-Adhesion and Chemotaxis Therapies

Anti-adhesion therapies prevent the interaction between the endothelium of blood vessels and the integrins on a subset of white blood cells, preventing immune cell infiltration into organs and thus tamping down the immune response. Natalizumab (Tysabri) was the first drug in this class to be approved for use in CD, after the Phase 3 ENCORE trial demonstrated efficacy.¹ A monoclonal antibody targeting the a4 integrin subunit, it had broad effects, blocking the gut-specific a4ß7 integrin as well as the brain a4ß1 integrin. Thus, the antibody was also effective in the treatment of multiple sclerosis, by reducing immune surveillance in the brain. Unfortunately, long-term natalizumab has been associated with increased susceptibility to JC virus infection and subsequent development of progressive multifocal leukoencephalopathy (PML).²

Because of this risk of PML, development of gut-specific anti-integrin therapies were undertaken, culminating in the FDA approval of vedolizumab (Entyvio), a a4ß7-specific monoclonal antibody.³

Other second-generation anti-adhesion therapies are still in clinical trials. In phase 2 trials for UC and CD, abrilimumab (AMG181/MEDI7183) targets a4ß⁷ on WBCs like vedolizumab. Etrolizumab,⁴ which targets only the ß7 subunit on WBCs, is currently in Phase 3 trials for UC. PF-00547659,⁵ which targets enterocyte Mucosal Addressin Cell Adhesion Molecule-1, has completed phase 2 for UC and CD.

Because these second generation anti-adhesion therapies are designed to be gut-specific, there is a hypothesis that they may result in lower risk of infections (supported based on extensive impressive data with vedolizumab) than existing anti-TNF therapies. Consequently, head-to-head trials between anti-adhesion therapies and anti-TNF therapies are needed to determine whether these new therapies provide equivalent efficacy with improved safety; as it stands there is currently a set of two trials registered on clinicaltrials.gov to compare Etrolizumab vs adalimumab (Humira), but they are not yet in the recruiting phase.

In contrast to the aforementioned gut-specific injectable therapies, Ajinomoto Pharmaceutical has tested an oral small-molecule inhibitor (AJM300) of the a4 integrin subunit,6 demonstrating short-term efficacy. The authors hope that the pharmacokinetics of this drug, with its short half-life, will facilitate easy cessation should PML occur, and that the subsequent resumption of immune activity would prevent significant brain damage. However, given the significant harm caused by PML, the evidence level required for such a a4 agent to reach market will be quite high for the FDA and the European Medicines Agency. A biologic targeting a2 integrin, vatelizumab, is in Phase 2 studies for UC, but would likely encounter similar safety concerns to natalizumab and now AJM300.

A related approach involves inhibition of immune cell chemotaxis: the signaling that targets immune cells to different tissues. Several therapies are being pursued in this vein, including: 1) RPC1063, a sphingosine 1-phosphate 1 receptor modulator that inhibits lymphocyte egress from lymph nodes, which recently completed phase 2 trials for UC; 2) GS-5745, a monoclonal antibody targeting matrix metalloprotease-9 (MMP-9), a pro-inflammatory enzyme involved in wound repair and chemotaxis, in phase 1 trials for UC; 3) GSK3050002, a monoclonal antibody targeting chemokine (C-C motif) ligand 20, in phase 1 trials for UC; and 4) E6011, a monoclonal antibody inhibitor of chemotaxis being explored in Japan in Phase 1/2 trials.

Anti-IL-12/23 Therapies

Ustekinumab (Stelara) is a monoclonal antibody targeting p40, a subunit of both IL-12 and IL-23. It is on the market for psoriasis, and has proven effective in phase 3 trials for Crohn’s disease. It is believed to act through both inhibition of IL-12-mediated maturation of Th1 cells, and IL-23 mediated stimulation of Th17 cell survival and proliferation. With the completion of phase 3 trials, ustekinumab is anticipated to reach market within the next two years. Other compounds in this class include MEDI2070, an IL-23 specific agent that has finished recruitment for a phase 2 study. AMG139 is another IL-23 specific agent, which is in phase 1 dose-ranging studies for CD, and BI655066 is an IL23p19 sub-unit specific monoclonal antibody in phase 2 trials for CD. Based on the pipeline, it appears as if several therapies targeting this pathway will be available for CD in the future.

JAK Inhibitors

JAK inhibitors work by blocking the activation of the intracellular enzymes Janus Kinases 1-3, which transduce cytokine signals and generally active immune cells. The different agents under investigation vary in their selectivity for the different JAK molecules. Tofacitinib (Xeljanz) is a small-molecule oral JAK inhibitor which is FDA approved for rheumatoid arthritis, and in a head-to-head trial with adalimumab was found to be numerically superior without reaching statistical significance.7 Tofacitinib is currently in phase 3 clinical trials for UC and in phase 2 trials for CD. ASP015K/ JNJ54781532 is another JAK inhibitor (selective for JAK1/3) in phase 2 trials for UC, while GLPG0634 is a JAK inhibitor with similar selectivity in phase 2 trials for CD. Given the approval of Tofacitinib for rheumatoid arthritis (RA), it is likely that JAK inhibitors will reach the market soon, assuming they prove safe and effective in IBD. With the recent rejection of agent for RA in Europe on the basis of safety data, the fate of Tofacitinib for IBD is not a foregone conclusion in the USA.

Immune Cell Modulation

Other therapies focus on modulating the aberrant T-cell responses thought to be an important underpinning in the pathogenesis of IBD. One interesting approach being used in UC is directly tamping down the Th3-immune response believed to be involved in the pathogenesis of IBD. SB012, which is being investigated in a Phase 1/2 trial currently, is a rectally administered formulation of a DNAzyme that degrades GATA-3, a key transcription factor mediating the Th3 response. Another approach involves therapies to expand the regulatory T-cell (Treg) compartment that regulates inflammation. Low dose IL-2 has been shown to expand Treg populations and has clinical evidence supporting efficacy in auto- immune conditions, including alopecia⁸ and graft-vs- host disease.⁹ This approach is now being investigated in a phase 1&2 trials in UC and CD patients.

Similar immune modulation is being explored by Qu Biologics in phase 1/2 CD studies with a proprietary technology they have labeled site-specific immunomodulators derived from bacterial products, which are believed to alter macrophage function.

Microbiome-Targeted and Anti-Microbial Therapies

With the continuously evolving understanding of the host-microbiome interactions that underpin IBD, therapies designed to target the microbiome have received significant attention in recent years. Unfortunately, both probiotics¹⁰ and fecal microbiota transplant (FMT)¹¹ have not yielded consistent results in IBD and further work is still being undertaken. FMT in particular is seeing a large amount of continued research activity, given its low cost of acquisition and use. A phase 1 trial is ongoing in CD patients, and a phase 2/3 trial for FMT in pediatric IBD patients has been registered but is not yet open to enrollment. A phase 2 FMT trial is currently in the recruitment phase for patients with UC-associated pouchitis, and a phase 1 trial exploring pre- and post- FMT shifts in host microbiota population in patients with mild to moderate UC is also recruiting. One hypothesized problem with FMT in IBD is that the increased immune response in IBD patients may overwhelm the transplanted microbiota; to test this theory a phase 1/2 trial using serial FMTs is being pursued in CD patients. Another phase 4 study is looking at antimicrobial ablation with FMT rescue therapy in UC and Crohn’s colitis patients.

With the failure of probiotic studies in recent years, attention has shifted to prebiotics – compounds that shift the microbial composition, usually by serving as preferential metabolites for “good bacteria” to increase their relative presence. Synergy-1, a 1:1 oligosaccharide/ inulin mixture, has recently completed a Phase 2 trial in UC patients and results are pending. Unfortunately, previous pilot trials of fructo-oligosaccharides were very poorly tolerated by IBD patients due to high rates of bloating and discomfort, with 26% (vs. 8% in placebo) choosing to discontinue in the FOS arm, and additionally did not demonstrate clinical benefit.¹² In a related vein, studies of partial enteral nutrition, as a potential replacement to the poorly tolerated enteral nutrition approach, are being pursued in CD patients.

A third, perhaps more traditional approach, involves ablation of perceived “bad” gut microbiota that may be contributing to IBD. One approach being pursued in CD patients is the ablation of intra-macrophage bacteria using a combination of ciprofloxacin, doxycycline, and hydroxychloroquine. Another antimicrobial trial explores the hypothesis that CD is caused by an infection by mycobacterium avium subspecies paratubuclerosis (MAP) using a combination anti-MAP therapy of clarithromycin, rifabutin, and clofazimine.

Mucosal Barrier Enhancement

A different approach to treating IBD involves enhancing the mucosal barrier, as opposed to suppressing the immune system. The pathway with the strongest evidence using this approach is phosphatidylcholine, a key component of the mucosal barrier. Recent phase 2 trials of LT-02, a delayed release formulation of phosphatidylcholine, showed efficacy in UC patients,¹³ and phase 3 trials are being planned.

Natural Products

Herbal compounds used in other medical cultures, along with other natural products, have received increasing amounts of attention as potential therapies for IBD; especially as anti-inflammatory claims become backed by experimental evidence. Andrographis paniculata extract (HMPL-004) is a plant extract with broad anti-inflammatory properties (inhibiting TNF, NF- kB, and IL-1B)¹⁴ currently in phase 3 trials for UC as an alternative to mesalamine.^15,16 Flaxseed lignan- enriched complex (FLC), is another dietary extract with anti-inflammatory properties that is currently being investigated in phase 2 trials for UC. STW5 is an herbal preparation that has been shown to be efficacious in IBS¹⁷ and in murine colitis¹⁸ and a phase 2 trial has been registered at clinicaltrial.gov for UC patients. Tripterygium glycosides (T2), an extract of Tripterygium wilfordii Hook F, is a traditional Chinese medicine used in inflammatory conditions now being investigated in phase 2/3 trials for CD. Curcumin, a potent NF-kB inhibitor,¹⁹ is being explored alongside thiopurines in phase 3 trials to prevent post-op recurrence of CD. Milk-derived gangliosides, believed to be anti-inflammatory,²⁰ are being explored in early phase 1 trials in IBD patients.

Other Therapies

There are several other therapies in the pipeline for IBD that cover a wide range of modalities. Recruitment has opened for a Phase 2/3 clinical trial exploring hyperbaric oxygen for the treatment of UC. The mechanism of action is believed to broad anti-inflammatory properties.²¹ Other novel mechanisms of action under active clinical investigation include: 1) an oral antisense inhibitor of SMAD7 (Mongersen) which has completed phase 2 studies in CD; 2) small-molecule inhibition of toll-like receptor (TLR) 2 and TLR4 (via CD14): VB- 201, in phase 2 trials for UC; 3) umbilical cord blood stem cells (FURESTEM-CD) in phase 1/2 trials for CD; 4) placenta-derived cells (PDA001) in phase 1 trials for CD, 5) allogenic mesenchymal stromal cells in phase 1 trials in pediatric CD, and 6) AVX-470, a parenteral bovine anti-TNF that is oral bioavailable in the gut, which just completed phase 1 trials in UC patients.

CONCLUSION

The recent advances in our understanding of the pathogenesis of IBD have led to an explosion of drugs in IBD pipeline. In particular, MOA with multiple drugs in late-stage development include anti-adhesion therapies, anti-IL12/23 therapies, and JAK inhibitors. Barrier enhancing and microbiome-altering therapies are also being pursued, but these pipelines are less robust.

In addition to the aforementioned successes and promising candidates, there have also been several failures in recent years. Most notably, the recent negative trial of Trichuris suis ova appears to be the end of parasitic therapy, although the parasitic enzyme P28GST, derived from Schistosoma, is being explored as a post-resection agent in CD patients in phase 2 trials to prevent the recurrence of ileo-colonic disease. The negative trials for anti-IL-13 (tralokinumab) and anti- IL-17 (secukinumab) therapies have led to refocused basic mucosal immunology questions, continuing the feedback loop between bench and bedside research.

Additionally, phase 3 trials are limited in their ability to inform us how to best use a given therapy, demonstrating only clinical superiority to placebo. For instance, we have had access to infliximab since 1998, but we still continue to study how to best optimize its use.22,23 Currently, our approach to medical management of IBD is largely one of trial and error, starting with less potent drugs with safer side effect profiles, and escalating after clinical failure. We select more potent agents largely by fiat, as head-to-head trials of more potent agents, such as anti-TNFs or anti-TNFs and vedolizumab, are just starting to be performed. As we move forward, work is being done to move towards a more evidence-based approach. Future predictive models that could include genetic and clinical markers may be able to predict which patients are more likely to respond to or fail a given therapy, to avoid the slow, empiric approach currently being used. With increased understanding of the genetic24 and environmental factors that lead to IBD, we have come to appreciate that UC and CD likely have multiple underlying pathogenic routes which likely explain the variable responses to drugs seen between patients. As we can advance and align this knowledge with an expanding array of MOA for the treatment of IBD, one can envision that going forward, we will be able to select specific agents by MOA for a patient’s particular IBD subtype, rapidly producing better outcomes.

FRONTIERS IN ENDOSCOPY, SERIES # 16

Mirizzi Syndrome: A Rare but Relevant Biliary Entity

Kimberley Davenport,

Douglas G. Adler

Mirizzi Syndrome (MS) is a rare clinical entity that presents a formidable challenge when encountered. The constellation of a contracted gallbladder, obstructive jaundice, gallstones, pain and cholecystitis should arouse suspicion of MS. Here, we discuss the importance of a multidisciplinary team approach which includes a skilled endoscopist and surgeon. Treatment for each patient must be individualized, as specific MS types necessitate distinct surgical approaches.

Kimberley Davenport, University of Utah School of Medicine, Gastroenterology and Hepatology. Douglas G. Adler MD, FACG, AGAF, FASGE, Associate Professor of Medicine, Director of Therapeutic Endoscopy, Director, GI Fellowship Program, Gastroenterology and Hepatology, University of Utah School of Medicine, Huntsman Cancer Center, Salt Lake City, UT

CASE REPORT

A 64 year-old man presented to our facility with a one-day history of right upper quadrant pain, scleral icterus, and intermittent fever and chills. The patient’s vital signs included a temperature of 97.8, a pulse of 71, a respiration rate of 14, and a blood pressure of 124/80. On physical exam, he was mildly uncomfortable with key physical exam findings of right upper quadrant abdominal pain to palpation and on deep inspiration, scleral icterus, and jaundice. An abdominal ultrasound demonstrated mild intrahepatic biliary ductal dilation with at least one stone visualized in the gallbladder. The wall of the gallbladder was found to be slightly thickened without pericholecystic fluid and the common bile duct was measured at 11mm. A contrast-enhanced CT of the abdomen and pelvis was obtained and revealed prominent intrahepatic ductal dilation and what was interpreted as choledocholithiasis. Notably, the common bile duct had more distension proximally near the stone and less distension distally. GI and surgery consultations were obtained. A plan of preoperative ERCP followed by laparoscopic cholecystectomy was agreed upon.

ERCP revealed intrahepatic ductal dilation and proximal extrahepatic ductal dilation. Initial cholangiogram revealed what appeared to be a single, round 30 mm filling defect consistent with a stone eccentrically obstructing at the level of the CHD (Figure 1). Immediately proximal to the stone, there was visible dilation of the left and right hepatic ducts as well as the intrahepatic ducts. An inflated 15-18mm occlusion balloon could be pulled across the site of the stone without any apparent movement of the stone itself. Of note, the cystic duct was never seen to fill and was presumed to be obstructed. At this point it became apparent that the stone was actually within the cystic duct and was extrinsically compressing the CBD, consistent with a Mirizzi syndrome. An 8.5Fr x 12cm plastic biliary stent was inserted into the CBD across the site of extrinsic compression, with the proximal end of the stent in the CHD. (Figure 2) The patient improved clinically over the next 24 hours following biliary decompression. The patient was then referred for his cholecystectomy.

At surgery, the gallbladder was noted to be inflamed and adherent to the CBD, with what appeared to be a cholecystocholedocho fistula between the two at the level of the gallbladder neck/proximal cystic duct. Opening of the gallbladder revealed the impacted stone at the level of the fistula, which was then removed. Cholecystectomy was then carried out with subsequent incision of the CHD and removal of the impacted stone. The CHD was felt to have been damaged too severely by the stone/fistula combination for simple T-tube placement. The patient then underwent biliary reconstruction via a Roux-en-Y hepaticojejunostomy, although the distal CBD was left in continuity. The plastic bile duct stent was left in as a guide during surgery. The patient did well postoperatively and without complication.

A follow-up ERCP 8 weeks later demonstrated brisk flow of contrast through the biliary tree as well as a patent hepaticojejunostomy with free flowing contrast and bile into the small bowel. No filling defects were noted, indicating an absence of any residual or recurrent stones. Overall, the patient was felt to have developed a Type IV Mirizzi syndrome.

DISCUSSION

In developed countries, the incidence of gallstone disease has been rising of late with the majority of cases involving cholesterol stones. In the U.S. alone, an estimated 20 – 25 million adults suffer from some form of gallstone disease. Epidemiological studies have found that gallstone disease correlates highly with obesity, diabetes and metabolic syndrome.1 Though gallstones are understood to be multifactorial from an etiology point of view, one property these risk factors all share seems to be hypercholesterolemia: a condition that can allow supersaturation of bile by cholesterol with subsequent precipitation of gallstones.¹ Gallstones can lead to a variety of conditions including cholangitis, cholecystisis, gallstone pancreatitis, and even gallstone ileus.²

Mirizzi Syndrome (MS) is a rare complication of cholelithiasis.^3,4 Classically, the common hepatic duct (CHD) or the common bile duct (CBD) become obstructed from mechanical compression and surrounding inflammation by gallstone impaction at either the cystic duct or the gallbladder neck.^2,5 Compression by the impacted stone results in biliary obstruction which can then cause obstructive jaundice and in some patients also lead to cholangitis. ^4,6 From there, this process has the potential to further evolve into an internal biliary fistula, or even complete obliteration of the CHD.³

Overall, the incidence of Mirizzi Syndrome is rare, discovered only in 0.7 – 1.4% of patients undergoing cholecystectomy.⁷ Management has historically been difficult due to the inadequacy of pre-operative diagnosis as well as the surgical challenge it presents given the presence of active inflammation, dense adhesions, and distorted biliary ductal anatomy.^5,8

The term Mirizzi Syndrome refers to a collection of four subtypes of the disease commonly acknowledged as the Csendes Classification model.⁹ Type I is the most dominant form of MS and is characterized by extrinsic compression of the CBD due to an impacted stone at the cystic duct or the gallbladder neck. ^4,10 Types II, III and IV all include cholecystocholedochal fistulas.¹¹ Type II describes a fistula where 1/3 of the CBD circumferential wall has eroded.^4,9 Type III refers to a larger fistula with erosion of 2/3 of the circumferential wall of the CBD.^4,9 Finally, Type IV denotes a fistula that has caused circumferential damage to the CBD and thus requires reconstruction of the CBD.^4,9

Pathophysiology

Mirizzi Syndrome begins when a gallstone becomes impacted at the cystic duct or gallbladder neck and causes an inflammatory response. The offending stone then applies external pressure on the bile duct, eventually leading to erosion of the CBD with possible fistulization.¹²

Once this situation is established, episodes of biliary colic cause fibrosis and gallbladder atrophy.^12,13 Ongoing inflammation and proximity allow the gallbladder and/ or the cystic duct and/or the CBD to fuse together.¹² An impacted gallstone at this location likely causes a pressure ulcer which then develops necrosis. The necrotic tissue can enable partial stone migration into the CBD and ultimately the production of a chronic fistula.¹² Such cholecystocholedocal fistulas are the hallmark of Type II, III and IV Mirizzi Syndrome, but they are still exceedingly rare. In fact, most biliary fistulas are actually cholecystoduodenal, joining the gallbladder to the small bowel.¹¹ Despite advanced imaging, most fistulas are found intra-operatively during cholecystectomy.^4,11

Clinical Presentation

Mirizzi Syndrome is difficult to diagnose clinically because of its non-specific symptom profile.^5,6 Because MS resembles several other conditions, its differential diagnosis includes choledocholithiasis, cholecystitis, cholangitis, gallstone ileus, and gallbladder cancer.^5,11,12,14 Clinical presentation is non-specific, but obstructive jaundice is a common symptom – especially for types II, III and IV.⁴ RUQ pain is also frequently seen, along with a fever. Laboratory values often reflect elevated liver enzymes, hyperbilirubinemia, leukocytosis, and a high CA-19-9.¹²

A reported 28% of MS types II, III and IV cases also have also been found to have concurrent gallbladder cancer.^11,12 Notably, longstanding gallstones is one of the primary risk factors for both MS and gallbladder cancer.¹² Average age of onset for MS is around 61 years.⁹ Most MS patients have had gallstone disease for a mean of 29 years.¹²

Diagnosis

Lack of pathognomonic patterns or reliable clinical or laboratory indicators have made the diagnosis of MS difficult to distinguish from common choledocholithiasis.^5,15 Optimal management of MS and avoidance of iatrogenic bile duct injury during cholecystectomy depends on accurate preoperative diagnosis, although this cannot be made in all circumstances.¹⁰ Several modalities are available for biliary imaging including transabdominal ultrasound, CT, MRCP, endoscopic ultrasound (EUS) and ERCP.¹² Transabdominal ultrasound (US) is typically the initial imaging test ordered for suspected biliary disease because it is non-invasive, although it’s ability to detect choledocholithiasis is limited and the test is highly operator dependent.² US has high sensitivity to findings consistent with MS such as gallstones in the gallbladder neck, acute cholecystitis, a shrunken gallbladder and a dilated CHD.¹⁰ CT scans have the capacity to demonstrate dilated intra and extrahepatic ducts with gallstones in the biliary tree, but in general are a poor test to detect MS or choledocholithiasis.⁵ EUS is ideal for detecting choledocholithiasis but may fail to detect MS if the stone is located too proximally for the EUS transducer to visualize.¹⁶ MRCP (Magnetic Resonance Cholangiopancreotography) is noninvasive and has a high sensitivity for finding pericholicystic inflammation and cholecystobiliary fistulas.¹¹ However, ERCP (Endoscopic Retrograde Cholangiopancreotography) is the gold standard for diagnosis of MS.⁹ The sensitivity of ERCP for diagnosis of MS approaches 90%.^11,12 ERCP is both diagnostic and therapeutic.¹¹ Diagnostically, ERCP identifies ductal abnormalities and can distinguish with precision the cause, level and degree of biliary obstruction.¹⁰ Therapeutically, ERCP is used for stone clearance if the stone is endoscopically accessible.⁸ It also facilitates biliary decompression prior to cholecystectomy in patients with MS via stent placement, as was the case in our patient.^6,8 If a preoperative diagnosis of MS is not obtained, most experienced surgeons would recognize the entity in the operating room.

Treatment

The goals of treating patients with MS include: removal of the impacted stone and gallbladder, restoration of bile drainage and repair of the anatomical defect.^6,11 Preoperative ERCP can confirm the presence of MS.⁹ It also allows for placement of a temporary stent – providing critical decompression of the obstructed biliary duct.¹² Such decompression alleviates progression of any fistulas.¹⁴ Moreover, the stent will serve as a landmark in subsequent surgery to help minimize the risk of ductal injury.4 Preoperative ERCP is also a viable alternative for patients who are not candidates for open cholecystectomy (OC).¹²

Removal of the gallbladder and the impacted stone along with repair of the malformed anatomy is performed laparoscopically or by open surgery. OC has historically been the surgical standard of care for MS.⁴ However, LC is fast gaining acceptance as a viable alternative to OC.^6,11 The main advantage conferred by OC is a lower risk of iatrogenic bile duct injury than LC.¹⁴ This is large part due to the feasibility of a fundus first approach enabled by OC.17 Morbidity from OC has been reported to be 3% for MS type I. However, OC performed on types II and III correlate with a higher morbidity rate (15 – 26%) due to more complicated anatomical deformities.⁴ The biggest risk associated with OC is iatrogenic injury to the CBD.⁵ Such risk stems from the technical challenge presented by anatomical distortions, cholecystocholedocal fistulas, and adhesions in Calot’s triangle encountered in MS patients undergoing OC.^4,5 Disadvantages of OC include a larger incision which provides a higher risk of infection and wound dehiscence.⁸ Additionally, OC entails a longer recovery.⁶

Laparoscopic Cholecystectomy (LC) for treatment of MS has been somewhat controversial.¹⁰ Indeed, some surgeons still consider MS as a contraindication to laparoscopic cholecystectomy.^4,6,9 Nonetheless, LC has become a viable alternative to OC as experience and enhanced instruments continue to improve outcomes with this procedure.⁶ LC involves removal of the gallbladder, the impacted stone and suturing the biliary defect.⁸ Its advantages are that it is minimally invasive and by extension entails a lower risk of infection, produces less blood loss, and offers a shorter hospital stay.⁸ Some disadvantages are that it is technically demanding, requires a high degree of expert skill and thus a longer duration for the procedure.⁸

In general, LC is indicated for the less complicated MS as in Type I. Open surgery is indicated for higher risk cases of MS, difficult dissections (due to anatomical malformations or acute inflammation), and patients who have failed LC.⁸ In some cases, higher grades of MS: Type II, III and IV, may require open biliary-enteric bypass to repair extensive destruction of the bile ducts or strictures.¹¹ Such complete biliary reconstruction is termed a Roux-en-Y hepatico-jejunostomy and involves anastomosis of the jejunum with the fistula to close the eroded duct.¹⁸ Lastly, postoperative ERCP after complete healing of the site removes the temporary stent.⁸ The incidence of iatrogenic complications is reported to range between 0 – 14%.3 Such adverse events can be severe and include cholangitis, bile leakage from perforation of the CBD or perforation of the gallbladder, bile duct strictures from fistula repair, post-ERCP pancreatitis, and sepsis.3 Regardless of the intervention, a high risk of morbidity exists with treatment of MS.⁹

CONCLUSION

Mirizzi Syndrome is a rare clinical entity that presents a formidable challenge when encountered. The constellation of a contracted gallbladder, obstructive jaundice, gallstones, pain and cholecystitis should arouse suspicion of MS. A preoperative diagnosis is critical to optimal management and is best confirmed by cholangiography during ERCP, although not all patients have the diagnosis made prior to interventions. Once a definitive diagnosis of MS is made, a multidisciplinary team approach including a skilled endoscopist and surgeon offers the best outcome. Treatment for each patient must be individualized, as specific MS types necessitate distinct surgical approaches. Preoperative ERCP with stenting can restore bile flow and mitigate cholangitis, thus enhancing safety of subsequent surgery.

A Special Article

The City Criteria: A Review of Toponyms Used in Naming Diagnostic Guidelines

February 2016 • Volume XL, Issue 2

Alexander Gerald Chen,

Kheng-Jim Lim

Alexander Gerald Chen¹ Kheng-Jim Lim² 1Undergraduate, Columbia University, New York City, NY ²Division of Gastroenterology and Hepatology, Rutgers-Robert Wood Johnson Medical School, New Brunswick NJ

INTRODUCTION

Based on the Greek word …t….. (kriterion), “criterion” is defined as the standard upon which a decision or judgment is based. The medical field abounds in criteria to aid in the diagnosis of diseases. Traditionally, classification schemes were named after individuals, giving rise to numerous medical eponyms (e.g. Ranson’s criteria), however, of late, eponyms have been abandoned and toponyms, names based on places, have come into vogue (e.g. the Atlanta criteria). No particular rule appears to guide this nomenclature other than the fact that a major meeting in which experts met to collaborate on the rules of the criteria. Most of the observations in modern medicine cannot be credited solely to an individual as the majority of today’s research is produced by joint effort, thus the simpler solution is use the name of the locale where the experts met and analyzed the research to formulate the guidelines.

Some of these criteria are a useful set of rules to follow in the diagnosis (e.g. the Rome Criteria) or treatment (e.g. the Toronto Consensus) of specific conditions. Similar to the utility of the instruction manual for a new piece of complex equipment, the average clinician may find the guidelines useful, as the various criteria offer a substantial road map in the diagnosis and treatment of diseases without significant deviation from the standard of good care.

The use of criteria by the practitioners of medicine is variable and depends on the popularity of the criteria and the incidence or prevalence of the disease. A criterion for diverticular disease diagnosis is thus more often used than one for endoscopic grading of esophagitis. The authors, realizing these limitations, aim to summarize the criteria in gastroenterology and assess their impact by using the citation indexing database “Web of Science” managed by Thomson Reuters.

All accompanying images are in the public domain and a world map is provided for reference.

Amsterdam Criteria for Lynch Syndrome
Rational

The authors of the Amsterdam criteria1 for hereditary non-polyposis colorectal cancer (ICG-HNPCC) or Lynch Syndrome came together with the goal of creating a simple system to help clinicians identify Lynch Syndrome for which there was little data about at the time.

Criteria

A patient is said to have Lynch Syndrome if he or she meets all the following criteria:
3 relatives with colorectal cancer (one of which is a first-degree relative of the other two)
= 2 successive generations affected
= 1 of the three diagnosed before age 50

Citation History

Citations for “Vasen HFA, Mecklin J-P, Meera Khan P, Lynch HT. The international collaborative group on hereditary non-polyposis colorectal cancer (ICG- HNPCC). Dis Colon Rectum 1991; 34: 424-425”

Naming

The Amsterdam Criteria was the result of the effort of 30 authorities in their respective fields from eight different countries who met in Amsterdam in 1990.

Atlanta Classification for Pancreatitis
Rational

Considering the many forms and complications of acute pancreatitis, it is no surprise that many classification systems for acute pancreatitis existed before the creation of what is now known as the Atlanta Criteria.2 This system set itself apart by being intended for clinical practicality and it defines many of the terms associated with acute pancreatitis.
Acute Pancreatitis The inflammation of the pancreas with possible involvement of other tissue or distant organ systems.
Severe Acute Pancreatitis Acute pancreatitis associated with organ failure and possibly local complications such as necrosis, abscess, or pseudocyst.
Mild Acute Pancreatitis Acute pancreatitis with minimal organ dysfunction and uneventful recovery. No indicators for severe acute pancreatitis present.
Acute Fluid Collections Occur early in acute pancreatitis, located within or close to the pancreas and always lack a wall of granulation or fibrous tissue.
Pancreatic Necrosis The diffuse or focal areas of nonviable pancreatic parenchyma, typically associated with peripancreatic fat necrosis.
Acute Pseudocysts A collection of pancreatic fluid enclosed by a wall of fibrous or granulation tissue, the result of acute pancreatitis, pancreatic trauma or chronic pancreatitis.
Pancreatic Abscess A circumscribed intra-abdominal collection of pus, usually near the pancreas, containing little or no pancreatic necrosis, the result of acute pancreatitis or pancreatic trauma.

Citation History

Citations for “Bradley EL III. A clinically based classification system for acute pancreatitis. Summary of the international symposium on Acute Pancreatitis, Atlanta, GA, September 11 through 13, 1992. Arch Surg 1993; 128: 586-90.”

Naming

This consensus was the result of the effort of 40 experts in their respective medical fields from around the world coming together in Atlanta, Georgia to decide upon these definitions.

Chicago Criteria for Achalasia
Rational

With the development of high resolution manometry (HRM), clinicians are able to more accurately measure the pressurization of the esophagus during peristalsis. However, there was no agreed upon usage of HRM to diagnosis motility disorders until the study published that is now referred to as the Chicago Criteria,3 which is summarized as follows:
Type I Minimal esophageal pressurization
Type II Absent peristalsis with esophageal pressurization
Type III Lumen destroying spasm on HRM

Citation History

Citations for “Pandolfino JE, Ghosh SK, Rice J, Clarke JO, Kwiatek MA, Kahrilas PJ. Classifying esophageal motility by pressure topography characteristics: a study of 400 patients and 75 controls. Am J Gastroenterol 2008; 108: 27-37”

Naming

The data for the study leading to the Chicago Criteria came from the Northwestern Memorial Hospital manometry laboratory located in Chicago, Illinois.

Glasgow Criteria for Pancreatitis
Rational

The Glasgow scoring system⁴ is intended to determine the severity of pancreatitis within 48 hours of a patient’s admission. It is actually a modification of a scoring system by Imrie et al.⁵ meant to increase accuracy and simplicity.

Criteria

The scoring system is a set of possible factors that the patient may exhibit. Three or more factors defines severe pancreatitis.
Age > 55
White Blood Count > 15,000/µl
Blood Glucose > 180 mg/dl
PaO2 < 60 mmhg
Serum Calcium < 8 mg/dl
Serum Albumin < 3.3 g/dl
Blood Urea Nitrogen > 45 mg/dl
Lactate Dehydrogenase > 600 U/L

Citation History

Citations for “Blamey SL, Imrie CW, O’Neill J, Gilmour WH, Carter DC. Prognostic factors in acute pancreatitis. Gut 1984; 25”

Naming

This criterion was put forth by Glasgow University and the Royal infirmary of Glasgow.

Glasgow Classification of Alcoholic Hepatitis
Rational

Although grading systems for alcoholic pancreatitis have existed before the Glasgow alcoholic hepatitis score⁶, the authors of this classification system wanted to create a clinically useful system that more accurately identified patients with higher mortality risks in order to better inform treatment decisions.

Criteria

Each factor is given a score of 1, 2 or 3. Then, all the factor scores are combined for a total score. A total score greater than or equal to 9 is associated with a poor prognosis and increased risk of mortality.

Citation History

Citations for “Forrest EH, Evans CDJ, Stewart S et al. Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score. Gut 2005; 54: 1174-9”

Naming

The data for this study was obtained from patients presenting with alcoholic liver disease to the Glasgow Royal Infirmary and the Victoria Infirmary which is also in Glasgow.

Los Angeles Criteria for Esophagitis
Rational

The creation of the Los Angeles criteria⁷ for esophagitis was intended to implement a universally accepted standard for grading the severity of gastroesophageal reflux disease (GERD). This system was intended to be easier to use and more clinically practical than the many existing classification systems for GERD.

Criteria

This system allows clinicians to interpret endoscopically observed peptic lesions and grade the severity of the GERD into one of the following categories:
Grade A 1 ≤ mucosal breaks, ≤ 5 mm long that does not extend between tops of two mucosal folds
Grade B 1 ≤ mucosal breaks, >5 mm long that does not extend between tops of two mucosal folds
Grade C 1 ≤ mucosal breaks, continuous between tops of = 2 mucosal folds but involves < 75% of esophageal circumference
Grade D 1 ≤ mucosal breaks that but involves = 75% of esophageal circumference

Citation History

Citations for “Armstrong D, Bennett JR, Blum AL., et al. The endoscopic assessment of esophagitis: a progress report on observer agreement. Gastroenterology 1996; 111: 85-92”

Naming

The study leading to this criterion was performed at the symposium of the World Congress of Gastroenterology in Los Angeles, earning its name.

Marseille Classification of Pancreatitis
Rational

The main goal of the Marseille Symposium was to clarify the ambiguity in the literature concerning terms such as “Acute pancreatitis” which writers defined differently. The Marseille classification sought to solve these problems with a single well defined set of criteria for classifying pancreatitis. It has been noted in at least one study⁸ on pancreatitis how difficult it is to obtain the official Marseille publication, which was also apparent when trying to obtain an originating document for the purposes of the citation history. As a result, what seemed to be the most widely used document9 based on the Marseille classification was used for the purposes of the citation history.

Criteria

The Marseille classification of pancreatitis subdivided pancreatitis into “acute” and “chronic”
Acute Pancreatitis Defined as restitution of the pancreas when the cause of the disease is removed, such as a gallstone.
Chronic Pancreatitis Defined as the progression and or worsening of general lesions despite removing the source of the disease, such as alcoholism.

Citation History

Citations for “Sarles H, Sarles JC, Camatte R et al. Observations on 205 confirmed cases of acute pancreatitis, recurring pancreatitis, and chronic pancreatitis. Gut 1965. 6; 545”

Naming

The Marseille symposium on pancreatitis took place in Marseille, Italy.

Milan Criteria for Liver Transplantation
Rational

The Milan criteria¹⁰ was developed to analyze the effectiveness of liver transplantation as a treatment for unresectable hepatocellular carcinomas in patients with cirrhosis. The need for such a criteria was recognized because of the limited supply of livers for transplantation and the uncertainty of transplantation as a viable treatment.

Criteria

The Milan criteria considers someone with unresectable hepatocellular carcinomas eligible for liver transplantation if they fall into one of these two categories: Number of Tumors Size ≤ 3 Each < 3 cm
Only 1 < 5 cm

Citation History

Citations for “Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carinomas in patients with cirrhosis. N Engl J Med 1996; 334: 693-699.”

Naming

This classification system is known as the Milan criteria because multiple institutions that contributed to this study were all located in Milan, Italy. For example, the patients whose medical information was used to complete this study were all seen at the Division of Gastrointestinal Surgery of the National Cancer institute in Milan, Italy.

Milwaukee Criteria for Sphincter of Oddi Dysfunction
Rational

The Milwaukee criteria¹¹ deals with overlaps in the etiology of the motor dysfunction of the sphincter of Oddi by trying to develop patient group classifications that describe the severity of their sphincter of Oddi dysfunction.

Criteria

The Milwaukee system uses a scoring method, determining the severity of a patient’s SOD. Factors
A Biliary-like pain
B Elevated liver function tests documented = 2 times
C Delayed drainage of contrast medium at endoscopic retrograde cholangiopancreatopgraphy (ERCP)
D Dilated common bile duct with corrected diameter = 12mm at ERCP

Classification:
Type I All four factors present
Type II Factor A in addition to = 1 other factors
Type III Only factor A present

Citation History

Citations for “Hogan WJ, Greenen JE. Biliary dyskinesia. Endoscopy. 1988; 20: 179-183”

Naming

This criteria was formulated after an extensive study and a meeting of experts in Milwaukee, United States.

The Oslo Definitions for Celiac Disease
Rational

The incidence of celiac disease (CD) has been increasing in the United States over the past few decades, very often going undiagnosed.¹² With greater recognition and literature concerning CD arising, the Oslo definitions¹³ seek to create a consensus concerning the definitions for the various types of this multifaceted disorder and its related terms. The Oslo definitions came about as the result of a literature review concerning CD related terms from the database PubMed.

Criteria

The Oslo definitions cover a vast array of CD related terms, for simplicity only the definitions of different types of CD are listed here.
Celiac Disease A Chronic small intestinal immune-mediated enteropathy caused by dietary gluten in genetically pre-disposed individuals.
Typical CD Gluten-induced enteropathy with signs of malabsorption. The use of this term is discouraged because “typical” implies this form of CD is the most common when in fact the presentation of CD has changed over time to include symptoms such as anemia, fatigue and abdominal pain.
Atypical CD Used only in reference to typical CD and its use is discouraged. Traditionally, this term has been used to describe patients with gluten-induced enteropathy who do not have weight loss but may have irritable bowel syndrome symptoms, liver dysfunction or gastrointestinal symptoms.
Symptomatic CD Characterized by clinically evident gastro-intestinal and/or extraintestinal symptoms resulting from gluten consumption.
Asymptomatic CD Used to describe patients who do not present common symptoms of CD
Classical CD CD defined as showing signs and symptoms of malabsorption such as diarrhea, steatorrhea, weight loss or growth failure must be present.
Non-classical CD CD presenting without signs and symptoms of malabsorption
Silent CD Equivalent to asymptomatic CD. The use of this term is discouraged.
Subclinical CD CD below the threshold of clinical detection. Often used in reference to silent CD.
Overt CD Most often used to describe clinically evident gastrointestinal or extra-intestinal symptoms. The use of symptomatic CD is encouraged as a replacement of Overt CD.
Refractory CD Describes persistent or recurrent symptoms of malabsorption and signs of villous atrophy despite a gluten free diet for man than 12 months.
Latent CD Because the authors of the Oslo definitions found 5 different definitions for Latent CD, its use is discouraged to minimize confusion.
Potential CD Refers to people with normal small intestinal mucosa but who are at a higher risk for developing CD as indicated by positive CD serology. This term is used, however, with different definitions.

Citation History

Citations for Ludvigsson JF, Leffler DA, Bai JC, et al. The Oslo definitions for celiac disease and related terms. Gut 2013; 62: 43-52”

Naming

The team of 16 physicians from seven countries responsible for the Oslo definitions collaborated over the phone and internet but also had a meeting in Oslo, Norway.

Prague Criteria for Barrett’s Esophagus
Rational

The Prague classification system for Barrett’s Esophagus¹⁴ was developed in order to create one easily understood and effective method of describing Barrett’s Esophagus. Before this system, there was not only an absence of effective criteria but an abundance of ineffective methods for classifying Barrett’s Esophagus.

Criteria

The Prague system consists of two components, a “C” number and an “M” number.
Circumference (C) Describes the height above the gastroesophageal junction for which there is Barrett’s mucosa completely encircling the circumference of the esophagus.
Maximum (M) Describes the maximum height any “tongue” or continuation of the Barrett’s mucosa reaches in the esophagus.

Using this system, a description of a Barrett’s esophagus with a maximum circumferential height of 3cm and an absolute maximum height of 4cm can be abbreviated as “C3M4”.

Citation History

Citations for “Sharma P, Dent J, Armstrong D, et al. The development and validation of an endoscopic grading system for Barrett’s esophagus: The Prague c & m criteria. Gastroenterology 2006; 131: 1392-1399”

Naming

This criterion was first put forth at the United European Gastroenterology Week in Prague, September 2004.

Rome Criteria For Irritable Bowel Syndrome
Rational

What is referred to today as the Rome Criteria has a long history¹⁵ which makes it difficult to single out one particular paper as the “originating” paper. Because of this, both the first diagnostic criteria for irritable bowel syndrome that the Rome Criteria has been based off of and the most recent Rome Criteria are presented. The evolution of the Rome criteria is conveniently laid out by W. Grant Thompson in his article Road to Rome.¹⁵

Criteria

The Manning criteria¹⁶ for IBS presents six factors of IBS, the more of which a patient presents with the more likely it is that he or she actually has IBS. The six symptoms are:
1. Abdominal distention
2. Alleviation of pain by bowel action
3. More frequent stools with onset of pain
4. Looser stools with onset of pain
5. Rectal passage of mucus
6. A sensation of incomplete evacuation

The Rome III criteria¹⁷ for Irritable Bowel Syndrome follows in the long tradition of the Rome criteria, building upon the Rome II criteria to update diagnosis and treatment recommendations. Concerning IBS, the diagnostic criteria is as follows:
Recurrent abdominal pain or discomfort at least 3 days a month in the last 3 months associated with at least 2 of the following:
1. Improvement with defecation
2. Onset associated with a change in frequency of stool
3. Onset associated with a change in form (Appearance) of stool

Citation History

Citations for “Manning AP, Thompson WG, Heaton KW, Morris AF. Towards positive diagnosis of the irritable bowel. Br Med J 1978;2:653-654”
Citations for “Longstreth G, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology 2006; 130: 1480-1491”

Sendai Consensus Guidelines for Management of Intraductal Papillary Mucinous Neoplams and Mucinous Cystic Neoplams of the Pancreas
Rational

The increased recognition of two types of non- inflammatory cystic lesions of the pancreas, intraductal papillary mucionous neoplams (IPMN) and mucinous cystic neoplasms (MCN), prompted the working group of the International Association of Pancreatology to put out what is now known as the Sendai consenss guidelines¹⁸ for the management of IPMN and MCN.

Criteria

The Sendai consensus guidelines seek to answer 6 clinical questions with 18 subdivisions. Like the Sydney system, there is no practical method to summarize the Sendai consensus guidelines. Instead, the 6 areas of IPMN and MCN management it is concerned with are listed here.
1. Definition and Classification
2. Preoperative evaluation
3. Indication for resection
4. Method of resection
5. Histological questions
6. Method of follow-up

Citation History

Citations for “Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology. 2006; 6: 17-32”

Naming

The Sendai consensus guidelines were formulated during the 11th Congress of the International Association of Pancreatology which was held in Sendai, Japan.

Sydney System for the Classification of Gastritis
Rational

The Sydney Working Party developed the Sydney System¹⁹ in order to create a universal system that took into account the widespread use of endoscopic targeted biopsy and recognition of the H. pylori infection’s role in gastritis. It combines the etiology, topography and morphology of gastritis to create a working formula for its classification. It should be noted that The Sydney System was actually put fourth as six papers in the Journal Of Gastroenterology and Hepatology however for the purposes of this review, only the histological division was used for the citation history and criteria because it was the most frequently cited of the Sydney System papers.

Criteria

The Sydney System is not easily reproducible; to do so would be tantamount to including the entirety of the original paper so simply the main components of the histological division, as outlined in the paper, are named here.
Etiology Pathogenic associations
Topography Pangastritis, gastritis of antrum, gastritis of corpus
Morphology Graded variables: Inflammation, activity, atrophy, intestinal metaplasia, H. Pylori Non-Graded variable: Non- specific, specific

Citation History

Citations for “Price AB. The Sydney system: histological division. Gastroenterol. Hepatol. 1991;6: 209-22”

Naming

This criteria was the result of the efforts of the Sydney Working Party.

Toronto Consensus Guidelines for Medical Management of Nonhospitalized Ulcerative Colitis
Rational

Acknowledging the advancement of medical care for patients with Ulcerative Colitis (UC), the working group responsible for the Toronto consensus guidelines²⁰ conducted a thorough and systematic literature review in order to reevaluate the management of UC.

Consensus

The Toronto consensus guidelines include 34 statements on 5 classes of drugs, in addition to other conclusions.

Like the Sendai consensus guidelines, it would not be practical to include all the statements of the Toronto consensus here. The paper nicely summarizes its finding in a single table, whose main categories are listed here.
1. Statements regarding 5-ASA
2. Statements regarding corticosteroids
3. Statements regarding immunosuppressants
4. Statements regarding anti-TNF therapy
5. Statements regarding other agents

Citation History

Because the Toronto consensus guidelines came out last year, reporting its citation history is not practical or an accurate measure of its acceptance.

Naming

The working group met for 2 days in Toronto, Canada.

A CASE REPORT

Hypertensive Urgency Secondary to Tablet Retention in a Patient with Achalasia

February 2015 • Volume XXXIX, Issue 2

Stanley Yakubov,Kadirawel Iswara,Ira Mayer,Rabin Rahmani

Achalasia is a rare disease (incidence of 1.6 cases per 100,000) that is due to degeneration of inhibitory neurons in the myenteric plexus that leads to failure of lower esophageal sphincter relaxation. It can occur at any age from childhood to old age, with both sexes equally affected. Patients complain of dysphagia of solids and liquids, non cardiac chest pain, regurgitation, weight loss and cough. Surgery is the standard of care for achalasia, but endoscopic intervention (e.g. botulinum toxin injection) can server as a temporizing measure. We report a rare case of an elderly female who presented with dysphagia, weight loss, headaches and diaphoresis and found to be in hypertensive urgency secondary to esophageal tablet retention.

Stanley Yakubov MD¹ Kadirawel Iswara MD² Ira Mayer MD² Rabin Rahmani MD² ¹Department of Medicine ²Division of Gastroenterology, Department of Medicine, Maimonides Medical Center, Brooklyn Campus of Albert Einstein College of Medicine, Brooklyn, NY

INTRODUCTION

Achalasia, meaning “failure to relax”, is a rare disease that may occur from childhood to old age, but most commonly happens between the ages of 25 and 60 with both sexes equally affected.^5,6 Achalasia was initially known as cardiospasm and was treated with a sponge attached to the distal end of a carved whalebone. In 1937 Lendrum noted that the syndrome was caused by incomplete relaxation of the lower esophageal sphincter (LES) and renamed it as achalasia.¹ We report a rare case of an elderly female who presented with dysphagia, weight loss, headaches and diaphoresis and found to be in hypertensive urgency secondary to esophageal tablet retention.

Case Description

An 82 year-old female with past medical history of hypertension and achalasia presented to the emergency department with severe headaches and diaphoresis. On further questioning, she reported difficulty swallowing solids and liquids and unintentional weight loss of 13 pounds over a 5-month period. Home medications included amlodipine and valsartan. On admission, her temperature was 96.7 ?F, blood pressure 207/110 mmHg, pulse 90 beats/min, respiratory rate of 20 breaths/min, and oxygen saturation of 95% on room air. Physical examination and laboratory analysis were unremarkable. Telemetry monitoring and intravenous (IV) administration of anti-hypertensive medication for presumed hypertensive urgency was instituted with subsequent improvement of her blood pressure (BP). Computed tomography of her chest and abdomen showed markedly dilated distal esophagus with fluid and debris (Figure 1). Esophagogastroduodenoscopy (EGD) revealed a fluid filled esophagus with 41 undigested tablets (Figure 2). The tablets were removed (Figure 3) using a Roth net and subsequent achalasia pneumatic balloon dilation was performed with good results. The patient was subsequently discharged from the hospital tolerating a soft diet and with significant improvement in her BP.

Discussion

Achalasia is failure of relaxation of the LES due to degeneration of inhibitory neurons in the myenteric plexus. Inhibitory neurons release nitrous oxide and vasoactive intestinal peptide neurotransmitters and cause muscle relaxation.⁶ It has been hypothesized that the degeneration of these inhibitory neurons in achalasia is associated with class II HLA antigen DQw1 and related to herpes and measles infection.¹ Achalasia is a rare disorder with incidence of 1.6 cases per 100,000 and is about 200 fold more frequent in patients with Down syndrome.^5,6 Symptoms often include dysphagia of solids and liquids, non cardiac chest pain, regurgitation, weight loss and cough.^2,3 Complications include retention esophagitis, aspiration pneumonia in up to 8% of patients and esophageal squamous cell carcinoma with estimated risk ranging 30 times higher than in the general population.⁶ Diagnostic studies include barium swallow, endoscopy and esophageal manometry.² Achalasia typically appears on radiographs as a dilated esophagus that terminates with a “bird beak” appearance. The therapeutic goal in achalasia is to reduce the LES pressure and allow gravity to facilitate esophageal emptying. For patients that are surgical candidates, Heller myotomy is the treatment of choice. Alternative treatment options include medications, botulinum toxin injection and endoscopic intervention. The efficacy of botulinum toxin injection at 1 month is up to 90%, but is only up to 46% at 12 months.³ After 5 years, endoscopic pneumatic dilation has a response in up to 85% of patients in retrospective study, but only in 26% in prospective study. Complications include hemorrhage in roughly 0.4% and perforation in up to 10%.6 Endoscopic balloon dilation was found to be superior to endoscopic botulinum toxin injection with better symptom relief, 68.2% vs. 40.6% respectively, and required less additional therapy, 25% vs. 46.6% respectively. Laparoscopic myotomy with fundoplication provided better symptom relief than all other surgical and endoscopic techniques, however, the overall complication rate after laparoscopic myotomy was higher than for endoscopic balloon dilatation, 6.3% vs. 1.6% respectively.⁴ Patients who are unable or unwilling to undergo any procedures, or in whom botulinum toxin injections fail can choose to undergo medical treatment for achalasia. Medical treatment often revolves around nitrates and calcium channel blockers as they relax the smooth muscle of LES. Studies have shown that calcium channel blockers efficacy varies greatly and is 50-90% at 6-18 month follow-up and side effects such as peripheral edema, hypotension, and headache were seen in up to 30%.³ In patients with concomitant hypertension, calcium channel blockers have the additional benefit of acting as an anti-hypertension medication.

CONCLUSION

Although EGD and balloon dilation were successful in relieving dysphagia in our patient, careful BP monitoring and periodic dysphagia questioning should be considered in all patients with achalasia and hypertension who are treated with calcium channel blockers.

Furthermore, achalasia should be considered in all individuals with dysphagia. Early recognition and treatment of achalasia will prevent complications and allow for a better quality of life.

INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #9

Infection Risk Among Elderly with Inflammatory Bowel Disease

February 2015 • Volume XXXIX, Issue 2

Sasha Taleban

With an aging population, the number of older patients with Crohn’s disease (CD) and ulcerative colitis (UC) and the health care costs associated with their care is expected to increase. This trend will lead to a subsequent rise in the use of immunosuppression. The risk of infection, particularly as a result of opportunistic infections in the setting of immune modifying and biologic therapy, is of utmost concern to providers and a common reason for hospitalization. In addition to medications, ongoing active intestinal inflammation, multimorbidity, malnutrition, immunosenescense, hospitalization and surgery all contribute to the predisposition to infection. Recognizing and addressing these risk factors is key to managing older IBD patients in a cost-effective manner.

BACKGROUND

The inflammatory bowel diseases (IBD), chronic inflammatory conditions of the intestine, are comprised of Crohn’s disease (CD) and ulcerative colitis (UC). Long believed to be a disease of the young, a growing number of IBD patients are over the age of 65.¹ Compared to non-IBD elderly patients, the costs associated with caring for elderly IBD patients may be two fold higher.²

Unique challenges exist in the diagnosis and treatment of CD and UC in the elderly. Multimorbidities and atypical clinical presentations can cast doubt on the diagnosis. IBD management can be complicated by the patient’s functional status and polypharmacy even as the disease course may be milder when diagnosed in advanced age. Additionally, the lack of medical efficacy trials and appropriate clinical endpoints (i.e., subjective versus objective) in older IBD patients adds to the complexity of treatment decisions. One of the important considerations in the treatment of elderly patients is the development of serious infection. Multiple factors, often existing in tandem among elderly, increase the susceptibility to infection. These include ongoing active intestinal inflammation, polypharmacy, multimorbidities, poor nutrition, immunosenescence, hospitalization, and surgery. Immunosuppressive therapy, especially a combination of biologics (i.e., anti-TNF agents) and thiopurines (i.e., azathioprine, methotrexate), used to induce and maintain disease remission in adults, has been associated with an increased risk of infection and decreased response to vaccination in the elderly.^3,4

The spectrum of infections in IBD is wide and can vary from uncomplicated viral upper respiratory infections to gram-negative sepsis. Strategies to prevent infection through vaccination and universal precautions are key. Early recognition and management of risk factors is significant in blunting the effect of serious infections. In a health care system moving towards tying reimbursement to quality measures, prevention of infection in elderly IBD is part of sound medical practice and important in managing costs.

Epidemiology and Cost

Between 10-30% of individuals with IBD are over the age of 60, while 10-15% are diagnosed as elderly.^1,5,6 As IBD prevalence rates increase and because the disease is associated with a relatively unchanged life expectancy, the number of elderly Crohn’s disease and ulcerative colitis is expected to grow. Since many patients with IBD transition to old age with their disease, this necessitates a lifetime of care. By 2050, the US census bureau projects the expected number of elderly to double.⁷ Over the same time, Medicare spending will increase from 2.6% of the gross domestic product to 9.2%.⁸ Compared to non-IBD patients, IBD patients are seven times as likely to incur healthcare costs, five times more likely to have an outpatient clinic visit, and three times as likely to undergo an inpatient stay.²

Maintenance of disease remission in CD and UC is directly associated with improved patient outcomes and quality of life. In patients with moderate to severe active IBD, thiopurines and biologics may be the most effective options. Over the last two decades, the use of these medications has increased. While this has decreased IBD-related hospitalizations and surgeries, there has been an associated increased rate of adverse events attributable to immune suppression, namely malignancy and serious infections.^10,11 Pneumonia, cellulitis, and perianal and intraabdominal abscesses are commonly cited serious infections, often leading to an inpatient stay.¹² Infection-related hospitalizations of IBD inpatients are associated with longer hospital days and higher hospitalizations costs.¹³

Risk Factors for Serious Infections in Elderly IBD

Multiple factors influence infection risk in elderly IBD patients.Multimorbidity, polypharmacy, immunosenescence, malnutrition, immunosuppressive agents, hospitalization and surgery all play important roles. When evaluating all potential factors, active intestinal inflammation is the strongest predictor of serious infection.¹² Treatment with infliximab, a biologic, is associated with a higher risk of infection in the absence of higher mortality, suggesting that the mortality rate with treatment of active disease outweighs the risks associated with the anti-TNF, including infection.¹²

Persistent active gut inflammation can predispose to infection. Dysbiosis, or disruption of the gut microbiota, thought to be in part associated with pathogenesis and changing disease activity in IBD,¹⁴ predisposes to Clostridium difficile infection. C. difficile colitis, much like CMV colitis, is associated with more severe IBD and may reflect incompletely controlled active inflammation.^15,16 Advanced age is a well-known risk factor for the development of C. difficile infection, which in the elderly is associated with significant morbidity and mortality, accounting for a 20% readmission rate and a 9% mortality rate in hospitalized patients.¹⁷

Multimorbidity

As the prevalence of many diseases rises with age, multimorbidity becomes more prevalent over time affecting 35% of Americans over the age of 65 and 70% of those over the age of 80.¹⁸ One third of patients over 65 have four or more comorbidities and both the number and proportion of patients with multiple comorbidities is expected to grow.^18,19 The resulting costs are revealing, as two-thirds of Medicare patients with multimorbidity account for 96% of Medicare expenditures.18 In elderly IBD, the most common comorbid conditions, cardiovascular illness, chronic lung disease, and diabetes,²⁰ can increase susceptibility to complications and effect medical treatment options. Anti-TNFs, for instance, are contraindicated in New York Heart Association Class III/IV heart failure, while corticosteroids can worsen diabetes.²¹

Polypharmacy

Multimorbidity often requires several prescriptions, and older IBD patients take an average of 7 medications on a daily basis.²⁰ Additionally, older patients are at increased risk for adverse events due to the changes in drug metabolism and decreased drug clearance in the elderly. In the setting of a lower glomerular filtration rate, the clearance of corticosteroids in older patients is decreased, potentiating any systemic side effects, including infection.¹ Polypharmacy is associated with increased risk of drug-drug and drug-condition interactions which need to be carefully considered when managing older IBD patients. For example, antibiotic and proton pump inhibitor use can predispose to C. difficile colitis.²²

Malnutrition

In IBD, malnutrition may result from small bowel resection, malabsorption, medication side effects, and changes in diet. Comorbid conditions impact the nutritional state of elderly. In one study across Europe, the United States, and South Africa, over a third of hospitalized older adults met the criteria for malnutrition.²³ In active IBD, severe malnutrition affects a third of patients and serves as a risk factor for mortality in hospitalized patients.^13,24 Poor nutrition is a recognized risk factor for opportunistic infections.²⁵

Immunosenescence

While poor nutrition is associated with an impaired immune system, aging is associated with immunosenescence, a gradual deterioration of the immune system associated with impaired stem cell regeneration, neutrophil and macrophage dysfunction, altered barrier function, and decreased production of B-cells and T-cells.^26-28 These changes can increase the susceptibility to infection and the persistence of infections due to an inability to clear the pathogen. The elderly have been shown to have higher rates of bacteremia and sepsis and incident rates of sepsis have increased 20% faster in elderly when compared to younger patients.^29,30 In older IBD patients on immunosuppression, the risk of severe infection is greater than younger patients.³

Overall, respiratory infections, including pneumococcal pneumonia and influenza, are the most common type of infection in IBD patients. Among opportunistic infections in CD and UC, herpes zoster may be most often seen.³¹ Many of the common infections in IBD are vaccine-preventable and in older adults, these infections tend to have a more severe disease course.⁴ Nonetheless, the vaccination rates in IBD patients are suboptimal, in part because it is not a point of discussion during office visits.³² Once patients are scheduled to undergo vaccination, immune suppression therapy can reduce their efficacy. Compared to patients on monotherapy with biologics or thiopurines, adults on dual therapy have a decreased response to vaccines.⁴

Medications

For many providers caring for elderly IBD, the potential adverse effects secondary to immune suppression are particularly concerning. In older patients, data regarding safety of anti-TNFs is derived mainly from the rheumatology literature, where the results are mixed.^33,34 In rheumatoid arthritis, infliximab at higher than standard dose (10 mg/kg) when combined with methotrexate led to more than a threefold increased risk of serious infection compared to those who received methotrexate alone (P = 0.013).³⁵ In IBD patients, a large retrospective study evaluating the use of infliximab and adalimumab found an increased rate of severe infection (11% vs. 0.5%) compared to patients treated with other IBD medications.³ A retrospective case-control study from the Mayo Clinic showed no increase in opportunistic infection with combination anti-TNF and thiopurine therapy.³¹ A community-based retrospective cohort study of patients on anti-TNF therapy found that 44% of older patients versus 32% of younger patients developed infection, but this was not statistically significant.³⁶ Another study examining claims data of >20,000 matched Crohn’s disease patients found rate ratios of 6.18 and 1.75 for opportunistic infection and sepsis in patients on combination anti-TNF and thiopurine therapy, but this was not statistically significant. Other studies have suggested an increased risk of adverse events or an increased rate of anti-TNF discontinuation in patients > 60 years old.^38,39 After 24 months, 47% of older anti-TNF users stopped therapy compared to 10% of younger patients.³⁹ Among the 38 older IBD patients who ceased therapy, 8 (21%) stopped therapy due to infectious complications. Six of the eight were either on concomitant thiopurines or corticosteroids.³⁹ Although dose or duration with monotherapy infliximab does not appear to increase the risk of serious infection, it’s unclear if this holds true for combination infliximab and thiopurine therapy.¹²

Narcotic and corticosteroid therapy have consistently been associated with serious infections in IBD. Narcotics are associated with almost a two-fold increase in infections.¹² Meanwhile, corticosteroids appear to drive the infection risk among patients undergoing medical therapy, especially in two- or three-drug regimens that include thiopurines.^12,31 A population-based cohort Canadian study revealed a time-dependent risk of infection among corticosteroid users in incident older IBD patients.⁴⁰ Despite these findings and guidelines that strongly state against the use of corticosteroids for maintenance therapy in CD and UC,^21,41 one study showed that 32% of older IBD patients were on chronic corticosteroids while just 10% were treated with thiopurines or biologics.²⁰

Hospitalizations and Surgery

Rates of hospitalization for UC and CD are rising and this has been associated with significantly increased costs.⁹ Infections account for over a quarter of all IBD hospitalizations and infection-related inpatient stays are associated with excess hospital stay, higher costs, and a four-fold increased mortality.¹³ Elderly patients account for an inordinately high percentage of IBD-related hospitalzations.^1,42 These hospitalizations are associated with increased costs and mortality rates in older IBD patients even when adjusting for comorbidity.⁴²

Among elderly, nosocomial infections cause a particularly high disease burden. Older patients have longer length of stays and are more likely to be discharged to skilled nursing facilities.⁷ The inpatient elderly patient is at higher risk for C. difficile- associated diarrhea, nosocomial pneumonia, foley- associated urinary tract infections, and intravenous catheter-associated infections. These infections have been associated with worse patient outcomes in IBD patients.^16,43

Although most hospitalized and outpatient IBD patients can be treated effectively with medical therapy, surgical intervention is often required. Using the Nationwide Inpatient Sample, older patients were less likely to undergo nonelective surgery for UC but as likely to undergo CD-related surgery as their younger counterparts.⁴² The overall risk of complications between elderly and nonelderly patients was similar.⁴² A recent population-based cohort study found that elderly IBD patients prescribed corticosteroids were significantly more likely to have undergone surgery.⁴⁰ Few studies report on the non-medication related risk of infectious complications after IBD-related surgery. A single center study found that after controlling for duration of disease, previous surgery, medications, and comorbidity, patients ≥60 years old had a higher post- operation wound infection rate than younger patients (13% vs. 1%).⁴⁴

Most studies evaluating the risk of infection following IBD-related surgery have examined the effect of preoperative anti-TNF therapy on postoperative complications. A meta-analysis reported a significantly higher rate of infectious postoperative complications in anti-TNF treated CD patients (OR 1.45, 95% CI: 1.03- 2.05) but not in UC.⁴⁵ The data regarding the preoperative use of corticosteroids and immunosuppressants and the associated postoperative complications is mixed, especially in the elderly.⁴⁶ Part of the controversy with preoperative biologic and thiopurine therapy is that disease activity, itself a risk for postoperative infection, often is not accounted for in the studies examining postoperative infections.

Strategies Going Forward

Health care costs for chronic medical conditions like IBD are significant and are expected to grow with an aging population. Recognizing the factors behind these costs and minimizing their impact is key. Among elderly patients, the clinical and financial burden associated with adverse events like infection is substantial. Because clinical symptoms in IBD often do not correlate with active inflammation, an important strategy to balance the risk of therapy and potential infectious complications is objective assessment of disease activity through labs, imaging, and colonoscopy. Ongoing objective evaluation can help ensure that patients are adequately treated and decreases the risk of hospitalization and surgery. Due to the mild disease course of IBD and concern for adverse events associated with immunosuppressives in the elderly, a “step-up” treatment approach, utilizing nonimmunosuppressives before advancing therapy, often is used to treat underlying inflammation. Advanced age is not a contraindication for use of thiopurines and biologics, and in moderate to severe disease, these medications may be indicated. In general, monotherapy with either biologics or thiopurines, rather than the combination of the two, is typically preferred in older IBD patients.

Beyond assessing patients for appropriate therapy, other strategies to prevent infection among elderly IBD patients exist. In hospitalized patients, these include appropriate antibiotic use to avoid C. difficile and limiting urine foley catheters and the duration of mechanical ventilation to prevent hospital-acquired pneumonia.⁴⁷ Among IBD patients specifically, limiting corticosteroid use for induction of remission in IBD, updating vaccinations for influenza and pneumococcal pneumonia, and the use of sterile techniques for central venous catheters placement are not only imperative for effective patient care but are part of the Physicians Quality Reporting System (PQRS) by the Centers for Medicare and Medicaid Services (CMS).⁴⁸

Malnutrition and polypharmacy are potentially modifiable risk factors for infection in elderly IBD. Assessing nutritional status is an important aspect of care in IBD. Nutritional care involves identifying deficiencies and providing appropriate supplementation. Polypharmacy can provide challenges in IBD management and in the elderly, medication reconciliation can often identify unnecessary prescriptions.⁴⁹ Part of an effective approach to malnutrition and polypharmacy involves a multi-disciplinary collaboration between dieticians, pharmacists, primary care physicians, and gastroenterologists.

There is a paucity of data in elderly IBD and the risk of infection in the age group. Further research is needed examining the natural history of IBD, the efficacy and complications of various medical and surgical therapies, appropriate clinical goals of therapy, and the most common infections among elderly patients. Until then, guidelines and recommendations that direct the care of all adult IBD patients can be utilized in the elderly to prevent serious infections. The American College of Gastroenterology suggest testing for tuberculosis, hepatitis type B, and in endemic areas, specific fungal infections, prior to initiation of biologics.^21,41 Additionally, the CDC recommends patients over the age of 65 undergo vaccinations for influenza, pneumococcal pneumonia, and zoster. In the setting of immunosenescence and multiple comorbidities, older adults may benefit from post-vaccination titers to determine if further booster shots are needed.

GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, #6

Median Arcuate Ligament Syndrome

February 2015 • Volume XXXIX, Issue 2

Ihsan Al-Bayati,

Richard W. McCallum

In this article, we discuss the pathophysiology, diagnosis and treatment of median arcuate ligament syndrome (MALS), an uncommon disorder characterized by epigastric abdominal pain accentuated by meals and weight loss associated with nausea,vomiting and gastroparesis.

Median arcuate ligament syndrome is an uncommon disorder first described in the 1960s. It is characterized by epigastric abdominal pain accentuated by meals and weight loss associated with nausea, vomiting and gastroparesis. Abnormal gastric electrical rhythm has also been reported. Abdominal bruit is a striking feature that is present in some cases. It is a diagnosis of exclusion that should be considered when there is a subjective presentation of severe epigastric and right upper quadrant abdominal pain which is out of proportion to objective findings. Whether using Doppler study, CT angiography, MRA or angiography, the main and most important goal is assessing both inspiratory and expiratory phases of the celiac artery to demonstrate reduction in the compression during inspiration. The treatment is surgical release of the median arcuate ligament to achieve decompression of the celiac artery and the celiac plexus. An evolving role for endoscopic ultrasound both in diagnosis and management is also discussed.

Ihsan Al-Bayati, MD, First Year Resident, Department of Internal Medicine, Texas Tech University, Paul L. Foster School of Medicine Richard W. McCallum, MD, Professor and Founding Chair of Medicine, Department of Internal Medicine Director, Center of Neurogastroenterology and GI Motility, El Paso, TX

INTRODUCTION

Median arcuate ligament syndrome (MALS), also known as celiac artery compression syndrome (CACS), Dunbar syndrome and celiac axis syndrome is a cause of chronic epigastric and right upper quadrant abdominal pain that is explained by the median arcuate ligament, a fibrous tissue connecting the two crura of the diaphragm, compressing the celiac artery and its companion structure, the celiac ganglion.¹ Theories explaining the pathophysiology of the disease suggest either neurogenic or vascular origin.² The clinical presentation is with abdominal pain, weight loss and gastroparesis. It is a diagnosis of exclusion. Most patients will undergo extensive laboratory and imaging workup looking for the diagnosis and some might undergo unnecessary surgical procedures like cholecystectomies and appendectomies.³ The treatment traditionally has been surgical with the goal of releasing the median arcuate ligament (MAL), resulting in restoration of blood flow to the celiac artery and relieving the entrapment of the celiac ganglion fibers.^4,5

Etiology and Pathophysiology

MALS or CACS, also named Dunbar syndrome is a chronic epigastric and right upper quadrant abdominal pain exacerbated by eating and explained by the compression of the celiac artery by the median arcuate ligament at the level of the diaphragm.⁴

Understanding the anatomy of the MAL and the extensive collateral blood supply formed by the celiac artery, superior mesenteric artery (SMA) and the inferior mesenteric artery (IMA) is a key to understanding the pathophysiology of MALS.

The MAL is a fibrous structure that connects the diaphragmatic crura and crosses the aorta just proximal to the origin of the celiac artery. The celiac plexus originates from somatic branches of the phrenic and vagus nerves, parasympathetic preganglionic and sympathetic postganglionic fibers, and preganglionic splanchnic nerves. Its anatomic relationship to the celiac artery origin means that the MAL would compress both the celiac artery as well as the celiac ganglion.6 (Figure 1).

It was first suggested that the compromise of blood supply by compression of the celiac artery would lead to post prandial ischemia and hence worse abdominal pain. However the SMA and IMA are widely patent in this entity and the stomach has extensive collateral blood flow from the gastric and epiploic arcades leading to the conclusion that ischemia is not the explanation for the abdominal pain and other associated symptoms. It was suggested later that pressure on the celiac plexus might be the main etiological factor in MALS2 and thus it could also explain the accompanying findings often present in addition to the abdominal pain, namely nausea, vomiting, gastroparesis, and gastric electrical dysrhythmias.

Many theories have been proposed to explain this altered anatomy including congenital origin as it has been found in children and twins,^7,8 as well as traumatic origin.⁹The presentation in adults could be explained by a combination of a congenitally early take off origin of the celiac artery and/or an abnormally thickened MAL with or without accompanying arteriosclerosis in the vessel that may predispose to the “narrowing” finding on expiration.

Clinical Manifestation

Most patients report chronic epigastric and right upper quadrant abdominal pain which is accentuated after meals. Weight loss is explained by reluctance to eat for the fear of provoking pain. There are also symptoms that are manifestations of delayed gastric emptying, namely nausea and vomiting. In addition the normal gastric electrical rhythm has been reported as irregular (e.g. tachygastria) contributing to nausea and vomiting as well as impaired gastric motility. This is all consistent with the neurogenic pathophysiology of the syndrome by inhibiting the gastric neuromuscular function.² As previously stated, these patients usually undergo extensive workups including computed tomography (CT) scans, magnetic resonance imaging (MRI), angiographies, and some even undergo surgical procedures including cholecystectomies, appendectomies, laparoscopic or even gynecological procedures to make the diagnosis or at least try to relieve the symptoms[10].

On physical examination one striking feature is the finding of an abdominal bruit present in up to thirty five percent of patients based on a review of cases from 1963 to 2012.⁶ In addition there is epigastric and/or right upper quadrant tenderness. Other non-specific findings might be weight loss and cachexia.

Making the Diagnosis

As previously explained, MALS is a diagnosis of exclusion to be considered when the subjective presentation of upper abdominal pain is dominant in the absence of any objective findings. Other causes of upper abdominal pain including but not limited to gastroesophageal reflux disease, pancreatitis, cholecystitis, gastric outlet obstruction and chronic intestinal ischemia from vasculitis or arteriosclerosis have to be considered. Extensive testing and therapy directed at these suspected causes have been unsuccessful.

This syndrome is seen more in females ranging in age between 40-60 years. The fact that the abdominal pain is exacerbated by eating and the possible presence of a bruit along with significant weight loss raises the index of suspicion for the diagnosis.⁴ Imaging is required to confirm the celiac artery compression by the MAL and other imaging is necessary to exclude any other causes of the patients’ symptoms.

The diagnosis can be made through different imaging modalities including duplex ultrasound, CT angiography, magnetic resonance angiography, and arteriography. The findings that are specific for the diagnosis include compression of the celiac artery with changes in the degree of obstruction related to inspiration and expiration, post compression dilation, and elevated velocities of blood flow.^6,11 This is caused by two physiological phenomena; the first is that the aorta is displaced both anteriorly and inferiorly during inspiration. Second, as the diaphragm moves down during inspiration, the crura will relax and the compression on the celiac artery will be relieved.

Duplex Ultrasound

Performed during deep expiration, duplex ultrasound shows increase in the blood flow velocity across the compressed area of the celiac artery and supports the presence of constriction caused by the MAL.¹² An example of the change in velocities is illustrated in two cases reported by Alper Ozel et al.¹³ In the first patient, the peak systolic blood flow velocity during deep inspiration and expiration were 135 cm/second and 308 cm/second, respectively. In the second patient, the peak systolic blood flow velocity during inspiration and expiration were 276 and 430 cm/second, respectively. The advantages of duplex ultrasound over CT angiography or arteriography are that it is noninvasive, less expensive and does not expose the patient to radiation or contrast.

CT Angiography (CTA) and Magnetic Resonance Angiography (MRA)

CTA has several advantages in making the diagnosis over arteriography.1 It shows the diaphragm and its relation to the celiac and SMA. One can rotate the three dimensional images in real time into different viewing angles to find the optimal one. All these options can be achieved with a single dose of contrast and a single dose of radiation compared to arteriography where each view requires additional contrast and radiation exposure, besides the fact that it is less invasive and less expensive than arteriography.

MRA has further advantage of no radiation exposure.¹¹ Both CTA and MRA can be used to document post-operative relief of compression.¹⁴

Arteriography

The gold standard for diagnosis of MALS is the lateral view of aortic angiography.⁵ It shows asymmetric focal narrowing in the origin of the celiac artery of more than 50% during expiration with or without distal dilation. Again, the narrowing changes with the respiratory cycle, being improved during inspiration (Figures 2 and 3). Collaterals may be seen in the anteroposterior view as well as retrograde filling of the celiac via the dilated gastroduodenal artery.

Venkat Kalapatapu et al proposed a new technique to confirm the diagnosis of MALS.¹⁵ The idea was to steal the blood supply from collaterals by injecting a vasodilator after selective cannulation of the SMA; a positive test leads to reproduction of symptoms. Four out of eight patients who had celiac artery compression and patent SMA had positive test and underwent successful surgical treatment. Three out of four were asymptomatic at follow up and one patient had mild abdominal discomfort.

Treatment

When the diagnosis is confirmed with imaging in patients with persistent and unexplained upper abdominal pain by evidence of celiac artery compression, there is no medical therapy. Surgery is the traditional option for those patients. There are different modalities of surgery. The traditional approach is decompression of the celiac artery and celiac plexus by the division of the fibers of the MAL.^2,16 Another approach does achieve decompression with angioplasty and vascular reconstruction but does not address the role of the celiac plexus.^17,18 Laparoscopy and robotic-assisted laparoscopic approach have been utilized successfully.^6,14,19,20 Intraoperative pre- and post- decompression flow velocity studies are performed routinely to increase the success of the procedure. Post-operative angiography usually still shows some mild compression of the celiac artery (<30%) during expiration.

Evolving and New Concepts

Endoscopic ultrasound (EUS) can be a good predictor of response to surgical decompression and a good way to strengthen the diagnosis of MALS. The technique is EUS guided injection of the celiac ganglion with xylocaine and monitoring over the next weeks whether there is any symptom improvement (Figure 4). If so, then there would be more confidence in the diagnosis and hence the decision for surgery.

Another role for EUS is EUS-guided injection of xylocaine and alcohol into the celiac ganglion to further enhance the results of post-surgical decompression when there is some remaining abdominal pain component. EUS guided therapy could also replace the need for repeated surgery should there be recurrence of the symptoms during long term follow up.¹⁸

Outcome and Prognosis

Following surgical decompression, the outcomes have varied widely in the literature mainly because the patients differed in presentations and comorbidities. While symptoms have resolved in most patients after intervention, some others did not have appreciable clinical benefit.^3,21

Post-operative pain relief was achieved in most patients treated with open or laparoscopic median arcuate ligament decompression.6 Reilly et al. reported in their study the outcome of 51 patients followed after surgical treatment for a mean of 9 years.²¹ They concluded that the factors that were associated with the best success rate were post prandial pain (81 percent of patients were cured), age between forty and sixty (77 percent of patients were cured) and pre-surgical weight loss of 20 pounds or more (67 percent of patients were cured). On the other hand patients with an atypical pain pattern, age more than 60, psychiatric disorders or alcohol abuse and weight loss of less than 20 pounds showed less success rate after intervention. In addition if patients had required chronic narcotic use to address pain prior to surgery their response was also less optimal.

SUMMARY AND HIGHLIGHTS

MALS is an uncommon cause of chronic epigastric and right upper quadrant abdominal pain that is out of proportion to any objective data gathered by diagnostic testing.
Pain is not controlled medically and patients may be requiring narcotics.
Additional accompanying findings are nausea, vomiting, unexplained gastroparesis and weight loss.
Whether using Doppler ultrasound, CT angiography, MRA, or angiography, obtaining both inspiratory and expiratory phases is crucial to make the diagnosis since relief of compression on the celiac artery during inspiration must be demonstrated.
Surgical decompression relieves abdominal pain, nausea, vomiting, gastric dysrhythmia, and gastroparesis in most patients but a subset have some continuing pain component.
There are new roles for EUS in the management of MALS.

A) Pre-operatively, it could be a good predictor for surgical response by monitoring patients’ symptom relief after EUS-guided celiac ganglion injection.

B) It has a therapeutic role of celiac plexus neurolysis to supplement the surgical outcome. Furthermore, it could be an alternative to future repeat surgery.

A CASE REPORT

Henoch Schonlein Purpura: A Known But Often Forgotten Culprit in Gastrointestinal Bleeds

January 2015 • Volume XXXIX, Issue 1

Minesh Mehta,Richard P. Rood

¹Minesh Mehta, MD, ²Richard P. Rood, MD, FACP, FACG, AGAF, FASGE, ¹Department of Internal Medicine, ²Digestive Disease Division, University of Cincinnati Medical Center, Cincinnati, OH

INTRODUCTION

We describe an adult case of Henoch Schonlein Purpura presenting with abdominal pain and gastrointestinal bleeding. Colonoscopy revealed multiple erythematous, hemorrhagic, and ulcerated lesions throughout the colon. Biopsies of skin lesions were consistent with leukocytoclastic vasculitis and positive for IgA immunoflourescence.

Case Report

A 45-year-old Caucasian female with primary biliary cirrhosis presented with a 4-day history of nausea, vomiting, diarrhea and abdominal pain.

The abdominal pain started in the right lower quadrant but progressed into a more diffuse, generalized abdominal pain. She quickly developed mucoid, non-bloody diarrhea. Her appetite diminished and she subsequently developed nausea and vomiting. Within 24-48 hours after the onset of gastrointestinal (GI) symptoms, she developed a rash on both lower extremities that began on the feet and spread to the upper legs, groin and arms. The rash was painful and burning in nature but not pruritic. The patient denied recent medication changes, sick contacts, recent insect bites or any history of a similar rash. On review of systems she noted diffuse myalgias and arthalgias but denies fevers, chills and night sweats.

Her medications included albuterol, aspirin, ferrous gluconate, prozac, furosemide, omeprazole, oxycodone, potassium supplement, simvastatin, topiramate and ursodiol. Her past medical and surgical history included diabetes mellitus, depression, hyperlipidemia, primary biliary cirrhosis, lymphedema, meningioma with resection, an incisional hernia repair, debridement of abdominal wound, a laparoscopic cholecsytectomy and a total abdominal hysterectomy during which a small bowel resection was done.

On admission her vitals were normal. Her exam was significant for multiple discrete coalescing 2-10mm erythematous and violaceous palpable, non-blanching, petechiae and purpura involving feet, legs, groins and arms. Her lower extremities also showed signs of chronic venous stasis with 2+ pitting edema. Her abdominal exam exhibited positive bowel sounds, mild tenderness to palpation and distension but there were no peritoneal signs.

Laboratory analysis showed anemia with hemoglobin of 11.5 g/dL and mild hypokalemia.^3,4 Alkaline phosphatase was elevated to 169 (baseline for her) however the rest of her liver panel was negative. Urinalysis revealed 12 RBCs and 30 mg/dL protein. Computed tomography (CT) scan of the abdomen revealed diffuse wall thickening of the colon and distal ileum with inflammatory stranding without evidence of bowel obstruction.

An infectious workup for the diarrhea was pursued including stool cultures, ova and parasites, Clostridium difficile toxin and stool white blood cells. Additionally, an autoimmune panel was sent since vasculitis was on the differential. Inflammatory bowel disease was considered, and the patient was scheduled for a colonoscopy. Dermatology was consulted for skin biopsy. The infectious workup was negative. The complete autoimmune panel was negative except for anti-mitochondrial antibodies. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were elevated to 90 and 8.5 respectively. She developed dark, bloody, sticky stools on her second day of admission with a concomitant drop in hemoglobin. She was scheduled for colonoscopy and started on IV solumedrol 60mg daily.

Biopsy of the skin lesions revealed a positive IgA immuno-fluorescence. Colonoscopy gross findings showed focally, edematous, erythematous, hemorrhagic, thickened and ulcerated lesions of the sigmoid, descending and transverse colon highly suggestive of vasculitis. Colonic pathologic findings showed chronic inflammatory infiltrate with a peri-vascular orientation. A few small vessels showed lymphocytes within their walls.

DISCUSSION

The combination of clinical presentation and positive IgA immuno-fluorescence on dermatopathology supports our diagnosis of HSP. HSP is a leukocytoclastic vasculitis involving IgA immune complex deposition in small vessels. It is classically a clinical diagnosis characterized by palpable purpura, abdominal pain, arthritis/arthalgias and hematuria. Biopsy of the skin and kidney play a confirmatory and prognostic role. In general, prognosis is good, except for patients with renal involvement.¹ HSP has a peak incidence in the first and second decades of life with the annual incidence in children estimated at 14 per 100,000.³ The incidence of HSP in adults is significantly less at 1.3 per 100,000, with a mean age of presentation at 50 years old. Adults suffer higher rates of severe and atypical gastrointestinal complications.3 Mucosal gastrointestinal involvement typically affects the small bowel, however our patient had significant colonic involvement. Steroid therapy improves GI symptoms by decreasing intestinal wall edema and might prevent complications like intussusceptions.⁴

CONCLUSION

We report a 45-year-old female with a history of primary biliary cirrhosis presenting with a GI bleed caused by HSP. In this patient, abdominal pain and bloody diarrhea were the initial symptoms followed by purpuric rash. While gastrointestinal involvement is common in HSP, the diagnosis is difficult when gastrointestinal symptoms precede cutaneous manifestations. Primary care physicians should consider HSP in a PBC patient that presents with abdominal pain. Identifying HSP early as the cause of GI bleed is important because management of HSP includes steroids. Initiating proper therapy early in the disease course can prevent complications like perforation, intussusception, massive GI bleed and bowel infarction requiring surgical intervention.