Page 75 – Practical Gastro

LIVER DISORDERS

Introduction to a New Series: Liver Disorders

October 2014 • Volume XXXVIII, Issue 10

The incidence of newly diagnosed liver disease in the United States is estimated to be 72 per 100,000 population, with hepatitis B and C, alcohol, and nonalcoholic fatty liver disease being the most common etiologies.1 Chronic liver disease and cirrhosis was ranked as the tenth leading cause of death in the United States in 1998,2 and data show that this statistic has remained essentially the same over last 15 years.¹ Further the economic impact of liver disease is quite substantial, with chronic liver disease and viral hepatitis accounting for $1.8 billion annually in inpatient costs. Further, hospitalizations for nonalcoholic fatty liver disease has increased 97% since 2000.^3,4

The substantial burden of liver disease necessitates that healthcare providers treat liver disease proactively. It should be a higher public health priority, and use of non-invasive tests to screen for early stages of fibrosis should be performed.5 New therapies for hepatitis B and C as well as advances in liver transplantation have provided a significant improvement in the short- and long-term management of liver diseases. The goal of this series is to provide a detailed review of the liver and biliary system, which healthcare professionals may use as a reference point in their clinical practice as well as research initiatives. This series will review liver diseases at large, with a focus on fibrogenesis, non alcoholic fatty liver disease, HIV and the liver, and transplantation in patients with hepatitis B or C or HIV infection. Specifically, the article topics included in this series are:

Assessment of liver function tests
Hematological disorders of the liver
Cirrhosis of the liver
Hepatic fibrogenesis
Hepatic failure
Hepatic encephalopathy
Portal hypertension
Ascities
Jaundice and cholestasis
Primary biliary cirrhosis
HIV and liver disease
Autoimmune hepatitis and overlap syndrome
Drug-induced liver disease
Inherited metabolic disease
Nonalcoholic liver disease and nutrition
Alcoholic liver disease
Liver diseases and pregnancy
Liver in systemic diseases
Extrahepatic manifestations of liver disease
Space-occupying lesions/diagnostic approach
Primary malignant neoplasms of the liver
Hepatic transplantation

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A CASE REPORT

A Rare Complication of PEG Tube Placement

September 2014 • Volume XXXVIII, Issue 9

Tanmayee Bichile,Thandar Aung,John Vainder

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INTRODUCTION

Percutaneous gastrostomy (PEG) tube placement is generally regarded as a safe and minimally invasive procedure.¹ First described in 1980, it is now a widely accepted procedure for patients at high risk of malnutrition, with inadequate oral intake over a long period and whenever they are likely to require enteral nutrition for more than 4-6 weeks. Despite its good safety record, PEG placement can be associated with significant complications.² Although the most common complication with PEG placement is periostomal wound infection, injury to intrabdominal organs may occur with the colon being the most commonly injured structure .³ We describe a case of transhepatic placement of PEG tube, which was managed conservatively once diagnosed.

CASE PRESENTATION

A 57 year-old obese, Caucasian female (BMI of 31.6kg/m2) presented to the emergency department (ED) with sudden onset of altered mental status and difficulty breathing. Her past medical history was significant for a total hip replacement, anxiety, depression and chronic hepatitis C. She was found to be septic and the hospital’s sepsis protocol was initiated. Her hospital course was complicated by acute respiratory failure, requiring mechanical intubation for 13 days and acute kidney injury, requiring temporary hemodialysis for two weeks. After fourteen days of treatment for sepsis, intubation and hemodialysis, her mental status slowly improved to normal. Despite this improvement in mental status, she complained of difficulty swallowing, most likely from her prolonged intubation. A video swallow study demonstrated aspiration. PEG tube placement was recommended.

A PEG tube was inserted with the pull method; antibiotics were given prior to procedure. The final position of the gastrostomy tube was confirmed by endoscopy and the skin marking was noted to be 3 cm at the external bumper (due to her obesity and generalized anasarca). She tolerated tube feeds six hours after PEG placement.

On the second post procedure day, her abdominal exam remained benign without any issue tolerating tube feeds. On the third day, in order to evaluate a temperature of 100.3 and diarrhea, a computed tomography (CT) scan of abdomen with contrast was performed. It showed the PEG tube traversing a small portion of the liver with surrounding non-specific induration as it progressed towards the stomach; the liver was otherwise within normal limits. An infectious diseases consult attributed the fever to oxacillin and she remained afebrile once the drug was discontinued.

Liver enzyme tests were normal throughout her hospitalization and her hemoglobin remained stable. A repeat video swallow study revealed that she no longer had evidence of aspiration. A week was given for the PEG tube tract to mature and it was removed endoscopically nine days later without medical issues. The patient was discharged to subacute rehabilitation.

DISCUSSION

Percutaneous endoscopic gastrostomy placement is based on the concept of sutureless approximation of a hollow viscus (in this case the stomach) to the abdominal wall. The first PEG was successfully performed by Dr. Michael W.L. Gauderer in 1975 in the pediatric operating room of University Hospitals of Cleveland in a 4.5 month old child.⁴ Since its inception, PEG tube placement has been widely used as an alternative route for providing enteral nutrition. In the United States alone, 100,000 to 125,000 PEG procedures are performed annually.⁵

The main indications for PEG placement are feeding access and gastric decompression.6 This commonly includes patients with temporary or chronic neurologic dysfunction including those with brain injuries, cerebrovascular accidents, cerebral palsy, neuromuscular and metabolic diseases and impaired swallowing. Head and neck trauma and upper aero-digestive surgery are also important indications. In patients with advanced abdominal malignancies causing chronic obstruction or ileus, a PEG tube can decompress the intestinal tract.²

Complications associated with PEG can be categorized as those related to upper endoscopy (cardiopulmonary compromise, aspiration, hemorrhage, perforation), related to the procedure itself (injury to intra-abdominal organs, bleeding) and post-procedural complications (wound infection, abscess, necrotizing fasciitis, buried bumper syndrome, clogged tube, dislodged tube).²

Mortality from percutaneous endoscopic gastrostomy placement is <1%. Major complications requiring surgical intervention occur in 6-7% while minor complications are reported in 17-24% patients.⁷

Liver injury as a result of a PEG placement is rare. Our literature search with PUBMED and MEDLINE resulted in seven reported cases in the last thirty-seven years. Of these, four required surgical intervention and removal of the PEG tube.^1,8,9,10 The other three were managed conservatively.^11,12 No mortality with PEG insertion through liver has been reported.

Our case describes a woman with inadvertent transhepatic placement of a PEG tube with successful endoscopic removal nine days later. PEG tube placement traversing the liver may be avoided by using careful technique and the usual precautionary steps. An additional method of verification is the ??‘safe tract’t? technique, where a syringe attached to a needle is advanced slowly through the abdominal wall with retraction of the barrel. A ?‘safe tract’? is established by endoscopic visualization of the needle in the gastric lumen and simultaneous return of air into the syringe. Return of fluid or gas in the syringe without intragastric needle visualization suggests entry into bowel or a solid organ interposed between the abdominal wall and stomach.²

CONCLUSION

An injury to the liver during percutaneous endoscopic gastrostomy placement, although rare, can cause acute decompensation requiring emergent surgery. At the same time, some patients can be managed conservatively. An abdominal exam with attention to hepatomegaly may be helpful. Careful selection of patients, reviewing indications and benefits before the procedure, is also important so as to avoid its overutilization and undue complications. Thorough knowledge of the indications, contraindications and fundamental principles of technique constitutes the most important safety factor.2 In our patient despite using the above technique of ‘safe tract’, appropriate transillumination and confirming air return, the PEG tube traversed the liver. This was thought to occur due to patient?s obesity, generalized anasarca, variant anatomy and chronic liver disease from hepatitis C. In obese patients or patients with generalized anasarca, we propose a potential use of abdominal ultrasound immediately prior to or post procedure to confirm and avoid this rare complication.

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INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #90

Diagnosis and Management of IgG4-associated Pouchitis

September 2014 • Volume XXXVIII, Issue 9

Darren N. Seril,Bo Shen

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Chronic pouchitis is an inflammatory complication of total proctocolectomy with ileal pouch- anal anastomosis that can be difficult to manage. The role of IgG4-associated inflammation in pouchitis is continuing to emerge. In this article we cover diagnosis and effective treatment options that should be considered early in the management of pouch patients with established IgG4-associated pouchitis.

INTRODUCTION

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is currently the surgical procedure of choice for medication-refractory ulcerative colitis (UC) and UC-associated colonic neoplasia as well as familial adenomatous polyposis. A large portion of UC patients with IPAA will develop inflammation of the ileal pouch reservoir, commonly known as pouchitis.¹ However, the exact etiology and pathogenesis of ileal pouch inflammation are not entirely clear. It is likely that pouchitis (especially chronic pouchitis) arises due to similar factors that cause inflammatory bowel disease (IBD): for example, predisposing genetic factors, aberrant microbiota-host interactions, and immune-dysfunction.1 Indeed, this possible overlapping etio-pathogenesis has led to the notion that pouchitis can be useful as a model of IBD with a defined starting point (the exposure of the pouch to the fecal stream upon ileostomy reversal).² Given that pouchitis is responsive to antibiotic therapy in many cases, it is presumed that a disruption of the normal composition of commensal bacteria in the pouch (?dysbiosis?) is a common causative factor.³ A subgroup of pouchitis patients appears to have an immune-mediated inflammatory process characterized by an increase in the co-occurrence of autoimmune disorders (AImD),⁴ extra-intestinal disease manifestations (EIM) such as primary sclerosing cholangitis (PSC),^5,6 and the presence of serum autoantibodies.^7-10 These patients with ?‘immune-mediated pouchitis?’ (IMP) appear to have a greater tendency to having chronic antibiotic-refractory pouchitis (CARP) than patients without these features.^8-11

The role of immunoglobulin G4 (IgG4) in immune function and disease pathology continues to be defined. IgG4 has unique properties that likely have a significant impact on its immuno-biology.¹² The part played by IgG4 in autoimmune pancreatitis (AIP) has been well characterized. It is now thought that AIP consists of at least 2 subtypes, AIP type 1 and type 2.¹³ AIP type 1 is defined histologically by an IgG4-enriched lymphoplasmacytic tissue infiltrate. Elevated serum IgG4 and tissue infiltration by IgG4-expressing plasma cells are hallmarks of AIP type 1, and the histopathological measurement of IgG4-expressing cell infiltration is incorporated in some diagnostic criteria for AIP.^13,14 In contrast, AIP type 2 is marked by neutrophil infiltration and destruction of pancreatic ducts, as well as a lymphoplasmacytic infiltrate lacking a prominent IgG4-positive component.¹³

The association between IgG4 and AIP, as well as IgG4-associated manifestations at other organ sites, has led to the concept of IgG4-related disease (IgG4-RD), of which AIP type 1 is thought to be a pancreatic manifestation.¹⁵ Nearly every organ system can be involved in the spectrum of this systemic disease, including the salivary glands, pancreaticobiliary system, and intestines.^{15, 16} Our group has reported that a subgroup of IPAA patients expressing elevated serum levels of IgG4 ¹⁷ or having a pouch inflammatory process associated with infiltration by IgG4-expressing plasma cells ¹⁸ is marked clinically by a propensity for antibiotic-refractory disease. While the exact role played by IgG4 in the pathogenesis of pouch dysfunction remains undefined, it is becoming clear that IgG4-associated pouchitis may have distinctive clinical characteristics and response to therapy. The focus of this review is on the emerging role of IgG4 in pouchitis and the implications for diagnosis and management.

IgG4 Immunobiology and Pathogenesis Properties of IgG4

Our current understanding of the part played by IgG4 in disease is incomplete. Typically, IgG4 constitutes a minority of total IgG,¹⁹ and its production requires long-term exposure to an inciting antigen.²⁰ Based on this observation, it has been suggested that IgG4 may take part in immune tolerance to chronic antigenic stimulation ²¹ and attenuation of the allergic reaction.²² IgG4 is also notable for a poor ability to induce complement-mediated cytotoxicity.^23,24 In addition, IgG4 may have anti-inflammatory actions.^12,25 Based on these purported functions, the question of how IgG4 takes part in disease pathogenesis remains unanswered. Indeed, there is limited evidence of disease causation despite a well-documented association between IgG4 and diseases such as AIP.

IgG4 and Autoimmune Pancreatitis

Elevated IgG4 has been observed in multiple immune-mediated diseases, including known AImD such as rheumatoid arthritis (RA).^26,27 However, the association of IgG4 with disease has been most extensively studied in AIP. AIP type 1 is characterized by a prominent IgG4-positive lymphocyte infiltration as well as storiform fibrosis and obliterative phlebitis. Hyper-gammaglobulinemia is a common feature of AIP, and elevated serum IgG4 has been recognized in a high percentage of patients, specifically those with type 1.²⁸ The sensitivity of elevated serum IgG4 in diagnosing AIP was greater than 90% in some studies,²⁹ and had good accuracy in differentiating AIP from pancreatic cancer.³⁰ Serum IgG4 levels may also be useful as a marker of steroid response in AIP.³¹ The infiltration of IgG4-expressing plasma cells is more frequently observed in pancreatic tissue from patients with AIP type 1 than other etiologies of pancreatic pathology, including pancreatic adenocarcinoma.³² Validated criteria for the diagnosis of AIP, such as the Histology, Serology, other Organ involvement, and Response to therapy (HISORt) criteria, include the histological parameter of ?abundant? IgG4-positive plasma cells on immunostaining (typically defined as >10 IgG4-positive plasma cells per high power microscopy field [HPF]).¹⁴ However, a direct role of IgG4-expressing cells in the pathogenesis of AIP has not been established.

The observation that manifestations of AIP type 1 outside of the pancreas are also associated with the infiltration of IgG4-expressing plasma cells suggests that this type of AIP is a systemic IgG4-associated disease.¹⁵ Indeed, over the last several years, IgG4 involvement at many different organ sites has been recognized, including the salivary glands,33 biliary tree,34 skin,³⁵ kidneys,³⁶ lungs,³⁷ and thyroid gland,³⁸ leading to the notion of IgG4-related disease (IgG4-RD). However, evidence that directly links IgG4 to the causation of IgG4-RD is lacking, even though changes in serum IgG4 levels can correspond to corticosteroid treatment response.³¹ There is evidence that elevations of IgG4 in the serum and at the tissue level can occur in association with inflammation at intestinal sites, including the ileal pouch, in the absence of other overt features of IgG4-RD.

IgG4 and Pouchitis

An association between ileal pouch inflammation and an elevated serum IgG4 level, or tissue infiltration by IgG4-expressing plasma cells, has been noted in a subgroup of IPAA patients. As will be discussed below, these associations may have implications for the classification and treatment of pouchitis in these patients. Our group reported a case of a 27 year-old man with IPAA and a background of UC and PSC, as well as Hashimoto?s thyroiditis (but not AIP) that presented with diarrhea and findings of pouchitis on pouch endoscopy. He was noted to have an elevated serum IgG4 level (194 mg/dL), and histologic evaluation of pouch and afferent limb biopsies revealed a mixed lamina propria infiltrate of neutrophils and lymphocytes, with immunohistochemical staining of pouch biopsies showing greater than 10 IgG4-expressing plasma cells per HPF.³⁹ Of note, histologic analysis of the terminal ileum samples from the same patient obtained at the time of total colectomy showed no evidence of IgG4-positive cell infiltration. The patient responded clinically to budesonide therapy. This initial report indicated that IgG4-associated inflammation may take part in pouchitis, and also indicated that an IgG4-associated inflammatory process can arise de novo following surgery, and in association with other features of autoimmunity.39 In addition, this case raised the possibility that IPAA patients with ?‘IgG4-associated inflammation’? may be more susceptible to CARP and benefit from corticosteroid therapy.

Pouchitis and Elevated Serum IgG4 Levels

The clinical characteristics of patients with pouchitis and concomitant serum elevation of IgG4 were further assessed in a prospective study of symptomatic IPAA patients. Among 124 pouch patients with underlying UC, serum IgG4 was reported to be elevated (>114 mg/dL) in 10 (8%) patients, of whom none had concurrent AIP.¹⁷ The group of patients with pouchitis and elevated serum IgG4 had higher Pouchitis Disease Activity Index (PDAI) symptom sub-scores. In addition, significantly more patients with elevated serum levels of IgG4 (5/10 [50%]) had CARP compared to patients with a normal serum IgG4 level (23/114 [20%]).¹⁷ In a subsequent study of 97 IPAA patients with underlying UC, a significantly higher median serum level of IgG4 was detected in patients with positive IgG4 histology (defined as >10 IgG4-expressing plasma cells per HPF on pouch biopsies) compared to those with negative IgG4 histology.¹⁸ In that study, 4/28 (14%) patients with positive IgG4 histology versus 3/69 (4%) patients with negative IgG4 histology had elevated serum IgG4; however, the difference was not statistically significant. Overall, there was no correlation between elevated serum IgG4 and tissue infiltration by >10 IgG4-expressing plasma cells detected in the ileal pouch.18 These studies indicate that serum IgG4 elevation may be a useful biological marker of an increased risk for CARP. However, it is apparent that an elevated IgG4 serology does not reliably correspond to increased IgG4-positive cell infiltration in the ileal pouch (and vice versa). This is similar to the observations in AIP type 1, in which a lack of concordance between IgG4 serology and histology has been noted in as many as one-third of cases.¹⁵ As already mentioned, serum IgG4 levels mirrored corticosteroid response in some studies of AIP type 1,³¹ but the reports have been conflicting. Similarly, serum IgG4 levels may be useful in predicting symptom relapse in some patients following successful treatment, but relapse has been noted in the presence of persistently normal post-treatment IgG4 levels as well.⁴⁰ Whether a higher concordance between serum IgG4 and tissue infiltration is characteristic of IgG4-RD (such as AIP type 1) compared to an ‘?IgG4-associated?’ inflammatory process has yet to be addressed.

IgG4 Histology in Pouchitis

The identification of increased numbers of infiltrating IgG4-positive plasma cells in pouch biopsies appears to be associated with an increased propensity for refractoriness to antibiotic therapy. In the study by our group noted above, 28/97 (29%) symptomatic IPAA patients had >10 IgG4-expressing plasma cells in the ileal pouch mucosa. Nineteen of these patients (68%) with IgG4-positive immunostaining of pouch mucosal biopsies had CARP, as compared to 30/69 (43.5%) patients without IgG4-positive cells in the pouch.¹⁸ It is noteworthy that there was no difference in regards to the incidence of Crohn?s disease (CD) of the pouch or irritable pouch syndrome (IPS) between patients with and without increased numbers of infiltrating IgG4-expressing cells in pouch tissues. In addition, the incidence of PSC (29%) and concomitant AImD (39%) were significantly greater among IPAA patients with elevated tissue IgG4-expressing plasma cells than those without elevated IgG4 histology (10% and 19%, respectively).18 Thus, IgG4-associated pouchitis (as defined by an increased number of infiltrating IgG4-positive plasma cells) is characterized clinically by an increased incidence of CARP as well as a concurrence with clinical markers of an immune-mediated process.

The presence of IgG4-expressing plasma cells in pouch biopsy specimens is relatively common in symptomatic IPAA patients. In a recent study, among 98 IPAA patients with symptoms of pouch dysfunction and immunohistochemical staining for IgG4-positive cells, 76 (78%) had one or more IgG4-positive plasma cells per HPF in biopsy specimens.⁴¹ Tissue infiltrations by >10 IgG4-expressing plasma cells per HPF was detected in biopsy specimens from 27/98 (28%) patients. In addition, similar to the prior study by Navaneethan et al.,¹⁸ a significantly greater proportion of patients with CARP had elevated IgG4 histology (17/31, 55%) as compared to all other etiologies of pouch dysfunction (10/67, 15%).⁴¹ It is tempting to conclude that elevated IgG4 in these patients is a by-product of an underlying aberrant immune response. However, we have found that while there is marked overlap between elevated IgG4 expression (either in the serum or in plasma cells infiltrating the pouch tissue) and other immune markers, there is more pronounced concurrence with autoimmune thyroid disease, microsomal antibody expression, and PSC in patients with CARP. This association between certain immune markers may explain the observation that microsomal antibody expression and increased tissue infiltration by IgG4-expressing plasma cells are risk factors for CARP rather than an increasing number of immune markers per se.⁴¹ A summary of the studies investigating the association between elevated IgG4 and pouch dysfunction is shown in Table 1.

Pouchitis and IgG4-related Disease

It is not clear if any of the cases of ‘?IgG4-associated pouchitis7rsquo;? represent an ileal pouch manifestation of IgG4-RD. As alluded to above, IgG4-RD is comprised of an ever-increasing group of systemic inflammatory disorders whose diagnosis depends primarily on the finding of characteristic histologic features (including elevated IgG4-expressing plasma cells), and often multi-organ involvement. The frequent use of corticosteroids in patients with pouchitis may confound the signature histological findings of IgG4-RD. To date, none of the cases of pouchitis with elevated IgG4 that have been reported had extra-intestinal features that can be defined as IgG4-RD.^17,18,41 The exception may be the concurrence of ?IgG4-associated pouchitis? with PSC.^18,41 It is possible that some of these cases had undiagnosed IgG4-sclerosing cholangitis (IgG4-SC) rather than PSC,^42,43 thus establishing a case for IgG4-RD in pouchitis. The distinction may be more than semantic in nature. The prominence of IgG4-expressing plasma cells may imply corticosteroid sensitivity as well as responsiveness to therapy targeting B-cells, analogous to the case in AIP and other IgG4-RD. However, whether ?IgG4-pouchitis? and ?IgG4-associated pouchitis? are distinct entities with differing clinical features and response to therapy has yet to be established.

Diagnosis Of IgG4-Associated Pouchitis
Measurement of Serum IgG4 Levels

If there is sufficient clinical suspicion for IgG4-associated pouch inflammation, screening for IgG4 levels can be sought by checking of serum IgG subclasses. In published studies, the cut-off value for elevated serum IgG4 has varied from 114 to 140 mg/dL. However, the incidence of elevated serum IgG4 underestimates the frequency of IgG4-associated inflammation as defined by tissue infiltration by IgG4-expressing plasma cells,^18,41 which is used in the criteria for IgG4-RD. The response of IgG4 serum levels to treatment has yet to be studied in patients with pouchitis. Prospective studies are needed to determine if changes in IgG4 levels correspond to clinical response to therapy, as well as loss of response or relapse, as was the case in some reports of AIP.³¹ However, in a case report of an IPAA patient with pouchitis and elevated IgG4, clinical response to budesonide therapy was not associated with a reduction in the serum IgG4 level.³⁹

Pouch Endoscopy and IgG4 Histology

While serum IgG4 level can be used as a non-invasive screening test, endoscopy with biopsies should be performed in IPAA patients in whom IgG4-associated inflammation (as well as IgG4-RD) is suspected. In the case of the ileal pouch, biopsies of the afferent limb, pouch body, and the anal transition zone (or cuff) should be obtained. Infiltrating IgG4-expressing plasma cells are detected in biopsy specimens by standard immunohistochemical staining methods, and are typically expressed as the number of immunostain-positive cells per HPF. There are currently no standardized criteria for the number of HPF that should be viewed to obtain the number of infiltrating IgG4-positive plasma cells. Similarly, the number of infiltrating IgG4-expressing plasma cells that is used to define a ?positive? sample has for the most part been extrapolated from the reports in AIP. Some studies in AIP have utilized a 4-tiered scoring system of IgG4-positive cell numbers: for example, 0 to 5 IgG4-positive cells per HPF (regarded as negative), 6 to 10 cells (mild), 11 to 30 cells (moderate), and greater than 30 cells (severe). IgG4-expressing plasma cell levels defined as ?moderate to severe? (i.e., >10 positive cells/ HPF) have been associated with a diagnosis of AIP.³² The Mayo Clinic HISORt criteria for AIP utilizes a cut-off of >10 IgG4-positive cells/HPF.14 However, the recommended cut-off for IgG4-positive cell number used in defining IgG4-RD varies bases on the organ site, with the number varying from >10 IgG4-positive cells/HFP in the liver and bile duct to greater than 200 in the skin.¹⁶ In addition, an IgG4-RD consensus group recommended an IgG4-to-total IgG-positive cell ratio greater than 0.4 in establishing the diagnosis of IgG4-RD.¹⁶ It is not clear if these same thresholds are valid in the small intestine and ileal pouch. Furthermore, the usefulness of these cut-offs in the setting of ?IgG4-associated? inflammation in the absence of other features of IgG4-RD (i.e., other characteristic histological features and multi-organ involvement) is undefined. The diagnostic value of the IgG4-to-total IgG-positive cell ratio in those organ sites is also unknown. The studies examining IgG4 histology in pouchitis reported on IgG4-positive cell numbers alone. Further prospective studies are needed to correlate IgG4-positive plasma cell numbers with disease activity and relevant clinical endpoints in IPAA patients. This would permit a standardized approach to the quantitation of IgG4-expressing cell numbers, including the quantitation of total IgG-expressing cells and the number of HPF utilized in the analysis. Still, based on the studies to date, the use of greater than 10 IgG4-expressing plasma cells as a definition of elevated IgG4-positive cell infiltration appears to delineate a group of pouchitis patients at increased risk for CARP.^18,41

While useful for diagnosing IgG4-associated inflammation, mucosal biopsies may underestimate the prevalence of IgG4-positive cell infiltration. In a report by Hartman et al. in IBD patients, IgG4-.expressing plasma cells were present in the submucosa or muscularis mucosa in 86% of resection samples, but were detected in the lamina propria in 23% of resection samples, and in only 25% of biopsy samples.⁴⁴ Despite this possible limitation, immunohistochemical staining for IgG4-expressing plasma cells in biopsy samples is likely a more sensitive measure of IgG4-associated inflammation in the ileal pouch than IgG4 serology. Indeed, our group has noted a lack of correlation between the presence of elevated IgG4-expressing plasma cells in the ileal pouch and serum IgG4 levels.¹⁸ Furthermore, in the recent study of 98 IPAA patients with IgG4 immunostaining mentioned above, 27 (27.5%) patients had greater than 10 IgG4-expressing plasma cells per HPF on biopsy histology, and only 2/27 (7%) patients with elevated tissue infiltration by IgG4-expressing plasma cells had concomitantly elevated serum IgG4 (including 1/17 (6%) patients with CARP).⁴¹ Thus, pouch endoscopy with biopsy and staining for IgG4 is warranted if serum IgG4 is normal (or low) but suspicion for an IgG4-associated process remains. Of course, the diagnosis of ?IgG4-associated pouchitis? is not complete in the absence of endoscopic findings consistent with ileal pouch inflammation. The modified Pouchitis Disease Activity Index (mPDAI) is useful in this regard, with a score of greater than 5 being diagnostic of pouchitis.⁴⁵ In addition to facilitating a diagnosis of pouchitis and IgG4-associated inflammation, pouch endoscopy can also be used to assess for mechanical abnormalities of the pouch (e.g., pouch strictures and sinuses) that may be alternative causes of symptoms or suggestive of an alternate diagnosis, such as Crohn?s disease (CD) of the pouch.1 It should also be noted that inflammation of the anal transition zone (cuffitis) can be a cause of symptoms in IPAA patients and can also be associated with a prominent IgG4-associated inflammatory process, although this relationship has yet to be studied in depth.

Other Serologic and Radiologic Evaluations

Other serologic measures are for the most part of limited value in evaluating a patient with suspected or confirmed IgG4-associated pouchitis. However, given the overlap between IgG4 and PSC in a subgroup of patients, it would be appropriate to check a comprehensive metabolic panel to assess for liver enzyme or total bilirubin abnormalities that may be due to an early onset of hepato-biliary disease.^42,434 are increased in symptomatic IPAA patients with CARP as compared to those without CARP, and there appears to be an overlap of these immune markers with IgG4 in some patients with refractory pouchitis.⁴¹

As is the case for other etiologies of pouchitis, imaging studies are not routinely used in the diagnosis of IgG4-associated pouchitis. If there is concern for pouch-related obstruction or a mechanical pouch complication, then abdominal x-ray, computed tomography, or pelvic magnetic resonance imaging may be indicated.

Clinical Presentation and Disease Course

Patients with IPAA and IgG4-associated inflammation can present with typical symptoms of pouchitis, including increased stool frequency, urgency, stool blood, abdominal pain, pelvic pain, and fatigue. Other systemic features such as fevers, night sweats, and weight loss would be atypical findings, and should raise concern for a superimposed infectious process such as Clostridium difficile infection of the pouch ⁴⁶ or cytomegalovirus infection of the pouch,⁴⁷ as well as pouch-associated sinus tract or fistula with abscess. As noted above, mechanical complications of the pouch can mimic some of the clinical features of pouchitis;⁴⁸ however, pain in the region of the sacrum and coccyx that sometimes accompanies a posterior pouch sinus tract would not be typical of IgG4-associated pouchitis. If IgG4-associated pouchitis occurs in the setting of IgG4-RD, the patient may have diverse symptoms based on the involvement of other organs in the IgG4-related disease process.¹⁵ For example, IgG4-SC may present more often with obstructive jaundice than PSC.⁴⁹

The natural history of IgG4-associated pouchitis has yet to be fully characterized. There is some evidence that IgG4-associated pouchitis is marked by a more severe clinical presentation: pouchitis patients with elevated serum IgG4 had significantly greater PDAI symptom sub-scores as compared to those with normal serum IgG4.¹⁷ Furthermore, as described above, there is evidence that IPAA patients having an elevated serum IgG4 level or increased tissue infiltration by IgG4-expressing plasma cells are at increased risk for CARP, and therefore more frequently require anti-inflammatory or immunosuppressive therapy.^18,41 Whether these patients are at risk for other adverse outcomes, including more frequent hospitalization or pouch failure,⁵⁰ is an area of ongoing research. It has been reported that elevated serum IgG4 adversely impacts the disease course of PSC: IgG4-positive individuals had a shorter interval until liver transplantation,^42,51 and patients with PSC-UC were reported to have reduced colectomy-free survival.⁵² The impact of IgG4-associated pouchitis on the occurrence of mechanical complications of the pouch has yet to be studied as well.

IgG4 and Implications for Treatment Corticosteroid Therapy

A characteristic feature of AIP (as well as other IgG4-RD) is responsiveness to corticosteroid therapy.^40,53 Indeed, corticosteroid responsiveness is among the criteria for AIP.¹⁴ This may have implications for the treatment of IgG4-associated inflammation in intestinal sites, including in pouchitis. As noted above, pouchitis patients with elevated serum IgG4 and increased tissue infiltration by IgG4-expressing plasma cells are at an increased risk for CARP and the need for immunosuppressive therapies in order to achieve symptom remission.^18,41 While the efficacy of corticosteroid therapy in this context has yet to be substantiated by large clinical studies, our group reported a case of IgG4-associated pouchitis that responded clinically to budesonide therapy.³⁹ Furthermore, observation in our clinical practice indicates that, in general, these patients respond favorably to budesonide therapy, such that in many cases it is considered the 2^nd line of therapy if they have demonstrated dependence on or refractoriness to standard antibiotic regimens. An area of ongoing study is the clinical response of IPAA patients with IgG4-associated pouchitis to oral budesonide therapy. The response of serum IgG4 levels to corticosteroid therapy has not been studied in pouchitis patients; however, our group has observed that budesonide therapy may be associated with a reduction in the number of IgG4-expressing plasma cells infiltrating the pouch mucosa (unpublished data).

The rate of clinical relapse following corticosteroid therapy is similarly unexplored in pouchitis patients. The reports in AIP patients indicate that relapse is common following treatment with corticosteroids. In a large study in Japan, more than 90% of AIP patients treated with corticosteroids had experienced disease relapse at 3 years of follow-up.⁴⁰ Patients with AIP type 1 have been reported to be more susceptible to disease relapse following corticosteroid treatment compared to those with AIP type 2.⁵⁴ Similarly, in one study, half of the corticosteroid-responsive PSC patients with elevated IgG4 had biochemical relapse after treatment.⁴³ In the study of a French cohort of patients with IgG4-RD, 90% (19/21) had response to corticosteroid therapy as defined by clinician survey responses, but 12 of the corticosteroid-responsive patients eventually required other immunosuppressive therapies.⁵⁵ Thus, perhaps analogous to other chronic inflammatory diseases such as IBD, corticosteroids are useful in inducing IgG4-RD remission but not in maintaining remission.

Immunomodulators and Anti-TNF-? Therapy

Medications that are routinely used in the management of IBD, including immunomodulators (e.g., azathioprine, methotrexate, and mycophenolate mofetil), have also been employed in patients with IgG4-RD.⁵⁶ However, assessments of their efficacy have been limited to case reports and series, and the usefulness of these agents in the treatment of IgG4-associated pouchitis has not been explored. Anti-tumor necrosis factor-a (TNFa) therapy has been employed in the treatment of IgG4-RD as well. For example, a patient with features suggestive of IgG4-RD consisting of pancreatic pseudo-tumor (likely AIP type 1), elevated serum IgG4, and severe IgG4-associated pan-colitis experienced symptom relapse following corticosteroid and azathioprine therapy, and had lost response to infliximab. The patient was eventually treated successfully with adalimumab.⁵⁷ Similarly, a case of severe IgG4-related ocular adnexal disorder, refractory to corticosteroids, was responsive to infliximab.⁵⁸ In a report by Hartman et al., greater than 80% of surgical resection specimens from IBD patients who were refractory or intolerant of anti-TNFa therapy contained elevated IgG4-expressing plasma cells.⁴⁴ This may suggest that IBD with IgG4-associated inflammation is prone to treatment refractoriness, similar to the case of IgG4-associated pouchitis. Alternatively, the IgG4-expressing plasma cells in these patients may play a role in the host response to biological therapy. The elaboration of antibodies against anti-TNFa biologics (especially infliximab, as well as adalimumab) is a cause of infusion reactions and loss of treatment response.⁵⁹ The host response to those biologics may be mediated in part by an IgG4 response. For example, IgG4 was reported to constitute a considerable portion of anti-adalimumab antibodies in patients with RA.⁶⁰ It remains to be determined if elevated IgG4 in pouchitis patients is a determinant of reduced responsiveness to anti-TNFa therapy, or is itself a response to therapy that results in medication-neutralization and loss of response.

B-cell Targeting Therapy

The presence of an IgG4-associated inflammatory process in the pouch, including in the setting of IgG4-RD, suggests that a B-cell targeting approach would be useful. In fact, rituximab therapy was successful in the treatment of 9 of 10 patients with IgG4-RD who had persistence of disease despite diverse immunosuppressive therapies (including prednisone, azathioprine, 6-mercaptopurine, methotrexate, and mycophenolate mofetil).⁶¹ Treatments like rituximab may be particularly beneficial in IgG4-associated diseases by reducing memory B-cells.⁶² Further studies are needed to explore the effectiveness of targeted therapies in patients with IgG4-associated pouchitis, including rituximab. This approach has been established in principle by the favorable response of an IPAA patient with IgG4-expressing plasma cell infiltration of the pouch and the thyroid to rituximab therapy (unpublished data).

SUMMARY

The role of IgG4-associated inflammation in pouchitis is continuing to emerge. A proposed algorithm for the diagnosis and management of IgG4-associated pouchitis is shown in Figure 1. Elevated serum levels of IgG4 occur in a minority of symptomatic ileal pouch patients, but are associated with an increased prevalence of CARP. Similarly, a subgroup of chronic pouchitis patients has increased pouch tissue infiltration by IgG4-expressing plasma cells and a predilection for CARP. However, the correspondence between IgG4 serology and IgG4 histology is poor. ?IgG4-associated pouchitis? appears to have clinical features of an immune-mediated process, having a greater prevalence of concomitant AImD, as well as extra-intestinal manifestations of IBD (notably PSC) than those without elevated IgG4. IgG4-RD should be a consideration in patients with IgG4-associated pouchitis with typical histologic changes and involvement of other organ sites. Pouch endoscopy with mucosal biopsy, and histologic analysis with IgG4 immunostaining, are essential for the diagnosis of IgG4-associated pouchitis. The implications of an IgG4-associated inflammatory process for the treatment of pouchitis are continuing to be studied. Budesonide therapy may be an effective option that should be considered early in the management of pouch patients with established IgG4-associated pouchitis.

The authors declare no financial conflicts of interest.

Acknowledgement Bo Shen, MD is supported by the Ed and Joey Story Endowed Chair.

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UNUSUAL CAUSES OF ABDOMINAL PAIN, #6

Unusual Causes of Abdominal Pain

September 2014 • Volume XXXVIII, Issue 9

George W. Meyer

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CASE

A32 year old man presents with a 5 year history of vomiting. The vomiting is virtually continuous for 7 days. During the episodes he also has severe generalized abdominal pain. This is also associated with diarrhea, occasionally with blood. He seeks a dark room and puts himself in a ball lying on his side. He often has to go to the ED for IV fluids. He may lose up to 20 pounds during an episode. Between these 7 day episodes he is asymptomatic. They occur every 6 months. Each episode is a carbon copy of the others. There is no warning that these episodes are coming on.

UNUSUAL CAUSES OF ABDOMINAL PAIN

We solicit our readers to submit interesting and unusual cases of abdominal pain for consideration for publication. The case should be well documented, include images (if possible), at least one reference and no more than two authors.

ANSWER AND DISCUSSION

Diagnosis: Cyclic Vomiting Syndrome (CVS)
First described in France in 1861, the definition requires 4 items: 1) Three or more recurrent discrete episodes of vomiting; 2) Varying intervals of completely normal health between episodes; 3) Episodes are stereotypical with regard to timing of onset, symptoms, and duration; 4) Absence of an organic cause of vomiting. Some have suggested that it is necessary to rule out CNS tumor, malrotation of the gut and kinked ureter (IVP or CT with pain). Rome III criteria include: 1) Stereotypical episodes of vomiting regarding onset (acute) and duration (< 1 week); 2) Three or more discrete episodes in the prior year and 3) Absence of nausea/vomiting between episodes.

CVS was seen more frequently in children who would average 12 episodes per year. The literature is not clear on a sexual preference in children. In 1999, Prakash and Clouse reported on 17 cases of adult CVS over 10 years with the average age at onset of 35 years (14-73); average age at diagnosis: 41 years with no sexual preference. The average episode length was 6 days (1-21 days); symptom free interval was 3 months (0.5-6 months) with an average of 4 cycles per year.

The cause of this disorder is unknown but some patients seem to have a mitochondrial variant. >50% of CVS patients may have maternal inheritance of a mitochondrial DNA sequence variation.

Cyclic vomiting is considered to have 4 phases: Phase 1: Asymptomatic; Phase 2: Prodrome (many patients have no prodrome); Phase 3: Full blown vomiting episode; Phase 4: Recovery.

Patients who have multiple severe episodes may respond to prophylaxis with tricyclics, sometimes at doses > 100 mg per day. Cyproheptadine has been said to be therapeutic in some cases. Occasional patients may find some relief from Coenzyme Q-10 and/or l-carnitine. During the Prodrome stage the goal is to abort the episodes. Ondansetron and/or Aprepitant may be helpful. Most patients are very anxious in this prodrome period and may have a lessening of their anxiety with benzodiazepines. During the full blown vomiting episode the patient should be considered a medical urgency and should be admitted to the ED as quickly as possible with the objective to heavily sedate the patient, the theory being if the head is put to sleep then the CVS will go away.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #133

Coding for Malnutrition in the Adult Patient: What the Physician Needs to Know

September 2014 • Volume XXXVIII, Issue 9

Wendy Phillips

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At least half of all hospitalized patients are malnourished, which increases the duration of recovery, length of stay, as well as the resources spent to treat the patient. Reimbursement to cover the additional costs may only be realized if the malnutrition is identified, diagnosed, and treated by the physician while providing care for the primary illness. This article will discuss the importance of identifying and documenting malnutrition in hospitalized patients, with practical tips for licensed independent practitioners to aid in this documentation.

INTRODUCTION

Over 50% of hospitalized patients are malnourished upon admission.¹ These nutrition deficits can lead to muscle loss/weakness and, in turn, influence the risk for falls, pressure ulcers, infections, delay in wound healing, and increased hospital readmission rates.1 Malnutrition as a co-morbidity also increases the duration of recovery from the primary illness and, in turn, the length of stay. Finally, it not only adds to time in rehabilitation, but also increases the need for rehab after hospitalization.²

Not only is this unfortunate for our patients, but hospital costs soar. Given the added cost to care for these patients, it is important to capture reimbursement for this added co-morbidity from the insurance provider. Reimbursement may only be increased to cover these costs if the malnutrition is identified, diagnosed, and treated by the physician in combination with providing care for the primary illness. It is imperative that clinicians understand the criteria needed to identify and document malnutrition in order to maximize nutrition interventions to ensure best outcomes, and also capture reimbursement for the additional care provided. The goal of this article is to help clinicians identify and document malnutrition in hospitalized patients.

The inpatient prospective payment system through the Centers for Medicare and Medicaid Services (CMS) established Medicare Severity-Diagnostic Related Groups (MS-DRGs).2 Using this system, patients with the same diagnosis and similar clinical characteristics are assigned to an MS-DRG and the hospital receives a fixed payment amount based on the average cost of care for patients in that group. In addition to the principal diagnosis that necessitated the hospital stay, the patient may have additional conditions that increase the resources needed to care for him/her. These are known as either major complications or comorbidities (MCCs), or complications or comorbidities (CCs). The hospital receives a higher reimbursement for MS-DRGs associated with a CC, and an even higher reimbursement for MS-DRGs associated with MCCs. This same system is used to determine the Case Mix Index, which is a description of the level of severity of patients being cared for at that hospital. The International Classification of Disease, 9th Revision (ICD-9) codes translate medical diagnoses into numerical codes for billing and research purposes. Malnutrition is a qualifying diagnosis in the MS-DRG system, but several different ICD-9 codes can be used for the varying degrees of malnutrition. Table 1 provides an overview of these codes, with an indication of which ones are considered by CMS as Major Complications or Comorbidities (MCCs) or Complications or Comorbidities (CCs). Note: Since the United States will be transitioning to the 10th edition of the ICD codes in 2015; both ICD-9 and the equivalent ICD-10 codes are listed in Table 1.

Defining Malnutrition

While it is known that malnutrition results from inadequate nutrients, there is no universally accepted definition for malnutrition, or set of signs and symptoms for classifying the degree of malnutrition. Therefore, hospitals need to develop their own definitions of malnutrition based on evidence-based guidelines, professional practice, and the basic descriptions in ICD-9 codes (see Table 1).

Due to the lack of a universal definition for malnutrition, an International Consensus Guideline Committee was formed in 2009 to define malnutrition using an etiology based approach.1 Although CMS has not accepted this classification system, they have not accepted any other classifications or definitions for malnutrition either. Therefore, this system can be adopted by the hospital. A patient?s body mass index (BMI) may also be used to determine the degree of malnutrition, as defined by the Center for Disease Control and Prevention (see Table 2). Since the etiology of malnutrition is often multifactorial, more than one assessment criteria should be considered when determining the degree of malnutrition, including an evaluation of dietary intake by the registered dietitian (RD). However, only one assessment parameter is required to determine the degree of malnutrition for the purpose of reimbursement. Regardless of the classification system used, a policy needs to be created for defining malnutrition at each hospital. This policy should be used consistently amongst all disciplines for determining the degree of malnutrition for each patient who is admitted. Table 3 is an example policy that may be customized for use at a hospital.

Identifying and Treating Malnourished Patients

Patients who are screened by nursing as being at risk for malnutrition through the admission screening process should be referred promptly to the RD for a thorough nutrition assessment and classification of degree of malnutrition. Patients identified by other methods or clinicians as being malnourished, or at risk for malnutrition, should also be referred to the RD for further assessment. The RD will then implement a nutrition care plan for each patient with appropriate interventions to treat the malnutrition in conjunction with the medical care plan as determined by the physician. The RD will follow up on the response to the nutrition care provided during the hospital stay, and help to coordinate nutrition care after discharge, with the goal of preventing readmission for nutrition-related reasons.

The RD will document the nutrition assessment and diagnosis as it relates to the patient?s degree of malnutrition. Additional nutrition diagnoses may also be documented, addressing problems such as inadequate intake, vitamin and mineral deficiencies, or other nutrition-related issues. For each nutrition diagnosis, the RD will document the associated planned recommendations for nutrition intervention, as well as the patient?s goal/s, monitoring, and re-evaluation plan.

Once the RD has documented the degree of malnutrition as part of the nutrition diagnosis, the physician responsible for the care of the patient is notified (by a predetermined plan) of this diagnosis and the planned interventions or recommendations. Some examples of notification systems may include flagging of a progress note in the electronic medical record, text paging the physician or other licensed independent practitioner (LIP) with the patient specific information, discussion of the patient on medical rounds, or other methods of communication.

Historically, CMS regulations were in place in the ?Conditions of Participation? for hospitals that necessitated all nutrition interventions be ordered in the medical record by the physician responsible for the care of the patient. Since July 2014, these CMS regulations include RDs as authorized providers to write nutrition related orders for therapeutic diets, whether administered orally, enterally (tube feeding), or parenterally (total parenteral nutrition). However, some states and/or hospitals have not adopted policies allowing this level of care as of yet. Therefore, some physicians or other licensed health care practitioners may need to respond to RD requests to order nutrition interventions to treat the malnutrition identified.

Capturing the Malnutrition Diagnosis for MS-DRGs

As the RD is the expert in nutritional assessment, he/she should document the nutrition assessment in a clear, structured, and accessible manner for the health care team to facilitate action by the LIP using the RD?s assessments relating to the patient?s nutritional status. Tables 4, 5, and 6 provide examples of documentation that can be used to accomplish this. The RD can only document the nutrition diagnosis; the medical diagnosis must be determined and documented by the physician. The medical diagnoses documented by physicians are the only ones that can be used by the clinical documentation specialists to assign the appropriate ICD-9 codes for determination of the CMI and the MS-DRG for reimbursement for the hospital stay. Therefore, the physician must document in his/her notes the malnutrition diagnosis, including the degree of malnutrition. Refer to Tables 4, 5, and 6 for example documentation of these malnutrition diagnoses by the RD and LIP. To most reliably have the nutritional status reflected in the DRG of the hospital stay, documentation needs to be seen in the LIP?s progress note assessment and included in the discharge summary diagnoses.

Only one CC or MCC increases the relative weight, and hence, the dollar amount of total reimbursement of the assigned MS-DRG. Therefore, the diagnosis of malnutrition may not always change the actual reimbursement rate for a patient?s hospital stay. However, it is worthwhile to identify and correctly capture all possible diagnoses, including malnutrition, using ICD-9 (soon to be ICD-10) codes to include in the MS-DRG system by the coding department. Table 7 provides examples of DRGs that are changed as a result of malnutrition documentation by the LIP with the corresponding increase in CMI and reimbursement.

Although three malnutrition diagnosis codes qualify as MCCs (kwashiorkor, nutritional marasmus, and severe protein calorie malnutrition), kwashiorkor and marasmus are rarely seen in adults in the United States, and as such, should rarely be used to document malnutrition. If these codes are routinely documented as part of the principal or secondary diagnoses for the patient, the hospital has a high probability of receiving an audit by the Office of the Inspector General to verify the accuracy of the code assignment. Severe protein calorie malnutrition is the only remaining malnutrition code that is considered a MCC to increase the relative weight of the assigned MS-DRG. Table 1 lists the malnutrition diagnoses that are considered CCs.

If the RD documents malnutrition in his/her assessment, but the physician does not include malnutrition as a medical diagnosis, the coding department may send a query to the physician to see if he/she agrees. Efficient communication between the RD and physician during the patient?s hospitalization can alleviate the need for the coding department to send a query, saving time and healthcare resources.

CONCLUSION

Identifying and treating malnutrition in hospitalized patients is essential to improving patient outcomes. Documentation of the malnutrition diagnosis is also important for appropriate reimbursement to hospitals for the actual work done by the health care team. Consistency of diagnosing malnutrition at each hospital can be obtained by a multidisciplinary group writing the policy for defining malnutrition based on evidence based guidelines. As the head of the healthcare team, the physician should remain actively involved in the treatment of the malnutrition, while utilizing the care and expertise provided by registered dietitians.

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FRONTIERS IN ENDOSCOPY, SERIES # 13

Endoscopic Ultrasound Guided Intervention for Gastric Variceal Bleeding

September 2014 • Volume XXXVIII, Issue 9

Larissa L. Fujii-Lau,

Louis M. Wong Kee Song,

Michael J. Levy

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Acute hemorrhage from gastric varices (GV) is more severe and difficult to treat, often leading to a poorer patient prognosis, as compared to esophageal varices (EV). Currently, the recommended treatment of bleeding GV is endoscopic cyanoacrylate injection. Endoscopic ultrasound (EUS) may enhance variceal detection and improve therapeutic targeting. Newer endosonographic techniques have been developed to offer an alternative treatment and improve patient outcome. This article serves to review these EUS techniques used to treat GV.

INTRODUCTION

Gastric varices (GV) are found in up to 20% of patients with portal hypertension.¹ Approximately 5% of GV will have clinically-evident bleeding.² Acute hemorrhage from GV occurs less frequently than esophageal varices (EV), but is more severe and often requires more blood transfusions.¹

Soehendra et al. in 1986 reported on cyanoacrylate (glue) injection of GV, representing an important breakthrough in the endoscopic treatment of GV.³ Subsequently, many studies have demonstrated the efficacy of GV obliteration using cyanoacrylate injection. Despite the lack of large randomized control trials, current practice guidelines and expert consensus recommend the use of glue injection to treat GV.^{4, 5}

Endoscopic ultrasound (EUS) has been increasingly used as a therapeutic procedure, allowing precise targeting of structures. EUS-guided angiotherapy is an example of the growing practice of interventional EUS. Due to the lack of prospective randomized control trials comparing EUS and conventional endoscopic therapy, the use of EUS-guided therapy has been limited to few institutions. EUS may enhance variceal detection and improve targeting of therapy, particularly in patients in whom endoscopic treatments were ineffective due to failed therapy or the inability to adequately visualize the varices (e.g. subepithelial component). This review serves to highlight novel EUS techniques which have emerged as alternatives to standard glue injection for the treatment of GV.

EUS Detection of Gastric Varices

EUS-guided therapy of GV offers several potential advantages over conventional endoscopic treatment, including enhanced diagnosis, treatment, and follow-up. As EUS images deep to the mucosal lining, it has a higher sensitivity for variceal detection,33 particularly GV which often have a significant submucosal component.³⁴ In addition, EUS may visualize the entire variceal complex as well as the feeding and perforating vessels, which allows direct targeting of these sites. This is important as the risk of recurrent varices and hemorrhage have been shown to correlate with number of varices, their diameter, and the persistence of flow.^35-37 The use of Doppler before and after the injection of coils and/or cyanoacrylate allows monitoring of the treatment success.

EUS-Guided Coil Injection
Technique

In our practice, all EUS angiotherapy procedures are performed using a curvilinear echoendoscope with fluoroscopic assistance. Due to the length and complexity of the procedure, general anesthesia should be considered. Prophylactic antibiotics should be administered if a vessel is punctured through the gut lumen, with the use of post-procedure antibiotics advocated by some.

After identification of GV using a curvilinear echoendoscope, color or power Doppler should be used to anatomically delineate the variceal network with the goal of targeting either the feeding vessel for localized GV or the largest vein in diffuse GV. (Figure 1a-f) Once the target vessel is identified, a fine needle aspiration (FNA) needle is loaded with a coil. We prefer using a 22-gauge FNA needle to allow for 0.018 inch coils rather than larger needles and coils due to the ease of administration and potentially decreased risk of bleeding at the needle puncture site. The coiled diameter of the coil should be approximately 1.25-1.5 times the diameter of the targeted vessel, which typically results in use of 6-10 mm (straight length 70-140 mm) coiled diameters. We remove the stylet from the FNA needle and use the stylet to advance the coil until it lies just short of the needle tip. While some use a guidewire to advance the coil, we prefer use of the stiffer stylet which incurs no additional cost. Once the coil is loaded, the FNA needle is inserted through the echoendoscope channel and then advanced into the vessel. We typically puncture through the entire vessel and a short distance into deeper structures to anchor the coil. We then slowly advance the stylet to deliver the coil and minimally retract the needle to allow the coil to predominantly lie within the vessel itself. Finally, we often anchor a portion of the coil at the side of the vessel that lies closest to the echoendoscope. Throughout the procedure both endosonographic and fluoroscopic images are continuously monitored to ensure proper coil placement. Doppler should be performed to document the decreased blood flow and potential need for additional therapy.

Clinical Application

One group has reported on EUS-guided coil injection only for GV.⁴⁰ In 4 patients with cirrhosis-related GV, coil embolization was performed with eradication of GV in 3 (75%) cases. The first patient had 13 coils inserted throughout the GV complex, followed by 9 coils placed into a 13 mm perforating vessel. The subsequent 3 patients had 2-7 coils placed only into the perforating vessel, which ranged from 6-12 mm in size. No coils migrated in the 5 months of follow-up. The same group recently described a multicenter retrospective analysis on the use of coils versus cyanoacrylate to treat GV.³⁹ Due to its retrospective and non-randomized nature, the 2 groups should be compared cautiously. In the coil embolization only group, in which it is unclear whether some patients from their initial study were included, complete obliteration of the GV by injection into the perforating vein occurred in 10 of 11 patients (91%). Majority of cases had complete treatment of the perforating vessel within 1 session (9 patients; 82%). A mean of 5.8 (SD 1.2) coils were placed per patient. Although more patients required subsequent procedures in the cyanoacrylate group compared to the coil group, the authors commented that the endosonographers thought that coil injection was more technically demanding. Our single-institution experience with EUS-guided coil injection into GV encompasses 3 patients with underlying cirrhosis, malignant portal hypertension, or portal vein thrombosis. These patients underwent a total of 6 procedures with total of 14, 9, and 7 coils placed. In all 3 patients, there was no evidence of further GV bleeding after coil embolization during a median follow-up of 17 months. Two patients had bleeding episodes related to EV after obliteration of the GV complex, therefore these patients may benefit from endoscopic surveillance and treatment of EV after successful therapy of the GV.

EUS-Guided Cyanoacrylate Injection
Technique

Similar to coil injection, the targeted vessel should be thoroughly mapped using the EUS prior to cyanoacrylate injection. Only after careful planning of the projected glue insertion would we recommend preloading the FNA needle with cyanoacrylate in order to minimize the risk of glue occlusion within the needle. This technique is preferred over using the stylet during vessel puncture and subsequent removal of the stylet before the glue is loaded into the needle, which may increase the risk of withdrawing blood into the needle and insertion of a clot or air as the glue is then inserted through the needle. We use a 1:1 mixture of 2-octyl cyanoacrylate and lipoidol to allow for fluoroscopic monitoring during glue injection. As the risk of embolization increases with the volume of cyanoacrylate injected, it is recommended to use the least amount of glue possible to achieve decreased flow through the variceal complex.29 As there is a high cost of repairing an echoendoscope if glue becomes lodged within the channel, extreme care must be undertaken to immediately clean the echoendoscope thoroughly after each cyanoacrylate injection.

Clinical application

The first study on the utility of EUS-guided cyanoacrylate injection compared a historical group of patients who underwent conventional endoscopic glue injection during an acute GV bleeding episode with a group who underwent endoscopic glue injection during the acute hemorrhage followed by EUS surveillance and further glue injection until eradication.⁴¹ Primary hemostasis during the initial endoscopic procedure occurred in >95% of patients in both groups. The EUS group underwent an average of 2.2 (SD 1.7) procedures to completely obliterate GV in 43 of 54 patients (80%). No adverse events were reported during the EUS-guided injection. Those in the EUS surveillance group had significantly fewer episodes of recurrent GV bleeding as compared to those who received conventional endoscopic glue injection (26% vs 57%, p=0.002). Although the use of a historical cohort is not an ideal method to compare treatment strategies, this study introduced the concept that patients with a history of active GV hemorrhage may benefit from EUS surveillance and treatment of persistent GV to decrease the risk of rebleeding.

A case series on 5 patients with cirrhosis-related GV who underwent EUS-guided cyanoacrylate injection into a perforating vessel showed complete obliteration in all the patients after injecting a mean of 1.6 mL of glue.⁴² During a mean follow-up of 10 months, no adverse events or recurrent bleeding were observed. Focusing on the patients who underwent only EUS-guided glue embolization by the same authors in the study mentioned in the EUS-guided coil injection section, all 19 patients had complete obliteration of the feeding gastric vessel.39 The 5 patients reported in the initial case series were not included in the subsequent study. Only 42% of patients had successful treatment after 1 session of EUS-guided glue injection. A mean of 1.5 (SD 0.1) mL of cyanoacrylate was injected per patient. Although 12 adverse events occurred in 11 patients in the cyanoacrylate group, only 2 were symptomatic including fever (n=1) and chest pain (n=1). There were 9 asymptomatic pulmonary glue embolisms (47%) detected on routine chest CT scans performed in all patients in the EUS-guided glue injection group, which significantly lengthened their hospital stay.

EUS-Guided Combined Coil and Cyanoacrylate Injection

The injection of coils prior to glue theoretically provides a scaffold and helps anchor the glue, which may decrease the risk of embolization.³⁸ Binmoeller et al. described an ex-vivo experiment where a 1 mL of cyanoacrylate was injected into heparinized blood that contained a previously placed coil.³⁸ The glue clung to the fibers of the coil, allowing all of the glue to be removed with the coil in a single piece. Therefore, it was hypothesized that EUS-guided coil insertion followed by cyanoacrylate injection improves variceal obliteration while decreasing the risk of glue embolization.

The same group retrospectively analyzed 30 patients with acute or recent (<1 week) bleeding from GV who underwent EUS-guided coil and glue embolization of a feeding vessel.⁴³ Technical success of coil and glue injection occurred in all 30 patients, while immediate hemostasis was achieved in both patients with active bleeding. The majority (93%) of cases only had 1 coil placed and a mean of 1.4 mL of 2-octyl-cyanoacrylate was injected. No immediate adverse events, including clinical evidence of pulmonary glue embolisms, occurred. Of those with subsequent surveillance endoscopy, 96% had complete obliteration of the feeding vessel and no evidence of flow on color Doppler within the variceal complex. One patient had recurrent GV bleeding 21 days after the initial procedure, which was treated with a subsequent EUS-guided combined coil and glue injection. At follow-up endoscopies, the glue and coils were found to spontaneously extrude into the stomach and eventually form a scar. Prospective trials are needed to confirm the theoretical benefit of using coils to anchor the glue.

EUS-Guided Portosystemic Gradient Measurement and Shunt Placement

In patients whom the underlying cause of GV is unclear, a hepatic venous pressure gradient (HVPG) obtained via transjugular access may be required for the diagnosis of portal hypertension. Although the HVPG is an accurate surrogate marker for sinusoidal and post-sinusoidal portal hypertension, pre-sinusoidal disease is not often diagnosed due to the inability of the wedge hepatic vein pressure to accurately approximate the portal vein pressure. Therefore, direct portal pressure measurements may be required in these situations. Percutaneous direct portal vein access is challenging and carries a significant risk, so several centers have reported on the use of EUS-guided portal vein catheterization and pressure measurement in porcine models.[Lai et al., Giday et al.] Portal pressure measurement was successful in all pigs, and was shown to correlate with transabdominal ultrasound-guided transhepatic portal vein pressure measurement (r=0.91). We performed the first EUS-guided portosystemic pressure gradient in a human subject to help rule-out portal hypertension as the cause of the patient?s recurrent gastrointestinal bleeding from duodenal varices. The portal vein was accessed transduodenally with a 22-gauge fine needle aspiration (FNA) needle (Wilson-Cook Medical Inc., Winston-Salem, NC) and contrast injection under fluoroscopy confirmed vascular access with a blush of contrast that quickly disappeared. Portal blood was then aspirated through the needle, which was connected to an arterial line pressure catheter, and portal pressure was measured after calibration. The same technique was repeated after identification and transgastric puncture of the middle hepatic vein. The portal vein, hepatic vein, and portosystemic pressure gradient all correlated with prior interventional radiology measurements of the HVPG. Transjugular intrahepatic portosystemic shunts (TIPS) are performed by interventional radiologists when a patient has recurrent or refractory variceal bleeding. In the future, EUS-guided portosystemic shunt placement may be an option, particularly during the same session in which other EUS interventions have been unsuccessful. One experimental study on 10 live porcine models used a linear echoendoscope to identify intrahepatic branches of the portal vein and hepatic vein.⁴⁴ A 19-gauge needle was inserted transgastrically into an intrahepatic branch of the hepatic vein, and then advanced through normal liver parenchyma into a nearby intrahepatic branch of the portal vein. Venography was performed under fluoroscopic guidance to confirm position, followed by insertion of a 0.035-inch guidewire. After removal of the echoendoscope, a covered Zilver biliary self-expandable metal stent (ZILBS; Cook Endoscopy; Winston-Salem, NC) was inserted over the wire and deployed while monitoring fluoroscopic and endosonographic images. The chosen stent was 1-2 cm longer than the distance from the punctured hepatic vein to portal vein and the diameter approximated the diameter of the portal vein. Repeat venography was performed to confirm adequate placement. Four animals required an additional stent to be placed as the initial stent was not long enough to cover the intended distance. No adverse events occurred in any animal. Additional studies are required to understand the role and outcomes of EUS-guided portosystemic shunt placement in human subjects.

SUMMARY

Bleeding from GV remains a challenge for the endoscopist. Although the recommended treatment is endoscopic glue injection, novel approaches and techniques are being studied to improve outcomes in these patients. As most studies on these emerging modalities are limited to case series, additional research is required to determine the optimal treatment option for patients with GV hemorrhage. In addition, additional trials focusing only on the treatment of fundal varices are needed to determine the long-term outcomes of these therapies. Ultimately, the decision on how to treat GV will largely depend on local expertise and should be approached in a multidisciplinary manner incorporating standard endoscopy, EUS, and interventional radiology.

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GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, #1

Status of Pharmacologic Management of Gastroparesis: 2014

September 2014 • Volume XXXVIII, Issue 9

Richard W. McCallum,

Joseph Sunny, Jr

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Gastroparesis is characterized by delayed gastric emptying without mechanical obstruction of the gastric outlet or small intestine. The main etiologies are diabetes, idiopathic and post- gastric and esophageal surgical settings. The management of gastroparesis is challenging due to a limited number of medications and patients often have symptoms, which are refractory to available medications. This article reviews current treatment options for gastroparesis including adverse events and limitations as well as future directions in pharmacologic research.

INTRODUCTION

Gastroparesis is a syndrome characterized by delayed emptying of gastric contents without mechanical obstruction of the stomach, pylorus or small bowel. Patients can present with nausea, vomiting, postprandial fullness, early satiety, pressure, fullness and abdominal distension. In addition, abdominal pain located in the epigastrium, and distinguished from the term discomfort, is increasingly being recognized as an important symptom. The main etiologies of gastroparesis are diabetes, idiopathic, and post gastric and esophageal surgeries.¹ Hospitalizations from documented gastroparesis are increasing.² Physicians have both medical and surgical approaches for these patients (See Figure 1). Medical therapy includes both prokinetics and antiemetics (See Table 1 and Table 2).

The gastroparesis population will grow as diabetes increases and new therapies will be required. What do we know about the size of the gastroparetic population? According to a study from the Mayo Clinic group surveying Olmsted County in Minnesota, the risk of gastroparesis in Type 1 diabetes mellitus was significantly greater than for Type 2. The cumulative proportions developing gastroparesis over a ten year time period was 5.2% in Type 1 and 1.0% in Type 2, compared to 0.2% in controls. They concluded that gastroparesis is a relatively uncommon complication of diabetes.³ However in recent studies utilizing a more ?real world? population of diverse cultures and socioeconomic status, not represented in Olmsted County, there is a very different result. This new study concluded that approximately 165,000 Type 1 diabetes mellitus (14% of US patients with Type 1 diabetes) and 2.1 million Type 2 diabetes mellitus (9.4%) patients are currently seeking medical therapy for diabetic gastroparesis symptoms and had moderate to severe symptoms of diabetic gastroparesis within the previous seven days of being in the survey.⁴ The prevalence of diabetic gastroparesis is thus higher than previously reported and is significantly underdiagnosed and undertreated. The greater standardization and acceptance of radionuclide four hour gastric emptying and the SmartPill (wireless motility capsule) will facilitate more confidence in the evaluation of gastric emptying and with better recognition the full breadth of gastroparesis will be better appreciated as a relatively common and severe complication of Diabetes Mellitus. The predicted number with diabetic gastroparesis in the US is 4 million and combined with other etiologies of gastroparesis the overall figure approaches or exceeds ten million patients in the USA. This is essentially 3% of the population. Put in perspective, hepatitis C and celiac sprue are now both thought to be present in approximately 1% of the population.

Prokinetics Metoclopramide

Approved by the FDA in 1979, metoclopramide is the only gastric prokinetic registered in the United States. Metoclopramide blocks dopamine D2 receptors in the upper gastrointestinal tract as well as stimulates 5-HT₄ receptors resulting in augmented acetylcholine release which promotes gastric motility by affecting pre-synaptic and post-synaptic receptors in the gut wall. Overall, the medication leads to increased lower esophageal sphincter pressure, gastric tone, intragastric pressure, as well as coordinates antroduodenal motility with relaxation of the pylorus, resulting in faster gastric emptying. Dopamine inhibits lower oesophageal sphincter pressure and gastroduodenal motility.⁵ Levodopa was shown to increase gastric retention of a technetium labelled meal compared to placebo. Administration of metoclopramide with levodopa returned gastric emptying toward normal. This study demonstrated the inhibitory effect of dopamine receptors on gastric motility.⁶ Metoclopramide also provides antiemetic relief through inhibiting D2 dopamine within the chemoreceptor trigger zone of the brain as well as some antagonism of 5-HT3 receptors.⁷

Most of the research with metoclopramide occurred as long as thirty years ago. A multi-center placebo controlled trial in 1983 using a dose of 10 mg orally four times a day showed improved symptom outcomes and gastric emptying time in patients with diabetic gastroparesis.8 Two trials with a total of twenty three diabetic gastroparesis patients showed improvement in gastric emptying and symptoms over placebo.^9,10 Patients did have symptom improvement as far as nausea, vomiting, constipation, fullness and bloating; however, gastric emptying did not improve and did not correlate with symptom improvement in either study. Therefore, metoclopramide?s clinical efficacy is provided by a combination of pro-kinetic effects peripherally and antiemetic properties centrally.^8,9

Metoclopramide is available in oral, suppository, and injectable routes of administration. Oral formulations include tablet, liquid and dissolvable tablets. A trial of ten patients showed that subcutaneous metoclopramide (2 cc=10 mg) administration can lead to improvement in gastric emptying and symptoms. In the outpatient setting, subcutaneous metoclopramide in doses of 10 to 40 mg per day can be used as an adjunct to the patient?s oral medications since the plasma levels achieved are 80% of the intravenous levels thus overcoming the limitations of erratic absorption in the setting of gastroparesis and vomiting.11 This subcutaneous self administration essentially equates to IV use in the emergency department. The newly released metoclopramide ODT (Metozolv ODT) is an orally dissolvable tablet available in 5 mg and 10 mg, which facilitates patient compliance. The absorption occurs in the small bowel and not through the buccal mucosa. An intranasal route of administration is also being developed to address the challenges of gastroparesis by providing a continuous plasma level for the agent.

Adverse events are a significant detraction for metoclopramide. The United States Food and Drug Administration released a warning for metoclopramide in 2009 stating the medications risk of tardive dyskinesia, specifically with patients taking the medications for greater than three months.12 Overall, approximately thirty percent of patients cannot maintain long term use. The medication can cross the blood-brain barrier leading to inhibition of central D2 receptors involved in movement pathways such as the basal ganglion, manifesting in a wide array of involuntary movement disorders. An acute dystonic reaction can occur within the first few hours typically when given parenterally, which will resolve with discontinuation. Within the first few weeks and months, akathisia, anxiety, tremor, drug-induced Parkinsonism and depression can develop. These can be reversible within a few days to a few months after drug discontinuation or tapering of the dose, and sometimes adding carbidopa briefly. Also, benadryl is an antidote to reduce the anxiety and restlessness. Tardive dyskinesia is an irreversible movement disorder defined by disfiguring and involuntary movements. The reported incidence of tardive dyskinesia with metoclopramide has a large range from 0.1% to 29%. The length of treatment prior to symptom development was also variable from 14 to 20 months.3 Careful follow up of patients on chronic metoclopramide with actual office visits and not refilling prescriptions without seeing patients will prevent this possibility.

Domperidone

Domperidone is a dopamine receptor antagonist, which has both central antiemetic and peripheral prokinetic properties in the upper GI tract. However, the important distinction from metoclopramide is that it only minimally crosses the blood brain barrier. This leads to really no concerns about central nervous system side effects. Another distinction is domperidone is not a 5-HT₄ agonist. Unfortunately, domperidone is not easily available in the United States since the FDA withheld approval in 1989 due to borderline statistical significance related to sample size enrolled in the controlled clinical trials. The pharmaceutical company, Janssen, subsequently withdrew their application without pursuing further trials. To obtain domperidone, clinicians can request the medication through an Investigational New Drug Application through the FDA. Serum potassium and EKG should be performed on initial and subsequent evaluations, because of concerns about possible prolongation of the QT interval.¹³ In an extensive experience by the author in over 500 patients using high dose domperidone 80 to 120 mg per day, compared to usual European dosing of 40 mg per day, cardiac events have not been evident and QT prolongation is infrequent.¹⁴ The only side effects may be due to increased levels of prolactin resulting in gynecomastia, breast tenderness, galactorrhea and menstrual irregularities. Prolactin release occurs from stimulation of the pituitary gland. Both the pituitary and the chemoreceptor trigger zone emetic areas are regarded as being outside the blood brain barrier consistent with domperidone?s lack of CNS side effects. Chronic therapy does not appear to lead to decreased efficacy. The starting standard dose has been listed at 10 mg oral four times a day in other countries but clinical trials in the United States have used 20 mg four times a day and in clinical practice 30 mg four times a day can be used while also monitoring ECG at regular visits. The maximum dose recommended is 120 mg orally per day. We recommend a trial of domperidone in doses of 80 to 120 mg per day for up to 3 months as our current practice before patients can be considered as medical treatment failures.¹⁵ This approach results in 72% of patients achieving satisfactory control of symptoms.¹⁶.

Motilin Receptor Agonists

The macrolides class of agents are motilin receptor agonists of a particular chemical structure, which promote motility in the stomach and small bowel.¹⁷ Their unique molecular structure permits them to occupy the motilin receptor in the antrum of the stomach. The distinction of a ?particular channel structure? differentiates this class from small molecule motilin receptor agonists that are currently under development eg GSK 962040. In addition, another evolving motilin agonist is RQ-00201894, a small non-peptide motilin agonist shown to induce contractions in an animal model.¹⁸ The macrolide class includes erythromycin and azithromycin. Erythromycin lactobionate is well studied as a prokinetic. It can be given IV at up to 3 mg/kg every six to eight hours in the hospital setting to facilitate gastric and small bowel tube placement and decrease gastric residuals with tube feeding as well as treat post-operative ileus and as a preparation for performing upper GI endoscopy in the setting of GI bleeding. Based on a meta-analysis of oral prokinetics, erythromycin has better acute outcomes than domperidone, cisapride, and metoclopramide for both gastric emptying and gastrointestinal symptoms.¹⁹ Orally this medication has been determined to have limited long term efficacy because of concerns for tachyphylaxis after a few weeks. Both the liquid and tablet forms of erythromycin have been noted to increase gastrointestinal motility.20 Hence using a low oral dosing of 150 mg to 250 mg twice to three times a day is recommended to reduce ?saturation? of receptors.21 At this dose, erythromycin is not being used at an antibiotic dose so there are no concerns regarding patients developing bacterial resistance when the agent is being used frequently. Among patients with diabetic and idiopathic gastroparesis, erythromycin was shown to decrease symptoms and gastric emptying time with both oral and intravenous forms.²¹ Patients given intravenous erythromycin for post-vagotomy-antrectomy gastroparesis had improvement in initial phase of solid meal gastric emptying²² indicating that there are motilin receptors in the fundus of the stomach. QT prolongation is a possible side effect of macrolides, and erythromycin carries the greatest risk.23 Combined use of calcium channel blockers and macrolides can lead to hypotension and shock.²⁴ In an experimental model of proarrhythmia, erythromycin and azithromycin lead to similar prolongation of repolarization but erythromycin has greater proarrhythmic potential than azithromycin.²⁵ There are rare reports of erythromycin being associated with sudden cardiac death from QT prolongation due to P450 iso-enzyme inhibition. Azithromycin in a 500 mg dose intravenously was shown to be equally effective as erythromycin 200 mg intravenously in accelerating emptying time during nuclear studies²⁶ but recent concerns have also been raised regarding cardiac aspects of azithromycin. Azithromycin in clinically relevant doses was shown to activate recombinant human motilin receptors similarly to erythromycin.²⁷

5-HT₄ Receptor Agonists

Serotonin, also identified as 5-hydroxytryptamine (5-HT), has seven receptor subtypes. Enterochromaffin cells of the gastrointestinal mucosa secrete 5-HT after a meal, which stimulates adenyl cyclase and increases cellular cyclic AMP. 5-HT₄ receptor activation of efferent myenteric cholinergic excitatory neurons results in acetylcholine release leading to increase smooth muscle activity. Metoclopramide is both a 5-HT₄ receptor agonist and dopamine D2 receptor antagonist. Cisapride is a 5-HT₄ receptor agonist with no D2 receptor antagonism. Tegaserod is a 5-HT₄ receptor agonist with minimal 5HT3 effects but is also a 5-HT2B receptor antagonist.²⁸ Although tegaserod and cisapride were available for several years, they were withdrawn from the market due to increased cardiovascular side effects related to hERG K(+) cardiac channels.²⁹

The 5-HT₄ receptor agonists still being actively investigated are prucalopride and velusetrag, although they are being initially studied for constipation. Prucalopride does not affect the hERG potassium channel. Prucalopride showed no difference between placebo for corrected QT intervals or incidence of supraventricular or ventricular arrhythmias in a phase II trial among elderly patients with constipation.³⁰ Being a selective, high-affinity 5-HT₄ receptor agonist,³¹ it was shown to improve spontaneous complete bowel movements in a randomized, placebo controlled double-blind trial of 713 patients with constipation in Europe where it is now approved.³² It is also being considered for investigation for gastroparesis and dyspepsia in the USA. Velusetrag is a selective serotonin 5-HT₄ receptor agonist, and it was shown to accelerate gastric emptying after multiple doses in a study for chronic constipation.³³ Another novel 5-HT₄ agonist, naronapride, has demonstrated acceleration of gastric emptying following single and multiple oral administration to healthy human subjects in a randomized double-blind, placebo-controlled trial.³⁴ Further phase 2 trials are being planned for gastroparesis.

Acetylcholinesterase Inhibitors

Acotiamide has been proposed as a gastroprokinetic agent with a mechanism of action related to inhibiting acetylcholinesterase activity in the stomach. Hence, this agent facilitates acetylcholine release from cholinergic nerve terminals by blocking muscarinic autoreceptors, both M1 and M2, which regulate the release of acetylcholine. The mode of acetylcholinesterase inhibitory actions was found to be selective and reversible. There has been no affinity demonstrated for dopamine or 5-HT receptors distinguishing acotiamide from mosapride, a 5-HT₄ agonist, and itopride, an agent with both dopamine affinity and inhibition of acetylcholinesterase activity. It has an accompanying excellent safety profile and future studies and trials are required outside of Asia, where it has been mainly studied and is approved for ?functional dyspepsia?. Itopride was studied in Asia with some promise but its role has not evolved. It combined central antidopamine with peripheral cholinesterase activity, which augmented cholinergic function. Nizatidine (an h3 blocker) is also a partial prokinetic beyond its acid-inhibitory properties, based on cholinesterase inhibitor mechanisms.

Ghrelin Receptor Agonists

Ghrelin is released by neuroendocrine cells in the gastric fundus and duodenum. Endogenous ghrelin rises before and falls after a meal. The appetite stimulating signal appears to travel through the vagal afferent pathway, and this pathway could be impaired in diabetic gastroparesis. Intravenous ghrelin administration increases gastric emptying and ghrelin receptor agonists could become novel treatments for gastroparesis.³⁵ In a rat model, intravenous ghrelin was shown to accelerate gastric emptying.³⁶ Intravenous ghrelin has been shown to improve gastric emptying and meal related symptoms in idiopathic gastroparesis³⁷ and it has also been shown to increase gastric emptying in diabetic gastroparesis.³⁸

TZP-101 is synthetic selective ghrelin receptor agonist in clinical development. Intravenous administration daily for four days improved gastroparesis symptoms in a randomized, placebo-controlled study of 57 patients with diabetic gastroparesis.³⁹ Among ten patients with diabetic gastroparesis, TZP-101 produced significant reductions in radiolabelled solid meal half-emptying.⁴⁰ A recent phase 2a randomized, double-blind trial 92 patients receiving TZP-102, an oral ghrelin receptor agonist, showed no significant improvement in gastric emptying but did provide symptomatic relief.⁴¹ However, a subsequent phase 2b 12 week placebo controlled trial using 10 and 20 mg doses once per day for twelve weeks was not able to show any clinical efficacy versus placebo and subsequently pursuing TZP-102 in gastroparesis was abandoned by the company (Tranzyme).

RM-131 is a promising synthetic ghrelin receptor agonist under development demonstrating greater potency than human ghrelin in animal experiments. RM-131 was shown to improve early phase gastric emptying of solids and reduce upper gastrointestinal symptoms in type 1 diabetes mellitus patients with delayed gastric emptying in randomized, placebo-contolled, single-dose, two-period, crossover study.⁴²

A Phase 2 clinical trial was designed to evaluate the effect of relamorelin (Rm-131) on gastrointestinal (GI) motility, the symptoms of gastroparesis, and safety in patients with diabetic gastroparesis. The randomized, double-blind, placebo-controlled, adaptive, parallel-group study assessed relamorelin 10 mcg administered once daily, twice daily, or placebo-administered daily to patients with diabetic gastroparesis over a period of one month. The study was submitted and presented at DDW 2014. Relamorelin is effective in significantly accelerating gastric emptying in patients with diabetic gastroparesis and resulted in clinically important, significant improvements in vomiting. Vomiting episodes were reduced by 60% vs. placebo (p=0.033). In a large subgroup of patients who had vomiting at baseline (~60% of patients), relamorelin significantly improved a composite endpoint including the other subjective symptoms of diabetic gastroparesis?nausea, abdominal pain, bloating, and early satiety?vs. placebo, in addition to improving gastric emptying and vomiting (post hoc analysis). For the overall study group, there was a strong placebo effect for the subjective diabetic gastroparesis symptoms (nausea, abdominal pain, bloating, and early satiety), and relamorelin was associated with only numerical improvements vs. placebo that did not reach statistical significance.⁴³ This positive initial result is being followed by further clinical trials of this agent in gastroparesis.

Baclofen

?-Aminobutyric acid (GABA) is an important inhibitory neurotransmitter and is located throughout the gastrointestinal tract.⁴⁴ Baclofen is a GABA-B receptor agonist shown to increase lower esophageal sphincter pressure and decrease transient lower esophageal sphincter relaxation. It has been used to treat patients with refractory GERD.⁴⁵ The standard dose is 10 mg four times a day. The most common side effect of oral baclofen is drowsiness; it?s also noted to cause confusion, dizziness and fatigue. Baclofen was noted to accelerate gastric emptying time in a trial of thirty children with GERD.⁴⁶ Animal models have shown improved liquid and solid gastric emptying with baclofen.⁴⁷ However, randomized trials are lacking for gastroparesis.

Opioid Receptor Antagonists

Opiates such as morphine can delay gastric emptying and intestinal transit.⁴⁸ Gastroparesis patients may develop worsening symptoms if they are placed on narcotics either for back pain, peripheral neuropathy, or abdominal pain. Methylnaltrexone is mu-opioid receptor antagonist, which does not cross the blood brain barrier. The subcutaneous form has been shown in a randomized study of 133 patients to induce defecation rapidly without reversing the central analgesic effects of opioids.⁴⁹ In a randomized, double-blind, crossover placebo-controlled study, patients given morphine had a delay of gastric emptying, which was reversed when given methylnaltrexone.⁵⁰ However, methylnaltrexone was not shown to prevent post-operative nausea and vomiting in a prospective double-blind trial.⁵¹ In pre-marketing clinical trials, the most common side effects were abdominal pain, diarrhea, flatulence, and nausea. Randomized trials for methylnaltrexone in gastroparesis are lacking.

Antiemetics

Antiemetics should be used in combination with prokinetics to maximize symptom control in gastroparesis (see Table 2). Each antiemetic has its own mechanism of action based on blocking specific receptors in the chemoreceptor emetic center. For a given gastroparesis patient, it is difficult to know which antiemetic will be the most efficacious. Hence a series of antiemetics may be required to be used alone or in combination in an attempt to gain control of nausea and vomiting through antagonizing one or more receptors in the chemoreceptor trigger zone.

Phenothiazines

Phenothiazines are mainly dopamine and cholinergic receptor antagonists with the predominant site of action in the area postrema in the medulla oblongata. Examples includes prochlorperazine, promethazine, and trimethobenzamide. Sedation and extrapyramidal side effects such as slurred speech and dystonia are possible.⁵¹

Promethazine can be given by intravenous, intramuscular, oral, and rectal suppository routes. However, the intravenous route can cause injury related to phlebitis and even amputations have been reported with intravenous administration. It should be avoided in small veins such as the hand.⁵³

Muscarinic Receptor Antagonist

Patients with erratic drug absorption because of vomiting and gastroparesis benefit from transdermal medications. Scopolamine is a selective competitive antagonist of muscarinic cholinergic receptors. Sustained serum levels can produce antiemetic effects. Scopolamine is available as a 1.5 mg patch for three days. It is typically placed behind the ear to maximize absorption through that site with minimal subcutaneous fat. In postoperative patients, it was noticed to significantly decrease the risk of vomiting and nausea.⁵⁴ It is particularly attractive in the setting of gastroparesis where absorption can be unpredictable or oral medications not possible with active vomiting. The patch guarantees a sustained blood level over a 3 day duration. There is no evidence that the anticholinergic content in muscarinic receptor antagonists effects or delays gastric emptying.

5-HT³ Antagonists

Ondansetron, granisetron, and dolasetron inhibit 5-HT3 receptors in the area postrema. They also have peripheral effects via efferent fibers of the vagus nerve. They are antiemetics for chemotherapy and postoperative vomiting but now are also used for gastroparesis by oral or parenteral administration. Ondansetron orally dissolvable tablets are also available to facilitate absorption in very nauseated patients. Side effects are minimal although mild constipation has been reported. A generic version of ondansetron has increased accessibility to this drug class. However there are no controlled trials of 5HT3 antagonists in gastroparesis. Diabetic gastroparesis patients treated with ondansetron did not have improvements in gastric emptying.⁵⁵ Among 14 healthy volunteers, ondansetron did not affect the gastric emptying of solids.⁵⁶

Unfortunately, ondansetron can also interact with the hERG K(+) channel found in the heart leading to prolongation of cardiac repolarization.⁵⁷ In a study of inpatients for acute coronary syndrome or heart failure, ondansetron exposure led to a prolonged QTc in 31% and 46% respectively. In the heart failure group, QTc was prolonged by 18.3 +/- 20 msec.⁵⁸ Due to the risk of Torsades de Pointes, a potentially fatal heart rhythm, the FDA has removed the 32 mg intravenous single dose vial from the market.⁵⁹ These data are for IV administration and oral blood levels that are achieved are clearly much lower.

Granisetron is also available as a patch (Sancuso) providing plasma blood levels for up to seven days. In a double-blind, phase III, non-inferiority study, the patch controlled nausea and vomiting in 60% versus 65% for oral granisetron in the patient setting of chemotherapy.⁶⁰ An open label study of the granisetron patch was moderately effective in reducing nausea and/or vomiting in 83% of gastroparesis patients.⁶¹ Recent reports in gastroparesis have been promising and a double-blind trial is being planned by the pharmaceutical company (ProStrakan).

NK-1 Receptor Antagonists

High levels of substance P have been found in the area postrema and the vagal afferents from animal models.^62,63 Direct administration of substance P into the area of the nucleus tractus solitarii of the hindbrain induces emesis.⁶⁴ The action of substance P in these centers is controlled by the neurokinin-1 receptor (NK-�1) and antagonism of NK-1 receptor has shown antiemetic activity in animals given cisplatin.⁶⁵ A NK-1 receptor antagonist was an effective antiemetic against a variety of provoking agents including radiation, morphine, and copper sulfate in an animal model.⁶⁶

Aprepitant is a selective, oral nonpeptide antagonist of the NK1 receptor with the ability to penetrate the central nervous system. The earliest clinical trials were for patients receiving chemotherapy, specifically cisplatin. In a randomized, double-blind, placebo-controlled phase III study of 520 patients, 72.7% of group of patients receiving aprepitant, 5-HT3 antagonists and steroids had complete response (no emesis and no rescue therapy) versus 52.3% in the standard therapy group receiving 5-HT3 antagonist and steroids.⁶⁷ Based on retrospective data for chemotherapy patients, 42 patients treated with aprepitant and granisetron had a higher rate of complete response than 40 patients treated only with granisetron without significant difference in adverse drug events.⁶⁸ Aprepitant (Emend) is available in the United States for nausea and vomiting associated with chemotherapy and surgery. However, it has been adopted for use by gastroenterologists. Two case reports are available for the use of aprepitant for gastroparesis. One patient with refractory idiopathic gastroparesis responded to aprepitant 40 mg daily.⁶⁹ Another patient with refractory diabetic gastroparesis was able to tolerate aprepitant for four months prior to gastric electrical stimulation device placement.⁷⁰ A randomized, double-blind clinical trial is now being conducted by the NIH funded Gastroparesis Consortium utilizing a dose of 125 mg for the efficacy of aprepitant in gastroparesis and results are expected in 2015.

Cannabinoids

Cannabinoids are agonists of CB1 receptors in the brain and gut. They are both antiemetics and appetite stimulants. They can be used for patients who are refractory to other treatments. It should be noted that cannabinoids delay gastric emptying in healthy subjects.⁷¹ Chronic daily smoking of marijuana for greater than five years can lead to cannabis hyperemesis syndrome in a subset of subjects with genetically predisposed cannabinoid receptor sensitivity. This entity is characterized by unexplained recurrent nausea and vomiting, compulsive bathing in hot baths and showers, and abdominal pain. The majority of patients who stopped using marijuana had symptom improvement.⁷²

The earliest studies of cannabinoids were from the 1980s. In 1985, nabilone was compared to prochlorperazine for chemotherapy related emesis and was shown to be significantly superior in reducing vomiting episodes.⁷³ More recently, dronabinol was compared to ondansetron for delayed chemotherapy-induced nausea and vomiting in 2007. Among 61 patients, dronabinol and ondansetron were equally effective by themselves and combination therapy was not superior.⁷⁴ Dronabinol (Marinol) is available in the United States and the recommended antiemetic dosing is 5 mg orally three times a day ranging up to 10 mg three times a day. There are a subset of gastroparesis patients who definitely respond to this medication. In the few states in America where marijuana has been legalized, it can be an effective therapy when utilized on an ?as needed? basis for nausea and vomiting of different etiologies, including in gastroparesis patients. This is an entirely different method of use than chronic daily smoking for greater than five years, which leads to the episodes of ?cyclic vomiting? or ?cannabis hyperemesis syndrome?.

Tricyclic Antidepressants

In one hypothesis, gastroparesis symptoms of nausea and abdominal pain could be explained by neuropathic changes in sensory vagal and spinal nerves. In a study of vagal nerve integrity using sham feedings, impaired pancreatic polypeptide response was noted in diabetic gastroparesis but not idiopathic gastroparesis.⁷⁵ Nortriptyline, amitriptyline, and doxepin are available tricyclic antidepressants (TCAs). A chart review of 37 patients with functional nausea and vomiting showed an 84% response rate to TCAs with complete remission in 51%.⁷⁶ A randomized cross-over study of amitriptyline and placebo among functional abdominal pain patients showed improvement in symptoms after four weeks. The symptom improvement was not associated with a normalization of the perceptual responses to gastric distension.⁷⁷

Prospective, randomized and adequately powered trials have been lacking for tricyclics in gastroparesis. In a two year follow-up open labeled study, eighty-eight percent of patients treated for cyclic vomiting syndrome had improved clinical status by subjective global assessment.⁷⁸ Thirty-six chemotherapy patients in a double-blind, randomized, crossover study showed reduced emetic episodes when using a combination of intravenous metoclopramide and oral nortriptyline versus intravenous metoclopramide alone.⁷⁹

Nortriptyline did not differ in overall symptomatic improvement versus placebo for idiopathic gastroparesis in a just completed 12 week multicenter, randomized, double-masked, placebo-controlled dose escalation trial which was well powered and conducted by the NIH Gastroparesis Consortium.⁸⁰ However, nausea showed improvement in the first few weeks at low doses of nortriptyline (25 mg) while abdominal pain and early satiety improved in the latter part of the trial when doses were averaging 50 mg at night. In another retrospective study, the majority of 24 diabetic patients with nausea an and vomiting who failed prokinetics had symptomatic improvement after treatment with tricyclic antidepressants.⁸¹

Clearly the tricyclics and other neuromodulators need to be further studied in all etiologies of gastroparesis and also with specific symptoms.

Transcutaneous Stimulation

Transcutaneous stimulation of acupuncture sites for nausea and vomiting is an alternative form of therapy and has shown improved rates of gastric emptying and reduction of symptoms. This utilizes the nausea and vomiting acupuncture sites of PC6 near the wrist and ST36 on the leg as sites for cutaneous electrical stimulation.

Multiple trials have demonstrated the effectiveness of transcutaneous stimulation on nausea and vomiting. Twenty three women with significant nausea and vomiting in the first 14 weeks of pregnancy were enrolled in a randomized, crossover study between a sensory affect stimulation unit and an inactive placebo unit; twenty one experienced improvement with a sensory affect stimulation delivered through the volar surface of the wrist.⁸² More than 75% of over 100 patients with chemotherapy-induced sickness not adequately controlled with antiemetics alone had improvement with the addition transcutaneous electrical stimulation of the P6 antiemetic point.⁸³ Electrical stimulation of acupuncture points significantly increased the percentage of regular slow waves on electrogastrography in healthy humans.⁸⁴ A recently completed placebo-controlled multicenter clinical trial using a microstimulator developed by Transtimulation Research Incorporated showed improvement in gastroparesis symptoms after 4 weeks of use.⁸⁵ and more trials are anticipated. One mechanism of action is a change in vagal ratio indicating possible motor and sensory benefits attributed to peripheral and central vagal actions.

Expert Commentary on the Field

Combination therapy of antiemetics and prokinetics is our recommendation for symptomatic control in gastroparesis. Metoclopramide should be started at 5-10 mg three times a day before meals and at night time. If tolerated (in 60% or more of patients), doses can be increased up to 20 mg before meals and at night time plus or minus adjunctive role for subcutaneous administration. Scopolamine 1.5 mg patch behind the ear, replaced every 72 hours can overcome the limitations of nausea control by orally administered agents in settings of vomiting and gastroparesis and should be utilized in all patients particularly since it is well tolerated. Dissolvable ondansetron or phenergan are other options to be given on a scheduled regimen up to three times a day since nausea needs to be aggressively inhibited and not prescribed ?as needed?. Subcutaneous metoclopramide can be added for intermittent ?rescue? medication to avoid emergency room visits. If metoclopramide cannot be tolerated, then substitute domperidone 20 to 30 mg before meals and at night time. Marinol and granisetron (administered by a sustained 5 day patch, Sancuso) are other possibilities as degrees of intolerance and/or refractoriness are encountered.

The model of central emetic action combined with peripheral prokinetic activity is a very attractive approach to gastroparesis. Unfortunately this class is limited to metoclopramide and domperidone. Itopride was studied in Asia with some promise but its role has not evolved. It combined central antidopamine with peripheral cholinesterase activity, which augmented cholinergic function. There is also discussion about modifying metoclopramide by a polymerization method to limit its penetration of the blood-brain barrier thus overcoming its central nervous system side effects. In addition, there is an IND pending for a new dopamine-2/.dopamine-3 antagonist compound, which will overcome the past adverse event problems.

Gastroparesis remains a challenging syndrome to treat. Patients can be refractory to a limited field of currently available medications. As far as research in progress, ghrelin receptor agonists show the most promise. Despite promising results with double-blind randomized trials with TZP-102 indicating efficacy in the diabetic gastroparesis population, two recent trials failed to show efficacy versus placebo. The new ghrelin agonist relamorelin (RM-131) is a synthetic ghrelin agonist over 100 times more potent as a ghrelin agonist than TZP-102. Analysis of the data from 204 patients with diabetic gastroparesis indicates that relamorelin administered twice daily for four weeks in these patients with moderate to severe gastroparesis significantly improved gastric emptying, significantly reduced vomiting, and in a large (~60%) subgroup of the patients with vomiting at baseline, significantly improved a composite symptom score comprising nausea, abdominal pain, bloating, and early satiety.

Motilin agonists are still topical and despite setbacks in balancing dosing, half-life and timing of administration, there are ongoing studies of motilin agonists in Phase 1 and 2 levels of development.

5HT₄ receptor agonists have run into many difficulties with cardiac side effects but there is continued interest in this class and prucalapride as a survivor with no cardiac side effects is still being investigated and velusetrag is another selective 5HT₄ receptor agonist. Both agents have great potential to evolve into gastroparesis following focus initially on constipation.

There are important contributions forthcoming from the NIH funded Gastroparesis Consortium. The following pharmacological goals have been identified through histological and molecular structures in the gastric muscularis propria: 1.) Targeting nNOS/ Nitric oxide with precursor medications in settings where nNOS/NO are depleted. BH4 precursors such as Seprapterm have been used in animal models; 2.) Targeting interstitial cells of Cajal (ICC) epigenomics stem cells; 3.) Targeting the heme oxidase pathways with agents such as Hemin, or IL-10 which induce Hemin resulting in less reduction in heme oxygenase and loss of ICC in diabetic gastroparesis.

In the meantime, gastric electrical stimulation remains the mainstay of therapy for the 20-25% of patients failing all medical approaches. The recent modification of this approach by adding a pyloroplasty during the surgery ensures accelerated gastric emptying while at the same time the electrical stimulation is acting centrally to reduce nausea and vomiting via afferent pathways to the chemoreceptor trigger zone and augmenting vagal function to help gastric tone.

Article Highlights

An up to date summary of the established and putative gastric prokinetic agents and their mechanisms of action.
A major emphasis on the crucial contributions of antiemetics in the symptomatic control of gastroparesis patients – based on the fact that physicians do not recognize nausea as a dominant, under-appreciated and debilitating daily symptom.
Explores new antiemetic horizons involving transcutaneous electrical stimulation of acupuncture sites for nausea and vomiting.
Future advances in therapy will be based on knowledge gained from histological and cellular analysis of smooth muscle tissue specifically how to prevent loss of the Interstitial Cells of Cajal, inflammatory changes of interstitial neurons, and decreases in heme-oxygenase and nitric oxide synthase with a new spectrum of pharmacologic agents treating gastroparesis by addressing these abnormalities.

Authors? Declaration of Personal Interests

Richard W. McCallum has been on the Advisory Board of Smart Pill Corporation and Prostrakan Pharm. He has been a consultant for Tranzyme, Inc., Evoke, Rhythm and Medtronic Corporation. He has received research funding from Tranzyme, Takada, Salix, Novartis, Red Hill Pharma and Rhythm as well as current National Institutes of Health (NIH) funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ? Gastroparesis Consortium. Joseph Sunny has no declaration of personal interests.

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A Case Report

Poorly Differentiated Cecal Adenocarcinoma Presenting as Metastatic Disease to the Bone

August 2014 • Volume XXXVIII, Issue 8

J.K. Deutsch,N. Suda,P. Balachandran

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CASE

A 51 year-old African American male with a history of sciatica presented to the orthopedic clinic with progressively worsening posterior right hip and groin pain for three months. The pain worsened with weight-bearing activities, was alleviated by rest, but often woke him at night. He reported an unintentional weight loss of eight pounds over the same time, however he denied any gastrointestinal symptoms. On exam, there was minimal tenderness to palpation superior to the right greater trochanter. A plain radiograph of the pelvis discovered a right femoral neck fracture and follow-up computed tomography (CT) of the right lower extremity and hip revealed pathologic fracture of the right femoral neck with an associated lytic expansile lesion. The patient was scheduled for magnetic resonance imaging (MRI) of the right femur to be followed by orthopedic surgical intervention. He was also scheduled for a metastatic workup, including bone scan and CT of the chest, abdomen, and pelvis, in addition to routine labs and tumor markers.

The patient’s laboratory workup revealed a normocytic anemia, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and a mildly elevated alkaline phosphatase; there was no M spike in his serum protein electrophoresis (SPEP) and carcinoembryonic antigen (CEA) and prostatic specific antigen (PSA) were within normal limits. The pathology from a bone biopsy preceding orthopedic surgical intervention revealed a metastatic poorly differentiated adenocarcinoma. The patient?s bone scan (Figure 1) revealed an abnormal focus in the right femoral neck corresponding to the previously identified lesion on CT and a focal abnormality in the lateral margin of the right humeral neck. Further imaging with plain films and positron emission testing (PET/CT) noted increased uptake in several thoracic and lumbar vertebrae, several anterolateral ribs, the left anterior iliac crest and the left superior pubic ramus as well as uptake in the ascending colon, presumed to be the primary lesion.

The patient was seen in gastroenterology clinic for a colonoscopy. He denied any personal or family history of colon or breast cancer and denied ever having a colonoscopy. The patient underwent a diagnostic endoscopy and colonoscopy with gastric and cecal tubulovillous mass biopsy (Figure 2). He was found to have chronic gastric inflammation with H. Pylori and a poorly differentiated cecal adenocarcinoma with focal signet ring cell features (Figure 3).

The patient underwent radiation of the right hip and left rib lesions. He was seen by a surgical oncology team for right hemicolectomy, which revealed an 8×6.5 cm poorly differentiated adenocarcinoma invading into the submucosa, with involvement of 5 out of 13 regional lymph nodes. He will be followed for adjuvant chemotherapy.

DISCUSSION

While colorectal cancer remains the third most common cancer among adult men in the United States and the fourth most common cause of death from cancer,¹ skeletal metastases as a primary presentation of colorectal cancer is extremely rare. In two case series analyzing the site of primary cancer in skeletal metastases of unknown origin,^{2, 3} only 2 out of 104 patients (1.9%) with identified primary lesions had carcinoma of the colon while 48 (46%) had primary carcinoma of the lung. Both of these case series recommend a diagnostic workup including a thorough history and physical exam focused on the thyroid, breast and prostate. Routine laboratory analysis including complete blood cell count and blood chemistry that included electrolytes, liver enzymes, alkaline phosphatase and urinalysis, as well as ESR and SPEP were recommended. Serum tumor markers, namely CEA, cancer antigen 19-9 (CA19-9), CA125, alphafetoprotein (AFP) and PSA should be determined. Radiographic imaging should include a plain radiograph of the chest and affected bone in addition to a whole body scan and thoracic and abdominal CT imaging. It is not recommended to routinely perform a CT scan of the pelvis or an examination of the gastrointestinal tract because these seldom revealed the primary lesion.²

The incidence of bone metastasis from colorectal cancer ranges from 5.5-23.7%. ^4,5 Hepatic and pulmonary metastases are considerably more common in association with colorectal cancers, usually due to lymphatic spread of the disease into the venous system.^4,5 While many studies have reported bone metastasis in advanced disease or at the time of autopsy, these cases are often associated with hepatic and pulmonary metastases.^4,5,6,7 Katoh reports that the incidence of colorectal cancer metastasis to bone is increased in signet-ring cell carcinomas versus other histological types.⁵ Katoh also reported that all patients with bone metastasis at autopsy had accompanying liver metastasis, and 21 of the 28 patients with bone metastasis had accompanying lung metastasis.⁵ Additionally, there is a temporal pattern of organ involvement that exists among patients with colorectal cancer always involving the liver and lung before bone and never spread primarily to bone.4 Kanthan has described 60 cases of colonic adenocarcinoma with skeletal metastases only. Of these cases, rectal cancers were the most common primary sites with metastatic lesions most often seen in the vertebral column, pelvic bones, ribs, scapula, femur, fibula, humerus and skull.⁷

The mechanism of metastasis to bone in colorectal cancer is poorly understood. Many of the routes of spread implicate either liver or lung, or both, before malignant cells may reach bone. These are associated with lymphatic and nodal spread draining into the venous system. Only one route, via hematogenous spread, directly through the vertebral vein system may implicate bone metastasis without liver or lung⁵ as in this case.

This particular case is unique because our patient presented with skeletal metastases without evidence of hepatic or pulmonary involvement in a primary poorly differentiated cecal adenocarcinoma with focal signet ring cell features. While this entity has been described in the literature, this particular presentation remains exceedingly rare and should be noted for the thorough diagnostic workup despite literature recommendations against a gastrointestinal source of primary malignancy in skeletal metastases.

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Unusual Causes of Abdominal Pain, #5

Unusual Causes of Abdominal Pain

August 2014 • Volume XXXVIII, Issue 8

George W. Meyer

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CASE

A 70 Caucasian woman presents with a several month history of pain in the right lower quadrant. It does not radiate; it is 5/10 in severity during the day and better at night. It was worse at night especially when lying on the right side. Standing straight would make it better. She denied nausea, vomiting, diarrhea, weight loss or appetite change. She denied smoking, EtOH, MJ, illicit drugs; she does not take any medications, prescription or otherwise. She had a cholecystectomy 20 years previously. On physical examination her vital signs were normal. The abnormal physical findings were limited to the abdominal exam and back. Her abdomen was flat, soft with normal bowel sounds. She had kyphosis of the thoracic spine without pain on pressure over the spines. There was pain on palpation of the ribs in the right upper quadrant. The distance between her ribs and the pelvic rim was 2 finger breadths, or about 4 cm.

The patient has ribs on pelvis syndrome (RAP).¹ This entity is described in older women with osteoporosis and wedge deformities of the spines giving her an increased kyphosis. The normal distance between the ribs and pelvic rim is more like 4 FB?s or 8 cm. As the ribs get closer to the pelvic rim it is thought that the ribs press on the pelvic rim causing the pain, especially when not standing or sitting straight. The pain tends to be worse later in the day. Where RAP causes pain in the anterior part of the abdomen, a similar syndrome, costoiliac impingement syndrome causes pain in the back and groin. There is one surgical article which suggests that surgical removal of the 12th rib on the affected side may give pain relief if physical therapy is unsuccessful.²

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Nutrition Issues in Gastroenterology, Series #132

Short Bowel Syndrome in Adults – Part 1

August 2014 • Volume XXXVIII, Issue 8

John K. DiBaise,

Carol Rees Parrish

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INTRODUCTION

Short bowel syndrome (SBS) is a disabling malabsorptive condition associated with a high frequency of complications and high utilization of healthcare resources. SBS generally does not become clinically apparent until about three-quarters of the small bowel (SB) have been removed. Because of the wide range in SB length and its capacity to compensate for bowel resection, the definition of SBS should not be based solely on the length of remaining bowel. Experts in intestinal failure have, instead, proposed defining SBS as a condition resulting from surgical resection, congenital defect, or disease-associated loss of absorption, characterized by the inability to maintain protein-energy, fluid, electrolyte, or micronutrient balances when on a normal diet.¹ Nevertheless, the presence of < 200 cm of remaining SB is often used in order to facilitate a clinical diagnosis.

Etiology and Epidemiology

In adults, the more common causes of SBS include multiple resections for Crohn’s disease, massive resections due to catastrophic mesenteric vascular events, and malignancies (Table 1).^2,3 Postoperative vascular and obstructive catastrophes requiring massive intestinal resection seem to be increasing in incidence and in one recent series was the most common cause of SBS in adults.⁴ Notably, the operations leading to SBS after an open surgery appear to be different than after a laparoscopic approach – gastric bypass and cholecystectomy being most frequent with laparoscopy and colectomy, hysterectomy and appendectomy being the most common with the open approach in one series.⁵ The major mechanisms responsible after open surgery and laparoscopy appear to be adhesions and volvulus, respectively. While advances in the treatment of Crohn’s disease may lead to a reduction in SBS, these improvements have not translated into a reduction in the need for home parenteral nutrition (PN).⁶

The incidence and prevalence of SBS are unknown because there are no reliable databases. Estimates are based on information from home PN registries, for which SBS is generally the most common indication. Two recent studies limited to SBS patients reported the majority of patients being female and > 50 years of age.2,3 The multifactorial etiology, uncertainty regarding intestinal length and varying definitions of SBS contribute to the difficulty of comparing reports. In the U.S., the annual prevalence of home PN has been estimated at approximately 120 per million, of whom about 25% have SBS; this amounted to about 10,000 adults in 1992.⁷ These numbers do not reflect patients with SBS who did not survive, were able to be weaned from PN during the index hospitalization, or were able to be successfully weaned from home PN and, therefore, likely underestimate the prevalence of SBS.

Relevant Anatomy and Physiology

Three bowel anatomies may occur in SBS and are generally described in terms of location of the anastomosis after resection:

Jejuno-colic
Jejuno-ileocolonic
End-jejunostomy

The clinical manifestations and outcome of SBS vary depending upon the remaining bowel anatomy and its residual function. Consequently, an appreciation of the bowel anatomies seen in SBS along with basic gastrointestinal physiological considerations is helpful to better understand the prognosis and guide patient management.

Small Bowel

The proximal 100 to 150 cm of the jejunum is the primary site of carbohydrate, protein and water-soluble vitamin absorption.⁸ Fat absorption may extend over a larger length of SB if more fat is ingested. In a healthy adult, about 4 L of intestinal secretions (0.5 L saliva, 2 L gastric acid and 1.5 L pancreaticobiliary secretions) are produced in response to the food and drink consumed each day. Water absorption is a passive process resulting from the active transport of nutrients and electrolytes. Sodium transport creates an electrochemical gradient that drives the uptake of nutrients across the intestinal epithelium. Because the junctions between jejunal epithelial cells are considerable compared to other areas of the bowel, a rapid flux of fluids and nutrients occurs resulting in inefficient fluid absorption and iso-osmolar jejunal contents. Sodium absorption in the jejunum occurs against a concentration gradient, is dependent upon water fluxes and is coupled to the absorption of glucose.⁹ These factors become particularly important in the SBS patient who only has jejunum remaining.

In contrast to the jejunum, the ileum has tighter intercellular junctions resulting in less water and sodium flux.9 In the ileum, active transport of sodium chloride allows for significant fluid reabsorption and the ability to concentrate its contents. The distal ileum is also the primary site of carrier-mediated bile salt and B12 absorption. The ileum and proximal colon produce several hormones including glucagon-like peptides.1 and 2 and peptide YY that have transit/motility modulating (e.g., jejunal and ileal brake phenomena) and intestinotrophic properties.¹⁰ The benefit of the ileocecal valve in slowing transit and preventing reflux of colonic contents into the SB remains controversial as the benefit may instead reflect the retention of a significant length of terminal ileum.¹¹

Colon

The colon has the slowest transit, tightest intercellular junctions and greatest efficiency of water and sodium absorption. In health, generally 1 to 1.5 L/day of fluid enters the colon, where all except about 150 mL are reabsorbed. In SBS, the colon plays a vital role in fluid and electrolyte balance given the capacity to accommodate and absorb up to 6 L daily.¹² Complete loss of the colon often leads to fluid and electrolyte disturbances. In addition to the resorptive capabilities of the colon, bacterial fermentation of malabsorbed carbohydrates to short chain fatty acids (SCFA) with subsequent absorption in the colon provides an additional 10-15% of energy needs or up to 1000 kcal daily.¹³ Thus, the colon becomes an important organ for fluid and electrolyte absorption and for energy salvage in SBS.

Stomach and Pancreaticobiliary

Massive enterectomy is associated with transient gastric hypergastrinemia and hypersecretion that may last up to 12 months postoperatively.¹⁴ This may occur as a result of the loss of inhibitory hormones produced in the proximal gut (e.g., gastric inhibitory peptide and vasoactive intestinal peptide). This increases the volume and lowers the pH of secretions entering the proximal SB potentially aggravating fluid losses and leading to peptic complications and impairment in the function of digestive enzymes, further contributing to fat maldigestion. The use of antisecretory medications including proton pump inhibitors or histamine 2 receptor antagonists reduces gastric secretions, prevents peptic complications and may lead to improved digestion and absorption.¹⁵ Although some SBS patients with extensive proximal SB resections may lose sites of secretin and cholecystokinin-pancreozymin (CCK-PZ) synthesis leading to diminished pancreatobiliary secretions, the majority have extensive distal SB resections and demonstrate normal secretion of these substances.¹⁶ Resection of > 100 cm of terminal ileum decreases the reabsorption of bile acids into the enterohepatic circulation, resulting in a reduction in the bile salt pool, eventually exceeding the ability of the liver to synthesize adequate replacement.¹⁷ This bile acid deficiency results in impaired micelle formation and fat digestion, and manifests clinically as steatorrhea and fat soluble vitamin deficiencies. In addition, the entry of caustic bile acids into the colon causes net fluid secretion into the colon and accelerated colonic motility further increasing stool output.

Intestinal Adaptation

Intestinal adaptation is the process following intestinal resection whereby the remaining bowel undergoes macroscopic and microscopic changes in response to a variety of internal and external stimuli in order to increase its absorptive ability (Table 2).¹⁸ Enteral nutrients are of particular importance in promoting an adaptive response, presumably by stimulating pancreaticobiliary, gastrointestinal and gut hormone secretions.¹⁹ Adaptation is highly variable and usually occurs during the first two years following intestinal resection in adults. Both structural and functional adaptive changes can occur depending upon the extent and site of the intestine removed and the nutrient components of the diet (Table 3). The ileum is capable of both morphologic and functional adaptation. While those with a jejuno-colic anastomosis demonstrate functional SB adaptation, those with an end-jejunostomy show little to no adaptation. The colon also appears to undergo adaptive changes after massive intestinal resection.

Determining Remaining Bowel Anatomy and its Influence on Outcome

The large range of SB length, from about 300 to 800 cm in adults, underscores the importance of determining the SB length and segment/s remaining following any resection. The length and region of the SB remaining and the presence of even a part of the colon are important factors affecting the outcome of the patient with SBS. Establishing an accurate estimation of bowel length is often difficult as operative reports frequently record the amount of bowel removed rather than the amount remaining. SB length may also be estimated on a barium contrast SB series, which may also be useful to delineate other structural features such as the presence of bowel dilatation. Recently, computed tomography (CT) enteroclysis with three-dimensional reconstruction and calculation of SB length has been shown to provide similar information; however, this technique has not yet been adopted into clinical radiology practices.²⁰ Despite the importance of the remaining SB length in determining the clinical outcome in SBS patients.²¹ the ultimate determining factor of SBS severity and eventual outcome is the critical mass of functional intestinal absorptive epithelia remaining.

Because of differences in their adaptive ability, those with an ileal remnant have a better prognosis than those with only a jejunal remnant. In adults, terminal ileal resections > 60 cm generally require vitamin B12 replacement, while resections > 100 cm lead to disruption in the enterohepatic circulation resulting in bile salt deficiency and fat malabsorption.²² Extensive ileal resection also results in accelerated gastrointestinal transit due, in part, to the reduction in gut transit modifying hormones. The presence of the colon has been shown to be beneficial in SBS given its ability to absorb water, electrolytes and fatty acids, slow intestinal transit and stimulate intestinal adaptation. Indeed, those SBS patients with an end- jejunostomy are generally the most difficult to manage and are most likely to require permanent parenteral support.²³

Complications

A variety of disorders may complicate the course of the patient with SBS. These complications may result from the underlying disease, altered bowel anatomy and physiology, or treatment modalities including PN and the associated central venous catheter (Table 4).^24,25 Complications related to the altered bowel anatomy will be discussed below. Fluid, electrolyte and micronutrient complications will be discussed in future articles in this series.

Oxalate Nephropathy

Chronic kidney disease and calcium oxalate nephrolithiasis may complicate the course of SBS in those with a colon segment, occasionally leading to irreversible renal failure.²⁶ Normally, dietary oxalate is bound to intraluminal calcium and excreted in the stool. In SBS patients with fat malabsorption and a colon-in-continuity, calcium preferentially binds to unabsorbed fatty acids in the lumen leaving oxalate free to pass into the colon to be absorbed into the bloodstream and then filtered by the kidney. A reduction in bacterial breakdown of oxalate due to decreased Oxalobacter formigenes in the colon of SBS patients also contributes.²⁷ Furthermore, citrate usually prevents nucleation, the first step in renal stone formation; hypocitraturia is common in patients with malabsorption and is thought to be due to bicarbonate wasting in the stool. In the kidney, oxalate binds to calcium resulting in oxalate nephrolithiasis and risk of progressive obstructive nephropathy. To reduce the risk of this complication, correction of dehydration is of the utmost importance while use of calcium citrate supplementation, along with restriction of fat and oxalate-containing foods are advised. The clinical utility of Oxalobacter formigenes supplementation to increase oxalate destruction or cholestyramine to bind oxalate remains to be established. Urate nephrolithiasis is also relatively common in SBS patients with an ostomy and is related to chronic dehydration.

Metabolic Bone Disease

Osteomalacia, osteoporosis, osteopenia and secondary hyperparathyroidism may occur in SBS patients as a consequence of the PN, altered bowel anatomy causing malabsorption of macro- and micronutrients (especially vitamin D), medication use (e.g., corticosteroid use for treatment of an underlying disease) and other underlying patient factors such as gender, ethnicity, body size, and insufficient sun exposure.26 An assessment of bone density should be undertaken in all SBS patients and repeated every 2-3 years; annually in the patient with osteoporosis. The identification of significant bone disease should lead to an assessment of calcium, phosphorus, magnesium, vitamin D (25-hydroxy vitamin D), and parathyroid hormone status and for the presence of metabolic acidosis. In patients receiving PN, an assessment of the PN formula and additives is warranted. Conventional management includes exercise, sunlight exposure, minimizing alcohol use and eliminating tobacco use. Calcium, magnesium and vitamin D replacement and correction of metabolic acidosis should be implemented as needed. Given the very poor bioavailability of bisphosphonates, intravenous agents are preferred in SBS.²⁸ Collaboration with an endocrinologist is encouraged.

Liver Dysfunction and Cholelithiasis

Hepatobiliary complications including steatosis, cholestasis and cholelithiasis occur commonly in SBS patients and result both from contributions of the altered bowel anatomy and the PN required for support. For this reason, ‘intestinal failure-associated liver disease’ is the preferred term to describe these complications. Steatosis is more commonly seen in adults while cholestasis occurs more often in children; both can progress to end-stage liver disease. The mechanisms underlying the development of steatosis and cholestasis differ although overlap occurs.²⁹ The provision of > 1 g/kg/day of parenteral lipids and the presence of chronic cholestasis have been associated with the development of complicated liver disease.³⁰ Particularly in those with rapid worsening of liver tests, sepsis should be considered as should medications, supplements, other toxins, lack of enteral stimulation, altered bile acid metabolism, SB bacterial overgrowth, biliary obstruction, and co-existing chronic liver disease including viral, autoimmune and metabolic disorders. The composition of the PN should also be considered as excesses (energy content, dextrose, fat emulsion, methionine), deficiencies (choline, essential fatty acids, carnitine, taurine, glutathione) and duration of infusion (continuous versus cyclical) may contribute. The type of lipid emulsion (e.g., soybean-based [Intralipid, Fresenius Kabi or Liposyn, Abbott Laboratories], n-3 fish oil-based [Omegaven, Fresenius Kabi], combination of soybean, medium-chain triglycerides, olive oil and fish oil [SMOF, Fresenius Kabi]) may also be important. In the U.S., only the soybean-based lipid emulsion is currently available except by approval under a Food and Drug Administration investigational new drug application. Correction of an identified cause or alteration in PN or lipid composition often leads to an improvement in the liver tests. The clinical utility of ursodeoxycholic acid appears limited in this setting.29 In those who continue to progress, consideration of intestinal transplantation (with or without liver transplantation) should be given.

Cholelithiasis, usually cholesterol stones, occurs in up to 40% of adults with SBS; the formation of biliary sludge is even more common.³¹ The predominant factor contributing to stone development is the reduced concentration of bile acids due to the altered enterohepatic circulation leading to lithogenic bile. Gallbladder stasis, related to reduced cholecystokinin secretion in those with limited enteral intake, also contributes. Complications of cholelithiasis appear to occur more commonly among SBS patients than the general population, hence prophylactic cholecystectomy has been recommended in the SBS patient when abdominal surgery is being undertaken for other reasons.^31,32

Small Bowel Bacterial Overgrowth

Small bowel bacterial overgrowth (SBBO) appears to be common in SBS patients.³³ The presence 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 SBBO. In a recent retrospective pediatric study, SBBO was strongly and independently associated with PN use but was not associated with age, gender, underlying diagnosis, presence of ileocecal valve or antacid use.³⁴ Although SBBO may have potential benefit in terms of increasing energy extraction from malabsorbed carbohydrates, excess bacteria in the SB 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 and aggravate diarrhea leading to a reduction in oral intake, and potentially increase the risk of IFALD, central venous catheter infections and chronic gastrointestinal bleeding.

A number of limitations of the tests used to diagnose SBBO exist (i.e., most commonly SB aspirate with quantitative bacterial culture and hydrogen breath testing), which makes securing the diagnosis of SBBO in SBS challenging.33 This is particularly so with breath testing, due to rapid transit in the shortened bowel making it difficult to differentiate SB versus colonic hydrogen production. As a consequence, empiric antimicrobial treatment is often provided. This may be reasonable in the setting of SBS given the high likelihood of SBBO; however, the goals of treatment need to be clearly identified given the nonspecific nature of the symptoms present and the potential adverse effects and expense involved with antimicrobial use. A variety of oral broad-spectrum antibiotics can be used with success based on improvement in symptoms, reduction in stool output and/or weight gain.³⁵ The continuous use of low-dose antibiotics in SBS may be necessary. To reduce the risk of antibiotic resistance, periodic rotation of the antibiotic used or use of a poorly absorbable antibiotic is advised. Although evidence from controlled studies to support their utility is lacking, other strategies for controlling SBBO include limiting the use of antisecretory and antimotility agents, carbohydrate restriction, intermittent bowel flushing with polyethylene glycol, use of probiotic agents and bowel tapering operations.³⁶

OUTCOMES

SBS occurs in about 15% of adults undergoing intestinal resection; nearly 75% result from a single massive resection and the other 25% from multiple resections.³⁷ Approximately 70% of those with newly acquired SBS are eventually able to be discharged from the hospital.³⁸ Reports from the U.S. and France have demonstrated 2-year and 5-year survival rates for SBS at over 80% and 70%, respectively.^39,40 Survival rates were lowest in the end-jejunostomy and ultra-short (< 30 cm without a colon) SB groups. PN-dependency at 1, 2 and 5 years was recently reported at 74%, 64% and 48%, respectively.3 In multivariate analysis, PN dependency was reduced with a remaining colon > 57% and a SB remnant length > 75 cm. In this study, over 25% of the patients who eventually weaned completely from PN did so > 2 years after their last bowel resection. Other factors affecting survival in SBS include the patient’s age, primary disease process, co-morbid diseases, presence of chronic intestinal obstruction and the experience of the team managing the patient.23

The quality of life of SBS patients is lower than population controls regardless of their PN requirement.⁴¹ Although the transition from hospital to home on PN leads to significant improvements in patients’ quality of life,⁴² the quality of life remains worse in SBS patients on home PN compared to SBS patients not requiring PN.⁴³ Factors that seem to favor a better quality of life in home PN patients include strong self-esteem and good family/social support.^44,45 The effective management of symptoms like diarrhea and prevention of complications is important for improving quality of life, reducing health care costs and improving survival in SBS. Recently, a SBS-specific quality of life instrument was shown to be valid, reliable and sensitive with excellent psychometric characteristics to measure treatment-induced changes in quality of life over time.⁴⁶ Studies using this instrument are awaited.

CONCLUSION

Short bowel syndrome is associated with significant morbidity and mortality, a reduced quality of life and high health care costs. In Part 1 of this five-part series on SBS, we have reviewed the bowel-related physiological alterations that occur and the clinical consequences including potential complications. Subsequent parts of the series will review both conventional and novel treatment approaches in SBS and the importance of the oral diet and fluids in its management.

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INTRODUCTION

CASE PRESENTATION

DISCUSSION

CONCLUSION

INTRODUCTION

IgG4 Immunobiology and Pathogenesis Properties of IgG4

IgG4 and Autoimmune Pancreatitis

IgG4 and Pouchitis

Pouchitis and Elevated Serum IgG4 Levels

IgG4 Histology in Pouchitis

Pouchitis and IgG4-related Disease

Diagnosis Of IgG4-Associated Pouchitis Measurement of Serum IgG4 Levels

Pouch Endoscopy and IgG4 Histology

Other Serologic and Radiologic Evaluations

Clinical Presentation and Disease Course

IgG4 and Implications for Treatment Corticosteroid Therapy

Immunomodulators and Anti-TNF-? Therapy

B-cell Targeting Therapy

SUMMARY

CASE

UNUSUAL CAUSES OF ABDOMINAL PAIN

ANSWER AND DISCUSSION

INTRODUCTION

Defining Malnutrition

Identifying and Treating Malnourished Patients

Capturing the Malnutrition Diagnosis for MS-DRGs

CONCLUSION

INTRODUCTION

EUS Detection of Gastric Varices

EUS-Guided Coil Injection Technique

Clinical Application

EUS-Guided Cyanoacrylate Injection Technique

Clinical application

EUS-Guided Combined Coil and Cyanoacrylate Injection

EUS-Guided Portosystemic Gradient Measurement and Shunt Placement

SUMMARY

INTRODUCTION

Prokinetics Metoclopramide

Domperidone

Motilin Receptor Agonists

5-HT4 Receptor Agonists

Acetylcholinesterase Inhibitors

Ghrelin Receptor Agonists

Baclofen

Opioid Receptor Antagonists

Antiemetics

Phenothiazines

Muscarinic Receptor Antagonist

5-HT3 Antagonists

NK-1 Receptor Antagonists

Cannabinoids

Tricyclic Antidepressants

Transcutaneous Stimulation

Expert Commentary on the Field

Article Highlights

Authors? Declaration of Personal Interests

CASE

DISCUSSION

CASE

INTRODUCTION

Etiology and Epidemiology

Relevant Anatomy and Physiology

Small Bowel

Colon

Stomach and Pancreaticobiliary

Intestinal Adaptation

Determining Remaining Bowel Anatomy and its Influence on Outcome

Complications

Oxalate Nephropathy

Metabolic Bone Disease

Liver Dysfunction and Cholelithiasis

Small Bowel Bacterial Overgrowth

OUTCOMES

CONCLUSION

Diagnosis Of IgG4-Associated Pouchitis
Measurement of Serum IgG4 Levels

EUS-Guided Coil Injection
Technique

EUS-Guided Cyanoacrylate Injection
Technique

5-HT₄ Receptor Agonists

5-HT³ Antagonists