INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #98

Efficacy of Thiopurine Monotherapy in Ulcerative Colitis

October 2015 • Volume XXXIX, Issue 10
Raina Shivashankar,Edward V. Loftus

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The exact role of the thiopurines, azathioprine and 6-mercaptopurine in ulcerative colitis treatment algorithms has been debated. Specifically, their use in UC remains controversial since the evidence lies in small clinical trials. Here, we briefly review the evidence for thiopurine efficacy in UC.

Medical treatment of ulcerative colitis can be complicated, and it is usually stratified based on disease severity. The goal of therapy is to induce remission, followed by a maintenance regimen to continue clinical and endoscopic remission. The exact role of the thiopurines, azathioprine and 6-mercaptopurine, in UC treatment algorithms has been debated. Specifically, their use in UC remains controversial, since the evidence lies in small clinical trials. We briefly review the evidence for thiopurine efficacy in UC.

Raina Shivashankar, M.D., Edward V. Loftus, Jr., M.D., Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN

The incidence of ulcerative colitis (UC) has been increasing globally.1 Moreover, UC leads to significant economic burden; the total direct cost attributed to UC in the United States is an estimated $3.4-8.6 billion annually, and approximately 50% of patient costs arise from hospitalizations.2 Although some patients with UC ultimately require colectomy, many patients can be managed medically. Medical treatment for UC can be stratified based on disease severity; 5-aminosalicylates such as sulfasalazine, mesalamine and balsalazide form the foundation of therapy for mildly to moderately active disease, followed by immunomodulators and finally anti-tumor necrosis factor alpha (anti-TNF) agents. In recent years, there has been significant debate about the positioning of the thiopurine medications, azathioprine and mercaptopurine, in induction and maintenance treatment algorithms for UC. We sought to review the evidence for the utility of immunomodulator monotherapy in patients with UC.

The use of azathioprine for UC was first reported in 1966.3 Azathioprine is a pro-drug that is converted to 6-mercaptopurine (6-MP).3 Xanthine oxidase, thiopurine methyltransferase (TPMT), and hypoxanthine phosphoribosyl transferase then metabolize 6-MP into 6-thiouric acid, 6 methylmercaptopurine (6-MMP), and precursors of the active 6-thioguanine nucleotides (6-TGN), respectively.3 6-TGN is integrated into nucleic acid and ultimately inhibits the synthesis of protein, ribonucleic acid (RNA), and deoxyribonucleic acid (DNA); however, the mechanism of action of azathioprine has not been fully discovered.3 TPMT activity levels are routinely checked prior to initiation of azathioprine, since patients who lack TPMT activity are at high risk of severe myelosuppression. For those with normal TPMT levels, a dose of 2-2.5 mg/kg body weight/ day of azathioprine is usually recommended. In addition to the risk of myelosuppression, azathioprine and 6-MP carry the risk of idiosyncratic reactions such as fever, pancreatitis, rash, and arthralgias. Hepatotoxicity from azathioprine and 6-MP is specifically associated with 6-MMP levels. Although hepatoxicity can occasionally be seen with low 6-MMP levels, a 3-fold elevation in risk has been observed with high 6-MMP levels (levels >5700 pmol/8 x 108 red blood cells).4

In terms of its efficacy as an induction agent, azathioprine has had mixed results in UC. Ardizzone and colleagues studied the efficacy of azathioprine versus mesalamine in achieving corticosteroid-free remission (as defined both clinically and endoscopically) in steroid-dependent UC, and found azathioprine to be more effective.5 Sood and coworkers studied the efficacy of azathioprine in addition to sulfasalazine and corticosteroids compared to the latter two medications alone in inducing remission in severe UC, and found no significant difference in remission rates between the two groups.6 In 1990, Steinhart, et al. retrospectively reviewed outcomes of azathioprine initiation in a small clinic population of UC patients who were on corticosteroids.7 Azathioprine efficacy was defined as the ability to decrease prednisone to less than 50% of the pre-treatment dose without clinical relapse and improvement in clinical symptoms.7 Most patients (12 out of 16) responded to azathioprine, and the authors concluded that azathioprine was beneficial for UC patients who were resistant to or dependent on corticosteroids.7

Studies of the efficacy of azathioprine for maintenance of remission in steroid-dependent UC have also shown variable results. Sood and colleagues conducted a study in 2002 that assessed azathioprine and sulfasalazine or sulfasalazine and placebo in 35 patients with severe UC; all patients initially received corticosteroids.8 Fewer patients in the azathioprine and sulfasalazine group suffered from UC relapse compared to the group treated with sulfasalazine and placebo, and this difference was statistically significant.8 On the other hand, Sood and coworkers in another study found no significant difference in remission rates in UC patients who were on maintenance therapy with either azathioprine or sulfasalazine.9 However, this study was quite small (n = 25). Earlier studies also showed no significant difference between azathioprine and placebo in remission rates; for example, Jewell and Truelove showed no difference in 12-month remission rates (defined by endoscopic finding of inflammation or bright red blood per rectum) when azathioprine was compared to placebo.10

Due to the conflicting reports in smaller studies, several groups have tried to address the efficacy of azathioprine in UC using a pooled approach.11-14 In the systematic review by Leung, et al., 5 studies were analyzed to assess the efficacy of azathioprine on maintenance of UC remission in severe or steroid- dependent cases.11 Four out of five studies used 2-2.5 mg/kg body weight/day of azathioprine, and there was significant heterogeneity among these studies. Their pooled analysis showed slight efficacy of azathioprine in maintaining clinical remission in UC (risk ratio [RR], 1.42); however, this was not statistically significant (95% confidence intervals [CI], 0.93-2.17; p=0.109). The studies used in the meta-analysis were limited by small sample sizes (ranging between 25-80 participants), significant heterogeneity, and use of specific analyses, such as relative risk in a random effects model versus a fixed effects model and estimation of a pooled relative risk.11,12

Another meta-analysis in 2009 aimed to clarify these issues in patients with severe or steroid-dependent UC.13 Four studies, with a total of 89 patients, were analyzed to assess the efficacy of azathioprine/6-MP compared to 5-ASA or placebo in the induction of UC remission. This comparison did not show a significant difference between the two groups (OR, 1.59; 95% CI, 0.59-4.29.13 Additionally, six studies with a total of 124 patients were used to compare azathioprine/6-MP with 5-ASA or placebo for maintenance of UC remission; a statistically significant difference was found between the two groups (OR, 2.56; 95% CI, 1.51-4.34).13 Gisbert and colleagues further subdivided this section of the analysis to compare azathioprine/6-MP versus placebo and then azathioprine/6-MP versus 5-ASA; the former meta-analysis was statistically significant, favoring azathioprine/6-MP in the maintenance of UC remission, while the latter analysis failed to achieve statistically significant difference in efficacy.13 Therefore, the significance of the pooled estimate of azathioprine/6- MP efficacy in maintenance of UC remission is difficult to interpret.

A systematic analysis and meta-analysis by Khan and colleagues, using more rigorous study inclusion criteria, aimed to study the updated body of literature on the efficacy of azathioprine in the induction of UC remission and prevention of relapses.14 There were 2 randomized control trials that studied azathioprine efficacy in inducing remission in active UC. They found a trend towards benefit of azathioprine compared to placebo; however, this was not statistically significant (RR, 0.85; 95% CI, 0.71-1.01; p = 0.67). There was no statistically significant heterogeneity between the two studies; however, both studies were small (n=20- 25). In the three RCTs that studied use of azathioprine in maintenance of remission, there was a statistically significant benefit of azathioprine compared to placebo in preventing relapse. However, again, the studies included were small. Notably, the studies analyzed in this meta-analysis were the same as those studied in the Leung, et al. meta-analysis. Whereas Leung and colleagues analyzed all the trials together, Khan, et al. divided the studies into two groups, one group studying induction of remission and the other group analyzing maintenance of remission.

In a comparative effectiveness trial, Panaccione and colleagues recently studied 239 moderate-to-severe UC patients to assess corticosteroid-free clinical remission in those treated with infliximab alone, azathioprine alone, or combination therapy with infliximab and azathioprine.15 The study duration was 16 weeks, and the dose of infliximab was 5 mg/kg at weeks 0, 2, 6, and 14, and that of azathioprine was 2.5 mg/kg of body weight/day.15 A higher percentage of patients receiving combination therapy achieved corticosteroid-free remission at week 16 compared to either azathioprine monotherapy (p=0.032) or infliximab monotherapy (p=0.017).15 Additionally, mucosal healing at week 16 based on a Mayo endoscopic subscore of 0 or 1 was more likely to be seen in those treated with combination therapy rather than azathioprine monotherapy (p=0.001).15 There was a greater improvement in the total Mayo score and Inflammatory Bowel Disease Questionnaire (IBDQ)/Short-Form Health Survey (SF-36) scores in the combination therapy group when compared to the azathioprine or infliximab monotherapy groups.15 Therefore, this study suggests that combination therapy rather than azathioprine alone is better at inducing clinical and endoscopic remission of moderate-to-severe UC.

Overall, the data on thiopurine efficacy in UC is limited by small studies. While meta-analyses have found trends towards benefit of azathioprine over placebo in the induction and maintenance of remission in UC, these studies are limited by heterogeneity and method of analysis. Moreover, there is no definitive data from these studies that suggest azathioprine monotherapy would be beneficial for induction and maintenance of UC remission. It seems that the most important role of thiopurines in the medical treatment of UC may be as an adjuvant to biologic therapy. Perhaps earlier, more aggressive therapy with biologic therapy is warranted in steroid-dependent or severe UC patients. Thiopurine monotherapy can certainly be considered in steroid- dependent or refractory patients in whom biologic therapy is contraindicated, but this pool of patients seems to be small. Monotherapy with azathioprine or 6-mercaptopurine could also be considered in situations where access to biologic therapy is restricted.

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Current Developments in Endoscopic Suturing

Current Developments in Endoscopic Suturing

October 2015 • Volume XXXIX, Issue 10
Ali Siddiqui,David Lee,Juliana Yang

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Endoscopic suturing is an emerging technique in the field of therapeutic endoscopy that is rapidly broadening its potential indications for use. In this review, we summarize the variety of indications as described under current literature and provide an overview of the latest developments in endoscopic suturing, with specific focus on the Overstitch™ endoscopic suturing system.

Juliana Yang, MD1 David Lee, MD MPH1 Ali Siddiqui, MD2 Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX1 Division of Digestive and Liver Diseases, Thomas Jefferson University Hospital, Philadelphia, PA2

INTRODUCTION

Prior to the development of endoscopic suturing, surgical intervention was frequently utilized in the correction of transmural defects of the gastrointestinal tract. However, in recent years, advances in endoscopic technique and new technology have led to exciting improvements in the ability to close such defects endoscopically utilizing a minimally invasive approach. In addition to the closure of gastrointestinal fistulae and perforations, a wider proliferation of natural orifice transluminal endoscopic surgery (NOTES) has renewed interest in the ability to endoscopically close defects.1

Endoscopic suturing is among such techniques under development. Currently, in the United States, there is only one FDA-approved endoscopic suturing system on the market, the Overstitch™ endoscopic suturing system (Apollo Endosurgery, Austin, Texas).1 At present, the majority of techniques that have used this system remain at the experimental phase. However, numerous published case reports, case series and a small number of studies have described a variety of indications for which endoscopic suturing has been utilized.

In this review, we describe the technique for using the Overstitch™ endoscopic suturing system, as well as the applications of the Overstitch™ system.

TECHINIQUE

The Overstitch™ endoscopic suturing system is a disposable, single-use device designed to mount onto a double-channel endoscope, the Olympus GIF-2T160 or GIF-2T180 (Olympus America, Center Valley, Pennsylvania),2 allowing for the creation of either interrupted or running sutures. It was initially approved by the FDA in 2008, with an additional revision of the device in 2011.1

The current device is much simplified in comparison to its earlier predecessor. It consists of an end cap which mounts over the scope tip, with a hooked suture arm which is controlled via a hand lever attached near the hand controls of the endoscope (Figure 1).3 Suture material is passed from a cassette at the operator end of the endoscope through one of the operating channels, to a tissue anchor at the distal tip of the endoscope. Either absorbable (2-0 and 3-0 polydioxanone) or non- absorbable (2-0 and 3-0 polypropylene) suture material is available.3 In use, the tissue anchor is driven into the target tissue via the hooking motion of the suture arm. Repeated motion of the arm then allows for running sutures if desired. Once complete, a cinching device is used to secure the sutures. These techniques are illustrated in Figure 2.

To facilitate placement of full-thickness sutures, a helix device included in the kit may be passed through the second channel of the endoscope to screw into the target tissue. Retraction of the device then brings the target tissue into the path of the suturing arm, allowing for full-thickness suturing.2,3

APPLICATIONS
Closure of Defects

There has been a great deal of interest in developing endoscopic techniques by which transmural defects can be closed. Endoscopic suturing shows great promise in the ability to accomplish this, though these techniques have only been applied in a small number of case reports, case series and animal models.

There are a variety of clinical scenarios in which the Overstitch™ system has been used to close defects. The Overstitch™ system has been applied to help close chronic gastrocutaneous fistulae following removal of percutaneous endoscopic gastrostomy (PEG) tubes.4,5 This technique was used successfully following failure of prior attempts at closure by other means, such as endoclips, glue, and over-the-scope clips. Similarly, another case report demonstrated successful reduction of an enlarged PEG stoma using the Overstitch™ device.6

This Overstitch system has also been used to close a chronic esophago-pleural fistula that developed after a Booerhave syndrome.7 In this case, the fistula was refractory to prior therapy attempts using endoclips and esophageal stent placement. A follow-up esophagram 4 weeks after the initial suturing demonstrated a persistent small defect, which was effectively closed with repeat endoscopic suturing, argon plasma coagulation and fibrin glue.

Over the years, increasing interest in endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), natural orifice transluminal endoscopic surgery (NOTES), and peroral endoscopic myotomy (POEM) has led to the use of endoscopic suturing in the closure of partial and full thickness defects created during such procedures.

Kantsevoy et al.8 described a series of twelve consecutive patients who underwent ESD with subsequent closure using the Overstitch™ device. The mean size of the defects closed was 42.5 ± 14.8 mm, and there were no immediate or delayed adverse events.

Endoscopic suturing in NOTES procedures remains limited at present to animal models. Chiu et al.9 performed full-thickness gastric resections on a porcine model followed by effective and complete closure using the Overstitch™ device.

Several reports have also described successful closure of defects, intentional or otherwise, created during the course of performing POEM.10-12 Interestingly, a retrospective analysis comparing endoscopic suturing to clips in post-POEM closure found no significant difference in cost or length of closure time, length of stay, or complications.3

Stent Fixation

Fully covered self-expanding metal stents are often used to either relieve obstructive lesions within the gastrointestinal lumen, such as strictures or mass lesions, or to bridge over defects, such as perforations or fistulae. While the silicon covering of gastrointestinal luminal stents prevents leakage of luminal material from the sides of the stent and allows for easy stent removal in the future if necessary; the covered feature can also predispose these stents to migration. Previous attempts to anchor these stents in place using clips have shown inconsistent results.

At present, there have been only a few small studies that have examined the technique of using endoscopic suturing to anchor gastrointestinal luminal stents. Rieder et al.13 found within a porcine model that there was a significant increase in the force needed to displace a stent secured with sutures (n = 12; mean force 20.4 N; 95 % confidence interval [CI]: 15.4 – 25.4; P < 0.01) versus clips (n = 8; mean 6.1 N; 95 %CI 4.7 – 7.6). A subsequent proof-of-concept study in five patients demonstrated initial successful stent fixation to the esophageal wall by suturing, although there was one instance of stent migration attributed to a superficially placed suture.13 Fujii et al.14 reported a case series of eighteen patients who underwent esophageal stent fixation to the gastrointestinal luminal wall for a multitude of indications including esophageal perforations/fistulas/strictures, gastric fistulas and enteric fistulas. Complete clinical success was achieved in 56% of patients. However, the authors reported a stent migration rate of 33% even with suturing of the stent. More recently, Sharaiha et al.15 compared stent migration in patients who had placement of esophageal stents with and without endoscopic suture anchoring to the wall. They demonstrated that there was only an 11% stent migration in patients with suturing, compared to a 55% stent migration in the control group without sutures. A large multicenter retrospective analysis by Sharaiha et al.16 demonstrated even better rates of clinical success, 91.4% at 68 day follow up.

Overall, the currently available data seem to suggest improved stent migration rates when endoscopic suturing is used, with little adverse events directly attributable to the suturing technique.

Endoscopic Bariatric Therapy

There has been a great deal of interest recently in incorporating endoscopic suturing techniques into the fast-growing field of endoscopic bariatric therapy. Currently, these exploratory studies largely fall into one of three categories: endoscopic sleeve gastroplasty, repair of defects created during bariatric surgery, and post-bariatric surgery revision.

Endoscopic sleeve gastroplasty is an innovative application of endoscopic suturing involving the placement of sutures along the gastric wall to achieve gastric volume reduction in order to approximate the effect of a surgical sleeve gastrectomy. Abu Dayyeh et al.17 described this technique in a pilot feasibility study of 4 patients, which involved the placement of full- thickness, interrupted sutures using the Overstitch™ system to bring together the anterior wall and posterior wall of the stomach and therefore form a sleeve reminiscent of that created during a surgical sleeve gastrectomy. This technique has the advantage of being incisionless, minimally invasive, and potentially providing an alternative option for patients who would not make ideal surgical candidates or for whom surgical bariatric surgery would be overtreatment.3

A 2008 study by Fogel et al.18 using an older version of the suturing system (Endocinch™) reported an impressive 58% excess weight loss at 12 month follow up after endoscopic sleeve gastroplasty. However, subsequent studies have been unable to replicate such dramatic weight loss. More recently, utilizing the RESTORe suturing system, the latest iteration of the Endocinch device, Brethauer et al.19 reported a mean excess weight loss of 27.7% at 12 month follow up.

Two small studies have further evaluated the use of endoscopic sleeve gastroplasty using the Overstitch™ device for weight reduction. In a study of 20 patients, Lopez-Nava et al.20 reported a mean weight loss of 19.3 kg (17.8% of initial weight) at 6 months after the procedure. Similarly, Sharaiha et al.21 reported a mean weight loss of 33.0 kg at 6 months (30% of initial weight) in a study of 10 patients.

The results of these studies seem to indicate that endoscopic sleeve gastroplasty could potentially be a viable therapeutic option for specific subsets of the bariatric population, demonstrating modest weight reduction with minimal adverse effects. However, long- term data for sustained weight loss is unavailable, and at least one study19 using the RESTORe device seemed to demonstrate at least partial release of some of these sutures at 12 month follow up.

Endoscopic suturing has also been used in cases of post-bariatric therapy complications, such as marginal ulcerations, fistulae, and leaks. Jirapinyo et al.22 have described the use of endoscopic suturing in 3 patients who had developed marginal ulcerations after Roux- en-Y gastric bypass (RYGB) surgery that was refractory to medical therapy. In all three cases, endoscopic suturing was used successfully to close up the ulcer bed, leading to durable healing of the ulcer.

Finally, endoscopic suturing has been used for post- bariatric revision to tighten up dailated gastrojejunal stoma. It has been reported that increased stoma diameter is associated with weight gain following RYGB.23 Options for patients under these circumstances usually involved surgical revision.3 However, endoscopic suturing has the potential of being able to fix such enlarged stoma with less morbidity than surgery but still with efficacious outcomes.

Thus far, two studies have examined the effects of stoma reduction using endoscopic suturing, often referred to as transoral outlet reduction (TORe). Jirapinyo et al.24 performed TORe on a total of 25 patients with weight gain after RYGB and dilated gastrojejunal stoma. There was a 100% technical success rate, with a mean 77.3% reduction in stoma diameter from an average of 26.4 mm prior to the endoscopic procedure to an average of 6 mm (range 3-10 mm) after the procedure. The mean weight loss at 3, 6, and 12 month follow up was 11.5 kg, 11.7 kg, and 10.8 kg, respectively.

A multicenter, randomized study by Thompson et al.25 produced similarly positive findings. In this study, patients with weight gain or inadequate weight loss after RYGB and stoma larger than 2 cm were randomized to either a TORe intervention group or a sham procedure group. Compared to the control group, those that underwent TORe had significantly greater mean percentage weight loss (3.5% in the intervention group vs. 0.4% in the control group, P=0.021).

Further studies are still needed to refine this technique of stomal revision. For example, a recent study26 demonstrated even greater weight loss when full-thickness sutures were used for stoma reduction compared to superficial sutures, despite achieving similar stoma size reductions. Likewise, the ideal degree of stoma reduction still needs to be determined. Thompson et al.27 found an inverse relationship between the stoma size and weight loss.

CONCLUSION

Endoscopic suturing is an emerging technique in the field of therapeutic endoscopy that is rapidly broadening its potential indications for use. In this review, we summarize the variety of indications for which endoscopic suturing has been used, as described under current literature. Endoscopic suturing has been used to close a variety of transmural defects, as well as to anchor covered metallic endoluminal stents to the gastrointestinal wall and hence prevent their migration. There is also an expanding role for endoscopic suturing in bariatric therapy, including revision of dilated gastrojejunal stomas, fixing marginal ulcerations and other defects, and in primary use as endoscopic sleeve gastroplasty. While the currently available body of literature is small, there is active interest in exploring new areas of development for this technique, as well as further refining existing protocols. The coming years are sure to see even more advances in this burgeoning field.

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A CASE REPORT

Ampullary Carcinoid as a Rare Cause of Acute Relapsing Pancreatitis

September 2015 • Volume XXXIX, Issue 9
John M. Petersen,David H. Holloman

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Fewer than 150 cases of ampulla of Vater carcinoid have been reported. These lesions commonly present with abdominal pain, jaundice or gastrointestinal (GI) bleed. A significant percentage of tumors may be metastatic at the time of diagnosis. The patient in whom this carcinoid was found presented with numerous bouts of acute, relapsing pancreatitis. Endoscopic ultrasound (EUS), computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP) and ampullectomy were key in making the diagnosis. This case emphasizes the need for clinicians and endoscopists to consider structural or neoplastic lesions as a cause of relapsing pancreatitis not related to alcohol, autoimmune disease or biliary tract pathology. Endoscopic mucosal resection and ampullectomy may be an appropriate definitive treatment.

John M. Petersen, DO, FACG, FACP1 David H. Holloman, MD 2 Baptist Medical Center 1,2 Departments of Gastroenterology,1 Pathology1 Borland-Groover Clinic1 Jacksonville, FL

CASE

A 50-year-old African-American woman with Von willebrand disease had numerous bouts of periumbilical pain, nausea and vomiting with documented biochemical pancreatitis over a five month period. There was no alcohol abuse, and her gallbladder was normal on ultrasound and nuclear (HIDA) scan. The triglycerides were normal and her anti-nuclear antibody (ANA) was negative. There was no pertinent family history. Physical exam was normal with a soft abdomen that was non-tender and without mass, ascites or organomegaly. Laboratory data revealed a normal complete blood count (CBC) and normal liver enzymes with the exception of a gamma-glutamyl transpeptidase (GGT) of 68 mg/dl (normal 20-45). Her amylase levels, captured during the attacks of pain, ranged from 280 to 960 IU/L (normal 30-110 IU/L) and his lipase was 350 to 650 U/L(normal 25-250). Abdominal ultrasound and CT were negative. EUS revealed a 3.5 cm homogeneous, hypoechoic ampullary mass. The pancreatic duct was not dilated, the common bile duct (CBD) was 7 mm in the head of the pancreas and the pancreatic parenchyma was normal. The mass did not invade the CBD, pancreatic tissue or muscularis propria of the duodenum. (Figure 1). No adenopathy was noted; the liver had fatty infiltrate. After a saline lift, endoscopic ampullectomy was performed. (Figure 2) Post-removal ERCP revealed pancreas divisum with a normal accessory papilla. The CBD and pancreatic duct were patent and thus a stent was not placed. Pathologic evaluation revealed a neuroendocrine tumor consistent with a carcinoid tumor. There was no nuclear atypia, the margins were negative, and stains were positive for synaptophysin and chromogranin. (Figure 3) Histologically, the mitotic rate was 1/10 HPF. This was determined to be a low grade, well-differentiated tumor with +CD 56 and +l<i67 in only 2% of the cells.

The patient returned a month later and repeat endoscopy showed that there was no residual neoplastic tissue. Serum chromogranin-A was normal as was urine 5-HIAA and serum gastrin. An octreotide scan was negative for any foci of metastatic activity. Follow- up at 12 months revealed the patient asymptomatic, with a negative positron emission test (PET)/CT and octreoscan.

DISCUSSION

Carcinoid tumors of the ampulla of Vater are extremely rare, with less than 150 cases reported worldwide. These numbers suggest that ampullary lesions account for 0.05% of all carcinoid tumors. In contrast to carcinoid lesions of the mid-gut (jejunum, ileum and appendix), ampullary lesions very rarely cause the carcinoid syndrome, unless they are metastatic. Patients with these neoplasms often present with lingering abdominal pain and jaundice, if the CBD becomes encased. GI bleeds and weight loss or relapsing bouts of pancreatitis may occur.1 In the 105 patients tabulated by Hartel, 47% presented with metastatic disease, and 58% underwent Whipple resection.2 Metastases to regional nodes or the liver may be seen at the time of presentation. Carcinoid tumors of the ampulla may range in size from 0.5 cm to 6 cm. The time from first symptoms to actual diagnosis is typically greater than three months. Men and women are equally affected and the mean age at diagnosis is 48 years.3

Reports of relapsing pancreatitis have also been seen in carcinoid of the minor papilla.4 Cases of ampullary carcinoid prior to 2006 have typically been treated with duodenectomy, but as our case reveals, endoscopic ultrasound and endoscopic mucosal resection (EMR) can provide a sufficient non-surgical approach. EMR can be performed if the lesion invades into the submucosa, duodenal wall, CBD or pancreatic duct/parenchyma. Large tumors or those with nodal involvement are best treated with Whipple resection.5 Carcinoid tumors of the ampulla are typically benign despite their large size, and have an overall five-year survival of 90%. Non- functioning carcinoid tumors constitute 15-20% of all pancreatic neuroendocrine tumors. These lesions seem to have a higher malignancy rate than their hormonally functioning counterparts. They tend to be slow growing, and metastatic disease does not preclude extended survival.6

This case accentuates the need to consider structural and mass lesions in pancreatitis not related to alcohol, autoimmune, or biliary tract disease. Endoscopic ampullectomy may be curative.

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A SPECIAL ARTICLE

Single Balloon Enteroscope for Complete Colonic Examination in Patients with Failed Colonoscopy

September 2015 • Volume XXXIX, Issue 9
Kimberly Kolkhorst,Eric Hill,Patrick Brady

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Colonoscopy is the current gold standard for colorectal cancer screening; however 5-10% of colonoscopies performed are incomplete. If the cecum cannot be intubated, a full diagnostic evaluation has not been achieved. Standard options to complete the evaluation include air contrast barium enema, CT colonography, or repeat colonoscopy. In this article, we present our study of the use of a single balloon enteroscope (SBE) to reach the cecum as an alternative method for complete colonic examination in patients failing conventional colonoscopy.

Background & Aims

Colonoscopy is the current gold standard for colorectal cancer screening; however 5-10% of colonoscopies performed are incomplete. If the cecum cannot be intubated, a full diagnostic evaluation has not been achieved. Standard options to complete the evaluation include air contrast barium enema, CT colonography, or repeat colonoscopy. We studied the use of a single balloon enteroscope (SBE) to reach the cecum as an alternative method for complete colonic examination in patients failing conventional colonoscopy.

Methods

From October 2008 to June 2014 a total of 71 consecutive patients with previous incomplete colonoscopy were evaluated with colonoscopy using the SBE. After incomplete prior colonoscopy, the subjects underwent repeat colonoscopy using an Olympus SIF Q180 single balloon enteroscope. The primary endpoint was the rate of cecal intubation. Secondary endpoints included the total time of the examination, withdrawal time, complications, and findings.

Results

The mean age of patients was 63.5 years. 50 patients were female (70%). Indications for colonoscopy included surveillance for a personal history of colon polyps (n=21), average risk screening (n=19), family history of colorectal cancer (n=12), anemia (n=6), hematochezia (n=5), abnormal imaging (n=4), and other (n=4). Reasons for previous colonoscopy failure included tortuosity/looping (n=44), previous abdominal surgery/adhesions (n=20), diverticulosis/fixed, angulated sigmoid (n=5) and other (n=2). Colonoscopy to the cecum was successful in 70 of the 71 patients (98.6%). A total of 77 adenomas, 1 R-sided ischemic colitis and 2 carcinomas were found. All adenomas encountered were successfully removed. The mean total procedure time was 37 min (range 14-139 min) and mean withdrawal time was 16 min (range 4-122 min). Zero complications were encountered.

Conclusions

The SBE is longer, smaller in diameter, and more flexible than a standard colonoscope. The overtube adds stiffness but remains flexible enough to traverse colonic loops. This technique has the advantage of allowing direct endoscopic visualization of the colon with the potential for endoscopic therapies, as opposed to the alternative imaging modalities. Colonoscopy with the SBE is a useful technique in patients with a prior failed colonoscopy due to difficult anatomy or prior abdominal surgery.

INTRODUCTION

Colorectal cancer is the third most common cancer and the second leading cause of cancer death in the U.S. Colonoscopy is the gold standard for colorectal cancer screening and for removal of colorectal adenomatous polyps. Colonoscopic removal of adenomatous polyps reduces mortality from colorectal cancer by 53%.1 Substantial improvements in colorectal cancer screening rates have occurred but screening rates still fall short of desirable levels. In fact, 5%-10% of colonoscopies performed are incomplete.2 Multiple factors contribute to incomplete colonoscopy including: female sex, diverticular disease, low body mass index, prior abdominal or pelvic surgery, insufficient colon cleansing, long, redundant colon loops, fixed, angulated sigmoid colon and patient discomfort.3

Of all advanced neoplasms found in the colon, 33- 50% are found in the proximal colon and 4.3% have been shown to be missed by incomplete colonoscopy.4 If the cecum is not intubated, a full diagnostic evaluation has not been achieved and malignant/pre-malignant lesions may go undetected. This is particularly important since right-sided neoplasms are often flat or depressed and harder to detect with imaging modalities.5 In addition, proximal neoplasms may develop through different molecular pathways than sporadic left sided lesions with more rapid progression to cancer.6 Standard options for complete evaluation in the event of incomplete colonoscopy include air contrast barium enema, CT colonography, or repeat colonoscopy.7,8 We studied the use a single balloon enteroscope (SBE) to reach the cecum as an alternative method for a complete colonic exam in patients failing conventional colonoscopy. Prior studies using a double-balloon enteroscope or a push enteroscope have shown some success in completing the colonoscopy after a failed attempt with a standard colonoscope,9,10 however, only four studies have been reported using the single-balloon enteroscope for a difficult colonoscopy. These studies have been limited by small population size (range 14-30 patients) and lack of total procedure and withdrawal times.2,11,12,13

Methods

From October 2008 to June 2014 a total of 71 consecutive patients with a previous incomplete colonoscopy were prospectively evaluated using an Olympus SIF 180 SBE with overtube. Five different gastroenterologists trained in the use of the single balloon enteroscope system performed the procedures. The overtube was used in all cases. The endoscope was inserted to 50cm. It was then straightened by withdrawing the endoscope to reduce loops, followed by advancement of the overtube over the endoscope to stiffen it and prevent recurrent loop formation. This process was repeated until the cecum was reached. Balloon inflation was employed only if the position of the endoscope could not be maintained when reducing loops. Fluoroscopy was not used. Standard maneuvers including loop reduction, manual support, and patient position changes were employed.

Data for all 71 procedures was prospectively collected including: patient age, sex, indication for colonoscopy; reason for failure of the initial colonoscopy; cecal intubation rate; colonoscopic findings, total procedure time and withdrawal time. Patients with prior incomplete colonoscopy due to poor bowel prep or intolerance of the procedure were excluded from the study since these problems could be corrected without the need for special instruments. The study was approved by the University of South Florida and Tampa General Hospital Institutional Review Boards.

After an incomplete prior colonoscopy by the investigators (n=34), same day failure by the investigators (n=24), or referral due to incomplete colonoscopies by outside gastroenterologists (n=14), the subjects underwent a colonoscopy using the Olympus SIF Q180 single balloon enteroscope. Propofol, administered by an anesthesiologist or CRNA, was used for sedation in all patients. The primary endpoint was the rate of cecal intubation. Secondary endpoints recorded included the total time of the examination, complications, and findings.

Results

All patients with prior incomplete standard colonoscopy provided consent for colonoscopy with the SBE and were enrolled in the study. Of those patients, 50 (70%) were female and 21 (30%) male. The mean age was 63.5 years +/- 1.7 (range 29-84). Indications for colonoscopy (Table 1) included: surveillance for a personal history of colon polyps (n=21), average risk screening (n=19), family history of colorectal cancer (n=12), anemia (n=6), hematochezia (=5), abnormal imaging (CT colonography or air contrast barium enema) (n=4), and other (including weight loss, colovesicular fistula, change in bowels and abdominal pain) (n=4). Reasons for prior incomplete colonoscopy (Table 2) included: tortuosity/looping (n=46), previous surgery/adhesions (n=20), and diverticulosis/fixed,angulated sigmoid (n=5).

Colonoscopy to the cecum was successful in 70 of the 71 patients (98.6% cecal intubation rate). Of the 71 procedures performed, 37 (52%) detected polyps, 2 (3%) detected colon cancer and 1 (1%) detected right-sided ischemic colitis (Table 3). A total of 111 polyps were found and all were successfully resected. This included a large sessile lesion in the proximal transverse colon requiring lifting with submucosal saline injection, and piecemeal resection (Figure 1). 77 (69%) polyps were found to be tubular adenomas that ranged in size from 5mm to >2.5cm.The number, size and distribution of these adenomas is given in Table 4. Of the 2 colon cancers detected, 1 patient was found to have an ascending colon carcinoma and 1 patient with a cecal carcinoma (Figure 2).

The mean total procedure time was 36.5 min +/- 3.14 (range 11-139 min), with a mean withdrawal time of 14.7 minutes (range 6-122 min). Procedure time decreased as the operators gained more experience with the technique. The overtube was used in all cases, but the balloon on the overtube was inflated in only six cases. No complications were encountered. Due to the flexibility of the enteroscope, we were also able to perform retroflexion throughout the colon to view posterior aspects of folds and flexures (Figure 1b).

In the one patient in whom the SBE could not be advanced to the cecum, the ascending colon was reached. An additional 2 adenomas were found in the transverse colon on this examination that were not reached on the incomplete standard colonoscopy. A follow-up air contrast barium enema was performed on this patient, and due to colon tortuosity, the barium did not reach the cecum either.

Discussion

The single balloon enteroscope was initially designed for deep intubation of the small bowel. The SBE, however, has been shown to be useful not only for enteroscopy, but also for endoscopic retrograde cholangiopancreatography in cases of altered anatomy after small bowel surgery.14 Prior papers have cited the expanding use of the single balloon enteroscope for colonoscopy, but these studies are limited due to small patient size (range 14-30 patients) and lack of total procedure and withdrawal times.2,11,12,13 To our knowledge, the current series is the largest prospective study reporting the results of colonoscopy using a single balloon enteroscope after a prior incomplete colonoscopy using a conventional colonoscope. In our study, 98.6% of the SBE procedures were successfully completed after previous incomplete colonoscopy using a standard colonoscope. Our success rate compares favorably with the results of prior studies, with reported cecal intubation rates ranging from 93 to 100%.2,11,12,13 Zero complications occurred. For our study, fluoroscopy was not needed, balloon insufflation was used only if the position of the endoscope could not be maintained when reducing loops and standard manipulation maneuvers were infrequently required. Loop reduction was, however, necessary to facilitate advancement of the instrument but easily accomplished in most instances without balloon assistance.

The single balloon enteroscope is useful in achieving complete colonoscopy and therapeutic techniques in patients with a failed prior exam due to tortuosity, adhesions and fixed, angulated sigmoid colons. The SBE is longer, smaller in diameter, and more flexible than a standard colonoscope. The overtube adds stiffness but remains flexible enough to traverse colonic loops. Colonoscopy using the SBE has the advantage of allowing direct endoscopic visualization of the colon with the potential for endoscopic therapies, as opposed to the alternative imaging techniques which would require subsequent endoscopy for evaluation of positive findings. An additional advantage of the instrument is the ability to easily retroflex in virtually all areas of the colon to facilitate looking behind folds, and assessing the cecum, and hepatic flexures.

Use of this technique resulted in longer total procedure times (mean 36.5 min) and longer withdrawal times (mean 14.7 min) versus standard colonoscopy with mean total time of 15.84 min and mean withdrawal time of 8.77 min.15 Longer procedure times using the SBE were likely due to use of the overtube, difficult patient anatomy and longer time spent suctioning due to the longer, smaller diameter suction channel. Other limitations to use of the SBE include: requirement of active participation of an assistant to control the longer endoscope, air may escape via the overtube, colon preparation needs to be excellent due to limited suctioning capabilities and the flexible endoscope retroflexes easily. Despite these limitations, full visualization of the colon was achieved in all patients, two colon cancers were detected and all polyps encountered were completely removed.

One limitation to our study is that 69% of the procedures were performed by a single operator. However, four other endoscopists participated in the study and their success rates were 100%. Also, seventeen patients (24%) had prior incomplete colonoscopies by an operator other than the one performing colonoscopy with the SBE. It is possible that some of those procedures could have been completed with a conventional colonoscope by the second endoscopist.

The importance of a complete examination of the colon was illustrated due to the fact that two adenocarcinomas of the right colon, one right-sided ischemic colitis and multiple adenomas, not previously identified on prior standard colonoscopy, were detected using the SBE technique. Colonoscopy using the single balloon enteroscope is a successful technique in patients with difficult anatomy or multiple prior abdominal surgeries. Taking these factors into consideration, SBE may be the preferred instrument for initial colonoscopy in patients predicted to have a difficult colon to negotiate, and is certainly a good option for evaluation of patients with a prior incomplete colonoscopy. It can also be utilized for therapy of right sided lesions seen on imaging in patients with a prior incomplete standard colonoscopy. Prospective studies using SBE as the initial tool for colonoscopy in patients with features predicting a high rate of incomplete colonoscopy are warranted.

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INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #97

A Review of the Relationship Between Inflammatory Bowel Disease and Vitamin D

September 2015 • Volume XXXIX, Issue 9
Shail M. Govani,Peter D.R. Higgins

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There is increasing interest in the role of vitamin D in autoimmune diseases. Among patients with inflammatory bowel disease (IBD), a significant percentage are vitamin D deficient. It remains unclear whether this deficiency is related to the disease or is rather a result of malabsorption from the disease. The main driver of vitamin D levels, UV exposure, has been linked to decreased risk of inflammatory bowel diseases by epidemiological studies. Here, we will review the evidence linking vitamin D to inflammatory bowel diseases.

A wide range of evidence exists linking vitamin D and the immune system suggesting that lower levels maybe associated with autoimmune diseases. The main driver of vitamin D levels, UV exposure, has been linked to decreased risk of inflammatory bowel diseases by epidemiological studies. Animal studies have suggested that vitamin D could have a causal effect on inflammation in the GI tract and now small studies suggest that vitamin D supplementation could prevent relapse. Additional large prospective trials are necessary to demonstrate this causal link definitively.

Shail M. Govani MD MSc, Peter D.R. Higgins MD PhD MSc, Department of Gastroenterology, University of Michigan, Ann Arbor, MI

There is increasing interest in the role of vitamin D in autoimmune diseases. Among patients with inflammatory bowel disease (IBD), a significant percentage are vitamin D deficient.1-4 It remains unclear whether this deficiency is related to the disease or is rather a result of malabsorption from the disease. Epidemiological studies led to the initial hypothesis that there was a role of vitamin D outside of calcium metabolism and bone health. This was followed by basic science experiments demonstrating the role of vitamin D in immunological processes. More recently, there have been small clinical trials demonstrating an effect of vitamin D supplementation on the course of IBD. Here, we will review the evidence linking vitamin D to inflammatory bowel diseases.

The association between latitude and autoimmune diseases dates back to at least the 1960s when researchers studying multiple sclerosis (MS) noted an association between the incidence of the disease and latitude.5 The relationship between inflammatory bowel disease and latitude was explored in the 1990s in Europe.6 This study examined new cases of IBD between 1991 and 1993 across 20 centers in Europe and found higher incidences of both ulcerative colitis (UC) and Crohn’s disease (CD) in northern Europe compared to southern centers. More recent studies in Europe have focused on single countries in a retrospective manner. A French study showed an association between latitude and CD incidence in France between 2000 and 2002 but failed to find a similar association for UC.7 In contrast, a more recent population study in Finland found an association between UC incidence and latitude.8 These European population studies were in countries that are relatively genetically homogenous compared to the United States. A lingering confounder in those studies was the possibility that another environmental or genetic factor was playing a role in the incidence of IBD. Using the Nurses Health Study dataset in the United States, Khalili et al. found a relationship between both UC and CD and latitude.9 The risk of CD among women in the southern US was 0.48 (95%CI: 0.30- 0.77) while the risk of UC in the southern US was 0.62 (95%CI: 0.42-0.90). Looking at this possible association from another perspective, Kurtzke et al. found a relationship between altitude of residence and incidence of MS, with those living in the lowest lying regions in Switzerland exposed to less UV light which was associated with the highest MS incidence rate.10 More recently, a large database of hospitalizations in the United States has been used to show an association between the risk of inpatient surgery for Crohn’s disease and average UV light exposure in the patient’s state of residence.11 These studies taken together suggest there is some relationship between latitude, UV exposure, and autoimmune diseases such as IBD.

While these studies show an association exists, it is difficult to prove a causal relationship between autoimmune diseases and a deficiency of UV light, or indirect causality via a deficiency of vitamin D using epidemiological studies. Rodent experiments allow more direct assessment of the case for a causal link between vitamin D and inflammatory bowel diseases. The first step was confirmation of the expression of vitamin D receptor protein in immune cells.12,13 In further experiments with IL-10 knockout mice, models for inflammatory bowel disease, Cantorna et al. compared vitamin D deficient IL-10 knockout mice to knockout mice with sufficient vitamin D.14 Those mice with vitamin D deficiency had significantly more inflammation in the small intestine, lower body weight, and higher mortality. Further experiments with IL-10 knockout mice found that calcium and 1,25 dihydroxyvitamin D supplementation ameliorates inflammatory colitis, and that this benefit is mediated through the tumor necrosis factor-alpha (TNF-a) pathway.15

Retrospective studies of the relationship between vitamin D levels and IBD have recently been published and show a link between disease activity and deficiency. The Endocrine Society defines vitamin D insufficiency as levels of serum 25-OH vitamin D below 75 nmol/L (30 ng/ml) and deficiency as levels below 50 nmol/L (20 ng/ml).16 Vitamin D insufficiency among the IBD population is very high, affecting up to 78% of our patient population2 and deficiency affects a significant portion, up to 60%.17 As expected, there is significant variation in deficiency rates depending on the time of year the level is checked. In a study of CD patients in Ireland, 50% of the patients were deficient during winter months while only 19% were deficient during the summer.1 Comparing the rates of deficiency among healthy controls and CD patients, there does appear to be a difference. In another study from Ireland, 44 patients with CD and 44 age-matched controls were compared with regards to vitamin D levels in winter and summer.18 Of the patients with CD, 18% were deficient in the summer months compared to just 5% of the healthy controls. In the winter months, the rate of deficiency among the CD patients was 50% compared to 25% of the controls. A few studies have examined the effect of vitamin D levels on disease activity. IBD patients in Boston are deficient in vitamin D approximately 1/3 of the time, but those who normalize their vitamin D levels have a reduced risk of surgery (OR 0.56, 95%CI 0.32-0.98) compared to those who remain deficient.19

While the number of studies linking vitamin D and IBD is significant, only a few studies have examined the effect of supplementation on disease activity or outcomes. The largest study of the effect of supplementation was conducted in Denmark in 2005 in 108 patients with Crohn’s in remission based on CDAI and CRP.20 Patients were randomized to 1200 IU of vitamin D3 plus 1200mg calcium daily for a year versus only 1200mg calcium. Notably, the patients were not selected based on initial vitamin D status so only 1/3 of the population was deficient at initiation. The primary outcome of the study was risk of relapse based on CDAI increase of 100 or more and an absolute CDAI of 150 over the course of the year. Among those given vitamin D, the relapse rate was 13% whereas those given only calcium had a relapse rate of 29%. Using Cox proportional hazards, the hazard ratio of relapse was 0.42 among those taking the vitamin with a p value of 0.06. Despite a relatively low dose of supplementation, the average 25-OH vitamin D level did rise from 69 nmol/L to 96 nmol/L within 3 months in the treatment group. A recently published study from Ireland enrolled a similar group of patients with CD, i.e. those in remission and administered 2000 IU D3 versus placebo for 3 months.21 Among the 13 patients on therapy, only 9 achieved sufficient levels and it was among these 9 that the clinical and biochemical benefits were seen. Those with levels >75nmol/L had lower CRPs, and higher quality of life scores based on the IBDQ. The fact that 2000 IU was not sufficient to increase vitamin D3 to sufficient levels is not surprising based on prior research and the guidelines regarding supplementation. The Endocrine Society guidelines suggest that the patients that patients with deficiency receive 50,000 IU weekly and those patients with a malabsorption syndrome such as Crohn’s disease receive 6,000-10,000 IU daily.16 A pilot study of vitamin D supplementation in the Crohn’s population has corroborated the need for higher doses of supplementation.22 In that study, patients with Crohn’s were enrolled if they had evidence of moderately active disease based on CDAI between 150 and 400 and vitamin D levels <40. Patients were then started on 1,000 IU daily with a dose escalation every 2 weeks until their levels reached 40 ng/ml or 5,000 IU. Of the 18 patients enrolled, 14 required escalation to 5,000 IU daily and even among these, half did not reach the goal of 40 ng/ml suggesting that even higher doses would have been required to reach this target.

In conclusion, there appears to be mounting evidence that vitamin D plays a role in immune regulation and may influence the risk and activity of inflammatory bowel diseases. Higher levels appear to correlate with improved disease activity. The Crohn’s and Colitis Foundation of America is currently sponsoring a pilot clinical trial to examine the effects of 10,000 IU of daily vitamin D3 on clinical outcomes among patients with Crohn’s disease and vitamin D deficiency with patients receiving continued supplementation until they reach 50ng/ml. This randomized controlled trial will provide important prospective data on whether higher blood vitamin D levels do lead to improved outcomes.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #145

D-Lactic Acidosis: More Prevalent Than We Think?

September 2015 • Volume XXXIX, Issue 9
Luke White

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D-lactate acidosis, in which the D-isomer of lactate accumulates, is a disorder that has been reported in the setting of short bowel syndrome, and in particular, with high carbohydrate diets in children. In this article, we present information about D-lactate that will increase the readers’ level of vigilance for this disorder, which affects a broader group of patients than initially thought.

Luke White, D.O. Department of Critical Care Medicine, Memorial Hospital, South Bend, IN

REPRESENTATIVE CASE

A 60 year old male presented to the emergency department after being referred by his primary care physician for evaluation of ataxia and slurred speech.1 These symptoms had waxed and waned over the course of five months. He had undergone an MRI previously that showed only chronic small vessel disease; a CT of the head performed on the day of admission revealed similar findings.

Eight months prior to admission, the patient had suffered a small bowel volvulus necessitating resection of 420cm of necrotic jejunum and ileum. He also suffered from end-stage renal disease due to longstanding diabetes mellitus (DM) and hypertension, necessitating hemodialysis 3 times /week.

Within hours after admission the patient became unresponsive and was intubated. He was found to have a severe metabolic acidosis with a pH of 7.02 and an anion gap of 26. Lactate and blood urea nitrogen levels were normal. No osmolar gap was present and a toxicology screen was negative.

Hemodialysis was performed and the patient regained normal neurologic status. He was quickly extubated. D-Lactate, the dextrorotary isomer of lactate, was found to be markedly elevated on a blood specimen sent prior to dialysis. He recovered and was discharged with antibiotic therapy and counseling on dietary modifications. He was noncompliant with his recommended diet and was subsequently admitted multiple times with similar symptoms necessitating multiple intubations. These admissions usually occurred after meals heavy in carbohydrates (CHO) and immediately prior to scheduled sessions of dialysis.

Normal Human Metabolism

Lactic acid, like many organic molecules, consists of two mirror-image isomers. L-lactate is produced by the human body and is the isomer tested for in common “lactate” assays.

D-lactate, the mirror image of L-lactate, is produced in minute concentrations in human metabolism via the methylglyoxal pathway that converts acetone derivatives to glutathione.2 These concentrations are clinically insignificant in normal human metabolism.

Clinical Presentation and Mechanism of Encephalopathy

D-lactate toxicity generally occurs with serum D-lactate levels over 3 mmol/L3 and is associated with acidosis and a variably presenting encephalopathy. The clinical presentation of the patient with D-lactate toxicity is characterized by acidosis and encephalopathy in the context of the above risk factors. The encephalopathy of D-lactic acidosis is highly variable. Symptoms may include memory loss, fatigue, and personality changes or cerebellar symptoms such as ataxia or dysarthria. Severe cases may involve syncope, coma and respiratory failure, as occurred in the case described.1,4,5,6 Symptoms are similar in both humans and in ruminants, which suffer an analogous disease due to malabsorption and dehydration.2 The cerebellum appears to be most sensitive to elevated D-lactate levels; investigation of potential toxicity should include a careful exam of cerebellar function with speech, gait and balance testing.

The mechanism for D-lactate encephalopathy remains unclear. D-lactate freely passes into the cerebral spinal fluid.7 Serum and urine levels do not always correlate to symptoms4 and healthy volunteers infused with D-lactate showed no signs of encephalopathy even when concentrations reached up to 6.7 mmol/L.8 It has been proposed that given these findings, D-lactate may be a proxy for other neurotoxic organic acids that have not yet been identified.3,5 Some cases of D-lactate encephalopathy appear related to thiamine deficiency.9,5,3,10

Several findings suggest that D-lactate may be a direct player in precipitating neurologic symptoms. L-lactate buildup and acidemia do not by themselves cause encephalopathy. D-lactate directly infused into the brain in animal models, however, impairs memory and reduces brain cell survival.6

Symptoms of congenital pyruvate deficiency are similar to those seen in D-lactate toxicity.11 D-lactate (and acidosis itself) impairs the action of pyruvate dehydrogenase (PDH), interfering with pyruvate metabolism and inhibiting utilization of L-lactate as a fuel in the brain. As cerebellar PDH is already reduced relative to the serum, a relatively low concentration of D-lactate may lead to clinical symptoms, even as serum levels of PDH remain adequate.6,3

At-Risk Populations

D-lactate toxicity has been historically associated with patients suffering from short bowel syndrome (SBS). Ingestion, parenteral infusion via D-lactate containing fluids (such as Ringer’s lactate), peritoneal lavage, and impaired metabolism and excretion have all contributed to D-lactate toxicity in patients without SBS, though these causes are rare. It is likely that pathologic D-lactate buildup is under diagnosed; surveillance of 470 randomly selected hospital patients revealed detectable D-lactate levels in nearly 3 percent; less than two-thirds of these patients had a history of gastrointestinal surgery.4

Patients with SBS, particularly those with colon in continuity, but also those with small bowel bacterial overgrowth (SBBO), are at high risk for derangement of the balance of gut flora, as described below. These patients are most at risk when they suffer from the delivery of excess CHO to colonic bacteria and are unable to effectively metabolize and excrete the D-lactate produced.2,3,4,5 See Table 1 for at risk populations.

Laboratory Testing

The clinician should suspect D-lactate toxicity in the patient presenting with neurologic symptoms, a gap or non-gap acidosis, and risk factors for D-lactate overproduction or retention. Obtaining a D-lactate level may confirm an often difficult clinical diagnosis.

D-lactate is not detected in standard clinical lactic acid assays and requires a specific request from the lab. Despite this, an elevated concentration of D-lactate in the plasma always causes acidosis and usually leads to an increased anion gap. However, the anion gap may be lower than one would expect with similar concentrations of L-lactate or may even be normal.12 A fraction of D-lactate is excreted with sodium or potassium in the urine, which may lead to a relative non-gap (or low strong ion difference) acidosis. A normal anion gap does not therefore definitively exclude D-lactic acidosis.

Testing for D-lactate requires a targeted assay and usually will require the services of a reference laboratory. This author utilizes Mayo Laboratories (Mayo Medical Laboratories, Rochester MN. http:// www.mayomedicallaboratories.com). D-lactate can be measured easily in urine and plasma specimens. Given high levels of urinary D-lactate excretion, a urine specimen will be more sensitive for clinically significant D-lactate toxicity. The turnaround time between specimen receipt and result may be up to 8 days. Because of this, laboratory testing should be considered supportive of a clinical diagnosis; treatment should not be delayed if the suspicion for toxicity is high.

Causes
Bacterial Production and the Short Bowel Syndrome

Bacteria are almost always the predominant generator of D-lactate in mammals. Normal human gut flora is governed by a complex and still incompletely understood balance of factors. Normal human flora consists predominantly of Bacteroides and Firmicutes species; other species make up approximately 10% of the remainder. Concentrations of bacteria progressively increase by orders of magnitude from the stomach and duodenum to the colon.13

Both isomers of lactate are produced by usual human colonic flora as they metabolize small amounts of CHO, protein, non-absorbable starches, and fiber. The principal source of D-lactate production in the human gut is due to Lactobacillus and Bifidobacteri species.2 E. coli, Klebsiella pneumoniae and Candida freundii also produce significant quantities of D-lactate while producing minimal amounts of L-lactate.14 Some lactobacillus species are able to catalyze one lactate isomer to the other.15,16,2 Much of this lactate is converted to short chain fatty acids, which play an important role in the nutrition and maintenance of the mucosal integrity of the colonic epithelium.15

The delicate interplay of the healthy gut microbiome ensures that metabolites are appropriately utilized or excreted. Exposure of the colonic flora to excess (CHO), particularly in those with malabsorption, that presents more than the “usual” amount of CHO to the colon such as SBS or roux en y gastric bypass, can lead to an increase in lactate production via fermentation. This may occur either due to increased transit of CHO to the colon, to SBBO, or both.12

The luminal pH in the normal proximal small bowel is between 5.5 to 7.0. It becomes progressively more alkalotic through the jejunum and ileum. The cecal luminal pH is somewhat more acidotic (6.2) than the terminal ileum (7.6), but again becomes more alkalotic through the colon.17

As more CHO is fermented into lactate, luminal acidity increases and pH decreases. This decreasing pH selects for an increase in acid-tolerant fermenting bacteria, leading to a vicious cycle of fermenter overgrowth and increasing lactate production. Lactobacilli quickly become the predominant organism in patients suffering from SBS with malabsorption.14 Some of this lactate is translocated into the systemic circulation. While L-lactate is metabolized fairly readily, the human’s limited capacity for D-lactate metabolism and excretion,17 reduction of D-lactate metabolism due to acidosis,2 or interconversion between lactate isomers by certain lactobacilli,15,16,2 can all contribute to increasing concentrations of D-lactate.

Defects in CHO absorption via an anatomic or functional short gut are responsible for most cases of pathologic bacterial overproliferation. D-lactate toxicity has also been reported in patients with SBS after the administration of probiotics consisting of D-lactate producing species, overconsumption of D-lactate producing yoghurt, and with the use of antibiotics that allow Lactobacillus overproliferation.4,10,3,5,18

Other Sources of D-Lactate

While bacterial production accounts for the vast majority of cases of D-lactate toxicity, other causes have been reported. D-lactate appears to be elevated in at least some cases of diabetic ketoacidosis.19,20 One metabolic fate of D-lactate is conversion to fatty acids, but this can happen only in the context of high insulin levels,12 which most patients with DM lack.

D-lactate toxicity has also been reported with propylene glycol ingestion.21 Propylene glycol is a diluent used in the preparation of many liquid medications, such as lorazepam. While lactic acidosis is a well-known complication of propylene glycol toxicity, controlled infusion of propylene glycol causes dose- dependent increases in D-lactate, even as L-lactate (the only isomer measured in common lactate assays), decreases.22

D-lactate is sometimes directly administered via some formulations of Ringer’s lactate containing both isomers of lactate. One review associated administration of fluids containing D-lactate with worsened clinical outcomes.23 Peritoneal dialysate may also be a source of D-lactate.3,5

Sepsis, gut ischemia, and intestinal perforation have been associated with elevated levels of D-lactate. This is likely due both to increased production and translocation across the damaged intestinal mucosa.24,25,26 D-lactate has in fact been suggested as a sensitive and specific marker of mesenteric ischemia,26 though the lack of ready availability of a D-lactate assay in most institutions limits its utility in this respect.

Metabolism and Excretion

Not all patients with SBS suffer from D-lactate toxicity, even when their CHO ingestion is unrestricted. Impaired D-lactate metabolism superimposed on excess production likely plays a significant role in most cases of toxicity.5,27

Accumulation of D-lactate in the circulation is abnormal. While early studies suggested that humans could not metabolize D-lactate, a certain quantity of D-lactate can in fact be metabolized into pyruvate via D-2 hydroxy acid dehydrogenase (D-2 HDH).5

Unlike L-lactate, which is efficiently metabolized, the metabolism of D-lactate is relatively slow and limited to a relatively small amount.17 D-2 HDH is found principally in the kidney and liver; impairment of these organs may lead to reduced D-lactate metabolism. Acidemia itself also impairs D-lactate metabolism due to a decrease in PDH activity, potentially leading to a loss of homeostasis should lactate levels accumulate enough to cause significant acidosis.3

Low levels of insulin may promote the buildup of D-lactate. Insulin inhibits the conversion of triglycerides to fatty acids, increasing the amount of organic acids, including D-lactate, that are metabolized. Thus, physiologic insulin release concurrent with CHO ingestion may have a protective effect in minimizing D-lactate toxicity.12 Even otherwise healthy patients with DM demonstrate elevated levels of serum and plasma D-lactate.28

Pyruvate acts as an intermediate product in D-lactate metabolism. Thiamine, a cofactor in pyruvate metabolism, may be deficient in patients suffering from malnutrition. Thiamine deficiency has been associated with lactic acidosis.9 Patients suffering from SBS, abnormal gut flora and/or malabsorption syndromes are at increased risk for thiamine deficiency. This deficiency, when paired with the elevated lactate production from abnormal gut flora, may lead to large amounts of excess lactate that cannot be effectively metabolized.

The kidneys excrete a significant amount of D-lactate; the proportion excreted increases with increasing plasma concentrations.19 Limited metabolic potential makes renal excretion an important vehicle for elimination in cases of pathologic D-lactate production. While moderately decreased renal function does not seem to significantly reduce excretion,19 severe renal impairment, as in the case of patients dependent on hemodialysis, may lead to catastrophic levels of D-lactate.1

Treatment and Prevention

D-lactate is the product of a substrate (usually CHO), produced largely by fermentative bacteria, which is then ultimately metabolized or excreted. D-lactate toxicity generally arises from excess substrate along with some catalyst for production, from impaired metabolism, excretion, or both.1,12 Effective prevention and treatment entails targeting each of these pathways. The mainstays of treatment are CHO restriction, hydration, cautious use of probiotics, and avoidance of SBBO (see Table 2).

Diet

Patients with SBS who are at risk for SBBO should be encouraged to limit simple CHO intake (cakes, cookies, pie, candies, etc.) as well as sugar alcohols (sorbitol, mannitol, xylitol, etc.), fructose and other highly osmolar, fermentable compounds and excess fiber.29,30 CHO should be complex and modest in quantity (16), with small and frequent meals to avoid exposure of the gut flora to large, poorly absorbed boluses of CHO. It has also been suggested that fermented foods, such as yoghurt, sauerkraut and pickles be avoided given high preexisting concentrations of D-lactate.3

In the patient with D-lactic encephalopathy, temporary cessation of all enteric feeding is reasonable. Elimination of substrate to the gut should prevent bacterial production. Fasting has been associated with rapid improvement in D-lactate associated encephalopathy.7,5 Concomitant parenteral nutrition does not increase D-lactate levels, though it may reduce excretion as other organic acids compete with D-lactate for tubular excretion.7

Antimicrobial Strategies

SBBO is responsible for most cases of D-lactate toxicity; prevention of this overgrowth is important.31

Antibiotic therapy (see Table 3) may increase or reduce D-lactate production, depending on the gut flora selected for. Trimethoprim-sulfamethoxazole (TMP- SMX), doxycycline, and neomycin, for example, have each been associated with episodes of D-lactate encephalopathy.7,18,32 Each of these antibiotics has also been used in the treatment of SBBO.1,14,31 Likewise, metronidazole has been used successfully.30,16 but some lactobacilli in cases of D-lactate toxicity have exhibited metronidazole resistance.32 Rifaximin is increasingly used in the treatment of SBS with SBBO.31,33 Though lactobacilli can grow even at high intraluminal concentrations of rifaximin,34 to date no cases of D-lactate encephalopathy definitively associated with rifaximin use have been reported.

A four-year study of fecal bacteria, lactate production, and resistance patterns in patients suffering SBS demonstrated poor results when attempting to treat D-lactate toxicity with antibiotic therapy; neomycin and oral vancomycin were successful in reducing certain lactobacillus isolates, but did not affect symptomatic resolution.14 A patient suffering from multiple episodes of D-lactic acidosis after TMP-SMX and doxycycline use suffered no episodes when taking ciprofloxacin, and cultured lactobacilli demonstrated ciprofloxacin sensitivity.32 Amoxicillin has been used due to its effective coverage of lactobacilli and high intraluminal gut concentration, but did not prevent recurrence when taken chronically.1

Antimicrobial therapy should be selected with caution in patients at risk for SBBO as certain antibiotics may select for lactate-producing gut flora. While it is reasonable to treat acute episodes of D-lactate toxicity with antibiotic therapy targeting Lactobacillus species, chronic preventive antibiotic therapy has not demonstrated consistent effect. In the patient suffering from recurrent episodes of D-lactate encephalopathy, fecal culture and sensitivities should be considered to ensure appropriately targeted therapy. Given the complexity of the healthy gut milieu, no single antibiotic regimen is likely to yield satisfactory results on its own.

Enhancement of Metabolism and Excretion

Only a minority of patients who neglect dietary interventions will develop D-lactate toxicity, even if they are actively suffering from SBBO. One study of eleven patients with SBS and no neurologic symptoms demonstrated D-lactate overproduction in most fecal samples, but none in the urine.27 Symptoms should trigger a search for causes of impaired metabolism and excretion.

Thiamine deficiency may both result from malnutrition and poor absorption, and contribute to reduced clearance of D-lactate due to impaired pyruvate metabolism.9 The cerebellum is particularly sensitive to thiamine deficiency.11 In some instances of encephalopathy associated with excess D-lactate, thiamine supplementation alone has led to symptomatic resolution.11,35 It is reasonable to supplement the patient suffering from neurologic symptoms with thiamine,9,5,3,10 particularly as this same set of patients is also at high risk for Wernicke’s Encephalopathy, which may present with similar neurologic findings. We recommend aggressive treatment, supplementing all patients with neurologic symptoms at risk for thiamine deficiency with 500mg parenterally three times daily for 1-2 days and then 100mg orally or parentally indefinitely thereafter.

A significant proportion of D-lactate that accumulates in the serum is excreted in the urine.19 Impaired excretion can lead to D-lactate buildup. Maintenance of euvolemia is important in the prevention of D-lactate toxicity; aggressive hydration is crucial in its treatment. SBS is associated with dehydration, particularly in the case of malabsorption due to poor dietary adherence;29 consequently, patients suffering from SBBO may also suffer from renal hypoperfusion and reduced excretion of D-lactate. Of note, fluids such as Ringer’s lactate with racemic mixtures of lactate should be avoided.23

Hemodialysis effectively clears both isomers of lactate and has been successful in treating episodes of severe D-lactate toxicity.1,21,36 Anuric or oliguric patients already undergoing dialysis who suffer recurrent episodes of D-lactate toxicity may benefit from longer or more frequent hemodialysis sessions to promote clearance, as they have no other means of excretion. Patients with D-lactate toxicity already undergoing peritoneal dialysis should be considered for hemodialysis given the presence of D-lactate in peritoneal dialysate.3,5

Other Proposed Treatments

Bicarbonate has been given parenterally in the treatment of D-lactic acidosis.2,1,5 This may enhance D-lactate metabolism, as the responsible enzyme is impaired by acidosis. Notably, this is in contrast to recommendations that undifferentiated lactic acidosis (which is usually principally L-lactate) not be treated with bicarbonate.37 One case report reported symptomatic resolution with oral and intravenous bicarbonate administration.5 Bicarbonate has also been successful in the treatment of drunken lamb syndrome, an analogous process in ruminants, when given in conjunction with parenteral amoxicillin.38

Growth of lactate-producing fermentative bacteria both promotes, and is enhanced by, intraluminal acidosis. Antacids have thus been proposed3 as a potential treatment, but given the association of acid suppressive therapy with SBBO and increased intestinal transit time,33 they should be used with caution, if at all.

D-lactate levels in otherwise healthy patients with DM can be elevated,28 possibly due to insulin deficiency or resistance. Insulin has been suggested as a potential therapy for severe D-lactic acidosis on the principle that it may inhibit lipolysis and thus promote increased metabolism of D-lactate.12 This has yet to be widely evaluated; at present it seems prudent to simply pursue usual treatment for hyperglycemia.

SUMMARY

D-lactate toxicity remains an uncommon, but likely under recognized syndrome. It occurs principally in patients with SBS who suffer acute processes that impair the limited human capacity to metabolize and excrete D-lactate, but may be missed in other disease processes due to the wide variability in symptoms and delay in obtaining confirmatory testing. Wider recognition of the syndrome and careful monitoring of those at risk for it, paired with a multidisciplinary approach to encourage compliance with dietary recommendations, will help to prevent and reduce its incidence even further.

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GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, SERIES #11

Medicinal Plants for Digestive Disorders What Gastroenterologist Needs to Know

September 2015 • Volume XXXIX, Issue 9
Armando Enrique González-Stuart,Richard W. McCallum

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Medicinal plants have been used by all cultures throughout history and still continue to be an integral part of our modern civilization. From generation to generation, various ethnic groups around the world have used a wide array of plants to treat various gastrointestinal problems. With the remarkable surge of so-called complementary and alternative medicine, or CAM (currently known by the more accurate term of Integrative Medicine), it is imperative that the gastroenterologist be aware of both the potential risks as well as the benefits of using herbal medicine in his/her modern practice.

Herbal medicine is arguably the oldest form of healthcare known to humanity. Medicinal plants have been used by all cultures throughout history and still continue to be an integral part of our modern civilization. From generation to generation, various ethnic groups around the world have used a wide array of plants to treat various gastrointestinal problems. This practice is especially common among the Hispanic communities living along the United States-Mexico border. The principal afflictions for which various plants are ingested (either taken as tea made from a single plant – or multiple combinations) range from parasitic diseases, to bloating, ulcers, nausea, dyspepsia and diarrhea, just to name a few. Plants contain a myriad of secondary metabolites or phytochemicals, which may have a role in the treatment and prevention of various digestive disorders. With the remarkable surge of so-called complementary and alternative medicine, or CAM (currently known by the more accurate term of Integrative Medicine), it is imperative that the gastroenterologist be aware of both the potential risks as well as the benefits of using herbal medicine in his/her modern practice.

Armando Enrique González-Stuart, Ph.D., Professor of Phytotherapy and Integrative Medicine, O.L.L.I. at the University of Texas at El Paso Richard W. McCallum, MD, FACP, FRACP (Aust), FACG, Texas Tech University Health and Sciences, Department of Internal Medicine, Gastroenterology, Center for Neurogastroenterology and GI Motility, El Paso, TX

INTRODUCTION

Medicinal plants, collectively comprising various species of green plants as well as fungi (mushrooms), were arguably the first therapeutic agents known to humans.1

The use of herbs to cure diverse human and animal ailments predates recorded history. From Paleolithic cave dwellers to medieval healing monasteries as well as from Renaissance alchemists such as Paracelsus to the modern “techno era”, medicinal plants have been, and continue to have, an important part in the healing therapies applied in both human as well as veterinary medicine.2

The application of the plethora of species used in herbal treatments has been anything but haphazard. Well-known and mastered by the Hakims (physicians) of Arabic medicine as well as the Aztec and Mayan healers of ancient Mesoamerica, herbal medicine has been a part of highly systematized medical modalities throughout the orb. Such systems include, but are not limited to, Ayurveda, Siddha, and Unani-Tibb from India, Traditional Chinese herbology and Native American herbal healing (here indicating the totality of the American continent), to name only a few.3,4

The infamous slave trade also brought diverse African food and medicinal plants to the American continent (such as okra, hibiscus and castor oil plant, for example) that both enriched and diversified the conglomerate of European, Asian and Amerindian herbal pharmacopoeias.5,6,7

Dyspepsia

Various plants are available usually as teas or capsules, for the treatment of dyspepsia. Chamomile (German or Roman), as well as anise (green and star anise), various mints and licorice have been regarded as traditional medicine for centuries8 (See Table 1).

A study compared the efficacy of a ginger (Figure 1.) and artichoke supplementation compared to placebo for the treatment of dyspepsia. The design consisted of a 4-week prospective multicenter, double blind, randomized, placebo controlled, parallel- group format that compared the herbal combination versus placebo. A dose of two capsules per day was given before two meals (lunch and dinner) to the 126 participants suffering from dyspepsia. The study showed that after two weeks, only the treatment group showed a substantial decrease in symptoms of gastric discomfort including nausea, epigastric fullness, epigastric pain, and bloating. The researchers concluded that the herbal combination of ginger and artichoke leaf extracts appears safe and efficacious for the treatment of dyspepsia.9

Because medicinal plants usually contain hundreds of active ingredients, many are multifaceted, that is, they can be applied to various (apparently) unrelated ailments. One example is cinnamon (Cinnamomum verum), which can have both anti-flatulent as well as hypoglycemic properties.

Nausea and Vomiting

Certain medicinal plants can help to reduce nausea and vomiting due to various conditions such as motion sickness or vomiting that may accompany the early stages of pregnancy (hypermesis gravidarium). One of the plants most employed in traditional medicine against nausea and emesis is ginger (Zingiber officinalis- Zingiberaceae). The underground stem (rhizome) of this plant is considered to have “warming” properties by both Ayurvedic as well as Chinese medicine and has been recommended to treat both digestive as well as respiratory disorders throughout Asia for many centuries.

Ginger’s antiemetic effects are not completely understood, but it seems the plant’s main bioactive ingredients (gingerol and various shogaols) act directly on the gut via the peripheral nervous system but not via the central nervous system (CNS). Ginger’s phytochemicals may have beneficial anti-inflammatory actions as well as an inhibitory effect on platelet aggregation.10

Ginger can be taken as a tea or in capsules containing the dried and pulverized stem. In Europe, this plant is widely used to treat nausea and vomiting during the first trimester of pregnancy

Ginger extracts containing gingerols and shogaols exert their activity upon cholinergic and serotonergic receptors.

A systematic review of double-blind, placebo- controlled, randomized studies with ginger emphasized the possible efficacy of this plant on the prevention and treatment of nausea and vomiting of various origins. The review focused on pregnancy-induced nausea and vomiting, as well as nausea induced by chemotherapy. The authors hypothesized that ginger extracts do have a therapeutic role in the treatment of nausea and vomiting from various causes, and with minimal side effects. For this reason, the authors concluded, ginger preparations can be a potential alternative to traditional prokinetic pharmaceuticals such as domperidone, levosulpiride or metoclopramide, as well as conventional antiemetics like the phenotiazines and 5HT 3 antagonists, for example.11

Diarrhea

Traditionally, plants that are rich in tannins are used for the treatment of diarrhea due to their astringent properties. Many medicinal plants may also contain additional phytochemicals, such as quercetin (a polyphenolic compound with antioxidant and anti- inflammatory properties), that maybe useful in curtailing the symptoms.

Teas made form Guava leaves are used throughout the American tropics for the treatment of diarrhea in adults and children. The plant contains tannins, quercetin and is a good source of Vitamin C.

A review of the pharmacological experiments with guava in both in vitro and in vivo models found that guava’s diverse bioactive phytochemicals include phenolic, flavonoid, carotenoid, terpenoid and triterpene compounds. Extracts obtained from the leaves and fruits possess antispasmodic and antimicrobial properties that are useful for the treatment of diarrhea (including infantile rotavirus enteritis) and dysentery.12

Bloating (flatulence)

In herbal medicine, the term carminative refers to a plant whose active ingredients ease flatulence and colic in the gut. This property is usually due to volatile oils, as well as other phytochemicals produced by the plant.1,13

Some of the commonly used herbal products for treating flatulence include anise (Pimpinella anisum- Apiaceae) also known as green anise or European anise. European or green anise may be mistaken for another different spice with similar actions and flavor: star anise. Although star anise contains some of the same ingredients, it may not be safe to give to small children, since it may be neurotoxic (see Table 2 as well as description for star anise below).

Star anise (Illicium verum -Illiaceae), is also referred to as Chinese star anise (to differentiate it from the toxic Japanese star anise: I. anisatum). The fruits of this small Asian tree are used as a tea to relieve bloating and indigestion. Star anise and European (green) anise are different plants, although they contain some of the same ingredients. The fruits are star shaped (hence the vernacular name) and are rich in essential oils as well as terpenoid and phenolic compounds.

The phytochemicals act as carminatives as well as spasmolytics. The fruits’ antiseptic properties are due to anethol, since this compound has both antibacterial as well as antifungal actions. Traditionally, Star anise has been employed as a carminative as well as a eupeptic (substance that promotes good digestion). However, its use in children younger than 6 years of age should be undertaken only under the supervision of a professional due to the possibility of side effects due to the adulteration with another very similar species known as Japanese star anise, which can be very toxic to the nervous system.14, 15

Constipation

Caution should be practiced recommending using certain herbs as laxatives due to their potentially irritating effects on the gastrointestinal tract (See Table 3). These plants include aloe vera (whole leaf preparations including the latex and gel), as well as any species of rhubarb root. However, certain over- the-counter (OTC) medications), such as senna leaf (sometimes sold as a proprietary laxative known as Senokot�) are generally regarded as safe to use during limited periods. Chronic use as a laxative can darken the mucosa of the colon-an endoscopic observation referred to as melanosis coli.

When constipation is due to tension or stress, the anthraquinone-containing laxatives should be avoided due to their potentially irritating action on the gastrointestinal tract.16

Medicinal Plant Use on the U.S.-Mexico Border

The U.S./Mexico border is approximately 2,000 miles in length with a population of nearly 12 million inhabitants. People of Hispanic origin (principally of Mexican ancestry) comprise approximately 80% of the population living on the U.S. side of the border. The El Paso, Texas/Ciudad Juarez, Chihuahua international community comprises the largest US/Mexico border population.17

Various parameters related to healthcare activities are unique to the bi-national border region. These include, but are not limited to, the use of so-called complementary and alternative medicine (CAM), especially employing medicinal plants, by the predominantly Hispanic population. Even though a copious amount of research has been conducted in the U.S. to determine the extent of the formerly known alternative medical therapies by the general population, far less research has taken place within the largest ethnic minority living on the southwestern border.

A dearth of studies are available but have shown a higher prevalence of medicinal plant use among the Hispanic population. Research undertaken to evaluate the use of herbs and related supplements has shown that between 13-19% of the U.S. population report taking these products.18, 19 A study conducted in El Paso, Texas assessed the rates and types of herbal product use among patients interviewed at local hospitals and clinics. It is worth noting the El Paso’s population is 80% Hispanic. The results of the study demonstrated that 59% of the patients mentioned using various herbal supplements within the previous year.20

Plants Used in Mexican Traditional Medicine to Treat Digestive Problems

Throughout developing countries, the so-called “third world” nations, various gastrointestinal diseases continue to be one of the most challenging health issues. This is the case for various indigenous peoples of Mexico.21

Many of these ethnicities posses a wealth of native knowledge regarding the use of a wide array of plants to treat disease. According to the indigenous viewpoint on the healing characteristics of herbs, certain plants are employed in the treatment of a various diseases due to the particular plant’s characteristic taste or aroma.22 Healing herbs that possess astringent properties are used particularly to treat diarrhea and dysentery, while herbs with bitter and aromatic characteristics are used to treat pain and gastrointestinal cramping. For the treatment of diarrhea and dysentery, for example, plants rich in tannins are used. Many plants frequently employed in Mexican traditional medicine address bloating, diarrhea and other gastrointestinal problems. Guava (Psidium guajaba), Quassia amara, and wormseed (Dysphania ambrosioides), are good examples, but have only limited availability in the United States.23

Potential Toxicity of Certain Herbal Products

Practitioners of modern phytotherapy are well aware that the common saying: “if it’s natural, it must be safe” is not a realistic viewpoint. Many of the most toxic substances known to man (from the carcinogenic aflatoxins from microscopic fungi to the bacterial botulism toxins, for example) are naturally occurring substances. On the other hand, this does not mean that all herbal or fungal products are inherently dangerous.

However, of special concern is the great variability in quality control among the various foreign and domestic companies that market these “natural supplements” as OTC products. Since the majority of these products are classified in the United States as nutritional supplements rather than medications, they are not required to be under the direct supervision of the FDA.

Hepatotoxicity is a Concern for Certain Herbs

Certain herbs used in traditional medicine for the treatment of various illnesses are known to harm the liver, especially if taken internally for an extended period. A few examples include Creosote bush, the so-called “Chaparral” (Larrea tridentata -Zygophyllacaeae). The leaves and twigs of this xerophytic shrub are taken either as teas or pills to treat a myriad of afflictions, ranging from venereal disease to kidney and gastrointestinal tract ailments. The pills tend to be more concentrated and thus pose a greater risk for toxicity.

Comfrey (Symphytum officinale-Boraginaceae) as well as Colt’s foot (Tussilago farfara-Asteraceae) teas can also be liver toxic due to their content of pyrrolizidine alkaloids. Additionally, there are a few cases of kava kava (Piper methysticum- Piperaceae) hepatotxicity, especially if combined with certain medications or alcoholic beverages.24

Medicinal and Toxic Fungi

The use of medicinal fungi in traditional medicine is very common, especially in Oriental traditional medicine. Currently, they are available in health food stores throughout the U.S. Various species of higher fungi (“mushrooms”) are used to treat various ailments, including some types of cancer. They contain complex polysaccharides that act as immuno-modulators and may be useful as cytotoxic agents against certain cancer cell lines.25

On the other hand, toxic mushroom poisonings are usually accidental and occur through careless handling and misidentification when consuming mushrooms from the wild. Some species contain poisonous cyclopeptides that are very toxic to the liver and kidneys, sometimes causing death.

Interestingly, a natural compound known as silymarin, (derived from the medicinal plant known as Milk thistle (Silybum marianum – Asteraceae), is used by physicians in Germany as an antidote for mushroom poisoning, provided it is applied intravenously within 24 hours after ingestion of the offending species.26

CONCLUSION

Every day thousands of medicinal plant and fungal species are being taken by our patients to treat a wide array of ailments, from infant colic to stomach cancer. Scientific herbal medicine or phytotherapy is very commonly practiced in many regions, especially Western Europe, not only by herbalists but by physicians as well. Unfortunately, many species of plants used by indigenous traditional medicine in many developing countries have not been studied in depth. However, we have reviewed those that should be considered by gastroenterologists for incorporation into their practice regimens, in order to both enrich as well as diversify their therapeutic armamentarium. A better knowledge of the commonly used medicinal plants and their active constituents will aid the physician in more effectively communicating with the patient who may be taking some of these agents without officially informing their physician. In addition, it is important to assess the possibility of an herb-drug interaction. Overall, we can say that using certain herbal preparations for digestive problems available on the U.S. market today would have minimal to no unexpected toxic effects, apart from rare idiosyncratic allergic reactions or their proscribed use during pregnancy.

Although no official FDA approval process is currently in place, when used judiciously, a plethora of medicinal plant and fungal species can certainly add to the therapeutic repertoire of the Western physician.

We hope this review will prepare you to understand and incorporate certain herbs to improve the symptoms of patients with various entities.

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A CASE REPORT

Autoimmune Pancreatitis

August 2015 • Volume XXXIX, Issue 8
Tianna E. Johnson,Kenneth M. Sigman

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Autoimmune pancreatitis is an uncommon cause of recurrent and chronic pancreatitis. It may be characterized by clinical findings resembling pancreatic carcinoma posing a diagnostic challenge to practitioners. Misidentifying autoimmune pancreatitis as pancreatic carcinoma results in unnecessary surgeries for a condition that may be managed medically. Conversely, misdiagnosis of pancreatic carcinoma as autoimmune pancreatitis delays treatment of a potentially fatal malignancy. The pathogenesis, diagnosis and treatment of autoimmune pancreatitis are discussed in the context of a case presentation and literature review. This report summarizes the diagnostic criteria required to distinguish this disease from pancreatic carcinoma. In conclusion: 1) the diagnosis of autoimmune pancreatitis requires a multidisciplinary approach, 2) autoimmune pancreatitis should be strongly considered among the differential diagnosis in patients presenting with presumed pancreatic carcinoma and 3) thorough evaluation for this condition should be pursued to determine the most appropriate treatment and avoid unnecessary surgery.

Tianna E. Johnson, D.O., Internist Kenneth M. Sigman, M.D., Gastroenterologist Authors’ Affiliations at the Time of Article Submission: Baptist Health System and Trinity Hospital

INTRODUCTION

Autoimmune pancreatitis represents a small percentage of all forms of recurrent and chronic pancreatitis.1 It occurs due to a primary pancreatic autoimmune process or as a secondary component of a systemic autoimmune disorder.2 This condition accounts for approximately six percent of chronic pancreatitis cases in the United States.1

There are two subtypes of autoimmune pancreatitis.3 Type 1 is typically found in elderly men and is associated with systemic disease affecting extra-pancreatic organs such as the bile duct, kidneys, lymph nodes, and salivary glands.2,3,4 Elevated serum immunoglobulin four (IgG4) is a defining feature.2,3 Type II autoimmune pancreatitis is typically seen one decade before type I.2,3 It is not predominant to one gender, does not involve other organs with the exception of inflammatory bowel disease and is not linked with increased IgG4 levels.2,3 Both subtypes demonstrate lymphoplasmacytic infiltrate upon histologic examination.

The diagnosis of autoimmune pancreatitis requires a high index of suspicion and a multidisciplinary approach involving serologic tests, radiologic imaging, endoscopic imaging with tissue sampling, and sometimes surgical biopsies.1 The Mayo Clinic proposed the HISORt criteria to help better define and confirm the presence of this disease.

Autoimmune pancreatitis is treated with corticosteroids, typically beginning with 40 mg/d of prednisone daily for four weeks.1,3,5 The patient’s clinical status is thereafter reassessed and serologic and radiologic studies are repeated.1 If the response is appropriate, the dose is tapered by 5 mg/week until completion.1 Azathioprine or rituximab are used for patients who have contraindications to taking steroids or to treat recurrent relapses.1

A 69-year old Caucasian man presented with a 10 day history of jaundice accompanied by two weeks of dark colored urine, acholic stool and pruritus. He further admitted to resolved lower abdominal pain that lasted for two weeks and 30 pounds of intentional weight loss achieved with diet and exercise. He denied fever, chills, nausea, vomiting, dyspnea, prior jaundice, joint pain, ankle edema, dysuria and hematuria. His past medical history was pertinent for anemia, gallbladder disease and hyperlipidemia for which he had been taking lovastatin for seven years until two weeks prior to his presentation. He had no other personal or family history of gastrointestinal or autoimmune disorders or diabetes. His surgical history was significant for a cholecystectomy and Nissen fundoplication for a hiatal hernia. Social history was remarkable for smoking approximately five pipefulls per day for 53 years and consuming four beers per year plus an occasional glass of wine. He denied history of illicit or intravenous drug use, tattoos, or transfusions. He had no known drug allergies

All vital signs were within normal limits upon presentation. Physical was otherwise remarkable for jaundice with no other abnormalities.

A complete blood count revealed a hemoglobin of 12.6 (14-17 gm/dL), hematocrit of 36.9 percent (42- 52 percent) and normal white blood cell and platelet counts. A basic metabolic panel was remarkable only for a potassium of 2.8 mEq/L (3.5-5.1 mEq/L). A hepatic panel showed an alkaline phosphatase of 542 U/L (50- 136 U/L), alanine aminotransferase of 133 U/L (12-78 U/L), aspartate aminotransferase of 117 U/L (15-37 U/L), and total bilirubin of 11.2 mg/dL (0.2-1 mg/dL). Repeat total and direct bilirubin were 16.6 mg/dL and 9.8 mg/dL, respectively, within the same week. His amylase and lipase were normal. His hepatitis panel was negative. His carbohydrate antigen 19-9 (CA 19-9) was 236 U/mL (normal less than 55 U/mL). Repeat CA 19-9 less than two weeks later was 709 U/mL.

Computed tomography (CT) of the abdomen and pelvis without contrast showed a prominent common bile duct and mild edematous changes in the area of the pancreatic head with a small amount of fluid in the cul-de- sac. Endoscopic retrograde cholangiopancreatography (ERCP) revealed a lengthy stricture in the pancreatic duct suggesting a neoplasm, a malignant appearing distal bile duct stricture and a dilated proximal bile duct. Pancreatic and bile duct brushings were obtained and were negative for malignancy. Endoscopic ultrasound (EUS) with fine needle aspiration (FNA) of the pancreatic head was subsequently performed.

The patient’s serum IgG4 level was elevated based on hospital parameters at 138 mg/dL (2.4-121 mg/ dL). The patient’s FNA pathology report of his lymph node was benign. Two histologic specimens from the pancreatic head showed chronic active inflammation but no malignancy. One of two specimens was positive for an increased number of IgG4 cells consistent with autoimmune pancreatitis. The patient was treated with steroids and responded well to this. His CA 19-9 one month later was normal at 7 U/mL. Repeat liver enzymes were also all within normal limits after one month and remained normal six months after the patient’s biliary stent removal.

DISCUSSION

Various guidelines have been established to distinguish autoimmune pancreatitis from pancreatic carcinoma. The Mayo Clinic HISORt, Japanese Pancreas Society and Kim (Korean) criteria have emerged as leading diagnostic tools.2 Each share histology, imaging and serology as key diagnostic components; however, the Mayo Clinic model places more emphasis on core biopsy and response to steroid therapy.2 The Japanese strategy is more dependent upon imaging; steroid therapy is considered optionally inclusive.1 The efficacies of these criteria are reliant on the clinicians’ expertise.1 Both have similar trends of algorithmic progression to surgical intervention for suspected malignancy, with the Mayo Clinic and Japanese models having resection rates of 16.7% and 16.2%, respectively.1

Autoimmune pancreatitis presents diversely. Painless obstructive jaundice is noted in approximately 70% of patients.6 A third of individuals report abdominal pain and weight loss.6 Others are asymptomatic and are incidentally found to have laboratory derangements.6 Extreme cachexia, anorexia, and severe pain necessitating narcotics for relief are less suggestive of autoimmune pancreatitis.2 A lack of alcohol abuse or family history of pancreatitis further support the diagnosis of autoimmune pancreatitis.7,8

Increased serum IgG4 is the best serologic diagnostic marker for autoimmune pancreatitis; however, one study reports that only 44% of patients initially presenting with this disease had elevated levels.2,3 Serum IgG4 can also be elevated in pancreatic cancer.2 Guidelines therefore endorse a level above two times the upper limit of normal as being highly suggestive of autoimmune pancreatitis.2,3 Additionally, CA 19-9, often elevated in pancreatic cancer, may also be increased in autoimmune pancreatitis, but tends to decline with steroid treatment.2 An escalating CA 19-9 suggests malignancy rather than autoimmune pancreatitis.2

Core biopsy is considered the best mode of obtaining specimens to assess for autoimmune pancreatitis while fine needle aspiration is preferred for evaluating for pancreatic carcinoma.6 In the absence of malignant histology, biopsy samples demonstrating lymphocytic and plasma cell infiltrates along with fibrosis support the diagnosis of autoimmune pancreatitis especially when plasma cells are positive for abundant IgG4.1

Multiple imaging modalities have been used for the evaluation of autoimmune pancreatitis and preferences vary geographically.2 CT, ERCP, MRCP (magnetic resonance cholangiopancreatography) and EUS are commonly utilized.1,6,7 Classic findings for autoimmune pancreatitis on CT and MRCP include a pancreas that is diffusely enlarged with a rimmed capsule coupled with diffusely attenuated pancreatic duct; however, this disease can be represented by a wide radiographic spectrum.4,7 Pancreatic cancer is more likely to have a low attenuation mass and pancreatic ductal dilatation.2


Two to five percent of patients undergoing surgical resection for presumed malignancy are later discovered to have autoimmune pancreatitis.2,3 Some researchers propose that patients in this category have increased likelihood of postoperative complications such as diabetes and are at higher risk of needing additional invasive interventions later.6,8 Some of the major causes for the misdiagnosis of this condition are a lack of awareness of the disease or a widely accepted consensus of diagnostic criteria.6

CONCLUSION

Autoimmune pancreatitis is an under-recognized form of recurrent and chronic pancreatitis that can be medically managed. Though less prevalent than pancreatic carcinoma, it must be considered among the differential diagnoses for patients with questionable malignancy as early recognition may prevent unnecessary surgeries for presumed cancer. Distinguishing autoimmune pancreatitis from pancreatic carcinoma and other causes of pancreatitis remains a diagnostic challenge that requires a high index of suspicion along with a multidisciplinary approach. New diagnostic criteria
with increased sensitivity and specificity are needed to more definitively distinguish autoimmune pancreatitis from pancreatic carcinoma and to reduce morbidity and mortality.

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UNUSUAL CAUSES OF ABDOMINAL PAIN, #9

Unusual Causes of Abdominal Pain

August 2015 • Volume XXXIX, Issue 8
Stanley Yakubov,Rabin Rahmani

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Stanley Yakubov MD, Rabin Rahmani MD, Maimonides Medical Center, Brooklyn Campus of Albert Einstein College of Medicine, Brooklyn, NY

CASE

A 43 year old male with no past medical history presented to ER complaining of right lower quadrant pain for 3 days. He described the pain as sharp, constant, 8/10 in intensity, non-radiating, localized to the right lower quadrant, associated with nausea and worsened with coughing. He denied associated fevers, vomiting, diarrhea or constipation.

Vital signs on presentation showed temperature 98.1°F, blood pressure 130/84 mmHg, heart rate 80 beats/min, and respiratory rate of 20 breaths/min. On physical examination his abdomen was tense, non- distended, and normal bowel sounds were present. Patient was tender in RLQ with positive guarding, but no rebound. He was Dunphy’s sign positive. No tenderness at McBurney’s point noted. Rovsing’s sign, Obturator sign and Psoas sign were negative. No visible or palpable hernias were noted with and without coughing. The remainder of physical examination was unremarkable. Laboratory analysis showed a white blood cell (WBC) count of 9.5 K/Ul with 39% neutrophil count. The remainder of the laboratory tests were within normal limits. CT scan of Abdomen/Pelvis with contrast confirmed the diagnosis. Patient improved with conservative treatment and NSAIDS.

ANSWER AND DISCUSSION

Around 5% of all ER visits are due to a complaint of acute abdominal pain. Epiploic appendagitis (EA) also known as appendixes epiploica, hemorrhagic epiploitis, epiplopericolitis and appendicitis epiploica, is a fairly rare, benign condition of the epiploic appendages that occurs due to torsion or spontaneous venous thrombosis of a draining vein of the epiploic appendage. The resulting strangulation and inflammation leads to localized abdominal pain.

EA most commonly occurring in the second to fifth decades of life, with slightly higher incidence in middle aged males, although, it can affect anyone including young and healthy individuals. Obesity and heavy exercise are thought to be potential risk factors. First described by Vesalius in 1543, about 100 pedunculated fatty structures, also known as epiploic appendages, protrude from the serosal surface of the colon from the cecum to the recto-sigmoid junction. The average length of epiploic appendage is 3 cm, but can be as long as 15cm in length. Clustering in the sigmoid and cecal regions is what leads to the mistaken diagnosis of diverticulitis and appendicitis when the epiploic appendages become torsed or inflamed. Patients most commonly present with acute abdominal pain, more often in the left lower than right lower quadrant, without associated leukocytosis or fever. One-third of patients will have an elevated C-reactive protein.

EA is recognized and diagnosed with the use of ultrasound or CT scan, with CT scan being more sensitive and specific. EA should be entertained when diverticulitis, appendicitis and other causes of acute abdomen are ruled out. On CT scan EA presents as an oval shaped fat density, paracolic mass with fat stranding and thickened peritoneal lining. In addition, a central hyper-attenuating dot representing an engorged or thrombosed draining vein may be seen on CT. Complete resolution of symptoms typically occurs within 2 weeks with conservative treatment, primarily anti- inflammatory agents. No hospitalization or antibiotic use is required. Improved awareness of EA presentation as an acute abdomen will prevent unnecessary medical procedures and surgical interventions.

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A CASE REPORT

Staghorn Renal Calculus with Xanthogranulomatous Pyelonephritisand Renocolic Fistula

August 2015 • Volume XXXIX, Issue 8
Risheng Xu,Khawaja Azimuddin

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Risheng Xu, DO Former Triton Hospitalists at the Houston Methodist Willowbrook Hospital, University of Texas HSC at Houston Lyndon B. Johnson Hospital Academic Hospitalist Khawaja Azimuddin, MD FACS FASCRS Northwest Colon- Rectal Surgery Physician Association, Houston, TX

Reno-colic fistula is rare, and even fewer cases were reported in association with staghorn stones and xanthogranulomatous pyelonephritis (XGP). Here we present a case of reno-colic fistula initially presented as recurrent urinary tract infections (UTI) at outside facility and empirically treated with antibiotics without improvement. Patient was admitted to us and found to have staghorn renal calculus with renocolic fistula and pathology features of XGP. Renocolic fistulas complicating staghorn calculus and in association with features of XGP are rare. Although they may present as recurrent UTIs initially, further work up to rule out a fistula should be entertained as imagine modalities are limited in initial diagnosis of fistulas. A high clinical suspicion to rule out fistula should be kept when initial imaging shows staghorn calculus with XGP features. Repeat imaging with contrast is helpful in evaluating renocolic fistulas. Treatment involves nephrectomy with partial colectomy. Post operative prognosis is generally good.

INTRODUCTION

Renocolic fistula is a rare clinical entity. The initial presentation could be abdominal pain, hematuria, pyuria and flank pain which may mimic urinary colic secondary to nephrolithiasis or urinary tract infection. Here we present a case of a female patient initially diagnosed with urinary tract infection who was later found to have obstructive hydronephrosis due to large staghorn calculus, imaging features of xanthogranulomatous pyelonephritis (XGP) and renocolic fistula. She was subsequently treated with aggressive antibiotic therapy and surgical management with excellent recovery.

Presentation of Case

A 50 year-old female with remote history of nephrolithiasis presented to our hospital with a two- week history of dysuria, hematuria and abdominal pain radiating to the left flank. A few days prior to admission, she was seen at outside facility emergency department and was diagnosed with a urinary tract infection (UTI). She was given nitrofurantoin and discharged home. The patient completed the course of antibiotics but showed no clinical improvement and subsequently presented to our hospital for reevaluation. She denied fever and her abdominal exam was normal, except for left costovertebral angle percussive tenderness. On initial check, her white blood cell count was 10,000 with no left shift, and her urinalysis revealed 3+ protein, large blood, large leukocyte esterase, >200 WBC and 177 RBC with few bacteria and many white cell clumps. The patient had a non-contrast computed tomography (CT) of the abdomen and pelvis which showed a large, 4 cm staghorn calculus within left kidney, and an enlarged left kidney with hydronephrosis. Air was noticed within the inferior pole calices with surrounding perinephric fat stranding concerning for emphysematous pyelonephritis and features of XGP. Repeat CT with intravenous contrast revealed extrarenal extension of the infection into posterior perinephric and pararenal spaces and into the quadratus lumborum muscle with an abscess of 5.3 x 2.1 x 5.7cm. A percutaneous nephrostomy tube was placed. Post procedure imaging confirmed appropriate placement of the tube but contrast was noted to be in the descending colon (Figure 1) and in the previous abscess in the posterior abdominal wall, without apparent injury from nephrostomy tube.

Urine culture yielded Proteus mirabilis, which was empirically treated with broad-spectrum antibiotics. Given the imaging findings, exploratory laparotomy with left nephrectomy and segmental left colon resection was performed. The resected left kidney eventually showed XGP features on pathology. Cultures obtained during laparotomy subsequently grew Streptococcus bovis and Bacteroides fragilis. The patient tolerated the surgical procedure well, and no postoperative complications occurred. Eventually, antibiotics were simplified to oral ciprofloxacin and metranidazole and she was discharged from the hospital in ambulatory status. The patient was doing well 6 weeks post operatively.

DISCUSSION

Renocolic fistulas complicating XGP are rare. To our knowledge, less than 10 reports have been published thus far, and there is no large case series in English medical literature. Renocolic fistulas have been described since Hippocrates’ time in 460 A.D. Since its initial description, there have been more than 100 cases described.1,9 Many cases of renocolic fistulas were suspected to be secondary to chronic tuberculosis (TB) infections in pre-modern time.8 Modern cases of fistulas were associated with chronic XGP, nephrolithiasis, iatrogenic cause due to procedures, abdominal trauma and renal and colonic malignancy.9,10 Of these suspected causes of renocolic fistula, a majority of cases were reported with presence of XGP.

Xanthogranulomatous pyelonephritis was first described in 1916 by Schlagenhaufer.5 It is a variant of chronic pyelonephritis and is characterized by chronic inflammatory destructions of renal parenchyma and replacement with granulomatous tissue containing histiocytes and foamy cells. The exact etiology is unknown, but XGP is suspected to be caused by UTI, chronic urinary obstruction, hyperlipidemia, altered immune response, vascular occlusion and nephrolithiasis including staghorn calculus.1,2,3

XGP has a female prevalence, and has been reported to occur more in the 5 through 7th decades, but rarely in the pediatric population.1,4 Malek and Elder et al. have described a classification system of XGP (Chart 1). The exact pathogenesis of XGP causing renocolic fistula is unknown. It has been postulated that the chronic inflammatory and destructive process of the renal parenchyma and eventual perforation of the renal capsule with abscess formation and direct contact with colon is the cause of renocolic fistula.9

The clinical presentation of XGP is variable, mostly mimicking UTI symptoms, but the presence of gastrointestinal complaints rarely exist. Urinalysis usually shows pyuria and urine culture most commonly show E. Coli and Proteus mirabilis.1,6,7,8 Before the presence of effective tuberculosis treatment, many cases were associated with TB infection.9

Multiple imaging modalities have been used in the diagnosis of renocolic fistula, however yields have been limited. Intravenous pyelography (IVP) and contrast CT have been the most commonly utilized and reported imaging studies. Due to rarity and subtlety in clinical presentation, majority reported cases presented without initial radiographic evidence of fistula and XGP, and diagnosis was only confirmed on pathological tissues after nephrectomy.6,7 Retrograde pyelography has been reported to be helpful in confirming renocolic fistula.12 In our case, we were fortunate to have seen contrast in the perinephric space and descending colon as well as abscess formation within quadratus lumborum muscle.

The general treatment approach in patients with renocolic fistulas is to perform nephrectomy and partial colectomy simultaneously.1 Often, as in our case, treatment with broad spectrum of antibiotics may be necessary to stabilize or transition the patient to surgery.

CONCLUSION

Renocolic fistula complicated by XGP is rarely reported. Most cases of XGP were associated with obstructive nephrolithiasis and chronic UTI, especially in the presence of staghorn formation. Renocolic fistula should be considered in patients presenting with imaging evidence of XGP and staghorn calculus with recurrent UTIs. IVP and contrasted CT imaging have been reported in making diagnosis but with limited yields. When additional imaging is needed, retrograde pyelography has been reported to be helpful in confirming renocolic fistula. Nephrectomy and partial colectomy is the treatment of choice and usually with good clinical outcomes.

Acknowledgement

We would like to thank Houston Willowbrook Methodist Hospital Department of Radiology in helping with obtaining imaging used in this report.

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