Page 79 – Practical Gastro

Frontiers in Endoscopy, Series #9

Direct Percutaneous Endoscopic Jejunostomy: Who, When, How, and What to Avoid

February 2014 • Volume XXXVIII, Issue 2

While direct percutaneous endoscopic jejunostomy (DPEJ) is not yet widely practiced, advantages include longer durability compared to percutaneous endoscopic gastrostomy with jejunal extension (PEGJ) and less invasiveness than surgical methods with similar rates of complications. DPEJ placement does not require special equipment and is similar in technique to widely practiced percutaneous endoscopic gastrostomy (PEG), and thus should be more widely available. This article will review the current state of DPEJ, specifically addressing when and in whom it should be considered, the technical approaches to placement, and complications to avoid.

Introduction

Direct percutaneous endoscopic jejunostomy (DPEJ) was first described by Shike in 1987 as a method establishing long term enteral feeding in cancer patients with previous gastric resection.¹ DPEJ is an endoscopic procedure that places a percutaneous feeding tube directly into the jejunum similar to a percutaneous endoscopic gastrostomy (PEG) that places a feeding tube directly into the stomach. There are several approaches to long-term jejunal access, each with unique advantages and disadvantages (Table 1). Percutaneous endoscopic gastrostomy with jejunal extension (PEGJ) remains the most common endoscopic approach due to high reported initial success rates, but tube malfunction is common and requires frequent re-interventions. Percutaneous gastrojejunal feeding tubes are increasingly being placed fluoroscopically, which while not requiring sedation, does involve radiation exposure and may have similarly high tube malfunction rates. Direct percutaneous jejunostomy can also be performed through interventional radiology (IR-J), though there are only limited reports in the literature and it is not widely available.2 There are several surgical jejunostomy (SJ) methods including laparoscopic and needle-catheter techniques, which have success rates approaching 100%. However they require multiple skin incisions, general anesthesia, and if attempted laparoscopically may need conversion to open surgery.³ While DPEJ is not yet widely practiced, advantages include longer durability compared to PEGJ and less invasiveness than surgical methods with similar rates of complications. DPEJ placement does not require special equipment and is similar in technique to the widely practiced PEG, and thus should be more widely available. This article will review the current state of DPEJ, specifically addressing when and in whom it should be considered, the technical approaches to placement, and complications to avoid.

WHO
General Indications for Jejunal Feeding

General indications for jejunal feeding are the need to bypass the stomach due to gastric dysfunction or previous resection. Previous gastric resection can render the stomach dysfunctional both from impaired emptying and increased propensity to reflux. In addition, gastric resection may make the stomach difficult to access percutaneously. More specific indications for direct jejunal feeding include: gastric obstruction, gastroparesis, high risk of aspiration, previously failed gastric feedings, post-surgical or other anatomy that precludes gastric access, or need for jejunal decompression/venting. Gastrostomy is generally avoided in patients with anticipated esophagectomy due to concern that PEG may compromise the integrity of a future gastric conduit.^4,5

DPEJ Indications

Indications for DPEJ are summarized in Table 2. Maple et al. ⁶ reported the largest series of 307 patients undergoing DPEJ. In this report 28% of DPEJ were placed due to GI cancer, 21% for gastroparesis, 19% due to previous gastric surgery including partial or total gastrectomy and 13% due to high clinical risk of aspiration. The outcomes of DPEJ placement for specific clinical indications are summarized below.

Aspiration

Patients with recurrent aspiration pose a difficult challenge for clinicians and suffer high morbidity and mortality.⁷ Percutaneous gastrostomy has not been shown to decrease aspiration and aspiration pneumonia. In patients with a history of aspiration, recurrent aspiration after gastrostomy placement has been reported in 1162% of patients.⁸ Outcomes after PEGJ placement have also been disappointing with multiple studies unable to demonstrate decreased aspiration.^9,10,11,12 The poor results of PEGJ with recurrent aspiration may be explained by several factors: frequent PEGJ tube malfunction with clogging and proximal migration into the duodenum or stomach and possibly increased duodenal-gastric reflux due to an extension tube crossing the pylorus.

A few studies have reported decreased aspiration with direct jejunal feeding using SJ¹³ and DPEJ.^14,15 Panagiotakis et al.reported 11 patients who underwent DPEJ for recurrent aspiration.¹⁵ After DPEJ placement monthly aspiration events decreased significantly from 3.39 to 0.42. Another retrospective analysis compared 205 DPEJ and 58 PEGJ patients and reported aspiration in 18.1% of DPEJ vs. 31.0% of PEGJ patients though this difference was not statistically significant once adjusted for bed-bound status.¹⁶ In another report 16/18 patients with aspiration pneumonia who underwent surgical jejunostomy did not have recurrent aspiration.¹³ While the literature is limited, direct percutaneous jejunostomy feeding may reduce aspiration in high-risk patients.

Gastroparesis

Gastroparesis is a common indication for DPEJ placement.⁶ Good outcomes were recently reported in 14 patients undergoing DPEJ due to severe gastroparesis secondary to perioperative vagus nerve injury during lung transplantation.¹⁷ In these patients, DPEJ placement led to prolonged successful enteral feeding in 90% of patients. If PEG is required for gastric venting, a separate gastrostomy tube can be placed during the same procedure. Combined PEG/DPEJ has been shown to have decreased re-intervention rates and improved patient satisfaction compared to PEGJ alone.¹⁸

Chronic Pancreatitis

Up to 5% of patients with chronic pancreatitis will fail conservative treatment and are candidates for long term enteral feeding. In these patients, jejunal feeding provides nutritional support while minimally stimulating the exocrine pancreas. In one report, long term jejunal feeding in CP obtained by PEGJ or DPEJ decreased the percentage of patients with pain from 96% to 23% while increasing mean weight by 4.5kg over 6 months.¹⁹ A majority of the literature on jejunal feeding in pancreatitis has utilized PEGJ; however DPEJ has been reported successfully in patients with chronic pancreatitis as well.^20,21 While more studies are clearly needed, this preliminary data suggests that DPEJ may be an effective means for providing nutritional support in these patients.

Critically Ill Patients

Percutaneous feeding tubes are not often required in the critical care setting due to shorter length of stay, however indications for percutaneous jejunal feeding are similar to those in non-critically ill patients. Successful DPEJ use has been reported in 17 mechanically ventilated ICU patients requiring long-term jejunal feeding for previous aspiration pneumonia (9), failing gastric feeds (4), post-operative anastomotic leak (3) and duodenal obstruction (1).²² All had successful DPEJ placement with one complication of colonic perforation. The remaining 16 tolerated jejunal feedings at goal rates with no episodes of aspiration and 13 were ultimately discharged from the hospital with continued jejunal feedings.

Comparison of PEGJ vs. DPEJ

When considering long-term jejunal access, the endoscopist must choose between PEGJ and DPEJ approaches. PEGJ has higher reported success rates,^16,23 is generally considered less technically challenging, and is more widely taught in fellowship programs. However, with its longer and smaller caliber tube, PEGJs are prone to frequent clogging and tube migration. Fortunato et al. reported of 102 PEGJs in children, the mean number of jejunal tube replacements was 2.2 tubes per patient (range 1-14) with median tube functional duration of 39 days (range 2-274).²⁴ Tube failure was most commonly due to displacement (31%), clogged tube (22%), and mechanical failure (19%). Similarly high PEGJ malfunction rates were reported in a study following 75 adults with PEGJ placement over 9 months, 53% of patients had tube dysfunction and 41% of patients requiring tube removal or exchange.²⁵ A limited number of studies have directly compared PEGJ and DPEJ with results supporting longer durability and fewer malfunctions with DPEJ. Zopf et al. performed a retrospective analysis of 205 DPEJ and 58 PEGJ procedures and found that DPEJ functioned longer (272 days ± 414 vs. 130 days ± 223, p = 0.023) with less clogging (9.9% vs. 40%, p= 0.002) and tube migration (5.4% vs. 33.3%; p = 0.005).¹⁶ Fan et al. found that over 6 months follow-up, DPEJ was associated with signiﬁcantly longer feeding tube patency and less re-intervention (13.5% DPEJ vs. 55.9% PEGJ, p= 0.002).²³ These results are consistent with a retrospective study reported in abstract only demonstrating longer durability of combined PEG plus DPEJ compared to PEGJ alone.¹⁸ Finally a randomized prospective trial also reported only in abstract form reported fewer re-interventions and higher patient satisfaction with DPEJ over PEGJ.²⁰

DPEJ Contraindications

Contraindications to DPEJ (Table 2) are similar to PEG and include uncorrected coagulopathy (with standard threshold INR < 1.5 and platelets > 50,000), proximal GI obstruction that would prevent passage of the endoscope to the jejunum, and inability to oppose the small bowel to the anterior abdominal wall. Management of antithrombotics should follow published guidelines. PEG is considered a high-risk procedure for bleeding by the ASGE (American Society of Gastrointestinal Endoscopy) guidelines and similarly so should DPEJ placement.²⁶ Relative contraindications include severe obesity, peritoneal dialysis, ascites and neoplastic, inflammatory, or infiltrative diseases of the small bowel and/or anterior abdominal wall. In addition, other standard general contraindications to endoscopy apply as well.

WHEN

As recommended by ASGE Practice Guidelines²⁷ nasoenteric feeding is the preferred approach for patients expected to be able to resume oral feeding within 30 days. Therefore DPEJ should be considered in the management of patients with an indication for jejunal access expected to require enteral feeding for greater than 30 days.

If it is highly likely that jejunal feeding will be needed for > 30 days, it is not necessary to wait until then to place DPEJ. Alternatively, DPEJ placement is never urgently indicated and thus naso and oro-enteric feeding tubes can be used until clinical parameters are maximized for safe percutaneous placement or to determine if clinical improvement will eliminate the need for longer term jejunal feeding.

HOW
Pre-procedural Preparation

As an extension of ASGE guidelines for PEG, preprocedure laboratory evaluation is generally not required for DPEJ placement. Prophylactic antibiotics, typically cefazolin 1gm IV, are indicated unless the patient is already receiving other adequate antibiotic coverage. Anti-spasmodics such as glucagon and hyoscine can be used during the procedure to help reduce jejunal peristalsis. The procedure is performed with the patient in the supine position. DPEJ may be performed under conscious sedation, monitored anesthesia care, or general anesthesia. Procedure times are greater compared to PEG and therefore at our institution we now perform all initial DPEJ placements under general anesthesia to decrease aspiration risk during a prolonged procedure in the supine position. Use of CO2 for insufflation is also useful to reduce postoperative discomfort and risk of bowel over insufflation. Standard commercially available PEG kits can be used for the procedure with the only caveat that the looped guide wire and snare are long enough to pass through whatever enteroscope is used for the procedure. The authors most commonly use a pediatric colonoscope for DPEJ placement, but use of dedicated balloon and non-balloon enteroscopes have been reported as well.

Technique (see Figure 1)

DPEJ is technically similar to a pull PEG procedure with the main difference that additional procedural time is required to reach the small bowel and identify an appropriate area for direct jejunal puncture. The enteroscope is advanced into the jejunum and an appropriate puncture site is identified by observing transillumination of light in a discrete area on the anterior abdominal wall. To further confirm the site, external pressure using a single finger should produce a discrete indentation in the jejunal wall visualized by the endoscope. Both excellent transillumination and discrete ﬁnger indentation are required for safe jejunal puncture. After sterile skin preparation and local anesthesia, a sounding needle (typically 21 gauge 1.5-inch needle) is advanced into the jejunal lumen using the “safe-track” technique (see Table 4). Once visualized in the jejunum (Image 1), the tip of the sounding needle is immediately secured with a snare to prevent migration of the jejunum away from the abdominal wall. Using a scalpel, a stab incision is made immediately adjacent to the sounding needle and the larger trochar/needle cannula (~14 gauge) is inserted into the jejunum parallel to the sounding needle again using safe track technique and the snare is transferred from sounding needle to the trocar. From this point the procedure follows the same steps as a standard pull PEG technique. The looped guidewire is fed through the trochar, snared and withdrawn with the endoscope through the mouth. The jejunostomy tube is attached to the wire and pulled into place until the bumper is seated in the jejunum (Image 2). Endoscopic re-visualization can be performed at the operator’s discretion to conﬁrm placement, but is not necessary in uncomplicated procedures.

Leaving the jejunal port open immediately after successful placement facilitates small bowel decompression. Tube feeding can be initiated immediately at 25-50mL/hour and titrated to goal rate as tolerated. Feeding with standard polymeric formulas can be used in almost all patients unless there is concern for malabsorption or pancreatitis. There is little information regarding the time for secure adherence of the jejunum to the abdominal wall, thus it is advisable to wait at least 4 weeks prior to removal of a DPEJ. It is likely that mature stoma tract formation occurs much earlier unless the patient has poor wound healing from steroids, diabetes mellitus, immunosuppression, or severe malnutrition.

Success Rates

In the larger studies DPEJ success rates have ranged from 65-86% (Table 3).^6,16,28,30 Increased success is consistently reported in patients with prior gastric or esophageal resection. This is likely secondary to postoperative anatomy being conducive to passing the endoscope further into the small bowel and adhesions ﬁxing the jejunum to the anterior abdominal wall facilitating site identiﬁcation. In the largest series of DPEJ placement the most common reasons for failure were absent transillumination/finger indentation (20%), suboptimal transillumination/finger-indentation (5.5%), inability to reach the jejunum (2.6%), inability to pass the scope concomitant with failure to transilluminate (1.9%), and sedation complication (1.3%).⁶

As with other endoscopic procedures, DPEJ placement success appears to follow a learning curve. One study reported success rates of inexperienced operators (<66 procedures) was 63.7% compared to 77.5% and 74.5% in medium (67-187 procedures) and highly experienced endoscopists (>188 procedures) respectively.16 Obesity has also been shown to decrease successful DPEJ placement in two studies. The first reported patients with abdominal wall thickness on CT scan <3cm (vs. ≥3cm) had successful placement 73% vs. 39% (p= 0.003) of the time with no successful placements when thickness exceeded 4 cm.²⁹ In the second study, increasing BMI was directly associated with decreased success rates with BMI < 18.5 (96% success), BMI 18.5-24.9 (81% success), BMI 25-29.9 (73% success) and BMI > 30 (60% success).³⁰

If DPEJ is initially unsuccessful, PEGJ can be placed during the same procedure, although there is data that repeat DPEJ attempt under general anesthesia with a dedicated balloon enteroscope is often successful.³¹ A number of helpful hints have been described to aid in successful DPEJ placement (Table 5).

Adjunctive Techniques

Several adjunctive methods to the standard DPEJ technique described above have been reported. Adding fluoroscopy to the procedure allows confirmation that the endoscope has passed the ligament of Treitz and can be a useful tool to visually guide the sounding needle to the snare.³² A success rate of 97.5% was reported in a series of 40 patients utilizing the selective use of a 15 cm long drainage needle with intermittent fluoroscopic guidance.³³ The authors felt that using a longer needle facilitated deeper penetration in obese patients in whom traditional transillumination or jejunal indentation may not be feasible. The use of ultrasound during DPEJ has also been described to help delineate a targeted loop of jejunum, confirm close proximity to the anterior abdominal wall, and rule out intervening viscus when transillumination has failed. ³⁴ Routine use of fluoroscopy and ultrasound have not been widely adopted, but they remain useful modalities to consider in potentially difficult patients.

Perhaps the most promising adjuvant technique for DPEJ placement has been the use of single³⁵ and double-balloon enteroscopy (DBE). Song et al. reported a series of 10 patients who failed standard DPEJ with pediatric colonoscopes and subsequently underwent repeat DPEJ with DBE with 100% success.³¹ The reasons for initial failures were inability to transilluminate (5 patients), altered anatomy of efferent limb (3 patients), and limited endoscopic advancement due to looping and small-bowel angulation (1 patient each). The authors further reported 93% success (27/29 patients) utilizing DBE for initial DPEJ placements. In this series repeat DPEJ with DBE was performed under general anesthesia in almost all patients. The authors hypothesized that improved outcomes with DBE were due to the ability to pass further into the small bowel from reduced instrument looping and a more flexible tip on the DBE scope allowing passage through small bowel angulation and narrowing.

WHAT TO AVOID
Inappropriate Indications

DPEJ placement should be considered only with extreme caution for patients with small bowel motility disorders or for patients with eating disorders such as anorexia or bulimia, functional nausea or vomiting, or patients with chronic pain (Table 2). If there is concern that small bowel feeding would not be tolerated, a trial of nasojejunal feeding prior to more invasive DPEJ placement is warranted.

Complication Rates

Reported complications from the larger DPEJ studies are summarized in Table 3. Complications are generally rare, but severe adverse events reported in 2-6.3% of cases. These include jejunal volvulus, necrotizing fasciitis, bowel perforation, and bleeding. Small bowel volvulus is a potential complication of jejunostomy regardless of placement technique as the relatively unfixed small bowel can rotate around the single point fixation of the jejunostomy. Small bowel volvulus is likely less common in patients with previous abdominal surgery due to adhesions that may fix the small bowel at multiple locations. Use of T-fasteners to establish additional points of jejunal fixation near the site of the DPEJ may reduce the risk of jejunal volvulus. As noted previously obesity decreases success rates and it has 34 also been associated with a trend towards more adverse events. In one series the adverse event rate was 19% in patients with BMI > 25 and 4 of 5 severe adverse events also occurred in patients with BMI > 25.³⁰

CONCLUSION

DPEJ provides direct jejunal access without the morbidities of surgery. It should be considered whenever long-term jejunal access is required. The most common indications are altered gastric anatomy, gastroparesis, GI malignancies, and recurrent aspiration. Limited data suggests that DPEJ provides more reliable long-term functionality, fewer re-interventions, and decreased risk for aspiration compared to the more commonly practiced PEGJ. DPEJ use has been limited due to
perceived need for greater technical expertise, however
the procedure is very similar to the pull PEG technique with the distinction that greater time and caution is required while identifying the site for direct jejunal access. Placement success can be improved by using a number of helpful hints and adjuvant techniques including use of balloon enteroscopy. Complication rates are similar to other methods of direct jejunal feeding tubes and include volvulus, necrotizing fasciitis
and persistent jejunal fistula. At this time improvements
in DPEJ techniques and further prospective studies comparing DPEJ to other methods of jejunal access are needed, but present data suggest that DPEJ should be more frequently practiced.

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Inflammatory Bowel Disease: A Practical Approach, Series #87

Diagnosis and Management of Microscopic Colitis: A Review of the Literature

February 2014 • Volume XXXVIII, Issue 2

Jesse A. Green

The vague presentation of microscopic colitis is similar to celiac disease, irritable bowel syndrome (IBS), or inflammatory bowel disease (IBD). Its diagnosis can be complicated further with concurrent celiac disease or IBD. Treatment is usually aimed at shortening the duration of symptoms. In this paper we will discuss current methods of diagnosis, confounding issues, and treatment.

Introduction

The term microscopic colitis encompasses two separate diagnoses: lymphocytic colitis and collagenous colitis. The names describe the change to the colonic mucosa that is not due to an infectious cause, ultimately causing chronic watery, non-bloody diarrhea without other physical findings. It affects women more commonly than men and presents usually above the age of 65.¹ Microscopic colitis can be confused with diseases that present similarly, such as celiac disease, IBS or IBD.

A colonoscopy is often normal and biopsies of the colonic mucosa are required to make a definitive diagnosis. It is easy to distinguish collagenous colitis from lymphocytic colitis by the presence of a thick subepithelial collagen band whereas the telltale sign of lymphocytic colitis is infiltration of the colonic epithelium with lymphocytes. The two conditions under the umbrella of microscopic colitis have an association with other autoimmune disorders like celiac disease, rheumatoid arthritis, thyroid disease or diabetes mellitus. In patients with concurrent celiac disease or IBD, the diagnosis of microscopic colitis is often difficult. The goal of treatment is to shorten the duration and control symptoms and can be accomplished successfully in most cases.² In this paper we will discuss current methods of diagnosis, confounding issues and treatment.

Definition

Microscopic colitis is defined by symptoms of chronic, watery diarrhea without identification of an infectious cause, often without endoscopic lesions or radiographic findings but only with histologic abnormalities.^{3, 7}

Epidemiology

With increased awareness and improved diagnostic capabilities, microscopic colitis has become a common diagnosis. The incidence of microscopic colitis is 10/100,000 in the United States.⁴ Lymphocytic colitis is slightly more prevalent and has a 5.5/100,000 incidence,⁵ whereas collagenous colitis currently has an incidence of 4.6/100,000.⁶ The average age of diagnosis in microscopic colitis is 60-65 and patients older than 65 have five times the risk of developing microscopic colitis.⁶ The other risk factors for developing microscopic colitis include female gender, personal history of malignancy, hypothyroidism or celiac disease.⁶

Pathogenesis

The etiology is multifactorial and the exact mechanism remains unknown. However, it is believed that a dysregulated immune response to a luminal agent leads to reduced sodium and chloride absorption as well as active chloride secretion.⁷ The diarrhea can be defined as secretory. One study showed that the thick collagen band found in collagenous colitis may act as a diffusion barrier and down-regulate tight junction molecules.⁸ Medications that have been implicated in causing microscopic colitis include H2 blockers, PPI, SSRI’s, carbamazepine, simvastatin, and ticlopidine.^{9 10, 11} Lansoprazole, for example, a potent and commonly used PPI has been extensively studied for its association with microscopic colitis.^12,13,14 A case study of 850 patients who were switched from omeprazole to lansoprazole showed direct correlation of lansoprazole with intermittent diarrhea characterized as lymphocytic and collagenous colitis on histology. When lansoprazole was discontinued, follow-up biopsies revealed resolution with normalization of colonic histology.¹⁵

Clinical Findings

Symptoms may include some or all of the following: intermittent or persistent watery diarrhea, abdominal cramps, fecal urgency or incontinence, weight loss, or nausea. A complete history helps differentiate this disease from other causes of chronic, watery diarrhea. It is important to obtain a thorough medication list, which includes both prescription and over-the-counter drugs. Physical exam is usually unremarkable.

Laboratory markers are generally not useful for the diagnosis or for assessing disease activity. A stool sample should be collected as a first step. Although not routinely used for diagnosis, there are an increased number of CD3+ T cells found in the lamina propria and intraepithelial compartments in both lymphocytic and collagenous colitis.^{16, 17} There are no specific autoantibodies implicated as markers for microscopic colitis.¹⁸ Autoantibodies against GnRH or GnRH-R, seen in IBS are not frequently observed in microscopic colitis patients.¹⁹ Interestingly, there is an increased incidence of HLA DQ2 in both subtypes of microscopic colitis.

Diagnostic Modalities (Table 1)

The test of choice is a colonoscopy with biopsies. Histology of colonic biopsies which show inflammation of the mucosa and thickening of the subepithelial collagen layer, as in collagenous colitis, or an increase in the number of lymphocytes in the surface epithelium as in lymphocytic colitis.²⁰ Flexible sigmoidoscopy may be sufficient; however, negative findings do not exclude the possibility of this disease.²¹ It is important to take multiple biopsies throughout the colon, as collagenous and lymphocytic colitis may be patchy. However, greater than 90% of findings are present in the left colon.^{22, 23, 24}

Endoscopy and Pathology

Colonoscopy is usually grossly normal (figure A). However, a coarse and nodular surface of the mucosa may be seen in collagenous colitis. Erythema and tortuous vasculature with diffuse cloudiness of the mucosa have been noted in early development of collagenous colitis.²⁵ Mild edema and loss of vascularity can be seen (figure B). A “cat-scratch” appearance of the colonic mucosa may occur in collagenous colitis, further defined as “mucosal tears” (figure C).²⁶ This finding is explained by the barotrauma in the colon with decreased compliance due to the rigidity of collagen in the subepithelium. Histologically, collagenous colitis is described by colonic mucosal subepithelial collagen deposits 7-100 micrometers in diameter (figure D) (normal being 1-7 micrometers). Subepithelial collagen layer that is greater than 10 micrometers is a common finding. Lymphocytic colitis is characterized by mononuclear infiltrates with few neutrophils and eosinophils in the lamina propria and intraepithelial lymphocytes greater than 20 per 100 surface epithelial cells (figure E) (normal are 3-5/100 cells). Focal cryptitis (figure F) is sometimes present. Epithelial damage, such as cellular flattening and mucin depletion may occur.²⁷

Diagnostic Dilemmas and Associations with the Disease (Table 2)

Microscopic colitis may be diagnosed in patients with concomitant IBS, IBD or celiac disease. Others include chronic ischemia or infectious colitis, hyperthyroidism, carcinoid, VIPoma, or persistent NSAID. A‘quick way’to distinguish chronic diarrhea in a patient with microscopic colitis from a patient with IBD is the preserved mucosal architecture.²⁸ One study found that there is a 70-fold increase in risk for an individual with celiac disease to develop microscopic colitis when compared with the general population.²⁷ Concomitant celiac disease is present in approximately 5% of the patients with microscopic colitis.²⁹ IBD may have focal areas of microscopic colitis. It is more common to have concurrent autoimmune disease, including celiac disease, with collagenous colitis as compared to lymphocytic colitis (53% to 26% respectively).³⁰ Distinguishing celiac disease from microscopic colitis requires serological tests, such as anti-tTG antibodies.^{31, 33} Collagenous colitis must be differentiated from ischemic colitis, as both will demonstrate a thickening of the connective tissue band, seen with a three-color histologic staining protocol, [Masson’s trichrome].³¹ Collagenous colitis may be a systemic autoimmune disorder with extraintestinal manifestations such as arthritis and thyroiditis. A Duke study revealed an association between seronegative spondyloarthropathy with collagenous colitis in 7% of patients with confirmed collagenous colitis.³² There is an increased relative risk of lung cancer in women with collagenous colitis.³³ Smoking and chronic alcohol uses have been implicated as risk factors for development of microscopic colitis.³⁴

Management Goals and Treatment

Quality of life is directly proportional to disease activity in patients with microscopic colitis.³⁵ Clinical remission is not always associated with histological remission and relapses are common. The goal of pharmacological treatment is to improve symptoms while minimizing side effects.A treatment algorithm is outlined in Figure F. Prior to initiating pharmacologic treatment, it is important to remove any drugs that may be contributing to symptoms. Next, associated conditions should be properly managed. Dietary modifications are helpful in those patients who notice an association between certain foods. However patients with isolated microscopic colitis, sans celiac disease, do not adequately respond to dietary gluten withdrawal.³⁶ Symptomatic treatment with anti diarrheal agents such as loperamide is appropriate Colloidal bismuth, cholestyramine, sulfasalazine, and mesalamine may be added if diarrhea is not controlled. Failing these patients require systemic steroids, but they have a high chance of relapse following steroid cessation.^37,38,39 Budesonide is more effective and has fewer side effects. Oral budesonide is the first-line therapy to induce remission in microscopic colitis ⁴⁰ with more than 80% of patients experiencing clinical and histologic remission.²⁷ However, in unresponsive patients or those unable to tolerate steroids, immunosuppressive agents should be considered. Induction therapy with infliximab for 6 weeks and then maintenance with adalimumab every 2 weeks has been shown to be effective in refractory disease.⁴¹ Methotrexate and azathioprine have also shown efficacy in intractable disease.⁴²

Summary

Lymphocytic colitis and collagenous colitis can be both categorized under the general umbrella of microscopic colitis. Clinical symptoms include chronic, non-bloody, watery diarrhea and histologic findings of lymphocytic proliferation or collagen thickening in the colonoscopic mucosa. These diseases are thought to be autoimmune in origin and have associations with celiac disease, thyroid disease, and diabetes mellitus. The etiology still remains unclear. Goals of treatment remain the elimination of exacerbating factors and controlling symptoms.

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A Case Report

The Use of Epsilon Aminocaproic Acid in a Case of Massive Hemorrhage from Cytomegalovirus Colitis in a Patient with Multiple Myeloma Treated with Bortezomib

February 2014 • Volume XXXVIII, Issue 2

Steven D. Deas,Marc D. Hopkins,Louis M. Varner

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Introduction

Epsilon aminocaproic acid (EACA) blocks fibrinolysis by binding competitively to plasminogen and preventing binding to fibrin. It has been primarily used following thoracic surgery as an adjunctive therapy to help treat persistent postoperative bleeding.¹ We report a patient with lower gastrointestinal bleeding from cytomegalovirus (CMV) colitis who was treated successfully with EACA.

Case Report

A 56-year-old African American man presented to our medical center with a single episode of hematochezia associated with diffuse, cramping abdominal pain. The patient, who had been diagnosed with multiple myeloma several months before, had received two rounds of bortezomib and dexamethasone induction chemotherapy, and was hemodialysis dependent because of myeloma cast nephropathy. In addition to chemotherapy, he had received a single dose of radiation therapy to a lumbar vertebral lesion.

The patient’s medical history was otherwise significant for diabetes mellitus, hypertension and hypothyroidism. He was on insulin and antihypertensive medications as well as acyclovir and fluconazole for infectious prophylaxis while on chemotherapy. He reported no drug allergies. Though he had a history of heavy alcohol use over a period of decades, he quit drinking after he was diagnosed with myeloma. He denied tobacco or illicit drug use.

On presentation, he was tachycardic but normotensive and his physical exam was remarkable only for the presence of bright red blood in the rectal vault. He was noted to have a hemoglobin level of 7.5g/ dL (from a baseline of 10g/dL). His leukocyte count was 10,700 with a neutrophilic predominance and his platelet count was 241,000. He had a normal coagulation profile, blood urea nitrogen and transaminase levels. His alkaline phosphatase was mildly elevated, but stable over time.

After admission to the medical ward, he had several more episodes of hematochezia, which required transfusion of two units of packed red blood cells. Colonoscopy on the following day revealed discontinuous areas of non-bleeding ulcerated mucosa at the splenic flexure, the transverse colon and the ascending colon. The ulcers appeared superficial and irregular with normal intervening mucosa.

The differential diagnosis for hematochezia with ulcerated mucosa included infectious and ischemic colitis as well as inflammatory bowel disease. He had no history of previous bleeding or abdominal pain to suggest undiagnosed inflammatory bowel disease, and though he was on hemodialysis, had no significant hypotension to suggest ischemic colitis. He had received a single treatment of radiation therapy to a lumbar spine lesion in recent weeks, but the pattern of his disease was not consistent with radiation-induced injury to the gastrointestinal tract. Clostridium difficile toxin evaluation was negative. Therefore, due to the endoscopic appearance of the lesions, as well as his immunocompromised state, viral etiology was suspected.

Multiple biopsies were obtained and revealed marked acute and chronic inflammation with granulation tissue. Within the granulation tissue were a number of cells with atypical cytologic features including nuclear pleomorphism, irregular nuclear contours and nuclear hyperchromasia. Rare cells showed putative intranuclear inclusions. Though immunohistochemical studies for cytomegalovirus failed to highlight biopsied tissue, the lesions were highly suspicious for cytomegalovirus 50 (CMV) colitis and the patient was found to be CMV IgG positive. He was treated empirically with intravenous gancyclovir. CMV colitis often develops as a result of reactivation during immune suppression, but interestingly has never before been reported as an adverse effect of bortezomib therapy.

There was no active bleeding at the time of colonoscopy, however the patient developed repeated episodes of hematochezia the following day and ultimately required transfer to the intensive care unit and multiple transfusions of blood and blood products. Transfusion requirement eventually came to a total of fifteen units of packed red blood cells as well as multiple units of fresh frozen plasma and platelets. The surgical consultant felt that total colectomy carried a high risk in this patient with multiple co-morbid conditions and recommended supportive care and continued treatment with gancyclovir, while reserving colectomy as a last therapeutic option.

In an effort to limit blood product transfusions, he was treated with epsilon aminocaproic acid (EACA) which was dosed intravenously at 4 grams every twelve hours. On days of dialysis, it was dosed following the hemodialysis session. Following the initiation of EACA therapy, there were no further episodes of hematochezia for the remainder of his hospital course. EACA was discontinued and the patient was monitored for three days prior to discharge.

On the night after discharge, he experienced recurrent rectal bleeding and was readmitted. EACA was restarted and hematochezia improved. Repeat colonoscopy showed non-bleeding ulcerated mucosa throughout the entire colon which was improved from prior endoscopy as well as an actively bleeding ulceration in the proximal ascending colon with a bleeding vessel which was endoscopically treated with an injection of epinephrine and hemostatic clipping. Bleeding did not recur and he was discharged home.

Discussion

Epsilon aminocaproic acid binds competitively to plasminogen, blocking the binding of plasminogen to fibrin and subsequent conversion to plasmin, effectively inhibiting fibrinolysis. Adverse effects reported with EACA use include thrombosis, myalgia and myopathy and intrarenal obstruction from ureteral clots or glomerular capillary thrombosis. It is contraindicated for use in patients with disseminated intravascular coagulation or an active intravascular thrombosis.

In a recent Cochrane review of 16 trials in a total of 1035 surgical patients, it has been shown to reduce the need for allogeneic blood transfusions in the perioperative period, especially during cardiac surgery. In cardiac surgery, there also appeared to be a significant decrease in perioperative blood loss. While there was no significant improvement in mortality, there was no significant increase in rate of occurrence of myocardial infarction, stroke, or thromboembolism.² EACA has also been used successfully in the treatment of hemorrhage following complicated dental extractions,³ in patients with aneurysmal subarachnoid hemorrhage,⁵ recurrent epistaxis due to hereditary hemorrhagic telangiectasia,5 and in traumatic hyphema.⁶

The use of oral EACA in radiation-induced hemorrhagic gastritis has been described in a single case report,⁸ but until now there are no reported cases describing the use of EACA in hemorrhage from a lower gastrointestinal source. In patients with diffuse hemorrhagic colitis, in which endoscopic therapy is not adequate and surgery is not a preferred option, treatment with EACA may be an additional treatment strategy to reduce the need for the transfusion of blood and blood products. Further study is needed to determine the true efficacy and safety of EACA in gastrointestinal hemorrhage.

The opinions or assertions herein are the private views of the authors and are not to be construed as reflecting the views of the United States Air Force or the Department of Defense.

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A Case Report

Epiploic Appendagitis: Underappreciated, Easily Misdiagnosed and Often Masquerading as an Acute Abdomen

January 2014 • Volume XXXVIII, Issue 1

Stanley Yakubov,Po Cheng Chu,Kadirawel Iswara,Ira Mayer

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Introduction

Epiploic appendagitis (EA), also known as appendicitis epiploica, is an uncommon, benign condition of the epiploic appendages that occurs due to torsion or spontaneous venous thrombosis of a draining vein.³ The resulting strangulation and inflammation leads to localized abdominal pain.⁵ Moreover, EA is a self-limited condition that often mimics other serious surgical conditions such as acute diverticulitis, appendicitis and even cholecystitis.³ We report a case of left lower quadrant pain presumed to be acute diverticulitis with possible abscess formation and diagnosed as epiploic appendagitis by computed tomography (CT) scan of abdomen/pelvis.

Case Description

A 44 year-old male with past medical history of gastroesophageal reflux and peptic ulcer disease presented with four days of severe left lower quadrant abdominal pain, nausea and constipation. At the onset of his symptoms he was seen at a local emergency department (ED) where he was diagnosed and treated for presumed diverticulitis with metronidazole and ciprofloxacin. However, the pain subsequently worsened and he was referred to our institution for evaluation and treatment.

His vital signs upon arrival in the ED were a temperature of 97.4°F, blood pressure 110/71 mmHg, heart rate 67 beats/min and respiratory rate of 18 breaths/min. He described his pain as sharp, 10/10 in intensity, localized to left lower quadrant (LLQ), non-radiating and it was associated with nausea, but no vomiting. On physical examination his abdomen was tense, non-distended, tender in the LLQ with positive guarding, but no rebound and normal bowel sounds were present. Laboratory analysis showed a white blood cell (WBC) count of 6.7 K/Ul with 67% neutrophils. The remainder of the laboratory tests and physical exam were unremarkable.

He was started on broad-spectrum antibiotics for presumed diverticulitis with possible abscess formation, and he was given morphine for symptomatic relief. CT scan of abdomen/pelvis with contrast was performed showing an oval-shaped fat density (Figure 1) in the left lower quadrant anterior to the sigmoid colon characteristic of epiploic appendagitis. His clinical presentation improved with conservative treatment including non-steroidal anti-inflammatory drugs (NSAIDs) and he was discharged home after resolution of his symptoms.

Discussion

Epiploic appendagitis can affect anyone including young and healthy individuals, although obesity and heavy exercise are thought to be potential risk factors.² It most commonly occurs in the second to fifth decades of life, with slightly higher incidence in middle aged males.^1,3 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.³ In 1956, Lynn et al. created the term epiploic appendagitis to describe inflammation of epiploic appendages.¹ The size and number of epiploic appendages increase in the lower abdominal quadrants, with the sigmoid colon accounting for approximately 57% of epiploic appendages, followed by the cecum 26%, ascending colon 9%, transverse colon 6% and descending colon 2%.⁴

EA can be either primary or secondary. Primary EA is caused by torsion or spontaneous venous thrombosis of a draining vein of the epiploic appendage.¹ Secondary EA is related to lymphoid hyperplasia or is secondary to an inflammatory process in adjacent organ such appendicitis, diverticulitis, cholecystitis or colitis.⁴ Patients most commonly present with acute abdominal pain, more often in the left lower than right lower quadrant, without associated leukocytosis or fever.¹ Our patient presented with the classic presentation of EA. It 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. EA appears on CT as an oval-shaped fat density (Figure1), paracolic mass with fat stranding and thickened peritoneal lining.² Complete resolution of symptoms typically occurs within two weeks with conservative treatment, primarily anti-inﬂammatory agents.⁴

CONCLUSION

The infrequency of epiploic appendagitis makes this condition an unusual and difﬁcult diagnosis for many physicians. Therefore, improved awareness and recognition of EA can lead to fewer misdiagnoses, thereby decreasing redundant medical procedures as well as unnecessary surgical interventions.

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Epidemiology of Gastrointestinal Cancers, #2

Changing Epidemiology of Esophageal Cancers Worldwide – What Do We Learn?

January 2014 • Volume XXXVIII, Issue 1

Janeesh Sekkath Veedu,

C.S. Pitchumoni

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Here we report the incidence of esophageal cancer (EC), the tenth most common and the eighth most deadly type of cancer worldwide with more than 80% of deaths in developing countries. The epidemiology of EC has undergone a dramatic downward shift worldwide in the last 30 years. The aim of this review is to summarize important epidemiological data that has widespread clinical implications.

INTRODUCTION

Esophageal cancer (EC) is the tenth most common and the eighth most deadly type of cancer worldwide with more than 80% of deaths in developing countries.¹ The epidemiology of EC has undergone a dramatic downward shift worldwide in the last 30 years. EC is primarily of two distinct histological subtypes: squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). The major differences between ESCC and EAC are summarized in Table 1. ESCC was the dominant subtype in most areas of the world, although the dominant histologic subtype of EC in the Western world is currently EAC,^2,3 attributed to an increase in the incidence of Barrett’s esophagus (dysplastic gastric epithelium in the squamous esophagus), in the last three decades,⁴ ESCC accounted for greater than 90% of all ECs in the 1970s. The incidence increases with age, EAC occurring on an average 10 years earlier than ESCC. The other rare histological subtypes include small cell carcinoma, melanoma, carcinoid tumor, choriocarcinoma and metastatic diseases from lymphomas and sarcomas (Table 2). The aim of this review is to summarize important epidemiological data that has widespread clinical implications. The search of literature was made using PubMed and Google Scholar with the following keywords- esophagus, cancer, incidence, epidemiology and only publications in English language, selected based on their merit, were included.

Global Epidemiological Trends

Large differences in incidence exist between Asian and Western populations, and between countries, up to 500 fold,⁵ (Figure 1) and even within a particular country. The estimated worldwide incidence of EC was 455,784 in 2012 with 400,156 deaths and is expected to be around 576,000 in 2015 with 486,000 deaths.⁶ The highest rates in both males and females were found in Southern and Eastern Africa and Eastern Asia with lowest rates observed in Western and Central America⁶ (Fig.1). West Africa and Middle Africa have very low rates, which are in sharp contrast to Eastern and Southern Africa. An esophageal cancer belt (EC belt) with the highest incidence rates for ESCC in the world⁵ – exists in an area that extends from the border of the Caspian Sea and Turkey through the Southern republics of the former Soviet Union and into Northern China (Fig 2). Malawi has the highest incidence and mortality in the world followed by Turkmenistan6 (Table 3). Among the developed nations, Australia and New Zealand have the highest rates followed by North America, Central and Eastern Europe.

The incidence as well as mortality has drastically decreased in China, Hong Kong, Japan, Korea and Singapore while it is increasing in Taiwan and Vietnam. Cixian county in China has one of the highest rates of incidence in China and the world.⁷

Epidemiological Determinants

Substantial differences exist in the incidence of EC based on gender, ethnicity, country of origin, dietary habits and environmental factors.

Gender

In the West men develop ESCC three to four times more often and EAC six to eight times more than women.⁴ Interestingly there has been a large decrease in the male to female incidence rate ratio (IRR) of ESCC among all ages and particularly in age group>70.⁸ There is a steady and substantial decline in sex ratio with increasing age in EAC, unrelated to menopause.⁹ Incidence in women is 5.1 times that of men in the US.⁶ The rapid increase of EC, currently in the top ten by incidence from 1975-2004⁸ is due to the increase in men more than women,⁸ even though EAC is rapidly increasing among white women similar to white men.¹⁰ The highest mortality rates among both sexes are found in Eastern and Southern Africa, and in Eastern Asia. South Asian women had a higher risk than men with a six-fold difference in risk between Pakistani and Bangladeshi women, whereas there was no difference by sex in Blacks or Chinese.¹¹

The pathogenesis for a higher incidence of EC in men is speculative. Risk factors, like estrogen exposure, BMI and H.pylori infection, have provided no evidence of causing the sex ratio imbalance.⁸ Estrogen in women as a protective factor has long been postulated without convincing data. Studies of hormone replacement therapy,¹² including estrogen therapy,¹³ and childbearing,¹⁴ did not support estrogen theory, although breast feeding was found to be protective.¹³ Estrogen receptors in esophageal tissue have been identified, and in vitro studies indicate that estrogens might inhibit esophageal carcinogenesis.¹⁴ Erosive GERD may be more prevalent in younger men compared to women.¹⁵ Other differences between the sexes that may explain the higher incidence of EAC include android obesity (abdominal or metabolic obesity), and factors that promote GERD.^16,17 The epidemiological differences in the prevalence of premalignant lesions between both genders is elaborated under Barrett’s esophagus.

Esophageal Squamous Cell Cancer

Currently ESCC is predominantly a disease of the developing world (90% of EC) with a majority of cases in the cancer belt. There are also areas of high incidence of ESCC in industrialized countries, including northwestern France, Iceland, Scotland, and Finland. In the UK, Bangladeshis had a six times higher risk of ESCC compared to Pakistanis.¹¹

The incidence of ESCC is higher in males than females and higher in black men than white men.¹⁸ Higher BMI, in sharp contrast to EAC is considered as protective factor for ESCC. Red meat, lamb, and boiled meat and higher drinking temperature¹⁹ were found to be associated with the risk of ESCC, whereas fruits and vegetables, white meat, poultry, fish, and liver were protective for unclear reasons.²⁰ Fungal-contaminated, various nitrosamine-containing food stuffs and hot beverages, spicy food,²¹ deficiency of β-carotene, vitamin A, C and E and minerals zinc, selenium and molybdenum as risk factors for EC have been studied.²² Tylosis, a rare disorder associated with hyperkeratosis of the palms of the hands and soles of the feet, is associated with high incidence of ESCC.¹⁸

In the United States there is a higher incidence in coastal South Carolina and metropolitan Washington D.C./Baltimore compared to other states.¹⁸ Tobacco smoking and alcohol consumption are major risk known factors for ESCC in US, explaining over 90% of cases in men²³ and to a lesser extent EAC.

Acetaldehyde, the primary metabolite of ethanol forms adducts with DNA and this adduct is responsible for the carcinogenic effect of alcoholic beverages.²⁴ Patients with ESCC, particularly alcoholics, current smokers, and those with the ALDh3-2 allele and multiple Lugol-iodine staining lesions on endoscopy, have an increased risk of superficial head and neck squamous cell carcinoma.²⁵ Previous history of lye ingestion is well known to cause strictures and ESCC with incidence varying from 2.6 to 7.2% in the tracheal bifurcation.²⁶ There is a 1000- to 3000-fold increase in the incidence of EC after lye-ingestion with a latent period as long as 60 years.²⁷

The risk of developing EC is higher in celiac disease with the age-adjusted incidence rates esophageal cancer being 50 per 100,000 person-years (normal, 3.9).^28,29 However current data shows that this risk is only short term mostly in the first year of diagnosis.³⁰ Achalasia is associated with the development of EC, even though the risk is low.³¹ Brucher et al reported EC to occur in achalasia patients 140 times the rate compared to the general population.³²

Esophageal Adenocarcinoma

Major risk factors for EAC are BE (a metaplastic change of the normal stratified squamous cells of the the lower esophageal sphincter (e.g., nitro-glycerin, esophagus to specialized columnar epithelial cells),³³ anticholinergics, beta agonists, and benzodiazepines) GERD, overweight and obesity among others. The increase the risk of BE and hence EAC.38 growing epidemic of obesity parallels the increase The absolute risk of EAC in Barrett’s is in the incidence of GERD and the rise of EAC.³⁴ controversial. As the only known premalignant lesion, The previously observed increase in EAC incidence it is recognized as a precursor of the majority of cases might have slowed now³⁵ possibly due to a change of EAC39 with a 30-125 higher risk than in the general in the natural progression of Barrett’s or an increased population.40 The risk for conversion from BE to EAC exposure to protective factors.³⁵ Aspirin and PPI use is 0.5% per year, and is thought to occur up to 15 years have been reported to decrease the risk of transition after diagnosis.10 The diagnosis and management of from BE to EAC^36,37 while drugs known to relax the lower esophageal sphincter (e.g., nitro-glycerin, anticholinergics, beta agonists, and benzodiazepines) increase the risk of BE and hence EAC.³⁸

The absolute risk of EAC in Barrett’s is controversial. As the only known premalignant lesion, it is recognized as a precursor of the majority of cases of EAC³⁹ with a 30-125 higher risk than in the general population.⁴⁰ The risk for conversion from BE to EAC is 0.5% per year, and is thought to occur up to 15 years after diagnosis.¹⁰ The diagnosis and management of high grade dysplasia (HGD) in patients with Barrett’s esophagus is extremely controversial.⁴¹ Lesions in a good number of patients with high-grade dysplasia may even regress or persist and not develop cancer, the basis of recommendation for a less aggressive approach in management.⁴¹ Since BE is a strong risk factor for EAC, endoscopic screening of patients with Barrett’s has been advocated by many.^42-44 However, the US Preventive Services Task Force has not published any guidelines for or against screening of EAC.

Earlier studies which created an alarming picture of BE and EAC appears to be exaggerated. A systematic review of 47 studies showed the overall incidence of BE to be 6.1 cases per 1000 person years.^45-44 The absolute risk of EAC after a diagnosis of BE, in recent studies was several times lower, up to 4 to 5 times, than the risk reported in previous studies, which forms the basis for current surveillance guidelines.^46,47,48,49 The risk of EAC among patients with BE may be small that in the absence of dysplasia, routine surveillance of such patients is of doubtful value^50-52 (Table 5).

The impact of widespread use of Proton Pump Inhibitors (PPIs), on the increasing incidence of BE is contradictory. PPI treatment provides the short term benefit of symptom reduction and healing of esophagitis, and probably a long-term chemoprevention benefits of reduced progression of dysplasia and cancer.⁵³ High dose of PPI therapy for up to 5 years gives variable results and benefits.^54-56,57-61 In a 13 year prospective study of 188 patients on PPI treatment the incidence of EAC was 0.31%, which is among the lowest incidence recorded in patients with BE undergoing endoscopic surveillance.⁶² In contrast, patients treated with PPIs with mild or absent GERD symptoms were found to have significantly higher odds of EAC compared with severe GERD symptoms.⁶³

The incidence of EAC seems to parallel the rising epidemic of obesity since the mid-70s.⁶⁴ The rise in obesity accounted for 6.5% increase in EAC that occurred from 1973 to 2005 and 7.6% in the year 2005.⁶⁵ Obesity-associated EAC risk was found to be higher among men than women.⁶⁶ The positive association between increasing BMI and GERD in the USA is not consistently seen in other countries.^67,68 BMI solely may not be a risk factor for Barrett’s¹⁶ pointing more towards android obesity as the risk factor. Abdominal obesity appears to increase the risk of BE whereas gluteofemoral obesity protective.⁶⁹ Diabetes may be a risk factor for BE, independent of obesity and other risk factors.⁷⁰

Helicobacter pylori (H. pylori), a gram negative bacterium, has been studied worldwide and in individuals of all ages in various diseases. Conservative estimates suggest that 50 percent of the world’s population carry H pylori, predominantly in developing countries where water supply and sanitation are inadequate. H. pylori infection is a well known risk factor for gastric malignancy with a risk of up to 6 times that of the normal population.⁷¹ Additional data will be discussed in the next paper on gastric cancers in this series.

The recent advances in treatment of H pylori, a gastric carcinogen, and its effective eradication are postulated to be one major reason for the increase in EC.^2,72,73 Chronic H. pylori infection results in atrophic gastritis, decreased acid production, and thus a lower likelihood for severe GERD. H. pylori infection is associated with lower rates of Barrett’s and EAC, in particular the more virulent CagA-positive strain of the bacteria,⁷⁴ which are associated with a higher frequency of gastric cancer.⁷⁵

Geographical Analysis

United States of America

The US ranks 67 in the incidence of EC in the world,⁶ which is a significant drop from 20 in 2002. It is estimated that there will be 18543 (men 14799 and women 3744) new cases of EC in 2015 with 17469 deaths (men 14055 and women 3414).⁷⁶ According to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) registry data, the incidence of EAC has increased 5-fold in the past 3 decades.⁷⁷ The incidence of ESCC was the highest three decades ago, at about 21 per 100,000 and has decreased by more than 60% since then to 7.6 per 100,000 in 2002.⁷⁸ ECr represents 1.1% of all new cancer cases in the U.S.⁷⁹ Rates for new EC cases have been falling on average 0.9% each year over the last 10 years. Death rates have been falling on average 0.6% each year over the same period. The number of new cases of EC was 4.4 per 100,000 per year with number of deaths 4.3 per 100,000 per year.⁷⁹

The incidence and mortality of EC has been increasing among white men, stable among white women, and decreasing in black men and women.⁸⁰ White men have the highest incidence of EAC while black men had higher rates of ESCC¹⁰ which has been declining in the recent past.^4,34,81,82 The incidence of EAC although low among African Americans has increased from 0.4/100,000 to 0.9/100,000 among men and 0-0.2/100,000 among women.⁸³ There is a wide geographic variability in incidence rates and trends, especially for EAC in males: age standardized rates were highest in the Northeast (17.7 per 100,000) and Midwest (18.1) with both being significantly higher than the national estimate (16.0). In addition, the Northeast annual percent changes (APC) were 62% higher than the national estimate (3.19% vs. 1.97%). Lastly, incidence rate ratios (IRRs) remained fairly constant across calendar time, despite changes in incidence rates.⁸⁴

Overall incidence of EC is higher among African Americans than Whites (8.4 vs. 8.0 cases per 100,000 persons). Among African Americans, ESCC remains the predominant subtype who have EC rates six times higher than whites.⁴ This rate is seen despite the fact that GERD is equally prevalent in blacks than whites in the United States.⁸⁵ Survival rates by ethnicity also reveal differences, the 5-year survival rates (%) between whites and African Americans with localized lesions being 36% versus 20% and regional lesions 18% versus 11%.⁸⁶

Europe

UK has the highest age standardized rate (ASR) in Europe (6.5) followed by The Netherlands (6.3). The incidence rates for EC in the UK, France, Portugal, Spain, Germany, Belgium, Italy, Denmark, Netherlands, and Greece for the periods 1960 to 1964 to 1985 to1989⁸⁷ and Finland⁸⁸ had been increasing and that ESCC had been overtaken by EAC as the leading histologic subtype.^87,88 A recent study of (n=43,753) which examined the incidence rates of EAC in England and Wales between 1971 and 2001⁸⁹ found that the age standardized rates increased rapidly by 39.6% and 37.5% for men and women, respectively.⁸⁹ This increase was seen among different socioeconomic levels; those in the more affluent groups had a higher incidence of EAC compared to others.⁸⁹ EC incidence in South-Asians and Blacks is lower, compared to whites, by approximately two and one third respectively.⁹⁰ In Sweden, EC and gastric cancer have not been increasing since 2005, compared to an increase during the period 1970-2000.⁹¹ In UK ‘non-White’ groups had a lower incidence of esophageal, colorectal, and pancreatic cancer compared to Whites and a higher incidence of liver and gallbladder cancer.¹¹ Differences in risk between Indians, Pakistanis and Bangladeshis for cancer of the esophagus, stomach, liver and gallbladder exist. Whites had the highest incidence of EC (5.8) followed by Indians and Bangladeshis. Interestingly Chinese in England had a low rate compared to whites and Indians.¹¹ The lower incidence in all ethnic groups compared to Whites was largely due to their lower incidence of EAC rather than of ESCC. The rates of EC among South Asians were lower than both their countries of origin and whites in the UK.^{11, 90}

Iran

Iran, a country with different ethnic groups, has one of the highest incidences of EC. The high incidence of the disease in particular in the north of the country provides an opportunity as well as a challenge to understand the pathogenesis of the disease and possible preventive measures.^92-94 EC is now only the 6th most frequent malignancy in Iranian males, a drop from 2nd and 4th among women, a drop from 3rd. In one survey by the Iran cancer institute, 9% of all cancers and 27 % of gastrointestinal cancers were esophageal. ESCC is the most common accounting for 90% of cases. Age adjusted incidence rate of ESCC in the province of Golestan and further to the East was one of the highest for any single cancer that has been reported worldwide. The infamous Asian EC belt extends to the east from the Caspian littoral area in Iran through Turkmenistan to the northern provinces of China. Other parts of Iran have variable rates of EC from 3 to 15 cases per 100,000 population.

The exact etiology for this high incidence is speculative.^74,95 Consumption of wheat flour, exposure to residues from opium pipes, drinking hot tea and chewing NASS (a mixture of tobacco, lime hash and other ingredients) are often suspected.⁹⁶ A family history of EC, low socioeconomic status, and malnutrition are additional suspected factors. Investigating the association between tea drinking habits in Golestan and risk of EC, Islami and associates noted that nearly 98% of the study cohort drank black tea over 1 liter a day and 39% drank tea at temperature < 60 degree Celsius, 38.9 at 60-64 and 22% at higher temperature. Drinking very hot tea is a noted association with the increased risk of EC. The high prevalence of Human Papilloma Virus DNA in different anatomical sites of ESCC patients from Mazandaran region in north of Iran suggests a role for HPV. ⁹⁷

Genetic factors are also suspected to play a role. Ten genes (CYP1A1, CYP2A6, CYP2E1, GSTM1, GSTP1, GSTT1, ADh3, ADH3, ALDh3, and O6MGMT) are suspected to have a role in risk for EC among three Iranian ethnic groups with varying rates of EC. The high risk patients from Golestan province had higher frequency of four alleles speculated to favor carcinogenesis (CYP1A1 m1, CYP1A1 m2, CYP2A69, and ADh31).⁹⁸ Despite a genetic predisposition EC rates, for reasons not clear, have decreased sharply in the recent past even in the high incidence areas.⁹⁹

China

China has one of the highest incidences of EC in the world with a very high mortality rate. The age-standardized mortality decreased by 41.6% from 1973 to 2005.¹⁰⁰ EC is the 4th most common cause of cancer death with the crude mortality rate in 2004–2005 being 15.2/100,000, which represented 11.2% of all cancer deaths.¹⁰¹ The age-standardized mortality of EC per 100,000 was 18.1 for men and 8.2 for women in China, compared to 8.5 and 3.4 in the world, 4.9 and 1.0 in United States, for men and women, respectively.¹⁰² China being a vast country, there is a huge geographic variation in the incidence. The six high-risk areas include Cixian and Shexian in Hebei Province, Linzhou in Henan Province, Yangcheng in Shanxi Province, Nan’ao in Guangdong Province and Yanting in Sichuan Province.¹⁰³ Large cities like Shanghai and Beijing have experienced a greater decrease in EC incidence over the past several decades, when compared with rural areas such as Cixian.¹⁰⁴ According to the Shanghai cancer registry data, the incidence of EC had signiﬁcantly decreased, by 59%, between 1975 and 1988.¹⁰⁵ The current ASR of EC in China is 6.7/100,000.⁶

Tobacco smoking, alcoholism, low intake of vegetables and fruits were responsible for 46% of EC mortality (87,065 deaths) and incidence in 2005.¹⁰⁶ About 17.9% of EC deaths among men and 1.9% among women were attributable to tobacco smoking, about 15.2% of EC deaths in men and 1.3% in women to alcohol drinking, and 4.3% EC deaths in men and 4.1% in women to low vegetable intake. The fraction of EC deaths attributable to low fruit intake was 27.1% in men and 28.0% in women.¹⁰⁶ However several other epidemiological studies done in high risk areas contradict the above and have shown that smoking and alcohol drinking play a much less signiﬁcant role in the etiology of EC.^{107, 108}

In high-risk areas, with endoscopic screening and cytology, precursor lesions such as dysplasia may be detected in asymptomatic individuals with early-stage cancer.¹⁰⁹ Squamous dysplasia was strongly associated with ESCC risk; the relative risk (RR) being 28.3 for persons with severe dysplasia as compared to normal subjects.¹¹⁰ A map of China is provided that highlights the high risk EC areas. In Linxian province general malnutrition, and deﬁciencies in selenium, zinc, folate, riboﬂavin, and vitamins A, C, E, and B12, were associated with an increased risk of ESCC.¹¹¹ Environmental carcinogens were found in high concentrations of nitrates and nitrites, the precursors of nitrosamine, in drinking water samples, and nitrosamine in food samples was noted.¹¹² High concentrations of nitrate nitrogen in well water correlated with ESCC incidence in two studies.^{113, 114}

There was no significant increased risk of ESCC among individuals infected with H. pylori.¹¹⁵ Drinking tea at a high temperature signiﬁcantly increased risk of EC, after adjustment for confounding factors, including alcohol consumption and cigarette smoking.¹¹⁶ Human papilloma virus (HPV) infection, and especially HPV 16/18 E6/E7, with gene mutations and association with p53 overexpression, may contribute to the extremely high incidence of ESCC observed in Xingjian.¹¹⁷

Genetic polymorphisms, including CYP1A1, CYP2E1, and MTHFR, have been associated with ESCC risk in the Chinese population.¹¹⁸ Three genome-wide association studies of EC published since 2010 was consistently identiﬁed 10q23 as a susceptibility locus for ESCC.^119-121

Japan

EC is the 12th most common malignancy and the ninth most common cause of cancer death in Japan, with an estimated 19683 new cases and 12440 deaths in 2012.⁶ ESCC remains the predominant type with no dramatic increase in EAC.¹²² The age-adjusted incidence rate (per 100,000 population) increased from 8.3 to 11.7 during the period 1975–2006 among men but changed little among women, who had an estimated rate of approximately 1.5 during that period.¹²³

Alcohol consumption and cigarette smoking are two major risk factors for EC with prevalence of current drinking being 36.4% among men and 6.9% among women¹²⁴ and smoking being 38.2% in men and 10.9% in women.¹²⁴ Alcoholics had a 3.3-fold increased risk as compared with non-alcoholics and there is also a dose-response relationship between the amount of alcohol consumed, frequency of consumption, and ESCC risk.¹²⁵ In a study on genetic polymorphisms of alcohol-aldehyde dehydrogenases and glutathione S-transferase M1 and drinking, it was clearly evident that drinkers who were ALDH*1/2 heterozygotes had a signiﬁcantly increased risk of developing ESCC.¹²⁶ Both smokers and drinkers had more than 100-fold the risk of developing ESCC that was associated with genetic risk- ADH1B and ALDh3.¹²⁷ Genetic polymorphisms in alcohol- metabolizing genes, DNA repair genes, and folate-metabolizing genes were linked to ESCC risk.^128,129

The association of diet or eating habits and ESCC risk is not convincing.¹³⁰ The Japan Public Health Center-based Prospective Study examined the relationship of fruit and vegetable intake with ESCC and showed that a 100-gram per day increase in consumption of total fruit and vegetables was associated with an 11% decrease in ESCC incidence.¹³¹ Interestingly the study did not show any ESCC risk with intake of pickled vegetables. An inverse association between yoghurt intake and ESCCis seen and was also shown with EAC in a previous study in Europe.¹³² A strong, positive association between gastric atrophy and ESCC risk has been shown in three studies.^133-135 Interestingly there has been no study on the association between Helicobacter pylori and ESCC in the Japanese population.¹³⁰ Less Known Risk Factors- New But Not Established

India

In India, a country with diverse populations and lifestyles, the rates for EC vary across regions and ESCC is the predominant type (Table 4). The estimated incidence of EC in 2012 was 41774 with an ASR of 4.1/100,000 among both sexes with a higher incidence in men (ASR=5.4/100,000). The projected incidence in 2015 is 59420 (35513 in men and 23907 in women. The highest rates were observed in Chennai in South India among men (ASR = 8.4 per 100,000) and in Bangalore among women (ASR = 7.5 per 100,000).¹³⁶ In the ﬁnancial capital, Mumbai, the rates are 6.1 and 4.4 per 100,000among men and women, respectively.¹³⁶

The Kashmir valley warrants special mention as it is on the southern border of the ‘EC belt’ with EC constituting more than 20% of all cancers, the most common type being ESCC.¹³⁷ High incidences in Kashmir have been associated with the consumption of hot salted tea, sun-dried, smoked foods, tobacco in the form of hookah (water-pipe for smoking flavored tobacco) and various genetic factors.²² Tobacco use, inhalation and oral, is quite common in India¹³⁸ with the level of risk varying from 2-fold to 16-fold in different case-control studies. Chewing tobacco with pan (betel-leaf) was more harmful than chewing only tobacco.¹³⁹ Hookah use, and nass chewing as in Iran were associated with two- and three-fold increase, respectively of ESCC risk.¹⁴⁰ Protective effect of vegetarian diet on EC is controversial. Consumption of fresh fish was protective while tea consumption, was shown to be a risk factor¹⁴¹ probably due to thermal injury to the esophageal lining.¹³⁹

Africa

Limited data of incidence and mortality rates from Africa showed that ESCC is the predominant type with an estimated 27,900 new cases and 26,600 deaths in 2008.¹⁴² EC is a leading cause of cancer death among both men and women in East Africa, and among men in South Africa. Incidence and mortality rates in these two regions are more than 7 times as high as the rates in Western, Middle, or Northern Africa among men and more than 4 times as high among women.¹⁴² EC was the most common cancer in men and the third most common among women in the North Rift Valley of Kenya.¹⁴³ Certain geographic locations had higher rates for women compared with men. Zimbabwe has the highest incidence of EC for both sexes, ranked fourth among men and fifth among women.⁵

There has been no study explaining the reasons for this high burden of EC. The suspected risk factors include smoking, alcohol intake, poor dietary patterns such as consumption of a maize-based diet that is low in fruits and vegetables,^144-146 and contamination of maize with fungi that produce fumonisins, a cancer-initiating agent in experimental animals.^147,148 It was found that in Malawi, Kaposi sarcoma, cancer of the cervix and EC were the major causes of the increasing trend in cancers in the country. The increase in EC was found to be in line with the increase in Kaposi’s sarcoma suggesting a link between the two.¹⁴⁹

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Nutrition Issues in Gastroenterology, Series #125

Magnesium — So Underappreciated

January 2014 • Volume XXXVIII, Issue 1

Tamara Karosanidze

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Magnesium is essential to many metabolic processes, yet hypomagnesemia is common in hospitalized patients, especially in the critically ill. With high morbidity and mortality rates reported in hypomagnesemic patients, prompt diagnosis and treatment is of utmost importance. This article will review magnesium basics including assessment tests, etiologies of hypomagnesemia and provide guidance on effective ways of treating magnesium deficiency.

Introduction

Magnesium (Mg), the fourth most abundant cation in the body, is a co-factor in more than 300 enzymatic reactions and plays an important role in the synthesis of proteins, DNA and RNA.¹ It is crucial for muscle contraction and relaxation, nerve function, heart rhythm, vascular tone and bone formation.² Ninety-nine percent of total body Mg is intracellular (bone, skeletal muscle, soft tissue) with only ~1% found in serum and red blood cells (extracellular). A large percentage (70-80%) of serum Mg is ionized (easily filtered by the kidneys), 20-30% bound to proteins (mainly albumin), and only ~1-2% complexed with anions.^2-5 Magnesium homeostasis is maintained by the intestines, bone and the kidneys. It is absorbed most efficiently in the ileum with some absorption occurring in the colon via a passive paracellular mechanism and stored in bone; excess Mg is excreted by the kidneys as well as through the feces. Only about 30-50% of total dietary Mg consumed is absorbed in the intestines as other nutrients present in the gut (fiber, phytates, oxalates, phosphates) can bind the cation and decrease its absorption. Magnesium status determines Mg absorption with more of this mineral absorbed if Mg levels are low. Kidneys reabsorb ~ 95% of filtered Mg and excrete only ~ 3 – 5% in the urine,^2,3,6 unless rapid infusions are given.

Assessment of Magnesium Status
Serum Magnesium

Several methods exist for evaluating Mg levels. The most common in clinical practice is the measurement of serum Mg concentration. The test is widely available and inexpensive, but does not correlate with tissue stores of magnesium. Serum Mg is a poor predictor of total body Mg content because only 0.3% of total body Mg is found in serum.²

Urinary Excretion Test

The urinary Mg excretion test is not commonly used in clinical practice, as it requires collection of a 24-hr urine specimen, which can be challenging to obtain. Renal Mg excretion follows a circadian rhythm with the greatest amount of Mg excreted at night; therefore, having a complete 24-hr urine collection is essential for accurate assessment of absorption and excretion. High urinary Mg excretion is indicative of renal wasting whereas a low level may suggest inadequate intake or absorption.²

Magnesium Loading Test

“Magnesium retention test” or “loading test” is a more sensitive indicator of Mg deficiency. It has been used to identify patients with suspected Mg deficiency while normomagnesemic. If more than 60-70% of Mg is excreted in the urine following an intravenous load, Mg deficiency is unlikely. This test, despite its better sensitivity, can still result in false positive or false negative results. Normal renal handling of Mg is necessary for this test to be useful. Magnesium losses due to diabetes, medications or alcohol ingestion may result in a false negative test, whereas with compromised renal function, one may see false positive results. Senescence may be a confounding factor as older individuals tend to retain more Mg than younger patients.^2,6 The Mg retention test should not be used in patients with renal impairment or in transplant patients receiving cyclosporine or tacrolimus, both of which cause urinary Mg wasting.

Hypomagnesemia

Hypomagnesemia is defined as a serum Mg concentration < 1.8 mg/dL (normal range: 1.8 mg/dL – 2.3 mg/dL).⁵ Causes of hypomagnesemia include poor oral intake, omission of Mg from parenteral solutions, altered absorption and increased gastrointestinal losses in patients with diarrhea, malabsorption or bowel resection/ bypass surgery. Patients with diabetes, renal tubular disorders, hyperthyroidism or hyperaldosteronism, refeeding and those following surgery are at risk for Mg deficiency. Many medications can also cause Mg wasting. Transplant patients are particularly prone to the development of Mg deficiency due to a direct effect of tacrolimus and cyclosporine on the renal tubules, which results in enhanced urinary Mg loss. See Table 1 for causes of hypomagnesemia.^2,7,8 Signs and symptoms of Mg deficiency are listed in Table 2. Ventricular arrhythmia is the most life-threatening complication of hypomagnesemia.

Treatment of Hypomagnesemia

Hypomagnesemic patients usually do not develop symptoms until serum Mg falls below 1.2 mg/dL.⁵ Asymptomatic patients should be treated with oral Mg supplements whenever feasible, whereas severe hypomagnesemia (Mg < 1 mg/dL) warrants treatment with parenteral Mg. Magnesium sulfate (MgSO₄) is the most commonly utilized preparation for intravenous administration; Mg oxide is the most commonly used oral supplement.⁷ Intramuscular injections of Mg sulfate are associated with significant pain; therefore, a slow, continuous IV infusion is preferable. In symptomatic patients, Mg supplementation should be continued for 3-7 days as normalization of serum Mg will not be reflective of total body Mg stores.⁶ Intravenous Mg repletion should be given slowly, over 8 – 24 hours. A rapid IV push over 1-4 hours (the most common way to administer Mg in the hospital setting) will increase serum Mg above physiologic levels exceeding the renal threshold and up to 50% of the infused Mg will be excreted in the urine.^5,8,9 Not only are the electrolyte shortages a significant reason to ensure efficacy, but more importantly, if patients are going to benefit from IV Mg, it must be retained in the patient.

There are no universal Mg repletion guidelines and different institutions have developed their own protocols. It has been suggested by consensus statements to give IV Mg sulfate (8-12 g) in the first 24 hrs, followed by 4-6 g daily for 3-4 days.¹⁰ At our institution, hypomagnesemia is commonly treated with intravenous piggyback (IVPB) infusion of 1-2 g MgSO₄ over 1-4 hours. A practice change has been made to infuse Mg over a longer period of time (12-24 hours) for better retention to ensure that the Mg given to patients is retained, especially in the era of IV Mg shortages. Adding IV Mg to the standing IV fluid already infusing has been an effective way to achieve this.

As mentioned earlier, asymptomatic patients should be treated with oral Mg (See Table 3 for a listing of products). Supplements are usually given at doses ranging from 300 to 600 mg/day. As the absorption of Mg from the gastrointestinal tract is poor (only ~ 20-50% of oral Mg absorbed) and aggressive supplementation can lead to diarrhea,¹¹ it is recommended that Mg supplements be administered in divided doses 3-4 times/day to reduce their laxative side-effects.⁶ See Table 4 for guidelines on treating hypomagnesemia with IV and oral supplements. It should be noted that sufficient renal function is needed prior to providing Mg supplementation. Hypermagnesemia may develop in patients with renal compromise and is commonly seen in patients with acute renal injury or advanced kidney disease. It can also be iatrogenic, for example when large doses of Mg-containing laxatives and antacids are used.^2,8 If a significant decrease in the glomerular filtration rate (GFR) is noted, the dosage of Mg supplementation should be reduced. Mg therapy should be ceased in severe hypermagnesemia (serum Mg > 4.8 mg/dL) and treated with IV calcium infusion and/or hemodialysis.^2,6

CONCLUSION

Hypomagnesemia can be detrimental to hospitalized patients. Since “normal” serum Mg does not rule out Mg deficiency, under-diagnosis is common. By recognizing the limitations of the widely utilized serum Mg level, clinicians are faced with an important responsibility to accurately identify patients at high risk for Mg deficiency. Patients with diabetes, poor diets, alcoholism, malabsorption, and those on chronic diuretic therapy fall into this high risk category. Treatment of hypomagnesemia should be dictated by patient’s risk factors, clinical symptoms and kidney function. Most importantly, when IV Mg is used, it should be infused over a longer period of time to achieve efficacy and for cost-effective management of hypomagnesemia.

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Unusual Causes of Abdominal Pain, #1

Abdominal Wall Pain

January 2014 • Volume XXXVIII, Issue 1

George W. Meyer

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CASE

A 40 year old woman presents with a several year history of burning abdominal pain located at the right edge of the rectus sheath at the level of the umbilicus. It may radiate irregularly to different areas near the point of most severe pain. The pain is often worse during the week and improved over the weekend. The pain is 5-7/10, often brought on 2-3 hours after starting work on Monday when sitting at the computer, relieved by standing up and walking around. It rarely bothers her during the weekend. On physical examination the Vital Signs are normal and the only abnormal physical finding is point tenderness at the right edge of the rectus sheath at the level of the umbilicus. Carnett’s sign is positive. What is the diagnosis and how should it be treated?

Answer and Discussion

One of the most common, yet frequently not considered, causes of chronic or recurrent abdominal pain is abdominal wall pain.

The A-delta nociceptor (pain receptor) is the nociceptor associated with pain on the skin or muscle associated with a cut, trauma, etc. When the A-delta nociceptor is involved the patient can point to the pain with one finger. The C nociceptor innervates such places as the periosteum and peritoneum. The pain associated with the C nociceptor comes on slowly, is dull and nauseating, and cannot be localized with one finger.

The nerve roots from the T-8 to T-12 nerves sweep posteroanteriorly to the abdominal wall where they turn anteriorly at the lateral edges of the rectus sheath to reach the surface of the abdominal wall. T-8 is usually at the level of the xiphoid; T-10 at the umbilicus; and T-12 at the symphysis pubis. These nerves are associated with an artery and nerve and there is a fatty deposit at the rectus sheath when they make their anterior turn. It is thought that this fatty plug, which acts as a shock absorber, may get inflamed and cause pain. This disorder has been called Abdominal Cutaneous Nerve Entrapment Syndrome or ACNES.

Other sources of abdominal wall pain include the corners of long abdominal incisions and insertion points for laparoscopic instruments.

The patients with abdominal wall pain can point with one finger to the point of maximum discomfort. Often there is a subtle indentation in the abdominal wall. When the examiner’s finger is on this point and the patient tries to straight leg raise (both legs at the same time) s/he has an increase in the pain (Carnett’s sign). If Carnett’s sign is negative, then the diagnosis of abdominal wall pain should be reassessed.

Once the diagnosis has been confirmed, if it is correct, all that is needed is a trigger point injection with 1% Xylocaine and Triamcinolone. A 5 mL syringe with a 22 or 23 gauge needle, 1.5- 2 inches long (~5 cm) is all that is needed. After drawing 1 mL of 1 % Xylocaine, we add 40 mg (1 mL) Triamcinolone to the syringe. After proper skin cleaning has been performed, the needle is inserted into the place where the pain is most severe. Most of the 2 mL is injected into the point of most pain. The physician may also inject smaller amounts in the surrounding tissue but this may not be necessary. If the diagnosis is correct and the injection was in the proper location, the pain is usually completely resolved within minutes. This often gives permanent relief but some patients require several injections, usually spaced at increasing intervals before total resolution is achieved. Rarely, permanent nerve destruction with absolute alcohol or 5-6 % phenol may be required. Referral to pain medicine experts may be indicated for long term relief.

To review, a good history and a proper physical examination will lead to a diagnosis of abdominal wall pain. Trigger point injection with Xylocaine and Triamcinolone should give relief. Try it; your patients will like it.

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Frontiers in Endoscopy, Series #8

Advanced Imaging of the Gastrointestinal Lumen

January 2014 • Volume XXXVIII, Issue 1

Pushpak Taunk,

Arush Singh,

Virendra Joshi

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Endoscopy has been the gold standard for the evaluation and management of a multitude of gastrointestinal pathologies ranging from premalignant lesions such as Barrett’s esophagus and colonic adenomas to inflammatory conditions such as ulcerative colitis and Crohn’s disease. In recent years there have been significant technological advances, such as optical magnification and high definition (HD) cameras, dye-based chromoendoscopy, electronic chromoendoscopy, confocal laser endomicroscopy, and nascent technologies such as endocytoscopy and molecular labeling. This review will describe the use of advanced endoscopic technologies, their basic risks and benefits, and their clinical applicability.

Introduction

Endoscopy has been the gold standard for the evaluation and management of a multitude of GI pathologies ranging from premalignant lesions such as Barrett’s esophagus and colonic adenomas to inflammatory conditions such as ulcerative colitis and Crohn’s disease. In recent years there have been significant technological advances that allow the endoscopist to detect and resect a greater number of lesions more accurately with fewer biopsies. These exciting technologies have improved upon standard white light endoscopy (WLE) and include enhancements such as optical magnification and high definition (HD) cameras, dye-based chromoendoscopy, electronic chromoendoscopy, confocal laser endomicroscopy, and nascent technologies such as endocytoscopy and molecular labeling. This review will describe the use of advanced endoscopic technologies, their basic risks and benefits, and their clinical applicability.

White Light Endoscopy

Traditionally, white-light endoscopy has been used for direct visualization of GI mucosa. Although WLE has the benefit of accurate color representation, it may not offer the most detailed images. In fact, traditional endoscopes are based on the standard definition (SD) television monitors of yesteryear. These are displayed in a 4:3 aspect ratio with approximately 640 pixels in width by 480 pixels in height, producing an image of just under 400,000 pixels.¹ HD televisions are now the norm, and HD endoscopes are also becoming more commonplace. Similar to the 720p HD television format, these endoscopes can have as many as 720 pixels in height, producing an image composed of nearly 1 million pixels. However, unlike the HD television format, which is displayed in a 16:9 widescreen aspect ratio, HD endoscopes are typically shown in a 5:4 aspect ratio to better match the round endoscopic lens. This HD endoscopic image provides increased picture clarity and a recent meta-analysis showed a marginal benefit in detection of both colonic polyps and adenomas when compared to SD endoscopy, with a number needed to treat of 25.² Typical high-resolution endoscopes magnify images roughly 30 to 35-fold, but specialized optical zoom endoscopes can magnify the image up to 150-fold.³ The two types of magnification include optical and digital, with optical magnification employing a movable lens in the tip of the endoscope, allowing a closer image while maintaining the same high resolution.⁴ Digital magnification, however, only moves the image closer to the display and is limited by fewer pixels in the same display area, thereby resulting in decreased image fidelity.⁵ Moreover, digital magnification typically only allows for a magnification of 1.5 to 2x, given a suitable processor and video equipment.¹ Thus, the best combination is an HD endoscope equipped with an optical zoom, known as high-resolution endoscopy (HRE) with magnification. In one prospective randomized crossover study, HRE with magnification was found to be equally efficacious when compared with both dye-based chromoendoscopy with indigo-carmine or narrow-band imaging (NBI) chromoendoscopy for the detection of high-grade dysplasia or early cancer in Barrett’s esophagus.⁶ Moreover, HD colonoscopy was found to detect more adenomas per patient, more right-sided adenomas, and more flat adenomas when compared to SD white light endoscopy in a RCT from 2011.⁷ Another study from 2013 showed a 3-fold increase in detection of dysplasia in IBD patients when using HD colonoscopy compared to SD colonoscopy.⁸ The downsides to HD colonoscopy with optical magnification include added expense when compared to SD endoscopes and a slightly larger insertion tube diameter and tip, potentially impacting maneuverability during difficult cases.³

Dye-Based Chromoendoscopy

Dye-based chromoendoscopy has traditionally used either Lugol’s solution (0.5%-3% potassium iodide and iodine in water), methylene blue 0.5% solution, or indigo carmine 0.1-0.4% solution (Figure 1). These dyes can be applied throughout the gastrointestinal mucosa to enhance endoscopic visualization. Images obtained can display the mucosal topography and borders in finer detail, particularly of subtle lesions such as nonpolypoid adenomas.⁹ Both Lugol’s solution and methylene blue are classified as absorptive stains, as they are actively taken up by epithelial cells. For example, applying Lugol’s solution will result in the normal esophageal mucosa staining intensely greenish brown for 5-8 minutes after spraying, while dysplastic and neoplastic areas will not take up the dye.⁹ Studies have shown that Lugol’s solution improves visualization of squamous cell cancer in patients at increased risk, such as alcoholic patients and those with head and neck cancers.¹¹

Methylene blue is actively absorbed by intestinal epithelial cells and not squamous epithelium and is thus better suited to enhance detection of the metaplastic columnar epithelium present in Barrett’s esophagus.¹¹ Canto et al showed that using this dye resulted in a more targeted approach to Barrett’s esophagus lesions with fewer biopsies when compared to random sampling, as well as more biopsy specimens containing columnar epithelium.¹² Furthermore, in a randomized control trial, Kiesslich et al found that surveillance colonoscopies conducted in patients with ulcerative colitis (UC) using methylene blue dye resulted in significantly more intraepithelial neoplasia found (32 vs 10 lesions) in 165 patients with a sensitivity and specificity of 93% for differentiation between neoplastic and nonneoplastic lesions.¹³ Thus, the American Gastroenterological Association (AGA) recommends surveillance colonoscopies with image-enhanced endoscopy (such as using dye for contrast) in patients with longstanding UC9 (Figure 3). However, there are some concerns regarding oxidative DNA damage with methylene blue and possible complications such as acute colitis, and thus, this dye is not used as frequently as indigo carmine.¹⁴

Indigo carmine is a non-absorptive dye used mainly for its ability to better delineate borders of lesions, which is most helpful to accentuate nonpolypoid lesions. In fact, it is used routinely in Japan to better evaluate for gastric cancer after the completion of a standard white light endoscopic examination.¹⁵ It is also well suited to delineate colonic lesions, and studies have shown that using indigo carmine after mucosectomy to assess for residual lesions has resulted in a reduction of local neoplastic recurrence from 8.7% to 0.5% (p < 0.01).¹⁶

Computerized Virtual Chromoendoscopy

Virtual chromoendoscopy can be considered a catchall term for a collection of newer technologies that have recently been able to emphasize various wavelengths of light in order to improve the visualization of abnormal GI mucosa. NBI, flexible imaging color enhancement (FICE), and i-scan technologies will be discussed in this review. NBI technology uses two sets of physical filters placed in front of the endoscopic light source at the 415 nm wavelength (corresponding to blue light) and the 540 nm wavelength (corresponding to green light). The blue light wavelength corresponds to the primary absorption peak of hemoglobin and the green light corresponds to hemoglobin’s secondary absorption peak.3 This has the effect of emphasizing surface and submucosal capillaries and irregular microstructural capillary patterns, which have been shown to be highly associated with high grade dysplasia and early cancer.¹⁷ This technology can be helpful in characterizing neoplastic colonic polyps, but is prone to error based on the endoscopist’s experience with the technology (Figure 3). Also, NBI technology is unlikely to be routinely used due to its poor light intensity, especially in the stomach and colon.³

FICE technology is software-based and does not require the use of physical filters like NBI (Figure 4). The technology uses spectral emission methods to build single-wavelength images, which are then randomly assigned to red, blue, or green channels to create a virtually enhanced color image. The endoscopist can then select preset wavelengths to view (from 400 nm to 695 nm) or manually adjust the viewable wavelength in increments of 5 nm.³ At any time, a push button can switch the view between a FICE image and standard WLE.¹ This technology, as with NBI, can be coupled with optical magnification to enhance mucosal visualization. Compared with NBI, there are fewer studies evaluating the role of FICE. Although FICE is fairly accurate in the characterization of colorectal polyps, FICE does not improve detection of colonic polyps when compared with either standard WLE or chromoendoscopy with indigo carmine.³

Finally, i-scan is another digital post-processing method that comes with three modes of image enhancement, which are surface enhancement (SE), contrast enhancement (CE), and tone enhancement (TE).¹ Surface enhancement aids in the recognition of edges, contrast enhancement emphasizes depressed areas in view, and tone enhancement modifies the red, green, and blue color balance for the esophagus, stomach, and colon specifically. SE and CE can be adjusted between low, medium, and high, with multiple modes able to be applied together with a simple button push (i.e. low SE and high CE). Similar to NBI, the sensitivity and specificity of i-scan for the characterization of colorectal polyps are high.³ However, a randomized colonoscopy trial did not show any increased adenoma yield with i-scan when compared to HD colonoscopy.¹⁸ When compared to WLE images, i-scan images did not differ markedly in brightness or color, unlike NBI images¹ (Figure 5). Thus, both FICE and i-scan appear reasonably accurate for characterization of colorectal lesions, but do not enhance adenoma yield. More studies are required before they can be considered for routine clinical use.³

Confocal Laser Endomicroscopy

Confocal laser endomicroscopy (CLE) is a promising new technology that has the ability to deliver microscopic images in real-time during the endoscopic procedure. GI tissue is illuminated by a low-power laser, which then detects reflected fluorescence light through a pinhole.¹ The term confocal denotes that the illumination and collection system are in the same focal plane.¹⁹ The images obtained are sharp and of an extremely high resolution because only the light that is refocused through the pinhole is captured. Intravenous fluorescein (which does not stain nuclei) is generally used for contrast, as topically administered acriflavin (which does stain nuclei) has been found to be a mutagenic dye and potential human carcinogen.1 Two types of CLE exist, probe-based (pCLE) and endoscope-integrated (eCLE). pCLE passes through the accessory channel of most endoscopes and thus can be used with a bronchoscope, cholangioscope, etc. In addition, pCLE also has the advantage of being able to view video at 12 frames/second and thus, can image capillary flow. The disadvantages include a slightly lower resolution than eCLE and slightly smaller field of view.²⁰ The eCLE system acquires images at 1.6 frames/ second at a 1024×512 pixel resolution or 0.8 frames/ second at a 1024×1024 pixel resolution, resulting in approximately 1000-fold magnification.²¹ Given this, it is recommended that CLE be used in a targeted fashion for suspicious lesions. Moreover, CLE can help the endoscopist target the most suspicious area for biopsy by screening multiple areas of metaplasia/dysplasia during the actual procedure (Figure 6 and 7). This technique was applied in clinical practice in a study with 42 patients coming back for surveillance colonoscopy after previous polypectomy. In this study CLE was able to distinguish normal mucosa from regenerative and neoplastic mucosa with 99.2% accuracy.²² This can help reduce the number of unnecessary biopsies (the single greatest risk factor for major complications of colonoscopy) as well as target truly neoplastic lesions.²³ This was also shown to be the case in a study involving UC patients: the control group was biopsied with just WLE and the experimental group was given panchromoendoscopy with methylene blue and CLE. 21.2 biopsies were needed with the experimental group compared to 42.2 biopsies in the controls, with a negative predictive value (NPV) of normal mucosa on CLE of 99.1%.²⁴ Given these findings, CLE may very well help to abandon the practice of untargeted random biopsies in patients with UC.²¹ In Barrett’s esophagus, pCLE was also used to view the mucosa and prevent biopsies on normal-appearing tissue in vivo. This resulted in a 98.8% NPV, thus “allowing nearly risk-free elimination of the random biopsy when pCLE was negative,” saving money for Medicare and mitigating procedure risk in the process.²⁰ Unfortunately, there is a steep learning curve associated with the use of this technology, and it adds a substantial amount of time to the procedure. Its limited field of view also makes is unsuitable as a red-flag technique, and it needs to be incorporated with HD and dye-based or virtual chromoendoscopy to identify suspicious areas that need endomicrocopic evaluation. Thus, although the technology appears to be safe and accurate in expert hands, additional studies are needed to determine its complete use for routine clinical practice.³ Another evolving endomicroscopic technique is nCLE. The principle of needle-based Confocal Laser Endomicroscopy (nCLE) is to image organs within or adjacent to the gastrointestinal by means of a miniprobe inserted through an endoscopic needle placed under endosonographic guidance. The fundamentals of this technology, as well as the principle of operation of nCLE, are substantially similar to pCLE. The AQ-Flex 19 Confocal Miniprobe is compatible with the 19G-type needle only. It is expected to help differentiate the various types of cystic lesions (mucinous versus serous).

Developing Technologies

Endocytoscopy has the potential to deliver even more magnified images than CLE, up to 1400-fold. The technology is currently available in probe-based and endoscope-based forms, yet is still in the prototype phase of development. In essence, it is a high-powered light microscope projecting very highly magnified images that requires contact with the tissue surface.¹ This requires pretreatment with a mucolytic agent such as N-acetyl-cysteine as well as prestaining with a compound such as methylene blue.

Molecular imaging takes biomarkers such as fluorescent dye-labeled monoclonal antibodies against carcinoembryonic antigen (CEA) to help detect cancers and adenomas.³ The antibody is physically applied via the colonoscope and specific filters pick up the fluorescence on appropriate tissue. Multiple peptides are being tested, including those that target high-grade dysplasia in Barrett’s esophagus as well as cathepsin B, which is upregulated in colorectal cancer.

There is no doubt that existing methods of endoscopy will continue to grow more sophisticated through progressive technological advancement. Key in this progression is the ability to harness their increased sensitivity and individual benefits for the betterment of the patient. As these technologies are further studied some will be more efficacious than others, and those must be fully developed, refined, and possibly combined with others (such as chromoendoscopy with CLE) to realize their potential. Throughout this process, costs will continue to decline, hopefully to the point where many of the above mentioned technologies become a readily available option for the outpatient endoscopist. The next few years may well prove to be an exciting time in the field of advanced endoscopy.

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Introduction

WHOGeneral Indications for Jejunal Feeding

DPEJ Indications

Aspiration

Gastroparesis

Chronic Pancreatitis

Critically Ill Patients

Comparison of PEGJ vs. DPEJ

DPEJ Contraindications

WHEN

HOWPre-procedural Preparation

Technique (see Figure 1)

Success Rates

Adjunctive Techniques

WHAT TO AVOIDInappropriate Indications

Complication Rates

CONCLUSION

Introduction

Definition

Epidemiology

Pathogenesis

Clinical Findings

Diagnostic Modalities (Table 1)

Endoscopy and Pathology

Diagnostic Dilemmas and Associations with the Disease (Table 2)

Management Goals and Treatment

Summary

Introduction

Case Report

Discussion

Introduction

Case Description

Discussion

CONCLUSION

INTRODUCTION

Global Epidemiological Trends

Epidemiological Determinants

Gender

Esophageal Squamous Cell Cancer

Esophageal Adenocarcinoma

Geographical Analysis

United States of America

Europe

Iran

China

Japan

India

Africa

Introduction

Assessment of Magnesium StatusSerum Magnesium

Urinary Excretion Test

Magnesium Loading Test

Hypomagnesemia

Treatment of Hypomagnesemia

CONCLUSION

CASE

Answer and Discussion

Introduction

White Light Endoscopy

Dye-Based Chromoendoscopy

Computerized Virtual Chromoendoscopy

Confocal Laser Endomicroscopy

Developing Technologies

WHO
General Indications for Jejunal Feeding

HOW
Pre-procedural Preparation

WHAT TO AVOID
Inappropriate Indications

Assessment of Magnesium Status
Serum Magnesium