Page 75 – Practical Gastro

A 24-year-old man with native mitral valve Streptococcus mitis endocarditis presented to the emergency department with acute burning epigastric pain following three weeks of intravenous penicillin therapy. The patient described four days of near-constant pain of acute onset, unrelated to meals and unrelieved by H2-receptor blockers, proton pump inhibitors, and over the counter antacids. Exacerbation was described with leaning forward and deep inspiration, and partial remission was achieved only by lying still. The patient admitted to nausea without vomiting and review of systems was otherwise unrevealing. On examination, vital signs were within normal limits and his abdomen was soft and nondistended but tender to palpation in the epigastrium. There was no rebound tenderness, guarding or rigidity. A GI cocktail administered in the emergency department was ineffective, and intravenous hydromorphone resulted in modest pain reduction. The patient’s complete blood count, liver panel, electrolytes, renal function and serum lipase were all within normal limits, and following an unremarkable acute abdominal plain film series he was sent for computed tomography (CT) scan of the abdomen with intravenous contrast.

ANSWER AND DISCUSSION

Hepatic Infarction

The relative rarity of hepatic infarction is commonly attributed to the dual blood supply and extensive collateral circulation of the liver. There are multiple causes of hepatic infarction: iatrogenic ligation (e.g., following laparoscopic cholecystectomy), thrombosis, toxemia of pregnancy, polyarteritis nodosa, and emboli which may be bland, iatrogenic (e.g., following angiography or transarterial chemoembolization), or septic, which are almost always associated with infective endocarditis, as in this case. On presentation, hepatic infarction may result in epigastric or right upper quadrant pain in addition to fever, nausea and vomiting. Alternatively, hepatic infarction may be asymptomatic, detected only by biochemical tests and imaging studies. In the case of our patient, the initial CT with contrast demonstrated occlusion of the left hepatic artery with a small area of indistinct hypoattenuation in the posterior aspect of the left lobe of the liver, segment three (Figure 1, arrow), as well as several chronic-appearing renal infarcts. As there was no clear evidence of infarction on presentation and no prior abdominal CT for comparison, the timing of arterial occlusion and its relationship to the presenting complaints were uncertain, and the patient was admitted. Esophagogastroduodenoscopy performed on the day of admission was normal. On the second day of hospitalization, the patient’s abdominal pain intensified and routine laboratory tests were repeated with noted elevation in aspartate aminotransferase (145 U/L) and alanine aminotransferase (179 U/L). Repeat CT imaging showed occlusive thrombus in the left hepatic artery now with a large, wedge-shaped area of hypoattenuation consistent with infarction in the territory of the left hepatic artery (Figure 2, arrow). Recurrent emboli despite appropriate medical therapy represent a class IIa indication for surgical repair of a native heart valve. The risk of embolization with serious consequences in the setting of infective endocarditis is thought to be small and declines rapidly following antibiotic therapy, and though there are currently no data clearly showing a threshold for embolic events above which surgical intervention must be pursued, more than one instance of embolization while a patient is on appropriate therapy generally warrants surgical intervention. Our patient’s mitral valve replacement surgery was expedited on this basis and performed without complications.

Abdominal pain attributable to liver disease is encountered with malignancy, congestive hepatopathy, cystic disease and acute hepatitis, and is thought to be mediated primarily by the generation of visceral afferent signals transmitted within sympathetic nerves as a result of mechanical stretch of Glisson’s capsule. In symptomatic cases of hepatic infarction, pain is presumably secondary to irritation of these fibers. Additionally, presumptive nociceptive fibers within the hepatic parenchyma have been described by some authors, but these have not been extensively documented. Given the relatively low incidence of hepatic infarction in the general population and potential for vague or even asymptomatic presentation, a high clinical suspicion must be maintained when abdominal pain is encountered in the appropriate clinical scenario in order to promptly diagnose this condition.

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #134

Short Bowel Syndrome in Adults – Part 2 Nutrition Therapy for Short Bowel Syndrome in the Adult Patient

Carol Rees Parrish,

John K. DiBaise

Success of the patient with short bowel syndrome (SBS) depends on adaptation of the remaining bowel, which requires a combination of pharmacologic and nutrition therapies. Although the SBS diet is quite similar for those with and without colonic segments, there are a few key differences that should be noted. This is the second article in a five-part series on SBS, the focus of which is diet intervention in an effort to enhance adaptation, increase absorption and as a result, lessen stool output.

INTRODUCTION

Without aggressive use of pharmacological agents, diet alone will generally be ineffective in curbing the voluminous diarrhea experienced by patients with SBS. Nevertheless, diet therapy is an essential component of care in these patients. The cornerstone of diet therapy is manipulation of food intake to facilitate maximum nutrient and fluid utilization by decreasing the stool output. Stool output in SBS is driven by the fluid-substrate load exceeding the absorptive capacity of the shortened bowel; but other factors also contribute. For example, in addition to the loss of absorptive surface area, feedback mechanisms that control transit and acid and bicarbonate secretion are often lost (see Table 1). A clear understanding of these factors is essential to the selection of the best therapeutic interventions.

In a recent study assessing the typical micro- and macronutrient intake from the oral diet in patients with SBS prior to entry into a bowel rehabilitation program, the patients were found to be making food and beverage choices that would be expected to worsen their diarrhea and increase PN requirements. Furthermore, each subject had received little previous dietary instruction from their healthcare providers.¹ Our role as clinicians in the care of patients with SBS is to restore as much intestinal function as possible. This is achieved by optimal use of medications and by altering diet and fluid choices as much as the patient can tolerate. Tailoring the diet to an individual’s remaining bowel anatomy and providing the patient with a basic understanding of why diet and fluid modifications are important is essential to optimizing successful outcomes.

Nutritional Assessment — Getting Started

The initial evaluation of all SBS patients should include a comprehensive nutritional assessment. Information obtained should include a history pertinent to weight change, medication usage (including supplements and over-the-counter medications), presence of GI and other symptoms that may affect oral intake or fluid loss, potential signs/symptoms of micronutrient deficiencies, and physical assessment for signs of dehydration and malnutrition. Additional information that should be collected at baseline includes pertinent past medical, psychiatric, and surgical history, including comorbidities and the presence of bowel complications such as anastomotic strictures; chronic obstructions; enterocutaneous fistulae; and peritoneal drains. A nutrition support history should also be obtained, including information regarding the enteral and/or central venous access device, formula used, route and method of administration, and known prior complications. Finally, given the high level of motivation required to adhere to the dietary, fluid and medical treatments prescribed, it is useful to inquire about their education, motivation, support system and potential economic or other barriers.

Patients with SBS should be instructed on the measurement of daily fluid intake and urine/stool output, as periodic assessment of these parameters helps guide fluid needs. It is also useful to review a food diary, preferably over a period of a few days, to determine the SBS patient’s usual oral diet and daily energy intake. A baseline assessment of electrolytes and micronutrient levels (see micronutrient section below) should be obtained at the initial clinic visit. Given the high risk of metabolic bone disease in these patients, a bone density should be assessed at baseline and monitored every 1-2 years.

Oral Diet — Lessons Learned

Original evidence supporting the beneficial effects of diet therapy in patients with SBS is based on a limited number of studies that have included a small number of patients with various bowel anatomies.^2-9 These studies have generally demonstrated a decrease in stool output and an increase in absorption depending on the remaining bowel anatomy and the type and amount of carbohydrate and fat used. Specifically, those SBS patients with a colon segment remaining appear to derive the most benefit in terms of nutrient absorption and reduction in stool losses from a high complex carbohydrate, low-moderate fat diet. In an inpatient setting, Byrne et al. followed close to 400 patients over a 10 year period after providing intensive counseling and close monitoring for 2-4 weeks and further demonstrated the importance of the SBS diet on improving stool output and both nutritional and hydration status.¹⁰ They concluded that patients with colon benefited from a different diet than those without colon.

Luminal nutrients enhance post-resection intestinal adaptation by increasing splanchnic blood flow, stimulating pancreatico-biliary secretions, gut neuronal activity, and peristalsis. They also up- regulate selective nutrient transporters and digestive enzymes and stimulate local production and release of intestine-specific growth factors.¹¹ Importantly, nutrient complexity (i.e., whole foods) is associated with greater intestinal adaptation, presumably due to recruitment of greater digestive activity, the effects of which may ultimately decrease the need for parenteral nutrition (PN) support in SBS.

Patients with an end jejunostomy typically absorb more nutrients than fluid, so intravenous (IV) fluids may be required at least initially. In contrast, in those SBS patients with a jejuno-ileocolonic or jejuno- colonic anastomosis, sodium and water are absorbed more avidly, and these patients may require more supplemental nutrients than fluids. For all patients with SBS, the most important dietary interventions involve smaller, more frequent feedings, avoidance of simple sugars in any form and chewing foods extremely well. The long-term success of an optimized SBS diet requires intensive education, adequate nutrition counseling and monitoring to maintain compliance and achieve intestinal rehabilitation, PN independence, and enteral autonomy. One of the crucial roles of the dietitian is to translate all of the data into foods and meal plans that meet the individual’s preferences and lifestyle. The patient needs to be informed not only of what they need to avoid, but more importantly, what they can eat. In general, most stable adult SBS patients absorb only about one-half to two-thirds as much energy as normal; thus, dietary intake must be increased by at least 50% from their estimated needs (i.e., “hyperphagic” diet).^12,13 However, in some, this increased intake may contribute to excessive loss of micronutrients and fluids by worsening diarrhea.⁷ The establishment of daily calorie and fluid intake goals is achieved by careful monitoring. Adjustments may be needed based on tolerance, which is determined by symptoms, stool output, ongoing assessment of what they eat, and in so doing, assessment of the patients understanding of diet therapy, along with micronutrient levels, weight changes, and hydration status.

For some patients, instead of advising how many calories to eat per day, a more practical approach may be preferred. This entails a review of their normal intake followed by suggestions on where they can add actual foods, such as a half sandwich, a package of “Nabs,” or a teaspoon of olive oil. Reevaluating the plan and adjusting as the patient’s needs change, particularly during the adaptation period, is essential for the ongoing success of the SBS diet.

Diet Specifics

Fat

Fat is an excellent calorie source, yet depending upon the remaining bowel anatomy in a SBS patient, too much fat may exacerbate steatorrhea, resulting in loss of calories, fat-soluble vitamins and divalent minerals in the stool.^4,7,14 Medium chain triglycerides (MCT) are often recommended for use in patients with SBS as they are absorbed directly across the small bowel and colonic mucosa; however, it has been shown that only those with a remaining colon segment seem to benefit from their use.15 Furthermore, MCT contain fewer calories than dietary fat, are devoid of essential fatty acids, are not very palatable, and do not enhance intestinal adaptation.

Protein

Protein requirements will vary depending on where the patient is in the disease course. Protein of high biological value is always preferred over plant protein. Because nitrogen absorption is least affected by the decreased absorptive surface in SBS patients, no change in dietary protein is generally necessary and the use of peptide- based diets in these patients is unnecessary.^4,8,16,17 Oral glutamine is often recommended to patients with SBS; however, its clinical benefit is controversial and there is insufficient data to support its use in patients with SBS.18 Glutamine is also abundant and readily available in whole protein foods of high biological value such as meat, fish, poultry, eggs, and dairy.

Carbohydrate

The use of more complex carbohydrates as opposed to concentrated sweets reduces stool volume and enhances absorption in SBS.¹⁰ Lower fiber, complex carbohydrates are more readily digested and absorbed and should be a primary calorie/nutrient source irrespective of remaining bowel anatomy. Patients with a colon segment remaining may benefit from higher soluble fiber content, but not at the expense of reduced oral intake due to early satiety, particularly if weight gain is needed.

An emerging area of interest within the carbohydrate/starch group are the fermentable, oligo-, di-, mono-saccharides and polyols, or “FODMAPs.” FODMAPs are poorly absorbed, highly osmotic, and fermentable by gut bacteria. They are found in plant foods and liquid medications (e.g., sugar alcohols such as sorbitol and xylitol), as well as some enteral formulas (e.g., fructooligosaccharides, or “FOS”) and are associated with gas, bloating, cramping, and increased stool losses.^19-21 A modified FODMAP restriction (see Table 3) may be worthwhile in the patient who is failing routine SBS diet therapy, although further study of this approach is needed.

Lactose

While often restricted by clinicians in SBS, lactose has been shown to be tolerated by many SBS patients. Given the potential benefits of dairy foods, and because the symptoms of lactose intolerance are often dose- dependent, many people are able to tolerate at least some dairy products, especially if spread over the course of the day. In one report, patients with SBS were able to tolerate up to 20 grams of lactose per day (with no more than 4 grams from milk).^22,23 Of note, lactose is a FODMAP (see above) and, therefore, highly fermentable. Should a patient not tolerate lactose, it may not necessarily be due to lactase insufficiency.

Fiber

Patients with jejunostomies or ileostomies are commonly advised to add bulk-forming agents to their diet in an effort to thicken stool or ostomy output. While it may seem to improve the consistency of the stool, fiber can also result in the net loss of fluid from the bowel, as it not only pulls fluid from the mucosa, it also �soaks up’ fluid within the lumen, making it unavailable for absorption. Rather than thicken the fluid in the stool before it is lost to the patient’s stomal appliance, it would be better to try to enhance absorption of that fluid.24 Moreover, fiber may reduce the absorption of nutrients and, in those who are already having difficulty ingesting sufficient calories, the addition of bulking agents may further exacerbate the problem by leading to early satiety.

Despite the above, a trial of soluble fiber may occasionally be worthwhile in an attempt to slow gastric emptying and overall transit time in the SBS patient with rapid gastric and small bowel transit. Sources of soluble fiber include oatmeal, oat cereal, oat bran, lentils, apples, oranges, pears, strawberries, blueberries, nuts, legumes, ground flaxseeds, chia seeds, carrots, psyllium, guar gum, pectin, and rinds (especially dry citrus zest). These should be added slowly to give the patients GI tract time to adapt.

SBS patients with a colonic segment remaining can generate an additional 500-1000 calories per day from the absorption and utilization of short chain fatty acids that are produced by the bacterial fermentation of fiber and malabsorbed carbohydrates. Thus, the use of a moderate fat, higher complex carbohydrate diet containing fiber is recommended for the SBS patient with an intact colon.^6,10,25 Since it is more fermentable, soluble fiber is preferred over insoluble fiber.

Oxalate

Oxalate is a chemical compound found in many foods. After ingestion, oxalate generally binds to calcium within the bowel and is excreted. In patients with fat malabsorption, calcium preferentially binds to fat in the small bowel instead of oxalate. This leaves the oxalate freely available to be absorbed, but only in patients who have a portion of remaining colon, since oxalate can only be absorbed in the large intestine. After its absorption, oxalate is delivered to the kidneys for excretion (see Part I of this series). Maintaining adequate hydration and urine output is key to prevention of oxalate stones, and in some patients, dietary avoidance of high oxalate foods such as beets, spinach, rhubarb, strawberries, nuts, chocolate, tea, wheat bran, and all fresh, canned, or cooked dry beans (excluding Lima and green beans) is recommended.

Salt

Patients with SBS are at significant risk of sodium depletion. Normal stool sodium is approximately 4.8 mEq (110 mg) per day. In those SBS patients with a jejunostomy or ileostomy, daily losses can be as high as 105 mEq (2430 mg) per liter of stool. When persistent, sodium and fluid depletion may be associated with weight loss, failure to thrive, and impaired renal function.^25-27 Signs and symptoms of sodium depletion include low urine output, considerable thirst and fatigue. What makes sodium depletion difficult to appreciate in these patients is that creatinine levels may not accurately reflect renal function due to the low lean body mass many of these patients exhibit. Furthermore, serum sodium levels are usually maintained within the normal range by renin- and aldosterone-mediated renal conservation of sodium, as well as the contraction of the extracellular fluid compartment, misleading the clinician.^28,29 In patients with fatigue, overall failure to thrive and high stool output, an assessment of sodium status is advised (see Table 2).

In the patient with SBS, salty snacks are encouraged and liberal use of the salt shaker can help replace sodium lost in the stool. Salt tablets have been used, but can cause vomiting in some; in those on enteral nutrition support, salt can be added to the formula.⁵ Of course, ensure that SBS patients are not restricting salt due to comorbid conditions they had prior to developing SBS. See Table 3 and 4 for summary diet guidelines and a sample menu plan.

Vitamins/Minerals: What Makes Sense

Patients with SBS are at risk for multiple vitamin and mineral deficiencies and as such, lifelong monitoring and supplementation is needed. We recommend a baseline assessment of electrolytes and micronutrient levels (e.g., vitamins A, D, E, B12, folate, zinc, selenium, iron indices including ferritin, and essential fatty acids) should be obtained at the initial clinic visit. However, those micronutrients whose serum values are influenced by inflammatory states or infection (e.g., vitamin A, possibly D, zinc, and ferritin) should not be checked until those problems are corrected. There are no evidence- based guidelines directing which micronutrients to monitor or the optimal timing of how often to monitor them. As a consequence, the frequency of monitoring will generally depend upon the presence of existing or prior deficiencies. In the stable SBS patient on or off PN, a semi-annual assessment of micronutrients and essential fatty acids is advised. Because water- soluble vitamins are absorbed in the proximal small bowel, deficiencies in SBS patients are uncommon. In contrast, fat-soluble vitamin and essential fatty acid deficiencies are more commonly encountered and may require large doses to maintain normal plasma levels. When deficiency is identified, supplementation with aqueous preparations of vitamins A, D, and E in doses that normalize the plasma level is recommended.

Supplemental zinc, and occasionally copper and selenium, may be required in the presence of excessive stool losses. Supplementation is often based on clinical suspicion as many factors alter serum levels. Iron supplementation is not commonly needed, as iron is absorbed in the upper gastrointestinal tract, an uncommon site of resection in SBS patients. Supplemental iron may be needed if oral intake of iron is inadequate or when chronic gastrointestinal bleeding is present.

Food-bound vitamin B12 absorption will be impaired in those with more than 50 to 60 cm of terminal ileum removed.³⁰ These patients will require lifetime administration of supplemental vitamin B12. This is usually administered by injection on a monthly basis, however, synthetic oral B12 may be a preferred option in some. If oral is used, 1000 mcg/day is recommended and should be monitored the first 3, 6 and 12 months after initiating to ensure efficacy.31 In those plagued with small bowel bacterial overgrowth, a methylmalonic acid should be checked in addition to serum B12, as bacterial overgrowth not only vies with the host for ingested B12, but the B12 can be partially metabolized to inactive analogues that compete with B12 for binding and absorption.^32,33

Although many recommendations for micronutrient supplementation appear in the medical literature, very little evidence exists to guide the clinician. Hence, practitioners are left with logic and common sense when determining their approach. Until better evidence is available, encourage patients to first eat nutritious foods, then add a therapeutic multivitamin and mineral supplement, perhaps twice daily. A chewable, crushed, or liquid form may improve its bioavailability. Multiple individual vitamin and mineral supplements should be avoided whenever possible. One has to consider not only the osmotic effects these agents can have on stool output, but also the fluid needed to take them, not to mention the sheer cost of all of these supplements and the time in one’s day to take them all. For these reasons, we recommend periodically doing a “total pill count” and then asking, “is this reasonable, and does the patient have time for a life too?”

Special Consideration
Vitamin D

Patients with SBS requiring PN are at particularly high risk of vitamin D deficiency. Many factors contribute including inadequate sunlight exposure due to chronic illness; intake or tolerance to vitamin D-rich foods may be poor; dietary vitamin D may be malabsorbed; co-morbidities and medications may interfere with vitamin D metabolism; and, poor vitamin D status prior to developing SBS.³⁴ Furthermore, sustaining vitamin D is very difficult in many patients with SBS, in part due to the fact that PN solutions only contain 200 IU per day as part of the multivitamin preparation available. Serum vitamin D (as 25-OH vitamin D) and intact PTH with a baseline bone density scan should be done on all patients with SBS.

Vitamin D is one of the few individual supplements SBS patients may need in addition to a multiple vitamin/ mineral supplement. Many practitioners use 50,000 IU per week; however, some patients may do better with daily dosing if weekly dosing does not achieve efficacy.³⁵ Finally, liquid vitamin D may work when nothing else will; however, some insurance companies may need justification that other forms were not effective. Finally, direct sunlight to arms and legs,³⁶ or controlled UV exposure with a Sperti lamp (D/ UV Lamp–www.vitaminduv.com) may work in some recalcitrant patients.

Enteral Nutrition Support — When to Consider

There are few published reports of the use of home enteral nutrition (EN) support in SBS. In one recent report from a large home EN program in Canada, only 9 of 727 patients received home EN for SBS.36 Despite its apparent paucity of use in adults with SBS, in the SBS patient who cannot meet their nutrition and/or fluid needs orally, a trial of EN should be considered in an attempt to prevent the need of a central venous catheter and either PN or IV fluid support. This intervention may be most successful in those with some remaining colon, while its use in patients with an end jejunostomy may result in increased ostomy output that interferes with sleep and further impaired quality of life. If EN is pursued, we recommend a trial of nasogastric administration before considering more permanent percutaneous access. In the diet- and medication-optimized patient, it will be quite apparent early on if this plan will be successful based on change in stool losses. Administration of the formula into the stomach via continuous infusion is recommended in order to slow nutrient delivery in order to maximize nutrient:mucosal contact time, hence, optimizing absorption while limiting diarrhea.^38-43 Overnight infusion takes advantage of utilizing the GI tract when there is nothing else to compete with mucosal receptors for absorption; plus, it does not interfere with daytime activities. The use of a lower osmolality, standard polymeric formula that contains a mixture of LCT and MCT maintains mucosal structure and function and enhances bowel adaption; the addition of fiber as part of the enteral product or as a soluble fiber supplement is recommended in those patients with some colon remaining. In addition to not being superior to standard polymeric products, the hyperosmolar nature of elemental products may actually increase stool output. Finally, as there is no suitable bile salt supplement readily available, those patients with bile salt deficiency will benefit from a lower fat formula.⁴⁴

Parenteral Nutrition

Virtually all patients with SBS require parenteral nutrition (PN) support in the initial period following resection, and most will require PN at home after their discharge from the hospital. PN caloric requirements will depend on many factors such as need to gain (or lose) weight, ambulation/activity level, etc. and no one prescription fits all. PN should be initiated and adjusted to meet the patient’s fluid, electrolyte, energy, protein, and micronutrient needs. Overall energy content and macronutrient composition will depend to some degree upon the SBS patient’s oral intake and the level of repletion required. In situations of high ostomy output, increased fluid, potassium, magnesium, and zinc losses occur and need to be monitored and replaced appropriately. The amount of PN can be decreased when the patient demonstrates ability to take oral nutrition without excessive stool or ostomy output with appropriate weight maintenance or gain. In calculating PN volume and content, changes in the patient’s weight, labs, stool or ostomy output, urine output, and complaints of thirst should be considered. These patients remain at risk for micronutrient deficiencies and require periodic monitoring and supplementation in addition to PN.⁴⁵

Home PN is usually infused over 10 to 14 hours overnight in order to allow the patient freedom from the infusion pump during the day and potentially to reduce the risk of liver injury with long-term use. In some patients, the volume needed may cause high volume nocturnal urination. These patients may do better with less volume at night, and one or two liters of “chaser” IV fluids during the morning or evening before they hook up their PN for the night. Programmable infusion pumps are used by most consumers. Portable pumps that can be carried in a backpack or tote are also available for the PN consumer who needs to infuse during the day. Patient support groups such as the Oley Foundation (www.oley.org) are important sources of information on practical topics (e.g., body image, travel), education, and support and may reduce the risk of complications, enhance survival, and the quality of life of the patient receiving either EN or PN support.

CONCLUSION

Nutrition therapy is central to the successful management of the patient with SBS. Substantial and ongoing education at a level the patient/caregiver can understand from the outset is essential, and adequate time must be allotted for this purpose. As the bowel adapts and absorption improves, it is possible that diet interventions can be liberalized. Lifelong monitoring is necessary in all SBS patients and management goals often change over time. See Table 5 for additional SBS- related resources.

GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, #2

Dumping Syndrome: Updated Perspectives on Etiologies and Diagnosis

Irene Sarosiek

Dumping syndrome (DS) has historically been associated with gastric surgery and vagotomy, as well as diabetes mellitus (DM). This article provides an update on the etiologies and clinical spectrum that represent the current DS patient population.

INTRODUCTION

Dumping syndrome (DS) has long been associated with surgical procedures involving the stomach and small bowel. It was first described in 1913 as a condition which persistently afflicted a minority of gastric surgery patients. These patients exhibited postprandial gastrointestinal and vasomotor symptoms in connection with the rapid transit of chyme through the stomach. Before H. pylori was identified as the predominate etiology of chronic peptic ulcer disease, DS commonly developed after vagotomies and partial gastrectomies, which were routinely performed for the management of that condition. DS, therefore, received abundant attention in the literature during this time and valuable progress was made toward understanding its pathogenesis.

DS is the result of the rapid transit of chyme from the stomach to the duodenum. This causes the delivery of a large and hyperosmolar concentration of chyme into the small intestine. This may result in substantial hormonal and neural changes that shift fluid from general circulation to the intestinal lumen and the intestinal venous supply.i Indeed, the degree of rapid gastric transit has been positively correlated with the degree of blood volume contraction.ii Due to the release of hormones (such as VIP, serotonin, norepinephrine, and GLP-1) and autonomic responses to intestinal distension, the change of arterial blood volume may then result in the vasomotor symptoms such as weakness, faintness, and dyspnea. In addition, widespread reflex sympathetic activation may also mediate symptoms such as sweating and increased heart rate.i GI symptoms such as abdominal cramping, bloating, and diarrhea, characterize early DS, which typically begin within 30 minutes of eating.

In late DS, as in early DS, rapid gastric transit results in hyperosmolar chyme being expelled into the lumen of the small intestine. This hyperosmolarity causes a massive release of GIP and insulin in anticipation of substantial glucose absorption.^{i, iii} The humoral response turns out to be disproportionate to the occasion, however, and a reactive hypoglycemia develops. The symptoms of late dumping syndrome are explained by this reactive hypoglycemia, and include sweating, shakiness, difficulty concentrating, decreased consciousness, hunger, and sometimes syncope. The diagnosis of late dumping syndrome is made by the clinical presentation of late dumping symptoms and can be confirmed by an oral glucose test demonstrating low glucose levels sometimes less than 60 mg/dL at 2 or 3 hours.

Although the surgical treatment of peptic ulcer disease declined following the development of proton pump inhibitors, these surgeries are still performed for intractable disease. Additionally, accidental vagal nerve damage during Nissen fundoplications, as well as an increased number of gastric bypass surgeries, have kept DS very pertinent to current clinical practice.

DS may also be associated with non-surgical etiologies, the most prominent being diabetes.ⁱⁱⁱ Diabetes is a well-recognized etiology of rapid gastric emptying ^{iii, iv} and is attributed to early vagal damage from Wallerian nerve degeneration. Of course, more advanced neurodegeneration developing over time can lead to gastroparesis.

Due to the evolving etiologies of rapid gastric transit, as well as our improved understanding of its etiologies, a new characterization and profile of the symptomatic patient population with rapid gastric emptying (RGE) is warranted. This article reviewing our study further examines the distinct patient populations with RGE in the current era, with special attention to the clinical spectrum of the DS, new etiologies of DS, and diagnostic challenges.

METHODS

A retrospective chart review was conducted of patients who were referred to one of the investigators (RWM) at a tertiary GI motility center in El Paso, TX. Of the 309 patients evaluated from March 2009 to June 2012, charts were reviewed for patients with a gastric emptying test (GET) demonstrating rapid gastric transit, as well as symptoms consistent with DS.

The gastric emptying time was assessed by the standard 4-h scintigraphic method, established by the consensus recommendations by the American Neurogastroentereology and Motility Society and the Society of Nuclear Medicine.iii This standardized method for assessing gastric emptying includes a scrambled egg substitute (120 g, equivalent to two large eggs, or 60 kcal) labeled with 99mTc sulphur-colloid, two slices of whole wheat bread (120 kcal), 30 g of jelly (75 kcal), and 120 ml of water. The meal has a total caloric value of 255 kcal (72% carbohydrate, 24% protein, 2% fat, and 2% fiber). Anterior and posterior images of the stomach were taken immediately after eating, and then hourly for 4 hours (see Figure 1). Gastric retention of gamma counts was calculated by the Department of Nuclear Medicine. The geometric mean was calculated by taking the square root of the number of counts recorded on the anterior and posterior images. Data was also corrected for isotope decay. Rapid gastric transit in this study was defined as <50% isotope retention at 1 hour for women, and <35% retention at 1 hour for men. These gender- specific cutoffs are based on a study by Tougas et al.,iii which analyzed gastric transit in individuals without GI disease, and demonstrated that these cutoffs represent the 90th percentile in terms of gastric transit speed.

35 (11%) patients met these criteria for rapid gastric transit. These charts were reviewed with a focus on factors that could be attributed to the development and course of their pathophysiology. This included previous surgical procedures, diabetes mellitus, and preceding gastroenteritis-like illnesses in the period preceding the development of postprandial symptoms. In addition, attention was paid to comorbid conditions, medical treatments, and outcomes. When data on the chart was insufficient, telephone interviews were also conducted.

RESULTS

Of the 35 patients who met diagnostic criteria for DS, the mean age was 55, (ranging from 24-80 years), and 31 (88.6%) were females. The mean gastric retention at 1 hour was 27.9% for the women (5-49, SD ±15.8%) and 23.75% (20-30, SD ±4.1%) for the men. that 10 patients (28.6%) had comorbid DM (8 type II, see Table 1), 5 (14.2%) had a previous Nissen fundoplication with presumed vagal damage, and 1 (2.9%) had another surgery which caused DS (a gastric bypass, see Table 2 for surgical causes of DS). Notably, 19 (54%) patients were determined to have “idiopathic” DS, defined as the lack of an identifiable etiology of DS (see Table 3). Of these idiopathic patients, 6 (32%) were able to recall and describe an event consistent with a viral or bacterial gastroenteritis which immediately preceded their DS symptoms.

Important co-existing conditions among this patient group included 14 (40%) who reported depression, and 8 (22.9%) who reported an anxiety disorder. Additionally, 17 (48.6%) were treated for concomitant small bowel bacterial overgrowth. Migraines were identified in 5 (14.3%), and IBS had previously been diagnosed in 5 (14.3%).

It was noted that 13 patients (37.1%) had been previously labeled with a diagnosis of gastroparesis prior to their referral to our motility center, and 6 (46%) of those had been treated with metoclopramide or domperidone with suboptimal outcomes.

The treatment approaches for these patients included dietary modifications in all, dicyclomine (Bentyl) in 26 patients (74.3%), and somatostatin (Octreotide) in 6 (17.1%).

DISCUSSION

Our cutoff for defining rapid gastric transit in men and women was based on number of studies, which have demonstrated a significant difference between gastric emptying times in women and men, with women having slower transit times.iii iv v The standardized scintigraphic technique, utilized by Tougas et al., had demonstrated this discrepancy, and provided cutoff values for the 90th percentile in both men and women. We adopted these 90th percentile values as our cutoffs for defining rapid gastric transit in women and men (<35% retention at 1 hr in men; <50% retention at 1 hr in women). However, further studies will be needed to assess whether these 90% percentile cutoffs offer the optimal diagnostic sensitivity and specificity.

Our report highlights a patient population with a strong representation of non-surgical etiologies of DS. Our experiences with these patients underscore the importance of recognizing DS in those without a prior gastric surgery. Indeed, 29 patients were referred to our center over the 3 years from which data was obtained, with DS without a surgical cause. It is important to note here that our medical center does not specialize in a common cause of DS in the current era, namely bariatric surgery. This fact serves as an explanation for why our patient group was predominantely non-surgical DS. In general, surgery may lead to DS by reducing the volume of the stomach (such as in partial gastrectomy), inhibiting receptive relaxation (e.g. fundoplication), or disrupting the neural mechanisms which retard gastric emptying (occurring occasionally with vagotomy).

As we examined the non-surgical DS patients, we found a large proportion were “idiopathic”- an unexpected finding. In fact, our study involves the most idiopathic DS patients of any published study to our knowledge. As we focused on this group, we realized that although there was no demonstrable cause of the condition in these patients, the reality of their gastrointestinal dysfunction could not be overlooked. Many had severe, sometimes disabling symptoms, which was the reason for their referral to our center. In addition, previous interventions had usually not been helpful. These observations, and the proportion of patients in our study with truly idiopathic DS, underscore the importance of the awareness of this “new kid on the block” when explaining why dumping syndrome can develop. Our expectation is that increased awareness will contribute to appropriate management and referrals for these patients, and treatments with anti-motility instead of promotility agents.

In the past, it is possible that many in the idiopathic subgroup were diagnosed with non-ulcer dyspepsia. Indeed, non-ulcer dyspepsia has been associated with both rapid gastric transit and delayed.iii, iv However, Rome III criteria for functional dyspepsia only encapsulate postprandial fullness, satiety, epigastric burning, and epigastric pain.iii Therefore, DS can be clinically distinguished from non-ulcer dyspepsia on the basis of more severe abdominal cramping, as well as systemic symptoms (sweating, weakness, palpitations, etc.). If there is uncertainty about the diagnosis, and symptoms are severe, DS should be considered. In these cases a scintigraphic study can establish the diagnosis. Treatments such as diet, dicyclomine, and octreotide, rely on an accurate diagnosis of DS.

An interesting finding in our study among our idiopathic group was that 32% of idiopathic patients had experienced a preceding gastroenteritis. Although further studies would be needed to establish the veracity of this relationship, as well as the mechanism, a possible explanation for this is that these illnesses induced injury to duodenal receptors, namely fat and osmotic receptors which control gastric emptying. Another possibility is vagal nerve damage resulting in decreased fundic relaxation and accomodation, facilitating rapid emptying.

Among etiologic factors of DS in our patient group, DM was the most common. As previously mentioned, we would expect that at medical centers specializing in bariatric surgery, surgical causes of DS would make a bigger contribution. Additionally, the population of El Paso, Texas (the location of our motility center) is predominantely Hispanic, which nationality has a well-established genetic susceptibility to DM2. With the increasing prevalence of DM2, it is likely that the number of Americans with GI motility disorders will increase as well. Thus, the importance of the DM2 DS population cannot be ignored. Although long-standing DM has classically been associated with gastroparesis, previous studies have demonstrated that DM of shorter duration is linked to rapid gastric emptying.^{vi, vii} It is speculated that this RGE is due to early vagal damage, probably distal vagal damage, with gastroparesis evolving after more complete vagal loss. Although this temporal relationship is what is described in the literature, we observed DS in diabetes of long standing duration as well.

Another important conclusion to draw from our study is the utility of the scintigraphic GET. This test is key in distinguishing the diagnosis of gastroparesis from DS. Many of the patients in our study were previously labeled with gastroparesis, and indeed, some of the symptoms of gastroparesis are the same as in DS (e.g. nausea, vomiting, abdominal pain, and bloating). Some clinical differentiation may rest in the higher chance of nausea and vomiting in gastroparesis, and less severe abdominal pain than is present in DS. However, the past diagnosis of gastroparesis made in many of our patients emphasizes that gastroparesis symptoms can be almost indistinguishable from DS. Therefore gastric scintigraphy should be utilized when possible to definitively distinguish between gastroparesis and DS. Almost half our patients who had been previously labeled with gastroparesis had received prokinetics (domperidone or metoclopramide) before referral to our center. In these cases, we can assume that these treatments were not only ineffective, but also potentially worsened the symptoms. This finding underscores the usefulness of the GET.

The number of patients who identified themselves as having depression or anxiety in our study was high (49%). This finding is not surprising as it reinforces the well-known association of psychiatric disturbances with GI disease. For instance, CVS also has a high association with anxiety and depression.iii Similarly, IBS has a strong association with psychiatric illness; we have also found this to be a common comorbid condition in patients with DS. These associations between functional bowel disease and psychiatric illness emphasize the common pathogenic processes between mental health and the enteric nervous system. However, the lack of a specific diagnosis or poor response to misdirected therapies may have also contributed to the mental status of our frustrated and long suffering patients.

CRITIQUE

A potential limitation of our study was the criteria we used in the assessment of rapid gastric transit. In particular, because most studies on gastric transit testing have focused on delayed transit criteria, sufficient attention has not been paid to the early stages of the test. The early stages (first 30 minutes) are important, perhaps the most important, as this is the time frame during which early DS occurs. Thus, further studies outlining criteria for rapid emptying during earlier phases of the test might provide a more optimal method of diagnosing DS.

Our study design was not effective at identifying response to treatment in our patients. Studies addressing the effectiveness of anti-motility agents such as dicyclomine and somatostatin in DS patients would be helpful.

CONCLUSION

Many patients without a surgical history exhibit disabling DS symptoms in the setting of rapid gastric emptying. This included patients with DM2, those with a preceding gastroenteritis illness, and also those who had no predisposing factors for their symptoms. These findings emphasize a crucial role for scintigraphic GET in patients who have the symptoms of DS, even in the absence of a recent gastric surgery. This is essential to make the diagnosis of DS and effectively treat patients with this condition. Particularly in patients with DM and GI symptoms, a GET distinguished between gastroparesis and DS. With more precise diagnoses, this patient population will be better treated with focused therapies.

LIVER DISORDERS, #1

Evaluating Liver Disease in HIV-Infected Patients for the Primary Care Physician

Gaurav Singhvi,

George Tan

Patients with HIV are living longer given the improvement in antiretroviral medications, and consequently liver disease has emerged as one of the leading causes of morbidity and mortality in this cohort. Primary care providers will have to be aware of the major etiologies of hepatic injury in this special patient population. This article presents a broad overview of many major infectious and non-infectious factors that every clinician should keep in mind when managing these complex patients.

INTRODUCTION

HIV continues to be a major worldwide epidemic. Globally, there are approximately 40 million This significant decrease in mortality is a direct result of the development of HAART in the mid 1990’s.2,3 Though HAART has successfully prolonged longevity, HIV patients are now more likely to suffer significant morbidity and mortality from other disorders such as liver disease and its associated complications.4,5 In fact, liver disease has emerged as one of the leading causes of death in the HIV positive population. For example, in a retrospective chart review in a 280 bed hospital in Jamaica Plain, MA, HIV deaths due to liver disease increased from 11.5% in 1991, to 13.9% in 1996, to 50% in 1998-1999 (P = 0.003), while the rate of opportunistic infections and bacterial pneumonia declined accordingly.6 Additionally, a French mortality people living with HIV, and in the United States there are more than 1.1 million Americans infected with HIV with an incidence of nearly 60,000 new cases per year.2 In the past, many HIV patients died from pathogens that were able to invade an immunocompromised host, but more recently there has been a dramatic decline in the incidence of these fatal opportunistic infections.

This significant decrease in mortality is a direct result of the development of HAART in the mid 1990’s.2,3 Though HAART has successfully prolonged longevity, HIV patients are now more likely to suffer significant morbidity and mortality from other disorders such as liver disease and its associated complications.4,5 In fact, liver disease has emerged as one of the leading causes of death in the HIV positive population. For example, in a retrospective chart review in a 280 bed hospital in Jamaica Plain, MA, HIV deaths due to liver disease increased from 11.5% in 1991, to 13.9% in 1996, to 50% in 1998-1999 (P = 0.003), while the rate of opportunistic infections and bacterial pneumonia declined accordingly.6 Additionally, a French mortality people living with HIV, and in the United States there are more than 1.1 million Americans infected with HIV with an incidence of nearly 60,000 new cases per year.2 In the past, many HIV patients died from pathogens that were able to invade an immunocompromised host, but more recently there has been a dramatic decline in the incidence of these fatal opportunistic infections.

Evaluating Liver Disease in HIV-Infected Patients for the Primary Care Physician ?study described increasing proportions of liver death over a five-year interval (13.4% in 2000 to 15.4% in 2005), with a simultaneous rise in hepatocellular carcinoma deaths from 15% to 25% (P=0.03).⁷

Indeed, the long-term consequences of chronic liver disease is significant since it leads to a variety of grave sequelae and a decreased quality of life.5 Early effects of liver disease manifest in a variety of ways, from asymptomatic to generalized symptoms such as fatigue, nausea, loss of appetite, or abdominal pain. HIV related liver injuries may spontaneously resolve, although some patients may decompensate and develop jaundice, fibrosis, or cirrhosis, which in turn may lead to serious conditions such as gastric or esophageal varices, ascites, hepatocellular carcinoma, hepatic encephalopathy, and ultimately death. In addition to the impact on personal health, liver disease in HIV infected patients significantly increases health care costs, largely due to protracted hospital admissions.8 Before the widespread use of HAART, hepatologists rarely had a direct role in the management of HIV patients. Now, however, several studies are highlighting the need to focus on liver disease in HIV-infected patients.2 Undoubtedly, primary care physicians too will have to play an important role in the co-management of non- AIDS related HIV conditions. The aim of this article is to discuss several major etiologies (infectious versus non-infectious) and recommendations for generalists to consider when evaluating liver disease in the HIV- infected patient (see Table 1).

Infectious Hepatitis C

Of the approximately 40 million people living with HIV worldwide, roughly five million are also co-infected with the Hepatitis C virus (HCV).1 Of the 1.1 million HIV patients in the United States, 25-30% are also infected with HCV.9,10 HIV and HCV co-infection is common given the similar routes of transmission.9,11 In fact, over 60% of patients who acquired HIV infection via intravenous drug use are also infected with Hepatitis C.10 Liver disease has become a major cause of mortality in HIV patients primarily co-infected with HCV. For instance, in the North American AIDS Cohort Collaboration on Research and Design, HCV co- infected patients had an 85% increased risk of death.12 Furthermore, other cohort studies have shown that HCV related liver disease has emerged as one of the leading

causes of morbidity and mortality in co-infected persons partly due to a more rapid progression of liver disease in those with concurrent HIV infection.13 Patients with co-infection have an increased rate of progression to cirrhosis, decompensated liver disease, hepatocellular carcinoma, and death.14,15 It should be noted that although newly approved direct-acting antivirals (DAA) have the potential to cure patients infected with Hepatitis C, this may be more challenging in the HCV/HIV co-infected patient due to several barriers including high cost and adverse drug interactions between HAART and DAA.¹⁶

Hepatitis B

Similar to HCV, Hepatitis B virus (HBV) infection is also common among patients with HIV due to similar transmission routes.11 Of the 40 million people living with HIV globally, almost four million are chronically infected with Hepatitis B.1 In the United States, nearly 10% of the 1.1 million HIV patients also have HBV co-infection, with the rates of liver related morbidity and mortality higher in this group compared to patients infected with either virus alone.17 A retrospective study from an Iranian infectious disease center, which examined 124 HIV infected patients found HIV/HBV co-infected patients to have significantly higher serum AST and ALT concentrations, as well as higher rates of morbidity and mortality.18 Furthermore, it has been clearly established that HIV alters the natural history of both HBV and HCV by increasing viremia levels.9 Additionally, the histological course of HBV and HCV is exacerbated by HIV since it enhances the severity of liver fibrosis and hastens the risk of cirrhosis.19 Also worth mentioning is the fact that managing Hepatitis B in HIV co-infected patients is much more complicated due to the dual activity of several nucleoside analogues, the decreased response to interferons, and the more rapid development of lamivudine-resistant HBV.²⁰

HIV

In addition to HCV and HBV, HIV itself may play a major role in liver injury. For instance, Brau et al. found that a higher HIV RNA level was linked to a more rapid progression of liver fibrosis.21 while Mehta et al. reported that detectable HIV RNA levels (>400 copies/mL) were connected to a 3.8 fold higher risk of necroinflammation of the liver.22 Furthermore, the Swiss HIV Cohort Study showed that HIV RNA levels > 100,000 copies/mL was associated with an elevated ALT, independent of HAART.23 This independent association between greater plasma HIV-RNA levels and faster liver fibrosis progression has also been observed by others.19 Additionally, there is now growing evidence that HIV can harm the liver through both direct and indirect mechanisms. Directly, hepatic Kupffer cells and endothelial cells may be infected with HIV, and hepatic stellate cell receptors such as CXCR4 may be activated by HIV, which induces fibrogenesis.24 Moreover, abnormalities in liver function tests may be produced exclusively by direct inflammation of hepatocytes caused by HIV itself. The main mechanism theorized involves apoptosis and mitochondrial dysfunction coupled with HIV proteins, which stimulate hepatic inflammation.25 Indirectly, HIV can also damage a patient’s intestinal mucosa and alter the gut wall permeability, resulting in microbial translocation of bacterial endotoxins such as lipopolysaccharide (LPS), which has been shown to contribute to liver disease injury and progression.HBV.²⁶

Non-infectious HAART

While HIV itself may cause liver injury, its treatment may as well. Even though HAART has saved millions of lives and is one of the most successful breakthroughs in modern medicine,2 all antiretroviral medications carry the risk of hepatotoxicity. This hepatotoxicity may be associated with a single antiretroviral drug or with a cocktail of HIV medications, which are given in combination. These medication related injuries can range in severity from mild, transient elevations in liver function tests, to sudden and severe hepatic failure. Severe hepatic failure due to HAART was observed in approximately 10% of HIV patients in retrospective studies, with life threatening events appearing at a rate of 2.6 per 100 person years.8 The four primary pathways of HAART associated liver damage include mitochondrial toxicity, direct hepatocellular toxicity, hypersensitivity reactions, and immune reconstitution in the presence of HCV or HBV.¹

NAFLD

Nonalcoholic fatty liver disease (NAFLD), associated with the metabolic syndrome, is a term which comprises a spectrum of liver conditions that range from simple steatosis (fat alone) to steatohepatitis (NASH). These disorders are becoming increasingly common in HIV positive patients with and without chronic viral hepatitis. NASH is associated with advanced liver fibrosis and cirrhosis.27,28 Over the past decade it has been shown to be an early marker of cardiovascular disease as well, which is another emergent issue itself.29 The prevalence of NAFLD ranges between 14-31% in the general population,30 with approximately 6% affected by NASH.31 Unlike most other liver diseases, NAFLD remains a clinicopathologic diagnosis since there is no reliable biochemical, serologic, radiologic, or genetic marker of disease presence or severity. It is characterized by the presence of excessive fat in the hepatocytes of non-alcoholics.31 Non-invasive sonography, CT, and MRI may be effective at detecting steatosis, but only if greater than 33% of fat is present in the liver.34 The gold standard for diagnosis is liver biopsy,27 although this may be limited in many clinical care settings due to the lack of availability, the risk of complications (including pain, bleeding, and death), and the relatively high cost of the procedure.32,33 Nevertheless, NAFLD has become the most common etiology of chronic liver disease in HIV patients who do not have viral co-infection,35 as MRI and CT studies report a 37-42% rate of steatosis among HIV patients alone, and this percentage increases to 67% among those with HBV or HCV co-infection.36 Linking of steatosis to NAFLD involves an association with the metabolic syndrome, which involves visceral obesity, insulin resistance and diabetes mellitus, hyperlipidemia (especially hypertriglyceridemia), and hypertension.37,38 These metabolic abnormalities may accelerate liver fibrosis,38 and the rates of NAFLD in HIV patients will continue to rise as the degree of obesity and metabolic syndrome become more prevalent in the community.³¹

Overlapping Etiologies

While many individual etiologies of hepatic injury in HIV patients have been discussed so far, the underlying mechanism is most likely a more complicated, interactive, and multifactorial process, which is best summed up pictorially (Figure 1). As mentioned earlier, HIV itself or its treatment may cause liver damage. Therefore, since HIV RNA and HAART are opposing mechanisms of liver damage, HAART induced damage could be more noticeable in patients with well- suppressed viral loads, while HIV RNA generated hepatic injury might be more readily seen in patients with poorly controlled HIV viral loads.24 In addition, HAART related hepatotoxicity may be more likely to develop in patients with underlying HCV or HBV. For instance, studies indicate that HIV/HCV co-infected patients have higher degrees of liver fibrosis and an accelerated progression of liver disease,39,40 while HIV/ HBV co-infected patients on HAART are susceptible to clinically significant hepatotoxicity.17 Antiretroviral medications may also lead to the development of metabolic syndrome,31 with one mechanism seen in the protease inhibitor associated development of insulin resistance and dyslipidemia, both of which are risk factors for steatosis.41 Steatosis itself may cause liver damage, but it may also sensitize the liver making it more susceptible to inflammatory and immune mediated injuries.24 Both HAART and HBV/HCV co-infection may also affect the liver via immune mediated injury as well.1 Furthermore, alcohol and other hepatotoxins may exacerbate liver toxicity, and like HBV/HCV co- infection, this may directly cause mitochondrial injury in the liver and promote hepatic steatosis.^1,6,30

Recommendations for the Primary Care Provider (See Table 2)

Based on experience from managing other chronic medical conditions, primary care providers should be highly capable of overseeing and coordinating a multidisciplinary approach to HIV care. In fact, a study involving 5,247 patients linked to 177 physicians (102 generalists and 75 infectious disease specialists) showed that PCPs with experience in HIV management were able to provide high-quality care to complex HIV patients.42 Indeed, when working together with a team of specialists, there are several things that internists may do to help co-manage liver disease in HIV patients. First, the PCP should obtain baseline liver function tests and periodically monitor for hepatotoxicity. While evaluation of the risk versus benefit for many medications continues to be a dilemma for regulatory agencies, the US Food and Drug Administration (FDA) defines hepatotoxicity as aminotransferase levels exceeding three times the upper limit of normal and/or when bilirubin levels are more than twice normal.1 Next, all HIV patients should be screened for viral Hepatitis A, B and C, and if non-immune, these patients should be vaccinated against both HAV and HBV since the increased severity of hepatitis in patients with preexisting liver disease is significant.8,11 While there is currently no vaccine for the Hepatitis C virus, HIV patients should be educated on transmission patterns and counseled on safe sex and the risk of needle sharing.11 Along similar lines, excessive alcohol intake has been observed in one-third of HIV-infected individuals30 and clinicians should advise these patients to avoid consumption and limit the exposure of other 11 hepatotoxins such as acetaminophen. In addition, primary care providers should always encourage a healthy diet and exercise, since lifestyle may play a significant role in the development of liver disease among HIV patients. Studies have not only shown a link between BMI, high cholesterol levels, and diabetes in liver disease progression,26 but they have also highlighted the fact that optimum nutrition can improve the quality of life for persons living with HIV/AIDS, slow the progression of HIV to AIDS, and improve the tolerance to antiretroviral therapy.42 Lastly, health care providers must reinforce medication adherence, as there is a huge potential for adverse outcomes given the possibility of drug resistance, treatment failure, and progression of disease if medications are utilized inappropriately.⁴³

CONCLUSION

As patients with HIV are living longer and experiencing increasing morbidity and mortality from liver disease, primary care providers will have to be aware of the major etiologies of hepatic injury in this special patient population. This article presented a broad overview of many major infectious and non-infectious factors that every clinician should keep in mind when managing these complex patients. Internists will continue to play an important role in disease management of these patients in the future, and since primary care providers often develop a long lasting relationship and rapport with their patients, this provides an ideal setting for generalists to screen HIV patients for co-infections, vaccinate the non-immune, encourage healthy lifestyles and emphasize medication adherence at every visit. This reinforcement at both the primary care and specialty levels will ensure that patients do not receive fragmented care or conflicting information, but rather obtain coordinated care from health care providers working together to provide the best care for their patients.

LIVER DISORDERS

Introduction to a New Series: Liver Disorders

Rad Agrawal

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

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

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

A CASE REPORT

A Rare Complication of PEG Tube Placement

Tanmayee Bichile,Thandar Aung,John Vainder

INTRODUCTION

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

CASE PRESENTATION

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

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

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

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

DISCUSSION

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

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

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

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

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

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

CONCLUSION

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

INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #90

Diagnosis and Management of IgG4-associated Pouchitis

Darren N. Seril,Bo Shen

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

INTRODUCTION

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

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

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

IgG4 Immunobiology and Pathogenesis Properties of IgG4

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

IgG4 and Autoimmune Pancreatitis

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

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

IgG4 and Pouchitis

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

Pouchitis and Elevated Serum IgG4 Levels

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

IgG4 Histology in Pouchitis

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

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

Pouchitis and IgG4-related Disease

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

Diagnosis Of IgG4-Associated Pouchitis
Measurement of Serum IgG4 Levels

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

Pouch Endoscopy and IgG4 Histology

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

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

Other Serologic and Radiologic Evaluations

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

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

Clinical Presentation and Disease Course

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

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

IgG4 and Implications for Treatment Corticosteroid Therapy

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

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

Immunomodulators and Anti-TNF-? Therapy

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

B-cell Targeting Therapy

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

SUMMARY

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

The authors declare no financial conflicts of interest.

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

UNUSUAL CAUSES OF ABDOMINAL PAIN, #6

Unusual Causes of Abdominal Pain

George W. Meyer

CASE

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

UNUSUAL CAUSES OF ABDOMINAL PAIN

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

ANSWER AND DISCUSSION

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

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

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

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

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

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #133

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

Wendy Phillips

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

INTRODUCTION

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

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

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

Defining Malnutrition

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

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

Identifying and Treating Malnourished Patients

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

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

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

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

Capturing the Malnutrition Diagnosis for MS-DRGs

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

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

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

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

CONCLUSION

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

FRONTIERS IN ENDOSCOPY, SERIES # 13

Endoscopic Ultrasound Guided Intervention for Gastric Variceal Bleeding

Larissa L. Fujii-Lau,

Louis M. Wong Kee Song,

Michael J. Levy

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

INTRODUCTION

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

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

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

EUS Detection of Gastric Varices

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

EUS-Guided Coil Injection
Technique

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

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

Clinical Application

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

EUS-Guided Cyanoacrylate Injection
Technique

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

Clinical application

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

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

EUS-Guided Combined Coil and Cyanoacrylate Injection

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

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

EUS-Guided Portosystemic Gradient Measurement and Shunt Placement

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

SUMMARY

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