Page 61 – Practical Gastro

The etiologies of dysphagia are myriad, including intrinsic disorders of the esophagus, such as neoplasia, stricture, severe reflux disease and motility disorders. Extrinsic etiologies of dysphagia include compression from adjacent lymph nodes or vascular structures. The importance of extrinsic compression is emphasized in this case of a patient presenting with the acute onset of dysphagia to solids, found to have compression of the esophagus secondary to a tortuous aorta. Despite a relatively normal endoscopic exam, this patient demonstrated significant pathology during follow up barium esophagram. Clinical signs and symptoms cannot reliably distinguish extrinsic from intrinsic causes of dysphagia and thus dysphagia aortica, which can be associated with imminent aneurysmal rupture, should be considered in elderly patients with acute onset dysphagia.

Giulio Quarta MD, David M. Poppers MD, PhD, NYU School of Medicine, NYU Langone Medical Center, New York NY, Division of Gastroenterology

INTRODUCTION/PRESENTATION

Extrinsic and intrinsic causes of dysphagia are challenging to distinguish from one another, as they often present with similar signs and symptoms. Dysphagia due to any anomaly of the aorta is called dysphagia aortica. In this case we highlight the importance of contrast-enhanced esophagram in an elderly patient presenting with acute onset dysphagia.

A 91 year-old man with a history of gastroesophageal reflux, hyperlipidemia and coronary artery disease presented with the abrupt onset difficulty swallowing solids, associated with an unintentional weight loss of seven pounds over two months. Solid foods such as bread and potatoes were associated with intermittent symptoms. He denied odynophagia, distracted eating and did not wear dentures. Laboratory analysis, including serum hemoglobin and iron studies, was unremarkable.

Initial evaluation included an upper endoscopy which demonstrated a normal caliber esophagus and unremarkable squamocolumnar junction at 43cm from the incisors. The gastric mucosa in the antrum showed a patchy erythematous pattern; biopsies revealed reactive gastropathy without intestinal metaplasia or Helicobacter pylori. Chest X-ray revealed a prominent thoracic aorta with widening of the cardiac silhouette. A single-contrast barium esophagram revealed a dilated esophagus with extrinsic narrowing by a tortuous aorta and delayed esophageal emptying in the semi-upright position. Of note, cross sectional abdominal imaging revealed a normal aorta and branches.

Discussion

Pape first described dysphagia aortica in 1932, affecting women with short stature, old age, hypertension and kyphosis.¹ Compression of the esophagus can originate from tortuosity, dilation or aneurysm of an atherosclerotic aorta. Barium esophagram has been shown to be the most reliable method of diagnosis of this condition, and thoracic computed tomography (CT) facilitates early diagnosis. On endoscopy, pulsatile extrinsic compression resulting in stenosis with proximal esophageal dilation is considered diagnostic. Manometry can reveal local high-pressure regions associated with cardiac pulsation.² In cases of thoracic aortic aneurysm, endovascular repair is associated with significant improvement in symptoms and morbidity.³ Mild cases of dysphagia aortica are typically treated conservatively, and patients who are not surgical candidates may be managed with insertion of a percutaneous gastrostomy tube.² Dysphagia aortica is rarely considered in the differential diagnosis of dysphagia. Vascular extrinsic esophageal conditions such as dysphagia lusoria, in which esophageal compression from an aberrant right subclavian artery may produce a similar clinical presentation, should also be considered. Lack of awareness can lead to a significant diagnostic delay. Fatal cases of thoracic aorta aneurysmal rupture have been reported,⁴ especially when associated with alarm features such as chest or back pain. However, intrinsic etiologies of dysphagia, such as esophageal spasm or invasive esophageal cancer, may also be associated with similar symptoms, often confounding and delaying timely diagnosis and intervention. Routine imaging such as chest X-ray or thoracic CT can quickly and non-invasively be diagnostic. In elderly patients with kyphosis and hypertension presenting with dysphagia, we suggest that such conditions be entertained in the differential diagnosis, and that timely use of imaging studies be utilized to evaluate for extrinsic causes of dysphagia.

Gastrointestinal Motility And Functional Bowel Disorders, Series #21

Belching, Aerophagia and Rumination: Not Just Refractory Gastroesophageal Reflux Disease

Il J. Paik,

Craig R. Gluckman

High-resolution manometry and impedance studies have allowed physicians to now more confidently identify subtle differences between belching, aerophagia and rumination. Here, we discuss our increased ability to diagnose and differentiate patients with these and other related conditions and to treat often closely related entities.

Il J. Paik, MD, Assistant Professor of Medicine- Gastroenterology. Icahn School of Medicine at Mt Sinai. Director, Swallowing Center of the Mt Sinai Health System Digestive Disease Institute Director, Center for GI and Motility Disorders. Mt Sinai St Luke’s and Mt Sinai West Hospitals. Craig R. Gluckman, MBBCh, Gastroenterology Fellow, Mount Sinai Beth Israel, New York, NY

Widespread availability and utilization of esophageal impedance recording and pH monitoring in specialized motility centers has improved our understanding of belching, aerophagia and rumination. This new understanding has increased our ability to diagnose and differentiate patients with these and other related conditions. As the pathophysiology of these heterogeneous group of disorders becomes clearer, our ability to treat often closely related entities continues to improve. This benefits patients, who have often gone undiagnosed or incorrectly labelled, as well as the primary care doctors and gastroenterologists caring for these patients. Impedance studies, differentiating and diagnosing these very different conditions, has improved our understanding of gastroesophageal reflux (GERD) and its relationship to these disorders. High-resolution manometry and impedance studies have allowed physicians to now more confidently identify subtle differences between belching, aerophagia and rumination resulting in the correct treatment options being applied to these patients.

BELCHING
Introduction

Excessive belching has become one of the most common chief complaints that physicians address. Patients often present after an unremarkable endoscopic evaluation and clinical failure on multiple regimens of proton pump inhibitors (PPIs) and other acid- suppressing medicines. Historically, the diagnosis of excessive belching required a careful history and close observation during physical examination. Patients often describe a variety of symptoms and sensations to explain the act of belching as a primary symptom or in association with other upper gastrointestinal symptoms. This has led to a discrepancy between the subjective symptoms described by the patient and the ability of the clinician to make an objective diagnosis. An incomplete understanding of the pathophysiology of belching, aerophagia and rumination and the lack of diagnostic tests may have led to this discrepancy.

Currently, newer esophageal impedance testing now allows more accurate differentiation between these various conditions. Specifically, differentiating between various types of belching and correctly identifying it as an isolated condition or as a concomitant symptom in patients with GERD or functional dyspepsia is possible. This testing allows clinicians to improve their evaluation of patients with symptoms such as dysphagia, epigastric pain, persistent reflux and heartburn.

Belching (eructation) is the oral expulsion of a gas bolus from the upper gastrointestinal tract; this release can be audible or occur silently.¹ Gases, a normal constituent of the gastrointestinal tract, enter the esophagus and moves to the stomach with each swallow. Gases can also be released in the stomach by ingested food and drink. In the small intestines and colon, gases are produced by bacterial fermentation of luminal contents. These gases are released from the gastrointestinal tract proximally in the form of a belch and distally as flatus.²

Many patients with belching may not initially present to a healthcare provider. However, patients are likely to seek attention if their belching is responsible for a decreased quality of life or at the request of friends, family or co-workers. Patients with GERD and functional dyspepsia frequently complain of belching, but other symptoms usually predominate. Studies show that an excess of air swallowing and belching in these patients is a response to uncomfortable gastrointestinal sensations.³ Treatment with a PPI reduces the number of air swallows in patients with GERD but not in other subjects, which suggests that the unpleasant sensation of heartburn stimulates patients to swallow more air.⁴ So, belching is the physiological venting of excessive gastric air.⁵

Pathophysiology of Belching

The mechanism of belching has further been elucidated through the use of manometric studies and esophageal electrical impedance monitoring. (Figure 1) Air and saliva are pushed down through the esophagus into the stomach by peristalsis as the lower esophageal sphincter (LES) relaxes. Gastric air causes dilation of the proximal stomach and activates a vaso-vagal reflex. A belch begins with a transient lower esophageal relaxation (TLESR) triggered by distension of the fundus from this intragastric air and movement of air begins from the stomach into the distal esophagus. This is then followed by reflex relaxation of the upper esophageal sphincter (UES) as air moves up towards the proximal esophagus and then expelled orally. This physiological response of venting excessive gastric air is what the patient will perceive as a belch. This gastric belch reflex releases the uncomfortable sensation associated with gastric distension and is the gaseous equivalent of gastroesophageal reflux as both occur in the setting of a spontaneous and not swallow-induced TLESR. This gastric belch reflex is lost following a fundoplication procedure done for anti-reflux surgery as the ability for proximal stomach distension and TLESR are decreased. These patients are physically unable to belch and are often left with the uncomfortable sensations of bloating, flatulence and abdominal distension⁶, often referred to as the post-fundoplication gas-bloat syndrome.

This gastric belch needs to differentiated from a second type of belch identified in patients with isolated excessive belching. Initially detected in the 1990s with the use of intraluminal esophageal impedance monitoring of the flow of fluid and air in the esophagus, a new mechanism of belching was described. Now known as a supragastric belch, this second type of belching, which is physiologically different from a gastric belch, is characterized by air rapidly brought into the esophagus and immediate, rapid, oral expulsion without ever reaching the stomach. Combined use of high resolution manometry and impedance monitoring has discovered that this belch may be initiated by air which is sucked into the esophagus by creating a negative intrathoracic pressure or less commonly by pushed or injected air from an increase in pharyngeal pressures.⁷ This also identified patients with repetitive and multiple, instantaneous supragastric belches as only occurring in patients with supragastric belches and not with gastric belches.⁸

Impedance studies, with or without manometry, can now accurately differentiate patients with gastric belching from supragastric belching and other mimickers. From these studies, a supragastric belch has been defined as a rapid anterograde movement of gas (impedance >1000Ω), followed by its quick retrograde expulsion with a return to baseline impedance. (Figure 2) The incidence of air-containing swallows and gastric belches is similar in patients and controls but supragastric belches occur exclusively in affected patients.⁹

Initially a supragastric belch represents a voluntary response to an unpleasant gastrointestinal sensation, but over time patients may no longer be aware that their belches are under voluntary control, thus becoming excessive and repetitive. Supragastric belches almost always cease at night suggesting the presence of a behavioral disorder.¹⁰ Additional studies have shown that patients with excessive belching who were unaware that they were being studied or were distracted during the study had significantly reduced numbers of belches.¹¹ Typically, a patient belches while the physician is asking the questions, whereas a patient does not belch while responding to these questions.¹² These studies support the rationale for behavioral therapy as a method of treatment.

The estimated prevalence of supragastric belching in a tertiary referral population is 3.4% in patients being investigated with upper gastrointestinal symptoms.¹³ Not all patients diagnosed with supragastric belching report belching as their predominant symptom and, conversely, many patients who report excessive belching are not in fact belching by current manometric criteria.

Patients with esophageal hypomotility on high resolution manometry demonstrate an increase in the frequency of supragastric belching compared to the patients with normal motility.¹⁴ It is unclear whether the hypomotility led to supragastric belching or if some factor in patients with supragastric belching affected motility patterns. Further studies are needed to investigate this possible association.

Belching in Patients with GERD

Estimates of 40-49% of patients with GERD experience belching.¹⁵ Air swallowing promotes belching but does not facilitate acid reflux.¹⁶ Similarly, supragastric belching was more frequent in patients with typical reflux symptoms than in healthy subjects. Supragastric belches occur immediately prior (<1s) to the onset of the reflux episode suggesting that the supragastric belching occurs in response to the unpleasant sensation felt in those with reflux.¹⁷ Patients with severe reflux symptoms have more supragastric belching and subsequently more severe belching complaints. Thus, it has been suggested that GERD patients with troublesome belching symptoms could also be treated with speech therapy aimed at reducing the incidence of supragastric belches.¹⁸

Treatment of Belching

Supragastric belching is associated with significant reduction in quality of life and distressing psychosocial repercussions.¹⁹ Given that supragastric and excessive belching are likely behavioral disorders, cognitive behavioral therapy can be used as a treatment strategy. The primary step in treatment is offering reassurance and a thorough explanation of the cause of the belching. Speech therapy and breathing exercises can be utilized. Patients should be educated on modifying their habits, as supragastric belching is a self-induced, learned behavior.²⁰ For example, breathing exercises with the emphasis on abdominal breathing reduce the belching episodes through behavior modification.

Gum chewing has no effect on the frequency of gastric or supragastric belches, but in fact may exacerbate belching disorders by increasing the amount of air and saliva swallowed.²¹ Simethicone and similar drugs have not been found to be beneficial in patients with belching. Baclofen, a GABA_B receptor agonist, used in patients with refractory GERD to decrease TLESR, has been studied for its use in patients with belching. It was found to be effective in reducing both supragastric belching and aerophagia²² thus providing complementary therapy to behavioral modification.

Aerophagia

It may be difficult to differentiate aerophagia (Greek for ‘air eating’) and excessive belching. However, these two conditions are very different in terms of the direction of air movement in and out of the mouth and esophagus. Patients with aerophagia swallow air too often and in large quantities. In aerophagia, peristalsis of the esophagus actively moves air down the esophagus into the stomach, whereas in supragastric belching there is no esophageal peristalsis. Furthermore, a supragastric belch is completed within one single second, in contrast to aerophagia.²³ Intraluminal impedance monitoring has allowed accurate differentiation of these two conditions. (Figure 3) Supragastric belching is not a predominant symptom in patients with aerophagia but they do experience gastric belching episodes. Patients with aerophagia have symptoms of bloating, distension and flatulence. An abdominal X-ray may show increased intragastric and intra-intestinal air. The management of aerophagia is based on expert and local opinion as no standard treatment exists. Consideration of speech therapy could be considered, but no published reports exist.²⁴

Rumination

Rumination is an eating disorder characterized by recurrent regurgitation of recently ingested food or liquid into the mouth, followed by re-chewing, re- swallowing or expulsion. The effortless regurgitation of these recently ingested gastric contents occurs within 15-20 minutes of intake. The event is often proceeded by belching before fluid and food are regurgitated.²⁵ This condition was thought to predominantly occur in adults and children with developmental delay, but it also occurs in otherwise healthy people. Rumination was traditionally diagnosed based on the history provided by the patient, but esophageal manometry and impedance studies can be used to confirm the diagnosis. The characteristic manometric pattern of rumination shows an abrupt rise in intragastric pressure followed by an increase in intra-esophageal pressure in all channels. (Figure 4) This pressure rise has been referred to as the “R” wave, and occurs when the patient is asked to drink a liquid or swallow food. The importance of a diagnostic test in rumination syndrome is to exclude other conditions that present with postprandial vomiting and regurgitation such as achalasia and GERD. The mainstay of treatment for this condition is a thorough explanation of the disorder followed by behavioral therapy and breathing exercises to distract the patient while eating. In addition, rumination syndrome is associated with the setting of great stress and emotional factors, therefore often requiring concomitant care with a psychologist or counselling. Tricyclic antidepressants are also very helpful during the breathing and relaxation/ distraction approach.²⁶

CLINICAL PEARLS

Major advancements have been made in recognizing and differentiating belching, aerophagia, rumination and GERD as distinct clinical entities largely through the use of esophageal impedance. Supragastric belching differs from gastric belching in terms of its pathophysiology and often becomes a behavioral response to some ongoing, unpleasant gastrointestinal sensation like GERD. Reflux symptoms occur more commonly in patients with supragastric belching than in healthy controls. Patients with aerophagia have gastric belching due to excessive air swallowing. Rumination syndrome can be accurately diagnosed with impedance studies. Breathing exercises to distract the patient as well as behavioral therapy are the mainstay of treatment. It is hoped that as our understanding of these conditions continues to evolve, newer treatment options will also become available for these patients.

Nutrition Issues In Gastroenterology, Series #161

Lactic Acidosis: A Lesser Known Side Effect of Thiamine Deficiency

Kelly O’Donnell

A lesser known cause of elevated lactate levels in the critically ill patient is thiamine deficiency. Thiamine is a water soluble vitamin essential for carbohydrate metabolism. Given limited stores along with daily requirements, thiamine deficiency may occur quickly in patients presenting with persistent vomiting, malnutrition and alcoholism. The purpose of this paper is to help identify those patients at risk for thiamine deficiency and recognize signs and symptoms of deficiency including, but not limited to, elevated lactate levels.

INTRODUCTION

Lactate, produced by most tissues in the body, is an end product of anaerobic metabolism. Reasons for elevated lactate levels include, sepsis, shock or tissue hypoperfusion, ischemic bowel, uncontrolled source of infection, liver dysfunction, medications and thiamine deficiency, to name a few. Lactate is often used as a marker of illness severity with elevated levels associated with adverse outcomes and mortality as high as 80%.¹

Thiamine is a water-soluble vitamin with limited tissue storage. When oral intake is reduced, stores may be consumed in as quickly as 18-20 days.² Thiamine is a cofactor for pyruvate dehydrogenase during aerobic metabolism (glycolysis), facilitating the conversion of pyruvate to acetyl-CoA within the mitochondria. If a thiamine deficiency exists, pyruvate is unable to enter the citric acid cycle, instead being converted to lactate, which may lead to lactic acidosis.^3,4

Thiamine deficiency is largely a clinical diagnosis and if left untreated, may result in irreversible neurologic damage. Therefore, waiting for lab confirmation to confirm a deficiency is not advised. Moreover, plasma and serum thiamine levels have a low sensitivity and specificity, and are decreased in critically ill trauma patients and those requiring continuous renal replacement therapy.^3,5 Whole blood assays may be a better reflection of total body stores, but are impractical in an acute care setting due to cost or long turnaround time which can take up to 2 weeks. Additionally, there is not a specific blood level that correlates with the appearance of signs and symptoms of deficiency. Identifying patients with risk factors such as alcoholism, persistent emesis, and malnutrition is the key to detecting thiamine deficiency.^3,5-7 (see Table 1).

There are two major clinical manifestations of thiamine deficiency: Dry beriberi, which includes peripheral neuropathy and gait ataxia; more advanced symptoms include Wernicke’s encephalopathy with its classic triad of ataxia, confusion and ocular changes.^3,5,8 Wet beriberi includes high output heart failure, cardiac hypertrophy (especially of the right ventricle), lactic acidosis, and edema in lower extremities.^3,5,8,9 (See Table 2).

Case

A 35-year-old female with a history of bipolar disorder and prior self-inflicted abdominal injury, resulting in exploratory surgery and bowel resection, recently presented to surgery clinic for evaluation of her ongoing abdominal pain, daily vomiting and reflux symptoms. She was referred to gastroenterology and underwent esophagogastroduodenoscopy and manometry, which showed:

LA Grade C reflux esophagitis
Hiatal hernia
Erythematous duodenopathy
Lower esophageal sphincter hypotension

The hiatal hernia was felt to be contributing to her gastroesophageal reflux disease and esophagitis, as well as cholelithiasis precipitating her biliary colic. She was subsequently admitted to the hospital and underwent an elective laparoscopic Nissen fundoplication, hiatal hernia repair and cholecystectomy. In the operating room, she was noted to have significant steatosis with hepatomegaly. Despite this, her operation was completed successfully and she was transferred to the regular surgical floor post-operatively. When questioned about the appearance of her liver, the patient acknowledged a “few drinks” per week. A nutrition evaluation revealed that the patient had suffered a severe weight loss of 26 pounds (180 down to 154 lbs. or a 15% loss over the previous 3 months) from frequent vomiting and an inability to eat. This prompted the initiation of 100 mg of intravenous (IV) thiamine per day starting on post- operative day (POD) 1; a clear liquid diet was begun and intravenous normal saline continued. Liver function tests peaked on POD 2 with alkaline phosphatase rising to 22 U/L (40-150 U/L), ALT 62 U/L (<55 U/L) and AST 329 U/L (<35 U/L). During this time, lactic acid ranged from 1.0 to 1.3 mmol/L (0.5-2.2 mmol/L).

On POD4, she experienced confusion and dyspnea with a chest x-ray demonstrating bilateral pulmonary infiltrates suggestive of acute respiratory distress syndrome. She was transferred to the intensive care unit (ICU) and intubated. Her course was further complicated by severe lactic acidosis requiring a bicarbonate drip, sepsis requiring high dose vasopressors, and renal failure requiring continuous renal replacement therapy (CRRT). Low calorie parenteral nutrition with an additional 200 mg thiamine to avoid refeeding syndrome was initiated upon transfer to the ICU. She also continued to receive 100 mg IV thiamine. Although broad spectrum antibiotics were started, all percutaneous and central line blood cultures continued to be negative. A transthoracic echocardiogram showed a mildly dilated right ventricle.

On POD6, given persistent lactic acidosis and unable to identify a source of her sepsis, the patient returned to the operating room where she underwent a diagnostic laparoscopy converted to exploratory laparotomy with findings of 20-30 cm of dusky, dilated jejunum, but no evidence of spillage, injury, or septic source within the abdomen.

At this time, the patient’s family was again questioned about her alcohol use and it was revealed that the patient engaged in heavy drinking of 5-6 drinks per day up until the time of hospital admission. Based on this new information, as well as the preoperative excessive weight loss with persistent vomiting, a mildly dilated right ventricle, in addition to her lactic acidosis of unclear etiology, it was presumed the patient was thiamine deficient and thiamine was repleted aggressively with 500 mg IV three times per day over the next 3 days, followed by 250 mg IV thiamine daily for four more days.

Results

Supplementation with high dose IV thiamine was associated with a rapid reversal of lactic acidosis and a greater than 50% decrease in lactic acid levels within 8 hours (14.0 to 6.1 mmol/L) (see Table 4). Normalization of lactic acid levels occurred within 18 hours (POD7). Three days later, on POD10, she was weaned off pressor support and continuous renal replacement therapy was discontinued. She was extubated on POD 14. The patient subsequently underwent fascial closure, placement of retention sutures and was eventually discharged to a rehabilitation facility. Although liver failure and shock liver were considered as potential causes of her lactic acidosis, they typically take many days to weeks to correct.

DISCUSSION

Elevated lactate levels are often used as a prognostic tool in critical illness. There are many causes of lactic acidosis including sepsis, systemic hypoperfusion, medications and thiamine deficiency. Thiamine is essential for producing energy from glucose in the glycolytic pathway, but if a deficiency exists, pyruvate is instead converted to lactate (see Figure 1).

There is large variability in thiamine prescribing practices, most revolving around the treatment of alcoholics. Only one randomized, double blind study using different doses of parenteral thiamine exists to date.¹⁰ A therapeutic effect was seen with the 200 mg dose of intramuscular thiamine in alcoholic patients taking a memory test. However, the sample size was small, there was a high rate of non-completion and thiamine administration was of short duration (2 days).

Thiamine is both inexpensive and safe. Because of the potentially devastating effects of undertreating thiamine deficiency, recommendations of higher doses have appeared in the literature.¹¹ In the United Kingdom, 500 mg IV thiamine 3 times daily is prescribed followed by 250 mg IV or IM for 5 days.¹² The European Guidelines suggest 200 mg IV three times daily until symptoms resolve.¹³ American guidelines suggest the lowest amounts of thiamine, ranging from 50-100 mg IV daily for a period of at least 3 days.¹¹ (see Table 3).

Thiamine deficiency as a cause of lactic acidosis in the critical care setting may be undiagnosed or misdiagnosed as a symptom of sepsis or hypoperfusion. In a prospective, observational study, Donnino and colleagues found that 10% of septic ICU patients (n = 30) had thiamine deficiency on admission, and an additional 10% developed a deficiency within 72 hours, yet only one of the 6 deficient patients received thiamine during their hospitalization. According to the authors, this was due to a lack of clinical recognition. Overall, there was no correlation with thiamine and lactate levels, however, when patients with acute liver injury were excluded, there was a significant negative correlation between thiamine and lactic acidosis.⁴

Two recent reports involving lactic acidosis due to thiamine deficiency were attributed to parenteral nutrition with limited or no multivitamins.^14,15 All patients were admitted to the ICU and treated with 100 mg IV thiamine and within hours experienced a rapid decrease in lactate levels and ultimately a full recovery. In another case report, a 56-year-old alcohol misuser with recent weight loss and mild malnutrition was admitted to the ICU with lactic acidosis.¹⁶ He was treated with 300 mg IV thiamine and lactate levels normalized rapidly. This patient, however, experienced persistent cognitive deficits.

Of note, thiamine may be lost in critically ill patients receiving continuous renal replacement therapy (CRRT). In a prospective randomized crossover trial by Berger, et al., 11 intensive care patients on CRRT had trace element and thiamine levels analyzed during CCRT. Trace elements including copper, selenium, and zinc, as well as thiamine, were found in the effluent of each patient. Hence, patients on CRRT may need higher doses of thiamine, especially if they are malnourished or alcohol misuers prior to the initiation of CRRT.¹⁷

CONCLUSION

Elevated lactate levels are often found in critically ill patients, most often due to hypoperfusion. Thiamine deficiency as a cause of lactic acidosis in the critical care setting may be underdiagnosed. This particular case study patient was admitted to the hospital with 3 major risk factors for thiamine deficiency including alcoholism, persistent vomiting, and severe malnutrition. Upon transfer to the ICU, she exhibited symptoms of wet beriberi including dyspnea, respiratory distress, oliguria, mild right ventricular hypertrophy and lactic acidosis. No source of sepsis was ever identified. It is unknown whether thiamine supplementation is solely responsible for the decrease in lactate levels; however the rapid drop after intravenous administration is consistent with other case studies in the literature. At the very least, it was thought to have been an important component of her clinical response. In retrospect, it would have been ideal to have obtained a baseline plasma thiamine level to compare to the patient’s risk factors, signs and symptoms, the caveat being that waiting for blood draw results did not delay empiric treatment. Curiously, 100 mg of thiamine did not appear adequate to prevent lactic acidosis and only with the delivery of higher doses did this malnourished alcohol misuser respond. In addition, it may be that the CRRT pulled off a portion of the thiamine she received. Current guidelines for thiamine deficiency are not specific for the treatment of severe, life-threatening complications and more evidence is needed to clarify the appropriate dosage. Although most critical care practitioners would assume this case was a result of either septic shock lactic acidosis (∼ 25% of septic shock cases a source for infection is not found, nor do cultures grow anything), lactic acidosis from bowel ischemia (with the dusky bowel), lactic acidosis from poorly functioning liver and kidneys, or a combination of all three. However, in unexplained cases of lactic acidosis in a patient not responding as expected, consider thiamine deficiency. It is inexpensive and easy to treat.

Dispatches From The Guild Conference, Series #2

Pregnancy and Inflammatory Bowel Disease

Abhik Roy,

Uma Mahadevan

While IBD increases the risk of certain pregnancy complications and adverse pregnancy outcomes, active disease further increases these risks while sustained remission maximizes maternal and fetal health. A multidisciplinary team emphasizing the importance of medication adherence to achieve preconception disease control and maintain remission throughout pregnancy is recommended. Medication adjustments to reduce fetal exposure may be considered on an individualized basis in quiescent disease. The mode of delivery is determined by obstetrical indications, except for women with active perianal disease who should consider cesarean delivery.

Women with inflammatory bowel disease (IBD) often deal with the illness and its consequences during their childbearing years. Most will have safe pregnancies and healthy children, but there remains significant anxiety and misperceptions about fertility, pregnancy complications and medication toxicities. While IBD increases the risk of certain pregnancy complications and adverse pregnancy outcomes, active disease further increases these risks while sustained remission maximizes maternal and fetal health. A multidisciplinary team should emphasize the importance of medication adherence to achieve preconception disease control and maintain remission throughout pregnancy. Most medications, including aminosalicylates, thiopurines, and biologic agents, are low risk during pregnancy and compatible with breastfeeding. Medication adjustments to reduce fetal exposure may be considered on an individualized basis in quiescent disease. The mode of delivery is determined by obstetrical indications, except for women with active perianal disease who should consider cesarean delivery.

INTRODUCTION

The incidence of inflammatory bowel disease (IBD) peaks during the childbearing years, and the complexities of family planning and IBD management often coincide. Although most patients with IBD have successful pregnancies, anxiety and misconceptions about fertility, medication safety and the potential for adverse pregnancy outcomes are very common. Knowledgeable providers can positively impact IBD pregnancy outcomes by optimizing disease control, reducing medication-related risks and enhancing patient education. As always, a multidisciplinary team including the primary care provider, gastroenterologist, obstetrician, colorectal surgeon and pediatrician should be involved in the care of pregnant women with IBD.

FERTILITY

Though fear of infertility is common among IBD patients, women with quiescent disease and no prior pelvic surgery actually have similar infertility rates to the general population. Active disease, however, impairs fertility through a variety of mechanisms including pelvic inflammation, decreased ovarian reserve, poor nutrition, decreased libido, dyspareunia and depression. One well-established risk factor for infertility is prior pelvic surgery – which results in both scarring and adhesions. The post-operative infertility rate in ulcerative colitis patients who have undergone an ileal pouch anal anastomosis (IPAA) surgery is 48%, threefold higher than the 15% rate in medically treated patients.¹ Compared to open surgery, laparoscopic total proctocolectomy with IPAA may preserve fertility. Women of childbearing potential should be aware of the infertility risk of IPAA, and less invasive procedures may be considered.

Women who experience spontaneous abortion or difficulty conceiving should be assessed for other known risk factors for infertility, including vitamin D deficiency and celiac disease. If a woman remains unable to conceive after six months of calculated attempts, a reproductive endocrinology referral is warranted.

Less is known about male fertility in IBD, although certain medications have been shown to affect sperm quantity and quality. Sulfasalazine causes reversible infertility due to dose-dependent oligospermia and altered sperm motility and morphology. Methotrexate may reduce sperm quality, though this is reversible when the drug is discontinued. We recommend that men stop methotrexate at least 3 months before attempting conception though there have been no association with birth defects when the male has taken methotrexate prior to conception.

COMPLICATIONS

Women with IBD, independent of disease activity, experience higher rates of adverse pregnancy outcomes compared to age matched controls. A meta-analysis including more than 15,000 women with IBD found increased odds of preterm birth, small for gestational age infants and still birth.² Multiple population-based studies, however, have not detected an increased risk of congenital anomalies in IBD pregnancies. IBD is associated with higher rates of labor and delivery complications, including pre-eclampsia, preterm premature rupture of membranes and venous thromboembolism. Inadequate maternal weight gain has been identified as a predictor of adverse outcomes, and factors such inflammation, anemia, hypoalbuminemia and poor nutrition may also increase risk. Based on these findings, a maternal-fetal medicine specialist should monitor all pregnant patients with IBD, and serial ultrasonography for the assessment of fetal growth should be considered in the third trimester.

The Impact of Disease Activity on Pregnancy

Disease activity is the strongest predictor of adverse pregnancy outcomes. Active disease at conception increases the risk of spontaneous abortion and preterm birth, and disease flares during pregnancy increase the risk of preterm birth, still birth and low birth weight. An ulcerative colitis flare doubles the risk of low birth weight, and a Crohn’s flare triples it. These observations emphasize the critical importance of maintaining remission throughout pregnancy, beginning in the preconception period.

When patients conceive during disease remission and maintain quiescent disease throughout pregnancy, the risks of preterm birth and low birth weight are similar to matched non-IBD controls. Therefore, it is recommended that women achieve and sustain remission for at least three to six months before conception to maximize the chances of a successful and healthy pregnancy. Disease remission should be confirmed prior to conception using laboratory analysis, a fecal calprotectin and/or a colonoscopy or flexible sigmoidoscopy.

The Impact of Pregnancy on Disease Activity

It is unclear whether pregnancy itself adversely affects the course of IBD. Among women in remission at conception, the risk of subsequent disease exacerbation during pregnancy is higher in ulcerative colitis (33%) than in Crohn’s disease (20%).³ The reason for the higher rate of flare in ulcerative colitis is unclear, although overlapping immune pathways and less-aggressive disease management may contribute. A meta-analysis of more than 1,700 IBD patients found that disease activity at conception is strongly correlated with more flares during pregnancy.⁴ In this analysis, disease flares affected nearly half of pregnancies conceived during active disease, compared with approximately one- quarter of pregnancies conceived during remission.

It is important to note that inappropriate discontinuation of maintenance medications during pregnancy and the post-partum period increases the risk of disease flare. Patients should be educated about the importance of medication adherence to optimize preconception disease control and maintain remission throughout pregnancy.

Mode of Delivery

The mode of delivery in IBD pregnancies should largely be determined by patient preference and obstetric indications. Multiple studies have shown that cesarean delivery is more common among women with IBD compared to the general population due to concerns that vaginal delivery might trigger perianal disease. In reality, there is no association between mode of delivery and IBD natural history, and cesarean delivery should typically be recommended only for women with active perianal disease. While some colorectal surgeons also recommend cesarean delivery following IPAA to protect the pouch and preserve anal sphincter integrity, this has not fully been supported by the literature.

With regards to the risk of childhood IBD, there appears to be no link to the mode of delivery. Rather, studies estimate that a child has a 2-5% chance of developing IBD if a single parent has the disease and a 36% chance when both parents have IBD.^5-6

TREATMENT

Prior to initiating IBD therapy in a woman of childbearing age, the patient’s plans for pregnancy should be discussed and considered. Women should be aware that the dangers of active disease outweigh the risk of IBD therapies, and preconception counseling about the low risk of most medications may improve medication adherence during pregnancy. With the exception of methotrexate and thalidomide, most medications used to treat IBD are considered low risk and may be continued during pregnancy and breastfeeding. In accordance with recent FDA labeling revisions, the following discussion avoids the previously used pregnancy categories (A, B, C, D, X) in favor of a narrative risk summary, clinical considerations and a brief description of supporting data for the most commonly used IBD therapies.

Managing IBD Exacerbations in Pregnancy

In each trimester of pregnancy, patients (especially those with high-risk disease features) should be monitored for evidence of disease activity and poor nutrition using tools such as fecal calprotectin, serum inflammatory makers (though these may be unreliable in pregnancy) and gestational weight gain. Active disease during pregnancy commonly responds to standard medical therapy, and evaluation and treatment algorithms are the same as for the non-pregnant patient. There are, however, several considerations that are unique to pregnancy (Table 1).

Corticosteroids may be used to treat disease flares, though their use may be associated with an increased risk of pregnancy complications, including gestational diabetes, preterm birth, low birth weight and a possible increase in infant infections in the first four months of life.⁷ Although the benefits of controlling active disease likely outweigh these risks, corticosteroid use during pregnancy should be limited to the lowest effective dose for the shortest duration. Further, steroids should not be used as planned maintenance therapy during pregnancy. Both prednisone and budesonide are compatible with breastfeeding, though avoiding breastfeeding for three to four hours after ingestion of prednisone may limit the amount received by the infant.

The two most commonly used antibiotics in IBD management are ciprofloxacin and metronidazole. While quinolones have been shown to have no association with an increased risk of adverse pregnancy outcomes and are considered compatible with breastfeeding, metronidazole use is more controversial. Metronidazole use in the first trimester has been associated with a possible increased risk of orofacial clefts, and it is incompatible with breastfeeding due to potential toxicities. Amoxicillin-clavulanic acid is the preferred antibiotic during pregnancy, with a favorable safety profile and breastfeeding compatibility.

Indications for surgery do not differ in the pregnant patient and include bowel obstruction, perforation, and medically refractory disease. Non-emergent surgery should preferentially be performed during the second trimester.

5-Aminosalicylates

The 5-aminosalicylates (balsalazide, mesalamine, olsalazine and sulfasalazine) are considered safe in pregnancy, though two points should be kept in mind. First, the coating of delayed release Asacol HD contains dibutyl phthalate (DBP), which has been associated with congenital anomalies in animals at doses much higher than the therapeutic human dose. Asacol HD should therefore be discontinued in favor of alterative mesalamines during pregnancy. Second, women taking sulfasalazine should receive supplemental folic acid 2 mg daily to prevent folate deficiency. Though aminosalicylates enter breast milk, they are considered compatible with use during breastfeeding.

Methotrexate

Methotrexate is an abortifacient, teratogenic inhibitor of DNA synthesis and is contraindicated during conception and pregnancy. It has been associated with a constellation of congenital limb and craniofacial anomalies as well as developmental delay. Given the long half-life of the drug, women should not attempt conception within 3-6 months of methotrexate use. Furthermore, methotrexate should only be given to those women of childbearing potential who are adherent with one to two methods of contraception and take supplemental folic acid. Despite low levels of excretion in breast milk, methotrexate is also contraindicated during breastfeeding as it may accumulate in neonatal tissue. Though less is known about the impact of methotrexate use among men, we recommend stopping therapy at least three months prior to attempts at conception.

Thiopurines

Like methotrexate, thiopurines (azathioprine and 6-mercaptopurine) inhibit DNA synthesis, and at high doses are teratogenic in animals. While previous meta-analyses have shown thiopurine treatment to be associated with preterm delivery and an increased risk of congenital anomalies compared to healthy women (though not to unexposed IBD controls), many of the included studies were confounded by unmeasured disease activity.^8-9 In studies that have attempted to account for disease activity, the results have been mixed. While one has shown an increased risk of preterm delivery irrespective of disease activity,10 several have failed to detect an elevated risk of pregnancy complications or congenital anomalies.^11-14 However, infections at 9-12 months of age have been showed to be more common among infants exposed to thiopurine plus biologic therapy.¹² Given the overall body of evidence, we feel that it is reasonable to continue thiopurine monotherapy during pregnancy to maintain remission, as the risks associated with thiopurine use are likely outweighed by the risks of active disease. Due to the potential for delayed infant infections, women in deep remission with adequate trough biologic levels who are on combination thiopurine/biologic therapy may consider stopping the thiopurine before conception. Starting thiopurines for the first time during pregnancy should be discouraged due to their slow onset of action and unpredictable adverse events (bone marrow suppression and pancreatitis).

With regards to breastfeeding, clinically insignificant thiopurine concentrations have been found to peak in breast milk within 4 hours of maternal ingestion. Lactating mothers may consider avoiding breastfeeding during this interval.

Anti-tumor necrosis factor (TNF) Agents

The available data on the anti-TNF class suggest overall low risk for use during pregnancy, though the long term implications of intrauterine exposure remain unknown – particularly with regards to the development and function of the infant immune system.

Series of hundreds of women exposed to infliximab, adalimumab and certolizumab pegol have shown no adverse effect on pregnancy outcomes or congenital anomalies, and this has been confirmed in a systematic review including more than 1,500 anti- TNF exposed pregnancies.¹⁵ A recent meta-analysis also showed a similar rate of unfavorable pregnancy outcomes between women taking anti-TNF therapy and unexposed controls, including preterm delivery, low birth weight, and congenital anomalies.¹⁶ With the exception of certolizumab pegol, the anti-TNF agents are actively transported across the placenta (along with other maternal antibodies) beginning in the second trimester. With a majority of transfer occurring in the third trimester, cord blood infliximab and adalimumab concentrations at birth exceed maternal levels by up to fourfold and remain detectable in infants for over nine months.¹⁷ This raises concern about potential adverse effects on neonatal immune system development. While the ongoing prospective, multicenter Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO) registry of more than 1475 pregnant women with IBD has shown that third trimester anti-TNF exposure does not detrimentally affect infant growth rate, immune development, number of infections or achievement of developmental milestones, it is reasonable for women in sustained remission to consider third trimester dosing adjustments to reduce neonatal exposure (Table 2). Therapeutic drug monitoring with trough serum concentrations in the late second or early third trimester may help guide this pre-delivery dosing. Stopping anti-TNF therapy in the second trimester is not supported by the current data given the low risk of continuing therapy and potential risk of disease flare in the pregnancy and post-partum as well as the development of immunogenicity.

Infants exposed to anti-TNF agents should not receive live vaccines for at least the first nine months of life or until drug levels are undetectable. All other vaccinations may be given on schedule. This recommendation does not apply to certolizumab pegol, which is not actively transported across the placenta and does not reach significant levels in the infant. Pediatricians should be aware of intrauterine anti- TNF exposure so that vaccinations can be appropriately managed.

Combination therapy with an anti-TNF and thiopurine during pregnancy may be associated with a higher risk of preterm birth and any pregnancy complication, in addition to the risk of delayed infant infections (previously described).

There is clinically insignificant anti-TNF excretion into breast milk, with milk concentrations less than 1% of maternal plasma concentrations.

Non anti-TNF Therapies

The anti-integrin agents natalizumab and vedolizumab are both monoclonal antibodies that would be expected to actively cross the placenta. There has been no observed increased risk of preterm birth, low birth weight, or congenital anomalies among hundreds of women (most with multiple sclerosis) treated with natalizumab during pregnancy. Vedolizumab pregnancy safety data are extremely limited, though pregnant women treated with vedolizumab are being followed in several registries.

The newest FDA approved therapy for Crohn’s disease is the anti-interleukin 12-23 agent ustekinumab. A series of 26 exposed pregnancies reported a spontaneous abortion rate similar to the general population.¹⁸

Lastly, tofacitinib (an oral janus kinase inhibitor) has showed efficacy in ulcerative colitis in phase II trials, but human pregnancy outcome data are sparse.

BREASTFEEDING

As discussed previously, most IBD medications are compatible with breastfeeding. Though women are commonly concerned about drug transfer to the infant via breast milk, the PIANO registry found no increased risk of infection or developmental delay among nursing infants whose mothers were being treated with thiopurines or anti-TNF agents. Furthermore, there may be a protective effect of breastfeeding for mothers, as studies have shown a decrease in disease flares in the first postpartum year among mothers who were breastfeeding.¹⁹ LactMed is a free online database sponsored by the U.S. National Library of Medicine that provides reliable information on drugs and lactation.

SUMMARY

Women with IBD are at risk for pregnancy complications and adverse outcomes, and they should be managed as high-risk obstetric patients by a multidisciplinary team. Counseling about the importance of medication adherence to optimize and maintain disease control should begin in the preconception period. Disease activity is the strongest predictor of adverse pregnancy outcomes, and sustained remission maximizes the chance of a successful and healthy pregnancy. With the exception of methotrexate, most medications are low risk for continued use during pregnancy and lactation. On a case-by-case basis, medication adjustments to reduce fetal exposure can be considered. This includes thiopurine withdrawal from combination therapy and third trimester biologic dosing adjustments.

A Case Report

Nocardiosis in a Patient with Crohn’s Disease

Julie Nguyen,Swathi Paleti,John A. Bonino

INTRODUCTION

Nocardia is an intracellular pathogen with the potential to cause life-threatening disease, particularly in immunocompromised patients. Based on long-term data (nine years, 2000 patients), the incidence of Nocardia infection has been estimated at 0.01% in patients taking adalimumab.¹

The diagnosis of Nocardia is often limited by clinical suspicion and local expertise of the diagnostic laboratory.²

Case Description A 36 year old male with a history of Crohn’s disease, on chronic adalimumab therapy, presented to the emergency department after he sustained a forehead laceration while working in his backyard. The wound was cleansed in standard fashion and sutures placed. Later, during suture removal, he was noted to have a small single draining pustule. He was then prescribed a seven day course of oral trimethoprim-sulfamethoxazole.

Over the course of several days, he developed tender lymphadenopathy and fever prompting cessation of adalimumab and subsequent hospitalization. Wound cultures were obtained and subsequently grew Nocardia arthritidis.

Due to the development of a persistent cough, a computed tomography (CT) of his chest demonstrated multiple pulmonary nodules, some with cavitation. He was subsequently treated with a combination of intravenous (IV) trimethoprim-sulfamethoxazole and meropenem with improvement of his pustules and near complete resolution of the pulmonary nodules on subsequent imaging.

Discussion

Tumor necrosis factor (TNF) is a cytokine produced by activated monocytes, macrophages and T lymphocytes involved in cell-mediated immunity. TNF interacts with other cytokines, including interferon-delta, to generate an immune response to intracellular pathogens such as Myobacterium tuberculosis, Listeria, Histoplasma and Nocardia. Disruption of this pathway by anti-TNF medications, such as adalimumab, may increase rates of infection by such organisms.³

Nocardia are soil-borne, gram-positive, facultative intracellular bacteria. They are ubiquitous and found worldwide in dust, sand, soil and bodies of water. Respiratory transmission is presumed to be via contact with dust particles contaminated by the organism.⁴

Nocardia has a predilection for the lungs due to its ability to aerosolize, but infection may also occur via the skin or central nervous system.^5,6

Cutaneous infections typically occur through open wounds contaminated with soil. Lesions may manifest as localized abscesses and mimic infection from pyogenic bacteria. Infection may also spread to regional lymph nodes and mimic sporotrichosis.²

The laboratory diagnosis of Nocardia requires a high level of suspicion, since these organisms are slow-growing and may lead to premature disposal of cultures. Histologically, Nocardia are strictly aerobic bacteria with branching filamentous structures. Standard blood cultures are rarely found to be positive. Confirmation and speciation require specialized polymerace chain reaxtion (PCR) testing.⁴

Initial antibiotic therapy includes IV trimethoprim- sulfamethoxazole for a minimum of three weeks. After three weeks, patients without immune dysfunction may be switched to oral trimethoprim-sulfamethoxazole until infection resolution. For those who are immunocompromised, duration of treatment may be extended beyond six months.⁷

The prognosis is poor (mortality rate >50%) for immunocompromised patients with disseminated nocardiosis, even those treated with appropriate antibiotics.^5,8

CONCLUSION

Cutaenous Nocardiosis should be considered in inflammatory bowel disease patients on anti-TNF therapy presenting with atypical or difficult to treat cutaneous infections to ensure timely diagnosis and treatment.

Frontiers In Endoscopy, Series #34

Endoscopic Management of Large Duodenal Adenomas

Jeffrey H. Lee

Duodenal adenomas are often incidentally detected during routine upper endoscopies, yet data regarding effective management are scarce. With advances in endoscopic tools and techniques, duodenal adenomas are increasingly managed endoscopically. There are two main endoscopic resection techniques: endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). Compared to EMR during colonoscopy, EMR in the duodenum is much more arduous and complications are more problematic to manage. In this article, all practical points on how best to perform duodenal adenoma resection and data on follow-up are reviewed.

Duodenal adenomas are often incidentally detected during routine upper endoscopies, yet data regarding effective management are scarce. Owing to the potential for malignant transformation, duodenal adenomas should be excised whenever possible. Traditionally, surgical resection was the mainstay in removing duodenal adenomas. However, due to the anatomic location of the duodenal adenomas, surgeons often faced difficulties requiring extensive segmental resection or pancreaticoduodenectomy. With advances in endoscopic tools and techniques, duodenal adenomas are increasingly managed endoscopically. There are two main endoscopic resection techniques, endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). While most endoscopists are unfamiliar with the techniques of ESD, they are well acquainted with EMR, largely from frequent necessity during colon polyp removal. Compared to EMR during colonoscopy, however, EMR in the duodenum is much more arduous and complications are more problematic to manage. In this article, all practical points on how best to perform duodenal adenoma resection and data on follow-up are reviewed.

INTRODUCTION

Duodenal adenomas may occur sporadically or as a part of familial adenomatous polyposis (FAP) syndrome. FAP patients are more likely to present with multifocal disease than patients with sporadic adenomas.¹ Adenomas in the duodenum may occur at the ampulla or non-ampullary locations. The strategy in managing ampullary adenomas is markedly different than that of non-ampullary duodenal adenomas (NADA). In this review, we will only focus on NADA.

Duodenal adenomas may progress to carcinomas, somewhat resembling the process of colon adenoma to carcinoma sequence.² Cassani et al., in a retrospective study of 213 patients at a tertiary referral cancer center, reported while there was no difference between FAP and sporadic groups with progression to new dysplasia or cancer when observed without intervention, there was a significant difference in overall survival between the FAP and sporadic groups (P < 0.001). The range of time of progression to cancer was 3-161 months.

Therefore, observation is not ideal in managing duodenal adenomas, which leaves the affected patients with two alternate options: 1. Surgical resection 2. Endoscopic management with resection and/or ablation.

Management of Large Non-Ampullary Adenomas

Surgical resection of NADA often presents challenges mainly from location of the polyps in the duodenum. Compared to operations involving the stomach or colon, the surgical approach to the duodenum is demanding as it is bordered by other major organs in the retroperitoneal space.³

The goal of surgical resection would be primary resection and anastomosis of the duodenum; however, it is often not possible to have such an outcome, either secondary to the particular location of the polyp and/or the extent of polyps, thus resulting in duodenal resection, combined with jejunal anastomosis. Furthermore, as the pancreatic duct and bile duct join at the ampulla, patients may face pancreaticoduodenectomy for NADA when the adenoma involves the medial wall near the papilla in the second portion of the duodenum. Therefore, patients and surgeons frequently choose or advocate endoscopic means of therapy for NADA. While technically facile, endoscopic ablations by argon plasma coagulation (APC) or heater probe are not suitable in most cases, because the ablative attempt would not be able to cover the entire adenomatous area owing to the size of the adenoma(s). Consequently, patients and providers resort to endoscopic resection (ER) in managing NADA. In general, there are two ER techniques; endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). There are pros and cons in each technique. EMR is technically less challenging to perform than ESD, but provides multiple segmented specimens making it impossible to assess lateral-margin status. On the other hand, ESD provides the specimens in one piece allowing accurate evaluation of lateral-margins. Even though endoscopic resection has been successfully performed by EMR or ESD for benign mucosal and early malignant tumors in various locations of the gastrointestinal tract, ESD in the duodenum should be attempted only by experts with thorough preparation and discussion of the options with the patient and surgical colleagues; such discussions should consider technical difficulty, thinness of the duodenal wall, and the risk of immediate or delayed perforation.

Endoscopic Management of Large Non-Ampullary Duodenal Adenomas

1. Endoscopic Visualization of Duodenal Adenoma and Defining the Margins for Resection

To improve visualization of adenomas in the duodenum, one may use chromoendoscopy techniques by spraying diluted methylene blue or indigo carmine. However, preparation of the solution and spraying the dye necessitate additional steps in the resection procedure. With the advent of narrow band imaging (NBI) technology, the duodenal polyps can be better detected, obviating the need to employ the coloring agents. Once the margins are clearly visualized, the planned resection margin should be marked using a hot snare or ESD knife.

2. Preparation for Endoscopic Resection

Before the initiation of ER, intubation should be considered to protect the patient’s airway as the endoscope may be repeatedly advanced into the duodenum during the resection process. Regarding solutions to inject into the submucosal layer, there are multiple candidates with varying viscosity. The higher the viscosity, the longer the submucosal lift will last. Among the most viscous solutions are hyaluronic acid and hydroxypropyl methylcellulose, which are relatively inexpensive, but not readily available in the United States. Other viscous solutions include hypertonic solutions of sodium chloride (3.0%), dextrose (20, 30, or 50%), glycerol, and albumin. Albumin is ubiquitous in hospitals, yet expensive. Normal saline solution (0.9%) is inexpensive, available, and easy to inject. Though viscous solutions are often necessary for ESD, it is not imperative to have such solutions in EMR, where saline solution mixed with epinephrine may be readily used.

3. Techniques of Endoscopic Mucosal Resection

3a. Injection-assisted EMR

In this technique, a mixture of solution is prepared by injecting 10 cc of epinephrine (1:10,000) to either 250 mL or 500 mL of normal saline. Usually, a small amount of indigo carmine or methylene blue is added to provide blue color on the sub-adenomatous base after EMR. Once the solution is prepared, 10 cc aliquots can be made using syringes. Submucosal injection is performed by advancing the injection needle at the normal mucosa near the endoscopic edge of the polyp. To avoid transmural injection, the needle should be introduced as injection is being applied. Once the submucosal bleb is created, further injection of the solution should be carried out observing continuing elevation of the mucosal layer. There is no need to raise all areas of the edge before commencing on resection. Resection can be carried out using either cut or coagulation electrocautery with a preferred setting. Most endoscopists use blended cutting (more cutting than coagulation), rather than coagulation settings. This is because of the feared complication of delayed perforation from transmural thermal injury. There are no firm recommendations where EMR should begin in terms of location; EMR may be initiated at the proximal or distal end, or right or left edges, whichever would be strategically advantageous for complete resection. In terms of snare size, 15 mm is sufficient. Use of a larger size snare increases the risk of grabbing too much tissue, including the muscularis propria layer, because the duodenal wall is quite thin and delicate. To ensure the muscularis propria layer is not involved in the resection, it is vital to loosen the snare slightly by shaking after grabbing the segment to be resected before applying electrocautery. Bleeding can usually be managed using a coagulation grasper while performing EMR. Before completing the EMR session, it is also essential to inspect the EMR base to ensure no adenomatous tissue is remaining and to prevent delayed bleeding. Any suspicious tissue or visible blood vessels in the resection base should be treated at the time of EMR. Experts of ER prefer using a coagulation grasper rather than APC for treatment of residual tissue or vessels. When APC is used, one may occasionally observe insufflation of submucosal tissue from emitted argon gas. The significance of treating the base after ER was well illustrated in the study by Lépilliez et al.; the authors reported that there was no delayed bleeding when the resected base was treated by endoscopic clipping or APC, in contrast to a 22% bleeding rate without the treatment.⁴

3b. Band Ligation-assisted EMR (EMR-L)

Although EMR-L is minimally invasive and easy to perform in the esophagus, stomach, and rectum, EMR-L should not be employed in resecting duodenal adenomas. Different from the walls of the esophagus, stomach, or rectum, the duodenal wall is very pliable and thus suctioning of the polyp to apply a band can bring the entire wall into the banding cap, resulting in perforation when resected (Figure 1). EMR-L is based on the technique of variceal band ligation. When there is a sessile or flat polyp, suction is applied to the targeted area, and subsequently a band is applied to create a pseudopolyp. Once the pseudopolyp is created, it is resected using a snare with electrocautery. In general, there are two sizes available in EMR-L kit (Duette Multi-Band Mucosectomy device, Cook Medical Inc., Winston-Salem, NC), one for the diagnostic upper endoscope and the other for the therapeutic upper scope (one to fit endoscopes with outer diameters of 9.5 to 13 mm and the other 11 to 14mm). It is important to select proper endoscope and the band ligation kit to ensure precise fitting of the device. It is recommended to place one band and immediately cut the segment, rather than placing multiple bands and cutting all banded areas in sequence. By slightly overlapping the cutting area, while avoiding injury to the muscle layer, one can avoid leaving slivers of adenomatous tissue in between the bands.

3c. Cap-assisted EMR (EMR-C)

In this technique, an EMR cap is attached to the tip of the scope and submucosal injection is performed using an injection needle and the aforementioned solution mixture. Then, an EMR snare provided in the EMR kit (Olympus America Inc, Center Valley, Pa) is placed in the internal groove of the EMR cap, creating a loop. Next, the targeted lesion is suctioned into the cap and the snare is fastened while suction is still being applied. One caveat is, as mentioned under EMR-L section, suction should be applied with caution. Full suction is likely to bring the full thickness of the duodenal wall into the cap, resulting in perforations when resected. Therefore, it is paramount to apply a controlled suction; one-half or less of vacuum suction should be applied when EMR-C is performed in the duodenum. Furthermore, this technique should be reserved only for the experts with extensive experience in ER. Even then, a multidisciplinary approach should be employed alerting surgical colleagues before EMR-C is planned due to perforation risk.

4. Endoscopic Submucosal Dissection (ESD)

While EMR provides multiple segmented specimens, ESD allows resection of the entire segment in one piece, thus allowing clear discernment of margin involvement. In ESD, following injection of one of the aforementioned solutions under the targeted lesion, the submucosa is dissected by an electrosurgical knife. Thus, ESD allows excision of larger and deeper lesions with curative intent than can be resected by EMR. ESD, however, requires an extensive dedicated training, including repetitive practice at ex-vivo and live animal lab as well as closely supervised attempts in human cases, in order to attain competency.

Data regarding the efficacy and safety of duodenal adenoma resection are scarce. Kim et al. reported the result of their retrospective observations of 64 lesions in 62 patients who underwent endoscopic resection of duodenal subepithelial tumors in an academic setting. Injection assisted EMR was performed in 38 lesions, EMR-L in 18, and ESD in 8. The overall en bloc resection and complete ER rates were 96.9% (62/64) and 100% (64/64), respectively while complete pathologic resection was 76.6% (49/64). Ironically, ESD was independently associated with incomplete pathologic resection. Strikingly, the procedure-related bleeding and perforation rates were 6.3% and 4.7%, respectively. Follow-up data were promising showing no recurrence in patients who underwent complete ER at a median follow-up of 20 months (range 6-112 months).⁵ In the study reported by Cassani et al., 47/213 patients (14 FAPs and 33 sporadic adenomas) underwent EMR of their adenomas and 46/47 achieved endoscopically complete resection. The deep margin was positive in 4 resections (9%). Evidence of recurrence was seen in 3 patients (6%). All recurrences occurred within 1 year of EMR.

Hoteya et al. compared the outcomes of EMR and ESD in 129 endoscopic resections for NADA.⁶ The authors performed 74 ESD (49 lesions > 20 mm, and 25 lesions < 20 mm in diameter) and 55 EMR procedures. In terms of technical outcomes, the authors concluded that EMR was safer than ESD for small size NADA as perforation and delayed bleeding were significantly higher in both ESD groups than in the EMR group. The authors felt prophylactic endoscopic closure of large mucosal defects after ESD was useful in preventing the complications. Navaneethan et al. reported a systemic review on the efficacy and safety of endoscopic resection of duodenal polyps; in total, the meta-analysis included 440 patients (485 duodenal polyps) from 14 studies.⁷ The mean size of polyps ranged from 13 mm to 35 mm with 1.9% being adenocarcinoma. The majority of the polyps were sessile (92%) and located in the 2nd portion of the duodenum. EMR was successful in 93% (95%CI 89-97%) with immediate bleeding rate of 16% (95%CI 10-23%), delayed bleeding rate of 5% (95%CI 2-7%), and perforation rate of 1% (95% CI 1-3%). In addition, APC was applied post-EMR in 29% of the procedures to ensure complete eradication of the dysplastic tissue. Surgical intervention was required in 12 patients after initial EMR (3%); of which 8 cases of non-curative EMR and 4 for procedure related adverse events (3 perforations and 1 hemorrhage).

Follow-Up of Large Non-Ampullary Adenomas After Endoscopic Resection

In our hospital, we routinely keep patients for observation for 1-2 days post ER with follow-up blood counts the morning after the procedure. To protect the ER site, proton pump inhibitor is given either intravenously or by mouth.

Regarding diet, the patient is kept fasting on the day of ER. On post-operative day 1, clear liquids are given, which are advanced to full liquids for the following 2 days, and then soft diet for the ensuing 3 days.

If the patient has abdominal pain or rebound tenderness, delayed perforation should be considered and excluded. If abdominal pain persists and/or increases, computed tomography (CT) of the abdomen with oral and intravenous contrast is indicated, along with surgical consultation. If CT is indeterminate, diagnostic and/or therapeutic upper endoscopic examination is warranted. If a small perforation is noted, attempts to close it endoscopically can be made along with urgent surgical consultation.

1. Delayed Perforation

Even after successful ER, monitoring for delayed perforation is advised, especially when the duodenal adenoma is large and located in the 2nd portion of the duodenum or distal to the ampulla. Ideally, leaving a thin submucosal layer over the muscularis propria would be ideal, but is not always possible. This is even more difficult to achieve when the ER base is tethered to the muscularis propria layer by fibrotic scar tissue. Scar tissue may form from previous vigorous biopsies and/or ablative therapy by heater probe, electrocautery, or APC treatment. Therefore, if ER is planned or considered, one or two small biopsies at the periphery of the lesion would be ideal. The concern for delayed perforation should be heightened if the muscle layer is exposed and/or damaged during ER. The biliary and pancreatic enzymes may auto-digest the exposed muscle layer. Therefore, if endoscopic closure is possible, the application of clips should be attempted. However, as the duodenum is fixed in the retroperitoneum, opposing the mucosal/ submucosal defect is not straight forward. Furthermore, if a clip is placed on the muscularis propria layer, it can cause immediate perforation or enlarge a perforation that had already occurred. To divert the pancreatic enzymes and bile, one may consider placing naso- biliary and/or naso-pancreatic tubes; but placing these tubes are technically challenging and uncomfortable to patients. To circumvent this enigma after EMR/ESD of NADA, Hochberger et al. recently introduced a novel approach of placing a vacuum sponge, 2.5 cm long and 1.8 cm wide (Endo-Vac; Braun, Melsungen Germany) in the duodenum through an overtube (US Endoscopy, Mentor, Ohio, USA).⁸ Using this technique, the drainage tube connected to the sponge was externalized via the nose, and suction of approximately125 mmHg was applied. The authors also performed endoscopic closure using over-the-scope clip and endoclips immediately after EMR/ESD to reduce or eliminate the unprotected area. EGD on post-procedure day 4 showed no signs of perforation and excellent wound healing upon retrieving the sponge. Surgical management of perforations depends on the amount of time elapsed between the time of perforation and timing of surgery. Immediate surgical intervention would allow primary repair or resection of the perforated segment with primary anastomosis. However, when there is a delay in surgical management, a significant amount of bile and pancreatic secretions may collect in the retroperitoneal space, complicating the operation. At the operation, pus may be found in the retroperitoneal space during irrigation and aspiration (wash-out). In this situation, primary anastomosis is not possible; thus diverting surgical resection and anastomoses would be performed along with placement of multiple drainage tubes at the pockets of fluid collections in the retroperitoneum by consultation with interventional radiology. The recovery from this type of operation is lengthy and arduous, especially in the elderly where a long-term physical and occupational therapy would be needed.

2. Surveillance for Recurrence

In the aforementioned meta-analysis of EMR, the recurrence rate after EMR was 15% (95% CI 7-23%) over a median follow-up of 6-72 months, and endoscopic resection of recurrent polyps was successful in 62% (9%CI 37-87%).⁷ Therefore, it is crucial to provide a continuing endoscopic surveillance in this population after ER. The first esophagogastroduodenoscopy (EGD) post-EMR is usually performed in 3 months when the ER site is carefully examined for any residual lesions or early recurrence. If any residual polyp or recurrence is detected, endoscopic resection, biopsy, and/or ablative therapy may be performed. If EGD is unremarkable, it would be reasonable to perform a surveillance EGD in 1 year and then annually for several years; provided that the original adenoma(s) were absent of high-grade dysplasia or carcinoma.

Future Management of Large Duodenal Adenomas

Ichikawa et al. reported the safety and feasibility of laparoscopic and endoscopic cooperative surgery (LECS) for early non-ampullary duodenal tumors in 12 patients.⁹ In this study, 13 early duodenal lesions (10 adenocarcinomas, 2 neuroendocrine tumors, and 1 adenoma) in 12 patients were managed by LECS. All submucosal tumors were successfully resected en bloc and the defect in the duodenal wall was sutured after resection. For epithelial lesions, ESD was performed and the base of the ESD was reinforced via manual suturing. Notably, there were two intraoperative perforations in 2/11 epithelial lesions while ESD was being performed; these were successfully repaired via laparoscopic approach. The median procedure time was 322 minutes with no significant blood loss; 1 patient had minor leakage due to a pancreatic fistula.

The LECS technique emphasizes the importance of a multidisciplinary approach for this challenging task. As was previously emphasized, the most feared complication of duodenal adenoma resection is perforation. If the size of the perforation is small and surrounding mucosa and submucosal layers are available, it would be reasonable to attempt endoscopic closure using clips. However, when the size of perforation is greater than 2 cm, it would be difficult to close it by placing clips. Endoscopic suturing (ES) would be valuable in this situation, however ES is a difficult procedure to master and attain proficiency.¹⁰ While ES is being performed, more carbon dioxide can be introduced into the peritoneum, as well. It is imperative to ensure no pooling of fluid at the site of perforation, while ES is being attempted, by repositioning the patient as appropriate. Future research should focus on developing artificial tissue that can be sprayed to cover the perforation immediately (for example, such as fibrin glue or cyanoarylate);^11,12 this material would adhere to the mucosa creating instantaneous cover at the perforation.

CONCLUSION

Duodenal adenoma resection is a daunting task, which requires careful planning prior to attempted resection. The patient and the family should be invited to partner with providers in discussing therapeutic options, risks involved, and potential complications with their consequences. It would be ideal to discuss the case at multidisciplinary conference, in order to 1. find the best approach for effective treatment, and 2, seek early and active involvement of a surgeon as perforations are grave adverse events in a significant minority of patients. Following successful ER, the patient should be closely monitored for delayed complications and recurrence. Future endeavors should focus on development of effective and convenient diversion of biliary and pancreatic secretions in the duodenum, potential tissue covering/protectants and/or easier endoscopic suturing systems to solve the conundrum of endoscopic perforation management.

Nutrition Issues In Gastroenterology, Series #160

The Use of Medium-Chain Triglycerides in Gastrointestinal Disorders

Neha D. Shah,

Berkeley N. Limketkai

Medium-chain triglycerides (MCTs) are lipid molecules that are more readily absorbed and oxidized than most lipids. This unique characteristic of MCTs has led to interest in their use in the management of several gastrointestinal disorders, where MCTs have been primarily used to reduce fat malabsorption and to serve as a source of calories to optimize nutritional status. In this review, we discuss the composition of MCTs, its sources, and the roles that they potentially play in the treatment of various gastrointestinal disorders.

Structure

A fatty acid is a simple lipid molecule with a carboxylic acid group on one end and a hydrocarbon chain on the other.² The hydrocarbon chain length may range from 4 to 28 carbons and determines the classification of fatty acids: short chain (< 6 carbons), medium chain (6 to 12 carbons), long chain (13 to 21 carbons), and very long chain (≥ 22 carbons). Triglycerides are lipid molecules with three fatty acids attached to a glycerol backbone. Similar to simple fatty acids, the length of the fatty acid group determines the nomenclature of short- chain triglycerides (SCTs), medium-chain triglycerides (MCTs), and long-chain triglycerides (LCTs).

The presence of double bonds can vary within fatty acids. Saturated fatty acids do not contain any double bonds along the hydrocarbon chain, while unsaturated fatty acids do. Monounsaturated fatty acids contain a single double bond, while polyunsaturated fatty acids contain two or more double bonds. Most fatty acids can be endogenously synthesized, except for two long-chain polyunsaturated fatty acids: linoleic acid (18 carbons with 2 cis bonds at C9 and C12) and linolenic acid (18 carbons with 3 cis bonds at C9, C12, C15); these are considered essential fatty acids (EFAs) and must be obtained from the diet.

The fatty acid groups of MCTs include caproic acid, caprylic acid, capric acid, and lauric acid. Compared with LCTs, MCTs are smaller in molecular weight, water soluble, rapidly oxidized for energy, possess a lower smoke point (the temperature when volatile substances are produced and a blue-colored smoke is seen as a result of oxidation of oil) and are liquid at room temperature. MCTs only contain saturated fatty acids and therefore do not contain either of the EFAs, linoleic and linolenic acid. As MCTs do not contain EFAs, they also do not serve as a precursor to the synthesis of eicosanoids. MCTs provide fewer calories per gram than LCTs, 8.3 vs. 9.2, respectively.

Digestion and Absorption

The length of the fatty acid influences the process of its digestion and absorption within the gastrointestinal tract. The entry of triglycerides as LCTs from the stomach into the duodenum stimulates the enteric secretion of the hormone cholecystokinin (CCK) and pancreatic enzymes from the pancreas. CCK promotes further release of bile from the gallbladder to help emulsify the triglycerides into smaller fat droplets to maximize its digestion.3,4 Pancreatic lipase then cleaves the fatty acid chains from the triglycerides to form individual fatty acid molecules that then aggregate into micelles. Micelles are absorbed into the enterocytes along the intestinal brush border via passive diffusion or are shuttled by fatty acid transporters. Once in the enterocytes, the fatty acids are transported into the endoplasmic reticulum, reconverted into triglycerides, and packaged into chylomicrons.

The chylomicrons are released via exocytosis, enters and travels through the lymphatic system and eventually, drains into the subclavian vein to reach the bloodstream. In the intracellular space, long-chain fatty acids bind to carnitine for transport into the mitochondria for subsequent B-oxidation. In carnitine deficiency states that contribute to severe protein malnutrition (e.g., chronic malabsorption, small bowel obstruction, starvation), these long-chain fatty acids cannot be efficiently utilized and instead lead to accumulation of unoxidized fatty acids and impairment of ureogenesis, ketogenesis, and gluconeogenesis.⁵ Clinical sequelae may include hepatic steatosis, hepatomegaly, myopathy, and altered mental status.

By contrast, MCT digestion is rapid and simple. MCTs do not stimulate CCK secretion.^3,4 MCT absorption occurs via passive diffusion along the gastrointestinal tract into the portal system bound to albumin. No further packaging or modification of the MCT molecules is required. Moreover, MCTs are not dependent on the carnitine acyltransferase system for transport into the mitochondria for B-oxidation.⁵ This provides the ability for more rapid metabolism of MCTs and improved utilization even in states of protein deficiency (Table 1).

Sources

Most fats and oils of animal and plant origin contain LCTs (e.g., fish, avocado, nuts, seeds, corn, peanut, safflower, and soybean oil). By contrast, natural sources of MCTs include coconut oil and palm kernel oil, although these oils also contain LCTs. Commercial MCT formulations may either be comprised of naturally- derived MCT oil, 100% synthetic MCT oil (produced from medium-chain fatty acids that are hydrolyzed from coconut or palm kernel oil, purified, and then re- esterified onto a glycerol backbone), physical mixtures (blend of MCTs and LCTs), or structured lipids⁶ (Table 2). Structured lipids are synthetic lipid molecules with a mix of medium-chain and/or long-chain fatty acids attached to a glycerol backbone. In the clinical setting, it is not uncommon for healthcare professionals to tell their patients to use coconut oil to obtain MCTs. However, depending on the circumstance, this may worsen fat malabsorption due to the LCT content. Semi- elemental and elemental enteral formulas typically include MCTs to minimize need for digestion prior to absorption, although LCTs may also be included as a source of EFAs (Table 3). Clinical applications may include malabsorption disorders from pancreatic insufficiency or severe small bowel disease.

Dosage

Excessive intake of oral MCT oil has been associated with gastrointestinal distress, such as abdominal discomfort, cramping, gassiness, bloating, and diarrhea. A tablespoon (15 mL) of MCT oil contains 14 grams of fat and 115 calories. A maximum daily dose of 50-100 grams has been suggested for improved gastrointestinal tolerance; this is equivalent to 4-7 tablespoons (60-100 mL) per day (56-98 grams of fat and 460-805 calories).¹ The daily dose of MCTs should be increased as tolerated to the maximum daily dose, while equally dividing the dose across all meals. The MCTs can be easily mixed into a variety of foods and beverages. If MCTs are used in cooking, the temperature should be kept below 150° C (302° F) to reduce risk of its oxidation, otherwise the flavor of the food could be affected.¹ A tablespoon of MCT oil can also be administered through a feeding tube using a syringe along with a 30 ml water flush before and after its administration (See Table 4). In the severely fat-restricted patient, a source of EFAs will need to be provided in the diet along with MCT supplementation to prevent EFA deficiency. MCT oil does not require a prescription. Although MCTs possess unique characteristics, it is not considered to be a panacea and its use is intended to be administered along with other therapies to treat a disorder.¹

Use in Gastrointestinal Disorders
Pancreatic Insufficiency

Pancreatic insufficiency is characterized by a disruption in the exocrine function of the pancreas, which may result in decreased synthesis and/or release of pancreatic enzymes that normally assist in digestion of nutrients in the small bowel, particularly dietary LCTs. It may arise in acute or chronic pancreatitis, cystic fibrosis and as a consequence of pancreatic resection. The primary intervention for pancreatic insufficiency is pancreatic enzyme replacement therapy, and occasionally, acid- suppression therapy. There are limited studies at this time investigating the impact of oral MCT oil in pancreatic insufficiency. However, as MCTs do not require pancreatic enzymes for digestion, it is reasonable to consider them as a source of supplemental calories in these patients if needed.⁴

In chronic pancreatitis, there is interest in using MCTs to help reduce post-prandial pain. A small study of 8 adult pancreatic enzyme-sufficient patients with chronic pancreatitis found that consumption of an elemental enteral formula containing MCTs (69% of the total fat content; 9.8 grams per can), at least 3 times per day for 10 weeks, and <e; 20 grams of fat from the diet per day, resulted in minimal increases in serum CCK levels and a significant reduction in post-prandial abdominal pain.⁷ A study of 17 children with cystic fibrosis found no difference in absorption rates between a polymeric enteral formula (Isocal) with pancreatic enzyme replacement and elemental enteral formula (Peptamen) containing MCTs without enzyme replacement.⁸

Chyle Leaks

Chyle is a turbid or milk-colored fluid that primarily consists of LCT-containing chylomicrons and lymphatic fluid. Chyle originates in the small bowel where chylomicrons are formed and absorbed into the lymphatic system via the lacteals. Chyle then passes through the lymphatic system and enters the venous circulation via the thoracic duct. An obstruction or injury to the lymphatic system may result in a chyle leak into the pleural, pericardial, or peritoneal space. Common causes of chyle leaks include neoplasia, infection, radiation, and trauma.

The nutritional management of a chyle leak may initially include consumption of a fat-restricted or a fat-free diet, elemental enteral nutrition with MCTs, or a high-protein diet with MCT supplementation.^9,10

These interventions should only be used for the short term (approximately 2 weeks), as there is a risk of developing EFA deficiency with prolonged restriction of dietary LCTs. Once the chyle leak is closed, foods can be gradually re-introduced into the diet. If the chyle leak continues to persist despite these interventions, then parenteral nutrition is indicated. With parenteral nutrition, there is no need to restrict intravenous lipid emulsions, as they completely bypass the gastrointestinal tract and lymphatic system.

Three cases have been reported on the successful use of oral and/or nasogastric enteral feeding with MCTs for chylous fistulas that developed after neck dissections.¹¹ The patients had closure of their fistulas after two weeks on MCTs. In a retrospective review of 245 patients that underwent pancreatoduodenectomy or a total pancreatectomy, 40 patients who developed a chyle leak were placed on an MCT-containing enteral formula until they were able to transition to a fat free diet with oral MCT supplementation.¹² All patients experienced a decrease in chyle output without requiring surgical intervention or parenteral nutrition.

Short Bowel Syndrome

Short bowel syndrome (SBS) is defined by a significant anatomic (or functional) reduction in small bowel length, thus leading to compromise in the digestive and absorptive capacity of the small bowel. Significant malabsorption observed in these patients often manifest as diarrhea, unintentional weight loss, and fluid and electrolyte disturbances. The rationale behind the use of MCTs in SBS is to provide calories that are efficiently absorbed with minimal need for prior digestion.

At this time, there are only a few early case reports that have demonstrated potential benefit of MCTs in SBS. One case involved a 65 year-old woman with 76 cm of jejunum, 20 cm of terminal ileum, and an intact colon, who was admitted for chronic diarrhea and unintentional weight loss 3 years after extensive bowel resection for adhesions.¹³ Another case involved a 69-year-old man with 120 cm of remaining small bowel (mostly jejunum), who was admitted with chronic diarrhea and unintentional weight loss 2 years after his extensive bowel resection due to mesenteric thrombosis.13 Fecal fat excretion was elevated in both patients when given a LCT-rich regular diet or enteral formula. When switched to a sole MCT-containing enteral formula, fecal fat excretion was reduced and the patients experienced weight gain. Both patients afterwards were placed on a fat-restricted (LCTs) diet for 8-10 months that was supplemented with MCT.

The influence of bowel anatomy on the benefits of MCTs is yet unclear, although early studies suggest that the presence of an intact colon plays a significant role. In a randomized cross-over study of 19 SBS patients (9 without a colon; 10 with a colon), participants were initially administered high fat diets with either LCTs alone or an equal mixture of LCTs and MCTs in which the source of the MCT was either a MCT-containing margarine or MCT oil.¹⁴ When switched from the LCT to LCT-MCT diets, patients with an intact colon had no difference in fecal volume, while those without a colon had an increase in fecal volume. Interestingly, patients with a colon also experienced an increase in fat and overall energy absorption on the LCT-MCT diet, although those without a colon only had a marginal increase in fat absorption and no improvement in overall energy absorption. The study investigators suggest that the colon serves as a major organ for absorption of the water-soluble MCTs, similar to short-chain fatty acids and unlike the insoluble LCTs. The lack of improvement in energy absorption among those with ileostomies and jejunostomies was attributed to increased carbohydrate and protein loss. The use of MCTs can be considered in the management of patients with SBS and an intact colon.

Potential Use in Other Disorders

Due to their integral role in physiologic function, MCTs may have potential benefit in several non-gastrointestinal disorders. A discussion of these benefits is beyond the scope of this review, although we present a few unique examples of MCT use in diverse conditions.

Obesity

Due to its influence on thermogenesis and satiety, MCTs have been proposed to reduce obesity by increasing energy expenditure, reducing food intake and decreasing fat deposition in adipose tissue.^15,16 A systematic review and meta-analysis of 13 randomized controlled trials in healthy adults showed that when compared with LCTs, MCTs reduced body weight, waist and hip circumference, total body fat, total subcutaneous fat and visceral fat.¹⁷ Serum lipid levels did not differ.

Cardiovascular Disease

In cardiovascular disease, MCTs have been proposed to reduce hyperlipidemia based on observations that indigenous populations with high consumption of coconut flesh have low incidence of cardiovascular disease. However, a review of 8 clinical trials and 13 observational studies on the effect of coconut oil consumption on cardiovascular risk indicated that there is not enough evidence to support this practice.¹⁸

Alzheimer’s Disease

In mild to moderate Alzheimer’s disease, MCTs have been investigated to improve cognition based on the theory that decreased glucose metabolism in the brain may result in cognitive and memory impairment, so using MCTs as an alternative energy source as ketones for the brain should potentially counteract this impairment. Small studies have shown modest improvement in memory recall after consumption of MCT.19

Epilepsy

The ketogenic diet, which is a high fat, low carbohydrate diet, is often used as a treatment for refractory childhood epilepsy. A Cochrane review of the traditional ketogenic diet for epilepsy concluded that the use of the diet appears promising in treatment of epilepsy, but further studies are needed.²⁰ While the ketogenic diet often consists of LCTs, the use of MCTs in the ketogenic diet may be more appealing due to their greater potential to yield ketones for rapid oxidation. The MCT-rich ketogenic diet would additionally require less fat in favor of more carbohydrates to afford greater variety in the diet. However, a randomized trial of 145 pediatric patients with refractory epilepsy found no difference in efficacy between the MCT diet and the traditional ketogenic diet.²¹

CONCLUSION

MCTs possess unique characteristics of digestion, absorption, and oxidation that lead to great interest in their use in the management of gastrointestinal disorders. The facile absorption of MCTs without the need for bile or pancreatic enzymes makes them a good source of calories in the setting of malabsorption and steatorrhea from diseases, such as pancreatic or bile insufficiency. Due to their ability to bypass the lymphatic system, MCTs can also serve as a lipid source for patients with chyle leaks. As MCTs do not contain EFAs, supplementation with EFA containing vegetable oils will be necessary after 3 weeks to avoid deficiency.10 Although studies are limited, MCTs may be considered as a supplemental calorie source either alone, or as part of an enteral product, in certain gastrointestinal disorders.

Dispatches From The Guild Conference, Series #1

Practical Use of Therapeutic Drug Monitoring of Anti-TNF Therapy in IBD

Konstantinos Papamichail,

Adam S. Cheifetz

Anti-tumor necrosis factor therapy has revolutionized the care of inflammatory bowel disease. However, 10-30% of IBD patients show no initial clinical benefit to anti-TNF therapy and over 50% after an initial response lose response over time. Therapeutic drug monitoring can better explain and guide the management of patients with a loss of response to anti-TNF therapy. This review will focus on the role of TDM in guiding therapeutic decisions in IBD.

Some of this primary non-response and the majority of the secondary loss of response is due to sub-therapeutic drug concentrations and/or the development of anti-drug antibodies. Therapeutic drug monitoring (TDM) can better explain and guide the management of patients with a loss of response to anti-TNF therapy (reactive TDM). Reactive TDM has also been proven to be more cost-effective compared to empiric dose escalation of anti-TNF therapy based only on symptoms. Preliminary data demonstrate that proactive TDM with drug titration to a target concentration applied in patients showing clinical benefit can optimize anti-TNF therapy efficacy and cost. This review will focus on the role of TDM in guiding therapeutic decisions in IBD.

INTRODUCTION

Anti-tumor necrosis factor (TNF) therapy is the cornerstone of the treatment of patients with moderate to severe Crohn’s disease (CD) and ulcerative colitis (UC).¹ Nevertheless, up to 30% of patients with inflammatory bowel disease (IBD) show no initial clinical benefit to anti-TNF therapy (primary non-responders) and over 50% lose response within the first year of therapy.^2,3 Mechanisms underlying these undesired therapeutic outcomes involve pharmacokinetic or pharmacodynamic issues. The first are associated with inadequate drug concentrations due to the development of anti-drug antibodies or an increased non-immune drug clearance, while the latter are related to a non-TNF driven inflammatory process.2,3

Numerous exposure-response relationship studies have demonstrated that higher serum anti-TNF drug concentrations are associated with favorable objective therapeutic outcomes during both induction and maintenance therapy (Table 1).^4-24 On the other hand, low or undetectable drug concentrations are linked to anti- drug antibodies formation and treatment failure.3,25-27 These data suggest that in addition to “treating-to- target’ we should also be ‘treating-to-trough’ and that early proactive optimization of anti-TNF therapy may achieve better long-term therapeutic outcomes.

Therapeutic drug monitoring (TDM), defined as the evaluation of serum drug concentrations and anti-drug antibodies, has rationalized the management of IBD patients who lose response to anti-TNF therapy and improved therapeutic decision making. Reactive TDM allows for more individualized treatment (personalized medicine) when a secondary loss of response occurs. Moreover, it better directs care and prevents unnecessary drug exposure in patients who are unlikely to respond to more anti-TNF therapy.³

Preliminary data show that proactive TDM with drug titration to a target trough concentration applied in patients in clinical response or remission can improve the efficacy and potentially cost-effectiveness of anti- TNF therapy.^28,29 Proactive TDM may also be useful to better guide therapeutic decisions in other clinical scenarios, such as re-introduction of anti-TNF therapy after a drug holiday³⁰ or discontinuation of anti-TNF therapy in patients achieving deep remission.^31,32 This review will focus on the practical role of TDM of anti- TNF therapy in clinical practice.

Reactive TDM

Reactive TDM can better explain and guide the management of loss of response to anti-TNF therapy in IBD and has been proven to be more cost-effective than standard-of-care.^33-35 Patients with sub-therapeutic or undetectable drug concentrations and no anti-drug antibodies benefit more from escalation of treatment (by increasing the dose or decreasing the interval) compared to those switched to another anti-TNF agent.36 Moreover, higher drug concentrations after dose escalation are associated with re-capturing clinical response and improved clinical outcomes.^37-39 On the contrary, patients with therapeutic or supra-therapeutic drug concentrations benefit more when changing out of class to a drug with a different mechanism of action, as there is probably a shift to non-TNF driven disease.³⁶ A recent study showed that infliximab and adalimumab trough concentration of >3.8 and >4.5 µg/mL, respectively, measured at the time of loss of response distinguished patients who had a better long- term outcome from alternative therapies compared to those who escalated the anti-TNF therapy or switched to another anti-TNF agent.40 However, considering the lower response rate to a subsequent biologic, the limited pharmacological options, and the lack of a clear drug threshold, in practice we typically dose optimize to drug concentrations of >10-15µg/mL before stopping infliximab or adalimumab. On the other hand, patients with high anti-drug antibodies do better when switched to another anti-TNF rather than further dose escalation.36 Vande Casteele and colleagues, showed that patients with antibodies to infliximab >9.1 U/ml when loss of response occurred had a 3.6 times higher risk to fail a subsequent infliximab dose optimization.⁸ There are several laboratories that offer TDM and it is critically important to understand the assay and how the antibodies are recorded (Table 2). A proposed treatment algorithm for using reactive TDM for anti-TNF therapy is shown in Figure 1.

Proactive TDM

Recent data demonstrate that proactive TDM can optimize efficacy and potentially cost of anti-TNF therapy.^28,29 An observational study from our center was the first to show significantly greater infliximab durability in IBD patients in clinical remission who underwent proactive TDM and dose optimization to a therapeutic trough concentration of 5 to 10µg/mL when compared to patients receiving empiric dose escalation and/or reactive TDM.²⁸ Subsequently, the landmark Trough Concentration Adapted Infliximab Treatment (TAXIT) trial demonstrated that proactive TDM to a target concentration of 3-7µg/mL was associated with less need for rescue therapy and a higher rate of detectable drug concentrations compared to clinically- based dosing.29 Moreover, this randomized controlled trial showed that during the initial optimization phase dose escalation in patients with CD and a suboptimal infliximab concentration significantly increased the number of patients in clinical remission with a concomitant decrease in CRP levels.²⁹ A proposed treatment algorithm for using proactive TDM for anti- TNF therapy is shown in Figure 2.

Though the above studies relate to patients in the maintenance phase of anti-TNF therapy, exposure- response relationship studies show that higher drug concentrations during, or early after, the induction phase are associated with improved therapeutic outcomes (Table 1). These data imply that early optimization, even during induction therapy, may better optimize the efficacy of anti-TNF therapy. In fact, moderate to severely active patients with significant inflammatory burden are likely to benefit the most from proactive TDM as they have an increased drug clearance which predisposes to lower drug concentrations and development of anti-drug antibodies. Although clinically relevant drug thresholds can vary based on the assay used and the therapeutic outcome of interest, we typically aim for post-induction concentrations > 10 µg/mL both for infliximab and adalimumab.

Another aspect of proactive TDM is to guide treatment de-escalation in patients with supra- therapeutic drug concentrations through dose reduction, interval prolongation and/or withdrawal of an immunomodulator (IMM). The rationale for this treatment de-escalation is to potentially maximize both safety and cost-effectiveness of anti-TNF therapy. In our study, 15% of patients either stopped or de-escalated infliximab therapy based on TDM without any negative impact on their long-term clinical outcomes.²⁸ Similarly, 27% of patients in the TAXIT trial underwent dose de-escalation resulting in a significant reduction of treatment costs without any deterioration of remission rates.²⁹ Another study showed that the great majority (90%) of patients with trough concentration >8µg/ mL who de-escalated infliximab therapy to a target concentration of a 3 to 7µg/mL remained in deep remission after a median follow up of 8 months.41 Recently, a prospective study of 80 consecutive patients with IBD in clinical remission demonstrated that a TDM-based de-escalation approach was superior to blind adjustments of infliximab therapy based on symptoms and CRP.⁴²

Regarding IMM withdrawal as a de-escalating therapeutic strategy, our study showed that drug retention was similar between patients in clinical remission on mono- or combo-therapy who achieved an infliximab concentration of ≥5µg/mL, suggesting that “optimized monotherapy’ is feasible in this group of patients.²⁸ This is in line to another study which demonstrated that in patients receiving combination therapy, those with infliximab trough concentration ≥5µg/mL at the time of IMM discontinuation have a decreased risk for dose escalation, IBD-related surgery and drug cessation due to loss of response.⁴³ Furthermore, it was previously shown that although patients who continued to receive combination therapy had higher median trough infliximab concentration and lower CRP levels than those who discontinued IMM, no clear clinical benefit of combo-therapy was observed beyond 6 months.⁴⁴

Another potential role of proactive TDM is when anti-TNF therapy needs to be discontinued for reasons other than loss of response or adverse event (e.g. pregnancy, patient preference, health insurance issues) as preliminary evidence suggests that low or undetectable drug concentrations at the time of drug discontinuation are associated with sustained clinical remission after anti-TNF withdrawal.^31,32 Subsequently, when re-starting anti-TNF therapy after a drug holiday, a recent retrospective study showed that the absence of antibodies to infliximab and detectable infliximab trough concentrations after the first dose were associated with fewer infusion reactions and a better long-term response, respectively.³⁰

TDM Assays

There are several assays available for TDM of anti-TNF therapy, and currently none of them can be considered as the gold standard (Table 2).^45-57 The choice of assay in clinical practice typically depends on cost, local availability and physician’s preference and expertise. Recent data suggests that commonly used assays are generally comparable regarding drug concentrations, in contrast to anti-drug antibodies that still largely depend on the analytical properties of the assay used (Table 2). Consequently, clinically relevant thresholds of low or high titer anti-drug antibodies can vary among the currently available assays, making it difficult to compare results across studies. It is important to understand the assay used to avoid misinterpretations and erroneous therapeutic decisions, particularly as anti- drug antibodies can be reported in various ways that may make titers appear high and clinically significant when, in fact, they are not (Table 2). Recent data suggest that a new era in TDM is imminent as accurate, affordable, and easily accessible point-of-care testing and software- decision support tools that will incorporate a predictive pharmacokinetic model based on patient and disease characteristics are already underway.⁵⁸

Limitations

Before TDM can be widely applied into everyday clinical practice there are still several barriers that have to be overcome. These include out-of-pocket cost and health insurance reimbursement issues, time lag from collecting a serum sample to the result of the test, accurate interpretation and application of the results based on the assay used, and the optimal timing of serum sampling. Furthermore, additional data from well-designed prospective studies with a long-term follow up concerning all available biologics during both maintenance and induction therapy are urgently needed.

Despite these limitations, TDM appears to improve outcomes and the care of patients with IBD. A panel consisting of members of the Building Research in Inflammatory Bowel Disease Globally research alliance (BRIDGe; www.BRIDGeIBD.com), and recognized leaders in the field of TDM in IBD has recently published recommendations that helps clinicians on the appropriate timing and best way to interpret and respond to TDM results depending on the specific clinical scenario.⁵⁹

CONCLUSION

A TDM-based therapeutic strategy is likely to emerge as the new standard-of-care of utilizing biologics in IBD. Numerous studies demonstrate the association of adequate drug concentrations and improved clinical outcomes including objective measures of inflammation. Reactive TDM better directs care in those patients losing response to anti-TNF and is more cost-effective than empiric dose escalation. Additionally, although data are still limited, proactive, rather than reactive, TDM may prove even more effective in optimizing biologic therapies and the treatment of IBD. Nevertheless, before a TDM-based therapeutic approach can be widely implemented in clinical practice, several barriers should be first overcome regarding the type and cost of the assay used, optimal time of serum sampling and intinterpretation and application of the results.

Funding

K.P. received a fellowship grant from the Hellenic Group for the study of IBD.

Potential Competing Interests

K.P.: nothing to disclose; A.S.C: received consultancy fees from AbbVie, Janssen, UCB, Takeda, Prometheus, Miraca laboratories and Pfizer.

Introduction To A New Series: Dispatches From The Guild Conference

Dispatches from the GUILD Conference 2017

Uma Mahadevan

The Gastrointestinal Updates in Inflammatory Bowel and Liver Disease (GUILD) Conference is an annual CME conference held in Maui, Hawaii every February. Offering world class faculty, cutting edge interactive clinical sessions and workshops, the GUILD inaugural conference was held February 19- 22, 2017. The objective of the meeting is to provide the most up-to-date and practical information on the management of inflammatory bowel disease (IBD) and viral hepatitis, the two areas of our field that change at the most rapid pace, in an interactive and collegial environment.

To share our learning with the gastroenterology community at large, we introduce our new series based on discussions held at GUILD, beginning with the following article, “Practical Use of Therapeutic Drug Monitoring of Anti-TNF Therapy in IBD”.

We look forward to providing informative and educational articles covering IBD and Viral Hepatitis in Practical Gastroenterology over the following months.

For more information on the GUILD Conference visit: guildconference.com

A Case Report

A Case of Significant Gastrointestinal Involvement in Granulomatosis with Polyangiitis

January 2017 • Volume XLI, Issue 1

Erin Tompkins,Matthew Robles,Mark Cumings

Granulomatosis with polyangiitis (GPA) is a rare, autoimmune condition usually presenting with pulmonary and renal involvement. There are not many reports of gastrointestinal involvement and even fewer cases of disseminated disease. We present a case of biopsy-proven, active gastrointestinal GPA throughout the stomach, small intestine and colon. Patients may present with diffuse abdominal pain, making the diagnosis difficult. We suggest that unidentified or inadequately managed gastrointestinal involvement in GPA is a potentially serious condition. This disease manifestation must be maintained in the differential in at-risk patients with gastrointestinal symptoms, and appropriate imaging should be considered when clinical suspicion warrants.

CPT Erin Tompkins MD¹ CPT Matthew Robles, DO¹ Mark Cumings, MD² ¹Madigan Army Medical Center Department of Internal Medicine, Tacoma, WA ²Providence St. Peter Hospital, Olympia, WA

INTRODUCTION

Granulomatosis with polyangiitis (GPA) is a rare autoimmune condition usually presenting with pulmonary and renal involvement.^1,2 The prevalence of this condition is 3 in 100,000 people in the United States.^1,3 There are numerous studies documenting cerebral, cutaneous and cardiac manifestations, however, few reports of gastrointestinal involvement exist.^1,4,5 Even in patients with known GPA, abdominal symptoms are significantly more likely to represent common underlying etiologies rather than the vasculitis itself. GPA has been included in a group of systemic vasculitides that have been described as “great masqueraders” due to the ability of this condition to manifest itself in ways that differ widely from their more typical presentation.² For this reason, it is important to consider GPA when evaluating patients with a history of GPA who have abdominal complaints after more common etiologies have been ruled out. Here we discuss a case of GPA where both the upper and lower gastrointestinal tract demonstrated active vasculitis.

CASE

A 38-year-old woman presented with several months of postprandial periumbilical abdominal pain. Accompanying symptoms included anal pain upon defecation, fatigue, malaise, night sweats, weight loss, arthralgias and decreased oral intake. Her medical history was significant for granulomatosis with polyangiitis, manifested by pulmonary, renal, sinus and ocular involvement, in remission for three years and off of therapy. Her exam was notable for abdominal tenderness, supraclavicular lymphadenopathy, and a perianal ulceration. Initial workup was concerning for new onset anemia and a positive fecal occult blood test. Upon admission, upper endoscopic and colonoscopic evaluations were performed. Patchy erythematous mucosa, with erosions, was identified in the gastric body, antrum, duodenum, terminal ileum and descending colon; a large ulceration was seen in the splenic flexure.

With the exception of the ileal biopsies, neutrophilic infiltration and reactive capillary endotheliitis without granulomata, consistent with active gastrointestinal GPA, was noted pathologically. Additionally, left anterior cervical lymph node biopsy revealed low- grade follicular lymphoma, which was also noted in the terminal ileum. She was treated with high-dose glucocorticoids with pending transition to rituximab.

DISCUSSION

This is a rare case of gastrointestinal GPA in a young female with multiple organ system involvement. GPA is an ANCA-associated vasculitis, and most commonly presents with upper respiratory, pulmonary and renal manifestations, as seen in our patient.^1,4 Cutaneous, ocular and nervous system manifestations are less common but still described regularly.^1,2 Gastrointestinal involvement is not commonly seen.^1,6 Often, these cases are discovered after an extensive evaluation culminating in endoscopic evaluation with confirmatory pathology. Most of the described cases of intestinal involvement have been noted intraoperatively during bowel perforation repair. Given the potential severity of unidentified or inadequately managed gastrointestinal involvement in GPA, this disease manifestation must be considered in at-risk patients with gastrointestinal symptoms. Appropriate endoscopic workup with biopsies should be performed when clinical suspicion warrants. Missing a diagnosis of gastrointestinal GPA can have a serious impact on morbidity or mortality of the patient as life-threatening consequences, such as bowel ischemia and perforation, are potential complications.^5,6 Early recognition and management are paramount for appropriate patient care.