BOOK REVIEWS

The Little GI Book: An Easily Digestible Guide to Understanding Gastroenterology, 2nd Edition

October 2020 • Volume XLIV, Issue 10

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Author: Douglas G. Adler, MD, FACG, AGAF, FASGE
Publisher: SLACK Incorporated
Publication Year: 2020
ISBN-13: 978-1630917418
Book Price: $34.95

The Little GI Book: An Easily Digestible Guide to Understanding Gastroenterology is written by Dr. Douglas G. Adler, a tenured Professor of Medicine, director of therapeutic endoscopy and gastroenterology fellowship program director at the University of Utah School of Medicine. In the 2nd edition of this book, Dr. Adler includes the latest advances and changes in the diagnosis and treatment of many gastrointestinal (GI) disorders, while continuing his mission to create a simple, high-yield and enjoyable guide to the fundamentals of gastroenterology and hepatology.

This 280-page, pocket sized book is comprised of eight chapters separated by organ-specific diseases, including Esophagus, Stomach, Small Intestine, Colon and Rectum, Liver, Gallbladder and Bile Ducts, Pancreas and, finally, a general overview of endoscopes and endoscopy techniques such as colonoscopy, endoscopic retrograde cholangiopancreatography (ERCP), and endoscopic ultrasound (EUS), and other procedures. Each chapter generally begins with anatomy and physiology, and then delves into common organ-specific pathologies, which are often then sub-divided into pathophysiology, clinical presentation and, most importantly, the specialized diagnosis and treatment methods used by gastroenterologists. Throughout the text, there are numerous high-quality figures and color pictures of disease presentations visualized with endoscopy and endoscopic interventions results. Every chapter concludes with a list of references.

One of the core strengths of this book is its ability to create a window into the endoscopy suite, especially for individuals that have never stepped foot into one. In this book, there are pictures and descriptions of the types of endoscopic therapy used to treat a bleeding peptic ulcer, a common GI diagnosis, but also EUS images of a pancreatic mass surrounding the celiac artery and an explanation of how that position affects management. In addition, the benefit of the updated 2nd edition is the discussion of new advancements in the field of gastroenterology such as peroral endoscopy myotomy for the treatment of achalasia. This is not a textbook that covers the small details of the presentation, diagnosis, and management of every GI diagnosis, but instead, it focuses on providing a broad overview across the entire field of gastroenterology. This would not be the book to rely on for passing boards or shelf examinations; however, it is the ideal book for gaining practical, bedside knowledge to apply on any gastroenterology service. Overall, the combination of the book’s concise length, inclusion of the core GI diagnoses and friendly tone makes it an especially useful resource to resident physicians and upper-level medical students who desire a future in gastroenterology, as well as anyone who desires to have a strong foundation in gastroenterology.

Kevin Kurian, OMS-IV
UNT Health Science Center-Texas College of Osteopathic Medicine

Dawn Sears, MD, FACG
Chief of Gastroenterology
Baylor Scott and White Health
Temple, Texas
Twitter: @GutGirlMD

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FELLOWS’ CORNER

A Rare Differential: Afferent Limb Syndrome in Patients with an Ileal Pouch Anal Anastomosis

October 2020 • Volume XLIV, Issue 10
Aman Sharma,Islam Fayed,David M. Schwartzberg

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CASE PRESENTATION

A 47-year-old male with a history of ulcerative colitis complicated by acute toxic colitis resulting in an emergent onestage laparoscopic restorative proctocolectomy with J-pouch formation, presented with a 10 -year history of intermittent gastrointestinal obstructive symptoms beginning after his operation. Additionally, he endorsed colicky abdominal pain, nausea, episodic vomiting, bloating, and acid reflux. His symptoms appeared shortly after his J-pouch was created without improvement over the next decade. Multiple cross-sectional imaging studies have been performed but failed to demonstrate any signs of obstruction with transition point, evidence of retained rectum or pouch twist, and no abdominal wall hernia or pelvic sepsis. He was referred to an inflammatory bowel disease surgeon where office exam was negative for paradox puborectalis and repeat endoscopy validated no pouch twist, retained rectum, anastomotic leak and the bowel proximal to his pouch was able to be visualized. A Gastrografin enema was performed which revealed normal pouch filling, however, after evacuation a large amount of contrast was present in the small bowel proximal to the pouch.

QUESTIONS

  1. What is the diagnosis in this patient?
  2. What is the underlying pathology of this syndrome?
  3. How is this syndrome diagnosed?
  4. What are the management options in this patient?

Question 1.

This patient is suffering from afferent limb syndrome (ALS) after restorative proctocolectomy, which is caused by an acute angulation of the afferent bowel at the pelvic pouch inlet (Image A). ALS differs from efferent limb syndrome (ELS) in patients with a pelvic pouch as ELS is caused by a long exit-conduit from an S-pouch, while ALS is caused by an obstruction proximal to the ilealanal pouch.

Question 2.

Restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA) is the procedure of choice in patients who have ulcerative colitis, familial adenomatous polyposis, and select patients with Crohn’s disease.1 Despite a low failure rate of 3.4%, there are a variety of possible complications that can result in varying degrees of pouch dysfunction.2 Common postoperative complications are pelvic sepsis, hernia, pouch dysfunction due to inadvertent pouch-rectal anastomosis/pouch twists/outlet obstruction/paradoxical contraction, and the most common complication, small bowel obstruction (SBO).3 SBO in patients with an IPAA is frequently diagnosed by symptomatology and cross-sectional imaging and is a consequence of intra-abdominal adhesions, however, some patients with non-specific abdominal pain and bloating may have ALS. ALS can be due to acute angulation, intussusception of the distal ileum, or adhesions leading to obstruction of the afferent-limb at the bowel of the pouch inlet, typically with bowel trapped between the pouch and the sacrum.4 ALS is rare, occurring in just less than 2% of all patients after IPAA creation, and in 12% among patients who are displaying obstructive symptoms.4,5 ALS can present acutely after IPAA or years later.

Question 3.

ALS can present as abdominal pain, nausea, and vomiting, similar to symptoms of SBO, but without the typical radiographic findings seen with a bowel obstruction. Patients with ALS have often been worked up for various symptomatology, which typically begins with history, physical exam, and cross-sectional imaging of computed tomography (CT) to assess for adhesive small bowel obstruction. If the initial workup is negative, patients should undergo pouchoscopy to look for signs of Crohn’s disease or septic complications.

However, assuming symptoms are secondary to Crohn’s disease can lead to years of unneeded medical therapy when a mechanical issue needing corrective surgery is the underlying pathology. For this reason, the patient should be referred to a pouch specialist for formal workup. This includes an exam under anesthesia, flexible pouchoscopy to assess for pouch ulcers, a stricture at the pouch inlet or perianal fistulae to suggest Crohn’s disease/ pelvic sepsis, a pelvic magnetic resonance imaging to assess for retained rectum or pouch twist, and a Gastrografin enema (GGE) to assess for ALS or stricture. The typical finding for ALS of a GGE exam is contrast retention in a dilated pre-pouch small bowel after the patient has evacuated the Gastrografin (Image B).

Question 4.

The management of ALS involves a multidisciplinary team as endoscopic interventions and/or surgical management may be needed to correct the underlying obstruction at the pouch inlet. Endoscopic balloon dilation can be attempted, typically with a 20mm balloon, though almost half of patients require repeat dilations, and symptoms may continue to ultimately require operative intervention.4 Other endoscopic interventions such as needle-knife sinusotomy to divide the chronic scar at the angulated tissue have also had success.1 Surgically, patients can undergo resection of the angulated bowel with anastomosis, enteroenterostomy to bypass the segment adherent posteriorly to the pouch to avoid pouch mobilization (thus avoiding injury to the pouch or mesentery which can cause pouch ischemia), mobilization of the pouch with a pexy of the pouch and/or proximal small bowel, and pouch excision with the creation of an end-ileostomy.4 There is a 40-100% resolution of symptoms after surgical intervention, while around 40% of patients who undergo endoscopic interventions will need repeat endoscopic interventions.4,5 Though some series omit endoscopic interventions to correct ALS and refer the patient for surgery, endoscopic intervention by an experienced pouch-endoscopist may obviate the need for surgical intervention and should be attempted initially.4,5 This patient was able to undergo a laparoscopic adhesiolysis, abdominopelvic pouch mobilization, pouchopexy, and intraoperative pouchoscopy with diverting loop ileostomy. He was discharged uneventfully and able to tolerate a low-fiber diet without any abdominal pain or bloating. He underwent a GGE prior to stoma closure (Image C) which showed complete evacuation of the contrast from both his pouch and proximal small bowel. There were no further complaints of any abdominal pain or bloating after stoma closure.

CONCLUSION

Clinicians should be mindful when evaluating non-specific abdominal pain, bloating, or pouch dysfunction in patients who have undergone IPAA, as ALS can be elusive to diagnosis and so its presence must be germane during the workup. Complications such as afferent limb syndrome may be rare, however, may contribute to a delay in diagnosis in this patient population acutely or years after surgery. A multidisciplinary approach is necessary to properly identify the source of pathology and offer medical, endoscopic, or surgical correction.

References

  1. Holubar SD. Prevention, Diagnosis, and Treatment of Complications of the IPAA for Ulcerative Colitis. Dis Colon Rectum. 2018;61(5):532-536. doi:10.1097/ DCR.0000000000001094
  2. Delaney CP, Remzi FH, Gramlich T, Dadvand B, Fazio VW. Equivalent function, quality of life and pouch survival rates after ileal pouch-anal anastomosis for indeterminate and ulcerative colitis. Ann Surg. 2002;236(1):43-48. doi:10.1097/00000658-200207000-00008
  3. Ng K-S, Gonsalves SJ, Sagar PM. Ileal-anal pouches: A review of its history, indications, and complications. World journal of gastroenterology. World J Gastroenterol. Aug 21, 2019; 25(31): 4320-4342 doi: 10.3748/wjg.v25.i31.4320
  4. Read TE, Schoetz DJ, Marcello PW, et al. Afferent Limb Obstruction Complicating Ileal Pouch-Anal Anastomosis. Dis Col Rectum: May 1997 – p 566-569 doi: 10.1007/ BF02055380
  5. Kirat HT, Kiran RP, Remzi FH, Fazio VW, Shen B. Diagnosis and management of afferent limb syndrome in patients with ileal pouch-anal anastomosis. Inflamm Bowel Dis. 2011;17(6):1287-1290. doi:10.1002/ibd.21503

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A CASE REPORT

Dysphagia Aortica from Endovascular Leak After Thoracic Endovascular Aneurysm Repair

October 2020 • Volume XLIV, Issue 10
Sonal Gandhi,Malorie K. Simons,Joshua A. Sloan

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Achalasia is an esophageal motility disorder that causes peristaltic dysfunction and failure of the lower esophageal sphincter (LES) to relax upon swallowing. Pseudoachalasia is a mimicker of achalasia, but its pathophysiology and treatments are different. We present a case of an elderly woman with dysphagia. Manometry was most consistent with type II achalasia. Ultimately, the diagnosis of dysphagia aortica causing pseudoachalasia from a large, compressing thoracic aorta endoleak after a thoracic endovascular aneurysm repair (TEVAR) was made. This diagnosis altered her management course, avoiding possible intervention such as peroral endoscopic myotomy (POEM) versus laparoscopic Heller myotomy (LHM).

INTRODUCTION

Achalasia is a primary esophageal neuromuscular motility disorder of unclear etiology.1 It results from degeneration of the myenteric plexus causing failure of the lower esophageal sphincter (LES) to relax upon swallowing with esophageal body dysmotility (absent contractility, panesophageal pressurization, or spastic contractions).1,2 In order to make the diagnosis of achalasia, it is crucial to rule out other mimickers including medication effect and pseudoachalasia in the appropriate patients.3 Dysphagia aortica (DA) is a rare cause of pseudoachalasia. First described in 1932 DA is due to external compression of the esophagus by ectatic, tortuous or aneurysmal thoracic aorta due to age related degeneration.4 It is mainly seen in elderly women of short stature and with co-existing conditions such as hypertension and kyphosis. We present a case of an elderly woman with manometric findings consistent with Type II achalasia who was transferred to our center for peroral endoscopic myotomy (POEM). After careful review of clinical history, imaging and manometry, her symptoms were more consistent with DA from a large, compressing thoracic aorta, resulting in pseudoachalasia.

Case Report

A 75-year-old woman with a history of antiJo1 antisynthetase syndrome, steroid dependent interstitial lung disease on home oxygen, chronic pain on long-term opiates, severe pulmonary hypertension, and thoracoabdominal aortic aneurysm status post total thoracic endovascular aneurysm repair (TEVAR) three years prior with recent redo presented with six months of worsening dysphagia to solids and progressing to liquids. This resulted in weight loss, failure to thrive, and recurrent aspiration with declining lung function.

Diagnostic work up included computed tomography (CT) scan which revealed active type II endoleak extending from the TEVAR with lateral compression and displacement of the esophagus (Figure A). Barium esophagram was subsequently performed that showed a delay in esophageal emptying with retrograde flow and evidence of a short segment narrowing at the lower esophageal sphincter (LES) where the TEVAR intersects the LES (Figure B). Upper endoscopy demonstrated esophageal candidiasis without evidence of stenosis, external compression, or tight LES. An endoscopically placed manometry catheter showed no normal peristalsis, panesophageal pressurization in 5/10 swallows, and an integrated relaxation pressure (IRP) of 25.4 (Figure C). After a multidisciplinary discussion with the therapeutic endoscopists, motility and neurogastroenterology specialists, and vascular surgeons, her clinical presentation was deemed most consistent with pseudoachalasia due to endovascular leak causing compression as opposed to primary achalasia, thus limiting the utility of therapy directed towards achalasia. Additionally, the risk of endovascular repair was felt to outweigh benefits.

The patient opted for conservative management of her dysphagia, which improved with treatment for esophageal candidiasis and dietary modification to liquids, and pureed foods. After a lengthy hospital stay, she wished to focus her attention on comfort, and she was discharged home with hospice care.

Discussion

Pseudoachalasia is a diagnostic entity that is indistinguishable from primary achalasia. Most reports are from a malignant paraneoplastic effect, or circumferential compression and infiltration of the LES.5,6 DA, itself, is an uncommon cause of dysphagia due to compression of the LES; however, DA resulting in pseudoachalasia is exceedingly rare. To date, there is only one case report of a patient initially thought to have achalasia but then found to have DA from a thoracic aortic aneurysm causing pseudoachalasia.5 To our knowledge, we believe we present the first reported case of a TEVAR endoleak causing pseudoachalasia.

This case posed a significant diagnostic challenge. Manometrically the patient’s diagnosis was that of type II achalasia. With the advent of high resolution manometry (HRM), achalasia can be separated into three subtypes (Type I, II and III) based upon the esophageal pressure topography and the Chicago Classification.1,2 Diagnosing the correct achalasia phenotype has important prognostic and therapeutic implications. For example, Type II achalasia, defined by absent peristalsis, an elevated IRP and panesophageal pressurization in a minimum of 2/10 reclining swallows, responds to pneumatic dilation, POEM, or Heller myotomy.3

Our patient was a high risk surgical or POEM candidate due to her known cardiopulmonary disease, chronic steroids use, and position of the active endovascular leak near the LES; however, there were multiple factors that made her achalasia diagnosis questionable. First, opiates have been shown to cause dysphagia and manometry findings comparable to achalasia.7 Once opiates are stopped, esophageal motility returns to normal. For our patient, ceasing all opiate use would have resulted in significant morbidity and thus was a last resort. Secondly, her history was more consistent with pseudoachalasia: sudden onset of symptoms, marked weight loss, and an esophageal compression at the site of the endovascular leak.

DA is a rare cause of pseudoachalasia, and thus little is known about the underlying pathophysiology. This external compression may result in esophageal dysmotility based on the anatomic impact of the vasculature on the esophagus.8 In our patient it was the compression by the TEVAR and endoleak that was the most likely cause of her DA and subsequent pseudoachalasia. There was the additional confounder of chronic opioid use that cannot be ignored as a possible contributing factor; however, this would not account for the radiographic findings.

This case highlighted the importance of distinguishing pseudoachalasia from primary achalasia, as treatment options are different. Treatment for pseudoachalasia is aimed at the primary cause. In our case, this would be directed towards weaning off opiates and endovascular repair, for which the latter was deemed to be high risk with uncertain benefit. Achalasia is managed taking into account a number of factors including sex, age, subtype of achalasia, and patient preference with the management choices being laparoscopic Heller myotomy, pneumatic dilation, hydrostatic dilation, POEM, or botulinum toxin injection. To help differentiate pseudoachalasia from true achalasia, amyl nitrate could have been administered during manometry, resulting in LES relaxation in the latter. Unfortunately, this diagnostic option was considered too dangerous for our patient given her severe cardiopulmonary disease. This case highlights the importance of a thorough review of patients’ history and clinical presentation in combination with a multidisciplinary approach to decipher the true cause of dysphagia to most appropriately manage complex esophageal disease.

References

  1. Pandolfino JE, Gawron AJ. Achalasia: a systematic review. Jama. 2015;313(18):1841-1852.
  2. Kahrilas PJ, Bredenoord AJ, Fox M, et al. The Chicago Classification of esophageal motility disorders, v3.0. Neurogastroenterol Motil. 2015;27(2):160-174.
  3. Khashab MA, Vela MF, Thosani N, et al. ASGE guideline on the management of achalasia. Gastrointest Endosc. 2019.
  4. Wilkinson JM, Euinton HA, Smith LF, Bull MJ, Thorpe JA. Diagnostic dilemmas in dysphagia aortica. Eur J Cardiothorac Surg. 1997;11(2):222-227.
  5. Beqari J, Lembo A, Critchlow J, Hamden A, Kent MS. Pseudoachalasia Secondary to Thoracic Aortic Aneurysm. Ann Thorac Surg. 2017;103(6):e517-e518.
  6. Gockel I, Eckardt VF, Schmitt T, Junginger T. Pseudoachalasia: a case series and analysis of the literature. Scand J Gastroenterol. 2005;40(4):378-385.
  7. Ratuapli SK, Crowell MD, DiBaise JK, et al. Opioid-Induced Esophageal Dysfunction (OIED) in Patients on Chronic Opioids. Am J Gastroenterol. 2015;110(7):979-984. 8. Mucklow EH, Smith OE. Dysphagia and unusual radiographic appearances associated with the variable relationships of the aorta and lower oesophagus. J Fac Radiol. 1954;6(2):88-95.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #203

Metabolic Acidosis: Got Bicarbonate?

October 2020 • Volume XLIV, Issue 10
Kendra Glassman

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Acute or chronic metabolic acidosis is a condition that has serious complications. It develops from either increased acid production, increased enteric losses, or decreased renal acid secretion. Acutely, metabolic acidosis can cause serious cardiac and pulmonary complications; chronically, it can lead to alterations in protein catabolism, bone health, and hormonal changes. Correcting the metabolic acidosis is essential to minimizing these complications. Bicarbonate supplementation has been the mainstay for achieving acid-base balance; however, with ongoing medication shortages, clinicians must become creative with their treatment plan.

INTRODUCTION

The body’s ability to maintain acid-base balance is critical for health. The kidneys and lungs work harmoniously along with several buffering systems to maintain homeostasis. Acidemia occurs when arterial pH falls below 7.35, which can result in a metabolic, respiratory, or mixed acid-base disorder.1 When the concentration of hydrogen ions in the body is increased reducing the bicarbonate concentration, metabolic acidosis ensues.2 The three primary causes of metabolic acidosis are:3

  • Increased acid production
  • Loss of enteral bicarbonate in stool from pancreatic secretions
  • Decreased renal acid elimination or increased bicarbonate loss due to inability to “reclaim” filtered bicarbonate

Acute forms are most likely due to overproduction of acid; chronic forms are likely from the latter two causes.3

Acute metabolic acidosis can cause decreased cardiac output and arterial dilatation resulting in hypotension, decreased oxygenation, arrhythmias, and immune compromise.4 Chronic metabolic acidosis can lead to increased muscle degradation, increased osteoclastic activity, and alterations in endocrine function. Alterations in endocrine function include increased production of glucocorticoids and decreased production of thyroid hormones, insulin, and growth hormones.5,6 While using bicarbonate to treat acute forms of metabolic acidosis is controversial as it has not always been shown to improve outcomes,7 it is the mainstay for chronic metabolic acidosis to help improve cellular function and prevent long term complications.3

Mechanism and Classification

Identifying the cause of metabolic acidosis is essential to guiding treatment and preventing adverse events. It can be classified based on the three major mechanisms as listed above. See Table 1A and B for more in-depth mechanisms. A useful tool is the measurement of the anion gap.8,9 The anion gap is a value that represents the difference between the primary positively charged cation (Na+) and negatively charged anions (Cl- and HC03-) in the blood. Calculating the anion gap can also be helpful in classifying it as either elevated anion gap acidosis or normal (hyperchloremic) anion gap.10 Generally, excess acid production results in a high anion gap whereas excess base or decreased acid excretion by the kidneys results in hyperchloremic metabolic acidosis or normal metabolic acidosis.8,9

Increased Acid Production

Increased acid accumulation that leads to metabolic acidosis can occur in a variety of clinical settings and leads to an anion gap metabolic acidosis. The main causes are due to lactic acidosis; ketoacidosis due to uncontrolled diabetes, excess alcohol or fasting; ingesting substances such as methanol, ethylene glycol, diethylene glycol, or propylene glycol; aspirin or acetaminophen poisoning, or rarely, toluene ingestion, and finally, D-lactic acidosis.2,11

Loss of Bicarbonate

Metabolic acidosis related to loss of base or bicarbonate occurs due to several reasons. It can be due to diarrhea, ileostomy output, enterocutaneous fistulas, or short bowel syndrome where a significant amount of bicarbonate from pancreatic secretions can be lost in the stool. The kidney compensates by reabsorbing bicarbonate and increasing acid excretion rapidly. If volume depletion occurs, the kidney will also reabsorb increased NaCl to prevent intravascular loss.12,13 Bicarbonate reabsorption can be impaired in the setting of proximal renal tubular acidosis in diseases such as multiple myeloma.14 Further, base can be lost if urine is exposed to the GI tract in the case of any neobladder reconstruction (ileo-conduit) and therefore urinary chloride is absorbed in the colon in exchange for bicarbonate and consequently increases bicarbonate GI losses.14

Decreased Renal Acid Elimination

One of the most common causes of metabolic acidosis is decreased renal acid secretion in chronic kidney disease. Usually metabolic acidosis does not ensue until patients have progressed to stage 4 chronic kidney disease (CKD) where acids from the metabolism of protein are not excreted, resulting in metabolic acidosis.16,17 There are 2 mechanisms that responsible for the 3 types of renal tubular acidosis (RTA) that can cause metabolic acidosis:

  1. Defects in secreting or transporting H+ ions from the distal convoluted tubules cause distal RTAs and low renin/low aldosterone level induced RTAs.
  1. Increased bicarbonate losses from impaired reabsorption of bicarbonate causes, discussed earlier, results in a proximal RTA.15

Typical distal RTAs may cause severe acidosis, whereas low renin/low aldosterone secretion induced RTAs are often milder with hyperkalemia as the hallmark sign.18

Consequences

Bicarbonate is essential for health. Without it, serious consequences can result if untreated. Management of metabolic acidosis varies depending on acute or chronic status. In acute metabolic acidosis, symptoms usually do not develop unless pH falls to < 7.10, where patients can develop nausea, emesis, and an overall sense of malaise. In order to compensate, breathing often becomes more laborious resulting in longer, deeper breaths. Severe forms can have cardiac manifestations along with hypotension and shock, arrhythmias, and in the most extreme case, coma.4-6

Treatment has only been demonstrated to be beneficial in non-anion gap acidosis and continues to be controversial in high anion gap metabolic acidosis.7 There are risks associated with treatment in the latter case as it can lead to hypernatremia and volume overload in addition to hypotension, decreased cardiac output, and an increase in mortality.19 Many studies have not associated treatment with decreased mortality; yet most sources continue to recommend administering bicarbonate in severe acidemia (pH <7.10) to correct the acidosis with the intention of reversing
organ failure.7,20

Correction of chronic metabolic acidosis is essential. Symptomatically, patients experience less dyspnea due to decreased hypercapnic breathing.21 Metabolic acidosis can also lead to decreased muscle function, decreased bone mineral density, and influence hormone levels.5,22,23 In children, correction of the acidosis can result in improved skeletal growth.24 Patients with RTA can experience calcium containing kidney stones, which can be reversed with bicarbonate replacement.25 Progression to chronic kidney disease can be slowed down the when the acidosis is corrected.26

Treatment

Correcting metabolic acidosis depends on many factors including the degree and chronicity of acidosis, ongoing acid production or bicarbonate losses, renal function, and whether oral/enteral vs. parenteral sources are needed. Once these factors have been evaluated and the level of bicarbonate has been determined, calculating the bicarbonate deficit can be helpful in estimating the amount of bicarbonate needed. The following formula can be used:

While this provides a rough estimate of the bicarbonate needed it should not replace serial measurements of HC03 (CO2 on a basic metabolic panel) and pH in order to determine if further supplementation is required. The clinician must also be mindful of the serum potassium as it can become depleted with ongoing GI losses, but often appears normal in the setting of acidosis. Once the acidosis is resolved, potassium levels should be monitored and replete as needed.

Methods of Supplementation

Bicarbonate can be administered in several ways including orally/enterally, intravenously, and via dialysate during hemodialysis. Administering sodium bicarbonate is the most common and fastest method to correct metabolic acidosis,7 however, other sources are available. If administered as another anion such as citrate or acetate, the liver will convert it to bicarbonate. In the acute care setting, tromethamine (THAM), had previously been used, which is a non-sodium-based buffer to correct the acidosis, however it has been discontinued by the manufacturer and is no longer available in the United States.25 Acetate or citrate can also be given via sodium or potassium salts depending on the type of deficiency and supplementation needed. Of note, the typical Western diet, which is high in animal protein, can contribute to acid production. Recommending a diet rich in fruits and vegetables can lead to an increase in base load and may help with minimizing chronic acidosis.28 With the ever-increasing medication shortages, clinicians have become creative, using everyday sources of base such as baking soda as an alternative. Table 2 provides sources of bicarbonate supplementation.29-31

Parenteral Nutrition Shortages

With patients on parenteral nutrition (PN) support, maximizing acetate, which is converted to bicarbonate in the body, will help restore metabolic balance. This has been difficult given recent PN shortages.32 Most recently, potassium and sodium acetate have been on the TPN shortage list making replacing bicarbonate difficult. When possible, replacing losses via the enteral route during shortages is recommended, however, some patients are unable to tolerate any source of enteral replacement. Other options might be to use premade PN mixtures and reserving custom PN for patients in which it is needed. Table 3 and 4 lists helpful websites and tips to help manage parenteral shortages.

CONCLUSION

Metabolic acidosis can occur due to several mechanisms. The first step is to identify the cause and determine if this is an acute or ongoing process. If left untreated, either in the acute or chronic setting it can have deleterious effects. Treatment traditionally has been with sodium bicarbonate drips or acetate in parenteral nutrition solutions. Given the recent shortages, clinicians must become creative in finding alternate ways to maintain acidbase balance.

References

  1. Kraut JA, Madias NE. Metabolic acidosis: pathophysiology, diagnosis and management. Nat Rev Nephrol. 2010;6(5):274-285.
  2. Lim S. Metabolic acidosis. Acta Med Indones. 2007;39(3):145-150.
  3. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.583.
  4. Kimmoun A, Novy E, Auchet T, et al. Hemodynamic consequences of severe lactic acidosis in shock states: from bench to bedside. 2015; 19(1): 175. [published correction appears in Crit Care. 2017;21:40.
  5. Ballmer PE, McNurlan MA, Hulter HN, et al. Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans. J Clin Invest, 1995;95:39-45.
  6. Soares SBM, de Menezes Silva LAW, de Carvalho Mrad FC, et al. Distal renal tubular acidosis: genetic causes and management. World J Pediatr. 2019;15(5):422-431.
  7. Velissaris D, Karamouzos V, Ktenopoulos N, et al. The Use of Sodium Bicarbonate in the Treatment of Acidosis in Sepsis: A Literature Update on a Long Term Debate. Crit Care Res Pract. 2015;2015:605830.
  8. Emmett M. Anion-gap interpretation: the old and the new. Nat Clin Pract Nephrol 2006; 2:4.
  9. Emmett M, Narins RG. Clinical use of the anion gap. Medicine (Baltimore) 1977; 56:38.
  10. Kraut JA, Madias NE. Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol. 2007;2(1):162-174.
  11. White L. D-Lactic Acidosis: More Prevalent Than We Think? Practical Gastroenterol. 2015; Sept (9):26-45.
  12. Wesson DE, Laski M. Hyperchloremic metabolic acidosis due to intestinal losses and other nonrenal causes. In: AcidBase Disorders and Their Treatment, edited by Gennari FJ, Adrogue HJ, Galla JH, Madias NE. Boca Raton, Taylor and Francis, 2005, 487-499.
  13. Gennari FJ, Weise WJ. Acid-base disturbances in gastrointestinal disease. Clin J Am Soc Nephrol, 2008;3:1861-1868.
  14. Van der Aa F, De Ridder D, Van Poppel H. When the Bowel Becomes The Bladder: Changes In Metabolism After Urinary Diversion. Practical Gastroenterology 2012;July(7):15-28.
  15. Alexander RT, Bitzan M. Renal Tubular Acidosis. Pediatr Clin North Am. 2019;66(1):135-157.
  16. Kraut JA, Madias NE. Metabolic Acidosis of CKD: An Update. Am J Kidney Dis. 2016;67(2):307-317.
  17. Raphael KL. Metabolic Acidosis in CKD: Core Curriculum 2019. Am J Kidney Dis. 2019;74(2):263-275.
  18. Rodríguez Soriano J. Renal tubular acidosis: the clinical entity. J Am Soc Nephrol 2002;13:2160.
  19. Kim HJ, Son YK, An WS. Effect of sodium bicarbonate administration on mortality in patients with lactic acidosis: a retrospective analysis. PLoS One. 2013;8(6):e65283.
  20. Mitchell JH, Wildenthal K, Johnson RL Jr. The effects of acid-base disturbances on cardiovascular and pulmonary function. Kidney Int 1972;1:375.
  21. Ordóñez FA, Santos F, Martínez V, et al. Resistance to growth hormone and insulin-like growth factor-I in acidotic rats. Pediatr Nephrol 2000;14:720.
  22. Kalantar-Zadeh K, Mehrotra R, Fouque D, Kopple JD. Metabolic acidosis and malnutrition-inflammation complex syndrome in chronic renal failure. Semin Dial 2004;17:455.
  23. Bajpai A, Bagga A, Hari P, et al. Long-term outcome in children with primary distal renal tubular acidosis. Indian Pediatr. 2005;42(4):321-328.
  24. Wrong O. Nephrocalcinosis. In: Oxford Textbook of Clinical Nephrology, Davison AM, Cameron JS, Grünfeld J, et al (Eds), Oxford University Press, Oxford 2005. p.1375.
  25. Kallet RH, Jasmer RM, Luce JM, et al. The treatment of acidosis in acute lung injury with tris-hydroxymethyl aminomethane (THAM). Am J Respir Crit Care Med 2000;161:1149.
  26. Goraya N, Wesson DE. Clinical evidence that treatment of metabolic acidosis slows the progression of chronic kidney disease. Curr Opin Nephrol Hypertens 2019;28:267–277.
  27. Jaber S, Paugam C, Futier E, et al. Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial. Lancet 2018;392:31.
  28. Goraya N, Simoni J, Jo CH, Wesson DE. A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate. Clin J Am Soc Nephrol. 2013;8(3):371-381.
  29. Sodium Bicarbonate. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:// online.lexi.com.
  30. Potassium Bicarbonate. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:// online.lexi.com.
  31. Penniston KL, Nakada SY, Holmes RP, et al. Quantitative assessment of citric acid in lemon juice, lime juice, and commercially-available fruit juice products. J Endourol. 2008;22(3):567-570.
  32. American Society for Parenteral Nutrition Product shortages: https://www.nutritioncare.org/News/General_News/ Parenteral_Nutrition_Electrolyte_and_Mineral_Product_ Shortage_Considerations/.

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FRONTIERS IN ENDOSCOPY, SERIES #66

Dilation Assisted Stone Extraction:Techniques and Outcomes

October 2020 • Volume XLIV, Issue 10
Taylor Frost,Douglas G. Adler

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INTRODUCTION

Endoscopic retrograde cholangiopancreatography (ERCP), typically combined with endoscopic sphincterotomy (EST), has become the gold standard treatment for the management of common bile duct stones. Approximately 15-20% of patients who undergo EST will not achieve complete stone removal, necessitating either advanced endoscopic or surgical procedures.1 Factors that may predict difficult stone extraction include large stones (>12mm), multiple stones, stones above a stricture, and/or a small or tapered common bile duct.19 This review will focus on the indications, success rate, and adverse events of Dilation Assisted Stone Extraction (DASE) for difficult biliary stones.

Dilation Assisted Stone Extraction

Dilation Assisted Stone Extraction (DASE) was first introduced in 2003 by Ersoz, Tekesin, Ozutemiz and Gunsar to aid in the extraction of large or complex biliary stones.2 Since its initial description, DASE has been referred to by many names and now possess numerous synonyms which represent the same procedure. Dilation assisted stone extraction is often referenced as either full or limited endoscopic sphincterotomy plus endoscopic papillary large balloon dilation (EST+EPLBD) or biliary endoscopic sphincterotomy with biliary orifice balloon dilation (BES+BBD), or some combination thereof. Regardless, the procedure is performed in four stages; deep cannulation of the bile duct, endoscopic sphincterotomy of the papillary orifice, and balloon dilation of the biliary tree before finally extracting biliary stones. (Figure 1) In its first description, endoscopic sphincterotomy was performed at the papillary orifice and extended to the transverse fold. Dilation to 12-20mm, based on stone size, is then performed with a large diameter balloon (over the guidewire, esophageal/pyloric type balloons) immediately following sphincterotomy. Of note, balloon inflation is maintained until 20-45 seconds after the gradual disappearance of the waist of the balloon is observed as this is thought to indicate a progressive dilation of the orifice.

Endoscopic Papillary Balloon Dilation

Endoscopic Papillary Balloon Dilation (EPBD), also referred to as endoscopic sphincteroplasty, was first described in the early 1980s and has been advocated as an alternative to endoscopic sphincterotomy.3 The procedure is accomplished through pneumatic balloon dilation of the biliary orifice. It was postulated that EPBD preserved the function of the biliary sphincter (as opposed to biliary sphincterotomy, which permanently cuts the entire sphincter muscle) and thus may convey some advantage in regards to short and long term sequelae over endoscopic sphincterotomy. However, EPBD alone often did not produce a wide enough dilation for the retrieval of large biliary stones frequently resulting in a need for mechanical lithotripsy or other advanced procedures.4,5 After the advent of DASE, and the addition of balloon dilation to biliary sphincterotomy, endoscopists began to utilize larger esophageal/pyloric type balloons and in modern era the procedure is often referenced as Endoscopic Papillary Large Balloon Dilation (EPLBD) with or without sphincterotomy.

Comparison of Techniques
EST VS DASE

Endoscopic sphincterotomy with subsequent balloon catheter stone extraction is widely accepted as the standard therapy for common bile duct stones. However, sphincterotomy alone is often not effective in the removal of large common bile duct stones (>12mm).6 In fact, in the sentinel study describing the DASE procedure was only implemented after sphincterotomy had failed and resulted in a 89-95% success rate depending the degree of dilation performed.1 In regards to small bile duct stones (<12mm), EST alone and DASE have a similar success and complication rates although there may be a lower rate of stone reoccurrence with DASE.7

EST VS EPLBD

The use of endoscopic papillary large balloon dilation for the retrieval of large common bile duct stones has been heatedly debated throughout the literature and there are large differences in its utilization based on locoregional preferences.8 There are some studies, primarily performed in Asia, that suggest EPLBD is superior to or as effective as DASE or EST with similar complication rates.9,10,11 However, it has been postulated that this may be related to population-based characteristics and operator experience with EST.7,10 A randomized, controlled, multicenter study from the United States comparing EPLBD to EST demonstrated significantly higher rates of pancreatitis (15.4% vs 0.8%) and subsequent death (6.8% vs 0%). In this study patients who received EPLBD underwent more invasive procedures, had longer hospital stays, and more time off from normal activities.12 This study was terminated early given the adverse outcomes in the EPLBD group. The remainder of this article will focus on DASE as it is the most commonly utilized advanced procedure for large common bile duct stones within the United States and Europe.

Indications, Success Rates, and Potential Adverse Events of Dilation Assisted Stone Extraction (DASE) Indications (periampullary diverticula, large stones)

The indications for the use of DASE have expanded since its initial description as a rescue procedure following failed EST. Often the endoscopist must determine the degree of difficulty anticipated with the extraction of the stone(s) based on their size, shape, and location. However, there is some evidence that DASE has a higher success rate than EST combined with balloon extraction alone when utilized on stones are greater than 12mm, with higher success rates seen with DASE in progressively larger stones.13 Other factors that may influence the decision to perform DASE over EST which include periampullary diverticula, a tapered distal bile duct, or a sigmoid shaped bile duct.

Success Rates

There is considerable variation between the definition of success seen within the literature on DASE. Some authors report overall stone clearance rates while others rely upon stone clearance on initial ERCP. Factors including differences in sphincterotomy/dilation size, operator experience, and average stone size are often present which may have impact on the overall stone clearance rate and make it difficult to compare studies. However, reported success rates on the initial ERCP of patients undergoing DASE have ranged from 72- 98% with the majority of studies reporting >85% success.1,14,15,16,17,18 Furthermore, a comparison of DASE vs EST alone found that DASE had a higher rate of stone clearance on the first attempt with reduced overall procedure time and a lower need for mechanical lithotripsy.19 In one retrospective review, it was found that DASE success rates were greatest when stones were >15mm in size but these authors also found a higher rate of failure, requiring multiple ERCP procedures, once stones were greater than 20mm in diameter.20 Furthermore, it has been suggested that patients with a single stone may have a higher success rate than those with a greater stone burden.16

Adverse Events

The most common adverse events of DASE are pancreatitis, bleeding, and perforation. There have been several well-designed retrospective studies which have described rates of pancreatitis ranging from 0-5.9% and bleeding of 0-2.9%.6,9,12,13,14,16,18,21 One retrospective study had a particularly high overall complication rate with pancreatitis occurring in 8.9% of patients and bleeding in 9.2%.17 However, the majority of DASE cases in this study were performed after failed EST stone extraction which may have influenced the overall complication rate. It has been postulated that sphincterotomy size and balloon dilation diameter/duration may have some effect on bleeding and perforation risk.22 Sphincterotomy size often varies considerably between studies and operators, and is subjectively measured by the endoscopists. However, when described as “full length”, complication rates have been similar to those with partial sphincterotomy.4

There is also considerable heterogeneity in regards to balloon dilation diameter and duration of actual dilation time. Balloon dilation diameter should primarily be chosen based on bile duct size and stone diameter. Balloon dilation size can vary between 8-20mm with the majority of studies utilizing 15mm.23 Theoretically, larger dilation diameters should carry more risk of perforation. However, a retrospective review of 101 patients who underwent DASE with balloon dilation to 12-20mm had a similar complication rate to other studies.24 In regards to balloon dilation times, a prospective randomized trial comparing dilation durations of 30 and 60 seconds found no difference in overall stone clearance or complications including pancreatitis, perforation, and bleeding.25 Overall, perforation appears to be relatively rare following DASE with rates of 0-1.4%.9,17 It is important to consider the complication rate of DASE within the context of endoscopic sphincterotomy as this is an integral part of the procedure. When comparing sphincterotomy alone to DASE, one prospective study of 121 patients found no difference in rates of pancreatitis, stone/basket impaction, bleeding or perforation.9 Furthermore, there is some data that suggests a lower rate of bleeding and recurrence of common bile duct stones in patients who underwent DASE compared EST alone.6

Altered Anatomy

There have been relatively few studies describing DASE use in patients with Billroth II anatomy however, two retrospective studies describe 100% successful stone extraction in a combined 37 patients without any procedural related complications.26,27 DASE has also been utilized in patients with Roux-en-Y anatomy and, while technically difficult, has had a high success rate although case numbers are low.28

CONCLUSION

DASE is a safe and effective advanced endoscopic procedure for the extraction of difficult biliary stones. Dilation diameter and duration of dilation time varies considerably between operators and should be dependent on stone and bile duct size. Furthermore, operator experience must be considered when choosing sphincterotomy and dilation size. The complication rate of DASE appears to be similar to that of endoscopic sphincterotomy while successful stone extraction appears to be greater than EST alone in stones greater than 12mm.

References

  1. Samardzic J, Latic F, Kraljik D, et al. Treatment of common bile duct stones is the role of ERCP changed in era of minimally invasive surgery?. Med Arh. 2010;64(3):187-188.
  2. Ersoz G, Tekesin O, Ozutemiz AO, Gunsar F. Biliary sphincterotomy plus dilation with a large balloon for bile duct stones that are difficult to extract. Gastrointest Endosc. 2003;57(2):156-159. doi:10.1067/mge.2003.52
  3. Staritz M, Ewe K, Meyer zum Büschenfelde KH. Endoscopic papillary dilation (EPD) for the treatment of common bile duct stones and papillary stenosis. Endoscopy. 1983;15 Suppl 1:197-198. doi:10.1055/s-2007-1021507
  4. Mathuna PM, White P, Clarke E, Merriman R, Lennon JR, Crowe J. Endoscopic balloon sphincteroplasty (papillary dilation) for bile duct stones: efficacy, safety, and follow-up in 100 patients. Gastrointest Endosc. 1995;42(5):468-474. doi:10.1016/s0016-5107(95)70052-8
  5. Maydeo A, Bhandari S. Balloon sphincteroplasty for removing difficult bile duct stones. Endoscopy. 2007;39(11):958- 961. doi:10.1055/s-2007-966784
  6. Cipolletta L, Costamagna G, Bianco MA, et al. Endoscopic mechanical lithotripsy of difficult common bile duct stones. Br J Surg. 1997;84(10):1407-1409.
  7. Guo SB, Meng H, Duan ZJ, Li CY. Small sphincterotomy combined with endoscopic papillary large balloon dilation vs sphincterotomy alone for removal of common bile duct stones. World J Gastroenterol. 2014;20(47):17962-17969. doi:10.3748/wjg.v20.i47.17962
  8. Attam R, Freeman ML. Endoscopic papillary large balloon dilation for large common bile duct stones. J Hepatobiliary Pancreat Surg. 2009;16(5):618-623. doi:10.1007/s00534- 009-0134-2
  9. Feng Y, Zhu H, Chen X, et al. Comparison of endoscopic papillary large balloon dilation and endoscopic sphincterotomy for retrieval of choledocholithiasis: a meta-analysis of randomized controlled trials. J Gastroenterol. 2012;47(6):655- 663. doi:10.1007/s00535-012-0528-9
  10. Hwang JC, Kim JH, Lim SG, et al. Endoscopic large-balloon dilation alone versus endoscopic sphincterotomy plus largeballoon dilation for the treatment of large bile duct stones. BMC Gastroenterol. 2013;13:15. Published 2013 Jan 17. doi:10.1186/1471-230X-13-15
  11. Lai KH, Chan HH, Tsai TJ, Cheng JS, Hsu PI. Reappraisal of endoscopic papillary balloon dilation for the management of common bile duct stones. World J Gastrointest Endosc. 2015;7(2):77-86. doi:10.4253/wjge.v7.i2.77
  12. Disario JA, Freeman ML, Bjorkman DJ, et al. Endoscopic balloon dilation compared with sphincterotomy for extraction of bile duct stones. Gastroenterology. 2004;127(5):1291-1299. doi:10.1053/j.gastro.2004.07.017
  13. Li G, Pang Q, Zhang X, et al. Dilation-assisted stone extraction: an alternative method for removal of common bile duct stones. Dig Dis Sci. 2014;59(4):857-864. doi:10.1007/ s10620-013-2914-4
  14. Kuo CM, Chiu YC, Liang CM, et al. The efficacy of limited endoscopic sphincterotomy plus endoscopic papillary large balloon dilation for removal of large bile duct stones. BMC Gastroenterol. 2019;19(1):93. Published 2019 Jun 18. doi:10.1186/s12876-019-1017-x
  15. Kim HG, Cheon YK, Cho YD, et al. Small sphincterotomy combined with endoscopic papillary large balloon dilation versus sphincterotomy. World J Gastroenterol. 2009;15(34):4298-4304. doi:10.3748/wjg.15.4298
  16. Liu P, Lin H, Chen Y, Wu YS, Tang M, Lai L. Comparison of endoscopic papillary large balloon dilation with and without a prior endoscopic sphincterotomy for the treatment of patients with large and/or multiple common bile duct stones: a systematic review and meta-analysis. Ther Clin Risk Manag. 2019;15:91-101. Published 2019 Jan 9. doi:10.2147/TCRM. S182615
  17. Bang S, Kim MH, Park JY, Park SW, Song SY, Chung JB. Endoscopic papillary balloon dilation with large balloon after limited sphincterotomy for retrieval of choledocholithiasis. Yonsei Med J. 2006;47(6):805-810. doi:10.3349/ ymj.2006.47.6.805
  18. Di Mitri R, Mocciaro F, Pallio S, et al. Efficacy and safety of endoscopic papillary balloon dilation for the removal of bile duct stones: Data from a “real-life” multicenter study on Dilation-Assisted Stone Extraction. World J Gastrointest Endosc. 2016;8(18):646-652. doi:10.4253/wjge.v8.i18.646
  19. Tsuchida K, Iwasaki M, Tsubouchi M, et al. Comparison of the usefulness of endoscopic papillary large-balloon dilation with endoscopic sphincterotomy for large and multiple common bile duct stones. BMC Gastroenterol. 2015;15:59. Published 2015 May 16. doi:10.1186/s12876-015-0290-6
  20. Bisogni D, Manetti R, Talamucci L, et al. Efficacy and indications of dilation-assisted stone extraction for retrieval of “difficult common bile duct stones”: results and data analysis of a single Italian referral center for bilio-pancreatic disease treatment [published online ahead of print, 2019 Oct 14]. Minerva Med. 2019;10.23736/S0026-4806.19.06100-7. doi:10.23736/ S0026-4806.19.06100-7
  21. Ghazanfar S, Qureshi S, Leghari A, Taj MA, Niaz SK, Quraishy MS. Endoscopic balloon sphincteroplasty as an adjunct to endoscopic sphincterotomy in removing large and difficult bile duct stones. J Pak Med Assoc. 2010;60(12):1039- 1042.
  22. Park SJ, Kim JH, Hwang JC, et al. Factors predictive of adverse events following endoscopic papillary large balloon dilation: results from a multicenter series. Dig Dis Sci. 2013;58(4):1100-1109. doi:10.1007/s10620-012-2494-8
  23. Youn YH, Lim HC, Jahng JH, et al. The increase in balloon size to over 15 mm does not affect the development of pancreatitis after endoscopic papillary large balloon dilatation for bile duct stone removal. Dig Dis Sci. 2011;56(5):1572-1577. doi:10.1007/s10620-010-1438-4
  24. Heo JH, Kang DH, Jung HJ, et al. Endoscopic sphincterotomy plus large-balloon dilation versus endoscopic sphincterotomy for removal of bile-duct stones. Gastrointest Endosc. 2007;66(4):720-771. doi:10.1016/j.gie.2007.02.033
  25. Paspatis GA, Konstantinidis K, Tribonias G, et al. Sixtyversus thirty-seconds papillary balloon dilation after sphincterotomy for the treatment of large bile duct stones: a randomized controlled trial. Dig Liver Dis. 2013;45(4):301- 304. doi:10.1016/j.dld.2012.10.015
  26. Choi CW, Choi JS, Kang DH, et al. Endoscopic papillary large balloon dilation in Billroth II gastrectomy patients with bile duct stones. J Gastroenterol Hepatol. 2012;27(2):256-260. doi:10.1111/j.1440-1746.2011.06863.x
  27. Itoi T, Ishii K, Itokawa F, Kurihara T, Sofuni A. Large balloon papillary dilation for removal of bile duct stones in patients who have undergone a billroth ii gastrectomy. Dig Endosc. 2010;22 Suppl 1:S98-S102. doi:10.1111/j.1443- 1661.2010.00955.x
  28. Kim KH, Kim TN. Endoscopic papillary large balloon dilation for the retrieval of bile duct stones after prior Billroth II gastrectomy. Saudi J Gastroenterol. 2014;20(2):128-133. doi:10.4103/1319-3767.129478

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A SPECIAL ARTICLE

Bezlotoxumab for Prevention of Recurrent C. difficile Infection in High-Risk Patients

October 2020 • Volume XLIV, Issue 10
Maheep Singh Sangha,Colleen R. Kelly

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Recurrence of Clostridioides difficile infection (CDI) is a common occurrence and significantly increases hospitalizations, inpatient cost, morbidity, and mortality. While metronidazole, vancomycin, and fidaxomicin are approved for treatment, bezlotoxumab is the first drug approved by the FDA to prevent CDI recurrences. Results of phase 3 clinical trials from a pooled data set revealed that sustained cure from recurrence of CDI at 12 weeks was significantly higher in the bezlotoxumab group (63.5% [496/781]) in comparison to the placebo group (53.7% [415/773]). The number needed to treat in patients older than 65 years of age with recurrent CDI is six. Real-world data from a multicenter retrospective cohort study of 200 patients across 34 outpatient infusion centers in the United States revealed the overall CDI recurrence rate after a single infusion of bezlotoxumab was comparable to CDI recurrence reported for the overall population enrolled in the MODIFY I and II phase 3 clinical trials. Considering the high cost of bezlotoxumab, identifying a high-risk target population is essential to make this treatment cost-effective.

Clostridioides (formerly Clostridium) difficile is an anaerobic, gram-positive, spore-forming, toxin-producing bacillus which, in developed countries, is the leading cause of infectious diarrhea in hospitalized patients.1,2 Disruption of healthy gastrointestinal tract flora by antibiotics leads to loss of colonization resistance and opportunistic infection with C. difficile.3 Over the last decade, there has been a rise in Clostridioides difficile infection (CDI) related hospitalizations, healthcare costs, morbidity, and mortality; furthermore, approximately 30% of patients develop recurrent CDI after completing initial antibiotic therapy. Those who have suffered a previous recurrence have an increased risk of further recurrences, up to 60% after a third CDI episode.4,5 Other important risk factors for CDI recurrence are age > 65 years, immunosuppressive disease state or therapy, and antibiotic use.

Toxigenic strains of C. difficile produce two potent exotoxins: toxin A and toxin B, which are responsible for mucosal injury, acute inflammation (colitis), and diarrhea.5-7 Toxin B is ten times more potent than toxin A and thus, strains that do not produce toxin A can be as virulent as strains producing both toxin A and B.8 A “hypervirulent” strain, NAP1/BI/027, produces an additional binary AB toxin called CDT. CDT toxin results in the breakdown of gut wall promoting adherence of bacteria and increased uptake of toxin A and toxin B. Additionally, loss of TcdC function in NAP1/ B1/027 leads to hyperproduction of toxin A 16 times and toxin B 23 times by down-regulating feedback inhibitor associated with halting toxin A and B production.9 Moreover, increased spread and survival of this strain have also been associated with increased sporulation, also called hypersporulation.10 Thus this strain has been associated with severe disease requiring intensive care unit admissions, colectomy, and significantly higher mortality rates.5,6

Host immunity (passive or active) to C. difficile toxins may play an essential role in the severity of symptoms or risk of recurrence. Higher levels of anti-toxin A and anti-toxin B antibodies have been correlated with a protective effect against primary and recurrent Clostridioides difficile infection (rCDI).11-13

Multiple medications, including metronidazole, vancomycin, and fidaxomicin, are used to treat primary disease, but these do little to prevent CDI recurrence.14 Fidaxomicin may result in a lower incidence of rCDI when used early in patients with a non-NAP1/BI/027 strain; however, when compared to oral vancomycin, it does not appear to be more effective for the treatment of mild to moderate CDI.15 Fecal microbiota transplantation (FMT) has demonstrated high cure rates for rCDI, but regulatory questions, lack of long-term safety data, and the absence of standardized techniques for delivery of fecal microbiota has limited widespread application of FMT.16,17

With this in mind, a human monoclonal antibody against Clostridioides difficile toxin A (actoxumab) and toxin B (bezlotoxumab), were pursued as therapeutic agents to prevent rCDI in addition to the antibiotic therapy.18 After nine clinical trials, bezlotoxumab (BEZ; Zinplava), a novel agent, was approved by the FDA in 2016.7,12,19-24

PHARMACOLOGY

Bezlotoxumab (BEZ) is an IgG1 immunoglobulin (human monoclonal antibody) that binds to toxin B and prevents it from entering the gastrointestinal cell layer preventing colonic cell damage (Figure 1,).19,25,26 Bezlotoxumab does not bind to toxin A of Clostridioides difficile. There is a low potential for drug-drug interaction as bezlotoxumab is eliminated by catabolism. The long plasma half-life of 19 days allows the single-dose administration of bezlotoxumab to prevent rCDI. Ethnicity, gender, race, age, and comorbid conditions did not affect bezlotoxumab exposure. No dose adjustment is required in patients with renal or hepatic impairment.

There are no contraindications to bezlotoxumab, but caution is advised for use in patients with a history of congestive heart failure (CHF).27, 28 Per phase 3 clinical trials during the 12-week study period, a group of patients with a history of CHF treated with bezlotoxumab had a higher incidence of worsening CHF and adverse outcomes than the group of patients with a history of CHF treated with placebo.12 Based on these studies, it is not clear whether congestive heart failure was well controlled in these patients before administering bezlotoxumab or not.

CLINICAL TRIALS
Phase 1 and 2

After five, phase 1 trials evaluated the safety and efficacy of bezlotoxumab, a single dose of 10 mg/ kg to be administered intravenously over 60 mins were recommended.21,22,29

The first phase 2 trial was terminated early as animal data revealed that a combination of bezlotoxumab and actoxumab, a human monoclonal antibody that binds to toxin A, was more effective. Another phase 2, multicenter, randomized, doubleblind, placebo-controlled clinical trial with 200 patients, revealed lower recurrence rate and relative risk of recurrence of CDI associated with significantly longer time to CDI recurrence in the bezlotoxumab and actoxumab group compared to the placebo group.20 Data from the placebo-treated group showed no relationship between plasma antitoxin A antibodies and rCDI, whereas plasma antitoxin B antibodies were found to be protective against rCDI.

CLINICAL TRIALS
Phase 3 (MODIFY I and MODIFY II)

Two independent, multicenter, 12-week, doubleblind, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 patients (>= 18 years of age) evaluated the safety and efficacy of bezlotoxumab in patients receiving standardof-care antibiotics for primary or recurrent Clostridioides difficile. 12 Efficacy was assessed in a modified intention-to-treat (mITT) group.

While both trials randomized patients to single-dose administration of bezlotoxumab alone, bezlotoxumab and actoxumab or placebo along with standard-of-care antibiotics; MODIFY I initially also included an actoxumab alone arm which was terminated early after being associated with significantly increased rates of death caused by sepsis and lack of efficacy compared to bezlotoxumab and actoxumab arm (p=0.02).12,30 Randomization was stratified based on the oral standard-of-care antibiotic and the location of the patient (inpatient vs. outpatient).

Clostridioides difficile infection (CDI) was confirmed by a positive stool test and >= 3 loose stools in >=24 hours. Standard-of-care antibiotics included oral metronidazole, vancomycin, or fidaxomicin. Patients on oral vancomycin or fidaxomicin could receive intravenous metronidazole. The choice of standard-of-care antibiotic therapy and the day of administration of the study infusion was the health care provider’s preference. In most patients (94%), bezlotoxumab was administered within the first six days of standard-of-care antibiotics, with day 3 being the median administration day.12

The primary endpoint was defined as a new episode of CDI recurrence after initial clinical cure during the 12 weeks of follow up period. The initial clinical cure was defined as no loose stools for two consecutive days after completing standard-of-care antibiotic therapy for <=16 days. A secondary endpoint, also called global cure or sustained clinical response, was the sustained cure rate, which meant initial clinical cure as defined above and no recurrence of CDI through 12 weeks.

Results of MODIFY I and MODIFY II

In the pooled data set from the MODIFY I and MODIFY II trials, the initial clinical cure rate was similar in the bezlotoxumab group (80% [625/781]) and the placebo group (80.3% [621/773]). However, sustained cure at 12 weeks was significantly higher in the bezlotoxumab group (63.5% [496/781]) in comparison to the placebo group (53.7% [415/773]).12 For sustained cure, the adjusted difference between bezlotoxumab and placebo group was 9.7 percentage points (95% CI 4.8 to 14.5; p<0.0001), and the pooled data set results were mostly driven by MODIFY II trial.12 Approximately 71% of recurrences of CDI occurred within the four weeks of study infusion.

Importantly, the subgroup analysis of the pooled data set, recurrent CDI rates were statistically significantly lower in the bezlotoxumab group in comparison to the placebo group for patients >=65 years of age, those suffering a recurrent episode of CDI, immunocompromised patients and in severe CDI,12 defined as a Zar score of 2 or higher.31 The determination of immunocompromised patients was based on medical history or the use of immunosuppressive therapy. The number needed to treat to prevent one episode of recurrent CDI with bezlotoxumab was ten; however, that number decreased to six for patients with age >=65 and previous CDI in the past six months.12

The initial cure rate for patients receiving actoxumab-bezlotoxumab was 73% (568/773) in the pooled data set. The rate of recurrent CDI was also similar in the actoxumab-bezlotoxumab group compared to the bezlotoxumab group, suggesting that the neutralization of toxin B by bezlotoxumab is adequate to reduce the risk of recurrent CDI.29 Interestingly, the rate of CDI recurrence was significantly lower for hypervirulent strain (NAP1/ BI/027) for patients who received a combination of actoxumab-bezlotoxumab (11.8% [9/76]) in comparison to bezlotoxumab alone (23.6% [21/89]) and the placebo group (34% [34/100]).12 This information suggests that the combination of actoxumab and bezlotoxumab might provide better results for the hypervirulent strain (NAP1/ BI/027); however, more future studies are required to confirm this.

REAL-WORLD DATA

A retrospective study of 46 patients was done in five university hospitals in Finland (in Helsinki, Kuopio, Oulu, Tampere, and Turku).32 These patients were the first 46 patients to receive bezlotoxumab in Finland in April – December 2017. Polymerase chain reaction (PCR) was the only test used to diagnose CDI. Patients received bezlotoxumab on 0 – 7 days after the initiation of the standardof-care antibiotics. Vancomycin was used alone or along with another antibiotic in 80% (37 of 46) of patients as a standard-of-care. Eighteen patients received metronidazole, fidaxomicin, and tigecycline. Patients had a mean age of 66 years, out of which 24 were men and 22 were women. 29 of the 46 patients received bezlotoxumab in inpatient and the other 17 in an outpatient setting. Twentyeight patients were immunocompromised due to immunosuppressive treatment or other medical comorbidities. 78% (36/46) of patients had three or more known risk factors for CDI’s recurrence.

Results revealed that 73% (32/44) patients did not have rCDI in 3 months of bezlotoxumab treatment.32 71% (20/28) of immunocompromised patients and 63% (10/16) of patients with severe CDI based on the Zar score did not have rCDI in the three months.32 Two severely ill patients died within three months of bezlotoxumab infusion at Turku University Hospital. One patient died five days after bezlotoxumab infusion due to end-stage cardiac disease, and the other died approximately 45 days after bezlotoxumab infusion due to graftversus-host disease.

Another study using whole-genome sequencing calculated the difference in the same-strain relapse versus new-strain reinfection in MODIFY I/ II trials.33 Two hundred fifty-nine patients were evaluated for rCDI, out of which 76% (198/259) of the patients in the study experienced relapse with the same strain, whereas only 19% (50/259) had reinfection with a new strain. Ribotype 027 was associated with higher proportions of relapses as compared to other ribotypes. This study also revealed that a cumulative incidence of CDI relapse with the same strain in high-risk patients was significantly lower for patients treated with bezlotoxumab than patients not treated with bezlotoxumab (p<0.0001).33

One of the most extensive multicenter retrospective cohort study of 200 patients between April 2017 and December 2018 across 34 outpatient infusion centers in the United States was published recently.34 C. difficile was diagnosed using PCR (76.5%) and enzyme immunoassay (EIA) (23.5%). Patients received vancomycin (68.5%), fidaxomicin (30%), and metronidazole (1.5%) as a standardof-care antibiotics. The median time interval for bezlotoxumab infusion was 11 days from initiation of the standard-of-care antibiotics. Three patients were lost in follow up, and two chronically ill patients with multiple medical comorbidities died 40 days and 75 days post bezlotoxumab infusion. 86% of patients enrolled in the study had at least one CDI recurrence before bezlotoxumab infusion. 80% of patients had ≥2 risk factors for rCDI, most frequently age ≥65 years (67.7%), and ≥1 CDI episode in the past six months (61.5%). The study results revealed that the overall CDI recurrence rate after a single infusion of bezlotoxumab was 15.9%, which translates into 84.1% successful prevention of CDI recurrence in patients enrolled in the study.34 These results are comparable to 16.5% of CDI recurrence reported for the overall population enrolled in the MODIFY I and II phase 3 clinical trials.12

DISCUSSION

Data from MODIFY I and II phase 3 trials suggest that bezlotoxumab (15.7% [107/679]) decreases the recurrence rate of CDI when compared to placebo (25.6% [169/658]) in non-hypervirulent strains.12 The only possible severe side-effect of bezlotoxumab infusion is worsening congestive heart failure in patients with a history of heart failure. It will be pertinent to develop cost-effective guidelines for targeting high-risk elderly patients, considering the high cost (approximately $4000 for a 1000mg/40ml vial) of bezlotoxumab.35

FMT has also been effective for rCDI.36,37 It is vital to recognize that it is typically administered after a course of antibiotic therapy rather than as a primary treatment modality; bezlotoxumab is also a preventive agent used in association with a standard-of-care treatment. Large head-to-head clinical trials will be required to determine the efficacy of FMT compared to bezlotoxumab to prevent a recurrence. It is crucial to keep in mind that neither fidaxomicin nor bezlotoxumab has shown significant efficacy in preventing recurrent CDI in patients infected with the hypervirulent strain (NAP1/BI/027).

A post hoc pooled analysis revealed that the CDI recurrence rate was further lower for the bezlotoxumab group when the diagnosis was made using toxin EIA 14.5% (54/372) compared to PCR 19.6% (70/357); while rates were similar for the placebo group.38,39 Nucleic acid amplification tests (PCR) only identify the toxigenic DNA sequences but not the toxin protein, hence also detecting asymptomatic carriers of toxigenic strains of C. difficile. EIAs, which test directly for toxins A/B produced by the organism, are specific for active infection and predictive of poor outcomes compared to more sensitive nucleic acid amplification tests (NAAT), which detect toxigenic strains but not toxin protein.40 Thus, the number needed to treat (NNT) could be even lower for populations if EIA is used for diagnosis.39

Currently, there is no data for the use of bezlotoxumab in the pediatric population or pregnant and lactating patients. Phase 4 clinical trials will provide further insight into the role of bezlotoxumab in these population subtypes.

CONCLUSION

The future for the treatment of recurrent CDI appears promising. While participants with ≥three risk factors had the most significant reduction of CDI recurrence with bezlotoxumab, those with 1 or 2 risk factors also significantly benefited. We recommend that bezlotoxumab be considered in treating high-risk patients, >= 65 years of age, with more than one risk factor to prevent further CDI recurrence. Patients with concomitant antibiotics use, inflammatory bowel disease, and those not responding to FMT may also benefit from bezlotoxumab treatment. As bezlotoxumab may be administered to patients at any point during a course of CDI treatment, outpatient infusion would avoid unnecessary inpatient cost and is an economical option. It will be intriguing to see more clinical trials to assess the combined effect of bezlotoxumab and FMT or bezlotoxumab and fidaxomicin for the treatment of recurrent C. difficile infection.

References

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  15. Louie, T.J., et al., Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med, 2011. 364(5): p. 422-31.
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FROM THE PEDIATRIC LITERATURE

More Data on C. difficile and Pediatric IBD Outcomes

September 2020 • Volume XLIV, Issue 9

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Clostridioides difficile (C. diff), previously known as Clostridium difficile is a relatively common gastrointestinal tract infection and has a significant association with inflammatory bowel disease (IBD). C. diff infection and the C. diff carriage state may be difficult to differentiate in patients in IBD due to similar symptoms occurring with active IBD as well as with an active C. diff infection (diarrhea, abdominal pain, etc.). The authors of this study evaluated the progression to intestinal resection in pediatric patients with IBD diagnosed with C. diff carriage within one year of IBD diagnosis, and they evaluated fecal microbiome samples in such pediatric patients in relation to C. diff carriage state as well as in relation to a history of intestinal surgery.

Patients with Crohn disease (CD) from a single tertiary children’s hospital (age 21 years old or less) were retrospectively included in the study if they had stool samples as part of that institution’s IBD Biorepository and if they had C. diff testing within one year of the CD diagnosis. At the same time, a prospective study occurred for patients who were diagnosed with CD and who subsequently could provide stool sampling. Stool samples were analyzed for calprotectin levels and had C. diff polymerase chain reaction (PCR) testing as well as microbiome sampling performed by high throughput shotgun metagenomic sequencing (rapid parallel DNA sequencing). Metabolic pathways of bacteria were analyzed using nucleotide and peptide databases.

The retrospective aspect of the study demonstrated a C. diff positivity rate of 19% in the CD group with significantly more patients with C. diff having had antibiotic exposure within 30 days of testing. Most patients with CD were in the age range of 10 to 17 years, and the percentage of steroid exposure in the first year of life was not statistically different regardless of C. diff status. The rate of intestinal resection was significantly lower for patients with negative C. diff testing (21%) compared to patients with positive C. diff testing (67%). Additionally, patients with positive C. diff testing had a shorter mean time to intestinal resection (527 days) compared to patients with negative C. diff testing (1268 days). Univariate
analysis showed that steroid or anti-tumor necrosis factor (anti-TNF) medication exposure did not change results. Multivariate analysis demonstrated that only positive C. diff testing was associated with
the need for intestinal surgery in patients with CD

The subsequent prospective study demonstrated that 14% of patients with CD had positive C. diff testing, and 9% of patients with CD had a history of intestinal surgery. Similar to the retrospective cohort, patients with positive C. diff testing were significantly more likely to have had prior intestinal surgery. There was no difference in fecal calprotectin levels or reported IBD symptoms between groups. High throughput shotgun metagenomic sequencing demonstrated no overall difference in the fecal microbiome profile between patients with or without C. diff although there was a significant decrease in 123 taxa in patients with a positive C. diff infection. These taxa tended to be commensal organisms that had a potential mucosal protective effect. Metabolic profiles were not significantly different between patients regardless of C. diff status although patients that underwent intestinal surgery had 95 metabolic pathways that were altered compared to patients who had not had surgery (such as downregulated methionine biosynthesis pathways). Finally, patients with positive C. diff testing and a history of intestinal surgery had 47 bacterial species that were significantly reduced. These taxa were associated with protective gut function.

This study appears to show that young patients with CD and positive C. diff testing are at an increased risk of intestinal resection. These patients had microbiome changes noted as well suggesting the potential loss of a protective gut microbiome. The authors theorize that the early presence of C. diff in a young person with CD may be due to significant alterations in the microbiome leading to bowel inflammation and subsequent surgery.

Hellmann J, Andersen H, Fei L, Linn A, Bezold R, Lake K, Jackson K, Meyer D, Dirksing K, Bonkowski E, Ollberding N, Haslam D, Denson L. Microbial shifts and shorter time to bowel resection surgery associated with C. difficile in pediatric Crohn’s disease.

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FROM THE PEDIATRIC LITERATURE

Degree of Villous Atrophy and Outcomes in Children

September 2020 • Volume XLIV, Issue 9

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Celiac disease (CD) is an immune-mediated disease typically associated with gastrointestinal inflammation in response to gluten exposure.
Esophagogastroduodenoscopy (EGD) with
duodenal biopsies has been considered “gold standard” for CD diagnosis; however, recent pediatric guidelines such as the European Society for Paediatric Gastroenterology Hepatology and Nutrition Guidelines for the Diagnosis of Coeliac Disease (https://journals.lww.com/jpgn/ Fulltext/2012/01000/European_Society_for_Pediatric_Gastroenterology,.28.aspx) suggest that serology screening may be an adequate substitute for EGD with duodenal biopsy. In particular, a tissue transglutaminase IgA antibody (TTG IgA) level greater than 10 times the upper limit of the measured laboratory value has a high association with CD. It is unclear if the degree of villi damage seen in CD corresponds well with TTG IgA antibody titer levels, and the authors of this study evaluated the effectiveness of determining intestinal villi length (disease severity) in pediatric patients with a new diagnosis of CD in regards to their long-term health outcomes as adults.

This study occurred at a single tertiary hospital in Finland, and retrospective data was obtained from a CD database containing the records of 906 pediatric patients from 1966 to 2014. Medical data at the time of CD diagnosis was reviewed such as the presence of gastrointestinal symptoms and other extra-intestinal disease manifestations, and duodenal biopsy results from these patients were divided into three groups: partial atrophy, subtotal atrophy, and total atrophy. Growth impairment was determined by decreased growth velocity noted on growth charts. TTG IgA and endomysial antibodies (EMA) were recorded from patients from 2000 onward when such serum testing had become available. Finally, pediatric patients with CD who were now adults completed three questionnaires including a questionnaire reviewing complications and co-morbidities associated with CD, the Gastrointestinal Symptom Rating Scale (GSRS) to evaluate the presence of gastrointestinal symptoms, and the Psychological General WellBeing questionnaire (PGWB) to evaluate quality of life.\

The duodenal biopsies of the 906 pediatric patients demonstrated partial villous atrophy in 34%, subtotal villous atrophy in 40%, and total
villous atrophy in 26% of patients. Children with total villous atrophy had significantly more extraintestinal manifestations, anemia, and impaired growth while patients with less severe atrophy had less abdominal pain and less CD detected by serum screening. Children with more advanced stages of villous atrophy were diagnosed during the earlier years of the study although there was no difference in patient age throughout the study at the time of CD diagnosis. More severe villous atrophy was identified in patients with significantly shorter height, lower body mass index (BMI), lower hemoglobin levels, and higher celiacantibody levels (TTG IgA and EMA) at time of CD diagnosis.

A total of 503 adult patients with CD diagnosed as children were asked to participate in this study, and 212 of these patients (42%) completed all questionnaires. The adult patients with partial and subtotal villous atrophy were significantly younger than the adult patients with total villous atrophy. However, all three villous atrophy groups had no difference as adults in regards to comorbid conditions, complications from celiac disease, selfreported symptoms, overall health, adherence to a gluten-free diet, GSRS score, and PGWB score even after adjusting for current age, sex, year of CD diagnosis, and median BMI.
This study demonstrates that pediatric patients with CD and more severe villous atrophy (and more health-related issues as children) appear to have similar long-term outcomes as adults when compared to pediatric patients with less severe villous damage. We can use this information to inform pediatric patients with CD and their families about the importance of continuing a gluten-free diet throughout their lives in order to have good health outcomes.

The duodenal biopsies of the 906 pediatric
patients demonstrated partial villous atrophy in 34%, subtotal villous atrophy in 40%, and total villous atrophy in 26% of patients. Children with total villous atrophy had significantly more extraintestinal manifestations, anemia, and impaired growth while patients with less severe atrophy had less abdominal pain and less CD detected by serum screening. Children with more advanced stages of villous atrophy were diagnosed during the earlier years of the study although there was no difference in patient age throughout the study at the time of CD diagnosis. More severe villous atrophy was identified in patients with significantly shorter height, lower body mass index (BMI), lower hemoglobin levels, and higher celiac
antibody levels (TTG IgA and EMA) at time of CD diagnosis.
A total of 503 adult patients with CD diagnosed as children were asked to participate in this study, and 212 of these patients (42%) completed all questionnaires. The adult patients with partial and subtotal villous atrophy were significantly younger than the adult patients with total villous atrophy. However, all three villous atrophy groups had no difference as adults in regards to comorbid conditions, complications from celiac disease, selfreported symptoms, overall health, adherence to a gluten-free diet, GSRS score, and PGWB score even after adjusting for current age, sex, year of CD diagnosis, and median BMI.


This study demonstrates that pediatric patients with CD and more severe villous atrophy (and more health-related issues as children) appear to have similar long-term outcomes as adults when compared to pediatric patients with less severe villous damage. We can use this information to inform pediatric patients with CD and their families about the importance of continuing a gluten-free diet throughout their lives in order to have good health outcomes.

Kroger S, Kurppa K, Repo M, Huhtala H, Kaukinen K, Lindfors K, Arvola T, Kivela L. Severity of villous atrophy at diagnosis in childhood does not predict long-term outcomes in celiac disease. Journal of Pediatric Gastroenterology and Nutrition 2020; 71: 71-77.

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FROM THE LITERATURE

Impact of Serum ANA in Nonalcoholic Fatty Liver Disease

September 2020 • Volume XLIV, Issue 9

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To investigate the longitudinal impact of ANA on clinical outcomes and survival in nonalcoholic fatty liver disease (NAFLD), antinuclear antibody (ANA), was found in 16.9% of 923 biopsy-proven NAFLD patients, but none of them had histologic autoimmune hepatitis (AIH), or developed AIH after a mean followup of 106 months.

Although ANA-positive cases had a higher prevalence of nonalcoholic steatohepatitis at baseline, the occurrence of liver-related events, hepatocellular carcinoma, cardiovascular events, extrahepatic malignancy and overall survival was similar to ANAnegative cases.

Once AIH has been ruled out, the long-term outcomes and survival are not affected by the presence of ANA in patients with NAFLD.

Younes, R., Govare, O., Petta, S., et al. “Presence of Serum Antinuclear Antibodies Does Not Impact Long-Term Outcomes in Nonalcoholic Fatty Liver Disease.” American Journal of Gastroenterology, 2020; Vol. 115, pp. 1289-1292.

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FROM THE LITERATURE

Future High-Risk Adenomas After High-Risk Adenomas at Initial Screening

September 2020 • Volume XLIV, Issue 9

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To examine the risk of high-risk adenomas (HRA) at third colonoscopy stratified by findings on two previous examinations in a prospective screening colonoscopy cohort of US Veterans with a negative second examination, participants were identified who had three or more colonoscopies from CSP No. 380. The risk of HRA on the third examination, based on findings from the previous two examinations were evaluated. Multivariate logistic regression was used to adjust for multiple covariates. HRA was found at the third examination in 114 (12.8%) of 891 participants.

Those with HRA on both previous examinations had the greatest incidence of HRA at third examination (14/56 – 25%). Compared with those with no adenomas on both previous examinations, participants with HRA on first examination remained at significantly increased risk for HRA at the third examination at 3 years after a negative second examination (OR 3.41), 5 years (OR 3.14), and 7 years (OR 2.89).

In a screened population, HRA on the first examination identified individuals who remained at increased risk for HRA at the third examination, even after a negative second examination, supporting current colorectal cancer surveillance guidelines, which suggest a shortened, 5-year time interval to third colonoscopy after a negative second examination if high-risk findings were present on the baseline examination.

Sullivan, B., Redding, T., Hauser, E., et al. “HighRisk Adenomas at Screening Colonoscopy Remain Predictive of Future High-Risk Adenomas, Despite an Intervening Negative Colonoscopy.” American Journal of Gastroenterology, 2020; Vol. 115, pp. 1275-1282.

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