LIVER DISORDERS, SERIES #12

Cutting the Fat in Nonalcoholic Fatty Liver Disease

March 2022 • Volume XLVI, Issue 3
John E. Poulos,Peter T. Kalogerinis,Sophie Jeannin,Emanuel J. Poulos,Mackenzie R. Cole

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Nonalcoholic fatty liver disease (NAFLD) affects 30% of individuals in the United States. Up to one-third of patients with NAFLD go on to develop nonalcoholic steatohepatitis or NASH, which is characterized by inflammation and fibrosis leading to cirrhosis. As opposed to simple fat in the liver, NASH, if left untreated,can progress to advanced fibrosis, cirrhosis, liver decompensation, and liver-related death. NAFLD isassociated with the metabolic syndrome and patients with NAFLD have a higher risk of cardiovascularrelated death and development of diabetes. The gold standard for the diagnosis of NAFLD or NASHis liver biopsy; however, this has its limitations due to its invasiveness. The utilization of non-invasivemeasurements of hepatic steatosis and fibrosis are evolving to replace liver biopsy. There are currently noapproved therapies for the treatment of NASH nor accepted standard of care. The therapeutic options forNASH are largely limited to lifestyle modification and treatment of underlying conditions such as diabetesand hyperlipidemia. Several agents have been evaluated as potential treatments for NASH by improvingliver inflammation but have a limited effect on reducing hepatic fibrosis. Currently there are severalagents in development which show promise in reduction of hepatic fat content, inflammation, and fibrosis. In summary, the obesity epidemic and its association with the metabolic syndrome have led to NAFLD and/or NASH being the leading cause of liver disease in the United States. The recognition and treatment of this disease with its associated co-morbidities will avoid the long-term complications of this disease.

Background

According to data from the Centers for Disease Control, 42.5% of adult Americans are obese.1 Obesity in association with hypertension, dyslipidemia, and/or insulin resistance constitutes the metabolic syndrome (MS).2 Non-Alcoholic Fatty Liver Disease (NAFLD) is defined as the excessive accumulation of fat in the liver shown either by imaging or histology, in the absence of significant alcohol consumption or other secondary cause3 and is felt to be the hepatic manifestation of MS.The strong association of NAFLD with the MS and obesity has resulted in it being the number one cause of chronic liver disease.4 NAFLD is also associated with a complex relationship between environmental factors such as diet, changes in microbiota, and predisposing genetic variants.5 NAFLD may also encompass non-alcoholic steatohepatitis (NASH) and progress to cirrhosis of the liver. NAFLD is defined as the presence of greater than 5% hepatic steatosis (HS) without evidence of hepatocellular injury in the form of hepatocyte ballooning. NASH is defined as the presence of greater than 5% HS and inflammation with hepatocyte injury (e.g., ballooning), with or without any fibrosis.3 NAFLD is a major health issue due to its association with MS, type two diabetes mellitus (T2DM), and cardiovascular disease (CVD).6 The overall prevalence of NAFLD was found to be 38% and the prevalence of NASH at 14% in a large prospective study of middle-aged US cohort. NASH is more common in Hispanics and those with obesity and type 2 diabetes.7 The most common cause of death in NAFLD patients is not from liver-related causes but rather from coronary artery disease (CAD)8 with 48% of those with NAFLD dying from complications of CVD compared to only 7% due to liver disease.9 However, those with fatty liver disease do have a higher rate of liver-related death compared to the general population.9 Studies have shown that glucose intolerance and insulin resistance have been found to occur in the early stages of chronic liver disease and subjects with NAFLD are three times more likely to develop type 2 diabetes and 50% more likely to develop the MS than the general population.10,11 Conversely, the prevalence of NAFLD in patients with type 2 diabetes mellitus is more than 2-fold higher than in the general population.12 Furthermore, diabetes and obesity have also been associated with the development of liver cancer,13 most likely due to the progression from NAFLD to NASH and then to cirrhosis. NASH is the most rapidly increasing indication for liver transplant in patients without hepatocellular carcinoma (HCC), and has become the leading indication in women without HCC.14

Mechanisms of Hepatic
Damage in NAFLD/NASH

Proposed mechanisms for hepatic damage in NASH involve insulin resistance, toxicity from free fatty acids (FFA), generation of reactive oxidative species (ROS) or hormonal dysregulation. Within the hepatocyte fatty acid oxidation may occur within mitochondria, peroxisomes or endoplasmic reticulum.15 Peroxisome proliferator-activated receptor (PPAR) isoforms may have a role in NASH due to their modulation of fatty acid uptake, beta oxidation, ketogenesis, bile acid synthesis and triglyceride turnover.16 Patients with NASH may also have increased beta-oxidation of fatty acids with elevations in lipid peroxide intermediates and reactive oxygen species.17 Gut hormones such as leptin, ghrelin, and glucagon like peptide 1 may also have a role in the pathogenesis of NASH due to their ability to inhibit lipogenesis, lipo-apoptosis, decrease free fatty acids, increase insulin secretion and glucose uptake, and exhibit anti-inflammatory actions.18

Diagnosis of NASH

The diagnosis of NASH is usually suspected in patients with obesity or those with components of metabolic syndrome who present with abnormalities in liver function testing or incidental findings of fatty changes on imaging studies of the liver. Further evaluation as to the severity of inflammation or fibrosis may consist of liver biopsy. However, due to the invasiveness of this procedure, the diagnosis of NAFLD and or NASH is increasingly being based on non-invasive measures such as aspartate aminotransferase (AST) to platelet ratio index (APRI), FIB-4 index, NAFLD fibrosis score, commercially available testing such as FibrosureTM, FibrotestTM, enhanced liver fibrosis (ELF) scoreTM or imaging utilizing sheer wave elastography, transient elastography, or Magnetic Resonance Elastography (MRE) and proton density fraction measurements (PDFF).19 Traditionally noninvasive testing tends to have a high negative predictive value in ruling out people who have the disease rather than ruling in people who have the disease.20 Combining noninvasive testing utilizing elastography or MRE with FIB-4 testing or vibration controlled transient elastography with AST values may improve positive predictive values, increase area under the receiver operating characteristic curve (AUROC) and improve the detection of people who have the disease.21,22

Treatment of NASH

Currently, there are no approved medications to treat NASH and its secondary complications. Weight loss via dieting and exercise are the initial steps in treating NASH. 5% weight loss leads to reduction in hepatic fat and stabilization of fibrosis whereas 10% or more has been shown to elicit improvement in hepatic inflammation and fibrosis.23,24 In a recent 5-year follow-up of patients with NASH undergoing bariatric surgery, 84.4% had resolution of NASH with 70% showing a regression in fibrosis.25 The effects of exercise on underlying NASH are less clear, but from a large, retrospective assessment of biopsy proven NAFLD patients, moderate intensity exercise metabolic equivalents (METs) of 3.0-5.9 of total exercise per week was not associated with improvement in NASH severity or fibrosis. However, patients meeting vigorous (6 METs) activity did have improvement in NASH. A doubling of the vigorous activity recommendations was required to have a benefit on fibrosis.26 The Mediterranean diet (high complex carbohydrates, fiber and monounsaturated fats with a balanced omega 6-omega 3 ratio) has been shown to lead to reductions in hepatic fat content and improvement in components of the metabolic syndrome in the absence of weight loss.27 Nutritional counseling in association with a Mediterranean diet has been shown to elicit weight loss with normalization of hepatic enzymes, glycemic control, and hyperlipidemia.28 A recent meta-analysis of the Mediterranean diet revealed a reduction in BMI, hepatic fat, hypertriglyceridemia and homeostasis model assessment (HOMA).29 As to whether a greater benefit is seen with diet and/or exercise or weight loss remains to be elucidated. In the meantime, a healthy lifestyle of dieting and exercise are recommended in the treatment of NAFLD.

Vitamin E

Vitamin E is the most important lipid-soluble antioxidant located predominately in cell membranes, where it reduces free radicals rendering them inactive.30,31 Long-term administration of vitamin E at 800 U a day for 96 weeks decreased liver enzyme abnormalities, fat accumulation, and inflammation in patients with NASH without diabetes, but not hepatic fibrosis.32 Studies have shown that dietary supplementation with vitamin E is effective in reducing the pathologic progression of hepatic inflammation and steatosis but not fibrosis.33 In a meta-analysis of both adults and pediatric patients, administration of vitamin E was associated with a significant improvement in alanine aminotransferase (ALT), AST, fibrosis, and NAFLD activity score (NAS) at early and late follow up.34 The American Association for the Study of Liver Disease now recommends the use of vitamin E 800 units a day for the treatment of NASH in non-diabetic patients without cirrhosis.19

Silymarin

Silymarin may in fact be one of the most potent antioxidants found in nature due to the properties of free radical scavenger reactivity and favorable membrane-lipid/water partitioning it possesses.35 Studies have shown that courses of silymarin therapy reduce the biochemical and ultrasonographic changes induced by NASH to the liver.36 Silymarin has also been shown to reduce AST and ALT levels in patients with NASH compared to placebo,37 and to improve fatty infiltration of liver and liver function in children and adolescents.41 It may also be effective in preventing or alleviating many of the components of MS39 including CVD40 and diabetes.41 In a meta-analysis of 5 clinical trials in 602 patients, there was lower liver-related mortality and lower rates of hospitalization in patients treated with silymarin.42 In a clinical review of 296 patients utilizing silymarin for the treatment of liver disease, the incidence of death and serious adverse events was lower in the silymarin group with no significant adverse events.43 In a meta-analysis of eight randomized clinical trials, silymarin treatment led to a statistically significant greater reduction in the levels of transaminases compared to placebo, irrespective of weight loss.44

Carnitine

Carnitine is a naturally occurring non-essential amino acid synthesized in the body from amino acids lysine and methionine. It plays a vital role in energy production and fatty acid metabolism by shuttling fatty acids into the mitochondria of cells for energy production especially for cardiac and skeletal muscles. Studies have also shown that carnitine is helpful in insulin resistance45 and weight loss.46 Carnitine at a dose of 2 grams per day for a period of 24 weeks has also been shown to reduce hepatic enzyme abnormalities, hyperlipidemia, insulin resistance and hepatic inflammation in patients with NAFLD.47 Treatment of NAFLD patients with a combination of vitamin E, silymarin and carnitine revealed significant normalization of HOMA and fasting insulin levels, and, downtrends in AST, ALT, TC, TRG, HDL, LDL, HgbA1c, and HSCRP levels.48

Drug Candidates in Clinical Development Peroxisome Proliferator Activated Receptor (PPAR) Agonists

Pioglitazone and Rosiglitazone are thiazolidinediones (TZD), targeting PPAR-Gamma receptors. Trials involving TZDs revealed improvements in steatosis and inflammation but not fibrosis. Rosiglitazone treatment has been shown to improve hepatic enzyme abnormalities and steatosis but not inflammation. Its use has been tempered due to concerns over an increased risk of coronary events.49 Pioglitazone elicits improvement in insulin sensitivity and hepatic inflammation but is associated with weight gain.33 Current AASLD guidelines suggest the use of pioglitazone in biopsy proven NASH in patients with and without diabetes.19 Elafibranor is a dual PPAR alpha/delta agonist that improves glucose homeostasis, increases insulin metabolism, and reduces inflammation. Studies suggest some improvement in hepatic inflammation in NASH.50 However, in the Resolve-IT phase 3 trials, a 72week treatment with elafibranor failed to reach its endpoint of NASH resolution without worsening of fibrosis in comparison to placebo.51 Data for a 16-week trial evaluating saroglitazar, a dual PPAR alpha/gamma agonist for treatment of NAFLD revealed improvements in alanine aminotransferase levels, reductions in hepatic fat content, insulin resistance and dyslipidemia in patients with NASH. No reductions in liver stiffness measurements were noted, however this study may have been limited due to small sample size.52 Lanifibranor is a panPPAR alpha/delta/gamma agonist. Data from a 24-week trial showed significant improvements in steatosis, inflammation and fibrosis.53 This drug candidate is being evaluated in a large phase 3 NASH fibrosis population.

Farnesoid X Receptor Agonist (FXR)

FXRs are nuclear receptor transcription factors, expressed in the liver, that regulate insulin sensitivity and participate in lipid metabolism. Bile acids (BAs), natural ligands of the FXRs, are synthesized in the liver and promote insulin sensitivity and decrease gluconeogenesis and circulating triglycerides when bound to FXRs. Obetacholic acid OCA (6-ethylchenodeoxycholic acid) is a synthetic BA and an FXR activator. It increases peripheral glucose uptake, enhances glucose-stimulated insulin secretion, and inhibits hepatic lipid synthesis.54 In the Regenerate trial, a significant improvement in fibrosis was seen in 23% of the OCA treated group compared with 12% of the placebo.55 However, resolution of NASH did not differ between the treated and placebo group and concerns over pruritus and recent warnings of its use in patients with primary biliary cholangitis and advanced liver disease have hampered its approval by the FDA for the treatment of NAFLD. New generations of FXR agonists are currently in clinical development, both as single agents and in combination with other drug candidates.

THR-beta Agonists

Resmetirom is an oral thyroid receptor beta agonist that selectively binds to the liver bypassing the adverse effects of excessive thyroid hormone in extra-hepatic sites. A phase 2B study showed a significant improvement in reduction of liver fat by MRI-PDFF compared to placebo after 36 weeks of treatment. There were favorable reductions in atherogenic lipids such as LDL cholesterol, apolipoprotein-B, triglycerides, and lipoprotein(a).56 Data evaluating 52 weeks of therapy in non-cirrhotic patients with NAFLD revealed 52% reductions in hepatic fat by MRI PDFF and improvements in hepatic fibrosis by noninvasive measurements (26% reduction in elastography 12% for MRE measurements).57

Fatty Acid Derivative – Icosabutate

Icosabutate is an engineered eicosapentaenoic acid derivative with potent anti-inflammatory and antifibrotic effects acting primarily through the G-coupled protein receptor (GPR120) and the arachidonic acid related signaling pathways. In a 52-week phase 2b trial, subjects with biopsy confirmed NASH were randomized to icosabutate vs placebo. An interim analysis showed that treatment with icosabutate elicited reductions in ALT, AST, GGT, and ALP. Significant reductions in noninvasive fibrosis markers PRO-C3 and ELF score (both indirect markers of fibrosis) were seen. This indicates a possible role for this compound in fibrogenesis, glycemic control, and synthesis of key atherogenic lipoproteins.58

GLP-1 Agonists

Glucagon-like peptide-1 agonists are licensed for the treatment of type 2 diabetes and have been shown to reduce insulin resistance, decrease glucagon and free fatty acid concentrations, improve hgbA1c levels, delay gastric emptying and elicit weight loss.59 Liraglutide was compared to placebo in a phase 2 48-week trial for treatment of NASH. Thirty nine percent of patients on liraglutide had resolution of NASH in comparison to 9% in the placebo group. More patients in the placebo group (36%) had progression of fibrosis in comparison to liraglutide (9%).60 In a similar phase 2 trial, semaglutide, a GLP-1 agonist with a longer half-life, demonstrated a significantly higher efficacy for NASH resolution than placebo. However, there was no significant improvement in fibrosis when evaluated by liver biopsy at week 72.61 Semaglutide is being evaluated in a large phase 3 clinical trial in patients with NASH and Fibrosis. Other compounds including dual modes of action (GLP-1 agonist/Glucagon receptor agonist/GIP) are being evaluated.

FGF21 Analog

Efruxifermin is a fusion protein of human IgG linked to modified fibroblast growth factor 21. This agent is felt to have effects on protein, glucose, and lipid utilization. This agent has been shown to reduce hepatic steatosis, hepatic inflammation and fibrosis62 as well as improve insulin sensitivity and dyslipidemia in patients with type 2 diabetes.63 In a phase 2 trial evaluating efruxifermin there was a 12-13% absolute reduction and 63-72% relative reduction in hepatic fat. Improvement in abnormalities in hepatic enzyme function was seen and regression of fibrosis by 1 stage was seen in 55% and 2 stages in 28% of treated individuals. Complete resolution of NASH was seen in 1/3 of patients.64

CONCLUSION

The obesity epidemic has resulted in an increase in the incidence of metabolic syndrome and NAFLD and NASH. While several agents have shown improvement in hepatic steatosis and inflammation, their ability to elicit regression in fibrosis remains to be elucidated, notably for more advanced stages of fibrosis. Long term data regarding the ability of these newer agents, or combination therapy, to reduce hepatic inflammation and fibrosis are warranted.

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DISPATCHES FROM THE GUILD CONFERENCE, SERIES #43

Evaluation, Management, and Prevention of Diverticular Disease

March 2022 • Volume XLVI, Issue 3
Jason D. Eckmann,Aasma Shaukat

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Diverticular disorders are frequently encountered in the primary care setting. Diverticular bleeding is the most common cause of lower gastrointestinal bleeding. Low risk patients with uncomplicated diverticulitis can be managed in the outpatient setting, in some cases without the need for antibiotics. In patients with diverticulosis and persistent abdominal pain, chronic smoldering diverticulitis, segmental colitis associated with diverticulosis (SCAD), symptomatic uncomplicated diverticular disease (SUDD), and visceral hypersensitivity should all be considered. To avoid these complications, patients should be encouraged to lead an active lifestyle, consume a healthy diet, and avoid tobacco, alcohol, and certain medications. Contrary to conventional teaching, seeds and nuts do not need to be avoided.

INTRODUCTION

Colonic diverticulosis is a common syndrome involving protrusion of mucosa and submucosa through weak points in the muscular layer of the wall of the colon, resulting in sac-like pockets called diverticula. Diverticulosis can develop anywhere in the colon, but is more commonly encountered in Western populations in the left colon (distal to the splenic flexure), where sigmoid involvement occurs in >90% of patients with diverticulosis.1 In comparison, while diverticulosis is overall less common in Asian populations, right-sided (proximal to the splenic flexure) diverticulosis predominates.2–4 The likelihood of diverticulosis increases with age and has been estimated to be over 50-60% in patients >60 years.5,6 Rates are increasing worldwide, and are significant contributors to healthcare costs.7–9 Most patients are incidentally found to have diverticulosis on imaging or colonoscopy and remain asymptomatic. However, a small proportion develop complications including bleeding, inflammation, and chronic pain. In this article, we will review the common clinical syndromes seen in patients with diverticulosis (Table 1), and provide a practical approach to the evaluation, management, and prevention of these diseases for the primary care clinician.

Diverticular Bleeding

Diverticular bleeding is the most common cause of overt lower gastrointestinal (GI) bleeding in the United States,10–12 and is seen in up to 15% of patients with diverticulosis with an incidence of ~0.5 per 1,000 person-years.13–15 Bleeding occurs when the vasa recta, blood vessels which penetrate the colonic wall at the site of diverticulum formation, hemorrhage into the gastrointestinal lumen. Diverticular bleeding most commonly arises from the right colon, where the colonic wall is thinner and diverticula tend to have larger openings.10,15–17

Presentation

Patients with diverticular bleeding most commonly present with painless hematochezia.18 Some patients report cramping or bloating (likely related to the cathartic effect of blood in the GI tract), however predominant pain should prompt investigation into alternative etiologies such as ischemic colitis or inflammatory bowel disease (IBD). For most patients, bleeding is relatively minor and selflimited.16,19 However, in some cases, bleeding can be brisk, and patients may present with signs of hemodynamic compromise including hypotension and tachycardia. The abdominal exam is typically benign, and rectal examination usually reveals bright red or maroon stool.

Diagnosis

The diagnosis of diverticular bleeding is generally suspected based on typical clinical signs and symptoms. Additional testing to support the diagnosis should include laboratory evaluation with a complete blood count and basic metabolic panel, with endoscopy or radiographic studies utilized for both diagnostic and therapeutic purposes.

Management

Patients with suspected diverticular bleeding should be managed in the inpatient setting, with initial care focusing on adequate intravenous (IV) access, telemetric monitoring, and fluid and blood product resuscitation when indicated. Patients with hemodynamically significant diverticular bleeding despite initial resuscitation should be cared for in an intensive care setting. In these patients, upper endoscopy (EGD) is generally performed first to exclude a brisk upper GI bleed, which is the underlying etiology in 10-15% of patients with brisk hemotochezia.20 Once upper GI bleeding has been excluded, colonoscopy can be pursued after appropriate colonic preparation. While rare to identify a culprit bleeding diverticulum at the time of colonoscopy, a presumptive diagnosis of diverticular bleeding can be given in patients with diverticula who are found to have colonic blood with no alternative explanation.14,21 If active bleeding is found endoscopically, various tools can be utilized by the endoscopist to achieve hemostasis including epinephrine injection, cautery, and hemostatic clips.14,22 If colonoscopy fails to reveal a source, or if the patient cannot undergo colonoscopy, radiographic evaluation with computed tomography (CT) angiography or nuclear scintigraphy can be used to localize bleeding and guide angiographic intervention.

Acute Diverticulitis

Approximately 4-5% of patients with diverticulosis will develop diverticulitis, with an annual incidence in the United States of approximately 188/100,000 persons per year.23,24 Historically, diverticulitis was felt to develop from diverticular obstruction by fecaliths, seeds, or other solid material, leading to inflammation or perforation of the diverticulum.25 However, this obstructive etiology is now felt to be uncommon. More likely, a combination of altered motility, gut microbiome changes, and underlying genetic and lifestyle factors over time cause breakdown of the colonic mucosal barrier and altered immunity, ultimately leading to a localized inflammatory response.26

Subtypes

Diverticulitis can be divided into uncomplicated and complicated disease. Most cases of diverticulitis are uncomplicated, with inflammation isolated to the diverticulum and surrounding colonic mucosa. However, 12-15% of cases are complicated by phlegmon or abscess (70% of complications), perforation, obstruction, stricture, or fistula.26–28 In most cases patients recover fully after an episode of acute diverticulitis, but in 5-10% symptoms and ongoing inflammation persist, resulting in chronic or “smoldering” diverticulitis.29,30

Presentation

Patients with acute diverticulitis typically present with cramping lower abdominal pain, most commonly in the left lower quadrant. Patients may also report low grade fevers, nausea, poor oral intake, or a change in bowel habits. Rectal bleeding is not commonly seen in acute diverticulitis. Abdominal guarding, rigidity, palpable mass, or the presence of hemodynamic instability should raise suspicion for complicated diverticulitis. Both inflammatory markers and white blood cell count are typically elevated. Given the nonspecific symptoms and laboratory findings in acute diverticulitis, a clinical diagnosis of diverticulitis is only accurate in 40-65% of patients.31,32 Therefore, in most cases CT of the abdomen with IV contrast should be obtained to confirm the diagnosis given its high sensitivity and specificity for the disease (94% and 99%, respectively).33

Management

The key initial decision in patients presenting with acute diverticulitis is to determine the need for inpatient care. Otherwise young, healthy patients with mild uncomplicated diverticulitis can generally be managed as an outpatient, whereas patients with complicated diverticulitis generally require hospitalization.34–36 Additional populations requiring inpatient care include the elderly, immunosuppressed, patients with extensive medical comorbidities, and those with signs of sepsis, high fever, significant leukocytosis, severe pain, inability to tolerate oral intake, or who have failed outpatient management.34,37,38

Role of Antibiotics

Antibiotics have historically been the cornerstone of medical therapy for acute diverticulitis, although recent data suggest that in certain populations antibiotic therapy may not be necessary.30,39–41 A meta-analysis including over 2,500 patients with mild uncomplicated diverticulitis showed no difference in relevant clinical outcomes between those treated with antibiotics and those who were not.42 Therefore, most major societies now endorse selective rather than routine use of antibiotics in immunocompetent patients with mild uncomplicated acute diverticulitis.27,36,38,43 In patients with complicated disease, hospitalized patients, and those with uncomplicated disease at high risk for complications, a 7-10 day course of antibiotics with enteric coverage is recommended.28 Surgical intervention is generally not necessary in most cases of acute diverticulitis.44 However, in patients with overt perforation, fistula, obstruction, non-resolving or recurrent abscess, or those with uncomplicated disease who fail to improve despite medical management, surgical consultation should be obtained.38

Role of Surgery

Surgery is no longer recommended routinely for patients with recurrent episodes of uncomplicated diverticulitis. While quality of life overall seems to be improved after resection, recent literature suggest that partial colectomy reduces (but does not eliminate) the risk for recurrent diverticulitis, and that a significant portion of patients have ongoing abdominal pain despite surgical resection.45–48 Therefore, the decision to perform segmental colectomy in patients with recurrent diverticulitis should be an individualized one. Prior to pursuing surgical intervention, patients and clinicians should consider the severity and frequency of diverticulitis episodes, presence of complications, medical comorbidities, effect on quality of life, and the patient’s ability to tolerate surgical intervention.38

Role of Colonoscopy

Anecdotal evidence and conventional wisdom suggest colonoscopy should not be obtained during an acute episode of diverticulitis due to increased procedural difficulty, patient discomfort, and the theoretical potential for perforation.28 However, data reveal an increased risk of colorectal cancer (CRC) in patients with diverticulitis, particularly in those with complicated diverticulitis (6-8%).49,50 Therefore, follow-up colonoscopy is recommended 6-8 weeks after presentation in patients with complicated diverticulitis and those with a first episode of uncomplicated diverticulitis to exclude concomitant CRC.28,51 This can be deferred in patients in whom a high-quality colonoscopy has been performed within the last 12 months. Patients with recurrent episodes of uncomplicated diverticulitis do not require a colonoscopy following every episode; rather, they should follow conventional screening or surveillance intervals.28,51

Other Diverticular Disorders Segmental Colitis Associated with Diverticulosis (SCAD)

In approximately 1% of patients with diverticulosis, inflammation of the mucosa between diverticula can develop, termed segmental colitis associated with diverticulosis (SCAD, also known as diverticularassociated colitis).52,53 Unlike in diverticulitis, the inflammation in SCAD typically spares the diverticula themselves. The exact pathogenesis of SCAD is not fully understood, but likely results at least in part from localized ischemia, mucosal prolapse, and stasis of fecal matter leading to chronic inflammatory changes.54 Rather than distinct, acute episodes as in diverticulitis, patients with SCAD typically present with chronic symptoms of diarrhea, abdominal pain, and sometimes mild hematochezia. These symptoms may mimic other diseases such as irritable bowel syndrome (IBS) or IBD; in fact, it is likely that SCAD lies on the spectrum of IBD, with debate surrounding whether SCAD is a distinct entity or merely represents the coexistence of IBD and diverticulosis.55 CT imaging and colonoscopic evaluation reveals mucosal inflammation in an area of diverticulosis, typically sparing the rectum.55–57 Data for management are limited, but first line therapy typically involves a course of antibiotics and high fiber diet, similar to diverticulitis. With refractory symptoms, therapies traditionally used in IBD including mesalamine, oral steroids, and anti-tumor necrosis factor-alpha (TNF-a) agents can be considered.57,58

Symptomatic Uncomplicated Diverticular Disease (SUDD)

SUDD should be suspected in patients with diverticulosis and persistent unexplained abdominal pain, in the absence of radiologic or endoscopic evidence of active inflammation that would suggest an alternative etiology such as diverticulitis or SCAD. SUDD has been reported in 15-25% of patients with diverticulosis,59 however, there is controversy surrounding this diagnosis, and there is likely a significant overlap with disorders of gutbrain interaction (DGBIs, previously referred to as functional gastrointestinal disorders) such as IBS.

Proposed underlying mechanisms are similar to those for IBS, including visceral hypersensitivity, microbial dysbiosis, altered GI motility, and lowlevel inflammation.60–64 Given the similarities to DGBIs, neuromodulators such as tricyclic antidepressants may be beneficial to patients with SUDD.65 Numerous other treatments including fiber, probiotics, antibiotics, and aminosalicylates have been investigated with inconclusive results, and cannot be recommended at this time.66–72 Prevention of Diverticular Disease

Given diverticular disease’s prevalence and effect on quality of life, many patients inquire as to what can be done to prevent future or recurrent episodes. Importantly, the development of diverticular disease can be attributed both to genetic influences as well as lifestyle factors. Various genetic loci have been implicated, with estimates of up to 50% of the risk for diverticulitis attributable to genetic effect.73–77 While of primarily academic interest at this time, these genetic associations may allow for targeted therapies in the future.

There are numerous lifestyle interventions patients can follow to decrease risk of diverticulitis and other diverticular disorders. For years, patients with diverticulosis were counseled to avoid ingestion of seeds, nuts, popcorn, and related foods, due to the concern for obstructing diverticula and precipitating diverticulitis. As mentioned previously, this is now felt to be a rare inciting factor for diverticulitis. In fact, a largescale observational study of nearly 50,000 patients showed an inverse correlation between ingestion of these foods and development of diverticular disease.78 Rather, studies have associated diets that are low in fiber and high in red meat and refined sugars as leading to increased risk for the development of diverticular disease.79 Additional risk factors include obesity, sedentary lifestyle, as well as tobacco, opioid, alcohol, and nonsteroidal anti-inflammatory drug (NSAID) use.80– 86 Therefore, patients with diverticulosis should be encouraged to follow a high fiber diet which is low in red meat and refined sugars, and counseled to maintain an active lifestyle with the goal of achieving a normal body mass index. Additionally, depending on each patient’s individual habits, they should be advised to quit smoking, and minimize use of opioids, alcohol, and NSAIDs whenever possible.

CONCLUSION

Diverticular disorders are commonly encountered conditions whose evaluation, management, and prevention can prove challenging for patients and clinicians alike. Patients with suspected diverticular bleeding should be carefully monitored in the inpatient setting, and usually require colonoscopy for diagnosis and potentially therapeutic intervention. When diverticulitis is suspected clinically, CT should generally be obtained to confirm the diagnosis. Healthy patients with uncomplicated diverticulitis can be treated in the outpatient setting, some without antibiotic therapy. Surgical resection is generally only pursued in certain patients with complicated diverticulitis, but can be considered in those with recurrent uncomplicated diverticulitis after weighing risks and benefits. Colonoscopy should follow first episodes of complicated diverticulitis in those without recent high-quality colonoscopy. In patients with diverticulosis and chronic abdominal symptoms, SCAD and SUDD should be considered. While genetics are a significant factor in the development of diverticular disorders, patients should be counseled that lifestyle modifications including physical activity, healthy diet, and smoking cessation play important roles in decreasing risk for diverticular disease.

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  48. Bianchi M, Festa V, Moretti A, et al. Meta-analysis: longterm therapy with rifaximin in the management of uncomplicated diverticular disease. Aliment Pharmacol Ther. 2011;33(8):902-910. doi:10.1111/j.1365-2036.2011.04606.x
  49. Di Mario F, Miraglia C, Cambiè G, et al. Long-term efficacy of rifaximin to manage the symptomatic uncomplicated diverticular disease of the colon. J Investig Med Off Publ
    Am Fed Clin Res. 2019;67(4):767-770. doi:10.1136/jim-
    2018-000901
  50. Tursi A, Brandimarte G, Giorgetti GM, Elisei W. Mesalazine and/or Lactobacillus casei in preventing recurrence of symptomatic uncomplicated diverticular disease of the colon: a prospective, randomized, open-label study. J Clin Gastroenterol. 2006;40(4):312-316. doi:10.1097/01. mcg.0000210092.77296.6d
  51. Tursi A, Brandimarte G, Elisei W, et al. Randomised clinical trial: mesalazine and/or probiotics in maintaining remission of symptomatic uncomplicated diverticular disease–a double-blind, randomised, placebo-controlled study. Aliment Pharmacol Ther. 2013;38(7):741-751. doi:10.1111/apt.12463
  52. Kruis W, Meier E, Schumacher M, et al. Randomised clinical trial: mesalazine (Salofalk granules) for uncomplicated diverticular disease of the colon–a placebo-controlled study. Aliment Pharmacol Ther. 2013;37(7):680-690. doi:10.1111/ apt.12248
  53. Picchio M, Elisei W, Tursi A. Mesalazine to treat symptomatic uncomplicated diverticular disease and to prevent acute diverticulitis occurrence. A systematic review with meta-analysis of randomized, placebo-controlled trials. J Gastrointest Liver Dis JGLD. 2018;27(3):291-297. doi:10.15403/jgld.2014.1121.273.pic
  54. Camilleri M, Sandler RS, Peery AF. Etiopathogenetic Mechanisms in Diverticular Disease of the Colon. Cell Mol Gastroenterol Hepatol. 2020;9(1):15-32. doi:10.1016/j. jcmgh.2019.07.007
  55. Granlund J, Svensson T, Olén O, et al. The genetic influence on diverticular disease–a twin study. Aliment
    Pharmacol Ther. 2012;35(9):1103-1107. doi:10.1111/j.1365-
    2036.2012.05069.x
  56. Strate LL, Erichsen R, Baron JA, et al. Heritability and familial aggregation of diverticular disease: a population-based study of twins and siblings. Gastroenterology. 2013;144(4):736-
    742.e1; quiz e14. doi:10.1053/j.gastro.2012.12.030
  57. Sigurdsson S, Alexandersson KF, Sulem P, et al. Sequence variants in ARHGAP15, COLQ and FAM155A associate with diverticular disease and diverticulitis. Nat Commun. 2017;8:15789. doi:10.1038/ncomms15789
  58. Maguire LH, Handelman SK, Du X, Chen Y, Pers TH, Speliotes EK. Genome-wide association analyses identify 39 new susceptibility loci for diverticular disease. Nat Genet. 2018;50(10):1359-1365. doi:10.1038/s41588-018-0203-z
  59. Strate LL, Liu YL, Syngal S, Aldoori WH, Giovannucci EL. Nut, corn, and popcorn consumption and the incidence of diverticular disease. JAMA. 2008;300(8):907-914. doi:10.1001/jama.300.8.907
  60. Liu PH, Cao Y, Keeley BR, et al. Adherence to a Healthy Lifestyle is Associated With a Lower Risk of Diverticulitis among Men. Am J Gastroenterol. 2017;112(12):1868-1876.
    doi:10.1038/ajg.2017.398
  61. Strate LL, Liu YL, Aldoori WH, Giovannucci EL. Physical activity decreases diverticular complications. Am J Gastroenterol. 2009;104(5):1221-1230. doi:10.1038/ ajg.2009.121
  62. Hjern F, Wolk A, Håkansson N. Smoking and the risk of diverticular disease in women. Br J Surg. 2011;98(7):997-
  63. doi:10.1002/bjs.7477
  64. Ma W, Jovani M, Liu PH, et al. Association Between Obesity and Weight Change and Risk of Diverticulitis in Women. Gastroenterology. 2018;155(1):58-66.e4. doi:10.1053/j.gastro.2018.03.057
  65. Thomas GAO, Rhodes J, Ingram JR. Mechanisms of disease: nicotine–a review of its actions in the context of gastrointestinal disease. Nat Clin Pract Gastroenterol Hepatol. 2005;2(11):536-544. doi:10.1038/ncpgasthep0316 84. Strate LL, Liu YL, Huang ES, Giovannucci EL, Chan AT. Use of aspirin or nonsteroidal anti-inflammatory drugs increases risk for diverticulitis and diverticular bleeding.
    Gastroenterology. 2011;140(5):1427-1433. doi:10.1053/j. gastro.2011.02.004
  66. Aldoori WH, Giovannucci EL, Rimm EB, Wing AL, Willett WC. Use of acetaminophen and nonsteroidal anti-inflammatory drugs: a prospective study and the risk of symptomatic diverticular disease in men. Arch Fam Med. 1998;7(3):255-doi:10.1001/archfami.7.3.255
  67. Humes DJ, Fleming KM, Spiller RC, West J. Concurrent drug use and the risk of perforated colonic diverticular disease: a population-based case-control study. Gut. 2011;60(2):219-224. doi:10.1136/gut.2010.217281

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FROM THE PEDIATRIC LITERATURE

Celiac Disease and Functional Abdominal Pain in Children

March 2022 • Volume XLVI, Issue 3

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Both celiac disease and functional gastrointestinal disorders (FGIDs) can present with abdominal pain in children, and the similarity between these two disorders can be confusing since many patients with FGIDs, in actuality, have celiac disease. The authors of this study evaluated for the presence of functional abdominal pain disorders (FAPDs) and functional constipation (FC) in a group of children with celiac disease controlled on a gluten free diet.

Children were prospectively enrolled in this study between 2016 and 2018 at a tertiary children’s hospital in Italy, and study subjects were enrolled if they were between 4 and 16 years of age and had follow-up visits at the celiac disease outpatient clinic. Celiac disease diagnosis was made based on standard serologic testing followed by duodenal biopsy (based on European Society for Paediatric Gastroenterology, Hepatology, and Nutrition or ESPGHAN guidelines). During follow-up clinic visits, patients were checked for dietary compliance by tissue transglutaminase IgA antibody (TTG IgA) titers as well as by dietary recall. The presence of associated FAPDs and FC was evaluated using the Rome IV Diagnostic Questionnaire for Pediatric FGIDs. Additionally, a sibling of a child with celiac disease (or a cousin if no sibling was available) with negative TTG IgA titers were used as controls.

A total of 417 children with celiac disease and 373 control patients were used in the final study analysis. Time duration for TTG IgA titers normalization did not differ between children with celiac disease with or without an FAPD, including irritable bowel syndrome (IBS). Children with celiac disease had a significantly higher risk of developing an FAPD compared to controls (11.5% vs 6.7%; P< .05; relative risk [RR], 1.8; 95% CI, 1.1–3). Children with celiac disease also had a significantly higher risk of having IBS (7.2% vs 3.2%; P < .05; RR, 2.3; 95% CI, 1.1– 4.6). No such association was seen in the setting of functional dyspepsia, functional abdominal pain, and abdominal migraines, and there was no significant difference present in the time duration of FAPDs between patients with celiac disease and control patients. Logistic regression demonstrated that younger age at celiac disease diagnosis and higher TTG IgA titers at time of diagnosis predicted the risk of FAPD as well as IBS. Finally, FC was common in both children with celiac disease and controls, but FC was significantly more common in patients with celiac disease (19.9% vs 10.5%, respectively; P <0.001; relative risk, 2.1; 95% CI, 1.4–3.2).

Thus, celiac disease appears to be associated with the occurrence of both FAPDs and FC in children. The cause is unknown although nerve fiber dysfunction or microbiome changes may account for these findings. Pediatric patients with celiac disease and their families should be informed that such children may have abdominal pain and / or constipation after a celiac disease diagnosis is made, even if a child is compliant with a glutenfree diet.

Cristofori F, Tripaldi M, Lorusso G, Indrio F, Rutgliano V, Piscitelli D, Castellaneta S, Bentivoglio V, Francavilla R. Functional abdominal pain disorders and constipation in children on a glutenfree diet. Clinical Gastroenterology and Hepatology 2021; 19: 2551-2558.

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FRONTIERS IN ENDOSCOPY, SERIES #79

Updates to Colorectal Cancer Screening Recommendations and Future Implications

March 2022 • Volume XLVI, Issue 3
Jennifer L. Maranki,Cynthia Chuang

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Colorectal cancer (CRC) remains the second leading cause of cancer death in the United States, although there have been significant improvements in CRC incidence and mortality over time. Despite robust efforts in CRC screening, roughly one-third of eligible adults are not up to date with CRC screening. Trends in CRC incidence and mortality show an alarming increase in individuals below the age of 50, prompting the U.S. Preventive Services Task Force to update their 2016 recommendations on CRC screening. This update now recommends initiation of CRC screening at age 45 years instead of age 50 years for all average-risk adults. This review addresses the rationale for this update, highlights the recommended modalities for screening, discusses the role of programmatic screening, and posits the implications of this update to the gastroenterology community.

INTRODUCTION

Colorectal cancer (CRC) is the third most recommendations for screening and methods commonly diagnosed cancer and the second to increase adherence.2,3 The U.S. Preventive leading cause of cancer death in the U.S. It Services Task Force (USPSTF), along with several is estimated that almost 147,950 individuals were professional societies, publish recommendations for colorectal cancer screening, which were most recently updated in May 2021. The most remarkable update from the USPSTF 2016 recommendations is the endorsement of initiating colorectal cancer screening for average risk individuals beginning at age 45 years.4 This recommendation is in response to the body of evidence that rates of colorectal cancer are increasing among individuals younger than 50 years. While other societies had also previously recommended initiation of CRC screening at age 45, the USPSTF recommendations specifically inform insurance coverage and waiver of cost sharing for preventive services. This recommendation may improve CRC outcomes in younger adults, but may also impact access to care or further widen racial or ethnic disparities in screening and outcomes.

Incidence and Risk Factors

CRC affects approximately 4.4% of men and 4.1% of women in their lifetime.1 Age is in most cases the most important risk factor for CRC. The incidence rate roughly doubles for each five-year age group up until the age of 50 years, at which point it increases by about 30% for each subsequent 5-year period.5 The median age for diagnosis of CRC has been steadily declining, currently at 66 years, down from 72 years in the early 2000s, and nearly one-third of rectal cancers are diagnosed in those younger than 55 years. This downward shift in age is likely multifactorial, with CRC incidence decreasing in older age groups due to increased uptake of screening, and increasing incidence in younger adults.5,6 Overall, rates of CRC incidence have been slowly increasing in females while rates are declining in males. However, death rates from CRC have been substantially declining, with a large decline from 2000 to the present, correlating with increased uptake of colonoscopy (Figure 1).

Importantly, there are significant racial disparities in CRC incidence and mortality,

with highest rates among Non-Hispanic Blacks, followed by American Indians and Alaska Natives. In these ethnic groups, CRC incidence rates and death rates are 20% and 40 % respectively higher than those in Non-Hispanic Whites.7 These disparities are multifactorial, but in large part reflect socioeconomic status in the form of prevalence of risk factors and access to health care.8-10 Figure 2.
Modifiable risk factors for CRC include lifestyle and behavioral factors such as heavy alcohol intake, smoking, obesity, and a diet rich in red and processed meat. Nonmodifiable factors that increase risk include hereditary factors, a personal or family history of adenomas or CRC, and a personal history of inflammatory bowel disease.

Rates of CRC Incidence and Mortality Over Time

CRC incidence rates have been declining gradually since the mid-1980s, with an acceleration in the decline starting in the early 2000s, due to a positive change in modifiable risk factors and the widespread adoption of colonoscopy for screening. However, since the mid-1990s, incidence of CRC in younger adults (those aged less than 50 years) has been increasing, accounting for 11% of colon cancers and 15% of rectal cancers in 2020 compared to 5% and 9%, respectively, in 2010.1,11 These alarming trends provide the foundation for the change in recommendations for CRC screening.

New Screening Recommendations

The USPSTF relies on a panel of experts to provide evidence-based recommendations on a variety of clinical preventive services including preventive care, counseling, and screening. In May 2021, the USPSTF updated their 2016 guidelines for CRC screening, in part due to the growing body of data demonstrating increasing rates of CRC in younger adults. The USPSTF recommends screening for colorectal cancer in all adults aged 50 to 75 years, with a grade A strength of recommendation, indicating substantial net benefit. The USPSTF recommends screening for CRC in adults aged 45 to 49 years, with a grade B recommendation, indicating moderate net benefit. Additionally, the USPSTF recommends that clinicians offer CRC screening in adults aged 76 to 85 years, after consideration of the patient’s overall health, screening history, and preferences, with a grade C recommendation, indicating a small net benefit.4

The key update to the 2021 recommendation was to begin average risk CRC screening at age 45 years rather than at age 50 years. This recommendation was not based on clinical trials that would be expensive and taken years to perform, but rather microsimulation modeling studies that estimated the benefits of CRC screening beginning at age 45. These simulation studies used known cancer incidence and mortality data to provide updated model-based estimates of the benefits, burden, and harms of CRC screening strategies and to identify those that may provide an efficient balance of lifeyears gained (LYG) versus colonoscopy burden.12 Six widely accepted methods for CRC screening were used in the model: fecal immunochemistry testing (FIT), multitarget stool DNA testing, flexible sigmoidoscopy with or without FIT, CT colonography, or colonoscopy.

Two important assumptions were made in these models:

  1. all persons with an abnormal result on a non-colonoscopy screening test would subsequently undergo colonoscopy and
  2. full adherence with all procedures.

The modeling analysis demonstrated 49 strategies that were considered efficient options, and 41 of those strategies indicated screening starting at age 45 years. Lowering the age to commence screening at age 45 versus 50 was estimated to result in 5 additional LYG (22 vs. 27 LYG), 623 additional colonoscopies (161 vs. 784), and a minimal increase in complications.12 Keeping in mind that these models assumed 100% adherence, in real life the authors estimated that the true LYG would be diminished by between 4% and 25%. The long-term outcomes from the models may also help inform patients and clinicians to determine the best strategy for that particular patient, balancing LYG for risks and hassle of undergoing colonoscopy compared to more modest LYG with stool-based tests and colonoscopy minimization.

Recommended Colorectal
Cancer Screening Strategies

Although CRC screening by colonoscopy is by far the most common method for CRC screening in the U.S., randomized controlled trials have only shown a mortality benefit with the use of fecal occult blood testing (FOBT) followed by colonoscopy if FOBT is abnormal and flexible sigmoidoscopy with subsequent colonoscopy if polyps are detected.13 The effectiveness of colonoscopy in reducing mortality from both right and left-sided colon cancers has been demonstrated in observational studies.14,15 The USPSTF recommends seven different methods for CRC screening: 1) High-sensitivity gFOBT every year; 2) FIT every year; 3) stool DNA test with FIT (sDNA-FIT) every 1 to 3 years; 4) colonoscopy every 10 years; 5) CT colonography every 5 years; 6) flexible sigmoidoscopy every 5 years; and 7) flexible sigmoidoscopy every 10 years with FIT every year. The stool-based tests are considered two-step tests because any abnormal result requires a follow-up colonoscopy. Of the stool-based tests, annual FIT or annual sDNA-FIT provides a greater LYG than either annual high-sensitivity gFOBT or sDNA-FIT every 3 years. Further, modeling studies demonstrate that annual screening with sDNA-FIT would result in more colonoscopies than annual screening with FIT.4,16 Overall, colonoscopy every 10 years yielded the greatest LYG and CRC cases averted compared to the other methods, whether screening begins at age 50 years or at age 45 years, but this benefit was followed closely by sDNAFIT annually and flexible sigmoidoscopy every 10 years plus annual FIT.12

Given the challenges with CRC screening adherence, the main benefit of endorsing a variety of screening methods is that it allows ordering clinicians and patients to engage in shared decision making about patient-centered approaches to CRC screening while also acknowledging local variation in availability of endoscopy services. While CRC screening among individuals aged 50 years and older increased from 38% in 2000 to 66.8% in 2018, screening rates are still well below the U.S. Department of Health and Human Services Healthy People goal of 74.4%, and far short of prior goals set by the American Cancer Society of 80% by 2020.10 Each of the included screening tests comes with advantages and disadvantages. Some of the main issues regarding colonoscopy include access to facilities and physicians that perform colonoscopy in an appropriate time frame, the need for fasting and bowel preparation, potentially time off work plus a responsible person to provide transportation, need for sedation or anesthesia, risks associated with an invasive procedure, and up until recently, added costs associated with polypectomy. The main advantage of colonoscopy is the ability to remove any polyps at the time of the procedure, and determination of an appropriate surveillance interval based on the number, size, and pathology of those polyps. Conversely, stoolbased or two-step tests may often be performed in the privacy of one’s home, require no bowel prep, are non-invasive, but typically require annual adherence. Further, those with an abnormal stoolbased test then require a colonoscopy to complete the screening occurrence. Currently, that followup colonoscopy may be associated with significant out-of-pocket expenses.

Population-Based
Approaches to CRC Screening

In order to achieve the CRC mortality benefit suggested by the USPSTF modelling studies, population-based approaches to CRC screening that are not dependent on an individual’s insurance status or access to primary care are needed. CRC screening in the U.S. is largely an opportunistic process, with patients typically offered CRC screening in the context of a primary care office visit. Given that 25% of U.S. adults did not have an identified source of primary care in 2015, our current approach to CRC screening is unlikely to get us to desired screening targets.17 Studies have shown that patients who are older, more educated, earn more money, see a health care provider regularly, and have health insurance are more likely to be up to date with CRC screening.10 Additionally, certain racial and ethnic groups are disproportionately affected by this approach.10  The inclusion of stool-based tests in the paradigm for CRC screening allows for the implementation of population-based screening programs that provide the ability to systematically offer screening to all eligible members of population with standardized counseling, access, support, and monitoring. Levin and colleagues implemented an organized CRC screening program for Kaiser Permanente Northern California health plan beneficiaries using FIT and colonoscopy for eligible individuals aged 50 – 75 years and followed them for 15 years. Up-to-date status of screening more-than doubled from 38.9% in 2000 to 82.7% in 2015, and was associated with a 25.5% reduction in annual CRC incidence and a 52.4% reduction in cancer mortality.18 Other countries that have initiated programmatic screening have also shown reductions in CRC incidence and mortality.19,20

Anticipated Impact of 2021 USPSTF
Recommendations on Screening and
Access to Colonoscopy and Unintended Consequences

Although the USPSTF recommends several accepted approaches to CRC screening, colonoscopy is by far the most commonly employed method. Expanding CRC screening to begin at age 45 could lead to significantly increased demand for colonoscopies, with an additional 20 million Americans now eligible for CRC screening. Continued dependence on colonoscopy as the primary tool for screening will further strain our currently limited endoscopy resources, especially in rural and other areas where endoscopy services are scarce. Further work is needed to better understand whether screening with colonoscopy should be reserved for older patients who will have higher likelihood of polyps and CRC, and if other screening modalities, such as stool-based screening, should be encouraged in younger individuals. An unfortunate unintended consequence of the USPSTF update would be if colonoscopy resources are diverted to younger patients, resulting in decreased screening and CRC detection in older, higher risk individuals where CRC screening has been shown to have the greatest impact on LYG, CRC incidence, and CRC mortality. Endoscopists should plan how to be best positioned for these changes. This could mean increasing endoscopy capacity and access, and/or be prepared for more therapeutic procedures that will be required following positive stool- or imaging-based screening tests. As larger polyps are found on colonoscopies that follow stoolbased tests, the skills and therapeutic capabilities of endoscopists and their facilities will also need to expand. Our professional societies can play an important role in providing this education for endoscopists in practice, while our trainees in gastroenterology will benefit from this exposure during their standard fellowship.

The Patient Protection and Affordable Care Act (ACA) required most health plans to cover evidence-based preventive services that have been recommended by the USPSTF, including CRC screening. This important legislation has made CRC screening more affordable to many more people; however, health plans stop short by only covering the first screening test itself. If a positive stool-based test leads to a recommendation for a colonoscopy, that colonoscopy is considered diagnostic and subject to out-of-pocket costs that typically range from $99-$231.21 Patients who may have otherwise opted for a stool-based screening strategy may choose screening colonoscopy instead to avoid unpredictable cost sharing that may be associated with follow-up diagnostic testing. Even worse, we expect individuals in resource poor locations will forgo CRC screening altogether, further worsening health disparities. Unless followup colonoscopies are considered to be part of the screening process that is covered without cost sharing, cost will continue to be a barrier to patient acceptance of non-colonoscopy screening methods.

In addition, we support population-based approaches to CRC screening that do not rely on an individual’s insurance status, access to primary care, or geographic region. While programs instituted within individual primary care practices, health systems, and health plans will certainly help, population-based approaches that engage individuals both in and out of the traditional health care system are needed. Without populationbased approaches, recommendations to begin CRC screening at age 45 will threaten to worsen health care disparities as those well-positioned to access screening colonoscopies at age 45 will limit availability of screening in patients historically disadvantaged, including older patients. In summary, we agree that the evidence supports the USPSTF recommendations to commence CRC screening at age 45. However, due to already limited endoscopy resources, the updated recommendations may not result in the intended benefit of decreasing CRC mortality if not associated with other interventions. In geographic areas that cannot support the anticipated demand for colonoscopies, we support studying whether starting with non-colonoscopy-based screening strategies in younger individuals may be preferred. We also advocate for policy changes to recommend follow-up colonoscopies following positive screening tests be covered as part of CRC screening. Finally, institution of population-based CRC screening approaches are needed to ensure that we do not further widen access between individuals already engaged in healthcare and those that are not, which would lead to unintended consequences of worsening health disparities in CRC mortality.

References

  1. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 05 2020;70(3):145-164. doi:10.3322/caac.21601
  2. Whitlock EP, Lin JS, Liles E, Beil TL, Fu R. Screening for colorectal cancer: a targeted, updated systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. Nov 04 2008;149(9):638-58. doi:10.7326/0003-4819-149-9-200811040-00245
  3. Lin JS, Perdue LA, Henrikson NB, Bean SI, Blasi PR. Screening for Colorectal Cancer: An Evidence Update for the U.S. Preventive Services Task Force. 2021.
  4. Davidson KW, Barry MJ, Mangione CM, et al. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 05 18 2021;325(19):1965-1977. doi:10.1001/jama.2021.6238 5. Society AC. Colorectal Cancer Facts & Figures 20202022. Atlanta: American Cancer Society; 2020.
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  2. Sherman R, Firth R, De P, et al. Cancer in North America: 2012-2016. Volume One: Combined Cancer Incidence for the United States, Canada and North America. North American Association of Central Cancer Registries, Inc.; 2019.
  3. Fedewa SA, Flanders WD, Ward KC, et al. Racial and Ethnic Disparities in Interval Colorectal Cancer Incidence: A Population-Based Cohort Study. Ann Intern
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  4. Doubeni CA, Laiyemo AO, Major JM, et al.
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    Richardson LC. Vital Signs: Colorectal Cancer Screening Test Use – United States, 2018. MMWR Morb Mortal Wkly Rep. Mar 13 2020;69(10):253-259. doi:10.15585/ mmwr.mm6910a1
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  9. Doubeni CA, Corley DA, Quinn VP, et al. Effectiveness of screening colonoscopy in reducing the risk of death from right and left colon cancer: a large community based study. Gut. 02 2018;67(2):291-298. doi:10.1136/ gutjnl-2016-312712
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FROM THE PEDIATRIC LITERATURE

Pediatric Patients Who Have Celiac Disease and Inflammatory Bowel Disease

March 2022 • Volume XLVI, Issue 3

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Celiac disease (CD) can occur concomitantly in patients with inflammatory bowel disease (IBD); however, there is limited data regarding both of these diseases occurring in children. The authors of this study performed a multi-center, retrospective, observational study to evaluate such patients using data from the IBD Registry of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP). All patients were 17 years of age or younger, and IBD was diagnosed using the Porto criteria while CD was diagnosed using standard antibody tests for CD in addition to findings of villous atrophy on duodenal biopsy per the guidelines of the European Society of Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN). Patients with IBD and CD were compared to a control group of 98 patients with the sole diagnosis of IBD.

Patients with both IBD and CD comprised 49 patients from an eligible pool of 2,800 patients. Crohn disease was present in 26 patients (53.1%) while ulcerative colitis was present in 23 patients (46.9%). Females made up 53.1% of the study subjects. CD was diagnosed before IBD in 75.5% of patients (median interval 4.2 years). The median age at diagnosis for CD was 7.5 years while the median age at diagnosis for IBD was 11.5 years. When compared to patients with IBD alone, patients with CD and IBD were statistically more likely to have other associated autoimmune disease mainly consisting of thyroiditis (OR, 2.81; 95% CI, 0.97–8.37; P = 0.04). No difference was present between patients with IBD and CD versus IBD alone regarding immune suppression treatment regimens, surgery, or hospitalizations. Ileocolonic disease was less common in patients with CD and Crohn disease compared to control patients solely with Crohn disease. The risk of colectomy was significantly higher in patients with CD and ulcerative colitis compared to patients with ulcerative colitis alone (P=0.03). Growth delay was present at time of diagnosis in 7 patients (14.3%) with CD and IBD compared to 16 patients just with IBD (16.3%) (OR, 0.72; 95% CI, 0.26–1.98; P = 0.53). There was no statistical difference in reaching pubertal age between patients with CD and IBD compared to patients with IBD alone; however, patients with CD and IBD were significantly more likely to have pubertal delay (3.2%; OR, 5.24; 95% CI, 1.13–33.0; P = 0.02). Univariate analysis determined that growth delay and a younger age at IBD diagnosis were associated with pubertal delay. CD associated with IBD, intestinal surgery, and a higher number of hospitalizations also were associated with pubertal delay. Although pubertal delay was present, final heights of both male and female patients were similar between patients in the two groups

This study describes a unique phenotype in pediatric patients with CD and IBD and understanding the risk factors for development of other autoimmune disease as well as growth delay / pubertal delay is important, especially when explaining health outcomes to such patients and their families.

Bramuzzo M, Lionetti P, Miele E, Romano C, Arrigo S, Cardile S, Di Nardo G, Illiceto M, Pastore M, Felici E, Fuoti M, Banzato C, Citrano M, Congia M, Norsa L, Pozzi E, Zuin G, Agrusti A, Bianconi M, Grieco C, Guidici F, Aloi M, Alvisi P, on the behalf of the SIGENP IBD Group. Phenotype and Natural History of Children with Coexistent Inflammatory Bowel Disease and Celiac Disease. Inflammatory Bowel Diseases 2021; 27: 1881-1888.

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FROM THE LITERATURE

A Marker for Assessment of Prospective Risk in Barrett’s Esophagus

April 2022 • Volume XLVI, Issue 4

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To identify the small group with Barrett’s esophagus (BE) who will progress to advanced disease from the many who will not, assessment of p53 status has promise as a predictive biomarker, but analytic limitations and lack of validation has precluded its use. To develop a robust criteria for grading abnormal immunochemical (IHC) expression of p53 and to test its utility as a biomarker for progression in BE, the following was carried out.

Criteria for abnormal IHC of p53 were developed in BE biopsies and validated with sequencing to assess TP53 mutations. The utility of p53 IHC as a biomarker for progression of BE was tested retrospectively in 561 patients with BE, with or without known progression. The findings were prospectively validated in a clinical practice setting in 1487 patients with BE.

Abnormal p53 IHC highly correlated with TP53 mutation status (90.6% agreement), and was strongly associated with neoplastic progression in retrospective cohort, regardless of histologic diagnosis.

In a retrospective cohort, abnormal p53 was associated with a hazard ratio of 5.03 and hazard ratio of 5.27 for patients with exclusively nondysplastic disease before progression.

In a prospective validation cohort, p53 IHC predicted progression among nondysplastic BE, indefinite for dysplasia and low-grade dysplasia.

It was concluded that p53 IHC identifies patients with BE at higher risk of progression, including in patients without evidence of dysplasia. P53 IHC is inexpensive, easily integrated into routine practice, and should be considered in biopsy of all BE patients without high-grade dysplasia or cancer.

Redston, M., Noffsinger, A., Kim, A., et al. “Abnormal TP53 Predicts Risk of Progression in Patients with Barrett’s Esophagus Regardless of a Diagnosis of Dysplasia.” Gastroenterology 2022; Vol. 162, pp. 468-481, February 2022.

Murray H. Cohen, DO, “From the Literature” Editor, is on the Editorial Board of Practical Gastroenterology.

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FROM THE LITERATURE

Surgery vs. Chemoradiotherapy in Esophageal Squamous Cell Carcinoma

April 2022 • Volume XLVI, Issue 4

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A trial was carried out to investigate the noninferiority of CRT (chemoradiotherapy) relative to surgery for T1bN0M0 (ESCC) esophageal squamous cell carcinoma. The primary endpoint was overall survival, which was determined using inverse probability weighting with propensity scoring. Surgery consisted of an esophagectomy with 2- or 3-field lymph node dissection. CRT consisted of 2 courses of 5-FU on days 1-4 and cisplatin on day 1, every 4 weeks, with concurrent radiation.

From December 20, 2006 to February 5, 2013, a total of 368 patients were enrolled in a nonrandomized portion of the study. The patient characteristics in surgery arm and CRT arm, respectively, were as follows: Median age 62 and 65 years; proportion of males 82.8% and 88.1%; proportion of performance status 0, 99.5% and 98.1%. Comparisons were made using nonrandomized groups.

The 5-year overall survival rate was 86.5% in the surgery arm and 85.5% in the CRT arm. The complete response rate in the CRT arm was 87.3%. The 5-year progression-free survival was 81.7% in the surgery arm and 71.6% in the CRT arm. Treatment-related deaths occurred in 2 patients in the surgery arm and none in the CRT arm.

It was concluded that CRT is noninferior to surgery and should be considered for the treatment of T1bN0M0 (ESCC).

Kato, K., Ito, Y., Nozaki, I., et al for the Japan Esophageal Oncology Group of the Japan Clinical Oncology Group. “ParallelGroup Control Trial of Surgery Versus Chemoradiotherapy in Patients with Stage 1 Esophageal Squamous Cell Carcinoma.” Gastroenterology 2021; Vol. 161, pp 1878-1886.

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FROM THE LITERATURE

Evaluation of Pancreatic Neoplasm in Intraductal Location

April 2022 • Volume XLVI, Issue 4

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The International Consensus Guidelines that were updated in 2017 recommended surgery to all main duct intraductal papillary mucinous neoplasms (MD-IPMNs), with the main pancreatic duct (MPD) of 10 mm of more and those with mural nodules, regardless of size. To identify predictors of malignancy in MD-IPMN among preoperative factors, including MPD and mural nodule size, 26 benign MD-IPMNs (7 resected and 19 nonresected), and 32 malignant MD-IPMNs (31 resected and 1 nonresected), were included in this study.

MRCP, CT, EUS and cytology were performed using pancreatic juice collected by ERCP. Resected IPMNs were classified as benign or malignant by histologic examination and nonresected MDIPMNs by imaging, cytology, and observation. Cutoff values of candidate parameters were determined by receiver operating characteristic curves. Univariate and multivariate analyses by regression model were performed.

MPD and mural nodule size, as well as cytology results differed significantly between benign and malignant groups. Cutoff values of MPD and mural nodule sizes were 15 mm and 10

mm with areas under the curve of 0.66 and 0.86, respectively. Mural nodules of 10 mm or more (OR 8.32), and positive cytology (OR 42.5), were shown to be independent predictors of malignancy on multivariate analysis. When MD-IPMNs with either predictor were diagnosed to be malignant, sensitivities, specificities and overall accuracy for malignancy were 94%, 85%, and 90%, respectively. It was concluded that mural nodules of 10 mm or more and positive cytology were independent predictors of malignancy in MD-IPMN.

“Predictors of Malignancy in Main Duct Intraductal Papillary Mucinous Neoplasm of the Pancreas.” Uehara, H., Abe, Y., Kai, Y., et al. Gastroenterology 2022; 95:291-296.

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FRONTIERS IN ENDOSCOPY, SERIES #78

Endo-Mucosal Full-Thickness Resection

January 2022 • Volume XLVI, Issue 1
Zohaib Ahmed,Muhammad Aziz,Ali Nawras,Douglas G. Adler

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BACKGROUND

Polypectomy, endoscopic mucosal resection, and endoscopic submucosal dissection are endoscopic procedures performed to remove superficial tumors involving the mucosa and submucosa of the gastrointestinal system (GI).1 The efficacy and safety of these techniques are hampered in the presence of non-lifting epithelial lesions due to severe fibrosis and scarring, subepithelial lesions (SELs) emerging from muscularis propria (MP), and complex lesions that are difficult to approach endoscopically or at high risk for complications such as bleeding and/or perforation.2

Endoscopic full-thickness resection (EFTR) has emerged as an endoscopic resection technique for removing deep submucosal tumors (SMTs) in the GI wall.3

Suzuki and Ikeda were the first to describe EFTR in 2001.4 There are three EFTR techniques: clip-assisted EFTR, standard (direct) resection of the lesion followed by defect closure (“exposed” EFTR), and lesion resection by submucosal tunneling (non-exposed EFTR).2  In this manuscript, we will discuss the technical characteristics, indications, safety, and outcomes of EFTR.

Full-Thickness Resection Device

The FTRD (Full-thickness resection device) system consists of a plastic cap (13 x 23mm) preloaded with an FTRD clip and a 14-mm poly filament polypectomy snare, as well as accessory equipment including a tissue grasper and a high-frequency marking device or probe (see Figure1). Before endo-mucosal full-thickness resection with FTRD, the marking probe is used. This high-frequency marking probe is used to tag the target lesion before applying the FTRD, enabling detection and complete excision of the target tissue easier (see Figures 2 & 3). In contrast to the majority of endoscopic polypectomy snares, the FTRD system’s snare does not progress through the working channel; instead, the shaft runs along the scope’s exterior side, protected by a plastic sheath, leaving the working channel available for instrumentation.5

1. Clip-Assisted EFTR

Standard EFTR approaches entail the excision of a lesion followed by the closure of the defect with mechanical clips or endoscopic suturing devices. However, over-the-scope clip (OTSC) assisted EFTR is a newly developed “close then cut” technique for complete excision of epithelial and subepithelial lesions throughout the GI tract. This approach offers a potentially safer alternative that involves stabilizing and affixing the defect prior to resection of the target lesion.

Indications

Non-lifting epithelial lesions (e.g., adenoma) linked with significant fibrosis from earlier resection attempts, as well as SELs, such as neuroendocrine tumors, leiomyomas, some pancreatic rests, and gastrointestinal stromal tumors (GISTs) are potential indications for clip-assisted EFTR.6

Technique

After identifying the target lesion, the circumference of each lesion is pre-marked with a high-definition marking probe using the coagulation setting. Following that, the scope is withdrawn, and the FTRD system is attached to it. After re-inserting the scope, the lesion is pulled inside the distal plastic cap using the appropriate grasper with the intention to pull all layers of the stomach or bowel wall. The FTRD clip is then deployed, and the electrocautery snare is engaged with monopolar current and used in a standard manner to excise the clip-captured tissue in full-thickness. The specimen is subsequently removed, leaving the intestinal wall closed by the OTSC.5 (see Figures 4 and 5).

Safety and Efficacy

In a recent meta-analysis involving eighteen studies with 730 patients, Brewer Gutierrez et al. reported a pooled overall histological full resection rate (R0) of 82%. Lesions included in this study were difficult/residual colorectal adenomas, adenomas that involved a diverticulum or the appendiceal orifice, early cancers, colorectal SELs, and upper gastrointestinal lesions. Perforation and hemorrhage occurred in 0.1 and 2% of patients, respectively. There were no EFTR-related deaths.6

In a prospective multicenter study involving 181 participants, the efficacy and safety of the FTRD system for the removal of colorectal lesions were reported. EFTR was technically successful in 89.5%, with a 76.9% R0 resection rate. The R0 resection rate was 77.7% in 127 individuals with complicated adenomas and benign histology. Unsuspected cancer was found in 14 of the lesions, while 15 of the lesions were primarily known as malignancies. R0 resection was achieved in 72.4% of the cases, while 8 more instances exhibited profound submucosal infiltration >1000 m. As a result, only 13/29 patients were able to have curative resection (44.8%). R0 resection rate was 87.0% in the subgroup with subepithelial tumors (SETs) (n=23). In general, lesions < 2 cm had a greater R0 resection rate than lesions >2 cm (81.2 % vs. 58.1 %, p=0.0038). The rate of adverse events was 10%. Out of 181 patients, 10 experienced procedure-related moderate adverse events, such as hemorrhage, post-polypectomy syndrome which is defined as development of abdominal pain, fever, leukocytosis, and peritoneal inflammation in the absence of frank perforation, appendicitis (which was conservatively handled), and recurrent abdominal pain of unclear origin (5.5 percent ). 8 patients out of total 181 (4.5% ) developed severe adverse events which include perforation, appendicitis required laparoscopic appendectomy and enterocolonic fistula after EFTR.7 Benjamin Meier et al. in a multicenter retrospective study including 1,178 colorectal FTRD procedures reported an 80% R0 resection rate for difficult adenomas, early carcinomas, and subepithelial tumors. Full-thickness excision (visible of all layers of the colonic wall, including serosa, within the resection material) was histologically confirmed in 89.9% of the cases in the whole cohort. Compared to the rectum, the colon had a considerably greater rate of full-thickness resection (92.0 % vs. 83.3 %, P=0.0001). Histologically complete resection (R0) was accomplished in 80.0 % of the whole cohort. There was no significant difference in

R0 resection between the colon and the rectum (78.9% vs. 83.6%, P= 0.11) or between the lesions < 20 and > 20 mm (77.6 % vs. 81.0%, P =0.2). Compared to the overall cohort, R0 resection for SETs was considerably higher (97.1% vs. 80.0 %, P=0.0001). In addition, SET was a single significant independent predictor of R0 resection in multivariable analysis (P=0.009).

Procedure-related adverse events were reported in 142 patients (12.1%). Complications that necessitated additional surgical intervention, perforations, and obstructive stenosis are among the major side effects (3.1%). Minor side effects include bleeding, perforation, inflammation and infection and others which include stenosis after FTRD clip, misplacement of FTRD clip, clipping of grasping device (9.0%). Adverse events requiring surgical intervention include perforation, delayed perforation, appendicitis, and delayed bleeding.8

2. Standard EFTR (Exposed EFTR)

In contrast to clip-assisted EFTR, the standard EFTR approach is a “cut and then close” procedure that is generally utilized to remove gastric SELs from the MP. However, limited working space, limited mobility for defect closure, and substantial morbidity are associated with adverse events, including mediastinitis and fistula formation. Similarly, the use of traditional EFTR use in the colon is restricted due to an increased risk of perforation and inadequate defect closure.

Indication

Standard EFTR is best suited for gastric SELs < 3 cm arising from the MP. Although EFTR is technically viable for lesions larger than 3 cm, their extraction through the esophagus following en bloc resection can be harrowing, and the resulting esophageal wall defects may be difficult, if not impossible, to seal, increasing the risk of perforation.9

Standard EFTR Technique

The procedure begins with lesion marking utilizing high-definition marking probe to place coagulation dots along the lesion’s periphery, followed by peripheral incision and lesion enucleation with breach of MP. Finally, an endoscopic suturing device is used to close the defect.

Safety and Efficacy

In a retrospective analysis, Jian G. et al.’s colleagues included 100 gastric SMTs excised using EFTR. Efficacy of EFTR was measured in terms of rates of en bloc resection and was achieved in 98 cases (98 %). Ten patients (9.9%) experienced adverse events. Two patients developed intraoperative bleeding, one delayed bleeding, and seven patients had peritonitis. EFTR was ceased in one patient due to massive intraoperative bleeding, and conversion to laparoscopic surgery was necessary. One patient required laparoscopic surgery due to delayed bleeding, and other minor complications were resolved with conservative management. Overall tumor size > 3 cm was associated with difficult EFTR, which was defined as a procedure time ≥ 120 minutes and/or the occurrence of major adverse events, such as significant bleeding, abdominal pain, or peritonitis.10 Antonino G. et al., in their recent systematic review, evaluated 15 studies, mainly from Asia, reported 750 exposed-EFTR treated gastric SMTs. The complete resection and surgical conversion rate was 98.8% and 0.8%, respectively. The rate of major adverse events, including delayed bleeding, perforation, peritonitis, and infection, was 1.6%, 0.5%, 0.1%, and 0.9%, respectively. The rate of successful exposed EFTR and effective endoscopic defect closure was 98.3%.11

Another retrospective study by Ye L.P et al. included a series of 726 patients who underwent resection of 733 upper subepithelial lesions (1-4cm in size) originating from the muscularis propria via exposed EFTR and EFTR through submucosal tunneling. Adverse events including perforation (12.1%), immediate bleeding (1.8%), peritonitis (0.7%) and delayed bleeding (0.1%). Most lesions were leiomyomas (63%) and GISTs (34%) without residual lesions and a mean follow-up of 28 months. The major risk factors for incomplete resection were an extensive connection to the muscularis propria (p=0.007) and extraluminal growth (p=0.04).

Risk factors for perioperative perforation were large tumor size (p=0.04), extensive connection to muscularis propria (p=0.01) and extraluminal growth (p=0.04).12 Although conventional EFTR has been reported for resection of SELs in the colon, its safety profile limits its widespread usage at the moment, in large part due to the inability to consistently close the resection defect.13 Submucosal Tunneling Endoscopic Resection

(STER)

STER Technique

STER is a combination of peroral endoscopic myotomy and endoscopic submucosal dissection techniques.14 In this technique, a submucosal tunnel is constructed to serve as a working area for endoscope insertion and tumor excision. When compared to ESD, this method has a lesser chance of perforation since the integrity of the GI mucosa is preserved; it also provides better wound healing and a lower risk of infection. Furthermore, due to the deeper tumor origin, this technique is better suited for cancers coming from the muscularis propria layer, for which ESD resection is problematic.15

Indications

STER is appropriate for tumors arising from the MP with an intact overlying mucosa and no highrisk EUS characteristics. STER is usually effective for lesions less than 3.5 cm in diameter.19 Resection of larger lesions can be associated with technical problems, a lower probability of en bloc resection, and a higher risk of adverse events, including bleeding, mucosal laceration, and perforation.20

Contraindications

STER should not be performed if the mucosa is ulcerated.15 SMTs with irregular borders are more likely to be malignant and more challenging to resect using STER.16 There is a significant risk of perforation, persistent fistula development, and secondary infection when removing lesions involving a deep part of the muscularis propria.16

The Steps Involved in STER

1. Identification of Tumor

The first step of STER involves tumor identification. Injection of indigo carmine or methylene blue may be performed to help locate the tumor and guide the direction of subsequent tunneling.16

2. Submucosal Injection

A fluid cushion is subsequently generated through a submucosal injection of fluid, usually a saline solution with indigo carmine or methylene blue, 2-5cm from the SMT.17 Sometimes, epinephrine is added to the solution.

3. Generating Tunnel Entry

To create an entrance to the submucosal tunnel, a mucosectomy is performed, with the orientation of the incision being left to the operator.

4. Tunnel Generation

An electrosurgical knife is used to guide the endoscope through the incision. To further distinguish the submucosal and muscularis layers, a dye such as indigo carmine or methylene blue with or without epinephrine with saline as an injectate is utilized as the scope progresses to prevent damage while expanding the tunnel mucosa. To provide enough working area, the tunnel should be extended approximately 2 cm beyond the distal edge of the SMT.

5. Tumor Dissection and Removal

Various electrosurgical knives may be employed for a partial or full-thickness resection, depending on the degree of attachment of the lesion to the muscularis propria. It is recommended to avoid unnecessary breach of the adventitia or the serosal layer during an en bloc excision.18 The resected tumor is then extracted using a retraction device such as an endoscopic anchoring device, a rat-tooth forceps, or a retrieval net.

Efficacy and Safety

Chen et al., in a retrospective study, evaluated 180 patients with upper gastrointestinal submucosal tumors undergoing STER and reported a 90.6% en bloc resection rate. The overall complication rate was 8.3%. Pneumothorax and hydrothorax occurred in 10 patients (5.5%), clinically significant bleeding occurred in 2 patients (1.1%), the mucosal injury occurred in 2 patients (1.1%), and an esophagealpleural fistula occurred in 1 patient (0.6%).21 Xiu-He Lv et al. published a meta-analysis showing pooled complete resection and en bloc resection rates for SMTs undergoing STER was 95.5% and 94.6%, respectively. The most common complications related to STER were pneumothorax and bowel perforation. The pooled rate of subcutaneous emphysema and pneumomediastinum was 14.8%. The rate for pneumothorax was 6.1% and 6.8% for pneumoperitoneum. Additionally, the pooled rate of perforation was 5.6%. Only a few cases of bleeding were reported in only two studies.22

Li et al. found a 98.6% en bloc resection rate in their retrospective study of 74 patients who underwent STER for esophageal SMTs lesions. Perforation was reported in only one patient as an intraoperative adverse event. Pneumothorax and pneumoperitoneum were postoperative complications noted in 9 individuals.23 Mao et al., in their prospective study of 56 patients, reported a 100% rate of en bloc resection. Only 9 patients experienced adverse events, including pneumothorax, pleural effusion, and pneumoperitoneum.24 Chen et al., in their retrospective study of 290 patients with upper gastrointestinal SMTs treated by STER, reported an 89.3% en bloc resection rate. The overall incidence of complications was 23.4% (68/290).10.0 % of procedures (29/290) required intervention for complications. Major bleeding occurred in 5 patients (1.7%). Pleural effusion occurred in 49 patients, including 9 patients who developed pneumothorax.25 Wang et al., in their prospective study of 80 patients undergoing STER, reported a 97.6% en bloc resection rate. Complications included chest pain, subcutaneous emphysema, and pneumothorax in 8.75% (7/80) of cases, and all of them resolved with conservative therapy.26

CONCLUSION

Although EFTR technology is still in development, it is a less invasive technique when compared to surgery for specific neoplastic lesions. The development of reliable closure devices and the adoption of appropriate indications will continue to make EFTR more feasible. In addition, it will help patients minimize their financial, physical, and psychological burdens. Although the published results to date are encouraging, prospective comparative studies are required to determine the long-term effectiveness and safety of EFTR.

References

  1. Schmidt, A., B. Meier, and K. Caca, Endoscopic fullthickness resection: Current status. World journal of gastroenterology, 2015. 21(31): p. 9273-9285.
  2. Rajan, E. and LMWK. Song, Endoscopic full thickness resection. Gastroenterology, 2018. 154(7): p. 1925-1937. e2.
  3. Cai, M.Y., F. Martin Carreras-Presas, and P.H. Zhou, Endoscopic full-thickness resection for gastrointestinal submucosal tumors. Digestive Endoscopy, 2018. 30: p. 17-24.
  4. Suzuki, H. and K. Ikeda, Endoscopic mucosal resection and full thickness resection with complete defect closure for early gastrointestinal malignancies. Endoscopy, 2001. 33(05): p. 437-439.
  5. Wedi, E., et al., Full-Thickness Resection Device for Complex Colorectal Lesions in High-Risk Patients as a Last-Resort Endoscopic Treatment: Initial Clinical Experience and Review of the Current Literature. Clinical endoscopy, 2018. 51(1): p. 103-108.
  6. Brewer Gutierrez, O.I., et al., Endoscopic full-thickness resection using a clip non-exposed  method for gastrointestinal tract lesions: a meta-analysis. Endoscopy international open, 2020. 8(3): p. E313-E325
  7. Schmidt, A., et al., Colonoscopic full-thickness resection using an over-the-scope device: a prospective multicentre study in various indications. Gut, 2018. 67(7): p. 12801289.
  8. Meier, B., et al., Efficacy and Safety of Endoscopic FullThickness Resection in the Colorectum: Results From the German Colonic FTRD Registry. Am J Gastroenterol, 2020. 115(12): p. 1998-2006.
  9. Lu, J., et al., Endoscopic management of upper gastrointestinal submucosal tumors arising fromuscularis propria. J Clin Gastroenterol, 2014. 48(8): p. 667-73.
  10. Jian, G., et al., Factors that predict the technical difficulty during endoscopic full-thicknessresection of a gastric submucosal tumor. Rev Esp Enferm Dig, 2021. 113(1): p. 35-40.
  11. Antonino, G., et al., Efficacy and safety of gastric exposed endoscopic full-thickness resection without laparoscopic assistance: a systematic review. Endosc Int Open, 2020. 8(9): p. E1173-e1182.
  12. Ye, L.P., et al., Safety of Endoscopic Resection for Upper Gastrointestinal Subepithelial Tumors Originating from the Muscularis Propria Layer: An Analysis of 733 Tumors. Am J Gastroenterol, 2016. 111(6): p. 788-96.
  13. Brigic, A., et al., A systematic review regarding the feasibility and safety of endoscopic full thickness resection (EFTR) for colonic lesions. Surg Endosc, 2013. 27(10): p. 3520-9.
  14. Xu, M.-D., et al., Submucosal tunneling endoscopic resection: a new technique for treating upper GI submucosal tumors originating from the muscularis propria layer (with videos). Gastrointestinal endoscopy, 2012. 75(1): p. 195-199.
  15. Du, C., et al., Submucosal tunneling endoscopic resection: An effective and safe therapy for upper gastrointestinal submucosal tumors originating from the muscularis propria layer. World journal of gastroenterology, 2019. 25(2): p. 245-257.
  16. Yoshizumi, F., et al., Submucosal tunneling using endoscopic submucosal dissection for peritoneal access and closure in natural orifice transluminal endoscopic surgery: a porcine survival study. Endoscopy, 2009. 41(8): p. 707-11.
  17. Wang, H., et al., Submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors originating from the muscularis propria layer. European Journal of Gastroenterology & Hepatology, 2015. 27(7): p. 776-780.
  18. Wang, H., et al., Submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors originating from the muscularis propria layer. European Journal of Gastroenterology & Hepatology, 2015. 27(7): p. 776-780.
  19. Liu, B.R. and JT Song, Submucosal Tunneling Endoscopic Resection (STER) and Other Novel Applications of Submucosal Tunneling in Humans. Gastrointest Endosc Clin N Am, 2016. 26(2): p. 271-282.
  20. Chen, T., et al., Submucosal Tunneling Endoscopic Resection vs. Thoracoscopic Enucleation for Large Submucosal Tumors in the Esophagus and the Esophagogastric Junction. J Am Coll Surg, 2017. 225(6): p. 806-816.
  21. Chen, T., et al., Long-term Outcomes of Submucosal Tunneling Endoscopic Resection for Upper Gastrointestinal Submucosal Tumors. Annals of Surgery, 2017. 265(2).
  22. Lv, XH, C.H. Wang, and Y. Xie, Efficacy and safety of submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors: a systematic review and meta-analysis. Surg Endosc, 2017. 31(1): p. 49-63.
  23. Li, Q.-y., et al., Comparison of endoscopic submucosal tunneling dissection and thoracoscopic enucleation for the treatment of esophageal submucosal tumors. Gastrointestinal Endoscopy, 2017. 86(3): p. 485-491.
  24. Mao, X.-L., et al., Submucosal tunneling endoscopic resection using methylene-blue guidance for cardial subepithelial tumors originating from the muscularis propria layer. Diseases of the Esophagus, 2017. 30(4): p. 1-7.
  25. Chen, T., et al., Management of the complications of submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors. Endoscopy, 2016. 48(2): p. 149-55.
  26. Wang, H., et al., Submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors
    originating from the muscularis propria layer. Eur J Gastroenterol Hepatol, 2015. 27(7): p. 776-80.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #218

Nutritional Management of Infants with Necrotizing Enterocolitis

January 2022 • Volume XLVI, Issue 1
Patti H. Perks,Stephen M. Borowitz,Jonathan R. Swanson

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Necrotizing enterocolitis (NEC) is an inflammatory disorder of the gastrointestinal (GI) tract that primarily occurs in premature infants, contributing to infant morbidity and mortality. Term infants are also at risk of NEC, particularly infants with congenital heart disease (CHD), although the pathophysiology differs from that in preterm infants. Optimal nutritional management, both during and following NEC, is imperative for the developing infant. Options for parenteral and enteral nutrition have expanded, necessitating this update to a previously published article on Nutritional Management of the Infant with Necrotizing Enterocolitis.

INTRODUCTION

Necrotizing enterocolitis (NEC) is an inflammatory disorder of the gastrointestinal (GI) tract that primarily occurs in premature infants. NEC represents the culmination of pathological processes involving dysfunction of the gut epithelium, immune and hemodynamic systems, and intestinal dysbiosis.1 NEC is a leading cause of morbidity and mortality in the neonatal intensive care unit (NICU) and is associated with an increased risk of neurodevelopmental delay.2,3

A meta-analysis published in 2020 reported the global incidence of NEC in very low birth weight (VLBW) infants (birth weight < 1500 g) at 7%.4 Term infants are also at risk of NEC, particularly infants with congenital heart disease (CHD), yet the pathophysiology differs from that of preterm infants.2,3,5 Optimal nutritional management during and following NEC is imperative for the developing infant.

The pathophysiology of NEC is multifactorial,7 and shares overlapping clinical features with other acquired neonatal intestinal diseases.8,9 Risk factors predisposing to NEC include maternal and in utero factors as well as infant perinatal and postnatal factors.2,3,8,10-14 (Table 1)

The incidence of NEC in preterm infants peaks around 31 weeks post-menstrual age (PMA) with 95% of cases occurring by 34 weeks (PMA).2,15 Preterm infants have decreased immunocompetence coupled with an immature GI tract and dysmotility. Mature peristaltic patterns do not develop until 34-36 weeks’ PMA. Preterm intestinal defense systems against pathogens and toxins are underdeveloped. These systems include digestion, production of gastric acid, a mucin lining, and reduction of intestinal permeability.16 Nutrient maldigestion and malabsorption coupled with reduced GI contractility may predispose to stasis, small intestinal bacterial overgrowth (SIBO), dysbiosis, and ischemic damage to the premature bowel.16 Translocation of bacteria across the intestinal barrier precipitates an inflammatory cascade that can result in intestinal necrosis.2,11 The pathophysiology of NEC in late preterm or term infants is primarily the result of diminished perfusion of the intestinal tract that occurs with hypoxic-ischemic encephalopathy, placental insufficiency, certain forms of congenital heart disease such as hypoplastic left heart syndrome and single ventricle defects, or polycythemia and associated hyperviscosity.

Prevention strategies proposed for both preterm and term infants include early human milk feeding,2,14 antibiotic stewardship, probiotics,11 avoidance of acid inhibitors, infection prevention, avoidance of anemia, and adherence to feeding protocols.2

Clinical Presentation and Medical and Surgical Management

The clinical presentation of NEC varies from one infant to another. Disease severity is based on clinical markers. Non-surgical NEC includes mild ileus to moderate illness with focal pneumatosis intestinalis and dilated loops with or without portal venous gas. Medical management is indicated in these conditions. Surgery is typically indicated if the clinical condition worsens, which can be marked by:

  • hemodynamic instability
  • severe thrombocytopenia
  • disseminated intravascular coagulopathy (DIC)
  • peritonitis or pneumoperitoneum.7

Although commonly used as a definition, Bell’s criteria were not meant as a means of diagnosing NEC, but rather as a means of grading the severity of the NEC. There have been at least six more recent definitions of NEC, nearly all of which have better sensitivity and specificity than Bell’s criteria alone.17,18 The severity of the disease process determines which medical and/or surgical interventions are indicated.12 (Table 2)

NEC can present with abdominal distention, feeding intolerance, emesis, grossly bloody stools, diarrhea, and/or abdominal wall erythema. Differential diagnoses include sepsis-induced ileus, spontaneous intestinal perforation (SIP), meconium peritonitis, Hirschsprung-associated enterocolitis, food protein enterocolitis, malrotation with volvulus, or intestinal obstruction. Similar symptoms may result in misdiagnosis. Accurate diagnosis can impact reintroduction of feeds, particularly if cow’s milk protein or other dietary proteins need to be excluded from the infant’s or mother’s diet. SIP typically occurs within the first 10 days after birth in very preterm VLBW infants and requires surgical intervention. The perforation is usually isolated in the terminal ileum and the remainder of the bowel is healthy. Feeding intolerance is typically demonstrated by increased gastric retention, abdominal distention or fullness, inadequate stooling, and/or increased apnea, all of which can be seen in NEC.9

Identification of pneumatosis intestinalis in conjunction with previously mentioned clinical symptoms is diagnostic for NEC, and the diagnosis is supported by thrombocytopenia, neutropenia, DIC, elevated lactic acid levels, and/ or hyperkalemia and hyponatremia. With severe NEC, infants may develop generalized edema due to capillary leak and poor vascular tone, necessitating aggressive fluid resuscitation and inotropic support. Hyponatremia may occur, requiring significant sodium in

parenteral nutrition (PN). Acidosis from tissue injury and necrosis often mandates more acetate in PN. An infant with rapidly worsening NEC is at risk for poor renal perfusion and hyperkalemia; PN potassium delivery should be limited and requires close monitoring. Poor hepatic perfusion or excessive glucose delivery may impair fatty acid oxidation; lipid delivery may need to be temporarily reduced during hypertriglyceridemia24 which in infants may be defined as levels over 200-250 mg/dL. Clinical complications dictate nutritional adjustments. (Table 3)

In the post-acute catabolic phase, PN must then be optimized to provide 100% of estimated nutritional needs to support recovery and minimize lean tissue loss while continuing to promote growth.25 Adequate PN delivery requires central venous access unless fluid volumes greater than 140 mL/kg are provided.24 PN energy needs are generally estimated to be 10%–15% lower than enteral nutrition (EN) needs due to reduced stool losses and due to the absence of the thermic effect of food or the energy required for digestion and absorption. Energy needs of the sedated infant during the acute phase of NEC or post-surgery are lower and the timing of moving from catabolism to anabolism remains unclear.26 PN provision of ~ 75-80 kcal/kg with mean protein delivery of 3.5 gm/kg in the first week after surgery in infants < 32 weeks’ gestational age with NEC has been associated with improved head circumference growth without negative impacts.27 PN energy needs during the subsequent recovery phase need to be increased to support growth.

Enteral Nutrition Management Following NEC

Non-nutritive sucking during bowel rest, if feasible, can promote motility and mesenteric blood flow;24 wiping or swabbing the baby’s mouth (oral care) with colostrum or mom’s milk can provide the benefits of human milk.28 EN should be initiated as soon as clinically feasible following NEC to mitigate the negative impact of lack of GI stimulation and prolonged PN such as sepsis, cholestasis, SIBO, impaired growth, impaired neurocognitive development, and increased length of stay.24,29 Feeds can be safely started when there is evidence of return of GI function, demonstrated by stable vital signs and resolving thrombocytopenia7 reduction (not necessarily cessation) of nasogastric output, an improving abdominal exam, and normalization of abdominal x-rays or ultrasound.29,30,31 In several retrospective cohort studies, earlier re-initiation of EN (< 5-7 days) as compared to later re-initiation of EN (> 7 days) was associated with a lower risk of recurrent NEC and/or post-NEC strictures.32 Moreover, the risk of central line-associated bloodstream infection (CLABSI) was lower, likely the result of improved intestinal barrier function, and full feeds were reached sooner in the early EN group.32

Potential benefits of early feeding after GI surgery using human milk include digestibility, the delivery of immunoglobulins, and prebiotics (which may decrease the risk of infection), the delivery of mucin, and growth factors (which may promote intestinal adaptation), motility, and colonization with beneficial GI bacteria.1,25,29,33 For VLBW infants, early feeding with human milk, both mother’s own milk or pasteurized donor human milk (PDHM) as compared to intact cow’s milk protein formulas may promote intestinal maturation and decrease the risk of intestinal inflammation.1 Small cohorts of infants recovering from NEC experienced an increase in cytokine response with exposure to cow’s milk beta-lactoglobulin and casein.7

Initial EN volume of 10 or 20 mL/kg/d for the infant recovering from medical or less severe surgical NEC is reasonable, and an advance of 20 mL/kg/d has been shown to be tolerated without negative outcomes.30,31 Feeds should be advanced cautiously and fortified to meet protein and mineral needs. Feeding advances are tailored to the severity of illness and extent of surgical resection, if applicable, while monitoring clinical responses to advancing volumes. Quantification of ostomy output, if applicable, should be used to direct the rate of feeding advances and determine whether bolus versus continuous delivery of feeds is better tolerated. Bolus feeds may better stimulate intestinal adaptation than continuous feedings,7 however, continuous feeds allow for slower nutrient delivery which may facilitate improved absorption and feeding tolerance, especially in infants with short bowel syndrome (SBS).7 Overnight continuous

Initial EN volume of 10 or 20 mL/kg/d for the infant recovering from medical or less severe surgical NEC is reasonable, and an advance of 20 mL/kg/d has been shown to be tolerated without negative outcomes.30,31 Feeds should be advanced cautiously and fortified to meet protein and mineral needs. Feeding advances are tailored to the severity of illness and extent of surgical resection, if applicable, while monitoring clinical responses to advancing volumes. Quantification of ostomy output, if applicable, should be used to direct the rate of feeding advances and determine whether bolus versus continuous delivery of feeds is better tolerated. Bolus feeds may better stimulate intestinal adaptation than continuous feedings,7 however, continuous feeds allow for slower nutrient delivery which may facilitate improved absorption and feeding tolerance, especially in infants with short bowel syndrome (SBS).7 Overnight continuous

feedings with small daytime boluses facilitate PO trials during the day. Continuous delivery via gastric or small bowel access may promote tolerance of goal EN volumes when dysmotility or malabsorption are present,24 allowing the reduction or discontinuation of PN. Concentrating PN as feeds are advanced can optimize the delivery of energy, protein, and micronutrients until feeds can be fortified and advanced sufficiently to eliminate the need for PN.25

If mother’s own milk or PDHM are unavailable or limited, formula choice post-NEC will depend on whether cow’s milk protein intolerance is suspected. Some infants demonstrating cow’s milk protein intolerance do not improve with extensivelyhydrolyzed protein formulas and in such cases, an amino acid-based formula is appropriate. Infants with SBS may benefit from initial feeds with breast milk; if malabsorption with advancing volumes results in poor growth, dehydration, or electrolyte disarray, an extensively-hydrolyzed or amino acid containing formula containing medium chain triglycerides may aid absorption of nutrients, although evidence is limited and more research is needed.1,7

Human milk fortification or formula choice and concentration are tailored to the infant’s gestational age and energy and protein needs to support recovery and growth. Achieving a conservative protein goal of 2.5 g/kg/d requires enteral intake of over 200 mL/kg/d of unfortified breast milk, rarely feasible for young infants. Fortification is therefore needed. Human milk-based fortifiers provide increased nutrition while preserving many of the beneficial effects of human milk for preterm infants.34 Liquid cow’s milk-based fortifiers contain hydrolyzed protein and can be effectively used

to meet the nutritional needs of preterm infants when human milk-based fortifiers are not available. Fortification of human milk is often needed for term infants recovering from GI disease and the appropriate formula powder and/or modulars can be used to reach the needed calorie goal if human milk-based fortifiers designed for term infants are not available. Modulars are less frequently needed due to improved human milk fortifiers and formulas but may include a human milk-based calorie fortifier, protein modulars, medium chain triglycerides (MCT), or other oils, or a combination dextrose/MCT powder.

Preterm infants generally can absorb intact milk proteins; however, absorption may be impaired if pancreatic secretion is inadequate. Hydrolyzed protein, whether extensively or partially hydrolyzed, may promote protein absorption in the setting of pancreatic insufficiency. In the absence of cow’s milk protein intolerance or allergy, formulas containing intact protein may be well-tolerated if human milk is unavailable. Human milk contains some peptides which may contribute to its digestibility.1 Extensively hydrolyzed and elemental formulas do not contain lactose which is an important prebiotic. Undigested lactose in the large bowel undergoes fermentation which produces short-chain fatty acids (SCFAs), gas, and contributes to immune function and gut epithelial health.1 Infants with SBS may produce less lactase initially due to loss of bowel surface area as well as immature bowel mucosa and may have increased abdominal distention related to increased gas production and rapid intestinal transit. This may result in increased stoma output or excoriated perineal areas.1 This does not mean lactose needs to be eliminated; gradual introduction of lactosecontaining feeds may promote mucosal adaptation and production of the lactase enzyme. However, when concentrating formula, lactose content may be an important factor to consider based on GI symptoms.

Amino acid-based formulas contain glucose polymers instead of lactose and some proportion of MCT instead of long chain triglycerides (LCT). While intended for infants with cow’s milk sensitivity refractory to extensively hydrolyzed protein formulas, these are often used initially for infants recovering from NEC despite a lack of evidence to support this practice.1 MCTs may be more efficiently absorbed than long chain triglycerides among infants with SBS, however, the optimal amount of MCT and the duration of use remains unclear.1 LCT are important for production of docosahexaenoic and arachidonic acid, vital for eye and brain development1 and potentially instrumental in intestinal adaptation after bowel resection.7

Complications of NEC

Complications secondary to NEC are varied and can range from strictures occurring weeks after diagnosis, to the most serious complication of short-bowel syndrome due to loss of small intestinal length with or without intact colon. Post-NEC strictures may result in partial or total bowel obstruction; more common symptoms are intermittent or persistent abdominal distension, feeding intolerance, and/or intermittent or recurrent vomiting, and chronic or recurrent diarrhea that is sometimes bloody. Persistent or intermittent SIBO caused by intestinal stasis above the stricture produce some of these same symptoms.19

Infants who have lost the distal ileum as a result of surgical NEC are at risk of developing vitamin B12 deficiency, fat malabsorption, and bile acid malabsorption which may result in steatorrhea as well as watery diarrhea. Loss of the ileocecal valve also increases the risk for rapid intestinal transit and SIBO.

SIBO may exacerbate malabsorption and diarrhea and can cause vomiting, bloating, and abdominal distension, feeding intolerance, recurrent abdominal pain, weight loss, and occasionally fever.34 Diagnostic tests can be employed to diagnose SIBO, however, they are all poorly reproducible, and hence this largely remains a clinical diagnosis. Treatment is largely empiric, and a wide variety of antibiotics can be used. Recurring SIBO can be associated with chronic intestinal inflammation. Treatment with intermittent or rotating antibiotics may improve feeding tolerance, decrease the incidence of catheter associated infections, and decrease the risk of parenteral nutrition-associated liver disease.36 SBS describes a loss of functional bowel length which can occur following medical NEC and more commonly occurs following surgical NEC.

Key articles and resources can guide clinicians in managing short bowel syndrome. (Table 4)

Micronutrient Supplementation

Vitamin and mineral supplementation is an important component of EN support. If SBS, cholestasis, or fat malabsorption exist, a watermiscible form of the fat-soluble vitamins A, D, E, and K will be required. Additional vitamin D supplementation may be indicated when cholestasis and/or indications of metabolic bone disease are present.37 A serum 25-hydroxy vitamin D level can help determine what level of vitamin D supplementation is needed and for how long. Prematurity and GI fluid losses such as enterostomy output contribute to frequent need for additional zinc above the recommended daily enteral intake of 1.42.5 mg/kg/d.38 Zinc sulfate (10 mg/mL elemental zinc) suspension may be an option. Iron is absorbed in the duodenum and proximal jejunum. Adequate supplemental iron is needed if not provided by the formula or fortifier, or if absorption is impaired due to intestinal resection. Typically, a liquid iron such as Fer-in-solR at 2-4 mg/kg/d will meet iron requirements, taking into account enteral sources. Split dosing may promote better absorption.37 Calcium and phosphorous intake through adequate fortification and/or formula intake is ideal, but if calcium and phosphorus supplements are required due to malabsorption and metabolic bone disease, doses must be carefully calculated and given at separate times with close monitoring for enteral intolerance as well as potential hypercalcemia or hyperphosphatemia.39

Infants with ileostomies are at high risk of excessive fluid and sodium losses in their ileostomy effluent, resulting in total body sodium depletion, metabolic acidosis, and growth failure. Assessment of total body sodium via urine sodium measurement and adequate sodium supplementation are essential to promote growth.40

CONCLUSION

Successful nutritional management post-NEC requires teamwork and thoughtful attention to clinical signs and symptoms, growth, and GI tolerance with frequent problem-solving to reach nutritional goals. With current products and cautious advancements after early reintroduction of EN, it is possible to optimize nutritional and hydration status, as well as improve overall development.

References

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