FROM THE PEDIATRIC LITERATURE

More Data on C. difficile and Pediatric IBD Outcomes

September 2020 • Volume XLIV, Issue 9

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

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

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

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

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

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

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FROM THE PEDIATRIC LITERATURE

Degree of Villous Atrophy and Outcomes in Children

September 2020 • Volume XLIV, Issue 9

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

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

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

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

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


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

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

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FROM THE LITERATURE

Impact of Serum ANA in Nonalcoholic Fatty Liver Disease

September 2020 • Volume XLIV, Issue 9

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

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

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

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

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FROM THE LITERATURE

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

September 2020 • Volume XLIV, Issue 9

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

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

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

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

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FROM THE LITERATURE

Corticosteroids, TNF Antagonists and Outcomes from COVID-19 with IBD

September 2020 • Volume XLIV, Issue 9

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To characterize the clinical course of COVID-19 among patients with IBD and evaluate the association among demographics, clinical characteristics and immunosuppressant treatments on COVID-19 outcomes, study was carried out. Surveillance epidemiology of coronavirus under research exclusion for inflammatory bowel disease (SECURE-IBD), is a large international registry created to monitor outcomes of patients with IBD with confirmed COVID-19. Calculation of the age/standardized mortality ratios was carried out using multivariable logistic regression to identify factors associated with severe COVID-19, defined as intensive care unit admission, ventilator use and/or death.

A total of 525 cases from 33 countries were reported (median age 43 years, 53% men); 37 patients had severe COVID-19; 161 (31%) were hospitalized and 16 patients died (3% case fatality rate). Standardized mortality ratios for patients with IBD were 1.8, 1.5, and 1.7, relative to data from China, Italy and the United States, respectively. Risk factors for severe COVID-19 among patients with IBD included increased age (AOR 1.04), greater than 2 comorbidities (AOR 2.9), systemic corticosteroids (AOR 6.9), and sulfasalazine or 5-aminosalicylate use (AOR 3.1). Tumor necrosis factor antagonist treatment was not associated with severe COVID-19 (AOR 0.9).

It was concluded that increasing age, comorbidities and corticosteroids are associated with severe COVID-19 among patients with IBD, although a causal relationship cannot be definitively established. Notably, TNF antagonists do not appear to be associated with severe COVID-19.

Brenner, E., Ungaro, R., Gearry, R., et al. “Corticosteroids, But Not TNF Antagonists are Associated with Adverse COVID-19 Outcomes in Patients with Inflammatory Bowel Diseases: Results from an International Registry.” Gastroenterology 2020; Vol. 159, pp. 481-491.

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DISPATCHES FROM THE GUILD CONFERENCE, SERIES #33

Irritable Bowel Syndrome

September 2020 • Volume XLIV, Issue 9
Elizabeth J. Videlock,Lin Chang

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Irritable bowel syndrome (IBS) is a prevalent chronic functional gastrointestinal disorder characterized by the presence of chronic or recurrent abdominal pain associated with altered bowel habits. It is a multifactorial condition that has been recently redefined as a disorder of gut-brain interaction. The diagnosis is based on symptom criteria and limited diagnostic testing. In recent years, there have been significant advances in developing efficacious dietary, pharmacologic and non-pharmacologic approaches in the treatment of IBS. Management should focus on a patient-centered approach, reducing cost, continuity of care, and improving patient satisfaction and health related quality of life. This review discusses the epidemiology, clinical symptoms, and evidence-based and practical approaches to diagnostic evaluation and treatment of IBS.

Irritable bowel syndrome (IBS) is a functional bowel disorder (FBD) that is characterized by abdominal pain associated with diarrhea and/or constipation. IBS is one of the most common gastrointestinal disorders diagnosed in primary care and gastroenterology practices.1 In IBS, the gastrointestinal (GI) tract is grossly and histologically normal. For this reason, it has been referred to as a “functional” GI disorder. However, there is increasing evidence of distinct pathophysiologic mechanisms underlying IBS. Thus, IBS has now been redefined as a disorder of gut–brain interaction that is classified by GI symptoms related to any combination of the following: motility disturbance, visceral hypersensitivity, altered mucosal and immune function, altered gut microbiota, and altered central nervous system (CNS) processing.2

EPIDEMIOLOGY

Prevalence and Impact

A recent population-based study found that 30% met criteria for ≥1 FBD and 4.6% met Rome IV criteria for IBS (Table 1).3 Using the less stringent Rome III criteria (Table 1),4 the prevalence was 9%. IBS is subtyped by predominant bowel habit. Based on Rome IV subclassification criteria (Table 2), the prevalence of IBS with diarrhea (IBS-D), IBS with mixed symptoms (IBS-M), and IBS with constipation (IBS-C) are similar and < 5% are unsubtyped (IBS-U).3,5 IBS is more prevalent in women and younger individuals.1,6 Up to 50% individuals with IBS symptoms do not seek healthcare, and those who do have symptoms for an average of 7 years prior to being diagnosed with IBS.7 IBS is associated with a poorer health-related quality of life (HRQOL)8 and significant healthcare utilization and costs. It accounts for 10% to 15% of primary care visits and 25% to 50% of gastroenterology visits.9 The combined indirect and direct costs for IBS has been estimated to be $1.01 billion.10

Risk Factors

Post-infection IBS (PI-IBS) is defined as the onset of IBS symptoms following resolution of acute infectious gastroenteritis, characterized by two or more of the following: fever, vomiting, diarrhea, or a positive bacterial stool culture, in an individual without a history of IBS.11 GI infection is associated with about a 4-fold increase in risk of IBS-symptoms at twelve months in comparison to uninfected individuals.12 Risk factors for PIIBS include a preexisting GI condition, a history of more severe diarrheal illness, younger age, female gender, chronic stressful life events, or psychological disorders.13

There is an association between having IBS, including PI-IBS, and stressful life events in childhood and/or adulthood.14,15 A history of early adverse life events (EALs) or traumatic experiences during childhood increases an individual’s risk for IBS by at least 2-fold. These EALs include, but are not limited to, maladjusted relationships with a parent or primary caregiver, severe illness or death of a parent, a mentally ill or incarcerated household member, and physical, sexual, or emotional abuse.16 Two survey studies found that the majority of IBS patients believe that stress causes and triggers their symptoms.7,17

DIAGNOSIS

The differential diagnosis for the symptoms of IBS is shown in Table 3. The use of the Rome diagnostic algorithm (Figure 1)18 which is comprised of a medical history and physical examination, evaluation of GI symptoms and alarm signs or symptoms, limited diagnostic testing and use of symptom-based Rome IV criteria (Table 1),1 which are sufficient to make the diagnosis of IBS. Alarm features include rectal bleeding, weight loss, iron deficiency anemia, nocturnal diarrhea, and a family history of colon cancer, inflammatory bowel disease (IBD) or celiac disease.19 The presence of “red flags” or alarm features may indicate a need for further diagnostic tests but it should not exclude a patient from being diagnosed with IBS.19

The Rome IV criteria are currently the most widely used criteria for diagnosis of IBS and are accepted by regulatory agencies including the Food and Drug Administration (FDA). Symptom frequencies in the Rome IV criteria were based on US normative data. The purpose of the Rome criteria and the modifications in Rome IV are to improve the specificity (although this reduced the sensitivity) for the purposes of clinical research studies.20 However, in clinical practice, patients meeting Rome III or IV criteria can and should be diagnosed with IBS.

Recent AGA guidelines for the diagnostic evaluation of patients with IBS-D or chronic diarrhea recommend a fecal calprotectin or fecal lactoferrin to screen for IBD.21 A normal level is associated with a <1% chance that symptoms are due to IBD. In individuals with IBS symptoms, it is cost-effective to obtain celiac serologies when the prevalence of celiac disease is at least 1%.22 Serum IgA tissue transglutaminase (tTG) and an IgA level should be ordered. Because IgA deficiency can lead to a false-negative result, a test for IgG deaminated gliadin peptides can be ordered in IgA-deficient patients.21 While Giardia antigen and polymerase chain reaction (PCR) tests are recommended in patients with IBS-D symptoms, conventional ova and parasite stool testing is not recommended unless there is a history of recent travel to endemic areas.21 In 25-30% of patients with IBS-D symptoms, there is evidence of bile acid diarrhea23 and therefore, testing for bile acid diarrhea or an empiric trial of bile acid sequestrants is recommended.21 A blood test measuring circulating antibodies to cytolethal distending toxin B and vinculin (anti-CdtB, antivinculin) have been shown to be increased in IBS-D and possibly IBS-M.24 However, this test has a low sensitivity (<50%), and the major societies did not issue recommendations for or against the use of these serologic tests.21,25,26

Other routine blood tests, such as a metabolic panel and thyroid function tests, are rarely abnormal in patients with symptoms of IBS, and typically do not lead to an alternative diagnosis.27 Abdominal imaging such as a CT scan or ultrasound is not recommended in IBS patients without alarm signs or symptoms.

A colonoscopy should be performed according to the guidelines for colon cancer screening and surveillance in the general population in patients with IBS symptoms without alarm features.19 There is a low pretest probability of IBD and colonic neoplasia in these patients. However, if a colonoscopy is performed in a patient with diarrheal symptoms, colon biopsies should be taken in the right and left colon to rule out microscopic colitis and collagenous colitis.

The association between small intestinal bacterial overgrowth (SIBO) and IBS remains controversial. With the possible exception of predicting response to rifaximin in patients with IBS-D,28 there is limited clinical utility of testing for SIBO (e.g., lactulose hydrogen breath test) in patients with IBS. Society guidelines currently do not recommend testing for evaluation of IBS.19,25,26,29

Routine testing for carbohydrate malabsorption is generally not recommended in individuals with IBS symptoms.19,25,26,29 However, lactose breath testing can be considered when lactose maldigestion remains a concern despite avoiding dairy products. Similarly, fructose breath testing can be considered in patients suspected of having fructose maldigestion. Adult Sucrase Isomaltase Deficiency has been recognized in a very small subgroup of IBS-D patients and can be considered especially if there is no response to a low fermentable oligosaccharides, di-saccharides, and mono-saccharides, and polyols (FODMAP) diet.30,31

TREATMENT

Overall Approach

It is important to assess the severity and impact of symptoms on the patient’s HRQOL as they guide treatment. Patients with mild symptoms (i.e., do not impact daily activities) can be managed with providing a positive diagnosis of IBS, reassurance, education, and dietary guidance. Pharmacotherapy may not be required or can be used on an as needed basis. However, patients with moderate to severe symptoms (i.e., moderate to severe impact on daily activities) will benefit from the approaches used in patients with mild disease activity but also often require pharmacological and/or psychological therapies.

Understanding the biopsychosocial model of functional GI disorders which integrates clinical experience, pathogenesis with the bidirectional influence of psychologic and physiologic factors (brain-gut/mind-body interactions), and impact and clinical outcomes helps to guide management (Figure 2).2 The biopsychosocial model provides a clinical framework for the physician to integrate the broad range of biomedical and psychosocial factors that explain the illness experience.2

A successful healthcare provider–patient relationship is the foundation of effective care of IBS patients. The quality of this relationship improves patient outcomes. Components of a therapeutic provider–patient relationship include a nonjudgmental patient-centered communication, a careful and cost-effective evaluation, inquiry into the patient’s understanding of the illness, patient education, and involvement of the patient in treatment decisions which can empower them.

As many treatments target normalization of bowel habits, treatment approaches can differ based on IBS bowel habit subtype. The Rome algorithms for IBS-C and IBS-D are shown in Figures 3 and 4, respectively. The individual treatments are described below. References to primary literature can be found in the American College of Gastroenterology (ACG) monograph32 unless cited directly.

Diet and Lifestyle Changes

The majority of IBS patients perceive that symptoms are exacerbated by meals and that they have food allergies or intolerances.33 There is more evidence that food intolerance rather than food allergies contributes to IBS symptoms. However, there is currently not strong evidence that food panels, which measure IgG levels to certain foods, predict food intolerance in IBS. A 1- to 2-week food and symptom diary can help determine consistent food triggers that can guide dietary modification and avoid eliminating more foods than necessary. Controlled trials have demonstrated that a low FODMAP diet is efficacious in reducing overall and individual symptoms of IBS. Although a low FODMAP diet was recommended by GI societies, the quality of evidence was considered very low. Although efficacy is thought to extend to all bowel habit subtypes, there appears to be more evidence to support its efficacy in patients with non-constipating IBS. Success of the low FODMAP diet is more likely if the patient works with a dietitian.

While there are studies that demonstrate a reduction in IBS symptoms with a gluten free diet, the evidence is of low quality and it is not recommended by GI societies.

Bulking agents, namely soluble fiber such as psyllium, have been shown to be efficacious in IBS. All studies were conducted in IBS, and not specifically IBS-C, and no study reported data by predominant bowel habit. However, anecdotal experience suggests that bulking agents are more effective in IBS-C than other subtypes.

Physical activity is beneficial in reducing IBS symptoms compared to usual activity.34 Improving sleep may also be helpful as poor sleep quality correlates with worse IBS-related abdominal pain, distress and HRQOL.35

Pharmacological Therapies

Pharmacologic therapies and associated doses to treat IBS symptoms are listed in Table 5.

IBS-C

Laxatives

Osmotic laxatives, such as polyethylene glycol (PEG) or magnesium-containing products, are generally safe and well tolerated and can be considered in patients with mild IBS-C. In IBS-C, PEG has been shown to relieve constipation symptoms but not abdominal pain. Other osmotic laxatives, such as lactulose and sorbitol, are frequently associated with bloating and/or cramping in IBS patients. Stimulant laxatives (senna, bisacodyl) have been studied more in chronic (functional) constipation than IBS-C. They can be used if more effective than other therapies or on an as needed basis, but may cause abdominal cramping, urgency and loose stools.

Lubiprostone

Lubiprostone is a chloride channel (ClC-2) activator increases luminal chloride secretion. In randomized controlled trials (RCTs), lubiprostone improved stool consistency, straining, abdominal pain/discomfort and constipation severity. The most common side effects of lubiprostone are nausea and diarrhea. Taking lubiprostone with food helps to decrease nausea. Lubiprostone should be considered in patients with mild to moderate symptoms of IBS-C and when pain is not a predominant and persistent symptom.

Linaclotide and Plecanatide

Linaclotide is a minimally absorbed, guanylate cyclase C (GC-C) agonist that increases luminal secretion of chloride and bicarbonate via the cystic fibrosis transmembrane conductance regulator. In multiple clinical trials conducted in IBS-C patients, linaclotide at a dose of 290 μg per day has been associated with significant improvement of abdominal pain, bloating and constipation symptoms.

Plecanatide is a similar to uroguanylin, which is a natural ligand of the GC-C receptor that acts in a pH-dependent manner. Three RCTs showed that plecanatide significantly relieved abdominal pain and constipation symptoms compared to placebo. The main side effect of both GC-C agonists was diarrhea.

Based on their efficacy profile, these medications should be a mainstay in the treatment of IBS-C, particularly in patients with moderate to severe symptoms or when pain or bloating is a predominant symptom despite improvement in bowel habits.

Tenapanor

Tenapanor is a minimally absorbed, inhibitor of the GI sodium/hydrogen exchanger isoform 3 (NHE3) that increases excretion of sodium and water in stool. Tenapanor significantly improved abdominal pain and constipation symptoms and was approved by the FDA for IBS-C in 2019. It is not yet available.

Tegaserod

Several RCTs have demonstrated the efficacy of tegaserod, a selective 5-HT4 partial agonist, in improving symptoms of IBS-C and IBS-M compared to placebo.36 Tegaserod was suspended by the FDA in 2007 because of the higher incidence of cardiovascular ischemic events in patients compared to placebo (0.11% vs 0.01%). However, in 2019, the FDA approved the reintroduction of tegaserod for treatment of IBS-C in adult female patients <65 years of age with low cardiovascular risk. Tegaserod is contraindicated in patients with a history of myocardial infarction, stroke, transient ischemic attack, angina, ischemic colitis or other forms of intestinal ischemia.

IBS-D

Loperamide

Loperamide reduces diarrhea by acting directly on the intestinal smooth muscle via the µ-opioid receptor. Two small RCTs showed that it did not have a beneficial effect on global IBS symptoms or abdominal pain but reduced stool frequency. Although antidiarrheals can be used regularly, they are more commonly used on an as-needed basis (e.g., leaving the house, a long car trip, a meal, or a stressful event).

Eluxadoline

Eluxadoline is a mixed agonist of both µ- and a κ-opioid receptors and an antagonist of δ-opioid receptors and was approved by the FDA for IBS-D in 2015. RCTs demonstrated efficacy of both doses of eluxadoline in improving overall symptoms and stool consistency, frequency, urgency. The effect on abdominal pain was not as consistent. Due to an associated increased risk of pancreatitis, contraindications of using eluxadoline include lack of a gallbladder, known or suspected biliary duct obstruction, or sphincter of Oddi disease, alcohol intake of more than 3 drinks/day, a history of pancreatitis, structural diseases of the pancreas.

Rifaximin

Rifaximin is a broad-spectrum, minimally absorbed antibiotic that is approved to treat IBS-D. It has been shown to be superior to placebo in improving global symptoms, abdominal pain, diarrhea and bloating. Symptoms can return over time following treatment (e.g. within 3-6 months), but retreatment can be prescribed with up to two additional times for recurrent symptoms. Rifaximin is generally well tolerated.

Bile Acid Sequestrants

As previously mentioned, bile acid diarrhea is part of the evaluation of suspected IBS-D. Thus, an empiric trial of bile acid sequestrant therapy, such as cholestyramine (powder) or colesevelam (tablets) can be considered and may be effective in a subset of patients.

Alosetron and Ondansetron

5-HT3 receptor antagonists can slow gut transit and reduce visceral hypersensitivity and have been shown to be efficacious in treating IBS-D symptoms compared to placebo. RCTs demonstrated that alosetron significantly improved abdominal pain, diarrheal symptoms, and urgency in IBS-D. It is currently available under a risk evaluation and mitigation strategy for women with severe IBS-D who have failed traditional treatment. This restriction is due to the occurrence of rare GI-related serious adverse events including ischemic colitis and serious complications of constipation (rate of 1.1 and 0.66 per 1000 patient years, respectively).

The 5HT3 antagonist ondansetron is approved to relieve nausea and is currently being studied in IBS-D. A relatively smaller, placebo-controlled, crossover clinical trial with 3-week treatment periods demonstrated that ondansetron (4 mg tablets that could be titrated up to 8 mg three times daily) significantly reduced diarrhea but not abdominal pain.37

Multiple Subtypes

Antispasmodics

Antispasmodics are smooth muscle relaxants and significantly improve IBS symptoms including abdominal pain compared to placebo. They are commonly used in IBS, particularly to relieve postprandial GI symptoms. Hyoscyamine and dicyclomine area most commonly prescribed for IBS in the US.

Compared to placebo, peppermint oil, a smooth muscle relaxant, overall reduces IBS symptoms. Peppermint oil is available in a small-intestinalrelease formulation, which can reduce abdominal pain, discomfort and severity of IBS symptoms.38

Probiotics

There is considerable heterogeneity among probiotic RCTs in IBS. Many studies are small or of poor quality. In general, Bifidobacteria demonstrated some efficacy in reducing overall symptoms in IBS.19 Bifidobacteria animalis subsp. lactis DN-173 010, Bifidobacterium bifidum MIMBb75 and Escherichia coli DSM17252 have been recommended for relief of bloating, distension, and overall symptoms in IBS.32

Central Neuromodulators

Centrally acting agents, such as antidepressants, have been relabeled as gut-brain neuromodulators as they work both in the brain and the gut.2 The rationale for using central neuromodulators in IBS is that they may reduce visceral perception and potentially treat coexistent psychological symptoms. Tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and to a lesser extent serotonin–norepinephrine reuptake inhibitors (SNRIs) have been studied in IBS.

TCAs can be considered first-line treatment for IBS patients with predominant pain, especially if they have IBS-D since TCAs have anticholinergic effects and can reduce diarrhea. They can be started at 10-25 mg qhs and gradually increased to the lowest, most effective and tolerated dose (e.g., up to 75 or 100 mg). Because desipramine and nortriptyline have less anticholinergic and antihistaminic side effects compared with amitriptyline and imipramine, they are favored if constipation or sedation is a concern.

Most RCTs of SSRIs in IBS have been small. While SSRIs may improve global symptoms of IBS, they are not efficacious in relieving abdominal pain. They are generally tolerated better than TCAs. However, diarrhea may be a side effect and therefore they may be more useful in patients with constipation. They should be considered in patients with significant psychologic symptoms which can amplify IBS symptoms and/or negatively impact coping of symptoms.

SNRIs, such as duloxetine has only been assessed in a small IBS study,39 but there is substantial evidence of their pain inhibitory properties. Therefore, they may be efficacious in patients with chronic abdominal pain, particularly if TCAs are not effective or well tolerated. SNRIs have been approved to treat fibromyalgia and depression, which are often coexistent in IBS and thus may be an ideal agent in these overlap patients.

Psychological Therapies

The rationale of using psychological treatment for IBS is that symptoms can be triggered by stressful life events, there is a notable coexistence with psychiatric disorders, and central-acting therapies can reduce visceral perception. Cognitive behavioral therapy, relaxation therapy, multicomponent psychological therapy, hypnotherapy, and dynamic psychotherapy have been found to be effective in IBS. There are emerging studies demonstrating similar efficacy of internet based behavioral treatment, which may be more convenient and accessible than in-person treatments.

Fecal Microbiota Transplantation (FMT)

FMT has been assessed for the treatment of IBS. A recent meta-analysis of four studies showed no benefit of FMT for global IBS symptoms,40 but another meta-analysis found a beneficial effect for FMT from donor stool delivered via colonoscopy vs autologous stool based.41 Larger and higher quality studies are needed.

CONCLUSION

IBS is a common chronic GI disorder characterized by alterations in gut-brain interaction. It is a multifactorial, complex disorder that can be conceptualized using a biopsychosocial model. There are society guidelines for the diagnostic testing and treatment efficacy and safety in IBS which can help guide management, however, a patient-centered approach that considers multiple factors that affect treatment response are recommended. These factors include patient-related factors (comorbidities, treatment preferences, insurance, etc.), provider factors (past experience, knowledge and expertise, comfort and access to certain treatments, etc.) and system level factors (practice setting, location, reimbursement, etc.). Although beyond the scope of this review, we can look forward to emerging scientific data that will help enhance our understanding of IBS pathophysiology as well as advances in drug development for IBS.

References

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  3. Palsson OS, Whitehead W, Tornblom H, et al. Prevalence of Rome IV Functional Bowel Disorders Among Adults in the United States, Canada, and the United Kingdom. Gastroenterology. 2020.
  4. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology. 2006;130(5):1480.
  5. Black CJ, Yiannakou Y, Houghton LA, Ford AC. Epidemiological, Clinical, and Psychological Characteristics of Individuals with Self-reported Irritable Bowel Syndrome Based on the Rome IV vs Rome III Criteria. Clin Gastroenterol Hepatol. 2019.
  6. Camilleri M. Sex as a biological variable in irritable bowel syndrome. Neurogastroenterol Motil. 2020:e13802.
  7. Sayuk GS, Wolf R, Chang L. Comparison of Symptoms, Healthcare Utilization, and Treatment in Diagnosed and Undiagnosed Individuals With Diarrhea-Predominant Irritable Bowel Syndrome. Am J Gastroenterol. 2017;112(6):892 El-Serag HB, Olden K, Bjorkman D. Health-related quality of life among persons with irritable bowel syndrome: a systematic review. Aliment Pharmacol Ther. 2002;16(6):1171.
  8. Talley NJ, Zinsmeister AR, Van Dyke C, Melton LJ, 3rd. Epidemiology of colonic symptoms and the irritable bowel syndrome. Gastroenterology. 1991;101(4):927.
  9. Everhart JE. Functional Intestinal Disorders. Washington, DC: US Government Printing Office: US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.; 2008. Contract No.: NIH Publication No. 09-6443.
  10. Barbara G, Grover M, Bercik P, et al. Rome Foundation Working Team Report on Post-Infection Irritable Bowel Syndrome. Gastroenterology. 2019;156(1):46.
  11. Klem F, Wadhwa A, Prokop LJ, et al. Prevalence, Risk Factors, and Outcomes of Irritable Bowel Syndrome After Infectious Enteritis: A Systematic Review and Meta-analysis. Gastroenterology. 2017;152(5):1042.
  12. Ruigomez A, Garcia Rodriguez LA, Panes J. Risk of irritable bowel syndrome after an episode of bacterial gastroenteritis in general practice: influence of comorbidities. Clin Gastroenterol Hepatol. 2007;5(4):465.
  13. Whitehead WE, Crowell MD, Robinson JC, et al. Effects of stressful life events on bowel symptoms: subjects with irritable bowel syndrome compared with subjects without bowel dysfunction. Gut. 1992;33(6):825.
  14. Parker CH, Naliboff BD, Shih W, et al. Negative Events During Adulthood are Associated With Symptom Severity and Altered Stress Response in Patients With Irritable Bowel Syndrome. Clin Gastroenterol Hepatol. 2019.
  15. Bradford K, Shih W, Videlock EJ, et al. Association between early adverse life events and irritable bowel syndrome. Clin Gastroenterol Hepatol. 2012;10(4):385.
  16. Halpert A, Dalton CB, Palsson O, et al. What patients know about irritable bowel syndrome (IBS) and what they would like to know. National Survey on Patient Educational Needs in IBS and development and validation of the Patient Educational Needs Questionnaire (PEQ). Am J Gastroenterol. 2007;102(9):1972.
  17. Kellow JE, Guest Editor in Drossman DA, Chang L, Chey WD, Kellow JE, Tack J, Whitehead WE (Eds). Rome IV Diagnostic algorithms for common GI symptoms. 2nd ed. Raleigh, NC: Rome Foundation; 2016.
  18. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidencebased position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104 Suppl 1:S1.
  19. Lin L, Chang L. Benefits and Pitfalls of Change From Rome III to Rome IV Criteria for Irritable Bowel Syndrome and Fecal Incontinence. Clin Gastroenterol Hepatol. 2019.
  20. Smalley W, Falck-Ytter C, Carrasco-Labra A, et al. AGA Clinical Practice Guidelines on the Laboratory Evaluation of Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in Adults (IBS-D). Gastroenterology. 2019;157(3):851.
  21. Spiegel BM, DeRosa VP, Gralnek IM, et al. Testing for celiac sprue in irritable bowel syndrome with predominant diarrhea: a cost-effectiveness analysis. Gastroenterology. 2004;126(7):1721.
  22. Wedlake L, A’Hern R, Russell D, et al. Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoeapredominant irritable bowel syndrome. Aliment Pharmacol Ther. 2009;30(7):707.
  23. Pimentel M, Morales W, Rezaie A, et al. Development and validation of a biomarker for diarrhea-predominant irritable bowel syndrome in human subjects. PLoS One.
    2015;10(5):e0126438.
  24. Moayyedi P, Andrews CN, MacQueen G, et al. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS). J Can Assoc Gastroenterol. 2019;2(1):6.
  25. Moayyedi P, Mearin F, Azpiroz F, et al. Irritable bowel syndrome diagnosis and management: A simplified algorithm for clinical practice. United European Gastroenterol J. 2017;5(6):773.
  26. Tolliver BA, Herrera JL, DiPalma JA. Evaluation of patients who meet clinical criteria for irritable bowel syndrome. Am J Gastroenterol. 1994;89(2):176.
  27. Rezaie A, Heimanson Z, McCallum R, Pimentel M. Lactulose Breath Testing as a Predictor of Response to Rifaximin in Patients With Irritable Bowel Syndrome With Diarrhea. Am J Gastroenterol. 2019.
  28. The National Institute for Health and Care Excellence (NICE) Surveillance report 2017 – Irritable bowel syndrome (2008) NICE guideline CG61. London2017.
  29. Henstrom M, Diekmann L, Bonfiglio F, et al. Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome. Gut. 2018;67(2):263.
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  31. Ford AC, Moayyedi P, Chey WD, et al. American College of Gastroenterology Monograph on Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2018;113(Suppl 2):1.
  32. Eswaran S, Tack J, Chey WD. Food: the forgotten factor in the irritable bowel syndrome. Gastroenterol Clin North Am. 2011;40(1):141.
  33. Zhou C, Zhao E, Li Y, et al. Exercise therapy of patients with irritable bowel syndrome: A systematic review of randomized controlled trials. Neurogastroenterol Motil. 2019;31(2):e13461.
  34. Ballou S, Alhassan E, Hon E, et al. Sleep Disturbances Are Commonly Reported Among Patients Presenting to a Gastroenterology Clinic. Dig Dis Sci. 2018;63(11):2983.
  35. Chey WD, Pare P, Viegas A, et al. Tegaserod for female patients suffering from IBS with mixed bowel habits or constipation: a randomized controlled trial. Am J Gastroenterol. 2008;103(5):1217.
  36. Garsed K, Chernova J, Hastings M, et al. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014;63(10):1617.
  37. Weerts Z, Masclee AAM, Witteman BJM, et al. Efficacy and Safety of Peppermint Oil in a Randomized, DoubleBlind Trial of Patients With Irritable Bowel Syndrome. Gastroenterology. 2020;158(1):123.
  38. Brennan BP, Fogarty KV, Roberts JL, et al. Duloxetine in the treatment of irritable bowel syndrome: an open-label pilot study. Hum Psychopharmacol. 2009;24(5):423.
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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #202

Clostridioides difficile Infection: Is There a Role for Diet and Probiotics?

September 2020 • Volume XLIV, Issue 9
Christopher Ward,Colleen R. Kelly

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Clostridioides difficile is a spore forming bacterium leading to significant morbidity and mortality amongst hospitalized as well as non-hospitalized patients in the United States. While hospital acquired infections have reduced, in recent years we have seen an increase in community acquired infections. With the focus on antimicrobial therapies and fecal microbiota transplantation, it is important to understand the evidence behind probiotics and nutrition in the management of C. difficile infections. There is an abundance of new literature regarding the $40 billion a year probiotic industry, meanwhile patients require dietary advice following an infection. In this review, we aim to give the non-specialty clinician some clarity regarding these issues.

INTRODUCTION

Clostridioides difficile is an anaerobic, gram positive, spore forming bacterium that causes a spectrum of gastrointestinal symptoms ranging from mild diarrhea to colitis, toxic megacolon, intestinal perforation, and death. It is spread via the fecal-oral route and is frequently encountered in hospitals, affecting 1% of US hospital stays1 and nursing homes where antibiotic use is common. Concerningly, community-acquired infections are common, and recent research suggests other undefined causes of CDI, as many cases occur without a history of antibiotic use.2 There was a significant increase in CDI between 2000-2010, which has been attributed to increased detection with use of nucleic acid amplification testing, more virulent strains, and increased community antibiotic use. Since then, we have seen a reduction in healthcare associated CDI, though there are still almost half a million cases per year within the United States.3 Infection control measures, decreased fluroquinolone use, and improved antibiotic stewardship have been credited with these results.4

In recent years there has been an abundance of new literature on C. difficile with regards to management and prevention options. For the nonspecialty clinician, it is challenging to determine which data is high quality and what can be applied to their patients. With the spotlight on fecal microbiotatransplantation (FMT) and other non-antibiotic therapies for CDI, it is understandable that both clinicians and patients are seeking preventative options such as probiotics and nutrition. Here we evaluate the current evidence for these therapies in the prevention of CDI.

Probiotics

Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.5 The literal translation is “for-life”, which conveys that they are good, natural, and beneficial to biological functions. Proposed mechanisms for beneficial effects include modification of the gut microbiota, competitive adherence to the mucosa and epithelium, strengthening of the gut epithelial barrier, and modulation of the immune system to convey an advantage to the host.6 Probiotics are marketed as dietary supplements with colourful labels and vague claims of “friendly bacteria” to “improve gut health.” This 40 billion dollar a year industry,7 while extremely appealing to patients and healthcare professionals, operates without the strict oversight by the U.S. Food and Drug Administration that is required of drugs. A quick internet search reveals a plethora of websites recommending various probiotics as a means to improve one’s health for various indications, including after CDI. A 2010 survey of gastroenterologists found that 98% of respondents believed probiotics have a role in treating gastrointestinal illnesses or symptoms, despite the paucity of data to support their use. Sixty percent believed that the literature supported the use of probiotics in the treatment of CDI.8 Due to the lack of regulation and freedom to make general health claims on product labels, there is little incentive for manufacturers to conduct clinical trials to support specific indications for their products.9

The trouble with many of the available products is that quality control is often sub-optimal with inconsistencies and deviations from the information provided on the product label including misidentified, misclassified or non-viable strains, contaminated products, or diminished functional properties.10 The belief that probiotics “can’t hurt” has been challenged by case reports of bloodstream infections with probiotic organisms in critically ill patients leading to the recommendation that they be used with caution in immunocompromised patients and those with structural heart disease or central venous catheters.11 Microbiome analyses have shown that they may actually impede normal recolonization in the gut after a course of antibiotics.12 Despite this, probiotics are widely recommended by physicians to prevent CDI in patients being treated with antibiotics (primary prevention) or in patients being treated for CDI to prevent recurrences (secondary prevention). Costs range from $30 to $100 per month for the most commonly recommended formulations, which are frequently taken for extended courses and typically not covered by insurance. Given these costs, the desire to provide reliable health information to our patients, and the potential for harm, it is important to critically appraise data supporting the use of probiotics in CDI.

Evidence to support probiotics in the management of CDI comes mainly from meta analyses, which pool data from smaller trials of variable probiotic formulations and methodologies. There is a paucity of high-quality clinical trial data of probiotics in CDI, and most studies are underpowered, with CDI as a secondary outcome in studies done to assess prevention of antibiotic associated diarrhea (AAD). A 2016 global review of guidelines, strategies, and recommendations for CDI prevention4 labelled probiotics as an area of research, but were unable to recommend their use. There is currently insufficient evidence to recommend any probiotic for the primary or secondary prevention of CDI.

The Literature

The PLACIDE trial is the largest double-blind clinical primary prevention randomized controlled trial (RCT) to date.13 This multicenter trial in the United Kingdom enrolled nearly 3000 elderly inpatients who were at high risk of contracting CDI. Patients >65 years old receiving antibiotics were randomized to treatment with a multi-strain preparation composed of bifidobacterium and Lactobacillus acidophillus strains or placebo for 21 days. AAD including CDI occurred in 10·8% of the microbial preparation group and 10·4% of those treated with placebo. CDI was an uncommon cause of AAD and occurred in just 0·8% of the microbial preparation group and 1·2% of the placebo group. The authors concluded that probiotics were of no benefit in prevention of AAD or CDI.

Many nutritional websites and magazines broadly claim “high quality evidence” for probiotics in CDI, most citing the Cochrane Review in 2017 by Golbenberg et al, which looked at probiotics for primary prevention of CDI in adults and children, enrolling 8672 participants.14 It is important to highlight that 27 of the 31 studies analysed were felt to be of unclear or high risk of bias and more than half had missing data. The incidence of CDI was 1.5% in the treatment group and 4% in the control groups, a 60% risk reduction. They concluded a modest benefit of probiotics (number needed to benefit=42). However, in posthoc subgroup analysis these benefits only held up in trials enrolling participants with baseline CDI risk >5%, which is higher than the average risk in American hospitals and therefore has questionable clinical application. The conclusions of this Cochrane review have been criticized as misleading, in that only 4/31 trials showed benefits and small, poorly controlled studies had too much influence.9 Results were heavily influenced by 5 studies with CDI baseline risk >15%, far above that seen in any hospital setting in the world, raising important questions of the external validity. Major limitations of this meta-analysis were that included studies used many differing probiotic combinations and dosages, multiple trials were small/underpowered, single center, missing data, participants lost to follow up, and in some cases, no fecal samples were obtained.

An earlier Cochrane review of probiotics for treatment of CDI, which included four studies, concluded that there is insufficient evidence to support their use.15 Published in 2017, the PICO trial randomized 33 patients with an initial mild to moderate CDI to 28 days of a four-strain probiotic or placebo in addition to anti-CDI therapy and showed no difference in rates of CDI recurrence.16

In light of all this evidence and despite what product labels and websites will claim, probiotic prophylaxis for CDI prevention is not recommended by the American College of Gastroenterology,17 the Association for Professionals in Infection Control and Epidemiology.18 or the European Society of Clinical Microbiology and Infectious Diseases.19

Saccharomyces Boulardii
Hope for Recurrent CDI?

There were several publications in the 1990s involving Saccharomyces boulardii that showed promise regarding CDI secondary prevention.20 S. boulardii is a yeast that grows on lychee fruit. It was discovered by a French pharmacist who observed South-East Asian natives chewing the skins of the fruit to lessen the symptoms of cholera. It produces a protease that inactivates the receptor site for C. difficile toxin A, lending biologic plausibility to its use in CDI.21

A 1994 multicenter RCT showed decreased CDI recurrence in patients treated with S. boulardii in addition to either metronidazole or vancomycin in those who had already suffered a recurrence (34.6% with S. boulardii vs 64.7% with placebo).22 There was no benefit over placebo in patients with primary infection. A follow up study published in 2000 enrolled 168 recurrent CDI patients who were treated with a 28 day course of S. boulardii or placebo in addition to anti-CDI therapy.23 The benefits in this study were limited to the subgroup who were treated with high-dose vancomycin and S. boulardii (16.7% recurrence vs. 50% with placebo). Those who received low dose vancomycin or metronidazole had similar rates of recurrence whether they were treated with the probiotic or placebo. The study was small, with n=32 in the high-dose vancomycin group, hence, no firm conclusions can be drawn. Unfortunately, a larger planned trial was never conducted and the benefits of S. boulardii for secondary prevention remain unknown.

Dietary Probiotics

Following a CDI, many patients seek dietary advice to prevent recurrence. This is another area without robust evidence to guide us. Dietary sources of probiotics include fermented milk products (such as yogurt, kefir, and buttermilk), fermented vegetables (such as kimchi and sauerkraut), and fermented soy products (such as miso and tempeh). There have been several studies looking into the use of yogurt in prevention of AAD, but not CDI. In 2003, one center randomized 202 elderly hospitalized patients receiving antibiotics to receive 16 ounces of yogurt per day for a week. The control group received no yogurt. The yogurt group reported less antibiotic associated diarrhea (12% vs 24%, p=0.04) and less diarrhea days (23 vs 60 days). The role of dietary probiotics in CDI is unclear and it is important to note that following CDI patients may have lactose intolerance and post-infectious irritable bowel syndrome,24 so consumption of yogurt for that purpose may lead to worsening gastrointestinal (GI) upset.25

Nutritional Tips Following CDI

In the immediate recovery period from CDI, patients are at increased risk for postinfectious irritable bowel syndrome (IBS) and ongoing diarrhea and therefore should consider following general advice that is given to other patients with IBS. There is however a lack of evidence for any of the following nutritional recommendations in the setting of CDI and further studies are required. Patients with post infectious IBS may have associated lactose intolerance; therefore, we advise avoiding high lactose containing foods, in particular milk and other high lactose containing milk products for 2-4 weeks.24 Additionally, greasy foods, spicy foods,26 and excessive caffeine intake27 are often reported to cause GI distress and should be avoided at least in the short-term following CDI.

Microbiome

In recent years there has also been rapidly growing interest in the human gut microbiome in facilitating health benefits and its role in many diseases.28 No longer the “forgotten organ”29, the function of the microbiome is now being extensively investigated. Encompassing 1014 microorganisms, including bacteria, viruses, fungi, and protozoa;30 both human and animal models have shown the importance of the microbiome in resistance against CDI.31 Disruption of the microbiome is at the core of the pathogenesis,32 though we have yet to identify which specific microbes are responsible. Given the importance of the microbiome in the development of CDI, there are select diets that may improve or diversify the microbiome and alter one’s chance of developing an infection.

Select Diets

Several studies have shown the consumption of a Western diet, consisting of high animal protein and fat with low fiber has resulted in reduced diversity overall and specifically lower amounts of Bifidobacterium and Eubacterium.33-34 Consumption of a gluten free diet may lead to reduced diversity and increased pathogenic bacteria.35-36 A vegan or plant-based diet appears to promote microbiome diversity.37-38 From this it might be inferred that a Western or gluten free diet may be associated with increased CDI, meanwhile vegan or plant-based diets may be protective against the development of CDI. Further studies are needed before making recommendations on this.

Fiber

Dietary fiber is found in beans, grains, vegetables, and fruits. Most fiber is not absorbed, remaining in the gut where it improves the consistency of the stool.39 There are no human studies relating fiber intake to CDI, however animal studies have shown that a diet high in soluble fiber can help eliminate CDI quicker than diets high in insoluble fiber.40-42 The recommended amount of dietary fiber is 25g per day for moderately active Americans.43 Most individuals are unable to obtain this goal with diet alone. Fiber supplements may be recommended to meet this goal and there is evidence to support benefits in various GI conditions, including IBS,39 constipation,44 and post infectious GI symptoms,45 such as after CDI. We recommend products containing psyllium, a plant-based fiber, which absorbs liquid and provides bulk to the stool for our CDI patients. We suggest starting with 1 sachet in the evening to avoid side effects such as daytime gassiness that may occur when taken in the morning. Dose can be titrated to effect.

Sugar Alcohols

Sugar alcohols or polyols such as mannitol and sorbitol are found naturally in many foods such as pineapples, sweet potatoes, and carrots, but are also found in many processed foods and liquid medications. While some mouse studies have suggested that an increase in gut polyols is associated with increased susceptibility to CDI,46 there is no evidence in humans that increased dietary sugar alcohol intake is associated with CDI.

Food Additives

Research is well underway regarding artificial sweeteners and their alteration of the gut microbiome. Saccharin and sucralose have been shown to shift populations of microbiota.47 One study in Nature by Collins et al found that the hypervirulent strain ribotype 027 is able to grow on low concentrations of trehalose, a naturally occurring sugar that the food industry began using to improve texture and stability of products in the early 21st century, around the time that CDI rates skyrocketed.48 Trehalose is found naturally in small amounts in mushrooms and shrimp, however significantly higher amounts are added by the food industry to dried and frozen foods including ice cream and frozen vegetables as well as instant noodles, soups, and many baked goods. People who do not tolerate mushrooms may lack the enzyme trehalase and suffer GI symptoms with other trehalose containing foods.49 Any possible link between this and CDI is unclear. See Table 1 for summary of the evidence for probiotics or diet.

CONCLUSIONS

The treatment and recovery from CDI is multifaceted. There is currently no evidence that probiotics reduce the incidence or recurrence of CDI. They are an enormously lucrative market with little regulation or incentive for drug companies to perform the trials that could potentially lead to progress in this area. Disruption of the microbiome is at the core of the pathogenesis of this disease. Increasing the diversity of one’s microbiome can be achieved through consuming a plant-based diet with increased dietary fiber, however the link between these interventions and a reduction in CDI is yet to be made. There is much hope that altering the microbiome, through diet and/or use of probiotics will become frontline in the treatment and recovery from Clostridioides difficile infection, however further research is required.

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  36. Bonder MJ, Tigchelaar EF, Cai X et al. The infuence of a short-term gluten-free diet on the human gut micro biome. Genome Med. 2016;8:45.
  37. Tomova A, Bukovsky I, Rembert E, et al. The Effects of Vegetarian and Vegan Diets on Gut Microbiota. Front Nutr. 2019;6:47. Published 2019 Apr 17. 38. Wong MW, Yi CH, Liu TT et al. . Impact of vegan diets on gut microbiota: an update on the clinical implications. Tzu Chi Med J. (2018) 30:200–3. 10.4103/tcmj.tcmj_21_18
  38. Yang J, Wang HP, Zhou et al. Effect of dietary fiber on constipation: a meta analysis. World J Gastroenterol. 2012;18(48):7378-7383.
  39. Ward PB, Young GP. Dynamics of Clostridium difficile infection. Control using diet. Adv Exp Med Biol. 1997;412:63-75
  40. May T, Mackie RI, Fahey GC et al. Effect of fiber source on short-chain fatty acid production and on the growth and toxin production by Clostridium difficile. Scand J Gastroenterol. 1994;29(10):916-922.
  41. Frankel WL, Choi DM, Zhang W, et al. Soy fiber delays disease onset and prolongs survival in experimental Clostridium difficile ileocecitis. JPEN J Parenter Enteral Nutr. 1994;18(1):55-61..
  42. U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015 – 2020 Dietary Guidelines for Americans. 8th Edition. December 2015.
  43. El-Salhy M, Ystad SO, Mazzawi T et al. Dietary fiber in irritable bowel syndrome (Review). Int J Mol Med. 2017;40(3):607-613.
  44. Iacob T, Ţăţulescu DF, Dumitraşcu DL. Therapy of the postinfectious irritable bowel syndrome: an update. Clujul Med. 2017;90(2):133-138.
  45. Theriot CM, Koenigsknecht MJ, Carlson PE Jr, et al. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat Commun. 2014;5:3114
  46. Ruiz-Ojeda FJ, Plaza-Díaz J, Sáez-Lara MJ et al. Effects of Sweeteners on the Gut Microbiota: A Review of Experimental Studies and Clinical Trials [published correction appears in Adv Nutr. 2020 Mar 1;11(2):468]. Adv Nutr. 2019;10(suppl_1):S31-S48.
  47. Collins, J., Robinson, C., Danhof, H. et al. Dietary trehalose enhances virulence of epidemic Clostridium difficile. Nature 553, 291–294 (2018).
  48. Arola H, Koivula T, Karvonen AL et al.Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms. Scand J Gastroenterol. 1999;34(9):898-903.

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FRONTIERS IN ENDOSCOPY, SERIES #65

Endoscopic Ultrasound Guided Celiac Plexus Block and Neurolysis in the Treatment of Pancreatic Pain

September 2020 • Volume XLIV, Issue 9
Deema Sallout,Douglas G. Adler

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INTRODUCTION

Pancreatic diseases are considered to be among the most challenging when it comes to pain control and management. Treatment options can vary remarkably based on the underlying disease process, whether benign or malignant, acute or chronic, and patients frequently require a significant amount of opiates for pain control. Commonly employed methods for pain control include celiac plexus block (CPB) and celiac plexus neurolysis (CPN). Conventionally, these were achieved through a percutaneous approach; however, the endoscopic ultrasound (EUS) approach is increasingly being utilized in current practice. Numerous methods and approaches have been recognized and described in literature, with the efficacy and safety profiles of these procedures being the main topics of controversy. This article will review EUS-guided CPB and CPN, including indication, methods, and treatment outcomes.

BACKGROUND

Anatomy

The celiac plexus consists of a right and left ganglion that lie anterolateral to the aorta at the level of the celiac trunk, the first main vessel to branch off of the aorta below the diaphragm. The crura of the diaphragm lies posterior to the plexus; the kidneys, adrenals, and inferior vena cava are found laterally, and the pancreas overlies the celiac plexus anteriorly.1 The celiac plexus is predominantly innervated by sympathetic fibers that transmit both afferent and efferent signals from all upper abdominal viscera including the pancreas, liver, gallbladder, stomach, and the ascending and transverse colon.2 The celiac plexus receives splanchnic nerves from T5 through T12, which connect at the celiac plexus and pass through the crus of the diaphragm onto the spinal cord.3,4

Celiac Plexus Block (CPB)

CPB typically involves injection of a local anesthetic and a long-acting steroid into or around the celiac plexus. This process usually results in interruption of neuronal transmission from the celiac plexus, and therefore provides pain relief. The relief provided, however, is temporary, usually only lasting weeks to months, with 3 months being a typical duration of effect. Patients with chronic pain usually require repeated procedures if their pain responds to the initial injection.5 If a patient does not respond to an initial block it can be repeated to see if a second block is beneficial before abandoning further blocks.6

Celiac Plexus Neurolysis (CPN)

CPN involves injection of a neurolytic agent, typically absolute or dehydrated alcohol, into or around the celiac plexus, causing destruction of the ganglia. Bupivacaine is typically injected prior to the alcohol in order to provide analgesia, as the alcohol injection can be painful otherwise. CPN causes permanent nerve damage in an attempt to provide long-lasting pain relief. CPN is commonly reserved for patients with advanced inoperable pancreatic cancer or other intraabdominal malignancies.

Indications

Indications for CPB include management of pain associated with chronic pancreatitis. CPN, however, is usually utilized in the treatment of patients with advanced pancreatic cancer-associated pain.7

Methods

The principle underlying celiac plexus block (CPB), and celiac plexus neurolysis (CPN) is reducing or even eliminating transmission of pain signals from visceral afferent nerves of the celiac plexus. This is accomplished via injection of agents that reduces the intensity of, or disrupts, signal transmission. CPB and CPN have both been used in the management of pancreatic pain since the technique was first described by Kappis in 1914.3 CPB and CPN can be performed either intraoperatively or via fluoroscopic, ultrasound, or computed tomography-guidance.8 Endoscopic ultrasound-guided CPB/CPN was first reported in 1996 and is now widely performed.9 There are currently multiple approaches in current practice regarding EUS-CPB/CPN. All are performed with a linear echoendoscope (the radial echoendoscope does not properly visualize the ganglia in many cases and cannot perform therapeutic maneuvers). (Figure 1) The classic approach, known as the central technique, involves injection of the therapeutic agents into the potential space just anterior to the origin of the celiac artery (CA) itself. In another approach, the bilateral technique, involves injection of the therapeutic agents bilaterally with regards to the original of the CA.10 Intraneuronal and perineuronal variations exists as well, as do socalled “extended” blocks that inject agents along the length of the aorta down to, and sometimes beyond, the origin of the superior mesenteric artery (SMA).11 It should be noted that, in practice, some CPN or CPB procedures do not fit squarely into the techniques described below given local anatomy and vasculature.

Central Celiac Plexus
Block/Neurolysis Technique

An EUS FNA needle or a dedicated celiac plexus needle is advanced, under direct ultrasound guidance and with Doppler ultrasound, towards the origin of the celiac artery. The injectate is then delivered as a bolus into the potential space just anterior and superior to the origin of the CA.12 (Figures 2 and 3)

Bilateral Celiac Plexus
Block/Neurolysis Technique

The bilateral approach involves advancing an EUS FNA needle, or a dedicated celiac plexus needle, into the regions on both sides of the celiac artery and performing injections in these locations in an attempt to reach more nerve branches of the celiac ganglia. The bilateral approach can also be used if the central technique is not feasible due to local anatomy or interposed vasculature.13

Celiac Ganglia Neurolysis

Another possible approach is direct injection of the agent into the celiac ganglia, known as Celiac ganglia neurolysis (CGN). EUS-CGN was first described by Levy et al.27 in 2008. It involves identifying the celiac ganglia between the aorta and left adrenal gland on EUS, and injecting absolute alcohol directly into the ganglia until it becomes hyperechoic and no longer identifiable.10 The initial trial in 2008 concluded that direct injection into the celiac ganglia was more effective and achieved higher rates of pain relief. Multiple studies following the initial trial also concluded that the direct ganglia injections were more effective in reducing pain when compared to the classic approaches.27-29 Other studies, however, such as the 2008 trial by Adler et al. revealed no difference in efficacy in intraneuronal injections when compared to perineuronal injections. Whether there is a true difference in outcomes when comparing direct injections to the classic approach remains controversial.

Results

Efficacy

CPN for Treatment of Pancreatic Cancer Pain

A meta-analysis conducted in 2010 by Kaufman et al.14 showed that EUS-CPN is effective at controlling pain in patients with pancreatic cancer in 73% of cases. There were 2 studies, however, that reported no significant change in narcotic usage after the procedure.

Additionally, Catalano et al.15 concluded that the location of the cancer plays a role in the responsiveness to treatment. It was observed that patients with pancreatic cancers in the body or tail were more likely to respond to CPN, as opposed to patients with cancers in head of the pancreas.14

Another prospective randomized study by Ischia et al.16 observed that the efficacy of CPN and the degree of pain relief were significantly impacted by the stage of the underlying cancer.17 It should be noted, however, that CPN rarely provides patients with absolute pain relief. The more common outcome is for patients to experience a reduction in their opiate consumption, rather than elimination of pain.17

CPB for Pancreatitis and Benign Diseases

A prospective randomized trial conducted by Leblanc et al. in 200918 found that CPB for chronic pancreatitis pain was effective in about 60% of cases. Effectiveness was measured as reduction of pain to less than 50% of the patient’s baseline pain score, with the average effect lasting about 3 months.7 Other studies such as a retrospective study by Sey et al.19 reported efficacy rates as high as 78%, which the authors defined as subjective pain relief. A significant consideration is that the response observed following the initial procedure is predictive of the efficacy of repeated procedures to follow.19 Therein, the Leblanc study there was no difference between the central and the bilateral approach when applied to patients with chronic pancreatitis.18 Conversely, a study conducted by Sahai et al.12 concluded that the short term response initially was superior when the bilateral technique is performed. This superiority was thought to be due to the fact that the bilateral approach allows more medication to be injected and, therefore, potentially have a more rapid onset of action. Long term response, however, was not measured. One adverse event reported was trauma to the adrenal artery, and resulted in a self-limited bleed. This consequently led to the preference for the central technique on the part of these authors for patients with a bleeding diathesis.12

Adverse Events

EUS-CPB and EUS-CPN are considered to be safe procedures. A large case series conducted by O’Toole et al. showed that the overall complication rate for EUS-CPN was 3.2%, with no major complications.20 EUS-CPB had a 1.6% overall complication rate, with a major complication rate of 0.5%. Major complications were defined as bleeding events, perforations, neurologic sequelae, or deaths. Minor complications that were generally reported included temporary increase in pain, oxygen desaturation, anesthetic induced hypotension, and most commonly, diarrhea. Of note, the study conducted by O’Toole20 also revealed that rates of minor complications observed by the EUS approach were lower when compared to the percutaneous approach. The lower rate of complications, along with the ease of use may be why the EUS approach has been largely replacing the percutaneous approach.

For instance, paraplegia is a catastrophic complication that has been reported following the percutaneous approach to CPN, due to neurolytic agents tracking into the spinal cord. This adverse event was thought to be non-existent in the EUS approach. Nevertheless, a case report by Koker et al.21 described a patient that suffered from spinal cord ischemia following EUS-CPN using the bilateral injection technique, resulting in permanent paraplegia. This procedure was performed on a patient with advanced poorly differentiated ductal adenocarcinoma, and the extensive local invasion made identification of the injection sites difficult. Conversely, a 2013 literature review by Alvarez-Sanchez et al.22 reported 4 cases of retroperitoneal abscesses, and 3 cases of empyema that occurred after EUS-CPB. A brain abscess managed with IV antibiotics and antifungals in an immunocompromised host was the only infectious complication observed after EUS-CPN.22

Discussion

EUS approaches to CPB and CPN were first introduced in 1996 and were described as a safer alternative to the percutaneous approach. This is attributed to multiple factors, one of which is that the EUS method allows access to the celiac plexus from a direction that is anterior to the plexus itself, which minimizes the risk of trauma to spinal nerves and vasculature. In addition to the less invasive approach, the utilization of a doppler US for the procedure causes a significant reduction in injury rates to nearby vascular structures. In percutaneous CPN procedures, serious complications occurred in 1-2% of cases. The serious complications observed included paraplegia, paresthesia, aortic dissection, and pneumothorax.2,6,9,23,24 Nevertheless, most studies concluded that major complications occurring after EUS-CPB or CPN were extremely rare, and the complications observed were usually minor and self-limited such as diarrhea and transient hypotension.8,17 Another factor to consider is that the EUS approach allows for a more cost effective management, as it provides the endoscopist the opportunity to perform the procedure at the time of biopsy, staging or during other procedures such as endoscopic retrograde cholangiopancreatography (ERCP).6,17

The efficacy of both procedures was reported to be similar in terms of outcomes and pain relief in most studies.6,17,25 Some studies, such as the literature review by Sachdev, even reported higher efficacy rates in the EUS approach.7 Nonetheless, given the fact that the EUS approach has a significantly higher safety profile, and the fact that it may be more cost effective, the EUS approach has gained increased popularity in clinical practice.

Although several studies have shown CGN to be more efficacious at achieving pain relief as opposed to CPN, a randomized controlled trial (RCT) conducted by Fujii-Lau et al.26 observed that patients who underwent CGN had a shorter survival rate when compared to cases that underwent CPN. However, whether these findings were related to the technique of the procedure performed versus the natural progression and extent of the underlying disease remains controversial and will ultimately need more trials to reach a more accurate conclusion.

CONCLUSION

In conclusion, the EUS approaches to CPB and CPN are in widespread use. Most studies have concluded that it is a safe procedure with a relatively low risk of major complications when compared to the classic percutaneous approach. Most of the complications observed after EUS procedures were minor and self-limited. Several different EUS approaches have been introduced into clinical practice, and the various studies conducted have yielded similar results when it comes to efficacy and safety profile. Further trials performed on a larger scale are needed to adequately demonstrate the procedure’s efficacy and to compare the efficacy between various approaches, and at this time no specific method of performing EUS CPB or CPN has been shown to be ideal.

References

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  26. Fujii-Lau LL, Bamlet WR, Eldrige JS, et al. Impact of celiac neurolysis on survival in patients with pancreatic cancer. Gastrointest Endosc. 2015;82(1):46-56.e42.
  27. Levy MJ, Topazian MD, Wiersema MJ, et al. Initial evaluation of the efficacy and safety of endoscopic ultrasound-guided direct Ganglia neurolysis and block. Am J Gastroenterol. 2008;103(1):98-103.
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  29. Doi S, Yasuda I, Kawakami H, et al. Endoscopic ultrasoundguided celiac ganglia neurolysis vs. celiac plexus neurolysis: a randomized multicenter trial. Endoscopy. 2013;45(5):362- 369.
  30. Arcidiacono PG, Calori G, Carrara S, McNicol ED, Testoni PA. Celiac plexus block for pancreatic cancer pain in adults. Cochrane Database Syst Rev. 2011(3):CD007519.
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  37. Gress F, Schmitt C, Sherman S, Ciaccia D, Ikenberry S, Lehman G. Endoscopic ultrasound-guided celiac plexus block for managing abdominal pain associated with chronic pancreatitis: a prospective single center experience. Am J Gastroenterol. 2001;96(2):409-416.
  38. Ishiwatari H, Hayashi T, Yoshida M, et al. EUS-guided celiac plexus neurolysis by using highly viscous phenolglycerol as a neurolytic agent (with video). Gastrointest Endosc. 2015;81(2):479-483.
  39. Kapural L, Lee N, Badhey H, McRoberts WP, Jolly S. Splanchnic block at T11 provides a longer relief than celiac plexus block from nonmalignant, chronic abdominal pain. Pain Manag. 2019;9(2):115-121.
  40. LeBlanc JK, Al-Haddad M, McHenry L, et al. A prospective, randomized study of EUS-guided celiac plexus neurolysis for pancreatic cancer: one injection or two? Gastrointest Endosc. 2011;74(6):1300-1307.
  41. Loeve US, Mortensen MB. Lethal necrosis and perforation of the stomach and the aorta after multiple EUS-guided celiac plexus neurolysis procedures in a patient with chronic pancreatitis. Gastrointest Endosc. 2013;77(1):151-152.
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FROM THE PEDIATRIC LITERATURE

Early Feeding in Acute Pancreatitis

October 2020 • Volume XLIV, Issue 10

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Although acute pancreatitis (AP) in children typically is caused by different etiologies compared to adults, it still can be associated with severe disease complications, including the risk of mortality. There is evidence in the adult medical literature that early feeding in AP is safe and beneficial; however, no similar studies have been done in children. The authors of this study (from 3 tertiary children’s hospitals in Australia and Israel) performed a randomized, controlled trial over 13 years looking at the efficacy and safety of early feeding for children with AP. AP was defined as consisting of abdominal pain consistent with AP, serum amylase and/or lipase ≥ 3 times the upper limit of normal, and abdominal imaging demonstrating AP. Patients with AP associated with organ failure or AP due to biliary obstruction, autoimmune pancreatitis, or trauma were excluded from the study. These pediatric patients were prospectively divided into 2 groups: 1) patients with AP who were fed a low-fat diet only when their abdominal pain resolved (while kept on IV fluid initially), when their amylase and/or lipase levels declined, or per the discretion of the providing physician and 2) patients with AP who were given an unrestricted diet as soon as possible (less than 24 hours after presentation). Patients in the unrestricted diet group were given nasogastric or nasojejunal tube feeds if they could not eat orally in less than 24 hours. All patients underwent chart review as well as twice daily Wong-Baker Faces Pain Rating Scale scoring. Additionally, all patients were monitored in terms of analgesic use, weight, daily caloric intake, and estimated energy requirement (EER). The primary outcome of the study was time to hospital discharge based on no pain noted on the pain scale, no analgesic use, and the patient being able to reach 75–100% of EER.

In total, 33 children between 2 and 18 years of age were recruited into the study for which 15 patients (45%) were in the initial fasting group and 18 patients (55%) were in the early feeding group. No difference existed between the two groups in regards to age, weight, serum amylase and lipase levels, and pain scores at presentation. The median time to starting feeds was significantly shorter in the early feeding group (19.3 hours) compared to the fasting group (34.7 hours). Additionally, there was an earlier ability of the early feeding group to reach at least 50% of and greater than 75% of EER although the difference was not significant. Only one patient in the early feeding group required partial use of nasogastric feeds initially and no patients in either group required long term nasogastric or nasojejunal feeds. Both groups were similar in regards to the time required before being pain free, weight throughout hospital admission, and final amylase and/or lipase levels. Of note, two patients in the initial fasting group were readmitted to the hospital for AP, and only one patient in the early feeding group was re-admitted to the hospital for diarrhea not related to AP. At follow up (median of 49 days), patients in the early feeding group had a significantly higher weight compared to the early fasting group which had a median loss of weight.

This study demonstrates that early feeding in uncomplicated pediatric AP is safe and effective and may have better long-term outcomes in regards to weight after hospital discharge. An early feeding regimen also requires less intervention and may reduce unnecessary healthcare costs.

Ledder O, Duvoisin G, Lekar M, Lopez R, Singh H, Dehlsen K, Lev-Tzion R, Orlanski-Meyer E, Shteyer E, Krisnan U, Gupta N, Lemberg D, Cohen S, Ooi C. Early feeding in acute pancreatitis in children: a randomized controlled trial. Pediatrics 2020; 146(3): e20201149.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #201

Wilson’s Disease: The Copper Connection

August 2020 • Volume XLIV, Issue 8
Brian J. Wentworth,Matthew Stotts

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Wilson’s disease is a rare genetic disorder in which an inborn error of copper metabolism leads to excess copper accumulation in body tissues and significant organ dysfunction. While long-term prognosis is good in effectively treated patients, its diagnosis and management can be challenging given difficulties interpreting diagnostic testing, issues with medication tolerance and adherence, and restrictive dietary practices. In this setting, patients and clinicians must balance strategies to prevent excessive copper accumulation with ensuring minimal sacrifices to patients’ quality of life. This review aims to provide clinicians with a deeper understanding of human copper absorption and metabolism and a practical approach to preventing excess copper accumulation in these individuals.

INTRODUCTION

Wilson’s disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive condition first described by Dr. Samuel Alexander Kinnier Wilson in 1912 who noticed a familial clustering of liver disease and neuropsychiatric symptoms. However, it was not until the mid-20th century that the centrality of excessive copper accumulation and effective treatments were discovered.1,2 In 1993, our understanding of the disease was revolutionized with identification of mutations in the ATP7B gene.3,4

Although WD is rare, with a worldwide prevalence of 10 to 30 per 1 million, approximately 1 in 90 people are carriers of pathogenic ATP7B variants.3,5,6 Hundreds of specific mutations in this gene have been identified, meaning most affected patients with WD are compound heterozygotes with varying combinations of mutations.7,8 Given this genetic diversity, as well as more recent evidence pointing to epigenetic factors, clinical presentations of WD are inhomogenous.9

Pathophysiology

Copper is a trace element essential to normal human homeostatic functioning. It has a myriad of roles, including acting as a cofactor for numerous enzymes and helping maintain pigmentation, collagen cross-linking, red blood cell formation, iron absorption, and immune system function.10,11

However, in excess, copper can be toxic. An intricate transport system exists within the body to regulate serum levels.7 The ATP7B gene, located on chromosome 13, encodes a metal-transporting P-type adenosine triphosphate (ATPase). This ATPase is expressed primarily in hepatocytes and facilitates transmembrane transport of copper into bile. In addition, deficient ATP7B leads to a failure to incorporate copper into apoceruloplasmin, leading to the characteristic low serum levels of ceruloplasmin seen in WD.3

When mutated, the resulting absence or reduction in ATPase protein production leads to poor excretion of copper into bile. Urinary copper excretion increases in an attempt to compensate, but is less efficient than typical biliary efflux.7 Therefore, excess copper accumulates in hepatocytes, causing injury and eventual leakage of copper into the bloodstream, where it can deposit in downstream organs such as the brain, kidneys, and cornea (Figure 1).

Clinical Manifestations

The plethora of variant ATP7B alleles lead to varied presentations (Table 1).5,7 As an inborn error of metabolism, WD may present de novo in either the pediatric or adult population.

Hepatic

In the pediatric population, WD is rarely symptomatic before age five.7 Nonetheless, it must be considered in the differential diagnosis of asymptomatic patients older than a year with elevated aminotransferase levels.12 The latter is the most common presenting feature, however other hepatic manifestations of WD include acute hepatitis, hepatomegaly, cirrhosis (including portal hypertensive-related decompensations), and acute liver failure (ALF).

Neuropsychiatric

Neuropsychiatric manifestations are uncommon before age ten, typically occurring in the second to third decades of life with an average age of onset around 19 years. However, latent onset (up to age 72) has been described.7 Subtle signs may include declining academic performance, micrographia, or behavioral changes, with more overt presentations including depression, Parkinson’s-like symptoms, dysarthria, and dysphagia.7,12

Ocular

Up to 90% of patients with neuropsychiatric manifestations develop Kayser-Fleischer (KF) rings, which are caused by copper deposition in the corneal Descemet membrane.3,12,13 However, only about half of patients with primarily hepatic disease have KF rings. Another ocular finding is the sunflower cataract, reflecting copper deposits in the lens. Both KF rings and sunflower cataracts do not obstruct vision and improve with treatment. Recurrence suggests non-adherence to therapy.3,12

Other Extrahepatic Findings

WD also has other important extrahepatic manifestations. Perhaps best known is the development of a Coombs-negative hemolytic anemia, which can be the presenting symptom in 7-11% of patients.3,12 See Table 1 for a complete listing of findings.

Diagnosis

Major international liver societal guidelines offer slightly different algorithms to establish a diagnosis.3,12,14 Slit-lamp examination for KF rings, serum ceruloplasmin, and 24-hour urinary copper excretion are required for initial workup. The combination of KF rings, low ceruloplasmin (<20 mg/dL), and elevated urinary copper excretion (>40 µg/day) is pathognomonic for WD. However, this constellation of findings is frequently absent given the phenotypic variation in WD. Therefore, adjunctive use of liver biopsy and/or genetic testing may be necessary. Additional features such as the presence of significant liver or neuropsychiatric impairment, Coombs’ negative hemolytic anemia, or neuroimaging demonstrating copper deposition in the basal ganglia can be used to support a diagnosis of WD. Nonetheless, careful attention to the inherent limitations of the various testing methods is paramount (Table 2).

Biochemical Liver Tests

Aminotransferases are often mildly elevated in individuals with WD. In the setting of ALF, an alkaline phosphatase to total bilirubin ratio < 4 provides 94% sensitivity and 96% specificity.15 Interestingly, a low alkaline phosphatase level is uncommon outside of severe presentations.16

Ceruloplasmin

Measurement of this hepatically synthesized acute phase reactant is fraught with error. Current guidelines suggest that a ceruloplasmin level < 20 mg/dL is consistent with WD, but is only diagnostic when coupled with the presence of KF rings.3 Commercial immunological assays lack discrimination between apoceruloplasmin (lacking copper) and holoceruloplasmin, potentially leading to overestimation of levels and false normal values.3,7 In addition, inflammation and hyperestrogenemia can raise ceruloplasmin levels. Conversely, low levels may be seen in ATP7B heterozygotes (carriers) or patients with severe renal or enteric protein loss, end-stage liver disease, or inadequate copper supplementation in total parental nutrition.3

Serum Copper

Calculation of non-ceruloplasmin bound copper (the difference between serum copper and three times serum ceruloplasmin) has not been found to accurately distinguish WD from other causes of copper excess (i.e. ALF, chronic cholestasis, copper intoxication). Unfortunately, measurement of this parameter is also limited by overestimation of holoceruloplasmin, leading to a negative and uninterpretable value.3,4

Urinary Copper Excretion

Measurement of 24-hour urinary copper excretion (spot levels are unreliable) can suggest WD, but is not diagnostic on its own. While most symptomatic patients excrete >100 µg/day, 16-23% may excrete less, thus > 40 µg/day is used as a cut-off in most labs. However, patients with autoimmune hepatitis and ATP7B heterozygotes can have intermediate to elevated levels.3

Liver Biopsy and Hepatic Copper Content

Biopsy findings often mimic more common liver pathologies. Macrovesicular steatosis may be mistaken for NAFLD and interface hepatitis may falsely suggest autoimmune hepatitis. Identifiable copper by histochemistry is variable and thus unreliable. Ultrastructural tissue analysis can identify pathognomonic mitochondrial abnormalities, but this requires a high degree of a priori suspicion for WD.3

Normal hepatic copper content is < 50µg/g dry weight; in WD, levels are typically > 250µg/g. While the latter threshold is relatively specific, an important exception is chronic total parental nutrition (TPN) use, as up to 29% of patients on TPN have high levels of hepatic copper.17 Intermediate levels may be found in ATP7B heterozygotes and patients with chronic cholestatic disease. Therefore, measurement of hepatic copper content should be interpreted in the appropriate context. Additionally, the heterogenous deposition of copper in WD necessitates high-quality biopsy specimens.3

Genetics

Genetic testing of patients with suspected WD is controversial. A definitive diagnosis of WD can only be made in the presence of two known pathologic alleles. Thus, negative results can decrease, but not exclude, the likelihood of diagnosis given the possibility of unidentified variant alleles. Some authors, and the American Association for the Study of Liver Diseases (AASLD), advocate only for testing in equivocal clinical scenarios.3,8 In contrast, both the European Association for the Study of the Liver (EASL) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) advocate for universal genetic testing of suspected individuals.12,14 There is consensus, however, among experts and guidelines that first-degree relatives of patients with WD should receive genetic screening.

Treatment

Nutrition

A typical Western diet provides a copper content of 1,400µg/day for adult men and 1,100 µg/day for adult women. In normal health, only 50-120mg of copper is stored in the body, primarily within muscle and bones. As previously mentioned, copper is primarily excreted in bile with smaller amounts excreted in the urine (more if chelation therapy is used), and stool (non-absorbed dietary copper), totaling about 1 mg/day.18,19 Presently, the United States Food & Drug Administration (FDA) recommended daily intake of copper is 0.9mg (900µg). However, healthy adult individuals can tolerate up to 10mg daily before sustaining hepatotoxicity.20 Copper deficiency is uncommon in the absence of certain conditions such as gastrectomy or gastric bypass, excessive zinc supplementation or chelator use, Celiac disease, and Menkes disease (an X-linked recessive disorder caused by mutation in the ATP7A protein leading to impaired copper absorption).

Dietary guidelines by the major international hepatology societies suggest avoidance of high copper-containing foods (Table 3), particularly during the first year of treatment, as well as consultation with a registered dietitian.3,5,14

Avoiding copper-containing foods altogether is difficult for patients and may feel overly restrictive or provoke anxiety.6 However, the kinetics of human copper absorption are important for clinicians to understand. Absorption is inversely related to dietary copper content; thus, decreasing proportions of excess copper are absorbed as intake increases, although excretion does not quite match the amount ingested.21,22 Therefore, while limiting dietary copper is reasonable, outright avoidance of copper may not be necessary if patients are on appropriate pharmacologic treatment. It is reasonable to fully exclude organ meats (i.e. liver) and shellfish as these have copper contents far exceeding other foods. More recent literature also suggests that a lacto-vegetarian diet may promote both adherence and provide adequate micronutrients, as copper is less bioavailable than in typical omnivorous diets.6,23

Other dietary advice for patients includes avoidance of copper-containing multivitamins, which may contain half to over twice the recommended daily allowance.24 Patients should also avoid ingestion of copper through inorganic sources such as copper cookware and serving dishes. There is a theoretical concern about drinking water run through copper pipes.6 However, copper levels in municipal water sources vary greatly and avoidance is generally unnecessary with appropriate dietary modifications and pharmacologic treatment. In those on TPN, copper should be removed. A summary of these nutritional recommendations is available in Table 4.

Antioxidants

Antioxidants, primarily vitamin E, are an area of interest in the treatment of WD; unfortunately, little published data exists.25,26 Levels of vitamin E are known to be lower in patients with WD, yet there is no clear correlation between deficiency and clinical symptoms.27-29 Further study is warranted although there are currently no registered trials on clinicaltrials.gov.

Zinc Salts

Zinc salts may be used in combination with chelators for synergistic effects or alone as maintenance therapy. Zinc is a competitive inhibitor of copper absorption as it promotes enterocyte synthesis of the metal chelating peptide metallothionein. The latter protein has a higher binding affinity for copper and therefore this bound copper is eliminated via shed enterocytes into the fecal stream.6,30

Zinc chloride was the first salt utilized, but quickly abandoned given it caused significant gastric irritation.31 In 1997, zinc acetate (ZA) was approved by the FDA. This formulation is better tolerated and gastritis may be mitigated by concurrent consumption of a protein-rich snack or meal and use of a proton-pump inhibitor.

The recommended dosing of elemental zinc in adults is 50mg three times daily (single daily dosing is insufficient) and should be administered 30 minutes before or 2 hours after a meal. The timing of administration is important as the casein protein in cow’s milk and phytates contained in common foods such as corn, cereals, rice, and legumes interfere with zinc absorption.32 Additionally, if treating a pediatric patient less than 50kg, zinc dosing should be reduced to 25mg three times daily. To ensure efficacy (and adherence), clinicians should periodically check a 24-hour urine copper, with values <75µg/day indicating adequacy.3,30

Other zinc salts commonly utilized are zinc sulfate, zinc gluconate (ZG), and zinc picolinate, all of which are available over-the-counter. Some patients have turned to these preparations given intolerance to ZA and/or inadequate prescription insurance coverage. Interestingly, a recent retrospective study of 59 WD patients on zinc salt monotherapy found that half were taking nonprescription zinc. While target 24-hour urine copper levels achieved were highest in patients using ZA, levels were similar with ZG.30 Further head-tohead studies are needed to compare the different salts with respect to their pharmacokinetics and clinical efficacy.

Copper Chelation

Heavy metal chelators have been the mainstay of induction and maintenance therapy and promote urinary excretion of copper. The best-known is D-penicillamine, which also has the strongest evidence base for treatment of WD amongst all chelators.3,33 However, its use is somewhat limited by significant side effects (Table 5). D-penicillamine is also known to induce pyridoxine (vitamin B6) deficiency, which has varied manifestations including dermatitis, glossitis, angular cheilitis, irritability, neuropathy, and/or depression.34 Supplemental pyridoxine (vitamin B6) is therefore recommended at a dose of 25-50mg/day.3,14,23

An alternative chelator, trientine, is now typically preferred in clinical practice given a more favorable side effect profile.3,35-38 Patients and families should be informed, however, that chelator use (particularly D-penicillamine) is associated with worsening of neurologic deficits in up to 50% of patients during the induction phase. Unfortunately, the pathophysiology of the aforementioned phenomenon remains poorly understood but stabilizes with time.3,7

Specific dosing for both induction and maintenance is provided in Table 6. Chelators should ideally be administered an hour before or two hours after meals as food interferes with absorption. In stable patients, chelators may be taken closer to mealtime to improve adherence.3,14

Transplantation

Liver transplantation is only necessary in WD patients presenting with ALF or who have developed decompensated cirrhosis. Severe neurologic disease remains a controversial indication.39 Excellent outcomes have been achieved in heterogenous cohorts of both pediatric and adult patients, with 1-year, 5-year, and 10-year survival rates of 79- 88%, 73-83%, 60-87% respectively.40,41

Monitoring

There is little consensus regarding monitoring parameters and current guidelines are based upon expert opinion. In general, patients starting pharmacologic therapy should be monitored at least weekly (particularly if using chelators given the risk of neurologic deterioration) while titrating dosages, with less frequent visits as remission is achieved. Physical exam, complete blood count, biochemical liver tests, and 24-hour urine copper form the basis of this assessment. Initially, when chelation is used, urinary copper excretion should be significantly elevated, often >1000 µg/day during induction and then fall to between 200- 500 µg/day in the maintenance phase. Levels below 200 µg/day indicate either nonadherence or overtreatment and induction of copper deficiency.42 If zinc monotherapy is used, urinary copper excretion should be <75 µg/day.3,12 Annual slitlamp exams are recommended to ensure either recession or absence of KF rings to document therapeutic adequacy and adherence.12

Bone mineral density has also been shown to be severely reduced in children with WD, although it may stabilize with prompt treatment. However, it appears this skeletal abnormality is independent of vitamin D levels, as a small case-control study demonstrated similar serum 25-hydroxy vitamin D in both control and WD patients.43 Obtaining a baseline DEXA scan at presentation and after a year of therapy may be helpful to quantify the degree of demineralization and ensure stability.

CONCLUSION

WD is a rare but important cause of liver disease with many extrahepatic manifestations. Its complex genetics yield a spectrum of phenotypes seen in clinical practice. While untreated disease can lead to end-stage liver disease and devastating neurological consequences, timely identification and treatment is generally associated with a good prognosis.44 In symptomatic patients, chelation alone or in combination with zinc salts decreases systemic copper load rapidly. Maintenance therapy with zinc salts alone, particularly the ZA or ZG formulations, may be feasible and has a better side effect profile than chronic chelator use.

Although physicians may reference current societal guidelines when discussing nutritional treatment plans with their patients, the more practical approach to specific dietary guidance contained within this review is vital to patient satisfaction and treatment success.

References

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