Worldwide Burden of Functional Disorders

AD Sperber et al. Gastroenterology 2021;160:99–114. Full text PDF. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study

A global epidemiological study of functional GI disorders
• 73,076 adults surveyed (33 countries, 6 continents)
• Data collection: By Internet (24 countries), by household interview (7 countries), or both methods (China and Turkey, green).

Key findings:

  • Diagnostic criteria were met for at least 1 FGID by 40.3% persons who completed
    the Internet surveys and 20.7% of persons who completed the household surveys
  • FGIDs were associated with lower quality of life and more frequent doctor visits

My take: In industrialized countries, about 40% have functional GI disorders.

Related article: C Ma et al. Gastroenterol 2021; 160: 88-98. Full text: Epidemiologic Burden and Treatment of Chronic Symptomatic Functional Bowel Disorders in the United States: A Nationwide Analysis

From 2007–2015, approximately 36.9 million (95% CI, 31.4–42.4) weighted visits in patients of non-federally employed physicians for chronic symptomatic FBDs were sampled. There was an annual weighted average of 2.7 million (95% CI, 2.3–3.2) visits for symptomatic irritable bowel syndrome/chronic abdominal pain, 1.0 million (95% CI, 0.8–1.2) visits for chronic constipation, and 0.7 million (95% CI, 0.5–0.8) visits for chronic diarrhea. Pharmacologic therapies were prescribed in 49.7% (95% CI, 44.7–54.8) of visits compared to nonpharmacologic interventions in 19.8% (95% CI, 16.0–24.2) of visits (P < .001). Combination treatment strategies were more likely to be implemented by primary care physicians and in patients with depression or obesity. The direct annual cost of ambulatory clinic visits alone for chronic symptomatic FBDs is approximately US$358 million 

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Fatty Liver Disease in Children is Increasing

AK Sahota et al. Pediatrics 2020; DOI: https://doi.org/10.1542/peds.2020-0771. Incidence of Nonalcoholic Fatty Liver Disease in Children: 2009–2018

Key finding:  The incidence of an NAFLD diagnosis significantly increased over time, with 36.0 per 100 000 in 2009 and 58.2 per 100 000 in 2018 (P < .0001), based on study of a large integrated health care system in southern California

Expert Guidance on Current Management of IBD (Part 1)

A recent issue of Clinical Gastroenterology and Hepatology focused solely on the clinical features and management of inflammatory bowel disease. Even for those with expertise in IBD, there is a lot of useful information and concise reviews of what is known.

Here are some of my notes from this issue:

AN Ananthakrishnan et al. Clin Gastroenterol Hepatol 2020; 18: 1252-60. Changing Global Epidemiology of Inflammatory Bowel Diseases: Sustaining Health Care Delivery Into the 21st Century

Reviews risk factors and recommends the following as ways to lower risk of developing IBD for at-risk individuals:

  • Breastfeeding in infancy
  • Do not start smoking
  • Avoid vitamin D deficiency
  • Minimize non-steroidal anti-inflammatory drug use
  • Minimize antibiotic use especially for young children and during pregnancy
  • Encourage moderate physical activity, healthy weight, low stress and regular sleep
  • Diet high in fruit, vegetables, fiber, and fish

Reviews the epidemiology and notes that there has been a evidence of a decline in incidence in IBD in (at least) the Western world; however, because of compounding prevalence, it is expected that the number of individuals with IBD will continue to rise.  In Canada, for example, it is expected that the prevalence will rise from 0.7% in 2018 to 1% by 2030.

In newly industrialized countries, it is expected that rising incidence is going to substantially increase the global disease burden. The authors note the following as areas needed in research and clinical care to meet global IBD care burden:

  • tools for early diagnosis
  • early effective intervention to prevent irreversible bowel damage
  • precision medicine to select the right treatment for the right patient
  • need for less costly and more safe therapies
  • simple tools to monitor disease activity
  • primary disease prevention strategies, especially for those at high risk

CA Siegel, CN Bernstein. Clin Gastroenterol Hepatol 2020; 18: 1261-7. Identifying Patients With Inflammatory Bowel Diseases at High vs Low Risk of Complications

This article’s disease-stratification information overlaps with subsequent articles which detail the positioning of therapies for Crohn’s disease (CD) and ulcerative colitis (UC) respectively.

NH Nguyen, S Singh, WJ Sandborn. Clin Gastroenterol Hepatol 2020; 18: 1267-79. Positioning Therapies in the Management of Crohn’s Disease.

Some of the information summarized in this article:

Table 2 -Comparative Efficacy of Biologics for Moderate to Severe Active Crohn’s Disease (CD):

  • Infliximab: For induction: OR compared to placebo for remission: 5.90 (2.78-12.51); probability of remission 60%. For maintenance in those with clinical response: probability of remission SUCRA ranking: 48%; 0.68
  • Adalimumab: For induction: OR compared to placebo for remission: 3.80 (1.76-8.18); probability of remission 49%. For maintenance in those with clinical response: probability of remission SUCRA ranking: 58%; 0.97
  • Ustekinumab: For induction: OR compared to placebo for remission: 2.75 (1.76-4.32); probability of remission 41%.  For maintenance in those with clinical response: probability of remission SUCRA ranking: 39%; 0.36
  • Vedolizumab: For induction: OR compared to placebo for remission: 2.69 (1.36-5.32); probability of remission 40%.  For maintenance in those with clinical response: probability of remission SUCRA ranking: 42%; 0.52
  • Certolizumab pegol: For induction:  OR compared to placebo for remission: 1.36 (0.89-2.08); probability of remission 25%.  For maintenance in those with clinical response: probability of remission SUCRA ranking: 42%; 0.48

In deciding therapy, the authors specify factors that help classify as high-risk CD Table1):

  • Structural damage: large or deep mucosal lesions, fistula or perianal abscess, prior resections (especially if >40 cm)
  • Inflammatory burden: extensive disease involvement (ileal disease >40 cm or pancolitis), increased C-reactive protein, low albumin
  • Impact on quality of life: presence of stoma, >10 loose stools/week, lack of symptomatic improvement with prior biologics and/or immunomodulators, presence of anorectal symptoms, anemia, daily abdominal pain
  • Emerging predictors: antimicrobial antibody pattern, antimicrobial genetic peptide signature

Though the authors note a lack of adequate head-to-head comparative studies, they make some recommendations for treatment:

  • For severe disease, they suggest first-line therapy for CD would be infliximab or adalimumab in combination therapy regimen (with infliximab favored for higher disease severity)
  • For second-line therapy, they suggest ustekinumab for most patients in combination therapy or 2nd anti-TNF in those with loss or response due to immunogenicity or intolerance
  • For those with higher risk factors for adverse events (or preference) and moderate disease severity, the authors recommend vedolizumab as 1st line and ustekinumab as 2nd line.  For this same group with higher disease severity, they suggest ustekinumab as 1st line treatment.

Other key points:

  • In terms of risk of malignancy, the authors note that in a comprehensive systematic review of 23 RCTs of TNF-alpha antagonists in IBD, there was NO significant increase in the risk of malignancy with TNF-alpha antagonists.
  • In terms of combination therapy, the authors note that their has been an observed benefit which is “at least partly attributed to achieving a higher biologic trough concentration….no differences in efficacy of combination therapy vs infliximab were observed when evaluating patients by quartiles of infliximab trough concentration; however, currently this represents association rather than causation, and it is possible that superior remission rates drove higher trough concentrations, rather than vice versa.”

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Ups (mostly) and Downs with IBD Epidemiology

Two articles describe both increasing and decreasing trends in the prevalence of inflammatory bowel disease (IBD).

  • Y Ye et al. Inflamm Bowel Dis 2020; 26: 619-25, editorial 626-27
  • M Torabi et al. Inflamm Bowel Dis 2020; 26: 581-90, editorial 591-92 

The first study by Ye et al provides the familiar message that IBD prevalence has been increasing in pediatrics and adults.  This study examined 2 large claims databases.  The Optum database covered ~18 million annually during the study period (total ~57 million from 2007-2017) and Truven covered ~44 million annually (total ~240 million since 1995)

Key findings:

  • Pediatric IBD prevalence increased by 133% from 2007 to 2016: from 33 per 100,000 to 77 per 100,000. Crohn’s disease (CD) was twice as prevalent as ulcerative colitis (UC) in the pediatric population (46 vs 22)
  • Adult IBD prevalence increased by 123% from 2007 to 2016: from 215 per 100,000 to 478 per 100,000. The prevalence rates of CD and UC were similar in adults: 198 vs 181)
  • The Northeast region had the highest prevalence of IBD, followed by Midwest, South and then West.
  • Based on these prevalence data, there are an estimated 58,000 children (2-17) and 1.2 million adults with IBD in U.S.   Or, 1 in 1299 children and 1 in 209 adults.

Limitations:

  • Diagnosis and data derived from claims database
  • Cases can vary significantly based on how sensitive the definition for IBD is in a given study.  In this study, the authors indicate in supplementary material, that the prevalence rates could be doubled in adults if they chose a more sensitive/less specific case definitions.

The second study by Torabi et al, which utilized the Manitoba Epidemiology Database (n=1.2 million) showed a decrease in IBD incidence.  The authors examined 296 small geographic areas (SGAs) and found that many had persistently high IBD incidence rates.

Key findings:

  • The incidence of IBD decreased from 1990 when it was 23.6 per 100,000 to 16.2 per 100,000 in 2012.
  • In the study period (1990-2012), there were 3114 cases of CD and 3499 cases of UC diagnosed in Manitoba

In the discussion, the authors speculate on the reasons for the decline in IBD incidence in an area with high rates of IBD.  Some of the change may be related to changes in the population mix –more immigrants from areas with lower rates of IBD.  In the editorial, it is noted that a recent systematic review (Lancet 2018; 390: 2769-78) indicated that the “incidence of IBD is stabilizing in Western countries.”

My take: There are a lot kids and adults with IBD.  The preponderance of epidemiology studies point to increasing incidence and prevalence.

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IBD Shorts March 2020

Ustekinumab Predictor. At recent ACG meeting, PS Dulai presented data on 781 adult patients that was used to determine likelihood of ustekinumab response. Source: GIHepNews: New ustekinumab response predictor in Crohn’s called ‘brilliant’

Variable  & Points:

  • No prior anti-TNF agents:  2 points
  • No prior bowel surgery: 2 points
  • No smoking (current or prior): 1 point
  • No active fistulas: 1 point
  • Baseline albumin: >4.3    3 points, >3.9-4.3     2 points, >.3.2-3.9   0 points,     >2.5-3.2    -1 point, 2.5 or less   -3 points

Probability of Response Interpretation:

  • High if ≥5 points
  • Intermediate if 2-4 points
  • Low if 0 or 1 points

Infliximab outperformed golimumab for moderate-to-severe ulcerative colitis. S Singh et al. Clin Gastroenterol Hepatol 2020; 18: 424-31. Using data from three phase 3 trials (1793 patients), the authors found that infliximab worked more rapidly and with greater efficacy than golimumab.  At week 6, patient reported outcome of clinical remission was 50.0% and 38.9% (aOR 2.0).  After adjusting for patient variables, infliximab was superior in achieving clinical remission with aOR 3.01 (39% vs. 21%).

Increasing incidence of inflammatory bowel disease in Latin America and Caribbean. PG Kotze et al. Clin Gastroenterol Hepatol 2020; 18: 304-12. This systematic review examined incidence & prevalence of IBD over the last 30 years. In Brazil, for example, the incidence of Crohn’s disease jumped from 0.08 per 100,000 person-years in 1988 to 5.5 per 100,000 person-years in 2015.

IBD Passport Website: IBD Passport homepage. “IBD Passport is an award winning website that aims to provide comprehensive, practical and reliable information on all aspects of travelling with Crohn’s Disease or Ulcerative Colitis (Inflammatory Bowel Disease). IBD Passport is the first website to combine this information into one resource to make planning your trip easy. IBD Passport is a UK registered non-profit charity (Registered number: 1171268) with a global reach aimed to support IBD travellers of all nations and regions in the world.”

Adverse Effects of Low-Dose Methotrexate (≤20 mg/week). DH Solomon et al. Ann Intern Med. 2020. DOI: 10.7326/M19-3369. n=4786, median age 66 years. This was a secondary analyses of a double-blind, placebo-controlled, randomized trial. “With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs.” There were increased risks of gastrointestinal, infectious, pulmonary, and hematologic AE.

 

 

 

First Year of Life Antibiotics and Celiac Disease

Briefly noted:

A recent study (SD Sander et al. Gastroenterol 2019; 156: 2217-29) found an association between antibiotics in the first year of life and celiac disease.

The authors “collected medical information on 1.7 million children, including 3346 with a diagnosis of celiac disease” using nationwide register-based cohorts from Norway and Denmark.

Key finding:

  • “Exposure to systematic antibiotics in the first year of life was positively associated with diagnosed celiac disease,” pooled odds ratio 1.26.  Furthermore, there was a dose-dependent relationship with increasing number of exposures increasing the risk of celiac disease.

My take: The increase in prevalence of celiac disease over that past few decades is likely related to changes in our environment.  These changes affect nearly everyone, but some are more susceptible to immune-related disease that may be triggered by these environmental changes.  This study shows that early exposure to antibiotics is likely to be one of the environmental factors that increase the risk of celiac disease.

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Early Life Events and the Development of Inflammatory Bowel Disease

Full Text via AGA Journal Link: Events Within the First Year of Life, but Not the Neonatal Period, Affect Risk for Later Development of Inflammatory Bowel Diseases

A recent study (CN Bernstein et al. Gastroenterol 2019; 156: 2190-7; editorial 2124) delves into the topic of early life risk factors for the development of IBD. In the background, the author note that in 2018, 267,983 Canadians (0.73%) were estimated to be living with IBD and there is a forecast that this will increase to 402,853 by 2030.

This study used a Manitoba database and examined the records of individuals diagnosed with between 1984-2010. In addition, they correlated this data with individual data of the postnatal period between 1970-2010. From this database, they analyzed 825 individuals with IBD and 5999 matched controls.

Key Findings:

  • The strongest risk factor for the development of IBD was a maternal diagnosis of IBD with an odds ratio (OR) of 4.53; the OR was higher for CD at 5.98 compared to OR of 2.71 for UC
  • Infections in the first year of life was associated with an OR of 3.06 for IBD diagnosed before age 10 years, and OR of 1.63 for IBD diagnosis before age 20 years.  Only infections in the first year of life were correlated with IBD as infections during the first 3 years of life were not associated with a significant increased risk.
  • While infections in the first year of life were associated with an increase risk of IBD, the authors could not demonstrate that individuals who developed IBD had more infections than unaffected sibling controls (though they did have more infections than the entire control cohort).
  • Highest socioeconomic quintile, also, had an increased OR of 1.35.
  • Gastrointestinal illnesses (like abdominal pain) were not found to be associated with the later development of IBD.

It is unclear whether infections in early life increase the risk of IBD or whether other factors like antibiotics contribute to the higher rate of IBD.  The authors did not find more immunodeficiency disorders in the IBD cohort compared to controls.

My take: This study identified genetic risk as substantially greater than specific environmental risks.  However, the increasing incidence of IBD suggests that environmental factors are quite significant, as genetic risk factors are less likely to change enough to account for the changes in epidemiology.  As such, there are a few explanations:

  1. There are other unidentified environment risk factors
  2. Some individuals are more susceptible to the changes that have occurred in the environment; that is, their environmental exposures are not significantly different from their peers but are significantly different than individuals from 20, 40, 60 and 100 years ago.

From AGA Journal link

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Highest Reported Prevalence Rates for Eosinophilic Esophagits

A recent retrospective study (J Robson et al. Clin Gastroenterol Hepatol 2019; 17: 107-14) utilized a pathology database encompassing the vast majority of Utah pediatric cases to determine the incidence and prevalence of eosinophilic esophagitis (EoE) from 2011 to 2016.

The authors determined cases of EoE by looking for symptomatic children with isolated esophageal eosinophilia (more that 14 eos/hpf) in the absence of other comorbid conditions.

Key findings:

  • 1060 children met the criteria for a new diagnosis of EoE
  • Average annual incidence of EoE was 24 per 100,000 children; this is nearly double the previously reported rate 12.8 per 100,000 from Hamilton County, Ohio in 2003.
  • Prevalence of EoE was 118 per 100,000 children

The authors speculate on several factors that produced this increased incidence rate –all related to EoE risk factors:

  • Predominant non-Hispanic White population
  • High rates of atopy
  • Increased capture rate of their database
  • Also, the authors did NOT exclude PPI-responsive esophageal eosinophilia (which is a subtype of EoE and not a different disease

The authors note that “there is reason to believe that this [high incidence rate] is a conservative estimate:”

  • ~2% of pathology reports had 10-14 eos/hpf.  Further review of these cases would likely have identified some which have exceeded the >14 threshold
  • Some pediatric EoE cases are diagnosed by adult gastroenterologists who did not use the pathology databases

My take: This study shows high rates of EoE but comes as no surprise.  And, there are likely a large number of individuals with mild EoE which has not been diagnosed.  In my experience, families and physicians often overlook altered eating habits as related solely to behavior.  Useful questions to uncover dysphagia include the following: how long does it take your child to eat? does your child have to drink a lot of liquids when eating? does food get stuck frequently?

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Global Prevalence of Celiac Disease

Briefly noted: P Singh et al. Clin Gastroenterol Hepatol 2018; 16: 823-36. After a systemic review which selected 96 articles from a pool of 3843 published between 1991 through 2016, the authors determined a pooled global prevalence of 1.4% in 275,818 individuals based on seroprevalence (positive TTG or EMA).  Biopsy-confirmed celiac disease was noted in 0.7% in 138,792 individuals.

In their study, biopsy-proven disease was most prevalent in Argentina, Egypt, Hungary, Finland, Sweden, New Zealand, and India.

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Northern Latitudes -Higher Prevalence of Celiac Disease and Gluten Avoidance

A recent study (A Unalp-Arida et al. Gastroenterol 2017; 152: 1922-32) examines the relationship of latitude and the prevalence of celiac disease and gluten avoidance.

Using the NHANES 2009-2014 survey with 22,277 participants (6 years and older), the authors identified persons with celiac disease (based on serology) along with those who avoided gluten without a diagnosis of celiac disease.

Key findings:

  • 0.7% of participants had celiac disease and 1.1% avoided gluten without celiac disease
  • Celiac disease was more common among individuals who lived at latitudes of above 35 degrees and more common with higher socioeconomic status. Figure 2 map provides latitude lines. In the eastern U.S. the Georgia-Tennessee border corresponds to this latitude line and in the western U.S. the southern tip of Nevada lies on this line.
  • From 35 degrees to 39 degrees the odds ratio was 3.2, whereas the odds ratio was 5.4 for those above 40 degrees.  These odds ratios were independent of race, ethnicity, socioeconomic status and body mass index.
  • Similarly, the prevalence of gluten avoidance without celiac disease was twice as common among persons living north of 40 degrees compared with those residing at latitudes <35 degrees.
  • The findings on latitude were heavily influenced by the increased rate of celiac and gluten avoidance in the Northeast region (more so than in the West)

In their discussion, the authors note that “a North-South gradient in disease occurrence in genetically similar populations has been shown in studies of autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis.” Potential environmental factors could include lack of sunshine/vitamin D deficiency, hygiene, and infections.  A study comparing similar populations in Finland and Russia suggested a lower economic status/less hygiene increased the risk of celiac disease despite similar gluten exposure.  The authors note that there was NOT an increased risk in Northern Sweden compared to Southern Sweden.  In fact, this study of children found a higher rate of celiac disease in Southern Sweden (Arch Dis Child 2016; 101: 1114-18).

My take: This is another intriguing study regarding celiac disease epidemiology which strongly points to environmental factors accounting for marked variation in celiac disease prevalence.

More information on this topic from AGA Blog: Do More People Have Celiac Disease in the North vs the South?

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