Category Archives: Pediatric Gastroenterology Intestinal Disorder

Is Non-Celiac Wheat Sensitivity an Autoimmune Disorder?

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A recent study (P Mansueto et al. Am J Gastroenterol 2021; 116: 1015-1023. Autoimmunity Features in Patients With Non-Celiac Wheat Sensitivity). Thanks to Ben Gold for this reference.

The authors prospectively and consecutively studied 91 patients with Non-Celiac Wheat Sensitivity (NCWS) (F?M ratio 7:1); 76 healthy blood donors (HBD) and 55 patients with a diagnosis of irritable bowel syndrome (IBS) unrelated to NCWS served as controls.

NCWS was diagnosed based on absence of celiac serology, absence of villous atrophy (while receiving a gluten-containing diet), negative IgE-testing for wheat allergy (either serum or skin prick tests) along with resolution of symptoms off wheat and symptom reappearance wiht a DBPC wheat challenge.

Key findings:

  • Twenty-three patients with NCWS (25.3%) presented with autoimmune diseases (ADs); autoimmune thyroiditis (16 patients, 17.6%) was the most frequent. The frequency of ADs was higher in patients with NCWS than in HBD (P = 0.002) and in patients with IBS (P = 0.05).
  • In the NCWS group, antinuclear antibodies tested positive in 71.4% vs HBD 19.7%, and vs patients with IBS 21.8% (P < 0.0001 for both).
  • The frequency of extractable nuclear antigen antibody (ENA) positivity was significantly higher in patients with NCWS (21.9%) than in HBD (0%) and patients with IBS (3.6%) (P = 0.0001 and P = 0.004, respectively).
  • Among NCWS with comorbid autoimmunity, duodenal lymphocytosis was present in ~80% and others had eosinophilic infiltration (~90%), both suggestive of ongoing immune activation. (Duodenal eosinophilic infiltration was also noted in ~60% of those who had absence of autoimmune disease too)

The associated editorial by Galipeau et al notes that only 16% of those who self-report as “gluten-sensitive” will actually fulfill the current consensus criteria for a diagnosis of NCWS. The diagnosis is problematic because of the absence of a validated biomarker. While the current study shows association with autoimmune markers, other studies have shown some have markers of immune activation and others with non-IgE-mediated food sensitivities.

My take: These type of studies help us understand NCWS. Yet, without a more definitive biomarker, many people will be on a gluten-free diet needlessly.

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Dry Tortugas National Park (FL)

Colorectal Cancer: Rare in Pediatrics

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A recent retrospective single-center in Turkey study (2013-2018) reports 5 cases of colorectal cancer (CRC).

E Polat et al. JPGN Reports; 2021 – Volume 2 – Issue 1 – p e039 Full text: Colorectal Carcinoma in Childhood

Key points:

  • Patients were between 12-16 yrs of age and presented with bloody stools and weight loss
  • “CRC in childhood is very rare, usually diagnosed at an advanced stage and often has poor prognosis. CRC in children are mostly sporadic, roughly 10% of cases may have a predisposing condition…familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, Gardner syndrome, Turcot syndrome, Peutz-Jeghers syndrome, juvenile polyposis of colon, and ulcerative colitis.”

Review of Pyoderma Gangrenosum

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K Vaidy et al. JPGN Reports 2020; Full text: Treatment of Pyoderma Gangrenosum in Pediatric Inflammatory Bowel Disease

This in-depth report reviews pyoderma gangrenosum including the differential diagnosis, the pathophysiology/genetics, presentation/diagnosis and treatment approaches. Anti-TNF therapy: “Currently available published data support using an anti-TNF-α biologic agent as first-line therapy for severe PG therapy in pediatric IBD, as well as for those cases that have not responded to local therapies.”

Related blog posts -PG:

What Can We Conclude from Five Patients Treated with a Combination of Infliximab and Tofacitinib?

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Most often a letter to the editor would not grab my attention. A recent letter did: Full Text: Tofacitinib Is Safe and Effective When Used in Combination With Infliximab for the Management of Refractory Ulcerative Colitis (R Gilmore et al. Clin Gastroenterol Hepatol 2021; 1302-1303; reply 1303-1304 by JA Berinstein et al.)

This reported case series with 5 patients with severe ulcerative colitis (UC) who received a combination of tofacitinib and infliximab for at least 90 days were retrospectively reviewed. Tofacitinib dosing was de-escalated to 5 mg twice daily after 8 weeks. Thiopurine therapy was stopped with tofacitinib initiation.

Key findings:

  • Median duration of combination therapy was 9 months (range, 4–12 months). At 90 days, all patients had a reduction in Mayo score of ≥3. Four patients improved clinically and biochemically (Table 1), with 3 patients achieving steroid-free remission.
  • The only adverse event reported was one patient developing varicella zoster.

The authors letter title regarding tofacitinib being “safe and effective” is clearly overstated. The reply notes that in limited experience the group from the University of Michigan had a 50-year-old man develop severe pulmonary and CNS disease due to acquisition of legionnaires disease while on combination tofacitinib and infliximab.

My take: (borrowed from reply) “Efficacy and safety data obtained through rigorous randomized trials are needed…it is possible that long-term use of combination tofacitinib and infliximab will lead to an unacceptable risk of infection.”

Another study of tofacitinib: GR Lichtenstein et al. Inflamm Bowel Dis 2021; 27: 816-825. Tofacitinib, an Oral Janus Kinase Inhibitor: Analysis of Malignancy (Excluding Nonmelanoma Skin Cancer) Events Across the Ulcerative Colitis Clinical Program Key finding: With an exposure of 2576.4 patient years & 124 overall cohort tofacitinib-treated patients, 20 developed a malignancy

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Key West, FL

Microscopic Disease Does Not Predict Relapse in Crohn’s Disease

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AB Hu et al. Clin Gastroenterol Hepatol 2021; 19: 1226-1233. Full text: Ileal or Colonic Histologic Activity Is Not Associated With Clinical Relapse in Patients With Crohn’s Disease in Endoscopic Remission

In this retrospective study with 129 patients (mean age 25 yrs, mean disease duration 14.5 yrs) whose CD was in clinical/endoscopic remission, the authors examined factors associated with clinical relapse within 2 years; this included dose escalation, change in therapy, need for systemic steroids, or CD-related hospitalization or surgery.

Key findings:

  • Within 2 y of endoscopic evaluation, 42 patients (32.6%) had a clinical relapse.
  • There were no significant differences in proportions of patients with active ileal CD (23.8%), quiescent CD (28.6%), or normal histology (37%) between those who relapsed and those remaining in remission (P = .43). In addition, there was no no association between histologic features of active disease in ileal histology biopsies and symptom scores (Harvey Bradshaw index and simple inflammatory bowel disease questionnaire scores)
  • There were no significant differences in proportions of relapses among patients with active colonic disease (38.1%), quiescent disease (35.0%), or normal histology (27.9%, P = .73). 

My take: In terms of outcomes, clinical and endoscopic remission are important but whether histologic remission is needed is unclear (at this time).

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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.

Topiramate -2nd Line Agent for Cyclic Vomiting Syndrome

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H Mooers et al. AP&T 2021; https://doi.org/10.1111/apt.16457 Retrospective review of patients treated for cyclic vomiting syndrome with topiramate

“Response was defined as a global improvement in symptoms or >50% reduction in the number of CVS episodes, ED visits or hospitalisations.” 92% of patients had previously failed TCA therapy.

Key findings:

  • “Sixty-five percent (88/136) of patients responded to topiramate in an intent-to-treat analysis.”
  • “There was a significant decrease in the annual number of CVS episodes (18.1 vs 6.2, P < 0.0001), CVS-related ED visits (4.3 vs 1.6, P = 0.0029), and CVS-related hospitalisations (2.0 vs 1.0, P = 0.035).”
  • Fifty-five percent of patients experienced side effects, and 32% discontinued the medication as a result. The most common side effects were cognitive impairment (13%), fatigue (11%) and paresthesia (10%).

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Sacroiliitis, NAFLD, IMIDs -Concurring Problems with Inflammatory Bowel Disease

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I Levine et al. Inflamm Bowel Dis 2021; 809-815. Prevalence, Predictors, and Disease Activity of Sacroiliitis Among Patients with Crohn’s Disease

Key findings in this cross-sectional retrospective study (n=258, median age 30 yrs):

  • Overall, 17% of patients had MRI evidence of sacroiliitis, of whom 73% demonstrated bone marrow edema.
  • Female gender, back pain, and later age of CD diagnosis were associated with sacroiliitis (P = 0.05, P < 0.001, P = 0.04, respectively).
  • Disease activity (clinical, endoscopic, and radiographic), disease location and CD therapy were not associated with sacroiliitis on MRE.
  • More than two-thirds with MRE evidence of sacroiliitis were never seen by a rheumatologist.

A Lin et al. Inflamm Bowel Dis 2021; 947-955. Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis

Key finding:

  • Data pooled from 27 studies showed the prevalence of NAFLD among IBD patients was 32% (substantial heterogeneity); this is “statistically significantly higher than the prevalence of NAFLD in the general population (25.2%; P < 0.001)”

M Attauabi et al. Inflamm Bowel Dis 2021; 927-939. Systematic Review with Meta-analysis: The Impact of Co-occurring Immune-mediated Inflammatory Diseases on the Disease Course of Inflammatory Bowel Diseases

A total of 93 studies were identified, comprising 16,064 IBD patients with co-occurring IMIDs and 3,451,414 IBD patients without IMIDs. IMIDs included the following:

  • Unspecified autoimmune disease
  • Diabetes type 1
  • Asthma
  • Grave disease
  • Spondyloarthropathy
  • Ankylosing spondylitis
  • Iridocyclitis
  • Uveitis
  • Rheumatoid arthritis
  • Polymyalgia rheumatica
  • Psoriasis/psoriatic arthritis
  • Primary Sclerosing Cholangitis
  • Celiac disease
  • Pyoderma gangrenosum
  • Pernicious anemia
  • Autoimmune hepatitis
  • Sarcoidosis
  • Giant cell arteritis
  • Primary biliary cholangitis
  • Hashimoto thyroiditis
  • Episcleritis
  • Sjogren syndrome

Key findings: Patients with IBD and co-occurring IMIDs were at increased risk of having extensive colitis or pancolitis (risk ratio, 1.38; 95% Cl, 1.25–1.52; P < 0.01, I2 = 86%) and receiving IBD-related surgeries (risk ratio, 1.17; 95% Cl, 1.01–1.36; P = 0.03; I2 = 85%) compared with patients without IMIDs

Image below from Bahia Honda State Park (FL)

What is the Risk of Inflammatory Bowel Disease in Patients with Hirschsprung’s Disease

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Background: It is well-recognized that enterocolitis can occur in individuals with Hirschsprung’s disease, even after surgery. Case series have described cases of inflammatory bowel disease (IBD) in individuals with Hirschsprung’s which have some overlapping features with Hirschsprung disease-associated enterocolitis (HAEC). Those with IBD, however, have a constellation of clinical findings more typical of IBD and respond to treatments used in IBD.

A recent study from Canada (CN Bernstein et al. J Pediatr 2021; 233: 98-104. Increased Incidence of Inflammatory Bowel Disease After Hirschsprung Disease: A Population-based Cohort Study) provides more data regarding IBD in individuals with HD.

Key findings:

  • In the study from Ontario, 18 of 716 (2.5%) ultimately developed IBD (168.8 per 100 000 person-years), compared with 7109 of 3 377 394 children without Hirschsprung disease (0.2%, 14.2 per 100 000 person-years); thus, this represented a 12-fold increased risk.
  • In the study from Alberta and Manitoba, the OR of having had Hirschsprung disease before a diagnosis of IBD compared with controls was 74.9 (95% CI, 17.1-328.7) and 23.8 (95% CI, 4.6-123) respectively.
  • Crohn’s disease was more common after Hirschsprung disease than ulcerative colitis.

My take: I have personally seen IBD in HD and wondered how much increased risk that HD conferred. Now the question: what is the mechanism?

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Alongside the Seven Mile Bridge in the Florida Keys:

Obesity and Cellular Aging in Childhood

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A provocative study (MJ Baskind et al. J Pediatr 2021; 233: 141-149. Obesity at Age 6 Months Is Associated with Shorter Preschool Leukocyte Telomere Length Independent of Parental Telomere Length) suggests that obesity in infancy can result in shortened telomere length, which is a cumulative marker for cellular aging. Also, leukocyte telomere length (LTL) is associated with known risk factors for cardiometabolic disease, including obesity and smoking

The authors prospectively studied a group of 97 woman-infant dyads from the Latinx, Eating and Diabetes cohort. Key findings:

  • Obesity at 6 months was negatively associated (β = −0.21; P < .001) with leukocyte telomere length
  • However, there was a lack of association between obesity at earlier ages (2-5 years) and preschooler LTL in the same cohort
  • Any breastfeeding at 6 months was positively associated with leukocyte telomere length

From the associated editorial: JL Buxton, fulltext: Early Warning Signs? Infant Obesity and Accelerated Cellular Aging “These results are based on data from a relatively small sample and await replication in larger cohorts recruited from different populations.”

My take: This study shows that obesity could be affecting our bodies in ways that most of us have never contemplated.

Aerial view of the “the quicksands” off the coast of Key West:

“An Allergic Basis for Abdominal Pain”

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A recent post (Mechanisms of Postinfectious IBS & Functional Pain) reviewed a study which described how food antigens during an infectious process can result in meal-induced pain.

A recent review of this study (M Rothenberg. NEJM 2021; 384:2156-2158. An Allergic Basis for Abdominal Pain) provides more insight.

Key points:

  • “A peripheral immune mechanism involving local mast cells stimulated by food-induced local IgE may underlie the symptoms associated with IBS and functional abdominal pain; these findings prompt consideration of new therapeutic strategies to target mast cells and allergies.”
  • The article reviews the experimental methods/results used in both mice and humans. Mice that were treated with agents that interfered with allergy “including anti-IgE, mast-cell stabilizers, and histamine H1 receptor antagonists, attenuated the pathologic and symptomatic responses…mice [that were] deficient in mast cells or in histamine H1 receptor were protected” as well.
  • The study shows that a “bacterial infection can break oral tolerance to a dietary antigen…which in turn can lead to increased gut permeability.”
  • The findings in human “showed no evidence of systemic IgE against common foods” but localized reactions were identified in every IBS patient after allergen injection into rectal mucosa.

My take: This study adds to the evidence that specific foods can lead to localized tissue-specific allergic responses. Nevetheless, it is still a futile effort to look for systemic allergic food reactions in patients with IBS and functional GI disorders.

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