In June 2024 (special issue), Gastroenterology published an entire issue (193 pages) focused on celiac disease. There was a lot of useful information on almost every aspect of this disease. Below I have summarized some of the points.
The authors detail disorders with increased risk for CeD and which merit screening (see Table 2 below). Some disorders that merit screening that are more obscure include idiopathic pancreatitis, autoimmune hepatitis, delayed menarche, and chronic fatigue.
They note that type 1 diabetes mellitus could require serial screening. “Because CeD can manifest at any time and with greater frequency during the initial 5 years, conducting additional screenings in CeD-negative T1DM patients 2 and 5 years after T1DM diagnosis and those who later develop gastrointestinal (GI) symptoms may be advisable.” In addition, it is important to recognize that CeD serology testing is less reliable in patients with T1DM.
They note that the worldwide prevalence is between 0.7% and 2.9%. In this issue, most authors estimate the prevalence to be about 1% with more than 50% undetected.
There are many places with higher rates. In U.S. “children in Colorado had a 2.5-fold higher risk compared to Washington State…similar regional differences were seen …in Sweden, Finland, and Germany.”
They note the burden before and after diagnosis. Before diagnosis/undetected, there can be persistent symptoms, complications (eg. osteoporosis, decreased fertility) and impaired quality of life. Afterwards, there are increased costs of a GFD and psycho-social burden of GFD.
In terms of generalized screening compared to case-finding, the authors note that given the number of at-risk groups, the case-finding approach could entail screening >50% of the population.
V Abadie et al.New Insights on Genes, Gluten, and Immunopathogenesis of Celiac Disease, reviews the intricate details of genetic, biochemical, and immunologic studies, which together have revealed mechanisms of gluten peptide modification and HLA binding, thereby enabling a maladapted anti-gluten immune response.
What I was most interested in was the mechanisms behind ‘potential’ celiac disease (PCeD) in which patients have autoimmunity (+serology) but normal histology. In potential CeD, the anti-CD4+ T-cell response is present but decoupled from tissue cytotoxicity. However, notably, IL-21, a cytokine produced by gluten-specific CD4+ T cells in active CeD, is not up-regulated in potential CeD…In addition, patients with potential CeD lack the presence of an epithelial stress response associated with IL-15, HSP70, and HSP27 upregulation in epithelial cells.” “The presence of epithelial stress is a crucial prerequisite for the development of tissue damage.”
The authors retrospectively studied a cohort of children (n=782) with eosinophilic gastrointestinal disorders (EGID) including 592 with isolated eosinophilic esophagitis (EoE), 190 with EGID which included esophageal involvement (“EI”) and 35 EGD without esophageal involvement (“Non-EI”).
Key findings:
Abdominal pain was more frequent in EI than isolated EoE: 61% vs 45%, p=.002)
EI patients had more dense esophageal eosinophil infiltrate (peak) than isolated EoE: 115 vs 92; P=.036) and higher peripheral blood eosinophil level (0.44 vs 0.38; p=0.027)
94-Gene expression profiles from esophageal biopsies from a 168 subgroup showed that EoE and EI were not significantly different. The heat map for upregulated and downregulated gene expression was different based on disease activity but not significantly different between EoE or EI in either state.
My take (borrowed from authors): The similar molecular transcriptome between EI and EoE are indicative of a shared pathogenesis.
R Loomba et al. NEJM 2024; 391; 299-310. Tirzepatide for Metabolic Dysfunction–Associated Steatohepatitis with Liver Fibrosis
F Kanwal.N Engl J Med 2024;391:371-372. Dual Agonists for Management of Metabolic Dysfunction–Associated Steatohepatitis (Associated editorial)
Background: The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.
Methods: This was a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks.
My take: Until very recently, there were no effective pharmacologic agents for steatotic liver disease (SLD). Now it appears that there will be multiple effective agents. When newer agents for hepatitis C became available (Harvoni was FDA approved 10 years ago), there were concerns about the high cost. With SLD, this is an even bigger concern give the indefinite treatment period.
From editorial: “Overall, these data are encouraging. Clinicians providing care for patients with MASH will probably have an increasing number of options in their armamentarium. With a growing menu of effective treatments, harms and unacceptable side effects will be important considerations in making treatment decisions.”
Related article: YH Yeo et al. Annals of Intern Med 2024; https://doi.org/10.7326/M24-00. Shifting Trends in the Indication of Glucagon-like Peptide-1 Receptor Agonist Prescriptions: A Nationwide Analysis
NE Peters et al. NEJM 2024; 391; 56-59. Normalization of C1 Inhibitor in a Patient with Hereditary Angioedema
“An infant with genetically confirmed hereditary angioedema and low C1 inhibitor levels (but without previous episodes of angioedema) underwent liver transplantation for biliary atresia, an unrelated condition. Liver transplantation led to normalization of the C1 inhibitor level and function. To our knowledge, this represents the first patient to be potentially cured of hereditary angioedema.” This case report shows that liver-directed therapy can reverse hereditary angioedema.
T Asselah et al. NEJM 2024; 391:133-143. Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D
Key finding: At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group.
My take: This is a long (48 weeks) and difficult treatment (2 injection meds and lots of peginterferon side effects). However, there is a fairly good response rate.
This link to the article also has links to related AASLD guidelines (eg. management of portal hypertension). Table 2 summarizes the ~34 recommendations which include yearly evaluation with labs, ultrasound at least every 2 years in pediatric patients (age 3 yrs and older) and against routine use of ursodeoxycholic acid.
This article provides a good review on long-term use of PPIs. Table 1 provides indications that may require long-term use of PPIs:
Erosive esophagitis: symptomatic Los Angeles Grade B or Maintenance for Grade C-D
Symptomatic Nonerosive GERD
Peptic stricture
Biopsy-proven Barrett’s esophagus
PPI-responsive esophageal mucosal diseases: eosinophilic esophagitis or lymphocytic esophagitis
Peptic ulcer disease without modifiable risk factor
High-risk patients receiving antiplatelet therapy
Zollinger-Ellison
Idiopathic pulmonary fibrosis (per pulmonologist)
Table 2 provides customary advice: ensure patient has a good indication for PPI otherwise consider deprescribing, and use lowest effective dose. It also summarizes potential adverse effects/management.
My take: The author’s “take-home message” is appropriate as a smartphrase for counseling patients (slightly modified below):
Although proton pump inhibitor (PPI) use is common, only a few conditions warrant its long-term use. These conditions include severe erosive esophagitis, PPI-responsive eosinophilic esophagitis, chronic esophageal mucosal diseases, and peptic ulcer disease with risk of recurrence (and others).
When PPIs are required long-term, efforts should be made to use the lowest possible dosing necessary to manage patient symptoms and underlying condition.
In patients that do not meet indications for long-term PPIs, efforts should be made to deprescribe these medications.
Although PPIs are often linked to various adverse conditions, these potential associations are largely based on low-quality studies and do not prove an increase risk for these conditions. Multiple larger-scale studies have also demonstrated results showing no such associations besides a marginal increase in enteric infections.
In general, routine testing should not be performed on long-term PPIs unless risk factors for specific conditions exist. In those with risk factors, monitoring could be needed for low magnesium, vitamin B12 deficiency, chronic kidney disease, and osteoporosis.
Yesterday, the AAP put out a statement (see below) regarding the numerous lawsuits related to necrotizing enterocolitis. The lawsuits allege that formula companies did not provide physicians and patients warning that their products could increase the risk of necrotizing enterocolitis relative to breast milk or donated human milk.
Currently, when one searches for “NEC and lawsuits,” it is difficult to find these news reports due to dozens of law firm websites trying to attract clients. Per CNBC article, “close to 1,000 lawsuits have been filed against Abbott, Enfamil formula maker Reckitt Benckiser or both in federal or state courts.”
My take: These lawsuits are likely to exponentially increase the cost of formulas for all infants with little justification. It has been well-recognized for decades that there are many factors contributing to NEC; infants receiving human milk also develop NEC. For many infants in the NICU, sometimes there is no availability of human milk. What is going to happen to them if formula companies stop making premature formulas?
The most promising therapeutic to try to reduce the risk of NEC would be a safe probiotic. However, the FDA closed off this avenue (see: End of the Line for Probiotics for Preterm Infants). Even if the FDA reversed its position, no company would be willing to try to develop these products due to fear of litigation.
Background/Methods: A constitutional disease‐causing variant (DCV) in the SMAD4 or BMPR1A genes is present in 40%–60% of patients with juvenile polyposis syndrome (JPS). A total of 124 children with JPS were included: 69 (56%) DCV‐negative and 55 (44%) DCV‐positive (53% SMAD4 and 47% BMPR1A) with a median (interquartile range) follow‐up of 4 (2.8–6.4) years
Key findings:
DCV‐positive children were diagnosed at an older age compared to DCV‐negative children [median 12 years vs. 5 years, respectively, p < 0.001], had a higher frequency of family history of polyposis syndromes (50.9% vs. 1.4%, p < 0.001), experienced a greater frequency of extraintestinal manifestations (27.3% vs. 5.8%, p < 0.001), and underwent more gastrointestinal surgeries (16.4% vs. 1.4%, p = 0.002). All operations in the DCV‐positive group were performed in patients with SMAD4 mutations
DCV-positive children had more frequent new polyps: average of 12.2 versus 2 new polyps for every year of follow‐up
DCV-positive children had a lower frequency of rectal bleeding (56% compared to 93%) which could be a factor in later presentation
There was no difference in the burden of polyps between patients with SMAD4 and BMPR1A mutations. A higher frequency of gastric polyps was observed in the SMAD4 group (55.3%vs. 9.1% for the patients in the BMPR1A group ,p = 0.004). . HHT was observed only in the SMAD4 mutations group (20.7% vs. 0 in the BMPR1Agroup. p = 0.024)
My take: Children with DCV-positive JPS likely require more frequent surveillance than DCV-negative JPS.
ESPGHAN Juvenile Polyposis Syndrome Recommendations These recommendations are different in that they do not recommend EGD in the pediatric age group: “Surveillance of the upper GI tract in affected or at-risk JPS patients is not required in childhood or teenage years, unless there is unexplained anaemia or upper GI symptoms.”
Are You Familiar with CMMR-D? The term CMMR-D refers to constitutional mismatch repair deficiency. This occurs when an individual inherits two MMR gene defects (rather than one gene defect in Lynch syndrome); with CMMR-D screening recommendations include yearly endoscopic evaluation beginning at age 3 years or at diagnosis.
Recently, Dr. Steve Erdman gave our group a great update on polyposis disorders. My notes below may contain errors in transcription and in omission. Along with my notes, I have included many of his slides.
Key points:
There has been breath-taking progress in understanding of polyposis disorders. It is important to have genetic counselors participate to optimize testing and evaluation
In patients with suspected polyposis syndromes, a genetic diagnosis is very important and can help guide management
Family history is very important. If several family members have had GI or other cancers at a young age, more aggressive interventions are usually indicated. However, individual family members can have a wide variation in presentation
In patients with many polyps, it is worthwhile to alert family to the fact that some polyps can be missed on colonoscopy and to contact medical team if there are recurrent symptoms like rectal bleeding
Some disorders, like juvenile polyposis syndrome (JPS), the connection between polyp presence and cancer risk is not clear. The increased risk for colon cancer my remain after polypectomy.
For most individuals with adenomatous polyps, removal of the polyps prevents cancer development (in the GI tract) as there is a well-described adenoma-to-cancer sequence that typically takes 7-10 years to progress from adenoma to colon cancer
With FAP, the severity is related in part to the specific mutation. Mutations in the mutation cluster region are associated with an aggressive phenotype and mutations causing attenuated FAP are less aggressive
For FAP, timing of potential colectomy involves factors including severity as well as social factors. In teenagers in which there is a concern about being lost to follow-up, this is a factor that could influence earlier intervention
Many times a 2nd opinion in pathology can be helpful, especially if colon cancer is reported. However, histologic dysplasia can be tricky as well
Isolated CHRPE usually does not require evaluation. Dr. Erdman noted that sometimes genetic testing is offered to a family for reassurance. He discouraged colonoscopy in this setting unless a genetic diagnosis has been established or symptoms like rectal bleeding are present. The penetrance of APC mutations (development of polyps) can be quite variable (especially with attenuated form)
Case #1 presented a 14 yo with 50+ multilobulated pedunculated polyps which histologically were tubulovillus adenomas. Initial diagnosis was elusive despite extensive testing
Case#2 presented 8 yo twins. Aggressive management was indicated as 5 family members developed colorectal cancer prior to age 20 years.
Case#2 Improvements in testing allowed identification of a point mutation in the 1B promoter region of the APC gene
Case#3 presented a 16 yo with anemia and pain who was found to have a colonic mass related to mismatch repair mutation. Dr. Erdman indicated that obtaining adequate tissue for a diagnosis (“dig a hole”) is important. (As an aside, other colleagues have had the experience of tumors which were highly vascular and it is important to keep this possibility in mind)
Amsterdam II Criteria for Lynch Syndrome
Case#4 presented a 12 yo with neurofibromatosis (NF-1) who developed CRC and ultimately diagnosed with CMMR-D. This is a highly aggressive cancer susceptibility disorder with a very poor prognosis (see post: Are you familiar with CMMR-D?)
Case#5 presented two siblings (13 yo, 17 yo) who had half-sibling who died from CRC at age 25 yrs. This case illustrated “genetic anticipation” as each generation in this family with Lynch syndrome tended to develop CRC earlier in life. Amsterdam criteria can be helpful in identifying Lynch syndrome
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.
C Andrews et al. J Pediatr Gastroenterol Nutr. 2024;79:35–41. Impact of medication dosage on Helicobacter pylori eradication rates among pediatric patients
As I write this post on July 1st, I recollect having to learn the weight-based dosing of acetaminophen during my first day of pediatric internship. Even at this early stage, it was quite clear of the importance of getting the right dose. This article makes clear that there is a lot of room for improvement in dosing with regards to H pylori.
This retrospective study examined 144 children. Correct dosing was based on ESPGHAN-NASPGHAN guidelines:
Key findings:
The overall eradication rate was 73.6% (“well below the greater than 90% optimal eradication cut-off for H. pylori therapies”)
There was a high rate of improper weight‐based dosing: proton pump inhibitor(PPI) 31.2% (45/144), amoxicillin 31.7% (39/123), metronidazole (MET) 19.4% (12/62), clarithromycin (CLA) 23.9% (22/70), tetracycline 50% (6/12), bismuth 26.1% (6/23).
When PPIs were properly weight‐dosed, there was a 78.8% eradication rate that dropped to 62.2% with suboptimal dosing (p = 0.036, odds ratio [OR]: 2.26). The dose of PPI was incorrect in 45 patients.
When amoxicillin was properly weight‐dosed, successful eradication was achieved in 81% versus only 53.8% when improperly dosed (p = 0.002; OR: 3.64). The dose of amoxicillin was incorrect in 39 patients. There was no statistically significant impact on eradication rates with improper weight‐based dosing of MET, CLA, tetracycline, or bismuth.
My take: It is worthwhile to double-check on dosing for H pylori treatments -it results in better eradication rates. Also, in this study, as expected, quadruple therapy regimens had higher success rates (85% eradication); however, it was used in only 20 patients. In patients (virtually all of my patients) without known antimicrobial sensitivity, it has been my practice to use quadruple therapy (related post: Quadruple Therapy for Helicobacter Pylori Favored in Toronto Guidelines).
This retrospective study examined 546 children with esophageal atresia (EA) who underwent 1,473 surveillance endoscopies (2004-2023). The authors defined a hiatal hernia as at least 1 cm of gastric folds present above the level of the diaphragmatic pinch. “Actionable findings” were any finding that prompted a change in management.
Key findings:
A total of 770 endoscopies (52.2%) in 394 unique patients (72.2%) had actionable pathology
The most common actionable finding was esophagitis which lead to escalation of therapy (484 endoscopies in 32.9% of patients). However, de-escalation of therapy was common as well; this occurred in 233 patients (after 310 endoscopies)
Barrett’s esophagus (intestinal metaplasia) was identified in 7 unique patients (1.3%) at a median age of 11.3 years. 6 of 7 patients with Barrett’s were receiving acid suppression at time of diagnosis
Actionable findings leading to surgical intervention were found in 55 children (30 refractory reflux and 25 tracheoesophageal fistulas).
Significant predictors of actionable pathology included increasing age, long gap atresia, and hiatal hernia.
Symptoms were not predictive of actionable findings, except dysphagia (OR 5.80), which was associated with stricture.
Acid suppression was associated with a reduced odds of actionable findings (OR 0.78); however, there was still a high rate of actionable findings in this group. 51% of endoscopies while a patient had been receiving acid suppression had actionable findings.
Fundoplication was NOT associated with protection against actionable findings (OR 1.42)
Table 2 notes that 52 (3.5%) patients had eosinophilic esophagitis therapy escalated. Infrequently, non-esophageal diseases were identified: Celiac in 3 patients (0.2%), Crohn’s disease in 2 patients (0.1%), eosinophilic gastritis and/or duodenitis in 2 (0.1%), and H pylori in 4 patients (0.3%).
Proposed Management Algorithms:
Discussion Points (from authors):
Take multiple levels of esophageal biopsies: “Any surveillance esophagogastroduodenoscopy (EGD) should at minimum include 2 to 3 levels of esophageal biopsies”
Acid suppression recommendations: “Barrett’s esophagus is proposed to be an absolute contraindication to acid suppression wean; relative contraindications to weaning acid suppression include earlier erosive esophagitis, earlier failed acid suppression discontinuation attempt(s) with rebound esophagitis, or hiatal hernia; if acid suppression is weaned in these high-risk situations, we believe close follow-up endoscopy is warranted to assess for rebound pathology [which happened in nearly 20%].” And, “our practice is to empirically de-escalate acid suppression in children without contraindications to doing so when there is no gross esophagitis and biopsies show no or minimal inflammation (generally less than 5 eosinophils per high powered field).”
Consider doing endoscopy off acid suppression for approximately three months: “To maximize the information yield from the initial endoscopy, a patient may first wean off acid suppression approximately 3 months before endoscopy to permit evaluation for both anatomy and esophagitis off acid suppression. Subsequent surveillance is performed according to our algorithm and within at most 6 to 12 months of any acid suppression changes.”
The authors do not generally recommend pH-Impedance. “There are no consensus “normal” values for pH-impedance reflux parameters in either healthy or EA children, and pH-impedance has failed to show any predictive correlation with actual esophagitis in multiple pediatric studies. In particular, children with EA with “normal” numbers of reflux events cannot adequately clear their refluxate in the context of poor esophageal motility and can still develop reflux injury. pH-impedance tracings in EA require manual review by an experienced reader, with automated analysis being highly unreliable in the setting of low baseline impedance values.”
Limitations: 1. Some of the actionable findings may have been expected based on prior endoscopies (e.g. prior stricture) and could influence value of symptoms like dysphagia. 2. This population was skewed to patients with more severe EA as it is a subspecialty center. One indicator was that their group had 24% with long-gap EA compared to an overall expected rate of 10% in the general EA population 3. Retrospective study 4. Many of the patients were not truly “surveillance” endoscopies but were done due to reported symptoms
My take: It’s unfortunate that this article did not get published in a more mainstream pediatric journal (e.g. JPGN, J Pediatr, Pediatrics) or a more mainstream gastroenterology journal (eg. Gastroenterol, Clin Gastroenterol Hepatol, AJG) as this article provides a lot of great data and useful advice. More than 70% of subjects had actionable findings during the course of their follow-up, including more than 40% of 1 year-olds.
The algorithms above suggest that at minimum, EA patients should have endoscopy every 5 years (likely starting between 12-18 months). More frequent endoscopy (every 2-3 years) may be worthwhile in those with risk factors (e.g. long gap EA, hiatal hernia, and prior esophagitis) and follow-up endoscopy is needed sooner if change in therapy (stricture dilation, esophagitis treatment or treatment de-escalation).
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.
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