Linaclotide Now FDA-Approved for 2-5 Year Olds with Functional Constipation

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Ironwood Pharmaceutical Press Releasse, 5/27/26: FDA Approves Use of LINZESS® (linaclotide) in Pediatric Patients Two Years of Age and Older with Functional Constipation (FC)

An excerpt:

Expanded indication extends availability to children ages 2-5 with FC; previously approved in pediatric patients 6 years of age and older –
– LINZESS remains the first-and-only FDA-approved prescription therapy for pediatric FC…

Parents can mix the contents of the LINZESS capsule with applesauce or water, providing flexibility for administration in young children...

The FDA approval for pediatric patients ages 2-5 was supported by data from a 12-week Phase 3 randomized, placebo-controlled clinical trial evaluating LINZESS in pediatric patients aged 2-5 years with FC. In the study, LINZESS 72 mcg demonstrated improvement in spontaneous bowel movement frequency compared with placebo. The safety profile of LINZESS observed in the trial was generally consistent with the established safety profile from trials in adults with chronic idiopathic constipation (CIC) and older pediatric patients with FC...

LINZESS 72mcg is available as a once-daily treatment of FC for pediatric patients 2 years of age and older

My take: In this age group, typical over-the-counter laxatives including polyethylene gylcol, magnesium products, and senna products along with diet and behavior modification will be effective for most children. Most children will not need a prescription medication to manage their constipation.

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Perito Moreno Glacier

Association Between Hypermobility Disorders, Orthostatic Intolerance and DGBIs

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N Santucci et al. J Pediatr Gastroenterol Nutr. 2026;82:1394–1399. Open Access! Children and adolescents with disorders of gut–braininteraction with comorbid hypermobility and orthostaticintolerance have worse outcom

Methods: This was a retrospecitive study from a multidisciplinary pediatric DGBI clinic which examined the relationship between hypermobility spectrum disorders (HSDs) and orthostatic intolerance (OI). HSD terms included Ehlers–Danlos syndrome, hypermobile Ehlers–Danlos syndrome, and generalized hypermobility; OI terms included postural orthostatic tachycardia syndrome, dysautonomia, and orthostatic hypotension. Of 175 patients, 46% had HSD and 43% had OI; 26% had both HSD and OI.

Key findings:

  • Patients with both HSD and OI had significantly worse nausea, depression, disability, and somatization scores than others (p < 0.01). 
  • HSD and OI groups individually also showed worse outcomes than non-HSD/non-OI groups. Moderate correlations were found between depression and anxiety in OI and nausea and disability in HSD.
  • Patients with both HSD and OI (n=45) had worse NSS (p < 0.0001), PHQ-9 (p = 0.007), FDI (p = 0.001), and CSI (p < 0.001) compared to patients with either OI or HSD and patients with neither.

Discussion:

  • “Autonomic dysfunction may explain the shared GI symptoms for OI and HSD patients. GI blood flow, motility, and secretion are regulated by an integral neural mechanism involving inputs from the central nervous system and the enteric nervous system. “
  • “Formal diagnosis of HSD and OI can be challenging and often requires involvement of multiple subspecialists…Studies comparing these groups run the risk of under-reporting diagnoses or including patients without the diagnosis. Strict clinical criteria are required using guidelines.”
  • There may be a selection bias for these patients in a specialized clinic for DGBIs; this was not discussed in this article. There is likely an increased rate of screening for HD and OI in patients with more severe DGBIs given previous reports of association with DGBIs.

My take: HSDs and OI are highly prevalent in DGBIs. In this study, both of these disorders were associated with worsened symptoms.

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Marked Variation with Vibration Controlled Transient Elastography in Pediatric Metabolic Dysfunction Associated Steatotic Liver Disease

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Background: “Given the invasiveness of liver biopsy, the development of accurate non-invasive biomarkers of MASLD severity remains an area of active investigation… clinical practice has been shifting towards the use of point-of-care vibration controlled transient elastography (VCTE), based on extensive cross-sectional and longitudinal validation data in adults.11 However, despite increasing clinical use of VCTE to determine MASLD presence and severity in children, this technique lacks well-validated cut-points in this age range and, importantly, there are no data evaluating the implications of longitudinal changes.12–15…While a high (>12 kPa) LSM is concerning for progression to advanced fibrosis in adults,11 the optimal cutoff for defining an elevated LSM in pediatric MASLD has yet to be established.16, 17“

Methods: This was a longitudinal retrospective study of youth (n=149, mean age 14 yrs) with MASLD who underwent ≥2 VCTE studies.

Key findings:

  • Controlled attenuation parameter (CAP) and liver stiffness measurements (LSMs) showed marked intraindividual variability.
  • Changes in CAP and LSM did not predict categorical outcomes of ALT and GGT reduction, however were significantly positively associated with continuous ALT and GGT outcomes, independent of BMI percentile.
Individual variation in mean controlled attenuation parameter (CAP; panel A) and liver stiffness measures (LSM; panel B) over time. Solid black lines represent Loess lines.

My take (borrowed in part from the authors): “Given the substantial intra-individual variation and the current lack of validated definitions for clinically significant change in VCTE measures (CAP and LSM) in children with MASLD, serial VCTE measurements in individual pediatric patients should be interpreted with caution and not relied upon in isolation for clinical decision-making.”

While transient elastography is not reliable in pediatric MASLD, a related article suggests that it is helpful for pediatric autoimmune hepatitis: W Janczyk et al. J Pediatr Gastroenterol Nutr. 2026;82:1349–1356. Transient elastography for accurate staging of liverfibrosis and predicting complications in children withautoimmune hepatitis

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Cyproheptadine: “Vitamin P”

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C Baker et al. J Pediatr Gastroenterol Nutr. 2026;82:1321–1324. Cyproheptadine: The secret sauce

Mechanism of action:

  • A first-generation antihistamine with anti-cholinergic, anti-serotonergic, and local anesthesia properties; its precise mechanism of action is poorly understood.

Formulation/pharmocokinetics:

  • Enteral tablet and syrup formulations appear to be well absorbed with peak serum levels 6–9 h after dosing in adults.2 However, anecdotally in pediatrics, the side effect of somnolence is often felt much more quickly.

Uses (off-label):

  • Promote weight gain: “There is ample literature to support success in varying populations, including mild to moderately undernourished toddler-aged children and children with cystic fibrosis.4–6“
  • Cyclic vomiting syndrome
  • Functional abdominal pain and dyspeptic symptoms
  • Post-operative Retching After Fundoplication

Dosing (by indication):

  • “For cyclic vomiting syndrome prophylaxis, the recommended dose is 0.25–0.5 mg/kg/day divided every 8–24 h with a maximum dose of 12 mg a day.”
  • “For appetite stimulation, the recommended dose is 0.25 mg/kg/day divided twice daily, with a maximum dose ranging from 12 to 32 mg depending on patient age.”
  • “An effective dosing range for use in disorders of the gut–brain interaction (DGBIs) in pediatric patients (median age 9 years) of 0.13–0.2 mg/kg/day has been reported when used on average for 9 months, with a mean initial dose of 4.85 mg/day and final dose of 5.34 mg/day.1“
  • “A large, systematic review from France identified the median dose for all pediatric clinical indications to be 0.25 mg/kg/day…Many clinicians use once-daily dosing to improve adherence.”

Contraindications, Drug Interactions, and Complications:

  • “Cyproheptadine is contraindicated in newborns and premature infants due to the potential for CNS depression and a lack of evidence in its safety and efficacy.”
  • “Cyproheptadine has potential for multiple drug-drug interactions, and dose adjustments may be required with concomitant therapies.”
  • “Recent publications suggest that up to 30% of patients will experience mild and self-limited side effects while taking cyproheptadine.8 The most common side effects are somnolence, increased appetite, weight gain, and behavior changes.1, 8 Caution should be exercised in the use of cyproheptadine in children who are already considerably overweight…A rare side effect of adrenal insufficiency…has been documented in pediatric patients.”

My take: Because cyproheptadine is so useful for pediatric GI disorders, some of my colleagues have referred to it as “Vitamin P” (periactin). This review provides a lot of helpful data and guidance.

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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

Low Risk of Solid Organ Transplantation with Celiac Disease

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JB Doyle et al. Clin Gastroenterol Hepatol 2026; Risk of solid organ transplantation in individuals with celiac disease: a nationwide cohort study

Background: “Celiac Disease (CeD) is associated with immune-mediated diseases of the liver, including autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis. Individuals with CeD are also at increased risk for non-autoimmune diseases of the liver, including metabolic dysfunction-associated fatty liver disease…CeD has also been associated with chronic kidney disease and cardiovascular disease. Multiple studies have demonstrated that individuals with CeD have increased rates of end-stage renal disease than the general population, with particularly strong associations between CeD and
autoimmune nephropathy, diabetic nephropathy, and systemic lupus erythematosus (19-22).
Population-level data also suggests that individuals with CeD have an increased risk of
cardiovascular disease and ischemic heart disease>”

Methods: Population-based matched cohort study in Sweden. We identified individuals with biopsy-proven CeD diagnosed between 2000-2023 using the nationwide histopathology cohort ESPRESSO. We calculated the incidence of solid organ transplantation (liver, heart, kidney, and lung) in CeD patients and estimated the risk relative to the general population. There were  41,277 individuals with CeD and 196,863 age- and sex-matched comparators with a mean follow-up of 12.1 years.

Key findings:

  • There were 85 solid organ transplantations in patients with CeD (17.0 per 100,000 person-years) and 111 in matched comparators (4.6 per 100,000 person-years). This corresponded to an adjusted hazard ratio (HR) of 2.76 
  • The highest relative risk was for liver transplantation: HR 7.26; for kidney HR 1.85. For heart, HR was 2.35 did not reach statistical significance (CI: CI 0.84-6.61)

Discussion:

“Shared genetic susceptibility may explain physiological links between CeD and autoimmune liver disease, especially since we also detected an increase in liver transplantation prior to CeD diagnosis…owever, CeD patients in our analysis had an increased risk of liver transplantation relative to their nonaffected siblings, suggesting that CeD itself may be a risk factor beyond genetic predisposition”

My take: While nearly triple the incidence compared to the general population, the absolute increased risk of needing a solid organ transplant was about 1 in 10,000. For comparison, the risk of dying in a bicycle accident in one’s lifetime is about 1 in 5,000. Nevertheless, it may be worthwhile to screen for CeD in those with end-organ disease. Additionally, checking liver tests periodically in patients with CeD would be reasonable.

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Analysis of the 2025-2030 Dietary Guidelines for Americans

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In a previous post, I reviewed the 2025-2030 Dietary Guidelines for Americans (Have You Read the New “Dietary Guidelines for Americans, 2025-2030”?). For more insight into this topic, the following commentary is useful:

  • DK Tobias, FB Hu. NEJM 2025; 394: 1969-1971. The 2025–2030 Dietary Guidelines for Americans — Progress, Pitfalls, and the Path Forward

Background: “The Dietary Guidelines for Americans (DGAs), updated every 5 years by the U.S. Department of Agriculture (USDA) and the Department of Health and Human Services (HHS), set nutrition standards for federally supported programs, including school, military, and institutional meals; elements of the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) and the Supplemental Nutrition Assistance Program (SNAP); and related public education and implementation efforts. The DGAs also influence federal policies and regulations, clinical practice and health professional education, food marketing, industry formulation, and individual food choices.”

Key points:

  • “In the current cycle, although the DGAC [Independent Dietary Guidelines Advisory Committee] rigorously adhered to established procedures,3 its extensive report was not adopted as the guidelines’ scientific basis, and only 14 of its 56 specific recommendations were implemented. The USDA and HHS cited the committee’s evaluation of the evidence “through a health equity lens” … as their central rationale for dismissing most of its recommendations.”
  • “The new DGAs reintroduce the 1992 food pyramid, but invert it to feature meat, poultry, and full-fat dairy products more prominently, alongside vegetables and fruits, while relegating whole grains to the bottom wedge — an arrangement suggestive of a low-carbohydrate diet.”
  • “The new DGAs increase recommended protein intake to 1.2-to-1.6 g per kilogram of body weight per day — as high as double the adult recommended dietary allowance (0.8 g per kilogram per day).4 … But most Americans already consume well above the recommended dietary allowance of protein, primarily from animal sources,3 and there is little evidence that substantially increasing population protein intake confers additional health benefits.”
  • “The protein guidance appears to place greater visual and messaging emphasis on animal sources…This shift diverges from the broader scientific consensus, including the DGAC’s conclusion that dietary patterns higher in plant-derived proteins and fats, fruits, vegetables, and whole grains are associated with lower risks of chronic diseases, whereas higher intakes of red and processed meats are associated with increased risks.”
  • “The 2025–2030 DGAs embrace concise, consumer-oriented messaging, emphasizing that Americans should “eat real food” and eat less highly processed food.1 Although this advice reflects growing concern about ultraprocessed products, its lack of specificity regarding ingredients or quantitative thresholds limits its policy relevance.”
  • “Although the new DGAs continue to recommend limiting alcohol consumption, they no longer specify the quantitative upper limits included in previous guidelines, raising questions about the recommendations’ clarity and consistency.”
  • “Restoring confidence in the DGAs will require stronger scientific grounding and greater transparency in their development.”

My take: Many of the recommendations appear to fall in line with previous viewpoints expressed by RFK Jr, regardless of what independent experts have advised. Overall, the new guidelines do not represent a significant improvement from the previous guidelines due to the problems outlined in this commentary.

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Guanaco in Patagonia, Argentina

Surprise, Surprise – Measles Cases in South Carolina Occurred Where Vaccinations Are Lowest Plus One

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EA Serman, B Witrick, L Rennett. NEJM 2026; DOI: 10.1056/NEJMc2604004.
Clusters of Concern — Spatial Link between Childhood Undervaccination and Measles Outbreaks in South Carolina

An excerpt:

As of April 8, 2026, South Carolina had 997 confirmed cases of measles, of which 95.3% were reported to be among unvaccinated residents.2 Of these cases, 90.8% occurred in children (<18 years of age).2 Thus, school-based vaccination patterns provide a reasonable indicator of local pediatric susceptibility in the communities where transmission has occurred…

Spartanburg County (population, 380,000) was identified as the dominant cluster, containing 27 of 109 hot-spot tracts (24.8%). Of the 997 reported measles cases in the state, 940 (94.3%) occurred in Spartanburg County…

The mean vaccination coverage was lower in the schools with reported measles cases (coverage, 83.9%) than in those with no reported cases (coverage, 92.9%)…The locations of the 30 schools with measles exposure were not uniformly distributed: 26 (87%) were located within or adjacent to undervaccinated hot-spot tracts

In other health news, there is a reason why milk is pasteurized:

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Bepirovirsen: Breakthrough for Chronic Hepatitis B Infection

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  • J Hou et al. NEJM 2026. DOI: 10.1056/NEJMoa251513. Phase 3 Results of Bepirovirsen Treatment for Chronic Hepatitis B Virus Infection
  • A Lok. NEJM 2026. DOI: 10.1056/NEJMe2605575. A Major Step toward a Cure for Hepatitis B Infection (editorial)

Methods:

The B-Well trials enrolled patients with noncirrhotic chronic hepatitis B with suppressed HBV DNA during receipt of NA therapy and a low HBsAg level (≤3000 IU per milliliter). A total of 1838 patients were randomly assigned in a 2:1 ratio to receive bepirovirsen or placebo administered as a weekly subcutaneous injection for 24 weeks. The patients who had undetectable HBsAg and unquantifiable HBV DNA from week 24 to week 46 were eligible to discontinue NA therapy at week 48. The primary outcome of a functional cure was assessed at week 72.

Key findings:

  • In two phase 3 trials, 19% of patients with chronic hepatitis B infection had a functional cure with the antisense oligonucleotide bepirovirsen, 24 weeks after stopping all HBV treatment; functional cure was not seen with placebo.

Adverse events of grade 3 or higher were more common in the bepirovirsen groups than in the placebo groups (16% vs. 3%), with an increase in alanine aminotransferase (ALT) being the most common (6%) with bepirovirsen. In addition, adverse events requiring a dose interruption or delay were reported in 16% of the patients in the bepirovirsen groups as compared with 2% in the placebo groups.

My take:

  1. Currently, it is estimated that 240 million persons worldwide are living with chronic HBV. These trials represent a big step forward showing that many patients can achieve a functional cure (no detectable HBV) off all medications. Prevention of HBV, though, via immunization holds much more promise in reducing the number of individuals with poor outcomes due to HBV.
  2. Several of the adverse events — an increase in the levels of ALT and creatinine and a decrease in the platelet count — can be potentially serious if stringent monitoring (every 1 to 2 weeks) and strict trial-adopted guidelines regarding the pausing of therapy are not followed.

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Vonoprazan-Tetracycline: Effective Dual Rescue Regimen for H Pylori

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W Gao et al. Gastroenterol 2026; 170: 1473-1483. Open Access! Vonoprazan-Tetracycline Dual Regimen as Rescue Therapy for Helicobacter pylori Infection: Randomized Controlled Trial

Methods: In this prospective, open-label, randomized controlled trial(n=350), H pylori–positive adults with at least 1 prior eradication failure were allocated 1:1 to VT dual therapy (vonoprazan [20 mg, twice a day] and tetracycline [500 mg, 3 times a day]), or bismuth quadruple therapy (BQT; lansoprazole [30 mg, twice a day], colloidal bismuth [150 mg, 3 times a day], tetracycline [500 mg, 3 times a day], and metronidazole [400 mg, 3 times a day]) for 14 days.

Key findings:

Discussion:

  • “Potent acid suppression broadens the applicability of dual therapy, allowing a single sensitive antibiotic to achieve reliable eradication when gastric pH is maintained at ≥6 with potassium-competitive acid blockers.13–15“
  • “Antibiotic resistance is a major obstacle to the successful eradication of H pylori, particularly in rescue treatment. Surveillance data from the Asia-Pacific region (1990–2022) have shown persistently high resistance rates to metronidazole (52%), levofloxacin (26%), and clarithromycin (22%), whereas resistance to tetracycline and amoxicillin has remained low, both at ∼4%.17“
  • “Although high-dose amoxicillin dual therapy has been well studied and incorporated into guidelines for first-line treatment, the clinical potential of tetracycline-based regimens deserves similar attention.19,20“

Limitations: This was an open-label trial from a single center and did not include antibiotic resistance testing, which may limit generalizability to other regions or clinical settings.

My take (borrowed from authors): Vonoprazan combined with tetracycline is a simplified, penicillin-free rescue regimen, and may offer a practical option for the rescue treatment of H pylori infection. Its eradication rate was comparable to that of traditional tetracycline-metronidazole–based bismuth quadruple therapy, and was associated with fewer adverse events and better adherence. 

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Familial Adenomatous Polyposis (FAP): Cancer Incidences and APC Mosaicism

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From Bouchiba et al:

From the editorial: “Bouchiba et al10 present a Dutch cohort study providing the most comprehensive evaluation of cancer incidence and temporal trends in FAP to date. Among 1230 patients with FAP followed over 5 decades, one-third developed cancer despite major preventive advances, underscoring the persistent lifetime risk in FAP…the 12-fold higher risk compared with the general population and the frequent late-stage detection of gastric cancer are concerning and underscore the need for improved endoscopic surveillance strategies.”

From Terlouw et al:

Background: A substantial proportion of patients with adenomatous polyposis have no germline pathogenic variant in APC. The aim of this study was to determine the prevalence of APC mosaicism in these patients with unexplained polyposis

Key findings:

  • The rate of APC mosaicism was 9.4%. This rate was 14.3% (46 of 322) in patients who met the scope of national hereditary polyposis testing guidelines (≥10 adenomas before the age of 60 or with ≥20 adenomas before the age of 70)
  • In patients who did not meet the scope of national guidelines, the detection rate was 2.3% (5 of 219)
  • None of the children tested in this cohort inherited the mosaic variant.

My take:

  1. Despite increasing knowledge of FAP, frequent cancers continue to occur
  2. In those with features of FAP without identified pathogenic mutations, testing for APC mosaicism should be considered. In addition, in those with APC gene mutation, regular colonoscopy is recommended along with at least one esophagogastroduodenoscopy.

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