BE Lacy et al. Gastroenterology & Hepatology 2024; 20: 264-272. Open Access! Leaky Gut Syndrome: Myths and Management

Background: “Leaky gut syndrome is a recent diagnosis now popularized in the lay literature. It has been associated with a myriad of disorders (eg, Alzheimer disease, autism, dementia, diabetes, fibromyalgia),^5-8…Despite lay literature claims of gut permeability’s pathologic nature, it is important to understand that all individuals are subject to a baseline level of intestinal permeability, as normal intestinal physiology involves selectively permeable tight junctions that respond to a variety of biological factors…Minimal to no reliable evidence exists to suggest that leaky gut syndrome maintains a causative role in the pathogenesis of conditions that are most commonly associated with it in lay discussion, including fibromyalgia, chronic fatigue syndrome, allergies, headache, and brain fog.^11,19 “

Key Points:

• Myth: Leaky Gut Syndrome Is Common and Causes Extraintestinal Symptoms
• Myth: Leaky Gut Syndrome Develops Owing to Stress and Eating Gluten – “a variety of factors may influence intestinal permeability, including illness, antibiotic and drug use, alcohol consumption, and physical activity.^1,21-24“
• Myth: Leaky Gut Syndrome Is Just a Break in the Gut Lining 
• Myth: Leaky Gut Syndrome Can Be Confidently Diagnosed by Symptoms Alone  -“reported symptoms typically include bloating, abdominal pain, fatigue, headache, and food sensitivities, among dozens of other symptoms.^1,9 Such symptoms are nonspecific in nature”
• Myth: Leaky Gut Syndrome Can Be Readily Diagnosed by Blood Work and Standard Endoscopy -“Although available, the clinical utility of using orally ingested saccharide probes and in vitro techniques is limited partly owing to unknown normal values for comparison, lack of standardized protocols, and limited attempts at validation.⁴⁷…As noted previously, confocal laser endomicroscopy may provide valuable information on intestinal permeability, although it may not be as sensitive as once thought for the evaluation of food sensitivities.⁴⁵ For now, no validated tool exists to accurately diagnose leaky gut syndrome.³⁹…The utility of measuring zonulin in over-the-counter kits is thus suspect. Other plasma biomarkers measuring bacterial translocation, such as lipopolysaccharide-binding protein, may correlate more reliably with intestinal permeability.⁵² Currently, no blood test to diagnose leaky gut syndrome exists, and further investigation is needed to identify valid, reliable, and clinically useful serum biomarkers of impaired intestinal barrier function.”
• Myth: Leaky Gut Syndrome Can Be Diagnosed by Stool Studies -“stool testing for leaky gut syndrome has been marketed to consumers…such tests are unregulated, and minimal evidence exists to support their use in the clinical setting… Even if testing were to reliably measure intestinal permeability, results would be of unclear significance, as no standard of care currently exists for treating and managing leaky gut syndrome. “
• Myth: Leaky Gut Syndrome Can Be Cured by Diet and Probiotics -“a direct link between diet and treatment of leaky gut syndrome has not been established.” 
• Myth: Nutritional Supplements Can Cure Leaky Gut Syndrome -“although several nutritional supplements have been suggested to improve intestinal permeability, only glutamine has been shown to improve leaky gut syndrome in the context of IBD and IBS. More data are needed before any nutritional supplements, including glutamine, can be recommended in clinical practice”
• Myth: Medications Cannot Change Intestinal Permeability -“Several medications can alter intestinal permeability.” Examples include lubiprostone (for IBS), and prednisone and infliximab (for IBD).
• Myth: Once Leaky Gut Syndrome Develops, It Will Never Go Away -“no study has been performed to properly evaluate changes in symptoms and underlying pathophysiology over time.”

Overall:  A leaky gut “cannot be accurately diagnosed by symptoms, blood work, or stool studies. Although the term leaky gut syndrome implies changes in intestinal permeability, it is the rare patient who undergoes objective testing to identify changes in intestinal permeability…changes in intestinal permeability are not always deleterious, and the relationship with symptoms is unclear.”

My take: It is not unusual for me to take a deep breath and sigh when I see that I am about to see a patient with a chief complaint of a “leaky gut.” Typically, this visit will mean a lengthy discussion indicating that previous testing was not worthwhile and there are no specific treatments. Many times this discussion is not well-received.

Related blog post: Is Intestinal Function in Children with Autism Different?

Gastroenterology & Endoscopy News 4/12/24: Pain Management Protocol Reduces Opioid Use in Hospitalized IBD Patients

“Dr. Berry and his co-investigators developed the Proactive Analgesic Inpatient Narcotic-Sparing (P.A.I.N.-Sparing) protocol. The approach relies on scheduled nonopioid pain medications tailored to the severity of a patient’s pain (Figure). However, patients have the option to request opioid medication for uncontrolled breakthrough pain.”

Open Access! Berry, S.K., Takakura, W., Patel, D. et al. A randomized controlled trial of a proactive analgesic protocol demonstrates reduced opioid use among hospitalized adults with inflammatory bowel disease. Sci Rep 13, 22396 (2023). https://doi.org/10.1038/s41598-023-48126-0

The authors conducted a randomized controlled trial in hospitalized patients with IBD (n=33) to evaluate the impact of a proactive opioid-sparing analgesic protocol. 

Key findings:

Those randomized to the intervention tended to have lower pain scores than the control group regardless of hospital day (3.02 ± 0.90 vs. 4.29 ± 0.81, p = 0.059), used significantly fewer opioids (daily MME 11.8 ± 15.3 vs. 30.9 ± 42.2, p = 0.027), and had a significantly higher step count by Day 4 (2330 ± 1709 vs. 1050 ± 1214; p = 0.014)

My take: It is a good idea to have a set pain management pathway –especially if it works to reduce pain and reduce the risk of excess opioid use.

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.

MP McGowan, AL Peterson et al. J Pediatr 2024; 113928. Open Access! Universal Pediatric Cholesterol Screening: The Time Has Come!

Background: More than a decade ago, the AAP has previously “endorsed the National Heart, Lung, and Blood Institute’s pediatric cholesterol guidelines, recommending screening for all children between 9 and 11 years of age and, if normal, again between 17 and 21 years of age.” However, these guidelines conflict with “the US Preventive Services Task Force (USPSTF) [which] values the rigorous evidence from randomized controlled trials (RCTs).” The USPSTF has stated “there is insufficient evidence to assess the balance of benefits and harms of universal screening for cholesterol disorders in children and adolescents ages ≤20 years.⁷” In addition, ” recent data suggest only between 2% and 22% of children in the US are screened between the ages of 9 and 11.^{2, 3, 4, 5}”

What is Familial Hypercholesterolemia (FH)?

• Heterozygous FH (HeFH) “should be suspected in a child with an LDL-C of ≥160 mg/dL, after the exclusion of secondary causes and adherence to a heart-healthy diet, especially in the setting of a family history of ASCVD or with a parent with elevated LDL-C”
• “Homozygous FH (HoFH) [is] much rarer, occurring in 1:250 000-1:360 000 people…HoFH should be suspected in children with an LDL-C of ≥400 mg/dL in the setting of a family history of early ASCVD and/or with 1 or both parents having an untreated LDL-C of ≥190 mg/dL¹³“

Why Screening in Childhood is Important?

• “HeFH is the second most common potentially fatal genetic disorder in humans, affecting 1 in 250-300 people.⁸…Homozygous FH (HoFH) [is] much rarer, occurring in 1:250 000-1:360 000 people.”
• Given the limitations of family history and lack of findings on physical exam, universal screening is needed to avert symptomatic atherosclerotic vascular disease (ASCVD).
• Proof that screening can make a difference: “In a 20-year follow-up study, Luirink et al followed a cohort of individuals with genetically confirmed HeFH who had initiated statin therapy in childhood. When compared with their HeFH parents who had not had the benefit of childhood therapy, statins virtually eliminated excess ASCVD risk in adulthood.¹⁶ At age 40, 26% of parents had experienced a cardiac event and 7% had died of ASCVD, whereas only 1% of the those treated as children had needed a vascular procedure (coronary artery stenting) and none had died.¹⁶“
• “Currently available therapies have the potential to completely normalize LDL-C in children with both HeFH and HoFH.^12,17 Such normalization of LDL-C in childhood will presumably prevent future cardiac morbidity and mortality.”
• “An RCT in 214 children with HeFH aged 8-18 years found that those randomized to statin therapy experienced regression of carotid atherosclerosis, whereas those randomized to placebo experienced progression.²⁵ Importantly, no safety concerns with statin treatment were identified.²⁵ …in a follow-up study²⁶ …found that age of statin initiation was an independent predictor of the degree of carotid atherosclerosis, indicating that earlier initiation is protective.²⁶“
• Cost burden of screening could be less in childhood. There is a higher rate of insurance coverage in U.S. for children 0-17 years compared to adults 18-64 years: in 2022, it was >95% compared to 88% respectively.
• Identification of children with HeFH and HoFH has the potential to identify siblings and parents “through a process known as reverse cascade screening.”

Cholesterol-Lowering Therapy:

• Many with HeFH and HoFH will respond to statin therapy
• Some need the addition of ezetimibe
• For severe cases (esp HoFH) injectable agents (eg.  evinacumab-dgnb, an angiopoietin-like3 inhibitor) may be needed

My take: There is a strong case for universal screening for hypercholesterolemia in childhood to prevent cardiovascular disease.

Related blog posts:

• Treatment Outcomes in Children and Adolescents with Hypercholesterolemia
• Conflicting Cholesterol Guidelines –Massive Undertreatment or Massive Overtreatment?
• NEJM: Competing Visions for U.S. Health Policy, Evolocumab for Pediatric Familial Hypercholesterolemia, and the Cervical Cancer Vaccine
• Cholesterol controversy

J Vandenplas et al. JPGN 2024; 78: 386-413. An ESPGHAN Position Paper on the Diagnosis, Management, and Prevention of Cow’s Milk Allergy

In this lengthy report, the authors provide 72 recommendations/statements -as such it does not do a great job focusing on key points.

Some of the points:

• Changes in stool characteristics, feeding aversion, or occasional spots of blood in stool are common and in general should not be considered as diagnostic of CMA, irrespective of preceding consumption of cow’s milk.
• Overdiagnosis of CMA occurs much more frequently than underdiagnosis; both have potentially harmful consequences. Therefore, the necessity of a challenge test after a short diagnostic elimination diet of 2–4 weeks is recommended as the cornerstone of the diagnosis

Conclusions: “Accurate diagnosis, avoiding under- and overdiagnosis, is mandatory but remains challenging due to the lack of specific symptoms and adequate diagnostic tests…Reintroduction of CM protein in non-IgE-mediated allergy and OFC [oral food challenge] in IgE-mediated allergy are the “gold standard” diagnostic tests, yet these are often not performed by caregivers. As a result, there is a risk of overdiagnosis and the implementation of long-term elimination diets, posing potential nutritional risks. The choice of formula for the treatment of CMA should take into consideration cost and availability of the therapeutic formula. Cow’s milk eHF is the first choice treatment option.”

My take: Only a tiny number of individuals are going to remember 72 recommendations.

Related blog posts:

• Good Bowel Sound Podcasts: Cow’s Milk Intolerance and Hirschspurng Disease
• Overdiagnosis of Milk Allergy in Infancy and New Consensus Recommendations
• Best of Allergy Articles 2021 -Cow’s Milk Allergy/Allergic proctocolitis (Part 4)
• Best Allergy Articles 2021 -Cow’s Milk Allergy (Part 3)
• Best Allergy Articles 2021 -Cow’s Milk Allergy (Part 2)
• Best Allergy Articles 2021-Cow’s Milk Allergy
• Overdiagnosis of Cow’s Milk Protein Allergy in Infants and Formula Industry Influence

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.

GD Toit et al. NEJM Evid 2024;3(6) DOI: 10.1056/EVIDoa2300311. Follow-up to Adolescence after Early Peanut Introduction for Allergy Prevention

Methods: This follow-up trial (followed ~80% of initial randomized cohort) examined the durability of peanut tolerance at age 144 months after years of ad libitum peanut consumption.

Key findings:

• At age 144 months, peanut allergy remained significantly more prevalent in participants in the original peanut avoidance group than in the original peanut consumption group (15.4% [38 of 246 participants] vs. 4.4% [11 of 251 participants].
• Both groups (early peanut avoidance group and early peanut consumption group) had periods of prolonged peanut avoidance between 72 months and 144 months.

My take (borrowed from authors) Peanut consumption, starting in infancy and continuing to age 5 years, provided lasting tolerance to peanut into adolescence irrespective of subsequent peanut consumption.

Related blog posts:

• The Peanut Story -From NEJM Blog
• “Separating Fact from Fiction in the Diagnosis and Management of Food Allergy”
• Peanut Allergy Prevention Guidelines
• LEAP-ON Study: Early Peanuts Prevent Allergies
• The Peanut Story -Skin Patch Chapter
• Best Allergy Articles 2021-Cow’s Milk Allergy
• How Likely/Persistent is Eosinophilic Esophagitis with Peanut Oral Immunotherapy
• Georgia AAP Nutrition Symposium 2019: Food Allergy Immunotherapy
• The “EAT” Study | gutsandgrowth

Links: Prevent Peanut Allergy (National Peanut Board)

E Elkaragy et al. JPGN; 78:800–809. Efficacy of lubiprostone for functional constipation treatment in adolescents and children: Randomized controlled trial

Methods:In this single‐blinded, randomized controlled study with 280 patients (aged 8–18) s with FC, patients were randomized either to a weight‐based lubiprostone dose (n= 140) or conventional laxatives (n= 140), for 12 weeks, followed by4 weeks posttreatment follow‐up. Patients weighing <50 and ≥50 kg were administered lubiprostone 8 mcg TID or 24 mcg BID, respectively.

Key findings:

• Improvement in constipation was achieved in 128 (91.4%) patients in the lubiprostone group, and in 48 (34.3%) patients of the conventional therapy group (p< 0.001) and was sustained after treatment discontinuation
• Mild self‐limited colicky abdominal pain and headache were the most prevalent side effects in the lubiprostone group

In their discussion, they note that a clinical trial by Benninga et al., which was designed to evaluate the efficacy and safety of lubiprostone in patients with FC aged 6–17 years in a placebo-controlled design, concluded that lubiprostone was not superior to placebo in terms of efficacy (18.5% vs. 14.4% response rates), in contrast to this study.¹¹ Some of the factors that could account for the discrepancy: this trial did not enroll patients with a fecal impaction, lower enrollment of patients with prior laxative failure, and shorter duration of constipation.

My take: It is good to see pediatric data for lubiprostone! Particularly for milder constipation, it appears to be effective compared to typical laxatives.

Related blog post: Lubiprostone Study: Ineffective for Pediatric Functional Constipation

In the same issue of JPGN, a separate study showed that antegrade continence enemas may be helpful in children (n=33) with autism and soiling. One safety issue is tube dislodgement. In this study, the authors noted that three patients (9.1%) had inadvertent tube dislodgement, and all tubes were uneventfully replaced. One patient had behavioral issues that prohibited utilization of an ACE.

Related blog posts:

• ACE report -10 year effectiveness
• Pelvic AnoRectal Care Program (PARC)
• Do You Know the Best Way to Use Antegrade Enemas?