M Najem, E Dong. N Engl J Med 2024;390: e47. Esophageal Varices, White-Nipple Sign, and Portal Hypertensive Gastropathy

This case reported on a 66 year old with cirrhosis and variceal bleeding. “One varix had a “white-nipple sign” (Panel A, arrow), which indicates recent variceal hemorrhage and results from the formation of a fibrin plug at the site of a resolved thrombus.”

Related article: N Khan, A Shapiro. Case Rep Gastroenterol. 2011 May-Aug; 5(2): 386–390. The White Nipple Sign: Please Do Not Disturb

“Though not widely mentioned as a stigma of recent variceal hemorrhage, this finding was first reported by Chung and Lewis in 1984 [4]. They described it as a white nipple on top of a varix protruding into the lumen and noted its presence in up to 5% of cases of variceal bleeding. It was thought to represent a platelet-fibrin plug at the site of recent variceal rupture. They noted that dislodgement would be accompanied by jet-like bleeding and called it ‘Mount St. Helens’ sign’ due its volcanic-like eruption…As Chung and Lewis [4] initially suggested, it should ‘alert the endoscopist to take urgent measures to avert a disaster’. Recognizing it as such, attempts to dislodge the lesion must be avoided and endoscopic therapy should be undertaken.”

Related blog posts:

• New Paradigm in Treating Varices and Cirrhosis Management (in Adults)
• Why Carvedilol Is Considered Best Pharmaceutical Agent to Prevent Variceal Bleeding (in Adults)
• #NASPGHAN19 Liver Symposium (excellent presentation by Dr. Romero on varices in children and portal hypertension)
• Time to Adjust the Knowledge Doubling Curve in Hepatology For Platelets in the setting of cirrhosis: “Given the low risk of bleeding of many common procedures, potential risks of platelet transfusion, lack of evidence that elevating the platelet count reduces bleeding risk, and ability to use effective interventions, including transfusion and hemostasis if bleeding occurs, it is reasonable to perform both low‐ and high‐risk procedures without prophylactically correcting the platelet count...An individualized approach to patients with severe thrombocytopenia before procedures is recommended because of the lack of definitive evidence for safety and efficacy of interventions intended to increase platelet counts in patients with cirrhosis.” The authors note in Table 4, that the AASLD does not have a specific threshold for platelets, whereas other societies have used values of >30 or >50.

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.

B White, et al. Infammatory Bowel Diseases, 2024; XX, 1–13
https://doi.org/10.1093/ibd/izae107. Open Access! Inflammation-related Proteins Support Diagnosis of Inflammatory Bowel Disease and Are Modified by Exclusive Enteral Nutrition in Children With Crohn’s Disease, Especially of Ileal Phenotype

Background/Methods: The authors characterized the plasma levels of inflammation-related proteins (IRPs) in children with CD and ulcerative colitis (UC) compared with noninflammatory controls (non-IBD) and explored the effect of EEN in children with CD. Population included children with CD (n = 53), UC (n = 11), and non-IBD (n = 19). For 18 children with active CD, IRPs were measured before and after 8 weeks of EEN.

Key findings:

• Compared with non-IBD, patients with active UC and CD had different levels of 27 (24 raised, 3 decreased) and 29 (26 raised, 3 decreased) IRPs, respectively.
• Exclusive enteral nutrition modified the levels of 19 IRPs (13 increased, 6 decreased including CCL23, interleukin-24, interleukin-6, and MMP-1). 
• More pronounced changes in IRP profile were observed in patients with ileal involvement and a ≥50% decrease in fecal calprotectin during EEN.

The discussion notes that “these profiles also helped to uncover some of the underlining pathological mechanisms, with CD demonstrating enhanced levels of IRPs related to IFN-γ and Th1-associated pathways, whereas in UC we observed an enrichment in IRPs related to Th17 pathways.”

My take (borrowed from authors): Inflammation-related protein profiles could help to stratify patients likely to respond to treatment with EEN.

Related blog posts:

• CDED + PEN: An Alternative Diet to Exclusive Enteral Nutrition?
• Exclusive Enteral Nutrition for Crohn’s Disease -Less Effective in Those with Isolated Colonic Disease
• Outcomes with Enteral Nutrition
• Expect More on Microbiome Modulation with Enteral Nutrition

J Arai et al. Clin Gastroenterol Hepatol 2024; 22: 1217-1225.Association Between Vonoprazan and the Risk of Gastric Cancer After Helicobacter pylori Eradication

Methods: Using a population-based claims database in Japan, the authors identified patients who were prescribed a clarithromycin-based first regimen of Hp eradication between 2015 and 2018.

Key findings:

• Among 54,055 patients, 568 (1.05%) developed gastric cancer (GC) during the follow-up period (mean, 3.65 years).
• The cumulative incidence of GC was 1.64% at 3 years, 2.02% at 4 years, and 2.36% at 5 years in potassium-competitive acid blocker (PCAB) users and 0.71% at 3 years, 1.04% at 4 years, and 1.22% at 5 years in H2RA users. 
• Limitations: retrospective study with issues of selection bias and confounding.

In the discussion, the authors note PCABs are being used not only for Hp eradication but for peptic ulcers, reflux and several abdominal symptoms. “According to the results of our study, longer use of PCABs was particularly associated with the increased risk of GC after Hp eradication…it might be better to switch strong acid inhibitors including PCABs ad PPIs to H2RAs before reaching a lengthy prescription period (eg. more than 3 years).”

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X Peng et al. Clin Gastroenterol Hepatol 2024; 22: 1210-1216. Open Access! Efficacy and Safety of Vonoprazan-Amoxicillin Dual Regimen With Varying Dose and Duration for Helicobacter pylori Eradication: A Multicenter, Prospective, Randomized Study

This multicenter, prospective, randomized controlled, noninferiority trial enrolled patients (n=516) with treatment naive H pylori infection from 5 clinical centers. All patients received vonoprazan at 20 mg 2/day. The high dose amoxicillin was 750 mg 4/day and the low dose 1000 mg 2/day.

Key findings:

• The high-dose amoxicillin combination with vonoprazan regimen, for either 10 or 14 days, was effective and safe in eradicating H pylori, whereas the low-dose amoxicillin regimen for 10 days was less effective. The high-dose per protocol eradication rates were 90.9% vs 94.5 for 10 vs 14 days compared to 82.0% in the low-dose per protocol eradication rate (for 14 days).

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Q Zhuang et al Am J Gastroenterol 2024; 119(5):p 803-813, May 2024. Open Access! Comparative Efficacy of P-CAB vs Proton Pump Inhibitors for Grade C/D Esophagitis: A Systematic Review and Network Meta-analysis. (see prior post: Improved Efficacy with Vonoprazan for Severe Esophagitis). This maintenance treatment group mainly included PPI patients receiving a relatively low once-daily dose (e.g. omeprazole 20mg, lansoprazole 15 mg and esomeprazole 20 mg). Treatment failure rates noted below:

My take: These studies indicate that PCABs are more effective at healing erosive esophagitis as well as H pylori gastritis. However, particularly in patients with Hp infection, the use of PCABs is associated with an increased risk of gastric cancer. The exact long-term risk of strong acid inhibition is unclear, especially in those without a history of Hp infection.

Related blog posts:

• Synergistic Dangers: Helicobacter Pylori and Cancer Genes
• Treating Helicobacter Pylori Lowers The Risk of Gastric Cancer
• Why Vonoprazan Is More Effective For Erosive Esophagitis Than a Proton Pump Inhibitor
• Long Term Benefits of Helicobacter Eradication in U.S.
• Understanding FDA Approval of Vonoprazan-Based Therapies for Helicobacter Pylori
• Vonoprazan versus Lansoprazole for Initial Heartburn Relief
• Why Observational Studies Are Misleading & PPI Association with Kidney Stones
• PPIs: Good News on Safety
• Helicobacter Pylori: Relationship to Cancer and Dubious Beneficial Claims

S Kedia et al. Clin Gastroenterol Hepatol 2024; 22: 1295-1306. Open Access! Coconut Water Induces Clinical Remission in Mild to Moderate Ulcerative Colitis: Double-blind Placebo-controlled Trial

Background: “Coconut water (CW) possesses anti-inflammatory properties, can potentially manipulate the microbiome, is a rich source of dietary potassium,” and may be an effective treatment for mild to moderate ulcerative colitis (UC).

Methods: Along with standard medical therapy, four hundred mL of CW (200 mL 2/day) or placebo fluid was administered for 8 weeks to adults (CW, n = 49; placebo, n = 46) with mild to moderate UC

Key findings:

• Clinical response (57.1% vs 28.3%; odds ratio [OR], 3.4), remission (53.1% vs 28.3%; OR, 2.9), and proportion of patients with fecal calprotectin (FCP) <150 μg/g (30.6% vs 6.5%; OR, 6.3) all significantly favored CW group
• There was not a significant difference in endoscopic outcomes

The authors indicate CW may be a useful adjunct for mild to moderate colitis but should be avoided in those patients taking medications that affect potassium and those with chronic kidney disease.

My take: This would be a good study to repeat to confirm whether CW is helpful for colitis. Certainly too much CW (a high FODMAP beverage) can contribute to a laxative effect and elevated potassium in some people. If a person with colitis is stranded on an island, CW may help until a rescue arrives.

Related blog posts:

• Spice It Up! Curcumin for Ulcerative Colitis (2024)
• Nutrition Week (Day 7) Connecting Epidemiology and Diet in Inflammatory Bowel Disease | gutsandgrowth
• AGA Guidelines on the Management of Mild-to-Moderate Ulcerative Colitis | gutsandgrowth

D Ahuja et al. Clin Gastroenterol Hepatol 2024; 22: 1286-1294. Impact of Treatment Response on Risk of Serious Infections in Patients With Crohn’s Disease: Secondary Analysis of the PYRAMID Registry

In this prospective observational real-world treatment registry…

Key findings:

• Of 1515 adalimumab-treated patients, 763 (50.4%) were classified as responders at 6 months
• Compared with nonresponders, responders were less likely to have moderate to severe symptoms (55.6% vs 33%), or require steroids (45.5% vs 17.3%) or opiates (6.6% vs 1.3%) at baseline
• During follow-up evaluation, using stabilized inverse probability of treatment weighting, responders were 34% less likely to experience serious infections compared with nonresponders (hazard ratio, 0.66)

The study results are similar to a registry-based rheumatoid arthritis study by Strangfeld et al (Ann Rheu m Dis 2011; 70: 1914-1920), which showed effective treatment was associated with less steroid use and a decline int risk of serious infections.

My take: This study indicates that lack of control of CD increases the risk for complications and infections. So, while patients are concerned about medication adverse effects, the complications of foregoing treatment or ineffective treatment are usually more concerning.

S Pradham et al. J Pediatr 2024; 269: 113992. Management of Hematochezia in Infants with Congenital Heart Disease Admitted to the Acute Care Cardiology Unit: A Multicenter Retrospective Pilot Study

Methods: This was a multicenter retrospective review of patient characteristics and evaluation of all hematochezia events in patients (n=121 patients with 180 events) with CHD <6 months admitted to acute care cardiology unit at 3 high-volume tertiary care centers from February 2019 to January 2021. In total, 61% of affected patients had single-ventricle physiology (38% hypoplastic left heart syndrome). Most patients (81%) were full-term.

Key findings:

• 77% of hematochezia events were benign, and 23% were due to necrotizing enterocolitis (NEC). There were no surgical interventions for NEC or deaths from NEC. 
• Those with NEC were significantly younger (34 vs 56 days, P < .01) and smaller (3.7 vs 4 kg, P < .01). Single-ventricle physiology was significantly associated with NEC.
• Bloodwork (CBC, WBC, CRP, Blood Culture) did not aid diagnosis

My take: If concerned about NEC which is increased in those with congenital heart disease, obtain an AXR. Overall, the outcomes of NEC in this cohort were good –all resolved with medical management.

Related blog posts:

• Briefly noted: Necrotizing Enterocolitis After Onasemnogen Abeparvovec for Spinal Muscular Atrophy
• Image Only: Pneumatosis Intestinalis in Necrotizing Enterocolitis
• Updated Outcome Data for Necrotizing Enterocolitis
• Plasma miR-1290 -Specific Biomarker for Necrotizing Enterocolitis
• The Impact of Maternal Antibiotics on Necrotizing Enterocolitis and Death in Neonates

TC Tang et al. JPGN 2024;78:1317–1328. Proton pump inhibitors, antibiotics, and atopy increase the risk of eosinophilic esophagitis in children with esophageal atresia

In this retrospective study (2005-2020) with 184 children, key findings:

• Of 184 children with EA, 46 (25%) developed EoE during this period
• Children with EoE and EA received PPI for significantly higher durations (p = .018) and at significantly higher cumulative doses (p = .017) than controls. (Controls were children with EA who did not develop EoE)
• Food allergy (adjusted odds ratio [aOR], 7.317, family history of atopy (aOR, 3.504), and infantile antibiotic exposure (aOR, 1.040) were also significantly associated with an increased risk of developing EoE in the EA cohort

Discussion: “This is congruent with the emerging evidence in the general pediatric population that there is an increased risk of EoE development in individuals who undergo acid suppressive therapy. A possible explanation for these findings is that acid suppressants inhibit gastric parietal cell function and elevate the gastric pH, thereby impairing peptic digestion of dietary allergens, potentiating sensitization, and facilitating the development of allergic diseases like EoE.” Other potential explanations could include PPIs could increase mucosal permeability and/or contribute to dysbiosis.

“Hence, the routine use of PPIs for the first year of life as recommended by the current guidelines may need to be revisited..”

My take: This study shows a clear association of PPIs with development of EoE in this cohort. Due to the study design, it is difficult to be confident regarding causality due to possible selection bias (patients who received PPIs may be those with more predisposition to EoE). Nevertheless, this study suggests that prolonged use of PPIs, even in groups at risk for reflux damage, needs to be carefully considered and possibly directed by objective markers of reflux.

Related blog posts:

• Do Acid Blockers Given to Infants Increase the Risk of Allergic Disease?
• 2018 Pediatric GERD Guidelines
• Unfavorable Trends in Reflux Management of Infants & Update on USNWR Rankings
• Is Reflux Really a Disease in Premature Infants?
• Good Episode of Bowel Sounds on Reflux

AJ Sanyal et al. NEJM 2024; DOI: 10.1056/NEJMoa2401755. A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis

Background/Methods: “Dual agonism of glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor may be more effective than GLP-1 receptor agonism alone for treating metabolic dysfunction–associated steatohepatitis (MASH). The efficacy and safety of survodutide (a dual agonist of glucagon receptor and GLP-1 receptor) in persons with MASH and liver fibrosis” was studied in “48-week, phase 2 trial, we randomly assigned adults with biopsy-confirmed MASH.” (n=293)

“Dual agonism of glucagon receptor and GLP-1 receptor may be more effective than GLP-1 receptor monoagonism for treating MASH, because the extrahepatic benefits of GLP-1 receptor agonism (glucose control, reduced appetite, and weight loss) are combined with direct hepatic effects (increased energy expenditure, lipolysis, and mobilization of hepatic fat) associated with glucagon receptor agonism.”

Key findings:

• Improvement in MASH with no worsening of fibrosis occurred in 47% of the participants in the survodutide 2.4-mg group, 62% of those in the 4.8-mg group, and 43% of those in the 6.0-mg group, as compared with 14% of those in the placebo group
• A decrease in liver fat, assessed by MRI-PDFF, content by at least 30% occurred in 63% of the participants in the survodutide 2.4-mg group, 67% of those in the 4.8-mg group, 57% of those in the 6.0-mg group, and 14% of those in the placebo group; improvement in fibrosis by at least one stage occurred in 34%, 36%, 34%, and 22%, respectively. 
• Adverse effects were more frequent with survodutide than with placebo included nausea (66% vs. 23%), diarrhea (49% vs. 23%), and vomiting (41% vs. 4%); serious adverse events occurred in 8% with survodutide and 7% with placebo.

The discussion notes that “in a phase 2 trial, treatment with the GLP-1 receptor monoagonist semaglutide resulted in a significantly higher percentage of patients with MASH resolution than placebo but not in a significantly higher percentage of patients with improvement in fibrosis stage.²⁶” Thus, the improvement in fibrosis, which was seen in this study with survodutide,will need to be examined in future studies.

My take: Earlier this year, the selective thyroid hormone receptor beta agonist resmetirom gained conditional approval from the Food and Drug Administration as the first pharmacotherapy for MASH with moderate-to-advanced liver fibrosis.⁵  It looks like there will be a number of pharmacologic agents available in the coming years. Cost and availability will be ongoing concerns. In addition, determining when/how these agents will be used in the pediatric population will not be clear for quite a long time.

Related blog posts:

• Resmetirom for MASH
• Resmetirom (Rezdiffra) -FDA Approved for MASH with Moderate to Advanced Fibrosis
• You No Longer Have Fatty Liver Disease-You Have Steatotic Liver Disease!
• Good Review on Newest Medications for Obesity
• Online Aspen Webinar (Part 6) -NAFLD and NASH
• Fatty Liver Feast (of Articles): NAFLD 2020
• ACG Review (Zobair Younassi, MD): NAFLD and NASH