Algorithm for Neonatal Acute Liver Failure

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K Borovsky et al. JPGN 2021; 73: 80-85. Applying an Age-specific Definition to Better Characterize Etiologies and Outcomes in Neonatal Acute Liver Failure

This single-center retrospective study with 43 patients (over 11 year timeframe) identified etiology and outcomes for neonatal acute liver failure (NALF).

Key findings:

  • Etiologies included viral infection (23%), gestational alloimmune liver disease with neonatal hemochromatosis (GALD-NH) (21%), cardiac-associated ischemia (16%), other ischemia (14%), genetic etiologies (9%), Trisomy 21-associated myelodysplasia (TAM) (7%), hemophagocytic lymphohistiocytosis (HLH) (2%), and not identified (7%)
  • Infants with viral etiologies had the highest alanine aminotransferase (ALT) at presentation (1179 IU/L, interquartile range [IQR] 683–1585 IU/L) in contrast to low levels in GALD-NH (23 IU/L, IQR 18–64 IU/L)
  • Across all etiologies, only 33% were alive at 1 year
  • Among laboratory values at presentation, alpha-fetoprotein (AFP) was significantly higher in patients that survived with their native liver (P = 0.04)

Figure 4 provides a helpful management algorithm for NALF. Figure 4 is similar to the slide below (shared by lead author).

  • -Consider empiric acyclovir in those with INR >/= 2.0 in the first 30 days of life
  • -In those with normal to low elevation of aminotransferases, consider empiric IVIG while undergoing workup. Part of workup should include either MRI or lip biopsy for GALD
  • -In those with moderate to severe elevation of aminotransferases, workup should include assessment for viral, HLH and genetic etiologies. Fulminant viral hepatitis or HLH likely with Ferritin levels >10,000. Hypoglycemia and hyperammonemia is suggestive of metabolic/mitochondrial disorder
  • -Liver biopsy may be needed if etiologies not identified

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Pediatric Adoption of “Treat to Target” & Difficulty “Unlearning”

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A good article for the next journal club: Clinical Practice Survey of Repeat Endoscopy in Pediatric Inflammatory Bowel Disease in North America (J Moses et al. JPGN 2021; 73: 61-66)

Key findings:

  • 65% of respondents (n=238 of 2300 responded to survey) perform repeat endoscopy to assess for endoscopic remission in pediatric IBD as part of routine clinical practice (usually 9 to 12 months later)
  • “Symptoms are not sufficient to follow IBD patients” was reported by 82% of those who repeat endoscopy
  • “I perform endoscopy based on clinical, biomarker, and/or imaging trends” was reported by 81% of those who do not repeat endoscopy
  • In those inclined to do repeat endoscopy (n=134 total), the authors state there was a significant difference based on years in practice but this is difficult to discern based on the data presented in Table 1; the numbers in both groups are much greater than the number of total patients in each group. They state in the repeat endoscopy group (n=134), the practitioner experience was n=58 (1-5 yrs), n=43 (6-10 yrs), n= 34 (11-15 yrs), and 70 (>15 yrs) and the “no repeat group” (n=67 total) was n=43 (1-5 yrs), n=33 (6-10 yrs), n=21 (11-15 yrs), and n=37 (>15 yrs). Apparently, according to the discussion, those in practice more than 15 years were less likely to recommend a ‘treat-to-target’ endoscopy.
  • There is also a discrepancy in the report with regard to ImproveCareNow participation, stated to be 63% in the abstract and 71% in the results section

Discussion: I would propose that the first part of a journal club start with these two lines from the discussion: “As the paradigm of clinical endpoints has evolved in the management of IBD, there has been a shift from using clinical symptoms to drive major therapeutic decisions to using endoscopic assessment. This lag time to adopt new practices in medicine has been highlighted in research demonstrating the slow adoption of new clinical practices by physicians, possibly related to the difficulty with “unlearning” common practices and shifting to new ones.” As an aside, 77% of the survey respondents were in an academic practice; it would be fun to see how the section chief views this assertion.

While the majority of survey respondents supported repeat endoscopy in all patients, the discussion point above is making a different distinction (“drive major therapeutic decisions”). I think a much higher proportion of practitioners would endorse endoscopy prior to major therapeutic decisions. However, with regard to supporting more widespread routine followup in all of those in clinical remission, the discussion references data from a single retrospective pediatric cohort study with 104 patients (Inflamm Bowel Dis 2017; 23: 1447-1453), that 30% of patients in clinical remission had active disease on endoscopy.

My take: As alluded to in the conclusion, long-term data from prospective studies are needed to determine the benefit (or lack of benefit) of followup endoscopy, especially in patients with combined clinical/biomarker remission.

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How Likely/Persistent is Eosinophilic Esophagitis with Peanut Oral Immunotherapy

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BL Wright et al. Clin Gastroenterol Hepatol 2021; 19: 1151-1159. Gastrointestinal Eosinophil Responses in a Longitudinal, Randomized Trial of Peanut Oral Immunotherapy

Background: “The incidence of EoE during OIT has been estimated at 2.7%.” (AJ Lucendo et al. Ann Allergy Asthma Immunol 2014; 113: 624-629)

Methods: Twenty adults with IgE-mediated peanut allergy were randomly assigned to groups given peanut OIT (n = 15) or placebo (n = 5) in this prospective study. Serial gastrointestinal biopsies were collected at baseline (n = 21, 0 weeks), following dose escalation (n = 10, 52 weeks), and during the maintenance phase (n = 11, 104 weeks)

Key findings:

  • At baseline: 3 of the 21 subjects (14%) had esophageal peak eosinophil counts ≥15 eos/hpf and all subjects had dilated intercellular spaces (DIS)
  • At 52 weeks: OIT induced or exacerbated esophageal eosinophilia (EoE) at 52 weeks with peak eosinophil counts ≥15 eos/hpf in 4 of 7 patients [57%] who did not have EoE at baseline. EoE did not develop in patients receiving placebo
  • At 104 weeks: In 4 of 6 participants (67%), OIT-induced EoE and gastrointestinal eosinophilia resolved by the end of the maintenance phase
  • One patient developed a clinical diagnosis of EoE.

The discussion notes overlap between EoE and IgE-mediated food allergy. The risk of EoE in patients with IgE-mediated food allergy is 118 times that of the general population (4.7% vs 0.04%) (J Allergy Clin Immunol Pract 2017; 5: 369-375). Also, the authors note that in this study all of the peanut allergic subjects had evidence of epithelial barrier dsyfunction.

My take: This small study shows, that for most adult patients, the development of EoE during OIT is often transitory.

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2021 AGA Guidelines For Crohn’s Disease

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A series of articles details the 2021 AGA Guidelines for Crohn’s disease (CD) including a clinical practice guideline (pg 2496-2508), a clinical decision support tool (2509-2510), a spotlight summary (pg 2511), a technical review (2512-2557), and a review of the recommendations (pg 2557-2262). I will highlight the first article.

JD Feuerstein et al. Gastroenterol 2021; 160: 2496-2508. Full text: AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn’s Disease

Full text: Spotlight

For me the most important of their recommendations was #7:

  • In adult outpatients with moderate to severe CD, the AGA suggests early introduction with a biologic with or without an immunomodulator rather than delaying their use until after failure of 5-aminosalicylates and/or corticosteroids.

Other points:

From Spotlight:

Radiomic Imaging in Crohn’s Disease

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X Li et al. Gastroenterol 2021; 160: 2303-2316. Development and Validation of a Novel Computed-Tomography Enterography Radiomic Approach for Characterization of Intestinal Fibrosis in Crohn’s Disease

Methods: This article describes the development a computed-tomography enterography (CTE)–based radiomic model (RM). This retrospective multicenter study included 167 CD patients who underwent preoperative CTE and bowel resection. 1454 radiomic features were extracted from venous-phase CTE and a machine learning–based RM was developed based on the reproducible features using logistic regression. The RM was validated in an independent external test cohort recruited from 3 centers.

Key findings:

  • In the training cohort, the area under the ROC curve (AUC) of RM for distinguishing moderate–severe from none–mild intestinal fibrosis was 0.888.
  • In the test cohort, the RM had an AUC of 0.816.
  • RM was more accurate than visual interpretations by either radiologist (radiologist 1, AUC = 0.554; radiologist 2, AUC = 0.598; both, P < .001) in the test cohort

My take: This CT approach with RM allowed for accurate characterization of intestinal fibrosis in CD. The images look pretty cool too.

SC Option for Infliximab

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S Schreiber, S Ben-Horin et al. Gastroenterol 2021; 160 2340-2353. Full text: Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease

Methods: Overall in this phase 1 randomized, open-label study in patients with either ulcerative colitis or Crohn’s disease, 66 and 65 patients were randomized to CT-P13 SC (every 2 weeks) and CT-P13 IV, respectively

Key findings: The pharmacokinetic noninferiority of CT-P13 SC to CT-P13 IV, and the comparable efficacy, safety, and immunogenicity profiles

These findings are in agreement with similar studies performed in patients with Rheumatoid Arthritis.

My take: If confirmed with additional studies, it is likely that SC infliximab treatment will be a useful alternative to intravenous infliximab. This is similar to data presented with vedolizumab which is currently administered intravenously.

Graphical Abstract

Looking at the Mycobiome to Distinguish Clostridium difficile Infection vs. Carriage

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Y Cao et al. Gastroenterol 2021; 160: 2328-2339. Fecal Mycobiota Combined With Host Immune Factors Distinguish Clostridioides difficile Infection From Asymptomatic Carriage

Key findings:

  • The ratio of Ascomycota to Basidiomycota was dramatically higher in patients with CDI than in Carrier and Control (P < .05).
  • Using 4 fungal operational taxonomic units combined with 6 host immune markers in the random forest classifier can achieve very high performance (area under the curve ∼92.38%) in distinguishing patients with CDI from Carrier.

My take: It is interesting that fecal fungal diversity (mycobiome), in addition to bacterial diversity, is reduced in those with Clostridium difficile infection (CDI) compared to both control groups and those with Clostridium difficile asymptomatic carriage.

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Another reason to get vaccinated

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)

New Way to Diagnosis of Wilson’s Disease: ATP7B Peptides

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CJ Collins, F Yi et al. Gastroenterol 2021; 160: 2367-2382. Full text: Direct Measurement of ATP7B Peptides Is Highly Effective in the Diagnosis of Wilson Disease

There continues to be challenges in the diagnosis of Wilson’s disease (WD). Genetic testing, per the authors and Vasrome (varsome.com), have found more than 649 pathogenic mutations and another 692 mutations that are VUS. Definitive diagnosis with genetic testing requires 2 known pathogenic variants. Other features, including Kayser-Fleischer rings and ceruloplasmin, have limited sensitivity and/or specificity.

Methods: Two hundred and sixty-four samples from biorepositories at 3 international and 2 domestic academic centers and 150 normal controls were used.

Key findings:

  • Two ATP7B peptides were found to have a sensitivity of 91.2%, specificity of 98.1%, positive predictive value of 98.0%, and a negative predictive value of 91.5%.
  • In patients with normal ceruloplasmin concentrations (>20 mg/dL), 14 of 16 (87.5%) were ATP7B-deficient. In patients without clear genetic results, 94% were ATP7B-deficient.

Discussion: As with other tests, ATPB7 peptide testing has limitations. Most patients with WD have pathogenic mutations that often result in protein misfolding, absence of decay of messenger RNA and enhanced degradation; hence, low ATPB7 levels; however, disease-causing mutations that affect protein activity but not protein concentration will generate false-negative results.

My take: “ATP7B peptide analysis identified WD patients in a large majority of cases and reduced ambiguities resulting from genetic analysis and Cp (ceruloplasmin) levels. This noninvasive assay can serve as an adjunctive test for the diagnosis of WD and is expected to fundamentally advance the use of proteomic technology for a rapid screening tool.

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