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Genetic Basis of Eosinophilic Esophagitis

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Cincinnati Children’s Research Horizons: Two Genes Associated with Familial EoE

Researchers (first author Tetsuo Shodaand senior author Marc Rothenberg) at “Cincinnati Children’s have identified two rare gene variants associated with inherited forms of eosinophilic esophagitis (EoE) that may also play roles as acquired mutations among the larger population of people with non-familial EoE.”  

Citation of article: Shoda, T., Kaufman, K.M., Wen, T. et al. Desmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis. Nat Commun 12, 6795 (2021). https://doi.org/10.1038/s41467-021-26939-9

The findings regarding the genes desmoplakin (DSP) and periplakin (PPL) were published Nov. 23, 2021 in Nature Communications (Link to article: Desmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis). “The proteins generated by these genes are found in the epithelial layer of the esophagus amid structures called desmosomes that help bind cells together. These variants of DSP and PPL appear to weaken the epithelial barrier, making the tissue more prone to damage from inflammation-causing eosinophils.”

Methods: Using whole-genome sequencing, the researchers discovered the variants among five members of a family that had multiple generations of members with EoE.  The team tested another 61 families with familial EoE and found 13 having either the DSP or PPL variants.

Key Findings:

  • The authors “estimate that these gene variants account for about 21% of patients with familial EoE”
  • “A series of functional analyses using an organotypic-like ALI culture system demonstrated that modulating wild-type DSP and PPL expression in vitro was functionally sufficient to induce changes in epithelial integrity (e.g., acantholysis) and barrier impairment, processes that are dysregulated in EoE”
  • “DSP and PPL loss occurs in non-familial EoE, substantiating that the pathway identified initially by rare familial EoE cases is broadly applicable to familial and non-familial EoE”

My take:

  1. This article provides data showing that genetic alterations affecting the epithelial barrier are important in the pathophysiology of EoE.
  2. Often EoE is compared to eczema. This finding of altered epithelial barrier is analogous to eczema where many cases are due to a mutation in a protein called filaggrin, which is important in reducing the gap between skin cells (related blog: Eczema Rarely Linked to Food Allergy).

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Frequency of Strictures in Pediatric Eosinophilic Esophagitis

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D Burnett et al. JPGN Reports 2021; Free Access: Incidence of Pediatric Eosinophilic Esophagitis and Characterization of the Stricturing Phenotype in Alberta, Canada doi: 10.1097/PG9.0000000000000136

This retrospective study (2015-2018) identified 185 new cases of eosinophilic esophagitis (EoE).

Key findings:

  • Eight of 185 (4%) patients had endoscopically confirmed esophageal strictures, 4 of which required mechanical dilation. (The authors note a Dutch study which demonstrated a 14% stricture rate)
  • Eleven of 185 (5.9%) patients had more subtle signs of esophageal narrowing, but no focal strictures
  • Pain was reported after 15% of all scopes, including 50% of the 28 scopes with focal strictures
  • For patients <15 years old living in Edmonton, the incidence over the 4 years was 11.1 cases per 100,000 person years
  • EoE was more common in urban setting: incidence 10.6 versus 4.1 per 100,000 person-years, respectively

My take: This article provides useful data on the likelihood of stricturing EoE in the pediatric population in an area with a high incidence of EoE.

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Where Did the Blood Go? Case Report

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M Tracy et al. JPGN Reports 2021; Free Access: Where Did the Blood Go?: A Meckel’s Diverticulum Bleed Without Hematochezia or Melena doi: 10.1097/PG9.0000000000000119

In this case report, a 2 yo with acute anemia along with acute on chronic abdominal pain was diagnosed with a Meckel’s diverticulum. After diagnostic studies, “a blood-filled mass arising from the ileum was identified and resected by the surgical team. Pathology was consistent with Meckel’s diverticulum with heterotopic gastric mucosa.”

My take: This is a rare presentation of a Meckel’s diverticulum. Besides bleeding, per the authors, “common presentations of Meckel’s diverticulum include diverticulitis/perforation (16%-20%), bowel obstruction (about 14%), and intussusception (12%).” 

Related blog post: NASPGHAN Postgraduate Course (2017): Strictures, GI Bleeding Pancreatic Fluid Collections

Can We Predict Which Patients With Irritable Bowel Will Respond to Dietary Manipulation Based on Their Microbiome?

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Quote From Martin Short

In a recent post regarding Next-Generation Treatment for H pylori, the authors denigrated the term “empiric” treatment and said a more accurate term would be “hopeful” therapy. There are a lot of areas in our field in which hopeful therapy is a mainstay, especially in those with non-organic abdominal pain (eg. irritable bowel syndrome). Even with the benefit of a therapeutic ‘regression to the mean,’ treatment is often unsatisfactory.

Thus, it is a very positive sign that a recent article provides an indication of which patients are most likely to benefit from dietary manipulation:

K Vervier et al. Gut 2021;gutjnl-2021-325177. doi: 10.1136/gutjnl-2021-325177. Online ahead of print: Open Access: Two microbiota subtypes identified in irritable bowel syndrome with distinct responses to the low FODMAP diet

Methods: A prospective single centre case–control study recruited participants (n=56 pairs) from 2016 to 2019. The authors included adults (18–68 years of age) meeting the Rome IV criteria for diarrhoea-predominant or mixed type IBS (IBS-D and IBS-M, respectively) with respective household controls. 

Key findings:

  • Baseline IBS cases pre-diet identified two distinct microbiota profiles, which we refer to as IBSP (pathogenic-like) and IBSH (health-like) subtypes.
  • IBSP microbiomes were enriched in Firmicutes and genes for amino acid and carbohydrate metabolism, but depleted in Bacteroidetes species.
  • IBSH microbiomes were similar to controls.
  • On the low FODMAP diet, IBSH and control microbiota were unaffected, but the IBSP signature shifted towards a health-associated microbiome with an increase in Bacteroidetes (p=0.009), a decrease in Firmicutes species (p=0.004) and normalization of primary metabolic genes. The clinical response to the low FODMAP diet was greater in IBSP subjects compared with IBSH (p=0.02).
  • 50% of IBS cases manifested a ‘pathogenic’ gut microbial signature. This shifted towards the healthy profile on the low FODMAP diet; and IBSP cases showed an enhanced clinical responsiveness to the dietary therapy
A) Beta diversity analysis of IBS cases and healthy controls: principal coordinate analysis for the two first components identifies two distinct clusters among cases, described as cluster 1 (cl1, red) and cluster 2 (cl2, blue). Overall dispersion of household controls is represented in grey.

My take: Currently, what is a “pathogenic” microbiome is unclear at least to me. However, changes in the microbiome do occur with dietary manipulation and are likely involved in response to treatment for IBS and other disorders.

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What We Know Right Now About Omicron and About Boosters

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This article shows that the booster shot lowers the risk of death by 90% compared to those who did not receive the booster shot in those 50 years of age or older. R Arbel et al. NEJM 2021; DOI: 10.1056/NEJMoa2115624. Open Access: BNT162b2 Vaccine Booster and Mortality Due to Covid-19

Key Findings:

  • A total of 843,208 participants (50 years and older) met the eligibility criteria, of whom 758,118 (90%) received the booster during the 54-day study period. Death due to Covid-19 occurred in 65 participants in the booster group (0.16 per 100,000 persons per day) and in 137 participants in the nonbooster group (2.98 per 100,000 persons per day). The adjusted hazard ratio for death due to Covid-19 in the booster group, as compared with the nonbooster group, was 0.10 (95% confidence interval, 0.07 to 0.14; P<0.001).

This twitter thread from Ashish Jha provides insight into the current understanding of the Omicron variant.

Equitable Access to Liver Transplant

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R Rosenblatt et al. Hepatology 2021; 74: 2808-2812. Open Access. Equitable Access to Liver Transplant: Bridging the Gaps in the Social Determinants of Health

The problem:

“Evaluation for organ transplantation, a life-saving procedure, involves a multistep, highly selective process. Initially, referrals to appropriate subspecialists and a transplant center are required. During evaluation, candidates undergo formal assessment of adequate social support, psychological health, health insurance, adherence, and understanding of treatments. Each step in the transplant evaluation process is an opportunity for inequity to insert itself, resulting in disparate access to listing for transplantation. This manifests through mechanisms related to poor health literacy, lack of insurance or high copay, poor social support, and geographical location. Culture incapacity by health providers and implicit bias at the provider level and health care system level can create additional barriers. Examples of health inequities include lower referral rate for LT and inferior outcomes among Black and Latinx compared to White patients,(3) while, in addition to race/ethnicity, sex and health literacy(4) also strongly correlate with the likelihood of listing. SES [socioeconomic status] affects both waitlist mortality and post-LT survival as well.”

This article proposes policy measures to counter the deleterious effects of SDOH [social determinants of health]—identify and reduce implicit bias, expand and optimize telemedicine, and improve community outreach. “Structural racism, access to affordable insurance, health literacy, and substance abuse therapy are equally important factors that contribute to health disparities and inequities and warrant further commentary and research, but are outside the focus of this policy piece.”

Related blog post: Getting a Seat at the Liver Counter

Albumin in Liver Disease -When It’s Helpful

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RK Jagdish et al. Hepatology 2021; 74: 2848-2862. Albumin in Advanced Liver Diseases: The Good and Bad of a Drug! (Review)

Useful review –

  • Explains biologic properties -typically 10-15 g of Albumin is synthesized daily (reduced in advanced liver disease). The half-life is between 12-18 days
  • Physiologic functions: oncotic effects, transports proteins/molecules/medications, antithrombotic effects, modulates inflammatory pathways
  • Main uses: beneficial in patients undergoing large-volume paracentesis or who have hepatorenal syndrome or spontaneous bacterial peritonitis.
  • Studies have shown possible modest benefit in long-term albumin administration in patients with cirrhosis, especially ANSWER study which showed a reduction in ascites recurrence, HRS, encephalopathy, infections, hospital admissions and death. Costs of long-term infusion and the lack of benefit in the ATTIRE trial indicate the need for more studies to determine the best approach in this population.
  • Main adverse effects: allergic and transfusion reactions, volume overload, antibody formation and coagulation derangements
  • Generally, albumin infusions are not recommend for correcting isolated hypoalbuminemia. The primary disorder (eg. acute stress, trauma, infection, malignancy) should be treated.

History of Medicine: Hepatitis C Discovery –“A Triumph of Curiosity and Persistence”

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MC Ghany et al. Hepatology 2021; 74: 2813-2823. Free Access: The 2020 Nobel Prize for Medicine or Physiology for the Discovery of Hepatitis C Virus: A Triumph of Curiosity and Persistence

This great little article humanizes and summarizes the discovery of Hepatitis C with first hand accounts and anecdotes.

A couple of interesting points:

  • Until you know the call is from Stockholm (and not a prank), the 4 am call informing you were awarded a Nobel prized is quite irksome
  • All of the Nobel Laureates (none are hepatologists) advocate for a vaccine but note that making it is difficult due to so many quasispecies. Only a fraction of the estimated 72 million persons with chronic HCV infection have been diagnosed and received curative therapy
  • Advice for young people: “There is no elevator to success. You have to take the stairs…It’s a step-by-step, slow process”
  • Hepatology humor:  “Is life worth living?” “It depends upon the liver.” 
Key milestones in HCV virology and therapeutics. Abbreviation: SVR, sustained virological response.

Only Tweets: PA Branding, Maternal Death Rates, Mask Mandates, Mix-Match Boosters, and Costly Way to Determine if You Have Feet

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From NPR

This article (link: PAs want to be called physician associates) notes that “Physician assistants, as they are still legally called, have been steadily granted greater autonomy over the years since 1967, when the Duke University School of Medicine graduated four former Navy medics as the nation’s first class of PAs.”

And from The Onion:

From The Onion

How to Lower Placebo Effects in Crohn’s Disease Trials

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A Almradi et al. J Crohns Colitis 2021. https://doi.org/10.1093/ecco-jcc/jjab194. Clinical, endoscopic and safety placebo rates in induction and maintenance trials of Crohn’s disease: Meta-analysis of Randomised controlled trials

The authors searched MEDLINE, EMBASE and CENTRAL from inception to March 2021. Eligible studies were placebo-controlled trials of pharmacological interventions for CD

Key findings:

  • In 125 studies (91 induction, 46 maintenance), placebo clinical remission and response rates for induction studies were 18% [95% confidence interval (CI) 16-21%], and 32% (95%CI 29-35%), respectively, and for maintenance studies were 28% (95%CI 23-34%) and 30% (95%CI 24-37%), respectively 
  • Endoscopic remission and response rates (for placebo) in induction studies were 8% (95%CI 4–18%), and 16% (95%CI 11–23%), respectively
  • Trials enrolling patients with prior biologic exposure, longer disease duration and higher CD activity index scores were associated with lower placebo clinical remission rates
  • Increased duration of follow-up, more follow-up visits and a greater proportion of patients with colonic disease distribution were associated with higher clinical placebo rates

My take: These studies show fairly high placebo responses and thus they reinforce the need for well-designed trials with objective endpoints.

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