Topiramate -2nd Line Agent for Cyclic Vomiting Syndrome

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H Mooers et al. AP&T 2021; https://doi.org/10.1111/apt.16457 Retrospective review of patients treated for cyclic vomiting syndrome with topiramate

“Response was defined as a global improvement in symptoms or >50% reduction in the number of CVS episodes, ED visits or hospitalisations.” 92% of patients had previously failed TCA therapy.

Key findings:

  • “Sixty-five percent (88/136) of patients responded to topiramate in an intent-to-treat analysis.”
  • “There was a significant decrease in the annual number of CVS episodes (18.1 vs 6.2, P < 0.0001), CVS-related ED visits (4.3 vs 1.6, P = 0.0029), and CVS-related hospitalisations (2.0 vs 1.0, P = 0.035).”
  • Fifty-five percent of patients experienced side effects, and 32% discontinued the medication as a result. The most common side effects were cognitive impairment (13%), fatigue (11%) and paresthesia (10%).

Related blog posts:

Sacroiliitis, NAFLD, IMIDs -Concurring Problems with Inflammatory Bowel Disease

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I Levine et al. Inflamm Bowel Dis 2021; 809-815. Prevalence, Predictors, and Disease Activity of Sacroiliitis Among Patients with Crohn’s Disease

Key findings in this cross-sectional retrospective study (n=258, median age 30 yrs):

  • Overall, 17% of patients had MRI evidence of sacroiliitis, of whom 73% demonstrated bone marrow edema.
  • Female gender, back pain, and later age of CD diagnosis were associated with sacroiliitis (P = 0.05, P < 0.001, P = 0.04, respectively).
  • Disease activity (clinical, endoscopic, and radiographic), disease location and CD therapy were not associated with sacroiliitis on MRE.
  • More than two-thirds with MRE evidence of sacroiliitis were never seen by a rheumatologist.

A Lin et al. Inflamm Bowel Dis 2021; 947-955. Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis

Key finding:

  • Data pooled from 27 studies showed the prevalence of NAFLD among IBD patients was 32% (substantial heterogeneity); this is “statistically significantly higher than the prevalence of NAFLD in the general population (25.2%; P < 0.001)”

M Attauabi et al. Inflamm Bowel Dis 2021; 927-939. Systematic Review with Meta-analysis: The Impact of Co-occurring Immune-mediated Inflammatory Diseases on the Disease Course of Inflammatory Bowel Diseases

A total of 93 studies were identified, comprising 16,064 IBD patients with co-occurring IMIDs and 3,451,414 IBD patients without IMIDs. IMIDs included the following:

  • Unspecified autoimmune disease
  • Diabetes type 1
  • Asthma
  • Grave disease
  • Spondyloarthropathy
  • Ankylosing spondylitis
  • Iridocyclitis
  • Uveitis
  • Rheumatoid arthritis
  • Polymyalgia rheumatica
  • Psoriasis/psoriatic arthritis
  • Primary Sclerosing Cholangitis
  • Celiac disease
  • Pyoderma gangrenosum
  • Pernicious anemia
  • Autoimmune hepatitis
  • Sarcoidosis
  • Giant cell arteritis
  • Primary biliary cholangitis
  • Hashimoto thyroiditis
  • Episcleritis
  • Sjogren syndrome

Key findings: Patients with IBD and co-occurring IMIDs were at increased risk of having extensive colitis or pancolitis (risk ratio, 1.38; 95% Cl, 1.25–1.52; P < 0.01, I2 = 86%) and receiving IBD-related surgeries (risk ratio, 1.17; 95% Cl, 1.01–1.36; P = 0.03; I2 = 85%) compared with patients without IMIDs

Image below from Bahia Honda State Park (FL)

Pediatric Gastroenterology Hospitalists –Job Wanted?

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A recent article (M Latorre et al. Clin Gastroenterol Hepatol 2021; 19: 871-875) describes “A Practical Guide to Establishing a Gastroenterology Hospitalist Program (in adult GI)”

Our group had flirted with the idea of a GI Hospitalist (GIH) many years ago when one of the partners expressed some interest. To establish this type of job takes a lot of planning.

Some of the key points:

  • “Proactively incorporating scheduling measures to provide the GIH with coverage and backup is important; otherwise the job can become easily overwhelming.” Outpatient faculty have to provide coverage to assure the individual is protected and covered for emergencies, weekends, and holidays. “Creating dedicated shifts with daily start and stop times allow for more control over the GIH’s hours.”
  • The authors note that when they began their GIH, the outpatient faculty rotated and assisted with afternoon consults/procedures to protect GIH from long days and burnout.
  • In adult medicine, a GIH can help improve GI practice profitability by allowing outpatient doctors to increase office revenue and endoscopic procedures. In pediatrics, it is possible that a GIH would generate more billings than outpatient counterparts due to increased procedural demands for inpatients.
  • GIH can improve patient care (timely endoscopy, focus on inpatient problems), improve continuity, and reduce costs similar to other hospitalists.

My take: If there is adequate help, especially to prevent long days and increased night call, this model could work in pediatric GI as well.

Related blog posts:

This story below was NOT from ‘The Onion.’ NPR 6/10/21:

How Insurance Companies Can Help Stop the Pandemic in the U.S.

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From AJC, Hashem Dezhbakhsh: An incentive to encourage vaccination

This is a good read. An excerpt:

Vaccine hesitancy, which can prolong the pandemic, is a textbook example of a negative consumption externality, where an individual’s choice can harm or impose costs on others. Indoor smoking, drunk driving, or littering are other examples…

One policy option is to use the insurance mechanism, with risk assessment and risk pricing as its enforcing arms….

For example, a risky driver has a higher auto insurance premium than a safe driver, a smoker has a higher health insurance premium than a non-smoker,…Similarly, health insurance premiums, deductibles, and co-pays can be set higher for those who are unvaccinated...

Using risk pricing to set insurance premiums and co-pays for these individuals makes good sense and is fair policy. It incentivizes individuals to vaccinate, while also providing a fairer insurance pricing system by charging those with self-selected higher risk a higher price, instead of shifting their medical costs to others through uniform insurance pricing.

Hydrangeas

Why It Is Hard to Stop Immunosuppression with Autoimmune Hepatitis and Lower Bone Density with Fatty Livers

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C Schulthei et al. Hepatology 2021; 73: 1436-1448. Full text: Next-Generation Immunosequencing Reveals Pathological T-Cell Architecture in Autoimmune Hepatitis

This is highly technical study of 60 patients with AIH. “Our key finding was a clearly biased signature of TRBV-J gene usage in peripheral and liver-infiltrating T-cells of patients with AIH, independent of AIH predisposing HLA-DRB1 alleles. This signature was unaffected by immunosuppressive treatment and not related to complete biochemical disease remission. This suggests that treatment acted on T-cell functionality rather than on the underlying pathological T-cell architecture in this disease that has a high relapse rate.”

My take (borrowed from authors): “Patients with AIH show profound and persisting T-cell architectural changes that may explain high relapse rates after tapering immunosuppression.”

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LF Chun et al. J Pediatr 2021; 233: 105-111. Hepatic Steatosis is Negatively Associated with Bone Mineral Density in Children

Key findings:

  • Using a community-based sample of 235 children, the authors found that there was a significant negative relationship between liver MRI-PDFF and BMD z score R = −0.421, P < .001).
  • There was no significant association between vitamin D status and BMD z score (P = .94).
  • Children with clinically low BMD z scores were found to have higher alanine aminotransferase (P < .05) and gamma-glutamyl transferase (P < .05) levels compared with children with normal BMD z scores.

My take: This study shows another organ that is affected in children with fatty liver disease; other associated problems include increased risk for cardiovascular disorders, pancreatic dysfunction/diabetes, cancer, polycystic ovary syndrome, and neurologic disorders

Related blog posts:

Image below near the Seven Mile Road on the Florida Keys:

What is the Risk of Inflammatory Bowel Disease in Patients with Hirschsprung’s Disease

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Background: It is well-recognized that enterocolitis can occur in individuals with Hirschsprung’s disease, even after surgery. Case series have described cases of inflammatory bowel disease (IBD) in individuals with Hirschsprung’s which have some overlapping features with Hirschsprung disease-associated enterocolitis (HAEC). Those with IBD, however, have a constellation of clinical findings more typical of IBD and respond to treatments used in IBD.

A recent study from Canada (CN Bernstein et al. J Pediatr 2021; 233: 98-104. Increased Incidence of Inflammatory Bowel Disease After Hirschsprung Disease: A Population-based Cohort Study) provides more data regarding IBD in individuals with HD.

Key findings:

  • In the study from Ontario, 18 of 716 (2.5%) ultimately developed IBD (168.8 per 100 000 person-years), compared with 7109 of 3 377 394 children without Hirschsprung disease (0.2%, 14.2 per 100 000 person-years); thus, this represented a 12-fold increased risk.
  • In the study from Alberta and Manitoba, the OR of having had Hirschsprung disease before a diagnosis of IBD compared with controls was 74.9 (95% CI, 17.1-328.7) and 23.8 (95% CI, 4.6-123) respectively.
  • Crohn’s disease was more common after Hirschsprung disease than ulcerative colitis.

My take: I have personally seen IBD in HD and wondered how much increased risk that HD conferred. Now the question: what is the mechanism?

Related blog posts:

Alongside the Seven Mile Bridge in the Florida Keys:

Obesity and Cellular Aging in Childhood

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A provocative study (MJ Baskind et al. J Pediatr 2021; 233: 141-149. Obesity at Age 6 Months Is Associated with Shorter Preschool Leukocyte Telomere Length Independent of Parental Telomere Length) suggests that obesity in infancy can result in shortened telomere length, which is a cumulative marker for cellular aging. Also, leukocyte telomere length (LTL) is associated with known risk factors for cardiometabolic disease, including obesity and smoking

The authors prospectively studied a group of 97 woman-infant dyads from the Latinx, Eating and Diabetes cohort. Key findings:

  • Obesity at 6 months was negatively associated (β = −0.21; P < .001) with leukocyte telomere length
  • However, there was a lack of association between obesity at earlier ages (2-5 years) and preschooler LTL in the same cohort
  • Any breastfeeding at 6 months was positively associated with leukocyte telomere length

From the associated editorial: JL Buxton, fulltext: Early Warning Signs? Infant Obesity and Accelerated Cellular Aging “These results are based on data from a relatively small sample and await replication in larger cohorts recruited from different populations.”

My take: This study shows that obesity could be affecting our bodies in ways that most of us have never contemplated.

Aerial view of the “the quicksands” off the coast of Key West:

“An Allergic Basis for Abdominal Pain”

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A recent post (Mechanisms of Postinfectious IBS & Functional Pain) reviewed a study which described how food antigens during an infectious process can result in meal-induced pain.

A recent review of this study (M Rothenberg. NEJM 2021; 384:2156-2158. An Allergic Basis for Abdominal Pain) provides more insight.

Key points:

  • “A peripheral immune mechanism involving local mast cells stimulated by food-induced local IgE may underlie the symptoms associated with IBS and functional abdominal pain; these findings prompt consideration of new therapeutic strategies to target mast cells and allergies.”
  • The article reviews the experimental methods/results used in both mice and humans. Mice that were treated with agents that interfered with allergy “including anti-IgE, mast-cell stabilizers, and histamine H1 receptor antagonists, attenuated the pathologic and symptomatic responses…mice [that were] deficient in mast cells or in histamine H1 receptor were protected” as well.
  • The study shows that a “bacterial infection can break oral tolerance to a dietary antigen…which in turn can lead to increased gut permeability.”
  • The findings in human “showed no evidence of systemic IgE against common foods” but localized reactions were identified in every IBS patient after allergen injection into rectal mucosa.

My take: This study adds to the evidence that specific foods can lead to localized tissue-specific allergic responses. Nevetheless, it is still a futile effort to look for systemic allergic food reactions in patients with IBS and functional GI disorders.

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IBD-Like Microbiome in at-Risk Twins

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Thus far, the relationship of the microbiome and inflammatory bowel disease has been a ‘chicken and the egg which came first’ conundrum. A new study (EC Brand, MAY Klaassen et al. Gastroenterol 2021; 160: 1970-1985. Full text pdf: Healthy Cotwins Share Gut Microbiome Signatures With Their Inflammatory Bowel Disease Twins and Unrelated Patients) offers some insight into this issue.

Methods: Fecal samples were obtained from 99 twins (belonging to 51 twin pairs), 495 healthy age-, sex-, and body mass index–matched controls, and 99 unrelated patients with IBD. Whole-genome metagenomic shotgun sequencing was performed.

Key findings:

  • No significant differences were observed in the relative abundance of species and pathways between healthy cotwins and their IBD-twins.
  • Compared with healthy controls, 13, 19, and 18 species, and 78, 105, and 153 pathways were found to be differentially abundant in healthy cotwins, IBD-twins, and unrelated patients with IBD, respectively.

Discussion: “The gut microbiome composition of individuals at increased risk of developing IBD (i.e. healthy cotwins from IBD-discordant twin pairs) displays IBD-like signatures on a species and pathway level…The overlap in gut microbial features between healthy cotwins at increased risk of developing IBD and related and unrelated IBD patients suggests that these IBD-like microbiome signatures might precede the onset of IBD. This potentially opens new avenues for diagnosis and therapy in individuals with pre-symptomatic IBD.”

My take This study indicates that the microbiome changes in persons with IBD are also found in their healthy twins. In many ways, this is similar to the frequent finding of abnormal serology in Crohn’s disease; ASCA antibodies were considered much less helpful as a diagnostic test after the realization that ~20% of healthy first degree relatives also have detectable levels.

Figure 4 (pg 1979) shows the relative abundance of a selection of IBD-associated species and highlights similarities between the healthy cotwins and IBD twins.

Related blog posts:

IBD Updates: Microbiome afer surgery, Anti-TNF agents NOT changing hospitalizations/surgeries, Biobanking Genetics

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X Fang et al. Inflamm Bowel Dis 2021; 27: 603-616. Full Text: Gastrointestinal Surgery for Inflammatory Bowel Disease Persistently Lowers Microbiome and Metabolome Diversity

  • Methods: The UC San Diego IBD Biobank was used to prospectively collect 332 stool samples (every 6 months) from 129 subjects (50 ulcerative colitis; 79 Crohn’s disease). Of these, 21 with Crohn’s disease had ileocolonic resections, and 17 had colectomies.
  • Key finding: Intestinal surgeries in IBD patients seem to reduce the diversity of the gut microbiome and metabolome in IBD patients. Colectomy has a larger effect than ileocolonic resection.
  • Limitations: Confounding variables (eg. antibiotics) and selection bias (patients with more severe disease

C Verdon et al. Inflamm Bowel Dis 2021; 27: 655-661. No Change in Surgical and Hospitalization Trends Despite Higher Exposure to Anti-Tumor Necrosis Factor in Inflammatory Bowel Disease in the Québec Provincial Database From 1996 to 2015

Key findings:

  • 34,644 newly diagnosed patients with IBD (CD = 59.5%)
  • The probability of first and second hospitalizations remained unchanged in Québec and the probability of major surgery was low overall but did increase despite the higher and earlier use of anti-TNFs. However, the authors note that “in the present study, biologics use under the public reimbursement plan was 13% in patients with UC and 16% in patients with CD.”
  • My take: This study is provocative but probably misleading; it is quite likely that use of anti-TNF agents do lower the risk of hospitalization and surgery.

K Gettler et al. Gastroenterol 2021; 160: 1546-1557. Full text PDF: Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort

  • Methods: The authors used the Mount Sinai BioMe Biobank, which contains genetic data on
    32,595 patients. After rigorous phenotype validation, 19,541 individuals were retained, of whom 339 were IBD patients (273 CD, 28 UC, and 37 individuals who were classified as both) and 19,202 were controls
  • Key findings: In this study, the authors identified several rare VEO-IBD variants with high genetic penetrance using the biobank samples and then replicated results in large case control African American and European data sets.
  • One of the variants with the highest genetic penetrance located in the gene LRBA was predicted to result in a deleterious change to the amino acid structure. Reduced expression of CTLA-4 secondary to the variants we identified in LRBA may result in autoinflammation that contributes to IBD. “Targeting reduced CTLA-4 expression is an exciting treatment venue, because expression of CTLA-4 has been shown to be increased by chloroquine treatment in vitro.”
  • Enteropathy is present in 63% of all known individuals with LRBA deficiency, with 27% having chronic diarrhea as the presenting symptom

Mangroves in John Pennekamp State Park (Key Largo)