Predicting Risk of Celiac Disease in High-risk Families

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CR Meijer et al. Gastroenterol 2022; 163: 426-436. Open access: Prediction Models for Celiac Disease Development in Children From High-Risk Families: Data From the PreventCD Cohort

B Lebwohl, L Greco. Gastroenterol 2022; 163: 368-369 (editorial). Open access: Can We Predict the Onset of Celiac Disease?

Design: “In this study, the investigators analyze long-term follow-up data from the PreventCD trial, a randomized trial of infants [n=944] with a first-degree relative with CD that was designed to test the strategy of low-dose gluten introduction at age 4 months. The trial did not show that this strategy reduced the risk of CD development,7 but the abundant data collected during this trial have allowed these investigators to study risk factors for the development of CD among the trial participants.” The median f/u was 8.3 yrs.

Key points from study and editorial:

  • 135/944 (14%) children developed CD (mean age, 4.3 years)
  • CD developed significantly more often in girls (P = .005) and in Human Leukocyte Antigen (HLA)-DQ2 homozygous individuals (8-year cumulative incidence rate of 35.4%
  • Prediction application calculator with screening recommendations https://hputter.shinyapps.io/preventcd/. This screening calculator generally recommends screening every 6 months for those at greastest risk and every 12 months for those at lower risk.

HLA testing in this setting has historically been performed primarily due to its excellent negative predictive value. Because HLA DQ2 and DQ8 are present in nearly 100% of people with CD, the primary value of its use has been in ruling out CD when an individual is found to have neither haplotype. This study shows some usefulness in predicting the likelihood of CD.

My take: This study showed 14% of high-risk children developed celiac disease and the number is likely to escalate with more time. In first-degree relatives, checking HLA-DQ2/8–typing may help determine frequency of screening in asymptomatic individuals –though simply choosing to screen every 1-2 years would be a reasonable alternative.

It should be noted that current expert guidelines provide divergent advice; “NASPGHAN recommends that asymptomatic children in high-risk groups (including first-degree relatives) be screened, 4 but the United States Preventive Services Task Force concluded that the evidence is insufficient to warrant recommending for or against screening asymptomatic individuals.”

Related blog posts:

Westchester Lagoon, off Tony Knowles Coastal Trail. Anchorage, AK

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.

IBD Updates: SC Vedolizumab, PRODUCE study: Specific Carbohydrate Diet, Racial Epidemiology of IBD, and Microbiome in UC

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Briefly noted –all of these articles are open access:

A Volkers et al. AP&T 2022; https://doi.org/10.1111/apt.17153 Open access: Real-world experience of switching from intravenous to subcutaneous vedolizumab maintenance treatment for inflammatory bowel disease. In this prospective cohort study, patients (n=135) with IBD who had ≥4 months IV vedolizumab were switched to SC vedolizumab. 

Key findings:

  • 4 patients with Crohn’s disease had loss of response.
  • 9% of patients were switched back to IV vedolizumab due to adverse events or fear of needles.
  • Median clinical and biochemical disease activity remained stable after the switch. Median vedolizumab serum concentrations increased from 19 μg/ml at the time of the switch to 31 μg/ml 12 weeks after the switch (p < 0.005).

Related blog posts:

HC Kaplan et al. Am J Gastroenterol 2022 Jun 1;117(6):902-917. Open access: Personalized Research on Diet in Ulcerative Colitis and Crohn’s Disease: A Series of N-of-1 Diet Trials. In this study, 21 patients (completed trial) were randomized to 1 of 2 sequences of 4 alternating 8-week SCD (specific carbohydrate diet) and MSCD (modified specific carbohydrate diet) periods.

Key findings: “SCD and MSCD did not consistently improve symptoms or inflammation.” “Some individuals had improvement in symptoms and fecal calprotectin compared with their UD, whereas others did not.” The authors note that it took 18 months to recruit 54 patients for this study across 19 research sites.

Related blog posts:

EL Barnes et al. Inflamm Bowel Dis 2022; 28: 983-987. Open access: Racial and Ethnic Distribution of Inflammatory Bowel Disease in the United States The authors electronic health records from 337 centers from January 2013 to December 2018 with nearly 40 million patients in U.S.

Key findings:

  • Black adult patients were significantly less likely than White patients to have a diagnosis of CD (odds ratio [OR], 0.53) or UC (OR, 0.41). Pediatric Black patients were also less likely to have a diagnosis of CD (OR, 0.41) or UC (OR, 0.38)
  • Adult Hispanic patients were less likely to have a diagnosis of CD (OR, 0.33) or UC (OR, 0.45) compared with non-Hispanic patients. Similarly, pediatric Hispanic patients were less likely to have a diagnosis of CD (OR, 0.34) or UC (OR, 0.50).
  • Thus, these data suggest that CD and UC are modestly less prevalent among patients of non-White races and Hispanic ethnicity

M Frioirksmork et al. Inflamm Bowel Dis 2022; 28: 1081-1089. Open access: Similar Gut Bacterial Composition Between Patients With Ulcerative Colitis and Healthy Controls in a High Incidence Population: A Cross-sectional Study of the Faroe Islands IBD Cohort. This cross-sectional study from the Faroe Islands (which has very high incidence of IBD) consisted of 41 patients with established ulcerative colitis and 144 age- and sex-matched healthy controls.

Key findings: There was a similarity in bacterial community composition and absence of the beneficial Akkermansia genus in both groups.

Neuromodulators & Gastroparesis (Bowel Sounds Episode)

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A recent Bowel Sounds had some very useful insight into gastroparesis/dyspepsia. This bowel sounds was particularly interesting with regard to gastric electrical stimulation (very effective in highly selected group) and pyloric botox. It also reviewed many of the difficulties in diagnosis/overlap with dyspepsia.

Listen here: http://buzzsprout.com/581062/11110065

Useful references:

  • Lu PL, Di Lorenzo C. Gastroparesis in the Pediatric Patient: Children are Not Little Adults. Gastrointest Disord. 2020, 2(2), 86-95
  • Lu PL, Moore-Clingenpeel M, et al. The rising cost of hospital care for children with gastroparesis: 2004-2013. Neurogastroenterol Motil. 2016 Nov;28(11):1698-1704.
  • Lu PL, Teich S, et al. Improvement of quality of life and symptoms after gastric electrical stimulation in children with functional dyspepsia. Neurogastroenterol Motil. 2013 Jul;25(7):567-e456.
  • Orsagh-Yentis DK, Ryan K, et al. Gastric electrical stimulation improves symptoms and need for supplemental nutrition in children with severe nausea and vomiting: A ten-year experience. Neurogastroenterol Motil. 2021 Sep;33(9):e14199.

Neuromodulator Algorithm for Adults with Disorders of Gut-Brain Interaction from @Liane428:

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Liver Briefs: Hep C Undertreated, Mystery Hepatitis Pediatric Cases, & AAP Hyperbilirubinemia Guidelines

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Yesterday’s link to a funny 2 minute eulogy did not work right and has been fixed. Here is the updated link and it should work: Humor: Eulogy

In response to this video, Steven Liu sent me a link to a a Weird Al Yankovic:YouTube: Word Crimes. This link would probably be helpful for those reviewing a poorly-written journal submission when providing feedback (& hopefully not sent to anyone trying to provide information via a GI blog).

————-

USA Today (8/9/22): Fewer than a third of insured Americans with hepatitis C receive timely treatment, CDC study shows

“More than 95% of people infected with hepatitis C can be cured with a simple course of antivirals…[the CDC] looked at nearly 50,000 insured patients diagnosed with hepatitis C between January 2019 and October 2020 and found less than one-third received treatment within a year of their diagnosis, according to the study published Tuesday in the Morbidity and Mortality Weekly Report...Treatment was lowest among patients who had state-administered Medicaid plans, with about 23% receiving it. About 28% people covered by Medicare and 35% with private insurance received treatment within the year.”

“Cases of hepatitis C rates have skyrocketed as the opioid epidemic worsens, jumping from an estimated 2,700 infections in 2011 to 57,500 infections in 2019, according to the CDC.”

NY Times (7/26/22): Viral Infections and Gene Variant Are Linked to Child Hepatitis Cases

“Two small studies…suggest a possible explanation for the hepatitis cases: In a small subset of children with this particular gene variant, dual infections with A.A.V.2. (adeno-associated virus 2) and a helper virus, often an adenovirus, trigger an abnormal immune response that damages the liver….As of July 8, 1,010 probable cases had been reported from 35 countries, according to the World Health Organization”

AR Kemper et al. Pediatrics 2022; https://doi.org/10.1542/peds.2022-058859. Open Access: Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation

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.

Dreaded Nausea (2022) Plus Skills or Pills

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C DiLorenzo. Front Pediatr 2022; https://doi.org/10.3389/fped.2022.848659. Open Access: Functional Nausea Is Real and Makes You Sick

Couple of key pointers:

Diagnosis:

  • ” I tend to refrain from ordering gastric emptying studies in patients with nausea unless vomiting hours after eating occurs.” According to the article, this is mainly due to the overlap symptoms of gastroparesis and functional dyspepsia, the suboptimal reliability of testing, and the uncertain value of testing in targeting therapy.
  • “Much like in most other DGBI, diagnostic tests in patients with chronic nausea should only be indicated in the presence of other alarm signs or features (weight loss, severe pain, bilious vomiting, etc.) (29). Upper endoscopies are particularly unhelpful with 98% reported to be normal in patient with nausea as the predominant symptom”

Treatment:

  • “Most beneficial treatment is hypnotherapy.” Cognitive behavioral therapy is likely helpful.
  • Medications that may be useful: cryproheptadine, STW5 (an herbal supplement), scopolamine patch, and erythromycin (when there is gastroparesis); “use of psychotropic agents such as amitriptyline, buspirone, and mirtazapine (which decrease visceral hyperalgesia, improve accommodation or accelerate gastric emptying may be justified in selected cases.” There is little evidence that classical antiemetics such as ondansetron are beneficial for functional nausea.
  • Also consider wrist acupuncture &/or commercially available devices based on the same principle, endoscopic injection of botulinum toxin in the pylorus; implantation of a gastric pacemaker improves drug-refractory nausea. Treatment of anxiety and depression, if present, is also beneficial.

My take: This is a useful review on a tough disorder to manage.

Related blog posts

Related article: PD Browne et al. Clin Gastroenterol Hepatol 2022; 20: 1847-1856. Open Access! Skills or Pills: Randomized Trial Comparing Hypnotherapy to Medical Treatment in Children With Functional Nausea

This article found that hypnotherapy was more effective than standard medical therapy during the first 6 months and similar subsequently in children with functional nausea. Standard medical therapy was a progression of treatment:

RNA Interference (Fazirsiran) for Liver Disease Associated with Alpha-1-Antitrypsin Deficiency

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P Strnad et al. NEJM 2022; 387: 514-524. Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency

Background: “Z-AAT accumulation has been correlated with liver fibrosis, a finding that suggests that reducing Z-AAT production may improve hepatic phenotypes…RNA interference (RNAi) is a naturally occurring cellular mechanism that regulates gene expression. Fazirsiran (previously ARO-AAT) is an investigational RNAi therapeutic that contains a synthetic, double-stranded, small interfering RNA duplex conjugated to N-acetylgalactosamine, which binds to the hepatocyte asialoglycoprotein receptor to facilitate endosomal uptake and intracellular delivery…Fazirsiran causes degradation of AAT and Z-AAT messenger RNA, thus reducing both AAT and Z-AAT protein synthesis in hepatocytes.” Fazirsiran has already shown effectiveness in a mouse model and had an adequate safety profile in a phase 1 study with healthy volunteers.

Methods: Phase 2, open-label, multicenter trial enrolled adults with the PI ZZ genotype and liver fibrosis. They received fazirsiran subcutaneously on day 1 and week 4 and then every 12 weeks

Key findings:

  • All the patients had reduced accumulation of Z-AAT in the liver (median reduction, 83% at week 24 or 48)
  • Fibrosis regression was observed in 7 of 15 patients and fibrosis progression in 2 of 15 patients after 24 or 48 weeks
  • There were no adverse events leading to trial or drug discontinuation. Four serious adverse events (viral myocarditis, diverticulitis, dyspnea, and vestibular neuronitis) resolved. Most common adverse events were arthralgia and transient increase in creatinine kinase (each in 4 patients). It was noted that there was a gradual decrease in mean FEV1 through week 52 but no evidence that this was due to fazirsiran treatment.

The authors note that reduction in Z-AAT accumulation is expected to yield clinical benefit since the liver is a regenerative organ.

My take: This is an exciting development for patients with AAT-associated liver disease but a larger, placebo-controlled treatment trial with longer duration is needed to confirm whether fazirsiran will be a useful therapeutic agent for AAT deficiency.

After reviewing this study, I contacted one of the authors (Dr. Teckman) to find out about the status of pediatric studies. His response:

  • A larger, phase III study is going to start enrolling soon (for adults) to better define the risks, benefits, dose, length of therapy and patient selection which will hopefully lead to full FDA approval. The next phase of fazirsiran for adults will have many sites and St Louis will be one. Patients are welcome to contact me.
  • Trials with fazirsiran for children are being designed. Time frame 1-3 years. Other drugs are also close to opening studies for kids, as well.
  • Several other drugs that appear promising for AAT are also in phase I, II, soon III. That’s great news. I commonly refer patients to “clinicaltrials.gov” but they can contact me or the Alpha-1 Foundation for information.
  • All patients should read the extensive and very informative patient literature on the Alpha-1 Foundation web site; www.alpha1.org.
  • All patients should enroll in the Alpha-1 Registry. This is a scientific, IRB approved registry which is non-interventional and does not commit patients to anything, but which will permit them to be contacted and kept informed about potential trials. It is for anyone who carries any number of many abnormal genotype; ZZ, SZ, MZ, null, etc.
  • All eligible people who are anywhere near a site should be enrolled in the Childhood Liver Disease Research Network; www.childrennetwork.og. This is a non-interventional, NIH- sponsored network which studies pediatric liver disease. ZZ and SZ patients ages 0 years to 25 years can enroll. You do not need to change doctors or care sites. Many patients stay with their docs they have but contribute to the study once a year.

Related blog posts:

  • Alpha-1-Antitrypsin Deficiency (review May 2020). 35% of adults with ZZ genotype show clinically-significant liver fibrosis. Risk factors for advanced fibrosis: male gender, metabolic syndrome/obesity, and alcohol consumption.
  • Liver Shorts March 2020 (A1AT Heterozygosity worsens NAFLD/contributes to cirrhosis)

Imminent COVID-19 BA.5 Variant Booster

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From Eric Topol: The imminent BA.5 vaccine booster

Key points:

  • “There are no data for a BA.5 booster in people…Each year the flu vaccine quadrivalent program is updated using mice data, so there’s certainly a precedent for using such data.”
  • “It’s actually striking that in 2 months from the June 28th FDA meeting, there is a BA.5 vaccine booster made at scale. That is finally in keeping with all the excitement about the plasticity of the mRNA vaccine platform, that it could be ideal for rapid updating.”

The End of the Vitamin D Epidemic (VITAL Study)

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MS LeBoff et al. NEJM 2022; 387: 299-309. Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults

SR Cummings, C Rosen. NEJM 2022; 387: 368-370. VITAL Findings — A Decisive Verdict on Vitamin D Supplementation

In an ancillary study of the Vitamin D and Omega-3 Trial (VITAL), the investigators tested whether supplemental vitamin D3 would result in a lower risk of fractures than placebo. Design: VITAL was a two-by-two factorial, randomized, controlled trial with 25,871 participants with a median followup of 5.3 years.

Key findings:

  • Supplemental vitamin D3, as compared with placebo, did not have a significant effect on total fractures (hazard ratio, 0.98), nonvertebral fractures (hazard ratio, 0.97), or hip fractures (hazard ratio, 1.01). 

From the editorial:

  • This study reinforces a recent trial which found that Vitamin D supplementation did not significantly improve bone mineral density/structure with high-resolution CT.
  • “There is no justification for measuring 25-hydroxyvitamin D in the general population or treating to a target serum level.” Exceptions may include some patients at high-risk for deficiency like persons living in residential settings with little sunlight exposure and those with malabsorptive conditions (eg. celiac disease, cholestatic liver disease).
  • “Providers should stop screening for 25-hydroxyvitamin D levels or recommending vitamin D supplements and people should stop taking vitamin D supplements to prevent major diseases or extend life.”

NY Times (7/27/22): Study Finds Another Condition That Vitamin D Pills Do Not Help

“The first part of VITAL, previously published, found that vitamin D did not prevent cancer or cardiovascular disease in trial participants. Nor did it prevent falls, improve cognitive functioning, reduce atrial fibrillation, change body composition, reduce migraine frequency, improve stroke outcomes, protect against macular degeneration or reduce knee pain. Another large study, in Australia, found that people taking the vitamin did not live longer.”

My take: This should be the end of the Vitamin D epidemic. Will it?

Related blog posts:

Understanding Hiccups Plus TikTok & Unhealthy Eating Habits

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FW Woodley et al. JPGN Reports. 2022. August 2022 – Volume 3 – Issue 3 – p e209. Open access: Significant Temporal Association of Esophageal Air Events (Supragastric Belches, Air Swallows, and Gastric Belches) With Hiccups: A Case Study in an Adolescent

This report showed a significant temporal association between esophageal air events (EAEs) and hiccups using impedance-pH monitoring (I-pHM). EAEs include air swallows, gastric belching, and supragastric belching

This article reviews physiology of hiccups:

  • “Hiccups are physiologically normal but can become pathological when they occur with increasing regularity or for extended periods of time (1). The occurrence of hiccups is mediated through a reflex arc that consists of 3 basic branches: (1) afferent/sensory limb involving vagal, phrenic, and sympathetic nerves; (2) medulla and possibly the cervical spine (8) where central processing occurs; and (3) efferent/motor limb involving motor fibers of phrenic nerves and accessory nerves that innervate the diaphragm and intercostal muscles, respectively (1,9). A hiccup may be caused by any disturbance that triggers one of these branches (1).”

Understanding reasons for hiccups may help with treatment:

  • “We initially tried treating this patient’s hiccups with acid suppression. When symptoms persisted despite H2 blocker, PPI, and cyproheptadine therapy, I-pHM confirmed minimal GER and allowed us to focus instead on other treatments: behavioral techniques, diaphragmatic breathing, and baclofen.”

My take: It is nice to see a correlation between hiccups and physiology with I-pHM. In some patients, baclofen along with diaphragmatic breathing may be a consideration prior to definitive testing.

Related blog posts:

Unrelated article (but interesting): Brooks R, Christidis R, Carah N, et al Turning users into ‘unofficial brand ambassadors’: marketing of unhealthy food and non-alcoholic beverages on TikTok. BMJ Global Health 2022;7:e009112.

Key point: This study examines the marketing of unhealthy food and non-alcoholic beverages on TikTok. Videos posted by top food brands frequently feature branding, product images, engagement and celebrities/influencers. These videos reach billions of views.

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