Category Archives: Gastroenterology

Only 3% Make It Through the Donor Screening Process for Fecal Microbiota Transplantation

Posted on by

A recent letter (Z Kassam et al. NEJM 2019; 381: 2070-2) describes the arduous process involved in being selected as a stool donor for fecal microbiota transplantation (FMT).

In a previous blog (2015), it appeared that 17% of donors were accepted for FMT: Rejected! Most Stool is Not Good Enough for FMT This current review of the donor program from a stool bank (OpenBiome) prospectively evaluated 15,317 donor candidates from 2014-2018.

Key finding:

  • Only 3% (n=386) made it through all the steps to become donors

Reasons for exclusion:

Stage 1: common reasons for exclusion:

  • geographical -living too far away to donate regularly
  • BMI >30
  • social history
  • travel history
  • not in age range

Stage 2: “failing” the 200-item clinical assessment –common reasons for exclusion:

  • lost to followup
  • allergic disorders/asthma
  • receiving medications/supplements
  • mental health concerns
  • infectious disease history
  • social history/sexual history/other reasons

Stage 3: “failing” the stool and nasal screening which included (in 2016) carbapenem-resistant Enterobacteriacea (CRE), extended-spectrum beta-lactamase-producing organisms (ESBL) and MRSA. –common reasons for exclusion:

  • lost to followup
  • infectious disorders (including C diff in 7 patients)

Stage 4: “failing” serological screening

  • lost to followup
  • abnormal LFTs, CBC or infection

Related blog posts:

Island Ford, Sandy Springs, GA

Surprising Genetic Mutations in Polyposis Study

Posted on by

A recent cross-sectional study (PP Stanich et al. Clin Gastroenterol Hepatol 2019; 17: 2008-15, editorial 1942-44) identified a high frequency of genetic mutations among adults with at least 10 colonic polyps (cumulative burden of either adenomatous or hamartomatous).

This study had 3789 subjects who underwent multigene panel testing (MGPT) from 2012-16.

  • All subjects had at least 14 CRC-associated genes tested: APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53
  • A subset had 3 more newly recognized polyposis genes: GREM1, POLD1, and POLE

Key findings:

  • A mutation in at least 1 gene was found in 13.7%
  • In those with fewer than 20 cumulative adenomas, 7.6% had a disease-associated genetic mutation with the majority (5.3%) being nonpolyposis CRC genes
  • Younger patients, 18-29, were more likely to have mutations in any gene.  For example, among patients with 10-19 polyps, these younger patients had a mutation in one of these genes in 27.8%; this is more than double the rate in any other age group.
  • Hamartomatous polyps, regardless of number, had a very high yield with genetic testing: 40% with 10-19 polyps and 72% with 20-99 polyps.

Limitations:

  • There is a referral bias in that the population was derived from a testing laboratory (Ambry)
  • In clinical practice, genetic testing frequently results in variants of unknown significance

My take: This study shows that genetic mutations are fairly frequent in patients with cumulative polyp burden of 10 or more, especially in younger age groups.  The surprising finding is the high frequency of nonpolyposis CRC genes.  Thus, in patients with adenomatous polyposis, testing beyond APC and MUTYH may be needed.

Related blog posts:

Atlanta Botanical Garden

Grading Treatment Response in Eosinophilic Esophagitis

Posted on by

Full Text Link: A Conceptual Approach to Understanding Treatment Response in Eosinophilic Esophagitis

Also, related articles:

  1. D Bushyhead et al. Gastroenterology 2019; 157: 944-5. This practical teaching case report noted that oral immunotherapy (OIT) has been shown to trigger new onset EoE in 2.7% (AJ Lucendo et al. Ann Allergy Asthma Immunol 2014; 113: 624-9).
  2. R Alexander et al. Clin Gastroenterol Hepatol 2019; 17: 2371-3. This study compared eating behaviors of adults with active EoE (n=10), inactive EoE (n=10) and control patients (n=10).  Not surprisingly, those with active EoE took longer to eat (18.3 min compared to 12.4 min, and 13.0 min respectively) and had more drinks after a single bite (11.6 compared with 5.1 and 2.5 respectively)

Related blog posts:

How to Make a Study Look Favorable for Reflux Surgery Compared to Medical Treatment

Posted on by

A recent study (SJ Spechler et al. NEJM 2019; 381: 1513-23) on first glance appears to support surgery as more effective than medical treatment for refractory heartburn.

Only ~20% of enrolled patients were included in the reported outcomes!

Here’s what happened.  Among a cohort of VA patients (n=360, mean age 48 years) who were reportedly refractory to PPI-treatment:

  • 78 were excluded during prerandomization
  • 42 had relief of their heartburn during a 2-week omeprazole lead-in (20 mg BID)
  • 70 did not complete trial procedures
  • 23 had non-GERD disorders
  • 99 had functional heartburn

This left 78 patients who underwent randomization.  All patients in this highly-selected group had undergone endoscopy with biopsy, impedance-pH testing, and esophageal manometry.  18 of 27 (67%) had treatment success with surgery compared to 7 of 25 patients treated with baclofen/PPI and 3 of 26 with control medical treatment (PPI alone).

Key points:

  • Careful evaluation is needed in any patient with refractory heartburn, especially if contemplating surgery.  Most will either respond to PPI treatment or have a disorder other than reflux; the authors note that 122 patients (out of 360 patients) did NOT have reflux –99 had functional heartburn.
  • Careful instruction in PPI use can be helpful.  Omeprazole and similar agents should be taken 30 minutes before meals.
  • The authors noted that in addition to reflux, that reflux hypersensitivity can “respond to fundoplication…treatment success was 71% among the 14 with reflux hypersensitivity and 62% among the 13 with abnormal acid reflux.”

Limitations: The VA population is not representative of the general population; this trial had a predominance of white males. Also, it is hard to exclude that some of the ‘success’ of the procedure could relate to a powerful placebo response.

My take: This trial reinforces the notion that reflux surgery is helpful in very few highly-selected patients.

Related blog posts:

Fecal Microbial Transplantation -Evidence for Use Beyond Recurrent Clostridium Difficile

Posted on by

Briefly noted: GR D’Haens, C Jobin. Gastroenterol 2019; 157: 624-36. This review sums up the emerging evidence for use of fecal microbial transplantation for conditions besides recurrent Clostridium difficile infection.

Table 2 succinctly provides list of disease, types of study/evidence, and potential effect.

  • Among gastrointestinal diseases, the authors note that there is an “overall positive” effect for ulcerative colitis, “suggestive” benefits for IBS, GVHD, post-antibiotic diarrhea, constipation, and hepatic encephalopathy.  No effect has been evident with Crohn’s disease or pouchitis.
  • Among nongastrointestinal diseases, the authors note a “suggestive” benefit in autism and metabolic syndrome and “unknown” effect with psoriasis and multiple sclerosis.

My take: The review indicates a need for more studies and the need to define which factors in fecal material mediate the therapeutic effects.

Related article: OC Aroniadis. Lancet Gastroenterology and Hepatology; 2019. https://doi.org/10.1016/S2468-1253(19)30198-0. In this double-blind, randomized, placebo-controlled crossover trial in patients aged 18–65 years with moderate-to-severe IBS-D with 48 patients, FMT (capsule study) was safe, but did not induce symptom relief at 12 weeks compared with placebo.

Related blog posts:

What to Tell Patients About Ranitidine From AGA

Posted on by

Here’s the link: Talking to your patients about ranitidine  Thanks to John Pohl for sharing this information.

Oct. 3, 2019

Talking to your patients about ranitidine

The recent FDA safety alert might be causing concern among your patients about their heartburn treatment.

The FDA recently released several safety alerts on ranitidine formulations, including the brand-name drug Zantac, that were found to contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA) at low levels. NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests and animal studies. NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables. This contaminant is similar to was recently found in losartan, an angiotensin II receptor blocker used to treat hypertension, that was recalled by the FDA.

The FDA is continuing to test ranitidine products from multiple manufacturers and is assessing the potential impact on patients who have been taking ranitidine. 

With the voluntary recall of 14 lots of prescription ranitidine capsules distributed by Sandoz Inc., as well as the voluntary recall of over-the-counter (OTC) ranitidine tablets (75 mg and 150 mg), labeled by Walgreens, Walmart, and Rite-Aid and manufactured by Apotex Corp, your patients might be asking a lot of questions about whether to continue to using their medicines and what alternatives are available. 

TALKING TO YOUR PATIENTS 

The FDA safety alerts have been covered by various media outlets since early September. This may cause your patients to question whether they should stay on or start using ranitidine products. When discussing the recall with your patients, let them know that: 

  • Ranitidine is an H2 blocker (antihistamine) — available OTC and in prescription strength — used to prevent and relieve heartburn associated with acid ingestion and sour stomach. It reduces stomach acid and works longer but not as quickly as antacids.
  • Not all ranitidine medicines marketed in the U.S. are being recalled and the FDA is not recommending individuals stop taking all ranitidine medicines at this time.
  • It might be prudent to hold off taking Zantac until a final FDA conclusion.
  • Multiple drugs are approved for the same or similar uses as ranitidine. Other treatment options are available, both prescription and OTC, for patients who are concerned about ranitidine.
  • Life-style modifications may reduce or eliminate the need for heartburn drugs for long-term use. These may include weight loss, avoiding tobacco or a change in eating patterns. Share AGA’s patient education content on gastroesophageal reflux disease (GERD) for more tips for your patients.

Related blog post: Preliminary Recommendations from NASPGHAN on Ranitidine Warnings

Gluten-Free –No Evidence It is Helpful for Healthy Individuals

Posted on by

A recent study (ID Croall, et al. Gastroenterol 2019; 157: 881-3) provides additional data indicating that a gluten-free diet does not confer health benefits to healthy individuals.

A double-blind randomized placebo 2-week trial with 30 healthy adults divided subjects into two groups –some received flour sachets to consume with organic gluten (14 g) and some received a gluten-free blend (rice, potato, tapioca, maize, buckwheat flour). Both groups were instructed to take their flour sachets twice a day along with a gluten-free diet (GFD).

Key finding: The group receiving gluten did not experience any increase in gastrointestinal symptoms or fatigue compared to the placebo group.

My take: While this study lasted only 2 weeks and had a small sample size, nevertheless, it adds to the literature indicating that a GFD is unlikely to be beneficial in otherwise healthy individuals. Those who stick with a GFD should seek the help of a well-qualified dietician.

Related blog posts:

Portland, OR. Portland aerial trams –between the city’s South Waterfront district and the main Oregon Health & Science University (OHSU) .

Combination Therapy Still Works for Inflammatory Bowel Disease (Part 1)

Posted on by

There is speculation that the use of therapeutic drug monitoring (TDM) may obviate the advantages of combination therapy. However, there is plenty of data supporting combination therapy including a recent retrospective population-based study (LE Targownik et al. Clin Gastroenterol Hepatol 2019; 17: 1788-98).

This ‘real-world’ study (2001-2016) utilized the Manitoba IBD database and included 852 persons with Crohn’s disease (CD) and 303 with ulcerative colitis (UC).

Key findings: 

  • In persons with CD, combination therapy (immunomodulator with a TNF antagonist) was associated with lower treatment ineffectiveness with an adjusted hazard ratio (aHR) for ineffectiveness at 0.62.  The ineffectiveness in UC persons was lower at 0.82 but did not reach statistical significance.
  • When looking at specific time frames, among patients with CD, at 1 year, combination therapy the rate of ineffectiveness-free treatment was 74.2% for combination therapy compared to 68.6% for monotherapy; at 2 years, the rates were 64.0% and 54.5% respectively.
  • Combination therapy in CD was associated with increased time to first IBD-related hospitalization with aHR of 0.53 and with lower rates of switching anti-TNF agents (aHR 0.63).  Lower rate of surgery (aHR 0.76) did not reach statistical significance.
  • The choice of immunomodulator (6-MP/AZA vs MTX) and the choice of anti-TNF agent (IFX or ADA) did not significantly influence the overall benefit of combination therapy.  Though, AZA was the main concomitant treatment (92%).
  • 90% of the patients in the study who received combination therapy had received immunomodulator therapy prior to combination therapy.  This is in contrast to the SONIC study in which patients were naive to both agents.
  • 57% of IFX users and 43% of ADA users received concomitant therapy.

My take: Combination therapy has been associated with higher response rates to IBD therapy.  This advantage has to be weighed against potential adverse effects.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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.

Wizard Island. Crater Lake, OR

Appropriate Proactive Therapeutic Drug Monitoring

Posted on by

This blog post and tomorrow’s post highlights two articles on proactive therapeutic drug monitoring (pTDM) for inflammatory bowel disease.  The first article (K Papmichael et al.  Clin Gastroenterol Hepatol 2019; 17: 1655-68) summarizes a meeting of 13 international IBD specialists who reached consensus on 24 statements after a review of the literature.

Full Text Link:  Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases

Key Recommendations:

  • For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics.
  • Reactive TDM was appropriate for all biologic agents both for primary non-response and secondary loss of response

Background/Rationale for pTDM:

  • “Numerous studies have demonstrated a positive correlation between serum biologic drug.concentrations and favorable therapeutic outcomes”
  • “Low or undetectable drug concentrations can lead to immunogenicity and treatment failures”
  • “TDM…is an important tool for optimizing biologic therapy…Data suggest that pTDM, with drug titration to a target trough concentration, performed in patients with clinical response/remission can also improve the efficacy of anti-TNFs”

Table 4  Scenarios of Applying Therapeutic Drug Monitoring of Biological Therapy in Patients With Inflammatory Bowel Disease

1-4: Anti-TNFs:

  • It is appropriate to order drug/antibody concentration testing in responders at the end of induction for all anti-TNFs.
  • It is appropriate to order drug/antibody concentration testing at least once during maintenance for patients on all anti-TNFs.
  • It is appropriate to order drug/antibody concentration testing of anti-TNFs at the end of induction in primary non-responders.
  • It is appropriate to order drug/antibody concentration testing for all anti-TNFs in patients with confirmed secondary loss of response.

5-8: Vedolizumab -agreement only on ordering TDM in non-responders or those with loss of response

9-12: Ustekinumab  -agreement only on ordering TDM in non-responders or those with loss of response

From Table 5: Biological Drug Concentrations and Anti-Drug Antibodies When Applying Therapeutic Drug Monitoring in Inflammatory Bowel Disease

  • Infliximab: 15. In the presence of adequate trough drug concentrations, anti-drug antibodies are unlikely to be clinically relevant.
  • Infliximab: 19. The minimal trough concentration for infliximab post-induction at week 14 should be greater than 3 μg/mL, and concentrations greater than 7 μg/mL are associated with an increased likelihood of mucosal healing.
  • Adalimumab: 22. The minimum drug concentration at week 4 for adalimumab should at least be 5 μg/mL. Drug concentrations greater than 7 μg/ml are associated with an increased likelihood of mucosal healing.
  • Certolizumab: 24 & 25: The minimum concentrations for certolizumab pegol at week 6 should be greater than 32 μg/mL and 15 μg/mL during maintenance.
  • Golimumab 26 & 27: The minimum drug concentration at week 6 for golimumab should at least be 2.5 μg/mL and 1 μg/mL.during maintenance

My take: This article provides extensive literature to reinforce their recommendations.  Most of the trough levels mentioned are minimum levels that need to be achieved.

 

“Intestinal Microbiota Transplant” -New Terminology for Fecal Transplant

Posted on by

A recent letter to the editor (A Khoruts, LJ Brandt, Am J Gastroenterol 114: 1176) suggests that the terms “Fecal Transplant” or “Fecal Microbiota Transplantation” (FMT) should be abandoned in favor of “intestinal microbiota transplant.”

  • First of all, the authors argue that the word “fecal” is no longer accurate as some transplants occur by swallowing capsules of purified microbiota and the days of “blending raw stool near the bedside are largely over.”
  • Secondly, the term “fecal” is highly problematic.  “We are hard-wired to perceive feces to be disgusting.”
  • Third, the media sensation from the terms FMT or fecal transplant “has not translated into substantial positive consequences, such as funding research…[or] philanthropic fundraising.”

Thus, the authors advocate “Intestinal Microbiota Transplant” or IMT.

My take: (borrowed from authors) It is time to “abandon the scatologic humor that is arguably threatening further development of this promising therapeutic approach.”

Related blog posts:

Sunrise at Crater Lake, OR