Category Archives: Gastroenterology

FDA Warning on Eluxadoline (Viberzi)

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Briefly noted: The FDA has issued a safety warning for patients with irritable bowel syndrome who have had their gallbladder removed.

FDA Warns of Increased Risk of Serious Pancreatitis with irritable bowel drug eluxadoline (Viberzi) in patients without a gallbladder

An excerpt:

Viberzi is a prescription medicine used to treat irritable bowel syndrome in adults when the main symptom is diarrhea (IBS-D)…From May 2015, when Viberzi was first approved, through February 2017, FDA received 120 reports of serious cases of pancreatitis or death.* Among the 68 patients who reported their gallbladder status, 56 of them did not have a gallbladder and received the currently recommended dosage of Viberzi. Seventy-six patients were hospitalized, of which two patients died.

My take: Now that this warning has been issued, there may be additional cases identified. While this medication is mainly used in adults, pediatric gastroenterologists need to be aware of this risk in counseling potential patients.

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Two for the PPI Team

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Medicine safety is not nearly as straight-forward as most people would expect.  Virtually all medicines have the potential for adverse reactions.  In addition, there are often conflicting reports on how frequent adverse reactions occur; furthermore, negative studies demonstrating safety may be published less frequently due to publication bias.

This problem is compounded by the frequent misunderstanding of statistics.  Frequently, risks of medications are expressed as an odds ratio.  So, if an adverse reaction occurs twice as often with the medication than without the medication, the odds ratio would 2.0.  Yet, if the adverse reaction is rare (eg. one in a million), then the absolute increase in risk remains minuscule.

Proton pump inhibitors have received a lot of press, often about rare increases in adverse reactions. But, there are many potential benefits to these medications and numerous studies demonstrating fairly good safety profiles.  A few more studies (thanks to Ben Gold for these references) on their safety have recently been published:

  • 1. “Long-term Proton Pump Inhibitor Use is Not Associated with Changes in Bone Strength and Structure” LE Targownik et al. Am J Gastroenterol 2017; 112: 95: 101.
  • 2. “Proton Pump Inhibitors Do Not Increase Risk for Clostridium difficile Infection in the Intensive Care Unit.” DM Faleck et al. Am J Gastroenterol 2016; 111: 1641-8.

In the first study, the authors examined 52 PPI-users (>5 yrs) and 52 non-PPI users with mean age of 65 years.  They underwent quantitative CT , DXA, and markers of bone metabolism. “There were no differences detected..between the two groups.”  The conclude that PPIs were not associated with changes that increase a risk of fracture and “provide further evidence that the association between PPI use and fracture is not causal.”

In the second study, the authors analyzed data from 14 ICUs 2010-2013 and identified 18,134 patients (mean age 66-67 yrs) who met inclusion criteria.  271 (1.5%) developed Clostridium difficile infection (CDI) in the ICU.  The main risk factor for CDI was antibiotics with adjusted Hazard Ratio (aHR) of 2.79.  “There was no significant increase in risk for CDI associated with PPIs in those who did not receive antibiotics (aHR 1.56; 95% CI, 0.72-3.35).”  “PPIs were actually associated with a decreased risk for CDI in those who received antibiotics (aHR 0.64; 95% CI 0.48-0.83).”  The authors also noted that even those who received the highest doses of PPIs, “there was no risk for health-care facility-onset CDI.”

My take: PPIs can be life-saving medications and can alleviate a lot of suffering.  These studies pushback on some of the concerns about PPI risk.

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Correlation between Microbiome and Irritable Bowel Syndrome

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I vaguely remember jokes that I heard as a teenager about computers that could analyze stool or urine and then come to remarkable conclusions about the person’s health or extramarital problems.  Fast-forward a few decades and these jokes are not so far off.

A recent study (J Tap, M Derrien, et al. Gastroenterol 2017; 152: 111-23) describes an intestinal microbiome ‘signature’ associated with severity of irritable bowel syndrome (IBS).  Thanks to Ben Gold for highlighting this article.  (He placed this one on my desk: “Jay -FYI -It is all about the poop!”)

In this study, the authors collected fecal and mucosal samples from adult patients who met Rome III criteria for IBS.  They started with an exploratory set of 149 subjects (110 with IBS, 39 controls).  Subsequently, they used a validation cohort of 46 subjects (29 with IBS, 17 controls).

Key findings:

  • “By using classic approaches, we found no differences in fecal microbiota abundance or composition between patients with IBS vs healthy patients.”  But, “a machine learning procedure, a computational statistical technique, allowed us to reduce the 16S ribosomal RNA data complexity into a microbial signature for severe IBS, consisting of 90 bacterial operational taxonomic units.”
  • This microbial signature showed IBS to be associated negatively with microbial richness, exhaled CH4, presence of methanogens, and enterotypes enriched with Clostridiales or Prevotella species.  Figure 6 provides a graphic summary of the study and the microbial signature.
  • The authors note their findings were not explained by differences in diet or medications.
  • Overall, the microbial signature has a low sensitivity and thus at this point does not have clinical applicability.

My take: There are a number of studies showing that our gut microbiome is associated with numerous conditions, including IBS, inflammatory bowel disease, and metabolic syndrome.  Having our poops analyzed by a computer to tell us what is wrong does not seem all that funny anymore.

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Image Only: Living with Irritable Bowel Syndrome

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Image Only: Candida Esopagitis

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In a patient who presented with trouble swallowing, his endoscopy showed candida esophagitis.  “Oral antifungal therapy was initiated in the patient, and within 2 weeks after starting therapy, his pain on swallowing was reduced. A repeat endoscopy performed 12 weeks after the initiation of antifungal therapy showed a marked reduction in the number and severity of esophageal lesion.”

FDA Approves Plecanatide (Trulance) for Adults with Idiopathic Constipation

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Here’s the link: FDA approves Trulance for Chronic Idiopathic Constipation (Jan 19.2017).  Plecanatide is a guanylate cyclase-C agonist.

An excerpt:

Trulance, taken orally once daily, works locally in the upper GI tract to stimulate secretion of intestinal fluid and support regular bowel function.

The safety and efficacy of Trulance were established in two 12-week, placebo-controlled trials including 1,775 adult participants. Participants were randomly assigned to receive a placebo or Trulance, once daily. Participants in the trials were required to have been diagnosed with constipation at least six months prior to the study onset and to have less than three defecations per week in the previous three months, as well as other symptoms associated with constipation. Participants receiving Trulance were more likely to experience improvement in the frequency of complete spontaneous bowel movements than those receiving placebo, and also had improvements in stool frequency and consistency and straining.

Trulance should not be used in children less than six years of age due to the risk of serious dehydration… The safety and effectiveness of Trulance have not been established in patients less than 18 years of age.

The most common and serious side effects of Trulance was diarrhea.

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Achalasia -Updated Epidemiology

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In this new era of high resolution manometry, there is an increasing incidence of achalasia.

Briefly noted:

JA Duffield et al. Clin Gastroenterol Hepatol 2017; 15: 360-5. In this study from South Australia, using a large database (2004-2013), the annual incidence of achalasia was between 2.3 and 2.8 per 100,000 persons. Mean age at diagnosis was 62 years.

S Samo et al. Clin Gastroenterol Hepatol 2017; 15: 366-73. In a similar study from Chicago, the authors estimated that the yearly city-wide incidence averaged 1.07 per 100,000; however the average in the neighborhood closest to the hospital (and possibly with better case capture) was 2.92 per 100,000.

My take: These studies identified incidence rates that are about double the rates that were reported prior to the availability of high resolution manometry.

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How Much Do We Really Know About Fecal Microbiota Transplantation?

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A recent study (SJ Ott et al. Gastroenterol 2017; 152: 799-811) followed 5 patients who were treated with a sterile fecal filtrate (via nasojejunal tube) for recurrent Clostridium difficile infection (CDI) for a minimum of 6 months.  This open-label study noted that this fecal filtrate transfer eliminated the symptoms of CDI in all 5 patients.

A summary of this important study is available in the AGA blog:

Here’s an excerpt: What is the Active Ingredient in FMT for CDI?

Stool was collected from 5 donors selected by the patients and fully characterized according to FMT standards. The stool was then sterile filtered to remove small particles and bacteria, and the filtrate was transferred to patients in a single administration via nasojejunal tube.

Fecal samples were collected from patients before and at 1 week and 6 weeks after FFT. Microbiome, virome, and proteome profiles of donors and patients were compared….

They identified about 300 different proteins in each of the filtrates they analyzed—most proteins were of human origin, but the filtrates also contained 20–60 bacterial and fungal proteins. The major human proteins in the filtrate proteome were human enzymes such as intestinal-type alkaline phosphatase, chymotrypsin-like elastases, and α amylases. Bacterial proteins included metabolic enzymes and redox proteins without obvious microbiome-modifying properties, such as glyceraldehyde-3-phosphate dehydrogenase, phosphoenolpyruvate carboxykinase, glutaredoxin-1, or thioredoxin-1…

Ott et al propose that the active component of FMT therapy might not be living bacteria, but bacterial components, antimicrobial compounds of bacterial origin (bacteriocins), or bacteriophages that contribute to a healthy intestinal microenvironment. These could be common to all successful FMT therapies and even rather unspecific regarding the bacterial strain(s) used for therapies. They propose that bacteriophages affect community dynamics of gut microbiota to resolve dysbiosis.

My take: This is a provocative study that challenges us to rethink how FMT works. Ultimately, treating CDI needs to be more precise.

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Latiglutenase Not Effective for Celiac Disease, Plus One

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A recent study (JA Murray et al. Gastroenterol 2017; 152: 787-98) examined the effectiveness of  latiglutenase for celiac disease.  Latiglutenase (aka ALV003) is an oral medicine which is a mixture of two recombinant gluten-targeting proteases.

The concept of latigluenase is that a medicine that degrades the gluten protein could obviate the need for a gluten free diet.  Unfortunately, in this study with 494 patients with celiac disease for at least 1 year, the medicine at various doses for 12 to 24 weeks was ineffective. There was no difference between the medicine and placebo with regard to villous height:crypt depth ratio, number of intraepithelial lymphocytes or serologic markers of celiac disease.  Symptom scores increased in both the active treatment group and the placebo group.  While this was a negative study, the authors did note some effect on symptom domains on higher dosing regimens. “This observation suggests that treatment with latiglutenase may affect symptoms before showing clinically meaningful effects on serologic and histologic end points.

A second study (RS Choung et al. Gastroenterol 2017; 152: 830-9) examined prevalence and morbidity of undiagnosed celiac disease in Olmstead County. After excluding patients with celiac disease, sera from 30,425 adults and 830 children were tested for tissue transglutaminase IgA antibody (tTG)  and endomysial antibody (EMA).  Case definition: patients were considered to have celiac serologically if tTG titer was 2.0 U/mL or greater with a positive EMA. The prevalence of celiac disease was 1.1% in adults and 1.0% in children. The majority of patients with celiac disease (>80%) have not received the diagnosis.  By comparing those with positive celiac serology to matched controls (2 controls for each positive), the authors determined that undiagnosed celiac disease was associated with increased rates of hypothyroidism (OR 2.2) but no other significant morbidities.  Median followup period was 6.3 years.

My take: A promising new therapy for celiac disease, latiglutenase, looks like it will not be effective and there are a lot of individuals with celiac disease who are unaware of their diagnosis.

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

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Colon Cancer at Younger Ages

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From USA Today: Colon and rectal cancers surge in millennials and GenX

An excerpt:

Someone born in 1990 has double the risk of early colon cancer and quadruple the risk of early rectal cancer as someone born in 1950…

Most of the nation’s 135,000 annual cases and 50,000 deaths related to colon and rectal cancer still occur among people over age 55. But the share of cases involving younger adults has risen to 29% for rectal cancer and 17% for colon cancer, the study showed. About 11,000 people in their 40s and 4,000 under 40 were diagnosed in 2013…

Known risk factors for colon and rectal cancer include obesity, inactivity and diets high in red and processed meat and low fruits, vegetables and whole grains.

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