Category Archives: Gastroenterology

When A Disease Turns Out to Be Fictitious -The Sad Story on Sphincter of Oddi Dysfxn

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When parents make up diseases in their children, the consequences can be dire.  What happens when doctors find out that a disease that they have been treating probably doesn’t exist?

  • Cotton PD et al. “Effect of endoscopic sphincterotomy for suspected sphincter of Oddi dysfunction on pain-related disability following cholecystectomy: the EPISOD randomized clinical trial” JAMA 2014; 311: 2101-2109.

A detailed analysis of this study (Gastroenterol 2015; 148: 440-44) and the author’s reply provides some insight into that questions and helps place this study and its results into context.

Key points from the Gastroenterology Selected Summary:

Background:

  • “Sphincter of Oddi dysfunction (SOD) is the term used to describe an episodic abdominal pain syndrome, typically occurring in young to middle-aged women in the setting of prior cholecystectomy…SOD remains a diagnosis of exclusion.”

Design:

  • “The investigators conducted a double-blind, sham-controlled, randomized trial at 7 US tertiary centers, enrolling 214 adult post-cholecystectomy patients with debilitating abdominal pain due to suspected biliary SOD (predominantly type III).” Sham patients underwent ERCP, manometry, and pancreatic duct stenting.
  • Patients were randomized 2:1 to sphincterotomy or sham; those randomized to sphincterotomy and subsequently shown to have a hypertensive pancreatic sphincter were then re-randomized (1:1) to have biliary or combined biliary/pancreatic sphincterotomies.

Results:

  • “Most patients in both study groups experienced considerable reduction in their pain disability scores…the proportion meeting the trial’s 1-year primary endpoint was higher among those treated with sham compared with sphincter ablation (37% vs. 23%, P=.01)”
  • “The manometry findings did not predict treatment success.”  There were no other useful predictors of success identified (eg. elevated liver enzymes, prior stone at cholecystectomy)
  • Adverse effects from procedures included 26 cases of acute pancreatitis (2 severe) and 2 perforations.

Discussion:

  • “The results of this trial are fascinating…the authors, many of whom had dedicated entire careers to the management of these patients using the very procedure they have now conclusively shown to be futile, may be understandably disheartened by the results.”
  • Numerous limitations of the study are noted.  In particular, “the 1-year time frame of the trial is likely to have been too short to capture the deleterious impact of prophylactic pancreatic duct stenting, which…has been associated with interval induction of pancreatic ductal abnormalities mimicking chronic pancreatitis.”
  • “It is our view that the authors’ data…provide an unambiguous mandate for imposing an immediate moratorium on subjecting this group of patients to ERCP.“

Dr. Cotton’s reply:

  • “It may be premature to discard the whole concept of sphincter dysfunction as a cause of pain.”
  • He indicates that “gallbladder dyskinesia” is another related question and was the reason for surgery in half of EPISOD subjects.
  • The results of the study “clearly show the need for equally stringent studies to answer the many remaining questions.”

For those who read this much of this post:  I wanted to let you know that yesterday’s online post on early peanut introduction was updated with recommendations from the associated editorial.

Related blog posts:

Another headline from Freaknomics Website follows. Of course I probably should think twice about poking fun at typos given the volume of them on this blog.

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Taking One ‘Bite’ At A Time -For Celiac Diagnosis

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A small study (reference from KT Park’s Twitter feed –Gastrointestinal Endoscopy DOI: http://dx.doi.org/10.1016/j.gie.2014.10.024) suggests that taking a single biopsy per pass rather than two biopsies per pass results in better quality specimens:

Link: Endoscopic Biopsy Technique in the Diagnosis of Celiac Disease

Here are the results and conclusion of the abstract:

Results

Patients (N = 86) were enrolled, 47% with known celiac disease, 36% with suspected celiac disease, and 17% with an unknown celiac disease status. Well-oriented biopsy specimens were noted in 66% of patients with the single-biopsy technique and 42% of patients with the double-biopsy technique (P < .01). Analysis of matched pairs showed improved orientation with the single-biopsy technique (odds ratio 3.1; 95% confidence interval, 1.5-7.1; P < .01). This persisted in subgroup analysis of patients with known celiac disease (P = .02), villous atrophy (P = .02), and a final diagnosis of celiac disease (P < .01).

Conclusion

The single-biopsy technique improves the yield of well-oriented duodenal biopsy specimens. Endoscopists should consider taking only 1 biopsy specimen per pass of the forceps in patients undergoing biopsies of the duodenal mucosa.

Related blog posts:

I'm the one on the right

I’m the one on the right

Accelerated Infliximab Dosing in Acute Severe Ulcerative Colitis -plus one link

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A small retrospective study (n=50) suggests that more rapid induction with infliximab may improve response and lower colectomy rate in acute severe ulcerative colitis (UC).

Link: Accelerated Infliximab in Acute UC

Here’s the abstract:

Background & Aims

Administration of infliximab to patients with acute severe ulcerative colitis (ASUC) (rescue therapy) can reduce the rate of early colectomy (within 12 months), but long-term rates of colectomy are the same as those of the pre-biologic era for these patients. The half-life of infliximab is shorter in patients with ASUC than in patients with non-severe UC, so more frequent dosing might be required to produce a therapeutic effect.

Methods

We performed a retrospective analysis of 50 hospitalized patients who received infliximab for steroid-refractory ASUC at a single academic center from September 2005 through 2013. In 2011 an accelerated dosing strategy for infliximab was introduced; we compared outcomes of standard and accelerated dosing regimens. One group of patients (n = 35) were placed on a standard dosing regimen for infliximab and then given the drug at 0, 2, and 6 weeks and then every 8 weeks thereafter. A second group (n = 15) were placed on an accelerated regimen and received 3 induction doses of infliximab within a median period of 24 days. Rates of colectomy were compared between the groups during induction and follow-up periods.

Results

There were no differences between groups in median baseline levels of C-reactive protein, albumin, or hemoglobin. The rate of colectomy during induction therapy was significantly lower with the accelerated regimen (6.7%, 1 of 15) than with the standard regimen (40%, 14 of 35) (Fisher exact test, P = .039). The standard regimen was associated with shorter time to colectomy (log-rank test, P = .042). Among patients who completed induction therapy, subsequent need for colectomy was similar between the groups during the follow-up period. Multivariate analysis showed that factors independently associated with successful induction therapy were level of albumin (g/L) when the treatment began (P = .003) and the accelerated dosing regimen (P = .03).

Conclusions

In patients with ASUC, an accelerated infliximab induction strategy reduces the need for early colectomy. An intensified infliximab dosing strategy in response to clinical or laboratory signs of breakthrough inflammation merits consideration in prospective studies.

One other link: IBD and College: Do the two play nicely (from Jeremy Adler and UofM) -describes college transition issues for our IBD patients.  Probably the most important piece of advice: “Take your medicine.”  Many really good kids decide to see what happens off therapy, often to their detriment.

Do We Still Need PPI-REE?

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“It is on shaky ground that one defines a disease by a response to therapy rather than by its clinical and mechanistic characteristics.” This is noted in a recent editorial (Clin Gastroenterol Hepatol 2014; 12: 2023-25, study: 2015-22).

The editorial makes this comment because the related study finds that the esophageal tissue from eosinophilic esophagitis (EoE) patients with proton-pump responsive EoE (PPI-REE) was indistinguishable from patients with EoE who do not respond to PPIs.

The study examined 196 consecutive patients and performed immunohistochemistry to examine major basic protein (MP), eotaxin-3, and tryptase.  Key finding: none of these markers were able to distinguish EoE from PPI-REE; however, these 3 assays did identify EoE with 100% accuracy compared with controls.

From the editorial: “We can approach EoE as a disease in which use of PPIs is the first step in treatment, and diet and steroids represent step-up therapy…We may not understand why some patients with EoE respond to PPIs yet others do not.”  It is possible that genetic testing in the future will allow us to distinguish which patients will benefit from PPIs, topical steroids or diets.

Bottomline: Now that it is well-recognized that a substantial portion of EoE patients benefit from PPIs, is it necessary to try to use a separate label for this subset? Probably not.

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In the News …CRE due to ERCPs

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Carbapenem-Resistant Enterobacteriaceae (CRE) are difficult to treat infections.  A recent story in USA Today noted their association with endoscopic retrograde cholangiopancreatography (ERCP)/duodenoscopes.  According to the article, the FDA is working with the manufacturers to eliminate this risk.  Compared to other endoscopes, the side-viewing scopes are more technically-difficult to clean because of its “elevator” mechanisms.  “The biggest cases involved dozens of patients and multiple deaths.”  It is likely that more frequent and easier-to-treat infections may be transmitted as well; these types of infections generally do not result in full-fledged epidemiological investigations. Here’s the link: “Deadly bacteria on medical scopes trigger infections” This link has particularly good diagrams explaining resistant organisms.  It is important to emphasize that these infections, to my knowledge, have not been reported with the more common endoscopic procedures.  Because of technical differences in the scopes, the standard cleaning procedures are effective for upper endoscopies and colonoscopies. Related posts:

Miralax -More Scrutiny, Research Study

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A recent NY Times article is probably ‘required reading’ for all pediatric gastroenterologists, pediatricians, and family practitioners:

Here’s the link: Mirlax -Scrutiny for a Childhood Remedy

Here are some excerpts:

The [FDA] agency has asked a team of scientists in Philadelphia to look more closely at the active ingredient in Miralax and similar generic products, called polyethylene glycol 3350, or PEG 3350. While outlining the scope of the research, the agency also disclosed that its scientists had discovered trace amounts of two potential toxins in batches of Miralax tested six years ago.

The news is likely to surprise parents and some doctors.

“Every pediatric GI physician, I would guarantee you, has told a family this is a safe product,” said Dr. Kent C. Williams, a gastroenterologist at Nationwide Children’s Hospital in Columbus, Ohio. Now, he worries, “it may not be true.”

Doctors have long recommended these laxatives for their convenience and on the grounds that very little PEG 3350 is absorbed in the intestines. But the F.D.A. says there is little data on its absorption in children, especially the very young and chronically constipated. The agency never approved long-term daily use of the laxatives, even in adults….

Moreover, for years the F.D.A. has received occasional reports of tremors, tics and obsessive-compulsive behavior in children given laxatives containing PEG 3350. It is not known whether the laxatives are the cause….

The F.D.A. said that it had tested eight batches of Miralax and found tiny amounts of ethylene glycol (EG) and diethylene glycol (DEG), ingredients in antifreeze, in all of them. The agency said the toxins were impurities resulting from the manufacturing process.

Those tests were conducted in 2008..The agency again tested PEG 3350 laxatives from five makers in 2013, Mr. Ventura said. None had detectable amounts of EG or DEG. “The amounts were so low,” he added, and “complied with internationally recognized safety standards.”

Bottomline: The previous pediatric studies of Miralax that have been published have shown favorable benefits and not disclosed adverse effects.  It is difficult to exclude the possibility that there is a small subset of children in which Miralax results in adverse effects.  As with many medications, more pediatric data is needed.

Question: Will this or should this change how Miralax is discussed with families?

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Can an Altered Microbiome Explain Persistent Symptoms in Treated Celiac Disease?

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A recent study (Am J Gastroenterol dii:10.1038/ajg.2014.355) from Helsinki examined 177 patients with celiac disease.  Their goal was to investigate whether altered intestinal microbiota may be associated with persisting gastrointestinal symptoms in celiac patients who had been following a strict gluten-free diet (GFD) for at least 3 years.

After administering a questionnaire (Gastrointestinal Symptom Rating Scale or GSRS) to those with negative celiac antibodies and normal small bowel mucosa (n=164), the researchers identified the 18 subjects with the highest total score (persistent symptom group) and compared them to the 18 subjects with the lowest total score.  Three duodenal biopsies during endoscopy had been frozen and were subsequently analyzed for their microbial DNA.  In each group, one microbial profile was unsuccessful.

Key findings:

  • In the persistent symptom group, there was lower relative abundance of Bacteroidetes (15% vs. 25%, P=0.01), lower Firmicutes (33% vs 46%, P=0.05) and higher relative abundance of Proteobacteria (40% vs 21%, P=0.04).
  • The “microbial richness,” measured as a number of detected genera or operational taxonomic units (OTUs), was reduced in patients with persistent symptoms.  On average, patients with persistent symptoms had 32 genera and 72 OTUs per sample; in contrast, those without symptoms, on average had 37 genera and 106 OTUs.

Some of the strengths of this study include the normal villous architecture for all of the patients; this helps exclude refractory celiac disease as an etiology for the persistent symptoms.  In the discussion, the authors note that the “intestinal microbiota composition in healthy adults is relatively stable and can tolerate normal stress in the intestine caused by, e.g. daily changes in diet.” The speculate that long-term untreated celiac disease “may disrupt a stable intestinal microbiota community that, in some patients, could then reform in a dysbiotic state.”

The limitations of this study include the difficulty of excluding small intestinal bacterial overgrowth which could be related and the difficulty of excluding coexisting irritable bowel syndrome.  Like most studies regarding the micro biome, this study cannot “show causality or distinguish the effects of different bacteria to the persistent symptoms.”

Bottomline: Treated celiac patients with persistent symptoms have a different duodenal microbiome compared to treated celiac patients whose symptoms resolved with a gluten-free diet.

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Taking a History: Man versus Computer

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As noted in a previous blog (“The future of gastrointestinal disease and symptom … – gutsandgrowth), a well-designed computer program (Link: Computer-generated history) allows GI patients to provide a history that is better than a history taken by a physician.

Here’s a link: LA Times Business review of this report

Here’s the abstract of the study:

Computer-Generated Vs. Physician-Documented History of Present Illness (HPI): Results of a Blinded Comparison

Christopher V Almario, William Chey, Aung Kaung, Cynthia Whitman, Garth Fuller, Mark Reid, Ken Nguyen, Roger Bolus, Buddy Dennis, Rey Encarnacion, Bibiana Martinez, Jennifer Talley, Rushaba Modi, Nikhil Agarwal, Aaron Lee, Scott Kubomoto, Gobind Sharma, Sally Bolus, Lin Chang and Brennan M R Spiegel

Objectives:

Healthcare delivery now mandates shorter visits with higher documentation requirements, undermining the patient–provider interaction. To improve clinic visit efficiency, we developed a patient–provider portal that systematically collects patient symptoms using a computer algorithm called Automated Evaluation of Gastrointestinal Symptoms (AEGIS). AEGIS also automatically “translates” the patient report into a full narrative history of present illness (HPI). We aimed to compare the quality of computer-generated vs. physician-documented HPIs.

Methods:

We performed a cross-sectional study with a paired sample design among individuals visiting outpatient adult gastrointestinal (GI) clinics for evaluation of active GI symptoms. Participants first underwent usual care and then subsequently completed AEGIS. Each individual thereby had both a physician-documented and a computer-generated HPI. Forty-eight blinded physicians assessed HPI quality across six domains using 5-point scales: (i) overall impression, (ii) thoroughness, (iii) usefulness, (iv) organization, (v) succinctness, and (vi) comprehensibility. We compared HPI scores within patient using a repeated measures model.

Results:

Seventy-five patients had both computer-generated and physician-documented HPIs. The mean overall impression score for computer-generated HPIs was higher than physician HPIs (3.68 vs. 2.80; P<0.001), even after adjusting for physician and visit type, location, mode of transcription, and demographics. Computer-generated HPIs were also judged more complete (3.70 vs. 2.73; P<0.001), more useful (3.82 vs. 3.04; P<0.001), better organized (3.66 vs. 2.80; P<0.001), more succinct (3.55 vs. 3.17; P<0.001), and more comprehensible (3.66 vs. 2.97; P<0.001).

Conclusions:

Computer-generated HPIs were of higher overall quality, better organized, and more succinct, comprehensible, complete, and useful compared with HPIs written by physicians during usual care in GI clinics.

Looking More Closely at a Persistent Question

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Virtually everyday, families that I care for are trying to ascertain the link between their GI symptoms and the foods in their diet.  Many authoritative recommendations on irritable bowel have concluded that “food allergies (symptoms caused by an immune response) are rarely the culprit in IBS patients. Most IBS patients with food-related symptoms have food sensitivities or intolerances, which are not caused by an immune response.” (From Univ Virginia Irritable Bowel Diet PDF)

Whether the process is a sensitivity or an immune-reaction, many patients are quite sensitive to certain foods and many have had improvement with a low FODMAPs diet.

A much closer look at this problem with confocal laser endomicroscopy (CLE), in a pilot study (Gastroenterol 2014; 147: 1012-20), has shown measurable changes within five minutes of a food challenge that takes place during an endoscopy.  In this study, the researchers examined 36 patients with IBS who had suspected food intolerance and 10 control patients with Barrett’s esophagus.  Then during an endoscopy, the researchers used provoking solutions of cow’s milk, wheat, yeast, or soy.  The subjects had CLE before and after the challenges. To enhance visualization of changes, subjects had fluorescein dye injected intravenously prior to examination of the duodenum.

Results

  • In 22 of 36 patients, the challenges were considered positive.  These patients had mucosal changes including increase in intraepithelial lymphocytes, followed by disruption of the villi tips/shedding of cells, then fluorescein leakage into the lumen.
  • None of the control patients exhibited these changes.
  • 19 of 22 patients with positive challenges had a >50% reduction, after 4-weeks, in symptom score with individualized diet based on inciting antigen.

Bottomline:

This provocative study indicates that subtle mucosal changes can occur in a number of IBS patients in a quick and direct response to food challenges.  Perhaps when we look closer with technologies like CLE we will find more answers as to why certain foods provoke symptoms in adults and children with IBS.

Related blog posts:

Also noted –web-based information on gastroparesis: