Category Archives: Gastroenterology

The Latest on Lynch Syndrome

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Briefly Noted:

AGA Guidelines on Diagnosis and Management of Lynch Syndrome: JH Rubenstein et al. Gastroenterol 2015; 149: 777-82. Technical Review 783-813. Patient Guideline Summary 814-14.

MB Yurgelun et al. Gastroenterol 2015; 149: 604-13.  Multigene panel testing from 1260 individuals with clinical Lynch syndrome.  9% had Lynch syndrome mutations identified, 5.6% had other cancer predisposing genes (eg. BRCA1) identified, and 479 had variants of uncertain clinical significance.

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“Men Sometimes See Exactly What They Wish To See” and Gluten Sensitivity

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For me, a recent study (AD Sabatino et al. Clin Gastroenterol Hepatol 2015; 13: 1604-12, editorial 1613-15) was particularly interesting.  While it had “positive results,” these findings were based almost entirely on the results of three patients.

In brief, this study examined 61 adults (w/o celiac disease) who believed that gluten induced intestinal and extraintestinal symptoms.  These individuals were randomized to receive either 4.375 g/day of gluten or rice starch via capsules.  This amount of gluten is equivalent to 1 sandwich or 2 slices of bread.

Findings:

  • Overall, intake of gluten significantly increased symptoms compared to placebo (P=.034), including bloating, pain, foggy mind, depression, and aphthous stomatitis.
  • Looking at a scatterplot (Figure 4), it is abundantly clear that all of these findings are driven by 3 patients.
  • “In the vast majority of patients the clinical weight of gluten-dependent symptoms was irrelevant in light of the comparable degree of symptoms experienced with placebo”
  • “Our study did not provide any progress in identifying possible biomarkers of NCGS [non-celiac gluten sensitivity]”

This type of study, with mixed conclusions, led the editorialists to quote Spock (from Star Trek):

“In critical moments, men sometimes see exactly what they wish to see.”

Then, the editorial provides a historical context of NCGS with a review of the relevant prior studies.  Other comments:

  • “These findings can be a Rorschach test of sorts, in which the viewer draws interpretations that are  based on his or her prior beliefs about NCGS.”
  • The authors note that both the gluten and the control arm likely had a significant nocebo effect (negative placebo effect),
  • “This trial, like its predecessors, seems only to contribute to the uncertainty about NCGS.”

Related blog posts:

Yellowstone Canyon

Yellowstone Canyon

 

A 6-Year Study of Amitriptyline, Escitalopram, and Functional Dyspepsia

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A recent theme on this blog has been the difficulty of studying inexpensive therapies.  The issue is that there are not strong incentives for pharmaceutical companies to invest in treatment trials when the potential for profits is meager.  Fortunately, there are other funding mechanisms.  A recent study (NJ Talley et al. Gastroenterol 2015; 149:340-9), sponsored by the NIH, still was challenging.  One of the reasons is that when medicines are already approved by the FDA that can be used off-label and this can undermine recruitment.

Due to difficulty with enrollment, the researchers of this current study expanded to a total of 8 sites (initially 5) and settled for 292 patients rather than their goal of 400.  After a baseline washout of 2- to 4-week with assessment, patients with Rome II criteria for functional dyspepsia (FD) were assigned in a randomized, double-blind trial to either placebo, amitriptyline 50 mg, or escitalopram 10 mg for 10 weeks.

Exclusion criteria:

  • History of depression and not using antidepressants.
  • Anxiety
  • Symptom resolution with antisecretory therapy (eg. proton pump inhibitors)
  • History of esophagitis, ulcers, or organic gastrointestinal disease
  • Major physical illness
  • Drug/alcohol abuse
  • Nonsteroidal anti-inflammatory drugs

Inclusion criteria:

  • Required: previous normal EGD within 5 years
  • 18-75 years

Key terms:

  • “ulcer-like dyspepsia” pain centered in the upper abdomen is the predominant symptom
  • “dysmotility-like dyspepsia” non pain symptom predominates: fullness, bloating, early satiety, and nausea

Key Findings:

  • Adequate relief was noted in 40% of placebo-treated, 53% of amitriptyline-treated, and 38% of escitalopram-treated patients
  • Ulcer-like FD given amitriptyline were >3-fold more likely to report adequate relief compared with placebo for odds ratio of 3.1
  • Delayed gastric emptying was associated with being less likely to report adequate relief with an odds ratio of 0.4
  • Safety: while adverse effects were common, “there was no overall difference between the 3 arms (except in neurologic symptoms, with highest rates in the escitalopram arm) suggesting that…TCAs will be generally well tolerated at low doses.”

The associated editorial (pages 270-2) notes that the overall benefits of amitriptyline were modest.  They also reviewed the NORIG study (JAMA 2013; 310: 2640-9) which examined nortriptyline and placebo for idiopathic gastroparesis (n=130).  Similar to this study from Talley et al, the NORIG study found a lack of response to tricyclic antidepressants in this cohort with delayed gastric emptying and dysmotility; “the lack of efficacy in patients with dyspepsia with delayed gastric emptying suggests the possible utility of scintigrahic testing to select patients” for amitriptyline therapy.

Bottomline: This well-designed study supports the use of amitriptyline, but not escitalopram for the use of FD, mainly in those with pain-predominant symptoms.

Related blog posts:

Mt Washburn, Yellowstone

Mt Washburn, Yellowstone

Intervention in Gallbladder Disease

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A recent review (Baron TD, et al. NEJM 2015; 373: 357-65) provides a useful review of surgical and interventional approaches to gallbladder disease.

One recommendation in particular caught my attention:

“Recent data favor early laparoscopic cholecystectomy over medical management with delayed cholecystectomy. In one randomized trial involving patients with uncomplicated acute cholecystitis, laparoscopic cholecystectomy, when performed within 24 hours after the onset of cholecystitis, significantly reduced morbidity, length of hospital stay, and costs without increasing the need for conversion to open surgery.” (References: JAMA Surg 2015; 150: 129-36, Ann Surg 2013; 258: 385-93)

The authors’ Table 1 provides diagnostic guidelines and disease severity guidelines.

  • Grade 1 (mild): acute cholecystitis in otherwise healthy patient with mild local inflammatory changes and without organ dysfunction
  • Grade 2 (moderate) any of the following: leukocytosis >18K, palpable tender mass in RUQ, symptom duration >72 hr, marked local inflammation (gangrenous or emphysematous cholecystitis, pericholecystic or hepatic abscess, biliary peritonitis)
  • Grade 3 (severe) any of the following: hypotension requiring dopamine or norepinephrine, decreased consciousness, hypoxia, oliguria or creatinine >2.0 mg/dL, INR >1.5, or platelet count <100K

The review highlights the NOTES procedure, percutaneous cholecystotomy, and peroral endoscopic drainage (transpapillary vs. transmural).

Related blog post: Early Surgery For Acute Cholecystitis

Grand Tetons from Jackson Lodge

Grand Tetons from Jackson Lodge

What is an Entrustable Professional Activity?

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It has been said that the difference between a haircut and a coiffure is about $30.

When I was reviewing an article (Rose S, et al. Gastroenterol 2014; 147: 233-42 -thanks to Ben Gold for this reference), the previous joke came to mind.  While I’m sure that there has been a lot of hard work to improve the effectiveness of gastroenterology fellowship training, I find the term “entrustable professional activity” (EPA) to be a strange term to define specific goals for educational assessment and competency.

Bottomline: For those in training and for those doing the training, entrustable professional activity is the new buzzword.

Briefly noted -unrelated studies:

Wang H et al. J Pediatr 2015; 166: 1404-9.  This study examined 4976 among the “Children of 1997,” a prospective population-representative Chinese birth cohort.  They “did not find adiposity [to] be a factor in the development of emotional/behavioral problems in early adolescence” (age 11 years).

Niemi AK, et al. J Pediatr 2015; 166: 1455-61. Treatment of methymalonic academia by liver or combined liver-kidney transplantation. This study identified fourteen transplant recipients; the 6 who had isolated liver transplant underwent transplantation much earlier at an average age of 17 months whereas the mean age for transplantation was 8.2 years.  The mean serum MMA dropped from 1648 μmol/L to 305 μmol/L (at four months post-Tx).  This level is still 1000-fold elevated but was low enough to eradicate episodes of hyperammonemia.  In addition, it was associated with stabilization of neurocognitive development.

Another Way of Preventing Recurrent Clostridium Difficile

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I frequently tell families that Clostridium difficile is the ‘Forrest Gump’ of bacteria; it tends to do well when its competitors are decimated.  One of the problems with Clostridium difficile infection (CDI) has been recurrence.  This occurs in part because after treatment of CDI the microbiota of the host remains vulnerable to recurrence.  This has been one of the rationales behind the use of probiotics.  However, probiotics have not been very effective.  As such, more research has been directed in this area.  This includes a recent study (Gerding DN et al. JAMA 2015; 313: 1719-27) which showed that administration of spores of nontoxigenic Clostridium difficile can prevent recurrent CDI.

While fecal microbiota transplantation (FMT) has been very effective in treating CDI, there is definitely a yuck factor.  In addition, more targeted therapy is desirable.  In this study, the authors enrolled 173 patients (157 completed treatment) at 44 study centers as part of a phase 2, randomized, double-blind placebo-controlled, dose-ranging study.  After completion of antibiotics (metronidazole or vancomycin), participants received 1 of 4 treatments with a nontoxigenic C difficile strain M3 (NTCD-M3).

Key findings:

  • Recurrence of CDI were reported in 14 (11%) of NTCD-M3 patients compared with 13 (30%) placebo patients.
  • 69% of NTCD-M3 patients were colonized.  Recurrence in this group (n=86) occurred in 2 (2%) compared with 12 (31%) of NTCD-M3 non-colonized patients.
  • Fewer adverse events were noted in NTCD-M3 group compared with placebo patients with serious events occurring in 3% and 7% respectively.

Bottomline: These nontoxigenic oral spores of NCTD-M3 were well-tolerated and significantly reduced the risk of recurrent CDI.

Related blog posts:

What “Treat-to-Target” Could Look Like in Crohn’s Management

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A recent study (treat to target full text -Bouguen G et al. Clin Gastroenterol Hepatol 2015; 13: 1042-50) proposes  a “new paradigm for the management of Crohn’s disease.”  The concept of treating-to-target has been discussed in several previous blogs:

The concern with the traditional management has been ongoing damage to the bowel in many patients and lack of optimizing long-term outcomes.  The authors in the report make the following points:

  • Only 10% of Crohn’s disease (CD) patients experience prolonged remission of symptoms
  • Even asymptomatic patients often have evidence of active inflammation on endoscopy
  • The majority of patients will require surgery
  • Two big obstacles: delay in initiation of highly effective therapy (eg. combined biologic/immunosuppressant) and underestimation of disease activity due to poor correlation of symptoms to actual disease activity

While the fact that the majority of patients are at risk, some populations are at increased risk including the following:

  • those who smoke cigarettes
  • patients younger than 40 years at diagnosis
  • stricturing or penetrating disease
  • need for surgery
  • inability to wean corticosteroids
  • deep ulcerations on endoscopy

However, the authors note that “the lack of adequate data in this area of research makes risk stratification very difficult in clinical practice.” The authors review several studies:

  • ACCENT-I
  • Step-Up Top-Down trial
  • IBSEN population-based cohort study
  • SONIC
  • The Leuven cohort study
  • EXTEND trial

The data from these studies is used to base their argument of pursuing mucosal healing/more aggressive treatment, though they acknowledge that one risk is potentially subjecting some patients to overtreatment.  The review indicates that mucosal healing (MH) is defined endoscopically as “the disappearance of ulceration” and that endoscopy is the tool for testing for MH for the near-term, but that other markers including MRE and surrogate biomarkers may be useful alternatives.

The authors’ Table 1 list their proposed recommendations for CD, modeled after similar recommendations for Rheumatoid Arthritis.  The Four Key points:

  1. The physician and patient need to agree on the treatment target strategy
  2. The primary target for treatment of CD should be absence of endoscopic ulceration
  3. The use of both clinical symptoms and objective measures of inflammation (endoscopic or imaging) is required in routine clinical practice to guide treatment decisions
  4. Until the desired treatment target is reached, MH should be assessed every 6 months until the disappearance of ulceration and every 1-2 years thereafter.  Drug therapy should be adjusted accordingly.

Limitations on this strategy:

  • Cost of assessment–both endoscopy and MRE are expensive
  • Cost of therapies
  • While MH can be achieved in a higher percentage of patients, there are some patients who will not respond to any of the currently available therapies
  • Risk of therapies.  Some patients will develop adverse effects from the available therapies which will limit their therapeutic options.
  • This proposed strategy has very limited data in clinical practice

Take-home message from the authors: The “natural history” is not likely to improve unless the overall, symptom-based, therapeutic strategy for CD is changed.

Atlanta Zoo, Wreathed Hornbill

Atlanta Zoo, Wreathed Hornbill

 

 

Modest Evidence That Antidepressants Improve Functional Esophageal Disorders

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A systematic review (Weijenborg PW, et al. Clin Gastroenterol Hepatol 2015; 13: 251-9) identified 15 randomized, placebo-controlled trials as well as 1 conference abstract and 2 case reports that provided evidence that antidepressants can be helpful for esophageal pain.

Antidepressants that were included included tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Table 1 list the studies; most of these drugs were dosed at low doses (eg. TCAs typically 25-50 mg).

Key findings:

  • Esophageal pain thresholds increased by 7% to 37% after antidepressant therapy
  • Functional chest pain improved by 18% to 67%
  • Heartburn improved over a range of 23% to 61%

Take-home message (from authors): “The results of the trials included in this systematic review provide modest evidence that both TCAs and SSRIs modulate esophageal sensation and reduce functional chest pain.”

Related blog posts:

Cumberland Island

Cumberland Island

Understanding Functional Abdominal Distention

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A recent study (Barba E, et al. Gastroenterol 2015; 148: 732-9) provides insight into why some patients develop functional abdominal distention.

In this prospective study of 45 patients (42 women), the researchers performed numerous tests to determine the reasons for abdominal distention.  Most patients had CT scan (n=39), and electromyography (EMG) of the abominothoracic wall (n=32) both at baseline and during distention. In addition, 15 patients underwent EMG-guided biofeedback.

Findings:

  • Abdominal distention was associated with diaphragm contraction (~19% increase from baseline) and intercostal contraction (~14% increase from baseline).
  • There was an increase in thoracic antero-posterior diameter compared with basal values with increase in anterior abdominal wall protrusion.
  • Biofeedback treatment was effective in reversing these changes.  This indicates that the distention is under voluntary control.

The authors use the term for the changes that cause the abdominal distention as “abdominal accommodation.”  They note that “in healthy subjects, an increase in intra-abdominal contents induces relaxation and ascent of the diaphragm, which permits cephalic expansion of the abdominal cavity with minor protrusion of the anterior wall.” In this study, the distention was determined in real-life settings to be due to “a paradoxical contraction of the diaphragm, that pushed abdominal contents downward, and relaxation of the anterior abdominal wall.”

Bottomline: These experiments provide a ‘proof-of-concept’ regarding the mechanisms of abdominal distention, though these experiments are not practical for most patients with these symptoms.

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pH Probe Testing: Rumors of My Death are Premature

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Several years ago, an “obituary” was written for the pH probe (Putnam PE,J Pediatr.  2010; 157(6):878-80) due to the presumed superiority of pH-impedance (pH-MII) studies in detecting gastroesophageal reflux disease (GERD)  As noted in previous blogs (see below), there have remained a number of concerns with the assumption that pH-MII is an improvement over pH studies without impedance.  Several recent studies elaborate on those concerns:

  1. Cheng F-K F, et al. Clin Gastroenterol Hepatol 2015; 13: 867-73
  2. Patel A, et al. Clin Gastroenterol Hepatol 2015; 13: 884-91
  3. Vaezi MF. Clin Gastroenterol Hepatol 2015; 13: 892-94 (editorial)

In the first study, the authors identified 221 patients and retrospectively reviewed GERD testing from 2006-2011.  Prior to testing, 97% had received prescribed PPIs before testing; however, PPIs were discontinued for at least 1 week prior to evaluation which included upper endoscopy, esophageal manometry, and pH-MII.

  • 21 (10%) had erosive esophagitis
  • 61 (27%) had nonerosive reflux disease with increased pH
  • 18 (8%) had nonerosive reflux disease with abnormal impedance
  • 30 (14%) had hypersensitive esophagus
  • 18 (8%) had functional heartburn
  • 30 (14%) had other functional disorders
  • 43 (19%) were undetermined

Thus, this retrospective study showed that the majority (roughly 2/3rds) of patients with GERD symptoms on PPI therapy did not have GERD based on objective testing.  The authors chose to test off PPI therapy “because we postulated that the pretest probability of GERD diagnosis was low, primarily given their lack of response to PPI.”

In the second study, 187 subjects (≥18 years) underwent pH-MII testing in a prospective study from 2005-2010.  49.7% were tested off proton pump inhibitor therapy. Abnormal acid exposure time consistently predicted symptomatic outcome.  The authors note that performing pH-MII off PPI therapy best predicts response to antireflux therapy

In the third reference, the editorial which commented on the second, there are several useful points:

  • “There is little doubt that pH-impedance testing provides a more sensitive means of comprehensively identifying reflux events in a given patient. However, to date, studies have failed to demonstrate that it provides any significant additional clinical benefit.”
  • “Caution must be exercised when incorporating the added objective data from non-acidic or weakly acidic reflux events into treatment decision-making…Studies including Patel et al have not shown that knowledge regarding continued non-acid or weakly acid reflux events alter patient outcomes.”
  • “Wireless pH testing is generally better tolerated and provides longer measurement duration”
  • The use of symptom indices are too subjective.  “Recent data question the use of these indices especially in those with refractory symptoms and minimal reflux by pH or impedance testing.”  SI and SAP could be altered by chance occurrences….”A colleague expert in esophageal diseases …once said: “I know the tests are no good but I don’t know what else to use.'”
  • “Let us simplify our approach on the basis of available data and not use measures that we know are suboptimal at best.”

After looking at these studies and the previous pH probe obituary, I’m reminded of a story.  Several religious leaders were asked what they wanted someone to say at their funeral.  A few stated that they wanted their congregants/flock to comment on their values, like piety and charity.  However, one said, “I hope they say, ‘Look he’s moving!'”

Bottomline: There is no reliable evidence that pH-MII testing improves outcomes over conventional pH probe testing. In fact, the use of pH-MII, by lowering the specificity for GERD, could have a detrimental effect.  With either test, holding acid suppression for 1 week (with PPIs) is likely to be helpful in interpreting the results.

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.

Zoo Atlanta

Zoo Atlanta