Category Archives: Gastroenterology

Does buspirone help functional dyspepsia?

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A recent randomized, double-blind, placebo-controlled crossover functional dyspepsia (FD) trial showed that 4 weeks of treatment with buspirone (10 mg TID) improved overall symptom severity, including early satiety and bloating (Clin Gastroenterol Hepatol 2012; 10: 1239-45).

This study enrolled 17 patients (13 women) with a mean age of 38.5 years.  There were two 2-week treatment periods and a 2-week washout in between.  Patients filled out a dyspepsia symptom score before treatment and at the conclusion.  In addition, patients underwent gastric emptying by using breath tests and barostat measurement.

Overall symptom score was improved with buspirone compared to placebo: 7.5 ± 1.3 vs. 11.5 ± 1.2.  Symptoms of postprandial fullness, early satiety, and abdominal bloating all improved significantly.

Buspirone treatment increased gastric accommodation compared with placebo: 229 ± 28 vs. 141 ± 32 mL respectively.  Overall, gastric emptying was not affected by buspirone treatment; however, delayed emptying of liquids was evident (half-life = 64 vs. 119 minutes respectively).

The effect of buspirone on FD appears to be primarily related to improvement in gastric accommodation.  Impaired accommodation has been identified in about 40% of FD patients.  Buspirone which is a 5-HT1A receptor agonist acts on cholinergic nerve endings and leads to relaxation of the proximal stomach.

Buspirone also is used for the treatment of anxiety.  In the present study, baseline anxiety scores were not correlated to symptom improvement but these scores were not followed at the end of treatment.

In this small study, buspirone was well tolerated and had similar adverse events as placebo.  In previous studies, it has been associated with light-headedness, dizziness, and nausea.

Given the small scale of the study, it would be premature to consider buspirone a proven treatment for FD; however, this study provides the framework for larger studies to determine more conclusively the role of buspirone for FD.

Related blog entries:

Bystander effect –Genovese syndrome

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Genovese syndrome is more commonly called the “bystander effect” (NEJM 2013; 368: 8-9).

“Genovese syndrome” was coined after the brutal stabbing of Catherine Genovese in Queens, NY on March 13, 1964.  What was astonishing was that ~38 people either observed the attacks or heard the victim’s pleas for help and did nothing.  This prompted a large amount of psychological research.  The central factor identified as the reason for the bystander effect was the diffusion of responsibility.

Awareness of the bystander effect is increasingly important in medicine where large teams often are involved in the care of complex patients.  Sometimes it is difficult even to answer “Who is my doctor?”

When many doctors are involved in the care of a patient, it is easy for a passive approach to patient care to develop.  How can this be reversed?

  • Bystanders are far more likely to intervene when they are friends with one another.  Thus, encouraging collegial interactions is important.
  • Understanding that oral communication, even briefly, with the primary care team is crucial.  Written communication is useful for documentation, but important information should be relayed directly.
  • An initiative by the U.S. Agency for Healthcare Research and Quality, TeamSTEPPS (Team Strategies and Tools to Enhance Performance and Patient Safety) may be helpful in improving. team-based skills (TeamSTEPPS Home)

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Teduglutide for Short Bowel Syndrome

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More data on teduglutide indicate its potential for short bowel syndrome (SBS) (Gastroenterol 2012; 143: 1473-81, editorial 1416-20).  Treatments for SBS are needed.  One year of parenteral nutrition often costs the health care system in excess of $100,000 per year.  This cost does not account for laboratory studies, health care visits, complications, and hospitalizations.  Treatment of intestinal failure with transplantation “may cost upwards of $1 million.”

In this study of adult patients with an average of 50 years, teduglutide was given in a prospective randomized double-blind study to 42 patients and another 43 patients received placebo. The dose of 0.05 mg/kg/day via subcutaneous injection was chosen based on a previous trial which showed that a higher dose was less effective.  Among these patients, the most common reasons for SBS were vascular disease (34%), Crohn’s disease (21%), volvulus (11%), and injury ((9%).

Bottom line:

  • Teduglutide over a 24-week study was more effective than placebo.  63% of study patients had a drop in parenteral nutrition requirement of more than 20% compared with only 30% of the placebo group.
  • The mean reduction in parenteral nutrition support of teduglutide-treated patients was 4.4 L/week compared with 2.3 L/week for placebo-treated patients.
  • Citrulline, a biomarker of mucosal mass, was increased in the teduglutide group.  In the treatment group, citrulline increased by 20.6 μmol/L compared with 0.7 μmol/L for the placebo group.

How does teduglutide work?  Teduglutide is a much more stable analog of glucagon-like peptide-2 (GLP-2).  The latter is released by the distal small bowel and colon.  GLP-2 promotes intestinal epithelial growth and increases transit time.

What are the adverse effects of teduglutide? First, there is a concern that teduglutide could promote colonic adenomas based on studies in mice.  GLP-2 receptors are present in the lung, and brain (including hypothalamus); its effects in these areas is poorly understood.  In addition, abdominal pain, distention, nausea, peripheral edema, and nasopharyngitis were more common in the treatment group. The long-term consequences of teduglutide therapy are not known.

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Acupuncture for irritable bowel syndrome

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No medical therapy has been shown to alter the natural history of irritable bowel syndrome (IBS).  A number of therapies have been used to improve the symptoms.  More data has been published on whether acupuncture is an effective therapy (Am J Gastroenterol 2012; 107: 835-47)

A number of treatment approaches have shown that several medical treatments are more effective than placebo, including soluble fiber, some antispasmotics, peppermint oil, antidepressants, and agents that act on the 5-HT receptor.  In addition, cognitive-behavioral therapy and hypnotherapy seem to be more effective than placebo.  Dietary therapies (see blog links below) are helpful in some patients.  However, many patients have a poor response to all of these approaches.

To examine whether acupuncture may be effective for IBS, the authors of the current study reviewed 1421 citations and identified 17 eligible randomized controlled trials (RCTs) with >1800 patients.  Only trials that used accepted traditional Chinese medicine methods of acupuncture were included.

Key findings:

  • Among the five sham-controlled trials, there was no significant difference detected between true acupuncture and sham acupuncture in terms of effects on symptoms or quality of life.  The standardized mean difference in post-treatment between the groups was -0.11 (difference between two groups) –confidence limits -0.35 to 0.13 for symptom severity and -0.03 for quality of life –confidence limits -0.27 to 0.22.
  • A selected summary on this article in Gastroenterology (2012; 143: 1683-84) notes that the largest RCT in the U.S. found that sham acupuncture and true acupuncture were both superior to a control arm (Am J Gastroenterol 2009; 104: 1489-97).
  • When acupuncture was compared with medical therapies in 5 trials (4 with antispasmodic, 1 with sulfasalazine), acupuncture was more effective, RR=1.28 for symptom improvement.  These studies were non blinded and the overall effect was modest.
  • When acupuncture was added to traditional Chinese medicine in 4 RCTs, the addition of acupuncture improved the endpoints of IBS symptom severity (RR=1.17).

This study should reduce the stress of practitioners of acupuncture.  Whether they apply true acupuncture or sham acupuncture, the results may be equivalent.  In these studies, sham acupuncture did have a high “placebo effect.” At the same time, this study indicates that the comparison medical treatments (most in these RCTs are not used in Western medicine) were less effective than acupuncture.  So where does that leave us?

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Failure of PPI test

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Identifying patients gastroesophageal reflux with a so-called ‘PPI test’ is not effective (Clin Gastroenterol Hepatol 2012; 10: 1360-66).

This study examined data from the previous Diamond study (Gut 2010; 59: 714-21).

In short, among 308 patients who were evaluated by endoscopy and pH probe, 197 had GERD identified by the presence of reflux esophagitis, pH <4 for 5.5% or positive symptom association monitoring.  Then all patients were given esomeprazole 40 mg once a day for two weeks.

A positive response to PPI Rx was observed in 69% of those with GERD and in 51% of those without GERD.  If response was defined as ‘the absence of the most bothersome symptom in the last 3 days of treatment,’ then GERD patients had a 54% response compared to 35% of Non-GERD patients.

While the PPI test is a failure, in many clinical situations, symptom response to therapy may be more important than the reason for the symptoms. The attached link provides a nice synopsis: Study Finds ‘PPI Test’ a Poor Predictor of GERD : Internal Medicine …

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Best strategy for dose escalation of infliximab

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At least 50% of patients with long-term infliximab therapy require dose escalation.  However, dose escalation can mean doubling the dose or shortening the infusion interval.  So which strategy is best?  A recent article provides some insight into this question (Inflamm Bowel Dis 2012; 18: 2026-33).

In this multicenter retrospective study of 168 Crohn’s disease (CD) patients, the outcome of patients who had dose-doubling (n=112) to 10 mg/kg/dose/8 weeks was compared with patients whose infusion intervals were halved to 5 mg/kg/dose/4 weeks (n=56).  The entire cohort had a mean age of 25 years and a mean disease duration of 12 years.  39% had a history of previous intestinal surgery.  Concurrent use of thiopurines was noted in 68% and concurrent use of methotrexate in 4%.

Sustained response at 1 year to dose-doubling strategy was 50% compared with 39% in the interval-halving group.  Favorable factors included nonsmoking status, normal C-reactive protein, and CD diagnosis between 16-40 years of age.

It is noted that a subsequent dose escalation was experienced by 28 of the 87 patients who had loss of response after first dose escalation.  Regained response occurred in 9 (32%) of this cohort.

The authors indicate that increasing the dose to 10 mg/kg/8 weeks is likely preferable due to convenience and cost.  At the same time, it is apparent that shortening the infusion interval is not likely to be more effective than dose doubling.

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Mechanisms of irritable bowel syndrome

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An excellent succinct review of the various peripheral mechanisms of irritable bowel syndrome (IBS) has been published (NEJM 2012; 367: 1626-35).  Understanding these mechanisms is crucial in developing and targeting appropriate therapy.

Peripheral factors affecting IBS (Table 1 in review):

  1. Colonic motility –affects up to 45% of diarrhea-predominant IBS and 25% of constipation-predominant IBS.  Specific factors include enteroendocrine cell products (eg. 5-HT, granins), organic acids (eg. bile acids, short chain fatty acids [SCFAs]) impaired bile acid synthesis.
  2. Colonic motor and sensory response to food ingestion. Factors like fat content of meal can contribute to pain, urgency and diarrhea.
  3. Sensing responses in small bowel and colon.  Food stimulation of enteroendocrine cell products may trigger diarrhea, bloating and pain.
  4. Colonic mucosal permeability.  This may lead to malabsorption of carbohydrates or fats and subsequently increased levels of SCFAs.  Also, could trigger immune activation and altered feedback of bile acid synthesis.
  5. Mucosal immune activation.  Previous gastroenteritis along with mast cells, T lymphocytes, and circulating cytokines may be involved factors.
  6. Colonic microbiome.  There may be increased types of some bacteria (eg. firmicutes).  Antibiotics and probiotics could influence the microbiome. Fermentable oligosaccharides, disaccharides, and polyols (FODMAPs) are a group of foods that may trigger IBS symptoms, possibly due to a relationship with the colonic microbiome.

With regard to gluten intolerance, the author notes that the prevalence of celiac disease among IBS is similar to that among controls; however, a subgroup of individuals with diarrhea-predominant IBS respond to a gluten-free diet.

Some genetic factors have been identified which can contribute to IBS:

  • mutation in the guanylate cyclase C secretory pathway
  • mutations that increase the risk of postinfectious IBS
  • genetic variability in bile acid synthesis
  • variation in expression of neurotransmitters and cytokines

Towards the end of the review, the author notes that “IBS is no longer regarded as an idiopathic bowel dysfunction” due to stress.  The specific factors that have been identified will likely be further defined and likely lead to more specific individualized therapy.  Potential treatments:

  • diets -including gluten-free and FODMAPs
  • bile acid sequestrants and 5-HT3 antagonists
  • prokinetics or secretagogues in patients with constipation-predominant IBS
  • probiotics and non-absorbed antibiotics
  • antiinflammatory agents
  • tignt-junction modifiers
  • biofeedback

Previous related blog entries:

Additional references:
  • -J Pediatr 2009; 155: 416.  n=43 children & 56 control pts.  High incidence of abnormal lactulose (65%) breath test with IBS but not control pts (7%).  (lactulose 10g given in 20mL)
  • -Gastroenterol 2009; 137: 766.  Notes relatively weak data supporting use of antispasmotics, probiotics, and antidepressants for IBS.
  • -Am J Gastroenterol 2010; 105: 859-865.  n=466 & 451 controls.  IBS pts with lower incidence of adenomas (7.7.% vs 26%).  9% had diverticulosis (lower).  Microscopic colitis present in 1.5%.
  • -Gastroenterol 2002; 123: 2105-07. & 2108-2131. AGA guidelines for IBS
  • -Gastroenterol 2007; 133: 799.  Natural hx of functional disorders: 20% persist w same Sx, 40% develop other Sx, 40% get better.  Large study from Olmstead county (n=1365)
    • -Clin Gastro & Hep 2005; 3: 397.  managing pts c severe IBS; advocates low dose tricyclics..
  • -Am J Gastro 2003; 98: 412-9.  use of neomycin for SBBO in IBS (43% response). 84% IBS pts c abnl lactulose vs 20% placebo
  • -Gastroenterol 2003; 124: S1152.  only 4 of 33 IBS pts had abnl jejunal samples
  • -J Musculoskel Pain 2001; 9:107-113.  78% of fibromyalgia pts c abnl BHT.

Don’t forget the liver for APC patients

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A recent case report serves a useful reminder that patients with APC gene mutation are at risk for hepatoblastoma (JPGN 2012; 55: 334-36).  A comprehensive review on this subject and APC gene disorders in general (along with related disorders) can be found at the following link: (APC-Associated Polyposis Conditions – GeneReviews™ – NCBI …)

One of the authors of the online link is a well-established expert in the field (Randall W Burt, MD) and updated the link in October 2011.

With regard to hepatoblastoma:

“The risk for hepatoblastoma in FAP is 750 to 7500 times higher than in the general population, although the absolute risk is estimated at less than 2%. The majority of hepatoblastomas occur prior to age three years.”

Screening for hepatoblastoma in FAP?

“Efficacy in individuals with FAP is unclear. Screening protocols in Beckwith-Wiedemann syndrome, in which the risk for hepatoblastoma is also increased, often include frequent (every 2-3 months) abdominal ultrasound examinations and measurement of serum alpha-fetoprotein concentrations and have resulted in early detection of hepatoblastomas. Screening for hepatoblastoma in FAP using the same protocol may be considered from infancy to age five years. However, the optimal interval for hepatoblastoma screening in FAP is not known, although it has been recommended that screening should occur at least every three months.”

Additional references:

  • -Liver Tx 2008; 14: 1545.  Reviews predisposing conditions to hepatoblastoma & HCC, screening & Rx.  Disorders include Beckwith-Wiedeman, FAP, tyrosinemia, GSD type II, PFIC type 2, Alagille, EHBA, HBV, TPN-cholestasis/extreme prematurity.
  • -J Pediatr 2005; 146: 204.  Review of Cincy experience and algorithm for hepatoblastoma management.
  • -H F A Vasen, G M G Möslein, A Alonso, et al. Guidelines for the clinical management of Familial adenomatous polyposis (FAP) Gut 2008 57: 704-713
  • -Polymnia Galiatsatos, ,William D. Foulkes. Familial Adenomatous Polyposis Am J Gastroenterol 2006;101:385–398
  • -Gastroenterol 2001; 121: 195-197 &198-213. Guidelines & technical review of genetic testing for FAP & HNPCC.

How new therapies impact colectomy in UC patients

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Has the need for colectomy changed with the increasing use of more potent medical therapies for ulcerative colitis (UC)?  One article gives some insight into this question (Inflamm Bowel Dis 2012; 18: 1641-46).

This French study followed 151 patients with newly diagnosed UC from 2000-2008; median followup was 58 months. During this time, 21 patients (14%) underwent colectomy.  1.3% required colectomy in the first year following diagnosis.

Looking closer at their study, 55% of patients had pancolitis.  Cyclosporin usage, typically given in refractory cases, was the only medication determined to be a predictive factor for surgery.

Medication usage during study period:

  • 68% oral mesalamine products
  • 72% systemic corticosteroids
  • 7% methotrexate
  • 49% azathioprine
  • 9% cyclosporin
  • 30% had received at least one anti-TNF agent

The authors concede several limitations, including the evolving nature of UC treatment.  Yet, they conclude that colectomy still is frequently needed and the use of IBD medications, including anti-TNF, “does not appear to reduce the long-term need for surgery in UC.”

I take issue with the last sentence.  Whether anti-TNF agents prove to be a disease-modifying treatment over the long-term is not known.  In this particular cohort, only 30% were even exposed to these agents.  My conclusion: we need a study designed to answer the question.  This would require larger numbers of patients followed prospectively for many years.

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Ustekinumab for Crohn’s Disease

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Ustekinumab is emerging as an option for inflammatory bowel disease.  A study examining its effectiveness for TNF-refractory Crohn’s disease has been published (NEJM 2012; 367: 1519-28).

In this trial, members of CERTIFI (Crohn’s Evaluation of Response to Ustekinumab Anti-Interleukin-12/23 for Induction) from 153 centers in 12 countries assessed the efficacy of Ustekinumab in 526 adult patients.  The primary outcome was a clinical response (CDAI >100 point drop) at 6 weeks.

Ustekinumab (currently approved for plaque psoriasis) is a ‘fully human IgG1κ monoclonal antibody’ which blocks the activity of interleukin-12 (IL-12) and interleukin-23 (IL-23) by inhibiting receptors on T cells, natural killer cells, and antigen-presenting cells.  IL-12 and IL-23 have been implicated in the pathophysiology of Crohn’s disease.

This study of ustekinumab was a 36-week randomized, double-blind, placebo-controlled phase 2b trial.  The first 8 weeks were for induction.  After induction, based on response, patients were enrolled in a 28-week maintenance phase.  Initial dosing was 1, 3, or 6 mg/kg of intravenous ustekinumab or placebo.  Maintenance dose was 90 mg subcutaneously.

Patients were permitted to continue receiving stable doses of drugs.  However, entry requirements included a washout period for intravenous glucocorticoids (3 weeks), TNF antagonists (8 weeks), and natalizumab (12 months).

Results:

  • 36.6%, 34.1% and 39.7% of ustekinumab patients (1, 3, and 6 mg/kg respectively) responded at 6 weeks compared with 23.5% of placebo.  The difference was statistically significant for 6 mg/kg/dose.
  • Maintenance therapy (among responders) noted increased clinical remission with ustekinumab compared with placebo 41.7%  vs 27.4%.
  • Overall rates of infection were similar. Serious infections were noted in 6 patients receiving ustekinumab compared with 1 placebo-treated patient.  Infusion reactions were uncommon.
  • Patients who did not have a response to ustekinumab in the induction phase did not benefit from additional ustekinumab in the maintenance phase.

Overall, in this study, patients dosed at 6 mg/kg during induction were more likely to have a response but not more likely to have a remission.  Since all patients in this study had failed at least one TNF antagonist and 50% had failed at least two, the benefit of ustekinumab in other Crohn’s disease patients remains undefined.

Related blog entries:

CHOOSE TNF TRIAL | gutsandgrowth

Vedolizumab -another new IBD treatment | gutsandgrowth

Adding Methotrexate to anti-TNF therapy | gutsandgrowth