Extensive Workup Not Needed for IBS

Another study has shown that an extensive workup is not needed for IBS (Clin Gastro Hepatol 2013; 11 956-62).

In this study from Denmark, the authors enrolled 302 patients aged 18-50 from a primary care setting with suspected IBS.  250 patients completed the entire study including a 1-year followup.  These patients fulfilled Rome III criteria and had no alarm signals which were the following:

  • Unexplained weight loss >3 kg
  • Rectal bleeding
  • Unexplained fever or anemia
  • Family history of inflammatory bowel disease (IBD) or colorectal cancer (CRC)
  • Abnormal physical exam

Patients were randomly assigned to either an extensive diagnostic group which included blood tests (including celiac screen & lactase gene test), stool exams, and sigmoidoscopy or to a “positive strategy” which involved testing only with a blood count (CBC/diff) and C-reactive protein.

The group which underwent a more extensive workup had no cases of serious disease, like IBD or CRC identified.  11 patients were identified with lactose intolerance, 1 patient had a rectal adenoma, 1 patient had a benign polyp, and 1 patient had giardiasis.

Overall, the authors and the accompanying editorial (pgs 963-964) conclude that the positive strategy was noninferior to the more extensive evaluation.  One limitation of this study was that patients had carried symptoms compatible with IBS for an average of 7 years before enrollment.

Take-home message: this study “adds to the growing body of evidence in favor of a relatively minimal symptom-based approach to diagnosing IBS.”

Related blog posts:

IBS Symptoms in Patients with Celiac Disease

While a gluten-free diet (GFD) is the optimal treatment, adult patients with celiac disease still have a high prevalence of irritable bowel symptoms (IBS) (Clin Gastroenterol Hepatol 2013; 11: 359-65).

The authors examined the prevalence of IBS symptoms by reviewing cross-sectional and case-control studies in adults with celiac disease (≥16 years old).  Initially, the literature search identified 624 studies; the vast majority did not fit the study requirements.  Seven studies (n=3383 participants) reported the prevalence of IBS symptoms in celiac disease.  These studies took place between 2002 to 2011 in five different countries.  IBS was defined using either Rome I, II, or III criteria.  Only one of these studies assessed adherence to a GFD by using negative tissue transglutaminase antibodies on the 2 most recent outpatient visits.

Results: IBS symptoms were present in 38% of all patients with celiac disease.  The pooled odds ratio was higher for celiac disease than controls (OR 5.6, with 95% CI 3.23-9.7).  Nonadherence to a GFD increased the likelihood over those who were adherent by an odds ratio of 2.69

Take-home message: IBS symptoms are present in a high proportion of patients with celiac disease.  While a GFD may improve these symptoms, some individuals will have persistent symptoms.

Related blog entry:

Is functional pain more common in children with … – gutsandgrowth  Previous blog entry examines functional abdominal pain in children and celiac disease.

Additional references:

  • -JPGN 2011; 53: 216. Case report of refractory celiac treated with 6-MP.
  • -Clincal Gastroenterol & Hep 2011; 9: 13. Celaic with persistent symptoms: consider poor adherence**, SBBO*, pancreatic insufficiency*/subclinical pancreatitis, refractory celiac (rare), PLE, giardia, malignancy, lactose intolerance, functional d/o*, microscopic colitis, Crohn’s*, NSAIDs
  • -Gastroenterol 2009; 136: 81, 91, 99, 32. Refractory celiac can be divided into 2 types; 2nd type assoc c abnormal IEL and has poor prognosis. Risk of non-hodgkins lymphoma 3.8-5 .3 fold over gen population in larg Sweish study. n=37869 c NHL, 236,408 controls, 613,961 1st degree relatives. Relatives c 2 fold risk. Absolute NHL risk ~1 in 1421 person-yrs for celiac pt.
  • -Clin Gastroenterol & Hep 2007; 5: 445-450. Causes of nonresponsive celiac.
  • -NEJM 2007; 356: 2548. Nonresponsive due to inhaled gluten in farm setting.
  • -Clin Gastro & Hep 2007; 5: 445. Gluten exposure in 36%, IBS n 22%, lactose intol 8%, refractory CD 10%
  • -Gastroenterol 2011; 141: 1187.  Prevalence of celiac similar in IBS as general population though higher number (7%) with celiac antibodies (esp gliadin).

What is the risk with Rifaximin?

While no one knows how quickly resistance of gut microbes will develop in response to rifaximin, the likelihood of resistance is high and this should temper its usage (J Clin Gastroenterol 2013; 47: 205-11).

Rifaximin, along with other antibiotics, has been shown to relieve symptoms in certain cohorts of irritable bowel syndrome (IBS) patients.  Generally, the results of these studies have been modest (see below); however, because it is a “gut specific” antibiotic with minimal systemic absorption (<1%) and therefore minimal adverse effects, it has been considered a reasonable and safe treatment by many.  It has been useful as well for traveler’s diarrhea, hepatic encephalopathy, and colonic diverticular disease.  With regard to IBS, the major concern is that this is a chronic disorder and repeated usage will result in antimicrobial resistance.

Resistance to rifaximin could result in serious consequences if it provoked a class effect resistance.  Rifaximin belongs to the rifamycin class of antibiotics which treat numerous diseases including tuberculoses, meningococcal disease, Clostridium difficile, and methicillin-resistance Staphylococcus aureus.

Given the limited number of suitable alternatives and emerging resistance patterns, wise stewardship of our current antibiotics is essential, though unlikely.  It is not difficult to foresee a rise in mortality from some infectious problems that are easily treated currently.

Related references:

  • -JPGN 2011; 52: 382.  Double-blind, placebo-controlled study of rifaximin in children with RAP.  n=75.  Not effective in this study.
  • -NEJM 2011; 364: 22 (pg 81-editorial). About 10% improvement over placebo in pts with IBS-D. Effects lasted up to 3 months.
  • -DDW 2010, 475 abstract. Target 1 & Target 2. n=623, n=637. Relief of IBS in ~41% vs ~32% placebo. 550mg TID x 14days.

Related blog posts:

FMT -fecal microbiota transplant

An excellent review of FMT, especially in regard to C difficile infection, has been published (Am J Gastroenterol 2013; 108: 177-85)  Thanks to Ben Gold for sharing this reference.

FMT has been around for a long time.  It is first documented in the 4th century as a treatment for food poisoning or severe diarrhea.  Its current application has focused on C difficile infection (CDI), though its use in a number of other settings is being explored.  This includes irritable bowel syndrome and inflammatory bowel disease.

This articles makes several useful points.  In the ‘how to do it’ section, the author notes that at the NIH, donor screening includes screening for pathogens in the stool:

  • Bacteria: C difficile, Listeria monocytogenes, Vibrio cholera, Vibrio parahemoltyicus, H pylori
  • Parasites: Giardia, Cryptosporidium, Isospora (acid fast stain)
  • Viruses: Rotavirus
  • Blood: for Hepatitis A IgM, Hep B (HBsAg, anti-HBc ([gG & IgM]), HIV, Syphilis, HCV

However, the author notes that testing in the community tends to rely on screening only for enteric pathogens (stool tests only).  Donors should be excluded if they have received antibiotics in the preceding 3 months, if they participate in high-risk sexual behaviors, recent tattoo piercing, or recent incarceration.  Additional exclusions: history of IBD, IBS, immunocompromise, morbid obesity, metabolic syndrome, atopy, and chronic fatigue.

Related donors may provide a better long-term outcome.  In a recent review, FMT using a related donor yielded a 93% CDI resolution compared with 84% for unrelated donors.

Nuts and bolts:

  1. Donor is instructed to take a double dose of milk of magnesia at bedtime the night before procedure.
  2. Soft stool is passed into a clean plastic container; preference is for stool to be produced within 8 hour of FMT.  Stool does not need to be frozen or refrigerated (though can be refrigerated).
  3. Saline is added to the stool which is stirred and shaken (some use blenders, some use milk or water as suspending solutions).
  4. Typical amount of stool would be 50 g in 250 cc diluent.  For colonic administration, about 300 cc are administered in cecal region.  For duodenal administration, about 60 cc are administered.
  5. Prior to administration, it is best to filter the mixture through gauze pads to remove particulate matter that would interfere with administration.
  6. Though the author notes that there have been recommendations to prepare stool under a hood as stool is considered a level 2 biohazard, he states that this is not practical and in fact, the stool in this situation is the safest stool that gastroenterologists encounter.
  7. Recipients receive a colon lavage before the procedure regardless of route of FMT administration. If possible, all antibiotics are withheld 3 days prior.
  8. On the morning of administration, the author instructs recipient to take two lopermide tablets.

As positive experience gains in CDI, further efforts in a number of other diseases (>30 listed in Table 1 of article) with altered microbiome will be explored.  Thus far, FMT has been used in autism, fibromyalgia, metabolic syndrome, multiple sclerosis, obesity, and even parkinson’s disease.

Hippocrates stated “All disease begins in the gut.”  Given the diversity of diseases in which FMT is being examined, this sentiment may be close to the truth.

Related blog entries:

UVA Links

My alma mater, the University of Virginia, has a fair amount of useful GI educational material on their website.

Here are a few links:

Low FODMAP Diet

Irritable Bowel Syndrome (IBS) diet

Short Bowel Syndrome Diet (Long Version)

Nutritional Considerations for Patients with Inflammatory Bowel Disease

Fiber (dietary recommendations handout)

Gluten-free Diet

Linaclotide –not for kids

Linaclotide has been approved for adults (≥18 years) with chronic constipation and constipation-predominat irritable bowel syndrome (IBS-C) (Gastroenterol & Hepatol 2012; 8: 653-60).

Linaclotide is a 14-amino acid peptide that stimulates guanylyl cyclase C (GCC) receptors.  It mimics the endogenous peptides guanylin (15 amino acids) and uroguanylin (16 amino acids) which activate GCC through a cascade which activates CFTR to increase luminal levels of bicarbonate, chloride and water.  This in turn improves gastrointestinal transit.

There were several trials undertaken to assess the efficacy of linaclotide in IBS-C:

  • 47 patients (36 women) with IBS-C were treated with linaclotide (100 μg or 1000 μg) or placebo –5 day study. The 1000 μg dose significantly decreased colonic transit time compared with placebo.  No serious adverse events were reported.
  • 420 patients were enrolled in a 12-week, randomized, double-blind, placebo-controlled, dose-ranging study.  The population was 92% female, 80% caucasian with a mean age of 44 years.  337 patients completed the study.  There were improvements in the number of complete spontaneous bowel movements (CSBMs) per week and in abdominal pain.  Additional results:
  1. With 300 μg dose, there were 3.93 CSBMs/week, with150 μg dose 2.79 CSBMs/week compared with 1.47 for placebo.
  2. With 300 μg dose, there was -0.90 in pain score, with 150 μg dose -0.71 compared with -0.49 for placebo.  Overall, abdominal pain improved in 31.1-38.7% of linaclotide-treated patients compared with 22.7% of placebo-treated patients.

For chronic constipation, four trials (n=42, n=310, n=630, and n=642) have shown increased CSBMs/week.  On average, a dose of 290-300 μg dose resulted in 1.8-2.7 CSBMs/week, a dose of 145-150 μg dose resulted in 1.6-2.0 CSBMs/week compared with 0.5-0.6 CSBMs/week for placebo.  Changes in stool frequency were also reflected in quality of life scores.  When linaclotide was stopped, patients reverted to similar stooling rates as placebo-treated patients but no rebound effects were noted.

Prior to approval of linaclotide, lubiprostone (Amitiza) had been the only FDA-approved medication for IBS-C.  For chronic constipation, polyethylene glycol is another approved treatment.

Related blog entries:

Acupuncture for irritable bowel syndrome

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?

Related blog entries:

Mechanisms of irritable bowel syndrome

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.

Increased bile acids in diarrhea-predominant IBS

The role for bile acids in causation of irritable bowel gets a closer look in a recent publication (Clin Gastroenterol Hepatol 2012; 10: 1009-15).

This study randomly selected 52 participants (26 with diarrhea-predominant IBS, 26 with constipation predominant IBS) from a cohort of 700 IBS patients followed at the Mayo clinic along with 26 healthy volunteers.  The ages of the patients ranged from 29-51. Subsequently, these patients underwent additional testing following a 4-day high fat diet.  Of note, 5 of the IBS-D patients had a history of cholecystectomy compared with one patient in the other two groups.

In these patients, bile acid concentrations were measured in the stool and serum levels of 7α-hydroxy-4-cholesten-3-one (C4).In the IBS-D patients, serum levels of C4 were significantly higher than in the other two groups.  38% of the IBS-D group had elevated C4 levels; these elevated levels correlated with increased stool concentrations of bile acids.

The authors note that bile acid malabsorption has been identified frequently in patients with unexplained chronic diarrhea and that these patients often respond to bile acid sequestration (eg. cholestyramine or colesevelam).  Another interesting finding was that obesity was associated with elevated bile acid levels. Overall, the cohort with IBS-D had an average BMI of 29.5.

So, what conclusions can be drawn?

  • Serum C4 levels may be using in identifying patients with bile acid malabsorption
  • Bile acid sequestration agents may be worth a try in some cases of IBS-D and this study provides a rationale

Additional references:

-Alim Pharmacol Ther 2009; 30: 707-17.  Bile acid malabsorption in IBS-D.

Why didn’t patient with documented reflux get better with PPI?

There are numerous problems with pH studies; many of these problems have been alluded to in previous blog entries (see below).  Another problem is that these studies are not highly predictive of response to therapy (Gut 2012; 61: 501-506).

This French study from three centers examined 100 consecutive patients (58 females) with an average age of 50 years.  All patients had reflux symptoms, namely regurgitation and/or heartburn.  PPI dosage was not standardized and reflux symptoms were quantified with recall questionnaires.

The authors note that up to 40% of patients with reflux symptoms have inadequate symptom relief with a 4-week course of single dose proton pump inhibitor (PPI) therapy; the aim of their study was to investigate which factors on pH probe-impedance (pH-MII) would predict a response to therapy.

Definition: Nonresponders were patients who had more than 2 days of mild symptoms per week while receiving a standard or double dose of PPI treatment for 4 weeks

Results:

  • No reflux pattern on pH-MII was associated with a response to PPIs. Table 2 in the study looked at multiple factors including SI, SAP, time for acid exposure, and number of reflux events.
  • Lower BMI (≤ 25 kg/m-squared), non-erosive reflux, and normal pH study were associated with poor PPI response
  • Other factors associated with poor PPI response: female gender, irritable bowel syndrome (IBS), and functional dyspepsia.
  • Response rates: 58% of individuals with BMI >25, 71% with esophagitis, 23% with functional dyspepsia, 30% with IBS
  • Among responders, 77% were receiving a single dose PPI

Some of the poor response may be related to the study population.  Only 35% had abnormal acid exposure.  In total, 67% were determined to have abnormal pH studies, though this was due to a large fraction having a positive symptom-reflux association analysis.

However, this study population likely reflects a typical clinical group of patients diagnosed with GERD and demonstrates some of the shortcomings of pH-MII in clinical practice.  Even patients with abnormal pH-MII studies, the presence of functional dyspepsia and IBS were strongly associated with PPI failure.

Previous related blog entries:

HEROES trial

Impedance recommendations from PIG

Gastroesophageal Reflux: I know it when I see it

Treating reflux does not help asthma

Unexplained chest pain