Category Archives: Gastroenterology

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.

Related blog entries:

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

Targeted aspirin therapy to improve colorectal cancer survival

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A recent study shows that a specific subset of patients with colorectal cancer are most likely to benefit from aspirin therapy (NEJM 2012; 367: 1596-606).

This study used data from two prospective cohort studies, the Nurses’ Health Study (n=121,700) and the Health Professionals Follow-up Study (n=51,500).  Among these patients, data was analyzed from 964 in whom there was known information on the presence or absence of the PIK3CA mutation.  In total, only 161 of these 964 patients had mutations in PIK3CA; 66 of these took aspirin and 95 did not.

Mutations in PIK3CA affect the gene encoding phosphatidylinositol-4,5-bisphosphonate-3-kinase and occur in 15-20% of colorectal cancers.  Up-regulation of this gene enhances prostaglandin E2 synthesis and prostaglandin-endoperoxide synthase 2 (also known as cyclooxygenase-2) which results in the inhibition of apoptosis in colon-cancer cells. Due to this mechanism, the authors hypothesized that blocking this pathway with aspirin would have a beneficial outcome with regard to tumor molecular characteristics and patient outcomes.

Mutations in PIK3CA were detected with PCR and pyrosequencing after DNA extraction from paraffin-embedded tissues.

Among patients with mutated-PIK3CA colorectal cancers, regular use of aspirin after diagnosis was associated with better survival.  Hazard ratio for cancer-related death was 0.18 and overall death rate also was lower with hazard ratio of 0.54.  In patients without this mutation (wild-type PIK3CA), regular use of aspirin was not associated with a survival advantage; hazard ratio of cancer-specific survival was 0.96 and overall survival hazard ratio was 0.94.

While this study had data on a large number of other characteristics, including BRAF, KRAS, CIMP, LINE-1, and microsatellite instability, it lacked statistical power to examine many of these other modification effects.

These data, if confirmed, indicate a role for aspirin in colorectal cancer patients with PIK3CA mutations.

Related blog entries:

How helpful are antioxidants for chronic pancreatitis pain?

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The ‘ANTICiPaTE’ study shows that antioxidants are not helpful in the typical patient with chronic pancreatitis (Gastroenterol 2012: 143: 655-63).  While chronic pancreatitis is a rare problem for the pediatric population, I was drawn to this study because I had to see what the acronym stood for: ANTI-oxidant therapy for painful Chronic Pancreatitis Therapy Evaluation.

In brief, this study was a double-blind placebo-controlled single-center randomized trila of Antox version 1.2 in patients with painful chronic pancreatitis.  The ingredients of this antioxidant included selenium, ascorbic acid, d-α-tocopherol and multiple secondary ingredients.  Antioxidant levels were measured as well and did increase on study medication.

Results: after 6 months, pain scores were reduced by 1.97 from baseline in placebo group and 2.33 in the antioxidant group.  The -0.36 difference was within the 95% confidence interval (-1.44 to 0.72).  Quality of life measures were similar as well.

The discussion points out that the largest randomized study (Bhardwaj et al) found that antioxidants were effective in relieving pain in chronic pancreatitis.  So why the discrepancy? Possible reasons:

  • 1. Different populations: Bhardwaj study had a younger population: 31 years compared with 50 years in current study
  • 2. Different etiologies: The Bhardwaj study had only 31% with alcoholic etiology for chronic pancreatitits compared with 72% in current study
  • 3. Comorbid conditions:  The Bhardwaj study had 28% smokers compared with 80% in current study
  • 4. Antioxidant constituents differed
  • 5. Chance

Take-home message: While there are notable differences between this study and the Bhardwaj study, the present study is more indicative of typical chronic pancreatitis patients in the U.S. and indicates that antioxidants are not effective in this population. For the pediatric population, the Bhardwaj study has more applicability; however, the present study diminishes optimism that antioxidants will be effective.

What are the alternatives? Both surgical and endoscopic treatments can be considered for chronic pancreatitis, though neither has consistently been effective at reducing pain.

Additional references:

  • -Bhardwaj P, et al. Gastroenterology 2009; 136: 149-59.  Antioxidants for chronic pancreatitis pain.  antioxidant included 600mcg selenium, 0.54g ascorbic acid
  • -Gastroenterol 2011; 141: 1690.  Surgical Rx outperformed medical Rx. n=79.  Only 5% of surgical pts needed more Rx.  47% of endoscopic pts eventually needed surgery, 68% of endoscopic pts had repeated procedures.
  • -NASPGHAN Postgraduate Course 2011: Exercise helpful in reducing pain/depression, coffee/green tea may help. Surgery (eg Puestow) -most commonly for pain —>75-80% good outcome.  Rarely Frey procedure & investigational pancreatectomy (harvesting islet cells) -n=24 in Minnesota. May benefit from dual sphincterotomy -bilary/pancreatitic (33% improve) but increased complications (pancreatitis, cholangitis, restenosis)
  • -Am J Gastro 2010 105: 1884.  –cleaning out ducts w ERCP-1/3rdimprove (some worsen)
  • -Clinical Gastro & Hep 2011; 9: 541.  steatorrhea (w pancreatitis) typical adult dosing of pancreatic enzymes: 40,000-50,000 IU lipase/meal & 1/2 dose for snacks.
  • -Gastroenterol 2011; 141: 536.  Pregabalin reduces pain in chronic pancreatitis -randomized control trial.

Related blog entries:

Does pancreas divisum cause pancreatitis?

Recurrent pancreatitis and genetic underpinnings

Pain changes brain

Consensus guidelines after polypectomy

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The US Multi-Society Task Force (MSTF) on colorectal cancer has updated their recommendations and provided an update on the literature as well (Gastroenterol 2012; 143: 844-57).

Their recommendations are summarized in Table 1 of this article.  In brief, repeat colonoscopy is recommended at the following interval:

  • 10 years –If no polyps or small (<10 mm) hyperplastic polyps in rectum/sigmoid
  • 5-10 years –if 1-2 small (<10 mm) tubular adenomas
  • 3 years –if 3-10 tubular adenomas or if adenoma with high-grade dysplasia
  • ❤ years –if >10 adenomas
  • 1 year  –if serrated polyposis syndrome

Other important points include the recommendation of adopting split-dose bowel preparations and avoiding interval fecal testing within 5 years after colonoscopy.  If the bowel preparation is poor, the MSTF recommends that in most cases colonoscopy should be repeated within 1 year.  Newer techniques like chromoendoscopy, narrow band imaging, and magnification endoscopy have not been adequately studied to recommend them as part of  a surveillance strategy.

Related blog entries:

Colonoscopy, Split-dosing bowel preps, and Ottawa scores

Aspirin prophylaxis for colorectal cancer?

Additional references:

  • -Gastroenterol 2010; 138: 73, 27 (ed). Overutilization of colon screening in low risk situations and underutilization in high risk situations in clinical practice.
  • -Clin Gastro & Hep 2010; 8: 795. Juvenile Polyps. Describes frequent rate of recurrence (3 of 18 among single polyps) & 45% overall. n=257. 39% with at least 2 polyps. Among those with multiple polyps, 7 had mutations in either SMAD4 (mothers against decpentaplegic drosophilia), BMPR1A (bone morphogenetic protein), or PTEN (phosphatase & tensin homolog). Their recs: recheck with scope in 1-3 years depending on polyp burden and presence of dysplasia.
  • -Clin Gastro & Hep 2009; 7: 1217. Fewer polyps detected as day progresses at a VA hospital n=477 pts. 27% decline in polyp detection.
  • -NEJM 2009; 361: 1179. Review of screening for colorectal cancer.
  • -Gastroenterol 2009; 137: 792. Use of CT colonography -current appraisal.
  • -Ann Intern Med 2009; 150: 1-8. Says endoscopists miss most cancers on right side & colonosopy reduces cancer by ~60% primarily due to left-sided cancers.  Most, 73%, of colonoscopies not done by GI/colorectal surgery.
  • -Gastroenterol 2008; 134: 1570. Update recommendations from ACS, ACR, US Multi-society task force.
  • -Clin Gastro & Hep 2005; 3: 633.  Inherited polyposis syndromes & genetic testing.
  • -Clin Perspectives in Gastro 2002; 5: 329.  Polyp techniques & complications. If entrapped snare, consider cutting off snare handle & pulling on 1 wire. Alternative us to use snare as guidewire & push scope beyond wire. For large stalks, consider using snare as tourniquet for 5 min. Consider pure (or blended) coagulation at settings 20-30W.
    Injection of fluid into the submucosa beneath the polyp increases the distance between the polyp and the deeper layers of the colon. Using a sclerotherapy needle normal saline is injected at the edge of the polyp raising a bleb. No specific volume of normal saline is used. The objective is to raise a large bleb with marked elevation of the polyp. The snare is then placed around the base of the polyp and it can be removed with electrocautery. If bleeding is a consideration then a solution of epinephrine can be used at a 1:10,000 concentration. The advantage of cautery is that residual tissue is usually destroyed although this is usually not a consideration when removing juvenile polyps.Hot biopsy forceps are usually used to ablate diminutive polyps (< 5 mm in diameter). The coagulation current applied should be low. 10-15 watts applied for 1-2 seconds. The technique is generally safe but serious complications including bleeding or perforation have been reported.The cold snare technique is safe in small polyps. (< 5 mm) The rationale is that the vessels feeding the polyp are small and the risk of bleeding is low. The advantage is that without cautery there is not deep tissue damage. Submucosal injection may make the procedure safer.

RFA doesn’t always work for Barrett’s

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As noted previously in a related blog (Preventing Cancer in patients with Barrett’s Esophagus), Barrett’s esophagus (BE) is not a frequent issue in pediatric gastroenterology.  However, some esophageal problems that start in childhood can predispose to this condition later in life. Certainly, BE is a frequent clinical issue in adult gastroenterology.

Three articles in this month’s Gastroenterology provide some useful information.

  • Gastroenterology 2012; 143: 564-66
  • Gastroenterology 2012; 143: 567-75
  • Gastroenterology 2012; 143: 576-81

An editorial on these three articles is available on page 524.

The first reference describes three cases of high-grade dysplasia and adenocarcinoma that developed after ‘successful’ radiofrequency ablation (RFA).  Thus, the authors advocate continued surveillance following RFA and caution in using RFA to patients with low-risk BE.

The second reference describes an elaborate model to determine if RFA is cost-effective.  Based on their assumptions, “initial RFA might not be cost-effective for patients with BE without dysplasia.”   Though, the authors indicate that one of the cost savings was that RFA was more effective and less costly than endoscopic surveillance.  The authors acknowledge that their analysis is limited by assumptions and that the only alternative would be a large multicenter randomized trial with a long followup.

The third study examined 37 RFA patients.  22 were classified as complete responders and 15 were incomplete; complete responders had no intestinal metaplasia after fewer than 3 ablation sessions.  Risks for persistent intestinal metaplasia were uncontrolled weakly acidic reflux despite twice-daily PPI therapy, longer length of BE, and larger hiatal hernias.

Increased bile acids in diarrhea-predominant IBS

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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.

According to the study which you would never qualify for…

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When I give patients advice on treatment, I rely on well-designed studies to help select the medications/treatments that are most likely to be effective.  It is interesting to ponder how applicable these studies are and how closely they reflect the patient population that I’m seeing.  A recent article indicates that in a tertiary referral center for inflammatory bowel disease, the majority of patients would be excluded from participation in these studies (Clin Gastroenterol Hepatol 2012; 10: 1002-07).

These authors performed a retrospective cohort study of patients presenting to the Mount Sinai Medical Center between January 2008 and June 2009.  For Crohn’s disease (CD) patients, the authors selected 7 published randomized control trials of biological therapy for patients with moderate-severe disease (ACCENT 1, CLASSIC 1, CHARM, PRECISE 1, ENCORE, ENACT, and SONIC).  For Ulcerative Colitis (UC), they selected ACT 1 and ACT 2 trials for moderate-severe UC.

Only 31.1% of 206 patients with IBD would have been eligible to participate in any of the selected RCTs.  The average age of their patients was about 35 and did not differ significantly among patients who would qualify compared to those who would not.

Among the CD patients, the inflammatory phenotype was most likely to qualify; 37 patients with inflammatory disease behavior would have been eligible.  While only 54% (37 of 68) of the inflammatory phenotype would have qualified, this accounted for 86% of the total population who would have qualified (only 34% of the entire CD cohort would have been eligible for study participation).

Among the UC patients, there were no disease characteristics or demographics associated with eligibility; that is, there was a similar distribution of disease extents, Mayo scores, disease duration, gender, and age among the patients who qualified and those who did not.

Reasons for exclusion: stricturing or penetrating disease, steroid dosing, comorbities, concomitant therapies, or prior exposure to biologics.

The authors note that the results from this study mirror that from similar studies with other chronic diseases including rheumatoid arthritis, chronic obstructive pulmonary diseases, and congestive heart failure.

When the authors looked at the trial-ineligible patients, 60% had a response to biological therapy. The response rates for ineligible patients (compared to eligible patients) were lower for CD patients but not for UC patients (Figure 2 in study).

While stringent criteria for eligibility limit the external validity of the study results, these criteria are in place for multiple reasons.  Less rigid selection criteria would require larger study populations, longer duration studies, and greater costs.

The issue of study applicability is even a bigger problem in pediatrics.  This is primarily due to fewer high quality studies in children. As such, many clinical judgements require extrapolation from adult studies.

Related blog post:

Interpreting industry-funded studies