Category Archives: Gastroenterology

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

What is the risk of colon cancer in IBD?

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Some recent studies have shown that colorectal cancer complicating IBD may not be as common as previously thought or may be decreasing in incidence (Gastroenterology 2012; 143: 375-81 & Gastroenterology 2012; 143: 382-89 ).

The first study used a nationwide cohort of 47,374 Danish patients with IBD over a 30-year period.  During a 178 million person-years of follow-up evaluation, 268 patients with ulcerative colitis (UC) and 70 patients with Crohn’s disease (CD) developed colorectal cancer (CRC).  The risk was comparable to the general population (RR 1.07)!  Furthermore, the relative risk for CRC decreased over sequential time periods: 1.34  (1979-88) to 0.57 (1999-2008).

Increased risk:

  • UC diagnosed in childhood or adolescence
  • longer disease duration
  • patients with primary sclerosing cholangitis

Their conclusion, ‘the overall risk of CRC in patients with UC has decreased markedly over time and no longer exceeds that of the general population, at least in the first decade after diagnosis.”  And, based on their data, patients with Crohn’s disease are not at increased risk for CRC.

The second study from California used a large Kaiser Permanente database from 1998-June 2010.  29 cancers were identified in CD (n=5603) and 53 in UC (n=10,895) patients.  The incidence per 100,000 for CRC was 75 for CD, 76 for UC, and 47 for general population.

These authors conclude that there is an increased risk of CRC in a community-based IBD population between 1998-2010 despite advances in medical treatment.

To understand the discrepancy of these reports, the same issue provides an editorial (page 288).  My take is that the current incidence of CRC is lower than in previous reports but that the risk factors identified in the Danish cohort (see above) likely remain important.

Additional references:

  • -Gastroenterol 2009; 136: 718. 22% of cancers occurred before recommended surveillance in adults (only 9% if exclusion of patients who had IBD and cancers diagnosed at same time).
  • Colon Cancer Survival Calculator http://www.mayoclinic.com/calcs-Gastro 2010; 138: 207-2177 (entire issue)
  • -JAMA 2009; 302: 649. Aspirin use likely increases survival after dx of colon cancer. Commentary-Gastro 2010;138: 2012.
  • -NEJM 2009; 361: 2449. molecular basis of colorectal cancer
  • -Gut 2008; 57: 1246. IBD and colon cancer
  • -IBD 2007; 4: 367. 5ASA Rx did not reduce rate of cancer in large study of UC/CD -review of 18,000 colorectal cancer cases. IBD increased risk of CRC 6-7-fold..
  • -Clin Gastro & Hep 2006; 4: 1346. aminosalicylates reduce CRC.
  • -Gastroenterol 2006; 130: 1030, 1039, 1350. 600 patients followed for 35 yrs: CRC by colitis duration: 2.5% @ 20yrs, 7.6% @ 30yrs, 10.8% @ 40yrs. 5 year survival was 73% among those with cancer. 2nd study showed main CRC risk in UC pts is among those with extensive colitis.
  • -Clin Gastro & Hepatol 2004; 2: 1088. Lower cancer risk in this cohort, n=1460. CRC 0.4 @10yrs, 1.1% @ 20yrs, 2.1% @ 30yrs. Lower CRC may be due to more surgery in Rx failures & use of 5-ASA.
  • -Clinical perspectives in Gastro 1999; 2: 9 & 25. (review) surveillance/ overview take 4 bx q10cm. start p 8yrs in pancolitis & 15yrs for left-sided dz. Cancer risk: ~5% at 20yrs + 1%/yr p 20yrs in pancolitis.
  • -Gastroenterol 2003; 125: 1311. Advancement of dysplasia to cancer in UC.

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

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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

ELEVATE study

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Another clever acronym for the following:  Eltrombopag Evaluated for Its Ability to Overcome Thrombocyopenia and Enable Procedures (NEJM 2012; 367: 716-24).

Eltrombopag is an oral thrombopoietin-receptor agonist which is approved for use in chronic immune thrombocytopenia.

This double-blind, placebo-controlled trial evaluated whether eltrombopag increased platelet counts and reduced platelet transfusions in patients with chronic liver disease & platelet counts less than 50,000 per cubic millimeter.  145 patients received eltrombopag (75 mg once a day) and 147 received placebo.  Patients received therapy for 14 days. Elective procedures were scheduled no more than 5 days after the final dose of study medication (days 15 to 19).

Key findings:

  • Transfusions of platelets were reduced in the treatment group: 28% of patients compared with 81% in placebo group.
  • No differences in significant bleeding episodes noted.
  • Portal venous thrombosis was increased in treatment group with 6 patients compared with 1 patient in placebo group.

Study limitation: no standard practice with regard to use of platelet transfusions for thrombocytopenia (especially with platelet counts between 50,000-80,000)

Platelet transfusions can be problematic with cirrhosis.  Platelet transfusions have a short duration of efficacy, reactions to transfusions can occur, and multiple transfusions can result in antiplatelet antibodies. Nevertheless, the conclusions from this study: ‘until better identification of risk factors for the development of thrombosis…have been conducted, eltrombopag is not recommended as an alternative to platelet transfusion.’

Epidemic of Prescription Drug Overdoses

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More information on the epidemic of drug overdoses: MMWR 2012: 61: 10-13.

In 2007, in U.S. one death due to unintentional drug overdose occurred every 19 minutes (27,000 cases), primarily due to opioid analgesics.  In addition, for every death, there were nine persons admitted for drug treatment, and 35 emergency room visits.

The escalating drug use can be quantified.  In 1997, drug distribution through pharmacies delivered the equivalent of 96 mg of morphine per person whereas in 2007 the amount was 700 mg per person; 700 mg is enough for every person in U.S. to receive a three-week course of Vicodin (hydrocodone/acetaminophen 5mg q4 hours).

Only 10% of these patients were seeking care from multiple doctors; yet this 10% accounted for 40% of the cases of overdosage.

Prevention strategies:

  • Prescription data to prevent doctor shopping & reduce inappropriate use of opioids/selling excessive opioid prescriptions
  • Enforcing laws against ‘pill mills’
  • Improve medical practice in prescribing opioids

Additional references/previous blog entries:

Epidemic: Responding to America’s Prescription Drug Abuse Crisis  Whitehouse plan

Pediatric pharmaceutical poisoning

Deadly consequences of pain management

Why “therapeutic dose” of codeine can kill

Abatacept for IBD?

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Doesn’t work (Gastroenterology 2012; 143: 62-69).  While this study indicates that Abatacept was not effect for either Crohn’s disease (CD) or ulcerative colitis (UC), it was useful nevertheless.

In brief, the study examined four placebo-controlled trials of abatacept for induction and maintenance therapy in both CD and UC.  The induction studies included 451 CD patients and 490 UC patients.  The maintenance studies had 90 CD and 131 UC patients.

Results for induction:

  • CD: Clinical response: 17%, 10%, 15% for abatacept dosing of 30, 10, and 3 mg/kg.  Placebo 14%
  • UC: 21%, 19%, 20%  for abatacept dosing of 30, 10, and 3 mg/kg.  Placebo 29.5%

Results for maintenance:

  • CD: 24% abatacept vs 11% placebo
  • UC: 12.5% vs 14% placebo

The premise of this study was that T-cell activation requires co-stimulatory signaling via T cell CD28 and CD80 or CD86 on the antigen-presenting cell.  Abatacept (CTLA4-Ig) which is effective for psoriasis, rheumatoid arthritis, and juvenile idiopathic arthritis was thought to have potential; it blocks costimulation pathways involved in T-cell activation which was shown to be helpful in animal model of colitis.

So why did it not work?  The editorial in the same volume (pages 13-16) suggests the following possibilities:

  • Abatacept would be more likely to work when naive T cells are actively recruited into inflammation rather than memory T cells which are predominant in IBD
  • CD28-related pathways may not be important in IBD pathogenesis
  • Abatacept may have impeded Treg function in addition to preventing T-cell activation (explained in Fig 1D)
  • Blockade of CD28 pathways could have resulted in unfavorable changes in cytokine profiles from T-cell differentiation (Th1 vs Th2)

The implication of this study is that not all T-cell mediated inflammatory disease respond to the same treatment approaches.  The complexity of intestinal immune responses necessitates ongoing clinical studies to determine which promising therapies will be useful.

Pregnancy after Liver Transplantation

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As there are about 14,000 women of reproductive age in the U.S. who have undergone liver transplantation (LT), data about the outcomes of pregnancy are important for counseling.  A review and meta-analysis (Liver Transpl 2012; 18: 621-29) provides some information; going forward the National Transplantation Pregnancy Registry (NTPR) which was established in 1991 offers the promise of additional insight.

In the current review, Deshpande et al found 8 of 578 studies which met inclusion criteria; in total 450 pregnancies in 306 LT recipients were examined.  While healthy live births were the most common outcome, there were several pertinent risks identified.  The main concerns were development of preeclampsia, rejection/graft loss as well as the potential for birth defects.  While miscarriage rates were similar to the general population (15.6% compared with 17.1%), the following were much higher:

  • preeclampsia 21.9% vs. 3.8% in general population
  • cesarean section delivery 44.6% vs. 31.9% in general population
  • preterm birth 39.4% vs. 12.5% in general population

While rates of rejection and graft loss are not given for the entire cohort, specific study results were discussed.  In one study, rates of acute rejection ranged from 2% to 8% and loss of graft within two years of pregnancy occurred in 6-11%.

Similar to rejection data, the data for birth defects was not uniformly reported.  Specific study results were discussed and included several birth defects: 1 patient with total anomalous pulmonary venous return, 1 with pyloric stenosis, 2 with hypospadias, 1 with tracheoesophageal fistula, 1 with unilateral cystic kidney, and 2 with ventricular septal defects.

Take-home message:

Liver transplant recipients can have successful pregnancies but should be considered high risk.  Active reporting to established registries can give more accurate and up-to-date information.

Related post:

Alive and well? 10 years after liver transplantation