Category Archives: Gastroenterology

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

Fish intake may reduce liver cancer

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In a large Japanese adult population (n=90,296), the consumption of n-3 fatty acids and fish was associated with reduced risk for hepatocellular cancer (HCC) (Gastroenterology 2012; 142: 1468-75 and editorial 1411-12).

HCC ranks fifth among cancer incidence and third for mortality worldwide.  Many factors contributing to HCC cannot be modified.  The main factors subject to modification include diet and avoidance of viral hepatitis.  Dietary studies are methodologically-challenging due to difficulties assessing diet and due to the complex nature of diets.  Without going into any significant detail, this study shows an inverse relationship between fish intake and incidence of HCC.  The hazard ratio for the highest quintiles compared to the lowest were 0.56-0.64 depending on the specific dietary agent.  The specific n-3 polyunsaturated fatty acids (PUFA) examined included eicosapentaenoic acid (EPA), docosapentaenoic adic (DPA), and docosahexaenoic acid (DHA).

HCC Established Risk Factors:

Age, males, family history of HCC, HCV/HBV infection, alcohol, cirrhosis, tobacco, aflatoxin exposure, Hereditary Hemochromatosis, α-1 antitrypsin deficiency, primary biliary cirrhosis

Likely Risk Factors:

Diabetes, obesity, NAFLD

Possible Risk Factors:

Red meat, saturated fat, fructose, oral contraceptives

Possible Protective Factors:

Coffee, micronutrients (vitamin D, vitamin E, selenium), white meat (fish, poultry), and n-3 fatty acids

Related blog posts:

Looking for trouble

Live longer -drink more coffee

Drink Up!

More about coffee

One for the PPI team

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While this blog in previous posts has pointed out some shortcomings of proton pump inhibitors (PPIs), at the same time this class of medications remains a crucial part of pediatric gastroenterology practice.  In most patients, the benefits of these medications far outweigh the potential risks.

One of the risks has been a low rate of increased infections due to lowering gastric acid which provides some protection against enteric infections.  More information about PPIs show that these medications are not likely to increase the risk of small intestinal bacterial overgrowth (SIBO) (Am J Gastroenterol 2012; 107: 730-35 –thanks to Ben Gold for showing me this article).

In this retrospective study from 2004-2010, 1191 patients were included with 566 receiving PPI therapy.  Mean age: 63 years for PPI users and 59 years for nonusers. Glucose breath hydrogen testing (GBHT) for bacterial overgrowth did not differ significantly between PPI users and nonusers.  The authors acknowledge that there have been conflicting reports previously between the use of PPIs and the development of SIBO (see Table 5 of article); interestingly, SIBO with PPIs has occurred predominantly in studies from Europe.  The authors note that while achlorhydria leads to SIBO, the intermittent surges of acid production with PPIs should be sufficient to prevent SIBO.

Additional references/previous blog posts:

  • Proton pump inhibitors–infection risk with cirrhosis
  • The Medical Pendulum and Gastroesophageal Reflux
  • -Gastroenterol Hepatol 2011; 7: 10-2.  Risk of infections with PPIs.
  • -Gut 2007; 56: 802-8.  SIBO with IBS.
  • -NEJM 2010; 363: 2114. large Denmark study. 5082 fetuses with PPI exposure (out of 840,968 live births. Risk of birth defects NOT increased with exposure during 1st trimester. Possible slight increase with preconception use except with omeprazole.
  • -Gastroenterol 2010; 139: 1115. Review of safety of PPIs.
  • -Gastroenterol 2010; 139: 93. n=167,000. PPIs associated with hip fracture risk, OR 1.3, in patients with other risk factors.
  • -Gastroenterol 2010; 138: 896-904. 5 yrs of PPI -no increase risk in hip/spine fx.
  • -Arch Intern Med 2010; 170: 765-71, 747 (ed). PPI not related to hip fx (n=161,806) women 50-79. INCREASE risk of spine fx, hazard risk 1.47
  • -Arch Intern Med 2010; 170: 772-8. PPIs increase risk of CDT (hazard ratio 1.42 –42% increase in risk), n=1166.
  • -Arch Intern Med 2010; 170: 784-90. n=101,796.  Risk of nosocomial infection: OR 1.74 for daily PPI, OR 2.36 if BID Rx; thus ~70% increase risk of nosocomial infection.

Aspirin prophylaxis for colorectal cancer?

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A recent article in The Lancet has provided additional information about the use of aspirin for cancer prevention, especially colorectal cancer (Rothwell PM et al. Lancet 2012; published online March 21. DOI: 10: 1016/S0140-6736 (11)61720-0).  In the commentary on this article (DOI: 10: 1016/S0140-6736 (11)61654-1), the potential benefits of aspirin are placed into context and previous studies are reviewed.  In short, the data from a number of studies suggest that aspirin lowers the risk of cancer.

In Rothwell’s study, which pooled data from 51 randomized trials, aspirin at any dose reduced the risk of non-vascular death by 12% and cancer death by 15%.   Benefit was seen within 3 years for high-dose (>300 mg/day) and after 5 years for low doses (<300 mg).  The cumulative numbers of patients in the reviewed studies was approximately 40,000 in each arm.  These studies were divided and examined under separate categories to assess primary prevention for vascular events and to assess effects on cancer deaths.

Yet, these encouraging results though have not been seen in several large randomized trials; the editorial notes that “the Women’s Health Study (WHS) of 39,876 women treated with alternated day 100 mg aspirin over 10 years and the Physicians’ Health Study (PHS) of 22,071 men treated with alternate-day 325 mg aspirin for 5 years.  After 10-12 years of folllow-up, aspirin was not associated with reduced risk of colorectal cancer.”  In addition, as noted in previous post, ( Who needs aspirin?/Arch Intern Med 2012; 119: 112-8) a large study with over 100,000 patients also did not show reduction in mortality from vascular or non-vascular events.

Whether alternate-day dosing of aspirin (in WHS and PHS studies) undermines its efficacy in preventing cancer is not clear.  Until more data are available, aspirin for chemoprevention is best-suited for those with increased cancer risk (eg. history of colorectal cancer & hereditary cancer syndrome) and low risk of GI bleeding.  Rates of bleeding due to aspirin are about 4% per year and for serious bleeding about 2% per year. In addition, other adverse effects, including macular degeneration, have been reported with aspirin use (Ophthalmology 2012; 119: 112-8).

Additional references:

  • Link to pdf copy of cited article:http://extremelongevity.net/wp-content/uploads/asa-ca.pdf
  • -Lancet 2011; 377: 31-41. Aspirin effect on cancer mortality -decreased by 30-40% (esophageal, gastric, pancreatic, colorectal)
  • -Lancet 2010; 376: 1741 – 1750. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lowers risk of colon Ca.
  • -JAMA 2009; 302: 649. Aspirin use likely increases survival after dx of colon cancer.
  • -Gastro 2010;138: 2012. Commentary on aspirin for decreasing risk after diagnosis of colon cancer.
  • -NEJM 2007; 356: 2131, 2195. Aspirin can decrease high-expressing COX-2 colon adenoca; not recommended as routine prophylaxis at this time

Who needs aspirin?

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Despite a lot of good press for aspirin with regards to prevention of cardiovascular events and cancer prevention, determining who should take aspirin is quite tricky.  This blog entry will discuss the vascular rationale and a subsequent post will tackle the potential of aspirin for colorectal cancer prevention.

At this time, the cardiovascular disease (CVD) rationale includes preventing myocardial infarction [MI] and stroke.  These are the main determinants of risk/benefit for taking aspirin.  In 2009, guidelines from US Preventive Services Task Force (USPSTF) for taking aspirin were published (Ann Intern Med 2009; 150: 396-404).  The following link can be used to access this article:

http://www.uspreventiveservicestaskforce.org/uspstf09/aspirincvd/aspcvdrs.pdf

The recommendations include the following:

Men <45:  Not encourage aspirin for MI prevention

Women <55: Not encourage aspirin for stroke prevention

Men 45-79:  Encourage aspirin when CVD benefit.  Benefit likely if:

  • 45-59 years, 10 -year CVD risk ≥4%
  • 60-69 years, 10-year CVD risk ≥9%
  • 70-79 years, 10-year CVD risk ≥12%
To calculate 10-year CVD risk: http://www.mcw.edu/calculators.htm
Risk factors: age, high blood pressure, diabetes, smoking, history of CVD, total cholesterol level, and HDL cholesterol level

Women 55-79:  Encourage aspirin when stroke benefit.  Benefit likely if:

  • 55-59 years, 10 -year stroke risk ≥3%
  • 60-69 years, 10 -year stroke risk ≥8%
  • 70-59 years, 10 -year stroke risk ≥11%

To calculate 10 -year stroke risk: http://my.clevelandclinic.org/p2/stroke-risk-calculator.aspx

Risk factors: age, high blood pressure, diabetes, smoking, history of CVD, atrial fibrillation, and left ventricular hypertrophy

In addition, it is noted that aspirin is NOT recommended when other NSAIDs are being administered or if history of GI ulcers/risk of serious GI bleeding.

While these recommendations are a useful starting point and the risk calculators are fascinating, the absolute benefit of aspirin remains unclear.  A recent article on this subject indicates that aspirin may not improve mortality (Arch Intern Med. 2012;172(3):209-216. doi:10.1001/archinternmed.2011.628).  This article reviewed nine large randomized placebo-controlled studies, each with at least 1000 participants.  In total, more than 100,000 patients were described in these studies.  While CVD events were reduced by 10%, there was no reduction in mortality for cardiovascular disease (OR 0.99) or for cancer (OR 0.93) among aspirin takers over a mean of 6 years.  Most of the reduction in CVD events were due to a lower rate of non-fatal MI (OR 0.80).  In addition, there was an increase in significant GI bleeding among patients taking aspirin (OR 1.31)

Due to these results, the authors conclude that routine use as primary prevention is not warranted; “treatment decisions need to be considered on a case-by-case basis.”

Additional reference:

  • –Arch Intern Med 2012;172:217-218.  Aspirin Therapy in Primary Prevention: Comment on “Effect of Aspirin on Vascular and Nonvascular Outcomes”

Will NOTES come to pediatrics?

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Natural orifice translumenal endoscopic surgery (NOTES) has been receiving increasing attention and is being considered as a potential alternative to laparascopic surgery; but it will be a long time before NOTES comes to pediatrics.  Initial studies for several indications have been published in the last few years and this experience has recently been reviewed (Gastroenterology 2012; 142: 704-10).

Potential operations include the following:

  • Cholecystectomy.  This has been accomplished transgastric and transvaginally.  One multicenter study published experience with 362 transgastric cases and another with 551 transvaginal cases.
  • Thyroidectomy via a translingual approach.
  • Esophageal myotomy via a transesophageal approach.
  • Appendectomy via a transvaginal approach.
  • Rectal cancer resection via a transrectal approach.

Thus far, complications have been low & no deaths; only infrequently has a laparascopic or open procedure been needed to salvage the operation.  The main limitation to further use of NOTES has been adequate instrumentation and a critical mass of investigators to explore this technique.  As expertise develops in this area, a much larger number of procedures will be undertaken.  In many ways, NOTES is akin to laparascopy in its early days.  Potential advantages of decreased pain and faster recovery are the motivation to continue to work on NOTES.

Preventing Cancer in patients with Barrett’s Esophagus

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Though Barrett’s esophagus is rare in pediatric gastroenterology, concerns about esophageal cancer are fairly frequent.  In addition, some conditions that increase the risk of esophageal adenocarcinoma start in childhood.

One way to lessen the risk of Barrett’s esophagus in adults is through the use of medications (Gastroenterology 2012; 142: 442-52).  This study was a pooled analysis of six population-based trials with a total of 1226 esophageal adenocarcinoma (EAC) patients and 1140 esophagogastric junctional adenocarcinoma (EGJA) patients.  NSAIDs (aspirin and nonaspirin) lowered the risk of both EAC and EGJA, with OR of 0.68 and 0.83 respectively.

Although this study suggests a possible role for NSAIDs in preventing cancer in patients with Barrett’s esophagus, the risks and benefits for this intervention need to be individualized.

Related previous blog post: More bad news for smokers

Additional references:

  • -Gastroenterology 2011; 141: 2000. Lower risk of Barrett’s in pts taking NSAIDs & statins. n=570.
  • -Gastroenterology 2011; 141: 1179. Overall, patients with BE and LGD have a low annual incidence of EAC, similar to nondysplastic BE. There are no risk factors for progression and there is significant interobserver variation in diagnosis, even among expert pathologists.
  • -NEJM 2011; 365: 1375. Large Danish study, n=11028. Lower incidence of Barrett’s than previous estimates. Relative risk of 11.3 compared to general population for adenoca of Esophagus with absolute annual risk of 0.12%. Barrett’s patients have the same life expectancy as general population (ed. pg 1437). Detecting cancer only ~1 in 1460 scopes with screening whereas Barrett’s detected in 10% of pts.
  • -Gastroenterology 2011; 141: 417, 460. Durable effects of ablation, n=127..
  • -Gastroenterology 2011; 140: 1084. AGA statement on Barrett’s . Recs screening only in those with multiple risk factors (age 50, male, chronic GERD, white, incr BMI)
  • -Clin Gastro & Hep 2010; 8: 565. Guidelines suggest that screening for Barrett’s is not justified w/o alarm symptoms (dysphagia, odynophagia, wt loss, anemia, hematemesis)
  • -Gastroenterology 2010; 138: 2260. n=11,823. Decrease risk of esophageal adenoCa in patients taking NSAIDs & statins.
  • -Gastroenterology 2010; 138: 854. Nice review.
  • -Gastroenterology 2010; 138: 5. Survival equivalent to general population according to Mayo study, n=366. In Barrett’s patients, leading cause of death was cardiovascular (28%). Esophageal cancer resulted in 7% of deaths. Study presented at ACG Oct 26, 2009.
  • -Clin Gastro & Hepatology 2009; 7: 1266. no benefit from surgery for Barrett’s & unclear if chemoprevention works.
  • -Gastroenterology 2009; 137: 763. Suggests surveillance with Barrett’s is not beneficial.
  • -NEJM 2009; 360: 2277, 2353.. Radiofrequency ablation can be effective.
  • -Gut 2008; 57: 1200-06. Utility of endoscopic Rx.
  • -Clin Gastro & Hep 2008; 6: 1206; editorials: 1180, 1181, 1183.. n=2107 with Barrett’s. 79 w surgery and 80 w endoscopic Rx.
  • -Gastro & Hep 2006; 2: 468. 2-8% of pts in general population have Barrett’s. >90% of ptsc Barretts will never develop cancer. Screening has not been proven to be effective in lowering rate of death from cancer. ~40% of US population has heartburn; only 8000-9000/yr develop esoph adenoCa. Also, the presence of Barrett esophagus does not decrease life expectancy.
  • -Gastroenterology 2005; 129: 1825-31. 1.6% incidence of BE in adult Swedish population. Alcohol, smoking increase risk.

Disruption of KLF4 is the real villain for gastric cancer

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The only reason I’m posting this article is the word “Villin” in the title of the article (Gastroenterology 2012; 142: 531-42); I wondered what this was.  In this study, the authors show that “disruption of KLF4 in villin-positive gastric progenitor cells promotes the formation and progression of tumors in the antrum of mice.”  For the uninitiated,  an editorial on pages 424-27 of the same issue explains the entire article and the significance of the findings.

Kruppel-like factor 4 (KLF4) is a protein in multiple tissues that is important in cell differentiation, inflammation, and carcinogenesis.  Villin is an actin-bundling protein found in the apical brush border of absorptive tissue.  Villin-expressing gastric progenitor cells are typically quiescent but undergo division during inflammatory insults.

This is important in understanding gastric cancer because for a long time it was unclear why cancer would develop in the stomach where there is frequent turnover of the mucosa.  It is likely that more quiescent cells live long enough to accumulate cancer-promoting mutations/changes.  This study adds support to this hypothesis, at least in mice.

Gluten sensitivity without celiac disease

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Gluten free is big business.  In a range of conditions, eliminating gluten has been advocated to improve symptoms.  The most frequent problem in which a gluten-free diet (GFD) may be beneficial is irritable bowel syndrome (IBS).  A selected summary in Gastroenterology discusses this topic (Gastroenterology 2012; 142: 664-73).

This review highlights an article that showed improvement in a double-blind randomized trial (Am J Gastroenterol 2011; 106: 508-14) & then reviews the topic more broadly.  The study is the first randomized controlled trial that suggests that nonceliac IBS patients may improve with a GFD.  The study looked at 34 patients with IBS who had improved with a GFD & had no evidence of celiac disease (either negative HLA-DQ2/DQ8 or duodenal biopsy).  Then 19 patients had 16g of gluten per day reintroduced; control patients were offered equivalent food that was gluten-free.  The gluten products in the study were free of fermentable oligo-, di-, monosaccharides and polyols to avoid confounders (What to make of FODMAPs).  The patients who continued a GFD had less reported pain, bloating and tiredness.  The GFD group reported good control of symptoms the previous week in 68% vs. 40% in the study group.

The commentary notes that ‘gluten sensitivity’ is big business, accounting for 1.3 billion in 2011 expenditures.  Companies like General Mills, Betty Crocker, PF Chang’s, and Subway are offering gluten-free choices.  Since immune activation and low-grade inflammation may be important for IBS, it is possible that some foods trigger these processes.  At the same time, individuals with reported gluten sensitivity have not been shown to have increased intestinal permeability; this is in contrast to celiac disease (BMC Med 2011; 9; 23).

There may be more patients with IBS who will benefit from a GFD due to gluten sensitivity than patients with celiac disease.

Additional references:

  • -Nutr Clin Pract. 2011;26:294-299.  A gluten-free diet (GFD) is commonly recognized as the treatment for celiac disease. It also has been investigated as a treatment option for other medical conditions, including dermatitis herpetiformis, irritable bowel syndrome, neurologic disorders, rheumatoid arthritis, diabetes mellitus, and HIV-associated enteropathy. The strength of the evidence for the use of a GFD in these nonceliac diseases varies.
  • -Clin Gastro & Hep 2007; 5: 844. GFD in IBS pts (w/o celiac)
  • -Am J Gastro 2009; 104: 1587. Gluten sensitivity in IBS (w celiac)
  • -Gastroenterology 2011; 141: 1187. Prevalence of celiac similar in IBS as general population though higher number (7%) with celiac antibodies (esp gliadin).
  • -Am J Gastro 2008; 103: S472 (abstract P687) Serology for Celiac in IBS patients same as in controls. n=566. n=555 controls.
  • -Clin Gastro & Hep 2007; 5: 844. d-IBS patients may respond to gluten-free diet, especially if positive HLA-DQ2 expression or positive celiac serology.
  • -Lancet 2001; 358: 1504-08. n=300 uninvestigated pts w IBS criteria & 300 controls. 66 w positive serology; 14 w biopsy-proven celiac dz, 43 w normal biopsies. Odds ratio of 7 to have celiac compared to control group (2 w biopsy-proven disease).