Category Archives: Gastroenterology

HEROES trial

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HEROES is definitely a catchy acronym (Arch Intern Med 2011; 171: 1929-36); HEROES is short for Helicobacter eradication relief of dyspeptic symptoms.

In pediatric practice, when Helicobacter pylori infection is identified, efforts are made to eradicate it.  However, studies have not been conclusive about whether this is beneficial for individuals with ‘functional dyspepsia.’  A 2006 Cochrane review of 21 trials found only 6 were positive for eradication.  Previous trials had not focused on primary care patients who may be more prone to respond.  As such, the investigators randomly assigned 404 patients (adults with average age of 46 years) into a group (n=201) treated with antibiotics and a control group (n=203); this was a randomized double-blind placebo-controlled clinical trial at a single center.  All eligible patients had to meet the Rome III criteria for functional dyspepsia and have H pylori infection.  Individuals with heartburn and irritable bowel were excluded. The antibiotic group received omeprazole, amoxicillin, and clarithromycin whereas the control group received omeprazole and placebo –both groups received treatment for 10 days.

In the antibiotic group, 49% achieved at least a 50% reduction in symptoms at 12 months; the control group had a 36.5% response.  Overall, 78.1% of the antibiotic cohort improved compared with 67.5% in the control cohort.

Although the findings of the study indicate improvement with a course of antibiotics, what to do with these results is not clear.  Worldwide, at least 50% of the population is infected by H pylori.  In addition, dyspeptic symptoms afflict up to 40% of the adult population in Western countries.  Due to the enormity of these problems, translating the results of this study into practical treatment strategies is difficult.

Additional references:

  • -JPGN 2011; 52: 387. Impact of Rome III criteria on yield. Still 2.8% w/o alarm symptoms that had significant endoscopic findings.
  • -Clin Gastro & Hep 2008; 6: 746. Antidepressant venlafaxine not effective in functional dyspepsia in double-blind, randomized, placebo-controlled study. n=160.
  • -Cochrane Database Syst Rev 2006; (2): CD002096. Rx of H pylori in functional dyspepsia.
  • -Gastroenterology 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)
  • -Gastroenterology 2007; 132: 1684.  Changes in cerebral blood flow during gastric balloon distention in dyspepsia.
  • -Gastroenterology 2006; 130: 1466-79. Functional gastroduodenal d/o. Acid suppression is 1st line Rx.
  • -Gastroenterology 2005; 129:1753-55, 1756-80, 1711. Mgt & guidelines for dyspepsia. In pts < 55 w/o alarm sx, test for H pylori and rx c PPI. In pts who don’t respond, consider EGD. Other Rx unclear: prokinetics, anticholinergics, antidepressants.
  • -Gastroenterology 2004; 127; 1239. Review of functional dyspepsia. Rx initial c acid-blocker/prokinetic reasonable, if not helpful, consider tricyclic, or clonidine. Eliminate H pylori. Sumatriptan may help
  • -J Pediatr 2005; 146: 448, 500.  Dyspepsia in children often associated with delayed GE and reduced gastric volumes
  • -Gastroenterology 2003; 125: 1219-26. Algorithm suggested:1. chech H pylori 2. Rx c PPI/H2RA.  3. If persists, EGD.  If EGD neg, consider elavil
  • -Clinical Gastro & Hepatology 2003; 1: 356. Increased Mast cells noted.
  • -Gastroenterology 2002; 123: 1778, 2132. Use of hypnosis for NUD.
  • -Ann Intern Med 2001; 134: 361-369. Meta-analysis of H pylori & NUD. Non-significant/minor improvement c eradication.

TNF antagonists and UC

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In my fellowship (15 years ago), the use of thiopurines (eg. azathioprine, 6-mercaptopurine) for ulcerative colitis was debated.  Many physicians urged colectomy rather than using these drugs which could have long-term consequences.  At the time, the risk of thiopurines was less well-understood.  Over time, the use of these agents has become common when mesalamine products were ineffective.  The same issue comes up with TNF antagonists versus colectomy.

A recent study provides more information on the effectiveness of adalimumab for patients with moderate-to-severe UC but does not settle this debate (Gastroenterology 2012; 142: 257-65).  In this study, termed ‘ULTRA-2’ (Ulcerative colitis long-term remission and maintenance with adalimumab 2), the  efficacy of adalimumab for induction & maintenance of remission was studied in 494 patients.  This was a randomized, double-blind, placebo-controlled study; average age was 40 years.

Clinical remission in the adalimumab group were 16.5% at 8 weeks (9.3% placebo).  At 52 weeks, 17.3% in the adalimumab group were in remission (8.5% placebo).  Among patients naive to anti-TNF agents, the response rate was 21.3% at week 8 & 22% at week 52.  Safety overall was similar in both groups; however, in the adalimumab group one patient developed gastric cancer and one developed squamous cell carcinoma.

The authors conclude that adalimumab is safe and more effective than placebo in inducing and maintaining remission among patients with moderate-to-severe UC.

A second study, also published this past month, looks at the use of infliximab for maintenance therapy for UC (Inflamm Bowel Dis 2012; 18: 201-11).  Patients who had achieved benefit from ACT-1 and ACT-2 studies were followed for three years.  Dosage of infliximab could be adjusted.  A total of 229 patients entered the study.  During the study, 70 patients (30.6%) discontinued infliximab due to adverse effects (10.5%), lack of efficacy (4.8%) or other reasons (15.2%); the majority were able to continue infliximab.  The authors indicate that no new safety issues were identified. Yet, there were two deaths among the infliximab group including a 19 year-old nonsmoker who developed lung cancer and a lethal case of histoplasmosis.

Because the improvement compared to placebo is modest with both of these agents, the question about whether to use these medications or proceed to surgery in UC patients is unanswered.

Additional references:

  • -Aliment Pharmacol Ther. 2008 Oct 15;28(8):966-72. Epub 2008 Jul 24.  Long-term outcome of adalimumab therapy for ulcerative colitis with intolerance or lost response to infliximab: a single-centre experience.
  • -Am J Gastroenterol (Oussalah A et al) 2010; 105: 2617-25. Multicenter study of IFX for UC
  • -Gastroenterology 2010; 138: 2282. Severe pediatric UC. 25/33 responded to IFX. colectomy rate 19% at 1 year.
  • -Gastroenterology 2009; 137: 1204 (ed), 1250. lower colectomy rates at 54wks in IFX vs placebo (+concomitant meds): 10% vs. 17%.
  • -Clin Gastro & Hep 2008; 6: 1112. Do NOT use CYA post infliximab and vice versa. n=19. 1 death due to sepsis. Remission rates occur in ~1/3rd but are of short duration.
  • -NEJM 2005; 2462. 69% clinical response @ 8 weeks (vs. 37% placebo) & 45% at week 54 (vs. 20% placebo).
  • -JPGN 2004; 38: 298. 82% short-term response, 63% sustained response; n=16.

More bad news for smokers

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Add two more cancer risks for tobacco smoke (Gastroenterology 2012: 142: 233-40, 242-47).  There is now evidence linking tobacco smoke to 18 different cancers and tobacco smoke is probably the most preventable cause of death in the world.

In the first study, the investigators examined 3167 patients with Barrett’s esophagus.  This retrospective study followed patients for 7.5 years.  Patients who were current smokers (any form of tobacco) had double the risk of developing high-grade dysplasia or cancer compared to those who had never smoked.  Former cigarette smokers had a hazard ratio of 1.53.

In the second study, 386 patients with Lynch syndrome were analyzed during a 10 month period.  The hazard ratio for developing colorectal adenomas was 6.13 for current smokers and 3.03 for former smokers compared with patients who never smoked.  In addition, the authors identified a trend for developing adenomas based on pack-years.

Two more reasons to quit smoking.  On a side note, my grandmother said quitting smoking was the easiest thing that she ever did.  So easy, she did it a thousand times.

Additional references:

  • -Gastroenterolgy 2005; 129: 1825-31.  1.6% incidence of BE in adult Swedish population. Alcohol & smoking increase risk.
  • -NEJM 2011; 365: 1222. Treating smokers -useful review.
  • -NEJM 2011; 365: 1193. Cytisine -inexpensive- helps with smoking cessation (8.4% success vs 2.4%in placebo)
  • -NEJM 2008 358; 2249. Smoking and role of social networks.
  • -Gastroenterology 2011; 141: 2000. Lower risk of Barrett’s in pts taking NSAIDs & statins. n=570.
  • -Gastroenterology 2011; 141: 1179. Lower risk of Barrett’s in pts with low-grade dysplasia than previously noted -similar to non-dysplastic Barrett’s.
  • -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; 140: 1084. AGA statement on Barrett’s . Recs screening only in those with multiple risk factors (age 50, male, chronic GERD, white, incr BMI)
  • -NEJM 2005; 352: 1851. Cases of Lynch can be missed when following screening guidelines.
  • -Gastroenterology 2010; 138: 207-2177 (entire issue) Colon cancer, Lynch syndrome
  • -Gastroenterology 2008; 135: 380.  Review of colon cancer screening and prevention -2008 up-to-date- literature review
  • -Gastroenterology 1967; 53: 517-27.  Seminal article.  Lynch HT showed gene-related cancer in family cancer syndrome -different than polyposis syndromes.

What to make of FODMAPs

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Consumption of FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) may trigger irritable bowel syndrome (IBS) symptoms.  Some research indicates that a diet low on FODMAPs may be beneficial (J Hum Nutr Diet 2011; 24: 487-95).  This study tried to assess whether a low FODMAPs diet which had been reported from a single center in Australia would be effective for IBS.

In this study, consecutive patients with IBS were divided into two groups.  39 received standard dietary advice based on UK National Institute for Health and Clinical Excellence (NICE) guidelines.  43 patients were placed on a low FODMAP dietary advice.  Patients were selected into each group consecutively (not randomized). This study reported a 76% satisfactory symptom response in the FODMAP group vs a 54% response in the control group (p=0.038).  Overall, 86% of FODMAP group had improved composite score compared with 49% of standard treatment group. Specific improvements were noted in bloating, abdominal pain, and flatulence.  The average age of the study population was 38 and 71% were females.  60% had diarrhea-predominant IBS.

NICE guidelines for IBS:

  • Healthy eating principles: regular eating, taking time to eat
  • Limit high fat foods and fizzy drinks
  • Limit insoluble fiber for diarrhea and gradually increase for constipation
  • Limit sugar-free sweets and foods with sorbitol
  • Limit fruit to 3 portions/day
  • Avoiding ‘resistant’ starch may be useful (eg. sweetcorn, green bananas, part-baked and reheated bread)
  • Addition of oats and linseeds may be helpful

Low FODMAP diet

  • Reduce high fructan foods (eg wheat and onion)
  • Reduction in high galactooligosaccharide foods (eg chickpeas, lentils)
  • Reduce high polyol foods and polyol-sweetened sources.  Replace with suitable fruits and vegetables
  • In patients with lactose malabsorption, reduce high lactose foods (eg milk, yoghurt) to smaller volumes or substitute lactose-free products
  • In those with fructose malabsorption, decrease excess fructose

Of course, reading the author’s description of a low FODMAP diet is confusing.  Translation:

Include more bananas, blueberries, lettuce, potatoes, gluten-free breads or cereals, rice, oats, hard cheeses, lactose-free milk, sugar, molasses, and artificial sweeteners that do not end in “ol.”

Avoid/eliminate apples, pears, canned fruits in natural juices, high-fructose corn syrup, cows’ milk (due to lactose), soft cheese, broccoli, cabbage, pasta, bread, baked goods from wheat/rye, mushrooms, and sweeteners like sorbitol or others that end in “ol.”

Since this diet has attracted more widespread attention, basic familiarity is important for all physicians who treat IBS.  A useful resource to explain this diet is the Wall Street Journal:

http://online.wsj.com/article/SB10001424052970204554204577023880581820726.html

This link has a good table illustrating the recommended dietary choices.

Whether FODMAPs will be superior to other dietary advice for IBS is still uncertain.  Though, given the limited number of effective treatments for IBS, this small study is a promising development.

Additional references:

  • -Clin Gastro & Hep 2009; 7: 706. n=17. 13 responded to very low carb diet (<20g/day)
  • -Clin Gastro & Hep 2008; 6: 765. Dietary triggers for IBS include fructose/fructans: honey, high fructose corn syrup, wheat, fruits.
  • -IBD 2006; 13: 91. Dietary guidelines for IBS.
  • -Clin Gastro Hepatol 2005; 10: 992-996. Obesity increases IBS symptoms; diet with low fat, high fruit/fiber have fewer symptoms
  • -Gut 2004; 53: 1459-1464. Food elimination based on IgG antibodies. Patients did better on diet with implicated foods than with control diet (diet was blinded/randomized).
  • -Am J Gastro 2011; 106: 508-514. randomized, double-blind trial showing efficacy of GFD for non-celiacs.  60% vs 32& placebo response.
  • -Nutr Clin Pract. 2011;26:294-299.  GFD for non-celiacs.
  • -Gastroenterology 2011; 141: 1941./Am J Gastro 2011; 106: 915.  Exercise improves IBS symptoms.

Holes in the fiber theory

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Since the 1970s, it has been accepted that diverticular disease is related to low fiber intake and the Western diet.  Problem is that this might not be right (Gastroenterology 2012; 142: 205-10).  In this observational cross-sectional study (n=2104), low dietary fiber was not associated with diverticulosis; just the opposite.  High fiber intake, after adjusting for other factors, had an adjusted prevalence ratio of 1.3.  Due to the nature of the study, there may be potential bias that would not be present with a prospective study, especially with regard to dietary recall.  An editorial in the same issue (pg 205-07) lists three other studies; two of these also could not demonstrate a protective effect of fiber.  In addition to these findings, this study did not find an association between fat, red meat, physical activity and diverticulosis.

Although these data throw a big question mark regarding the pathogenesis of diverticular disease, this does not mean you should throw away your fiber bars quite yet.  Although low fiber may not cause diverticular disease, several large prospective studies have been completed which convincing show an association with lower complications/hospitalizations among individuals with higher fiber intake.  In addition, increased fiber in the diet has been shown to lower cardiovascular complications.

Additional references:

  • -Br Med J 1971; 2: 450-54.  Seminal article on diverticular disease and association with Western countries with low fiber intake.
  • -Am J Clin Nutr 1994; 60: 757-64.  Prospective study showing benefits of fiber in preventing diverticular complications (n=47,888); RR=0.58 for developing symptomatic diverticulitis.
  • -BMJ 2011; 343: d4131.  EPIC study, n=47,033, showing benefit of fiber in reducing hospitalizations due to diverticular dz over 12yrs (0.59 RR)
  • -NEJM 1999; 340: 169. fiber does not decrease Colon Ca risk.
  • -NEJM 2000; 342: 1149 & 1159. fiber does not decrease risk of recurrent adenomas.
  • -Am J Clin Nutr 2000; 70: 1433-1438. Fiber lowers cholesterol & can decrease risk of heart attack by 15%.

Pain changes brain

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For several years, there has been research showing changes in PET scans and functional MRI in association with functional abdominal pain.  A recent article goes a step further showing microstructure  brain changes in patients with chronic pancreatitis (Gut 2011; 60: 1554-62).

This study examined 23 patients with pain due to chronic pancreatitis and 14 controls.  Using a 3T MR scanner, apparent diffusion coefficients (ADC) and ‘fractional anistotropy’ (FA) values were assessed in numerous parts throughout the brain.  This new technology, uses an MRI for diffusion tensor imaging which assesses changes in white and grey matter microstructure not evident with more conventional imaging.  Chronic pancreatitis patients had increased ADC in the amygdala, cingulate cortex, and prefrontal cortex.  In addition, FA values were reduced in the cingulate cortex and secondary sensory cortex.  These areas of the brain with these changes are known to be involved in the processing of visceral pain.  Microstructural changes were correlated to patients’ clinical pain scores.  Some of the changes can be influenced by other factors including alcohol usage, depression, Alzheimer’s or diabetes.

This study echoes findings from others that demonstrate structural reorganization of the brain in association with chronic pain.

Additional references:

  • -Gastroenterology 2010; 139: 1310. n=15 IBS women, 12 controls.  IBS pts have emotional modulation of neural responses to visceral stimuli (eg rectal stimulation) –based on functional MRI studies.
  • -Gastroenterology 2006; 130: 26 & 34. Functional MRI measured in response to barostat show increased sensitivity in pts c IBS. Also, altered 5-HT signaling in IBS-D & IBS-C.
  • -J Pediatr 2001; 139: 838-843. Pts c IBS, RAP more sensitive to visceral perception in rectum and stomach respectively.
  • -Gastroenterology 2005; 128: 1819. Brain response to visceral aversive conditioning –>similar cortical responses between actual and anticipated stimuli.
  • -Cereb Cortex 2010; 20: 1409-19.  Changes in brain anatomy associated with neuropathic pain following spinal cord injury.
  • -J Am Acad Child Adolesc Psychiatry 2010; 49: 173-83.  White matter microstructure changes in adolescents with major depression.