Author Archives: gutsandgrowth

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About gutsandgrowth

I am a pediatric gastroenterologist at GI Care for Kids (previously called CCDHC) in Atlanta, Georgia. The goal of my blog is to share some of my reading in my field more broadly. In addition, I wanted to provide my voice to a wide range of topics that often have inaccurate or incomplete information. Before starting this blog in 2011, I would tear out articles from journals and/or keep notes in a palm pilot. This blog helps provide an updated source of information that is easy to access and search, along with links to useful multimedia sources. I was born and raised in Chattanooga. After graduating from the University of Virginia, I attended Baylor College of Medicine. I completed residency and fellowship training at the University of Cincinnati at the Children’s Hospital Medical Center. I received funding from the National Institutes of Health for molecular biology research of the gastrointestinal tract. During my fellowship, I had the opportunity to work with some of the most amazing pediatric gastroenterologists and mentors. Some of these individuals included Mitchell Cohen, William Balistreri, James Heubi, Jorge Bezerra, Colin Rudolph, John Bucuvalas, and Michael Farrell. I am grateful for their teaching and their friendship. During my training with their help, I received a nationwide award for the best research by a GI fellow. I have authored numerous publications/presentations including original research, case reports, review articles, and textbook chapters on various pediatric gastrointestinal problems. In addition, I have been recognized by Atlanta Magazine as a "Top Doctor" in my field multiple times. Currently, I am the vice chair of the section of nutrition for the Georgia Chapter of the American Academy of Pediatrics. In addition, I am an adjunct Associate Clinical Professor of Pediatrics at Emory University School of Medicine. Other society memberships have included the North American Society for Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN), American Academy of Pediatrics, the Food Allergy Network, the American Gastroenterology Association, the American Association for the Study of Liver Diseases, and the Crohn’s and Colitis Foundation. As part of a national pediatric GI organization called NASPGHAN (and its affiliated website GIKids), I have helped develop educational materials on a wide-range of gastrointestinal and liver diseases which are used across the country. Also, I have been an invited speaker for national campaigns to improve the evaluation and treatment of gastroesophageal reflux disease, celiac disease, eosinophilic esophagitis, hepatitis C, and inflammatory bowel disease (IBD). Some information on these topics has been posted at my work website, www.gicareforkids.com, which has links to multiple other useful resources. I am fortunate to work at GI Care For Kids. Our group has 17 terrific physicians with a wide range of subspecialization, including liver diseases, feeding disorders, eosinophilic diseases, inflammatory bowel disease, cystic fibrosis, DiGeorge/22q, celiac disease, and motility disorders. Many of our physicians are recognized nationally for their achievements. Our group of physicians have worked closely together for many years. None of the physicians in our group have ever left to join other groups. I have also worked with the same nurse (Bernadette) since I moved to Atlanta in 1997. For many families, more practical matters about our office include the following: – 14 office/satellite locations – physicians who speak Spanish – cutting edge research – on-site nutritionists – on-site psychology support for abdominal pain and feeding disorders – participation in ImproveCareNow to better the outcomes for children with inflammatory bowel disease – office endoscopy suite (lower costs and easier scheduling) – office infusion center (lower costs and easier for families) – easy access to nursing advice (each physician has at least one nurse) I am married and have two sons (both adults). I like to read, walk/hike, bike, swim, and play tennis with my free time. I do not have any financial relationships with pharmaceutical companies or other financial relationships to disclose. I have helped enroll patients in industry-sponsored research studies.

Vitamin D, IBD, and Causality

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The importance of vitamin D has been noted in this blog previously (Common to be “D-ficient” ).  Now a study implicates vitamin D as a risk factor for developing inflammatory bowel disease, especially for Crohn’s disease (Gastroenterology 2012: 142: 482-89).  It is known that vitamin D influences innate immunity.  As such, it may play a role in the susceptibility to Crohn’s disease (CD) and Ulcerative colitis (UC).

This prospective study included 72,719 women (age 40-73) enrolled in the Nurses’ Health Study.  Research subjects completed an assessment of diet and lifestyle along with 25-hydroxy vitamin D [25(OH)D] levels.  The 25(OH)D levels were predicted; this prediction was based on a validated model which included vitamin D intake, sun exposure, race, and body mass index (J Natl Cancer Inst 2006; 98: 451-9).  This model was validated against directly measured 25(OH)D levels.

During nearly 1.5 million person-years of followup, 122 incident cases of CD and 123 cases of UC occurred.  The adjusted hazard ratio (HR) for the highest quartile of 25(OH)D was 0.54 for CD and 0.65 for UC compared to the lowest quartile.  Compared with a level less than 20, the highest quartile HR was 0.38 for CD and 0.57 for UC.

In addition, the authors identified a significant inverse association between dietary supplemental vitamin D and UC; an insignificant reduction in CD risk was noted with dietary intake.  Although it is difficult to determine causality, these data convincingly show that ‘healthy’ levels of vitamin D are associated with a lower risk of IBD.

Proven treatments for mitochondrial disorders

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The title is misleading; the most frequent treatments are unproven and not tailored well to the numerous disorders lumped under the term ‘mitochondrial disease.’  A nice review on what’s up-to-date with ‘mito’ disorders is in a recent NEJM (NEJM 2012; 366; 1132-41).

The first part of the review details the structure and function of the mitochondria including those pesky pathways for the production of ATP: glucose –>pyruvate through glycolysis.  In turn, pyruvate –>lactate –>acetyl coenzyme A (CoA).  Acetyl CoA generates NADH & flavin via tricarboxylic acid cycle.  Fatty acids and glutamine can also serve as substrates.  NADH & FADH2 fuel oxidative phosphorylation through five coupled mitochondria protein complexes.  Coenzyme Q10 helps transport electrons across the complexes.

Primary and secondary mitochodrial disorders.

  • 1000 genes encoding mitochondrial proteins have been identified in humans
  • 228 mutations of protein-encoding nuclear DNA (nDNA) and 13 mitoDNA (mtDNA) have been linked to human disorders
  • Secondary mito disorders include mito dysfunction due to viral infections and ‘off-target’ drug effects.  Specific drugs include valproic acid, statins, halothane, doxorubicin, and aspirin
  • Mito dysfunction is seen in a number of other diseases including Alzheimer’s, Parkinson’s, cancers, cardiac disease, diabetes, and obesity

Diagnosis:  Biopsy specimens from patients can be studied to assess cellular and mitochondrial physiology in comparison to healthy samples.  This review does not discuss molecular testing for mutations; however, an extensive list of genes associated with mitochondrial disorders (mtDNA & nDNA) is listed in Figure 2; a supplementary online appendix to the article explains these mutations in more depth.

Four potential treatments –all with a goal of increasing ATP production:

  • genetic therapy
  • small molecule treatment
  • metabolic manipulation
  • diet/exercise

Previous Cochrane review (2006) has not found evidence to support the use of any therapeutic interventions.  More recent trials have shown limited positive effects on clinical or biochemical end points but have not led to a New Drug Application with the FDA.  A few specific disorders that have treatments include the following:

  • Idebenone (a CoQ10 variant) for Friedreich’s ataxia & Leber’s hereditary optic neuropathy
  • Ketogenic diet for improving seizures in children with electron-transport defects
  • Cyclosporin A for secondary mito dysfunction in Ulrich’s congenital muscular dystrophy & Bethlem’s myopathy
  • Overview of current trials: http://www.clinicaltrials.gov/ct2/results?term-mitochondrial+disease

As one of my colleagues (LS) has said, making a diagnosis of a mitochondrial disorder is like getting the license plate of the bus that ran you over.  Until treatments improve, this is pretty much the case.

Additional reference:

  • -Mitochondrion 2011; 11: 679-85. Why are there no proven therapies for genetic mitochondrial diseases?
  • -J Pediatr 2011; 158: 802.  Developing liver toxicity with VPA is a contraindication to OLTx (even in the absence of documented mitochondrial dz).  Rx with carnitine and d/c VPA.  82% of 17 children died w/in 1 yr of OLTx.  POLG1 mutations are associated with Alpers syndrome.
  • -Pediatrics 2007; 120: 1326. Diagnosis and complications of mitochondrial disease.
  • -Pediatrics 2007; 119: 722. long-term outcome of mito dz –variable.
  • -NEJM 2003; 348: 2656. Review

GCSF for acute-on-chronic liver failure

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When chronic liver patients decompensate, there are a number of considerations, including concerns about spontaneous bacterial peritonitis, GI bleeding, and renal insufficiency.  A new study looks at another treatment to improve the outcome of these patients.  Consecutive patients with acute-on-chronic liver failure (ACLF) were randomly assigned to granulocyte colony-stimulating factor (GCSF) therapy (n=23), 5 μg/kg subcutaneously, or placebo (n=24) (Gastroenterology 2012; 142: 505-12).

The average age in this study was 40 years with the most common etiology being liver disease related to alcohol. The GCSF group, treated with 12 doses over 1 month, had higher leukocyte and platelet counts at 1 week.  More importantly, at day 60, the GCSF had higher survival, 70% vs 29%.  In addition, therapy was associated with lower Child-Turcotte-Pugh (CTP), model for end-stage liver disease (MELD) and sequential organ failure assessment (SOFA) scores.

GCSF has been shown to improve results in animal models and has been used in chronic liver disease.  The mechanism for improvement following GCSF is not clear.  One role could be in the prevention of sepsis due to increased neutrophils; patients on GCSF had less multi-organ failure which is often precipitated by sepsis.  Another factor could be an element of hepatic regeneration induced by GCSF.  It was noted that CD34 cell population increased in the liver tissue after 4 weeks of GCSF protocol.

Additional reference:

  • -Dig Liver Dis 2007; 39: 1071-76.  Use of GCSF for 5 days was not effective for acute -on-liver disease

Ivacaftor for Cystic Fibrosis

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Recent FDA approval of Ivacaftor (Kalydeco) is a promising step for a subset of patients with cystic fibrosis who have the G551D mutation.  This drug enhances the cystic fibrosis transmembrane regulator (CFTR) gene in these patients; only ~4% of CF patients or about 1200 patients in the US have this genetic defect.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm289633.htm

Additional references:

-NEJM 2011; 365: 1663. Effect of VX-770 -a CFTR potentiator -mild improvement in study of 167 pts. (Ivacaftor).
-NEJM 2010; 363: 1991. Effect of VX-770 -a CFTR potentiator -mild improvement in study of 39 adults.

Curing Hepatitis C without interferon

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In the face of increasing morbidity and mortality, better therapies for Hepatitis C have emerged which if applied broadly have an opportunity to change the outcome.  Recently, several articles have highlighted the possibility of treating individuals without interferon.

  • Lok et al. NEJM 2012; 366: 216-224
  • Chayam et al. Hepatology 2012; 55: 742-48
  • Zeuzem et al. Hepatology 2012; 55: 749-58.

In the Lok study, 21 null responders (patients who failed to achieve ≥2log10 decline in HCV RNA after ≥12 weeks of peginterferon and ribavirin) were divided into two groups. In Group A, 36% of patients were able to achieve SVR12 using a combination direct-acting antivirals (DAAs) with non-overlapping resistance profiles — without the use of interferon. Group A patients received BMS-790052 (an oral, first-in-class, NS5A replication complex inhibitor) and BMS-650032 (an oral NS3 protease inhibitor). In Group B which included peginterferon and ribavirin the SVR12 was 100%. There were no serious adverse events, or discontinuations.  The most common side effects were diarrhea, fatigue, headache, and nausea.

In the Chayam study, the combination of BMS-790052 (now called daclatasvir) and BMS-650032 (now called asunaprevir) examined this combination of DAAs in null HCV responders with genotype 1B (in Japan).  Ten patients received both drugs for 24 weeks. All nine who completed treatment had an SVR.  One patient stopped the medication due to elevated bilirubin and lymphopenia which occurred following an apparent infectious gastroenteritis.

In the Zeuzem study, tegobuvir (a nonnucleoside polymerase inhibitor) and GS 9256 (an NS3 serine protease inhibitor) with RBV (n=15), with PEG/RBV (n=15) and without ribavirin (n=16) were administered in three arms for 4 weeks, followed by dual therapy with PEG and RBV.  The primary end point was rapid virologic response (RVR), defined as HCV RNA <25 IU/mL.  Reductions (mean) for HCV RNA were -4.1 log10 IU/mL for dual therapy, -5.1 log10 IU/mL for triple therapy, and -5.7 log10 IU/mL for quadruple therapy.  RVR was noted in 7% of dual Rx, 38% of triple therapy, and 100% of quadruple therapy.

These studies indicate that even for difficult to treat HCV patients that new oral medications are on the horizon that will increase cure rates and may allow effective regimens that do not include interferon.  This is good news because until recently regimens with interferon were more likely to provoke adverse reactions that to guarantee a cure.

Links to relevant blog entries on HCV:

HCV now more deadly than HIV

The cost of progress in treating Hepatitis C

Looking for trouble

Treating reflux does not help asthma

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Studies in adults have looked at the use of PPIs for asthma and have not shown improvement (see references below).  Now a trial of lansoprazole suggests the same is true in children (JAMA 2012; 307: 373-81).  This study was a randomized double-blind placebo-controlled study of 306 children with a mean age of 11; the participants were recruited from 19 academic medical centers in the US.  149 children received lansoprazole and 157 received placebo.  The dose of lansoprazole was 15mg in patients weighing less than 30kg, and 30mg in those weighing more than 30kg.

Those treated with lansoprazole did no better than placebo with regard to symptoms and lung function.  The main outcome was the asthma control questionnaire (ACQ) score. The lansoprazole group had a mean change in this score of 0.2 units which was not a meaningful change. More precise measures of lung function including forced expiratory volume also did not differ.

In a subgroup of 115 patients who had esophageal pH studies, the prevalence of GER was 43%.  Yet, no treatment effect for lansoprazole was observed for any asthma outcome.

Not only did lansoprazole not help, the treatment group experienced more adverse effects, including respiratory infections (relative risk 1.3), sore throats (RR 1.3), and episodes of bronchitis (RR 2.2).  Though not statistically significant, the treatment group had more activity-related fractures, six compared to one in the placebo group.

This study took several years to complete (2007-2010).  I congratulate the authors, especially the third author Benjamin Gold, for this excellent work.

http://www.ccdhc.org/doctors/gold.html

Additional references:

The Medical Pendulum and Gastroesophageal Reflux

GERD and respiratory/ENT issues:

  • –Gastroenterology 2009; 137: 1844. Critical review of below NEJM article. ‘a subset of asthmatics will have objective detection of GERD without typical symptoms…work by Amer Lung Assn suggests that twice daily PPI will not be helpful’..however, ‘perhaps 3-6months of PPI may still be reasonable until we can accurately identify subgroups of pts who may respond.’ –Gary Falk, Cleveland Clinic
  • –NEJM 2009; 360: 1487, 1551. Use of PPIs (nexium 40mg bid) in poorly-controlled asthma with no symptoms of GER –did not help w asthma control & pH studies were not predictive of response. n=412 adults. 40% c abnl pH studies in each group (nexium vs. placebo).
  • –Clin Gastro & Hep 2007; 5: 1379. Review of ENT findings and reflux.
  • –Am J Gastro 2007; 102: 716. Poor specificity of ENT findings for diagnosis of laryngopharyngeal reflux.
  • –Aliment Pharm Ther 2007; 25: 385-92. meta-analysis. Rx c PPIs not more effective than placebo in resolving ENT symptoms presumed to be due to GER. Editorial suggests some patients may benefit, but better tools are needed to identify them.
  • –Gastroenterology 2010; 139: 1887. PPIs decreased postnasal drainage compared to placebo. n=75. (50% vs 5%) age discrepancy in patient populations.
  • –Clin Gastro & Hep 2010; 8: 741 (excellent editorial), 770 (article on rabeprazole improving heartburn Sx in pts with laryngitis), n=82. Editorial suggests 1-2month trial of BID PPI and if not effective, then little to offer. May change when studies looking at surgery (after impedance) outcomes.
  • –Gastroenterology 2010; 139: 754. 716 (editorial). Acoustic cough & reflux. Study recorded cough during pH measurement. n=71. ‘causality cannot be established until effective treatment’ available.

All bleeding stops

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Although the title is technically true, there are preferred ways to stop GI bleeding (Clinical Gastroenterol & Hepatol 2012; 10: 234-39).  This article summarizes the approach for nonvariceal upper GI bleeding.

Recommendations:

  • Endoscopy within 24 hours following ABCs/adequate resuscitation.  Use of a promotility agent prior to endoscopy may be helpful (in pediatric patients: erythromycin ~3 mg/kg)
  • Correct coagulopathy but do not delay endoscopy.
  • Consider nasogastric tube placement.
  • Do not use somatostatin or octreotide.
  • High-risk endoscopic stigmata should receive endoscopic hemostasis.  These lesions include actively spurting, oozing blood, nonbleeding visible vessel, and an adherent clot.
  • Pigmented dots or clean base ulcers do not require endoscopic hemostasis.
  • Endoscopic management includes clips, thermocoagulation, or sclerosant injection alone or in combination with epinephrine injection.  Epinephrine alone is not recommended for high risk lesions.
  • If a clot is found, attempts to remove it should be made to visualize underlying lesion.  If clot is adherent, intensive IV PPI therapy may be sufficient.  A typical dose would be esomeprazole 80mg bolus (for an adult) followed by 8 mg/hour for 72 hours.
  • Stable patients can be fed within 24 hours.
• IV PPI dose: 1mg/kg bolus followed by 0.1mg/kg/hr infusion.

Additional references:

  • -Ann Intern Med 2010; 152: 101-113. Consensus recommendations on UGI bleeding. Early endoscopy (<24hrs), data support attempts to dislodge clots, consider clips or thermocoagulation for Rx. Preendosocpy PPI can be helpful.
  • -Clin Gastro & Hep 2010; 8: 651. Article suggests second look only if difficult visualization on initial endoscopy (eg unable to remove clot).
  • -Ann Intern Med 2010; 152: 101-13. Systematic review of on UGI bleeding. Use IV PPI bolus, then continuous PPI if high risk stigmata after endoscopic Rx. Hospitalize for at least 72hrs.
  • -Gastroenterology 2010; 138: 1252. Review of upper GI bleeding.
  • -Clin Gastro & Hep 2009; 7: 828. Review of recurrent GI bleeding with negative initial evaluation.
  • -Gastroenterology 2008; 134: 1836. Frequent high dose oral PPI also effective with bleeding ulcers: prevacid 120mg x1, then 30mg q3hrs compared favorably with 90mg IV followed by 9mg/hr. n=66. intragastric pH >6 for 68% of study in IV PPI vs. 65% in oral PPI. 1st hour -more rapid onset with IV PPI.
  • -Gastroenterology 2007; 133: 1694. Position statement & review on obscure bleeding.
  • -Ann Intern Med 2003; 139: 843-857. Consensus on nonvariceal bleeding. Rec: lansoprazole 90mg bolus, then 6mg/hr x 72hrs or pantoprazole 80mg then 8mg/hr in high risk lesions
  • -Clin Gastro & Hep 2006; 4: 1459. Trends in non-variceal bleeding between 1993-2003 do NOT show improved outcomes with PPI. Overall mortality fairly steady @3.5%
  • -Clin Gastro & Hep 2005; 3: 959. WCE should be 2nd step in obscure bleed, p egd/col.
  • -NEJM 2004; 351: 488. case review.
  • -Gastroenterology 2002; 123: 17-23. IV erythromycin, 20 minutes before endoscopy, helped clear stomach (82% clear vs. 33% c placebo). Adults in this study received 250 mg. (thus, children probably need 3-4 mg/kg)
  • -Gastro Endosc 2002; 56: 174. erythromycin helpful-3mg/kg IV over 30 min
  • -Gastroenterology 2002; 123: 407-13. Endoscopic Rx of adherent clots c PUDz helpful (epinephrine injection, cold guillotining of clot, then coagulation cautery); Editorial on 632-635 emphasizes vigourous washing BUT NOT to remove adherent clot unless in centers with low rebleeding rates. Additionally, PPIs very helpful in preventing rebleeding in this situation (NEJM 1997; 336: 1054-8).
  • -NEJM 1999; 341: 38. Occult bleeding
  • -Gastroenterology 2000; 118: 197. AGA position statement.
  • -Gastro Endosc 2001; 53: 853 & 859. ASGE guidelines/algorithm for upper & lower GI bleeding

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).

Is a biopsy necessary in Celiac disease?

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Yes, at least for now.  That is the conclusion of a recent editorial (JPGN 2012; 54: 310-11) regarding Kurpa et al (JPGN 2012; 54: 387-91).  The article by Kurpa et al discusses the utility of the ESPGHAN criteria for diagnosis of celiac disease.  Among the patients with strongly positive TTG (> 100 units), 94% had a diagnosis of Celiac disease confirmed with biopsy; in addition, this result correlated well with positive endomysial antibody and with positive DQ2/8. In those with TTG (30-99 units), Celiac disease was diagnosed in 69% of children and 86% of adults.

Additional references:

  • -JPGN 2011;52: 554. May not need to biopsy if TTG >100 & responds to GFD
  • -Clin Gastro & Hep 2011; 9: 320. Nat’l hx in children with +serology. n=106. 33% developed villous atrophy c/in 2 yrs.
  • -Gastroenterology 2010; 139: 763. Mortality NOT worsened in undiagnosed celiac dz in Olmstead County, though bone density decreased. n=129 of 16,847. (?milder cases undiagnosed)
  • -J Pediatr 2010; 157: 373, 353. Even pts w/o villous atrophy & +serology, benefited from GFD with regard to GI symptoms and serological markers.
  • -JPGN 2010; 50: 397. n=250. +association
  • -Mohamed BM, et al. The Absence of a Mucosal Lesion on Standard Histological Examination Does Not Exclude Diagnosis of Celiac Disease.  Dig Dis Sci. 2007 May 9;
  • -JPGN 2009; 49: 52. deamidated gliadin -new, accurate biomarker for celiac. n=302.
  • -Gastroenterology 2009; 137: 88. Increased mortality in undiagnosed celiac –4-fold increase. Also, increasing prevalence ~4 fold in last 50 yrs.
  • -Gastroenterology 1967; 52: 893-897. Seminal article ‘gluten as culprit in celiac’
  • -Gastroenterology 2009; 136: 816. Mild enteropathy w Celiac –still needs GFD
  • -JPGN 2008; 47: 618. duodenal bulb always abnl, n=665
  • -Clin Gastro & Hep 2008; 6: 753. Incidence of autoimmune diseases less in those compliant with diet. n=178.
  • -Clinical Gastro & Hep 2008; 6: 426. Usefulness of deamidated gliadin antibodies (about as useful as TTG). In this study with n=216 celiac pts and 124 controls, TTG had sensitivity of 78% and 98% specificity.
  • -JPGN 2007; 45: 497. ~1% of UK kids c celiac; 90% missed. Avon study (ALSPAC). n=5470 screened from cohort of 13,971
  • -NEJM 2007; 357: 1731. Nice review which suggests the introduction of gluten 4-7 months in healthy infants. HLA DQ2 present in 90-95%; HLA DQ8 in remainder. Both also present in gen population, 30-40%. Scalloping of mucosal folds often seen. Can stain bx for CD3, CD8 receptors. More refractory cases stain only for CD3 (neg for CD8).

Stimulants for constipation

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Overall, 12-19% of Americans are affected by chronic constipation (Am J Gastroenterol 2004; 9: 750-59).  Despite the fact that constipation problems are widespread, the amount of useful research available to guide treatment is quite limited.  Two recent articles do offer some information:

  • Clin Gastroenterol Hepatol 2011; 9: 577-83.
  • Gut 2011; 60: 209-18.

The first reference examined the use of bisacodyl in a randomized, double-blind placebo-controlled study in the UK.  During the 4-week treatment period, patients receiving 10mg/day bisacodyl (n=247) had increased stools, from 1.1 per week to 5.2 per week.  Stool frequency also increased to 1.9 per week in the placebo group (n=121).  All secondary endpoints including constipation-associated symptoms (eg. quality of life indices, physical discomfort) improved significantly compared to placebo.  Average age of patients in this study was 55 years.  The main adverse effect was diarrhea –mainly during the 1st week of therapy.

A selected summary in Gastroenterology (Gastroenterology 2012; 142: 402-404) reviews the first study and makes several useful points:

  • Stimulant laxative use has been hindered by myths & misconceptions along with lack of supporting data.  Most recent studies do not support a role of stimulant use in causing enteric neuropathies, a cathartic colon or increasing the risk of colon cancer
  • Osmotic laxatives have been favored in guidelines but this has not been bolstered by supporting data
  • Only recently have two large randomized controlled studies proven the efficacy and safety of stimulant laxatives over the short-term
  • Long-term prospective studies are not available on the use of stimulant laxatives.

The second reference is a systematic review and meta-analysis of randomized controlled trials (RCTs) of pharmacologic therapy for chronic idiopathic constipation.  Twenty one eligible RCTs were identified: eight laxative studies (n=1411), seven prucalopride studies (n=2639), three lubiprostone (n=610), and three linactolide trials (n=1582).  All of these studies showed treatment was superior to placebo. These studies involved subjects who were mainly adults (>90% older than 16 years).

The results showed benefit from both stimulant and osmotic laxatives.  Overall, the osmotic and stimulant laxative studies showed higher response than the pharmacologic agents like prucalopride, lubiprostone, and linaclotide.  Nevertheless, between 50% and 85% of patients did not fulfill criteria for response to therapy.

Additional references:

  • -J Clin Gastro 2003; 36: 386-389.  Safety of stimulants for long-term use.
  • -Am J Gastro 2005; 100: 232-242.  Myths about constipation.  Stimulants have not been proven to cause a “cathartic colon”
  • -J Pediatr 2009; 154: 258.  Constipation associated w 3-fold increase in health utilization/cost.
  • -Clin Gastro  Hep 2009; 7: 20.  Review of complications assoc c constipation in adults.
  • -Pediatrics 2008; 121: e1334.  Behavioral therapy ineffective in treating childhood constipation.
  • -NEJM 2008; 358: 2332, 2344.  Use of methylnatrexone for opioid-induced constipation & trial of n=620 of prucalopride for severe constipation.  Both drugs were helpful.
  • -Gastroenterology 2004; 126: S33. Review of pediatric incontinence.
  • -J Pediatr 2004; 145: 253-4.  Prevalence of encopresis 15% /constipation 23% in obese children  (n=80).  Questionnaire administered to 80 consecutive obese children.
  • -Gastroenterology 2003; 125: 357.  Longterm constipation followup.  one-third with persistent constipation; 60% better at 1 year.  (tertiary referral group)
  • -Pediatrics 2004; 113: 1753 & e520.  When constipation & toileting difficulties both occur, constipation usually precedes toileting problems