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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.

Interpreting industry-funded studies

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Yesterdays’ blog entry discussed how patient selection affects the external validity of studies (According to the study which you would never qualify for…).  Today, we look at how physicians interpret studies based on a relevant article (NEJM 2012; 367: 1119-27).

In a randomized study, 269 respondents (from a pool of 503 board-certified internists)were presented with a series of three hypothetical abstracts (27 in all) and were queried about their confidence in the results.  The presumption was that “the methodologic rigor of a trial, not its funding disclosure, should be a primary determinant of its credibility.”  One of the questions that was asked was the following: “Do you think that pharmaceutical company funding is likely to influence the outcome of scientific studies…in favor of the drug in question?”

Results:

  • Physicians were more likely to identify high-rigor trials as rigorous (odds ratio, 3.95); in turn, physicians were more willing to prescribe drugs reported in high-rigor trials.
  • Physicians were less likely to view a trial as having a high level of rigor if funding source was a pharmaceutical company (odds ratio 0.63).

Both the article and the editorial (pages 1152-53) indicate a good deal of concern that industry-funded studies are “downgraded” as compared to NIH-funded studies.  Though, is it really surprising?  There have been well-publicized controversies with industry-funded research:

  • Withholding of critical data and negative results (eg. rofecoxib Alzheimer studies)
  • Ghostwritten articles (eg. promotion of gabapentin)

In addition, the perception is that industry-sponsored studies are more prone to bias due to a financial stake in the outcome.

Due to these previous problems, gaining full confidence in industry-funded studies could take a long time.  As stated by Friedrich Nietzsche:

“I’m not upset that you lied to me, I’m upset that from now on I can’t believe you”

A much more expansive discussion on the issue of industry-funded studies can be found at the following link (thanks to Jeff Lewis for this):

http://www.guardian.co.uk/business/2012/sep/21/drugs-industry-scandal-ben-goldacre

I think if the authors of the study and the NEJM editor read this link they might change their tune from “Believe the data” to “Missing data poisons the well for everybody.”  A particularly insightful example in the link includes how the industry withheld negative data on paroxetine in pediatric patients for commercial reasons.

You really should read the attached link to understand why skepticism of industry-funded studies is justified.

Additional references:

  • -Am Heart J 2012; 164: 186-93.  Rofecoxib: under-reporting of cardiovascular events in Alzheimer studies.
  • -JAMA 2008; 299: 1800-12.  Promotion of rofecoxib with guest authorship.
  • -Ann Intern Med 2006; 145: 284-93.  Promotion of gabapentin.

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

Portopulmonary Hypertension

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A useful update: Liver Transpl 2012; 18: 881-91.

Definition: When pulmonary artery hypertension (PAH), mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, occurs in the setting of of portal hypertension and no alternative cause of the PAH exists (eg, collagen vascular disease, congenital heart disease, or certain drugs), it is known as portopulmonary hypertension (POPH).

  • Mild POPH: MPAP < 35 mm Hg
  • Moderate POPH: MPAP ≥ 35 mm Hg & <45 mm Hg
  • Severe POPH:  MPAP ≥ 45 mm Hg

Patients with moderate POPH and severe POPH, if not improved with medical therapy, have high mortality rates and these are generally considered contraindications for liver transplantation.

POPH is associated with high pulmonary vascular resistance ≥ 240 dyn(sec)(cm¯5 ) and with  pulmonary wedge pressure < 15 mm Hg.

Difference between POPH and hepatopulmonary syndrome:

From the following link: Portopulmonary hypertension and hepatopulmonary syndrome “Abnormal intrapulmonary vascular dilatation, the hallmark of hepatopulmonary syndrome, can cause profound hypoxaemia that can be very difficult to treat. By contrast, portopulmonary hypertension results from excessive pulmonary vasoconstriction and vascular remodelling that eventually leads to right-heart failure.”

Pathophysiology: unclear.  Most but not all cases are associated with cirrhosis.

Frequency: 6-8% of cirrhotic patients.

Diagnosis: while dyspnea may be present, routine screening with echocardiography is part of liver transplantation evaluation.

Prognosis: retrospective study from Mayo clinic (n=74, 1994-2007) noted 5-hr survival of 14% for untreated patients, 45% treated with vasodilators, and 67% who underwent liver transplantation.

Treatments: Table 6 in article.

  • PDE5 Inhibitors (oral): Tadalfil, Sildenafil
  • Endothelin Receptor antagonists (oral): Ambrisentan, Bosentan
  • Prostacyclins (IV): EPO, Trepostinil
  • Prostacyclins (Inhalation): Iloprost , Tyvaso
  • Liver transplantation: 79 patients with LT for POPH 2007-2011

Beta-blockers may have adverse effect.

Noncirrhotic POPH: Worldwide, infection with Schistosoma mansion is likely the most common reason; severe disease may occur in 10% of the 200 million people who are infected.  When noncirrhotic POPH occurs without cirrhosis or Schistosoma mansion, this requires a high degree of clinical suspicion as well as awareness of this disorder.

Additional references:

**Hepatology 2008; 48: 13, 196. POPH: pulmonary arterial htn associated w portal htn:

  • -resting pulm artery pressure > 25mmHg
  • -pulm capillary wedge pressure <15mmHg
  • -pulm vascular resistance >240dynes(s)(cm to -5)
  • -measure c trans thoracic echocardiography
  • -female sex, autoimmune dz were risk factors
  • -avg age associated was 53yrs whereas idiopathic PAH avg age is 36yrs

**NEJM 2008; 358: 2378. Review. Hepatopulmonary Syndrome – New England Journal of Medicine  Hepatopulmonary syndrome, a separate but related condition characterized by hypoxemic respiratory insufficiency due to increased intrapulmonary shunting
**Liver Tx 2007; 13: 680. Hepatopulmonary syndrome experience at CHOA

Sirolimus and transplant mortality

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A surprise to me was a recent study which identified sirolimus as a risk factor for increased mortality and graft loss in HCV-positive liver transplant patients (Liver Transpl 2012; 18: 1029-36, commentary 1003-1004).

Sirolimus mechanism of action: inhibits mammalian target of rapamycin (mTOR) which is a phosphoinositide 3-kinase which affects cell proliferation, angiogenesis, and immune function.  For transplant patients, sirolimus blocks interleukin-2-induced stimulation of T lymphocytes.

Black box warnings for sirolimus: FDA warns that sirolimus can increase risk of hepatic artery thrombosis, graft loss, and death with de novo sirolimus-based treatment.

What’s different about HCV transplants? HCV reinfection occurs immediately during liver transplantation and “unlike all other indications, graft survival and patient survival have not improved” (between 1991-2001).  HCV transplant survival continues to be 10-15% lower than non-HCV transplant survival.  Immunosuppression allows more rapid progression of HCV; this allows ~20% of recipients to develop cirrhosis within 5 years of transplantation.

The authors of the study analyzed 26,414 patients (12,589 with hepatitis C virus) from the Scientific Registry of Transplant Recipients (SRTR) database; all recipients were >18 years.  Among this database, 1685 liver transplant recipients received sirolimus; in the majority, it was administered along with a calcineurin inhibitor.  A multivariate analysis of patient mortality showed the following were risk factors for increased mortality:

  • recipient age
  • donor age
  • hepatocellular carcinoma
  • diabetes
  • creatinine

Tacrolimus-based immunosuppression was associated with superior survival. Whereas, the use of sirolimus was associated with increased mortality in patients with HCV, even when adjusting for confounding variables (eg. renal function, and cancer).  In patients who received sirolimus at baseline, the adjusted HR for mortality at 3 years was 1.29 (p=0.0053).  In non-HCV patients, the adjusted HR for the sirolimus group was 1.09  (p=0.40).  Also, duration of exposure to sirolimus was directly correlated with worse outcomes.  Why?

This is not clear.  It is recognized that the study has several limitations.  Due to the nature of the SRTR database, there is not adequate information on how sirolimus may have affected viral load, histologic progression or causes of death.  Despite attempts to control for risk factors, it is possible that the sirolimus group did have higher disease severity.  Nevertheless, sirolimus effects on multiple cellular functions may have deleterious consequences in certain subsets of patients.

GI & Nutrition Problems in Rett Syndrome

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A nationwide survey of 983 patients with Rett syndrome identifies a high prevalence of GI and nutritional problems (Motil KJ et al. JPGN 2012; 55: 292-98).

Parents from 983 female patients with Rett syndrome responded to the study questionnaire; this was a 59% response rate from the 1666 families in the North American Rett Database.  Patients included those who fulfilled clinical criteria for diagnosis or who had MECP2 gene (methyl-CpG-binding-protein).

Prevalence of GI problems were listed in article’s Table 2 and included the following:

  • Gastrointestinal problems 92%
  • Feeding problems 81%
  • Constipation 80%
  • Poor weight gain 38%
  • Gastroesophageal reflux 39%

Z-scores for height-for-age, weight-for-age, and BMI are presented for ages 0-40 (see Table 1) -these are all significantly lower than age-matched healthy children.

Important findings:

  • Surgical interventions were common: 11% had fundoplication, 28% gastrostomy, 3% and cholecystectomy
  • Many gastrointestinal symptoms improved with age.  However, short stature, gastrostomy tube, and bone health issues were more common in older patients.
  • Bone fractures are 3- to 4-fold higher than in healthy children

Addtional references:

  • -J Pediatr 2010; 156: 135.  Longevity in Rett syndrome –about 1/2 survive to age 40.
  • -Ann Neurol 2010; 68: 944-50.  Rett diagnostic criteria
  • -JPGN 2007; 45: 582-90.  Growth/feeding issues in Rett syndrome

Lessons on Stature from Asthma Treated with Steroids

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A study of the effects of budesonide for the treatment of asthma should be carefully considered by those of us who treat eosinophilic esophagitis with “topical” steroids; also, this study has applicability to Crohn’s disease patients receiving chronic glucocorticoids.  Mean adult height was 1.2 cm lower in the budesonide-treated asthmatics than in the placebo group (NEJM 2012; 367: 904-12).

This was the main finding at the end of the Childhood Asthma Management Program (CAMP) clinical trial.  This report examined 943 of 1041 (90.6%) participants  who had received either 0.4 mg of budesonide, 16 mg of nedocromil or placebo daily for 4 to 6 years.  Treatment with these agents began between ages 5 to 13.

The reduction in adult height was to similar in adulthood as it was after 2 years of treatment; there was not catch up growth.  With regard to the adult measurements, 96.8% of the adult women were at least 18 years and the adult men were at least 20 years of age.

Other findings:

  • Larger daily dose: each microgram per kilogram was associated with -0.1 cm drop
  • Other risk groups: Hispanic ethnic group, female sex, greater body mass index, longer duration of asthma, and higher Tanner stage at initiation

The authors note that 0.2 mg dosage of budesonide has been shown to be effective to control asthma symptoms in children 5-11 years.  The “lowest effective dose” should be used; “the effect on adult height must be balance against the large and well-established benefit of these drugs in controlling persistent asthma.”

Related links:

Looking better or feeling better in EoE?

Guidelines for Eosinophilic Esophagitis

Choosing topical therapy for EoE

The undiscovered country

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.

Gluten avoidance -quite common

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In a pediatric Boston cohort of 579 patients presenting for celiac evaluation but no previous diagnosis, 7.4% had previous gluten avoidance (J Pediatr 2012; 161: 471-5). In this cohort, the mean age at presentation was 8.7 years.

Independent predictors of gluten avoidance and the odds ratio (OR) included the following:

  • Irritability OR 3.2
  • Family history of celiac OR 2.2
  • Diarrhea OR 2.5
  • Pervasive developmental disorder OR 5.3

From my perspective, many families and sometimes referring physicians are convinced that their child has celiac disease before subspecialty evaluation. While a gluten-free diet may reduce some gastrointestinal symptoms even in the absence of celiac disease, it is probably helpful for families to complete diagnostic testing and to obtain dietary counseling prior to implementing a gluten-free diet.

Previous related blog entries:

“There is More to Life Than Death”

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This commentary helps explain some of the reasons for recent recommendations to drop PSA screening for prostate cancer and to stop mammograms for women ages 40 to 49 while at the same time showing how these decisions are not in fact ‘no-brainers.’ (NEJM 2012; 987-89).

With both decisions, the U.S. preventive services task force (USPSTF) focused on mortality data.  For prostate cancer, the pivotal trial was the U.S. Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) that showed no difference in mortality between a PSA-screened group and a control group.  Besides detailing a few limitations of the study, the authors note that separate epidemiologic data show a 75% decrease in men presenting with advanced prostate cancer since the introduction of PSA screening. Furthermore, a European study showed advanced cancers were 40% more likely in the control group as well.

Patients with more advanced prostate cancer are prone to bone pain and urinary obstruction; whereas, patients who undergo unnecessary surgery (b/c prostate cancer was not going to kill them) may develop incontinence and impotence.

For breast cancer, similarly, identifying smaller breast cancers may allow more conservative therapy. This has to be weighed against increased anxiety, discomfort, and biopsies for those with false-positive mammograms.

Conclusions:

“Basing decisions on the outcome of death ignores vital dimensions of life that are not easily quantified…It is neither ignorant nor irrational to question the wisdom of expert recommendations that are sweeping and generic.  There is more to life than death.”

On a side note, one of the authors (Jerome Groopman) has written several books.  My favorite of his: “The Measure of Our Days.”

Why call it botulinum?

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“Clostridium botulinum is a neurotoxigenic, anaerobic, gram-positive, spore-forming bacillus named after an outbreak of sausage poisoning in the late 1700s.” Botulus is latin for sausage.  Hence the name.

This and other facts about foodborne botulism are presented in a clinical problem-solving case (NEJM 2012; 367: 938-43).

Key information:

  • For foodborne botulism to develop neurotoxins must be absorbed from the gastrointestinal tract.
  • Fewer than 35 cases are reported annually in U.S.
  • Initial GI symptoms typically occur 12-72 hours after spore ingestion and can include constipation, cramps, vomiting, and less commonly diarrhea.
  • Biggest risk factors: home-canned foods or injecting black-tar heroin
  • Prolonged ventilatory support and antitoxin are cornerstones of treatment
  • Typical features: “Dozen D’s” dry mouth, diploplia, dilated pupils, droopy eyelids, droopy face, diminished gag reflex, dysphagia, dysphonia, difficulty lifting head, descending paralysis, and dyspnea.

To avoid being the next case report, if you like to can your own food, follow the guidelines in the link below:

National Center for Home Food Preservation | USDA Publications