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.

Thiopurines = Low Efficacy for Crohn’s

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The enthusiasm for thiopurine therapy for Crohn’s disease (CD) had already dropped a lot before two pivotal articles were recently published that confirmed the modest efficacy:

  • Cosnes J, et al. Gastroenterol 2013; 145: 758-65
  • Panes J, et al. Gastroenterol 2013; 145: 766-74
  • Gastroenterol 2013; 145: 714-16 (editorial)

The Cosnes study (from the GETAID group) reports an open-label randomized trial in 147 adult patients with newly diagnosed CD (from 2005–>2010) and risk factors for disabling disease who were recruited from 24 French centers.  Risk factors for disabling disease:

  • Age <40 years
  • Active perianal lesions
  • Corticosteroid use within 3 months of diagnosis

The characteristics and Paris classification are detailed in the paper’s Table 1. Patients were divided into early azathioprine or “conventional” treatment. Patient’s were followed for 3 years.  Azathioprine was dosed at 2.5 mg/kg/day.  The primary endpoint was the proportion of trimesters spent in corticosteroid-free and anti-tumor necrosis factor (TNF)-free remission.

Results:

  • 67% of azathioprine group achieved the primary endpoint compared with 56% in the conventional group.  The difference in achieving the primary endpoint was not statistically significant between the two groups.  Also, 41 (61%) of the conventional group were placed on azathioprine (mean time 11 months after enrollment).
  • The azathioprine group patients were more likely to not have perianal surgery (96%) compared with the conventional group patients (82%).
  • Adverse events included pancreatitis in 7 (10%) of azathioprine group compared with 1 (1%) of conventional group.  Elevated liver function tests were noted in 3 (4%) compared with 1 (1%) respectively.  No cases of neutropenia were noted in early azathioprine group.

The latter finding is interesting especially as the authors did not check thiopurine methyltransferase (TPMT) assays in a systematic manner.

Panes et al (for the AZTEC study group) performed a prospective double-blind trial of adult patients with a recent CD diagnosis (<8 weeks).  This study enrolled 131 patients from 31 centers in Spain.  68 received azathioprine (2.5 mg/kg/day) and 63 received placebo.

Results:

  • After 76 weeks of treatment, 30 (44.1%) azathioprine patients and 23 (36.5%) placebo-treated patients were in sustained corticosteroid-free remission (P= .48).
  • Relapse rates were lower in azathioprine group compared with placebo: 11.8% vs 30.2%.
  • Serious adverse effects were more frequent in the azathioprine group compared with placebo: 20.6% vs. 11.1% (P= .16).  In the azathioprine group, 7 (10%) developed pancreatitis, 16 (24%) developed leukopenia, 9 (13%) developed anemia, and 9 (13%) developed abnormal liver function tests.  Infections were more common in the placebo-treated group (24%) compared with 12% in the azathioprine group

The accompanying editorial should be mandatory reading for all health care providers who help manage inflammatory bowel disease (IBD) patients.  The editorial traces how thiopurines (azathioprine and 6-mercaptopurine) became an accepted cornerstone of IBD treatment.  In adults, after initial disappointing results from Summers et al (Gastroenterol 1979; 77: 847-69), efficacy was demonstrated in a seminal study by Present et al (NEJM 1980; 302: 981-87).  However, the authors note that a recent Cochrane review reported that “thiopurines are not effective for induction of remission, but are effective for maintenance of remission.”

The editorial notes that a high degree of efficacy was demonstrated from a small but influential pediatric study of 55 patients.  After a high remission rate (89%) for all patients, this study showed that among those in remission, “1 patient (4%) in the 6MP group had a relapse within 180 days of achieving remission, compared with 7 patients (28%) in the placebo group.”

The editorial draws the following conclusions from the current studies:

  • “The remaining indications for primary therapy with thiopurines are maintenance of steroid-induced remission/steroid sparing in patients with CD that is not newly diagnosed, and prevention of postoperative recurrence.”
  • “The strongest indication for thiopurines may be as part of combination therapy.”
  • “If TNF antagonists had a similar low cost as generic thiopurines, there would likely be little debate regarding an evolution toward treatment of CD with TNF antagonists, either as monotherapy or ideally as combination therapy.  Currently, the annual costs of TNF antagonists is 10-20 times that of thiopurines.”
  • Because of the difference in cost.., “the use of thiopurines in CD is likely to persist, despite the shrinking number of indications, the modest effect size, and the suboptimal safety profile.”

Related blog posts:

Pediatric Fatty Liver Disease -in the news

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An excerpt from The Wall Street Journal, Fatty Liver Disease: More Prevalent in Children (also covered by this blog previously: Increasing prevalence of pediatric NAFLD | gutsandgrowth):

A type of liver disease once thought to afflict primarily adult alcoholics appears to be rampant in children.

image

Some 1 in 10 children in the U.S., or more than 7 million, are thought to have the disease, according to recent studies.

The condition, in which the normally rust-colored organ becomes bloated and discolored by yellowish fat cells, has become so common in non-drinkers that it has been dubbed nonalcoholic fatty liver disease.

The disease’s prevalence is alarming doctors who worry about its progression to nonalcoholic steatohepatitis, or NASH, when the fatty liver becomes inflamed and cells are damaged. That leads to the end stage of cirrhosis, when the liver forms scar tissue and ultimately stops working.

Organ Damage

Some facts about nonalcoholic fatty liver disease:

  • About 10% of children in the U.S. are thought to have the condition.
  • Several factors likely contribute, including genetics, obesity, diet and insulin resistance.
  • It has no detectable symptoms.
  • Weight loss is the standard treatment for earlier stages of liver disease.

The condition’s rise is tied to the obesity epidemic—about 40% of obese children have it—but isn’t caused solely by being overweight. The disease appears to be growing among normal-weight children too, experts say.

And even though obesity rates are starting to level off, the prevalence of fatty liver disease continues to rise, they say.

It also has no symptoms, which means a person could have it for decades without knowing. 

Full link:

Fatty Liver Disease: More Prevalent in Children

Related blog entries:

Review of Button Batteries

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A recent open access article reviews button batteries and reiterates algorithm from poison control (noted in previous blog post: Button Battery Algorithm Link | gutsandgrowth).  This article has some excellent figures detailing the extent of the problem and has relevant pictures of radiographs and mucosal damage.

Here’s the reference:

International Journal of Pediatric Otorhinolaryngology 77 (2013) 1392–1399

Here’s the link:

http://authors.elsevier.com/offprints/PEDOT6686/7551db6b14c8aabfa827016d69367c08 …

Precise Identification of C difficile Transmission

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A recent study uncovers some useful information about C difficile by using whole-genome sequencing on 1250 separate C difficile cases (NEJM 2013; 369: 1195-205).

Between 2007-2011, the authors used genetic sequencing to determine the similarity of C difficile cases.  They were able to successfully sequence 1223 (98%) of the identified cases.  Of these isolates, 71% were from inpatients, 25% from outpatients, and 4% from patients at other hospitals. To determine similarity, they compared single-nucleotide variants (SNVs) between the isolates.  If isolates were related, it was anticipated that there would be 0 to 2 SNVs between transmitted isolates (95% prediction if less than 124 days apart).

This study was from the Oxford University Hospitals which provide all acute care and 90% of hospital services in Oxfordshire, United Kingdom (~600,000 population).

Results:

  • Only 35% of cases were genetically related to at least one previous case.
  • Of the 333 (35%) with ≤2 SNVs (consistent with transmission), and 126 (38%) had close hospital contact with another patient, 120 (36%) had no hospital or community contact with another patient.
  • 13% of cases were genetically related (≤2 SNVs) but without any evidence of plausible contact.
  • 45% of C difficile cases were genetically distinct (>10 SNVs from any previous case) from all previous cases.  This indicates that the source of the infection was not from another symptomatic case; most likely these cases were acquired from asymptomatic persons or an environmental reservoir.
  • There were reductions in the rate of C difficile infection during the 4-year study.  The authors relate this to changes in antibiotic prescribing behavior, specifically the restriction of fluoroquinolones and cephalosporins.

Aspects of the setting may limit some of the conclusions.  For example, the study was conducted in a nonoutbreak setting and the hospitals had established measures to limit transmission from symptomatic patients.  These included the following:

  • isolation of patients with suspected C difficile
  • daily hypochlorite disinfection
  • monitoring of compliance

These measures will decrease nosocomial transmission.  However, at the same time, some of the genetically distinct cases could still have been acquired in the hospital setting from asymptomatic hospital sources. While the authors concede a number of limitations, this study is quite helpful in understanding the role of hospitals in controlling C difficile infection.

Take-home message: the fact that only 35% of cases were related to other symptomatic cases indicates that hospital control measures by themselves will not be effective.  The most important aspect in reducing C difficile infection will be optimizing antibiotic usage.

Related news media: On the same day of that I read this study, there was an article in the Atlanta Journal Constitution (“PLEASE wash your hands … Please.”) which describes a first-hand account of C difficile infection which contributed to a slow recovery from intestinal surgery.  The article contained some questionable assertions including that C difficile was “impossible to eradicate” and that her immune system trapped C difficile in peritoneal abscesses which required drainage (these abscesses were more likely related to the initial operation). However, the article is a stark reminder that many hospital staff do not follow basic hand washing recommendations.  The article is really bad PR for the named hospital.

Related blog posts:

Reference for Mitochondrial Hepatopathies

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This morning’s blog discussed mitochondrial liver disease.

Another useful reference:

The Journal of Pediatrics Volume 163, Issue 4 , Pages 942-948, October 2013  Mitochondrial Hepatopathies: Advances in Genetics, Therapeutic Approaches, and Outcomes  Way Seah Lee, MD and Ronald J. Sokol, MD

Mitochondrial Liver Disease

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A recent review provides advice for the evaluation of the child with suspected mitochondrial liver disease (JPGN 2013; 57: 269-79).

Clinical presentations:

  • Acute in a child with no history of hepatic dysfunction
  • Chronic liver and CNS dysfunction
  • Onset of liver disease in patient with known CNS disorder

Suggested Tiered Diagnostic Evaluation: Table 1 provides extensive suggestions.

  • 1st tier: CMP, INR, AFP, CPK, Phos, CBC/d, ammonia, Lactate/pyruvate (preferably 1 hour after feeding), serum ketone bodies, serum acylcarnitine profile, carnitine profile, urine organic acids, serum amino acids, urine acylglycines and 2-ethylmalonic acid quantification, plasma thymidine (especially if intestinal dysmotility), quantitative serum methylmalonic acid, CSF analysis (lactate and pyruvate, amino acids, protein)
  • 2nd tier: genotyping for more common genes (eg. panel with POLG1, DGUOK, MPV17), other genetic tests based on tier 1 testing (see table for details)
  • 3rd tier: liver biopsy, skin biopsy, and muscle biopsy (see table for details)
  • 4th tier: additional genetic tests based on 1st three tiers

Table 2 describes potential evaluations in other organs.  For example, for brain, MRI, EEG and CSF.

Table 3 lists ~27 mutation/syndromes and clinical features.

The last three words from the conclusion of the publication are not supported by the review.  The authors state that this systematic approach “can aid in making a timely, accurate, and cost-effective diagnosis.”  While the authors do not provide estimates of the expense of these tests, they are probably very expensive, though less costly than a failed liver transplantation.

Bottomline: “Available technology to aid in diagnosis has improved substantially.  Nonetheless, diagnosis of suspected mitochondrial disease in children is complicated.”

Related blog post:

Proven treatments for mitochondrial disorders | gutsandgrowth

Challenging assumptions

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While this topic is not directly related to pediatrics or pediatric gastroenterology, I found a recent article regarding the treatment of back pain with steroids interesting.  This study challenges a treatment algorithm of using steroids to relieve inflammation triggering back pain.  The investigators showed that steroids per se are not more beneficial then saline in improving back pain.  Here is an excerpt from the NY Times, http://t.co/RF5O78odWe:

Questioning Steroid Shots for Back Pain

By NICHOLAS BAKALAR

Injecting steroids into the area around the spinal cord, known as an epidural, is the most commonly used treatment for back pain, but a new review of studies suggests that injecting any liquid, even plain saline solution, works just as well.

Researchers pooled the results of 43 studies involving more than 3,600 patients who got various kinds of injections for back pain. As they expected, they found some evidence that epidural steroid injections provided more relief than steroid injections into the muscles.

But the study, published online in Anesthesiology, also found that there was little difference between the amount of relief provided by steroidal and nonsteroidal epidural injections.

The researchers suggest that any liquid injected epidurally can help reduce inflammation, enhance blood flow to the nerves and clean out scar tissue.

Comment: There are inherently many limitations in pooling 43 studies and trying to reach a definitive conclusion.  Nevertheless, this study challenges some long-term treatment approaches.

Breakfast: a marker for heart-healthy habits

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Summary of study (Circulation 2013; 128: 337-343) from Epocrates (emphasis in blue by blog):

Study Question:
Is eating breakfast or not associated with risk for coronary heart disease (CHD) among men residing in the United States?
Methods:
Data for this analysis were from the Health Professionals Follow-up Study, an ongoing prospective study of male health professionals. Approximately 97% of participants were of white European descent. Eating habits, including breakfast eating, were assessed in 1992 in 26,902 American men, ages 45-82 years, who were free of cardiovascular disease and cancer. Participants were followed through mailed biennial questionnaires that ascertained medical history, lifestyle, and health-related behaviors. Cox proportional hazards models were used to estimate relative risks and 95% confidence intervals for CHD, adjusted for demographic, diet, lifestyle, and other CHD risk factors.
Results:
Participants who did not report eating breakfast were younger than those who did, and were more likely to be smokers, to work full-time, to be unmarried, to be less physically active, and to drink more alcohol. Men who reported that they ate late at night were more likely to smoke, to sleep <7 hours a night, or to have baseline hypertension compared with men who did not eat late at night. The late-night eating abstainers were more likely to be married and to work full-time, and ate on average one time less per day than the late-night eaters. The mean diet quality of the participants was high among participants, regardless of their breakfast or late-night eating status. During 16 years of follow-up, 1,527 incident CHD cases were diagnosed. Men who skipped breakfast had a 27% higher risk of CHD compared with men who did not (relative risk, 1.27; 95% confidence interval, 1.06-1.53). Compared with men who did not eat late at night, those who ate late at night had a 55% higher CHD risk (relative risk, 1.55; 95% confidence interval, 1.05-2.29). These associations were mediated by body mass index, hypertension, hypercholesterolemia, and diabetes mellitus. No association was observed between eating frequency (times per day) and risk of CHD.
Conclusions:
The investigators concluded that eating breakfast was associated with significantly lower CHD risk in this cohort of male health professionals.
Perspective:
These data suggest that time of meals is associated with other lifestyle behaviors. Adjustment for body mass index, hypercholesterolemia, hypertension, and diabetes [resulted in the relationship between breakfast (and late-night meals) and CHD no longer being significant.] Physicians may use this information to assist in the identification of those who may be at risk and need to improve lifestyle habits. However, it is unlikely that eating breakfast by itself would confer significant protection against heart disease.

Full text available at http://circ.ahajournals.org/content/128/4/337

Related blog post:

Skipping breakfast –boomerang effect for obesity | gutsandgrowth

Fizzy Drinks and Sugar Intake

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A report on the “Effect of Carbonation on Brain Processing of Sweet Stimuli in Humans” (Gastroenterology 2013; 145: 537-39) highlights how the addition of carbonation could lead to increased consumption of sugar products.  The authors examined neural activity in response to carbonated beverage consumption with the aid of functional MRI.  An easy-to-read analysis of this study can be found at this link:  Carbonation affects brain processing of sweet stimuli : Family …

An excerpt:

Carbonation produces a decrease in the neural processing of sweetness-related signals, particularly those from sucrose, a small functional neuroimaging study shows.

The findings, which suggest that the combination of CO2 and sucrose might increase consumption of sucrose, could have implications for dietary interventions designed to regulate caloric intake, according to Dr. Francesco Di Salle of Salerno (Italy) University and his colleagues.

To assess the interference between CO2 and perception of sweetness, as well as the differential effects of CO2 on sucrose and aspartame-acesulfame, (As-Ac, an artificial sweetener combination commonly used in diet beverages), the investigators performed two functional magnetic resonance imaging (fMRI) experiments to evaluate changes in regional brain activity…

The first experiment, performed in nine volunteers, analyzed the effect of carbonation in four sweet Sprite-based solutions, including one carbonated and sweetened with sucrose, one noncarbonated and sweetened with sucrose, one carbonated and sweetened with As-Ac, and one noncarbonated and sweetened with As-Ac. The second experiment evaluated the spatial location of the strongest neural effects of sour taste and CO2 within the insular cortex of eight subjects.

On fMRI, the presence of carbonation in sweet solutions “independently of the sweetening agent, reduced neural activity in the anterior insula (AI), orbitofrontal cortex (OFC), and posterior pons … the effect of carbonation on sucrose was much higher than on perception of As-Ac,” they noted, explaining that “at the perceptual level … carbonation reduced the perception of sweetness and the differences between the sensory profiles of sucrose and As-Ac.”

This effect may increase sucrose intake, but is also favorable to diet beverage formulations being perceived as similar to regular beverage formulations, the investigators reported…

It may be that taste and CO2-related information influence food choices and intake through integration in the tractus solitarius with input from the gastrointestinal tract, they suggested, explaining that “the reduced discrimination between sucrose and As-Ac induced by CO2 would promote the consumptions of low-calorie beverages and would converge with CO2-induced gastric distention in limiting caloric intake.”

This study was supported in part by the Coca-Cola Company. One author, Dr. Rosario Cuomo, was sponsored by the Coca-Cola Company. The remaining authors reported having no disclosures.

Related blog posts:

 

Food Safety: Confusion with Use-by and Sell-by Dates

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From the LA Times, http://t.co/9Tt2C4EOPf, an except:

Sell by, use by, best by. Most consumers use the dates stamped on foods to decide what to toss out — and they are often discarding food that’s good to eat, according to a report…

Those dates are manufacturers’ suggestions for when an item is at its peak, or efforts to help stores manage their inventory, and not indications of food safety, the report from the Natural Resources Defense Council and the Harvard Food Law and Policy Clinic says.

More than 90% of Americans say they use date stamps to decide whether to discard food, the report notes.

“I don’t know of any data that consuming a product beyond the date has caused illness,” said Ted Labuza, a professor of food science and engineering at the University of Minnesota who has studied shelf life for decades.

There are several ways that products can be contaminated and can cause illness, including poor handling on farms or in factories and stores, and improper treatment by consumers.

Wednesday’s report follows one about food waste from the NRDC showing that 40% of our food is discarded, resulting in losses of $165 billion a year….People are throwing away food because they believe it’s not safe, she said. And they also may be eating unsafe food because they put too much trust in those date labels.

While there is no research of the exact role those dates play in the 160 billion pounds of annual food waste in the U.S., estimates based on British studies suggest it could be $275 to $455 worth of food per household per year, the report said.

Business suffers, too, as millions of dollars of food is discarded before it’s sold based on those dates, the report said. There is a “dizzying” array of state laws regarding date stamps on food, including no regulations in nine states, Gunders said….

The NRDC report calls for three major changes:

—Putting sell-by dates — meant for businesses — into code so they are invisible to consumers.

—Establishing a uniform date labeling system that differentiates dates for safety from those for quality.

—Increasing the use of safe-handling instructions.

… Among the possibilities being considered is a two-date system that’s clearly marked for the retailer and the consumer.

U.S. Rep. Nita Lowey (D-N.Y.) said she planned to reintroduce the Freshness Disclosure Act, which she had previously proposed, to establish a consistent food-dating system. She said in a statement Wednesday that consumers now were “left in the lurch, forced to decipher the differences between ‘sell-by’ and ‘best if used by,’ and too often food is either thrown out prematurely, or families wind up consuming dangerous or spoiled food. The status quo is really quite absurd.”