Websites recommended by GI families

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Some useful websites that I recommend have been identified by patient’s or their families. They include the following:

As an unrelated aside, a recent commercial might be of interest to anyone who enjoys a little ‘potty humor:’  Kmart’s ‘Ship My Pants’ Commercial [HD] – YouTube

Related blog post:

Oley: Check it out | gutsandgrowth

Paris Classification of Pediatric Crohn’s Disease

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A recent study described the phenotypic results of a prospective, web-based registry of new-onset pediatric inflammatory bowel disease (IBD) in 17 European countries and Israel (Inflamm Bowel Dis 2013; 19: 378-85).

The EUROKIDS Registry included 582 pediatric Crohn’s Disease (CD) patients classified according to Paris classification:

  • 16% with L1 involvement of the terminal ileum only
  • 27% with L2 colonic involvement only (more common in younger children)
  • 53% with L3 involvement of the ileum and colon
  • 4% with L4 isolated upper GI disease.  Upper tract disease can be further subdivided into L4A esophagogastric disease and L4B jejunal/proximal ileal disease.
  • *Upper GI disease can coexist with L1, L2 or L3.  In this study, 34 (6%) had esophageal involvement, 102 (18%) had gastric involvement, and 100 (17%) had duodenal involvement.
  • In this study, 165 of the 507 patients did not undergo small bowel imaging. Of those who did, 64% had small bowel follow-through, 38% had MRI, 6% CT, and 5% video capsule.

Other findings:

  • Perianal disease (e.g.. fistula or abscess) noted in 9% at diagnosis.
  • Granulomas were found in 43% of patients who had biopsies from at least 10 segments of the GI tract
  • 82% of CD patients had nonstricturing, nonpenetrating disease (B1), 12% had stricturing disease (B2) and 5% had penetrating disease (B3).  2% had both stricturing and penetrating disease.
  • Extraintestinal manifestations were seen in 20% of the study population.
  • The authors estimated that the diagnostic yield of upper endoscopy  in the workup for pediatric IBD was  7.5% and for intubation of the ileum/ileoscopy 13%.

Study limitations included a selection bias of centers and pediatric gastroenterologists with a special interest in IBD.  Also, in this registry, older adolescents are underrepresented. In about one-third of the centers, patients older than 15 years are seen primarily by adult gastroenterologists.

Don’t Fix What’s Not Broken

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A recent study provides information about elective switching from infliximab (IFX) to adalimumab (ADA) in stable Crohn’s disease (CD) (Inflamm Bowel Dis 2013; 19: 761-66).  As a practical matter, patients and families inquire about switching therapy due to potential convenience and flexibility.  Thus far, there is little data to guide clinicians.  As such, the authors explored this question by designing an open-label study which would allow enrollment of any patients who had stable disease for >6 months (Harvey-Bradshaw Index ≤ 8) on IFX therapy.

In total, 29 patients with CD were enrolled with an average age of 39.  Twelve had previous resections.

Key results:

  • 21 patients (72%) were able to remain on ADA at 54 weeks.  8 patients discontinued ADA due to disease activity (n=3), side effects (n=4), or other symptoms (n=1).
  • 4 patients were restarted on IFX therapy; 1 required dose intensification.
  • At 54 weeks, 13 patients indicated a preference for IFX due to efficacy (n=9) or safety profile (n=4).  12 patients indicated a preference for ADA.  4 patients had no preference.

The authors state that a recommendation to avoid elective switching.  In their study, 28% were not able to be maintained on ADA therapy, more patients preferred IFX after experiencing both therapies, and switching back to IFX has been associated (in some) with reduced efficacy.  The main concern with an elective switch is the potential loss of response with very limited therapeutic alternatives.

The authors note that their study showed better results with an elective change than a previous study (the SWITCH trial, n=73).  In the SWITCH trial, “elective switch from IFX to ADA in patients with stable CD led to 47% of patients requiring dose intensification or interruption of treatment” in the ADA arm compared with 16% of patients who continued IFX therapy.  (Adalimumab in Crohn’s Disease Controlled by Infliximab)

The better outcomes in the current trial may have been due to selection of patients with milder disease and the more frequent use of concomitant immunosuppression.  In the current trial, 52% had concomitant immunosuppression (48% thiopurine, 4% methotrexate); in contrast, only 17% received concomitant immunosuppression in the SWITCH trial.  Another important difference was that the patients in the current trial received 160-80 loading doses rather than 80-40 induction.  Also, the trial designs were different.  The current trial enrolled patients without randomization; in contrast, the SWITCH trial randomized some patients to continue IFX and others to change to ADA therapy.

Related reference:

  • -Gut 2012; 61: 229-34. SWITCH trial.

Related blog references:

Food Marketing Detectable on Functional MRI

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The applications of functional magnetic resonance imaging (MRI) are burgeoning.  One recent usage has been on the effect of food logos on brain activation in obese and healthy children (J Pediatr 2013; 162: 759-64 & editorial 672-73).

After a pilot validation study to select food and nonfood logos, the authors recruited 10 healthy children with mean body mass index (BMI) at 50th percentile and 10 obese children with mean BMI at the ~98 percentile.  After completing reports on measures of self-control, the children underwent functional MRI while viewing food and nonfood logos.

The key findings were that healthy weight children, when viewing food logos, demonstrated greater activation in brain regions associated with cognitive control/self-control including Brodmann’s area 10 and the inferior frontal gyrus bilaterally.  Obese children showed greater activation in ‘reward’ regions of the brain when shown food logos.

While these studies should be considered preliminary due to the small sample size, they are intriguing nevertheless.  The editorial takes these findings and places them into context.

  • Children view ~6000 commercials annually; the majority feature calorie-dense and nutrient poor foods
  • “Any food can be marketed in any way, to any age group, and even the most vulnerable demographic groups can be targeted.”
  • “It is tempting to suggest interventions…to help resist marketed foods.”  However, the author notes that this strategy will fail due to increases in the “toxic influence” of advertising.
  • “Food brands are already commonplace in …sporting facilities, schools..in online advergaming..and in social media.”
  • “Targeted advertising has been related to greater consumption of high-calorie foods (eg. fast foods) by African-American and Hispanic children”
  • Policy initiatives “to turn back the tide of childhood obesity” are needed; studies that show a direct impact on children’s brains may be persuasive in compelling change.  Without these changes, companies will continue doing neuroscience research and will exploit their findings.

Bottom-line:  If one uses an analogy to tobacco, it is not quite 1964 for the food industry.

“In 1964 the Surgeon General of the U.S. (the chief doctor for the country) wrote a report about the dangers of cigarette smoking. He said that the nicotine and tar in cigarettes cause lung cancer. In 1965 the Congress of the U.S. passed the Cigarette Labelling and Advertising Act. It said that every cigarette pack must have a warning label on its side stating ‘Cigarettes may be hazardous to your health.'” History of Tobacco – Health & Literacy Special Collection

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Trouble Sleeping and Gastroesophageal Reflux

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Determining whether reflux is causing an infant to have trouble sleeping is quite difficult as a practical matter.  A recent retrospective study adds information to this topic but opens up a can of worms (JPGN 2013; 56: 431-35).

The main problem is that clinical reflux occurs in the majority of infants and that sleeping problems are ubiquitous as well.  This leaves the door open to testing a lot of infants. At the  same time, effective therapeutic options are limited.  So, identifying that reflux is causing trouble sleeping, when feasible, may be akin to getting the license plate of the truck that ran you over.

In this retrospective study (2008-2010) of 24 infants with a median age of 5 months, 18 were receiving acid-suppressing medications prior to evaluation.  Determination that reflux was causally associated with awakenings and arousals was determined with symptom association probabilities (SAP) based on 2-minute measurement intervals with multichannel intraluminal impedance/pH monitoring/simultaneous polysomnography; SAP was considered significant if ≥95%.

Findings: Seven patients had a positive SAP for arousals due to GER (5 exclusively related to non-acid GER).  Nine patients had a positive SAP for awakenings due to GER (4 exclusively related to non-acid GER).

There were several limitations of the study.  Besides the small size, the main limitation of this retrospective study was a selection bias.  Other limitations included a large number of patients with comorbid conditions and the coincident usage of acid-suppressing medications.  19 of 24 patients had one or more significant comorbid conditions: laryngomalacia in 10, prematurity in 5, genetic syndromes in 3, esophageal atresia in 1, and SLE in 1.

Take-home point: This study is in agreement with the general consensus that GER (acid and non-acid) may trigger sleep interruptions in infants. Nevertheless, given the lack of impact on management, only rarely will infants with poor sleep benefit from these investigations.

Related blog entries:

How Histamine-2 Receptor Blockers May Cause Problems for Preemies

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Previously, this blog has noted an association between ranitidine usage and necrotizing enterocolitis (NEC) (see below).  Now, another study provides insight into a potential mechanism (JPGN 2013; 56: 397-400).

This study examined the fecal microbiota in 76 premature infants who were enrolled in a case-controlled, cross-sectional study.  25 infants receiving H2-blockers were compared with 51 matched controls.

Results: microbial diversity was lower, relative abundance of Proteobacteria was increased, and Firmicutes was decreased in the stools of infants receiving H2-blockers.

While this study did not specifically examine the effect of H-2 blockers on NEC (no infants in this study had NEC), there are multiple reasons why the findings should be a cause for concern.

  • Gastric acidity acts as a natural defense against bacterial growth and H-2 blockers (as well as proton pump inhibitors) inhibit this defense
  • Previous studies have shown an association between NEC and with diminished microbial diversity/increased Proteobacteria.  Proteobacteria include well-known pathogens like Klebsiella, Shigella, Escherichia coli, and Citrobacter.

Related blog entries:

Finding the Right Specialist

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A recent clinical problem-solving case report highlights the fact that seeing the right specialist helps a great deal with pattern recognition (NEJM 2013; 368: 1345-51).  In this report, intriguingly titled “The Essential Element” the authors describe a 21-year-old who presented with refractory hemolytic anemia along with low albumin, low alkaline phosphatase, and elevated total & direct bilirubins.  Her course was somewhat protracted due to treatment of hemolytic anemia and lack of recognition of underlying hepatocellular disease.  After readmission three months later the diagnosis of Wilson’s disease was made and quickly she underwent orthotopic liver transplantation.

A couple of pointers from this article for me included the following:

  • Parenchymal injury from the oxidative effect of copper leads to the hepatocellular injury.  Release of copper also causes oxidative damage of erythroctye membranes.
  • The low alkaline phosphatase which is characteristic of Wilson’s is potentially due to the oxidative damage from free radicals or by competition at the active site of the alkaline phosphatase enzyme.
  • The combination of hemolysis with liver dysfunction should prompt consideration of Wilson’s.

Most hepatologists would quickly recognize the pattern presented in this case report.  Getting the patient to the right physician is the key.

Comprehensive review on Wilson’s:

Diagnosis and treatment of Wilson disease: An update – American …  AASLD Guidelines for Wilson disease.  This is an excellent resource for diagnosis and management.

Budesonide for Ulcerative Colitis

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Budesonide (Uceris) has been formulated with the MMX delivery technology and now has been FDA approved for mild to moderate ulcerative colitis in adults.  The potential advantage of budesonide compared with conventional corticosteroids is for targeting anti-inflammatory activity to the colon with less systemic side effects.  The potential downside includes the high cost.  According to one website (see below), the average wholesale cost is just below $1500 per month.  In addition, only a minority of individuals responded to budesonide in published studies:

Induction of Remission in Studies 1 and 2 (reference below)

Treatment Group

Study 1 n/N (%)

Study 2 n/N (%)

UCERIS 9 mg

22/123 (17.9)

19/109 (17.4)

UCERIS 6 mg

16/121 (13.2)

9/109 (8.3)

Reference Arm*

15/124 (12.1)

13/103 (12.6)

Placebo

9/121 (7.4)

4/89 (4.5)

Treatment Difference between UCERIS 9 mg and Placebo (95% CI)†

10.4% (2.2%, 18.7%)

12.9% (4.6%, 21.3%)

Data for budesonide for pediatric patients with ulcerative colitis is not available.

Ultrasound Unreliable to Exclude Fatty Liver

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More information on the sensitivity of ultrasonography for detecting fatty liver is available in the setting of living-related liver transplantation (Transplantation 2013; 95: DOI: 10.1097/TP.0b013e31828d1588).

In this study the authors retrospectively examined the degree of steatosis from 492 living liver donors who had normal ultrasounds and normal aminotransferase levels. The median age of the donors was 30.1 year and the median BMI was 22.4 kg/meter-squared.

Background: According to the authors, if liver histology shows severe macrosteatosis (>60%), transplantation is canceled.  Furthermore, in cases of moderate macrosteatosis (30-59%), the risks/benefits need to be considered on an individual basis due to increased risk of mortality; Spitzer et al (reference below) demonstrated that macrovesicular steatosis >30% was an independent predictor of reduced 1-year graft survival.  In addition, a previous report has indicated that both macrosteatosis and microsteatosis had similar impacts on postoperative  liver function.

Results:

  • 3 (0.6%) had severe total steatosis, moderate or greater steatosis was diagnosed in 4 (0.8%) for macrosteatosis, in 26 (5.3%) for microsteatosis, and 56 (11.4%) for total steatosis.
  • There were two identified risk factors BMI >23 kg/meter-squared and triglycerides >88 mg/dL.  Individuals with both risk factors had a 28.6% prevalence of moderate or greater degree of total steatosis compared with 6.6% with no risk factors.  In these individuals, a liver biopsy may be worthwhile.

Why this study matters for the non-transplant physician:  This study provides additional data that ultrasonography is not adequate to exclude significant degrees of fatty liver.

Study limitations included the retrospective analysis which relied on medical record accuracy, degree of steatosis was not based on a single pathologist, ultrasonography was not based on not based on a single radiologist, both BMI and triglycerides may vary based on age, gender, ethnicity and other factors.

Related blog entries:

Related references:

  • -Spitzer AL et al. Liver Transpl 2010; 16: 874-84.
  • -Liver Transpl 2013; 19: 437-49. Difficulty with precisely determining steatosis
  • -Hepatology 2011; 54: 1082.  U/S w ~85% sensitivity in detecting fatty liver.
  • -Gastroenterol 2008; 135: 1961.  Liver biopsy (in pediatrics) still needed as surrogates not accurate for correlating degree of fibrosis/injury.
  • -J Pediatr 2009; 155: 469.  Review.  No evidence-based guidelines for treating in pediatrics –main Rx wt loss/exercise.  Consider obtaining ultrasound.

Treatment of Short Stature

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While gastroenterology focuses more on being skinny than being short, understanding the current treatment approach to short stature is important.  Certainly, this is a common condition in a pediatric gastroenterology practice.  An update is available: NEJM 2013; 368: 1220-8.

This article presents the case of an 11-year-old with probable constitutional delay of growth and puberty (CDGP) who is projected to achieve an adult height of 5 ft 5 in.  It asks the question of the optimal management but does not answer this definitively.

Background:  Most children with short stature have either CDGP or familial short stature and are generally healthy.  The FDA has approved human growth hormone therapy for children with idiopathic short stature and height below the 1st percentile.  In the U.S. this amounts to more that 500,000 children (1% of children 4-13 years).  However, growth hormone is expensive $10,000-60,000 per year and achieves modest results, 1.2-2.8 inches in added final stature.

Key Recommendations:

  • Thorough evaluation of short stature especially if child’s height deficit is severe (<1st percentile for age), the growth rate is abnormal (<10% for bone age), predicted height is significantly different from midparental height, or body proportions are abnormal.
  • History of intrauterine growth retardation is important since 15% remain short throughout life.
  • Screening labs (according to the authors) include measurement of thyroid assays, checking for renal dysfunction (BUN, creatinine), assessing for inflammatory conditions (eg. sedimentation rate), checking tissue transglutaminase antibody, and assessing hematologic conditions (eg. complete blood count).  In addition, examination should look for evidence of Turner syndrome.
  • The authors discuss growth hormone testing.  IGF-1 serves as a screen but even provocative testing can miss mild cases of growth hormone deficiency.
  • Psychosocial well-being has not predictably improved with growth hormone treatment.
  • Treatment options: observation, growth hormone, or androgen use (eg. oxandrolone).  The latter will expedite growth but not significantly impact long-term height.

Are there risks to growth hormone therapy?

Yes.  There have been occurrences of intracranial hypertension, glucose intolerance, and slipped capital femoral epiphysis. The absolute risks are considered low.  Long-term risks are not entirely clear.  One study suggested a slight increased mortality rate with increased mortality from bone cancer and circulatory disorders.  A similar study did not confirm these findings.

What are the costs?

For idiopathic short stature, the cost has been estimated to be $35,000-50,000 per inch of height.

Who benefits the most?

Predictors of growth hormone response in idiopathic short stature include younger age at baseline, delay in skeletal maturation, and taller parents.  Also, daily administration achieves superior results to less frequent administration.

Related reference:

  • -J Clin Endocrinol Metab 2008; 93: 4210-7.  Consensus statement on the diagnosis and treatment of children with idiopathic short stature.