Category Archives: Uncategorized

Budesonide for Ulcerative Colitis

Posted on by

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.

ADHD patients– not at increased risk for Celiac disease

Posted on by

It seems that so many conditions have been linked to Celiac disease; perhaps, Celiac disease is to health problems as Kevin Bacon is to actors (Six Degrees of Kevin Bacon – Wikipedia, the free encyclopedia).  A notable exception may be ADHD (JPGN 2013; 56: 211-14).

In a prospective study from Turkey, a total 362 children between 5 and 15 years who were diagnosed with ADHD at a child psychiatry clinic (2007-2010) were evaluated.  Serum levels of tissue transglutaminase (TTG) IgA and IgG antibodies were obtained; serum IgA levels were determined in those with isolated TTG IgG positivity.  In addition, the authors identified a matched control group of 390 children.

Results:

  • TTG IgA seropositivity was noted in 4 patients with ADHD (1.1%) compared with 3 controls (0.8%).  Only one of the four ADHD patients had histologic evidence of celiac disease (0.27%).
  • There was a higher incidence of TTG IgG in the ADHD group, 3.9% compared with 0.5% in controls. However, serum IgA was normal in all of these patients (indicating that TTG IgA was likely reliable).  Followup TTG IgG testing was negative consistent with false positivity.

Perhaps this result is not surprising to those who have seen a ‘classic’ celiac disease presentation.  In these children who often had physical signs of malnutrition including a bloated abdomen, the effect of a gluten-free diet changed a “perfectly-behaved” (=listless) child into a very active toddler.  So, in these children, a gluten-free diet but not celiac disease triggered hyperactivity.

Related blog posts:

.

Why Social Media is Important for Doctors

Posted on by

The following link is to a NY Times article and below are a few excerpts:

http://well.blogs.nytimes.com/2013/03/21/doctors-and-their-online-reputation/?smid=tw-nytimeshealth&seid=auto

 “While most doctors have come to terms with the fact that their patients routinely go online for information about what ails them, they remain uneasy about a more recent trend: the Internet is quickly becoming the resource of choice for patients to connect with, learn more about and even rate their doctors. And while many have used Facebook, Twitter, LinkedIn or online medical community sites like Sermo to engage with friends and colleagues, few have communicated with patients as, well, doctors. Most abstain for one simple reason: they aren’t sure how to be a doctor online.”
The link discusses a new book by Kevin Pho (KevinMD) and Susan Gay.  “In“Establishing, Managing and Protecting Your Online Reputation: A Social Media Guide for Physicians and Medical Practices,” “Dr. Pho and Ms. Gay offer highly organized key points, useful statistics and exuberant testimonials from doctors who have successfully leapt over the digital divide. There is plenty of practical advice, too, on topics ranging from what to post and when to engage, confer or rebuff, to how to decide what might be unethical or T.M.I. (Answer: ‘Can you say it aloud in a full hospital elevator?”)The book is an excellent and helpful resource. But what elevates it beyond the category of valuable how-to manual is the passionate call to arms that resonates from all those well-enumerated directions and clearly labeled diagrams. Like it or not, the authors warn, the Internet has profoundly changed the patient-doctor relationship, and doctors must embrace its effects on patient care — or risk losing their own influence.'”The article also notes that on the internet many individuals without any scientific background may have equal footing with recognized experts.  Another subject broached in this article is the issue of ranking physicians.”The biggest risk of social media in health care,” they conclude, “is not using it at all.”
Related website resources:

Clostridium difficile in IBD

Posted on by

A useful review of Clostridium difficile infection (CDI) in the inflammatory bowel disease population has been published and makes several useful points (Inflamm Bowel Dis 2013; 19: 194-204). (Thanks to Ben Gold for suggesting this reference.)

Key points:

  • The incidence of CDI in IBD patients is increasing (faster than general population).  The prevalence of CDI in IBD was nearly eight times greater than non-iBD gastrointestinal patients in a recent population-based study (37.3 cases vs. 4.8 cases per 1000 discharges).
  • Though there is some conflicting data, CDI appears to worsen both short- and long-term outcomes in IBD patients.
  • Carriage (asymptomatic) rates in outpatient IBD patients is higher than the general population (8.2% vs. 1%) according to a recent study.
  • Endoscopic appearance of CDI is rarely classic in the setting of IBD.  Only 13% of hospitalized IBD patients with CDI had pseudomembranes (J Crohns Colitis 2010; 4: 194-98).  Thus, endoscopy has little utility in helping to distinguish IBD flare from superimposed infection.
  • Unique IBD risk factors for CDI: colonic disease and steroid use.
  • The review has a thorough discussion of the available testing and recommends testing only patients with unformed stools unless an ileus is present.
  • For recurrent disease, the authors suggest prolonged tapered vancomycin in adults: 125 mg QID for 10-14 days, then 125 mg BID x 1 week, then 125 mg QD x 1 week, then 125 mg QOD for 2-8 weeks.  Alternative approaches could included fidaxomicin, IVIG/antibody therapy, and fecal transplantation.

Related blog posts:

Fundoplication effects on esophageal motility

Posted on by

Trying to decide whether a child should undergo a fundoplication is often quite difficult.  The best candidates with gastroesophageal reflux disease (GERD) don’t need surgery because medical treatment is usually effective.  Typical patients who fail medical treatments may have numerous comorbidities that could cause a complicated postoperative course or failure of the procedure.

One aspect about the surgery that has been questioned has been whether surgery causes dysmotility of the esophagus.  A recent article describes a study, which enrolled only ten children who had surgery; however, these patients underwent extensive preoperative and postoperative evaluations to try to provide more information about the motility effects of fundoplication (J Pediatr 2013; 162: 566-73).

Patients were considered for surgery if they had failed medical therapy. Four of the ten patients were neurologically-impaired. Testing included automated impedance manometry, 24-hour pH-impedance, gastric emptying breath test, and GERD questionnaires (though the authors note that GERD questionnaires are not validated in children aged 1-12 years).  Median patient age was 6.4 years, with a range of 1-17 years.

Surgery: laparascopic anterior partial fundoplication

Results:

  • 4 patients developed postoperative dysphagia, two patients had redo fundoplications (one due to dysphagia and one due to persistent emesis).
  • Postsurgery, GER measures were reduced.  Total number of acid reflux episodes dropped from an average of 37 to an average of 10.  Total GER (acid and nonacid) episodes dropped from an average of 97 to an average of 66.  The percentage of time with pH<4 dropped as well from an average of 12.5% to an average of 3.1%.
  • Average gastric emptying time was unchanged: 64 minutes pre surgery and 63 minutes post surgery.
  • Conventional esophageal motility measures/peristaltic contractions were unaltered.  However, patients with postoperative dysphagia had longer gastric emptying times compared with those who did not develop postoperative dysphagia.

Related blog posts:

The Medical Pendulum and Gastroesophageal Reflux | gutsandgrowth

Gastroesophageal Reflux: I know it when I see it | gutsandgrowth

Related references:

  • -Gastroenterology 2011; 141: 1938 LOTUS study in JAMA summarized. JAMA 2011; 305: 1969. Medical rx outperformed surgery. 92% under control (remission) with long-term medical Rx vs 85% with surgery & fewer side effects of medical Rx.
  • -Clin Gastro & Hepatology 2009; 7: 1292, 1264 (editorial). 12 yr outcomes for surgery vs PPI. n=154 omeprazole, n=144 surgery. Similar long-term outcome ~50% with long-term remission.
  • -JPGN 2010; 50: 25. Reflux detected by impedance does NOT determine fundoplication outcome. n=34.
  • -JPGN 2006; 43: 185.  Effect of fundo: no change in  gastric motor activity & increased discomfort with distention
  • -Pediatrics 2006; 118: 2326. n=1142. Fundoplication decreased hospitalization rates for children <4yrs; in older children with developmental delay, there were increased hospitalization rates after fundoplication. (47% had no hospitalizations prior to fundoplication.)
  • -Clin Gastro & Hep 2004; 2: 978-984. Gilger et al. n=198. 63% required p-op medical treatment for recurrent GERD -retrospective review 1996-99.
  • -J Pediatrics 2011; 159: 597. Hypoglycemia (likely due to dumping) was common post-op. n=285. 24% of screened children with low glucose (only 1.3%of those without formal screening). 2/3rds with hypoglycemia had preceding hyperglycemia. Only 53% had dumping symptoms.  Many in this cohort were NICU pts -~1/3rd of pts had mean age of 3months & another ~1/3rd with mean age of 6months.Rx often was continuous feeds.
  • -Pediatrics 2006; 118:1828. 48,665 antireflux surgeries done from 1996-2003 (~7000/yr) in US
  • -Clin Gastro & Hep 2006; 4: 299. Frequent complications p-op and frequent need for GERD meds. dysphagia in 19%, dilation in 6%, repeat surgery in 2%, mortality in 0.8% (n=3145). 50% required GERD meds.
  • -Gastroenterology 2001; 121: 5-14 & 214.  Dysmotility with GER reflects severe disease & is present ~30%. According to this study, dysmotility does not affect postoperative outcome, is not corrected by fundoplication, may occur p-op, and requires no tailoring of surgical mgt.

Data on Allopurinol

Posted on by

Given the limited number of therapeutic options for inflammatory bowel disease (IBD), it is important to optimize each individual treatment.  Allopurinol can increase the effectiveness of thiopurines and if used properly can be safe (Inflamm Bowel Dis 2013; 19: 363-69).

The referenced study took place between 2004-2011 and examined 77 patients who failed monotherapy with a thiopurine due to “skewed” metabolism.  The average age of study participant was 38 years (28-45).  23% had previous surgery. Cotreatment with an anti-TNF occurred in 7 patients and with an 5-ASA i 17 patients.

Results:

  • Median 6-thioguanine (6-TGN) levels increased from 145 to 271 pmol/8 x10-to-the-8th. 6-methyl mercaptopurine (6-MMP) concentrations decreased from 10,110 to 265 pmol/8 x10-to-the-8th.
  • Leukopenia occurred in 16%, necessitating dose reductions.
  • Liver tests normalized in 81% with the addition of allopurinol
  • The median azathioprine dose while on combination therapy was 0.64 mg/kg/day and the median 6-mercaptopurine dose was 0.39 mg/kg/day.  While on mono therapy, median values were 2.05 mg/kg/day and 1.23 mg/kg/day respectively.
  • 21% had to discontinue combination therapy.
  • Combination therapy was continued at 6, 12, 24, and 60 months in 87%, 85%, 76%, and 65%.

Take-home Message:

Allopurinol can salvage failed thiopurine monotherapy, but only in a minority of these patients.  Allopurinol should be considered for patients unable to achieve therapeutic 6-TGN levels who have liver toxicity/elevated 6-MMP levels.  Careful attention to dose reduction of the thiopurine is essential to avoid life-threatening bone marrow suppression.

Related blog entry:

Thiopurine Metabolite Testing -NASPGHAN … – gutsandgrowth

Additional references:

  • -Aliment Pharmacol Ther 2010; 31: 640-47. use of allopurinol.
  • -Gastro & Hep 2008; 4: 505. use of allopurinol. Consider if pts unable to enter steroid-free remission AND on adequate AZA/6MP dose. ONLY in those who preferentially metabolize towards 6-MMP (~15% of population); thus subtherapeutic 6-TG levels and increased 6-MMP (>5700). Need adequate WBC >4.5 at start since this will decrease. Check labs every week x 4 at start, then qoweek x 4, then per routine.
  • -IBD 2008; 14: 1678. Experience with allopurinol in children -dose 100mg of allopurinol if >30kg and 50mg if < 30kg. AZA dose decreased to 25% of previous dose. n=13.
  • -Clin Gastro & Hep 2007; 5: 170 (editorial) & 209.  Use of allopurinol (100mg/day) in 20 adults.  Dose of 6-MP reduced 25-50% concomitantly.  Improved disease control w/o hepatotoxicity.  Important to follow counts closely for first 2 months.

Malnutrition Redefined

Posted on by

Defining malnutrition accurately is the focus of a new report (JPEN 2013; DOI: 10.1177/0148507113479972). Thanks to Kipp Ellsworth for this article.

The Pediatric Malnutrition Definitions Workgroup was formed in April 2010 and makes numerous relevant contributions to precisely defining malnutrition.  The reasons for this workgroup and report are to promote the following:

  • early identification of those at risk for malnutrition
  • allow better comparison of malnutrition prevalence & collect meaningful data
  • develop uniform screening tools
  • develop thresholds for intervention
  • improve assessment of outcomes

“Pediatric malnutrition (undernutrition) is defined as an imbalance between nutrient requirement and intake, resulting in cumulative deficits of energy, protein, or micronutrients that may negatively affect growth, development, or other relevant outcomes.”

First, malnutrition is subdivided into two categories: illness-related malnutrition and non-illness-related malnutrition.  Illness-related malnutrition refers to malnutrition caused by chronic conditions, burns, and surgery.  It is the predominant cause in developed countries.  Non-illness-related malnutrition refers to malnutrition caused by environmental or behavioral factors (including food aversions or anorexia).

Illness-related malnutrition occurs due to nutrient loss, increased energy expenditure, decreased nutrient intake, or altered nutrient utilization.

In brief, patients need to be assessed in five domains: anthropometrics, growth charts, chronicity, etiology/pathogenesis, and functional status.

Summary of recommendations:

  1. Record anthropometric variables on admission and serially.  These measurements include weight, height, BMI, mid-upper arm circumference (MUAC) and consider triceps skin fold (TSF) and mid-arm muscle circumference.  Obtain head circumference if younger than 2 years.
  2. In infants/children <2 years, measure length with recumbent board. In older patients unable to stand, consider alternative measurement like tibia length or knee height for a height proxy.
  3. Use the 2006 World Health Organization growth charts in patients younger than 2 years and the CBC 2000 growth charts for children 2-20 years. In addition, use corrected age (number of weeks/months premature + chronological age) for preterm infants until they are 3 years old.
  4. Use a decline in z score for individual anthropometric measurements as the indication of faltering growth.
  5. Use 3 months as a cutoff to classify as acute or chronic.
  6. Include description of predominant mechanism of malnutrition: decreased intake, increased requirements, excessive losses, or failure to assimilate/malabsorption.
  7. Recognize the role of inflammation on nutrition status.
  8. Assess impact of malnutrition: consider developmental assessment, lean body mass measurements, and measures of muscle strength.

By having a better established uniform definition of malnutrition, impact on outcomes will be easier to assess. In addition to the potential outcomes noted above (#8), others that will need to be examined in relation to malnutrition include length of hospital stay, wound healing, frequency of infections, behavioral problems, and disease-specific resource utilization.

This article also reviews previous definitions and potential problems with their usage.  For example, Waterlow criteria rely on percentiles and standard deviations and are used widely.  In hospitalized children, accurate serial weights and heights can be challenging due to fluid retention and poor mobility.

The authors note that malnutrition is likely underdiagnosed and inadequately treated.  Some recent estimates indicate that malnutrition is present “in 40% of patients with neurologic conditions, 34.5% in those with infectious diseases, 33.3% of those with cystic fibrosis, 28.6% in those with cardiovascular disease, 27.3% in oncology patients, and 23.6% in those with GI diseases. Patients with multiple diagnoses are most likely to be malnourished (43.8%).”

Bottomline: A lot of patients are malnourished.  Recognition of malnutrition (defining what is malnutrition) should improve outcomes.

Related blog posts:

How effective are aminosalicylates for pediatric UC?

Posted on by

In a prospective, multicenter, inception cohort study (JPGN 2013; 56: 12-18) with 213 newly diagnosed ulcerative colitis (UC) patients, oral aminosalicylate (5-ASA) therapy was effective in 86 (40%).  That is, 40% were considered to be in corticosteroid-free remission at 1 year using 5-ASA as primary maintenance therapy.

This study took place between 2002-2010.  Of 1669 children enrolled in the registry from 32 sites, 440 (26%) were diagnosed with UC.  Of this group, 353 had followup >1 year and 213 met inclusion/exclusion criteria; all patients had to be treated with only 5-ASA or corticosteroids in the initial 30 days following diagnosis.  Most of those excluded had other therapies.  Among those with primary oral 5-ASA treatment, only 98 started treatment without a steroid induction.

Some interesting aspects of the study group:

  • 82% had pancolitis
  • 62% had moderate/severe disease at diagnosis based on physician global assessment
  • No laboratory or clinical features were associated with a higher likelihood of response
  • Mean daily dosage of 5-ASA was 52 mg/kg/day; 23% had a dose >60 mg/kg/day

The authors note that improved patient adherence and possibly higher 5-ASA dosing schedules may improve response to 5-ASA treatment.

Related blog entry:

Once daily Mesalamine | gutsandgrowth

Expert review: Celiac disease

Posted on by

A recent article gives a concise expert update on Celiac disease (NEJM 2012; 367: 2419-26).

As this is an area that has been covered several times by this blog and is familiar to most of the followers, I will comment on a few issues that were particularly interesting to me.  Though, the review is thorough and a helpful reference on most aspects of celiac disease..

What is the gluten threshold?  In patients with celiac disease, a minimal degree of gluten contamination is difficult to avoid.  “The lowest amount of daily gluten that causes damage to the celiac intestinal mucosa over (the gluten threshold) is 10 to 50 mg per day (a 25-g slice of bread contains approximately 1.6 g of gluten).”  New regulations propose that foods which are labeled as gluten free have less than 20 ppm of gluten contamination.

When are intraepithelial lymphocytes increased in the duodenum?  The abnormal threshold is considered >25 per 100 enterocytes.

What proportion of celiac disease patients have been diagnosed?  According to a recent European study, only a small proportion (21%) of celiac patients are clinically recognized.

Best screening test currently? Anti-tissue transglutaminase (TTG) IgA antibody –both sensitivity and specificity are >95%.  Consider TTG IgG in patients with IgA deficieny or possibly deamidated gliadin IgG.

Potential complications of untreated celiac disease? Osteoporosis, impaired splenic function, neurologic disorders, infertility or recurrent abortion, ulcerative jejunoileitis, and cancer.

Biopsy needed? Usually, “although recent guidelines suggest that biopsy may not be necessary in selected children with strong clinical and serologic evidence of celiac disease.”

Population-based screening or case-finding?  At this time, population-based screening is not recommended.  Case-finding based on symptoms and screening of at-risk groups is recommended though this is likely to miss >50% of cases.

Related blog posts:

A-OK for Accutane

Posted on by

Another article has reaffirmed that isotretinoin (Accutane) does not increase the risk of IBD (JAMA Dermatol 2013; 149: 216-20).  Thanks to Mike Hart for this reference. However, this data will not reverse the millions of dollars that have been lost in litigation (Isotretinoin – Wikipedia, the free encyclopedia).

Using a large U.S. health claims database (68 million patients), the authors examined women ages 18-46 years who had received at least one oral contraceptive prescription between 2001-2009.  For each patient with IBD, 20 controls were identified in a nested case-control study design.

In total, 2159 IBD cases (1056 UC, 1103 CD) were matched with 43,180 controls.  Only 10 patients with IBD were exposed to isotretinoin compared with 191 controls.  The adjusted relative risk (RR) for IBD was 0.99; for ulcerative colitis the RR was 1.1 (confidence intervals 0.44-2.7) and for Crohn’s disease the RR was 0.91 (confidence interval 0.91).  For the meta-analysis which was a secondary part of this study, the RR for IBD with 5 studies was 0.94.

Conclusion: The study results do not suggest an increase risk of IBD with isotretinoin use.

Why did previous studies suggest a link between IBD and isotretinoin? The authors note that this is the first study to adjust for two main confounders, mainly a diagnosis of acne and use of oral tetracycline antibiotics.  Oral antibiotics, including tetracyclines, have been associated with IBD previously.  In addition, the design limits the confounding of contraceptive usage.

Limitations of this study:

  • Only women were studied; however, there are no known biologic factors that would make isotretinoin more problematic for males.
  • Other risk factors were not examined: smoking, ethnicity, diet, IBD family history

Additional references:

  • -Am J Gastroenterol 2009; 104: 2774-78.  Population-based study in Winnipeg, <40yrs.  n=1960 cases and 19,419 controls.  No differences in the proportions of IBD cases taking isotretinoin vs controls.  1.2% of IBD cases received isotretinoin prior to IBD diagnosis (n=25) compared with 1.1% of controls (n=213).  Mean # of days prior to IBD dx was 1102.  Thus, isotretinoin unlikely to be causally-associated with idiopathic IBD.
  • -IBD 2009; 12: Supplement -abstract O -0002  Increased risk of UC after isotretinoin.  OR 4.36 for developing UC
  • -Am J Gastroenterol 2009; 104: 2387-93.  7 country study found no causal association between isotretinoin & colitis.