Category Archives: Pediatric Gastroenterology Intestinal Disorder

One year later

Posted on by

It has been one year and 300 posts since I’ve started this blog.  I’ve enjoyed putting together my thoughts about recent articles.  In addition, I like being able to search for previous blogs for information that I find helpful.

Currently there are close to ~35 hits per day in addition to the email/wordpress followers (about 30).  This number has been increasing and it is fascinating to see that people from all over the world will sometimes stumble across this blog.

If you have suggestions for topics, articles or other ways to improve this pediatric GI blog, please send me an email at jjhochman@gmail.com.

Predicting Necrotizing Enterocolitis with Fecal Biomarker

Posted on by

A recent study has shown some promise in detecting necrotizing enterocolitis (NEC) with a fecal biomarker, S100A12 (J Pediatr 2012; 161: 1059-64).

In this prospective study of 145 preterm infants with a birth weight <1500 g, stool samples were collected on alternated days for 4 weeks.  Fecal S100A12 and calprotectin were measured.  Calprotectin in previous studies has been shown to be a poor marker for NEC.

Fecal S100A12, also called calgranulin C, belongs to a novel group of proinflammatory molecules. It is released by activated or damaged cells under conditions of cell stress and indicates phagocyte-specific damage.

18 (12.4%) developed NEC.  Fecal S100A12 levels were elevated in severe NEC and also at 4-10 days beforehand.  The sensitivity, specificity, positive predictive values, and negative predictive values were 70%, 68%. 37%, and 89% respectively.  Thus, there is limited utility of this stool test due to the limited sensitivity/specificity.  There is substantial overlap between control patients and patients who developed NEC.  Furthermore, fecal S100A12 levels are age-dependent.  Generally, they are higher early in life, likely due to increased mucosal permeability.

Calprotectin levels were elevated at the onset of NEC (median 349 mg/kg) and 48 hours before onset (median 83 mg/kg).  The difference at 48 hours prior to onset did not reach statistical significance.

Congenital Sucrase Isomaltase Deficiency

Posted on by

Congenital Sucrase Isomaltase Deficiency (CSID) has an extensive review in a recent JPGN supplement (JPGN 2012; supplement 2: S1-47).

A concise update of the clinical aspects is provided by William Treem (S7-S13).   Specific points that he makes includes the following:

  • CSID was first described in 1960 by Weijers and colleagues
  • Sucrase-isomaltase gene (3q25-26) identified in 1992; now more than 55 mutations have been described.  At least one of the four most common mutations are identified in about 80% of affected individuals.
  • Prevalence: estimates range from 1 in 500 to 1 in 2000 in caucasians; the prevalence is lower in other populations.  Some patients suspected of having CSID may be heterozygotes with low enzyme activity (but not truly deficient).
  • Clinical features determined by degree of enzyme deficiency and amount of sugar and starch consumed.  In the U.S. typically 60% of calories consumed are derived from carbohydrates and 30% from sucrose.  A typical U.S. adult consumes 150 lb of sugar per year.
  • Classical presentation: severe watery diarrhea and poor weight gain in a 9- to 18-month old after exposure to juices, baby foods/fruits, and other starches.
  • Other symptoms: gas/bloating, abdominal pain, irritable bowel syndrome
  • Diagnosis: intestinal biopsy analysis.  A potential pitfall includes mishandling of biopsy specimens. An alternative means of diagnosis is the 13-C sucrose breath test.
  • Treatment: 1. dietary avoidance results in improvement in many, though only 10% respond fully to diet. 2. enzymatic treatment. Baker’s yeast (Saccharomyces cerevisiae) contains a sucrase.  Development of sacrosidase (Sucraid) from Baker’s yeast has allowed 81% of patients to consume an unrestricted diet.  Dosing: 1 mL with meals/snacks if <15 kg and 2 mL if >15 kg.
  • Despite sacrosidase treatment, 27% of patients required strict sucrose restriction with either mild or strict starch restriction to maintain acceptable suppression of symptoms.
  • What is not noted in this summary–cost information: sucraid may cost as much as $3700 per month.  A similar product in Europe costs about $400 per month

Multiple other articles in this supplement address related subjects.

On page S31, information is given from parent support group.  This parent support group (CSIDinfo.com) offers dietary advice specific for each phenotype (A,B,C,D and F) which is based on their disaccharidase levels, ability to outgrow symptoms, and tolerance of starch and maltodextrins.

On page S34, the major genetic mutations are discussed.  Use of genetic testing will detect the majority with CSID which could become an alternative means of diagnosing CSID in this population.

Additional Information

Norovirus -now more important than rotavirus

Posted on by

Norovirus has become more important than rotavirus.  This is evident based on a recent review (NEJM 2012; 367: 2126-32).

Key points:

  • Noroviruses are the most common cause of acute gastroenteritis requiring hospital ER evaluation in U.S. adults.  It is predicted to become the most common cause of diarrhea in all age groups worldwide once rotavirus infection is controlled through vaccination.
  • Noroviruses are small nonenveloped single-stranded RNA viruses from the Calciviridae family.  There are six major genogroups.
  • Exposure can occur from other individuals, contaminated food/water, and environment sources, including nosocomial.
  • Chronic infection is common in immunocompromised hosts, perhaps 15-20% of some immunocompromised populations.  Evolution of the norovirus genome in patients infected for extended periods is relatively rapid (3.3% amino acid substitutions per year).
  • In normal hosts, viral shedding lasts 20-40 days; in the immunocompromised, shedding can occur for years.
  • Can be detected readily with RT-PCR assays.
  • There are no vaccines or specific viral agents available that have proven efficacy.  Passive antibody therapies have been given in individual cases.
  • Hand-washing is crucial, especially in the hospital.  In one study, 80% of hospital surfaces were contaminated with multiple norovirus strains—this study was done in a unit for children with immunodeficiencies.

Additional References:

Related blog entry:

Immunoglobulin deficiencies with DiGeorge Syndrome

Posted on by

I participate in a Children’s Healthcare of Atlanta multidisciplinary clinic to help provide care for children with DiGeorge syndrome/22q deletion.  As such, I am interested in a range of issues in these patients.  A recent discovery has been that humoral immunity and not just T-lymphocyte immunodeficiency occurs in a significant number of patients with DiGeorge syndrome (J Pediatr 2012; 161: 950-3).

A cohort of 1023 patients were identified from a number of registries that spanned 21 countries and 40 different contributors. Among this group, 3% were receiving immunoglobulin therapy and 6% over the age of 3 years had hypogammaglobulinemia (IgG <500 mg/dL).

Additional references/resources:

  • –Growth charts for 22q: http://www.22q.org/index.php/growth-charts
  • -J Pediatr 2011; 159: 332. 22q guidelines.
  • -J Pediatr 2009; 155: 560. n=64. 22q11.2 deletion found in <60% of DiGeorge Anomaly pts. DiGeorge Anomaly =(at least 2): congenital heart dz, immune deficiency, hypocalcemia. Also, 86/121 with deletion do not fulfill requirement of anomaly (“syndrome”).
  • -Mol Syndromol. 2011 January; 1(4): 192–209. “Introduction: The 22q11.2 deletion syndrome is increasingly recognized in pediatric patients with an incidence of approximately 1 in 3,000. GI manifestations are common and can impact significantly on feeding and growth. To date, there have been few papers on feeding disorders and isolated case reports of various GI anomalies. Methods: A retrospective chart review was conducted on 766 patients with confirmed 22q11.2 deletions followed in the 22q and You Center at CHOP. Data abstracted included GI symptoms, evaluation and management. Results: Average age was 15 years (0.2–62 years). Male:female ratio was 1:1. Ethnic distribution was predominantly Caucasian (67%), Hispanic (33%) and African-American (10%). 32% of patients had no GI symptoms. In patients with GI symptoms, nasopharyngeal reflux, feeding problems, gastroesophageal reflux and constipation were common. Diagnoses included dysmotility (27), intestinal malrotation (7), esophageal diverticula (5), gastroparesis (5), rectal prolapse (2), esophageal atresia (2), gallstones (2), imperforate anus (1), tracheo-esophageal fistula (1), pyloric stenosis (1), choledochal cyst (1), Hirschsprung’s disease (1), and celiac disease (1). About 27% of patients underwent GI testing. Upper GI series and modified barium swallowing study were frequently performed. 5% of patients underwent fundoplication. Feeding tubes were common (27%). Conclusions: Significant GI manifestations are frequent in patients with the 22q11.2 deletion syndrome. Clinicians need to be aware of these conditions to avoid delays in diagnosis. Moreover, all patients with GI symptomatology will benefit from evaluation with a gastroenterologist.”
  • -Pediatrics 2003; 112: 101.n=43; 1 in 5950 births. phenotype in 43 pts
  • -JPGN 2002; 35: 423 (56 Abstract) DiGeorge syndrome GI manifestations; 6 of 46 c malrotation, dysmotility in 7
  • -J Pediatr 2001; 139: 715. DiGeorge immunologic features.

22q Deletions Resources for Families

SUPPORT GROUPS & WEB RESOURCES

  1. 22Q Foundation

  2. DiGeorge syndrome – Wikipedia, the free encyclopedia

  3. Welcome to the Velo-Cardio-Facial Syndrome (VCFS) Educationa

  4. DiGeorge Syndrome – American Heart Association

  5. Living with 22Q – Dempster Family Foundation

  6. Friends of Quinn | Blog | Quinn Bradlee

EDUCATIONAL RESOURCES:

Monitoring TNF antagonists in inflammatory bowel disease

Posted on by

Previously, this blog has discussed the use of drug monitoring in inflammatory bowel disease (Drug levels for inflammatory bowel disease | gutsandgrowth).  A good review of this topic has been published recently (Clin Gastroenterol Hepatol 2012; 10: 1079-87).

Some of the useful pointers:

  • Factors that influence clearance of TNF antagonists are reviewed:
  1. Antidrug antibodies (ADA) increase clearance and worsen outcomes
  2. Use of concomitant immunosuppressives reduces the likelihood of ADA formation and increase drug concentration.   In the SONIC trial, use of azathioprine was associated with trough infliximab (IFX) levels of 3.5 μg/mL compared with 1.6 μg/mL with monotherapy.  Also, ADA was reduce: 0.9% compared with 14.6% in the monotherapy group. [Other studies though have found variable effects of cotherapy.]
  3. Low serum albumin and high CRP are associated with increased drug clearance
  4. Individuals with high body size and males are more likely to have increased drug clearance.
  • Better assays for measurement of IFX and adalimumab (ADL) are now available.
  • Currently a trial evaluating trough levels is underway: Trough Level Adapted Infliximab Treatment (TAXIT).  With this study, the accepted target range for trough levels is 3-7 μg/mL.  Levels >7 μg/mL are considered supratherapeutic and allows for a prolongation of dosing interval.  Preliminary data confirm that trough levels inversely correlate with CRP.
  • Proposed algorithm in individuals with loss of response & positive ADA.  If ADAs present at high titer, then switch to different TNF antagonist.  If low  titer, could either switch or attempt drug escalation.
  • With IFX, when antibodies to infliximab (ATIs) are present, the likelihood of responding to increased dose is less than 20% whereas changing to different TNF antagonist has about an 90% response (in patients who were previous responders).
  • Proposed algorithm in individuals with loss of response & negative ADA.  If subtherapeutic trough levels (IFX ❤ μg/mL, ADL <8 μg/mL, or certolizumab <27.5 μg/mL), then dose escalation is worthwhile.  If drug levels are therapeutic, then dose escalation will not be effective.
  • With IFX, more than 85% of patients will respond to drug escalation when the trough level is subtherapeutic. This is much more favorable than switching agents.
  • One other issue with ADAs is that they may be transient is some patients.  Perhaps one-fourth of ATIs may be transient which may explain why some individuals with ATIs may still respond to dose escalation.

These points give several reasons why drug monitoring is useful in individuals with loss of response and may help determine whether patients responding to therapy may be able to prolong dose intervals.  At the same time, when an individual is not responding to therapy, it is also important to determine if in fact active inflammation is present with objective markers and to consider alternative explanations for GI symptoms (eg. Clostridium difficile infection, irritable bowel, bacterial overgrowth, etc.).

Related blog entries:

Only one chance to make first impression | gutsandgrowth

When nothing else is working | gutsandgrowth

Infliximab for children with Ulcerative Colitis | gutsandgrowth

Adalimumab for children with Crohn’s disease | gutsandgrowth

CHOOSE TNF TRIAL | gutsandgrowth

Reliability of colonic manometry

Posted on by

As noted in a previous blog entry (Gastroesophageal Reflux: I know it when I see it | gutsandgrowth), it is often surprising how variable test result interpretation can be in the hands of experts.  The most recent example of this is with colonic manometry (JPGN 2012; 55: 548-51).

In the current study, 57 colonic motility studies were independently reviewed by 5 experts. The youngest and least experienced was 45 years old with 8 years of experience.  The oldest and most experienced was 63 years old with 28 years of experience.

Unanimous differentiation of normal and abnormal motility studies was present in 69%.  In 81% of the studies, 4 of 5 were in agreement about whether the study was normal.

Specific measurements noted the following:

  • Fairly high degree of agreement with fasting high-amplitude propagating contractions (HAPC): 66% with unanimous agreement,  and 82% with at least 4 of 5 observers in agreement.
  • The gastrocolonic response had the most inconsistency with only 19% in unanimous agreement and 45% with at least 4 of 5 in agreement.
  • The postprandial measurements were reported to be useful in only 3-24% of the studies.

Colonic manometry studies “require interpretation of a complex visual bowel motility pattern and are subject to interpretation bias.” One proposal by the authors of the study would be to limit colon motility studies to 60 minutes followed by bisacodyl stimulation.  Further studies will be necessary to determine whether this will improve the reliability of colonic manometry interpretation.

Related blog entries:

Testing worm therapy for chronic diarrhea/IBD in Monkeys

Posted on by

Today’s blog is an excerpt from BBC News (Thanks to Ben Gold for the tip).  The full link:

BBC News – Parasitic worms ‘treat diarrhoea‘

“Chronic diarrhoea could be treated using parasitic worms, a study of monkeys has suggested. Research published in PLOS Pathogens, suggests the treatment restores gut bacteria to a healthy state. Other work in mice has already suggested conditions such as ulcerative colitis could be treated in this way. A UK expert said parasitic worms were being investigated for a range of conditions, including multiple sclerosis and allergies.”

Captivity

“Inflammatory bowel diseases, like colitis, are often fuelled by a wrongly targeted response by the immune system to gut bacteria. Such diseases are more common in developed countries – and scientists suggest this is because people in developing countries have more exposure to parasitic worm (helminth) infections and therefore have a natural protection that has evolved as people and worms learnt to co-exist.


Recent studies have used parasitic worms to successfully treat inflammatory bowel disease in humans, but it is unclear exactly how they do this.

This latest study looked at monkeys because young macaques kept in captivity often develop chronic diarrhoea that can be hard to treat. Five macaques with diarrhoea were treated with parasitic worms called whipworms. Tissue samples were taken before and after treatment and it was found the balance of gut bacteria was restored to required levels. And four out of five animals had less diarrhoea and started to gain weight.

Dr P’ng Loke, of the New York University Langone Medical Center, who led the study, said: ‘The idea for treating colitis with worms is not new, but how this therapy might work remains unclear.  Our findings suggest that exposure to helminths may improve symptoms by restoring the balance to the microbial communities that are attached to the intestinal wall.’

The researchers now plan a study in humans to look at how pig helminth eggs might help alleviate the symptoms of colitis.

Compensating

Prof Graham Rook, of the centre for clinical microbiology at University College London, said a number of research teams were investigating the effects of parasitic worms in various conditions. ‘This is not part of the hygiene hypothesis [which says exposure to bacteria strengthened the immune system]. It’s the “old friends” hypothesis. We co-evolved with these things, so they had to be tolerated. We found ways of suppressing the immune systems, and in some way have come to depend on them.’ And he said the field of research as a whole would be “hugely significant”.  He added: ‘With helminths, if you get the dose right, you can probably live with worms and not have symptoms. But it may well be there is going to be a battery of molecules you could be dosed with to compensate for not meeting our “old friends”.’

THE WONDER OF WORMS

  • Parasitic worms are “old friends” and humans have lived with them for as long as we have existed.
  • And while people in developing countries still do so – and have low levels of inflammatory disease, the opposite is true in developed countries.
  • It appears our immune systems came to rely on parasitic worm infections as part of the way our body defended itself.
  • And when they are no longer there, it appears that may upset our immune systems.
  • Now researchers are looking at how the worms’ effects can be harnessed to treat conditions ranging from multiple sclerosis to allergies.
  • Hookworms and pig whipworms are amongst those being investigated.
  • Results are promising.
  • But those squeamish about dealing with worms or their eggs may not have to worry – it is more likely drugs will be developed that mimic their effects.”

Additional references:

  • -Gastroenterol 2012; 142: 55.  Helminth infection (with enterobiasis) did not reduce risk of IBD in large population-based study (924,000 Danish database).
  • -Gastroenterol 2005; 128: 825. Trichuris suis for UC. 43% improved vs 17% of placebo. Only mildy effective.
  • -Gut 2005; 54: 87-90. Trichuris suis for Crohn’s
  • -Gastroenterol 2005; 129: 768-69. (letter re safety)
  • -NEJM 2010; 363: 1476-78. Interactions between Helminths and immunogenicity.

Risk of pancreatitis with celiac disease

Posted on by

More data on the risk of pancreatitis in the setting of celiac disease has been published (Clinical Gastroenterol Hepatol 2012; 10: 1136-1142).

In this medical records review study, 28,908 patients in Sweden with biopsy-proven celiac disease (1969-2008) were compared with a control population of 143,746 to determine the risk of pancreatitis due to celiac disease. The median age at study entry was 30 years and included patients as young as 10 years.

Among these cohorts, 406 pancreatitis patients with celiac disease were identified.  The expected number would have been 143, yielding a hazard ratio of 2.85.  The risk for any type of pancreatitis within 5 years of diagnosis was 2.76.  All types of pancreatitis were increased including acute pancreatitis with gallstones, non-gallstone acute pancreatitis, and chronic pancreatitis.

What are potential reasons for this association between pancreatitis and celiac disease?

  1. Malnutrition may impair pancreas function
  2. Associated papillary inflammation could increase risk of acute pancreatitis
  3. The two diseases may share immunologic characteristics that increase the risk of both disorders
  4. Elevated levels of asymptomatic pancreatic enzymes could lead to some false-positive cases

Related blog entries:

How new therapies impact colectomy in UC patients

Posted on by

Has the need for colectomy changed with the increasing use of more potent medical therapies for ulcerative colitis (UC)?  One article gives some insight into this question (Inflamm Bowel Dis 2012; 18: 1641-46).

This French study followed 151 patients with newly diagnosed UC from 2000-2008; median followup was 58 months. During this time, 21 patients (14%) underwent colectomy.  1.3% required colectomy in the first year following diagnosis.

Looking closer at their study, 55% of patients had pancolitis.  Cyclosporin usage, typically given in refractory cases, was the only medication determined to be a predictive factor for surgery.

Medication usage during study period:

  • 68% oral mesalamine products
  • 72% systemic corticosteroids
  • 7% methotrexate
  • 49% azathioprine
  • 9% cyclosporin
  • 30% had received at least one anti-TNF agent

The authors concede several limitations, including the evolving nature of UC treatment.  Yet, they conclude that colectomy still is frequently needed and the use of IBD medications, including anti-TNF, “does not appear to reduce the long-term need for surgery in UC.”

I take issue with the last sentence.  Whether anti-TNF agents prove to be a disease-modifying treatment over the long-term is not known.  In this particular cohort, only 30% were even exposed to these agents.  My conclusion: we need a study designed to answer the question.  This would require larger numbers of patients followed prospectively for many years.

Related blog entries: