Congenital Sucrase Isomaltase Deficiency

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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

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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

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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:

Stopping criminality in ADHD

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While not much related to pediatric gastroenterology, I nevertheless found an article on the relationship between medication adherence for attention deficit-hyperactivity disorder (ADHD) and criminality to be provocative (NEJM 2012; 2006-14).

In this Swedish study with 25,656 patients, there was a significant reduction in the crime rate during periods of receiving the medication compared with nonmedication periods: 32% reduction for men and 41% for women.

Approximately 50% of the patients were between ages 15-24, 30% between 25-39, and the remainder >40 years.  Overall, 37% of the men had been convicted of any crime and 15% of the women.

To avoid possible bias from reverse causation, the investigators looked at whether the order of the change in medication status was important.  The criminality associations were significant regardless of the order, suggesting that this type of bias was unlikely.  The authors state that “it is possible that pharmacologic ADHD treatment helps patients to better organize their lives,” thereby decreasing their likelihood of crime.

There are many other concerns raised regarding ADHD medications, including adverse effects (eg. cardiovascular), overprescription, and side effects.  However, this inverse association with criminality should be added to other potential benefits.

Confronting Neglect

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A brief perspective article makes some useful points about involvement of child protective services (NEJM 2012; 367: 1976-77).

“A recent study of 595 high-risk children whose families were reported for CPS intervention showed no significant improvements in family functioning, social support, maternal education, or child behavior problems among children who received CPS intervention as compared with those who did not.”

The article concludes with an interesting quote:

“Theodore Roosevelt once said, ‘The welfare of each of us is dependent fundamentally upon the welfare of all of us.'”

While this is certainly true, it is difficult to figure out how to accomplish this sentiment.

Related post:

Is obesity neglect? | gutsandgrowth

Less stress after gastrostomy tube placement

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It has been said that it is easier to feed a child with a gastrostomy tube (GT) than by mouth.  Now a study reports improved maternal stress after GT placement (JPGN 2012; 55: 562-66), perhaps because it is easier to provide nutrition.

34 mothers from Norway took part in questionnaires (before, 6 months after, and 18 months after) as part of a study (2003-2005) to see how gastrostomy placement in a child affects maternal stress levels.  Median maternal age was 32 years.  The study was limited by a suboptimal response rate of 59% (34 of 59) and only 19 mothers answered questionnaires at all 3 timepoints.

While all of the children had some peristomal complications, 85% of the mothers reported that their preoperative expectations were met and that their child had improved quality of life.  Mothers had reduced psychological  distress at 6 and 18 months following placement, including less anxiety.

Related blog entries:

Monitoring TNF antagonists in inflammatory bowel disease

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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

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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:

Sedation Safety

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Many parents are terrified of anesthesia and other forms of sedation.  This fear is often not rationale given the excellent safety record.  Given the high publicity though, it is surprising how much variation occurs with regard to monitoring pediatric patients during procedures (Arch Pediatr Adolesc Med 2012; 166: 990-98, editorial 1067-68).  Thanks to Ben Gold for forwarding this article.

In this prospective observational study (2007-2011), 37 U.S. pediatric institutions which comprise the Pediatric Sedation Research Consortium collected data on subjects up to 21 years of age.  In total, data from 114,855 patients were collected.

The most common procedure specialties were radiology (59%), hematology/oncology (14%), and gastroenterology (9%); the most common procedures included MRI, lumbar puncture, bone marrow biopsy, upper endoscopy/colonoscopy, brainstem auditory response test, and catheter placement.

The ASA class were the following: 26% class 1, 56%  class 2, 17% class 3, and <1% class 4 & 5.  The location of procedures were predominantly in either radiology (51%) or sedation unit (43%).

Specific findings:

  • 5% of children did not have pulse oximetry monitoring; this included some ASA 3 and 4 patients.
  • 87% had noninvasive blood pressure monitoring
  • 67% had electrocardiogram (ECG) monitoring; ECG monitoring had the greatest variability in use among various providers
  • Radiologists were the least likely to use any of the measured monitoring modalities.  Pulse oximetry was used in only 33% of procedures in which the radiologist was responsible for sedation; this is compared with >90% of all other providers.
  • 45% were monitored with capnography
  • Guidelines for sedation (AAP, ACEP, ASA) were adhered to for 52% of subjects

While the authors frame the discrepancies as in part due to tailoring the sedation to the individual, they also argue for less variation because patients may have unknown diagnoses and due to iatrogenic error.  Currently, strong evidence-based data on sedation protocols is lacking.  As a consequence, expert opinion guides current practice.

While ECG monitoring had the most variation, it is known to be rarely needed in relatively healthy pediatric populations.  As such, the authors state that ECG monitoring “may be best used in those patients with specific cardiac pathologic features or when a rhythm disturbance is present.”

Use of pulse oximetry should not be overlooked.  Mild hypoxemia has been observed to precede more serious adverse events and may prompt interventions that preclude poor outcomes.

This report has many acknowledged limitations which are common with large database studies.  Nevertheless, the variability in monitoring should help guide ongoing improvement efforts.  While the study also showed very good outcomes (no deaths, one case of cardiac arrest), it is clear that the safety net could be better by making sure each procedure is monitored carefully.  According to AAP guidelines, the minimum consists of continuous pulse oximetry, and intermittent blood pressure monitoring; in addition, capnography (ETCO2) is encouraged.

Learning a lot from ChiLDREN (part 2)

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As noted in previous post (Learning a lot from ChiLDREN (part 1) | gutsandgrowth), several recent studies highlight the benefits of multisite collaboration to study infrequent pediatric liver problems.  In these studies, the Childhood Liver Disease Research and Education Network (ChiLDREN) has collected prospective longitudinal observational date from multiple centers; data from 10 centers provides useful information on the frequency of portal hypertension (PHT) in young adults with biliary atresia (BA) (JPGN 2012; 55: 57-73).

163 subjects were enrolled between May 2006 and December 2009.  Seven patients were excluded due to the presence of polysplenia which interferes with the assessment of PHT.

Demographics: subjects ranged in age from 1 to 25 years with a mean of 9.2 years.  56% were female, 75% were caucasian.

PHT was considered definite if there was either a history of a PHT complication (variceal bleeding, ascites) or if there were clinical findings c/w PHT (both splenomegaly and thrombocytopenia).  PHT was considered “possible” if either splenomegaly or thrombocytopenia was present and “absent” if no criteria were met.

  • PHT: definite in 80 (49%), possible in 27 (17%) and absent in 56 (34%)
  • 43 subjects had a history of PHT complications: 32 with esophageal variceal (EV) bleeding, 14 with ascites, and 8 with hepatopulmonary syndrome.
  • Of the patients with EV, only 3 had normal platelet count and normal spleen size.

Teaching points:

  1. One-third of subjects with EV bleeding survived with their native liver for at least 5 years.
  2. EV age of onset was highly variable; 7 had bleeding in the first two years of life.
  3. Growth parameters were fairly unremarkable in those with definite PHT.
  4. Long-term followup will be needed to identify factors which predict progression of PHT and the development of adverse outcomes.

Previous related blog posts: