Tag Archives: celiac disease

Gluten-related Disorders

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For those who missed a recent NASPGHAN Foundation webinar, I’ve attached two links (with permission from NASPGHAN foundation):

1. The PDF of the slides –these are very useful:

NASPGHAN GlutenWebinar 6_5_13 Final v34

2. Link to webinar, including CME:

http://limelightdc.com/clientarea/naspghan_gluten_webinar_06_13/landing_page.html

The experts provide a useful review of celiac, wheat allergy, and wheat intolerance.  For celiac screening, the webinar recommends avoiding a panel of serology tests in favor of isolated Tissue Transglutaminase IgA Antibody (possibly with serum IgA level.

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What really causes Celiac disease?

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A fascinating article in the NY Times delves into a number of environmental factors that are likely playing a role in the increasing incidence of celiac disease. Here’s the link (thanks to Kayla Lewis for this reference):

Some excerpts:
“Scientists are pursuing some intriguing possibilities. One is that breast-feeding may protect against the disease. Another is that we have neglected the teeming ecosystem of microbes in the gut — bacteria that may determine whether the immune system treats gluten as food or as a deadly invader.Celiac disease is generally considered an autoimmune disorder. The name celiac derives from the Greek word for “hollow,” as in bowels. Gluten proteins in wheat, barley and rye prompt the body to turn on itself and attack the small intestine. Complications range from diarrhea and anemia to osteoporosis and, in extreme cases, lymphoma. Some important exceptions notwithstanding, the prevalence of celiac disease is estimated to range between 0.6 and 1 percent of the world’s population….Yet the more scientists study celiac disease, the more some crucial component appears in need of identification. Roughly 30 percent of people with European ancestry carry predisposing genes, for example. Yet more than 95 percent of the carriers tolerate gluten just fine. So while these genes (plus gluten) are necessary to produce the disease, they’re evidently insufficient to cause it….

A recent study, which analyzed blood serum from more than 3,500 Americans who were followed since 1974, suggested that such a trigger could strike adults at any time. By 1989, the prevalence of celiac disease in this cohort had doubled.

“You’re talking about an autoimmune disease in which we thought we had all the dots connected,” says Alessio Fasano, head of the Center for Celiac Research and Treatment at the Massachusetts General Hospital for Children in Boston, and the senior author of the study. “Then we start to accumulate evidence that there was something else.”

Identifying that “something else” has gained some urgency. In the United States, improved diagnosis doesn’t seem to explain the rising prevalence. Scientists use the presence of certain self-directed antibodies to predict celiac disease. They have analyzed serum stored since the mid-20th century and compared it to serum from Americans today. Today’s serum is more than four times as likely to carry those antibodies…

your microbes change you, but your genes also shape your microbes — as do environment, breast milk, diet and antibiotics, among many other factors.

Such complexity both confounds notions of one-way causality and suggests different paths to the same disease. “You have the same endpoint,” Dr. Jabri says, “but how you get there may be variable.”…

In a far-flung corner of Europe, people develop celiac disease and other autoimmune diseases as infrequently as Americans and Finns did a half-century ago. The same genes exposed to the same quantity of gluten do not, in that environment, produce the same frequency of disease.

“We could probably prevent celiac disease if we just give the same environment to the Finnish children as they have in Karelia,” says Dr. Hyoty. “But there’s no way to do it now, except to move the babies there.”

Author of NY Times article:

Moises Velasquez-Manoff.  Also, he is the author of “An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases.”

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Celiac disease and less diabetes?

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While there is a well-recognized association between Celiac disease and insulin-dependent diabetes mellitus (IDDM), a recent study shows a lower prevalence of non-insulin dependent diabetes mellitus (NIDDM) and metabolic syndrome in patients with celiac disease (Gastroenterol 2013; 144: 912-17).

You-Tube Link: Patients With Celiac Disease Have a Lower Prevalence … – YouTube..Dr. Toufic A. Kabbani discusses his manuscript “Patients WithCeliac Disease Have a Lower Prevalence of Non-Insulin-Dependent Diabetes Mellitus and Metabolic Syndrome.”

A retrospective review of 840 patients with biopsy-confirmed celiac disease were compared with 840 random matched controls.  Controls were matched for age, sex, and ethnicity.  Mean age was 49.4 years.

Key findings:

  • 26 (3.1%) of celiac disease cohort and 81 (9.6%) (p <0.0001) had NIDDM.
  • 3.5% of celiac disease cohort and 12.7% of controls had metabolic syndrome.
  • Though celiac disease patients had lower BMI, these findings were still present after controlling for this variable.
  • Prevalence of NIDDM was strongly associated with age in both groups.  In celiac cohort, NIDDM occurred in 0% (n=343) of those <45, 3.1% in 45-64, and 9.3% in those >65.  In contrast, the control group had NIDDM in 3.5%, 11% and 19.3% respectively.

With regard to pathophysiology, the authors did not think the protection from NIDDM was related to malabsorption.  Evidence of malabsorption was more common in patients with CD and NIDDM than in those without NIDDM.

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Nuance in Celiac Serology Interpretation

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A recent study adds additional nuance to the interpretation of celiac serology (Clin Gastroenterol Hepatol 2013; 11: 398-403).

In this study the authors analyzed anti-TTG IgA levels from 104 consecutive pediatric and adult patients who were not IgA deficient.  The study took place between 2000-2009.  In addition, samples from 537 consecutive controls were available for comparison.

The study determined the likelihood of having celiac disease based on antibody level from four different companies and pre-test clinical factors.  The general population pretest probability was 1%; the pretest probability for their population was 6% if their were gastrointestinal complaints, 14% if weight loss/small stature was present, 11% for patients with anemia/iron deficiency, and 9% for patients with malabsorption.

Key findings:

Even in those with high antibody titers (>10-fold normal), if they were asymptomatic, only 53%-75% had celiac disease (depending on the individual assay).  That is, >10-fold elevation with some commercial assays did not correspond to >10-fold elevation in all of the assays leading to variable probabilities.

In patients with low level elevations (1-3 fold times the cut-off level), the probability of having celiac disease in asymptomatic individuals varied from 1% to 7%.  Thus, mild elevations in TTG IgA are not highly predictive in this asymptomatic population.  However, in those with pretest probability of 14%, the frequency of celiac disease varied among the four assays from 14% to 56%.

Take home message:  Not all assays for celiac disease are comparable.  While very high serology levels (>10 fold) are associated with celiac disease, in asymptomatic patients as few as 53% may have celiac disease.

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ADHD patients– not at increased risk for Celiac disease

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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.

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Expert review: Celiac disease

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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.

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Is functional pain more common in children with Celiac disease?

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A recent study adds information to the title question but does not resolve it (J Pediatr 2013; 162: 505-09).

The authors note that they expected to find a higher prevalence of abdominal pain and abdominal pain/functional gastrointestinal disorders among children with diagnosis of celiac disease.  They note that functional disorders have been more common after acute gastroenteritis and cow’s milk hypersensitivity of infancy presumably due to preceding inflammation.  Persistent low-grade intestinal inflammation and immune activation have been proposed as precipitating susceptibility to functional abdominal pain.

In this small retrospective study, a statistically significant difference in functional GI disorders was not observed.  Enrolled families were contacted by telephone at least 6 months after the diagnosis of Celiac disease.  They completed a telephone questionnaire and a separate Rome III questionnaire.

Celiac cases (n=49):  abdominal pain (24.5%), functional abdominal pain (4.8%), IBS (6.1%), dyspepsia (4.8%), abdominal migraine (4.8%), nonspecific abdominal pain (6.1%)

Control cases (n=48): abdominal pain (14.6%), functional abdominal pain (6.3%), IBS (2.1%), nonspecific abdominal pain (6.1%)

Given the question that the authors were trying to answer, this study was unlikely to be helpful.  Problems with the study:

  • The biggest problem is the small number of patients.
  • Cross-sectional design
  • Reliance of recall symptoms
  • Lack of information on dietary adherence
  • Collection of information from only parents contributed

Bottomline: While screening for celiac disease is common in patients with possible functional abdominal pain, treatment with a gluten-free diet may not resolve these symptoms. Functional abdominal pain is at least as common in children with celiac disease as in the general population.

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Shout out for Gluten-Free Camp

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One enjoyable aspect about my work with my colleagues has been their willingness to use their free time to participate and develop programs for children.  For many years, this has included several camps at Camp Twin Lakes, particularly Camp Oasis for children with inflammatory bowel disease. Most of the physicians in our group have given their time to support this camp.  In recent years, Larry Saripkin has spent a week there every summer  and Stan Cohen really established this camp in Atlanta.  In addition, our nurses have volunteered their time as well; they stay busy attending to the medical needs of these kids so they can enjoy a camp experience.

More recently, a camp for kids with celiac disease has been started, Camp WeeKanEatIt.   Under Jeff Lewis’ direction and fundraising, this camp has been started and allows kids  (8-17 yrs) who need to be maintained on a gluten-free diet to experience camp.  Siblings are allowed to attend as well.  Don’t forget this year’s camp dates: June 23-28!

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Duodenal IELs and the likelihood of celiac disease

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The diagnosis of celiac disease has definitely become more complex due to the interplay of serology, genetic markers, clinical response to gluten-free diets, and histology.  The Mayo clinic pediatric experience with duodenal intraepithelial lymphocytosis (IELs) with normal villous architecture highlights this issue (JPGN 2013; 56: 51-55).

Between 2000-2009, 56 children from the Mayo clinic pathology database of duodenal biopsies (n=1290) were identified.  Among this group, 48 had serological testing for celiac disease (CD).  Ultimately, 9 were labeled with CD, though only 5 met the ‘definite’ criteria.  Other conditions that were associated with increased IELs included the following:

  • Medication exposure
  • Inflammatory bowel disease
  • H pylori infection
  • Autoimmune conditions
  • IgA deficiency

So, which patients with duodenal IELs had CD?

  • “Definite” CD was used to define patients with elevations in two different serologic markers (TTG and EMA) or those with elevation in one serologic marker along with a documented clinical response to a gluten-free diet (GFD).
  • “Possible” CD described patients with normal serology, but serologic titer and clinical response was noted on a GFD.
  • “Unlikely” CD categorized patients with two negative serology markers who had compatible human leukocyte antigen haplotype and had clinical response to GFD.

In addition, if the IELs were predominantly on the villi tips, this increased the likelihood of CD.

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False-positive serology for Celiac disease

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It is prudent to exercise caution in establishing a diagnosis of Celiac disease (CD) in young asymptomatic children who are identified with screening serology (J Pediatr 2012; 161: 980-14).

In this Italian study, a nationwide, multicenter, prospective intervention trial was established to assess the role of age at gluten introduction on development of CD.  Subjects were recruited at birth who were at increased risk for CD; they had at least one first-degree relative with CD.

In their cohort, 96 children were identified.  In addition to having an affected first-degree relative, all children had positive serology (21 with positive tissue transglutaminase IgA antibody [tTG] and 1 with IgA deficiency/positive gliadin IgG antibody) and results of a small intestinal antibody.

While 72 had definitive CD, 24 were considered potential CD (serology positive/Marsh 0-1 histology) and asymptomatic.  The fascinating part of this study was the followup of the potential CD cases –21/24 continued on a regular diet.  Only 1 developed overt CD. 18 (86%) developed normal serology and 2/21 had fluctuating antibody levels after two years.

Based on their findings as well as consensus guidelines, the authors propose that asymptomatic young patients with abnormal serology should be followed for at least 3-6 months as long as tTG < 11 times ULN.

Other findings:

  1. Breastfeeding may have a protective role; individuals with overt CD had a shorter mean duration of breastfeeding than the potential CD group (4.2 months compared with 5.1 months).
  2. Gluten introduction at age 6 months did not increase risk of overt CD (compared to potential CD) relative to introduction at 12 months.

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