Tag Archives: celiac disease

Elevated Celiac Serology Associated with Reduced Infant Birth Weights

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Using a population-based study of 7046 singleton pregnancies (from the Netherlands), the authors of a recent study have shown an inverse relationship between levels of anti-tissue transglutaminase IgA (TTG) antibodies and fetal growth (Gastroenterol 2013; 144: 726-35).

Results:

  • Newborns of positive TTG (>6 U/mL) weighed 159 g less at birth than newborns of mothers who tested negative for TTG.  In addition, newborns with mothers who had intermediate TTG levels ( 0.8 U/mL to 6 U/mL) had growth restriction of 53 g.
  • Among the intermediate TTG group, the results were more pronounced (2-fold greater) in those carrying the HLA risk molecules for celiac disease.
  • These birth weight changes were not associated with maternal nutritional status or deficiencies related to hemoglobin, iron, folate, or vitamin B12 deficiency.
  • Gestational age was not affected by TTG titers.

In the discussion, the authors note that other studies have shown that undiagnosed celiac disease increases the risk for intrauterine growth retardation; this risk can be eliminated by treating celiac disease.  The latter is a risk factor for lower neuropsychological performance.  This study was the first that took into effect the different TTG titers and correlated with additional nutritional parameters.

The authors speculate that celiac disease could have direct effects on the placenta.  In addition, other nutritional parameters could play a role such as vitamin D and calcium which were not included in this study.  Another important consideration is that celiac disease can result in increased miscarriages.  As a result, the “true” effect on newborn growth may be underestimated due to a “survivor bias.”

Related blog posts:

Celiac hepatopathies

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There has been a longstanding recognition that celiac disease can be associated with elevated liver enzymes.  Two articles provide further information about celiac hepatopathies.

  • JPGN 2013; 56: 663-70
  • JPGN 2013; 56: 671-74

The first study describes a review of nine studies identified in a MEDLINE search for celiac disease and hypertransamminasemia (HTS) or autoimmune hepatitis (AIH). In total 2046 patients were identified.

Key findings:

  • 12% of patients with mild persistent HTS had celiac disease.  Among individuals with HTS, the relative risk for celiac disease was 11.59 compared to general population.
  • 36% of newly diagnosed children with celiac disease, has elevated aminotransferases.  A gluten-free diet normalized transaminases in 77% within 4 to 8 months.
  • Among children with celiac disease, 1.4% had AIH.  Among children with AIH, 6.3% had celiac disease.

While this meta-analysis had many limitations, it is clear that celiac disease needs to be considered in patients presenting with elevated aminotransferases and in patients with AIH.  In addition, other liver conditions like primary biliary cirrhosis and sclerosing cholangitis, which are infrequent in the pediatric population, are more common in patients with celiac disease.

The second study involved both retrospective (1995-2000) and prospective evaluation (2000-2012) of patients followed at a single center.  The authors sought to determine the long-term response to immunosuppressive treatment in children with autoimmune hepatitis (AIH) and celiac disease.

In their cohort of 79 AIH patients, 15 (9%) had celiac disease.  There was a similar frequency of type 1, type 2 and seronegative AIH among the celiac patients (47%, 20%, and 33%) compared with the entire cohort (55%, 34%, and 11%).  All 15 patients responded to treatment with prednisone and azathioprine or cyclosporine, along with a gluten-free diet.  When immunosuppressive treatment was withdrawn in 9 patients, 4 relapsed and 5 were maintained off immunosuppression for a mean period of 89 months. A much lower rate of immunosuppression withdrawal was achieved in those AIH patients without celiac disease.  24 of 64 attempted to stop immunosuppression; 5 (8%) were successful.

Take-home point of second study: All AIH patients should be screened for celiac disease as a gluten-free diet may increase the likelihood of withdrawal of immunosuppression.

IBS Symptoms in Patients with Celiac Disease

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While a gluten-free diet (GFD) is the optimal treatment, adult patients with celiac disease still have a high prevalence of irritable bowel symptoms (IBS) (Clin Gastroenterol Hepatol 2013; 11: 359-65).

The authors examined the prevalence of IBS symptoms by reviewing cross-sectional and case-control studies in adults with celiac disease (≥16 years old).  Initially, the literature search identified 624 studies; the vast majority did not fit the study requirements.  Seven studies (n=3383 participants) reported the prevalence of IBS symptoms in celiac disease.  These studies took place between 2002 to 2011 in five different countries.  IBS was defined using either Rome I, II, or III criteria.  Only one of these studies assessed adherence to a GFD by using negative tissue transglutaminase antibodies on the 2 most recent outpatient visits.

Results: IBS symptoms were present in 38% of all patients with celiac disease.  The pooled odds ratio was higher for celiac disease than controls (OR 5.6, with 95% CI 3.23-9.7).  Nonadherence to a GFD increased the likelihood over those who were adherent by an odds ratio of 2.69

Take-home message: IBS symptoms are present in a high proportion of patients with celiac disease.  While a GFD may improve these symptoms, some individuals will have persistent symptoms.

Related blog entry:

Is functional pain more common in children with … – gutsandgrowth  Previous blog entry examines functional abdominal pain in children and celiac disease.

Additional references:

  • -JPGN 2011; 53: 216. Case report of refractory celiac treated with 6-MP.
  • -Clincal Gastroenterol & Hep 2011; 9: 13. Celaic with persistent symptoms: consider poor adherence**, SBBO*, pancreatic insufficiency*/subclinical pancreatitis, refractory celiac (rare), PLE, giardia, malignancy, lactose intolerance, functional d/o*, microscopic colitis, Crohn’s*, NSAIDs
  • -Gastroenterol 2009; 136: 81, 91, 99, 32. Refractory celiac can be divided into 2 types; 2nd type assoc c abnormal IEL and has poor prognosis. Risk of non-hodgkins lymphoma 3.8-5 .3 fold over gen population in larg Sweish study. n=37869 c NHL, 236,408 controls, 613,961 1st degree relatives. Relatives c 2 fold risk. Absolute NHL risk ~1 in 1421 person-yrs for celiac pt.
  • -Clin Gastroenterol & Hep 2007; 5: 445-450. Causes of nonresponsive celiac.
  • -NEJM 2007; 356: 2548. Nonresponsive due to inhaled gluten in farm setting.
  • -Clin Gastro & Hep 2007; 5: 445. Gluten exposure in 36%, IBS n 22%, lactose intol 8%, refractory CD 10%
  • -Gastroenterol 2011; 141: 1187.  Prevalence of celiac similar in IBS as general population though higher number (7%) with celiac antibodies (esp gliadin).

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.

Related blog links:

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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