Tag Archives: celiac disease

Celiac Disease: “Ten Things That Every Gastroenterologist Should Know”

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Turns out that a recent review (AS Oxentenko, JA Murray. Clin Gastroenterol Hepatol 2015; 13: 1396-1404) is a succinct summary on celiac disease with questions focused on diagnosis, endoscopy, genetics/HLA typing, at risk groups, management, adherence, non responsive celiac patient, and refractory patients.  Most of these topics have been addressed previously on this blog.

However, here are a few pointers:

  • “Histologic improvement is slow in adults…Mucosal recovery, defined by a villous:crypt ratio of 3:1, was present in 34% at 2 years and 66% at 5 years, with healing complete in 90% by 9 years.”
  • “Mucosal recovery is faster and more complete in children, with 95% recovery in 2 years and 100% recovery long-term in children following a GFD.”
  • With nonresponsive celiac disease, “defined as a lack of response to 6 months on a GFD or a recurrence of celiac-related features despite compliance,” the authors recommend reviewing serology and biopsies.  Other etiologies to consider include bacterial overgrowth, autoimmune enteropathy, tropical sprue, Crohn’s disease, combined variable immunodeficiency, collagenous sprue, and eosinophilic gastroenteritis.
  • For refractory celiac disease with ongoing villous atrophy, this “should prompt immunophenotyping and T-cell rearrangement studies” of duodenal biopsies.

Briefly noted: ET Jensen et al. Clin Gastroenterol Hepatol 2015; 13: 1426-31.  The authors examined 88,517 patients who had undergone both esophageal and duodenal biopsies.  “Odds of EoE (eosinophilic esophagitis) were 26% higher in patients with celiac disease than in patients without celiac disease” (adjusted odds ratio 1.26).

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From the High Line, NYC

From the High Line, NYC

Celiac Disease and Neuropathy

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From GI & Hep News: Celiac Disease Associated with 2.5-fold Risk of Neuropathy

Here’s an excerpt:

The use of Swedish population registries enabled first author Dr. Sujata P. Thawani of Columbia University, New York, and her colleagues to find that the risk of neuropathy was increased both before and after a diagnosis of celiac disease (CD).

“We found an increased risk of neuropathy in patients with CD that persists after CD diagnosis. Although absolute risks for neuropathy are low, CD is a potentially treatable condition with a young age of onset. Our findings suggest that screening could be beneficial in patients with neuropathy,” they wrote (JAMA Neurol. 2015 May 11 [doi:10.1001/jamaneurol.2015.0475]).Neuropathy has a known association with CD, an immune-mediated disorder characterized by sensitivity to gluten with an incidence of about 1% in Western Europe…

Dr. Thawani and her associates used Swedish pathology registers to identify individuals whose small intestine biopsies showed villous atrophy between 1969 and 2008 (Marsh stage 3, n = 28,232)…Each CD patient was matched with up to five age- and sex-matched controls (n = 139,473) from the Swedish Total Population Registry, all of whom were diagnosed in the same year and were from the same county as the matched CD patient. 

Although 41.7% of CD patients were diagnosed in childhood, the median age at diagnosis was 29 years…

Surveillance bias may account for some of the increased risk for neuropathy…Notably, though, patients with a prior neuropathy diagnosis also were more likely to be diagnosed with CD, showing a bidirectional relationship. 

Grand Tetons

Grand Tetons

New Therapy for Celiac Disease: Larazotide Acetate

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A recent randomized controlled trial study (Gastroenterol 2015; 148: 1311-9) examined the effectiveness of larazotide acetate in 342 adults with Celiac disease (CD) who had ongoing symptoms despite the use of a gluten-free diet for at least 12 months.

Larazotide acetate is a locally acting, nonsystemic 8-amino acid oral peptide which is a tight junction (TJ) regulator.  “Larazotide acetate appears to prevent opening of intestinal TJs by promoting TJ assembly and actin filament rearrangement, which prevents gluten from reaching the intestinal submucosas and triggering an inflammatory response.”

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Patients received either placebo, 0.5 mg, 1 mg, 2 mg three times daily. The majority of patients had normalized serology at the start of the study.  Key findings:

  • “The 0.5 mg dose showed a 26% decrease in celiac disease patient-reported outcome symptomatic days (P =.017), a 31% increase in improved symptom days (P =.034), a 50% or more reduction from baseline of the weekly average abdominal pain score for 6 or more of 12 weeks of treatment (P =0.022), and a decrease in the nongastrointestinal symptoms of headache and tiredness (P =0.010).”
  • The 1- and 2-mg doses were no different from placebo for any end point.
  • Safety was comparable to placebo.

The authors state that is unclear why the higher doses were not effective “but may involve peptide aggregation … reducing activity in vivo.”

Bottomline: There would be a benefit for an adjunct to a gluten-free diet due to the difficulty in adherence and due to ongoing symptoms in some despite the use of a GFD; in some cases, symptoms may be induced by inadvertent deviation from GFD.  More data is needed to determine if larazotide acetate will be useful in this role.

Related blog post: Good Educational Two Minute Celiac Video | gutsandgrowth

Generation R Study: Insights into the Effects of Anti-Tissue Transglutaminase Antibody Positivity

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In a study from Rotterdam (Jansen MAE, et al. Clin Gastroenterol Hepatol 2015; 13: 913-20), the authors show that positivity for anti-tissue transglutaminase IgA antibodies (TTG) is associated with lower growth trajectories and bone mineral density.

This was a population-based prospective cohort study which examined children born from 2002-2006 (median age 6 years).  4249 children with TTG <7 U/mL were compared with 57 children with TTG >7 U/mL.  The authors specifically looked at those >70 U/mL as well. Children with a previous diagnosis of celiac disease were excluded.

Key findings:

  • Positive TTG serology was associated with reduced weight gain 0.05 standard deviation score (SDS) per year and less linear growth 0.02 SDS/year.
  • Children with positive TTG were shorter 0.29 SDS and weighed less 0.38 SDS.
  • Children with positive TTG had lower bone mineral density (BMD) 0.26 SDS less.
  • Children with positive TTG did not have increased gastrointestinal symptoms compared with control children.

The authors note that the majority of these effects (poor growth, shortness, lower BMD) were mostly present in children with TTG >10 times upper limit of normal.

Bottomline: Subclinical or potential celiac disease is associated with reduced growth and bone mineral density.

Briefly noted:  Emilsson L, et al. Clin Gastroenterol Hepatol 2015; 13: 921-27.  Using a Norwegian cohort study with 95,200 women and 114,500 children (199-2008), the authors showed that development of celiac disease was associated with maternal celiac disease and type 1 diabetes.  There was no significant association noted with intrauterine growth, or mode of delivery.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Cumberland Island

Cumberland Island

 

PPIs and Associated Heart Risk

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A NY Times review PPIs and Heart Attacks of PLos One study showing an association between PPI usage (eg. prilosec, prevacid, and nexium) and heart attacks -this study does not prove any causality, but is likely to spark some questions. Excerpt:

The widely used drugs known as proton pump inhibitors, or P.P.I.’s — gastric reflux preventives like Prilosec and Prevacid — may increase the risk for heart attack, according to analysis of data involving almost three million people.

A significant limitation of the study, in PLOS One, is that P.P.I. usage may be a marker of a sicker patient population, more subject to heart disease in any case.

Here’s NPR’s take on the same study: Data Dive -Possible Link Between PPIs and Heart Attacks

“The increase in risk is about 16 to 20 percent, depending on the particular drug involved”…

Someone with a low risk of heart attack doesn’t have much to worry about. “If your risk of a cardiovascular event or a heart attack is one in a million, now it is 1.2 in a million,” [Nigham] Shah [one of the authors] says.

“The problem is, it’s very easy to do studies of this sort that lead to conclusions that can be misleading,” says Dr. David Juurlink, a drug-safety researcher at the University of Toronto…

“Having a bad diet, drinking too much alcohol, smoking and all sorts of other things … might lead people to be on a PPI,” Juurlink says. One would expect those people to be at higher risk of heart attack, which leads Juurlink to think the medicine is likely not to blame.”

 

Also noted:

Wheat Intolerance Syndrome?

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Even though we’ve lived in our house for many years, some of our neighbors refer to our house as the ‘Walden’ house; the Waldens lived here for a long time before we did. Probably when we move, our neighbors will call our present home the “Hochman” house, regardless of who resides there.

I think nomenclature in medicine has a similar reluctance to adopt new terms.  A recent medical progress report (Guandalini S, Polanco I. J Pediatr 2015; 166: 805-10) suggests dropping the term “Nonceliac gluten sensitivity” (NCGS) in favor of “Wheat Intolerance Syndrome.”

It’s probably a good idea and their arguments are sound. Two key points:

  • “There is no proof that gluten is causing NCGS.”
  • It is likely that the majority of patients considered NCGS have not even eliminated celiac disease before instituting a gluten-free diet.

With regard to the first point, the authors note that recent studies have suggested that a “FODMAP” (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet is likely the culprit in many cases of so-called NCGS.  They review a pivotal double-blind study (see related blog post: An Unexpected Twist for “Gluten Sensitivity” | gutsandgrowth) there was no role for gluten “at least in these patients with IBS-like NCGS.”  In addition, other studies have demonstrated a strong role for a placebo/nocebo effect of dietary elimination.  “It is quite conceivable that a portion of patients with NCGS, and arguably a substantial one, fall in this category.”

With regard to the second point, it is not a good idea to initiate a gluten-free diet before excluding the diagnosis of celiac disease (hence the prior term: “nonceliac” gluten sensitivity).  A related comment from the authors is that a “Grade 1 [Marsh] intestinal lesion has traditionally been considered of a very low specificity for celiac disease.”  More testing in this circumstance can help determine if celiac disease is the reason, including checking the levels of ϒδ T-cell receptors in intraepithelial lymphocytes (very specific for celiac disease) and/or detection of IgA anti-tissue transglutaminase antibody deposits in intestinal mucosa.

Other pointers:

  • Genetic testing for HLA-DQ2 and/or HLA-DQ8 genotypes (which are nearly 100% in celiac disease) are present in about 40% of NCGS which does not differ from the general population
  • “Estimating the prevalence of NCGS is impossible.”  Estimates have ranged from 0.6% of the U.S. population to as high as 50% according to some websites.

Bottomline: While “Wheat Intolerance Syndrome” works fine for me, I think the term nonceliac gluten sensitivity is going to be around for a while.  Hopefully, more families and care providers will exclude celiac disease before contemplating this label and consider other foods as potential contributors to the symptomatology.

Related Reference: “Coeliac Disease and Noncoeliac Gluten Sensitivity” Meijer CR, Shamir R, Mearin ML. JPGN 2015; 60: 429-32.  This reference covers much of the same territory.  The Table 1 in this article nicely summarizes the relevant literature/studies from 2008-2014.

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How Likely is Celiac Disease if My TTG Test Is Only a Little Bit Abnormal?

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A terrific celiac serology study (Gidrewicz D, et al.Am J Gastroenterol 2015; -advanced online publication doi: 10.1038/ajg.2015.87) helps answer questions about the utility of serology in making diagnostic decisions. (Thanks to corresponding author J Decker Butzner for sharing reference.)

Using consecutive samples in a laboratory database with 17,505 patients, the authors retrospectively examined the performance of the tissue transglutaminase (TTG), endomysial antibody (EMA) tests and the ESPGHAN celiac guidelines for nonbiopsy diagnosis of celiac disease.  Among this large cohort, 775 with positive TTG and 574 with a negative TTG were biopsied.

Key findings:

  • If the TTG >10-fold the upper limit of normal (ULN) along with a positive EMA and symptoms were present, 98.2% had biopsies consistent with celiac disease.
  • If the TTG was 3-10-fold-ULN along with positive EMA, then 75.7% had biopsies consistent with celiac disease.  The histology of celiac disease (CD) was present in only 40% of the TTG 3-10-fold ULN if EMA was negative.
  • If the TTG was 1-3-fold-ULN along with positive EMA, 52.2% had CD-positive histology, whereas CD-positive histology was evident in only 13.3% of TTG 1-3-ULN if EMA was negative.
  • IgA deficiency is common in CD (“1in 60 vs 1 in 700” in general population)

Implications & Take-home points:

  • The researchers note that the positive predictive value of TTG drops when the prevalence of CD in the testing population is lower.  Thus, in their population and most clinical practice where the prevalence is below 35-40%, the PPV of the TTG-based tests drops to <80%.
  • While TTG-based tests have high specificity, there are multiple medical conditions that can cause a false positive (additional reference below), including autoimmune diseases like diabetes mellitus, inflammatory bowel diseases as well as infections, and liver disorders.
  • Asymptomatic patients with low TTG titers and negative EMA may benefit from following celiac serology rather than proceeding immediately to intestinal biopsy.
  • Using ESPGHAN nonbiopsy criteria (symptomatic child, TTG ≥10 ULN, positive EMA, positive HLA typing), there were four patients whose initial biopsies were not consistent with CD.  Thus these criteria identified 98.2% accurately who did not need an intestinal biopsy.  One of these four developed CD subsequently.  To achieve 100% PPV for non biopsy, the authors note that one would need an EMA titer ≥1:80.
  • Study limitations: retrospective study, lack of standardization between TTG assays

Bottomline: EMA improves the PPV of TTG testing, especially when low titer elevations are noted.  TTG alone is a highly sensitive test “with a 99.4% negative predictive value” in this study.

Related study: “Serum Anti-Tissue Transglutaminase Antibodies Detected during Febrile Illness May Not be Produced by the Intestinal Mucosa” J Pediatr 2015; 166: 761-3.  This case report describes two children with abnormal TTG (one more than 20-fold ULN)) both were EMA-negative. No mucosal anti-TTG was identified using two immunoassays.

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Taking One ‘Bite’ At A Time -For Celiac Diagnosis

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A small study (reference from KT Park’s Twitter feed –Gastrointestinal Endoscopy DOI: http://dx.doi.org/10.1016/j.gie.2014.10.024) suggests that taking a single biopsy per pass rather than two biopsies per pass results in better quality specimens:

Link: Endoscopic Biopsy Technique in the Diagnosis of Celiac Disease

Here are the results and conclusion of the abstract:

Results

Patients (N = 86) were enrolled, 47% with known celiac disease, 36% with suspected celiac disease, and 17% with an unknown celiac disease status. Well-oriented biopsy specimens were noted in 66% of patients with the single-biopsy technique and 42% of patients with the double-biopsy technique (P < .01). Analysis of matched pairs showed improved orientation with the single-biopsy technique (odds ratio 3.1; 95% confidence interval, 1.5-7.1; P < .01). This persisted in subgroup analysis of patients with known celiac disease (P = .02), villous atrophy (P = .02), and a final diagnosis of celiac disease (P < .01).

Conclusion

The single-biopsy technique improves the yield of well-oriented duodenal biopsy specimens. Endoscopists should consider taking only 1 biopsy specimen per pass of the forceps in patients undergoing biopsies of the duodenal mucosa.

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I'm the one on the right

I’m the one on the right

Can an Altered Microbiome Explain Persistent Symptoms in Treated Celiac Disease?

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A recent study (Am J Gastroenterol dii:10.1038/ajg.2014.355) from Helsinki examined 177 patients with celiac disease.  Their goal was to investigate whether altered intestinal microbiota may be associated with persisting gastrointestinal symptoms in celiac patients who had been following a strict gluten-free diet (GFD) for at least 3 years.

After administering a questionnaire (Gastrointestinal Symptom Rating Scale or GSRS) to those with negative celiac antibodies and normal small bowel mucosa (n=164), the researchers identified the 18 subjects with the highest total score (persistent symptom group) and compared them to the 18 subjects with the lowest total score.  Three duodenal biopsies during endoscopy had been frozen and were subsequently analyzed for their microbial DNA.  In each group, one microbial profile was unsuccessful.

Key findings:

  • In the persistent symptom group, there was lower relative abundance of Bacteroidetes (15% vs. 25%, P=0.01), lower Firmicutes (33% vs 46%, P=0.05) and higher relative abundance of Proteobacteria (40% vs 21%, P=0.04).
  • The “microbial richness,” measured as a number of detected genera or operational taxonomic units (OTUs), was reduced in patients with persistent symptoms.  On average, patients with persistent symptoms had 32 genera and 72 OTUs per sample; in contrast, those without symptoms, on average had 37 genera and 106 OTUs.

Some of the strengths of this study include the normal villous architecture for all of the patients; this helps exclude refractory celiac disease as an etiology for the persistent symptoms.  In the discussion, the authors note that the “intestinal microbiota composition in healthy adults is relatively stable and can tolerate normal stress in the intestine caused by, e.g. daily changes in diet.” The speculate that long-term untreated celiac disease “may disrupt a stable intestinal microbiota community that, in some patients, could then reform in a dysbiotic state.”

The limitations of this study include the difficulty of excluding small intestinal bacterial overgrowth which could be related and the difficulty of excluding coexisting irritable bowel syndrome.  Like most studies regarding the micro biome, this study cannot “show causality or distinguish the effects of different bacteria to the persistent symptoms.”

Bottomline: Treated celiac patients with persistent symptoms have a different duodenal microbiome compared to treated celiac patients whose symptoms resolved with a gluten-free diet.

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Family Feud with Allergies and Celiac Disease

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A recent article in Allergic Living highlights the common phenomenon of other family members not believing or not willing to make changes in the face of food allergies and celiac disease.

Here’s an excerpt:

Every day, adults and kids are diagnosed with food allergies or celiac disease, and they naturally expect that the people closest to them will take the most care – as they would with any serious health condition. After all, you should be able to trust your mom to keep gluten out of her gravy, and assume that, when your brother babysits your peanut-allergic daughter, he carefully reads the ingredients on that chocolate bar, right?

For too many living with food allergies and celiac disease, sadly the answer is no. In the fall of 2010, Allergic Living sent out a request for anecdotes of family experiences (both good and bad), and within days we were inundated with responses…

In the end, there is no magic cure that will work for every family because complex problems cannot be solved with simple solutions – and, as they say, you don’t choose your family. But clear and calm communication is vital, as is the ability for those living with allergies to put themselves in their relatives’ shoes.

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