Zonulin –Possible Biomarker for Gluten Sensitivity?

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A recent abstract indicated that there are high levels of zonulin in patients with gluten sensitivity as well as in patients with celiac disease.  These results are preliminary but could indicate a potential biomarker for this condition.  Here is a link to a review of these findings from NPR which includes commentary from Alessio Fasano: A Protein In The Gut May Explain Why Some Can’t Stomach Gluten

An excerpt:

Zonulin is an inflammatory protein first discovered by Fasano and his team in 2000. It helps regulate leakiness in the gut by opening and closing the spaces or “junctions” between cells in the lining of the digestive tract…

Giovanni Barbara and a team of researchers at the University of Bologna measured blood levels of zonulin in four groups of individuals: those with celiac disease, those with irritable bowel syndrome marked by diarrhea, those with self-diagnosed gluten sensitivity and healthy volunteers. Both celiacs and gluten sensitives turned up with remarkably high levels of zonulin in their blood. Those with IBS had elevated levels but less than half of celiacs or gluten sensitive individuals. Healthy volunteers had negligible blood levels of zonulin.

The results were presented in October as an abstract at the 23rd United European Gastroenterology Week in Barcelona, Spain.

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“Changing Paradigm in Hemolytic Uremic Syndrome”

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A recent study from the January 2016 Pediatrics (thanks to Michael Hart for this reference) demonstrates that more aggressive early volume expansion improved outcomes in hemolytic uremic syndrome compared with historical controls.  The full abstract is below.  An associated editorial (Shifting the Paradigm in Hemolytic Uremic Syndrome by David N. Cornfield) makes several points:

1. “The elegantly simple study design led to a relatively straightforward, yet palpably important conclusion that upon presentation, timely administration of sufficient intravenous fluids to increase the child’s body weight by 10% meaningfully decreases length of stay, need for admission to a PICU, use of renal replacement therapy, and the incidence of long-term sequelae.”

2. “The authors were willing, and able, to effectively challenge the standard approach for treatment of STEC-HUS. Over the course of the past several decades, care providers were wary of providing intravenous fluids in the context of renal insufficiency, owing to concerns over potential for fluid overload.”

3. “That the authors were able to demonstrate efficacy after enrolling only 38 children is remarkable. Outcomes were improved for almost every end point studied. The important end points that did not reach statistical significance, death, and central nervous system involvement likely result from a justifiable type 2 error.”

Abstract

BACKGROUND: Hemolytic uremic syndrome associated with Shiga toxin–producing Escherichia coli (STEC-HUS) is a severe acute illness without specific treatment except supportive care; fluid management is concentrated on preventing fluid overload for patients, who are often oligoanuric. Hemoconcentration at onset is associated with more severe disease, but the benefits of volume expansion after hemolytic uremic syndrome (HUS) onset have not been explored.

METHODS: All the children with STEC-HUS referred to our center between 2012 and 2014 received intravenous infusion targeted at inducing an early volume expansion (+10% of working weight) to restore circulating volume and reduce ischemic or hypoxic tissue damage. The short- and long-term outcomes of these patients were compared with those of 38 historical patients referred to our center during the years immediately before, when fluid intake was routinely restricted.

RESULTS: Patients undergoing fluid infusion soon after diagnosis showed a mean increase in body weight of 12.5% (vs 0%), had significantly better short-term outcomes with a lower rate of central nervous system involvement (7.9% vs 23.7%, P = .06), had less need for renal replacement therapy (26.3% vs 57.9%, P = .01) or intensive care support (2.0 vs. 8.5 days, P = .02), and needed fewer days of hospitalization (9.0 vs 12.0 days, P = .03). Long-term outcomes were also significantly better in terms of renal and extrarenal sequelae (13.2% vs 39.5%, P = .01).

CONCLUSIONS: Patients with STEC-HUS had great benefit from early volume expansion. It is speculated that early and generous fluid infusions can reduce thrombus formation and ischemic organ damage, thus having positive effects on both short- and long-term disease outcomes.

Related study showing that more aggressive fluid management also helpful in a pediatric cohort with clinical sepsis/shock: AA Arikan et al. J Pediatr 2015; 1301-5. “A protocol-driven implementation of a resuscitation bundle in the pediatric ED decreased acute kidney injury and need for renal-replacement therapy, as well as PICU and hospital LOS and mortality. Compared with patients prior to this bundle, there was increased fluid given (mean 56 mL/kg vs. 49 mL/kg) and initial bolus was given sooner (mean 34 min compared to 65 min).

Mt. Ranier

Mt. Ranier

NEJM: Functional Dyspepsia

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A recent NEJM had a concise review of functional dyspepsia (Talley NJ, Ford AC. NEJM 2015; 373: 1853-63).

With regard to functional dyspepsia in adults, the authors note that using the Rome III criteria, the global prevalence is between 5% and 11%.

While symptoms do not reliably distinguish organic and functional dyspepsia, they note that “with a relatively low rate of identification of organic disease, it is neither desirable nor realistic to perform this test [upper gastrointestinal endoscopy] in all patients with dyspepsia.”

Their review suggests several criteria to consider to help determine who needs endoscopy including age >55 yrs, GI bleeding, dysphagia, persistent vomiting, unintentional weight loss, family history of gastric or esophageal cancer, and iron-deficiency anemia.

With regard to workup, they suggest testing for H pylori non invasively with either breath testing or stool antigen testing.  The review covers treatment approaches including acid suppression (“effect is modest”), antidepressants (“tricyclic antidepressants…should be preferred over selective serotonin-reuptake inhibitors”), prokinetic agents, psychological treatments, and complementary approaches.  Figure 3 provides a helpful algorithm.

With regard to prognosis, “approximately 15 to 20% of people with functional dyspepsia have persistent symptoms and 50% have resolution of symptoms; in the remaining 30 to 35% of patients symptoms will fluctuate and meet the criteria for another functional gastrointestinal disorder.”

Briefly noted: “Acute Anxiety and Anxiety Disorders are Associated with Impaired Gastric Accommodation in Patients with Functional Dyspepsia” HG Ly et al. Clin Gastroenterol Hepatol 2015; 13: 1584-91.

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Sunrise in Sandy Springs

Sunrise in Sandy Springs

Why Does Enteral Nutrition Work for Crohn’s Disease? Is it due to the Microbiome?

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A recent study (K Gerasimidis et al. Am J Gastroenterol advance online publication 3 November 2015; doi: 10.1038/ajg.2015.357. Full Text: Extensive Modulation of the Fecal Metagenome in Children With Crohn’s Disease During Exclusive Enteral Nutrition) finds that treatment with Exclusive Enteral Nutrition further reduces microbiome diversity compared to healthy controls. This was an unexpected finding as the authors state: “we would expect EEN treatment to normalize the perceived ‘dysbiotic’ microbiota toward a healthier state.”

Reference from KT Park’s twitter feed. Here’s the abstract:

OBJECTIVES:

Exploring associations between the gut microbiota and colonic inflammation and assessing sequential changes during exclusive enteral nutrition (EEN) may offer clues into the microbial origins of Crohn’s disease (CD).

METHODS:

Fecal samples (n=117) were collected from 23 CD and 21 healthy children. From CD children fecal samples were collected before, during EEN, and when patients returned to their habitual diets. Microbiota composition and functional capacity were characterized using sequencing of the 16S rRNA gene and shotgun metagenomics.

RESULTS:

Microbial diversity was lower in CD than controls before EEN (P=0.006); differences were observed in 36 genera, 141 operational taxonomic units (OTUs), and 44 oligotypes. During EEN, the microbial diversity of CD children further decreased, and the community structure became even more dissimilar than that of controls. Every 10 days on EEN, 0.6 genus diversity equivalents were lost; 34 genera decreased and one increased during EEN. Fecal calprotectin correlated with 35 OTUs, 14 of which accounted for 78% of its variation. OTUs that correlated positively or negatively with calprotectin decreased during EEN. The microbiota of CD patients had a broader functional capacity than healthy controls, but diversity decreased with EEN. Genes involved in membrane transport, sulfur reduction, and nutrient biosynthesis differed between patients and controls. The abundance of genes involved in biotin (P=0.005) and thiamine biosynthesis decreased (P=0.017), whereas those involved in spermidine/putrescine biosynthesis (P=0.031), or the shikimate pathway (P=0.058), increased during EEN.

CONCLUSIONS:

Disease improvement following treatment with EEN is associated with extensive modulation of the gut microbiome.

My take: We really don’t know why EEN works and we have a lot to learn about a ‘healthy’ microbiome.

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New Hepatitis B Treatment Guidelines

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Link to full article: Updated Hepatitis B Treatment Guidelines from AASLD

With regard to pediatrics:

9A. The AASLD suggests antiviral therapy in HBeAg-positive children (ages 2 to <18 years) with both elevated ALT and measurable HBV DNA levels, with the goal of achieving sustained HBeAg seroconversion.

“Most studies required ALT elevation (>1.3 times ULN) for at least 6 months with HBV DNA elevations for inclusion. Given that HBV DNA levels are typically very high during childhood (>106 IU/mL), there is no basis for a recommendation for a lower-limit value with respect to treatment. However, if a level <104 IU/mL is observed, therapy might be deferred until other causes of liver disease and spontaneous HBeAg seroconversion are excluded.”

“Duration of treatment with oral antivirals that has been studied is 1-4 years. It may be prudent to use HBeAg seroconversion as a therapeutic endpoint when oral antivirals are used, continuing treatment for an additional 12 months of consolidation, as recommended in adults. It is currently unknown whether a longer duration of consolidation would reduce rates of virological relapse.”

“Children who stop antiviral therapy should be monitored every 3 months for at least 1 year for recurrent viremia, ALT flares, and clinical decompensation.”

9B. The AASLD recommends against use of antiviral therapy in HBeAg-positive children (ages 2 to <18 years) with persistently normal ALT, regardless of HBV DNA level.

Another nice summary of current treatment recommendations: P Martin et al. Clin Gastroenterol Hepatol 2015; 13: 2071-87.  Table 5 lists recommendations for treatment of HBeAg-positive.

  • The main group needing treatment (entecavir, tenofovir, or PEGinterferon alfa-2a) are those with HBV DNA >2000 IU/mL and elevated ALT.  Table 6 lists recommendations for those with HBeAg-negative.  Main group needing treatment are the same (HBV DNA >2000 IU/mL and elevated ALT).
  • With both groups (HBe-Ag negative and positive), “consider liver biopsy or transient elastography” if elevated HBV DNA >2000 and normal ALT.  If histologic disease present, consider treatment.
  • One point the authors make about therapy regards duration: “Historically, HBeAg seroconversion was considered a durable response, and discontinuation of antiviral therapy was recommended after a period of consolidation therapy of 6-12 months from the time of HBeAg seroconversion. However, patients who discontinue therapy …can experience recurrent viremia and ALT flares.  Thus, long-term therapy is justified.”
  • For HBeAg negative patients who have compensated liver disease, loss of HBsAg for 6-12 months may be discontinued from therapy.

Hepatitis C Prevalence Underestimated

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A recent study (BR Edlin et al. Hepatology 2015; 62: 1353-63) provides data suggesting that Hepatitis C virus (HCV) infection has been underestimated.

The number most commonly used is derived from the 2003-2010 National Health and Nutrition Examination Survey (NHANES) which showed 3.6 million in the U.S. with antibodies to HCV and 2.7 million currently infected.

The authors performed a systemic review and note that ~1 million people were excluded from this survey including a large number at high risk for HCV: ~500,000 incarcerated people, and 220,000 homeless people.

Based on their analysis, they conclude that “the number of US residents who have been infected with hepatitis C is unknown but is probably at least 4.6 million…and of these, at least 3.5 million… are currently infected.”

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The Ecology of Microscopic Life in Household Dust

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An interesting article about the fungi and bacterial in our households –has implications for our microbiome and for our predilection for allergies: full text: The Ecology of Microscopic Life in Household Dust

Barbera ́n A et al. The ecology of microscopic life in household dust. Proc. R. Soc. B 282: 20151139. http://dx.doi.org/10.1098/rspb.2015.1139 (reference from KT Park’s twitter feed)

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This article was summarized in by Mark Fischetti in Scientific American: full text: Men and Women Alter a Home’s Bacteria Differently

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“To biopsy or not to biopsy” –that is the question (for Celiac disease)

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First off -thanks to Ben Gold for the following reference and the blog title as well.

  • CM Trovato et al. Am J Gastroenterol 2015; 110: 1485-89.

In this retrospective study (alluded to in a previous post:Celiac Update September 2015 | gutsandgrowth), the researchers examined whether “biopsy-sparing” protocols for symptomatic children with high titers of serum anti-transglutaminase (anti-TTG) antibody levels (>10 times upper limit of normal [ULN]) would be suitable for asymptomatic patients.

Background: In 2012, the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) published guidelines that it is possible to omit endoscopic biopsies for celiac disease if patients older than 2 years of age had high anti-TTG titers (>10 times ULN), positivity for EMA, compatible HLA DQ2 or HLA DQ8 and were symptomatic.

Findings:

  • Among 196 patients, the 40 who were asymptomatic had severe Marsh lesions (3a, 3b, or 3c) in 92% compared with 91% of 156 who were symptomatic. In both groups, the remaining patients had either Marsh 1 or 2 lesions.
  • 94.4% of patients had improved serology during followup along with symptomatic improvement (in those with symptoms)

Bottomline:  Whether symptomatic or not, those with high antiTTG titers who meet all of the other ESPGHAN criteria have a very high probability of celiac disease.

Briefly noted: K Marild et al. Am J Gastroenterol 2015; 110: 1475-84. This study, based on a large prospective Norwegian cohort (72,921 children) that frequent infections (>10) in the first 18 months of life increased the risk of celiac disease with an adjusted odds ratio of 1.32 (highest infection quartile compared to lowest infection quartile).  However, alternative explanations, including surveillance bias and reverse causation, cannot be excluded.

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The Science Behind IBS Dietary Interventions

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A succinct review (BE Lacy. Clin Gastroenterol Hepatol 2015; 13: 1899-1906) reviews the topic of dietary interventions for irritable bowel syndrome (IBS).

Here are some of the points:

  • “True food allergies are present in 1% to 4% of the US population, but are not more prevalent in IBS patients.”
  • One study found that “more than 1 in 4 patients with self-reported NCGS [nonceliac gluten sensitivity] actually fulfill the diagnosis.”  In other words, most patients with self-reported NCGS do not have NCGS.
  • “The prevalence of lactase deficiency is similar, or slightly higher, in IBS patients compared with healthy subjects; however, the self-reporting of symptoms attributed to lactose intolerance is not reliable.”
  • Potential mechanisms of food triggering GI symptoms were discussed, including intestinal permeability, visceral hypersensitivity, small intestine bacterial overgrowth, and gut microbiome.

Another article which covers the same topic: PR Gibson et al. Gastroenterol 2015; 148: 1158-74.

 

Which Diet is Best for Irritable Bowel Syndrome?

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As noted in this blog previously, there has been increasing evidence that a low FODMAPs (fermentable oligo-, di-, monosaccharides and polyols) diet is an effective option for irritable bowel syndrome (IBS) in adults and children. Now, a study (L Bohn et al. Gastroenterol 2015; 149: 1399-1407) directly compares a low FODMAPs diet with an IBS diet in a multicenter, parallel, single-blind study of 75 patients (adults) with Rome III criteria for IBS.

The comparison IBS diet recommended regular meal patterns, avoidance of large meals, reduced intake of fat and reduced insoluble fibers, caffeine, and gas-producing foods, such as beans, cabbage and onions.  In addition, this diet recommended avoidance of spicy foods, coffee, alcohol, soft drinks, and sweeteners that end with “-ol.” This diet has been recommended by the British Dietetic Association and by the National Institute for Health and Care Excellence (NICE).  NICE Guidelines for IBS

Key findings:

  • 67 patients completed the study.  The severity of IBS symptoms improved in both groups (P<.0001) without a difference between the two groups
  • 19 (50%) of low FODMAPs had reductions in IBS severity scores of >50 compared with baseline and 17 patients (46%) in the ‘traditional’ IBS diet group had this degree of improvement.

My take: Diet changes often result in symptom improvement in IBS.  Both of these diets can be recommended in patients with IBS.

Atlanta Sky

Atlanta Sky