>99% Accuracy in Non-Biopsy Diagnosis of Celiac Disease

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Another large study (KJ Werkstetter et al. Gastroenterol 2017; 153: 924-35) shows a high accuracy of diagnosing celiac disease (CD) without a biopsy when very high celiac titers are identified in symptomatic patients. A previous study (n=898) this year also showed similar findings: The Non-Biopsy Diagnosis of Pediatric Celiac Disease

The current study (2001-2014) identified 743 consecutive pediatric patients with positive celiac serology (TTG-IgA). Key findings:

  • If TTG-IgA was higher than 10-fold the upper limit of normal and a separate sample tested positive for endomysial antibodies, then non-biopsy approach had a positive predictive value >99.6%.  The authors utilized a variety of TTG-IgA assays.
  • The authors noted that HLA-DQ2/DQ8 typing did not improve the accuracy of CD diagnosis.  “Negative results for HLA-DQ2/DQ8 in patients with TGA or EMA positivity are most likely false negative …or due to very rare risk-allele combinations not recognized by the test systems.”
  • “At least 50% of affected children in clinical practice will benefit from this nonbiopsy approach, which reduces burden and risks of endoscopy and anesthesia” and is more cost-effective.

The authors’ conclusion: “allowing omission of biopsies enables a correct diagnosis of CD in symptomatic children if TTG-IgA exceed 10xULN and positive EMA-IgA confirms celiac disease autoimmunity in a second blood sample. If one of these criteria is not fulfilled, biopsy should be performed to confirm the diagnosis.”

My take: This study provides convincing data that CD diagnosis does NOT require an intestinal biopsy under specific conditions.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  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.

The MH Score: Separating primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome

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“Sincerity is the key to success. Once you can fake that, you’ve got it made.”

–Groucho Marx

The above quote is not particularly related to this blog post –but I like it.

A recent study (F Minoia et al. J Pediatr 2017; 189: 72-8) provides data supporting a scoring system which helps distinguish primary hemophagocytic lymphohistiocytosis (HLH) from macrophage activation syndrome (MAS).

Background: “By convention, secondary HLH seen in rheumatic disorders is termed macrophage activation syndrome…occurs most commonly in systemic juvenile idiopathic arthritis (sJIA).”  Both HLH and MAS are life-threatening, though HLH tends to be more severe.  The treatment for the two disorders is much different.

HLH typically develops in the first year of life, though some remain asymptomatic until later.  Identification of pathologic mutations (primary HLH is not a single disease) is considered the gold standard, but this “takes weeks to complete and is not available in many resource-limited areas.”

In this study, the authors reviewed clinical features from 362 patients with MAS and 258 patients with HLH to develop a scoring system that more readily distinguished these conditions.The data from 80% of the patients was used to construct the scoring system and then this was validated with the remaining 20%.  MH Score:

  • Age of onset, years:                              0 points if >1.6 yr, 37 points if ≤1.6 yr
  • Neutrophil count, x 10 to the 9th/L:      0 points if >1.4, 37 points if ≤1.4
  • Fibrinogen, mg/dL:                               0 points if >131, 15 points if ≤131
  • Splenomegaly:                                      0 points if no, 12 points if yes
  • Platelet count, x 10 to the 9th/L:           0 points if >78, 11 points if ≤78
  • Hemoglobin, g/dL:                                0 points if >8.3, 11 points if ≤8.3

The age of onset and severe neutropenia are weighted the most heavily as they most heavily influence the odds ratio of having HLH; with multivariate analysis (Table 3), age of onset ≤1.6 yrs had an OR of 40.3, and neutrophil count ≤1.4 had an OR of 39.3.  All of the other parameters had OR between 2.9 and 4.4.  Hepatomegaly favored HLH as well but was not independently associated with the diagnosis.

How to use this scoring system:

  • In this cohort, the MH score ranged from 0 to 123.  The median value was 97 for HLH and 12 for MAS.
  • A cutoff of ≥60 yielded a sensitivity of 91% and specificity of 93% for the diagnosis of HLH.  Higher values increased the probability of HLH further.

Most laboratory studies were more abnormal with HLH; however, both ferritin elevation and LDH elevation were more pronounced with MAS.  Median ferritin was 5353 with MAS and 2910 with HLH.  Median LDH was 1230 with MAS compared with 696 with HLH.

This study validated the MH score for distinguishing HLH from MAS associated with sJIA; this can allow early introduction of aggressive treatment and appropriate genetic/immunologic evaluation.  The applicability of the MH score for distinguishing HLH from other conditions is unclear.  Further prospective evaluation of the MH score is needed.

My take: This is a very helpful study and is likely to influence diagnostic workup and management of these sick patients. Due to the liver and spleen abnormalities, pediatric gastroenterologists need to be able to recognize both HLH and MAS.

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Breastfeeding: Protection from Inflammatory Bowel Disease

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Xu L, et al. Systematic review with meta-analysis: breastfeeding and the risk of Crohn’s disease and ulcerative colitis. Aliment Pharmacol Ther. 2017;46:780-789.

https://doi.org/10.1111/apt.14291Thanks to Mike Hart for this reference.

From abstract:

Results

A total of 35 studies were included in the final analysis, comprising 7536 individuals with CD, 7353 with UC and 330 222 controls. Ever being breastfed was associated with a lower risk of CD (OR 0.71, 95% CI 0.59-0.85) and UC (OR 0.78, 95% CI 0.67-0.91). While this inverse association was observed in all ethnicity groups, the magnitude of protection was significantly greater among Asians (OR 0.31, 95% CI 0.20-0.48) compared to Caucasians (OR 0.78, 95% CI 0.66-0.93; P = .0001) in CD. Breastfeeding duration showed a dose-dependent association, with strongest decrease in risk when breastfed for at least 12 months for CD (OR 0.20, 95% CI 0.08-0.50) and UC (OR 0.21, 95% CI 0.10-0.43) as compared to 3 or 6 months.

From associated editorial by David Rakel:

This meta-analysis of 35 studies shows that there is a dose–response protective effect of the duration of breastfeeding on inflammatory bowel disease. The association shows as much as an 80% reduction in risk for both Crohn’s disease and ulcerative colitis for breastfeeding more than 12 months.

Breast Feeding Graph

Inflammatory bowel disease arises from a complex set of interactions related to genetic susceptibility, environmental exposures, and a dysregulated immune response to dysbiotic intestinal microbiota, according to the study authors. These data will give us one more reason to encourage breastfeeding, ideally for a year or more.

Related blog post: Nutrition Week (Day 7) Connecting Diet and Epidemiology in IBD

 

 

Assessing Neonatal Jaundice with Smartphone App

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A recent study (Taylor JA, et al. Pediatrics 2017; 140 (3) e20170312) reports on the effectiveness of a smartphone app, BiliCam, to detect total serum bilirubin (TSB) in a diverse sample of newborns < 7 days old.  Thanks to Ben Gold for this reference.

BiliCam uses a calibration card which is placed on the infant’s sternum to standardize the color (and jaundice) reading in the photo; the image goes via the internet to a server for analysis.

Key findings:

  • Estimated bilirubin levels using BiliCam were compared with TSB levels in 530 newborns which included 20.8% African American,, 26.3% Hispanic and 21.2% Asian American
  • The overall correlation was 0.91 were similar among all ethnic groups with correlations ranging from 0.88 to 0.92
  •  The sensitivity of Bilicam was 84.6% is for identifying infants with a TSB in the high-risk zone of the Bhutani nomogram. The sensitivity was 100% for identifying TSB > 17 mg/dL. Specificities were 75.1% adn 76.4% respectively.

For more commentary on this article: AAP Journals Blog: Bilirubin phone apps –our future calls!

My take: This article indicates that a digital image with Smartphone app analysis is much more accurate in detecting jaundice that a visual assessment.

Prospective Outcome Data for Infants with Gastroschisis

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A recent study (BS Fullerton et al. J Pediatr 2017; 188: 192-7) reports outcome data from 4420 neonates with gastroschisis from 175 North Amercan centers.

This study, using prospectively-collected data from the Vermont Oxford Network, was restricted to infants with birth weights >1500 g and gestational age >28 weeks.

Key findings from this cohort:

  • Survival was 97.8%
  • Length of stay (LOS) 37 day median
  • Sepsis, confirmed with either positive blood culture or CSF culture, “was the only independent predictor of mortality.”
  • In addition to gastroschisis repair, abdominal surgery was needed in 22.3%
  • At discharge, 57.0% were <10% weight for age; whereas, only 37.2% were born small for gestational age.
  • There were no outcome differences based on mode of delivery (eg. vaginal vs. cesarean)
  • Other congenital anomalies were noted in many infants, with 5.8% had an intestinal atresia: 4.6% jejunal/ileal, 1.9% colonic, 0.4% duodenal atresia.

My take: This contemporary study shows excellent survival of neonates with gastroschisis.  Sepsis, need for additional surgery, and poor growth remain important challenges.

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Bile Acid Therapy -18 Year Study

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JE Heubi et al (JPGN 2017; 65: 321-6) performed a phase 3, open-label, nonrandomized trial on the efficacy and safety of oral cholic acid for patients with Zellweger Spectrum disorders (n=20) and patients with bile acid synthesis disorders (BASD) (n=50). Cholic acid dosing: 10-15 mg/kg/day. Most common BASD were 3β-HSD (n=35), and 5β-reductase (n=10).  Based on this work, cholic acid is an FDA-approved agent.

Key findings:

  • Urine bile acid metabolite scores improved (P<0.0001) with cholic acid
  • Transaminases improved (AST, ALT) (P<0.0001)
  • Growth parameters, improved with weight gain reaching statistical significance
  • “Liver biopsies showed either stable findings or histologic improvement in all parameters except bridging fibrosis”
  • No study drug-related serious adverse events were noted
  • With Zellweger spectrum disorders, it is important to note that “there is no evidence that treatment with cholic acid has any impact on the extrahepatic disease.”

My take: Cholic acid helps the liver in these disorders which is particularly important for BASD. It is unclear if this improves outcomes in patients with Zellweger spectrum disorders as it has not been shown to improve extrahepatic disease.

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Fructose Restriction Improved Fatty Liver Disease in Children

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A recent study (J-M Schwarz et al. Gastroenterol 2017; 153: 743-52, editorial MB Vos, IR Goran Gastroenterol 2017; 153: 642-5 ) showed that restriction of fructose quickly improved fatty liver disease.

Several points from the editorial:

  • “The metabolic driver of buildup of fat storage in the liver is de novo lipogenesis (DNL) and fructose is a major substrate of DNL”
  • “In the healthy state, DNL is not expected to be a major contributor to lipid accumulation in the liver….[but] in a fatty liver, it has been estimated that 26% of the fat originates from DNL.”
  • Fructose is “limited in a natural diet…However, it is added to many processed foods and drinks in the form of cane sugar..and other types of sugars, going by ≥57 different names.”
  • Fructose is “commonly used in animal models to induce hepatic steatosis.”

The study is summarized in a recent AGA Journals Blog: Can Restricting Fructose Intake Reduce Fatty Liver Disease in Children?

An excerpt:

Jean-Marc Schwarz et al performed a clinical trial to investigate the effects of reducing fructose intake for 9 days in obese Latino and African American children with habitual high sugar consumption (fructose intake >50 g/day). They measured the effects of isocaloric fructose restriction on de novo lipogenesis, liver fat, visceral fat, subcutaneous fat, and insulin kinetics.

In their study, 41 children, 9−18 years old, had all meals provided for 9 days. The meals had the same energy and macronutrient composition as their standard diet, but with starch substituted for sugar, yielding a final fructose content of 4% of total kilocalories. The authors measured metabolic factors before and after fructose restriction. They measured liver fat, visceral fat, and subcutaneous fat by magnetic resonance spectroscopy and imaging.

Schwarz et al found that on day 10 of the diet, liver fat decreased from a median 7.2% at baseline to 3.8%, and visceral fat decreased from 123 cm3  at baseline to 110 cm3. Liver fat decreased in all but 1 of the 38 participants for whom paired data were available…

De novo lipogenesis decreased significantly after 9 days of fructose restriction; the de novo lipogenesis area under the curve value on day 10 decreased from 68% at baseline to 26% after the diet, in childen with low or high baseline levels of liver fat.

Insulin secretion during fasting and in response to an oral glucose tolerance test decreased significantly in children with low and high baseline levels of liver fat…

In an editorial that accompanies the article, Miriam B. Vos and Michael I. Goran say that it will be important to determine whether the effects of fructose reduction are sustained past 9 days…Vos and Goran state that it is important for physicians, nutritionists, schools, and parents to find ways to reduce fructose in the diets of children and patients with NAFLD.

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Early Results with Upadacitinib -a JAK1 Inhibitor for Crohn’s Disease

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From Gastroenterology & Endoscopy News: New JAK1 Inhibitor Treats Most Challenging Crohn’s Patients

An excerpt:

An experimental oral JAK1 inhibitor, upadacitinib (AbbVie), has been tested in the most clinically challenging patients with Crohn’s and yielded impressive results. The drug led to a clinical response in 61% of these patients and remission in 22%, the new data show…

William Sandborn, MD, chief of gastroenterology at the University of California, San Diego, who led the study. “It seems to be a really effective drug in a very difficult-to-treat patient population, and the oral route of administration is attractive.”

Dr. Sandborn’s group presented the findings at the 2017 Digestive Disease Week (abstract 974h).

The CELEST trial enrolled 220 patients with active, moderate to severe Crohn’s disease. Patients received 16 weeks of induction therapy with one of five dosing regimens of upadacitinib or a placebo…

Dr. Sandborn called the findings particularly impressive given that the study participants are the most refractory patient population ever recruited in a trial for Crohn’s disease. “And this is also one of the first trials to meet new FDA requirements for demonstrating clinical remission using patient-reported outcomes as well as endoscopic improvement,” he noted.

My take: It is exciting that another oral agent may be helpful. Tofacitinib, a different JAK1 inhibitor, has data supporting its use in ulcerative colitis but not with Crohn’s disease.

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