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Cytosponge for Eosinophilic Esophagitis

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A recent prospective study (DA Katzka et al. Am J Gastroenterol 2017; 112: 1538-44 -thanks to Ben Gold for this reference) provided more information regarding the potential utility of the cytosponge for eosinophilic esophagitis (EoE); the cytosponge has been studied for Barrett’s esophagus.

Background: 86 adult patients were recruited; 6 could not swallow sponge.  In the remainder, 105 procedures were performed comparing the cytosponge to standard endoscopic biopsies. The cytosponge technique can be completed in ~5 minutes without sedation. “All that is required is centrifuging the cytosponge specimen in its preservative to create a pellet followed by routine paraffin embedding and processing.”

Key findings:

  • Cytosponge was considered to have adequate specimen in 102 of 105 cases, compared with 104 of 105 with endoscopic sampling
  • Using a cutoff of <15 eos/hpf for inactive disease, the authors found that the cytosponge had a sensitivity of 75% and a specificity of 86%.
  • Six patients had active EoE on cytosponge with negative endoscopic biopsies.
  • 14 patients with active EoE with endoscopic biopsies had <15 eos/hpf with cytosponge
  • No complications were noted with cytosponge.

The sensitivity of 75% is likely due to inadequate contact between cytosponge and esophageal wall which could be related to technique, especially in those with a normal caliber esophagus.

My take: The cytosponge appears to identify active EoE in the majority of adult patients.  In those with abnormal cytosponge, the likelihood of active EoE would be very high; as such, it could be a useful biomarker.  It is still probable that many with normal cytosponge result would need endoscopy due to suboptimal sensitivity.

Related blog posts:

NEJM 2017; 377: e22. In this patient with lingual papillomas, hx/o melenoma, and both hyperplastic and adenomatous polyps, a genetic mutation identifying Cowden syndrome was identified.

Fatty Acid Intake and Risk of Ulcerative Colitis Flare

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A recent study (Barnes EL et al. Clin Gastroenterol Hepatol 2017; 15: 1390-6) found an association between the intake of certain fatty acids and the risk of an ulcerative colitis flare.  This is nicely summarized in the AGA Journals Blog.

Here’s the link: Does Consumption of Certain Fatty Acids Increase Risk of Ulcerative Colitis Flares?

Here’s an excerpt:

Diets with high levels of fatty acids such as myristic acid (found in palm oil, coconut oil, and dairy fats) increased risk of flare in patients with ulcerative colitis (UC), researchers report in the September issue of Clinical Gastroenterology and Hepatology. Their findings, from a prospective study of more than 400 patients in remission during treatment with aminosalicylates, could guide future studies of supplements or compounds that reduce risk of flares in patients with UC in remission…

Edward L. Barnes et al performed a prospective study of dietary patterns among 412 patients, from 25 sites, with UC in remission during monotherapy with an aminosalicylate (mesalamine, sulfasalazine, or balsalazide for at least 3 months before enrollment). Patients completed a validated food frequency questionnaire (on consumption of dairy, fruits, vegetables, eggs, meat, fish, cereals, breads, and starches, beverages, sweets, and baked goods) at enrollment and were followed for 12 months…

Forty-five patients (11%) had a relapse of UC within 1 year of study enrollment… In multivariable analysis, higher intake of myristic acid (odds ratio, 3.01) and alpha linolenic acid (odds ratio, 5.50) were associated with increased risk of relapse, although a dose–response relationship was retained only for myristic acid intake.

Other foods previously implicated in flares of UC, such as processed meat, alcohol, and foods high in sulfur, were not associated with an increased risk of flare.

Related blog posts:

From Andy Warhol Exhibit at the High Museum

Costs of Biologics for Inflammatory Bowel Disease

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A recent study examines the market share and costs of biologic therapies for inflammatory bowel disease:

Excerpt from abstract:

The average biologic-taking patient accounted for $25 275 PMPY in 2007 and $36 051 PMPY in 2015. The average paediatric biologic-taking patient accounted for $23 616 PMPY in 2007 and $41 109 PMPY in 2015. In all patients, the share of costs for biologics increased from 72.9% in 2007 to 85.7% in 2015 (81.7% in 2007 to 94.9% in 2015 in paediatrics).

Conclusion

The vast majority of costs allocated to out-patient IBD medications in the USA is attributed to increasing use of biologic therapies despite the relative minority of biologic-taking patients.

My take: Biologic therapies are costly but also very effective.

Related Blog Posts:

 

The Original Anti-TNF Therapy: Thalidomide

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A recent study (M Lazzerini et al. Clin Gastroenterol Hepatol 2017; 15: 1382-9) used data from 2 multicenter trials of 70 children to assess the efficacy of thalidomide in pediatric patients with refractory inflammatory bowel disease (37 with Crohn’s disease, 23 with ulcerative colitis)

Key findings:

  • 42 patients (60%) had clinical remission & 45 (64%) had clinical response at week 8
  • 38 patients (54%) had clinical remission or response at week 52. 29 of these patients had mucosal healing (no erosions or ulcerations) & 20 patients had histologic healing
  • 7 patients dropped out from study prior to 52 weeks due to side effects (n=5) or clinical relapse (n=2)

My take: I have not used thalidomide therapy and remain concerned about long term side effects (eg. peripheral neuropathy).  Though, the authors are correct that its safety “may be acceptable compared with the safety of other” treatments, especially if there are few remaining options.

Related blog posts:

Will We Still Need Liver Biopsies to Diagnose Biliary Atresia in a Few Years?

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A recent study (C Lertudomphonwanit, R Moura, L Fei, Y Zhang, S Gutta, L Yang, KE Bove, P Shivakumar, JA Bezerra. Sci Transl Med. 2017; 9: eaan8462) may change how we diagnose biliary atresia (BA) and provides an insight into potential pathogenesis. Link to study: Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia

Using large-scale proteomics, the authors screened 1129 proteins in a discovery cohort (n=70) of patients with BA.  They identified several proteins that were increased with BA. Matrix metalloproteinase-7 (MMP-7) was the lead biomarker.  Subsequently, they used two additional validation cohorts.  Human subjects were infants in enrolled in the Prospective Database of Infants with Cholestasis (PROBE) which is part of the NIDDK-funded ChiLDRen (www.childrennetwork.org).

Key findings:

  • 76 proteins were significantly overexpressed or underexpressed in BA compared with children with intrahepatic cholestasis (IHC).
  • MMP-7 was more accurate than gamma glutamyltranspeptidase (GGT).  The combination of MMP-7 and GGT had a AUROC of 0.94 in validation cohorts.
  • The authors further studied the role of MMP-7 by immunostaining and found it primarily was detected in cholangiocytes of intrahepatic bile ducts in infants with BA.  It was also identified in a few hematopoietic cells.
  • MMP-7 expression in the liver did not correlate with fibrosis.
  • MMP-7 serum levels increased in neonatal mice after bile duct epithelial injury induced by intraperitoneal rotavirus administration.
  • Using a mice model, they found that a MMP-7 inhibitor (batimastat) could block the development of BA in a mouse model (in 86% of cases) compared with 0% in control mice.
  • Overall, the authors note that coupled with GGT, MMP-7 serum levels result in “sensitivity and specificity of 97 and 94% respectively, at optimal cutoff, which provided positive and negative predictive values of 85 and 99% respectively, if one considers the prevalence of BA of 25.9% among infants with conjugated hyperbilirubinemia.”

My take: More work is needed.  However, these values suggest that MMP-7 and GGT combined may be more accurate than a liver biopsy in the diagnosis of BA.

Related blog posts:

South Kaibab Trail, Grand Canyon

More on PPIs and Kidney Disease & Brain Disease

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The most recent information and perspective on proton pump inhibitors and kidney disease:

From AGA: More Data on PPI Use and Kidney Disease

An excerpt:

The most recent study related to PPIs and CKD was a meta-analysis by Wijarnpreecha et al. presented at the American Society of Nephrology annual meeting and published in Digestive Diseases and Sciences. They found that any use of PPIs was associated with a 33 percent relative increase in risk for CKD/ESRD whereas no such risk was seen with H2RAs.

Talking to Your Patients
  1. Inform patients that, while this study does raise some concern about long-term PPI use and the potential contributions to kidney disease, the study does not show that PPI use causes kidney disease. No decisions should be made in haste as a reaction to this study. A brief explanation of the meta-analysis may also be helpful. 
  2. Reassure patients that the benefits of using PPIs often outweigh the possible risks. Let them know that you prescribed a PPI for a clear-cut indication, in the lowest possible dose, and for an appropriate period of time (lowest dose, shortest time). 

From the published abstract:

Results: five studies (three cohort studies and two case-control studies) with 536,902 participants met the eligibility criteria and were included in the meta-analysis. We found that individuals with PPIs use had significantly increased the risk of CKD or ESRD when compared with non-PPIs users (pooled RR of 1.33, 95% CI, 1.18-1.51). There was no publication bias of overall included studies assessed by the funnel plots.

My take: (borrowed from the AGA) This is an association, not proof of a causal relationship. Patients who use PPIs differ at baseline than those who do not. For example, patients who use PPIs are more likely to have diabetes or hypertension than patients who do not use PPIs, and are more likely to use additional nephrotoxic medications. Large retrospective studies are unable to completely adjust for these baseline differences. These differences, rather than PPIs themselves, may explain the observed association.

Related study: DCF Klatte et al. Gastroenterol 2017; 153: 702-10.  In this retrospective analysis with more than 100,000 new PPI users (Swedish cohort), PPI users (compared to H2 blocker users) had an increased risk for doubled levels of creatinine with a HR of 1.26, and an increased risk of end-stage renal disease with HR of 2.40. The risk of chronic kidney disease was increased with higher cumulative PPI exposures.

Related study: Effects of PPI on dementia –recent large study shows no association: H Taipale et al. The American Journal of Gastroenterology(2017) 112, 1802–1808 (2017) doi:10.1038/ajg.2017.196.  (Thanks to Ben Gold for this reference. This study examined more than 70,000 Finnish patients with Alzheimer’s disease (AD) (2005-2011) and 280,000 controls.  Results: PPI use was not associated with risk of AD with 3-year lag window applied between exposure and outcome (adjusted odds ratio (OR) 1.03, 95% confidence interval (CI) 1.00–1.05). Similarly, longer duration of use was not associated with risk of AD (1–3 years of use, adjusted OR 1.01 (95% CI 0.97–1.06); ≥3 years of use adjusted OR 0.99 (95% CI 0.94–1.04)). Higher dose use was not associated with an increased risk (≥1.5 defined daily doses per day, adjusted OR 1.03 (95% CI 0.92–1.14)).

Sunrise over the South Rim at the Grand Canyon

Understanding the New Therapies for Spinal Muscular Atrophy

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Pediatric gastroenterologists follow children with spinal muscular atrophy type 1 (Wernig-Hoffman disease) mainly due to feeding problems associated with the profound weakness. Two recent studies show promise for spinal muscular atrophy and are summarized in a “quick take” video: Quick Take NEJM video on SMA type 1

While these new therapies have improved the outcomes, long term data are needed.  With the adenovirus vector gene therapy, if the expression of the gene therapy declines, it may not be possible to do further infusions due to antibody development against the adeonviral vector.

With nusinersen, which has been approved for clinical use, the anticipated cost of $750,000 for the first year of therapy alone and ongoing need for intrathecal administration are problematic.

CFTR Modulators for Cystic Fibrosis

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Two more studies have shown the effectiveness of CFTR modulators for subsets of patients with cystic fibrosis.

  • JL Taylor-Cousar et al. NEJM 2017; 377: 2013-23
  • SM Rowe et al. NEJM 2017; 377: 2024-35.

In the Taylor-Cousar study, the authors treated patients with homozygous Phe508del cystic fibrosis with either combination tezacaftor-ivacaftor or placebo for 24 weeks. Combination therapy resulted in FEV1 that was 4% higher along with a 35% lower rate of pulmonary exacerbations than placebo.

In the Rowe study which examined patients some retained CFTR function (which occurs ~5% of CF patients), a prospective trial of tezacaftor-ivacaftor had a greater effect on increasing FEV1 than ivacaftor alone.  Ivacaftor monotherapy and tezacaftor-ivacaftor combination therapy were both more effective than placebo.

A related editorial (H Grasemann. pgs: 2085-8) helps provide context to help understand the importance of these studies.  His key point:

“Although CFTR modulator therapies have measurable beneficial effects on some aspects of the disease, there is still an unmet need for truly effective new therapies to be developed for all persons with cystic fibrosis.  The clinical efficacy of the current combination therapies for patients with cystic fibrosis who have the most common CFTR genotype (Phe508del/Phe508del) is suboptimal and falls within the range of established symptomatic therapies, such as nebulized inhaled hypertonic saline or recombinant human DNAse.”

This figure depicts the types of molecular defects: No functional CFTR with framshifts for deletions or insertions (class 1), CFTR trafficking defect due to misfolded protein (class II), defective channel regulation (class III), reduced cholirde conductance (class IV) , reduced synthessis (class V) or decreased CFTR stability (class VI)

Research for Fatty Liver Disease

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Recently the AASLD Postgraduate Course discussed emerging treatments for nonalcoholic fatty liver disease/nonalchoholic steatohepatitis. From AASLD News: Emerging Treatments for NASH 

Key point:

  • Quentin Anstee: “It is important to remember that our patients with fatty liver disease will most likely die of cardiovascular disease, not liver disease.”

Four principles in treating nonalcoholic fatty liver disease (NAFLD) to address both cardiovascular and liver risks.

  • Target obesity with lifestyle changes and, possibly, bariatric surgery.
  • Target metabolic syndrome to reduce cardiovascular disease risk using medications with additional liver-directed benefits.
  • Target liver disease to prevent progression of steatohepatitis to fibrosis and cirrhosis.
  • Minimize downstream complications such as hepatocellular carcinoma.

More than 60 phase 3 trials are underway –Primary Therapeutic Targets:

  • PPAR signaling (insulin signaling, glucose and lipid metabolism, energy homeostasis, inflammation)
  • FXR signaling (insulin sensitivity, glucogenesis, lipogenesis)
  • ASK1 signaling (apoptosis)
  • CCR2/CCR5 signaling (inflammation and fibrogenesis).

TPN Amino Acid Shortages Following Hurricane Maria

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Thanks to Kipp Ellsworth for this link: FDA Announcement Regarding Medical Product Shortages Related to Puerto Rico Production

An excerpt: the hurricane disrupted Baxter’s amino acids production facilities in Puerto Rico; Baxter is one of the largest manufacturers of this product serving the U.S. market. In order to help mitigate this shortage, the FDA has worked with Baxter to facilitate the temporary importation of amino acids for pediatric and adult formulations of IV amino acids from Baxter facilities in the United Kingdom and Italy.