How Many Kids with Reflux Actually Have Reflux?

Posted on by

A terrific recent retrospective study (LB Mahoney, S Nurko, R Rosen. J Pediatr 2017; 189: 86-91) examined how often children with reflux symptoms actually have reflux.

This study reviewed 45 children ≥5 years (mean age 11.8 years) who had undergone both upper endoscopy and impedance pH study (off PPI therapy). Inclusion criteria: no erosive esophagitis. Common symptoms included heartburn, abdominal pain, chest pain, and regurgitation.

Definitions:

  • Nonerosive reflux disease –had abnormal esophageal acid exposure
  • Reflux hypersensitivity -had normal acid exposure but had a positive symptom association to acid or nonacid reflux
  • Functional heartburn -had normal acid exposure and negative symptom association

Key findings:

  • 44% had functional heartburn, 29% with reflux hypersensitivity (27% acid, 2% nonacid), 27% had nonerosive reflux disease (NERD)
  • Response to a proton pump inhibitor (PPI) was not predictive of reflux phenotype: 58% with NERD, 67% with reflux hypersensitivity, and 55% with functional heartburn. Response to PPI was stated as “at least some symptomatic improvement with PPI use.”  There was not a difference in PPI response among those who received a dose <1 mg/kg and those ≥1 mg/kg.
  • Microscopic esophagitis was present in 17% in NERD, 25% with reflux hypersensitivity, and in 20% of functional heartburn

While this study has limitations, including referral bias, it is likely that these patients are typical for many pediatric gastroenterologists. The authors note that typical patients were “patients who underwent a PPI trial but continued to have persistent symptoms.”

My take: In a pediatric gastroenterology setting, the most common reason for “reflux” is actually functional heartburn.  Thus, in those with persistent symptoms, evaluation with endoscopy and pH probe is worthwhile, especially as there has been more attention to potential risks of PPI therapy.

Related blog posts:

View from Asheville, NC

Moving Away from Liver Biopsies

Posted on by

A recent review (EB Tapper, AS-F Lok. NEJM 2017; 377: 756-68) provides a good review of liver biopsy and liver imaging. My take of this review is that it highlights the emergence of noninvasive tools (imaging & fibrosis markers) which may supplant liver biopsy.  This article does not delve into how more widespread genetic testing may obviate a liver biopsy in many cases as well. The article notes that about 8% of persons in the U.S. have elevated liver enzymes.

Liver biopsy:

  • “A typical liver biopsy samples one fifty-thousandth of the liver.”
  • Limitations of liver biopsy: sampling error is common, biopsy interpretation is subjective, and biopsies can cause complications.  Pain is noted in 30-50% of patients, serious bleeding in 0.6%, injury to other organs (0.08%), and in rare cases, death (up  to 0.1%).
  • Cost: “the average direct cost of a percutaneous liver biopsy is $1448 (in 2016 U.S. dollars).” Transjugular biopsies are much more expensive.  In addition, there are unmeasured indirect costs, due to missing work.

Some prior blogs on liver biopsy

Blood tests:

  • The article details the formulas for biomarker measurements that predict the risk of fibrosis, inlcuding FIB-4, Lok Index, and NAFLD Fibrosis Score.
  • In most liver diseases, aspartate aminotransferase levels “exceed alanine aminotransferase levels when cirrhosis develops.”
  • Thrombocytopenia “is the earliest indicator of cirrhosis among routine blood tests…[due to] diminished liver function (throbopoietin underproduction) and portal hypertension (splenic sequestration).”
  • Proprietary algorithms to assess fibrosis have variable sensitivity, specificity –include FibroTest (aka FibroSure [LabCorp]), FibroMeter, HepaScore (Quest), FIBROSpect, and the Enhanced Liver Fibrosis Score.

Imaging:

  • Elastography with vibration-controlled transient elastography (VCTE) OR magnetic resonance elastography
  • “Elastography offers excellent negative likelihood ratios for advanced fibrosis but much poorer positive likelihood ratios.”
  • Patients with severe obesity are less likely to obtain adequate study with VCTE and could need magnetic resonance elastography to assess fibrosis.

My take: Noninvasive tests have already sharply reduced the need for liver biopsy.

Related posts:

Physician Team Cohesiveness

Posted on by

Recently, I attended our medical staff semi-annual meeting.  Two speakers (Dr. Usha Sathian and Dr. Lucky Jain) provided some impressive information about the growth of the hospital system’s outreach with ambulatory care services and about the development of Emory/associated institutions’ academic medicine advances.  The latter includes graduate medical education, extensive grants, and involvement in more than 1000 current clinical studies.  The number of trainees at all levels has grown incredibly.  These trainees are much more likely to stay in Georgia than trainees in many other parts of the country.

This growth corresponds to increases in the hospital’s bed capacity and technical abilities.  A third speaker, Dr. Joseph Rosenfeld, was honored for being both a community physician and attending physician for 40 years!  When he first arrived, there were eight pediatric ICU beds at Egleston Children’s hospital.  Now, there has been about an 8-fold increase.  The number of hospital beds has more than tripled.

Yet, sadly in my view, only a tiny number of physicians attended this meeting, a fraction that attended when the medical staff was much smaller.  Despite the huge increase in staff physicians, there is a dwindling number who attend meetings; this is true for grand rounds as well.  When I first arrived in town about 20 years ago, I looked forward to these meetings to engage and meet my colleagues.  In addition, due to ever larger number of subspecialists, it is much less frequent that when I rotate on hospital service that I will see the well-known neurologist, pulmonologist, endocrinologist, infectious disease expert and so many others.

I came away from the staff meeting with a tangible feeling that despite the incredible success of the system in developing improved capabilities that the feeling of working together as a team of subspecialists and generalists has diminished.  This makes me wonder whether other aspects of modern medicine and the worry over physician burnout are not related to increased isolation of physicians into their specialty silos and to cloistering into our computers and smartphones.

Though I feel grateful to be able to help children in my work, the biggest reason that I chose pediatrics was because of my admiration for the pediatricians I had met and my desire to both emulate their work and to work with them.  I think working closely together is one aspect that makes being a pediatric specialist worthwhile.

My take: Experts have recommended “peer support” to prevent burnout and increase job satisfaction.  My experience, which I suspect is shared widely, indicates that engaging with our peers is becoming less frequent.

Related blog posts:

Drug Development for Eosinophilic Esophagitis

Posted on by

Full text link: White Paper AGA: Drug Development for Eosinophilic Esophagitis (EoE)

I Hirano et al. Clin Gastroenterol Hepatol 2017; 15: 1173-83. This article reviews diagnostic criteria for EoE, clinical endpoints, and current/emerging treatments.

From AGA website-an excerpt:

Four important points from the white paper:

1. There is a complex inter-relationship between EoE, gastroesophageal reflux disease (GERD) and proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE). A substantial proportion of patients with esophageal eosinophilia will improve with PPI treatment.

2. The clinical features and presentation of EoE differ between children and adults. Poor symptom specificity among children has limited the ability to identify appropriate candidates for enrollment into clinical trials and has impeded the development of pediatric patient-reported outcome instruments.

3. Aside from pharmacologic approaches, EoE can be addressed with dietary modifications and/or endoscopic dilation.

4. We should remember that the diagnosis of EoE carries a potentially major financial burden on patients’ families, making identifying new, effective and affordable treatment options a priority.

Great Story -How CAR-T Came About

Posted on by

While chimeric antigen receptor T-cell (CAR-T) therapy does not have much to do with pediatric gastroenterology, the development of this therapy, described recently (L Rosenbaum NEJM 2017; 377: 1313-5), holds lessons about perseverance and chance that are widely applicable.

CAR-T involves genetically engineering the patient’s own T cells to kill tumor cells. It recently received FDA approval to treat patients up to 25 years of age with relapsed or refractory acute lymphoblastic leukemia.

The story of the survival of Emily Whitehead, the index patient for this therapy, is suitable for Hollywood.  The groundwork for this very expensive treatment dates back to 1893 with William Coley’s recognition of the immune system’s potential for treating cancer –he injected streptococcus into an inoperable osteosarcoma and observed tumor shrinkage.

Key Steps in this Story:

  1. University of Pennsylvania’s immunologist Carl June spent his career working on CAR-T. His wife died of ovarian cancer in 2001 and he resolved to develop this emerging immunotherapy that he had wanted for her.
  2. Barbara and Edward Netter provided key funding for this project in 2008.  They too had lost a close family member to cancer.
  3. Emily Whitehead nearly died due to CAR-T therapy which triggered cytokine-release syndrome, which was not a recognized entity at the time.  In part due to chance, extremely high levels (>1000-fold) of interleukin-6 (IL-6) were detected quickly due to the ability of the institution and prodding by the researchers to their colleagues.  This allowed the experimental use of tocilizumab, a monoclonal antibody that targets IL-6.
  4. Her survival helped reenergize this line of research.

My take (borrowed from author): “Therapeutic advances are motivated by more than money –that it’s the hope, vision, and perseverance of both patients and investigators that made this …possible.”

Acute esophageal necrosis ina a 63 year-old that resolved with conservative treatment.  “The cause is unknown..[it] occurs most commonly in the distal third of the esophagus, which is hypovascular” often in the setting of chronic disease.

Do these antibiotics make me look fat?

Posted on by

There has been a lot of interest and conflicting reports about whether antibiotics contribute to obesity.  Another interesting study on this theme:

  • ET Rogawski et al. JPGN 2017; 65: 350-6. 

The authors followed 1954 children twice weekly from birth to 2 years of age as part of the MAL-ED study.  There were 8 study sites, including in Bangladesh, India, Brazil, Pakistan, Nepal, South Africa, Peru, and Tanzania. Key finding:

  • Antibiotic use before 6 months of age was associated with increased weight from 6 months to 2 years of age.
  • Antibiotic use after 6 months did not affect growth.

The authors speculate: “If treatment of infections were the main mechanism, we would expect antibiotic exposure after 6 months to also have an impact.” Thus, they conclude that effects on the microbiome are likely a more important explanation.

My take (borrowed from te authors):  “Antibiotic use in low-resource settings” can improve growth, though the long-term consequences are not known.  In high-income settings, weight gain secondary to antibiotic exposure is more likely to be detrimental.

Related blog posts:

Patient T-shirt

 

Diet and Stress in Pediatric Eosinophilic Esophagitis

Posted on by

When it comes to eosinophilic esophagitis (EoE), I sometimes worry that some treatments are worse than the disease, depending on the severity of the EoE. A recent study (C Case et al. JPGN 2017; 65: 281-84) indicates that dietary therapy is often stressful for families.

This study examined children ages 2-18 during an annual American Partnership for Eosinophilic Diseases (APFED.org) patient education conference. What I found most interesting was Table 3. “Stress associated with eosinophilc esophagitis.”

Some of the data:

  • In response to ‘how stressful do you find the following since your child’s diagnosis of EoE?’ Family structure at mealtimes: Not stressful 13.5%, somewhat stressful 21.6%, moderate stressful 16.2%, significant stressful 32.4%, and severe stressful 16.2%
  • In response to ‘how stressful do you find the following since your child’s diagnosis of EoE? Buying and cooking separate foods/meals for your child: Not stressful 2.6%, somewhat stressful 21.1%, moderate stressful 21.1%, significant stressful 31.6%, and severe stressful 23.7%
  • In response to ‘how stressful do you find the following since your child’s diagnosis of EoE? Financial strain due to cost of food: Not stressful 10.5%, somewhat stressful 21.1%, moderate stressful 18.4%, significant stressful 23.7%, and severe stressful 36.3%
  • What is your current stress level in response to your child’s EoE? Not stressful 2.6%, somewhat stressful 15.8%, moderate stressful 36.8%, significant stressful 42.1%, and severe stressful 2.6%
  • 62% of respondents indicated that child’s EoE has affected marital relationship.

In addition, the study documented that “half of youth were affected by worry, anger, and sadness related to specialized diets.”  As this study relied on participants at an APFED meeting, this could skew the EoE population to be more severely affected.

My take: This study shows the emotional burden that dietary treatment of EoE places on families.

Related blog posts:

Berry College

Top Anti-TNF for Ulcerative Colitis

Posted on by

A recent retrospective cohort study (S Singh et al. Clin Gastroenterol Hepatol 2017; 15: 1218-25) compared infliximab and adalimumab in a nationwide Danish cohort of adults with ulcerative colitis (UC) from 2005-2014. The authors used propensity score and selected 171 patients who received infliximab (IFX) from a total of 1580 and 104 patients who received adalimumab (ADA) among a total of 139.

Key findings:

  • Patients who received ADA had higher hospitalization rates (HR 1.84) and a trend toward higher UC-related hospitalization (HR 1.71, CI 0.95-3.07) compared to IFX
  • Risk of abdominal surgery was not significantly higher in ADA patients (HR 1.35) compared to IFX
  • Serious infections were higher in ADA group, HR of 5.11 of needing hospitalization due to infections

There have been no randomized clinical trials  to determine if a specific anti-TNF agent is superior to another. In an associated editorial (MT Osterman, GR Lichtenstein, 1197-99), the authors note that while we don’t know which agent is superior, by comparing similar trials (ACT 1 & 2 for IFX and ULTRA 1 & 2 for ADA), “raw week 8 induction rates of clinical remission, clinical response, and mucosal healing are approximately 16%, 18%, and 19%, respectively, higher for infliximab”..”less dramatic differences favoring infliximab (approximately 9%, 13%, and 15%, respectively) are seen during maintenance at 1 year.”

My take: Due to the lack of randomized head-to-head studies, we do not know with certainty which anti-TNF is best for UC.  However, the data we have from retrospective cohort studies and from using raw data from prospective studies suggests that infliximab is effective in more patients.

Related blog posts:

University of Virginia Rotunda Pctures

 

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.

Briefly: Notable Recent IBD Publications

Posted on by

Vermeire S et al. Lancet 2017; 389: 266-75.  The “FITZROY ” study examined clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib, a orally administered selective JAK inhibitor.  This agent is 30 times more selective fo rJAK1 over JAK3. This study enrolled 174 patients in a phase II study. Key findings:

  • Among patients naive to anti-TNF agents, clinical remission (based on CDAI <150 at week 10) noted in 47% of filgotinib-treated compared with 23% of placebo group (P=.0077)
  • Among patients naive to anti-TNF agents, clinical response was noted in 67% of filgotinib-treated compared with 44% in the placebo group.

H Singh et al. Gastroenterol 2017; 153: 430-8.  Using the large Manitoba Epidemiology Database with 1.3 million population (2005-2014), the authors found that individuals with IBD had a 4.8 fold increase risk of Clostridium difficile infection.

T-D Kanneganti. NEJM 2017; 377: 694-6. This review examined the NLRP3 Inflammasome.  Neudecker et al (J Exp Med 2017; 214: 1737-52) identified microRNA miR-223 which functions “to suppress the Nlrp3 inflammasone during acute colitis.” Other useful points in this review of basic research:

  • “The majority of the immune cells in the body are located in the intestine, where they are spatially separated from more than 10 trillion microorganisms by a layer of mucus and a layer of epithelial cells.  Deterioration of this physical barrier …underlies inflammatory bowel disease.”
  • miR-223 is increased in the inflamed colon. “During inflammation, the expression of miR-223 is also upregulated..and the molecule binds to its complementary sequence in a regulatory part of Nlrp3 mRNA…lead[ing] to decreased Nlrp3 expression and the consequent dampening of interleukin-1β maturation and associated inflammation.”

Autoimmune Hepatitis and Hepatocellular Carcinoma

Posted on by

Briefly noted:

A Tansel et al. Clin Gastroenterol Hepatol 2017; 15: 1207-17.  This systematic review and meta-analysis identified 25 studies and 6528 patients examining the relationship between autoimmune hepatitis (AIH) and hepatocellular carcinoma (HCC) .  In these studies the median followup was 8.0 years.  Key findings:

  • The pooled incidence of HCC was 3.06 per 1000 patient-years
  • 92 of 93 patients who had HCC had evidence of cirrhosis before or at the time of their diagnosis

My take: This study demonstrates that AIH patients with cirrhosis are at increased risk for HCC.  In patients with AIH who do not have cirrhosis, there does not appear to be a significant risk of HCC.

Also: Link for Online Resource for Hepatopulmonary Syndrome (Canadian Sponsored site). This site has content for patients and for practitioners, including a useful video.

 

Related blog posts: