Category Archives: Pediatric Gastroenterology Intestinal Disorder

What I did not know …a few items

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  1. 6-Mercaptopurine (6-MP) often can be used when patients are intolerant of azathioprine. S Hubener et al. Clin Gastroenterol Hepatol 2016; 14: 445-53.  This retrospective study showed that 15 of 20 patients with autoimmune hepatitis and prior azathioprine intolerance responded to 6-MP.  This is somewhat unexpected as azathioprine is metabolized into 6-MP.  However, rather than 6-thiouracil, the “imidazol component of azathioprine, which is cleaved off…might trigger adverse reactions.”  Another artical on thiopurines (Aliment Pharmacol Ther 2016; 43: 863-883) (thanks to Ben God for this reference) provides a thorough review of the pharmacogenetics and pharmocokinetics of these medications.  While this review reinforces the recommendation to check TPMT before treatment, it notes that only a small proportion of thiopurine toxicity is related to deficient TPMT activity.
  2. There is no formal validated or consensus definitions of mild, moderate, or severe IBD. L Peyrin-Biroulet et al. Clin Gastroenterol Hepatol 2016; 14: 348-54.  While the Lemann index measures the cumulative structural bowel disease, the authors propose criteria which involves three areas of severity: impact of the disease on the patient (eg. clinical symptoms), inflammatory burden (eg. biomarkers, mucosal disease, disease extent), and disease course (eg. structural disease, intestinal resection, perianal disease, extraintestinal manifestations)
  3. Fundic gland polyps (often associated with proton pump inhibitor therapy) are not premalignant lesions. There is an “inverse correlation between the FGPs and gastric neoplasia.” S Varghese et al. Gastroenterol Hepatol; 2016; 12: 153-4.
  4. Parents of newborns do not know how to use car seats.  BD Hoffman et al (J Pediatr 2016; 171: 48-54) showed that 95% of car seats were misused (291 families).  Serious misuse was present in 91%.

 

Related blog posts: Lemann index: Short Takes on IBD Articles | gutsandgrowth

Gibbs Gardens has >20 million daffodils

Gibbs Gardens has >20 million daffodils

Chronic Granulomatous Disease and GI Involvement

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Chronic granulomatous disease associated inflammatory bowel disease primarily involves the anus and rectum (SK Khangura et. al. Clin Gastroenterol Hepatol 2016; 14: 395-402).  In this study from the NIH, among 78 patients with CGD-IBD enteric fisula were found in 18% (73% were perianal), colonic stictures were noted in 24% (80% in anorectal area).

Other findings:

  • -EGD showed inflammation in 21%, 74%, and 37% of patients in esophageal, gastric and duodenal biopsies respectively
  • -Small bowel disease was unusual, though two of the four patients with ileostomies had ileal ulcers
  • -” ‘Target-like lesions,’ which have a clear elevated center with surrounding erythema, were characteristic of mild disease
  • -Approximately 40% of CGD patients have GI tract involvement
  • -GI tract malignancy was not observed in this cohort
  • -24 patients had pancolitis

My take: This reference provides comprehensive details of the clinical features of a large cohort with CGD.

Which animals kill the most humans

Which animals kill the most humans

More on Anti-TNF Drug Levels (part 2) and a Few Mentions

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Another study (K Papamichael et al. Clin Gastroenterol Hepatol 2016; 14: 543-9) examined therapeutic drug levels with regard to infliximab induction and mucosal healing.

In this retrospective study with 101 patients with ulcerative colitis, 54 (53.4%) achieved mucosal healing between weeks 10-14, defined by a Mayo endoscopic score of 0 or 1.  97% of patients were treated with 5 mg/kg infusions.

Key finding:

  • Infliximab threshold concentrations of 28.3 mcg/mL at week 2, 15 mcg/mL at week 6, and 2.1 mcg/mL at week 14 were associated with mucosal healing.

My take: While this study provides information on what type of levels to expect at 2, 6, and 14 weeks, what is really important is figuring out which patients need higher doses of infusions from the start.

Unrelated, briefly noted:

R Yadlapati et al. Clin Gastroenterol Hepatol 2016; 14: 535-42. In this prospective blinded cohort study of 59 subjects, oropharyngeal pH testing (Restech Dx-pH) and salivary pepsin analysis was not able to distinguish between healthy volunteers and subjects with a combination of laryngeal and reflux symptoms.

M Moris et al. Clin Gastroenterol Hepatol 2016; 14: 585-93. This study reports increasing findings of small pancreatic cysts with more (and better) MRI imaging.

Y Kawamura et al. Clin Gastroenterol Hepatol 2016; 14: 597-605. This retrospective study shows, among almost 10,000 patients with fatty liver disease, that alcohol consumption of ≥40 g/day is an independent risk factor for hepatocellular carcinoma.

Strongloides

More on Anti-TNF Drug Levels

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B Ungar et al (Clin Gastroenterol Hepatol 2016; 14: 550-7) report median serum levels of infliximab (n=78) or adalimumab (n=67) in correlation with mucosal healing.

In this retrospective cross-sectional study of adult patients with IBD (median age ~35 years), the authors found a correlation with higher drug troughs and mucosal healing.

“Levels of infliximab above 5 mcg/mL…and levels of adalimumab above 7.1 mcg/mL identified patients with mucosal healing with 85% specificity. Increasing levels of infliximab above 8 mcg/mL produced only minimal increases in the rate of mucosal healing, whereas the association between higher level of adalimumab and increased rate of mucosal healing reached a plateau at 12 mcg/mL”

The authors propose a “therapeutic window” of 6-10 for infliximab and 8-12 for adalimumab.

Clin Gastro Trough Levels

Remarks from DDW

Remarks from DDW

Oral Cancer and Inflammatory Bowel Disease

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A recent study (KH Katsanos et al. Clin Gastroenterol Hepatol 2016; 14: 413-20) shows an increased risk of oral cancers in patients with inflammatory bowel disease (IBD). Because these cancers are infrequent, the absolute risk remains low.  However, this study provides some further insight into why other cancers may occur more often in IBD as well.

This retrospective study collated data on 7294 patients with IBD seen at a single New York center (2000-2011).  Key findings:

  • 11 patients (7 male) developed biopsy-proven oral cancer, most commonly of the tongue (n=6).  The overall oral cancer age-adjusted standardized incidence ration (SIR) was 9.77 and the SIR for tongue was 18.91.  These numbers could be influenced by a referral bias.
  • The average age for oral cancer in this study was 44 years.
  • Prior treatment for IBD had occurred in 7 patients, including 4 with a thiopurine, 1 with infliximab, and 3 with combination therapy.
  • One patient died.

Discussion:

  • Traditional risk factors for oral cancer: tobacco exposure (smoking, oral tobacco) and alcohol consumption.
  • The authors speculate that in their population that acquiring oncogenic HPV virus may have contributed to increased risk.  This is clearly a risk with cervical cancer which has been reported as increased in IBD populations as well.

Related blog post: Cancers Complicating Inflammatory Bowel Disease | gutsandgrowth

Gibbs Gardens

Gibbs Gardens

Rome IV -Pediatric Changes

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What are the changes in Rome IV for children and adolescents?  JS Hyams, C DiLorenzo et al (Gastroenterol 2016; 150: 1456-68) provide a helpful review.

Key point:

The ‘dictum’ that there was “no evidence for organic disease” as an criteria for functional disorders has been dropped in favor of “after appropriate medical evaluation the symptoms cannot be attributed to another medical condition.”  This subtle change discourages excessive investigations.

The functional disorders covered in this article include

  • H1 Functional nausea and vomiting disorders: H1a -cyclic vomiting syndrome, H1b -functional nausea and vomiting (NEW), H1c -rumination syndrome, H1d -aerophagia
  • H2 Functional abdominal pain disorders: H2a -functional dyspepsia, H2b -irritable bowel syndrome, H2c -abdominal migraine, H2d -functional abdominal pain -not otherwise specified
  • H3 Functional defecation disorders: H3a -functional constipation, H3b -nonretentive fecal incontinence

Other points:

  • “There are no published data on the treatment of isolated functional nausea and isolated functional vomiting”
  • “We have eliminated the requirement of pain to fulfill the criteria for FD” [functional dyspepsia]
  • Criteria for cyclic vomiting and abdominal migraines now require only 2 episodes in a 6 month period
  • Criteria for functional constipation requires only 1 month rather than 2 months (this is true for H3b as well).  The authors endorsed the NASPGHAN expert guidelines which included “no role for routine use of an abdominal x-ray to diagnose FC.”  The guideline discourages testing for cow’s milk allergy, hypothyroidism, celiac disease and hypercalcemia in the absence of alarm symptoms.

In a separate article, MA Benninga, S Nurko et al (Gastroenterol 2016; 150: 1443-55) describe the functional disorders affecting infants and toddlers.

In my view, the article in this special edition that incorporates the most changes regards functional disorders of the biliary tree (FGBD) (PB Cotton et al Gastroenterol 2016; 150: 1420-29). This is mainly due to data showing that sphincterotomy is no better than sham treatment for patients with post-cholecystectomy pain.  “The concept of sphincter of Oddi dysfunction type III is discarded.”  In addition, for biliary pain/’gallbladder dyskinesia,’ the authors also acknowledge that the role of obtaining a gallbladder ejection fraction is “controversial.”  “Symptoms suggestive of FGBD often resolve spontaneously so that early intervention is unwarranted.”  Ultimately, the authors state that “treatment recommendations are not firmly evidence-based.”

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Owl in Our Neighborhood

Owl in Our Neighborhood

Don’t Skip this Article -Rome IV Summary

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When I visited MIT, one of the slogans I heard was “Getting an Education from MIT is like taking a drink from a Fire Hose.” While this is a ridiculous notion, it is also true that the amount of information to consume, not just at MIT, but in so many areas is tremendous in quantity.  As such, one has to figure out what to read and what to toss.  For GI physicians, a recent summary (DA Drossman. Gastroenterol 2016; 1262-80) is worth a read due to the ubiquitous nature of the problems discussed.

Here were some key points:

  • “The possibility that passions or emotions could lead to the development of medical disease was first proposed by the Greek physician Claudius Galen.”
  • “Rome IV is a compendium of knowledge accumulated since Rome III” –10 years ago.

Some of the Changes:

  • New diagnoses:  Narcotic bowel syndrome, opioid-induced constipation, cannabinoid hyperemesis syndrome
  • Removal of functional terminology when possible…functional abdominal pain syndrome has been changed to centrally mediated abdominal pain syndrome
  • Threshold changes for diagnostic criteria
  • Addition of reflux hypersensitivity diagnosis.
  • Revision of Sphincter of Oddi  dysfunction disorder…  “driven by evidence that debunks the value of sphincterotomy for type III SOD.”
  • Emphasis that functional disorders exist on a spectrum with linked pathogenesis, particularly with regard to irritable bowel syndrome (IBS) subtypes.
  • Removal of the term discomfort for IBS criteria and using pain as the key criterion.

Approach to Patients with Functional GI Disorders:

  • The author discusses ways to engage patient to create partner-like interaction.
  • “Determine the immediate reason for the patient’s visit (eg. What led you to see me at this time?)”  Potential reasons: exacerbating factors, concern for serious disease, stressors, emotional comorbidity, impairment in daily functioning or hidden agenda (eg. disability, narcotics, litigation)
  • “Determine what the patient understands of the illness…What do you think is causing your symptoms?”
  • Provide a thorough explanation of the disorder.  “For example: ‘I understand you believe you have an infection that has been missed; as we understand it, the infection is gone but your nerves have even affected by the infection to make you feel like it is still there, similar to phantom limb.”
  • “Identify and respond realistically to the patient’s expectations for improvement (e.g. How do you feel I can be helpful to you?)”
  • Explain ways that stress can be associated.  “I understand you do not see stress as causing your pain, but you have mentioned how severe and disabling your  pain is.  How much do you think that is causing you emotional distress?”
  • “Set consistent limits..narcotic medication is not indicated because it can be harmful.”
  • “Involve patient in treatment plan (e.g. Let me suggest some treatments for you to consider).”
  • With regard to use of TCAs, the author explains that antidepressants can be used “to turn down the pain, and pain benefit occurs in doses lower than that used for depression.”  “Tricyclic antidepressants or the serotonin-norepinephrine reuptake inhibitors help control pain via central analgesia as well as provide relief of associated depressive symptoms.  The selective serotonin reuptake inhibitors are less effective for pain but can help reduce anxiety and associated depression.”
  • Establish an ongoing relationship.  “Whatever the result of this treatment, I am prepared to consider other options, and I will continue to work with you through this.”

My take: This summary provides a succinct update on a 6-year effort of 117 investigators/clinicians from 23 countries.  After reading this article, you will probably want to glance at the other articles in the same issue.

Vik Muniz Collage

Vik Muniz Collage

A closer look at the front wheel

A closer look at the front wheel

Varicella and Zoster Infections in Children with Inflammatory Bowel Disease

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A recent study (DJ Adams, CM Nylund. J Pediatr 2016; 171: 140-5) looked at a large database (1997-2012) with nearly 9 million admissions.  In this retrospective cohort, there were 4434 admissions related to varicella and 4488 due to herpes zoster.

  • Children with Crohn’s disease had a greater increased risk: Varicella OR 12.75, and Zoster OR 7.9 compared to the general population.
  • Children with ulcerative colitis had increased risk compared to general population but less compared to children with Crohn’s disease: Varicella OR 4.25, and Zoster OR 3.9
  • Overall, the risk of these infections improved among all groups over the 15 year study period

One significant limitation of this study is that children with IBD may have been hospitalized more readily out of concern for their vulnerability.  It is noted that there were no deaths due to these infections in the children with IBD.

My take (from the authors):  the increased risk of Varicella and Zoster “were comparable with that observed in children with HIV, malignancy, and primary immune deficiency.”  Given the difficulty of immunizing children on immunosuppressive treatments, at the very least, immunizing household contacts needs to take place.

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Fox Theatre on a Tuesday

Fox Theatre (Atlanta) on a Tuesday

Vitamin D and IBD, More Data

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Another large study (Kabbani TA, et al. Am J Gastroenterol. 2016;doi:10.1038/ajg.2016.53) links low vitamin D status with worse outcomes in IBD.

An excerpt from summary from HealioGastro: (Low vitamin D linked to higher morbidity, disease severity in IBD)

Binion and colleagues identified 965 IBD patients (61.9% Crohn’s disease; 38.1% ulcerative colitis; 52.3% women; mean age, 44 years) with up to 5 years of follow-up data in University of Pittsburgh Medical Center’s longitudinal IBD natural history registry…

At enrollment, 8.9% of patients were vitamin D deficient and 33.1% had vitamin D insufficiency vs. 4.9% and 23.6%, respectively, at the conclusion of the study period. Among patients who received vitamin D supplements, 67.9% achieved normal levels by the end of the study…

Overall, patients with low vitamin D levels required significantly more steroids, biologics, narcotics, computed tomography scans, emergency department visits, hospital admissions and surgeries compared with those who had normal mean vitamin D levels (P < .05). They also had worse pain, disease activity scores and quality of life (P < .05).

“More importantly, correction of vitamin D deficiency was associated with overall improvement in clinical status,” Binion said.

My take: Vitamin D levels are often low when patients are acutely ill and can improve without supplements in many; this accounts for some of the association with worsened outcomes.  True vitamin D deficiency and insufficiency does have negative physiologic effects and should be treated.

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Gibbs Gardens

Gibbs Gardens

 

Dreaded Nausea

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One symptom that is dreaded by both patients and physicians is nausea.  A helpful review on this topic (K Kovacic, C DiLorenzo. JPGN 2016; 62: 365-71) provides information on functional nausea.  A few points:

Diagnostic:

  • Endoscopy has low yield.  One cited study suggested that in the absence of clinical alarm symptoms, 98% of endoscopies were normal.
  • 4-hour nuclear medicine study ‘may be justified.’

Therapeutic: Numerous drug/alternative therapies are discussed -most with a paucity of data.  These include:

  • Alternatives agents: Ginger, STW5 (iberogast), peppermint oil
  • Antiemetics: Ondansetron, promethazine, prochlorperazine
  • TCAs: amitriptyline, nortriptyline, imipramine, doxepin
  • SSRIs: citalopram, fluoxetine, paroxetine
  • Anxiolytics: buspirone
  • Tetracyclic antidepressant: mirtazapine
  • Antimigraine: cyprohepatadine, propranolol, topiramate, levetiracetam
  • Prokinetics: erythromycin, metoclopropramide, domperidone
  • Others: fludrocortisone, aprepitant, cannabionids
  • Psychology: “early involvement of a psychologist and emphasis on coping strategies and maintaining functioning with continued school attendance is a primary goal.”

The authors note that retrospective data in children suggest that TCAs have a response rate of ~50% (defined as more than a 50% improvement).  In one study, the mean dose of amitriptyline was 50 mg at bedtime.

In a related study, Madani et al (JPGN 2016; 62: 409-13) describe their experience (retrospective review) using cyproheptadine in children with a range of functional gastrointestinal disorders.  The most common indications were functional abdominal pain (36%), functional dyspepsia (23%), combination disorder (17%) and abdominal migraines (12%).  Overall, they included 151 children and they report 110 (72.8%) had complete symptom improvement; the remainder had either partial or no improvement.  In those who responded, the mean initial dose was 0.14 mg/kg/day; the final mean dose was nearly identical. Adverse effects of sleepiness was reported in 13% and weight gain in 10%.

Related posts:

Link: Impressive “water swallowing” NEJM video (thanks to Jose Garza for sharing).  In a person who had undergone an esophagogastric bypass as a child.  Still photo below:

NEJM Chest