Do You Know the Best Way to Use Antegrade Enemas?

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Currently, there is no best way to use antegrade enemas.  This is the obvious conclusion after reading a study by S Kuizenga-Wessel et al (JPGN 2016; 62: 71-9).  In this study, the authors reviewed 21 articles and also surveyed 23 physicians involved in the care of children who receive antegrade continence enemas (ACE). While the study provides a lot of details, the bottom-line is that there is wide variation in outcomes, definition of success, workup prior to institution of ACE, and irrigation solutions (16 out of 23 used saline).  The only areas of agreement seem to be the following:

  • use of ACE daily: 22 of 23
  • use of antibiotics with placement: 23/23 (though wide variation in specific regimen)
  • indications for ACE were largely in agreement, including constipation with fecal incontinence (21 of 23), anorectal malformations (22 of 23) and spinal abnormalities (23 of 23); however, only 8 of 23 considered due to functional non-retentive fecal incontinence as an acceptable indication

With regard to the type of enema, the vast majority of physicians (19 of 23) only add a stimulant to the solution after initial failure.  Though, one study (J Pediatr 2012; 161: 700-4) has reported “that subjects who use stimulants from the very beginning had significantly better outcomes.”

My take: Like of a lot areas in medicine and throughout pediatric gastroenterology, there is wide variation in clinical treatment approaches.  Variation in treatment is obvious in the use of ACE.  Collaborative work and consensus building in management would improve success; that is, after we define what success looks like.

In the same issue a link to “History of Pediatric Endoscopy” is provided.  This is a ~15 minute video with interviews with many pioneers/leaders in pediatric gastroenterology.

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Golden Gate Bridge

Golden Gate Bridge

Predicting a Bad End in Drug-Induced Liver Injury

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A recent study (VL Re et al. Clin Gastroenterol Hepatol 2015; 13: 2360-68) examined a retrospective cohort of 15,353 patients with presumed drug-induced liver injury (DILI) to formulate a more sensitive model for predicting liver failure.

The authors note that Hy’s Law has good specificity but poor sensitivity.  In their population, Hy’s Law had a specificity of 0.92, negative predictive value of 0.99, sensitivity of 0.68, and a positive predictive value of 0.02.

  • Hy’s law (named for Hyman Zimmerman): AST or ALT > 3 ULN and total bilirubin ≥2 ULN indicate serious hepatotoxicity with >10% mortality rate.

By incorporating data from platelet count and total bilirubin, the authors devised a Drug-Induced Liver Toxicity ALF Score which had a high sensitivity of 0.91 but a lower specificity of 0.76.

  • DrILTox ALF Score = -0.00691292*platelet count + 0.19091500*total bilirubin (per mg/dL)
  • Example: platelet count of 145 & total bilirubin of 3.0 yields a valued of -0.4296 which is above cut off of -1.081 indicating an increased risk of ALF.

Thus, low platelet counts and high bilirubins are strong predictors of acute liver failure (ALF) in the setting of DILI.

My take: Overall, the incidence of ALF due to drugs remains fairly low and determining that a specific drug induced liver injury remains problematic.  This study shows that ALF can occur in those who do not meet Hy’s Law criteria and that more sensitive predictors are needed.

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How Effective is Zinc Therapy for Wilson’s Disease?

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A study from France (R Santiago et al. JPGN 2015; 61: 613-18) examined the use of zinc therapy for Wilson’s disease. Though the national survey had 90 children from 6 centers, there were only 26 who were treated with zinc and only 9 who had received zinc as a first-line single therapy.

Despite the small numbers, data on treating children with Wilson’s disease are fairly sparse; as such, this article provides some helpful information.

The study reviews zinc’s mechanism of action:

“Oral zinc induces enterocyte synthesis of metallothionein, a cystic-rich protein acting as an endogenous chelator for metals, which preferentially binds copper in the enterocyte and inhibits its entry into the portal circulation. Thereby, it reduces copper intestinal absorption and leads to copper elimination in fecal contents within senescent enterocytes.”

Key results:

  • “Median transaminase level normalized within 6 months from treatment initiation” in the entire cohort of 26 children.  However, 10 of 26 children had abnormal ALT at 6 months into therapy.
  • Zinc dose was gradually increased such that 38% eventually had doses “exceeding recommended doses” which were >75 mg/day in 6-15 years and >150 mg/day in those ≥16 years.
  • Overall, the authors thought that zinc appeared to be less effective.  Failure with zinc occurred in 5 of 9 (3 due to ineffectiveness, 2 due to poor adherence).  The authors note that decompensation has been reported in children and adults on zinc monotherapy.

The authors indicate that zinc therapy is likely most appropriate after an induction phase with chelators in most children.  Criteria for changing to zinc include the following: “patients should be clinically well…with normal transaminase levels and hepatic synthetic function, non-ceruloplasmin-bound copper concentration within the normal range, and 24-hour urinary copper excretion in the range of 200-500 mcg/24 h.”

Additional precautions with zinc acetate (which is often better tolerated than chelators), 4 of 26 children in this study had gastric irritation, including one child with a perforation.  Therefore, a low threshold for endoscopy should be set in a child with epigastric pain. Adherence can be problematic due to the timing & frequency (TID) of zinc administration.  Monitoring urinary zinc excretion can be useful to monitor compliance.

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Seattle Seafair

Seattle Seafair

Fecal Transplantation: “Frozen is as Good as Fresh”

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Besides pointing out that someone could make $13,000 per year selling their stool, a recent Washington Post story summarized a JAMA study (JAMA. 2016;315(2):142-149. doi:10.1001/jama.2015.18098) which indicated that frozen stool works as well as fresh stool in treating Clostridium difficile infection.

In this study:

Design: Randomized, double-blind, noninferiority trial enrolling 232 adults with recurrent or refractory CDI, conducted between July 2012 and September 2014 at 6 academic medical centers in Canada.

Key finding: In the per-protocol population, the proportion of patients with clinical resolution was 83.5% for the frozen FMT group and 85.1% for the fresh FMT group

Washington Post Summary In fecal matter transplants, frozen is as good as fresh

Here’s an excerpt:

The new study, led by McMaster University’s Christine H. Lee and published Tuesday in JAMA, found that patients given donations that had been frozen for up to 30 days fared just as well as those given fresh samples…

Lee and her colleagues administered one or two FMT enemas to 178 patients, splitting them into two groups to compare freshly-harvested samples and ones that had been frozen and defrosted. Thirteen weeks later, 85 percent of the fresh patients were diarrhea-free. In the frozen group, the success rate reached 83.5 percent – a margin that allows Lee and her team to dub the treatment “noninferior.”

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Bryce Canyon

Bryce Canyon.  This is where I was told to beware of ‘poison rock’ —  one drop can kill you

High Endoscopy Complication Rate After Intestinal Transplantation

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A recent study (J Yeh et al. JPGN 2015; 61: 636-40) indicated a high rate of endoscopy complications in pediatric patients who have undergone intestinal transplantation.

Key points:

  • Complications: In this single-center study with 1770 endoscopies (1014 sessions), the serious GI complication rate was 1.8% (32/1770).  The complications included 11 GI perforations, 13 GI bleeds, 6 GI hematomas, 1 gastric mucosa avulsion, and 1 distention from retained air. The authors’ database was not designed to capture cardiopulmonary complications.
  • In comparison, the authors note that adults without intestinal transplantation have an estimated a perforation rate of 0.09% and serious complication rates (GI and non-GI complications) of 0.15% for upper endoscopy and of 0.2% for colonoscopy. In addition, a large pediatric study of non-transplant patient endoscopies, found a perforation rate of 0.014% for EGDs and 0.028% for colonoscopies. Thus, the authors are reporting a perforation rate (11 of 1770) that is more than 20-fold higher than this pediatric study’s colonoscopy perforation rate.
  • Their techniques are well-described. For example, “for ileoscopies, 2 to 3 sites each consisting of 2 to 3 biopsies were also taken every 5 to 10 cm from the distal graft…typically surveyed up to 50 to 60 cm from the ostomy or ileocolonic anastomosis.”
  • The reasons for endoscopy were most frequently related to diarrhea/stool output in 35% and for surveillance in 32%.
  • The other interesting finding was that “of histology-proven rejections, 45% had normal-appearing endoscopies.”

The authors recommend that patients with intestinal transplantation should have endoscopy at a specialized center with teams who are intimately familiar with these children.

My take: I worry that the high complication rates reported at this center may indicate that individuals (perhaps in training) who are less familiar with the patient’s anatomy are performing many of these endoscopies.  I think individuals very familiar with the patient’s anatomy are best-suited to perform these endoscopies; this may limit some individuals at these specialized centers and may include some skilled endoscopists outside of intestinal transplant centers.

Related blog post: Something Bad is Going to Happen | gutsandgrowth

Galapagos

Galapagos

 

PPIs Alter the Microbiome

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A couple of comments –today’s blog (below) and yesterday’s blog both point out potential concerns with proton pump inhibitors (PPIs).  There is a danger that when publications emphasize the potential consequences of PPI use (including NPR’s recent piece on kidney disease and PPIs) that physicians and families will overlook the value of these medications.

With regard to the benefits of PPIs, there are a large number of studies supporting the effectiveness of PPIs for various GI conditions.  As a result, there is little being published on drug effectiveness at this time.  On a daily basis, these medications prevent a great deal of suffering, heal esophagitis, heal ulcers and contribute to improved health.  If one looks only at the negative side of the ledger, this could create harm.

My personal belief is that when PPIs are used, that it is important to consider both the advantages and the disadvantages.  If the benefits are unclear, this increases the necessity of evaluating the risks, especially in vulnerable populations.  In addition, when the benefits are unclear, determining the length of therapy and/or performing appropriate diagnostic workup becomes essential.

Also, for pediatric gastroenterologists reading this blog, it is important to realize that my blog’s following is tiny in comparison to the circulation of the Journal of Pediatrics and news organizations like NPR.  Therefore, we need to engage our pediatrician/family medicine colleagues to help make sure that PPIs are used effectively.  I am looking forward to the January 26 NASPGHAN webinar on this topic.

——–

The degree to which proton pump inhibitors (PPIs) affect the gut microbiome is unclear.  A recent study of 12 healthy volunteers (DE Freedberg et al. Gastroenterol 2015; 149: 883-85, Clearing Out My Desk | gutsandgrowth) indicated that this was not much; however, an even more recent study (F Imhann et al. Gut 2015 December 9 (Gut doi:10.1136/gutjnl-2015-310376))  suggests otherwise (abstract below) -their conclusion: “On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs.”  

Link: Proton pump inhibitors affect the gut microbiome

Abstract

BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or promoting colonisation by pathogens. In this study, we investigated the influence of PPI use on the gut microbiome.

METHODS: The gut microbiome composition of 1815 individuals, spanning three cohorts, was assessed by tag sequencing of the 16S rRNA gene. The difference in microbiota composition in PPI users versus non-users was analysed separately in each cohort, followed by a meta-analysis.

RESULTS: 211 of the participants were using PPIs at the moment of stool sampling. PPI use is associated with a significant decrease in Shannon’s diversity and with changes in 20% of the bacterial taxa (false discovery rate <0.05). Multiple oral bacteria were over-represented in the faecal microbiome of PPI-users, including the genus Rothia (p=9.8×10(-38)). In PPI users we observed a significant increase in bacteria: genera Enterococcus, Streptococcus, Staphylococcus and the potentially pathogenic species Escherichia coli.

CONCLUSIONS: The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome. These differences are in line with known changes that predispose to C. difficile infections and can potentially explain the increased risk of enteric infections in PPI users. On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs.

My take: It is likely that the effects on the microbiome are even more notable in infants/younger children; in neonates, the changes in the microbiome could increase the risk of serious diseases like necrotizing enterocolitis.

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Yosemite

Yosemite

The Prosecution Rests…PPIs on Trial

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For physicians who use proton pump inhibitors in a cavalier manner, a recent review (CM Stark, CM Nylund. J Pediatr 168: 16-22) provides a sobering reassessment of the potential side effects and potential complications of proton pump inhibitors (PPIs).  After finishing the article, the impression left was of a lawyer putting these medications on trial for high crimes and misdemeanors.

Here were the key points:

Infectious disease: PPI-induced hypochloridia is known to alter the gastrointestinal bacteria motif, allowing certain normally absent or depleted pathogenetic microorganisms to survive and proliferate.  This can lead to all of the following:

  • small bowel bacterial overgrowth
  • increased gastrointestinal infections (including Clostridium difficile, Salmonella, Campylobacter, and acute viral gastroenteritis)
  • pneumonia (particularly community acquired pneumonia and hospital acquired pneumonia)
  • upper respiratory infections
  • spontaneous bacterial peritonitis.

The magnitude of these associations is discussed in detail in the review.

Gastrointestinal disease: Use of PPIs has been associated with an increased incidence of the following:

  •  celiac disease which persisted after excluding prescriptions in the year preceding diagnosis (association does not prove causation)
  • benign gastric fundic polyps
  • rebound acid hypersecretion

Malabsorption: PPIs can affect absorption of multiple nutrients, though more studies are needed, particularly in the pediatric age group.

  • calcium: “there is significant evidence to suggest that PPI use can alter calcium and bone metabolism…associated with an increased risk of hip fractures in older adults….It is reasonable to hypothesize that PPI administration during adolescence and early adulthood could decrease an individual’s peak bone density.”
  • magnesium: PPI have been hypothesized to affect magnesium absorption.  “A study of 366 Canadian patients hospitalized with hypomagnesemia…found PPIs [were] associated with a 43% increased risk of hospitalization.”  More studies are needed to determine the whether this risk is truly significant.
  • iron, vitamin B12, and vitamin C absorption may be affected by PPI use.

Cardiovascular/Renal/Microbiome:

  • Cardiac: In adults, PPI use has been associated with adverse cardiac events.  The pathophysiology could have been pediatric implications.  PPIs can increase asymmetrical dimethylarginine (ADMA) which is an endogenous inhibitor of nitric oxide synthase.
  • Renal: PPIs have been associated with cases of acute interstitial nephritis
  • Microbiome: “PPIs alter the microbiome.”  Decreased diversity of the microbiome has been associated with a large number of medical conditions, including irritable bowel syndrome, inflammatory bowel disease, nonalcoholic fatty liver disease, necrotizing enterocolitis as well as many non-gastrointestinal conditions.  “The temporality of dysbiosis and subsequent disease development has  not been explored fully for most conditions.”

My take: PPIs can be life-saving and disease-altering medications.  At the same time, (per authors) “PPIs should not be prescribed without consideration for all short- and long-term side effects.”

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This Webinar Will Review Issues with Regard to Optimal PPI Usage and Includes My Esteemed Colleagues (Dr. Gold and Dr. Garza)

This NASPGHAN Webinar Will Review Issues with Regard to Optimal PPI Usage and Includes My Esteemed Partners (Dr. Gold and Dr. Garza)

Chronic Hepatitis B in North American Children

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As part of the Hepatitis B Research Network (HBRN), 343 children were enrolled in 7 U.S. and Canadian centers.  A recent study (KB Schwarz et al. J Pediatr 2015; 167: 1287-94) provides data on HBV epidemiology and a related commentary by Brian McMahon (1186-7) provides some useful advice on what is needed to further reduce HBV infection.

88 children were not enrolled.  More than half of these patients refused to participate, the other reasons included language barriers or inability to comply with follow-up.

Key findings:

  • 78% of the subjects in this study were Asian
  • 55% were adopted.  This high adoption rate likely skews some of the data because (according to the associated editorial) “children with HBV in the US..most are likely to be children of parents who immigrated to the US from endemic countries and not adoptees.”
  • 97% had international origins with either the child or a parent born abroad
  • HBV genotype B was most common (43%) followed by genotype C (32%), D (16%), A (5%), E (4%) or multiple (<1%).

In the editorial, Dr. McMahon notes that ascertaining the rate of a birth dose of HBV vaccine would be of interest.  In many countries, vaccination is started at ≥2 months and this is unlikely to prevent HBV transmission.  Two important public health issues for North America:

  • “First, all pregnant women, especially those foreign-born, need to be screened for HBsAg and if positive, their infants should receive HBV vaccine and hepatitis B immune globulin immediately after birth.”
  • “Second, all foreign-born children and adults who immigrate to the US or Canada should be tested for HBsAg.”

My take: This study provides an up-to-date snapshot of tertiary care for children with HBV in North America.  There are many opportunities to curtail (or hopefully eliminate) the impact of HBV in our communities and around the world.

AASLD Guideline (Nov 2015): Treatment of Chronic HBV 

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San Diego Zoo

San Diego Zoo