N-acetylcysteine for Acute Liver Failure

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A study which took 8 years to complete (2001-2009) and involved more than 20 pediatric liver transplant centers has shown that N-acetylcysteine (NAC) is NOT effective for nonacetaminophen acute liver failure in the pediatric population (Hepatology 2013; 57: 1542-49).

Eligible patients were drawn from a registry of pediatric acute liver failure (PALF) patients.  Among 607 who were enrolled in the registry, 271 were eligible for the NAC trial and 184 of these patients (families) agreed to participate.  The most common reasons for patients to be ineligible for the study included acetaminophen toxicity, previous NAC treatment, sepsis, and “reason unknown.”

The design of the study was doubly masked with patients stratified by age and hepatic encephalopathy.  Patients either received intravenous NAC (150 mg/kg/d) or D5W for up to 7 consecutive days.

Key findings:

  • No significant difference in 1-year survival: 73% of NAC patients and 82% of placebo patients
  • NAC patients had lower 1-year liver transplant free survival (p = 0.03): 35% in NAC group compared to 53% of placebo patients.

The study did have several limitations.  Despite the lengthy enrollment period, the absolute number of patients was only 92 in each group.  In addition, there were differences in the diagnoses in both groups and the ages of the groups, though these were unlikely to change the results.  With regard to diagnoses, both groups had ~60% with an indeterminate reason for PALF.  However, the NAC group had an increased number with metabolic diseases (14% compared with 5% in placebo group); the most common metabolic disease was Wilson’s disease (7 in NAC group and 3 in placebo group).  The NAC group had a median age of 3.7 years compared with 4.5 years for the placebo group.

Another limitation was in testing for acetaminophen-cysteine adducts (A-CA) which can be used as a marker of acetaminophen exposure.  This was performed retrospectively in 84 of the participants.  A-CA was positive in 9 (six from placebo and three from treatment arm).  Again, this was unlikely to change the results as there were no statistical differences in clinical features of those who were tested for A-CA compared with those who were not.

In some ways, the results are surprising due to prospective studies in adults showing benefit of NAC in ALF and a previous retrospective uncontrolled pediatric study suggesting efficacy in PALF.  Ultimately, this study proves again that pediatric patients are not “small adults” and highlights the need for prospective pediatric drug trials.

Bottom-Line:

NAC works for acetaminophen-induced ALF but is not helpful for other causes of PALF.

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Lunchroom Makeover

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A recent pilot study indicates that $50 and three hours can increase the chances that teens will eat their fruits and vegetables (J Pediatr 2013; 162: 867-9).  While the US Department of Agriculture has mandated alterations in what foods that schools offer for lunch, schools cannot force students to eat specific foods.  As such, the authors tried changing the convenience, attractiveness, and ‘normative nature of healthy foods’ in the lunchroom. These changes are part of a behavioral science called “libertarian paternalism.”

These field studies took place at two schools in western New York with students at 7-12 grade levels.  After implementing changes in the lunchrooms, researchers recorded tray waste on multiple dates.

Specific changes included the following:

Improved convenience:

  • “Healthy convenience line” with only submarine sandwiches and healthier sides (fruits/vegetables)
  • Salad served in see-through to-go containers

Improved attractiveness:

  • Lunch menu posted with nice color photos of fruits and vegetables
  • Fruit displayed in nice bowls or tiered stands

Normative behavior:

  • Verbal prompts by staff: “Would you like to try…”, “No veggie? How about…” “You can get another side with your meal. How about grabbing a piece of fruit?”
  • “Last chance for Fruit” sign displayed next to fruit basket at the cash register

The impact of the “smarter lunchroom:” actual fruit consumption increased by 18% and vegetable consumption increased by 23%.  The limitations of this study: no control school, did not track individual consumption, and small number of measured days.

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Global increases in IBD incidence

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Two more studies have shown increasing incidence of pediatric inflammatory bowel disease.

First in Victoria, Australia (mostly Melbourne) (Inflamm Bowel Dis 2013; 19: 1-6).

Over a 60-year span (1950-2009), a retrospective review was undertaken of ulcerative colitis (UC) pediatric patients. In total, 342 children were diagnosed with UC. Key finding: The number of reported cases increased by 11-fold during the study period with a marked increase since 1990 (0.15 –>1.61/100,000).  In addition, recently diagnosed children have had more extensive disease.

Next in Spain (Inflamm Bowel Dis 2013; 19: 73-80).

This retrospective study from hospitals’ databases looked at the incidence between 1996-2009 in the pediatric population (<18 years).  A total of 2107 patients were identified: 1165 with Crohn’s disease, 788 ulcerative colitis, and 154 IBD unclassified. Median age at diagnosis was 12.3 years.  Key finding: in the last 14 years, pediatric IBD incidence has almost tripled (0.9 –>2.8/100,000).

Both of these studies have limitations related to large retrospective reviews in terms of potential problems with capturing all of the patients and the potential for misdiagnosis.  However, the trend is clear.  In addition, these studies show incidence rates comparable to several other Western studies.  The increasing incidence of IBD ‘argue for a common environmental factor in their pathogenesis.’  While interest has focused on microbial factors, the basis for this increased incidence currently remains elusive.

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Nuance in Celiac Serology Interpretation

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A recent study adds additional nuance to the interpretation of celiac serology (Clin Gastroenterol Hepatol 2013; 11: 398-403).

In this study the authors analyzed anti-TTG IgA levels from 104 consecutive pediatric and adult patients who were not IgA deficient.  The study took place between 2000-2009.  In addition, samples from 537 consecutive controls were available for comparison.

The study determined the likelihood of having celiac disease based on antibody level from four different companies and pre-test clinical factors.  The general population pretest probability was 1%; the pretest probability for their population was 6% if their were gastrointestinal complaints, 14% if weight loss/small stature was present, 11% for patients with anemia/iron deficiency, and 9% for patients with malabsorption.

Key findings:

Even in those with high antibody titers (>10-fold normal), if they were asymptomatic, only 53%-75% had celiac disease (depending on the individual assay).  That is, >10-fold elevation with some commercial assays did not correspond to >10-fold elevation in all of the assays leading to variable probabilities.

In patients with low level elevations (1-3 fold times the cut-off level), the probability of having celiac disease in asymptomatic individuals varied from 1% to 7%.  Thus, mild elevations in TTG IgA are not highly predictive in this asymptomatic population.  However, in those with pretest probability of 14%, the frequency of celiac disease varied among the four assays from 14% to 56%.

Take home message:  Not all assays for celiac disease are comparable.  While very high serology levels (>10 fold) are associated with celiac disease, in asymptomatic patients as few as 53% may have celiac disease.

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Button Battery Algorithm Link

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The following website has a useful button battery algorithm (thanks to JL for forwarding this link):

One important point is that in an asymptomatic patient, a button battery in the stomach can be left alone if no coingestion with a magnet.  If gastric battery is > 15 mm and child is less than 6 year,  the recommendation is to check xray in 4 days and remove if still in stomach or whenever there are symptoms.
Of course, a button battery in the esophagus is a true endoscopic emergency. Recognizing that it is a button battery and not a coin can alter the outcome.
Related blog links:
Another link on foreign bodies, 2011: Postgraduate Course Syllabus – Slides, only – NASPGHAN.org (Look for the slides from Marsha Kay)

Fish Oil, IFALD, and Liver Fibrosis

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While there has been a lot of enthusiasm for the use of fish oil as a potential breakthrough for intestinal failure-associated liver disease, this has been based largely on the use of surrogate markers of liver disease and based on comparisons with the historical use of conventional intravenous lipids.  The latter problem has been discussed before on this blog (see links below).

A recent study begins to address the issue of surrogate markers by reinforcing the viewpoint that improvements in bilirubin and aminotransferases may not translate into improvement in liver fibrosis or other clinically-meaningful outcomes (JPGN 2013; 56: 364-69).  A previous pediatric study (J Pediatr 2010; 156: 327-31) showed failure of regression of hepatic fibrosis in 2 children receiving FOE therapy.

In this study, the authors sequentially examined 6 children on fish-oil lipid emulsions (FOE) who underwent multiple liver biopsies.  In this cohort, 5 of 6 children had gastroschisis and the mean gestational age was 35 weeks.  Median intestinal (small bowel) length beyond the ligament of Treitz was 26 cm and most children retained about 2/3rds of their colon.  Liver biopsies were obtained at the time of other open abdominal operations (eg. serial transverse enteroplasty, stoma takedown).

Key results:

  • Liver fibrosis persisted in 2 cases, progressed in 3 cases, and regressed in 1 case.
  • Histology and biochemistries indicated improvement in cholestasis and inflammation.
  • One patient has weaned off parenteral nutrition, two patients underwent isolated small bowel transplantation due to recurrent line infections, and three patients receive 25-40% of their calories parenterally.

The biggest limitation of this study besides the small number of enrolled patients was the relatively short  time period that was studied.  Only one patient who was studied had data reported for FOE more than 36 weeks.  The oldest age of any patient at the time of their last biopsy was 131 weeks old.

Take-home points:

  • “There is no direct evidence to support any one [proposed theoretical benefit of FOE] as clinically meaningful as yet.”
  • “Lipid minimization strategies are also effective in reducing cholestasis.”
  • “Many of the biopsies taken right at the time of FOE initiation” showed significant fibrosis which “speaks to how quickly fibrosis can develop.” One child had stage 2 fibrosis at 14 weeks of life.
  • “The biochemical resolution of cholestasis is at best a weak surrogate marker ..for…enteral independence and overall survival.”  “These findings make a strong case for early referral of children with short bowel syndrome to specialized intestinal rehabilitation centers.”

Related blog posts:

True red flags in recurrent abdominal pain

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For pediatricians and pediatric gastroenterologists alike, identifying which children need additional workup for recurrent abdominal pain (RAP) is facilitated by recognizing “red flags.”  “Red flags” are clinical features that indicate a higher likelihood of a nonfunctional disorder.  A recent study notes that reports of waking from sleep and joint pains do not distinguish functional from nonfunctional causes of RAP (J Pediatr 2013; 162: 783-7).

This study, performed between 2005 to 2008, had patients presenting to an outpatient pediatric gastroenterology clinic for RAP prospectively complete a detailed questionnaire. Data, though, was extracted retrospectively. In this population (n=606), 85% were Caucasian.  After their evaluation, patients with functional GI diseases (FGID, n=478) were compared with patients confirmed with Crohn’s disease (CD, n=128).  All FGIDs underwent biochemical testing, 41% had upper endoscopy, and 32% underwent colonoscopy.

Additional key findings:

  • Using a tree analysis, the cumulative sensitivity for Crohn’s disease was 54% with the presence of anemia, 78% when blood in stool was added to anemia, and 94% when weight loss was added as well.
  • FGID patients were more likely to report stress and headaches, more likely to have family history of FGID, and less likely to have anemia, hematochezia, or growth issues.
  • FGID patients were more likely to experience vomiting.

The sensitivity and specificity of these symptoms/signs will vary based on the population.  For a general pediatric clinic, it is likely that the sensitivity of these red flags would remain high; the specificity would likely be lower than in a pediatric gastroenterology office due to the increased prevalence of functional diseases in the general pediatric setting.

Related blog posts:

Fluctuating Elastase Levels in Infants with Cystic Fibrosis

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A recent study sheds light on the variability of elastase levels in both pancreatic sufficient (PS) and pancreatic insufficient (PI) infants with cystic fibrosis (CF) (J Pediatr 2013; 162: 808-12).

After eliminating infants who did not have elastase values prior to 3.5 months and after 9 months, the study consisted of 61 formula-fed infants who had been diagnosed with CF.  Diagnosis was established based on either a positive sweat test or having two known CF mutations.

Background: Pancreatic elastase is produced by pancreatic acinar cells and is not degraded during intestinal transit.  It can be measured while on pancreatic enzyme replacement therapy (PERT) because it is specific for human elastase rather than porcine elastase.  In addition, samples are stable at room temperature for weeks.

Among this cohort, 28 (46%) were homozygous for the F508del mutation. Infants were part of a large docosahexaenoic acid (DHA) study; as such, they were randomized to receive either standard formula or formula supplemented with DHA.  Monthly stool samples were collected.

Results:

  • Of 29 infants with initial fecal elastase <50 mcg/g, all had a value <200 mcg/g at one year.  However, 3 had a value >200 mcg/g at some time during the first year of life.
  • Of 36 infants with initial elastase <100 mcg/g, 32 had a level <100 mcg/g at 1 year.  Only one infant in this group had a value consistent with PS and this infant had a mutation associated with increased likelihood of PS.
  • Of 12 infants with initial values between 100-200 mcg/g, more variability was noted in their multiple samples.  This group accounted for the majority of infants who were reclassified from PI initially to PS after one year of life.  Among all 48 with values <200 mcg/g, 4 were considered PS at final evaluation.  However, 13 had values >200 mcg/g at some point.
  • 13 infants were considered PS at initial evaluation with a value >200 mcg/g.  At the study conclusion, 3 had values <180 mcg/g.
  • The majority of fluctuation in elastase values occurred during the first 6 months of life.

These results lead to the following conclusions:

  1. Fluctuations in elastase levels during the first year of life indicate that some infants with PS become PI and vice versa.  Retesting at one year of life is important.
  2. The authors recommend that all CF patients with elastase values below 200 mcg/g receive PERT.
  3. One can extrapolate these findings to other populations.  A single normal or abnormal elastase value may not indicate ultimately whether a patient will remain pancreatic insufficient or sufficient. Though, values <50 mcg/g are more likely to indicate persistent PI status.

The authors do provide some speculation regarding these fluctuations.  They note that “a fecal elastase obtained very early in life might not reflect the child’s true functional pancreatic status.  Intestinal mucosal damage can cause secondary pancreatic insufficiency by decreasing signaling of the pancreas from enteroendocrine cells.”

Related blog links:

References:

  • -JPGN 2007; 44: 219.  Use of elastase in CF.  Pancreas secretes elastase; not degraded & does not cross react with porcine elastase, thus allowing measurement even in individuals on enzyme treatment.  Excellent sensitivity/specificity.
  • -J Pediatr 2004; 145: 322 & 285,  A fecal elastase-1   >100mcg/g has a 99% predictive value for excluding pancreatic insufficiency.
  • -JPGN 2003; 36: 314, 392.  Fecal elastase-1 is marker for exocrince pancreatic function & enteropathy.
  • J Peds 2009; 155: supplement. Clinical practice guidelines for infants/children <2 years of age with CF:
  1. -routinely give salt 1/8-1/4tsp/day
  2. -measure elastase & supplement if PI
  3. -Dose: 2000-5000 units lipase per feed –can go as high as 2500 units/kg (max daily 10000 units/kg/day)
  4. -monitor & supplement ADEK
  5. -consider 7% saline Rx & azithromycin in symptomatic

How to gain too much weight –attend daycare?

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According to a provocative study (J Pediatr 2013; 162: 753-8), receiving childcare as opposed to parental care was associated with increased weight.

1649 children were enrolled in a prospective birth cohort in Quebec.  Information about childcare was completed by their mothers at ages 1.5, 2.5, 3.5 and 4 years.  In addition, body mass index (BMI) was checked at ages 4, 6, 7, and 10 years of age.

Compared with care at home, children who attended a center-based childcare or were cared for by a relative were at increased risk of being overweight or obese, with odds ratios of 1.65 for center-based care and 1.5 for relative-based care.  Furthermore, increased hours away from home was associated with increased odds; every 5 hours increased the likelihood by 9% in the first decade of life.

These associations could not be explained by a number of potential confounding factors including socioeconomic status, breastfeeding, maternal employment, and maternal BMI (along with many other factors). In addition, the authors note in their discussion that these results are in line with other large studies from a number of countries.  One hypothesis for relative-based care has been that this may involve less physical activity, especially by grandparents.

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Seeing is Believing

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As noted in a recent blog (Food Marketing Detectable on Functional MRI | gutsandgrowth), functional MRI is being studied for a number of applications.  Now, more data has emerged that a “pain signature” can be identified with this technology (NEJM 2014; 368: 1388-97).

Using a series of experiments, the authors enrolled 114 healthy participants and ultimately identified an imaging signature that was associated with heat-induced pain and increased nonlinearly with increasing stimulus intensity.  The first part of the study involved a machine-learning analyses after inducing physical pain by applying heat to the forearm of the participants.  The sensitivity and specificity were 94% or more in discriminating painful heat from nonpainful warmth, pain anticipation, and pain recall.  In the fourth part of the study, the authors showed that the signature response was reduced when an opiod analgesic (remifentanil) was administered.

Because this study enrolled otherwise healthy patients, the results cannot be extrapolated to other populations.  Nevertheless, it is likely that other painful conditions will have unique functional MRI signatures.

Pain is not easy to ascertain and obtaining functional MRIs is not likely to have a role in the near future as a clinical tool.  The concept of identifying a measurable pain biomarker though has been strengthened by this study.

Related blog entry:

Pain changes brain | gutsandgrowth