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Mortality from IBD

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A large Danish cohort provides useful information on the mortality effects of having inflammatory bowel disease (IBD) and how this has changed over the last three decades (Clin Gastroenterol Hepatol 2013; 11: 43-48).

Using a national cohort of all individuals living in Denmark between 1982-2010 (on average 5.3 million), the authors studied 36,080 patients with ulcerative colitis (UC) and 15,361 with Crohn’s disease (CD) in comparison to data from 2,858,096 matched controls (50 controls from each IBD patient) from the general population.  For UC, the median age was 45.2 years and for CD 36.3 years.

Findings:

  • With UC, the first year of diagnosis carried a higher risk of dying (HR 2.43) then rapidly declined to around HR 1.1 after 2 years.  Overall, long-term mortality was increased 10% among UC patients.  Mortality from UC decreased from 1982 to 2010 due to decreased mortalities from gastrointestinal disorders, including colorectal cancer.
  • Mortality was higher among patients diagnosed at younger ages.  Patients diagnosed with UC in childhood or adolescence had a 2.15-fold higher relative mortality than patients diagnosed with UC at 60-79 years.
  • Cause-Specific Mortality: during the first year after UC diagnosis, the HR ratio was increased markedly for gastrointestinal disease (HR 13.3) and infection (HR 9.17).  These areas were most prominent at 10+ years, but the HR ratios had decreased to 1.95 and 1.64 respectively at that time.
  • For CD, mortality was markedly increased in the first year with HR 3.69 and declined to HR 1.53 during years 2-4; HR was 1.49 at 10+ years following diagnosis.  Overall, long-term mortality was increased 50% among CD patients.  Unlike UC, no improvement in mortality rate occurred during the study.
  • Cause-Specific Mortality: during the first year after CD diagnosis, the HR ratio was increased markedly for gastrointestinal disease (HR 23.02) and infection (HR 10.19). These areas were most prominent at 10+ years, but the HR ratios had decreased to 3.67 and 2.70 respectively at that time.  Infections were not increased in the most recent decade, indicating that thiopurines and biologics have not increased the overall risk of fatal infections.
  • While the relative risk of cardiovascular disease was only slightly increased (HR 1.11 for both CD and UC), this is important given the overall frequency of cardiovascular disease in the population.  Presumably, systemic inflammation contributes to the formation of atherosclerosis.
  • Suicide was also increased, especially in the first year after diagnosis (HR 2.05 for UC and HR 1.37 for CD)

Strengths of study: since Denmark has free access to health care and all citizens have a unique 10-digit personal identification, this enables capture of virtually all patients with IBD.  Previous studies have validated the database to be accurate and that the IBD diagnoses have been validated.

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Gut microbiome and endogenous alcohol

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At first glance, it sounds like an ambitious project -develop a gut microbiome that produces alcohol.  It could obviate the need for “Duff” beer (Duff Beer – Wikipedia, the free encyclopedia).  Yet, a recent article has found that an altered microbiome with increased endogenous alcohol already exists and it is associated with nonalcoholic steatohepatitis (NASH) (Hepatology 2013; 57: 601-609).

In this study, the authors examined three pediatric populations: a healthy control group (n=16), obese group (n=25), and NASH group (n=22).  All NASH patients had undergone liver biopsy and met Kleiner’s criteria; in contrast, the obese group had normal LFTs.

Key study findings:

1. The microbiome from the obese and NASH patients were similar but had some striking differences compared with the control group patients (pie chart –Figure 2):

  • Bacteroidetes (including Bacteroides): 28.65% in healthy controls, 50.28% in obese, and 49.11% in NASH
  • Firmicutes (including Blautia and Faecalibacterium): 66.78% in healthy controls, 42.62% in obese, and 42.39% in NASH
  • Proteobacteria (including Escherichia): 0.87% in healthy controls, 3.13% in obese, and 6.03% in NASH

2. Elevated serum ethanol concentrations only in NASH population: ~26 μM in both control and obese groups compared with ~35 μM in NASH patients.

Under normal conditions, endogenous alcohol is produced in the human body and the intestinal microflora are the major source.  This gut-produced alcohol is quickly metabolized by the liver.  Due to similar histology between NASH patients and patients with alcoholic liver disease, it has been hypothesized that NASH patients may have elevated blood alcohol.  This study adds further evidence to this hypothesis and provides a potential mechanism; namely, increased bacteria like Escherichia and Bacteroides can increase endogenously-produced alcohol.

Will efforts to revert the microbiome to normal have therapeutic effects on NASH?  This important question will need to be addressed given the growing problem of fatty liver disease.

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Cognitive Behavioral Therapy for Childhood Abdominal Pain

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Cognitive behavioral therapy (CBT) can be effective for children with functional abdominal pain (JAMA Pediatr 2013; 167: 178-84).  Thanks to Ben Gold for this reference.

This prospective, randomized study recruited 200 children and their parents.  One group of child-parent dyads received ‘social learning and cognitive behavioral therapy’ (SLCBT) and the other group ‘education and support’ (ES).  Over the course of a year, children in the SLCBT group reported greater baseline decreases in gastrointestinal symptom severity and better pain-coping responses.  Parents in the SLCBT group reported greater decreases in ‘solicitous responses’ to their child’s symptoms along with decrease in maladaptive beliefs regarding their child’s pain.

The intervention in the SLCBT group was three 1-hour sessions approximately 1 week apart in which parents were taught social learning strategies 1) to reduce ‘solicitous responses’ to illness behavior, and 2) to model /reinforce healthier ways to respond to gastrointestinal discomfort.  Then, assessments were made at 1 week, 3 months, 6 months, and 12 months.

This study shows that CBT can be effective for functional abdominal pain, if you can find skilled therapist and families willing to participate.

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Stopping reflux with magnets

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Gastroesophageal reflux disease (GERD) can be treated by bolstering the lower esophageal sphincter with a surgically-implanted bracelet of powerful magnets (NEJM 2013; 368: 719-27).

In a prospective study, 100 patients with GERD were enrolled in this study.  The study was conducted in 13 centers in the U.S. and 1 in the Netherlands.  It was designed by Torax Medical.  There was no control group. The primary outcome was normalization of esophageal acid exposure or a 50% greater reduction in exposure at 1 year.

Patient selection:

  • Inclusion criteria: 18-75 years with at least 6-month history of GERD and partial response to proton pump inhibitor treatment.  All patients had to have abnormal pH probe studies at baseline.
  • Exclusion criteria: large hiatal hernia, grade C or D esophagitis (Los Angeles classification), BMI >35, Barrett’s esophagus, motility disorder, dysphagia more than three times a week, or allergy to implant components.

Results:

  • Primary outcome was achieved in 64% of patients.
  • Secondary outcomes: a reduction of proton-pump inhibitor (PPI) use of 50% or more was achieved in 93%.  In fact, at 3 years, 87% had completely eliminated the use of PPIs. Quality of life scores improved in 92%.
  • Adverse effects: most common was dysphagia (68% postop, 11% at 1 year, 4% at 3 years).  This often resolved after esophageal dilatation.
  • Six patients had the device removed.

The bracelet of beads contained sealed magnetic neodymium iron boride.  Each bead is connected by a small wire to the next.  The small wires allow for expansion of the bracelet. It is also designed to avoid compression of the esophagus as the beads can rest against each other.  In addition, the beads separate with the transport of food or if increased intragastric pressure (eg. belch or vomit).

The median time for the procedure of laparascopic placement was 36 minutes. This study brings the worldwide clinical experience to 497 magnetic implants.  To date, there have been no reported erosions or migrations.

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FMT -fecal microbiota transplant

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An excellent review of FMT, especially in regard to C difficile infection, has been published (Am J Gastroenterol 2013; 108: 177-85)  Thanks to Ben Gold for sharing this reference.

FMT has been around for a long time.  It is first documented in the 4th century as a treatment for food poisoning or severe diarrhea.  Its current application has focused on C difficile infection (CDI), though its use in a number of other settings is being explored.  This includes irritable bowel syndrome and inflammatory bowel disease.

This articles makes several useful points.  In the ‘how to do it’ section, the author notes that at the NIH, donor screening includes screening for pathogens in the stool:

  • Bacteria: C difficile, Listeria monocytogenes, Vibrio cholera, Vibrio parahemoltyicus, H pylori
  • Parasites: Giardia, Cryptosporidium, Isospora (acid fast stain)
  • Viruses: Rotavirus
  • Blood: for Hepatitis A IgM, Hep B (HBsAg, anti-HBc ([gG & IgM]), HIV, Syphilis, HCV

However, the author notes that testing in the community tends to rely on screening only for enteric pathogens (stool tests only).  Donors should be excluded if they have received antibiotics in the preceding 3 months, if they participate in high-risk sexual behaviors, recent tattoo piercing, or recent incarceration.  Additional exclusions: history of IBD, IBS, immunocompromise, morbid obesity, metabolic syndrome, atopy, and chronic fatigue.

Related donors may provide a better long-term outcome.  In a recent review, FMT using a related donor yielded a 93% CDI resolution compared with 84% for unrelated donors.

Nuts and bolts:

  1. Donor is instructed to take a double dose of milk of magnesia at bedtime the night before procedure.
  2. Soft stool is passed into a clean plastic container; preference is for stool to be produced within 8 hour of FMT.  Stool does not need to be frozen or refrigerated (though can be refrigerated).
  3. Saline is added to the stool which is stirred and shaken (some use blenders, some use milk or water as suspending solutions).
  4. Typical amount of stool would be 50 g in 250 cc diluent.  For colonic administration, about 300 cc are administered in cecal region.  For duodenal administration, about 60 cc are administered.
  5. Prior to administration, it is best to filter the mixture through gauze pads to remove particulate matter that would interfere with administration.
  6. Though the author notes that there have been recommendations to prepare stool under a hood as stool is considered a level 2 biohazard, he states that this is not practical and in fact, the stool in this situation is the safest stool that gastroenterologists encounter.
  7. Recipients receive a colon lavage before the procedure regardless of route of FMT administration. If possible, all antibiotics are withheld 3 days prior.
  8. On the morning of administration, the author instructs recipient to take two lopermide tablets.

As positive experience gains in CDI, further efforts in a number of other diseases (>30 listed in Table 1 of article) with altered microbiome will be explored.  Thus far, FMT has been used in autism, fibromyalgia, metabolic syndrome, multiple sclerosis, obesity, and even parkinson’s disease.

Hippocrates stated “All disease begins in the gut.”  Given the diversity of diseases in which FMT is being examined, this sentiment may be close to the truth.

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Born this way

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“Baby I was born this way” is applicable to more than just Lady Gaga.  It looks like this mantra extends to functional somatic symptoms (FSS) (J Pediatr 2013; 162: 335-42).

This study which was part of a longitudinal birth cohort study, Copenhagen Child Cohort CCC2000, included 6090 children born in a well-defined geographical area around Copenhagen, Denmark in 2000.  At 5-7 year follow-up, a random sample of 3000 members of the cohort were selected; only 2912 were included as 79 were unreachable and 9 had died.  Subsequently, 1327 had complete data and were the final study sample.

FSS were measured by the Soma Assessment Interview.  In the first 10 months of living, regulatory problems which included at least 2 of 3 problems of feeding, sleeping, or tactile reactivity predicted impaired FSS at 5-7 years with aOR 2.9.  Maternal psychiatric illness during the child’s first year of life conveyed an aOR of 7.1.

FSS (ie, headache and recurrent abdominal pain) could develop due to a number of possible mechanisms:

  • hypersensitivity to stimuli
  • autonomic hyper-reactivity
  • regulatory problems may be risk factors for mood and anxiety disorders

While the strengths of this study included prospective data collection by health professionals and a fairly large sample size, there were still numerous limitations.  Measuring regulatory problems in infancy is not fully validated.  In addition, the designation of FSS is problematic as it is difficult to fully exclude organic etiologies which could present with similar complaints.

The association of maternal psychopathology with the development of FSS in their children is of interest.  It is not clear if this risk is due to nurturing effects (i.e., child’s capacity to self-regulate) or due to nature (i.e., inherited susceptibility).

Shout out for Gluten-Free Camp

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One enjoyable aspect about my work with my colleagues has been their willingness to use their free time to participate and develop programs for children.  For many years, this has included several camps at Camp Twin Lakes, particularly Camp Oasis for children with inflammatory bowel disease. Most of the physicians in our group have given their time to support this camp.  In recent years, Larry Saripkin has spent a week there every summer  and Stan Cohen really established this camp in Atlanta.  In addition, our nurses have volunteered their time as well; they stay busy attending to the medical needs of these kids so they can enjoy a camp experience.

More recently, a camp for kids with celiac disease has been started, Camp WeeKanEatIt.   Under Jeff Lewis’ direction and fundraising, this camp has been started and allows kids  (8-17 yrs) who need to be maintained on a gluten-free diet to experience camp.  Siblings are allowed to attend as well.  Don’t forget this year’s camp dates: June 23-28!

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New lipid emulsions — lacking data to support usage

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According to a systematic review of the literature regarding ω-3 (n-3FA) fatty acid lipid emulsions, there is a “lack of sufficient high-quality data to support the use of parenteral n-3FA lipid emulsions in children” (JPEN 2013; 37: 44-55). Thanks to Kipp Ellsworth for this reference.

The authors of this study researched 4 databases up to March 2011 and extracted relevant studies.  Five randomized controlled trials and 3 high-quality prospective cohort studies were included.  The strength of evidence was “consistently low or very low across all lipid emulsion comparisons and outcomes.”

Specific criticisms:

  • Few studies examined important outcomes like length of hospital stay or intensive care stay.
  • There was lack of data on growth, cognitive development or potential long-term effects/harms.
  • All of the studies in children varied considerably with regard to the dosing regimens, duration of administration, and duration of followup.
  • The studies were small with sample sizes ranging from 28-91 patients.
  • The 5 RCTs had unclear risk of bias due to inadequate blinding of participants and study personnel.
  • All of the RCTs were funded by the manufacturer.
  • While some biochemical outcomes improved, no difference in mortality has been identified.  A biochemical response is a poor measure of effectiveness.  In fact, several studies have shown deterioration in liver histology and fibrosis despite improved biochemical measures in infants on Omegaven.
  • For Omegaven (fish oil) treatment, all studies used a historical control group.  In these studies, typically the Omegaven dose was half the dose of Intralipid used in the control group.

This article (in its Table 1) identifies the constituents in the commercial available lipid products which include Intralipid, Clinoleic, Liposyn II, Omegaven, SMOFLipid, and Lipoplus.  Intralipid which is widely used is devoid of substantial arachidonic acid (ARA) and docosahexaenoic adic (DHA).  This is particularly important in premature infants as noted in recent blogs:

Omegaven, in particular, and SMOFLipid, to a lesser degree, have much more AA and DHA.  As such, both of these emulsions have the potential improve vision and cognitive outcome in premature infants.

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Duodenal IELs and the likelihood of celiac disease

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The diagnosis of celiac disease has definitely become more complex due to the interplay of serology, genetic markers, clinical response to gluten-free diets, and histology.  The Mayo clinic pediatric experience with duodenal intraepithelial lymphocytosis (IELs) with normal villous architecture highlights this issue (JPGN 2013; 56: 51-55).

Between 2000-2009, 56 children from the Mayo clinic pathology database of duodenal biopsies (n=1290) were identified.  Among this group, 48 had serological testing for celiac disease (CD).  Ultimately, 9 were labeled with CD, though only 5 met the ‘definite’ criteria.  Other conditions that were associated with increased IELs included the following:

  • Medication exposure
  • Inflammatory bowel disease
  • H pylori infection
  • Autoimmune conditions
  • IgA deficiency

So, which patients with duodenal IELs had CD?

  • “Definite” CD was used to define patients with elevations in two different serologic markers (TTG and EMA) or those with elevation in one serologic marker along with a documented clinical response to a gluten-free diet (GFD).
  • “Possible” CD described patients with normal serology, but serologic titer and clinical response was noted on a GFD.
  • “Unlikely” CD categorized patients with two negative serology markers who had compatible human leukocyte antigen haplotype and had clinical response to GFD.

In addition, if the IELs were predominantly on the villi tips, this increased the likelihood of CD.

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Three PEG Pediatric Cleanouts

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Several articles highlight the use of polyethylene glycol (Miralax) as a bowel prep for children:

  1. JPGN 2013; 56: 215-19
  2. JPGN 2013; 56: 220-24
  3. JPGN 2013; 56: 225-28

These studies and the accompanying editorial (pg 115) show fairly good results with PEG cleanout regimens.

The first study compared PEG versus senna in a blinded, prospective randomized trial.  After enrolling 30 children (6-21 years of age) at a planned interim analysis, the study showed superiority of PEG (1.5 g/kg/day) when used for 2 days prior to colonoscopy.  In addition to laxatives, patients were instructed to consume full liquid diet for 2 days prior to procedure & clear liquid on day prior (up to 3 hours before procedure).  In the PEG group, good or excellent cleanout scores were noted in 88% compared with only 29% in the senna group. There were no significant adverse effects or electrolyte changes which are well-detailed in this study (Table 2).

The second study evaluated a 1-day regimen with 46 children in a prospective open-label study.  238 g of PEG was mixed with 1.9 L of gatorade and administered over several hours.  Patients (8-18 years) were instructed to take only clears after noon the day prior to procedure Only 37 (82%) were able to take the full preparation.  43 (93%) took at least 75% of the preparation.  Despite issues with tolerance and nausea/vomiting (noted in 60%), 77% were rated as having an effective cleanout.

The third study enrolled 45 children (5-21 years) in a prospective study of a 1-day bowel preparation. Patients <45 kg received 136 g of PEG solution with 32 ounces of Gatorade; patients >45 kg received 255 g in 64 ounces.  44 children completed study.  Patients were told to take PEG over 3 hours the evening prior to procedure and allowed clears until 3 hours prior to procedure.  In this group, nausea was noted in 34% and vomiting in 16%.  However, patients reported that preparation was easy in 61% and tolerable in 39%.  The quality of the preparation was considered excellent in 23%, good in 52%, fair in 23% and poor in 2%.  There were no significant electrolyte changes.

Take Home Message:

Numerous small studies show that PEG solutions can be used as a safe, effective bowel preparation in children.  Shorter duration preparations are more convenient and may result in nausea or vomiting.

In our institution, we frequently use PEG cleanouts.  However, typically our doses of PEG are lower (eg. 136-168 g) and often combined with an enema to complete cleanout process.  Unlike adult preparations, we have not instructed families in split-dose regimens mainly due to concerns about the ability of pediatric patients to adhere to these regimens.

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