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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Heart-healthy Mediterranean Diet

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From AJC (see link below): “The study lasted five years and involved about 7,500 people in Spain. Those who ate Mediterranean-style with lots of olive oil or nuts had a 30 percent lower risk of major cardiovascular problems compared to those who were told to follow a low-fat diet but who in reality, didn’t cut fat very much. Mediterranean meant lots of fruit, fish, chicken, beans, tomato sauce, salads, and wine and little baked goods and pastries.” Methods (at NEJM.org) “In a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years.”

Related blog entry: Six years later-Mediterranean diet comes out on top | gutsandgrowth

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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Pediatric NAFLD histology score

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Pathologists may be more interested in this article than many pediatric gastroenterologists (J Hepatol 2012; 57: 1312-18).  Yet, the development of the pediatric NAFLD (non-alcoholic fatty liver disease) histological score (PNHS) is likely to be helpful, particularly in research of NAFLD.

In this study, an initial training set of 203 children with biopsy-proven NAFLD were examined.  After designing a scoring system, the PNHS was validated in another 100 children.  The mean age was 12.4 years.

PNHS = 100 x esp(Zphs)/[1 + exp(Zphs)]

Zphns = -8.4 + (2.5 x steatosis) + (3.5 x ballooning) + (3.4 x lobular inflammation) + (0.87 x portal inflammation)

This score is easily calculated by entering the individual histological features at the following website:

  • steatosis 1-3 (1=5%-33%, 2=34%-65%, 3=≥66%)
  • ballooning 0-2 (0=none, 1=few, 2=many)
  • lobular inflammation 0-3 (0=none, 1=<2 under 20x, 2=2-4 under 20x, 3=>4 under 20x)
  • portal inflammation 0-2 (0=none, 1=mild, 2=more than mild)
  • http://rcc.simpal.com/RCEval.cgi?RCID=RPCxtv#Result

Results:

  • In NASH patients, the mean PNHS was 89 ± 20.5 compared to 21.9 ± 24.5 in the non NASH patients.
  • There was a high level of agreement between categorization of NAFLD cases using PNHS compared with pathologist diagnosis.
  • NASH patients were much more likely to have metabolic syndrome (64%) compared with 38% for non-NASH patients
  • Of the histologic features, ballooning was the feature that most distinguished the cohorts.  In 66% of NASH patients, few or many ballooning hepatocytes were noted, whereas 96% of non-NASH patients had no ballooning noted.
  • With PNHS of ≥85, the sensitivity is 76-77% and the specificity is 91-97% for NASH.  This will decrease the number of ‘borderline NASH’ cases in pediatric cohorts.

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Vaccine successes and ambitions

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“Designing Tomorrow’s Vaccines” is a fascinating assessment of the success of vaccines as well as a look into the what future vaccines may accomplish (NEJM 2013; 368: 551-60).

First, I like the quote from Thomas Jefferson noted in the article:

“I avail myself of this occasion of rendering you a portion of the tribute of gratitude due to you from the whole human family.  Medicine has never before produced any single improvement of such utility…mankind can never forget that you have lived. Future nations will know by history only that the loathsome small-pox has existed and by you has been extirpated.”  Letter to Edward Jenner (May 14, 1805).

Jefferson’s enthusiasm was not without merit.  “In the 20th century alone, smallpox claimed an estimated 375 million lives.”  Yet, “since 1978, not a single person has died from smallpox.” Unfortunately, at this time, every year “more than 1.5 million children (3 per minute) die from vaccine-preventable diseases.”

Previous success in the U.S: Comparison of the estimated number of cases per year in the 20th century with the number of deaths in the year 2002 from the same diseases:

  • Poliomyelitis: 1.63 million vs 0
  • Diptheria: 17.6 million vs 0
  • Measles: 5.03 million vs 36
  • Pertusis: 1.47 million vs 6632
  • Rubella: 4.77 million vs 20
  • Smallpox: 4.81 million vs 0

Despite these advances, vaccines have “yet to realize their full potential.”  Effective vaccines are needed for malaria, HIV, and tuberculosis.  Vaccines for influenza which rely on 50-year-old technology need to be improved.

So how can this be achieved?

  • Improved knowledge of atomic structure/structural biology has provided new insights into neutralizing antibodies along with specific antibody reactions. This can counter immune evasion by targeting highly conserved regions
  • Millions of gene sequences encoding antibodies within a single individual can be analyzed to improve vaccine design
  • Genomewide sequencing of microbes has improved selection of vaccine targets
  • Improvements in delivery systems, like using viruslike particles or nanoparticles; alternatively, gene-based delivery of vaccines is feasible
  • Recombinant techniques has allowed a shift from egg-based methods

What is not on the horizon  — a vaccine for the half-truths that permeate the discussion.

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Aptly titled “The Cost of Technology”

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A brief commentary in JAMA makes some real useful observations regarding the effects of the electronic medical record on patient care (JAMA 2012; 2497-98).   The article describes a drawing by a 7-yer-old girl of her doctor who has an outstanding reputation among his peers.  Yet, in the drawing he is staring at the computer, and his back is to the patient.

The author notes that “when a physician focuses on a patient with complete attention, this simple act of caring creates a connection between two human beings. Almost immediately, the patient begins to feel, well, cared for, and this becomes a first step toward helping that person feel better.”

The computer is now a third player in this dynamic.  We “find ourselves entering more and more data while we are trying to listen to and talk with our patients.”  “By default, the patient moves down to second place…it is becoming the new reality.”

Physicians have to develop electronic records that allow us to record our thinking and improve efficiency so that we have more time to communicate with patients.  Can this be accomplished?

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Liver transplant outcomes in the boonies

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It looks like living in the boonies (URBAN DICTIONARY: BOONIES) does not make a big difference in pediatric liver transplantation (LT) outcomes (J Pediatr 2013; 162: 313-8).

The authors analyzed 3307 pediatric patients using the United Network Organ Sharing (UNOS) database between 2004-09.

Key outcomes for rural location:

  • Associated with greater risk of allograft rejection in the first 6 months after LT with an OR 1.27 (27% compared with 22.9% of urban patients).  The risk allograft rejection was not statistically significant at 1 year post LT (OR 1.18).
  • Associated with lower risk of post transplantation lymphoproliferative disorder (PTLD) with an OR of 0.64.  In total, 2.4% of rural patients experienced PTLD compared with 3.8% of urban patients.
  • Allograft loss and survival were similar for rural patients as for patients: 21.3% and 14.1% respectively compared with 20.7% and 12.7%.

The opposite risk ratios with regard to rejection and PTLD indicates that rural status may have greater rates of nonadherence with maintenance immune-suppression. However, the lack of a larger discrepancy in outcomes comes as a pleasant surprise, particularly as rural status is a known risk factor for worse health outcomes in many other complex chronic diseases.  Perhaps, this study validates the high level of skill and teaching on the part of pediatric liver transplant teams as well.

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