Category Archives: Pediatric Gastroenterology Intestinal Disorder

Hemophagocytic Lymphohistioctosis: Advances

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A recent medical progress report provides a concise update on hemophagocytic lymphohistiocytosis (HLH) (J Pediatr 2013; 163: 1253-59).

  • Table 1 summarizes the subtypes of HLH.
  • Atypical presentations include colitis and hypogammaglobulinemia.
  • Table 2 provides the diagnostic criteria.
  • The treatment approach is outlined as well.  In the short-term, with primary HLH, the goal is controlling the hyperinflammatory state (often with dexamethasone and etoposide).  The long-term goal aims to definitively correct the underlying genetic defect by allogeneic hematopoietic stem cell transplantation (HCT)

Other points:

  • A genetic diagnosis of familial HLH can be made in 40-80% of HLH cases with the identification of PRF1, UNC13D, STX11, and STXBP2 genes.
  • UNC13D are the predominant defects identified in Caucasians in U.S.
  • PRF1 is most common in African-American patients.
  • Ferritin remains an excellent screening tool.  A level >500 mcg/L is suggestive (but not specific) for HLH; a level >10,000 has much greater specificity (96%) along with fairly high sensitivity (90%).
  • HLH is commonly referred to as macrophage activation syndrome (MAS) in the setting of a rheumatologic illness.
  • There is no broad consensus on management of secondary HLH.  In MAS, therapy often includes pulsed steroids and/or cyclosporine.

Related blog post:

Expert Commentary on GERD Surgery in Infants

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In this month’s “GI & Hepatology News,” Dr. Ben Gold and Dr. Jose Garza comment on antireflux surgery in infants (page 12) (related article on page 1 of same issue). Initial reference: JAMA Surg 2013 [doi: 10.1001/jamasurg.2013.2685]. See the following link.  They comment on the lack of workup for many of these infants who undergo this major surgery and the frequent lack of involvement by pediatric gastroenterologists.

PDF: December issue – American Gastroenterological Association

Risk of Vitamin B12 Deficiency with Persistent PPI Usage

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From NY Times, nyti.ms/1kwQHPF :

People who use certain acid-suppressing drugs for two years or longer are at increased risk of vitamin B12 deficiency, which can lead to anemia, neurological problems or dementia, researchers reported on Tuesday.

The drugs in question are called proton-pump inhibitors, or P.P.I.’s, and histamine 2 receptor antagonists, and they are available by prescription and over the counter under brand names like Prevacid, Prilosec and Nexium. Nearly 157 million prescriptions were written for P.P.I.’s alone last year.

“People who are taking these medications are more likely than the average person to be vitamin B12 deficient, and it’s a potentially serious problem,” said Dr. Douglas A. Corley, senior author of the new study, published in The Journal of the American Medical Association. “This raises the question of whether people taking these medications for long periods should be screened for vitamin B12 deficiency.”

Dr. Corley has received funding from Pfizer, which makes a P.P.I. called Protonix.

He and his colleagues at Kaiser Permanente in Oakland, Calif., examined the medical records of 25,956 adults who received vitamin B12 deficiency diagnoses between 1997 and 2011, comparing them with 184,199 patients without B12 deficiency during that period.

Patients who took P.P.I’s for more than two years were 65 percent more likely to have a vitamin B12 deficiency, the researchers found. Higher doses of P.P.I’s were more strongly associated with the vitamin deficiency, as well.

Twelve percent of patients deficient in vitamin B12 had used P.P.I.’s for two years or more, compared with 7.2 percent of control patients. The risk of deficiency was less pronounced among patients using H2RA’s long term: 4.2 percent, compared with 3.2 percent of nonusers.

The new study is the largest to date to demonstrate a link between taking acid suppressants and vitamin B12 deficiency across age groups. Earlier small studies focused primarily on the elderly.

Robert J. Valuck, a professor of pharmacy at the University of Colorado in Aurora, was surprised that the association in the new report was strongest in adults younger than age 30. “It’s not safe to assume vitamin B12 deficiency is only an issue in the elderly,” he said.

Bottomline: patients (not just elderly) on chronic PPIs may need to be tested for vitamin B12 deficiency.

Related blog entries:

Are we missing Vitamin B12? | gutsandgrowth

Looking behind and looking forward in EoE (part 2)

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While yesterday’s article was good, today’s is really forward-thinking (Gastroenterol 213; 145: 1289-99).  Last year in this blog, I reviewed the use of microRNA for studying EoE (MicroRNA signature for eosinophilic esophagitis | gutsandgrowth), this study expands on this idea with the development of the EoE diagnostic panel (EDP) which is a 96-gene quantitative polymerase chain reaction assay.

The authors (one of whom [JG] has joined our group) used this assay initially in 15 pediatric with EoE, in 14 pediatric non-EoE, and then in a subsequent cohort of 194 pediatric and adult patient samples (fresh or formalin-fixed tissue from one esophageal biopsy).  Of the latter cohort, 91 had histologically-active EoE, 57 had either non-EoE or EoE in remission, 34 were histologically-ambiguous, and 12 had reflux.

Results -first of all you have to see the results to get the best sense of how impressive they are.  Numerous figures show the EDP depictions of patients’ EoE transcriptome patterns.

  • EDP had approximately 96% sensitivity and 98% specificity; EDP’s utility could be underestimated due to limitations in the current ‘gold standard’ for diagnosis
  • EDP can distinguish EoE in remission from healthy controls as well as identify patients exposed to swallowed glucocorticoids.  Thus, with current patients in remission, the tissue may appear healthy; nevertheless, EDP identifies molecular changes in this tissue.
  • EDP can distinguish EoE from reflux

What this study means:

  1. Currently both the diagnostic standards (eg. cutoff values for eosinophils) and remission standards remain questionable.  This molecular test has the potential to raise the standard for both diagnosis and response to treatment.
  2. EDP may elucidate differences in EoE pathogenesis which could vary from patient to patient.
  3. EDP may help in prospective trials and help in clinical practice by identifying patients who are most likely to benefit from the treatments that are available.
  4. EDP may help overcome the patchy nature of eosinophil distribution.
  5. EDP serves as a model for how molecular testing could influence many inflammatory conditions including asthma, inflammatory bowel disease and biliary atresia.

While I think this study is going to be highly influential, I have one unanswered question:  how much will it cost?  In the conclusion, the authors state “the EDP offers an accurate, rapid, informative, and low-cost diagnosis.”  Yet, the authors do not elaborate on the expense of this technology.

Related blog entries:

A Cautionary Tale –Is it Medical Child Abuse?

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From Jeff Schwimmer’s twitter feed:

A story in the Boston Globe highlighting the difficulty of differentiating Mitochondrial Disease from Medical Child Abuse; the latter term is now preferred over Munchausen Syndrome by Proxy. Her gastroenterologist was involved due to stooling problems (this child underwent a cecostomy tube) and feeding issues:

b.globe.com/1b6Vy4E -part 1.

PART 2: The family battles the state.

More bad press or Boston Children’s:

‘Campaign of Terror’: One of the Best Hospitals in the …

Looking behind and looking forward in EoE (part 1)

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Two important articles are provide additional insight into eosinophilic esophagitis (EoE).

In the first (Gastroenterol 2013; 145: 1230-36), the authors performed a retrospective review of the Swiss EoE Database (SEED). This SEED should not be confused with our SEED center (Home- The SEED Center of Atlanta– SouthEast Eosinophilic …).  While the database contains 783 EoE patients, only 200 who were followed by the senior author and had complete data were included.  The enrollment period dates back to 1989.

Demographics: 153 men, mean age 39 years old, 94.5% had dysphagia at time of diagnosis and 35.5% had chest pain.  66% had concomitant allergies.

Terminology: The authors defined strictures as low-grade if a standard 9 mm endoscope could pass but met resistance, intermediate if a 6 mm endoscope could pass, and high-grade if it could not be passed with a 6 mm endoscope.

Results:

  • 37.5% (n=75) had strictures (other endoscopic findings noted in Table 2)
  • Peak eosinophil count (median): 35 proximally and 28 distally
  • Figure 2 showed the evolution of endoscopic features based on diagnostic delay.  With increasing diagnostic delay, there developed a preponderance of a mixed fibrotic/inflammatory picture whereas in those whose symptoms were of much shorter duration, the endoscopic features were often inflammatory without fibrosis.
  • For example, if diagnostic delay was between 0-2 years, then fibrotic findings were noted in 46.5%; in contrast, 87.5% had fibrotic features if symptoms had been present for > 20 years.
  • Strictures increased from 17.2% in those without significant diagnostic delay to 70.8% in those with symptoms present for > 20 years.
  • The authors note that diagnostic delay was greatest in those who developed symptoms in the first decade of life.

Study limitations: The categorization of strictures is straightforward; however, newer tools like the EndoFlip can detect esophageal narrowing more accurately.  Other limitations are related to retrospective nature of study and its reliance on patient’s reported outcomes (subject to recall bias).  Thus, the estimation of diagnostic delay may be inaccurate.

Take home message:

This article reinforces the concept that the presentation of EoE changes with time and that the long-term consequence of untreated EoE is increasing fibrosis and stricturing of the esophagus.

Related blog entries:

GIKids Resource

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For those of you who have not visited GIKids.org website:

GIKids – A Resource for Pediatric Digestive Disorders

It has literally A-Z handouts on pediatric GI problems for families, including four new handouts:

Educated or Misinformed –Leading to Hemorrhagic Disease of the Newborn

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“Hemorrhagic Disease of the Newborn,” now termed “Vitamin K Deficient Bleeding,” has reemerged as a problem. Many well-intentioned parents are refusing vitamin K to keep things more ‘natural’ for their infants.  This phenomenon is likely encouraged by some alternative health websites and other parents; babies who are breastfed are at increased risk of vitamin K deficiency (without prophylaxis).  Unfortunately, they are playing Russian roulette with their infant’s safety. In addition, many practitioners will not readily recognize this disorder because of the effectiveness of Vitamin K prophylaxis that has been provided since 1961.

An excerpt from the St. Louis Dispatch provides more information: Four babies hemorrhage after parents refuse vitamin K shot, a practice on the rise

Maternity care providers here and nationwide are on high alert for life-threatening vitamin K deficiencies in newborns, at the same time they are seeing more parents refusing a routine preventive injection.

The Centers for Disease Control and Prevention released a report last month about four babies in Nashville, Tenn., who hemorrhaged after their parents refused vitamin K injections at birth. The babies were diagnosed with life-threatening vitamin K deficiency bleeding between February and September. Three had bleeding in the brain, and one had gastrointestinal bleeding. They survived, but the infants with brain hemorrhages could have long-term neurological problems.

“Not giving vitamin K at birth is an emerging trend that can have devastating outcomes for infants and their families,” CDC director Dr. Tom Frieden stated in the report. “Ensuring that every newborn receives a vitamin K injection at birth is critical to protect infants.”

The vitamin is necessary for normal blood clotting, but because vitamin K does not transfer well across the placenta, most babies are born with low levels. The deficiency can lead to a rare, sudden bleeding disorder up to 6 months of age.

The CDC investigation found that parents refused the injection for several reasons, including a concern about an increased risk for cancer from the injection, an impression that it was unnecessary and a desire to minimize exposure to “toxins.” A 1992 study associated vitamin K and childhood leukemia, but the findings have been debunked by subsequent studies…

The number of parents refusing is more alarming at birth centers, which provide care led by midwives who support natural birth. Among the most recent 75 births at the Birth and Wellness Center in O’Fallon, Mo., 23 percent refused the injection, and 14 percent opted for the oral dose, said Jessica Henman, the center’s certified nurse midwife.

The CDC studied a random sample of births this year in the Nashville, Tenn., area and found that parents of 3.4 percent of 3,080 newborns discharged from hospitals had refused the vitamin K injection, while parents of 28 percent of 218 born at birth centers had refused…

A newborn not getting the injection is 81 times more likely to get the late form of the disorder than a baby who gets the shot, according to the CDC. [my emphasis in bold]

Related link from Stanford:  Guidelines for Vitamin K Prophylaxis – Newborn Nursery at LPCH

Bottomline: When seeing an infant with bleeding, ask about vitamin K prophylaxis after birth.

If a parent caused intracranial hemorrhage in an infant by shaking the infant, they would probably be jailed.  What should be done in these cases?

Related blog post:

Bleeding due to vitamin K deficiency | gutsandgrowth

Something New with FMT

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“Resentment is like drinking poison and then hoping it will kill your enemies.” –Nelson Mandela

A brief review on Fecal Microbiota Transplantation (FMT) (Gastroenterol 2013; 145: 946-53) made a few points that I was not familiar with and reiterated many other important aspects.

  • With regard to preparation of FMT, early data suggests that using water rather than saline may result in better resolution of Clostridium difficile infection (CDI)
  • Adequate volumes of FMT material are needed, with rates as high as 97% CDI resolution with infusions >500 mL
  • While preliminary data suggested higher CDI resolution with colonoscopy infusion, a recent randomized controlled trial indicated that duodenal infusion was as effective as colonoscopic administration
  • Short-term data indicate very low adverse effect rates
  • While the only accepted role for FMT outside of clinical trials is for CDI, the review examined the potential benefit for inflammatory bowel disease (IBD), irritable bowel syndrome, chronic fatigue syndrome, and metabolic/cardiovascular disorders.
  • With IBD, there are currently 6 registered trials testing FMT for patients with IBD.  Preliminary data have been more evident in small studies with ulcerative colitis.
  • The rationale for FMT in IBD is that IBD patients have reduced diversity and altered microbial flora.  “However, it is not clear whether these differences are a cause or a consequence of the development of IBD.”

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Fiber Intake and Crohn’s Disease

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There are several lines of evidence that diet can contribute to the development and treatment of Crohn’s disease.

From a treatment standpoint, the most dramatic data has been with the effectiveness of enteral nutrition as a treatment option.  In addition other environmental factors like being raised on a farm and use of antibiotics have been shown to alter the risk for Crohn’s disease; the former has been associated with a reduction in risk and the latter with an increased risk.

A new prospective study from 170,776 women followed over 26 years in the Nurses’ Health Study has identified up to a 40% reduction in the risk of Crohn’s disease among the highest fiber intake quintile (24 g/day) in comparison to the lowest intake quintile (12 g/day) (Gastroenterol 2013; 145: 970-77, editorial 925).  Link to abstract: http://dx.doi.org/10.1053/j.gastro.2013.07.050 …

Specific findings:

  • Fruit intake was associated with greatest risk reduction.  The median daily intake of fiber from fruit in the highest quintile was 6 g/day which is equivalent to 2 fruits (eg. banana or orange).
  • Vegetable intake was not associated with protection from Crohn’s disease.
  • The editorial notes that “reverse causation was addressed by evaluating cumulative exposure and including a 2-4 year lag period.”
  • However, the women in this study may not be representative and fiber intake could be an epiphenomenon.  The women in the highest quintile were also less likely to smoke, use aspirin and have a body mass index <30 kg/m-squared.
  • Fiber intake did not significantly reduce the risk of ulcerative colitis

Bottomline: the “Institute of Medicine recommends that daily fiber consumption should be 14 g of fiber for every 1000 calories.”  Thus, if one were to follow the guidelines by the IOM, all individuals would be consuming enough fiber to potentially reduce their risk of Crohn’s disease by 40%.  Other fiber benefits include improve bowel habits, lowered cholesterol levels, weight loss, and lowered diabetes risk.

Related blog links:

Also, in the past week, I posted a blog regarging Hepatitis C (Wiping out Hepatitis C | gutsandgrowth).  Another helpful review of the emergence of new therapies comes from yesterday’s NPR.  This story also reported that the expected (not yet set) cost of sofusbuvir will be $90,000!  Here’s the link:

http://www.npr.org/blogs/health/2013/12/05/248934833/fda-set-to-approve-hepatitis-drug