Barrett’s Esophagus –refer to cardiology?

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According to a study which examined cause-specific mortality, patients with Barrett’s esophagus may be better off following up with a cardiologist than a gastroenterologist (Gastroenterol 2013; 144: 1375-83).

This study derived data from UK’s Clinical Practice Research Datalink.  8448 patients with Barrett’s esophagus were matched with 155,212 controls based on age, sex and general practice.

Key findings:

  • Patients with BE had increased risk of death from esophageal cancer leading to a 10-year risk of 1.9%.  The absolute mortality rate due to esophageal cancer was 1.44 per 1000 person-years.  Compared to the general population, this was a 4.5 fold relative increase.
  • Ischemic heart disease resulted in 168 patient deaths, nearly 4-fold the number that died of esophageal cancer.
  • Overall, individuals with Barrett’s esophagus had a 21% relative increased risk of all causes of death; the majority were not due to esophageal cancer.  32% were related to circulatory disorders, 24% were due to nonesophageal cancer, and 15% were due to respiratory disease.

While this was a large study, there remain several limitations; most of these are due to reliance on electronic records for the diagnosis of Barrett’s.  Also, some individuals with Barrett’s may have been identified due to other high risk conditions such as cirrhosis (endoscopy for varicose) which could contribute to excess mortality.  In addition, many controls likely had undiagnosed Barrett’s.  Even the attribution of the cause of death can be quite difficult, especially with a database study.

Nevertheless, the population-based setting likely means that the results are likely meaningful to a broad population.

Take-home message: While Barrett’s esophagus increases the risk of death from esophageal cancer, it is possible that strategies which focus on nonesophageal causes of death may be more effective than esophageal surveillance for increasing longevity.

Related blog entries:

The Pediatric Nutrionist Blog

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One of my colleagues, Kipp Ellsworth, at Children’s Healthcare of Atlanta has started a pediatric nutrition blog: 

The Pediatric Nutritionist | Covering the world of infant, child … (www.childrensnutrition.org)

The site contains:

  • Core lectures section containing several presentations addressing the basics of pediatric nutrition
  • Feature Articles (long-form articles covering expansive clinical nutrition topics)
  • Protocol Development (articles covering institutional efforts to develop nutrition support protocols for various populations)
  • Journal Club
  • Clinical Vignettes (short-form articles or discussions on issues facing  clinical practice)

I’ve reviewed the site and I think it will be a useful resource for pediatric gastroenterology providers as well as general pediatricians.  Kipp has had a twitter feed which has provided links to a large number of nutrition articles and this site is likely to be a helpful extension.  Already on the site, there are a few powerpoint lectures; the one on formulas for infants and children provides a particularly good overview.

Neutrophil function as a biomarker for Acute Liver Failure

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More data on impaired neutrophil function in acute liver failure (ALF) and subacute liver failure (SALF) is available (Hepatology 2013; 57: 1142-52).

This study examined 15 ALF patients and 10 SALF patients in a cross-sectional case-control cohort design who were admitted to the liver ICU at King’s College Hospital between 2008-2010.  The median age for the ALF group was 33 and for the SALF group it was 52.5.  Ultimately 10 survived without liver transplantation; the remainder either died or underwent liver transplantation.

Neutrophil function was assessed on admission and then serially every 3-4 days in several ways; these assays were compared with 6 septic controls and 11 healthy controls.  Phagocytic activity was measured with a “Phagotest,” which quantifies opsonization of labeled E. coli. Oxidative burst was measured with the “Burtest,” which determines the percentage of phagocytic cells that produce a reactive oxygen species.  Other tests examined neutrophil phenotype and cytokine measurements (TNF-α, IL-1β, IL-6, CXC8/IL-8, IL-10, and IL-17).

Key findings:

  • Impaired neutrophil phagocytic activity in both ALF and SALF cohort on admission predicted non survival without liver transplant (p=0.01).
  • Neutrophil expression of CD-16 was significantly reduced in ALF cohort on day 1 (p<0.001).

Take-home message:

This study demonstrates specific defects in neutrophil function in ALF/SALF that are similar to impaired bactericidal function in severe sepsis.  Neutrophil function assays, while not available at the bedside at this time, are important biomarkers in ALF/SALF for increased susceptibility for sepsis and death.

Related blog posts:

Mixed-review for Thiopurines

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In this era of biologic agents for inflammatory bowel disease (IBD), the estimation of the risks and the benefits of thiopurines has been changing (Clin Gastroenterol Hepatol 2013; 11: 395-97).

The referenced article is an editorial that reviews new data on thiopurines as well as provide a background for their usage.

Main points:

  • After the SONIC trial, the usage of combination therapy in many IBD patients has regained favor with the main question: “How long to continue combination therapy?”
  • STORI trial evaluated withdrawal of infliximab (IFX) in patients on combined therapy.  More than 40% of patients who were withdrawn from IFX relapsed at 1 year.
  • After >20 years of thiopurine usage, more data is available on both short-term and long-term risks/benefits.  The risk of lymphoma in IBD patients on thiopurines is “4-fold increased…in the 6 evaluated studies.” Nonmelenoma skin cancer risk is increased by a hazard ratio of 5.9 in ongoing users and 3.9 in past thiopurine users.
  • At the same time, more recent studies have lowered the expectation of benefit for thiopurines (AZTEC trial, Cosnes study).

Related references:

  • Cosnes et al. Gastroenterol 2012; 142: s161.
  • Gastroenterol 2012; 142: 63-70.
  • Med Clin North Am 2010; 94: 93-113.

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Frequency of Functional Pain Overlap in Pediatric Crohn’s Disease

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If a patient with Crohn’s disease has pain, it may signal a flare-up of the inflammatory process.  Other causes like secondary infections, strictures, and functional pain need to be considered as well.  Functional pain can be particularly challenging.  A recent study reports on the prevalence of functional pain overlap in this setting (Inflamm Bowel Dis 2013; 19: 826-31).

This study prospectively enrolled 307 patients from two centers; it was a substudy to a cognitive behavioral therapy trial.

Patients in remission were defined by the following:

  • all normal laboratory findings:erythrocyte sedimentation rate <10, albumin >3.5, C-reactive protein <1 mg/dL
  • absence of clinical signs/symptoms of inflammatory bowel disease: 3 or less stools per day, no bloody stools, no nocturnal stools, no strictures, no concurrent steroid therapy
  • no escalation in medical therapy or clinical relapse in previous 6 months

Results: 139 of 307 patients had abdominal pain.  Among those with pain, 18 (13%) patients had functional abdominal pain (FAP). 10 of the 18 had either a colonoscopy or MRI in the previous year.  In these patients, the median PCDAI was 10.

This study noted a higher rate of depression in patients with both FAP and Crohn’s: 56%. This is compared with 29% of Crohn’s patients in remission without pain and 45% of Crohn’s patients with pain due to active disease.

Key points:

  • Pain with or without active disease can lead to an overestimation of disease activity based on PCDAI.
  • Depression is common in patients with pain, regardless of etiology
  • Current diagnostic criteria for FAP are flawed.  In fact, the Rome III criteria for FAP which specify absence of organic disease.
  • Biomarkers and imaging modalities are the best tools to exclude active disease.

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Treating Allergic Reactions to Infliximab

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This week on the GI bulletin board there was a brief discussion about overcoming allergic/anaphylactic reactions to infliximab.  A reference and a thoughtful response by Athos Bousvaros (in italics) follows:

Inflamm Bowel Dis. 2001 Feb;7(1):34-7. Successful desensitization and therapeutic use of infliximab in adult and pediatric Crohn’s disease patients with prior anaphylactic reaction. Puchner TC, Kugathasan S, Kelly KJ, Binion DG.   

 IN summary:

1.  Premed with 4 days of steroids (1mg/kg up to 40mg), and hydrocortisone day of the infusion.

2.  Give two test doses (0.1 mg, 1 mg), each over 10 minutes,

3.  If no problems, run the infusion over 4 hours instead of two.

 

Getting antibodies to infliximab before the challenge may also be helpful.  If high levels of antibodies are present, the patient may be more likely to fail the challenge. WE can “rescue” about half our patients using this protocol, and keep them on infliximab. IMPORTANT that a physician is around during the challenge.

Given the potential for adverse reactions and the importance of not depleting useful treatments, it is definitely worthwhile to read the entire cited reference rather than the aforementioned summary.

Related blog entry:

Overcoming ATIs | gutsandgrowth

Hepatocellular Carcinoma after the Fontan Procedure

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Given the fact that chronic liver disease and cirrhosis can develop in patients after the Fontan procedure, it comes as little surprise that cases of hepatocellular carcinoma (HCC) are being reported as well (NEJM 2013; 368: 1756-57).

This letter to editor describes four patients ages 24 to 42 who developed HCC following a classic Fontan or a variation.  Three of the four had very elevated alpha-fetoprotein levels; the lowest of the four patients was 106 ng/mL.  The letter notes that cirrhosis “may develop…approximately 11 to 15 years after a Fontan procedure; an incidence of cancer of 1.5 to 5.0% per year” is estimated after development of cirrhosis based on previous studies.

The letter also describes difficulties with regard to potential screening and treatment.

Related blog entry/references:

Low Ceruloplasmin Levels in Pediatric NAFLD

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Pediatric patients with nonalcoholic fatty liver disease (NAFLD) undergo workup to exclude underlying diseases.  For many patients, this may include screening for Wilson’s disease with a ceruloplasmin level.  In a recent study, lower ceruloplasmin in 100 pediatric patients with NAFLD were associated with more severe NAFLD (JPGN 2013; 56: 370-75).

All patients had measurements of copper, iron, ceruloplasmin, transferrin ferroxidase activity, and ferritin; these assays were from archival serum samples from a cohort with biopsy-proven NAFLD. These patients had undergone testing for other etiologies of liver disease.

The authors were trying to determine if oxidative stress and its association with iron or copper may be playing a role in the severity of NAFLD.  Those with lower severity NAFLD score (< 5) had a mean ceruloplasmin of 36.4 mg/dL (standard deviation 5.3); in contrast,  those with higher severity NAFLD score (≥5) who had a mean ceruloplasmin of 28.1 mg/dL (standard deviation 7.2).  That is, there was an inverse association between ceruloplasmin levels and the severity of NAFLD score.  Lower ceruloplasmin was associated with increased inflammation, more ballooning histology, and more steatosis.

Key point:

Lower ceruloplasmin (<28.6 mg/dL) had a 92% specificity and 76% sensitivity for identifying more severe NAFLD.  Thus, even a borderline-low ceruloplasmin that does not suggest Wilson’s disease may be useful in discriminating children more likely to need a liver biopsy.

Related blog entry:

NAFLD Guidelines 2012 | gutsandgrowth

IBS Symptoms in Patients with Celiac Disease

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While a gluten-free diet (GFD) is the optimal treatment, adult patients with celiac disease still have a high prevalence of irritable bowel symptoms (IBS) (Clin Gastroenterol Hepatol 2013; 11: 359-65).

The authors examined the prevalence of IBS symptoms by reviewing cross-sectional and case-control studies in adults with celiac disease (≥16 years old).  Initially, the literature search identified 624 studies; the vast majority did not fit the study requirements.  Seven studies (n=3383 participants) reported the prevalence of IBS symptoms in celiac disease.  These studies took place between 2002 to 2011 in five different countries.  IBS was defined using either Rome I, II, or III criteria.  Only one of these studies assessed adherence to a GFD by using negative tissue transglutaminase antibodies on the 2 most recent outpatient visits.

Results: IBS symptoms were present in 38% of all patients with celiac disease.  The pooled odds ratio was higher for celiac disease than controls (OR 5.6, with 95% CI 3.23-9.7).  Nonadherence to a GFD increased the likelihood over those who were adherent by an odds ratio of 2.69

Take-home message: IBS symptoms are present in a high proportion of patients with celiac disease.  While a GFD may improve these symptoms, some individuals will have persistent symptoms.

Related blog entry:

Is functional pain more common in children with … – gutsandgrowth  Previous blog entry examines functional abdominal pain in children and celiac disease.

Additional references:

  • -JPGN 2011; 53: 216. Case report of refractory celiac treated with 6-MP.
  • -Clincal Gastroenterol & Hep 2011; 9: 13. Celaic with persistent symptoms: consider poor adherence**, SBBO*, pancreatic insufficiency*/subclinical pancreatitis, refractory celiac (rare), PLE, giardia, malignancy, lactose intolerance, functional d/o*, microscopic colitis, Crohn’s*, NSAIDs
  • -Gastroenterol 2009; 136: 81, 91, 99, 32. Refractory celiac can be divided into 2 types; 2nd type assoc c abnormal IEL and has poor prognosis. Risk of non-hodgkins lymphoma 3.8-5 .3 fold over gen population in larg Sweish study. n=37869 c NHL, 236,408 controls, 613,961 1st degree relatives. Relatives c 2 fold risk. Absolute NHL risk ~1 in 1421 person-yrs for celiac pt.
  • -Clin Gastroenterol & Hep 2007; 5: 445-450. Causes of nonresponsive celiac.
  • -NEJM 2007; 356: 2548. Nonresponsive due to inhaled gluten in farm setting.
  • -Clin Gastro & Hep 2007; 5: 445. Gluten exposure in 36%, IBS n 22%, lactose intol 8%, refractory CD 10%
  • -Gastroenterol 2011; 141: 1187.  Prevalence of celiac similar in IBS as general population though higher number (7%) with celiac antibodies (esp gliadin).

Impaired Esophageal Function in Neurologically-Impaired Neonates

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There are a multitude of gastrointestinal problems that develop in infants who have hypoxic-ischemic encephalopathy (HIE).  One of the most pressing needs is determining how best to feed these infants.  A recent study provides more information on the aberrant esophageal function of these infants (J Pediatr 2013; 162: 976-82).

Design:  provocative esophageal manometry was performed in 34 neonates (27 with HIE and 7 controls).  HIE inclusion criteria included the following:

  1. >36 weeks gestational age
  2. acute perinatal event: abruption, cord prolapse, severe fetal heart rate abnormality
  3. signs of encephalopathy per Sarnat staging at birth

The characteristics of the HIE neonates is further defined and divided into those who were treated with hypothermia and those who received traditional care.  All but one infant had an abnormal brain MRI.

Key results:

  • Peristaltic reflexes, upper esophageal sphincter contractile responses (much greater in HIE patients), lower esophageal sphincter relaxation responses (much lower in HIE patients) and esophageal body coordination and clearance were all noted to be abnormal.
  • Infants treated with hypothermia had greater upper esophageal sphincter contractile responses and improved esophageal clearance (noted by decreased peristaltic durations).

Overall, this study demonstrates prolonged and poorly coordinated peristaltic responses in neonates with HIE.  There are no effective treatments for this type of esophageal dysmotility.  As such, even with current management approaches including gastroesophageal reflux medications and fundoplication, children with HIE remain at risk for aerodigestive malfunction and aspiration.

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