Northern Latitudes -Higher Prevalence of Celiac Disease and Gluten Avoidance

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A recent study (A Unalp-Arida et al. Gastroenterol 2017; 152: 1922-32) examines the relationship of latitude and the prevalence of celiac disease and gluten avoidance.

Using the NHANES 2009-2014 survey with 22,277 participants (6 years and older), the authors identified persons with celiac disease (based on serology) along with those who avoided gluten without a diagnosis of celiac disease.

Key findings:

  • 0.7% of participants had celiac disease and 1.1% avoided gluten without celiac disease
  • Celiac disease was more common among individuals who lived at latitudes of above 35 degrees and more common with higher socioeconomic status. Figure 2 map provides latitude lines. In the eastern U.S. the Georgia-Tennessee border corresponds to this latitude line and in the western U.S. the southern tip of Nevada lies on this line.
  • From 35 degrees to 39 degrees the odds ratio was 3.2, whereas the odds ratio was 5.4 for those above 40 degrees.  These odds ratios were independent of race, ethnicity, socioeconomic status and body mass index.
  • Similarly, the prevalence of gluten avoidance without celiac disease was twice as common among persons living north of 40 degrees compared with those residing at latitudes <35 degrees.
  • The findings on latitude were heavily influenced by the increased rate of celiac and gluten avoidance in the Northeast region (more so than in the West)

In their discussion, the authors note that “a North-South gradient in disease occurrence in genetically similar populations has been shown in studies of autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis.” Potential environmental factors could include lack of sunshine/vitamin D deficiency, hygiene, and infections.  A study comparing similar populations in Finland and Russia suggested a lower economic status/less hygiene increased the risk of celiac disease despite similar gluten exposure.  The authors note that there was NOT an increased risk in Northern Sweden compared to Southern Sweden.  In fact, this study of children found a higher rate of celiac disease in Southern Sweden (Arch Dis Child 2016; 101: 1114-18).

My take: This is another intriguing study regarding celiac disease epidemiology which strongly points to environmental factors accounting for marked variation in celiac disease prevalence.

More information on this topic from AGA Blog: Do More People Have Celiac Disease in the North vs the South?

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Good Safety Data on Infliximab vis a vis Malignancy and Hemophagocytic Lymphohistiocytosis

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Using data from 5766 pediatric participants with inflammatory bowel disease in a prospective DEVELOP study (JS Hyams, MC Dubinsky et al. Gastroenterol 2017; 152: 1901-14) provide more reassurance regarding the safety of infliximab.  This study took place between 2007 to 2016 and accounted for 24,543 patient-years of followup.  While the study examined rates of malignancy, the SEER database does not include non-melanoma skin cancer; thus, the authors did not have a suitable comparator for this outcome; there were two cases of basal cell carcinoma in the study population.  This article’s abstract was published on this blog previously: Infliximab Not Associated with Malignancy

Key findings:

  • There was NO increased risk of malignancy or hemophagocytic lymphohistiocytosis (HLH) in patients exposed to infliximab as monotherapy.
  • Malignancy risk was 0.46 per 1000 patient-years in patients with infliximab exposure compared with 1.12/1000 patient-years in patients who had no exposure to biologics.
  • HLH risk was 0 in those with infliximab monotherapy compared with 0.56 per 1000 patient-years in those who had no exposure to biologics.
  • Patients exposed to thiopurines with or without biologics did have increased risks of malignancy compared with comparative populations. 13 of 15 patients who developed a malignancy and all 5 patients who developed HLH had thiopurine exposure.
  • Thiopurine exposed patients had 0.75 malignancy events per 1000 patient-years compared to 0.27 malignancy events per 1000 patient-years for patients who had no thiopurine exposure
  • Thiopurine exposed patients had 0.29 HLH events per 1000 patient-years compared to 0 HLH events per 1000 patient-years for patients who had no thiopurine exposure
  • In their discussion, the authors note that after discontinuation of thiopurine therapy for 1 or more years, the standardized incidence ratio (SIR) for malignancy approached the non-exposed group (1.48 compared to 1.30); whereas ongoing or recent thiopurine exposure had SIR of 4.45.

Limitations: Study duration (<10 years). Hard to detect changes in rare malignancies

My take: In this largest prospective pediatric cohort to date, there is NO increased risk of malignancy (excluding non-melanoma skin cancer) or HLH with infliximab therapy; however, there is a trend towards increased risk among those with thiopurine exposure. Nevertheless, as malignancy is a rare event, very low increased risk of malignancy with infliximab cannot be entirely excluded.

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For HLH:

 

Better Diet, Lower Mortality

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Nutrition science is hampered by the inability to randomize people into various treatment approaches.  Thus, when we see that some individuals who, for example, eat more fish, we are unable to conclude that the difference in their outcome is related to their diet or related to other factors that we cannot control.  It could be that individuals who eat fish may exercise more, have more money, smoke less or have less stress.

That being said, we can find associations that may be meaningful.  Into this mix, another study (M Sotos-Prieto et al. NEJM 2017; 377: 143-53) find that a better diet quality is associated with lower total and cause-specific mortality.

This study analyzed two large cohorts:

  • The Nurses’ Health Study -a prospective study with 121,700 RNs –enrollment initiated in 1976
  • The Health Professionals Follow-up Study with 51,529 health professionals enrollment initiated in 1986

Diet quality was evaluated with three scoring systems:

  • The Alternate Healthy Eating Index with 11 food components
  • The Alternate Mediterranean Diet Score with 9 food components
  • The Dietary Approaches to Stop Hypertension (DASH) with 8 food components

Key findings:

  • “A 20-percentile increase in diet-quality scores was associated with an 8 to 17% reduction in mortality”
  • “Worsening diet quality over 12 years was associated with an increase in mortality of 6 to 12%.”
  • “Taken together, our findings provide support for the recommendations of the 2015 Dietary Guidelines Advisory Committee that it is not necessary to conform to a single diet plan to achieve healthy eating patterns.”
  • “Common food groups in each score that contributed most to improvements were whole grains, vegetables, fruits, and fish or n-3 fatty acids.”

Like most nutrition studies, this one has limitations.  Strengths of this particular study include the prospective design, large sample sizes, repeated assessments of diet/lifestyle, multiple diet assessments, and high rates of followup.

My take: There is no doubt that diet quality is associated with improved longevity. Better diets are highly likely to be the reason why many people live longer.

Dupont Forrest, NC

“March of Science”

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A fascinating commentary (“The March of Science –The True Story”  L Rosenbaum NEJM 2017;377: 188-91) discuss issues regarding mistrust of science in this age of ‘alternative facts.”

Here are some key points:

  • “Nutrition science may be the area that provides the most ammunition for distrust, given the combination of uncertainty, public interest, and powerful preferences. Indeed, skepticism of most nutrition science is warranted, given the often insurmountable challenges of controlled, blinded experimentation…The confluence of these factors..often invoked to condemn the scientific process more generally: Why should I believe you people when you people are always changing your minds?”
  • “Remarkable gains in human longevity are just one manifestation of science’s success–but….’No one wants to hear about the plane that lands.'”
  • There has been a shift “in the tone of public discussions of science.” Instead of someone being “wrong,” they are now “corrupt” or “evil.”
  • Due to potential for condemnation, there is fear of “venturing into the fray” which “means that the public hears far more from science’s critics than its champions. This imbalance contributes to “science is broken” narratives ranging from claims about the pervasiveness of medical error to the insistence that benefits of our treatments are always overhyped.
  • Changing the narrative: “we have to learn to tell stories that emphasize that what makes science right is the enduring capacity to admit we are wrong. Such is the slow, imperfect march of science.”

My take: Widespread skepticism and confirmation bias have the potential to disrupt highly effective medical treatments by confusing them for those that are unproven.

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Dupont Forest, NC

 

Predicting Future Liver Disease with GGT Levels in Biliary Atresia Patients

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A recent study (AJ Freeman, VL Ng, S Harpavat, A Hrycko, Z Apted, P Bulut, T Leong, SJ Karpen. Clin Gastroenterol Hepatol 2017; 15: 1133-35) describes the predictive value of γ-glutamyltransferase (GGT) in predicting thrombocytopenia/portal hypertension among biliary atresia patients.

In this retrospective study from three centers who had followup for at least 4 years, GGT values at 2 years of age were examined among biliary atresia patients (n=46) who continued with their native liver.

Key findings:

  • GGT ≥100 U/L had a predictive positive relationship with thrombocytopenia at 4, 5, and 6 years of age.  Patients with elevated GGT had lower platelet count (160 vs. 211) and their values continued to decline. GGT ≥100 U/L at 2 yrs predicted thrombocytopenia (<150) at age 4 with a sensitivity of 0.88, specificity of 0.57.
  • Patients with normal GGT values had “essentially stable platelet counts over the next 4 years.” GGT <100 U/L at 2 yrs predicted a low risk of thrombocytopenia with negative predictive value of 0.89, 0.92, and 0.93 at age 4, 5, and 6 respectively.

My take: This study quantitates a useful point –patients with biliary atresia and elevated GGT values are likely to develop evidence of portal hypertension.

Brevard, NC

Hazardous Toys: Jarts and Magnets

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I had completely forgotten about Jarts until reading a recent editorial by Athos Bousvaros (J Pediatr 2017; 186: 6-7). He succinctly describes how these lawn darts were ultimately removed from the market primarily due to the advocacy of a father who became a strong advocate after the death of his daughter.

A more complete description of the effort to remove Jarts -from Mental Floss website: How One Grieving Father Got Lawn Darts Banned

Dr. Bousvaros, in commentary on a study on high-powered (neodymium) magnets (Rosenfeld D et al. J Pediatr 2017; 186: 78-81) describes the similarities between these magnets and the jarts.  Both have caused catastrophic injuries and death.  However, the recent removal of these magnets from the market was overturned.  There is no national tracking system for magnet ingestions in U.S. or Canada.  However, the referenced study demonstrated a dramatic reduction  in medical/surgical procedures in 2014-2015 (n=10) when a ban was placed compared to 2011-2012 (n=29).

For U.S physicians, all we can do currently is to report to the CPSC (Consumer Product Safety Commission) all magnet-related injuries and to publicize the dangers of these hazardous products.  To report: go to CPSC website (link: CPSC website) and “report an unsafe product” on the right side of the page.

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Big Study of Primary Sclerosing Cholangitis

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This blog has reviewed multiple publications on primary sclerosing cholangitis (see blog posts below). Now, a study from 37 centers with 7121 patients with PSC has been published: TJ Weismuller et al. Gastroenterol 2017; 152: 1975-84. Given the relative infrequency of PSC, this retrospective report offers more insight into the predictors of the clinical course of PSC.

Key points:

  • Most of the patients in the study had large duct PSC (89.8%); 3.6% had small duct disease and 6.6% had overlapping PSC/autoimmune hepatitis.
  • Mean age of cohort at diagnosis was 38.5 yrs.
  • 70% of PSC patients developed IBD with ulcerative colitis (UC) about 5-times more common than Crohn’s disease.
  • 37% of patients met the primary endpoint of either liver transplantation or death
  • Individuals with small duct PSC had a favorable outcome; only one of 254 (0.4%) developed cholangiocarcinoma (CCA). Risk of primary endpoint was much lower in small duct PSC compared with classical PSC with an adjusted hazard ratio of 0.23.
  • Individuals with PSC/AIH variant also had a reduced risk of primary endpoint compared with classical PSC with an adjusted hazard ratio of 0.73.
  • Overall, CCA occurred in 594 patients (8.3%); the incidence of CCA changed markedly with the age of the patient.  In the youngest group (<20 years), the rate was 1.2 per 100 patient-years, it was 6.0 in 21-30 yr-olds, 9.0 for 31-40 yr-olds, 14.0 fr 41-50 year olds, 15.2 for 51-60 yr-olds, and 21.0 per 100 patient-years in those older than 60 years.
  • The absence of IBD, particularly UC, was associated with a lower risk PSC clinical course. Patients with UC had increased liver disease progression compared with patient’s with Crohn’s disease, with a HR of 1.56.
  • The median transplant-free survival time was 14.5 years; the estimated survival was approximately 21 years in the entire cohort

It is noted that an important limitation is that the cohort is from specialist centers and may not reflect a more typical population-based cohort; that is, this patient population is likely to be severely affected.

My take: Patients with small-duct PSC have a much lower risk of disease progression.

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