6-Thioguanine Levels in Autoimmune Hepatitis

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A recent retrospective study (MA Sheiko et al JPGN 2017; 65: 80-5) examines the issue of azathioprine (AZA) metabolites and outcomes in pediatric autoimmune hepatitis (AIH).

Study characteristics:

  • 66 children
  • Mean age of diagnosis 9.6 years
  • Mean follow-up 2.9 years
  • Study period 2002-2013

Key findings:

  • 79% achieved biochemical remission (defined as ALT ≤50 U/L); mean time was 6.2 months
  • 6% required liver transplantation
  • 18% were weaned off immunosuppression and remained in remission
  • 6-thioguanine (6-TGN) levels ranging from 50 to 250 (pmol/8 x 10 to 8th red blood cell count) were associated with biochemical remission

“Our study suggests that AZA dosing of approximately 1.2 to 1.6 mg/kg/day will achieve 6-TGN levels of 50 to 250 pmol, which is sufficient to maintain biochemical remission in the majority of patients.“

This is significantly lower than dosing recommended for inflammatory bowel disease (recommended levels 250-450). The associated editorial (pg 2-3, N Kerkar) cautions that while “lower levels are sufficient for maintaining biochemical remission…higher levels, similar to that used in IBD, are required for inducing remission.”

My take: Lower doses of azathioprine are likely to maintain biochemical remission and cause fewer side effects.  Metabolite levels can be helpful to assure reasonable levels of 6-TGN and to assure medication adherence.

Related blog entries:

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.

Shem Creek, SC

Neonatal Cholestasis for Neonatologists

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I recently had the opportunity to review the topic of neonatal cholestasis with my neonatal colleagues.  I reviewed two related conditions: parenteral nutrition associated liver disease (PNALD) and neonatal acute liver failure (NALF).  Some of the material incorporates recommendations from NASPGHAN cholestasis guidelines and from NASPGHAN cholestasis slidesets. Much of the slideset information is publicly available on a YouTube lecture by Dr. Linda Book (link at bottom).

Full lecture: Neonatal Cholestasis for Neonatologists

Some screenshots:

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.

 

Vitamin D3 vs Vitamin D2

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Vitamin D3 appears to be more effective at increasing vitamin D levels than vitamin D2 according to a recent study: From MedicalNewsToday: Vtiamin D Guidelines May Be Changing Following New Study

An excerpt:

The researchers measured vitamin D levels in 335 South Asian and white European women over two winter periods. They chose winter because, due to a reduction in sunlight exposure, vitamin D levels tend to be lower at this time.

The women were split into five groups: those consuming vitamin D-2 in a biscuit; those consuming vitamin D-3 in a biscuit; those consuming vitamin D-2 in a juice drink; those consuming vitamin D-3 in a juice drink; and those receiving a placebo.

The study found that vitamin D-3 was twice as effective at raising vitamin D levels in the body as vitamin D-2.

Participants who received the D-3 in a biscuit raised their levels of vitamin D by 74 percent, while those receiving the vitamin in juice saw a 75 percent increase. Those receiving D-2 had a 33 and 34 percent increase, respectively. The placebo group experienced a drop of 25 percent across the same period.

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“Sell by”/Expiration Dates for Medications

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A recent NPR story/ProPublica research reiterates the fact that many medications remain potent long after their expiration dates: That Drug Expiration Date May be More Myth Than Fact

Here’s an excerpt:

Tossing such drugs when they expire is doubly hard. One pharmacist at Newton-Wellesley Hospital outside Boston said the 240-bed facility is able to return some expired drugs for credit, but had to destroy about $200,000 worth last year. A commentary in the journal Mayo Clinic Proceedings cited similar losses at the nearby Tufts Medical Center. Play that out at hospitals across the country and the tab is significant: about $800 million per year. And that doesn’t include the costs of expired drugs at long-term care pharmacies, retail pharmacies and in consumer medicine cabinets…

Pharmacists and researchers say there is no economic “win” for drug companies to investigate further. They ring up more sales when medications are tossed as “expired” by hospitals, retail pharmacies and consumers despite retaining their safety and effectiveness…

Whatever the solution, the drug industry will need to be spurred in order to change, says Hussain, the former FDA scientist. “The FDA will have to take the lead for a solution to emerge,” he says. “We are throwing away products that are certainly stable, and we need to do something about it.”

My take: Don’t expect any action on this issue anytime soon.  At the very least, this will may persuade some family members not to throw away some medications that are likely still effective.

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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Piedmont Park, Atlanta

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.

Related blog posts:

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