Is obesity neglect?

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Usually not –according to a thoughtful commentary on this controversial topic (J Pediatr 2012; 160: 898-99).

Suggested criteria for child removal:

  • 1. High likelihood for serious and imminent harm
  • 2. Reasonable likelihood that coercive intervention will be effective
  • 3. Absence of alternative options for addressing the problem

However, “allowing a child to lose all opportunity to live into healthy adulthood when effective treatment is available runs contrary to the central mission of child rearing…When this occurs, regardless of the cause, it must be all about the child, and something must be done.”

Related blog posts:

Treating diabetes with surgery

Lower leptin with physical activity

Staggering cost of obesity

Additional references:

Assessing and discussing risk of lymphoma in IBD

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A recent article has shown that the absolute lymphoma risk from medications in children and young adults with IBD is quite low (Inflamm Bowel Dis 2012; 18: 838-43).

In this single center study from 1979-2008, 1374 pediatric IBD patients had charts reviewed to determine whether lymphoma developed.  In total, two male patients who had received thiopurines developed lymphoma (one Hodgkin, one anaplastic large cell) in 6624 patient-years of follow-up.  Both patients are alive after chemotherapy.  Mean follow-up was 4.8 years per patient.  The absolute lymphoma incidence rate was 3 per 10,000 patient-years; after thiopurine exposure, the rate was 4.5 per 10,000 patient-years compared to an expected 0.58 per 10,000 patient-years.

In this study, 22% of the patients had received TNF inhibitors.  None developed lymphoma.  The risk of biologics could not be fully assessed due to a limited study period: 713 person-years taking the medication.

The risk of thiopurine-associated lymphoma was similar to previous studies but did not reach statistical significance.  As related in other studies, the risk of biologic agents, like Remicade, Humira, and Cimzia, is heavily influenced by whether patients had also received immunomodulators.

One useful way to try to convey this risk has been with diagrams.  One useful diagram is a palette of one thousand people or of 10,000 people showing the absolute risk and one showing the risk for other complications like infection.  You can make your own by going to the following link:

Download Communication Tools

RiskComm

Additional references/blog entries:

Only one chance to make first impression

Biologics | Living Longer | Arthritis Today Magazine -From Arthritis magazine: biologics improve survival in Rheumatoid arthritis

Why “therapeutic dose” of codeine can kill

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While this blog has described some of the huge problems with the overuse of narcotics (Deadly consequences of pain management), another danger with narcotics occurs especially with codeine due to its metabolism via the CYP2D6 pathway; codeine is particularly risky in young children.  A reminder of this is a recent case report (Pediatrics 2012; 129: e1343-1347).

During my training, I was told by an ENT doctor that he never prescribed codeine in children less than 6 years of age due to safety concerns.  While he could not explain the mechanism, this case report does.  This case report describes three children with severe cases (two were fatal) from North America.  In the two fatal cases, gene duplications encoding Cytochrome P450 2D6 (CYP2D6) caused a significantly greater production of morphine from its parent drug, codeine.  This risk of respiratory depression may be enhanced in ENT cases especially in children with obstructive sleep apnea.

The risk from codeine involves individuals who are ‘ultra-metabolizers’ of CYP2D6; this is because the metabolized drug in this case, morphine, is more potent than the parent drug, codeine.  Other opioids that are similar to codeine, like hydrocodone and oxycodone, may have additional risk as well.  Ultra-metabolizers include up to 7% of all caucasians.  In addition, 5-10% of caucasians are poor-metabolizers which would result in a lack of therapeutic effect with codeine.

While ultra-metabolizers of CYP2D6 function are prone to codeine toxicity, poor-metabolizer individuals will have an exaggerated response when the parent drug is more potent than its metabolites.  In addition, there are numerous drugs (not metabolized by CYP2D6) which interact to inhibit the function of CYP2D6 (eg. diphenhydramine).  Thus, these drugs can potentiate the effect of CYP2D6 on its substrates.

Other drugs commonly used by gastroenterologists and metabolized by CYP2D6 include tricyclic antidepressants, most SSRIs, metoclopropramide, ondansetron, and promethazine.  In ultra-metabolizer individuals, many of these drugs will not work because the quickly-produced metabolites, unlike the parent substrate, do not have therapeutic effects.

Additional references:

  • N Engl J Med 2004; 351: 2827-31.  Codeine Intoxication Associated with Ultrarapid CYP2D6 Metabolism. 62 year old: “12 hours after the last dose of codeine, the blood level of morphine was 20 to 80 times as high as the blood level that would have been expected on the basis of measurements in healthy persons ” due to ultrametabolism of CYP2D6 in combination with inhibition of CYP3A4 activity by other medications
  • CYP2D6 – Wikipedia, the free encyclopedia
  • Drug and Alcohol Dependence 89 (2007) 190–194. Association of CYP2D6 ultrarapid metabolizer genotype with deficient patient satisfaction regarding methadone maintenance treatment
  • What happens when codeine is used with drugs – WorstPills.org –

Case finding for hepatitis C

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A previous post noted the failure of risk-based screening for hepatitis C virus (HCV) (Unknown unknowns for Hepatitis C).  Because risk-based screening has not been effective, the CDC has proposed a different strategy, one time testing of all baby boomers:

http://www.cdc.gov/nchhstp/newsroom/HepTestingRecsPressRelease2012.html

“On the eve of the first ever National Hepatitis Testing Day (May 19), the Centers for Disease Control and Prevention is issuing draft guidelines proposing that all U.S. baby boomers get a one-time test for the hepatitis C virus. One in 30 baby boomers – the generation born from 1945 through 1965 – has been infected with hepatitis C, and most don’t know it.”

Breastfeeding: protection from asthma

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Good news for breastfed babies –breastfeeding may reduce risk of wheezing and asthma for several years (J Pediatr 2012; 160: 991-6).

In this prospective birth cohort study of 1105 infants from New Zealand, detailed feeding information was obtained at 3, 6, and 15 months which allowed calculation of breastfeeding duration. This information was correlated with information about wheezing and asthma collected at 2, 3, 4, 5, and 6 years.

Findings (after controlling for confounding variables):

  • Each month of exclusive breastfeeding was associated with significant reductions in asthma at all timepoints.  The effect was most prominent at younger ages.
  • The authors estimate that if every infant in the cohort had been exclusively breastfed for 6 months, that asthma would have been reduced by 50% at 2 years, 42% at 3 years, 30% at 4 years, 42% at 5 years, and 32% at 6 years.
  • In atopic children, the effects of exclusive breastfeeding are more pronounced.  In this study, exclusive breastfeeding for ≥3 months reduced asthma at ages 4, 5, and 6 by 62%, 55%, and 59% respectively.

The authors note that not all studies have found that breastfeeding improves asthma.  However, most of these studies reported outcomes in older children.

Related Posts:

Breastfed babies less likely to develop fatty liver

More evidence that breastfeeding improves cognitive development

Additional references:

  • -NEJM 2011; 364: 701, 769.  Living on a farm decreases risk of childhood asthma.
  • -Thorax 2009; 64: 604-9. Breastfeeding and asthma in children followed for 8 years.
  • -Br Med J 2007; 335: 815-20.  Longer time of breastfeeding does not reduce allergy/asthma. n=17,046 pairs of mother-infant (13,889 followed up at age 6.5yrs)

NAFLD Guidelines 2012

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Given the pervasiveness of Non-alcoholic Fatty Liver Disease (NAFLD), updated practice guidelines are worth a look (Hepatology 2012; 55: 2005-23, also in Gastroenterology 2012; 142: 1592-1609)).  While the review includes updated information on incidence, prevalence, risk groups, natural history, the focus remains on specific graded recommendations.

These AGA/AASLD/ACG guidelines do not recommend screening adults due to uncertainties surrounding diagnostic tests and treatment.  This includes high risk populations such as diabetics and bariatric patients.  In addition, unlike recent obesity guidelines from the AAP (Pediatrics 2007; 120: S164-192), these guidelines do not recommend screening children for NAFLD.

Specific management recommendations:

  • Exclude competing etiologies in patients with suspected NAFLD: iron studies, autoantibodies, Wilson’s, viral hepatitis, celiac serology, muscle disease
  • Consider liver biopsy in higher risk patients: metabolic syndrome patients, patients with higher NAFLD Fibrosis score, or before treatment
  • Serum/plasma CK18 is promising biomarker.  Not recommended for routine practice at this time.

Treatment Recommendations:

  • Weight loss (3-5%) helps steatosis and greater losses (up to 10%) may be needed to improve necroinflammation.
  • Metformin –not recommended for liver disease in NASH/NAFLD.
  • Pioglitazone can be used to treat steatohepatitis; however, “long-term safety and efficacy of pioglitazone in patients with NASH is not established.”
  • Vitamin E at 800 units/day improves liver histology in biopsy-proven NASH.  Not recommended without biopsy-confirmed NASH, in diabetic patients, or patients with cirrhosis.  Concern with Vitamin E in adults has been an association with increased all-cause mortality in some studies (but not in others).
  • Avoid alcohol in patients with NAFLD

Website to download PDF version:

http://www.gastro.org/journals-publications/news/societies-develop-new-nafld-clinical-practice-guideline

Another opinion on which patients to biopsy:

http://www.gastro.org/journals-publications/aga-perspectives/june-july-2012/should-we-routinely-do-liver-biopsy-in-nafld-patients

Related posts:

A liver disease tsunami

What do you know about the “exposome”?

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I had not heard of the term “exposome” until last week (Gastroenterology 2012; 142: 1403-4).  However, this term was coined in 2005 (Cancer Epidemiol Biomarkers Prev 2005; 14: 1847-50).    This term is meant to describe the environmental analog of the genome.

Particularly with the gastrointestinal tract, environmental exposures are often considered a cofactor in disease development.  While there has been an increased understanding of the role of genes in the development of disease, it is abundantly clear that environment exposures can independently cause disease or act as a ‘second hit.’  The gastrointestinal tract is exposed to fluids which contain a multitude of elements and microorganisms, and to foods with their variability in nutrients, microbes and pollutants.  Other environmental factors include smoking, ionizing radiation, noise, breastfeeding, medications, and antimicrobials.

This cited commentary explains how environmental scientists are trying to unravel the ‘exposome.’

  • Bottom-up strategy:  measure external sources of the individual exposome at multiple time points.  This strategy may benefit from improvement in informatics, remote & personal sensing devices.
  • Top-down strategy: examines internal milieu including blood, biologic specimens, and transcriptomics/proteonomics.  Early examples include distinct signatures associated with specific environmental exposures.

Both strategies require validation to understand how external exposures trigger internal changes and disease expression.  Promising fields in gastroenterology for the study of the exposome include IBD, gastrointestinal cancers, functional disorders, and even obesity.  It is likely that studies of the exposome will answer questions about why the frequency of so many diseases are changing much more readily than studies of the genome.

Related blog posts:

Eat your veggies…if you don’t want to get sick

Why are we seeing so many more cases

Additional references:

  • -PLoS One 2010; 5 e10746.  Novel associations between type 2 diabetes and specific chemical exposures.
  • -Nature 2006; 444: 1027-31.  Obesity-associated gut microbiome.
  • -BMC Med Genomics 2010; 3: 17.  Chemical factors associated with disease-related gene expression data.

Unknown unknowns for Hepatitis C

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“ [T]here are known knowns; there are things we know that we know.
There are known unknowns; that is to say there are things that, we now know we don’t know.
But there are also unknown unknowns – there are things we do not know, we don’t know.		 ”
—United States Secretary of Defense, Donald Rumsfeld February 2002

Reading a recent epidemiology article reminded me of the preceding referenced quote  (Hepatology 2012; 55: 1652-61).  This study took a close look at knowledge of being infected with hepatitis C virus (HCV) and what HCV infection may indicate.

The study identified 30,140 participants through the National Health and Nutrition Examination Survey (NHANES) conducted from 2001-2008.  The Centers for Disease Control (CDC) obtains nationally representative data on the health and nutritional status of noninstitutionalized civilians across the U.S.  NHANES uses a ‘complex, stratified, and mulitstage probability sampling design and collects information from approximately 5,000 persons per year using standardized household interviews, physical examinations, and testing of biologic samples.’

Participants 6 years of age or older who tested positive for anti-HCV antibodies were sent a report.  Out of the 30,140 participants, 393 (1.4%) had evidence of past or current HCV infection; 170 were available for the study investigators.  Only 49.7% were aware of HCV status prior to receiving NHANES letter.  Furthermore, only 3.7% were first tested for HCV because they or their doctor thought they were at risk for infection; most were tested as part of a routine exam (perhaps detected after elevated ALT values) (46.7%), due to symptoms (15.9%), or blood donation (9.7%).

Another aspect of the study was determining the participants’ understanding of HCV infection.  Correct responses to the HCV survey were more likely in individuals between 40-59 years of age, white non-Hispanics, and patients who had seen a doctor about their HCV infection.  Specific questions often answered incorrectly included the following:

  • whether HCV could be contacted by kissing –only 68% knew this was false
  • whether HCV could be transmitted sexually –only 64% knew this was true
  • whether HCV could be acquired during birth if mother had HCV –only 57% knew this was true

Take home points:

  • Risk-based screening for HCV will continue to fail.  Physicians may not elicit adequate information and patients may deny risky behaviors even if asked.
  • Approximately half of patients in this cohort were unaware of HCV infection.
  • Many misconceptions about HCV persist even among those who had received counseling.

Related blog posts:

Pediatric HCV Guidelines

HCV now more deadly than HIV

The cost of progress in treating Hepatitis C

Additional resource:

http://www.cdc.gov/hepatitis/RiskAssessment/  This website allows individuals to assess their risk for hepatitis.

TODAY is worrisome for a lot of tomorrows

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The TODAY study (NEJM 2012; 366: 2247-56 and editorial 2315-16) =Treatment Options for Type 2 Diabetes in Adolescents and Youth.

While the study has a catchy acronym, the findings are disturbing.  Eligible patients (n=699) were 10 to 17 years old were followed on average over 3.86 years; they were divided into three groups:

  • Metformin 1000mg BID –48% achieved primary outcome (glycated hemoglobin <8% for at least 6 months).
  • Metformin with lifestyle changes –53% achieved primary outcome.  The lifestyle counseling that patients received in the study likely exceeded the typical counseling that most patients receive in clinical practice.
  • Metformin with rosiglitazone (4mg BID) –61% achieved primary outcome.  While this group had the best glycemic response, this group also had the greatest increase in BMI.

Other findings:

Comorbid conditions were common:

  • Hypertension: at baseline in 81 (11.6%) and new cases during study 155 (22.2%)
  • Dyslipidemia (LDL): at baseline in 23 (3.3%) and new cases during study 49 (7%)
  • Triglyceridemia: at baseline in 127 (18.2%) and new cases during study 70 (10%)
  • Microalbuminurina: at baseline in 44 (6.3%) and new cases during study 72 (10.3%)

Frequent adverse events noted with medications (Table 2 in study): gastrointestinal symptoms noted in about half of all study participants in each group, rash noted in about 40%, and elevated LFTs in about 40%.

Take home messages (borrowed from editorial):

“Most youth with type 2 diabetes will require multiple oral agents or insulin therapy within a few years after diagnosis”

“Fifty years ago, children did not avoid obesity by making healthy choices; they simply lived in an environment that provided fewer calories and included more physical activity.”

“Public-policy approaches–sufficient economic incentives to produce and purchase healthy foods and to build safe environments that require physical movement…will be necessary to stem the epidemic of type 2 diabetes and its associated morbidity.”

Related posts:

Treating diabetes with surgery

Cardiovascular disease for the entire family

Staggering cost of obesity

Lower leptin with physical activity

Reasons for refeeding syndrome

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Refeeding syndrome (RFS) is defined as the potentially fatal shifts in fluid and electrolytes that may occur in malnourished patients who are abruptly refed either enterally or parenterally.  The biochemical hallmark is hypophosphatemia.  Other changes can include hypokalemia, hypomagnesemia, and thiamin deficiency.  RFS can worsen the prognosis of children with celiac crisis as well (JPGN 2012; 54: 522-5).

A chart review from Lucknow, India from Jan-Dec 2010, identified 5 cases of RFS among 35 celiac patients.  All were severely malnourished.  All had anemia, hypoalbuminemia, hypophosphatemia, hypokalemia, and hypomagnesemia.  All improved with initial caloric restriction followed by gradual escalation of caloric intake along with electrolyte supplementation.

This article shows that a variety of causes of malnutrition can lead to refeeding syndrome. Considering refeeding syndrome in any severely malnourished child may help improve the prognosis by altering the nutritional management.

Additional references:

  • Nutr Clin Pract 2012; 27: 34-40. Reviewed refeeding syndrome publications since 2000.  Hypophosphatemia occurred in 96% of cases (26 of 27).
  • Crit Care Med 2010; 14: R172-R178.  Refeeding syndrome with anorexia.
  • Nutrition 2010; 26: 156-67. Review of refeeding syndrome treatment.
  • Nutr Clin Pract 2008; 23: 166-71.  Death due to refeeding syndrome.
  • JPEN 1990: 14.1; 90-97. Refeeding syndrome review.
  • Crit Care Med 1990; 18: 1030-1033. Review.