Weight of the Nation

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A perspective article, NEJM 2012; 367: 389-391, addresses the topic of whether Americans are ready to solve the problem of obesity.  Short answer: No!

The article discusses the Institute of Medicine (IOM) report “Accelerating Progress in Obesity Prevention: Solving the Weight of the Nation” along with the accompanying HBO documentary (HBO: The Weight of the Nation).

“The centerpiece of THE WEIGHT OF THE NATION campaign is the four-part documentary series, each featuring case studies, interviews with our nation’s leading experts, and individuals and their families struggling with obesity. The first film, CONSEQUENCES, examines the scope of the obesity epidemic and explores the serious health consequences of being overweight or obese. The second, CHOICES, offers viewers the skinny on fat, revealing what science has shown about how to lose weight, maintain weight loss and prevent weight gain. The third, CHILDREN IN CRISIS, documents the damage obesity is doing to our nation’s children. Through individual stories, this film describes how the strong forces at work in our society are causing children to consume too many calories and expend too little energy; tackling subjects from school lunches to the decline of physical education, the demise of school recess and the marketing of unhealthy food to children. The fourth film, CHALLENGES, examines the major driving forces causing the obesity epidemic, including agriculture, economics, evolutionary biology, food marketing, racial and socioeconomic disparities, physical inactivity, American food culture, and the strong influence of the food and beverage industry.”

While the IOM report identifies a need for structural changes in our environment, public opinion consistently focuses on personal responsibility.

  • 64% identify overeating, lack of exercise, and watching too much TV as the biggest causes
  • 18% identify external factors as the biggest causes, including exposure to junk food, lack of safe places to play, limited availability of healthy foods

Obstacles for addressing this problem also include the following:

  • Obesity-prevention efforts may further stigmatize individuals. The article specifically cites criticism aimed at ‘ads that aired in Georgia;’ these were pulled after concerns of increasing obesity stigma.
  • “Issue-attention cycle” problem.  “This pattern occurs when initial public alarm over the discovery of a problem and optimism about its quick resolution are replaced by the realization that solving the problem will require some public sacrifice and will displace powerful societal interests.”

Related blog posts:

Is obesity neglect?

NAFLD Guidelines 2012

Treating diabetes with surgery

Lower leptin with physical activity

Staggering cost of obesity

Do medicines work for GERD infants?

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“Absence of evidence is not evidence of absence.” Carl Sagan

If medicines work for infantile GERD, it is difficult to prove (Winter H, et al. JPGN 2012; 55: 14-20).  The cited study is the latest having difficulty proving that proton pump inhibitors are effective in infants.  In this randomized, double-blind, placebo-controlled multinational study from 33 centers, 98 infants (1-11 months) were enrolled.  My colleague, Dr. Benjamin Gold, was one of the researchers.  Initially, a 2-week open-label treatment was given which was followed by a 4-week randomized phase.   Study participants had to have a clinical diagnosis of GERD with at least one GERD symptom  –at least twice per week in a 4-week period:

  • vomiting/regurgitation
  • irritability
  • supraesophageal manifestations (cough, wheeze, stridor)
  • respiratory symptoms triggered by feedings
  • feeding difficulties

The treatment administered was weight-based dosing of esomeprazole:

  • 3-5 kg:     2.5mg
  • 5-7.5kg    5mg
  • 7.5-12kg  10mg

Daily symptoms were captured with an interactive voice response system.  Among the initial 98 patients enrolled, 80 reached the randomization phase.  During the initial 2-week period, 81 (82.7%) had symptom improvement based on physician global assessment.  During the double-blind phase, 48.8% of placebo-treated patients and 38.5% of esomeprazole-treated patients discontinued therapy due to symptom worsening.  While the time for discontinuing esomeprazole was longer in a posthoc analysis, the primary outcome, discontinuation rate, was not significantly different.

So what is the reason that this was a negative study?  While the reasons are unclear, all of the following are possible:

  • Patient selection/lack of accurate diagnosis.  Mixed-population was recruited for the study –though this type of population is similar to clinical practice.
  • Dose of esomeprazole.
  • Inadequately powered study.  If the effectiveness of PPIs is small, a much larger population is needed.
  • Maybe these agents don’t work in infants.  Infants secrete less acid than children and adults; thus, acid blockers may not work as well. (The Medical Pendulum and Gastroesophageal Reflux)

Why not give PPIs even if they don’t work?  The previous link discusses many of the potential adverse problems that are possible with medical treatment of GERD. However, even if a medicine does not harm does not mean you should do something because it ‘might’ do some good.  An example of this is the apocryphal tale of the famous pianist who died one day in the middle of a recital. (I saw this in a journal article but cannot remember the reference.)  The manager came out to announce his death.  A man in the audience shouts, ‘Give him an enema.’ Initially, the manager tries to ignore him. After the man yells this three times, the manager responds, ‘the poor man is dead…what good will an enema do?’ The voice replies, ‘What harm will it do?

Additional references:

  • -JPGN 2010; 50: 609-18. Pantoprazole helped improve symptoms but there were no significant differences compared to placebo in withdrawal rates due to lack of efficacy. n=128.
  • -NASPGHAN 2009, Abstract#21. Meds/Rx of NICU pts did not shorten hospital stay or promote wt gain, n=1149. Abstract#26. prevacid more effective than ranitidine in infants.
  • -J Pediatr 2009; 155: 601 (letter). Should not be used to treat symptoms unless proven to be reflux.
  • -JPGN 2009; 49: 498. GERD guidelines.  “In infants and toddlers, there is no symptom or symptom complex that is diagnostic of GERD or predicts a response to therapy.” Identical response to placebo (vs prevacid) in largest double-blind randomized study (54% at 4 weeks) (J Pediatr 2009; 154: 514-20.)  Reflux is “not a common cause of unexplained crying. irritability..in otherwise healthy infants.” “There is no evidence to support the empiric use of acid suppression for the treatment of irritable infants.”

“Fatal attraction”

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Today’s 33Charts topic Children and Magnets: a Fatal Attraction gives an update on rare earth magnet ingestions (neodymium) along with some other useful links.

Addendum: Also a link from NY Times on 8/17/12: http://www.nytimes.com/2012/08/17/business/for-buckyballs-toys-child-safety-is-a-growing-issue.html?_r=1&nl=todaysheadlines

Previous posts on this topic:

More on magnet ingestions

Magnet ingestion –urgent removal needed

How helpful are probiotics?

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Nobody really knows.  Claims about their efficacy are often based on poorly designed studies.  Efficacy of each strain for specific conditions and with specific dosing is often lacking.  One recent negative study demonstrates that probiotics are often not beneficial (J Pediatr 2012; 161: 40-3).

In this randomized, double-blind placebo controlled study of 106 Polish children (1-48 months of age), Lactobacillus reuteri had no effect in preventing nosocomial diarrhea in patients admitted for non-diarrheal illnesses.  While the authors contemplate that this could be due to the strain of probiotic chosen or the dose, it is clear that evidence that probiotics prevent infectious diarrhea “is still scant.”

This conclusion is backed by a large meta-analysis (JAMA 2012; 307: 1959-69).  While the study concludes that the use of probiotics is associated with a lower risk of antibiotic-associate diarrhea (RR 0.58), it predicted that the number to treat for one person to benefit would be 13.  The study was based on a systematic review of 82 randomized clinical studies.  Yet, overall the quality of the research was considered low; the studies were often had shortcomings:

  • 59 studies “lacked adequate information to assess the overall risk of bias”
  • 64 did not indicate if treatment randomization was blinded
  • 31 did not report an intent-to-treat analysis
  • 41 did not include a calculation of the study’s statistical power to detect differences
  • 17 trials were industry-sponsored and 52 did not clarify their funding/potential conflicts of interest
  • 59 did not report on adverse events specifically related to probiotic use; few trials addressed the risk of fungemia or sepsis
  • Trials rarely specified antibiotic agents; thus, it is difficult to know if a particular probiotic would be better with certain types of antibiotic therapy or duration.

Additional references/links:

  • Potential and pitfalls of probiotics with necrotizing enterocolitis
  • -JPGN 2010; 51:24. VSL#3 helpful for IBS, n=509 (4-18yr olds). 1 per day for <11yr, 2/day in 12-18yr olds
  • -Pediatrics 2008; 121:e850. Culturelle, during pregnancy and early infancy, not effective in preventing atopic dermatitis. Did increase wheezing.
  • -J Pediatr 2008; 152: 801. Probiotic helped reduce colic sx in 30 preterm infants, Lactobacillus reuteri
  • -Pediatrics 2007; 119; e124. Probiotics reduced colic in breastfed babies more than simethicone. n=83, Lactobacillus reuteri, 10-8th power per day. Decreased crying 18 minutes per day at 1 week compared to simethicone & by 94 minutes/day at 4 weeks (95% response vs 7% of simethicone)
  • -Neurogastroenterol Motili 2007 (Quigley EM, et al), 19: 166-72. Review of probiotics and IBS.
  • -NASPGHAN 2007, author: Brian Dunlap, H. Yu, Y Elitsur. abstract -most commercial yogurts have LOW concentrations of probiotics.
  • -JPGN 2006; 43: 550. Review of probiotics for specific conditions.
  • -J Pediatr 2006; 149: 367. Probiotics reduce risk of antibiotic assoc diarrhea. If 7 pts (on abx) are treated with probiotics, one fewer will develop AAD.
  • -JPGN 2006; 42: 454. Evidenced-based review of probiotics.
  • -Pediatrics 2005; 115: 1-4 & 171 editorial.  Probiotics decreased NEC in this study.
  • -Gastroenterol 2004; 126: 1620-33.  Review of probiotics, prebiotics and antibiotics in IBD.

Comparing diets in EoE

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There remains a limited number of therapeutic options with EoE.  Dietary therapy can be effective as well as burdensome.  A closer look at dietary treatment effectiveness was recently published (J Allergy Clin Immunol 2012; 129: 1570-8 –thanks to Seth Marcus for alerting me to this article).

Due to eligibility requirements, only 98 patients of an initial 513 met criteria.  The findings from this study may be difficult to generalize because of the following:

  • Highly selected patient population
  • Retrospective study.   Dietary therapy was NOT chosen randomly.
  • Study originates from a specialized center (Cincinnati) which attracts atypical cases of EoE

That being said, the study asks some important questions. What is the remission rate for skin test-directed elimination diet in comparison to six food group elimination diet (SFED) and to an elemental diet?  The SFED actually composed two groups (in my opinion, this is a significant flaw in the study design & has a limiting effect on the conclusions).  The ‘classical’ SFED (42% or 11/26) eliminated the six most common food groups (milk, soy, wheat, egg, nuts, fish/shellfish) whereas a ‘modified’ SFED (58% or 15/26)  combined the classical SFED with foods eliciting positive skin-testing.

Some of the authors terminology:

  • Complete remission: 1 or fewer eosinophils/hpf
  • Partial remission: 2-5 eos/hpf
  • Partial resolution: 6-14 eos/hpf
  • Remission: <15 eos/hpf
  • Non-remission: >15 eos/hpf

Skin prick tests (SPFs) were performed to as many as 62 foods and 11 environmental allergens and graded 0-4.  0 equated to negative control & 4 equated to histamine control -all interpreted at 15 minutes after placement.

Atopy patch tests (APTs) were interpreted at 48 hours with scoring between 0-4.  A score of 2 indicated “erythematous with generalized induration.”  Any score of 2 or higher was considered positive.

Food reintroduction process: “Food reintroductions were initiated only when the peak eosinophil count was less than 15 eosinophils/hpf. If symptoms occurred after reintroduction of a food, patients were instructed to discontinue that food, wait approximately 10 to 14 days, and then reintroduce another food…. A food reintroduction was considered successful if no symptoms were reported and the postpeak eosinophil count was less than 15 eosinophils/hpf.”

Why were so many patients excluded?  The main causes were 181 patients did not meet strict EoE criteria, 122 patients received glucocorticoids, and 52 patients had another eosinophilia-associated condition; less common reasons included patient age >21, being part of a separate drug trial, obvious noncompliance, different diet regimen, and not having 2 consecutive EGDs separated by dietary intervention.

How many endoscopies are needed for dietary therapy?   In this study, the average patient had 8.5 EGDs at Cincinnati.  The greatest number of EGDs took place among patients assigned to an elemental diet (average >11); these patients also had a longer followup period compared to the other two groups: 2.9 years compared with 1.1 for SFED and 2.1 for directed diet.

  • All three diets resulted in improvement in eosinophil count.
  • Overall Remission rates: 96% elemental, 81% SFED, 65% directed diet
  • Complete Remission rates:  59% elemental, 39% SFED, 30% directed diet

One interesting set of data is in Table 4.  This gives the pass rate for various foods with single and multiple food reintroductions.  Milk for example had a pass rate of 35% among the 17 patients who had this as a single food reintroduction.  The values ranged from a low pass rate of 29% for strawberries to a high pass rate of 78% for cocoa and 75% for pork. Soy, eggs, and wheat all hovered near 60% pass rate.

Conclusions by authors:

1. “SFED is no less successful than directed diet and consistent with unreliability of skin testing …Our data…undermine the value of skin test-directed dietary management. ” This is due to the fact that the disease mechanism is not an IgE-mediated disease (skin testing primarily detects IgE-mediated allergens).

2. Elemental diet is superior at inducing histologic remission. However, “multiple studies indicate that adherence is inversely related to the number of foods eliminated.”

Previous related posts:

Guidelines for Eosinophilic Esophagitis

Looking better or feeling better in EoE?

Look of improvement on an EoE diet

Eosinophilic Esophagitis -Six Food Group Diet

MicroRNA signature for eosinophilic esophagitis

The undiscovered country

 

Liver biopsy risk in children

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A recent retrospective study from Oslo looks at risk factors and safety of liver biopsy (JPGN 55: 82-87).

Among 190 patients who underwent 275 ultrasound-guided liver biopsies (interventional radiology), there were four major complications –two were due to post-biopsy bleeding, one was due to variceal bleeding within 12 hours, and one was due to the development of pain/acidosis, and tachycardia.  28 patients had minor bleeding.   There were no mortalities, though one patient dropped hemoglobin in half (11.6 to 5.3).

In their patient population, the following had increased risk for major complications:

  • Focal space-occupying lesion/tumor (n=25) OR 2.84  for all bleeding risk; patients with these lesions typically had more biopsy passes (average 4.9)
  • Acute liver failure (n=12) OR 26.1 for major complication risk
  • Low-molecular weight heparin therapy (n=18)  OR 2.43 for all bleeding risk

Not identified as risk factors for complications in this cohort:

  • Low platelet count (<70 [n=14])or coagulopathy (INR>1.7 [n=18]),  –all received blood products before biopsy
  • Aspirin treatment (often used in transplant population to prevent hepatic artery thrombosis) (n=55)  OR 0.96
  • Liver transplant patients (n=97) -odds ratio was lower than entire cohort (OR 0.52)

Additional references:

  • -JPGN 2011; 53: 202. Good safety results with IR liver biopsy, n=249. 2/249 had drop in Hgb of 2g -no transfusions needed, no mortalities.
  • -Clin Gastro & Hep 2010; 8: 877. 0.5% complication rate, n=2740. No deaths. Bleeding was most common risk –increased with advanced liver disease.
  • -Hepatology 2009; 49: 1017. AASLD Position Paper
  • -Gastroenterol 1978; 74: 101 & 103. Early article discussing safety of LBx and that most pts could be d/c’d w/in 6 hours.
  • -JPGN 2005; 41: 639. Safety of liver biopsy in infants less than 3 months (w/o U/S). complication rate was 18% including sedation-related, 1 bile leak, and 3 needed PRBCs.
  • -JPGN 2003; 36: 364. Ultrasound useful.
  • -Can J Gastroenterol 2000; 14: 543-548.  Mortality rate 3/10,000
  • -Clin Perspectives Gastroenterol 2002; 5: 117. Rec ultrasound, plts >75K, PT c/in 3 secs of normal; observation for 3-6hrs in adults.
  • -NEJM 2001; 344: 495. Liver bx review.
  • -Hepatol 27: 1220-26, 1998. U/S marking reduces complications
  • -Fox VL, Cohen MB, Whitington PF, Colletti RB. Outpatient liver biopsy in children (n=450). J Pediatr Gastroenterol Nutr 1996;23:213-6.  High mortality rate reported, primarily in bone marrow transplant patients
  • -JPGN 2000; 31: 536-39. Safety of liver biopsy in children, n=249.

More on anti-glycan antibodies in Crohn’s disease

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As noted in recent blog entry (Serology in IBD), anti-glycan antibodies have some usefulness in inflammatory bowel disease.  More data on the utility of these antibodies is available in a study which examined the presence of these antibodies in both a pediatric and adult cohort (Inflamm Bowel Dis 2012; 18: 1221-31).

Anti-L, Anti-C, anti-chitobioside (ACCA), anti-laminaribioside (ALCA), anti-mannobioside and anti-Saccaromyces cervisiae (ASCA) antibodies were tested in 131 pediatric patients (59 CD, 27 UC, 45 controls) and in 728 adult patients (355 CD, 129 UC, 244 controls).  In this study, 78% of pediatric CD patients had at least one serological marker.  ASCA was most accurate for CD diagnosis; it was present in 63% of the pediatric cohort. 

Combined usage of these antibodies helped differentiate CD from UC.  While sensitivity for detecting CD was 78% with the presence of one serological marker, the presence of three (or more) markers increased the specificity to 93% (for CD compared to UC); however, the presence of this many markers occurred in only 28%. Increasing antibody levels also correlated with complicated CD behavior, CD-related surgery and ileal disease location.

Serology in IBD

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Serological antibodies against a number of antigens have shown some utility in differentiating inflammatory bowel disease (IBD) from non-IBD and in distinguishing Crohn’s disease (CD) from ulcerative colitis (UC).  A recent article evaluated 204 articles in a systematic review of these serological markers (Inflamm Bowel Dis 2012; 18: 1340-55).

The study has several useful tables and a long list of references.  In its Table 1, 10 serologies are listed with a range for prevalence in CD, UC, alternative GI conditions, and in healthy population.  Table 2 summarizes the data in terms of sensitivity, specificity, positive predictive value, negative predictive value for these antibodies in determining IBD from non-IBD.

With regard to specific antibodies, the review highlights 10 antibodies:

1. Anti-neutrophil cytoplasmic antibodies (ANCA).  Autoantibody directed against a constituent of neutrophil granules.  With IBD (especially UC), an atypical perinuclear (pANCA) staining pattern with indirect immunofluorescence and DNase-sensitive make this pattern different from ANCA due to vasculitis.

2-7. Anti-glycan antibodies –directed against cell wall microbes and reflect interaction between the immune system and glycosylated cell wall components of microbiota.

2. Anti-Saccharomyces cerevisiae (ASCA IgA and IgG) –antibodies directed against yeast cell wall.  While ASCA antibodies are commonly found in CD patients, 20-25% (or higher in some studies) of healthy relatives will test positive for these antibodies as well.  Approximately 6% of relatives of UC patients will be ASCA-positive.

3. Anti-laminaribioside carbohydrate IgG antibodies (ALCA) –antibodies directed against laminaribioside

4. Anti-chitobioside carbohydrate IgA antibodies (ACCA) –antibodies directed against chitobioside

5. Anti-mannobioside carbohydrate IgG antibodies (AMCA) –antibodies directed against mannobioside

6. Anti-L –antibodies directed against laminarin (large polysaccharide)

7. Anti-C –antibodies directed against chitin (large polysaccharide)

8. Anti-OmpC.  OmpC is a transport protein of E coli

9. Anti-I2.  I2 is a Pseudomonas-associated antigen

10. Anti-CBir1.  CBir1 is a bacterial flagellin antigen

Conclusions:

  • Serology has only limited value for the initial diagnosis of IBD.
  • Serology has ‘better value’ in differentiating CD from UC, though there is substantial variability in serologic responses in both diseases.  Probably, serology is most useful in unclassified IBD (IBD-U) in preoperative setting; serology may help predict risk of developing complications among patients undergoing pouch surgery.
  • Serology is useful in predicting a complicated disease course. The presence and magnitude of these antibodies are strong predictors of disease progression.

Additional references:

  • Pediatrics. 2010 Jun ;125 (6):1230-6.  Shortcomings of the inflammatory bowel disease Serology 7 panel. 
  • -Clin Gastro & Hep 2008; 6: 1105. Increased immune reactivity/markers associated with aggressive disease.
  • -IBD 2006; 12:1122. Expression of I2 antibodies (against a bacterial antigen of psedomonas fluorescens) was highly associated with clinical response to diversion. 15/16 with I2-pos had clinical response; 2/11 I2-neg had clinical response.
  • -IBD 2008; 14: S4 abstract 0010. Practical experience with IBD serology (n=90) much less accurate than reported by Prometheus: overall accuracy of 63% (vs 92%), 66% sensitivity (vs 93%), 59% specificity (vs 95%), 75% PPV (vs 96%), and 49% NPV (vs 90%). In this population, 34% of known IBD were incorrectly predicted. Of 32 who did not have any evidence of IBD after clinical investigation, 40% (13) were seropositive.
  • -Clin Gastro & Hep 2008; 6: 1105. Increased immune reactivity/markers associated with aggressive disease.
  • -IBD 2008; 14; 129. Serologic markers not very useful clinically.
  • -Pediatrics 2007; 119: e193. IBD serology performed poorly in comparison to combination of Hgb/ESR with regard to sensitivity (60% vs. 83%), specificity (92% vs. 96%), positive predictive value (60% vs. 79%) for IBD in children, n=227. Also one third of all positive serology in patients w/o IBD. The positive predictive value in patients w/o rectal bleeding was 35% vs 60% for routine tests.
  • -Gastroenterol 2006; 131: 366. antibodies against laminaribioside, chitobioside, and mannan have predictive value in detecting Crohn’s disease.
  • -Gastroenterol 2006; 130: 1078. Unaffected relatives positive for either OmpC or ASCA in 20% in large cohor (n=619 unaffected relatives. OmpC present in up to 44% of CD pts, up to 24% of UC pts, and 6% of controls.

α1-antitrypsin review

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For a brief and useful review of α1-antitrypsin (A1AT) deficiency: Clin Gastroenterol Hepatol 2012; 10: 575-80.

One of the pieces of information that is fairly new in the review: “the most promising strategy for treating liver disease in patients with A1AT deficiency is to decrease the accumulation of polymerized A1AT by stimulating its autophagy in hepatocytes.”  Both carbamazepine and rapamycin have been capable of this in transgenic mice; this has been associated with reduced liver fibrosis.

General recommendations from review:

  • In patients with cirrhosis due to A1AT deficiency, screening for HCC is appropriate (Looking for trouble)
  • Limit alcohol consumption and tobacco exposure
  • Assure vaccination for hepatitis A & B
  • Decompensated liver disease managed in standard fashion

Additional references:

  • Tegretol may help treat/prevent fibrosis –study in Pittsburgh (at least 14yrs old, ZZ) –can call 855-428-2281 David Perlmutter
  • -NEJM 2010; 363: 1863-64.  Autophagy in A1AT deficiency
  • -Hepatology 2007; 45: 1313. Review of meeting on A1AT deficiency
  • -JPGN 2006; 44: 99. High prevalence of alpha-1 heterozygosity in chronic liver disease. Multiple other polymorphisms may contribute to liver disease in some (heterozygous HFE gene, 1 mutation for Alagille may worsen EHBA [Hepatology 2002; 36: 904-12.], glutathione-S-transferase P1 polymorphism seen c CF liver disease
  • -JPGN 2006; 43: 136-138. Variable degree of liver involvement in Sibs with PiZZ disease.
  • -Clin Gastro & Hep 2005; 3: 390. factors associated c severe dz in adults include male gender and obesity.
  • -JPGN 2003; 37: 347 (62A) NSAIDs may worsen liver dz.
  • -Clin Perspect in Gastro 2002; 5 (1) : 40. (review)