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About gutsandgrowth

I am a pediatric gastroenterologist at GI Care for Kids (previously called CCDHC) in Atlanta, Georgia. The goal of my blog is to share some of my reading in my field more broadly. In addition, I wanted to provide my voice to a wide range of topics that often have inaccurate or incomplete information. Before starting this blog in 2011, I would tear out articles from journals and/or keep notes in a palm pilot. This blog helps provide an updated source of information that is easy to access and search, along with links to useful multimedia sources. I was born and raised in Chattanooga. After graduating from the University of Virginia, I attended Baylor College of Medicine. I completed residency and fellowship training at the University of Cincinnati at the Children’s Hospital Medical Center. I received funding from the National Institutes of Health for molecular biology research of the gastrointestinal tract. During my fellowship, I had the opportunity to work with some of the most amazing pediatric gastroenterologists and mentors. Some of these individuals included Mitchell Cohen, William Balistreri, James Heubi, Jorge Bezerra, Colin Rudolph, John Bucuvalas, and Michael Farrell. I am grateful for their teaching and their friendship. During my training with their help, I received a nationwide award for the best research by a GI fellow. I have authored numerous publications/presentations including original research, case reports, review articles, and textbook chapters on various pediatric gastrointestinal problems. In addition, I have been recognized by Atlanta Magazine as a "Top Doctor" in my field multiple times. Currently, I am the vice chair of the section of nutrition for the Georgia Chapter of the American Academy of Pediatrics. In addition, I am an adjunct Associate Clinical Professor of Pediatrics at Emory University School of Medicine. Other society memberships have included the North American Society for Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN), American Academy of Pediatrics, the Food Allergy Network, the American Gastroenterology Association, the American Association for the Study of Liver Diseases, and the Crohn’s and Colitis Foundation. As part of a national pediatric GI organization called NASPGHAN (and its affiliated website GIKids), I have helped develop educational materials on a wide-range of gastrointestinal and liver diseases which are used across the country. Also, I have been an invited speaker for national campaigns to improve the evaluation and treatment of gastroesophageal reflux disease, celiac disease, eosinophilic esophagitis, hepatitis C, and inflammatory bowel disease (IBD). Some information on these topics has been posted at my work website, www.gicareforkids.com, which has links to multiple other useful resources. I am fortunate to work at GI Care For Kids. Our group has 17 terrific physicians with a wide range of subspecialization, including liver diseases, feeding disorders, eosinophilic diseases, inflammatory bowel disease, cystic fibrosis, DiGeorge/22q, celiac disease, and motility disorders. Many of our physicians are recognized nationally for their achievements. Our group of physicians have worked closely together for many years. None of the physicians in our group have ever left to join other groups. I have also worked with the same nurse (Bernadette) since I moved to Atlanta in 1997. For many families, more practical matters about our office include the following: – 14 office/satellite locations – physicians who speak Spanish – cutting edge research – on-site nutritionists – on-site psychology support for abdominal pain and feeding disorders – participation in ImproveCareNow to better the outcomes for children with inflammatory bowel disease – office endoscopy suite (lower costs and easier scheduling) – office infusion center (lower costs and easier for families) – easy access to nursing advice (each physician has at least one nurse) I am married and have two sons (both adults). I like to read, walk/hike, bike, swim, and play tennis with my free time. I do not have any financial relationships with pharmaceutical companies or other financial relationships to disclose. I have helped enroll patients in industry-sponsored research studies.

Neonatal cholestasis and Down syndrome

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A retrospective Swedish study adds some useful information on the incidence of neonatal cholestasis with Down syndrome (J Pediatr 2012; 161: 899-902).

In this retrospective study of all neonates born between January 2005-September 2011 in Stockholm , a total of 206 newborns were identified as having Down syndrome.  This represents an incidence of 1 in 880 newborns.

  • 3.9% (n=8) had cholestasis
  • 47% (n=96) had congenital heart disease
  • 11.2% (n=23) had GI disorders: duodenal stenosis (n=7), duodenal atresia (n=4), omphalocele (n=3), Hirschsprung disease (n=2), esophageal atresia/duodenal atresia (n=1), jejunal atresia (n=1), and other conditions (n=5)
  • 3.4% (n=7) had bone marrow diseases including transient abnormal myelopoiesis

All eight children with cholestasis had congenital heart disease.  However, severe cholestasis was only seen in the 3 patients with concomitant bone marrow disease. Two of these patients died and one developed cirrhosis/chronic liver disease. All cholestatic patients had involvement of other organ systems.  As this was a retrospective study, some milder cases of neonatal cholestasis may not have been detected.

In children with concomitant bone marrow disease, neonatal cholestasis may forebode an increased risk for severe disease.  While all 3 of the newborns with severe disease also had congenital heart disease, most infants with combined congenital heart disease/cholestasis (n=5) did not have a severe case.

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Six year outcomes with bariatric surgery

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Recently I read that suicides were increased in a group of individuals who underwent bariatric surgery.  This piqued my interest in finding the reference (JAMA 2012; 308: 1122-31 -21 authors).

This Utah study was a prospective trial between 2000-2011 involving 1156 severely obese participants between 18-72 years of age.  There were 3 groups.  The treatment group of 418 underwent Roux-en-Y gastric bypass (RYGB).  The second group (control group 1 =CG1) sought bariatric surgery but did not have surgery, and the third group (control group 2 =CG2) were a randomly selected population-based sample.

All participants had BMI ≥35.  RYGB group had average BMI of 47.3, CG1 was 46.3 and CG2 43.8.  The respective average age was 42.5, 43, and 49.4 years.  In CG1, 84 had undergone bariatric surgery by six years; in CG2 17 had undergone bariatric surgery by six years.

Results at six years:

  • Weight loss: RYGB (92.6% retained at followup): 27.7% loss of initial body weight; CG1 (92.6% followup) 0.2% weight gain, and 0% in CG2 (98% followup)
  • Diabetes remission rate: RYGB 62%, CG1 8%  and CG2 6%.  In addition, there was a 5- to 9-fold reduction in the risk of new diabetes in surgical patients compared to nonsurgical controls.
  • Mortality: No improvement in mortality was evident at six years.  RYGB 12 deaths, CG1 14 deaths  and CG2 3 deaths. None of the RYGB deaths occurred within 30 days of surgery.
  • Suicide:  all 4 patients who took their own life were in the RYGB group and 2 of 3 poisonings (undetermined intention) were in the RYGB group as well.
  • Mental health: The authors note an absence of improvement in the SF-36 mental component score in the surgical group which is in contrast to the SF-36 physical component score.
  • Glucose/insulin, Lipids & Blood pressure: Marked improvements in all of these parameters were noted at six years (Table 2).

It appears that much longer followup will be needed to show mortality benefits from bariatric surgery* and that preoperative/postoperative psychological assessment is needed.

* Mortality benefit has been evident in some studies (see references below)

Related blog entries:

References:

  • -JAMA 2011 [doi: 10.1001/jama.2011.817]). Large study failed to show that roux-en-Y gastric bypass prolonged life. n=850 VA pts to 41,244 controls. Same group showed no cost savings during initial 3 yrs: Med Care 2010; 48: 989-98.
  • -NEJM 2011; 365: 1365. Increased frequency of bariatric surgery in adolescents.

Complications from surgery:
Early: bowel obstruction, DVT, GI bleed, leaks, pul embolism, wound infection
After 30 days: anastomotic stricture, bowel obstruction, gallstones, dehiscence, fistula, Bleeding, Incisional hernia, nutrient deficiencies (iron, B12; calcium, Vit D (w RYGB), folate, B6/riboflavin)
Suggested Nutrient Monitoring–every 3 months x 3, then yearly: Vitamin A, B12, Folate, Ceruloplasmin, Vit D-25OH, Iron studies, Zinc, thiamine, Selenium, Intact PTH, Mg, PT/PTT
Suggested supplements per references: Calcium c vitamin D 1200mg, Iron, MVI with zinc/selenium
Also if duodenal switch, add Vitamin A and Vitamin D3 1200units daily or 50,000 units weeekly

Supplements:
Roux-en-Y: MVI 200%, Calcium 1500-2000mg, Fe at least 18-27mg/day, B complex (optional)
Gastric Band: MVI, Calcium, B complex (optional)
Biliopancreatic/duodenal switch: MVI, ADEK: A 10,000 IU, D 2000 IU, K 300 mcg, Calcium, Fe, B complex

  • –NASPGHAN 2011:

Bariatric surgery:
Complications from gastric band: food impaction, erosion (now banned in Finland!), band slippage, gastric volvulus, band too tight, port infection

Roux-y gastric bypass:
anastomotic leak 1.2%, anastomotic ulcers/stricture

If post-op pain: epigastric –>do EGD & if neg do ‘RUQ w/u’, RUQ –> check U/S, LFTs possibly CT
If post-op vomiting –>do EGD
If post-op nausea –>Rx PPI and EGD if not improving
Anastomotic stricture in stomach –>dilate to 10-12mm in 1 session

  • -NEJM 2009; 361: 445/520. perioperative safety.
  • -NEJM 2007; 357: 741, 753, 818. Bariatric surgery improves mortality rate.
  • -NEJM 2007; 356: 2176. Review
  • -Gastro 2006; 130: 1848, 1564, 1617. Bariatric surgery frequently improves steatosis/NAFLD. Less improvement if ongoing insulin resistance.
  • -J Pediatr 2005; 147: 10-19. Review of bariatric surgery. suggests gastric bypass/gastric banding for adolescents.
  • -Pediatrics 2004; 114: 217-23, & 252, 253, 255. Consensus panel recommendations and commentary.

Note: Medication dosages should be checked in standard references for individual patients.  The blog may have transcription errors with regard to dosages listed with references.

Azathioprine metabolite measurement for Autoimmune Hepatitis

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While obtaining azathioprine (AZA) metabolite levels in inflammatory bowel disease has proven clinical utility, there is less data with regard to autoimmune hepatitis (AIH).  Now a study of 70 adults with AIH reports that therapeutic levels of 6-thioguanine (TGN) (>220 pmol/8 x 10 to the 8th) are associated with remission (Hepatology 2012; 56: 1401-8).

Patients in this study had an average age of 61 years; the average participant had a diagnosis of AIH for 8 years at the start of the study. For induction of remission, patients had received a combination of prednisolone along with AZA.  AZA was started at 1 mg/kg/day and gradually increased to 2 mg/kg/day.  All patients had a complete response to steroids prior to AZA dose escalation.

Outcome from this study was characterized by ability to maintain remission with ALT <33 IU/L and/or relapse which was indicated by ALT >2 x ULN (upper limit of normal) or liver histology showing active disease.

Serial measurements of red blood cell TGN and methylmercaptopurine nucleotides (MeMPNs) were obtained over two years.

Results:

  • 53 patients maintained remission and 17 did not.
  • Those in remission tended to be receiving lower doses of AZA (1.7 vs 2 mg/kg/day) but had higher average TGN levels (237 vs 177 pmol/8 x 10 to the 8th)
  • TGN levels >220 pmol/8 x 10 to the 8th best predicted remission
  • There was no measurable difference in thiopurine methyltransferase (TPMT) activity between the two groups (remission vs relapse).
  • Two patients developed cholestasis and this was associated with high MeMPN levels.

The authors note that several previous studies did not demonstrate a relationship between TGN levels and efficacy.  This is likely related to patient selection (all in remission at start in current study), repeated TGN levels, and the definition of remission.

Conclusion: Obtaining metabolites in adherent patients may be beneficial in patients with active disease to assist with dose modification and in individuals with potential AZA toxicity.

Related blog entries:

Congenital heart disease and the Liver

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A useful review on this topic: Hepatology 2012; 56: 1160-69.

As a result of the successes of surgery for congenital heart disease (CHD), the majority of patients (~85%) with complex CHD survive into adulthood.  Hepatic complications are common in these patients either from the primary cardiac defect, from the surgical procedure, from transfusion or from medications.

Several liver diseases also have congenital heart disease manifestations include the following:

  • Alagille syndrome: 25% with CHD including peripheral pulmonic stenosis and tetralogy of Fallot
  • Abernethy malformation: ASD, VSD, and PDA
  • Biliary atresia splenic malformation syndrome: numerous forms of CHD
  • Mitochondrial fatty acid oxidation disorders: cardiomyopathy

CHD defects associated with hepatic dysfunction:

  • Right-sided failure: single ventricle physiology after Fontan, d-Transposition, Eisenmenger syndrome, Ebstein’s anomaly, tetralogy of Fallot with pulmonary regurgitation.  These disorders lead to passive venous congestion of liver with hepatic zone 3 sinusoidal dilation and sometimes zone 3 necrosis due to ischemia.  Biochemically, a cholestasis pattern predominates.
  • Left-sided failure: left ventricular outflow obstruction/coarctation of aorta, VSD, repaired complete atrioventricular septal defect.  This is associated with hypoperfusion and can lead to ischemia with increased transaminases as well as fibrosis.

Specific issues reviewed include the following:

  • Acute cardiac dysfunction
  • Cardiac dysfunction after Fontan
  • Complications of portal hypertension
  • Imaging (there have been reports of HCC following Fontan)
  • Transplantation: isolated cardiac, isolated liver transplantation, combined heart-liver transplantation

Related blog entry:

Fontan and PLE | gutsandgrowth

Skipping breakfast –boomerang effect for obesity

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A recent article shows unfavorable biochemical variables associated with skipping breakfast in obese children and adolescents (J Pediatr 2012; 161: 871-4).

After recruiting 174 Brazilian subjects (6-16 years) through advertising, the investigators assessed their body composition with dual-energy-dray adsorptiometry and assessed fasting blood glucose and lipid profiles.  Face-to-face interviews with parents determined the frequency of skipped meals.  The median BMI in the cohort was 27.

Results:

  • Skipping breakfast was commonplace.  Only 46% of subjects consumed breakfast daily.  Skipping lunch or dinner was infrequent, approximately 10% and 22% at times skipped lunch and dinner respectively.
  • Consumption of breakfast was inversely correlated with the odds of obesity (OR 0.73).
  • Skipping breakfast was correlated with increased glucose, triglycerides, and very low density lipoprotein cholesterol.

The authors speculate that a prolonged period of fasting in the morning could affect ghrelin secretion which promotes increased food intake.  In addition, ghrelin could affect pancreatic insulin secretion.

Related blog entries:

Dietary supplements — safe and effective?

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Most people consider dietary supplements as likely to be beneficial but at the very least ‘there not going to make you worse.’  That sentiment is wrong.  A review recently published has shown that some dietary supplements may increase the risk of cancer (Journal of the National Cancer Institute 2012; 104: 732-39).

Nearly half of the US adult population uses one or more dietary supplements but there is very little evidence that these supplements reduce cancer risk; in fact, the contrary is true.  Based on numerous studies, the authors make extensive comments regarding the studies of antioxidants, folic acid, and vitamin D/calcium which are summarized below.

Antioxidants

While observational data has suggested benefits from fruit and vegetable consumption, data on antioxidant supplement consumption has not shown a beneficial effect.  The review highlights a number of studies with regard to β-carotene, vitamin A, vitamin C, and vitamin E/α-tocopherol.  Specifically, vitamin C and E do not protect against total cancer incidence. α-tocopherol and β-carotene do not protect against cancer or cancer mortality.

  • The Selenium and Vitamin E Cancer Prevention Trial (SELECT) followed 35,533 men at average risk for prostate cancer for approximately 5.5 years.  This study was halted due to lack of benefit.  In addition, the extended followup reported that α-tocopherol significantly increased the risk of prostate cancer by 17%.
  • The β-carotene and Retinol Efficacy Trial (CARET) had a 39% increase in lung cancer incidence compared to the placebo arm.
  • In two of three large studies of β-carotene, the intervention increased the risk of all-cause mortality.
  • The Nutritional Prevention of Cancer (NPC) extended followup found that selenium supplementation statistically increased the risk of squamous cell skin cancer by 25% and non-melanoma skin cancer by 17%.

Folic Acid

Folic acid which is a synthetic oxidized form of folate is commonly used in fortification and supplements.  Recent meta-analysis of randomized controlled trials (RCTs) has found no effect of folic acid supplementation on the risk of colorectal adenomas over a 3-year treatment period.  In addition, one study demonstrated an increased risk of advanced colorectal adenomas (relative risk = 1.67).  Also, in observational studies, higher intake of folic acid has been linked with increased prostate cancer risk.

Vitamin D and Calcium

The Institute of Medicine published recommendations with regard to Vitamin D and calcium intake in 2011 and found that “there is not enough evidence to state that there is a causal association between low vitamin D intake and increased cancer risk.”  The authors summarize several conflicting results with regard to breast, colorectal, and prostate cancers. In addition, a recent meta-analysis of RCTs indicated that calcium supplementation was associated with a statistically-increased myocardial infarction risk.

Why are supplements so widespread if they are not beneficial and potentially dangerous?

  • The authors also summarize regulatory efforts.  In 1990, due to unsubstantiated health claims by food manufacturers, Congress passed the Nutrition Labeling Education Act (NLEA).
  • To limit FDA authority over supplements, at the behest of nutritional supplement manufacturers, in 1994 Congress passed the Dietary Supplement Health and Education Act.  This classified supplements as food and limited the role for the FDA.
  • In 2006, in reaction to deaths from ephedra, Congress passed the Dietary Supplement and Non-prescription Drug Consumer Protection Act.  This allows the FDA to collect adverse reports on supplements but did not give additional regulatory powers.

Conclusions from this review

  1. In populations with a high background of normal nutrient status, risk is accentuated if there can be harm at higher doses.  For selenium (in the NPC study), apparent benefits have been confined to individuals with the lowest baseline blood selenium levels.
  2. It is not reasonable to assume that consumption of a single nutrient would exert a chemopreventive effect equally in all tissues.  In addition, there are substantial variations in formulations and doses of supplements available.
  3. Efficacy and harm are typically tested over several years.  Given the natural history of cancer, it may take decades to assess supplement impact.
  4. Multiple consensus recommendations have indicated that supplements do not prevent cancer and do not prevent chronic disease (Table 1 in reference).  The most recent was from the American Cancer Society in 2012. “Present knowledge indicates that dietary supplements do not lower cancer risk.”
  5. Despite the evidence, the authors note that believers in supplements are unlikely to accept ‘mainstream’ science.  Some may think that unconventional treatments are ignored by science for monetary reasons. Some may think that these products are regulated and would not be offered if they were not beneficial.

Related post:

common to be “d-ficient” | gutsandgrowth

Risk of pancreatitis with celiac disease

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More data on the risk of pancreatitis in the setting of celiac disease has been published (Clinical Gastroenterol Hepatol 2012; 10: 1136-1142).

In this medical records review study, 28,908 patients in Sweden with biopsy-proven celiac disease (1969-2008) were compared with a control population of 143,746 to determine the risk of pancreatitis due to celiac disease. The median age at study entry was 30 years and included patients as young as 10 years.

Among these cohorts, 406 pancreatitis patients with celiac disease were identified.  The expected number would have been 143, yielding a hazard ratio of 2.85.  The risk for any type of pancreatitis within 5 years of diagnosis was 2.76.  All types of pancreatitis were increased including acute pancreatitis with gallstones, non-gallstone acute pancreatitis, and chronic pancreatitis.

What are potential reasons for this association between pancreatitis and celiac disease?

  1. Malnutrition may impair pancreas function
  2. Associated papillary inflammation could increase risk of acute pancreatitis
  3. The two diseases may share immunologic characteristics that increase the risk of both disorders
  4. Elevated levels of asymptomatic pancreatic enzymes could lead to some false-positive cases

Related blog entries:

Working on biomarkers for Biliary Atresia

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Two studies have tried to identify biomarkers to facilitate the diagnosis of biliary atresia (BA).

  • JPGN 2012; 55: 366-69
  • JPGN 2012; 55: 370-75

The first study looks at the serum of 24 patients with BA & 24 cholestatic controls.  Several circulating microRNAs (miRNAs) were associated with BA.  The miR-200b/429 cluster could correctly classify up to 85% of patients.

The second study took serum samples from 42 infants with BA, 38 infants with non-BA cholestasis, and 36 healthy controls.  Using mass spectrometry and enzyme-linked immunosorbent assays, they identified a candidate biomarker, Apo C-II, which was down-regulated in BA samples compared to healthy controls, but relatively upregulated compared with cholestatic non-BA samples.  The sensitivity of this model was 94% and the specificity was 92%.

Given the consequence of a missed diagnosis of BA, further work to identify biomarkers with even better sensitivity/specificity will be necessary to change current diagnostic algorithms.

Previous related blog entries:

Looking ‘Sily’ taking this herb?

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Taking milk thistle (silymarin) does not seem to improve disease status or symptoms with chronic hepatitis C (JAMA 2012; 308: 274-82).

This multicenter, randomized, double-blind, placebo-controlled study examined 154 patients with chronic hepatitis C (HCV).  Mean age was 54 years (71% male).  The study required participants to have an ALT ≥ 65 U/L and all patients had been previously unsuccessfully treated with interferon-based therapy.

Silymarin (Silybum marianum) is an extract of milk thistle.  In the HALT-C trial, 33% of patients with chronic HCV and cirrhosis reported current or past use of silymarin.  It has been shown to have anti-inflammatory and immunomodulator properties via inhibition of NG-κB; in addition, it may have direct effects on HCV replication.

Of the 154 patients, 52 received placebo, 50 received 420-mg silymarin dose, and 52 received 700-mg dose. The trial name was ‘Silymarin in NASH and C Hepatitis’ or SyNCH.  All patients were instructed to take medication three times a day. Only 2 patients in each group (~4%) met the primary outcome of an ALT ≤ 45 U/L.  In addition, HCV RNA levels remained unchanged and were similar between placebo-treated patients and silymarin-treated patients.

In addition, there were no significant changes in physical or mental health components of quality-of-life scores: CES-D (Center for Epidemiologic Studies-Depression), CLDQ (Chronic Liver Disease Questionnaire), and SF-36 (Short-Form 36).

Adverse effects were similar, though silymarin-treated patients had increased GI adverse effects,12% vs 5% among placebo-treated patients.   Though, the study was not powered to detect significant differences with respect to adverse effects.

The major limitation of the study was the patient selection; that is, patients not responsive to interferon may not be representative of all patients with chronic HCV.  While newer HCV therapies have become much more effective, due to their expense, effective less-costly therapies would be helpful.

Unfortunately, milk thistle/silymarin is not likely therapeutic for HCV and thus not cost-effective either.

Related blog entries:

Facts or persuasion in health care decisions?

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A thought-provoking perspective article in the NEJM 2012; 367: 1677-79 makes the argument that public health organizations/health professionals should be providing facts to inform people and not try to persuade or dissuade  them from screening for health conditions.

Examples of persuasion:

  • “The early warning signs of colon cancer: You feel great. You have a healthy appetite. You’re only 50.” (ad from New York Times Magazine from Memorial Sloan-Kettering Cancer Center)
  • “If you haven’t had a mammogram, you need more than your breasts examined.” (from American Cancer Society, 1970s)

The problem with persuasion messages is that they are ‘stripped of useful facts’ that indicate that screening can have harms as well as benefits.

For colon cancer, most 50-year-olds who feel great will not develop colon cancer.  The National Cancer Institute estimates that a 50-year-old has a 6 in 1000 chance of developing colon cancer in the next 10 years; the chance of death from colon cancer in that period 2 in 1000.  The advantages of colon screening would be to reduce that risk further: 67% with colonoscopy and 26% with sigmoidoscopy.  Screening, however, could result in bleeding, anesthetic complications, or perforation.

The tactics of persuasion rely on making people feel vulnerable and offering them hope.  Informed decisions allow appropriate expectations about the true benefits relative to harm.