Brain and body benefits of chocolate?

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Chocolate has been receiving a lot of good press, including purported benefits in weight loss (Arch Intern Med 2012;172:519-521.) and now for cognitive function (NEJM 2012; 367: 1562-64).

The first article looked at the chocolate consumption of 975 subjects who completed food frequency questionnaires.  The mean age of these participants was 57 years.  “After controlling for multiple potential confounders including sex, physical activity, fruit and vegetable intake, depression, and total caloric intake, frequency of chocolate consumption continued to be associated with lower BMI.”

The second study shows a correlation with a countries’ annual per capita chocolate consumption and the number of Nobel laureates per 10 million population.  The highest per capita rate of Nobel prizes is in Switzerland!  The author notes that cocoa and other flavonols seem to be effective in slowing or reversing reductions in cognitive performance that occurs with aging and have other potential benefits.  One of the limitations in the author’s analysis included reverse causation —that is enhanced cognitive performance could stimulate more countrywide chocolate consumption.  This seems more plausible to me.  Fortunately for readers of this intriguing study, the author did provide a relevant disclosure: “Dr. Meserli reports regular daily chocolate consumption, mostly…Lindt’s dark varieties.”

Vision and persistence in developing liver transplantation

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A concise perspective article examines the history and challenges of developing liver transplantation into an accepted treatment for end-stage liver disease (NEJM 2012; 367: 1483-86).

Key points:

  • Thomas Starzl 1st attempted liver transplant in 1963.  The 3-year-old boy with biliary atresia did not survive the operation; the next 5 attempts were failures as well with the longest survivor lasting only 23 days.  A moratorium of nearly 4 years was placed after these initial failures.
  • Improvements in immunosuppression were a key advance, including antilymphocyte serum in 1966.  During the 1970s, 70% of liver-allograft recipients died shortly after surgery.
  • Brain death concept, accepted in 1968, allowed for better donor organs (less ischemia)
  • Key immunosuppression advance was in 1979 when Roy Calne (Cambridge) reported the use of cyclosporin for organ transplantation.  Between 1980-81, 70% (n=40) of Starzl’s patients survived more than one year.
  • In 1983, National Institutes of Health at a consensus conference concluded that liver transplantation should be considered a ‘clinically applicable, lifesaving procedure.’
  • Other improvements, such as better organ procurement protocols and preservation along with further improvements in immunosuppression have helped improve 1-year and 5-year survival rates to climb, >85% and >70% respectively in 2010.
  • In 2010, 6291 patients underwent liver transplantation.
  • Remaining challenges include inadequate organ supply, recurrent primary hepatic disease (eg. hepatitis C), adverse drug effects, and post-transplantation complications.

The persistence and vision of Starzl and Calne has been recognized with the Lasker-Debakey Award (Lasker-DeBakey Clinical Medical Research Award – Wikipedia, the …).

Once daily Mesalamine

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Based on the literature, it is not clear that there is any need to give melamine more than once a day; this is often in contrast to labeling for many of these products:

  1. Inflamm Bowel Dis 2012; 18: 1785-94 
  2. Inflamm Bowel Dis 2012; 18: 1885-93

The 1st study identified 11 relevant randomized studies, after excluding 6870 that were considered irrelevant. Five of these studies were single blind and one was open-label; the remainder were double-blind randomized trials. In total, these studies examined 4070 patients.

Mesalamine products studied: Mesalazine (Salofalk), MMX mesalamine, Asacol, and Pentasa

Summary of findings:

  • Failure to induce clinical remission: relative risk (RR) with once daily 0.95; absolute risk 421 per 1000 in once daily group
  • Failure to induce clinical improvement: RR 0.87; absolute risk 398 per 1000
  • Failure to maintain clinical remission at 12 months: RR 0.92; absolute risk 286 per 1000
  • Failure to adhere to study medication regimen: RR 1.21; absolute risk 128 per 1000

Thus, this meta-analysis indicates that once daily dosing is as effective as conventional dosing for both induction and maintenance, at least with the formulations that were tested. Also, in this meta-analysis, adherence was not improved with once daily therapy, though some previous studies have indicated that once daily therapy may be helpful particularly in the first few months of treatment.

The 2nd study examined 213 patients for maintenance of UC remission; patients were randomized to receive either Asacol 2.4 g once a day (QD) or 800 mg three times a day (TID). Patients were treated at 32 UK centers and had an average age of 50 years. Relapse rates were 31% for QD therapy and 45% for TID over 1 year.  This study showed that QD was noninferior to TID and possibly superior, perhaps due to improved adherence.

Perhaps it is time to give all mesalamine products once a day.

Six years later-Mediterranean diet comes out on top

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This month a followup letter provides long-term data on the outcomes of individuals assigned to either a low-carb, low-fat, or Mediterranean diet (NEJM 2012; 1373-74).

An initial study posted two-year results.  Now after an additional four years, the following results were noted:

  • Among the 259 participants (80% of original groups and 95% who completed the initial two years), 67% had continued their original assigned diet.
  • For the entire 6-year period, the total weight loss was 3.1 kg in the Mediterranean group, 1.7 kg in the low-carb group and 0.6 kg in the low-fat group.
  • At 6 years the change in the ratio of LDL to HDL were similar in all three groups though the low-carb group had the most favorable results with a reduction of 0.16.
  • At 6 years, the reduction in triglyceride levels from baseline were significant for the Mediterranean group (21.4 mg/dL) and the low-carb group (11.3 mg/dL).
  • All of the groups had regained some of their weight loss from the initial 2-year period.  The most favorable outcomes were noted in the Mediterranean diet and then the low-carb diet in this workplace intervention trial.

Related blog entries:

“Beyond the bombs: cancer risks of low-dose medical radiation”

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The catchy title comes from a Lancet editorial (Lancet 2012; 380: 455-57); the related article (Lancet 2012; 380: 499-505) details the radiation risk posed by CT scans.

While concerns about imaging radiation exposure have become commonplace, the evidence for the risk has been more in the theoretical realm rather than proven.  That is, the risk projection models were based on studies of survivors of the atomic bombs in Japan.

The retrospective study in Lancet examines 178,604 children who underwent CT between 1985-2002.  Typical followup was 10 years (maximum followup of 23 years).  None of these children had cancer at the time of CT.  The study determined the number of leukemias that developed more than 2 years following CT and brain tumors which occurred more than 5 years after CT.  This lag time was done to avoid any confounding of cancer that may have been present and not detected at time of CT.

Key results:

  • 74 patients developed leukemia and 135 developed brain tumors.  There was a dose-related risk: 0.036/mGy for leukemia and 0.023/mGy for brain tumors.  Thus, the relative risk of leukemia in patients who had at least 30 mGy was 3.18; whereas, brain cancer risk for a cumulative dose of > 50 mGy was 2.82. [1 mGy=1 mSv]
  • If typical doses of CT administered, 2-3 head CTs could triple the risk of a brain tumor and 5-10 head CTs could triple the risk of leukemia.
  • The absolute risk remains low.  In patients less than 10 years, one excess case of leukemia and one brain tumor would be expected for 10,000 head CT scans.

Goal with CT scans:

  1. ALARA: as low as reasonably achievable –for every study.  Newer protocols allow lower radiation doses while preserving good image quality.
  2. Think carefully about each CT.  It is estimated that 20-50% of CTs could be replaced with another type of imaging or not done at all.

For the skeptics about the risk of CT scans, the editorialist concludes that this study confirms “that CT scans almost certainly produce a small cancer risk…we must redouble our efforts to justify and optimize every CT scan.”

Related blog entries:

How much radiation from your CT scanner? | gutsandgrowth

More imaging needed? | gutsandgrowth

Magnetic resonance enterography for Crohn’s disease …

Additional references:

  • -AJR 2001; 176: 289-96. Estimated risks of radiation-induced fatal cancer from pediatric CT
  • -Br J Radiol 2012; 85: 523-28.  Justification of CTs -some not needed
  • -AJR 2010; 194: 868-73.  Lower CT radiation doses in pediatric patients.  ‘Image gently’
  • -Arch Intern Med 2009; 169: 2078-86.

Outcomes with STEP procedure

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While the serial transverse enteroplasty (STEP) procedure has been considered a major advance in the management of short bowel syndrome (SBS), long-term data are in short supply.  5-year outcomes from Toronto with regard to 12 patients offers some insight into the effectiveness of this operation (J Pediatr Surg 2012; 47: 931-37).

The 12 patients selected for this study received STEP prior to January 2005.  The other 19 STEP patients at this institution were not included due to lack of long-term followup. Among the 12 patients, 6 had intestinal atresia, 3 had NEC, 1 had gastroschisis, 1 had volvulus, and 1 had Hirschsprung disease.

Key results:

  • 7 patients weaned off parenteral nutrition successfully –one took 4 years; one patient continued on parenteral nutrition.
  • 2 patients died of liver failure, 2 patients received liver-intestinal transplant.
  • STEP increased small bowel length from a median of 110 cm to 128 cm.  The dilated portion that received STEP changed from a median length of 31 cm to a median of 57 cm; this resulted in a median bowel caliber change from 6 cm to 2 cm.  The overall effect was an overall increase in small bowel length of 40%.
  • Biochemical markers improved.  For example, citrulline increased from 18 μmol/L pre-STEP to 33 μmol/L at 12 months, and 48 μmol/L at 5 years post-STEP.  Fecal fat malabsorption (based on 72 hr collections) improved from >40% to ~20% 6 months after STEP.
  • Indications for STEP: bacterial overgrowth (n=7), intestinal failure associated liver disease (IFALD) (n=5).
  • Complications: suture line bleeding due to ulcerations in one patient, 2 patients had leakage at suture line in immediate post-op period.  The latter 2 cases were ascribed to limited experience with technique; the surgeons now use a 2.5 mm staple instead of a 3.5 mm.

Take home points:

  1. Authors comment: “our approach is to only consider patients who plateau in their parenteral nutrition weaning or develop complications such as PN cholestasis…patients who continue to show intestinal adaptation are not offered surgery despite the presence of bowel dilatation”
  2. “It takes up to an average of 1 to 2 years to see the improvement in intestinal function after a STEP.”  While the authors may be correct about this timeframe, in their figure 3, two came off PN at one month post-STEP, four achieved this goal 6 months after STEP and another 12 months following STEP.
  3. Why does STEP work? Either improved intestinal function due to increased absorptive surface or due to healing of existing mucosa; the latter may occur with resolution of dilated,  inflamed bowel associated with bacterial overgrowth.

Related blog entries:

Four advances for intestinal failure | gutsandgrowth

IFfy outcome | gutsandgrowth

Additional STEP references:

  • -JPGN 2007; 45: 174, 257.
  • -J Pediatr Surg 2003; 38: 425-429. Initial description of STEP procedure from Kim HB et al.
  • -Clin Gastro & Hep 2006; 4: 1237. STEP in 4 patients helped to decrease or eliminate TPN requirements.
  • Images for step procedure

Cholestatic Kawasaki Disease

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Periodically, Kawasaki disease (KD) will present with fever and cholestasis (JPGN 2012; 55: 380-83).

The authors of this study which took place between 2003-2010 reviewed the presentation of children less than 16 years of age who presented with fever on admission (>38.5), total bilirubin >3 mg/dL and elevated ALT values.  In all 24 patients who met criteria for review; 5 (21%) had KD.  Patients with KD ranged in age between 1-10 years.

The other causes included viral hepatitis in 13 (EBV, HAV, CMV, Adenovirus, HSV), 4 had drug-induced cholestasis, 1 with cholelithiasis, and 1 with a choledochal cyst.

In almost 20% of KD patients, the presentation does not meet all of the diagnostic criteria: at least 5 days of fever and 4 of 5 following conditions: bilateral nonpurulent conjunctival injection, oral mucosal changes, peripheral extremity changes (edema/erythema of palms/soles, desquamation of fingers/toes), rash, cervical lymphadenopathy (unilateral, >1.5 cm).

Also, for those who did not receive yesterday’s blog on NASPGHAN postgraduate course, check out the following link:

NASPGHAN Postgraduate Course 2012 | gutsandgrowth

Additional references:

  • Kawasaki disease – Wikipedia, the free encyclopedia

  • -J Pediatr 2011; 158: 644.  Infliximab may work better than IVIG for Kawasaki.
  • -J Pediatr 2009; 155: 695.  Reviews recent experience & criteria for Kawasaki.
  • -Pediatrics 2004; 114: 1708. guidelines from AAP for Kawasaki.

Median Arcuate Ligament Syndrome

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PEDIATRIC SURGERY UPDATE: VOL 39 NO 03 SEPTEMBER 2012 has a concise review of Median Arcuate Ligament Syndrome (MALS) along with some references -listed with other references below (thanks to Ben Gold for this reference).  MALS occurs when a fibrous portion of the diaphragmatic crura crosses the celiac artery and compression occurs. This disorder is described as a diagnosis of exclusion.  Symptoms may include weight loss, nausea, abdominal pain, vomiting, and diarrhea.  Imaging modalities including CT angiography, MR angiography or arteriography can increase the suspicion for this disorder.

While not alluded to in this reference, one of the problems is knowing whether MALS is a spurious finding.  That is, in young individuals there is typically a robust blood supply to the intestine and it is not clear whether compression of the celiac trunk is responsible for specific symptoms as there is a compensatory blood supply.

Fortunately this disorder is very rare (or at the very least rarely recognized).  One of the most experienced vascular surgeons relayed his experience over more than three decades.  He stated that he had operated on four cases of suspected MALS –two improved with surgery.  A better batting average than Chipper Jones! –but a lot fewer at bats.

References:

  • –Median arcuate ligament syndrome – Wikipedia, the free encyclopedia “It is estimated that in 10-24% of normal, asymptomatic individuals the median arcuate ligament crosses in front of (anterior to) the celiac artery, causing some degree of compression.”
  • – Median Arcuate Ligament Syndrome – YouTube
  • -Alehan D, Dogan OF: Pediatric surgical image. A rare case: celiac
    artery compression syndrome in an asymptomatic child.  J Pediatr Surg.
    39(4):645-7, 2004
  • – Gander S, Mulder DJ, Jones S, Ricketts JD, Soboleski DA, Justinich CJ:
    Recurrent abdominal pain and weight loss in an adolescent: celiac artery
    compression syndrome. Can J Gastroenterol. 24(2):91-3, 2010
  • – Said SM, Zarroug AE, Gloviczki P, Shields RC: Pediatric median arcuate
    ligament syndrome: first report of familial pattern and  transperitoneal
    laparoscopic release. J Pediatr Surg. 45(12):e17-20, 2010
  • – Aschenbach R, Basche S, Vogl TJ: Compression of the celiac trunk caused
    by median arcuate ligament in children and adolescent subjects: evaluation
    with contrast-enhanced MR angiography and comparison with Doppler US
    evaluation.  J Vasc Interv Radiol. 22(4):556-61, 2011
  • – Ozel A, Toksoy G, Ozdogan O, et al: Ultrasonographic diagnosis of
    median arcuate ligament syndrome: a report of two cases. Medical
    Ultrasonography 14(2): 154-157, 2012
  • – Wani S, Wakde V, Patel R, et al: Laparoscopic release of median arcuate
    ligament. J Minim Access Surg 8(1): 16-18, 2012
  • – “Median arcuate ligament syndrome”.Curr Treat Options Cardiovasc Med 2008 10 (2):
  • -“Median arcuate ligament syndrome: evaluation with CT angiography”. Radiographics 2005; 25 (5): 1177–82.

NASPGHAN Postgraduate Course 2012

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Postgraduate course syllabus: naspghn.informz.net/

So far I’ve looked at the first few talks from the postgraduate course syllabus (see link above), including CVS slides by B Li.  Several good pointers are given.  For example, for abortive therapy, he recommends use of Zofran 0.3 mg/kg/dose.  Page 17 of course book details preventative measures.  Also, with regard to amitriptyline, he recommends starting at 0.3 mg/kg and titrating as needed up to 1-1.5 mg/kg/day.  Mitochondrial-type support often helpful as well (eg. CoQ10 10 mg/kg/day divided BID).

At the end of this lecture are a couple of questions –see how you do:

  1. Which NASPGHAN Consensus diagnostic criteria for CVS is the most specific?
    1. positive family history of migraine
    2. vomiting at least 4 times/hour at peak
    3. well between episodes of vomiting
    4. each attack resembles the others
    5. associated pallor and listlessness
  2. All of the potential mechanisms below have been implicated in CVS except:
    1. HPA axis activation
    2. migraine vascular changes
    3. autonomic nervous dysfunction
    4. mitochondrial dysfunction
    5. serotonin receptor polymorphisms

page22image7408 page22image7568

3. NASPGHAN recommended evaluation of a child with episodic vomiting:

  1. a. electrolytes, BUN, Cr
  1. electrolytes, BUN, Cr & UGI
  2. electrolytes, BUN, Cr, UGI & ultrasound
  3. electrolytes, BUN, Cr, UGI, ultrasound & endoscopy
  4. electrolytes, BUN, Cr, UGI, ultrasound, endoscopy & MRI
  1. Which is the best initial approach to the 11 year old child with CVS who has failed multiple medications and missed 4 weeks of school?
    1. consult psychology for anxiety and stressors
    2. redo all laboratory and radiographic testing
    3. consider induced sleep in the PICU
    4. hospitalize and observe teenager in episode
    5. add a second prophylactic medication
  2. Which statement best applies to the preventative approach to CVS?
    1. step‐wise increases in medicines are rarely required
    2. life style modifications are not recommended
    3. after anti‐migraine agents, anticonvulsants are used
    4. toddlers should receive propranolol first line
    5. topirimate does not cause cognitive dysfunction

    Answers: 1. d;2.e;3.b;4.a;5.c

Foreign body talk: if object >2cm or longer than 5 cm, may have difficulty passing.

Also a link to the meeting notes and abstracts:
naspghan.org/wmspage.cfm?parm1=723 …

NASPGHAN POSTGRADUATE COURSE Table of Contents

MODULE A: WHAT GOES IN, MUST COME OUT: CLINICAL GASTROINTESTINAL ISSUES

FROM PROPRANOLOL TO INDUCING COMA: CARING FOR A CHILD WITH INTRACTABLE CYCLIC VOMITING SYNDROME (CVS)………………………13 INCONTINENCE WITHOUT FECAL IMPACTION    …………………………….23 ELIMINATION DIETS: RISKS AND BENEFITS……………………………………..37

MODULE B: LIVER BEYOND VIRUS, METABOLIC, STORAGE, TUMORS

METABOLIC LIVER DISEASE: WORKING THROUGH THE MAZE ……………….51 UPDATE ON ALPHA‐1‐ANTITRYPSIN DEFICIENCY         ……………………………61 THERE IS A LIVER MASS ON THE ULTRASOUND: WHERE DO YOU GO FROM HERE? ….75

MODULE C: THE INFLAMED INTESTINE

GI INFLAMMATION, IMMUNE FUNCTION AND IBD          ………………………………87 MY STOMACH IS BUGGING ME!: THE MICROBIOME IN IRRITABLE BOWEL SYNDROME ……………………………………………………………………………………………101                                                                                                THE SORE BOTTOM: PERIANAL INFLAMMATORY BOWEL DISEASE         ……111 RESCUE ME FROM MY IBD: UPDATES ON INFLAMMATORY BOWEL DISEASE THERAPY ………………………………………………………………………………………………125

MODULE D: IMAGING AND ACCESSING THE TUBES

LOOKING DEEPLY INTO THE NOT SO SMALL INTESTINE ……………………………..137 PUTTING TUBES WITHIN TUBES: ENTERAL THERAPEUTIC ACCESS    ………….151 IMAGING THE PANCREATO‐BILIARY TREE                …………………………………….169 UPDATE ON CRITICAL FOREIGN BODY INGESTIONS  ………………………………….189

MODULE E: WHEN ALL ELSE FAILS: LIVER, INTESTINE AND POUCH

THE KID IS ON THE LIST: KEEPING COMPLICATIONS AT BAY FOR THE
NON‐TRANSPLANT HEPATOLOGIST ……………………………………………………201 TRICKS OF THE TRADE FOR INTESTINAL FAILURE ……………………………….213 GASTROINTESTINAL AND LIVER COMPLICATIONS OF BONE MARROW TRANSPLANT                                                                    …………………………225 POUCH DYSFUNCTION AND SURVEILLANCE: WHAT ARE MY OPTIONS? .235

How strong is the case for HCC screening?

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Not that strong.  The AASLD guidelines for hepatocellular carcinoma (HCC) have faced additional scrutiny and an editorial reviews the basis for HCC screening recommendations (Hepatology  2012; 56: 793-96).

According to the authors, there have been two randomized controlled trials of HCC screening in China.  One that did not demonstrate benefits of HCC screening relied on resection as the treatment for early-stage HCC.  However, a large proportion of those with screen-detected HCC did not undergo resection.

The second trial demonstrated benefit but had several issues.  First, the statistical analysis has been criticized as faulty due to the cluster randomization method while analyzing with an individual patient basis method.  In addition, most North American cases of HCC are related to HCV rather than HBV; thus, the results may not be applicable.

The editorial counters that there are additional lines of evidence that HCC screening is effective for HCV and that an adequate RCT in this country will never be feasible.  Specifically, they suggest that an adequate study would need 10,000 subjects.  This would be further complicated by informed consent; an Australian study has shown that 90% of patients would refuse randomization and prefer to undergo screening.

The editorial points out that advancement in treatments have lowered the likelihood of morbidity in patients identified through screening as well.

As part of their conclusion, the authors quote Sir Austen Bradford Hill who conducted the first RCT in humans: All scientific work is incomplete…liable to be upset by advancing knowledge.  That does not confer upon us a freedom to ignore the knowledge we already have, or to postpone the action it appears to demand at a given time.”

Related blog entry:

Looking for trouble | gutsandgrowth

Additional references: