Drink Up!

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Green tea and coffee have a lot of advocates and a number of articles suggest that each can have beneficial effects for the liver.  This month’s Hepatology describes how a green tea component, epigallocatechin-3-gallate (EGCG), inhibits hepatitis C viral (HCV) entry. ECGC acts by blocking viral attachment to target cells with all HCV genotypes; it does not affect viral replication.  Other components of green tea do not have this effect.  A complete description of green tea components is described in the discussion of the article, Hepatology 2012: 54: 1947-55.  Also, there have been preliminary dosing studies in healthy volunteers which have shown that EGCG is safe at doses of 800mg daily for four weeks.  This would be the equivalent of drinking 8-16 cups of green tea per day (Clin Cancer Res 2003; 9: 3312-19).  In order to eliminate HCV, however, even higher amounts of EGCG would be likely.

 

Coffee also has been studied and has been associated with decreasing liver fibrosis.  In addition, coffee may enhance response to HCV treatments.  To my knowledge, there have not been extensive studies of either coffee or green tea for pediatric patients.

Additional References:

  • -Gastroenterology 2011; 140: 1961. Coffee (3 cups/day) increases response to PEG/RBV in HCV
  • -Hepatology 2009; 51: 201. Coffee decreases fibrosis. n=177.
  • -Hepatology 2009; 50: 1360. Coffee intake associated with slower progression of HCV liver disease
  • -Hepatology 2009; 50: 970. Coffee -2 cups per day decreases risk of liver fibrosis & HCC. Coffee has methylxanthin which inhibits connective tissue growth factor.

It’s often elemental

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A recent post on the pediatric GI listserv (GI Bulletin Board) this past month discussed protracted diarrhea of infancy.  The posting noted that this was a frequent problem that would hospitalize infants (in the first 6 months of life) for weeks & often would require parenteral nutrition.   “The cause of protracted diarrhea of infancy is usually ill-defined and is characterized by chronic nutritional failure, septic complications, and a high mortality.” ( Am J Dis Child 1973:125:358-364).  The availability of elemental diets have made this problem quite infrequent.  These infants often improve quickly, even with severe diarrhea.
Congenital diarrhea, rather than acquired diarrhea, remains much more of a challenge.  However, our understanding has improved a great deal in the past two decades.  My approach in this area relies a lot on the teachings I received as a fellow and from articles in the literature, especially the work of Dr. Martín.
For congenital diarrhea, my approach & differential diagnosis  are as noted below:
Approach:
1. Measure inputs/outputs for carefully –may need to use rectal ‘ng tube’ to assess stool output.  Check stool electrolytes.  Careful IVFs needed.
2. Trial of neocate (contains glucose polymer) excludes congenital lactase deficiency/most disaccharidase deficiencies.
3. Trial of RCF excludes glucose-galactose malabsorption.
4. The, remaining cases are considered protracted diarrhea of infancy (PDI):
  • PDI with normal villi: consider congenital chloride diarrhea, congenital sodium, sodium co-transporter deficiencies, heparan sulphate deficiency, glycosylation defect, neurogenin-3, congenital short gut.
  • PDI with abnormal villii/villous atrophy: post-infectious, autoimmune/allergic enteropathies, IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked).  If villous atrophy w/o inflammation, consider microvillus inclusion disease and tufting enteropathy.
DDx/specific entities to consider with congenital diarrhea:
1-Microvillus inclusion disease- An experienced pathologist should be able to establish this diagnosis with EM.
2-Congenital Na diarrhea –  these patients have a high volume secretory diarrhea that is very alkaline and contains high concentrations of the Na+.
3-Congenital disorder of glycosylation- in the absence of PLE, this should be taken off the list.
4-Glucose-galactose malabsorption-  all the GGM patients should have (at least at some point) +4 clinitest.   An RCF (Ross Carbohydrate Free) trial is a wonderful screen for GGM as the stool output will go to the normal range without carbohydrates.  It should be noted that sucrase-isomaltase deficiency improves with RCF as well.
5-Congenital enterokinase deficiency- if the child’s diarrhea persists while
on Neocate, you have essentially ruled out this disorder.
6-Autoimmune enteropathy -consider if the diarrhea is secretory
in nature; look specifically at the intraepithelial (normal in IPEX), lamina propria (increased number of CD8 and CD4 in IPEX) lymphocytes. IPEX is also associated with increased mucosal eosinophils. Also, serum IgE level is usually very high in IPEX patients. If there is  any evidence of glucose intolerance, check for anti-islet cell antibodies.
7-Ileal bile acid receptor defect- The diarrhea is generally in character
and is exacerbated with addition of dietary fats. The diarrhea should
improve with a trial of cholestyramine and a low fat diet.  Bile acid
absorption by the ileum may be measured using the bile acid analogue
75Se-homocholic acid-taurine test. (give a trial of cholestyramine if
75Se-homocholic acid-taurine testing is not available.)
8- Congenital chloride diarrhea (CCD)- Probably the most common congenital
diarrhea-these patients generally have fecal chloride concentrations that
exceeds the concentration of cations (Na+ and K+).
9- Chylomicron retention disease- You can certainly rule this out by H&E as
enterocytes are laden with fat.  However, this can be missed this if patient is fasted for a prolonged period of time before the biopsy was taken.  Interestingly, unlike all other enterocyte specific congenital diarrhea, this disorder will be accompanied by carbohydrate and AA malabsorption while on a fat containing enteral diet.
10. Mutant neurogenin-3- check immunostains on the small intestinal, colonic biopsies for chromogranin A to see if there is a paucity or agenesis of the enterochromaffin cells.  At UCLA, they are actively performing DNA sequencing for this disorder and can have results within a week. If this is needed, contact Dr. Martín & he can send a copy of the UCLA approved IRB form and a kit to isolate DNA from saliva.
Contact info: Martín G. Martín M.D., M.P.P.
Professor of Pediatric Gastroenterology and Nutrition
Director of the UCLA Center for Pediatric Diarrheal Diseases
David Geffen School of Medicine at UCLA
Mattel Children’s Hospital at UCLA
Box 951752
Los Angeles, CA 90095-1752
Phone: 310-794-5532; Fax: 310-206-0203
11.  In older infants, consider: Lysinuric protein intolerance -LPI is an inborn error of metabolism caused by defective transport of cationic amino acids at the basolateral membrane of enterocytes and renal tubular cells.  Typically presents after weaning from breast milk or formula.
12. Sucrase-isomaltase deficiency -these infants improve with lactose-containing formula.  May present after a gastroenteritis when they are switched from a standard formula or breastmilk.
Additional References:
  • -J Peds 2008; 153: 586.  case report of congenital chloride diarrhea with useful references.
  • -J Pediatr 2007; 150: 198.  Review.  Newborn with diarrhea.
  • -NEJM 2006; 355: 270, 236 (editorial).  mutant neurogenin-3.  This defect result in diarrhea with all substances except water.  Lack of enteroendocrine cells on biopsy.
  • -JPGN 2004; 38: 16 (invited review of neonatal enteropathies)
  • -JPGN 1999; 28: 137.  Sucrase-isomaltase.

Looking for trouble

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Although cirrhosis is an infrequent problem in pediatric gastroenterology, there are several important management aspects.  One of these is surveillance for hepatocellular carcinoma (HCC).  In this month’s Hepatology, Poustchi et al describe the “feasibility of a randomized control trial for liver cancer screening” (Hepatology 2012; 54: 1998 & editorial 1898).  Not surprisingly, the authors conclude that such a trial is not possible with informed consent.  As such, the effectiveness and cost-effectiveness may not be determined.  Although the consensus is in favor of screening, there are potential disadvantages like discovering non-cancer nodules leading towards unnecessary invasive investigations.

The AASLD considers screening for HCC worthwhile in patients with cirrhosis.  When HCC is discovered early, treatment can be effective.  For example, if HCC meets Milan criteria–either 1 tumor <5cm or 2-3 < 3 cm each– OLT has 91% 1 yr survival.

Most U.S. physicians (74%) report that they screen all of their patients with cirrhosis; however,  population-based studies of Medicare patients show only 6.6% receive regular surveillance (Hepatology 2010; 52: 132-41) & only 12% of veterans with HCV-infected cirrhosis (Ann Intern Med 2011; 154: 85-93).  Better ways of consolidating screening can bridge this gap & perhaps catch cases of HCC amenable to treatment.  This may be another area where an EMR can help with patient/doctor reminders.

Current practice recommendations for cirrhotic patients: Ultrasound every 6 months (with or without AFP).  This recommendation is supported by the AASLD, EASL, and APASL.  The efficacy of HCC surveillance is reviewed further in the January “Education Practice” article: Clin Gastro & Hepatatol 2012: 10: 16-21.

Additional references:

  • Gastroenterology 2011; 141: 1240. Risk of HCC from HBV related to ALT and HBV DNA levels.
  • NEJM 2011; 365: 1118. Review. For cirrhotics/advanced liver dz, recs U/S & AFP q6-12months.
  • Hepatology 2010; 53: 1020. updated guidelines from AASLD. Suggests U/S as screen q6months.
  • J Pediatr 2011; 159: 617. BA associated with HCC.
  • Hepatology 2010; 51: 1972. NASH cirrhosis pts develop HCC. 12.8% over .32 yrs (compared with 20.3 % of pts with HCV cirrhosis). Alcohol & age were independent variables that increased risk.
  • Gastroenterology 2009; 137: 110, editorial page 26. AFP has at best 66% sensitivity for HCC.
  • Gastroenterology 2009; 136: 138, 39(ed). HCC occuring c HCV ~1%/yr in HALT-C study. prolonged Rx -not helpful. n=1005. Best surveillance is US. Only 60% of pts c HCC received surveillance. Hepatolgy 2005; 42 : 1208.
  • Gastroenterologyo 2008; 135: 111. DM & obesity associated with increase risk of HCC in patients with HBV/HCV.
  • Gastroenterology 2008; 134: 1612. Increasing LTx for HCC affects others on Tx list.
  • Gastroenterology 2007; 132: 2557. review
  • Clin Gastro & Hep 2006; 4: 252 Review.
  • Hepatology 2005; 42: 1208. AASLD guidelines for management.
  • Gastroenterology 2004 (November) 127; supplement 1:S1–S323. Review of HCC. S108: screen with alpha-fetoprotein AND U/S every 6-12 months in individuals with cirrhosis or advanced disease (not needed in individuals with mild disease).
  • Clinical Gastro & Hep 2003; 1: 10-18. Review.
  • Gastroenterology 2004; 126: 1005. HCC survival improved when detected as part of surveillance.

Only one chance to make first impression

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Infliximab (IFX) came into clinical practice in 1998 after impressive results, published in the New England Journal of Medicine, demonstrated remarkable success in refractory Crohn’s disease  and even allowed resolution of fistulas.  Due to its expense and perceived risks, IFX has been typically reserved for treatment failures & significant perianal disease.  Although there have been discussions about ‘top-down’ therapy for many years, more and more it has become apparent that the best opportunity to influence the natural history of Crohn’s disease is early in the course; and perhaps in some cases of ulcerative colitis early IFX treatment may be worthwhile.  Clinical experience and treatment trials have shown that IFX response is significantly greater in Crohn’s disease than ulcerative colitis.  
Data on the postoperative course of Crohn’s disease has been informative on this approach as have large studies demonstrating that IFX is likely at least as safe as any other medication treatments for moderate-to-severe disease (eg. thiopurines, corticosteroids, methotrexate, tacrolimus).  With regard to postoperative Crohn’s disease, it has been shown that microscopic disease may develop within one week of intestinal resection.  More than 70% of postoperative patients develop significant mucosal recurrence within 12months (i2 or greater); yet, symptoms may not develop for a much longer time.  When significant mucosal disease is present, it may already be too late to achieve optimal response to IFX and similar agents due to remodeling of the intestinal submucosa.  Early in the course of Crohn’s disease, the vast majority of patients have an inflammatory phenotype (Cosnes J, et al. Inflamm Bowel Dis. 2002; 8:244-25), whereas later in the course, stricturing and penetrating disease are increasingly common.  

Postoperative mucosal scoring system:

• i1 – 5 or fewer apthous lesions

• i2 – more than 5 apthous ulcers with normal mucosa between, or skip areas of larger lesions

• i3 – diffuse apthous ileitis with diffusely inflamed mucosa

• i4 – diffuse inflammation with large ulcers, nodules or narrowing

 Rutgeerts et al. Gastroenterology 1990;99:956-83

Top-down approach:

Benefits: higher efficacy, lower disease-related complications, decrease surgery, improvement in catchup growth/bone formation (both not shown in AZA trials)

Risks: higher costs (but probably cost-effective)

**IFX therapy early may save health care costs by reducing surgery/hospitalizations:  Jewell DP et al, Eur J Gastroenterol Hepatol 2005, Leombruno JP et al Pharmacoepidemiol Drug Saf 2011

Conventional approach with accelerated step-up:

Risks: lower efficacy, higher infection risk/mortality with repeated steroids

Benefits: possibly lower cost

Potential drawbacks with azathioprine or 6-mercaptopurine (thiopurine class):

  • IBD 2011; 17: 2138. AZA can achieve remission in only ~30%.
  • Canc Research 2009; 69: 7004.  AZA is carcinogen– incorporated into DNA & changes sun absorption.  Skin cancer risk never drops when stopping med.
  • Gastro 2011; 141: 1621: CESAME (n=19,486)  thiopurines associated with NHL risk.  HR 5.28.
**Much of the information on this posting was influenced by presentations at “Advances in IBD 2011.”  Specific speakers that influenced this posting include Robert Baldassano, Marla Dubinsky, and Miguel Regueiro.

Additional References:

  • IBD 2009; 15: 1583. Postoperative mgt: low risk (1st surg, short stricture) –>no Rx; moderate risk (<10yrs of dz, long stricture, inflammatory dz)–>6MP; high risk (penetrating dz, >2 surg) –>IFX.  Post-op scope @6-12mo
  • JPGN 2009; 48 suppl 2: S72
  • Clin Gastro & Hep 2009; 7:183. Long term results with surgery for small bowel Crohn’s. n=865 surgeries. Risk for repeat surgeries: younger age, upper small bowel location, stricturing
  • Gastroenterology 2009; 136: 441. IFX prevents recurrent Crohn’s post-op. n=24. 1/11 w recurrence vs 11/13 control patients.
  • Am J Gastro 2008; 103: S412 (abstract 1054) IFX reduces post-op recurrence. clinical recurrence 0% at week 54 vs 39% of controls. n=23. 90% in IFX group with endoscopic remission vs 15% of placebo group.
  • Lancet 2008; 371: 660-667.   top-down strategy more likely to achieve endoscopic remicssion after 2yrs: 73% vs 30%. n=129.
  • NEJM 2010; 362: 1383. Sonic study. Combination AZA/IFX with greater efficacy. 56.8% remission in combo Rx vs IFX monotherapy.
  • Gut 2010; 59: 1363.   n=121.  Co-treatment helpd reduce complications & flares relative to monotherapy (& azathioprine appeared to be more effective than methotrexate).
  • JPGN 2009; 49: 183.  REACH pediatric trial showed good perianal dz response to infliximab.

Deadly consequences of pain management

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A big part of a pediatric gastroenterologist’s daily practice is trying to help patients with recurrent abdominal pain.  The goals are to determine the reason for the pain and then to offer the best therapy.  In many cases, these goals can be quite difficult.  With regard to diagnosis, the majority of patients have ‘functional’ pain and the diagnosis is in part a diagnosis of exclusion, trying to rule out other potential etiologies.  With regard to treatment, this is also difficult.

Narcotics are not often given for pediatric abdominal pain, but are used under certain circumstances.  These medications can have unintended consequences.  One consequence of frequent narcotic usage is that individuals may tolerate pain more poorly after receiving narcotics.  A useful review of narcotic overuse was published in the New England Journal of Medicine in 2010.  (NEJM 2010; 363: 1981).

“Deaths from unintentional drug overdoses in the United States have been rising steeply since the early 1990s …and are the second-leading cause of accidental death, with 27,658 such deaths recorded in 2007.”  11,499 of the deaths in 2007 were due to unintentional narcotic overdose.  In comparison, in the same year, there were about 6,000 deaths from cocaine & 2,000 deaths from heroin.

Besides the number of deaths, the other alarming factor has been a sharp rise (10-fold since 1990) in the usage of narcotics in the past two decades.  One of the factors driving this increase has been a compassionate interest in relieving pain.  The availability of these drugs throughout the country even in remote regions allows these abusable drugs to be more accessible than illicit drugs like cocaine and heroin.   While the availability of these medications may increase the rates of suicide, most opioid-overdose deaths are tragic accidents. Often, laboratory tests identify one or more substances in addition to the opioid, indicating that the depressant effects of alcohol or other drugs were additive  in causing death.

With regard to gastroenterology/pediatric gastroenterology, another important aspect of narcotics use is the association of increased mortality risk with inflammatory bowel disease.  This has been shown by analyzing a registry for infliximab (IFX) (Lichtenstein G, DDW 2010, abstracts#T1039 & T1040.).  In the TREAT registry with 6273 patients (3334 treated with IFX), the only risk factors for increased mortality/increased infections were steroids and narcotics.  This study also showed that IFX did not increase mortality, serious infections, malignancy or lymphoma in this cohort.

Additional Reference:

Clin Gastro & Hep 2008; 6: 978. Refractory abdominal pain review.  ‘Narcotics over time increase frequency, duration and intensity of pain.’ Practical recommendations:
treat constipation, withdraw narcotics, consider mental health (CBT/hypnosis/psychotherapy/stress mgt), and possible TCA or SNRI therapy.

More evidence that breastfeeding improves cognitive development

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A large cohort study from the United Kingdom with 11,101 term infants and 778 preterm infants shows improved cognitive development when infants are breastfed.  J Pediatr 2012; 160: 25-32.  There have been a number of previous studies as well that have shown that breastfed children have an IQ that is ~5 points higher than nonbreastfed children; however, when adjustment for confounders, especially maternal education, this effect is weaker.  Since this is an observation study (randomized blinded study would be impossible), it is difficult to control for all variables.  Nevertheless, prolonged breastfeeding, more than 2 months in preterm and more than 4 months in term infants, is associated with higher cognitive development.

Additional references:

  • Am J Clin Nutr 199; 70: 525-35.
  • BMJ 2006;  333: 945.
  • Arch Gen Psychiatry 2008; 65: 578-84.
  • Paediatr Perinat Epidemiol 2003; 17: 81-90.

Other refences:

  • J Pediatr 2009; 155: 421.  Breastfeeding may have possible protective effect from developing inflammatory bowel disease.  Review of multiple studies.
  • J Pediatr 2002; 141: 764.  Breastfeeding may protect against obesity.
  • BMJ 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)

The cost of progress in treating Hepatitis C

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Background information on Hepatitis C (HCV):

  • —170 million people worldwide infected with HCV, 2.7 milllion people in U.S. infected
  • —27% of worldwide cases of cirrhosis are due to HCV
  • —25% of cases of hepatocellular carcinoma are due to HCV
  • —Established treatment with pegylated interferon (PEG IFN) and ribavirin have ~40% response rates in genotype 1 (74% of HCV in U.S.) and relapses are not uncommon among responders

New treatments for Hepatitis C (in combination with previous treatments):

  • —Two new drugs: Boceprevir (BOC) & Telaprevir (TVR)
  • —Overall sustained viral response (SVR) with BOC combination 63-66% vs 73-79% with TVR combination treatment
  • —Both trials demonstrate marked improvement over previous
  • Mechanism of action: —Protease inhibitor binding to NS3 HCV target
  • —BOC: Wholesale cost $1100/week (20-44 weeks)
  • —TVR: 12weeks cost: $49,000
Previous treatments for hepatitis C typically cost about $5000 per month (http://www.familydrugguide.com/family/ub/view/Consumer_Reports_Health/526033/4/hepatitis_c_drugs).  The addition of these newer drugs could add another $50,000 to the cost of treatment.  In some cases which respond well to the newer treatments, shorter treatment periods will lower the increase in cost.  Although these drugs are expensive, they may be lifesaving and may obviate the need for liver transplantation.  Due to the potential complications of HCV, more medications are in the pipeline.  They may be easier to take but are likely to be expensive as well.  The safety & effectiveness of these medications have not been demonstrated in published pediatric studies.
Article References:
  • Hepatology 2011; 54: 1433.  Updated AASLD HCV treatment guidelines
  • NEJM 2011; 364: 1195-206, Editorial pg. 1272. Addition of boceprevir, in 1097 previously untreated pts increased SVR. In whites, 40%–>67% & in blacks from 23% –>42%. Medication given after lead-in of 4 weeks. More frequent anemia in boceprevir-treated patients (SPRINT-2 study).Boceprevir dosing: 800mg (4 capsules) TID with food. (trying to space out doses evenly).
  • NEJM 2011; 365: 1014. n=540. Telaprevir study: extended SVR 72%. In pts with rapid viral response (RVR) at 4 & 12 weeks (no detectable HCV), Telaprevir12weeksPegRbv24 was as effective as Telprevir12weeksPegRbv48. Dosing for study: Teleprevir 750mg TID, PEGalfa-2a 180mcg/wk, RBV1-1.2gm per day.  Rash in 37% (severe in 5%), anemia in 39% (severe in 6%).
  • NEJM 2011; 364: 2405, 2417, 2429 (review). Telaprevir addition:  up to 75% response in HCV genotype 1 pts. n=1095 in 1st study, n=833 in 2nd study (re-treatment study)
  • Gastroenterology 2011; 140: 746. Summary of results of boceprevir (used with IFN -alfa 2b 1.5/kg) & telaprevir (used with IFN -alfa 2a 180mcg). “Similar effectiveness” thus far. Telaprevir used for 12 weeks without lead-in period.  TVR: most frequent problem -rash & then anemia.  In practice, dosing in adults: Telaprevir will be used at 750mg TID in combination with IFN-2a 180mcg & RBV 1-1.2g/d. & used for 1st 12 weeks of Rx. This will allow ~50% of patients to have shorter Rx duration:  if HCV RNA RVR –>24week total vs 48week total in those w/o RVR.  Both drugs best for genotype 1.

Good News for Celiac Disease

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With the discovery of precise serologies to identify celiac disease, the likelihood of complications of celiac disease has been changing.  In addition, the presentation of celiac disease is different now.  Instead of seeing children with malabsorption and abdominal distention, many children and adults are identified with mild or no symptoms.  Also, the risk of severe complications including malignancy and autoimmune disease has been reevaluated based on larger cohorts.  Twenty years ago, the risk of these complications did serve as a motivator for continuation of a gluten free diet (GFD).   While a GFD remains important, these risks are much lower than previously reported.  The most recent article to support this contention is the following:

Clinical Gastroenterology and Hepatology 2012; 10: 30-36.  This study examined ~45,000 patients with either celiac disease (villous atrophy, Marsh score of 3), duodenal inflammation (Marsh 1 or 2), or latent celiac disease (normal mucosa & positive serology).  After the first year, there was no significant increase risk for GI cancers.  During the first year, cancers that were identified may not have been causally-related to celiac disease but due to coincident detection.

This article due to its large cohort is very useful, but other articles have come to different conclusions.  Irregardless, there are still compelling reasons to continue a GFD.  Many individuals feel better on a GFD & did not recognize prior symptoms.  Maintaining this diet probably lowers the risk of developing certain autoimmune conditions and definitely improves bone health.

Other recent &/or related articles:

–Gastroenterology 2010; 139: 763. Mortality NOT worsened in undiagnosed celiac disease (identified by review of serology) in Olmstead County, though bone density decreased. n=129 of 16,847. (?milder cases undiagnosed)
–J Pediatrics 2010; 157: 373, 353. Even patients without villous atrophy & positive serology, benefited from GFD with regard to GI symptoms and serological markers.
–JAMA 2009; 302: 1171-78. n=29,096. Mortalitiy increased in celiac disease: 35% for latent, 72% for inflammation, 39% for celiac dz.

–Clin Gastro & Hep 2008; 6: 753.  Incidence of autoimmune diseases less in those celiac patients who were compliant with GFD. n=178.

–Gastroenterology 2002; 123; 1428-1435. n=12,000.  Risk for cancer 1.3 odds ratio (lower than in previous studies).

The Medical Pendulum and Gastroesophageal Reflux

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In so many areas of pediatric gastroenterology, there is a gradual development of enthusiasm for a medical treatment.  In the vast majority, the enthusiasm goes too far and closer scrutiny often determines a more limited role for this medical treatment or potential adverse effects that were not initially appreciated.  The latest example of this may well be with the use of proton pump inhibitors (PPIs) for gastroesophageal reflux disease, particularly in infants and individuals with asthma.  Although these medications may not have reached their apogee, more and more their effectiveness for so many ailments has been questioned.  In this month’s issue of JPGN, this is highlighted (JPGN 2012; 54: 8-14).  The article which emanates from the offices of the FDA discusses the fact that the usage of PPIs has increased 11-fold from 2002-2009 in infants <12months of age; 404,000 prescriptions were dispensed to 145,000 infants in the U.S. in 2009.    At the same time, althougth there have been four randomized controlled trials of PPIs in infants, NO studies have demonstrated the effectiveness of these drugs in this population.  As a consequence, the authors recommend that these drugs be restricted to infants with endoscopically-proven GERD/erosive esophagitis.  No other tools are sufficient to identify infants who are likely to respond.  Perhaps the reason why these agents work less well in infants is due to the fact that acid secretion is much less in infants than in children and adults.  For example, at 4months of life, average acid secretion rate in infants is ~27-fold lower than in adults (Am J Dig Dis 1969; 14: 400-14). As a consequence, their symptoms may not be responsive to acid reduction treatments.

Other related references on GERD in infancy:

–JPGN 2010; 50: 609-18. Pantoprazole helped improve symptoms but there were no significant differences compared to placeblo 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.
–JPGN 2009; 49: 498. NASPGHAN GERD guidelines. “In infants and toddlers, there is no symptom or symptom complex that is diagnositc of GERD or predicts response to therapy.” Identical response to placebo (vs prevacid) in largest double-blind randomized study (54% at 4 weeks) (J Pediatrics 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.”

GERD and respiratory/ENT issues:

–Gastroenterology 2010; 139: 1887. PPIs decreased postnasal drainage compared to placebo. n=75. (50% vs 5%) age discrepancy in patient populations.
–Clin Gastro & Hep 2010; 8: 741 (excellent editorial), 770 (article on rabeprazole improving heartburn Sx in pts with laryngitis), n=82. Editorial suggests 1-2month trial of BID PPI and if not effective, then little to offer. May change when studies looking at surgery (after impedance) outcomes.
–Gastroenterology 2010; 139: 754. 716 (editorial). Acoustic cough & reflux. Study recorded cough during pH measurement. n=71. ‘causality cannot be established until effective treatment’ available.
–Gastroenterology 2009; 137: 1844. Critical review of below NEJM article. ‘a subset of asthmatics will have objective detection of GERD without typical symptoms…work by Amer Lung Assn suggests that twice daily PPI will not be helpful’..however, ‘perhaps 3-6months of PPI may still be reasonable until we can accurately identify subgroups of pts who may respond.’ –Gary Falk, Cleveland Clinic
–NEJM 2009; 360: 1487, 1551. Use of PPIs (nexium 40mg bid) in poorly-controlled asthma with no symptoms of GER –did not help w asthma control & pH studies were not predictive of response. n=412 adults. 40% c abnl pH studies in each group (nexium vs. placebo).
–Clin Gastro & Hep 2007; 5: 1379. Review of ENT findings and reflux.
–Am J Gastro 2007; 102: 716. Poor specificity of ENT findings for diagnosis of laryngopharyngeal reflux.
–Aliment Pharm Ther 2007; 25: 385-92. meta-analysis. Rx c PPIs not more effective than placebo in resolving ENT symptoms presumed to be due to GER. Editorial suggests some patients may benefit, but better tools are needed to identify them.

GERD and surgery:

–Gastroenterology 2011; 141: 1938.  LOTUS study in JAMA summarized in this review. (JAMA 2011; 305: 1969) Medical treatment outperformed surgery. 92% under control (remission) with long term medical Rx vs 85% with surgery & fewer side effects of medical treatment.
–Clin Gastro & Hepatology 2009; 7: 1292, 1264 (editorial). 12yr outcomes for surgery vs PPI. n=154 omeprazole, n=144 surgery. Similar long term outcome ~50% with long term remission.

–Pediatrics 2006; 118:1828. 48,665 antireflux surgeries done from 1996-2003 (~7000/yr) in US

–Clin Gastro & Hep 2006; 4: 299. Frequent complications post-op and frequent need for GERD meds.  Dysphagia in 19%, dilatation in 6%, repeat surgery in 2%, mortality in 0.8% (n=3145). 50% required GERD meds.

–Clin Gastro & Hep 2004; 2: 978-984. Pediatric study.  n=198.  63% required post-op treatment for recurrent GERD -retrospective review 1996-99.

Proton Pump Inhibitors and reported adverse effects:

-Risk of Hypomagnesemmia -2011. http://www.fda.gov/drugs/drugsafety/ucm245011.htm
–NEJM 2010; 363: 2114. large Denmark study. 5082 fetuses with PPI exposure (out of 840,968 live births). Risk of birth defects NOT increased with exposure during 1st trimester. Possible slight increase risk with preconception use except with omeprazole.
–Gastroenterology 2010; 139: 1115. Review of safety of PPIs.
–Gastroenterology 2010; 139: 93. n=167,000. PPIs associated with hip fracture risk, OR 1.3, in patients with other risk factors.
–Gastroenterology 2010; 138: 896-904. 5yrs of PPI -no increase risk in hip/spine fx.
–Arch Intern Med 2010; 170: 765-71, 747 (ed). PP not related to hip fx (n=161,806) women 50-79. INCREASE risk of spine fx, hazard risk 1.47
–Arch Intern Med 2010; 170: 772-8. PPIs increase risk of Clostridium difficile infection (hazard ratio 1.42 –42% increase in risk), n=1166.
–Arch Intern Med 2010; 170: 784-90. n=101,796. OR 1.74 for daily PPI, OR 2.36 if BID Rx; thus ~70% increase risk of nosocomial infection.
–Clin Gastro & Hep 2010; 8: 504. Increased bacterial overgrowth with PPI use.

-JAMA 2009; 301: 2120-2128. Use of PPIs associated with INCREASED hospital acquired pneumonia by ~30%. Could result in 180,000 HAP cases/yr with ~33,000 deaths. n+ 63,878 admissions, 52% on PPIs or H2RAs (83% PPIs, 17% H2RAs). H2RAs NOT associated with HAP cases.
–Gastroenterology 2009; 137: 80. PPIs induce acid-related symptoms in ~22% vs 7% of placebo in healthy volunteers.
–Ann Intern Med 2008; 149: 391-398. Risk for pneumonia associated with short-term PPI use, not long term
–Clin Gastro & Hep 2007; 5: 1418. Increases risk of bacterial gastroenteritis.
–JPGN 2007; 45: 395, 421. Increasing use of PPIs-4-fold from 2000-2003; 0.5% of all infants. No safety/efficacy data.
–J Pediatrics 2007; 150: 262. Long term use (up to 11yrs of usage) of PPIs in 166 children; minimal problems: 2 c nausea, 2 c skin rash, 1 c diarrhea, 1 c agitation.
–JAMA 2006; 296: 2947-53. Risk of bone fracture –odds ratio 1.44-2.65 with long-term PPI treatment (>1yr); UK study looked at 1.8million

Clostridium difficile -Current Battlelines

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The most recent how to treat Clostridium difficile with fecal microbiota transplantation is described in a review article, Clinical Gastroenterology & Hepatology; 2011: 9:1044-49.  This article details the rationale and effectiveness of this approach.  Indications include 2-3 recurrent episodes or moderate/severe episode not responding to conventional treatment. Workup for donors to minimize the risk of transmission is discussed.  The article points out that fecal transplantation can be accomplished by nasogastric or transpyloric tubes or can be delivered directly via colonoscope or via retention enema.

Additional information on this topic:

–Am J Gastro 2000; 95: 3283-5.
–Clin Inf Dis 2003; 36: 580-5.

More C difficile references:

  • –NEJM 2010; 364: 422, 473. Fidaxomicin – a macrocytic abx –more effective than vancomycin (92% vs. 90%) and with lower recurrence (15% vs 25%). Dose 200mg BID. n=629.
  • –NEJM 2010; 362: 197, 264 (editorial). 1st article: n=200. Rx with monoclonal antibodies (against toxins A & B) -single infusion (10mg/kg) –reduced recurrence rate from 25% vs 7% & among those with previous recurrence, the rate was reduced from 38% to 7%.
  • –NEJM 2011; 365: 1693. Host/pathogen factors. n=4143.
  • –Gastro 2009; 136: 1152, 1206. “reining in recurrent C. diff”
  • –JPGN 2009; 48 suppl 2: S63-65. Cohen MB. ~35% of patients now w/o antibiotic exposure.
  • –Curr Opin Gastro 2008; 25: 24-35. Use of sacchromyces boulardii(1gm/d)x 2 weeks w Vanco may reduce recurrence by >50&.
  • –Journal of Pediatrics 2009; 154: 607. n=198.  Virulent NAP1 strain present in~19% from 2 children’s hospitals.
  • –NEJM 2009; 360: 637. C diff (even toxigenic strains) present in ~50% of healthy newborns. Not convincingly associated with any illnesses in newborns –possibly due to lack of receptor in infants (J Clin Invest 1992; 90: 822-9).