The more you know the more you see

Posted on by

And the more you see, the more you know.  Case in point: gestational alloimmune liver disease (GALD), also referred to as congenital alloimmune hepatitis (CAH) which itself is often referred to as neonatal hemochromatosis (NH).  Now, GALD is more readily identifiable and has better treatments to prevent progression to liver-related complications.  A recent study (J Pediatr 2011; 159: 612-16) shows that GALD can result in fetal death; this finding is a relatively logical extension from the work in this area over the last decade but would not have been feasible without the prior recognition that most cases of neonatal hemochromatosis stem from GALD.

GALD is mediated by fetal complement via activation of the terminal complement cascade.  The presence of C5b-9 complex, an antigen that is part of this cascade, is unique to cases of NH and allows diagnosis, particularly in case in which extrahepatic siderosis is not present. In the reference above, a retrospective study enabled autopsies of six stillborn fetuses and two extreme premature infants who had family histories compatible with NH (along with appropriate controls); the autopsy cases were identified as having GALD– based on liver immunostains with C5b-9 complex.  The implications of this study for pediatricians:

  • When faced with a newborn with coagulopathy or liver failure with family history of stillbirth, consider linking the events immediately & evaluate for NH.  However, this clue has limited utility as NH is the most frequent reason for liver failure in newborns; though, many  newborns with liver failure are often treated for sepsis prior to consideration of NH.
  • Establishing a proper diagnosis, allows management of subsequent pregnancies.  GALD is extremely likely to recur in subsequent pregnancies & can be treated by administration of IVIG to expectant at-risk mothers.

Additional references:

  • -J Pediatr 2011; 159: 813.  Study of ALF in young infants.  38% were indeterminate, ~14% NH, 12% herpes.  n=148. 60% survived w/o OLT, 24% died, 16% OLT
  • -Hepatology 2010; 51: 2061 (edit 1888). Fetal hepatocyte injury involves terminal complement cascade –very good article from Whittington et al. NH being renamed ‘congenital alloimmune hepatitis’
  • -J Pediatr 2009; 155: 566-71. n=16. 75% with good outcome –Rx’d with IVIG (1gm/kg) and exchange transfusion (7 had double volume ET and 6 had less). Appeared to reduce need for liver transplant. Some response with regard to hypoglycemia was fairly quick but most parameters like coagulopathy improved slowly ~2 weeks. Previous historical survival ~36%. (5 of 10 w transplant and 2 of 9 w/o transplant).
  • -Pediatrics 2008; 121: e1615. Weekly IVIG during pregnancy after 18th week of gestation very effective in preventing severe NH
  • -Hepatology 2006; 43: 654. Review by Whitington. MRI detects disease in ~90%. Mucosal biopsy abnl in about 2/3rds of patients. Explains iron homeostasis and alloimmunity.
  • -Liver Tx 2005; 11: 1323 (ed), 1417. Medical treatment ineffective, try transplant. “All who drink of this remedy recover in a short time except those whom it does not help, who all die. It is obvious, therefore, that it fails only in incurable cases.” –Galen, circa 100AD
  • -JPGN 2005; 40: 544. NH is probably an alloimmune dz.
  • -Lancet 2004; 364: 1690-8.

When nothing else is working

Posted on by

The situation when “nothing else is working” comes up with a number of pediatric gastroenterology phenotypes, including inflammatory bowel disease, encopresis, and functional abdominal pain.  With severe refractory Crohn’s disease, the use of Thalidomide has been explored (JPGN 2012; 54: 28-33).  In this recent description of 12 refractory patients (three females), followed over an average of 4.6 years, thalidomide was associated with improvement in many outcome measures.  All patients were refractory to multiple other medical therapies (particularly infliximab and adalimumab).  Five of seven patients with fistulas had complete resolution, Harvey-Bradshaw index improved (11.8–>3.9), steroid dependency improved (daily dose 13.9–>2.3mg/day), sedimentation rate improved (35–>14), and both hospitalizations & surgeries decreased.

However, 42% developed peripheral neuropathy and adverse reactions resulted in discontinuation in nine of the patients.  The peripheral neuropathy developed on average 43 months into treatment (range 12-79 months) and clinically resolved in all patients within 2-3 months after discontinuation.  All patients enrolled participated in close monitoring as required by the FDA STEPS program —system of thalidomide education and prescribing safety.

Additional references:

  • -JPGN 2003; 37: 522, UK experience. 4/6 developed peripheral neuropathy.
  • -J Pediatr 2004; 145: 856. use for JRA
  • -JPGN 2001; 32: 322-25. Irreversible neuropathy noted in patient after 9 months of Rx.
  • -JPGN 1999; 28: 214.  Response w/in one month
  • -Pediatrics 1999; 103: 1295. (in Behcet’s)
  • -Gastroenterology 1999; 117: 1271 & 1278.  22 men c refractory Crohn’s, dosed @ 200mg qhs: 9 clinical remission & 16 c response. 12 steroid-dependent men @50 or 100mg qhs: 44% off steroids over 12 weeks.
  • -JPGN 2000; 31 (supp 2) A611. Dose 1.5-2mg/kg/day in 5 males.

Rest easy with enteral nutrition

Posted on by

Exactly how long can we leave enteral formulas (ready-to-feed) hang while families rest?  Probably 12 hours according to a recent article (Nutr Clin Pract 2011; 26: 451).  This prospective study involving 30 pediatric patients studied the outcomes in those who received continuous enteral feedings using decanted formula for a minimum of 12 hours.  In this study, patients received both polymeric and peptide based formulas.  Cultures of the formula were obtained.  Among 111 usable cultures, 100 showed no growth, 6 had growth considered below FDA threshold for contamination & 5 (in two patients) had coliforms identified.  No patient developed clinical symptoms.  In these two patients, the authors speculate that contamination occurred due to a combination of exogenous source (touching) as well as possible endogenous source (retrograde movement of bacteria from patient’s gastrointestinal tract).

This small study lends support to extended hang times of up to 12 hours as long as the feeding sets are carefully managed with aseptic technique, clean gloves & avoiding touching formula.  Instead of more frequent changes to formula, this approach can allow parents to sleep while their children receive enteral nutrition and for nurses to pursue other activities for hospitalized patients.

The context for the study was a FDA recommendation for an 8-hour hang time based on conservative recommendations from manufacturers.  The FDA recommendation may have been influenced by a report in 2001 of an enteral powdered formula contaminated with Enterobacter sakazakii which lead to the death of a premature infant.

It should be noted that ready-to-feed enteral formulas are commercially sterilized prior to hanging whereas powdered formulas cannot be commercially sterilized.

Additional references:

  • -MMWR 2002; 51: 297-300.
  • -J Hosp Infect 2005; 59: 311-316.

A liver disease tsunami

Posted on by

The extent and consequences of nonalcoholic fatty liver disease (NAFLD) are far-reaching and like a tsunami will be quite destructive (Gastroenterology 2011; 141: 1249.)  In this article, the epidemilogy of nonalcoholic steatohepatitis is discussed.  NAFLD was  the 3rd most common cause of liver transplantation in this cohort (n=35781).  It is projected to be the #1 reason for liver transplantation by 2025.  Although the outcomes in NAFLD are similar to other liver transplant patients, it is difficult to imagine that so many patients will need such an aggressive treatment approach.

Another recent article, discusses the correlation of vitamin E, uric acid, and diet composition with histology in NAFLD (JPGN 2012; 54: 90-96).  This study involved 149 patients.  The study demonstrates that in these patients, their diet is insufficient in Vitamin E intake. Also, although reported sugar-sweetened beverage consumption was low, uric acid which often reflects total fructose consumption was associated with NASH histology.  As noted in the references below, concerns about low antioxidants, especially Vitamin E, as well as sugary beverages has been an ongoing concern for NAFLD for at least a decade.

For pediatric gastroenterologists/hepatologists, nonalcoholic fatty liver disease is increasingly common but remains difficult to treat; the best treatment is weight loss.  A recent educational pamphlet was published by the NASPGHAN Foundation (http://www.gastrokids.org/files/documents/digestive%20topics/english/NASPGHAN%20Fatty%20Liver%20Fact%20Sheet%2011.2011%20(1).pdf).  The advice for families is the following:

• Avoid sugar drinks

• Drink mostly water and some low fat milk

• Get at least 60 minutes of physical activity every day

• Limit TV and screen time to one hour or less per day

• Make half your plate vegetables at mealtimes

• Eat breakfast everyday

Other things that can harm the liver should be avoided, like drinking alcoholic beverages.  Studies in teens with NAFLD have shown some benefit from the natural form of Vitamin E.

Although this advice applies to patients with NAFLD, it sounds like good advice for everyone.

Additional References:

  • -Hepatology 2011; 54: 1082.  U/S w ~85% sensitivity in detecting fatty liver.
  • -JPGN 2011; 52: 740.  n=20.  Some improvement in LFTs with culturelle
  • -Gastroenterology 2011; 140: 124.  High prevalence in middle aged US cohort: 46% NAFLD, 12% NASH. n=400.
  • -Hepatology 2010; 52: 472.  High dose ursodeoxycholic acid ineffective for NASH in double blind randomized trial. n=185.
  • -Hepatology 2010; 52: 79.  Meta analysis of trials for NAFLD.  No effective Rx at this point.  Thiazolidinediones helped with steatosis/inflammation but caused wt gain.  L-carnitine helped histology in 1 trial.
  • -Hepatology 2010; 51: 1961, 1972. 1– increased fructose assoc with increased fibrosis in NAFLD. 2–increased HCC risk.  Alcohol intake is addt’l risk factor along with NAFLD.  2.6% of NASH pts with HCC (compared w 4% of similar HCV pts).
  • -NEJM 2010; 362: 1675.  n=247.  Vitamin E 800 IU/day helpful.  Pioglitazone not helpful.
  • -Gastroenterology 2010; 138: 905.  Iron overload, but not HFE mutations, associated with more severe NASH
  • -J Hepatol 2009; 51: 918-24.  Soft drinks assoc with fatty liver independent of metabolic syndrome.
  • -Hepatology 2009; 50: 1818.  Lack of benefit from Betaine.
  • -J Pediatr 2009; 155: 469.  Review.  No evidence-based guidelines for treating in pediatrics –main Rx wt loss/exercise.  Consider obtaining ultrasound evidence.
  • -J Hepatology 2009; 51: 371.  risk factors for fibrosis progression.
  • -Hepatology 2009; 50: 68.  Activity helps NAFLD independent of activity level.
  • -JPGN 2009; 48: 587. review of meds.
  • -Gastroenterology 2008; 135: 1961.  Liver biopsy (in pediatrics) still needed as surrogates not accurate for correlating degree of fibrosis/injury.
  • -Gastroenterology 1999; 116: 1413.  spectrum of pathology in NASH.  Bx correlated with outcome
  • -Gastroenterology 1988; 95: 1056.  Sentinel article on NASH ‘alcohol-like liver disease in non-alcoholics’
  • -Clin Gastro & Hep 2008; 6: 1396.  Bariatric surgery appears to improve or resolve NASH. n=15 studies with 766 paired liver biopsies.
  • -Clin Gastro & Hep 2008; 6: 1249.  Cytokeratin 18 levels associated with NASH in at risk patients (bariatric patients). n=99.
  • -Hepatology 2008; 48: 792-98. NASH increased with age and with presence of DM.  Severe fibrosis assoc with ferritin, ALT, and DM.
  • -Gastroenterology 2008; 135: 1176.  n=74.  Use of pioglitazone for NASH was helpful in adult patients.
  • -Hepatology 2008; 48: 119.  Antioxidants Vit C (500mg)/Vit E (600IU) c lifestyle changes was NOT better than lifestyle changes alone. n=53 children. Rx’d for 24 months
  • -Gastroenterology 2008; 134: 1682.  Review.
  • -Clin Gastro & Hep 2008; 6: 26-29.  Review.  Risk factors for NASH: obesity, age>50y, non-black ethnicity, female, type II DM, HTN, AST>45, AST/ALT ratio >0.8-1, low platelet count.  Rec:  exclude other causes, check U/S or CT, if risk factors, conside liver biopsy, lifestyle modification
  • -Gastro 2007; 133: 1814.   Prevalence data for increased ALT from NHANES 1999-2004.
  • -NASPGHAN 2007 Postgraduate Course Jeff Schwimmer.  20% of NAFLD pts have normal wt.  9.6% of all children have NAFLD.
  • -Clin Gastro & Hep 2007; 5: 496.   n=88; 55% of women with PCOS had NAFLD.
  • -Clin Gastro & Hep 2006; 4: 1537.  Combination of Vit E & urso x 2yrs may be beneficial. n=48.  Regression of steatosis  noted in this small study along with improved enzymes.
  • -JPGN 2006; 43: 413.  Invited review of NAFLD.
  • -NEJM 2006; 355: 2297, 2361.  pioglitazone for NASH -helps with histology; not ready for routine use.
  • -Pediatrics 2006; 118: 1388.  Schwimmer.   n=742 autopsy study; estimates 9.6% overall prevalence of fatty liver for ages 2-19 (>6.5 million in U.S.). 38%  obese had steatosis; 23% of all NAFLD had NASH, 9% had bridging fibrosis
  • -Hepatology 2006; 44: 802, 865.  Long term f/u of NASH (avg 13.6yrs): increased cardiovascular deaths (15.5% vs 7.5% control), increased liver-related deaths 2.8% vs. 0.2% controls.  Risk of HCC and cirrhosis proven.
  • -Hepatology 2006; 44: 458.  Prospective study of 84 children; 7%c >grade I fibrosis; 58% with some fibrosis.  Almost all have evidence of insulin resistance
  • -Clin Gastro & Hep 2006; 4: 639.  Orlistat helped decrease ALT and steatosis on U/S beyond its effect on weight reduction.  n=52.  double-blind, placebo-controlled.  Rx 120mg TID x 6 months.
  • -Liver Transplantation 2006; 12: 523.  Review of NAFLD & Liver transplant.  NAFLD likely the main reason for cryptogenic cirrhosis in adults.
  • -Pediatrics 2006; Schwimmer.   n=954 autopsy study, 32% obese had steatosis; 23% of all NAFLD had NASH, 9% had bridging fibrosis
  • -Aliment Pharm Ther 2005; 21: 871.  pilot study of metformin, 500mg bid in children; 50% nl ALT  (equivocal in adults), high insulin in 95% of pts c NASH
  • -J Pediatr 2003; 143:  500-5.
  • -Hepatology 2005; 42: 641-649. pediatric NAFLD pathology
  • -Hepatology 2004; 40: 1387-95.  Nearly 1 in 3 in US have NAFLD.
  • -Clin Gastro Hepatol 2006; 3: 1260.   Alcohol and NASH are synergistically bad. (increase ALT)
  • -J Pedsiatr 2005; 147: 835.  Low adiponectin in children c NAFLD (lower than other overwt children).
  • -Surgery 2004; 135: 48-58.  Wt loss improves liver histology
  • -Gastroenterology 2005; 128: 1898.  Significant sampling variability (can lead to misdiagnosis)
  • -Hepatology 2005; 42: 44. NAFLD in 25% of pts c clinical liver dz & 20% of pts w/o suspected liver dz (n=3345, Italy)
  • -Clin Gastro & Hepatol 2004; 2: 1048 & 1059 (review/editorial) & 1107. pilot study of VIT E vs VIT E/pioglitazone, n=20.
    NASH in 3% lean, 20% obese, & ~50% morbidly obese.  100% of obese/diabetes have at least mild steatosis, 50% c NASH, & ~20% c cirrhosis.
  • -Hepatology 2004; 39: 770-78.  URSO probably doesn’t help NASH.
    -NEJM 2004; 351: 1147.  n=282 obese children; 11% mod obese c incr ALT, 21% of severely obese.
  • -JPGN 2004; 38: 48.  Rx c vitamin E &/or wt loss.  Both are helpful.
  • -J Peds 2003; 143: 500.  Fasting glucose/insulin, ALT/AST, and BMI are predictive of portal inflammation and fibrosis.  1-4% of all children have elevated transaminases (10-25% of all obese patients).
    HOMA-IR =fasting insulin (microU/ml)/ fasting glucose/22.5.  Insulin resistance is when HOMA-IR is greater than 2.  Fibrosis present in 63% of pts, n=43.
  • -JPGN 2003; 37: 342 (47A) use of metformin 500mg bid, n=10; 3 had transient diarrhea/abd pain. (50A) 3/40 children c NASH c early cirrhosis. 31 c portal fibrosis
  • -Gastroenterology 2003; 125: 1053-59.  Obesity increases risk of death due to cirrhosis.
  • -Clinical Gastro & Hepatology 2003; 1: 384-87.  Use of pioglitazone for NAFLD & obesity.
  • -Gastroenterology 2002; 123: 1702-4, 1705-25. AGA position statement and technical review.
  • -Gastroenterology 2003;124: 71-80.  increased ALT in 2.8% of population -mostly in overwt/obese.
  • -JPGN 2002; 36: 54-61.  With MRI,  21 of 22 (BMI>95th%) c elevated hepatic fat; those c abnl ALT, n=12, had more severe cases of fatty liver c fat content >18%.
  • -Ann Intern Med 1989; 111: 473-8.  Clinical dx of nonalcoholic fatty liver dz without Bx has only 59% predictive value.
  • -Gastroenterology 2004; 126: 1287-92.  Pts c elevated liver enzymes (NASH) are not at higher risk for statin hepatotoxicity.
  • -Gastroenterology 2002; 122: 1649-1657.  Review
  • -NEJM 2002; 346: 1221-1231. Review  AST/ALT ratio greater than 1 suggests increased fibrosis.  Consider bx if obese, greater than 45, type 2 DM, or increased AST/ALT ratio.
  • -Hepatology 2002; 35: 1485-93.  significant complications & decreased survival c obesity-related cryptogenic cirrhosis.  higher rates of progressive HCV & HCC c obesity.
  • -Gastroenterology 2001; 121: 710-724.  Review.
    Reasons for Liver Bx  1. poor correlation between clinical/lab findings & histology –thus for staging  2. assure correct dx; may be wrong in ~44%
  • -Clin Gastro & Hepatology 2004; 2: 262.  Coexistant DM worsens outcome in NASH.
  • -J Pediatr 2000; 136: 727. N=2450.  6% of overweight children with increased ALT, 10% of obese children.  1% of obese children with 2x normal.  50% of obese adolescents with alcohol ingestion (4 or more/month) had increased ALT.  Decreased antioxidants, elevated triglycerides, increased age, and increased hgbA1C were addt’l risk factors.
  • -Gastroenterology 2001; 121: 91-100.  HTN, insulin resistance, and ALT were predictors of fibrosis.
  • -J Pediatr 2000; 136: 734. N=11. Daily vitamin E 400-1200 IU/day noramalized ALT in patients c NASH.
  • -J Peddiatr 2000; 136: 739.  Ursodeoxycholic acid is not effective in NASH. N=31.
  • -J Pediatr 1999; 134: 132 & 160..  Low antioxidants with NASH

What’s critical to you

Posted on by

Over the past ten years, there has been increasing scrutiny with regard to iatrogenic hyponatremia.  Specifically, one of the concerns has been that the administration of hypotonic fluids will result in hyponatremia and potential complications.

In our hospital system, several years ago the hospital administration circulated a list of the new critical laboratory values that would be used to notify physicians of severe derangements.  The goal of selecting a critical value is to improve the outcome of patients by allowing a more rapid and direct communication of an abnormality.  At the same time, it takes time to contact physicians and most physicians do not want to be called too often.

I carefully reviewed the critical values list and was very concerned that the value to call for hyponatremia was <120.  When I protested, I was informed that in fact the sodium critical value had not been changed and had been in place “without a problem” for more than ten years.  In addition, the critical value cutoff at several other children’s hospitals was similar (range was between 120-130).

Despite these reassurances, I remained concerned that this was not the right policy, particularly as alterations in sodium are frequently due to physician error and need to be addressed promptly.  This led to a number of discussions with the laboratory and ultimately to a retrospective review (Guarner, J; Hochman, J; Kurbatova, E; Mullins, R.  Study of outcomes associated with hyponatremia and hypernatremia in children.
Pediatric and developmental pathology 2011;14(2):117-23.)  During a six month period, 53,099 sodium tests were reviewed with 166 having sodium values of 124 or less.  Some of the important findings include the following:

  • Mortality was 42% in patients with sodium values <120mmol/L
  • Treatment was instituted more rapidly when physicians were notified
  • Half of the patients with hyponatremia were receiving hypotonic fluids.

At this time, our critical value for sodium has changed so that physicians are now notified if sodium is less than 125.  Do you know your institution’s critical value?  Are your patients receiving hypotonic fluids?  Something to think about.

Another article in Pediatrics adds more insight into the prevention of hyponatremia (Pediatrics 2011; 128: 980 -983).  Moritz and Ayus reiterate their arguments from 2003 that hypotonic fluids should not be used routinely in children due to the risk of hyponatremia and associated complications.  They cite 20 studies completed over the last seven years which indicate that isotonic fluids are safe and prevent hyponatremia.  “There can no longer be any justification for the routine administration of hypotonic fluids in hospitalized children….On the basis of today’s standards, hypotonic fluids would not receive FDA approval for routine use.”  The main concern about hyponatremia is hyponatremic encephalopathy –this remains a common medical emergency (Pediatrics 2008; 121 (6): www.pediatrics.org/cgi/contnet/full/121/e1577).  Early in the hospital course and in the immediate postoperative period are timeframes that have been noted to have increased incidence of hyponatremia.  However, hyponatremia (<135) is common at all times and affects ~25% of hospitalized patients (Arch Dis Child 2008; 93: 285-287).  So, with your next admission, think about lactated ringer’s or normal saline instead of half-normal.

Additional References:

  • -Pediatrics 2011; 128: 857.
  • -J Peds 2008; 153: 444-447 (letters and references on this topic).
  • -Am J Clin Pathol 2007; 127: 56-59.  Critical Na values.
  • -J Pediatr 2008; 152: 33 & 4.  Frequent p-op hyponatremia.
  • -NEJM 2008; 359: 1018.  Hyponatremia associated with poor prognosis in patients awaitng OLT.
  • -Hepatology 2006; 44: 1535.  Hyponatremia (Na <130) associated with increased mortality & ascites reaccumulation.
  • -J Pediatr 2004; 145: 584. Recs 20-80ml/kg of isotonic fluid to correct hypovolemia prior to typical maintenance fluids (to avoid hyponatremia due to hypovolemia).  Says that isotonic fluids for maintenance may be problematic if cardiopulmonary or renal dz.
  • -Pediatrics 2004; 113; 1395.  Advocates use of isotonic saline (0.9%).  States that hypotonic fluids lead to hyponatremia in many cases b/c of excessive ADH in many patients.
  • -NEJM 2005; 352: 1550 & 1613. Hyponatremia related to Boston Marathon & London Marathon

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

Posted on by

Maybe your mother was right –you should eat your vegetables!   For a long time, it has been known that dietary changes can be used to treat Crohn’s disease.  The specifics about what type of diet and the reasons for how diet promotes a healthy gastrointestinal tract are being unraveled.  A person’s diet affects their microbiome; and, a number of recent articles have highlighted the microbiome in both functional and nonfunctional disorders (see below).

An even more fascinating article is in last week’s New England Journal of Medicine (NEJM 2012; 366: 181).  This article discusses two publications which show how certain dietary components interact with intestinal immune receptors.

  • Kiss EA et al. Science 2011 October 27 (Epub ahead of print).
  • Li Y et al. Cell 2011; 147: 629-40.

This NEJM article implicates a typical ‘Western’ diet as a contributor to inflammatory bowel disease (IBD).  However, a diet high in vegetables may prevent or reduce inflammation.  One mechanism whereby vegetables affect the GI tract is through the AhR (aryl hydrocarbon) receptor.  Some vegetables, like broccoli, cabbage, and brussel sprouts, are natural ligands for this receptor.  A mouse model has shown that AhR deficiency “results in increased epithelial vulnerability, immune activation, and altered composition of the microbiota.”  In addition, AhR is down-regulated in the intestinal tissue of persons with IBD.  AhR ligands are associated with increased interleukin-22 which promotes intestinal integrity.

Additional work regarding the optimal diet are ongoing.  There has been an interest in a ‘carbohydrate specific diet.’  This year’s NASPGHAN meeting (abstract #48)  presented data on this diet from a retrospective study.  This poster described five patients on monotherapy (diet alone) and at 6 months –good results in four patients (80%).  A few prospective studies are underway; in fact, a prospective study with patients from our office will be presented at this year’s DDW.  Initial results look promising (personal communication from lead investigator, Stan Cohen).

Additional references:

  • -Gastroenterology 2010; 139: 1816, 1844.  Microbiome & affect on IBD vs mucosal homeostasis.
  • -J Pediatr 2010; 157: 240.  Microbiota in pediatric IBD -increased E coli and decreased F praunsitzil in IBD pts.
  • -Gastro 2011; 141: 28, 208.  GM-CSF receptor (CD116) defective expression & function in 85% of IBD pts. n=52.
  • -Scand J Gastro 2001; 36: 383-8.  Elemental & polymeric diets successful in maintaining remission in ~43% of adults with complete steroid withdrawal.
  • -Clin Gastro & Hepatology 2006; 4: 744.  10 weeks of exclusive modulen (along with clears) had 79% response rate (n=37).  Better histologic response than steroids.
  • -J Pediatr 2000; 136: 285. Nutritional treatment w polymeric diet is effective w/in 8 weeks in 32/37.
  • -JPGN 2000; 31: 3 & 8.  EN about as effective as steroids for primary Rx.
  • -Can J Gastroenterol 1998; 12(8):544-49. Patients, diets and preferences in
    a pediatric population with Crohn’s disease.
  • -Gastroenterology 1988; 94:603-610. Chronic intermittent elemental diet improves growth failure in  children with Crohn’s disease.
  • -JPGN 1989; 8:8-12. Nutritional support for pediatric patients with inflammatory bowel disease.
  • -J Pediatr 2000; 136: 285-91. The role of nutrition in treating pediatric Crohn’s disease in the new millennium.

Minimizing malnutrition in Biliary Atresia

Posted on by

A retrospective study in Liver Transplantation reviews a single center experience with the use of parenteral nutrition (PN) in patients with end-stage liver disease due to biliary atresia (Liver Transpl 2012; 18: 121-129).  In this study which spanned the past twenty years, 25 PN BA patients were compared to 22 non-PN BA patients –all patients were younger than 36 months.  PN was started when maximal enteral nutrition failed to improve markers of malnutrition (triceps skinfold thickness, & mid-arm circumference).  Among the PN BA patients, there was a higher gastrointestinal bleeding rate and ascites; however, there was no difference in the rates of bacteremia, length of intensive care unit stay after liver transplantation, or patient/graft survival.  The authors speculate that the outcome for the PN BA patients would have been much worse without the PN as malnourished BA patients are at increased risk for graft failure and post-transplant complications.  It is noteworthy that PN patients did have progression of their liver disease that seemed to accelerate with the administration of PN, perhaps due to PN-associated cholestasis.  Specific changes included higher bilirubin levels, lower platelet counts, worsened coagulopathy, and higher calculated PELD scores.

Additional References:

  • Hepatology 2007; 46: 1632-38.  Growth failure and outcomes in infants with BA.
  • J Pediatr 2005; 147: 180-85.  Outcomes of 755 BA patients listed for liver transplantation.

Why are we seeing so many more cases

Posted on by

In this month’s Gastroenterology, two articles offer some insight into this question for two separate problems.

With regard to inflammatory bowel disease, (IBD) –both Crohn’s disease and UC –there is an increasing prevalence and incidence worldwide (Gastroenterology 2012; 142: 46-54). This article identified 8444 previous citations and then identified 262 studies with relevant data.  Overall, the highest incidence and prevalence of these disorders occurs in Europe and North America.  In North America, Canada has the highest prevalence with 0.6% of the population having IBD.

After going through the statistics, the authors offer some discussion on why IBD is increasing.  In the developing parts of the world, some of the increase is due to the ability to detect and differentiate these disorders due to improving access to medical care/colonoscopy.  In the areas of the world with the highest incidence/prevalence, environmental risk factors are playing an important role.  Potential factors include microbial exposures, sanitation, lifestyle behaviors, medications, and pollution.  These factors are supported by other epidemiological studies which show that individuals who move from low prevalence areas to higher ones are at increased risk for IBD, especially among first generation children (Gut 2008; 57: 1185-91).  Furthermore, in low prevalence regions, IBD is increasing with more industrialization (Chin J Dig Dis 2005; 6: 175-81, Indian J Gastroenterol 2005; 24: 23-24.)  Exact mechanisms are poorly understood; however, even in the U.S. it is recognized that rural/farm exposure at a young age reduces the likelihood of developing IBD at a later age (Pediatrics 2007; 120: 354).

Celiac disease, likewise, has seen an increase in prevalence.  With celiac disease, the proliferation of widely available and more accurate serology has been crucial in the identification of more patients.  However, like IBD, there is likely a role for changing microbial environment contributing to an increasing case burden.  Recently, reports have shown that the risk of celiac disease can be influenced at birth (Gastroenterology 2012; 142: 39-45).  Although the absolute risk was modest, there was an increased risk demonstrated with elective but not emergent cesarean delivery among a large nationwide case-control study from Sweden.  Among the cohort of 11,749 offspring with biopsy-proven celiac (with matched control group of 53,887), elective cesarean delivery resulted in an odds ratio of 1.15 (confidence intervals 1.04-1.26).  This study confirmed other studies which have shown an increased risk with cesarean delivery (Pediatrics 2010; 125: e1433-e1440).  Some of the strengths of this Swedish study, included the fact that the deliveries were separated based on elective or emergency cesarean delivery and were controlled for whether the mother had celiac disease.  (Pregnant women with celiac disease have an increased risk of cesarean delivery.)  The authors speculate that the reason why elective cesarean deliveries increase the risk of celiac disease is that microbial exposures at birth likely influences perinatal colonization –>affects intestinal immune response and mucosal barrier function. Offspring of women with emergency cesarean delivery would be more likely to be exposed to bacteria from the birth canal and no significant increase risk of celiac disease could be identified in this group.

Thus how we are born and where we live make a big impact on the likelihood of developing these GI disorders.

Additional References:

  • -Gut 2011; 60: 49-54. n=577,627 Danish children. Use of antibiotics associated with increase risk of Crohn’s disease (but not UC), especially at younger ages (3-11month of age, & 2-3yrs of age). Each course increased risk by 18%. In children with >7 courses, relative risk was 7.3. especially penicillins.
  • -NEJM 2011; 364: 701, 769. Living on a farm decreases risk of childhood asthma.
  • -Nature 2011; 476: 393. ‘Stop killing beneficial bacteria.’  For example, killing H pylori likely increases risk of esophageal adenocarcinoma
  • -Gastroenterology 2011; 141: 28, 208. GM-CSF receptor (CD116) defective expression & function in 85% of IBD pts. n=52.
  • -Gastroenterology 2010; 139: 1816, 1844. Microbiome & affect on IBD vs mucosal homeostasis
  • -J Pediatr 2010; 157: 240. Microbiota in pediatric IBD -increased E coli and decreased F praunsitzil in IBD pts.
  • -J Pediatr 2009; 155: 781. early child care exposures lessens risk for asthma.
  • -IBD 2008; 14: 575.  Role of E coli in Crohn’s
  • -Lab Invest 2007; 87: 1042-1054. Role of E coli in Crohn’s
  • -Pediatrics 2007; 120: 354. Crohn’s less common after repeated exposure to farm animals in 1st year of life.

More practical information and links to other websites can be found at http://www.gicareforkids.com.

Diagnostic tests hardly ever help patients poop

Posted on by

Virtually everyday pediatric gastroenterologists like myself see children with constipation problems; managing constipation is often a Sisyphean task.  Recent articles (JPGN 2011; 53: S2: 49, 55) reiterate what all pediatric gastroenterologists already know –constipation is almost always a management problem and only rarely a diagnostic problem.  Rarely do children with constipation need diagnostic tests.  These articles recommend testing only if alarm features are present, including the following:

  • Delayed meconium passage at birth
  • Bilious vomiting
  • Bloody stools
  • Fever
  • Bladder disorders
  • Poor response to conventional treatment
  • Abnormal exam

Additionally, these articles state that about 25% of functional constipation problems may persist into adulthood.  Among the patients who respond poorly to treatment, constipation, especially if associated with soiling (aka. encopresis), can be very detrimental for obvious social reasons.  This group of patients can be very challenging.  Many of the patients do not perceive the problem to be as severe as their parents and may be unwilling to work on fixing the problem.

Clinical experience has been that younger children respond better than older children. Perhaps, this is due to a greater ease of imposing a specific treatment plan in younger children along with the fact that the physiological and behavioral changes associated with chronic constipation are not as well-established.

Other pertinent aspects of treatment and diagnosis include the following:

Abdominal xrays are not very helpful (JPGN 2010; 51: 155.) and should mainly be reserved for those in whom a rectal examination cannot adequately be performed, such as very uncooperative patients, and in patients with concerns about abuse (or concerns about psychologic impact of exam).

Also, despite earlier reports of potential sacral abnormalities in children with chronic constipation or non-retentive soiling, a fairly large prospective MRI study (J Pediatr 2010; 156: 461-5) (n=158) found that only 3% had lumbar sacral abnormalities and none required neurosurgery (1 with spina bifida occulta, 3 with terminal filum lipomas).

In addition to the scholarly references below, some useful practical sources of information can be identified by going to my office website, http://www.gicareforkids.com and clicking “constipation.”

Additional references:

  • -JPGN 2011;52: 574.  n=117.  Describes outcome with placement of a cecostomy/appendicostomy for irrigations of colon.  69% success with antegrade enemas.
  • -Gastroenterology 2009; 137: 1963. Increased rectal compliance not associated with treatment response.
  • -J Pediatr 2009; 154: 258. Constipation associated with 3-fold increase in health utilization/cost.
  • -Clin Gastro Hep 2009; 7: 20. Review of complications associated with constipation in adults.
  • -Pediatrics 2008; 121: e1334. In this study, behavioral therapy was ineffective in treating childhood constipation.
  • -JPGN 2007; 44: 5.  Review of nonretentive fecal incontinence.
  • -J Pediatr 2006; 148: 62. Higher compliance is noted in children with functional fecal retention/encopresis; thus, larger stool volume need to reach intrarectal pressure of the urge to defecate.
  • -J Pediatr 2005; 147: 700-04.  69% of infants with constipation recovered within 6 months (then 15% relapsed).
  • -Gastrointestinal Endoscopy 2004;  60(1):39–43.  A new technique for management of intractable constipation in children: percutaneous endoscopic colostomy of the left colon
  • -JPGN 2004; 38: 75.  Colostomy in 10 children with intractable constipation.
  • -J Clin Gastro 2003; 36: 386-389.  Safety of stimulants for long-term use.
  • -Am J Gastro 2005; 100: 232-242. Myths about constipation. Stimulants have not been proven to cause a “cathartic colon”
  • -JPGN 2004; 39: 448. review
  • -J Peds 2004; 145: 409. 8/88 patients with intractable constipation with spinal cord lesions (6 with tethered cords). 6/7 better p surgery. Intractable was defined as  <2BMs/week x 3 months despite laxative treatment. Only one patient had physical exam finding.  This was a retrospective study.
  • -Gastroenterology 2003; 125: 357. Long-term constipation followup.  One-third had persistent constipation; 60% better at 1 year. (tertiary referral group)
  • -Pediatrics 2004; 113: 1753 & e520. When constipation & toileting difficulties both occur, constipation usually precedes toileting problems.
  • -NEJM 2003; 349: 1360.  Review.
  • -Arch Pediatr Adolesc Med 1999; 153: 377.  Digital exam  performed in only 23% at time of referral to specialist.

 

 

Drink Up!

Posted on by

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.