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About gutsandgrowth

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

Potential and pitfalls of probiotics with necrotizing enterocolitis

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Recent developments in necrotizing enterocolitis (NEC) have focused on the potential role of new biomarkers and preventive strategies (JPEN 2012; 36: 30S-35S).  In this report, the clinical/diagnostic features of NEC are reviewed:

  • classic form develops between 29-32 weeks corrected gestational age
  • features include feeding intolerance, abdominal distention, bloody stools
  • imaging features: pneumotosis intestinalis, portal venous gas, paucity of gas, fixed bowel loops
  • full term or late NEC usually occurs in the setting of risk factors like congenital heart disease, exchange transfusions, gastroschisis, and neural tube defects
  • spontaneous intestinal perforation due to glucocorticoids or indomethacin may be confused with NEC.  It usually occurs earlier than NEC

This review describes the potential for new biomarkers, including urinary I-FABP & fecal calprotectin. These assays would need to be available with very short turn-around time given the often rapid development of NEC.

Finally, this articles discusses the evidence for preventive measures.  Human milk has been shown to decrease NEC and gradual introduction of feedings remains important. With regard to microbial colonization, NEC does not occur until at least 8-10 days postpartum coincident with anerobic bacterial colonization of intestinal tract.

This has led to attempts to alter the colonization to decrease NEC incidence. 16 randomized controlled trials with 14 different probiotics have been completed.  Most are underpowered.  “The available trials do not permit a decision to be made with respect to optimum strain, dosing, or protocol.”  In a cautionary note, a preterm pig model demonstrated an increase NEC incidence with the use of a specific probiotic (Pediatr Res 2011; 69: 10-16).  Furthermore, probiotics are plagued by a lack of adequate quality control.

Additional references:

  • -Ann Surg 2010; 251: 1174-80.  Non-invasive biomarkers for NEC.
  • -J Peds 2011; 158: 672-74.  Caution advised with probiotics for NEC.
  • -J Peds 2011; 159: 392. n=124 cases (248 controls). retrospective study suggested that abx exposure is a risk factor for NEC (3-fold risk).  Abx -marker for illness or true predisposing factor?
  • -NEJM 2011; 364: 255-64.  NEC review.
  • -Cochrane Database Syst Rev 2011; 3: CD005496.  Probiotics for NEC.
  • -NEJM 2011; 364: 1877. Probiotics likely helpful in preemies with birth wt >1000gm.
  • -NEJM 2010; 364: 255.
  • -Pediatrics 2010; 125: 921-30.  Meta-analysis of probiotics for NEC.
  • -JPS 2009; 44: 1072-76. Mortalitiy of NEC expressed by birth weight.
  • –Pediatrics 2008; 122: 693-700. Multicenter trial of probiotics in VLBW for NEC prevention.
  • -J Pediatr 2008; 153: 339. Cluster of NEC due to norovirus.
  • -Pediatrics 2007; 119; e164. Rate of 0.4% among large cohort of infants w/o indocin, steroids & w slow delayed feedings.
  • -Pediatrics 2006; 117: e137. H2-blockers associated with increased NEC (?causal)
  • -Pediatrics 2005; 116: 1064. CRP helpful. If CRP was persistently normal, antibiotics were aborted and enteral feeds restarted safely.
  • -Pediatrics 2005; 115: 1-4 & 171 editorial.  Probiotics decreased NEC in this study.
  • -J Pediatr 2003; 143: 543. Images of pneumotosis.

The heart connection

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Cardiac changes with biliary atresia (BA) are surprisingly common– Gastoenterology 2011; 141: 1264-72.  In this study, 48 patients with BA, listed for liver transplantation, underwent echocardiography between 2004-2010.  The median age was 8 months.  Significant increases in left ventricle wall thickness (23% increase) and mass (51% increase) were noted; in addition, functional changes were noted as there was an increase in LV shortening fraction (8% increase).  Features of ‘cirrhotic cardiomyopathy’ were evident in 72% of infants (29/40).  The authors conclude that these heart changes likely contribute to prolongation of posttransplant hospitalization.

Additional References:

  • -J Am Coll Cardiol 2010; 56: 539-49
  • -J Hepatol 2010; 53: 179-90.

Add it to the list

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A recent review article (NEJM 2012; 366: 158-64) describes a common, chronic recurrent granulomatous inflammatory disease that manifests as painful, deep-seated inflamed lesions (including sinus tracts and abscesses); it typically starts after puberty.  This disease is due in part to aberrant healing processes and impaired mechanical integrity. Investigations have shown that tumor necrosis factor α is involved in the pathogenesis of hidradenitis suppurativa.  There are a lot of similarities between hidradenitis suppurativa and Crohn’s disease as well as some overlap as up to 17% of individuals with Crohn’s disease have hidradenitis suppurativa.  In addition, hidradenitis suppurativa can be confused with Crohn’s disease especially when buttocks/perianal lesions are present.

Key clinical points with this disease:

  • Affects skin with apocrine glands
  • Long delay in diagnosis is common though disorder may affect 1% of population
  • Incision and drainage is not effective treatment –lesions recur
  • Few randomized studies –most often treated with combination of antibiotics (eg. clindamycin & rifampin)
  • More severe disease may benefit from TNF inhibitors or possibly complete surgical excision
For pediatric gastroenterologists, hidradenitis suppurative is another to add to the Crohn’s differential diagnosis list:
 

Infectious etiologies: 

Histoplasma , Amebiasis, CMV, C. diff, Klebsiella oxytoca, Actinomycosis, HIV

Noninfectious etiologies:

Sarcoidosis, Vasculitis (HSP,dermatomyositis, Wegener’s, SLE), FMF, allergic colitis, Hirschsprung’s, autoimmune enteropathy, Chronic granulomatous disease, glycogen storage dz, 1B, Hermansky-Pudlak syndrome, Wiskott Aldrich syndrome, NEMO (NF-kB essential modifier) deficiency, Leukocyte adhesion deficiency, SCID, Behcet’s, FELS/hemophagocytic lymphohistiocytosis, Typhlitis

Additional reference for hidradenitis suppurativa:

  • -Br J Dermatol 2010; 162: 195-7.

Crohn’s Disease and differential diagnosis -references:

  • -JPGN 2010; 51: 690. Discusses sarcoid (check angiotensin converting enzyme), CGD, Hermansky Pudlak
  • -JPGN 2010; 50: 99. Perianal dz in young children may be due to autoimmune neutropenia.
  • -IBD 2008; 14: 1443. Phagocyte dysfunction. Also, discusses Hermansky-Pudlak, GSD 1B, chronic granulomatous disease, Chediak-Higashi, leukocyte adhesion deficiency, cylic neutropenia, congenital neutropenia
  • -JPGN 2006; 42: 405. Vasculitis mimicking IBD.
  • -NEJM 2005; 352: 489-94.
  • -J Clin Gastroenterol 1992; 15: 17-23.
  • -NEJM 2003; 349 (26): 2541-49.  Table 2. (Gold et al.)

Hepatic ciliopathies

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As our understanding of pathophysiology improves, frequently this results in reclassification of diseases.  Perhaps the best example in pediatric hepatology is gestational alloimune liver disease/congenital alloimmune hepatitis, formerly called neonatal hemochromatosis  (see previous post).  Hepatic ciliopathies are less commonly discussed and thus far have not resulted in abandoning previous nomenclature. These hepatic ciliopathies are related to fibrocystic disease proteins which localize to the primary cilia.  Ductal plate malformation is the main pathology that underlies the liver disease in ciliopathies.  The characteristics of one of these disorders, congenital hepatic fibrosis (CHF) in autosomal dominant polycystic kidney diseae (PKD) involving 19 patients is described in this month’s JPGN (JPGN 2012: 54: 83-89).  Portal hypertension was the main manifestation.  “Hepatocellular function was preserved and liver enzymes were largely normal.”  In patients with AD-PKD-CHF, this was  due to PKD1 mutations with probable contributions from modifier genes.  One interesting finding was that in the identified families, the parents who were affected by polycystic kidney disease did not have CHF.

Although this study demonstrates that CHF and portal hypertension can occur with AD-PKD, CHF and portal hypertension are a characteristic finding with AR-PKD.  With AD-PKD, the liver cysts originate from biliary microhamartomas (von Meyenburg complexes) and are not in continuity with the biliary tree.  In contrast, patients with AR-PKD have cystic dilatations of the biliary system; this combination is called Caroli syndrome.  Due to these differences, unlike AR-PKD, AD-PKD does not typically result in portal hypertension.

Additional references on congenital hepatic fibrosis:

  • -Hepatology 2010; 52: 2223. Review. Medical/Surgical & Tx options.
  • -Am J Med Genet C Semin Med Genet 2009; 151C: 296-406.  Liver disease and kidney disease in ciliopathies.
  • -NEJM 2008; 359: 1477.  Review of autosomal dominant polycystic kidney disease.  ~80% develop liver cysts.
  • -NEJM 2007; 356: 1560. Nice pic of resected liver with polycystic liver disease in 51 year old.
  • -J Pediatr 2006; 149: 159. Review and NIH protocol for enrolling patients. Clinical GI issues: recurrent cholangitis, portal htn, cholelithiasis, and cholangiocarcinoma.
  • -Pediatr Transplantation 2005; 9: 634-9.
  • -Hepatology 2004; 40: 774-82.
  • -Surg Endosc 2005; 19: 130-32.
  • -Gastorenterol Clin N Am; 2003; 32: 857-75. “Heritable disorders of the bile ducts”


The more you know the more you see

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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

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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

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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

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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

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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

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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.