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Commentary From the Section on Gastroenterology, Hepatology, and Nutrition

October 19, 2023

Commentary From the Section on Gastroenterology, Hepatology, and Nutrition

The Section on Gastroenterology, Hepatology, and Nutrition (SOGHN) is dedicated to improving the care of infants, children, and adolescents with gastrointestinal and nutritional disorders by providing an educational forum for the discussion of problems and treatments relating to gastroenterology, hepatology, and nutrition. The section links pediatric gastroenterologists with primary care pediatricians and other subspecialists in its educational endeavors. A chapter speaker’s bureau has provided updates on common gastrointestinal problems as well as new treatments for hepatitis C. SOGHN has also undertaken more recent roles in policy by authoring clinical reports, including upcoming reports on neonatal cholestasis, fecal microbial transplantation, and constipation. The SOGHN remains committed to the principles of diversity, equity, and inclusion. We are happy to provide these contributions of reflections on important articles published in Pediatrics over 3 quarter centuries to celebrate the 75th anniversary of the journal. All articles were chosen by the authors.

First Quarter Century (1948 - 1973)

The Biochemical Narthex*

*An entrance hall leading to the central chamber (nave) of a church

Susan S. Baker, MD, PhD, FAAP1, Robert D. Baker, MD, PhD, FAAP2, Buford L. Nichols, MD, FAAP3

Affiliations: 1Professor of Pediatrics, University at Buffalo; 2Professor of Pediatrics, University at Buffalo; 3Professor of Pediatrics, Children’s Nutrition Research Center, Texas Children’s Hospital, Baylor College of Medicine

Highlighted Article From Pediatrics

Harry Shwachman opened the portal for pediatric gastroenterology in the Western Hemisphere. He returned to Harvard Medical School after serving in the military in 1945 and was assigned by Dr. Sidney Farber as clinical lab director and chief of the nutrition clinic at Boston Children’s Hospital. The focus of the clinic was on celiac and cystic fibrosis patients. The diagnosis of both required duodenal intubation for biopsy histology or enzyme assays.1 Pediatric clinics in Europe reported syndromes of carbohydrate intolerance in the early 1960s by measuring mucosal enzymes.2 These studies were confirmed by Dahlqvist.3 Shwachman recognized the clinical value of quantitative disaccharidase assays and was the first North American to publish a clinical/ biochemical paper. This enabled American Pediatric Gastroenterologists to recognize and treat lactase and sucrase deficiencies.

In 1965, Townley and Shwachman2 reported disaccharidase activities of the small bowel in children. Prior to this work an assessment of disaccharidase activity was indirect; the disaccharide was given orally, and hydrolysis products were identified in the blood glucose response. This in vivo method could not quantify disaccharidase deficiency but could identify clinical responses. Townley and Shwachman obtained small bowel samples via a capsule (Rubin or Crosby) using fluoroscopy for duodenal placement. Histology of the biopsy was assessed before performing an in vitro analysis of the glucose production by the homogenate specific substrate.3,4 They were able to associate secondary low disaccharidase levels with celiac disease. They presented data on a patient with primary congenital sucrase deficiency. This manuscript provided the basic work on which was built an understanding of the activity of disaccharidases, symptoms of disaccharidase deficiency, and congenital deficiencies. The report supported acquiring small bowel biopsies, demonstrating that obtaining clinical biopsies for in vitro analysis was feasible and could provide important clinical information even in neonates.

By 1965, breath testing became a readily accessible in vivo window to diagnose malabsorption of carbohydrates. The hydrogen breath test (BT) is the product of carbohydrate fermentation of the undigested carbohydrate by colonic bacteria. If lactase is lacking, the unhydrolyzed disaccharide is malabsorbed and microbes in the colon use it for metabolic functions producing H2 gas, which is exhaled in the breath. Similarly, unhydrolyzed sucrose is fermented by colonic bacteria to produce H2 gas. A positive test is characterized by a rise of more than 20 ppm of H2 over the baseline. Stable isotopes are identified by the variants in mass, which can be measured by mass spectrometers. Spectrometers can test the ratio of 13C to 12C masses in fed substrates oxidized by mitochondria and excreted in breath CO2. In the clinical BT the 13CO2 to 12CO2 ratio in breath is measured as a product of biological processing and oxidation to 13CO enriched breath over time.5

Since publication of this manuscript, access to gastrointestinal mucosal tissue improved with the introduction of flexible fiber optic endoscopes in the 1970s and the subsequent development of video processing.6 These allow targeted biopsies of visualized mucosa with a very low rate of adverse events.

The DNA sequences of lactase and sucrase genes were reported in 1988.7,8 These sequences opened new understandings of Dahlqvist assays. Lactase deficiency is clearly different between congenital and acquired forms. The down regulation of lactase expression appears to be a historical adaptation to weaning that was not preserved in cultures where dairy is an important food.9

Starch digestion in adults requires 3 genes: pancreatic and salivary α- amylase, which solubilizes starch to dextrin, and 2 mucosal maltase genes expressing 4 activities with different dextrin specificities. α- amylase is deficient in the infant and the activity of mucosal maltase-glucoamylase (MGAM) provides α-glucogenesis in the infant but becomes suppressed by amylase products at weaning. The human mucosal maltases and lactase are fully developed at birth. In early infancy, starch is digested by highly active mucosal MGAM, but with amylase maturity, it shifts to less active mucosal maltase (SIM).10 Many coding mutations in the SIM gene have been reported in patients with low biopsy sucrase enzyme activities. These account for about a third of the reported biopsy sucrase deficiencies.11 Based on reported gene variants, the estimated prevalence of congenital lactase deficiency is 1.3 and for congenital sucrase-isomaltase deficiency 31.4 per 100,000 births.12 Based on clinically indicated biopsies, lactase deficiency was found in 32% and sucrase deficiency in 9%.13

Diagnosis and treatment for disaccharidase deficiencies has advanced since 1965. In addition to strict dietary disaccharide elimination, active yeast supplements are available for clinical management of lactase14 and sucrase deficiency.15 The Townley and Shwachman manuscript opened the door for these advancements.


  1. Fanos JH. “We kept our promises”: an oral history of Harry Shwachman, MD. Am J Med Genet A. 2008;146A(3):284-293
  2. Townley RR, Khaw KT, Shwachman H. Quantitative assay of disaccharidase activities of small intestinal mucosal biopsy specimens in infancy and childhood. Pediatrics. 1965;36(6):911-921
  3. Dahlqvist A. Method for assay of intestinal disaccharidases. Anal Biochem. 1964;7:18-25
  4. Dahlquist A, Semenza G. Disaccharidases of small-intestinal mucosa. J Pediatr Gastroenterol Nutr. 1985;4(6):857-865
  5. Nichols B, Baker RD, Baker SS. Overview of breath testing in clinical practice in North America. JPGN Reports. 2021;2(1):e027
  6. Lightdale JR, Liu QY, Sahn B, et al. Pediatric endoscopy and high-risk patients: a clinical report from the NASPGHAN endoscopy committee. J Pediatr Gastroenterol Nutr. 2019;68(4):595-606
  7. Hunziker W, Spiess M, Semenza G, Lodish HF. The sucrase-isomaltase complex: primary structure, membrane-orientation, and evolution of a stalked, intrinsic brush border protein. Cell. 1986;46(2):227-234
  8. Mantei N, Villa M, Enzler T, et al. Complete primary structure of human and rabbit lactase-phlorizin hydrolase: implications for biosynthesis, membrane anchoring and evolution of the enzyme. EMBO J. 1988;7(9):2705-2713
  9. Robayo-Torres CC, Nichols BL. Molecular differentiation of congenital lactase deficiency from adult-type hypolactasia. Nutr Rev. 2007;65(2):95-98
  10. Nichols BL, Baker SS, Quezada-Calvillo R. Metabolic impacts of maltase deficiencies. J Pediatr Gastroenterol Nutr. 2018;66(suppl 3):S24-S29
  11. Deb C, Campion S, Derrick V, et al. Sucrase-isomaltase gene variants in patients with abnormal sucrase activity and functional gastrointestinal disorders. J Pediatr Gastroenterol Nutr. 2021;72(1):29-35
  12. de Leusse C, Roman C, Roquelaure B, Fabre A. Estimating the prevalence of congenital disaccharidase deficiencies using allele frequencies from gnomAD. Arch Pediatr. 2022;29(8):599-603
  13. Nichols BL Jr, Adams B, Roach CM, Ma CX, Baker SS. Frequency of sucrase deficiency in mucosal biopsies. J Pediatr Gastroenterol Nutr. 2012;55(suppl 2):S28-30
  14. Baijal R, Tandon RK. Effect of lactase on symptoms and hydrogen breath levels in lactose intolerance: a crossover placebo-controlled study. JGH Open. 2021;5(1):143-148
  15. Robayo-Torres CC, Diaz-Sotomayor M, Hamaker BR, et al. 13C-labeled-starch breath test in congenital sucrase-isomaltase deficiency. J Pediatr Gastroenterol Nutr. 2018;66 Suppl 3(suppl 3):S61-S64

Percutaneous Liver Biopsy Is Still an Indispensable Diagnostic Aid

Estella M. Alonso, MD

Affiliation: Lurie Children’s Hospital

Highlighted Article From Pediatrics

During the first week of my pediatric GI fellowship in July 1988, I was tasked with obtaining a percutaneous liver biopsy on a small infant who had recently received a reduced size liver transplant graft. I observed 2 similar procedures earlier that morning and then was carefully guided through the steps to obtain liver tissue with a Jamshidi needle through an anterior approach. The patient was sedated at the bedside and the site was determined by physical examination. The tissue was processed the same day and revealed that the patient had acute cellular rejection. It was an indelible moment in my fellowship. Training at one of the largest pediatric liver transplant programs of that era, there were many mornings that we performed 3-4 liver biopsies in the early hours before ward rounds. Reflecting on the manuscript by Walker et al describing the first large-scale experience with pediatric needle liver biopsy, I believe that their account of a safe method to obtain liver tissue, even in the smallest of children, launched the nascent field of pediatric hepatology. In a time when the pathophysiology of the majority of chronic pediatric liver diseases was unknown, liver histology was a fundamental tool that helped us connect the dots. We discovered that children suffered from many of the same diseases as adults; autoimmune hepatitis, primary sclerosing cholangitis, Wilson’s disease, and drug-induced liver injury. Liver histology identified mitochondrial injury as an important feature of Reye syndrome. Liver biopsy was the most efficient way to diagnose many storage diseases, and small pieces of liver tissue could be used to identify specific metabolic defects. And of course, the ability to perform multiple biopsies with rapid processing has always been a cornerstone of post-transplant care for children receiving liver grafts.

One of the fundamental principles that enabled acceptance of the procedure was that it could be performed safely, and safety has been a persistent concern addressed in the literature over the past 50 years. In the 1980s, the discussion focused on whether the procedure was safe for children with coagulopathy and thrombocytopenia. Indeed, these patients did have a higher rate of bleeding complications, but in most cases, the diagnostic benefit in acutely ill patients clearly outweighed that risk. Progress in the availability of transjugular biopsy for children has dampened this concern. In the 1990s, we demonstrated that the procedure could be safely performed in an ambulatory setting. The new millennium heralded the debate of whether ultrasound guidance provided a significant safety advantage. Now many percutaneous biopsies at our largest centers are performed in interventional radiology, and even if this practice is not safer, it is likely more efficient. Rarely does safety register as a significant concern when considering a liver biopsy in the current environment.

So that leaves us with a final consideration. In a world of rapid genetic sequencing, sensitive imaging modalities, and non-invasive tests of fibrosis, what role does needle liver biopsy play in diagnosis and management of pediatric liver disease? There is no question that it is still essential for the management of immunosuppression in both the transplant recipient and the patient with autoimmune liver disease. Staining for specific immune markers has proven to be a reliable method to identify liver injury secondary to immune dysregulation. Biopsy provides valuable diagnostic information in patients with atypical presentations of common disorders. Perhaps equally as important, it provides the experienced clinician a window to the hepatocyte and all of its supporting cast. It allows one to actually see the disease and, in that, appreciate the intensity and focus of the injury. As I reflect back on a 30-year career, some of my best memories are of sitting around a multi-head microscope viewing biopsies with the team, pointing out nuances, and developing treatment plans guided by pathology. Thank you to that team at the University of Minnesota who pioneered this procedure in children. It did stand the test of time as “a safe diagnostic aid in liver disease.”

Lessons Learned Despite an Enigmatic Disorder

Samuel A. Kocoshis, MD, FAAP

Affiliation: Professor of Pediatrics, University of Cincinnati College of Medicine, Medical Director, Intestinal Transplantation, Cincinnati Children's Hospital Medical Center

Highlighted Article From Pediatrics

In 1968, the understanding of non-infectious chronic infantile diarrhea was primitive at best. Its management was feckless and frequently ineffective. Diagnostic algorithms had not been developed, and the impulse of clinicians was to “rest the bowel” by minimizing oral intake. The nutritional value of transition feedings (eg, Coca Cola syrup, bananas, apple sauce, and toast) was woefully inadequate. Little was known of the pathophysiology or intestinal histology of non-infectious diarrhea. With the 20/20 vision of hindsight, we now know that some episodes thought 60 years ago to be non-infectious were due to pathogens that had not been recognized during that era. Furthermore, the genetic mutations resulting in congenital enteropathies were largely unknown.

Despite the above obstacles, Avery and colleagues embarked on an admirable effort to classify the serious diarrheal illnesses that they observed among young infants that often resulted in irreversible enterocolitis.

The authors of this paper defined intractable diarrhea of infancy as diarrhea that persisted for greater than 2 weeks in infants less than 3 months of age who had 3 or more stool cultures that were negative for known pathogens. These authors identified 20 patients who had received care for their intractable diarrhea at the District of Columbia Children’s Hospital between September 1963 and April 1967. Unfortunately, they included in this series 12 patients whose underlying causes of diarrhea were well established and whose prognosis was better than that of the patients with “idiopathic” enterocolitis. These 12 patients had cystic fibrosis (2 patients), disaccharidase deficiency (3 patients), Salmonella enteritis (1 patient), ulcerative colitis (1 patient), perinephric abscess (1 patient), urinary tract infection (1 patient), adrenal insufficiency (1 patient), ileal stenosis (1 patient), and Hirschsprung’s disease (1 patient). Nine of those 12 survived, but it is unclear how many of those disorders might have been secondary to the diarrhea or unrelated to the diarrhea. It is also unclear whether the patient purported to have ulcerative colitis might have had the same disorder as the 8 with “nonspecific enterocolitis.” Had the authors confined this case series to those infants suffering from “nonspecific enterocolitis,” they would have had a smaller more homogeneous series of 8 patients plus the 1 purported to have ulcerative colitis.

It is curious that the authors advocated for creation of a colostomy insofar as 3 of the 5 patients who underwent a colostomy died. Furthermore, only 1 of the 3 patients who failed to receive corticosteroids survived following a colostomy.

Several potential entities well recognized today could have accounted for the nonspecific enterocolitis experienced by the cohort without a recognized underlying etiology for their enteropathy. First, their clinical condition is very reminiscent of food protein-induced enterocolitis.1 Additionally, based on our current knowledge of the genetics of very early onset IBD and autoimmune enteritis, it is very possible that some of these infants suffered from regulatory T cell dysfunction as seen in X-linked immunodeficiency and poly endocrinopathy (IPEX) or an IPEX-like disorder.2 The pharmacological treatment of autoimmune enteropathy today, in addition to the use of corticosteroids, customarily includes sirolimus when IPEX is due to a forkhead box P3 mutation and abatacept when it is due to lipopolysaccharide-responsive beige-like anchor deficiency.3,4

The authors’ recommendations to use corticosteroids for the cohort with nonspecific enterocolitis would certainly be heeded today, but it is doubtful that any gastroenterologist or surgeon would heed the recommendation to perform a colostomy.

It is notable that parenteral nutrition, in its nascent phase in 1968, was offered to only 2 patients in this series. The authors prescribed no parenteral lipid due to their inexperience with this mode of alimentation. Furthermore, the amino acid solution provided was composed of hydrolyzed casein, a constituent of parenteral nutrition that was soon abandoned because of the poor bioavailability of its amino acids and its unacceptably high complication rate, which often provoked systemic hypersensitivity reactions.5,6

Regardless of the failure of corticosteroids or colostomy to save most of those patients with nonspecific enterocolitis, 2 observations were most important and have withstood the test of time. First, a systematic diagnostic approach is necessary when confronted by an infant with diarrhea and wasting. Second, permitting the infant with diarrhea to starve by withholding enteral nutrition can result in a condition of “irreversible tissue wasting” that can only be reversed by an aggressive regimen of parenteral and enteral nutrition. We see very few patients today similar to those described by Avery and colleagues. Possibly the tendency to “feed through” acute enteritis has contributed to improved outcomes. Supporting the concept of “feeding through” infantile diarrhea is a randomized trial published by Orenstein that showed that intractable diarrhea managed by enteral nutrition and fluid replacement was more likely to resolve than enteritis managed by stopping enteral feedings in favor of providing exclusive parenteral nutrition during recovery.7

In summary, the article by Avery and colleagues can be faulted for its inclusion of several diverse cohorts of patients and for its recommendation to perform colostomy on infants with enterocolitis, but it did heighten awareness of the importance of providing nutrition to infants with diarrhea. The paradigm shift in nutritional management of these infants stimulated by this paper by Avery and colleagues undoubtedly played a major role in saving millions of infants with early-onset diarrhea throughout the world.


  1. Nowak-Wegrzyn A, Warren CM, Brown-Whitehorn T, et al. Food protein-induced enterocolitis in the United States population. J Allergy Clin Immunol. 2019;144:1128-1130
  2. Baxter SK, Walsh T, Casadei S, et al. Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy and implications for clinical management. J Allergy Clin Immunol. 2022;149:327-339
  3. Yong PL, Russo P, Sullivan KE. Use of sirolimus in IPEX and IPEX-like children. J Clin Immunol. 2008;28:581-587
  4. Kiykim K, Ogulur I, Dursun E, et al. Abatacept as a long-term targeted therapy for LRBA deficiency. J Allergy Clin Immunol Pract. 2019;7:2790-2800
  5. Patel D, Anderson GH, Jeejeebhoy KN. Amino acid adequacy of parenteral casein hydrolysate and oral cottage cheese in patients with gastrointestinal disease as measured by nitrogen balance and blood aminogram. 1973;65:427-437
  6. Grimble GK, Silk DB. Peptides in human nutrition. Nutr Res Rev. 1989;2:87-108
  7. Orenstein SR. Enteric versus parenteral therapy for intractable diarrhea of infancy: a prospective, randomized trial. J Pediatr. 1986;109:277–286


The Journey to Provision of Total Parenteral Nutrition

Rachel Kassel, MD, PhD, FAAP

Affiliation: University of Alabama Birmingham

Highlighted Article From Pediatrics

Total parenteral nutrition (TPN) offers a means to nourish children born with congenital atresias and other structural gastrointestinal malformations, as well those with intestinal failure from a variety of etiologies. The elucidation of the circulatory system in the 17th century initiated a cascade of discoveries that led to the development of modern TPN.1,2 Venous infusions of glucose, plasma, and emulsified fat existed by 1910. In the 1930s-1940s, Robert Elman showed that protein hydrolysates could be safely infused intravenously. Subsequently, research aimed to identify the full gamut of nutritional components needed to make TPN, the quantities of ingredients needed, and safe methods to deliver these solutions. Stanley Dudrick and Douglas Wilmore conducted much of this research at Children’s Hospital of Philadelphia in the 1960s in beagle puppies.2,3 They then applied the work to infants with intestinal failure due to congenital conditions.3 In the puppies and human infants, they showed that TPN could be given for months and result in weight gain. However, TPN also often resulted in osmotic diuresis, fevers, superficial vessel phlebitis, hemolytic anemia, thrombocytopenia, and other complications.1,2,4 This led to trial of alternative concentrations, lipid emulsions, and intravenous catheters as well as to improvements in sterile technique. Fox and Krasna’s case series published in Pediatrics in 1973 includes infants with congenital atresias and necrotizing enterocolitis who received large-volume, lower osmolality peripheral parenteral nutrition, which did not produce the sclerosis seen with extravasation of more concentrated parenteral formulations.5 These infants needed parenteral nutrition for relatively short durations prior to returning to enteral feeding. The peripheral intravenous nutrition, which these infants needed for relatively short periods of time, resulted in the infants gaining weight. They successfully transitioned to enteral nutrition later in the course. The publication by Fox and Krasna remains one of few articles published in Pediatrics dedicated to parenteral nutrition used to prepare infants for later surgical interventions.

More concentrated solutions of parenteral nutrition using central lines eventually usurped use of dilute fluids peripherally to provide total parenteral nutrition, but the short-term use of peripheral parenteral nutrition persisted.2 Dilute formulas could not deliver the calories that especially adults needed and that led to edema in some patients. Central lines enabled delivery of hypertonic solutions within large vessels where dilution could quickly occur. Modern TPN consists of hypertonic solutions of nutrients whose constituents and relative proportions still remain to be optimized.


  1. Nakayama DK. The development of total parenteral nutrition. Am Surg. 2017;83(1):36-38
  2. Dudrick SJ, Palesty JA. Historical highlights of the development of total parenteral nutrition. Surg Clin North Am. 2011;91(3):693-717
  3. Wilmore DW, Groff DB, Bishop HC, Dudrick SJ. Total parenteral nutrition in infants with catastrophic gastrointestinal anomalies. J Pediatr Surg. 1969;4(2):181-189
  4. Vinnars E, Wilmore D. Jonathan Roads Symposium Papers. History of parenteral nutrition. JPEN J Parenter Enteral Nutr. 2003;27(3):225-231
  5. Fox HA, Krasna IH. Total intravenous nutrition by peripheral vein in neonatal surgical patients. Pediatrics. 1973;52(1):14-20

Second Quarter Century (1973-1998)

Paradigm Shift: Pancreatitis in Cystic Fibrosis – 50 Years Later

Adam Cohen, MD, FAAP

Affiliation: University of Alabama at Birmingham

Highlighted Article From Pediatrics

In 1975, Shwachman et al in a study entitled, “Recurrent Acute Pancreatitis in Patients With Cystic Fibrosis With Normal Pancreatic Enzymes,” described 10 patients with cystic fibrosis (CF) and pancreatic sufficiency who presented with acute recurrent pancreatitis. At the time of publication, our knowledge of CF was based on clinical findings with no clear understanding of the underlying defect. This was the first case series to describe this association. At the time of this article, sweat chloride testing in patients who met clinical criteria served as the primary method of diagnosis. As was described in this study, diagnosis of CF had been delayed in patients without pancreatic insufficiency. This description preceded the discovery of defective epithelial chloride transport secondary to abnormalities in the CF transmembrane conductance regulator (CFTR) gene. With implementation of genetic-based newborn screening for CF, CF can be diagnosed in the neonatal period irrespective of pancreatic function. Even as we have compiled more complete information that links phenotypic variation to individual patient genotypes, the correlation between pancreatic sufficient CF and acute pancreatitis persists. Interestingly, as the etiologies of pediatric acute and acute recurrent pancreatitis have been further investigated, abnormalities in the CFTR gene that do not produce the clinical findings of CF have been implicated in increasing risk for pancreatitis.

In patients with CF, pancreatitis was thought to occur mainly among pancreatic sufficient patients, as was described by Shwachman et al, and pancreatic insufficiency was thought to be irreversible. A proportion of patients with CF and pancreatic sufficiency could be expected to develop exocrine pancreatic insufficiency in the future. Some patients with CF, even those with a history of acute pancreatitis, have experienced partial recovery of pancreatic function on CFTR modulator therapy. As described by Shwachman et al, several patients with CF underwent transduodenal pancreatogram, of which half were found to have an abnormal pancreas and ductal abnormalities even in the setting of clinical pancreatic sufficiency. Acute and acute recurrent pancreatitis will continue to complicate the medical course of patients with CF even in the era of CFTR modulator therapy. As highly effective modulator therapies become more available in younger subsets of the population, this may change the age of presentation of pancreatitis as well as the age of onset and rate of pancreatic insufficiency in patients with typically severe phenotypes.

Of the 10 patients described in the Shwachman series, alcohol was felt to be a precipitating factor in several, and 1 patient had biliary disease. Alcohol ingestion is a modifiable risk factor for pancreatitis in the non-CF population. It will become increasingly important to educate patients with CF about the linkage between alcohol ingestion and pancreatic disease. As lifespan increases in patients with CF, providers will also need to monitor patients with CF for chronic and acute recurrent pancreatitis and be mindful that these conditions increase the risk for pancreatic cancer.

Shwachman et al described in depth the characteristics of these 10 patients, which showed the phenotypic variability in patients presenting with similar complaints. The knowledge and understanding that have been acquired in the last 40 years in the diagnosis and care of patients with CF has revolutionized our clinical approach and led to new highly effective therapies as well as ongoing research for more targeted therapies. The incidence of pancreatitis in this population is higher than that in the general population, and as more patients with CF and pancreatic sufficiency become at risk for pancreatitis, physicians will need to expand their understanding of the new long-term medical course of CF.


Infant Reflux: A Problem That Keeps Coming Up

Michael K. Farrell, MD, FAAP

Affiliation: University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center

Highlighted Article From Pediatrics

Infantile gastroesophageal reflux has plagued infants, parents, and physicians for centuries. In the 19th century, Dr. Eli Ives of Yale University wrote, “After nursing, the milk sometimes seems to regurgitate without the least effort. No serious evil will arise unless young, anxious mothers should give medicine and thus make the child sick.”1 Much has changed since then, but concerns and misunderstandings about infantile reflux persist.

What signs and symptoms should be attributed to reflux? Should acid suppression and/or formula changes be recommended? What is the role of allergy? The North American and European Societies of Gastroenterology, Hepatology and Nutrition published a guideline in 2018 that many practitioners now follow.2 However, the road to what consensus we have has not been smooth!

In this sentinel paper, Euler and Ament described the results of manometry performed in 15 children with reflux who ranged in age from 7 days to 2 years. They used a continuously perfused water catheter technique and measured lower esophageal sphincter (LES) pressure. Of 14 infants who had undergone an upper GI series, 4 showed reflux, 2 had a hiatal hernia, and 1 had a stricture. Eight underwent endoscopy, and 3 had evidence of esophagitis. The authors prescribed thickened feedings and upright positioning 24 hours a day for 3 weeks. If signs did not improve, the child underwent fundoplication. Children who did not improve had lower mean LES pressures (12.7 mm Hg) than those who responded to medical therapy (19.6 mm Hg).

This report has several deficiencies, including the wide range in age, the overlap in LES pressure in the 2 groups, and the relatively brief duration of medical therapy. No one today would prescribe 24-hour upright positioning, but these were among the first efforts to study and define the physiologic and pathologic underpinnings of infantile reflux. Sadly, in retrospect it is clear that this paper led to many unnecessary fundoplications.

Since the publication of this paper, we have made significant advances in understanding infantile reflux, but controversies persist. We understand infantile reflux as a maturational process. The major etiologic factor is transient inappropriate relaxation of the LES that improves with age. Most infants with reflux do not have esophagitis, yet clinicians often prescribe acid suppression medications. The role of allergies remains controversial.

We should continue to build on our predecessors’ efforts to understand infantile reflux. We must always acknowledge the anxiety and frustration this causes families but also remember to do no harm.


  1. Person HA. Lectures on the diseases of children by Eli Ives, MD, of Yale and New Haven: America’s first academic pediatrician. Pediatrics. 1986;77(5):680-686
  2. Rosen R, Vandenplas Y, Singendonk M, et al. Pediatric gastroesophageal reflux: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018;66(3):516-554


Third Quarter Century (1998-2023)

Apnea and Reflux: True, True, and Unrelated

Sudarshan R. Jadcherla, MD, FRCP (Irel), DCH, AGAF, FAAP

Affiliation: Professor of Pediatrics & Associate Division Chief of Neonatology, The Research Institute at Nationwide Children’s Hospital

Highlighted Article From Pediatrics

Assumptions of the causal associations between gastroesophageal reflux and apnea of prematurity have resulted in unnecessary pharmacological therapies, dietary modifications, use of breast milk substitutes, modifications of feeding methods, and prescriptions for postural change that have resulted in clinical consequences and increased parental anxiety and socio-economic burden. The 2002 sentinel study by Peter et al entitled “Gastroesophageal Reflux and Apnea of Prematurity: No Temporal Relationship” has debunked these mythic therapies and changed the field through the demonstration of the lack of temporal correlation between episodes of apnea, bradycardia, and/or desaturation and physiologic evidence of gastroesophageal reflux in premature infants.1 Subsequently, we have witnessed the development of precision diagnostics using pH-impedance technology. The application of these methods have further advanced our understanding of aerodigestive pathologies in high-risk infants.

Apnea of prematurity, sucking-swallowing-breathing-feeding difficulties, life-threatening events, gastroesophageal reflux disease, and aspiration syndromes constitute a spectrum of infantile aerodigestive disorders whose causal, ameliorating, developmental, and adaptational mechanisms involve multifactorial stimuli and multisystemic responses.2 Although gastroesophageal reflux is common in infants, its lack of association with one of these aerodigestive pathologies (ie, apnea of prematurity) was clarified in the paper by Peter et al.1 We have further advanced the scientific understanding that pharyngeal or esophageal stimulation can activate vago-vagal and vago-glossopharyngeal reflexes and, therefore, cross-systems (foregut-airway) interactions modulated by the vagus nerve via the nucleus tractus solitarius in the brain stem.3,4 Although prematurity is associated with inadequate development and maturation of neurological-airway-digestive systems, newer research methods have unraveled the mechanisms to elucidate what causes the signs of gastroesophageal reflux or apnea of prematurity. Concurrent pH-impedance methods have improved the understanding of the effects of proximal spread of the refluxate. Reflux effects are related to the degree of acidity (acid or weakly acid or alkaline), the physical properties of the refluxate (liquid or gas or mixed), and the extent of proximal spread (into pharynx or esophageal column). Reflux events can activate the contiguous enteric neural circuitry and elicit protective clearance reflexes that prevent the refluxate from the vicinity of the airway or can activate other airway reflexes associated with swallowing (cough, deglutition apnea, arching).5

Furthermore, using simulation and provocative manometry methods, further neuro-aero-digestive interdependence has been unraveled across the spectrum of aerodigestive diseases in infants. Esophageal or pharyngeal stimulation causing mechano-distention or chemo-sensitive provocation activates local vagal stretch and chemosensitive receptors to evoke the motor response within the pharyngo-esophageal column or the adjacent airway-glottal regions. When the airway motor apparatus is activated either directly or indirectly, deglutition apnea (cessation of air flow during swallowing) or laryngeal chemoreflex (apnea with swallowing, bradycardia followed by tachycardia, with repetitive swallowing-arching) can result.6

Certainly, this article was instrumental in changing the understanding of gastroesophageal reflux and its management. The evidence has encouraged physicians to view most cases of gastroesophageal reflux to stem from a transient maturational delay in achieving normal LES tone and to restrict dietary, medical, or surgical therapies to children with more severe reflux associated with growth deficiency. The evidence also supports physicians in providing a rationale to the parents for patience and anticipatory guidance, while optimizing nutrition and the feeding process, assessing feeding milestones, and monitoring growth metrics.


  1. Peter CS, Sprodowski N, Bohnhorst B, Silny J, Poets CF. Gastroesophageal reflux and apnea of prematurity: no temporal relationship. Pediatrics. 2002;109(1):8-11
  2. Sultana Z, Hasenstab KA, Jadcherla SR. Pharyngoesophageal motility reflex mechanisms in the human neonate: importance of integrative cross-systems physiology. Am J Physiol Gastrointest Liver Physiol. 2021;321(2):G139-G148
  3. Jadcherla SR, Gupta A, Coley BD, Fernandez S, Shaker R. Esophago-glottal closure reflex in human infants: a novel reflex elicited with concurrent manometry and ultrasonography. Am J Gastroenterol. 2007;102(10):2286-2293
  4. Jadcherla SR, Gupta A, Wang M, Coley BD, Fernandez S, Shaker R. Definition and implications of novel pharyngo-glottal reflex in human infants using concurrent manometry ultrasonography. Am J Gastroenterol. 2009;104(10):2572-2582
  5. Jadcherla SR, Gupta A, Fernandez S, Nelin LD, Castile R, Gest AL, Welty S. Spatiotemporal characteristics of acid refluxate and relationship to symptoms in premature and term infants with chronic lung disease. Am J Gastroenterl. 2008;103(3):720-728
  6. Hasenstab KA, Nawaz S, Lang IM, Shaker R, Jadcherla SR. Pharyngoesophageal and cardiorespiratory interactions: potential implications for premature infants at risk of clinically significant cardiorespiratory events. Am J Physiol Gastrointest Liver Physiol. 2019;316(2):G304-G312


Perinatal Conjugated Hyperbilirubinemia and the Prenatal Origins of Biliary Atresia

Richard Kellermayer, MD, PhD, FAAP

Affiliation: Professor of Pediatrics, Section of Pediatric Gastroenterology, Baylor College of Medicine

Highlighted Article From Pediatrics

The most important pediatric gastroenterology publication of the last 25 years in the journal Pediatrics is arguably that from Sanjiv Harpavat et al entitled “Patients With Biliary Atresia Have Elevated Direct/Conjugated Bilirubin Levels Shortly After Birth.”1 It is the epitome of clinical discovery arising from physician-centered academic education. The discovery from a brilliant young physician was woven into an outstanding publication through the mentorship from great academic physicians, Milton J. Finegold and Saul J. Karpen. “With teaching you will learn, and with learning you will teach” as the Roman saying goes, made famous by Phil Collins.

The discovery that pediatric patients with biliary atresia (BA) have perinatal conjugated hyperbilirubinemia also brought the proverb from Albert Szent-Györgyi to life: “seeing what everybody has seen and thinking what nobody has thought.” Dr. Harpavat “simply” or “luckily” thought of retrospectively analyzing direct and conjugated bilirubin levels from routinely acquired total bilirubin testing shortly after birth in patients who were subsequently diagnosed with BA. These laboratory data, however, were there for anyone to extract and examine. Yet, “luck only favors the prepared mind” (Louis Pasteur). It was Dr. Harpavat’s talent and determination toward solving the mysteries of BA, through the nurturing education by Drs. Finegold and Karpen, which prepared him for this discovery. His publication inspired the development of a perinatal screening program for BA2 and the subsequent high-impact findings and publications in this field.

This landmark article in Pediatrics has fueled Dr. Harpavat’s inspired devotion toward finding a treatment for BA, which has since enriched the academic life of so many students and colleagues. It nicely complements different epidemiologic observations including (1) complete monozygotic twin discordance for BA,3 (2) that a plant toxin can cause BA in in utero developing ruminants,4 and (3) that prenatal environmental influences increase the risk of BA in humans.5 These findings clearly point to the prenatal origins of BA, where a rare (~1/10,000) environmentally modulated mosaic genetic or epigenetic6 change in biliary dedicated ductal plate stem cells is the most likely key to pathogenesis. This manuscript has been cited over 15 times annually since its publication, underscoring its high impact.

This publication should always remind us that attracting and keeping outstanding physician minds in academic research and education must be a central goal in biomedicine!


  1. Harpavat S, Finegold MJ, Karpen SJ. Patients with biliary atresia have elevated direct/conjugated bilirubin levels shortly after birth. Pediatrics. 2011;128(6):e1428-e1433
  2. Harpavat S, Garcia-Prats JA, Shneider BL. Newborn bilirubin screening for biliary atresia. N Engl J Med. 2016;375(6):605-606
  3. Xu X, Zhan J. Biliary atresia in twins: a systematic review and meta-analysis. Pediatr Surg Int. 2020;36(8):953-958
  4. Harper P, Plant JW, Unger DB. Congenital biliary atresia and jaundice in lambs and calves. Aust Vet J. 1990;67(1):18-22
  5. Cavallo L, Kovar EM, Aqul A, et al. The epidemiology of biliary atresia: exploring the role of developmental factors on birth prevalence. J Pediatr. 2022;246:89-94
  6. Kellermayer R, Nagy-Szakal D, Harris RA, et al. The developmental origins of biliary atresia. The 64th Annual Meeting of the American Association for the Study of Liver Diseases. Chicago, IL: Hepatology; 2013;S1(58):1216
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