Growth and Development of a New Subspecialty: Pediatric Hepatology · 2013. 7. 30. · Pediatric Hepatology William F. Balistreri Several major forces converged to catalyze the formal

MASTER’S PERSPECTIVE

Growth and Development of a New Subspecialty:Pediatric Hepatology

William F. Balistreri

Several major forces converged to catalyze the formal emergence of a body of knowledgeand an organized focus on disorders of the liver in early life. Attendant to the developmentof a focused clinical subspecialty the pace of patient- and laboratory-based research in thefield quickened in parallel to decipher the consequences of genetic or metabolic aberrationson immature liver structure and function. The key research observations that catalyzed theemergence and subsequent rapid growth of Pediatric Hepatology include: (1) an under-standing of the dynamic events occurring during hepatobiliary development and theimportance of these physiologic variables that occur during liver maturation; (2) the recog-nition of the unique nature of inherited and acquired liver diseases that affect infants andchildren—such as biliary atresia and Reye’s syndrome; and (3) redefinition of the onceobscure inherited intrahepatic cholestatic diseases of the liver, which, in turn, providedinsight into normal and abnormal hepatobiliary physiology. The clinical advances werehighlighted by the development of specific approaches to the diagnosis and managementof liver disease in infants and children, including both liver transplantation and nontrans-plant treatment options. These seminal events led to the expansion of the workforce, creat-ing a critical mass consisting of individuals with focused, specialized skills and techniques.In-depth expertise allowed more accurate diagnosis and highly effective treatment strategiesfor advanced hepatobiliary disease in children. The demand for pediatric clinicians withexperience in advanced hepatology allowed sub-sub-specialization to flourish. Continuedmaturation of the field led to definition of hepatology-focused curricular elements andeducational content for Pediatric Gastroenterology training programs, and subsequentlythe development of program requirements for those who wished to acquire additionaltraining in Pediatric Hepatology. A significant rite of passage was marked by the electionof pediatric hepatologists to leadership positions in the American Association for the Studyof Liver Diseases (AASLD). Further validation of the field occurred with approval of thepetition for establishing a Certificate of Added Qualification in Transplant Hepatology bythe American Board of Pediatrics. Here I relate my perspective on the history of the advan-ces in our field and the contributions of many of the clinicians and scientists whose effortsled to the development of focused clinical, research, and training programs that improvedthe care of children with diseases of the liver. (HEPATOLOGY 2013;58:458-476)

The Challenge

Since there was not a single linear pathway itappeared at first to be a daunting task to reconstructthe history and sequence of events leading to the emer-gence and maturation of a field of subspecialization.Therefore, it was a bit overwhelming to be asked by the

editors of HEPATOLOGY to “look back on my career”and not only “tell us about your life story” but also“illustrate specifically the development of Pediatric Hep-atology.” However, I was deeply honored by the invita-tion and took the occasion to attempt to write not onlya self-reflection but an impression of how careers in our

Abbreviations: CAH, congenital adrenal hyperplasia; GC, gas chromatography; PFIC, progressive familial intrahepatic cholestasis; TLC, thin layerchromatography.

From the Department of Pediatrics, University of Cincinnati College of Medicine, Pediatric Liver Care Center, Cincinnati Children’s Hospital Medical Center(CCHMC), Cincinnati, OH.

Received May 1, 2013; accepted May 30, 2013.

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specialty have evolved. Therefore, it is with great pleas-ure that I humbly represent my fellow “early adapters”of the subdiscipline of Pediatric Hepatology.

Trees seem to be random, their arrival in fields andthe top of hills unexplainable, their growthmysterious.… The growth of trees is not repetitivebut additive, each year recorded in their flesh.

—Dust to Dust, Benjamin Busch

There was no “Grand Plan” for the study of liverdisease in children to evolve as a focused clinical andresearch discipline. The tree analogy seems appropri-ate: the “arrival” of Pediatric Hepatology was addi-tive—elements of the field have always been there butunnoticed until individuals ventured deeper into theforest. De facto, this branch sprung from the trunk ofPediatric Gastroenterology.

Often the clearest vision is through the“retrospectoscope”—indeed, upon looking back thecritical elements that stimulated the growth of thisfield can be identified. With this sharper image inmind, I would like to offer my perspective on a seriesof fortunate events that allowed all of us interested inthe care of infants, children, and adolescents with liverdisease to have a “home” of our own and to find ourindividual and collective identity. Let me start by pro-viding, as the Editors requested, my “life story.”

Personal Growth and Development

The clearest indication of the absence of a grandplan for my personal career development is the factthat I entered college as a journalism major. I was bornand raised in Geneva, New York, and during highschool my prime preoccupation was participating ininterscholastic sports. I envisioned a career as a sportswriter and thus, proudly, became the first in my familyto attend college. After one exciting year of travelingwith our university’s athletic teams, documenting theirsuccesses and failures, I realized that my passion wasnot to passively observe others addressing challenges,but to be actively involved in solving problems (aplayer, not an observer). I transferred schools, to amore challenging academic environment and changedmy major to biology/biochemistry. This heavy science

background combined with a dramatic exposure to thefield of medicine led to the “rest of the story.” Duringmy junior undergraduate year I developed mononucle-osis and was confined to the university infirmary forwhat was, even then, an extreme period, almost 2months. I felt well—but every time I asked my health-care providers about their treatment strategy, my prog-nosis, or the rationale for my “continued observation,”my questions went largely unanswered. There was nosubterfuge—they truly did not have evidence on whichto base their decision. It is possible that their concernwas related to the possibility that, if discharged, I might“spread the disease” around campus—after all, monowas considered to be the “kissing disease”! My frustra-tion blended with extreme respect, fascination, andultimately enlightenment. During one of those longnights in the infirmary, I reflected on the encounters ofthe day, and the gaps in basic understanding of a seem-ingly common disease process and its treatment. Thus,after my release I met with my guidance counselor andexpressed my interest in applying to medical school. Iwas told, ironically, that it was unlikely that my appli-cation would be successful given the “set back” of theprolonged confinement! That “low chance of success”conversation has remained a clear stimulus to me overthe years!

Two important life-changing events occurred duringmedical school. Of greatest importance, I met a nurs-ing student, Becky McLeod, who became my wife andmy major influence and support (Fig. 1). She has cre-ated and maintained stability in my life—allowing meto focus on the work at hand reassured by the factthat Becky has everything else in our lives “under con-trol.” The second event was a summer spent workingin the Pediatric Unit at Roswell Park Cancer Institute.This, at times, trying experience left me with a strongimpression of the resiliency of a child in the presenceof a serious illness. To see a child grow and thrive aftersurviving a devastating illness led to my decision tobecome a pediatrician.

A Simple Decision Algorithm: “Do What IsBest for the Child”

While an intern at Cincinnati Children’s Hospital(CCHMC) I admitted a patient with a puzzling

Address reprint requests to: William F. Balistreri, M.D., 3333 Burnet Ave., MLC 2010, Cincinnati, OH, 45229. E-mail: [email protected] VC 2013 by the American Association for the Study of Liver Diseases.View this article online at wileyonlinelibrary.com.DOI 10.1002/hep.26580Potential conflict of interest: Nothing to report.

HEPATOLOGY, Vol. 58, No. 2, 2013 BALISTRERI 459

clinical picture of anicteric liver failure with hypoglyce-mia, suggesting underlying metabolic liver disease. Mygoal was to solve the problem. The attending, Dr.William K. Schubert (Fig. 2), Chief of Staff andDirector of the Clinical Research Center, gave me freerein. Each morning he would look over my shoulderat my notes as I bumbled through a textbook-drivenworkup and reward me with an affirmative pat on theback. This experience stimulated my interest in meta-bolic pathways in the liver and experiments of naturethat occur when pathways go awry. Therefore, at theend of my internship I conceived a career plan ofstudy to focus on metabolic liver disease. I approachedDr. Schubert and asked if I could do a fellowship inPediatric Gastroenterology. His response—“What’sthat?” Nevertheless, he fully supported the concept andtogether we were able to take advantage of uniqueclinical and research opportunities that we encounteredon this uncharted path (as detailed below). I relatethat story to emphasize that there was no establisheddiscipline of Pediatric Gastroenterology and noobvious pathway to a focus on liver disease. Thisdespite the fact that gastroenterology is arguably theoldest pediatric subspecialty. Historically, the tradi-tional foundations of pediatric care were “GI-focused”—to ensure childhood health—as manifest bywell-paced growth and adequate nutrition, and to pre-vent the major causes of infant mortality: infectiousdiarrhea and malnutrition.1 Pediatric Gastroenterology

began to be “formally” recognized as a discipline sepa-rate from adult gastroenterology in the 1960s, whenearly practitioners, having been trained in InternalMedicine divisions of gastroenterology, were able tosuccessfully adapt and extrapolate their skills, expertise,and techniques to the care of children with gastrointes-tinal (GI) diseases. In turn, internist gastroenterologistsrecognized the unique nature and complexity of condi-tions that specifically affected infants (“children arenot little adults”) and were willing to defer to theirpediatrician colleagues.

The Rise (and Fall) of Reye’s

During my “GI Fellowship” at CCHMC a majorfocus of our clinical attention was Reye’s syndrome—acute encephalopathy and fatty degeneration of the vis-cera.2-7 In the early 1970s there was a marked increasein the incidence of this enigmatic disease and the abil-ity to recognize all stages of the illness. The challengeswere enormous, since the disease represented an acute,and potentially devastating, interaction between theliver and the brain. The pathogenesis was poorlyunderstood; the clinical, histologic, and biochemicalpicture suggested a generalized loss of mitochondrialfunction caused by an endogenously produced sub-strate or by an exogenous agent.8,9 The urinary meta-bolic profile was indicative of a pronounced catabolicstate with excessive lipolysis, inefficient mitochondrial

Fig. 1. Rebecca Ann McLeod,student nurse who would soonbecome Mrs. “Becky” Balistreri, RN.

460 BALISTRERI HEPATOLOGY, August 2013

beta-oxidation of fatty acids, and increased excretionof carnitine. This resembled the biochemical pictureseen in patients with known defects in hepatic fatty acidoxidation, such as the acyl-CoA dehydrogenase deficien-cies.10 Studies done at CCHMC uncovered a linkbetween Reye’s syndrome and aspirin administration,resulting in significant media attention.11,12 This led towarning labels on aspirin preparations and a dramaticdecline in the incidence of Reye’s syndrome beginningin the late 1980s. Thus, a dramatic life-threatening dis-order was virtually eliminated. In addition, insight intogenetic defects in the synthesis of mitochondrial pro-teins and enzymes affecting multiple organ systems,including the brain and skeletal/cardiac muscle, hadbeen elucidated.7,9,13 Therefore, this disease served as amodel for mitochondrial disorders, as subsequently seenin fialuridine-induced mitochondrial inhibition.14 This“public health triumph,” likely the first major develop-ment in the field of Pediatric Hepatology, stimulated theunification of individuals interested in the care andinvestigation of children with liver diseases.

Why Bile Acids?

One of the early research challenges presented to meby Bill Schubert was to solve the problem of Don-ald—an infant with persistent, intractable diarrheabeginning on the second day of life, which caused fail-

ure to thrive. At 4 months of age he weighed 3.5 kg,well below his birth weight of 4.4 kg. Attempts atrefeeding with a variety of elemental diets resulted inwatery diarrhea, dehydration, acidosis, and shock;thus, he was total parenteral nutrition-dependent.Daily stool weight averaged >500 gm/day (normal<100) and fecal fat excretion was >50% of the dailyintake. His serum cholesterol concentration was mark-edly depressed (<70 mg/dL). After several months ofevaluation and fruitless investigations I came across anarticle by Alan Hofmann that described the clinicalconsequences of resection of the ileum, the main siteof bile acid reabsorption.15 Donald manifested someof these clinical features; thus, my na€ıve thought wasthat he may well be malabsorbing bile acids. Indeed, ashort-term trial of cholestyramine resulted in an initialimprovement of his diarrhea, followed by a gradualexacerbation of his steatorrhea. This biphasic responsesupported the hypothesis that bile acid malabsorptionmight well be the cause of his prolonged diarrhea. Wedesigned a study to prove that theory. Evaluation ofbile acid kinetics in this patient with severe refractorydiarrhea confirmed our hypothesis that bile acid trans-port in the terminal ileum was altered. Fecal excretionof labeled bile acid (I4C-24-cholic acid) was increased,with the ratio of excretion of bile acid comparable tothat of a nonabsorbable marker, consistent with pri-mary bile acid malabsorption.16 The magnitude of lossof cholic acid was similar to that observed in infantswho had undergone ileal resection. We found that themarked loss of bile acid in stool led to severelyreduced levels of bile acid in bile, with low intralumi-nal bile acid concentrations, as well as the presence ofa contracted bile acid pool size. We were able to spe-cifically confirm the defect in ileal bile acid transportin subsequent studies with Jim Heubi, John Partin,and Joe Fondacaro.17,18 The mechanism of Donald’sdiarrhea was thus explainable—bile acid malabsorp-tion, as seen following ileal resection, led to elevatedbile acid concentrations in the colonic lumen, inducingsecretion of sodium and water. The effect of cholestyr-amine was paradoxical—initially binding bile acid andpreventing diarrhea but ultimately severely depletingsmall intestinal intraluminal concentrations of micelle-forming bile acids causing fat maldigestion/malabsorp-tion. Congenital defects in ileal bile acid transport arenow a recognized cause of intractable diarrhea.

An Established Mentor

Throughout my investigation of Donald I had beenin telephone contact with Alan Hofmann (Fig. 3),

Fig. 2. Dr. William K. Schubert, Chief of Staff and Director of theClinical Research Center, Cincinnati Children’s Hospital.


who had developed a strong research program at theMayo Clinic in Rochester, Minnesota, which focusedon the chemistry and biology of bile acids in healthand disease.19 In the spring of 1973 we began a seriesof discussions regarding the study of bile acid metab-olism in children and reached a point where itbecame clear that we needed better methods to pur-sue this line of investigation. By that point in timetwo groups, John Watkins working with Roger Lesterin Boston, and Harvey Sharp working with Jim Careyin Minneapolis, had begun to investigate bile acidmetabolism in early life.20 Watkins had demonstrated“immaturity” of mechanisms that control bile acidmetabolism leading to a “contracted” bile acid poolsize.21 He reasoned that this was the factor responsi-ble for insufficient fat absorption characteristic ofnormal newborn physiology.

Alan Hoffman invited me to work in his laboratoryin Rochester. We agreed that a period of study at theMayo Clinic would allow me to develop techniques tofurther investigate bile acid metabolism in children,including the use of nonradioactive-labeled bile acidsin place of radioactive isotopes for measurement ofbile acid kinetics. Thus, while learning the standardtechniques of bile acid analysis, gas chromatography(GC) and thin layer chromatography (TLC), we vali-dated the use of a stable isotope-labeled compound forthe determination of bile acid kinetics by isotope dilu-tion. By administering deuterated, as well as 14C-

labeled bile acids we were able to show that estimatesof the pool size and synthesis rate by both isotopesshowed good correlation and similar precision.22 Theavailability of bile acids labeled with stable isotopes,2H or 13C, allowed us to study bile acid metabolismby isotope dilution measurements in children withoutradiation hazard.

The Berry Plan and the“Philadelphia Story”

Next in the series of fortuitous circumstances wasthe fact that I was able to delay entry into the military.Since this was during the midst of the conflict in Viet-nam, and male physicians in training were subject tothe draft, I was at risk for premature termination ofmy training. However, I was deferred, thanks to theArmed Forces Physicians’ Appointment and ResidencyConsideration Program (Berry Plan).23 Not only was Iable to continue my training with Alan Hoffman, butwith his connections and influence I was able to carryout my 2-year military obligation at the PhiladelphiaNavy Hospital, which had an outstanding gastroenter-ology research unit lead by Don Castell. This, in turn,allowed me to make strong connections with the Uni-versity of Pennsylvania Liver Research Unit (BruceTrotman, Roger Soloway, and Don Ostrow) and subse-quently accepted a faculty position at Children’s Hos-pital of Philadelphia (CHOP) and the University ofPennsylvania. In collaboration with the Liver ResearchUnit we were able to establish methodology for techni-ques of liver perfusion and liver cell isolation and carryout clinical studies to assess the role of serum bile acidmeasurements in assessing liver disease.24-26 With thisbackground we began to focus on neonatal cholesta-sis—since that was the greatest clinical challenge atthat time.

The Problem and the Challengeof Neonatal Cholestasis

Clinicians had long been frustrated by the inabilityto effectively manage hepatobiliary disease in children.Contemporary therapeutic modalities were aimed pri-marily at management of the consequences of cholesta-sis—specifically, persistent and progressive disability,dominated by inadequate weight gain and intractablepruritus. Therapies directed at halting the progressionto endstage liver disease were not available and livertransplantation was not an option in the 1970s.

The largest number of patients we saw at CHOPconsisted of infants in whom a prompt differentiationof the cause of cholestasis was required. Specifically,

Fig. 3. Dr. Alan F. Hofmann, Mayo Clinic, Rochester, Minnesota.


the task was to sort out those with “Neonatal Hep-atitis” from infants with biliary atresia. The latter isan idiopathic, localized, complete obliteration or dis-continuity of the hepatic or common bile ducts at anypoint from the porta hepatis to the duodenum. Therapidly progressive fibro-obliterative process repre-sented a paradigm for other forms of hepatobiliaryinjury, perhaps reflecting a complex inter-relationshipbetween genetic predisposition and environmentalexposure.27-31 One of the earliest advances in PediatricHepatology was a refinement of the hepato-portoenterostomy operation (biliary-enteric anastomo-sis), which was devised in the late 1960s by MorioKasai.32-34 Nevertheless, those of us who were caringfor children with biliary atresia became increasinglydisheartened, for although the Kasai hepatic portoen-terostomy procedure was a reasonable initial approach,a significant proportion of children developed progres-sive biliary cirrhosis.29,31,35,36 For example, within a 2-year period 11 of my patients with biliary atresia diedof endstage liver disease.

Equally frustrating was the group of infants withwhat was termed “idiopathic neonatal hepatitis,” sincethe exact nature of most cases remained enigmatic.This diagnosis, by default, accounted for >65% of theneonates presenting with cholestasis. Our initial efforts,therefore, were focused on cholestasis of infancy inhopes of simplifying the nosology, and expanding thediagnostic possibilities beyond biliary atresia and neo-natal hepatitis. Our goal was to demystify and delin-eate the exact cause of their cholestasis. Specifically,patients labeled as having “Familial Neonatal Hep-atitis” were viewed as candidates for undiscoveredinborn errors in a fundamental physiologic processinvolved in generating bile flow. Specifically, the pat-tern of interfamilial recurrence suggested a geneticdefect in bile acid transport, biosynthesis, or detoxifica-tion.27,28,31 It was reasoned that elucidation of thenature of the defect would allow a better understand-ing of liver physiology and lead to effective therapy.

A Simple Theory. A testable hypothesis was thatexaggeration or persistence of the developmental defi-cits in hepatic bile acid synthesis or metabolismaccounted for a subset of “idiopathic neonatal hep-atitis.” 28,31,37 This seemed to be a reasonable concept.Bile acids are steroid compounds synthesized by theliver from cholesterol through a complex series of reac-tions involving multiple specific enzymatic steps. Thus,deficiency in activity of any of the constitutiveenzymes would theoretically result in diminished pro-duction of the “normal” primary bile acids that areessential for promoting bile flow. Contributing to the

cholestasis would be the concomitant overproductionand accumulation of hepatotoxic atypical bile acidssynthesized as intermediates in the pathway proximalto the inactive enzyme. The analogy that came tomind was that of the syndromes of congenital adrenalhyperplasia (CAH), which result from a defect inenzymes involved in the synthesis of another class ofcholesterol derivatives—the steroid hormones. Theclinical manifestations in patients with CAH are dueto the absence of a critical metabolite and accumula-tion of compounds that exert adverse effects. Recogni-tion allows replacement therapy. By analogy, thespectrum of presentation of inborn errors of bile acidbiosynthesis should reflect metabolite accumulationand endproduct deficiency, with the potential for caus-ing liver injury.37 The problem was how to accuratelydetect affected patients. We made crude attempts toanalyze the bile acid composition of infants with cho-lestasis using GC and TLC—however, it became clearthat a more sophisticated analysis would be required.

A Prototype

In parallel to our research efforts, we began todevelop a clinical program. My early role model wasAlex Mowat (Fig. 4), who had established a prototypefor Pediatric Liver Care Units at King’s College Hospi-tal (KCH) in London in 1970. Alex had developed aninterest in bilirubin metabolism in newborns andinfants. He served as a postdoctoral fellow at theAlbert Einstein College of Medicine under the guid-ance of Win Arias. The Einstein model was influential,

Fig. 4. Dr. Alex P. Mowat, who established one of the earliest proto-types for Pediatric Liver Care Units at King’s College Hospital (KCH) inLondon, with the author.


as Alex returned to KCH in 1970 with an appoint-ment as “Consultant Pediatrician and Pediatric Hep-atologist.” At the time of his appointment there hadbeen no sustained academic interest in liver disordersin children in the United Kingdom. Under Alex’sinfluence, hard work, dedication, and organizationalability the KCH became a first-class clinical service forchildren with liver disease combined with a productiveresearch unit. His vision also led to the recruitment ofparents of children on the Liver Service to developwhat has become the Children’s Liver Disease Founda-tion. Alex Mowat developed a close partnership withProfessor Ted Howard, a pediatric surgeon, therebyintegrating medical and surgical care of children withliver disease into this unique unit. Giorgina Mieli-Vergani joined as the unit grew to become a suprare-gional center in the UK for the treatment of hepato-biliary disease in children. Alex Mowat’s experience atKCH was compiled into his textbook Liver Disordersin Childhood, first published in 1979, which carefullycataloged and characterized the myriad patients caredfor by his “team” at KCH from 1970 to 1976.38 Inhis preface, Alex stated that his aim was to “summarizerecent developments and indicate some of the out-standing clinical problems in areas in which research isurgently needed.” His plea motivated me and othersto take up the challenge, stimulating focused investiga-tion in this discipline. This may have been the firsttime that we had the distinct sense that a new area ofsubspecialization was developing. Mowat’s vision there-fore predated the flurry of activity in Pediatric Hepato-logy attendant to the development of centers ofexcellence in Pediatric Hepatology around the world.

The Inflection (and Reflection) Point onthe Growth Curve

A major seminal event in the maturation of the dis-cipline, and in my personal development, was a meet-ing held in 1977 that focused on the codification anddelimitation of the field of interest of Pediatric Hepa-tology. An international workshop, sponsored by theNational Institutes of Arthritis, Metabolism, andDigestive Diseases (NIAMDD), was convened byNorm Javitt.39 This conference gathered together indi-viduals such as Morio Kasai, Alex Mowat, Daniel Ala-gille, Birgitta Strandvik, and Andrew Sass-Kortsak,among others. As stated by G. Donald Whedon(NIAMDD) “…one of the goals of this conference isto develop a uniform nomenclature with specific crite-ria for diagnosis. With the convergence of expertisefrom virologists, microbiologists, epidemiologists,

embryologists, immunologists, neonatologists, hepatol-ogists, pediatric gastroenterologists, pathologists, andsurgeons, we are going to either make great strides for-ward or build a new tower of Babel … as a spinoff ofthis conference, there may be a continuing effort toplan cooperative clinical trials or to set up a registry ofcases and a repository of sera or tissues. In this way,perhaps the limited number of cases seen in any onemedical center or in any one country when combinedwith several others can contribute to a meaningful database.” This conference clearly was a step forwardtowards clarifying the nosology of pediatric hepatobili-ary diseases and determining directions in research.

“An Offer I Couldn’t Refuse”

In 1978 I received an offer from Bill Schubert toreturn to Cincinnati. We were clearly ready to investi-gate the immature liver and its diseases, specificallyneonatal cholestasis. Schubert offered an environmentto carry out these studies and the resources, includinga dedicated mass spectrometer facility. CCHMC hadestablished programs for specialized care of complexpatients such as neonates and patients with cardiac dis-ease. In addition, CCHMC had a long history of suc-cessful experience as a center for renal and bonemarrow transplantation. In light of the growing num-ber of children with chronic liver disease in the pri-mary and secondary service areas of CCHMC and thenational reputation of the institution in patient careand research, our plan was to establish a formalizedPediatric Liver Care Center (PLCC). The goal of thePLCC was to focus on the evaluation and comprehen-sive care of patients with liver disease, including medi-cal, surgical, social service, and institutional support,including transplantation where required. This wouldbe combined with basic and clinical research into thephysiologic, biochemical, and immunologic aspects ofdisease. We hoped to create a network/support groupof parents of children with liver disease and we envi-sioned a training program for clinical and research fel-lows. The concept of the center, the first of its kind inthe United States, was unique because it integratednovel and existing aspects of liver patient care andtreatment with intensive ongoing research and educa-tion regarding pediatric liver disease.

Assembling the Tools

A significant force driving the nascent field of Pedi-atric Hepatology was the utilization of clinical andresearch procedures and techniques to investigate the


child with presumed liver disease. An important stepwas the development of a safe and reliable method to“sample” tissue for examination and analysis; thisgreatly aided the deciphering of the many potentialcauses of neonatal liver injury. The percutaneous liverbiopsy technique had been developed by Bill Schubert,who with Dick Hong showed the technique to be safein infants and children. They clearly demonstratedthat a diagnosis could be established by assessment oftissue biopsy specimens by light and electron micros-copy.40 In addition, liver tissue samples of adequatesize could be obtained to allow biochemical dissectionand enzyme analysis, which led to investigation intoaspects of disordered hepatic physiology and to a bet-ter understanding of metabolic liver disease. “Unique”pediatric liver diseases were therefore uncovered, suchas alpha-1-antitrypsin deficiency as a cause of “familialneonatal hepatitis.” This was first reported by HarveySharp, who used histologic techniques to document thatthe low serum levels of a-1-AT resulted from its reten-tion in the endoplasmic reticulum.41,42 Next, screeningstudies by Sveger and Eriksson documented that 15%-20% of infants with a-1-AT deficiency (PiZZ) presentwith neonatal cholestasis.43 In Cincinnati we weregreatly aided by our colleague Kevin Bove, a pediatricpathologist, who developed an interest and expertise ininterpretation of biopsy findings from children with avariety of hepatobiliary disorders.9,44

Immaturity of Hepatic Metabolic andExcretory Function: “PhysiologicCholestasis”

It became clear that if we were to study diseasessuch as neonatal cholestasis we needed to understandthe normal physiologic events occurring at this stageof liver development. A series of adaptations mustoccur during transition of the infant to extrauterinelife; specifically, the liver of a newborn must conformto the unique metabolic demands that result from dis-continuation of the bidirectional exchange of nutrientsthrough the placenta and the biotransformation mech-anisms shared with the mother.31 These maturationalchanges as the transition is made from an intrauterineexistence to independent life occur predominantlythrough enzyme induction triggered by substrate andhormonal input. The efficiency with which these ana-tomic and physiologic adaptations are establisheddetermines the ability of the newborn to cope with anew environment.31,45,46 Historically, there are dra-matic examples of inefficiency of hepatic metabolicand excretory function in early life, most notably

“physiologic jaundice” (unconjugated hyperbilirubine-mia characteristic of the newborn). We therefore werenot surprised to discover an analogous phase, whichwe termed “physiologic cholestasis.” We documentedthat in newborns there is a cholestatic phase of liverdevelopment, manifest by delayed hepatic clearance ofendogenous and exogenous compounds.45-47 The mor-phological and functional differences that characterizethe neonatal versus the mature liver are responsible notonly for a decrease in bile flow but also the productionof abnormal bile acids. This renders the developingliver uniquely vulnerable to exogenous insults such asE. coli sepsis with endotoxemia, the intravenousadministration of amino acids during total parenteralnutritional support, and hypoxia/hypoperfusion.44,48,49

Right Place, Right Time, Right Colleagues

Good fortune once again intervened—my first fel-low in Pediatric Gastroenterology at CCHMC wasFred Suchy, who enthusiastically joined me for studiesfurther delineating normal and abnormal hepatobiliaryfunction in neonates. We were able to document thatmultiple steps in the enterohepatic circulation werereduced in early life, evidenced by elevated serum bileacid levels, reduced intraluminal bile acid concentra-tions, and reduced hepatocellular transport (uptakeand excretion) of bile acids. Another striking feature of“physiologic cholestasis” was the presence of a largeproportion of “atypical” bile acids (yet typical for thedevelopmental phase) that are not found in adulthuman bile. Of note, the bile acid composition of bio-logical fluids in early life resembled that of adults withsevere cholestasis, suggesting that in the presence ofliver disease/cholestasis there is a reversion to“primitive pathways.” 27,37 A subsequent series of stud-ies further documented the inefficiency of hepaticexcretory mechanisms, which correlated with adecrease in hepatic bile acid excretion and decreasedbile flow.50 Fred Suchy, who very soon became anaccomplished independent investigator, then docu-mented delayed expression of bile acid transport pro-teins in the immature liver.51-55 Next, Ron Sokoljoined us as a fellow in 1980 and became interested instudying complications of cholestasis. He focused onvitamin E deficiency and developed a protocol fordetection and correction of this and other fat solublevitamin deficiencies in children with chronic cholesta-sis.56-58 Sokol later became a major leader for multi-center collaborative studies that have greatly advancedour understanding of pediatric hepatobiliary disease.Sue Moyer and John Bucuvalas followed and, shortly


thereafter, Jorge Bezerra joined us as a fellow and rapidlyestablished a highly productive research program devotedto studies of the pathogenesis of biliary atresia. The train-ing program continued to flourish, with the recruitmentof a large number of trainees focusing on Pediatric Hepa-tology—including Hassan A-Kader, Nada Yazigi, LooiEe, Jeff Schwimmer, Vicky Ng, Mike Leonis, KathyCampbell, Alex Miethke, Bernadette Vitola, Kyle Jensen,Samar Ibrahim, and Frank DiPaola—who have gone onto successful careers in our field.

A MASS-ive Recruitment

In the UK, Ken Setchell was applying mass spectrome-try (MS) methods to correlate clinical disease with bio-medical profiles, specifically related to steroid hormones.As a scientist in the Division of Clinical Chemistry at theMedical Research Council Clinical Research Centre hebegan to focus on cholesterol and bile acid metabo-lism.59-63 At a Bile Acid Symposium in 1983 in Cortina,during an informal discussion, I asked Ken for recom-mendations as to whom we could recruit to develop ournascent MS facility in Cincinnati to focus on bile acidmetabolism. The number one name on the list was his!Thus, Ken Setchell joined us a member of the faculty ofthe Department of Pediatrics in 1984 to become Directorof our Clinical Mass Spectrometry facility at CCHMC.He rapidly established the techniques of fast atombombardment-mass spectrometry (FAB-MS) and gaschromatography-mass spectrometry (GC-MS) to delin-eate disorders of bile acid synthesis. This facility was ulti-mately to become an international center for thediagnosis and treatment of liver disease caused by geneticdefects in cholesterol and bile acid synthesis.64,65

Inborn Errors of Bile Acid Biosynthesis

Mass spectrometric techniques, “biochemical finger-printing,” provide the most accurate means of charac-terizing defects in bile acid synthesis. The presumed defectcan be pursued using the screening modality of FAB-MSanalysis of a urine sample. If an abnormal pattern isdetected, the FAB-MS analysis can be complemented bydetailed GC-MS analysis to confirm the presumed inbornerror. These steps are necessary since signature metaboliteswill not be detected by routine methods for bile acid mea-surement. With Setchell’s methodology established, wewere ready to screen infants with cholestasis.

D423-Oxosteroid 5b-Reductase Deficiency: AnExperiment With an “n” of One (ActuallyTwo). In 1988 male twins who presented with cho-lestasis and coagulopathy in the first days of life were

referred to us for further evaluation. A similarlyaffected sibling had died at 4 months of age 3 yearspreviously with what was called “idiopathic neonatalhepatitis / giant cell hepatitis.” Our initial evaluationof the twins strongly suggested a defect in bile acidbiosynthesis. Setchell’s lab was able to document thattheir rate of primary bile acid synthesis was reduced,that cholic acid was absent from blood, and that gall-bladder bile contained only trace amounts of bileacids. Urine served as the main route of excretion,with the excreted compounds in the form of D423-oxo bile acids. This biochemical picture suggested adefect in bile acid synthesis—specifically, a lack of con-version of D423-oxo intermediates to 3a-hydroxy-5bproducts, a reaction catalyzed by cytosolic D423-oxos-teroid 5b-reductase66 (Fig. 5). The presumed patho-physiology of the hepatocellular and bile ductularinjury was directly attributed to inadequate synthesisof primary bile acids (cholic) needed to generate bileacid-dependent bile flow, and accumulation of hepato-toxic D423-oxo bile acids. These precursors wereshown to act as cholestatic agents by inhibiting cana-licular adenosine triphosphate (ATP)-dependent bileacid transport, the rate-limiting step in the overall pro-cess of bile acid transport across the hepatocyte.67

Of interest, electron microscopy of the twins liverbiopsies revealed abnormal collapsed bile canaliculi,suggesting that maturation of the canalicular mem-brane and transport system for bile acid excretionrequires a threshold concentration of primary bileacids in early development.68 This was consistent withstudies of fetal rat liver, in which poorly formed bilecanaliculi can be demonstrated by histology andimmunocytochemistry.69,70 Bile canalicular morpho-logic maturation in the immediate postnatal periodcorrelates with transition and acceleration of bile acidsynthesis. This demonstrates the relationship betweenthe pattern and pace of bile acid synthesis in fetal andneonatal rat liver and bile canalicular development.

In the analogy to CAH syndromes, we chose to usecholic acid (3a,7a,12a-trihydroxy-5b-cholanoic acid)as replacement therapy to treat these twins withD423-oxosteroid 5b-reductase deficiency. The ration-ale was that cholic acid would restore physiologicalfeedback inhibition of bile acid synthesis at the level ofthe rate-limiting enzyme, cholesterol 7a-hydroxylase(the role of farnesoid X receptor [FXR] and small het-erodimer partner [SHP]-dependent mechanisms werenot known at that time). The goal was to prevent fur-ther accumulation of potentially hepatotoxic D423-oxo bile acids. Cholic acid was administered orally inan empiric dose (10-15 mg/kg/day) and titrated


against the desired biochemical response of a reductionor disappearance of atypical metabolites in urine meas-ured by FAB-MS. Indeed, cholic acid therapy was foundto down-regulate endogenous bile acid synthesis by wayof feedback inhibition of cholesterol 7a-hydroxlase andD423-oxo bile acids disappeared. The twins recovered,thrived, and grew and developed normally.

Translational Medicine: Bed to Bench to Bed. Atpresent there are nine known primary defects in bileacid biosynthesis; each is specifically reflected by pre-cursor accumulation and excretion of unusual metabo-lites. For most of the defects molecular confirmationhas been accomplished by gene sequencing. In affectedpatients oral bile acid replacement therapy is lifesavingand is effective in reversing liver injury, as in the initial

twins.37,64,65,71,72 Inborn errors in bile acid synthesisaccount for at least 2% of the cases of liver disease ininfants, children, and adolescents, making this animportant and specific category of metabolic liver dis-ease.37,64,65 3b-hydroxy-D5-C27-steroid oxidoreductasedeficiency (3b-HSD), the most common inborn errorof bile acid biosynthesis, is usually manifest in earlychildhood; however, it has recently been described inadults.73,74 Molho-Pessach et al.74 reported a 24-year-old woman with cirrhosis of unknown etiology whosesister and cousin died of cirrhosis at ages 19 and 6years. The diagnosis of 3b-HSD deficiency was con-firmed and the affected family members were found tobe homozygous for a mutant allele inherited identical-by-descent. These cases illustrate the wide variation in

Fig. 5. Biosynthetic pathways for bile acid synthesis from cholesterol in man—indicating the point of the defect in synthesis in twins with fami-lial giant-cell hepatitis and the resulting metabolism of the accumulated precursors. The numbers indicate the key enzymes involved in the earlystages of the pathway: (1) cholesterol 7a-hydroxylase; (2) 3b-hydroxysteroid dehydrogenese/isomerase; (3) 12a-hydroxylase; (4) D423-oxoste-roid-5 b-reductase; (5) 3a-hydroxysteroid dehydrogenase. The defect in D423-oxosteroid 5 b-reductase activity led to an increased productionof D423-oxosteroids with subsequent metabolism of these precursors by side chain oxidation to D423-oxo bile acids and all-bile acids (shownin boxes). Reproduced from Reference 66.


expressivity of 3b-HSD deficiency and underscore theneed to consider a bile acid synthetic defect as a possi-ble cause of liver disease in patients of all ages.

Progressive Familial IntrahepaticCholestasis (PFIC)

A unifying stimulus leading to the development ofthe field of Pediatric Hepatology was the shared goalof defining the nature of the syndromes of intrahepaticcholestasis, a heterogeneous subset of neonatal choles-tatic diseases, each representing a series of specific syn-dromes with different prognostic implications.

The beginning of wisdom is to call things by theright names.

—Chinese Proverb

In the past 20 years the discovery of defects andgenes involved in hereditary forms of intrahepatic cho-lestasis has advanced our understanding of molecularmechanisms of bile secretion and further clarified thenature of many forms of “idiopathic neonatal hep-atitis.” The understanding of the importance of defec-tive bile acid synthesis and transport in thepathophysiology of intrahepatic cholestasis allowed fur-ther deciphering of the spectrum of disorders tradi-tionally known as “PFIC.” The clinical andpathologic features, as well as the natural progressionof this family of disorders, were highly variable. There-fore, the term was de facto imprecise. In an individualpatient, especially a firstborn, it was unclear whetherthe liver disease was indeed progressive or familial.

A series of studies that directly addressed the molec-ular mechanisms that control liver development andhepatic excretory function served as the biologic basisfor enhanced understanding of the molecular basis ofhepatobiliary dysfunction manifest as intrahepatic cho-lestasis.27,28,75 The heterogeneity reflected inheriteddefects in mechanisms involved in the generation ofbile flow, specifically canalicular transport proteinsresulting in substrate retention manifest as cholestasis.Patients with the most common types of PFIC wereshown to harbor mutations in genes encoding proteinsinvolved in bile acid transport: (1) ATP8B1 gene,encoding FIC1 (patients with PFIC Type 1); (2)ABCB11 gene, encoding the bile salt export pump(BSEP, patients with PFIC Type 2); and (3) ABCB4gene, encoding the multidrug resistance protein-3(MDR3, patients with PFIC Type 3). In addition, thecomplex phenotype, molecular genetics, and inheri-tance pattern of Alagille syndrome were defined, with

linkage to mutations in human Jagged1 (JAG1), whichencodes a ligand for the Notch receptor.76-78 TheNotch gene family encodes evolutionarily conservedtransmembrane receptors involved in cell fate specifica-tion during embryonic development. This locus con-trols the ability of cells that are nonterminallydifferentiated to respond to differentiation and prolif-eration signals. In Alagille syndrome, mutations inJAG1 disrupt the gene product, altering cell-to-cell sig-naling during development. These investigationsallowed classification of these disorders into distinctsubsets28 (Table 1).

To translate this knowledge into practical applicationsin the clinic, Jorge Bezerra and co-workers79 developedthe “Jaundice Chip,” which uses a “resequencing”platform that enables the detection of mutations ofthese genes. Studies also addressed the importance ofheterozygosity for these genes in creating genetic suscep-tibility to injury initiated by other agents such as drugs,toxins, or viruses. In addition, detailed understanding ofthe underlying pathophysiology of altered bile acidtransport allowed for the development of specific tar-geted therapy. Based on initial studies, ursodeoxycholicacid became popular as a therapeutic agent in patientswith intrahepatic cholestasis; this is now an acceptedform of therapy worldwide.80,81

Other Significant Advances

The body of knowledge related to hepatobiliary dis-ease in children expanded in other needed areas. Enig-matic disorders presenting as acute liver failure,chronic hepatitis, or hepatocellular carcinoma yielded

Table 1. Proposed Subtypes of Intrahepatic Cholestasis28

I. Disorders of bile acid synthesis:

1. 3b-hydroxy-C27-steroid dehydrogenase deficiency

2. D423-oxosteroid 5b-reductase deficiency

3. Oxysterol 7a-hydroxylase deficiency

4. 27-hydroxylase deficiency

5. 2-methylacyl CoA racemase deficiency

6. Peroxisomal defects (single-enzyme defects)

7. Amidation defects

II. Disorders of membrane transport:

1. PFIC, BRIC Type I 5 FIC1 deficiency (PFIC1) ATP8B12. PFIC, BRIC Type II 5 BSEP deficiency (PFIC2) ABCB113. PFIC, BRIC Type III 5 MDR3 deficiency (PFIC3) ABCB4

III. Disorders of embryogenesis

1. Alagille syndrome

2. ARC Syndrome (Arthrogryposis, Renal disease, Cholestasis)

IV. Acquired forms

1. Sepsis-related

2. Drug-induced Cholestasis

3. Intrahepatic Cholestasis of Pregnancy

V. Unclassified


to biochemical analysis and molecular dissection andwere proven to be caused by inborn errors of lipid,amino acid, or carbohydrate metabolism. The recogni-tion of the metabolic basis for liver disease allowed fortargeted nontransplant strategies for the managementof affected patients.82,83 In addition, early practitionersof Pediatric Hepatology in Taiwan were largely respon-sible for the initial steps towards reducing the globalburden of hepatitis B.84-88 The obvious solution tothis problem was to interrupt perinatal transmission byway of hepatitis B virus (HBV) vaccination combinedwith the administration of hepatitis B immune globu-lin at birth.85-87 This strategy has been nearly univer-sally applied, leading to a worldwide decrease in theprevalence of hepatitis B surface antigen (HBsAg) posi-tivity and a decrease in the incidence of HBV-relatedliver disease, including hepatocellular carcinoma.88

Pediatric Liver Transplantation

Despite these obvious successful advances, therewere many children who reached endstage liver disease.Thus, there was a need for alternative strategies—namely, the establishment of pediatric liver transplantprograms. Actually, the first recorded orthotopic livertransplantation was performed in a child with biliaryatresia.89 Continued advances were made since thatlandmark case with innovations in surgical techniques,methods of organ preservation, postoperative care, andimmunosuppression strategies. In the early 1980s theonly center performing liver transplantation in childrenwas that led by Tom Starzl in Pittsburgh; in that pro-gram the medical care was proved by a gifted group ofpediatric generalists (Basil Zitelli, Carl Gartner, JeffMalatack, and others) working directly with the trans-plant surgeons.90-92 In 1983, the National Institutes ofHealth Consensus Development meeting concluded

that “liver transplantation was no longer an experimen-tal procedure” and that it “deserved broaderapplication.” 93 Technological advances allowed rapidexpansion of this option to children. Liver transplanta-tion thus emerged as the standard of care for childrenwith irreversible acute and chronic liver failure andcertain metabolic disorders. As a result, the need forskilled, qualified “pediatric hepatologists” to managepatients before and after liver transplantation signifi-cantly increased.

Pediatric Liver Transplantation: The TeamApproach. One of the lessons derived from my ado-lescent interest in sports was the value of learning toplay on a team that has great diversity in background,knowledge, and specific skills. As part of our PLCCstrategy we established a liver transplant program—inaddition to Fred Suchy and I—the CCHMC “team”(Fig. 6) consisting of pediatric surgeons—Fred Ryck-man and John Noseworthy, along with nurse coordina-tors—Sue Pedersen and Joanne Mitchell. Workingside-by-side as clinical team, with shared responsibil-ities and perseverance, liver transplantation became arealistic, effective, and life-saving therapy for infantsand children with endstage liver disease.30,94,95 How-ever, a factor that limited more widespread applicationof liver transplantation was a lack of size-matcheddonors—a disparity compounded by the fact that themost common indication for liver transplantation inthe pediatric population was biliary atresia. In this dis-ease, liver replacement is often required at a young ageand small size because of the rapid progression. Thisepidemiologic disparity between donor size and recipi-ent needs led to the use of reduction hepatectomies/segment liver transplantation and the development ofother innovative transplant surgical techniques basedon reduced size grafts, including split liver transplanta-tion and the use of organs from living donors.96-99

These advances allowed more widespread applicationof liver transplantation for children. During 2011-2012, 64 centers performed at least one liver trans-plant in a patient <18 years of age; 23 programs per-formed 20 or more transplants in this populationduring that time frame.100 Pediatric pretransplant mor-tality has steadily decreased, most dramatically for can-didates less than 1 year of age. The number of newpediatric candidates added to the liver transplant wait-ing list was 704 in 2011.100,101 In 2011, there were477 deceased donor pediatric liver transplants and 59living donor transplants. Graft survival has continuedto improve for pediatric recipients. Despite this highsuccess rate, challenges remain, including the need for

Fig. 6. The CCHMC Liver Transplant Team (early 1990s): Sue Peder-sen, RN, Amy Hill, MD, Vicki Smith, RN, “Joey” with Fred Ryckman,MD, Bill Balistreri, MD.


targeted preoperative management to address the prob-lems of malnutrition, and improved methods to pre-vent graft loss while avoiding the consequences ofimmunosuppression, such as posttransplant lympho-proliferative disease (PTLD) and renal injury.99

A New Subspecialty Truly Emerges: TheField of Pediatric Hepatology

All elements were in place for expansion and valida-tion of Pediatric Hepatology. In the mid-1990s centersthat focused on Pediatric Hepatology became a com-ponent of many divisions of Pediatric Gastroenterol-ogy. Research flourished with the application of state-of-the-art cellular and molecular biology techniquesand the emergence of molecular genetics, whichenhanced our understanding and recognition of thepathophysiological and genetic basis of an increasingnumber of disorders of the liver in children.102 Withclinical and research efforts converging, the field rap-idly gained momentum. The next key ingredient toestablishing the formal field was to create and sustain acritical mass and validate the concept of PediatricHepatology as an academic subspecialty. In a decisionthat reflected validation and maturity, “Hepatology”was added to the name of the major Pediatric Gastro-enterology society—which became the North AmericanSociety of Pediatric Gastroenterology, Hepatology andNutrition (NASPGHAN). This is symmetrical withthe European Society for Pediatric Gastroenterology,Hepatology, and Nutrition (ESPGHAN). In 1993,perhaps as a measure of the growth of the field (or theverbosity of the author) the chapter on Liver Diseasein Infancy and Childhood in the 7th Edition of Dis-eases of the Liver (Leon and Eugene Schiff; editors) was104 pages long!103

Networking: Face-To-Face—Not Facebook

A community of colleagues interested in PediatricHepatology was being built. The increasing number of“practitioners” and the robust research enterprise cre-ated a demand for greater opportunities to meet andshare science, thus a gathering place was needed.Extensive discussions about research on liver diseasesin children among hepatologists, surgeons, patholo-gists, and basic scientists occurred at meetings and sci-entific fora. The annual meetings of the AmericanAssociation for the Study of Liver Diseases (AASLD)and Digestive Disease Week (DDW) were excellentvenues for enrichment and engagement. With theincreasing number of high-quality abstract submissions

and research addressing liver diseases in children, thesemeetings embraced pediatric input. Communicationwith colleagues facing similar “liver-related” issues inother countries was catalyzed by international confer-ences, such as the Falk Symposia. The excellent scien-tific basis and collegiality of these conferencesstimulated collaboration and promoted clinical andbasic research, which directly led to advances in Pedi-atric Hepatology.

Following my appointment to the National Diges-tive Diseases Advisory Board (NDDAB) in 1985, Iwas the chair of a conference addressing the issues of“Mechanisms and Management of Pediatric Hepato-biliary Disease.” This conference was organized andsponsored by the NDDAB, the National Institute ofDiabetes and Digestive and Kidney Disease (NIDDK),and the American Liver Foundation.104 The sessionsaddressed potential areas of research, such as morphol-ogy and functional differentiation of the liver, develop-ment of hepatic excretory function, and therapeuticstrategies directed to the spectrum of liver disease inchildren. These discussions brought to the attention ofthe research community some of the perceived needsand served to encourage research in pediatric hepato-biliary disease, specifically as collaborative studies incertain clinical areas.

In September 1994, another important symposiumthat focused on pediatric liver disease, “Biliary Atresia,Current Status and Research Directions,” was organ-ized by Jay Hoofnagle and sponsored by theNDDAB.29 The goal of the symposium was to addressthe pathogenesis and the clinical challenges presentedby biliary atresia, including the need for rapid and pre-cise diagnosis and improved management. The ulti-mate objective was to stimulate basic and translationalinvestigation regarding this enigmatic disease.29

Because a small number of patients were being seen inindividual centers and patients were not managed in auniform manner between centers, a collaborative, mul-ticenter study of biliary atresia was viewed as impera-tive.105,106 In 2002 the NIDDK of the NIH initiatedfunding of a consortium; the overall goal was to gatherclinical and biochemical data along with serum, tissue,and DNA samples in a prospective manner in order tofacilitate research. The consortium members generatedand tested hypotheses regarding the pathogenesis andoptimal diagnostic and treatment modalities for biliaryatresia and related disorders.28,105 What ultimatelyemerged is the encompassing Childhood Liver DiseaseResearch and Education Network (ChiLDREN), a col-laborative team of doctors, nurses, research coordina-tors, medical facilities and patient support


organizations. The ChiLDREN Network supports thediscovery of new diagnostics, etiologies and treatmentoptions for children with liver disease, and those whoundergo liver transplantation. The network also sup-ports training for the next generation of investigatorsof pediatric liver diseases.107

Subspecialty Certification in PediatricTransplant Hepatology

During a Strategic Planning Meeting held in 2000 theAASLD Governing Board set out to codify a body ofknowledge that would establish criteria to develop hepa-tology as a focused, distinct discipline within the medicalsubspecialty of gastroenterology and to identify the spe-cial training that individuals involved in “advanced”hepatology and liver transplantation required. The goalwas to ensure recognition of individuals who hadacquired the training, expertise, and skills to be consid-ered a “hepatologist.” 108 Up to that time the disciplineof hepatology was largely viewed as a focused researchactivity. However, the clinical profile was rapidly expand-ing, driven by the growth of liver transplantation pro-grams, the discovery of the hepatitis C virus, and thenascent epidemic of obesity-related liver disease.

As a member of the AASLD Governing Board atthat time (Fig. 7), I was excited about the concept andthe opportunity for the development of Advanced/Transplant Hepatology as a subdiscipline of gastroen-terology. Equally exciting, as the first pediatrician to beelected president of the AASLD, I had a unique per-spective and thus envisioned the impact on those of uswho were predominantly involved in the care of chil-dren and adolescents with liver disease.

Around that time the leadership of NASPGHANseparately addressed the question as to whether specialcertification or qualifications in Pediatric Hepatologywere necessary within the field of Pediatric Gastroen-terology.109 Data generated from a NASPGHANworkforce survey estimated that there were approxi-mately 300 practitioners of Pediatric Hepatology. TheUnited Network for Organ Sharing (UNOS) had spe-cific qualifications for the designation of pediatric livertransplant physicians, which included fellowship train-ing in Pediatric Gastroenterology with a minimumexposure of clinical care of 10 pediatric patients under-going liver transplant. Furthermore, it was requiredthat the trainee provide ongoing care for at least 20children who have undergone liver transplantation,under the guidance of a qualified liver transplant phy-sician and surgeon. The problem, therefore, for indi-viduals interested in training in the field or pursuingcareers focusing on Pediatric Hepatology was the needto find appropriate mentors and training programs.The NASPGHAN leadership recognized the demandfor validated practitioners and the need for increasedrecognition for individuals who achieved a specifiedlevel of competence in the field. It was also supportiveof codification of a knowledge base of informationrelated to liver diseases in children.

An AASLD task force led by Joe Bloomer was cre-ated and a “game plan” for the development of a pro-cess for certification in the subspecialty identified asTransplant Hepatology was rolled out. The proposalstated that qualified candidates upon successful com-pletion of the process, including an examination,would receive a Certificate of Added Qualification

Fig. 7. AASLD GoverningBoard 2000: Front (L to R):Gene Schiff, Bill Balistreri,Anna Lok, Pat Latham, WillLee, Joe Bloomer. Back:Arun Sanyal, Bruce Bacon,Michael Henderson, TomBoyer, Fred Suchy, TerryWright, Alan Wolkoff, Leon-ard Seeff, Nick LaRusso,Tony Tavill.


(CAQ) in Transplant Hepatology—equivalent to boardcertification in this new subdiscipline. As the nameimplies, this CAQ would denote knowledge of hepato-logy over and above that expected of a board-certifiedgastroenterologist. A needs assessment and workforceanalysis gathered information as to the volume andtype of patients referred to transplantation centers andthe special skills required to care for complex patients,before and after liver transplantation. This analysisdocumented that advanced/transplant hepatology wasconsidered by gastroenterologists to be a distinct disci-pline outside the purview of the typical practicing gas-troenterologist, regardless of the amount of hepatologytraining possessed by that individual. The task forceconcluded that a benefit to patient care would bederived if the discipline were codified with the certifi-cation process.110 Therefore, a CAQ proposal was sub-mitted to the American Board of Internal Medicine(ABIM) and to the American Board of Pediatrics(ABP), which cited the growing interest in adult andPediatric Hepatology, including the rapid expansion ofknowledge in the field. It emphasized the projectedprofound impact of certification on the quality ofexisting practice of advanced hepatology, by dictatingstandards to ensure competence and by providing aframework for monitoring continued competence. Theproposal was reviewed and endorsed by the ABIM andABP gastroenterology subspecialty boards, andapproved by the respective boards of directors.111 Theformal application was then approved by AmericanBoard of Medical Specialties (ABMS) in 2003.

A conjoined examination process for the CAQ wasdeveloped by a Test and Policy Committee on Trans-plant Hepatology which consisted of 10 members,two of whom were pediatricians (John Bucuvalas andPhil Rosenthal). The group defined requirements forcertification, including training and practice admis-sion requirements, and developed a detailed contentoutline as a “blueprint” for the initial certifyingexamination. This served to delineate the intellectualboundaries and knowledge that a certified subspecial-ist in Transplant Hepatology must acquire beyondthat learned during their GI Fellowship. The coreexamination included two separate modules—one forpediatrician applicants and one for internal medicineapplicants. In November 2006, the first certifyingexamination in transplant hepatology was adminis-tered to 47 ABP board-certified pediatric gastroenter-ologists and 83% passed. The Pediatric TransplantHepatology certifying examination is now offeredbiannually. Since the certification of the initial “class”of board-certified Pediatric Transplant Hepatologists,

89 certificates have been awarded in our subspecialtyas of December, 2012.112

The Accreditation Council for Graduate MedicalEducation (ACGME) was then responsible for estab-lishing the criteria for accreditation of training pro-grams in transplant hepatology. This ensured that avariety of educational objectives were in place, alongwith a curriculum, to allow individuals to becomeadequately trained and monitored. There are currentlyfive ACGME-certified programs in Pediatric Trans-plant Hepatology in the US.

Quo Vadis?

In my opinion the goals and expectations of theAASLD task force, which had the vision of certificationof liver disease specialists, have been met. The endresult is a thriving clinical and academic subspecialtythat continues to attract the “best and the brightest,”carry out high-quality basic and translational research,and use innovative strategies to improve patient care.The certification process ensures that those caring forpatients of any age with advanced liver disease possessthe necessary knowledge and training. The latter isgoverned by the high standards set by the ACGME.Buoyed by the success, the trend of “subspecialization”within the broad field of gastroenterology is viewed aslikely to continue.113

What Do We Want Subspecialty Training to LookLike in the Future? It is still a bit unclear as to theoptimal process for training the next generation oftransplant hepatologists. It has been suggested that thecurrent model of a dedicated year of training in Trans-plant Hepatology after a 3-year fellowship in gastroen-terology may be “unworkable and unsustainable.” 114-

116 This additional year of postgraduate training maynot be a popular option, a concern predominantlyrelated to the perceived financial disincentives. Oneproposal emanating from gastroenterology subspecialtygroups suggests that subspecialty training such asTransplant Hepatology be incorporated within the 3-year gastroenterology core fellowship. The endpointsfor training and the criteria for credentialing mightthen focus not on process measurement but on themeasurement of actual accomplishments or out-comes—the acquisition of competencies within thefield.114 In fact, pilot programs in Internal Medicineare being established that incorporate specialty specificmilestones that trainees must attain as they pro-gress.114,117,118 Of course, the ultimate desired out-come is the quality of care provided to our patients.


Reflection: The Past Informs the Future ofPediatric Hepatology

The lessons for me are enduring—focus, persevere,commit. While times may be different, I recall thatBill Schubert fostered independence and that AlanHofmann was kind enough to take the time to listento an unknown young fellow. These traits remain keyingredients to successful mentoring/career developmentof trainees. I also emphasize to trainees the value ofdedicating time to work within a community of like-minded individuals. It is also clear to me that detailedstudy of a single patient can lead to a new scientificand medical horizon.

A single “organ of interest” , the liver, has rapidlyreached a status in which an entire field of study iscommitted to its long-term health and longevity. Pedi-atric hepatologists are major components of clinicalpractices, education and training programs, and inves-tigative initiatives to advance human health and toimprove clinical care and outcomes. Research programsare providing insight into the combined role of geneticpredisposition and environmental factors in the expres-sion of a variety of liver diseases. This offers theopportunity to prevent or modify phenotypic expres-sion of diseases by addressing a potential chronic liverdisease during early life. For example, a major currentresearch goal is to define the pathogenesis of biliaryatresia and to develop effective preventative strategies.In the interim it is important to emphasize strategiesfor early recognition to allow for optimal intervention.

Despite the progress, our field is still quite underde-veloped. The cited advances and interventions haveclearly improved outcomes for children with liver dis-ease. Along the way we learned a great deal about hepa-tobiliary physiology, developmental biology, and therole of genetic variants in determining the risk of liverdisease and in predicting the response to therapy. Muchmore needs to be done. We must focus on ensuring thecontinued development of our field by training theworkforce of the future. In addition, definitive, cost-effective treatment strategies must be developed suchthat liver transplantation may not be needed in thetreatment of certain diseases, such as metabolic liver dis-ease. In this regard, it will be important for fundingagencies and foundations to continue to supportresearch and to foster innovation and collaboration inPediatric Hepatology. The success of the well-establishedmulticenter ChiLDREN Network serves to emphasizethat point. Societies such as the AASLD and NASP-GHAN must also continue to recognize the importantrole that pediatric hepatologists play in their missionand foster career development in the field.

The emerging number of pediatric patients withnonalcoholic fatty liver disease suggests that a focus onprevention and recognition of obesity is clearly needed.This combined with efforts to prevent liver disease inearly life, thoughtful medical management, precisedecision-making, and conscientious, creative, and cou-rageous use of nontransplant options can both save liv-ers and save lives.

Acknowledgment: I express my gratitude, admira-tion, and appreciation to all those who have made ourfield viable and vibrant. I especially want to recognizethe commitment and collaboration of the manyparents and patients who have dedicated their time toclinical studies which have clearly advanced our field. Ialso want to thank Mitchell Cohen and Frank DiPaolafor their critical review of this article. We have tried tocover the relevant elements in the development ofPediatric Hepatology, but could not include all namesand details in this brief overview. Please accept myapology if something or someone that individual read-ers deem important was excluded.

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Growth and Development of a New Subspecialty: Pediatric Hepatology · 2013. 7. 30. · Pediatric Hepatology William F. Balistreri Several major forces converged to catalyze the formal