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Harpavat S, Borovsky KA, Scheurer ME, Cavallo L, Erhiawarie FE, Vasudevan S, Vogel AM, Cerminara D, Tessier EM, Patel KR, Devaraj S, Shneider BL. A phase 2 trial of short-term intravenous N-acetylcysteine in biliary atresia after Kasai portoenterostomy. Hepatol Commun 2025; 9:e0729. [PMID: 40489761 DOI: 10.1097/hc9.0000000000000729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 03/19/2025] [Indexed: 06/11/2025] Open
Abstract
BACKGROUND For infants with biliary atresia, the only treatment that can establish bile flow and delay need for liver transplant is the Kasai portoenterostomy (KP). Unfortunately, the KP has variable success. In this study, we hypothesized that intravenous N-acetylcysteine (IV NAC) treatment following KP would improve bile flow. METHODS This was a phase 2 study following the two-stage "minimax" trial design. Participants received IV NAC (150 mg/kg/day) for 7 days after KP, and the primary endpoint was achieving total serum bile acids (TSBA) ≤10 μmol/L within 24 weeks of KP. Secondary endpoints were clinical markers and the occurrence of sentinel events. RESULTS There were 12 participants in stage 1 who received treatment, with none achieving TSBAs ≤10 μmol/L within 24 weeks of KP. As a result, no participants were enrolled in stage 2. There were 32 adverse events in 11 participants, including 5 serious adverse events which were considered part of the participants' natural clinical course and not directly attributable to NAC treatment. Analyses of secondary outcomes demonstrated no difference in clinical markers or occurrence of sentinel events between study participants and matched historical controls. CONCLUSIONS This study demonstrates how the two-stage "minimax" trial design can be used to efficiently evaluate potential therapies for BA. Although the primary endpoint was not met, NAC therapy was generally well-tolerated. NAC therapy may prove efficacious in future trials with (i) a less stringent primary endpoint and/or (ii) a longer course of treatment (NCT03499249).
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Affiliation(s)
- Sanjiv Harpavat
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA
| | - Kristin A Borovsky
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA
| | - Michael E Scheurer
- Division of Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA
| | - Laurel Cavallo
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA
| | - Franca E Erhiawarie
- Department of Pediatrics, Research Resources Office, Baylor College of Medicine, Houston, Texas, USA
| | - Sanjeev Vasudevan
- Department of Surgery, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA
| | - Adam M Vogel
- Department of Surgery, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA
| | - Dana Cerminara
- Department of Pharmacy, Texas Children's Hospital, Houston, Texas, USA
| | - Elizabeth M Tessier
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA
| | - Kalyani R Patel
- Department of Pathology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA
| | - Sridevi Devaraj
- Department of Pathology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA
| | - Benjamin L Shneider
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA
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Mysore KR, Cheng K, Suri LA, Fawaz R, Mavis AM, Kogan-Liberman D, Mohammad S, Taylor SA. Recent advances in the management of pediatric cholestatic liver diseases. J Pediatr Gastroenterol Nutr 2025; 80:549-558. [PMID: 39840645 PMCID: PMC11961318 DOI: 10.1002/jpn3.12462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 12/19/2024] [Accepted: 12/27/2024] [Indexed: 01/23/2025]
Abstract
Pediatric cholestatic liver diseases are rare conditions that can result from multiple specific underlying etiologies. Among the most common etiologies of pediatric cholestatic liver diseases are biliary atresia, Alagille syndrome (ALGS), and inherited disorders of bile acid transport. These diseases are characterized by episodic or chronic unremitting cholestasis. Due to the chronicity of these conditions, it is imperative to optimize medical management to improve patient quality of life, provide nutritional support, and reduce bile acid toxicity in efforts to slow disease progression. Cholestatic liver diseases remain the leading cause of pediatric liver transplantation, as many underlying disease etiologies have no curative medical therapies. In the present review, we provide an update on the nutritional, medical, and surgical management of pediatric cholestatic liver diseases. As recent advances have occurred in the field with the addition of ileal bile acid transporter (IBAT) inhibitors, we also review the results from prospective clinical trials, including their strengths and limitations. While recent clinical trials have demonstrated improved pruritus using IBAT inhibitors in ALGS and progressive familial intrahepatic cholestasis, establishing medical therapies proven to slow disease progression remains an area of unmet need.
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Affiliation(s)
- Krupa R Mysore
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Katherine Cheng
- Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | | | - Rima Fawaz
- Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA
| | - Alisha M Mavis
- Department of Pediatrics, Levine Children's Hospital, Atrium Health, Charlotte, North Carolina, USA
| | - Debora Kogan-Liberman
- Department of Pediatrics, Hassenfeld Children's Hospital at NYU Langone, New York, New York, USA
| | - Saeed Mohammad
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Sarah A Taylor
- Department of Pediatrics, Children's Hospital of Colorado, University of Colorado, Aurora, Colorado, USA
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Liu SH, Chen CC, Chao HC, Kong MS, Lai JY, Lai MW. Annual cholangitis more than twice predicts liver transplant in biliary atresia patients who achieve jaundice-free after Kasai portoenterostomy. J Formos Med Assoc 2025:S0929-6646(25)00006-3. [PMID: 39818465 DOI: 10.1016/j.jfma.2025.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/29/2024] [Accepted: 01/06/2025] [Indexed: 01/18/2025] Open
Abstract
BACKGROUND Biliary atresia (BA) is a progressive liver disease even after Kasai portoenterostomy (KPE), and the most common cause of liver transplant (LT) in the pediatric population. This study aimed to unveil the risk factors for LT in BA patients post-KPE. METHODS We conducted a retrospective study of BA patients in a northern Taiwan Children's Medical Center from Jan 2000 to Oct 2020. RESULTS A total of 65 BA patients (32 males, 33 females) were included. Seventeen (26%) patients received LT. Multivariate analysis showed higher serum direct bilirubin (cutoff ≥1.1 mg/dL) 3 months post-KPE (OR 8.17, p = 0.037) and higher peak yearly cholangitis episodes (OR 3.32, p = 0.008) independently predicted LT. In patients achieving jaundice-free (JF), yearly cholangitis frequency (OR 2.64, p = 0.032) independently predicted LT (cutoff ≥3). Concerning high cholangitis frequency, the independent predictor was the first cholangitis occurring 61-120 days post-KPE (OR 6.61, p = 0.034). In patients who achieved JF, bacteremia (OR 20.06, p = 0.037) and higher AST level 6 months post-KPE (OR 1.02, p = 0.016) independently predicted higher peak annual cholangitis frequency. CONCLUSIONS Higher direct bilirubin 3 months post-KPE (≥1.1 mg/dL) and higher peak annual cholangitis frequency predict LT in BA patients. The first cholangitis occurring 61-120 days post-KPE predicts higher peak annual cholangitis frequency. In patients who achieved JF, peak annual cholangitis episodes with a threshold of ≥3 independently predict LT. Bacteremia and higher serum AST levels at six months post-KPE predict higher peak annual cholangitis frequency.
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Affiliation(s)
- Su-Han Liu
- Division of Gastroenterology, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan City 33305, Taiwan
| | - Chien-Chang Chen
- Division of Gastroenterology, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan City 33305, Taiwan; Chang Gung University College of Medicine, No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan City, 33302, Taiwan
| | - Hsun-Chin Chao
- Division of Gastroenterology, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan City 33305, Taiwan; Chang Gung University College of Medicine, No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan City, 33302, Taiwan
| | - Man-Shan Kong
- Division of Gastroenterology, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan City 33305, Taiwan
| | - Jin-Yao Lai
- Department of Pediatric Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan City, Taiwan; Chang Gung University College of Medicine, No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan City, 33302, Taiwan
| | - Ming-Wei Lai
- Division of Gastroenterology, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan City 33305, Taiwan; Liver Research Center, Linkou Chang Gung Memorial Hospital, No.5, Fuxing St., Guishan Dist., Taoyuan City, 33305, Taiwan; Chang Gung University College of Medicine, No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan City, 33302, Taiwan.
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Miller PN, Baskaran S, Nijagal A. Immunology of Biliary Atresia. Semin Pediatr Surg 2024; 33:151474. [PMID: 39862687 DOI: 10.1016/j.sempedsurg.2025.151474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 01/07/2025] [Indexed: 01/27/2025]
Abstract
Biliary atresia is a progressive neonatal cholangiopathy that leads to liver failure. Characterized by inflammation-mediated liver injury, the immune system plays a critical role in the pathogenesis of this disease. Though several types of immune cells and mediators have been implicated in animal models of biliary atresia, emerging literature reflects the complex interplay of components of the immune response that contributes to disease progression in humans. Novel therapies targeting the immune system are needed to mitigate the devastating effects of biliary atresia. This review highlights the current literature on the components of the immune system that have been in implicated in biliary atresia and the rich interplay between the major arms of the immune system- innate and adaptive immunity- to cause the highly morbid consequences of this disease.
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Affiliation(s)
- Phoebe N Miller
- Department of Surgery, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Suruthi Baskaran
- Department of Surgery, University of Texas Health Science Center, 7703 Floyd Curl Drive San Antonio, TX 78229, USA
| | - Amar Nijagal
- Department of Surgery, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA; The Liver Center, University of California San Francisco, San Francisco, CA 94143; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
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Jeropoulos RM, Arroyo J, Davenport M. Predicting and optimising outcome for biliary atresia. Semin Pediatr Surg 2024; 33:151479. [PMID: 39884180 DOI: 10.1016/j.sempedsurg.2025.151479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 01/07/2025] [Indexed: 02/01/2025]
Abstract
Biliary atresia (BA) remains a disease of significant morbidity and mortality world-wide. Early and accurate diagnosis facilitates early intervention and improves outcomes. The gold standard in diagnosing BA is a liver biopsy followed by cholangiography, usually performed intra-operatively. Serum markers, like the aspartate aminotransferase-to-platelet ratio, matrix metalloproteinase-7 and several inflammatory cytokines have been recently investigated as non-invasive alternatives with varying degrees of success. Newer immunohistochemical analysis of liver biopsies, such as the expression of secretin receptors and Ki-67, from infants with BA have improved our understanding of the disease process and has shed a little light in predicting post-operative outcomes. There is little standardisation in the care of BA post operatively, though administration of steroids, prevention and treatment of cholangitis with antibiotics and anti-viral therapy for CMV+ve infants are becoming universally accepted as treatment. Experimental stem cell treatments show promise although remain in the out-of-reach future for now in routine clinical practice. This chapter aims to comprehensively describe recent knowledge on predicting the clinical outcomes of infants with BA, as well as optimising their care post operatively.
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Affiliation(s)
- Renos M Jeropoulos
- Dept of Paediatric Surgery, Kings College Hospital, London SE59RS, England, United Kingdom
| | - Jorge Arroyo
- Dept of Paediatric Surgery, Kings College Hospital, London SE59RS, England, United Kingdom
| | - Mark Davenport
- Dept of Paediatric Surgery, Kings College Hospital, London SE59RS, England, United Kingdom.
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Stetson A, Bondoc A, Tiao G. Revision Kasai portoenterostomy: A review of indications and outcomes. Semin Pediatr Surg 2024; 33:151476. [PMID: 39881457 DOI: 10.1016/j.sempedsurg.2025.151476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 01/07/2025] [Indexed: 01/31/2025]
Abstract
The Kasai portoenterostomy (KPE) can provide a surgical cure for children with biliary atresia (BA), without the need for a liver transplant (OLTxp). Revision KPE can be attempted following a failed initial KPE where biliary clearance is not achieved. The most common indications for revision KPE are recurrent jaundice or recurrent cholangitis, although it has also been performed for persistent jaundice or bile lakes. Outcomes are heterogenous but the best results appear to be with recurrent jaundice or limited episodes of recurrent cholangitis. In the setting of a failed KPE, providers must make a patient-specific decision about whether to attempt revision KPE versus proceed with OLTxp. While the choice is multifactorial, patients who undergo revision KPE likely do not have worse long-term outcomes than patients who undergo a single KPE.
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Affiliation(s)
- Alyssa Stetson
- Cincinnati Children's Hospital Medical Center, United States
| | | | - Greg Tiao
- Cincinnati Children's Hospital Medical Center, United States.
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7
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Zhang G, Zhang K. Analysis of the effect of hormone therapy on native liver survival after Kasai procedure for biliary atresia: A systematic review and meta-analysis of randomized controlled trials. Asian J Surg 2024; 47:5440-5441. [PMID: 38944610 DOI: 10.1016/j.asjsur.2024.06.092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 06/19/2024] [Indexed: 07/01/2024] Open
Affiliation(s)
- GuangLiang Zhang
- Traditional Chinese Medicine Hospital, Gong County, Yibin, Sichuan, China.
| | - Ke Zhang
- Traditional Chinese Medicine Hospital, Gong County, Yibin, Sichuan, China.
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Zhang Y, Liu S, Yang Q, Sun R, Liu J, Meng Y, Zhan J. Comparison of different Kasai portoenterostomy techniques in the outcomes of biliary atresia: a systematic review and network meta-analysis. Pediatr Surg Int 2024; 41:6. [PMID: 39592482 DOI: 10.1007/s00383-024-05920-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/18/2024] [Indexed: 11/28/2024]
Abstract
BACKGROUND Biliary atresia (BA) is a progressive disease affecting the bile duct structure and function, leading to poor outcomes without timely surgical intervention. Kasai portoenterostomy (KPE) is a commonly used treatment to restore bile flow. However, the success rate and postoperative outcomes of KPE vary with different surgical techniques, including laparoscopic, robot-assisted, and open approaches. METHODS Following the PRISMA guidelines, this study systematically searched PubMed, EMBASE, and Cochrane databases for literature on BA surgical techniques of KPE. Studies comparing two or all three techniques-laparoscopic, robot-assisted, and open-in terms of postoperative outcomes of KPE in BA patients were included. Utilizing the "gemtc" package in R version 4.3.3, NMA was conducted to compare postoperative clearance of jaundice (COJ) among different surgical techniques. We also performed traditional paired meta-analysis in which multiple surgical outcomes were compared. RESULTS According to the traditional definition of a successful KPE surgery, in terms of successful postoperative COJ, robotic-assisted Kasai portoenterostomy (RAKPE) shows advantage over open Kasai portoenterostomy (OKPE) and laparoscopic Kasai portoenterostomy (LKPE), while the outcomes between OKPE and LKPE are equivalent. However, statistically speaking, there is no significant difference among the three techniques. LKPE has a longer operation time and less intraoperative bleeding compared to OKPE. There are no statistically significant differences in hospital stay, cholangitis incidence, or liver survival rates at 6 months, 1 year, 2 years, or 5 years. CONCLUSION The surgical success rates of KPE with various technical aids are similar, highlighting the need to consider individual patient conditions and cost when choosing a surgical technique. Effective postoperative management is vital for preventing complications and slowing liver fibrosis. Future research should focus on improving surgical techniques and postoperative care to enhance long-term outcomes for BA patients. For those who cannot maintain liver function with KPE, timely LT consideration is crucial.
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Affiliation(s)
- Yanran Zhang
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, 300400, China
| | - Shaowen Liu
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, 300400, China
| | - Qianhui Yang
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, 300400, China
| | - Rongjuan Sun
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, 300400, China
| | - Jiaying Liu
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, 300400, China
| | - Yu Meng
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, 300400, China
| | - Jianghua Zhan
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, 300134, China.
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Tidwell J, Wu GY. Heritable Chronic Cholestatic Liver Diseases: A Review. J Clin Transl Hepatol 2024; 12:726-738. [PMID: 39130622 PMCID: PMC11310751 DOI: 10.14218/jcth.2024.00119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 05/14/2024] [Accepted: 05/28/2024] [Indexed: 08/13/2024] Open
Abstract
Chronic cholestasis due to heritable causes is usually diagnosed in childhood. However, many cases can present and survive into adulthood. The time course varies considerably depending on the underlying etiology. Laboratory data usually reveal elevated conjugated hyperbilirubinemia, alkaline phosphatase, and gamma-glutamyl transpeptidase. Patients may be asymptomatic; however, when present, the typical symptoms are pruritus, jaundice, fatigue, and alcoholic stools. The diagnostic methods and management required depend on the underlying etiology. The development of genome-wide associated studies has allowed the identification of specific genetic mutations related to the pathophysiology of cholestatic liver diseases. The aim of this review was to highlight the genetics, clinical pathophysiology, presentation, diagnosis, and treatment of heritable etiologies of chronic cholestatic liver disease.
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Affiliation(s)
- Jasmine Tidwell
- Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA
| | - George Y. Wu
- Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA
- Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
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10
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Davenport M, Superina R. Primary Liver Transplant in Biliary Atresia: The Case for and Against. J Pediatr Surg 2024; 59:1418-1426. [PMID: 38565475 DOI: 10.1016/j.jpedsurg.2024.03.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 02/27/2024] [Accepted: 03/10/2024] [Indexed: 04/04/2024]
Abstract
The role of liver transplantation as a primary procedure in biliary atresia has been argued over for at least 40 years, indeed since the coming of age of safe liver transplantation during the 1980s. Yet, it is not a common option in most series (usually ≤5%) and typically reserved for those with late presentations (arguably >100 days) with established cirrhosis. This review presents the pros and cons of primary liver transplant. The pros are based upon the observation that at best a Kasai portoenterostomy (KPE) is simply palliative in most, and at worse has no effect whatsoever on restoration of bile flow and is therefore pointless. Set against this are the cons: there is a dearth of prognostic tests (clinical, biochemical, or histological) at the time of presentation which may predict inevitable failure; the possibility of long-term native liver survival to adulthood in a proportion (albeit a minority); and the implied increased need for donor organs suitable for infants - a stressor for an already overstressed system. Improving results from KPE in terms of increasing the proportions clearing their jaundice and minimizing the effects of chronic liver fibrosis and cirrhosis would surely limit the siren calls for primary transplants but the key must be better discrimination at presentation with the use of biomarkers (circulatory or histological, individually or together) to enable better decision making.
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Affiliation(s)
- Mark Davenport
- Department of Pediatric Surgery, Kings College Hospital, London, SE5 9RS, UK.
| | - Riccardo Superina
- Department of Transplant and Advanced Hepatobiliary Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, IL, USA.
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Tam PKH, Wells RG, Tang CSM, Lui VCH, Hukkinen M, Luque CD, De Coppi P, Mack CL, Pakarinen M, Davenport M. Biliary atresia. Nat Rev Dis Primers 2024; 10:47. [PMID: 38992031 PMCID: PMC11956545 DOI: 10.1038/s41572-024-00533-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/10/2024] [Indexed: 07/13/2024]
Abstract
Biliary atresia (BA) is a progressive inflammatory fibrosclerosing disease of the biliary system and a major cause of neonatal cholestasis. It affects 1:5,000-20,000 live births, with the highest incidence in Asia. The pathogenesis is still unknown, but emerging research suggests a role for ciliary dysfunction, redox stress and hypoxia. The study of the underlying mechanisms can be conceptualized along the likely prenatal timing of an initial insult and the distinction between the injury and prenatal and postnatal responses to injury. Although still speculative, these emerging concepts, new diagnostic tools and early diagnosis might enable neoadjuvant therapy (possibly aimed at oxidative stress) before a Kasai portoenterostomy (KPE). This is particularly important, as timely KPE restores bile flow in only 50-75% of patients of whom many subsequently develop cholangitis, portal hypertension and progressive fibrosis; 60-75% of patients require liver transplantation by the age of 18 years. Early diagnosis, multidisciplinary management, centralization of surgery and optimized interventions for complications after KPE lead to better survival. Postoperative corticosteroid use has shown benefits, whereas the role of other adjuvant therapies remains to be evaluated. Continued research to better understand disease mechanisms is necessary to develop innovative treatments, including adjuvant therapies targeting the immune response, regenerative medicine approaches and new clinical tests to improve patient outcomes.
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Affiliation(s)
- Paul K H Tam
- Medical Sciences Division, Macau University of Science and Technology, Macau, China.
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| | - Rebecca G Wells
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Clara S M Tang
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China
| | - Vincent C H Lui
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China
| | - Maria Hukkinen
- Section of Paediatric Surgery, Paediatric Liver and Gut Research Group, New Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Carlos D Luque
- Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
| | - Paolo De Coppi
- NIHR Biomedical Research Centre, Great Ormond Street Hospital for Children NHS Foundation Trust and Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Cara L Mack
- Department of Paediatrics, Division of Paediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Children's Wisconsin, Milwaukee, WI, USA
| | - Mikko Pakarinen
- Section of Paediatric Surgery, Paediatric Liver and Gut Research Group, New Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
| | - Mark Davenport
- Department of Paediatric Surgery, King's College Hospital, London, UK
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Vutukuru S, Solanki S, Kanojia RP. Delphi Method Analysis and Consensus of Prevalent Distinctive Practices for Biliary Atresia Management after Kasai Portoenterostomy. J Indian Assoc Pediatr Surg 2024; 29:271-276. [PMID: 38912031 PMCID: PMC11192269 DOI: 10.4103/jiaps.jiaps_250_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/29/2024] [Accepted: 02/05/2024] [Indexed: 06/25/2024] Open
Abstract
Background Extrahepatic biliary atresia (BA) is seen in infants, with an incidence of 1 in 15,000 live births. The presentation is progressive jaundice, dark-colored urine, and clay-colored stools. Kasai portoenterostomy (KPE) is the commonly performed surgical procedure in these patients. Postoperatively, phenobarbitone, ursodeoxycholic acid (UDCA), steroids, and other drugs are given to improve bile drainage and prevent inflammation and fibrosis. However, a definitive protocol regarding the need for different drugs, dosage, and duration varies across individual surgeons and centers. No universally accepted protocol exists for postoperative management after KPE. Aim The aim of this study was to know the prevailing postoperative management of BA by subject experts and use the Delphi process to know if the experts want to change their practice based on the results from the survey. Material and Methods A questionnaire was made after discussing with two experts in the field of BA. The questionnaire was mailed to 25 subject experts. The first survey data were analyzed and shared with all responders. In the second survey, change in the management based on the results from the first survey was assessed. Results The Delphi questionnaire was answered by 17 experts. Postoperatively, prophylactic antibiotics are prescribed for 6-12 weeks by around 40% and >12 weeks by 30% of respondents. Phenobarbitone is prescribed for <3 months by nearly 50%. UDCA is prescribed for <3 months, ≤6 months, and 6 months-1 year by 47.1%, 23.5%, and 23.5% responders, respectively. Nearly 50% prescribe steroids (mostly prednisolone), and among them, two-thirds prescribe it for 6-12 weeks. Approximately 60% give antiviral drugs to children who are cytomegalovirus immunoglobulin M positive. In our survey, 50% of experts perform 5-10 KPE per year, and 25% each perform 10-15 and >15 KPE per year. The second survey noted that a significant percentage of responders want to change their practice according to consensus. Conclusion From our Delphi survey, an overview of the postoperative management of BA could be made. However, multicentric studies are required for uniform protocol on the postoperative management of BA.
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Affiliation(s)
- Sravanthi Vutukuru
- Department of Pediatric Surgery, Siddhartha Medical College, Vijayawada, Andhra Pradesh, India
| | - Shailesh Solanki
- Department of Pediatric Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ravi Prakash Kanojia
- Department of Pediatric Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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13
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Yoeli D, Mack CL, Luo Y, Chaidez A, De La Rosa NL, Wang Z, Cervantes-Alvarez E, Huang CA, Navarro-Alvarez N. Galectin-3 in biliary atresia and other pediatric cholestatic liver diseases. Hepatol Res 2024; 54:392-402. [PMID: 37950561 DOI: 10.1111/hepr.13987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 10/28/2023] [Accepted: 10/30/2023] [Indexed: 11/12/2023]
Abstract
AIMS Biliary atresia (BA) is characterized by intrahepatic inflammation and rapid progression of liver fibrosis. Galectin-3, a beta-galactoside binding protein, is a key regulator of inflammation and fibrosis. The aim of this study was to characterize circulating and hepatic Galectin-3 levels in children with BA. METHODS Plasma and liver samples were obtained from children with early BA at time of Kasai hepatoportoenterostomy, late BA at time of transplant, early and late other cholestatic liver diseases (CLD), and controls. Plasma Galectin-3 was measured using standard enzyme-linked immunoassay. Liver tissue was analyzed with multiplex immunohistochemistry and quantified using whole slide analysis. Statistical comparisons were made using nonparametric testing. RESULTS Plasma Galectin-3 in late BA was significantly higher than in early BA (20.82 [12.45-30.46] vs. 11.30 [8.74-16.83] ng/mL, p = 0.0096). Galectin-3 levels correlated with markers of disease severity and interleukin-6. There were significantly more Galectin-3+ M2 macrophages in late BA in comparison to late other CLD (162 [157-233] vs. 49 [33-59] cells/mm2, p = 0.03). The number of Galectin-3+ M2 macrophages correlated with the number of activated hepatic stellate cells and bile duct proliferation. CONCLUSIONS Plasma Galectin-3 is higher in late BA at time of transplant in comparison to early BA at time of Kasai. The number of Galectin-3 expressing M2 macrophages in late BA is elevated relative to late other CLD and was associated with other prognostic histological findings. Galectin-3 targeted therapy may be beneficial in slowing disease progression to cirrhosis in children with BA.
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Affiliation(s)
- Dor Yoeli
- Division of Transplant Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Cara L Mack
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Yuhuan Luo
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Alexander Chaidez
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Nathaly Limon De La Rosa
- Division of Transplant Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Zhaohui Wang
- Division of Transplant Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Eduardo Cervantes-Alvarez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Christene A Huang
- Division of Transplant Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Nalu Navarro-Alvarez
- Division of Transplant Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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14
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Eiamkulbutr S, Tubjareon C, Sanpavat A, Phewplung T, Srisan N, Sintusek P. Diseases of bile duct in children. World J Gastroenterol 2024; 30:1043-1072. [PMID: 38577180 PMCID: PMC10989494 DOI: 10.3748/wjg.v30.i9.1043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/26/2023] [Accepted: 02/04/2024] [Indexed: 03/06/2024] Open
Abstract
Several diseases originate from bile duct pathology. Despite studies on these diseases, certain etiologies of some of them still cannot be concluded. The most common disease of the bile duct in newborns is biliary atresia, whose prognosis varies according to the age of surgical correction. Other diseases such as Alagille syndrome, inspissated bile duct syndrome, and choledochal cysts are also time-sensitive because they can cause severe liver damage due to obstruction. The majority of these diseases present with cholestatic jaundice in the newborn or infant period, which is quite difficult to differentiate regarding clinical acumen and initial investigations. Intraoperative cholangiography is potentially necessary to make an accurate diagnosis, and further treatment will be performed synchronously or planned as findings suggest. This article provides a concise review of bile duct diseases, with interesting cases.
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Affiliation(s)
- Sutha Eiamkulbutr
- Department of Pediatrics, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Chomchanat Tubjareon
- Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Anapat Sanpavat
- Department of Pathology, Chulalongkorn University, Bangkok 10330, Thailand
| | - Teerasak Phewplung
- Department of Radiology, Chulalongkorn University, Bangkok 10330, Thailand
| | - Nimmita Srisan
- Department of Surgery, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Palittiya Sintusek
- Center of Excellence in Thai Pediatric Gastroenterology, Hepatology and Immunology, Division of Gastroenterology, Department of Pediatrics, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok 10330, Thailand
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15
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Trampert DC, Beuers U. A beneficial response of fetal wound healing gone bad in the bile duct: The overarching cause of biliary atresia? J Hepatol 2024; 80:387-389. [PMID: 38181824 DOI: 10.1016/j.jhep.2023.12.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 12/18/2023] [Indexed: 01/07/2024]
Affiliation(s)
- David C Trampert
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam, the Netherlands.
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16
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Sutton H, Karpen SJ, Kamath BM. Pediatric Cholestatic Diseases: Common and Unique Pathogenic Mechanisms. ANNUAL REVIEW OF PATHOLOGY 2024; 19:319-344. [PMID: 38265882 DOI: 10.1146/annurev-pathmechdis-031521-025623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2024]
Abstract
Cholestasis is the predominate feature of many pediatric hepatobiliary diseases. The physiologic flow of bile requires multiple complex processes working in concert. Bile acid (BA) synthesis and excretion, the formation and flow of bile, and the enterohepatic reuptake of BAs all function to maintain the circulation of BAs, a key molecule in lipid digestion, metabolic and cellular signaling, and, as discussed in the review, a crucial mediator in the pathogenesis of cholestasis. Disruption of one or several of these steps can result in the accumulation of toxic BAs in bile ducts and hepatocytes leading to inflammation, fibrosis, and, over time, biliary and hepatic cirrhosis. Biliary atresia, progressive familial intrahepatic cholestasis, primary sclerosing cholangitis, and Alagille syndrome are four of the most common pediatric cholestatic conditions. Through understanding the commonalities and differences in these diseases, the important cellular mechanistic underpinnings of cholestasis can be greater appreciated.
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Affiliation(s)
- Harry Sutton
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;
| | - Saul J Karpen
- Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Binita M Kamath
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;
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17
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Takeda M, Tsukui T, Cazares J, Tsuboi K, Ochi T, Shibuya S, Koga H, Lane GJ, Yamataka A. Prednisolone administration monitored by postoperative stool color achieves high jaundice clearance after laparoscopic portoenterostomy for biliary atresia. Pediatr Surg Int 2023; 39:299. [PMID: 37985521 DOI: 10.1007/s00383-023-05580-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/22/2023] [Indexed: 11/22/2023]
Abstract
PURPOSE Stool color (SC) for monitoring prednisolone use in biliary atresia (BA) patients after laparoscopic portoenterostomy (LPE) was reviewed. METHODS Subjects were 47 post-LPE BA patients given a reducing dose course of intravenous prednisolone. The course started at 4 mg/kg/day and gradually reduced, ultimately reaching a final total dose (TD) of 31.5 mg/kg. Normal SC indicated a course could progress until finished and was repeated until jaundice clearance (JC) was achieved. Abnormal SC persisting for two consecutive courses was the absolute indication for redo or liver transplantation (LTx). RESULTS JC was achieved in 38/47 (80.9%) LPE cases and 4/6 redos to give an overall JC rate (JCR) of 42/47 (89.4%). Outcomes after one course (n = 5; JCR: 80.0%; median TD: 30.0 mg/kg, interquartile range [IQR: 26.0-31.5]), two courses (n = 10; JCR: 90.0%; median TD: 62.5 mg/kg [IQR: 60.8-66.0]), three courses (n = 13; JCR: 92.3%; median TD: 90.0 mg/kg [IQR: 86.0-90.0]), four courses (n = 10; JCR: 80.0%; median TD: 120.0 mg/kg [IQR: 116.7-123.3]), five courses (n = 7; JCR: 100%; median TD: 156.0 mg/kg [IQR: 154.3-157.5]), six courses (n = 1; JCR: 100%; TD: 189.0 mg/kg), ten courses (n = 1; JCR: 100%; TD: 308 mg/kg). CONCLUSION Indications for repeat prednisolone and timing of redo/LTx based on SC monitoring appeared effective based on high JCR and successful redo/LTx. LEVELS OF EVIDENCE III.
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Affiliation(s)
- Masahiro Takeda
- Department of Pediatric Surgery, Juntendo University School of Medicine, Tokyo, Japan.
| | - Takafumi Tsukui
- Department of Pediatric Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Joel Cazares
- Department of Pediatric Surgery, Juntendo University School of Medicine, Tokyo, Japan
- Department of Pediatric Surgery, Hospital Regional de Alta Especialidad Materno Infantil, Monterrey, Mexico
| | - Koichi Tsuboi
- Department of Pediatric Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Takanori Ochi
- Department of Pediatric Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Soichi Shibuya
- Department of Pediatric Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Hiroyuki Koga
- Department of Pediatric Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Geoffrey J Lane
- Department of Pediatric Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Atsuyuki Yamataka
- Department of Pediatric Surgery, Juntendo University School of Medicine, Tokyo, Japan
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18
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Zhang Y, Zhang D, Chen L, Zhou J, Ren B, Chen H. The progress of autoimmune hepatitis research and future challenges. Open Med (Wars) 2023; 18:20230823. [PMID: 38025543 PMCID: PMC10655690 DOI: 10.1515/med-2023-0823] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 09/24/2023] [Accepted: 09/28/2023] [Indexed: 12/01/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic liver inflammatory disease with various immune system manifestations, showing a global trend of increased prevalence. AIH is diagnosed through histological abnormalities, clinical manifestations, and biochemical indicators. The biochemical markers involve interfacial hepatitis, transaminase abnormalities, positive autoantibodies, etc. Although AIH pathogenesis is unclear, gene mutations and immunological factors could be the leading factors. AIH usually presents as a chronic liver disease and sometimes as acute hepatitis, making it challenging to distinguish it from drug-related hepatitis due to similar clinical symptoms. Normalizing transaminases and serum IgG levels is essential in assessing the remission status of AIH treatment. Glucocorticoids and azathioprine are the first-line AIH treatment, with lifelong maintenance therapy in some patients. The quality of life and survival can be improved after appropriate treatment. However, certain limitations jeopardize the quality of treatment, including long treatment cycles, side effects, poor patient compliance, and inability to inhibit liver fibrosis and cirrhosis. Accurate AIH animal models will help us understand the pathophysiology of the disease while providing fresh perspectives for avoiding and treating AIH. This review will help us understand AIH better, from the cellular and molecular causes to the clinical features, and will provide insight into new therapy techniques with fewer side effects.
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Affiliation(s)
- Yang Zhang
- Graduate Department of Zhejiang Chinese Medicine University, Hangzhou, Zhejiang, China
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Dehe Zhang
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Ling Chen
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Jing Zhou
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Binbin Ren
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Haijun Chen
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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19
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Pandurangi S, Kim S, Asai A, Bondoc A, Balistreri W, Campbell K, Miethke A, Peters A, Rogers M, Taylor A, Attia SL, Gibbons T, Mullapudi B, Sheridan R, Tiao G, Bezerra JA. Customized Postoperative Therapy Improves Bile Drainage in Biliary Atresia: A Single Center Preliminary Report. J Pediatr Surg 2023; 58:1483-1488. [PMID: 36496264 PMCID: PMC10846645 DOI: 10.1016/j.jpedsurg.2022.10.050] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 09/22/2022] [Accepted: 10/19/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Controversies in management of biliary atresia (BA) after hepatoportoenterostomy (HPE) lead to variable treatment protocols. We implemented standardized medical management after HPE, customizing the use of antibiotics and corticosteroids based on patient-specific factors. METHODS In this retrospective analysis, 20 consecutive infants underwent HPE for BA and were compared to a historical cohort. Analysis of successful biliary drainage 3 months after HPE (defined as serum total bilirubin <2 mg/dL) was the primary endpoint; survival with native liver at 2 years was the secondary endpoint. RESULTS Sixteen of 20 (80%) infants had successful bile drainage, compared to 8 of 20 (40%) infants in the historical cohort (P = 0.0225). Sixteen of 20 patients in the new protocol have reached 2 years of age or required liver transplantation. Among the sixteen, 11 (68.8%) are alive with native livers versus 10 of 20 (50%) in the historical cohort (P = 0.0970). CONCLUSION This preliminary report suggests the potential benefit of tailored use of postoperative antibiotics and corticosteroids in improving biliary drainage after HPE. LEVEL OF EVIDENCE III.
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Affiliation(s)
- Sindhu Pandurangi
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Seung Kim
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Akihiro Asai
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Alexander Bondoc
- Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - William Balistreri
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Kathleen Campbell
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Alexander Miethke
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Anna Peters
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Michael Rogers
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Amy Taylor
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Suzanna Labib Attia
- Division of Gastroenterology, Hepatology and Nutrition and Department of Pediatrics, University of Kentucky Children's Hospital, Lexington, Kentucky, USA
| | - Troy Gibbons
- Division of Gastroenterology, Hepatology and Nutrition and Department of Pediatrics, University of Kentucky Children's Hospital, Lexington, Kentucky, USA
| | - Bhargava Mullapudi
- Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Rachel Sheridan
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Greg Tiao
- Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
| | - Jorge A Bezerra
- Division of Pediatrics, Children's Medical Center of Dallas, Dallas, Texas, USA; University of Texas Southwestern Medical Center, Dallas, Texas, USA.
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Abstract
Biliary atresia (BA) is the most prevalent serious liver disease of infancy and childhood, and the principal indication for liver transplantation in pediatrics. BA is best considered as an idiopathic panbiliary cholangiopathy characterized by obstruction of bile flow and consequent cholestasis presenting during fetal and perinatal periods. While several etiologies have been proposed, each has significant drawbacks that have limited understanding of disease progression and the development of effective treatments. Recently, modern genetic analyses have uncovered gene variants contributing to BA, thereby shifting the paradigm for explaining the BA phenotype from an acquired etiology (e.g., virus, toxin) to one that results from genetically altered cholangiocyte development and function. Herein we review recently reported genetic contributions to BA, highlighting the enhanced representation of variants in biological pathways involving ciliary function, cytoskeletal structure, and inflammation. Finally, we blend these findings as a new framework for understanding the resultant BA phenotype as a developmental cholangiopathy.
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Affiliation(s)
- Dominick J Hellen
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia
| | - Saul J Karpen
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia
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21
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Lu X, Jiang J, Shen Z, Chen G, Np YW, Xiao X, Yan W, Zheng S. Effect of Adjuvant Steroid Therapy in Type 3 Biliary Atresia: A Single-Center, Open-Label, Randomized Controlled Trial. Ann Surg 2023; 277:e1200-e1207. [PMID: 35170539 DOI: 10.1097/sla.0000000000005407] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To evaluate the efficacy and side effects of additional postoperative steroid therapy for type 3 BA versus the current routine care. SUMMARY BACKGROUND DATA Whether steroid therapy post-Kasai portoen-terostomy improves the outcomes of BA remains controversial. Clinical evidence from 2 randomized trials in the UK and USA do not support the routine use of steroid in the treatment of BA. METHODS In this open-label randomized controlled trial, patients with type 3 BA were randomized to routine postoperative treatment with or without 10 to 12 weeks of adjuvant steroid treatment. The primary outcome was the postoperative jaundice clearance rate with native liver at 6 months. The secondary outcomes included postoperative jaundice clearance rate at 3, 12, and 24 months, survival with native liver at 12 and 24 months, and SAEs within 3 months. RESULTS Overall, 200 participants were randomized and allocated into either steroid or control group (n = 100/group). The proportion of participants that are jaundice free without liver transplantation was significantly higher in the steroid group than in the control group at 6 months (54.1% vs 31.0%, P = 0.0015). The native liver survival rate was higher postoperatively in the steroid group than in the control group at 12 (66.3% vs 50.0%, P = 0.02) and 24 (57.1% vs 40.0%, P = 0.02) months. The survival time with native liver was significantly longer in the steroid group than in the control group (median survival, steroid vs control: not reached vs 1.21 years, P = 0.02). There were no significant differences between the 2 groups in the mean occurrence of SAEs within 3 months (steroid vs control: 0.63 vs 0.45, P = 0.20). CONCLUSIONS Postoperative adjuvant steroid intervention improved bile drainage and survival with native liver in type 3 BA patients, without increasing early-stage SAEs.
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Affiliation(s)
- Xuexin Lu
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
| | - Jingying Jiang
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
| | - Zhen Shen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
| | - Gong Chen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
| | - Ying Wu Np
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
| | - Xianmin Xiao
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
| | - Weili Yan
- Clinical Trial Unit (CTU), Children's Hospital of Fudan University, Shanghai, China
| | - Shan Zheng
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
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22
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Xie S, Wei S, Ma X, Wang R, He T, Zhang Z, Yang J, Wang J, Chang L, Jing M, Li H, Zhou X, Zhao Y. Genetic alterations and molecular mechanisms underlying hereditary intrahepatic cholestasis. Front Pharmacol 2023; 14:1173542. [PMID: 37324459 PMCID: PMC10264785 DOI: 10.3389/fphar.2023.1173542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 05/16/2023] [Indexed: 06/17/2023] Open
Abstract
Hereditary cholestatic liver disease caused by a class of autosomal gene mutations results in jaundice, which involves the abnormality of the synthesis, secretion, and other disorders of bile acids metabolism. Due to the existence of a variety of gene mutations, the clinical manifestations of children are also diverse. There is no unified standard for diagnosis and single detection method, which seriously hinders the development of clinical treatment. Therefore, the mutated genes of hereditary intrahepatic cholestasis were systematically described in this review.
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Affiliation(s)
- Shuying Xie
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Shizhang Wei
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Xiao Ma
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ruilin Wang
- Department of Pharmacy, 5th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Tingting He
- Department of Pharmacy, 5th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhao Zhang
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ju Yang
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiawei Wang
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lei Chang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Manyi Jing
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Haotian Li
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Xuelin Zhou
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yanling Zhao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
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23
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Harpavat S, Hawthorne K, Setchell KDR, Rivas MN, Henn L, Beil CA, Karpen SJ, Ng VL, Alonso EM, Bezerra JA, Guthery SL, Horslen S, Loomes KM, McKiernan P, Magee JC, Merion RM, Molleston JP, Rosenthal P, Thompson RJ, Wang KS, Sokol RJ, Shneider BL. Serum bile acids as a prognostic biomarker in biliary atresia following Kasai portoenterostomy. Hepatology 2023; 77:862-873. [PMID: 36131538 PMCID: PMC9936974 DOI: 10.1002/hep.32800] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 08/22/2022] [Accepted: 09/04/2022] [Indexed: 01/29/2023]
Abstract
BACKGROUND AND AIMS In biliary atresia, serum bilirubin is commonly used to predict outcomes after Kasai portoenterostomy (KP). Infants with persistently high levels invariably need liver transplant, but those achieving normalized levels have a less certain disease course. We hypothesized that serum bile acid levels could help predict outcomes in the latter group. APPROACH AND RESULTS Participants with biliary atresia from the Childhood Liver Disease Research Network were included if they had normalized bilirubin levels 6 months after KP and stored serum samples from the 6-month post-KP clinic visit ( n = 137). Bile acids were measured from the stored serum samples and used to divide participants into ≤40 μmol/L ( n = 43) or >40 μmol/L ( n = 94) groups. At 2 years of age, the ≤40 μmol/L compared with >40 μmol/L group had significantly lower total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, bile acids, and spleen size, as well as significantly higher albumin and platelet counts. Furthermore, during 734 person-years of follow-up, those in the ≤40 μmol/L group were significantly less likely to develop splenomegaly, ascites, gastrointestinal bleeding, or clinically evident portal hypertension. The ≤40 μmol/L group had a 10-year cumulative incidence of liver transplant/death of 8.5% (95% CI: 1.1%-26.1%), compared with 42.9% (95% CI: 28.6%-56.4%) for the >40 μmol/L group ( p = 0.001). CONCLUSIONS Serum bile acid levels may be a useful prognostic biomarker for infants achieving normalized bilirubin levels after KP.
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Affiliation(s)
- Sanjiv Harpavat
- Division of Gastroenterology, Department of Pediatrics , Hepatology and Nutrition, Baylor College of Medicine and Texas Children's Hospital , Houston , Texas , USA
| | - Kieran Hawthorne
- Arbor Research Collaborative for Health , Ann Arbor , Michigan , USA
| | - Kenneth D R Setchell
- Division of Pathology and Laboratory Medicine , Cincinnati Children's Hospital Medical Center , Cincinnati , Ohio , USA
| | - Monica Narvaez Rivas
- Division of Pathology and Laboratory Medicine , Cincinnati Children's Hospital Medical Center , Cincinnati , Ohio , USA
| | - Lisa Henn
- Arbor Research Collaborative for Health , Ann Arbor , Michigan , USA
| | - Charlotte A Beil
- Arbor Research Collaborative for Health , Ann Arbor , Michigan , USA
| | - Saul J Karpen
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics , Emory University School of Medicine , Atlanta , Georgia , USA
| | - Vicky L Ng
- Division of Gastroenterology, Hepatology and Nutrition , Hospital for Sick Children and University of Toronto , Toronto , Ontario , Canada
| | - Estella M Alonso
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics , Ann and Robert H. Lurie Children's Hospital of Chicago , Chicago , Illinois , USA
| | - Jorge A Bezerra
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics , Cincinnati Children's Hospital Medical Center , Cincinnati , Ohio , USA
| | - Stephen L Guthery
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics , University of Utah , Salt Lake City , Utah , USA
| | - Simon Horslen
- Division of Gastroenterology and Hepatology, Department of Pediatrics , University of Washington Medical Center and Seattle Children's , Seattle , Washington , USA.,Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics , University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh , Pittsburgh , Pennsylvania , USA
| | - Kathy M Loomes
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics , Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia , Philadelphia , Pennsylvania , USA
| | - Patrick McKiernan
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics , University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh , Pittsburgh , Pennsylvania , USA
| | - John C Magee
- Department of Surgery, Section of Transplant Surgery , University of Michigan Medical School , Ann Arbor , Michigan , USA
| | - Robert M Merion
- Arbor Research Collaborative for Health , Ann Arbor , Michigan , USA
| | - Jean P Molleston
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics , Indiana University School of Medicine and Riley Hospital for Children , Indianapolis , Indiana , USA
| | - Philip Rosenthal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics , University of California San Francisco , San Francisco , California , USA
| | | | - Kasper S Wang
- Division of Pediatric Surgery, Department of Surgery , Children's Hospital of Los Angeles, University of Southern California , Los Angeles , California , USA
| | - Ronald J Sokol
- Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition , University of Colorado School of Medicine and Children's Hospital Colorado , Aurora , Colorado , USA
| | - Benjamin L Shneider
- Division of Gastroenterology, Department of Pediatrics , Hepatology and Nutrition, Baylor College of Medicine and Texas Children's Hospital , Houston , Texas , USA
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Matcovici M, Stoica I, Smith K, Davenport M. What Makes A "Successful" Kasai Portoenterostomy "Unsuccessful"? J Pediatr Gastroenterol Nutr 2023; 76:66-71. [PMID: 36574004 DOI: 10.1097/mpg.0000000000003638] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVES Clearance of jaundice (CoJ) is the first key objective of Kasai portoenterostomy (KPE) for biliary atresia (BA) and its achievement is by far the best index of long-term prognosis. We sought to identify the reasons for failure [subsequent liver transplant (LT)] in this cohort. METHODS Review of single-center prospective BA database. Successful KPE was defined by achieving a postoperative bilirubin of ≤20 µmol/L. Pre-KPE and post-KPE variables were identified together with a multivariate logistic regression model to identify those observable at 3 months post-KPE. Data are quoted as median (range). A P value of ≤0.05 was significant. RESULTS One hundred thirty-five infants underwent KPE between January 2012 and December 2018, of which 90 (67%) achieved CoJ. From these 20 (22%) (Cohort A) underwent LT with the remainder continuing with native liver (Cohort B) (median follow-up of 4.15 years). There was no difference in age at KPE ( P = 0.41), APRi (aspartate aminotransferase-to-platelet ratio) ( P = 0.07), associated anomalies ( P = 0.7), and cytomegalovirus status ( P = 0.7) between the 2 groups. Postoperatively, both cholangitis [any episode, 18/20 (90%) vs 15/70 (21%); P < 0.0001] and portal hypertension (PHT) [gastrointestinal (GI) bleed, 10/20 (50%) vs 2/70 (2.8%); P < 0.0001] were significantly more common in cohort A. Univariate analysis showed that the most significant predictive values at 3 months for LT by 2 years were high APRi, bilirubin, international normalized ratio, and ultrasound (US)-detected ascites with multivariate logistic modeling confirming these variables with predictive values of r2 = 0.79, AUROC = 0.98. CONCLUSIONS Failure is not preordained at KPE but due to recurrent cholangitis and/or symptoms of PHT.
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Affiliation(s)
- Melania Matcovici
- From the Department of Paediatric Surgery, Kings College Hospital, London, United Kingdom
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25
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Davenport M, Madadi-Sanjani O, Chardot C, Verkade HJ, Karpen SJ, Petersen C. Surgical and Medical Aspects of the Initial Treatment of Biliary Atresia: Position Paper. J Clin Med 2022; 11:6601. [PMID: 36362829 PMCID: PMC9656543 DOI: 10.3390/jcm11216601] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/30/2022] [Accepted: 11/04/2022] [Indexed: 02/13/2024] Open
Abstract
Biliary atresia, a fibro-obliterative disease of the newborn, is usually initially treated by Kasai portoenterostomy, although there are many variations in technique and different options for post-operative adjuvant medical therapy. A questionnaire on such topics (e.g., open vs. laparoscopic; the need for liver mobilisation; use of post-operative steroids; use of post-operative anti-viral therapy, etc.) was circulated to delegates (n = 43) of an international webinar (Biliary Atresia and Related Diseases-BARD) held in June 2021. Respondents were mostly European, but included some from North America, and represented 18 different countries overall. The results of this survey are presented here, together with a commentary and review from an expert panel convened for the meeting on current trends in practice.
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Affiliation(s)
- Mark Davenport
- Department of Paediatric Surgery, Kings College Hospital, London SE5 9RS, UK
| | - Omid Madadi-Sanjani
- Klinik für Kinderchirurgie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Christophe Chardot
- Chirurgie Pédiatrique—Transplantation, Hôpital Necker—Enfants Maladies, Université Paris Descartes, 149 Rue de Sèvres, 75015 Paris, France
| | - Henkjan J. Verkade
- Center for Liver, Digestive and Metabolic Diseases, Universitair Medisch Centrum, 9713 AV Groningen, The Netherlands
| | - Saul J. Karpen
- Center for Advanced Pediatrics, 1400 Tullie Circle SE 2nd Floor, Atlanta, GA 30329, USA
| | - Claus Petersen
- Klinik für Kinderchirurgie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
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26
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Nishio T, Koyama Y, Fuji H, Ishizuka K, Iwaisako K, Taura K, Hatano E, Brenner DA, Kisseleva T. The Role of Mesothelin in Activation of Portal Fibroblasts in Cholestatic Liver Injury. BIOLOGY 2022; 11:1589. [PMID: 36358290 PMCID: PMC9687690 DOI: 10.3390/biology11111589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/18/2022] [Accepted: 10/27/2022] [Indexed: 11/05/2022]
Abstract
Fibrosis is a common consequence of abnormal wound healing, which is characterized by infiltration of myofibroblasts and formation of fibrous scar. In liver fibrosis, activated Hepatic Stellate Cells (aHSCs) and activated Portal Fibroblasts (aPFs) are the major contributors to the origin of hepatic myofibroblasts. aPFs are significantly involved in the pathogenesis of cholestatic fibrosis, suggesting that aPFs may be a primary target for anti-fibrotic therapy in cholestatic injury. aPFs are distinguishable from aHSCs by specific markers including mesothelin (Msln), Mucin 16 (Muc16), and Thymus cell antigen 1 (Thy1, CD90) as well as fibulin 2, elastin, Gremlin 1, ecto-ATPase nucleoside triphosphate diphosphohydrolase 2. Msln plays a critical role in activation of PFs, via formation of Msln-Muc16-Thy1 complex that regulates TGFβ1/TGFβRI-mediated fibrogenic signaling. The opposing pro- and anti-fibrogenic effects of Msln and Thy1 are key components of the TGFβ1-induced activation pathway in aPFs. In addition, aPFs and activated lung and kidney fibroblasts share similarities across different organs with expression of common markers and activation cascade including Msln-Thy1 interaction. Here, we summarize the potential function of Msln in activation of PFs and development of cholestatic fibrosis, offering a novel perspective for anti-fibrotic therapy targeting Msln.
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Affiliation(s)
- Takahiro Nishio
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yukinori Koyama
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hiroaki Fuji
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
| | - Kei Ishizuka
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
| | - Keiko Iwaisako
- Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Tataramiyakodani, Kyotanabe 610-0394, Japan
| | - Kojiro Taura
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, 2-4-20 Ogimachi, Kita-ku, Osaka 530-8480, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - David A. Brenner
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
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27
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Yang CZ, Zhou Y, Ke M, Gao RY, Ye SR, Diao M, Li L. Effects of postoperative adjuvant steroid therapy on the outcomes of biliary atresia: A systematic review and updated meta-analysis. Front Pharmacol 2022; 13:956093. [PMID: 36188593 PMCID: PMC9516003 DOI: 10.3389/fphar.2022.956093] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 08/19/2022] [Indexed: 11/30/2022] Open
Abstract
Background: Postoperative adjuvant steroid therapy is regarded as the conventional treatment for patients with biliary atresia (BA) who have undergone Kasai portoenterostomy (KP). However, whether the steroid therapy can improve BA outcomes is controversial. This meta-analysis aimed to evaluate the effects of adjuvant steroid therapy on the surgical prognosis of BA. Methods: We searched related studies published in PubMed, Embase, Web of Science, Cochrane, and the Chinese National Knowledge Infrastructure database up to May 2022. Data on the effect of steroid use on the clinical prognosis of the patients, including the jaundice clearance rate (JCR), native liver survival rate (NLSR) at 6, 12, and 24 months after KP, and the incidence of cholangitis, were extracted. Subgroup analyses based on age at KP, administration method, initial dosage, and steroid type were conducted. Statistical analysis was conducted using Stata/SE 12.0. Results: Eleven articles (a total of 1,032 patients) were included in the present meta-analysis. The results demonstrated that postoperative adjuvant steroid therapy improved JCR at the 6/12/24-month follow-up (RR: 1.35, 95% CI: 1.18–1.55, p < 0.001; RR:1.49, 95% CI, 1.12–1.99, p = 0.006; RR: 1.41, 95% CI: 1.14–1.75, p = 0.002) and improved NLSR at the 24-month follow-up (RR: 1.31, 95% CI: 1.03–1.68, p = 0.028). However, steroids could not significantly improve NLSR at the 6/12-month follow-up (RR: 1.06; 95% CI: 0.98–1.15; p = 0.17; RR: 1.22; 95% CI: 0.97–1.54; p = 0.095), and might not decrease the incidence of postoperative cholangitis (RR: 0.78, 95% CI: 0.60–1.01, p = 0.058). Furthermore, subgroup analyses confirmed that three variables (age at KP, administration method, and initial dosage) could affect the efficacy of steroids in BA patients. Conclusion: Postoperative adjuvant steroid therapy can significantly improve bile flow. The superiority of steroid therapy was more remarkable in patients aged ≤70 days at KP than in those aged >70 days. Additionally, intravenous followed by oral steroid administration method and medium initial dosage seemed to have the more reliable efficiency on bile flow. And patients treated by steroid had better long-term (24-month) native liver survival, but there is no significant effect on short-term native liver survival and postoperative cholangitis. Further studies are warranted.
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Affiliation(s)
- Chang-zhen Yang
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Research Unit of Minimally Invasive Pediatric Surgery on Diagnosis and Treatment(2021RU015), Chinese Academy of Medical Sciences, Beijing, China
| | - Yan Zhou
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Research Unit of Minimally Invasive Pediatric Surgery on Diagnosis and Treatment(2021RU015), Chinese Academy of Medical Sciences, Beijing, China
| | - Meng Ke
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Research Unit of Minimally Invasive Pediatric Surgery on Diagnosis and Treatment(2021RU015), Chinese Academy of Medical Sciences, Beijing, China
| | - Ru-yue Gao
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Research Unit of Minimally Invasive Pediatric Surgery on Diagnosis and Treatment(2021RU015), Chinese Academy of Medical Sciences, Beijing, China
| | - Shi-ru Ye
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China
| | - Mei Diao
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Research Unit of Minimally Invasive Pediatric Surgery on Diagnosis and Treatment(2021RU015), Chinese Academy of Medical Sciences, Beijing, China
| | - Long Li
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Research Unit of Minimally Invasive Pediatric Surgery on Diagnosis and Treatment(2021RU015), Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Long Li,
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28
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Bass LM, Ye W, Hawthorne K, Leung DH, Murray KF, Molleston JP, Romero R, Karpen S, Rosenthal P, Loomes KM, Wang KS, Squires RH, Miethke A, Ng VL, Horslen S, Kyle Jensen M, Sokol RJ, Magee JC, Shneider BL. Risk of variceal hemorrhage and pretransplant mortality in children with biliary atresia. Hepatology 2022; 76:712-726. [PMID: 35271743 PMCID: PMC9378352 DOI: 10.1002/hep.32451] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 02/24/2022] [Accepted: 02/25/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS The natural history of gastroesophageal variceal hemorrhage (VH) in biliary atresia (BA) is not well characterized. We analyzed risk factors, incidence, and outcomes of VH in a longitudinal multicenter study. APPROACH AND RESULTS Participants enrolled in either an incident (Prospective Database of Infants with Cholestasis [PROBE]) or prevalent (Biliary Atresia Study of Infants and Children [BASIC]) cohort of BA were included. Variceal hemorrhage (VH) was defined based on gastrointestinal bleeding in the presence of varices accompanied by endoscopic or nontransplant surgical intervention. Cumulative incidence of VH and transplant-free survival was compared based on features of portal hypertension (e.g., splenomegaly, thrombocytopenia) and clinical parameters at baseline in each cohort (PROBE: 1.5 to 4.5 months after hepatoportoenterostomy [HPE]; BASIC: at enrollment > 3 years of age). Analyses were conducted on 869 children with BA enrolled between June 2004 and December 2020 (521 in PROBE [262 (51%) with a functioning HPE] and 348 in BASIC). The overall incidence of first observed VH at 5 years was 9.4% (95% CI: 7.0-12.4) in PROBE and 8.0% (5.2-11.5) in BASIC. Features of portal hypertension, platelet count, total bilirubin, aspartate aminotransferase (AST), albumin, and AST-to-platelet ratio index at baseline were associated with an increased risk of subsequent VH in both cohorts. Transplant-free survival at 5 years was 45.1% (40.5-49.6) in PROBE and 79.2% (74.1-83.4) in BASIC. Two (2.5%) of 80 participants who had VH died, whereas 10 (12.5%) underwent transplant within 6 weeks of VH. CONCLUSIONS The low risk of VH and associated mortality in children with BA needs to be considered in decisions related to screening for varices and primary prophylaxis of VH.
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Affiliation(s)
- Lee M. Bass
- Department of PediatricsAnn & Robert H. Lurie Children’s Hospital of ChicagoNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
| | - Wen Ye
- Department of BiostatisticsUniversity of MichiganAnn ArborMichiganUSA
| | | | - Daniel H. Leung
- Division of Gastroenterology, Hepatology, and NutritionDepartment of PediatricsBaylor College of Medicine and Texas Children’s HospitalHoustonTexasUSA
| | - Karen F. Murray
- Division of GastroenterologyDepartment of PediatricsHepatologySeattle Children’s Hospital and the University of Washington School of MedicineSeattleWashington StateUSA
- Present address:
Cleveland Clinic Children’s Pediatric InstituteClevelandOhioUSA
| | - Jean P. Molleston
- Division of Gastroenterology, Hepatology, and NutritionDepartment of PediatricsRiley Hospital for ChildrenIndiana UniversityIndianapolisIndianaUSA
| | - Rene Romero
- Division of Gastroenterology, Hepatology, and NutritionDepartment of PediatricsChildren’s Healthcare of Atlanta and Emory University School of MedicineAtlantaGeorgiaUSA
| | - Saul Karpen
- Division of Gastroenterology, Hepatology, and NutritionDepartment of PediatricsChildren’s Healthcare of Atlanta and Emory University School of MedicineAtlantaGeorgiaUSA
| | - Philip Rosenthal
- Department of PediatricsUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
| | - Kathleen M. Loomes
- Division of Gastroenterology, Hepatology and NutritionThe Children’s Hospital of Philadelphia and Department of PediatricsPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Kasper S. Wang
- Department of Pediatric SurgeryChildren’s Hospital Los AngelesLos AngelesCaliforniaUSA
| | - Robert H. Squires
- Division of Gastroenterology, Hepatology, and NutritionDepartment of PediatricsUniversity of PittsburghSchool of Medicine and Children’s Hospital of Pittsburgh of University of Pittsburgh Medical CenterPittsburghPennsylvaniaUSA
| | - Alexander Miethke
- Division of Gastroenterology, Hepatology, and NutritionDepartment of PediatricsUniversity of CincinnatiCincinnatiOhioUSA
| | - Vicky L. Ng
- Division of GI, Hepatology and NutritionHospital for Sick Children and University of TorontoTorontoOntarioCanada
| | - Simon Horslen
- Department of PediatricsSeattle Children’s HospitalUniversity of Washington School of MedicineSeattleWashington StateUSA
| | - M. Kyle Jensen
- Department of PediatricsUniversity of UtahSalt Lake CityUtahUSA
| | - Ronald J. Sokol
- Department of Pediatrics‐Gastroenterology, Hepatology and NutritionUniversity of Colorado School of Medicine and Children’s Hospital ColoradoAuroraColoradoUSA
| | - John C. Magee
- Department of SurgeryUniversity of Michigan School of MedicineAnn ArborMichiganUSA
| | - Benjamin L. Shneider
- Section of Pediatric Gastroenterology, Hepatology and NutritionTexas Children’s Hospital and Baylor College of MedicineHoustonTexasUSA
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29
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Antala S, Taylor SA. Biliary Atresia in Children: Update on Disease Mechanism, Therapies, and Patient Outcomes. Clin Liver Dis 2022; 26:341-354. [PMID: 35868678 PMCID: PMC9309872 DOI: 10.1016/j.cld.2022.03.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Biliary atresia is a rare disease but remains the most common indication for pediatric liver transplantation as there are no effective medical therapies to slow progression after diagnosis. Variable contribution of genetic, immune, and environmental factors contributes to disease heterogeneity among patients with biliary atresia. Developing a deeper understanding of the disease mechanism will help to develop targeted medical therapies and improve patient outcomes.
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Affiliation(s)
- Swati Antala
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, USA
| | - Sarah A. Taylor
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, USA
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30
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Islek A, Tumgor G. Biliary atresia and congenital disorders of the extrahepatic bile ducts. World J Gastrointest Pharmacol Ther 2022; 13:33-46. [PMID: 36051179 PMCID: PMC9297290 DOI: 10.4292/wjgpt.v13.i4.33] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/10/2022] [Accepted: 06/13/2022] [Indexed: 02/06/2023] Open
Abstract
Biliary atresia (BA) and choledochal cysts are diseases of the intrahepatic and extrahepatic biliary tree. While their exact etiopathogeneses are not known, they should be treated promptly due to the potential for irreversible parenchymal liver disease. A diagnosis of BA may be easy or complicated, but should not be delayed. BA is always treated surgically, and performing the surgery before the age of 2 mo greatly increases its effectiveness and extends the time until the need for liver transplantation arises. While the more common types of choledochal cysts require surgical treatment, some can be treated with endoscopic retrograde cholangiopancreatography. Choledochal cysts may cause recurrent cholangitis and the potential for malignancy should not be ignored.
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Affiliation(s)
- Ali Islek
- Department of Pediatric Gastroenterology, Cukurova University School of Medicine, Adana 01320, Turkey
| | - Gokhan Tumgor
- Department of Pediatric Gastroenterology, Cukurova University School of Medicine, Adana 01320, Turkey
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31
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Study protocol of Phase 2 open-label multicenter randomized controlled trial for granulocyte-colony stimulating factor (GCSF) in post-Kasai Type 3 biliary atresia. Pediatr Surg Int 2022; 38:1019-1030. [PMID: 35391541 DOI: 10.1007/s00383-022-05115-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2022] [Indexed: 12/07/2022]
Abstract
Animal studies support RCT findings of improved liver function and short-term benefits using repurposed Granulocyte Colonic Stimulating Factor GCSF in adults with decompensated cirrhosis. We describe the protocol for phase 2 RCT of sequential Kasai-GCSF under an FDA-approved IND to test that GCSF improves early bile flow and post-Kasai biliary atresia BA clinical outcome. Immediate post-Kasai neonates, age 15-180 days, with biopsy-confirmed type 3 BA, without access to early liver transplantation, will be randomized 1:1 to standard of care SOC + GCSF at 10 ug/kg in 3 daily doses within 4 days of Kasai vs SOC + NO-GCSF (ClinicalTrials.gov NCT0437391). They will be recruited from children's hospitals in Vietnam, Pakistan and one US center. The primary objective is to demonstrate that GCSF decreases the proportion of subjects with a 3-month post-Kasai serum Total Bilirubin ≥ 34 umol/L by 20%, (for a = 0.05, b = 0.80, i.e., calculated sample size of 218 subjects). The secondary objectives are to demonstrate that the frequency of post-Kasai cholangitis at 6-month and 24-month transplant-free survival are improved. The benefits are that GCSF is an affordable BA adjunct therapy, especially in developing countries, to improve biliary complications, enhance quality of liver and survival while diminishing costly liver transplantation.Clinical trial registration: A phase 1 for GCSF dose and safety determination under ClinicalTrials.gov identifier NCT03395028 was completed in 2019. The current Phase 2 trial was registered under NCT04373941.
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Yang T, Yang S, Zhao J, Wang P, Li S, Jin Y, Liu Z, Zhang X, Zhang Y, Zhao Y, Liao J, Li S, Hua K, Gu Y, Wang D, Huang J. Comprehensive Analysis of Gut Microbiota and Fecal Bile Acid Profiles in Children With Biliary Atresia. Front Cell Infect Microbiol 2022; 12:914247. [PMID: 35782134 PMCID: PMC9247268 DOI: 10.3389/fcimb.2022.914247] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 05/24/2022] [Indexed: 12/12/2022] Open
Abstract
BackgroundBiliary atresia (BA) is the most common cholestatic liver disease in neonates. Herein, we aimed at characterizing the gut microbiota and fecal bile acid profiles of BA patients, defining the correlations between them, and evaluating the relationship between the clinical pathogenesis and changes in the gut microbiota and bile acid profiles.MethodsA total of 84 fecal samples from BA patients (n = 46) and matched healthy controls (HCs, n = 38) were subjected to sequencing by 16S rRNA gene amplification, and fecal bile acid were analyzed by targeted metabolomics.FindingsCompared with the controls, a structural separation of the intestinal flora of BA patients was uncovered, which was accompanied by changes in the composition of fecal bile acids. In the BA group, Actinobacillus, Monoglobus, and Agathobacter were enriched in patients without cholangitis (p < 0.05). Selenomonadaceae and Megamonas were more abundant in patients without recurrent cholangitis episodes (p < 0.05), while Lachnospiraceae and Ruminococcaceae were enriched in patients with multiple recurrences of cholangitis (p < 0.05). Postoperative jaundice clearance was associated with Campylobacter and Rikenellaceae (p < 0.05), and tauroursodeoxycholic acid was associated with jaundice clearance (p < 0.001).ConclusionBA patients are characterized by different compositions of gut microbiota and bile acids, and their interaction is involved in the process of liver damage in BA, which may be closely related to the occurrence of postoperative cholangitis and jaundice clearance.
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He L, Chung PHY, Lui VCH, Tang CSM, Tam PKH. Current Understanding in the Clinical Characteristics and Molecular Mechanisms in Different Subtypes of Biliary Atresia. Int J Mol Sci 2022; 23:ijms23094841. [PMID: 35563229 PMCID: PMC9103665 DOI: 10.3390/ijms23094841] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 04/23/2022] [Accepted: 04/24/2022] [Indexed: 02/01/2023] Open
Abstract
Biliary atresia is a severe obliterative cholangiopathy in early infancy that is by far the most common cause of surgical jaundice and the most common indicator for liver transplantation in children. With the advanced knowledge gained from different clinical trials and the development of research models, a more precise clinical classification of BA (i.e., isolated BA (IBA), cystic BA (CBA), syndromic BA (SBA), and cytomegalovirus-associated BA (CMVBA)) is proposed. Different BA subtypes have similar yet distinguishable clinical manifestations. The clinical and etiological heterogeneity leads to dramatically different prognoses; hence, treatment needs to be specific. In this study, we reviewed the clinical characteristics of different BA subtypes and revealed the molecular mechanisms of their developmental contributors. We aimed to highlight the differences among these various subtypes of BA which ultimately contribute to the development of a specific management protocol for each subtype.
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Affiliation(s)
- Lin He
- Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, China;
| | - Patrick Ho Yu Chung
- Division of Paediatric Surgery, Department of Surgery, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (V.C.H.L.); (C.S.M.T.); (P.K.H.T.)
- Correspondence: ; Tel.: +852-22554850; Fax: +852-28173155
| | - Vincent Chi Hang Lui
- Division of Paediatric Surgery, Department of Surgery, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (V.C.H.L.); (C.S.M.T.); (P.K.H.T.)
| | - Clara Sze Man Tang
- Division of Paediatric Surgery, Department of Surgery, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (V.C.H.L.); (C.S.M.T.); (P.K.H.T.)
| | - Paul Kwong Hang Tam
- Division of Paediatric Surgery, Department of Surgery, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (V.C.H.L.); (C.S.M.T.); (P.K.H.T.)
- Faculty of Medicine, Macau University of Science and Technology, Macau SAR, China
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Ludwig K, Santoro L, Ingravallo G, Cazzato G, Giacometti C, Dall’Igna P. Congenital anomalies of the gastrointestinal tract: the liver, extrahepatic biliary tree and pancreas. Pathologica 2022; 114:55-63. [PMID: 35212316 PMCID: PMC9040543 DOI: 10.32074/1591-951x-709] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 12/07/2021] [Indexed: 02/08/2023] Open
Abstract
Congenital anomalies of the liver, biliary tree and pancreas are rare birth defects, some of which are characterized by a marked variation in geographical incidence. Morphogenesis of the hepatobiliary and pancreatic structures initiates from two tubular endodermal evaginations of the most distal portion of the foregut. The pancreas develops from a larger dorsal and a smaller ventral outpouching; emergence of the two buds will eventually lead to the fusion of the duct system. A small part of the remaining ventral diverticulum divides into a "pars cystica" and "pars hepatica", giving rise to the cystic duct and gallbladder and the liver lobes, respectively. Disruption or malfunctioning of the complex mechanisms leading to the development of liver, gallbladder, biliary tree and pancreas can result in numerous, albeit fortunately relatively rare, congenital anomalies in these organs. The type and severity of anomalies often depend on the exact moment in which disruption or alteration of the embryological mechanisms takes place. Many theories have been brought forward to explain their embryological basis; however, no agreement has yet been reached for most of them. While in some cases pathological evaluation might be more centered on macroscopic evaluation, in other instances small biopsies will be the keystone to understanding organ function and treatment results in the context of congenital anomalies. Thus, knowledge of the existence and histopathological characteristics of some of the more common conditions is mandatory for every pathologist working in the field of gastrointestinal pathology.
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Affiliation(s)
- Kathrin Ludwig
- Department of Pathology, Azienda Ospedale-Università Padova, Padua, Italy
| | - Luisa Santoro
- Department of Pathology, Azienda Ospedale-Università Padova, Padua, Italy
| | - Giuseppe Ingravallo
- Department of Emergencies and Organ Transplantation, Section of Pathology, University of Bari, Bari, Italy
| | - Gerardo Cazzato
- Department of Emergencies and Organ Transplantation, Section of Pathology, University of Bari, Bari, Italy
| | - Cinzia Giacometti
- Department if Services, Pathology Unit, ULSS 6 “Euganea”, Camposampiero, Italy
| | - Patrizia Dall’Igna
- Department of Emergencies and Organ Transplantation, Pediatric Surgery, University of Bari, Bari, Italy
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Fligor SC, Hirsch TI, Tsikis ST, Adeola A, Puder M. Current and emerging adjuvant therapies in biliary atresia. Front Pediatr 2022; 10:1007813. [PMID: 36313875 PMCID: PMC9614654 DOI: 10.3389/fped.2022.1007813] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 09/26/2022] [Indexed: 11/21/2022] Open
Abstract
Following Kasai hepatic portoenterostomy (HPE), most patients with biliary atresia will eventually require liver transplantation due to progressive cirrhosis and liver failure. Preventing liver transplantation, or even delaying eventual liver transplantation, is the key to improving long-term outcomes. This review first examines the commonly used adjuvant therapies in post-HPE biliary atresia and the strength of the evidence supporting these therapies. Next, it examines the evolving frontiers of management through a comprehensive evaluation of both recently completed and ongoing clinical trials in biliary atresia. Promising therapies used in other cholestatic liver diseases with potential benefit in biliary atresia are discussed. Improving post-HPE management is critical to prevent complications, delay liver transplantation, and ultimately improve the long-term survival of patients with biliary atresia.
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Affiliation(s)
- Scott C Fligor
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Thomas I Hirsch
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Savas T Tsikis
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Andrew Adeola
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Mark Puder
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
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Abstract
Cholestatic jaundice is a common presenting feature of hepatobiliary and/or metabolic dysfunction in the newborn and young infant. Timely detection of cholestasis, followed by rapid step-wise evaluation to determine the etiology, is crucial to identify those causes that are amenable to medical or surgical intervention and to optimize outcomes for all infants. In the past 2 decades, genetic etiologies have been elucidated for many cholestatic diseases, and next-generation sequencing, whole-exome sequencing, and whole-genome sequencing now allow for relatively rapid and cost-effective diagnosis of conditions not previously identifiable via standard blood tests and/or liver biopsy. Advances have also been made in our understanding of risk factors for parenteral nutrition-associated cholestasis/liver disease. New lipid emulsion formulations, coupled with preventive measures to decrease central line-associated bloodstream infections, have resulted in lower rates of cholestasis and liver disease in infants and children receiving long-term parental nutrition. Unfortunately, little progress has been made in determining the exact cause of biliary atresia. The median age at the time of the hepatoportoenterostomy procedure is still greater than 60 days; consequently, biliary atresia remains the primary indication for pediatric liver transplantation. Several emerging therapies may reduce the bile acid load to the liver and improve outcomes in some neonatal cholestatic disorders. The goal of this article is to review the etiologies, diagnostic algorithms, and current and future management strategies for infants with cholestasis.
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Affiliation(s)
- Amy G Feldman
- Digestive Health Institute, Children's Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
| | - Ronald J Sokol
- Digestive Health Institute, Children's Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
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Abstract
"Biliary atresia (BA) is a common cause of jaundice in infancy. There is increasing evidence that newborn screening with direct or conjugated bilirubin leads to earlier diagnosis. Although the Kasai portoenterostomy is the primary treatment, there are scientific advances in adjuvant therapies. As pediatric patients transition to adult care, multidisciplinary care is essential, given the complexity of this patient population."
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Affiliation(s)
- Sara E Yerina
- Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, USA
| | - Udeme D Ekong
- Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, USA; Department of Pediatrics, Georgetown University School of Medicine, Washington, DC, USA.
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Reuland C, Cappiello CD. Cystic biliary atresia masquerading as a choledochal cyst. JOURNAL OF PEDIATRIC SURGERY CASE REPORTS 2021. [DOI: 10.1016/j.epsc.2021.102025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Kakos CD, Ziogas IA, Alexopoulos SP, Tsoulfas G. Management of biliary atresia: To transplant or not to transplant. World J Transplant 2021; 11:400-409. [PMID: 34631471 PMCID: PMC8465510 DOI: 10.5500/wjt.v11.i9.400] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 06/26/2021] [Accepted: 08/18/2021] [Indexed: 02/06/2023] Open
Abstract
Kasai procedure (KP) and liver transplantation (LT) represent the only therapeutic options for patients with biliary atresia (BA), the most common indication for LT in the pediatric population. However, KP represents by no means a radical option but rather a bridging one, as nearly all patients will finally require a liver graft. More and more experts in the field of transplant surgery propose that maybe it is time for a paradigm change in BA treatment and abandon KP as transplantation seems inevitable. Inadequacy of organs yet makes this option currently not feasible, so it seems useful to find ways to maximize the efficacy of KP. In previous decades, multiple studies tried to identify these factors which opt for better results, but in general, outcomes of KP have not improved to the level that was anticipated. This review provides the framework of conditions which favor native liver survival after KP and the ones which optimize a positive LT outcome. Strategies of transition of care at the right time are also presented, as transplantation plays a key role in the surgical treatment of BA. Future studies and further organization in the transplant field will allow for greater organ availability and better outcomes to be achieved for BA patients.
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Affiliation(s)
| | - Ioannis A Ziogas
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN 37212, United States
| | - Sophoclis P Alexopoulos
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN 37212, United States
| | - Georgios Tsoulfas
- Department of Transplant Surgery, Aristotle University School of Medicine, Thessaloniki 54622, Greece
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Parolini F, Boroni G, Betalli P, Cheli M, Pinelli D, Colledan M, Alberti D. Extended Adhesion-Sparing Liver Eversion during Kasai Portoenterostomy for Infants with Biliary Atresia. CHILDREN-BASEL 2021; 8:children8090820. [PMID: 34572252 PMCID: PMC8470555 DOI: 10.3390/children8090820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 09/08/2021] [Accepted: 09/14/2021] [Indexed: 11/29/2022]
Abstract
Background: Despite the fact that Kasai portoenterostomy (KPE) is the primary treatment for biliary atresia (BA), liver transplantation (LT) remains the ultimate surgery for two-thirds of these patients. Their true survival rate with the native liver reflects the original KPE and the burden of post-operative complications. We report an original modification of the adhesion-sparing liver eversion (ASLE) technique during KPE that facilitates the total native hepatectomy at time of transplantation. Methods: All consecutive patients with BA who underwent KPE at our department and subsequent LT at Paediatric Liver Transplant Centre at Papa Giovanni XXIII Hospital between 2010–2018 were retrospectively enrolled. All patients underwent ASLE during KPE. Patients’ demographic data, type of KPE, total transplant time (TTT), hepatectomy time (HT), intra-operative packed red blood cells and plasma transfusions, intra- and post-operative complications were noted. Results: 44 patients were enrolled. Median TTT and HT were 337 and 57 min, respectively. The median volume of packed red blood cell transfusion was 95 mL. No patients presented bowel perforation during the procedure or in the short post-operative course. No mortality after LT was recorded. Conclusions: In addition to the well-known advantages of the standard liver eversion technique, ASLE reduces the formation of intra-abdominal adhesions, lowering significantly the risk of bowel perforation and bleeding when liver transplantation is performed for failure of KPE.
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Affiliation(s)
- Filippo Parolini
- Department of Paediatric Surgery, “Spedali Civili” Children’s Hospital, 25123 Brescia, Italy; (G.B.); (D.A.)
- Correspondence: ; Tel.: +39-0303996201; Fax: +39-0303996154
| | - Giovanni Boroni
- Department of Paediatric Surgery, “Spedali Civili” Children’s Hospital, 25123 Brescia, Italy; (G.B.); (D.A.)
| | - Pietro Betalli
- Department of Paediatric Surgery, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy; (P.B.); (M.C.)
| | - Maurizio Cheli
- Department of Paediatric Surgery, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy; (P.B.); (M.C.)
| | - Domenico Pinelli
- Department of Surgery III, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy; (D.P.); (M.C.)
| | - Michele Colledan
- Department of Surgery III, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy; (D.P.); (M.C.)
| | - Daniele Alberti
- Department of Paediatric Surgery, “Spedali Civili” Children’s Hospital, 25123 Brescia, Italy; (G.B.); (D.A.)
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
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Hukkinen M, Ruuska S, Pihlajoki M, Kyrönlahti A, Pakarinen MP. Long-term outcomes of biliary atresia patients surviving with their native livers. Best Pract Res Clin Gastroenterol 2021; 56-57:101764. [PMID: 35331404 DOI: 10.1016/j.bpg.2021.101764] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 08/20/2021] [Accepted: 08/30/2021] [Indexed: 01/31/2023]
Abstract
Portoenterostomy (PE) has remained as the generally accepted first line surgical treatment for biliary atresia (BA) for over 50 years. Currently, close to half of BA patients survive beyond 10 years with their native livers, and most of them reach adulthood without liver transplantation (LT). Despite normalization of serum bilirubin by PE, ductular reaction and portal fibrosis persist in the native liver. The chronic cholangiopathy progresses to cirrhosis, complications of portal hypertension, recurrent cholangitis or hepatobiliary tumors necessitating LT later in life. Other common related health problems include impaired bone health, neuromotor development and quality of life. Only few high-quality trials are available for evidence-based guidance of post-PE adjuvant medical therapy or management of the disease complications. Better understanding of the pathophysiological mechanisms connecting native liver injury to clinical outcomes is critical for development of accurate follow-up tools and novel therapies designed to improve native liver function and survival.
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Affiliation(s)
- Maria Hukkinen
- Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki, Stenbackinkatu 11 PO Box 281, 00029, HUS, Finland.
| | - Satu Ruuska
- Department of Pediatric Gastroenterology, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki, Stenbäckinkatu 9/PO BOX 347, 00029, HUS, Finland.
| | - Marjut Pihlajoki
- Pediatric Research Center, Children's Hospital, University of Helsinki, Tukholmankatu 8, 00290, Helsinki, Finland.
| | - Antti Kyrönlahti
- Pediatric Research Center, Children's Hospital, University of Helsinki, Stenbackinkatu 11 PO Box 281, 00029, HUS, Finland.
| | - Mikko P Pakarinen
- Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki, Stenbackinkatu 11 PO Box 281, 00029, HUS, Finland.
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Jaffey JA. Canine hepatobiliary anatomy, physiology and congenital disorders. J Small Anim Pract 2021; 63:95-103. [PMID: 34409602 DOI: 10.1111/jsap.13410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/21/2021] [Accepted: 07/27/2021] [Indexed: 11/29/2022]
Abstract
The biliary system is an integral component of normal physiologic homeostasis and essential for survival. It acts as a conduit for the removal of detoxified and catabolised compounds as well as aids in fat digestion and absorption. Derangements in this system can have dangerous sequela that are associated with varying degrees of morbidity and mortality. Moreover, abnormalities in development of the biliary system can have varied and unpredictable changes on function and long-term outcome. The aims of this article were to review canine hepatobiliary anatomy, physiology and cholestasis as well as summarise congenital biliary disorders including human corollaries.
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Affiliation(s)
- J A Jaffey
- Department of Specialty Medicine, College of Veterinary Medicine, Midwestern University, Glendale, Arizona, USA
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Mohanty SK, Donnelly B, Temple H, Ortiz-Perez A, Mowery S, Lobeck I, Dupree P, Poling HM, McNeal M, Mourya R, Jenkins T, Bansal R, Bezerra J, Tiao G. High Mobility Group Box 1 Release by Cholangiocytes Governs Biliary Atresia Pathogenesis and Correlates With Increases in Afflicted Infants. Hepatology 2021; 74:864-878. [PMID: 33559243 PMCID: PMC8349381 DOI: 10.1002/hep.31745] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 12/11/2020] [Accepted: 01/06/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Biliary atresia (BA) is a devastating cholangiopathy of infancy. Upon diagnosis, surgical reconstruction by Kasai hepatoportoenterostomy (HPE) restores biliary drainage in a subset of patients, but most patients develop fibrosis and progress to end-stage liver disease requiring liver transplantation for survival. In the murine model of BA, rhesus rotavirus (RRV) infection of newborn pups results in a cholangiopathy paralleling that of human BA. High-mobility group box 1 (HMGB1) is an important member of the danger-associated molecular patterns capable of mediating inflammation during infection-associated responses. In this study, we investigated the role of HMGB1 in BA pathogenesis. APPROACH AND RESULTS In cholangiocytes, RRV induced the expression and release of HMGB1 through the p38 mitogen-activated protein kinase signaling pathway, and inhibition of p38 blocked HMGB1 release. Treatment of cholangiocytes with ethyl pyruvate suppressed the release of HMGB1. Administration of glycyrrhizin in vivo decreased symptoms and increased survival in the murine model of BA. HMGB1 levels were measured in serum obtained from infants with BA enrolled in the PROBE and START studies conducted by the Childhood Liver Disease Research Network. High HMGB1 levels were found in a subset of patients at the time of HPE. These patients had higher bilirubin levels 3 months post-HPE and a lower survival of their native liver at 2 years. CONCLUSIONS These results suggest that HMGB1 plays a role in virus induced BA pathogenesis and could be a target for therapeutic interventions in a subset of patients with BA and high HMGB1.
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Affiliation(s)
- Sujit K Mohanty
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Bryan Donnelly
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Haley Temple
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Ana Ortiz-Perez
- Translational Liver ResearchDepartment of Medical Cell BiophysicsTechnical Medical CentreFaculty of Science and TechnologyUniversity of TwenteEnschedeThe Netherlands
| | - Sarah Mowery
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Inna Lobeck
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Phylicia Dupree
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Holly M Poling
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Monica McNeal
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOH.,Division of Infectious DiseasesCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Reena Mourya
- Division of Gastroenterology Hepatology & NutritionCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Todd Jenkins
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Ruchi Bansal
- Translational Liver ResearchDepartment of Medical Cell BiophysicsTechnical Medical CentreFaculty of Science and TechnologyUniversity of TwenteEnschedeThe Netherlands
| | - Jorge Bezerra
- Division of Gastroenterology Hepatology & NutritionCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Greg Tiao
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOH
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Goh L, Phua KB, Low Y, Chiang LW, Yong C, Chiou FK. Analysis of Cholangitis Rates with Extended Perioperative Antibiotics and Adjuvant Corticosteroids in Biliary Atresia. Pediatr Gastroenterol Hepatol Nutr 2021; 24:366-376. [PMID: 34316471 PMCID: PMC8279824 DOI: 10.5223/pghn.2021.24.4.366] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 03/24/2021] [Accepted: 05/15/2021] [Indexed: 12/14/2022] Open
Abstract
PURPOSE There is no consensus regarding adjuvant therapies following Kasai portoenterostomy (KP) for biliary atresia (BA). This study aimed to analyze the effect of extended perioperative intravenous antibiotics (PI-Abx) and adjuvant corticosteroid on cholangitis and jaundice clearance rates in the 3 years post-KP in children with BA. METHODS Data of patients who underwent KP between 1999-2018 at a single center were retrospectively analyzed. Group A (1999-2010) received PI-Abx for 5 days, Group B (2010-2012) received PI-Abx for 5 days plus low-dose prednisolone (2 mg/kg), and Group C (2012-2017) received PI-Abx for 14 days plus high-dose prednisolone (5 mg/kg). RESULTS Fifty-four patients were included with groups A, B, and C comprising 25, 9, and 20 patients, respectively. The number of episodes of cholangitis was 1.0, 1.6, and 1.3 per patient (p=NS) within the first year and 1.8, 2.3, and 1.7 (p=NS) over 3 years in Groups A, B, and C, respectively. The jaundice clearance rate at 6 months was 52%, 78%, and 50% (p=NS), and the 3-year native liver survival (NLS) rate was 76%, 100%, and 80% (p=NS) in Groups A, B, and C, respectively. A near-significant association was observed between the incidence of cholangitis within the first year and decompensated liver cirrhosis/death at 3 years post KP (p=0.09). Persistence of jaundice at 6 months was significantly associated with decompensated cirrhosis/death at 3 years (p<0.001). CONCLUSION The extended duration of PI-Abx and adjuvant corticosteroids was not associated with improved rates of cholangitis, jaundice clearance, or NLS in patients with BA.
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Affiliation(s)
- Lynette Goh
- Gastroenterology, Hepatology & Nutrition Service, Pediatric Medicine, KK Women's and Children's Hospital, Singapore
| | - Kong Boo Phua
- Gastroenterology, Hepatology & Nutrition Service, Pediatric Medicine, KK Women's and Children's Hospital, Singapore
| | - Yee Low
- Department of Pediatric Surgery, KK Women's and Children's Hospital, Singapore
| | - Li Wei Chiang
- Department of Pediatric Surgery, KK Women's and Children's Hospital, Singapore
| | - Chen Yong
- Department of Pediatric Surgery, KK Women's and Children's Hospital, Singapore
| | - Fang Kuan Chiou
- Gastroenterology, Hepatology & Nutrition Service, Pediatric Medicine, KK Women's and Children's Hospital, Singapore
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El-Guindi MAS, Saber MA, Shoeir SA, Abdallah AR, Sira AM. Variant etiologies of neonatal cholestasis and their outcome: a Middle East single-center experience. Clin Exp Hepatol 2021; 7:205-214. [PMID: 34295989 PMCID: PMC8284164 DOI: 10.5114/ceh.2021.107066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 03/21/2021] [Indexed: 11/17/2022] Open
Abstract
AIM OF THE STUDY Neonatal cholestasis (NC) constitutes a large proportion of pediatric liver disorders. Nevertheless, awareness of the variant etiologies and how to manage them appropriately are lacking. So, out of a few specialized centers, many cases pass without appropriate management. This study aimed to present our tertiary level center's experience in NC that could increase the pediatrician's awareness of handling this problematic and common medical morbidity efficiently. MATERIAL AND METHODS It is a retrospective study in which we analyzed the NC cases admitted to the inpatient department within three years. For all recruited patients, the available data were retrieved and recorded. RESULTS A total of 412 patients were reviewed with 20 different etiologies diagnosed. The most common cause was biliary atresia (n = 151, 37%), followed by progressive familial intrahepatic cholestasis (n = 51, 12%), neonatal sepsis (n = 39, 9%), and cytomegalovirus (n = 33, 8%). Of the 412 patients, 394 (81%) had follow-up ranging from 1 to 36 months. A total of 173 patients improved with supportive and/or specific therapy, while 108 patients died at a median age of 6 months. The commonest cause of death was liver failure (40.7%), followed by pneumonia (28.7%), sudden death (13%), septicemia (6.5%), and hepatorenal syndrome (5.5%). CONCLUSIONS NC constitutes more than one-third of the inpatient admissions of all pediatric liver disorders and has a high rate of mortality. Awareness of the variety of etiologies and a rapid stepwise approach to diagnosis could have an impact on the outcome of this devastating disease.
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Affiliation(s)
- Mohamed Abdel-Salam El-Guindi
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, Egypt
| | - Magdy Anwar Saber
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, Egypt
| | - Samar Ahmed Shoeir
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, Egypt
| | - Ayat Roushdy Abdallah
- Department of Epidemiology and Preventive Medicine, National Liver Institute, Menoufia University, Egypt
| | - Ahmad Mohamed Sira
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, Egypt
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El-Araby HA, Saber MA, Radwan NM, Taie DM, Adawy NM, Sira AM. SOX9 in biliary atresia: New insight for fibrosis progression. Hepatobiliary Pancreat Dis Int 2021; 20:154-162. [PMID: 33349604 DOI: 10.1016/j.hbpd.2020.12.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 12/01/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Liver fibrosis is a hallmark determinant of morbidity in biliary atresia (BA) even in successfully operated cases. Responsible factors for this rapid progression of fibrosis are not completely defined. Aberrant expression of the transcription factor SOX9 and hepatic progenitor cells (HPCs) proliferation have roles in fibrogenesis in cholestatic disorders. However, they were not investigated sufficiently in BA. We aimed to delineate the relation of SOX9 and HPCs to fibrosis and its progression in BA. METHODS Forty-eight patients with BA who underwent an initial diagnostic liver biopsy (LB) and consequent intraoperative LB were recruited and compared to 28 cases with non-BA cholestasis that had an LB in their diagnostic workup. Liver fibrosis, tissue SOX9 and HPC expressions were studied in both BA and non-BA-cholestasis cases. Liver fibrosis, SOX9, and HPCs' dynamic changes in BA cases were assessed. Relation of fibrosis and its progression to SOX9 and HPCs in BA was assessed. RESULTS SOX9 and HPCs in ductular reaction (DR) form were expressed in 100% of BA and their grades increased significantly in the second biopsy. The rapidly progressive fibrosis in BA, represented by fibrosis grade of the intraoperative LB, correlated significantly to SOX9-DR and HPC-DR at the diagnostic (r = 0.420, P = 0.003 and r = 0.405, P = 0.004, respectively) and the intraoperative (r = 0.460, P = 0.001 and r = 0.467, P = 0.001, respectively) biopsy. On the other hand, fibrosis, SOX9-DR, and HPC-DR were significantly lower in non-BA cases at a comparable age (P < 0.001, P = 0.006, and P = 0.014, respectively). CONCLUSIONS Fibrosis in BA is rapidly progressive within a short time and is significantly correlated to SOX9 and HPCs. Assessment of targeting SOX9 and HPCs on fibrosis progression is warranted.
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Affiliation(s)
- Hanaa Ahmed El-Araby
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, 32511 Shebin El-koom, Menoufia, Egypt
| | - Magdy Anwar Saber
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, 32511 Shebin El-koom, Menoufia, Egypt
| | - Noha Mohamed Radwan
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, 32511 Shebin El-koom, Menoufia, Egypt
| | - Doha Maher Taie
- Department of Pathology, National Liver Institute, Menoufia University, 32511 Shebin El-koom, Menoufia, Egypt
| | - Nermin Mohamed Adawy
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, 32511 Shebin El-koom, Menoufia, Egypt
| | - Ahmad Mohamed Sira
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, 32511 Shebin El-koom, Menoufia, Egypt.
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Chung PH, Wong KK, Tam PK. Standard management protocol to improve the short-term outcome of biliary atresia. J Paediatr Child Health 2020; 56:1774-1778. [PMID: 33197970 DOI: 10.1111/jpc.14698] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 10/08/2019] [Accepted: 11/03/2019] [Indexed: 11/27/2022]
Abstract
AIM This study compared the outcomes of patients with biliary atresia (BA) treated according to a standardised protocol with historical patients. METHODS This is a single-centred retrospective study of BA patients treated from 1980 to 2016. A standardised treatment protocol was established since 2008 regarding peri-operative management. The outcomes being compared between the two groups (Groups I and II = before and after 2008, respectively) were jaundice clearance (JC), incidence of recurrent cholangitis, hospital admission and native liver survival (NLS). RESULTS A total of 128 patients were included (Group I = 100, Group II = 28). The overall median follow-up period was 15.3 years (I vs. II = 20.6 years vs. 5.1 years, respectively). There was no significant difference in the JC at the sixth month between the two groups (I vs. II = 60.0 vs. 82.1%, respectively, P = 0.07). The incidence of recurrent cholangitis was similar between the two groups (I vs. II = 39 vs. 35.7%, respectively, P = 0.45), but the median hospital admission episode per patient was non-significantly higher in Group I (I vs. II = 4.2 vs. 2.7, respectively, P = 0.08). There was an improvement in the 1-year NLS rate in Group II (I vs. II = 69.0 vs. 85.7%, respectively, P = 0.05). CONCLUSIONS The introduction of a standardised management protocol has improved the short-term outcome of BA patients, with a better 1-year NLS observed.
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Affiliation(s)
- Patrick Hy Chung
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Kenneth Ky Wong
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Paul Kh Tam
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
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Venkat V, Ng VL, Magee JC, Ye W, Hawthorne K, Harpavat S, Molleston JP, Murray KF, Wang KS, Soufi N, Bass LM, Alonso EM, Bezerra JA, Jensen MK, Kamath BM, Loomes KM, Mack CL, Rosenthal P, Shneider BL, Squires RH, Sokol RJ, Karpen SJ. Modeling Outcomes in Children With Biliary Atresia With Native Liver After 2 Years of Age. Hepatol Commun 2020; 4:1824-1834. [PMID: 33305153 PMCID: PMC7706301 DOI: 10.1002/hep4.1602] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/21/2020] [Accepted: 07/31/2020] [Indexed: 12/15/2022] Open
Abstract
Approximately 50% of infants with biliary atresia (BA) undergoing Kasai portoenterostomy show survival with native liver (SNL) at age 2 years. Predictors of disease progression after age 2 years are unknown, despite estimates of 20%-30% undergoing liver transplant (LT) between age 2 and 18 years. We sought to address this knowledge gap by developing prognostic models in participants of the multicenter prospective National Institutes of Health-supported Childhood Liver Disease Research Network. We extracted 14 clinical and biochemical variables at age 2 years to develop two models for future outcomes: 1) LT or death (LTD) and 2) first sentinel event (SE), either new onset ascites, hepatopulmonary syndrome (HPS), or gastrointestinal (GI) bleed. A total of 240 participants, enrolled between 2004 and 2017, were followed until a median age of 5.1 years (range, 2.0-13.3 years). Of these participants, 38 underwent LT (n = 37) or death (n = 1); cumulative incidence, 23.7% (95% confidence interval [CI], 16.2%-32.0%). Twenty-seven experienced either new-onset ascites (n = 13), HPS (n = 1), or GI bleed (n = 14). One participant had ascites and GI bleed concurrently; cumulative incidence, 21.5% (95% CI, 14.2%-29.8%) by age 10 years. The Cox proportional hazard model predicted risk of LTD, using total bilirubin, albumin, platelet count, and history of either ascites or cholangitis (BA LTD model), with a C-index of 0.88 (range, 0.86-0.89). A cause-specific hazard competing risk model predicted SE using platelet count and gamma glutamyltransferase levels (BA SE model) with a C-index of 0.81 (range, 0.80-0.84). Internal model validity was assessed using Harrell's C-index with cross-validation. Conclusion: Stratification using these models identified risk of poor outcomes in patients with BA SNL after age 2 years. The models may identify those who would benefit from enhanced clinical surveillance and prioritization in clinical trials.
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Affiliation(s)
- Veena Venkat
- UPMC Children's Hospital of Pittsburgh Pittsburgh PA
| | - Vicky L Ng
- Hospital for Sick Children University of Toronto Toronto Canada
| | - John C Magee
- University of Michigan Hospitals and Health Centers Ann Arbor MI
| | - Wen Ye
- University of Michigan Hospitals and Health Centers Ann Arbor MI
| | | | - Sanjiv Harpavat
- Texas Children's Hospital Liver Center, Baylor College of Medicine Houston TX
| | | | | | | | | | - Lee M Bass
- Ann & Robert H. Lurie Children's Hospital of Chicago Chicago IL
| | | | | | - M Kyle Jensen
- University of Utah School of Medicine Primary Children's Hospital Salt Lake City UT
| | - Binita M Kamath
- Hospital for Sick Children University of Toronto Toronto Canada
| | | | - Cara L Mack
- University of Colorado School of Medicine Children's Hospital Colorado Aurora CO
| | | | - Benjamin L Shneider
- Texas Children's Hospital Liver Center, Baylor College of Medicine Houston TX
| | | | - Ronald J Sokol
- University of Colorado School of Medicine Children's Hospital Colorado Aurora CO
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Cholangitis in Patients With Biliary Atresia Receiving Hepatoportoenterostomy: A National Database Study. J Pediatr Gastroenterol Nutr 2020; 71:452-458. [PMID: 32639448 DOI: 10.1097/mpg.0000000000002836] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Biliary atresia (BA) is a progressive form of liver disease in the neonatal period usually requiring hepatoportoenterostomy (HPE). Cholangitis is a common sequelae of HPE but data about which patients are at risk for this complication are limited. OBJECTIVE The objective of the study was to determine risk factors associated with cholangitis in a large retrospective cohort after HPE. METHODS The Pediatric Health Information System (PHIS) was queried for BA (ICD-9 975.61) and HPE (ICD-9-CM 51.37) admissions from 2004 to 2013. We performed univariate analysis and linear regression with dependent variables of ≥ 2 or ≥ 5 episodes of cholangitis, and independent variables of age at time of HPE, race, ethnicity, gender, insurance, ursodeoxycholic acid (UDCA) use, steroid use, presence of esophageal varices (EV), and portal hypertension (PH). RESULTS We identified 1112 subjects with a median age at HPE of 63 days and median number of cholangitis episodes of 2 within 2 years. On multiple regression analysis, black race (odds ratio (OR) 1.51, P = 0.044) and presence of PH (OR 2.24, P < 0.001) were associated with increased risk of ≥ 2 episodes of cholangitis, whereas HPE at >90 days was associated with less risk (OR 0.46, P = 0.001). Among those with ≥5 episodes, Asian race (OR 2.66, P = 0.038), public insurance (OR 1.72, P = 0.043), EV (OR 1.81, P = 0.017), and PH (OR 2.88, P < 0.001) were associated with higher risk. CONCLUSIONS Complications, such as cholangitis remain a common problem for patients, after HPE, with median of 2 episodes within 2 years. Higher rates of cholangitis are associated with portal hypertension whereas lower rate is associated with age at HPE of >90 days. Asians, patients with public insurance, and those with portal hypertension are more likely to have recurrent cholangitis.
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Does the Treatment After Kasai Procedure Influence Biliary Atresia Outcome and Native Liver Survival? J Pediatr Gastroenterol Nutr 2020; 71:446-451. [PMID: 32960536 DOI: 10.1097/mpg.0000000000002837] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Biliary atresia (BA) is a rare and progressive idiopathic disease affecting the biliary tract that can lead to end-stage liver disease. The main treatment is Kasai portoenterostomy (KP). The use of adjuvant therapy (AT; prophylactic antibiotics and steroids) after KP aims to prevent cholangitis and reduce the need for liver transplantation (LT), but there is a lack of evidence on their effectiveness. We investigated the impact of significant changes in the post-KP protocol on the overall outcomes of BA. METHODS We enrolled 43 consecutive infants undergoing KP at Bambino Gesù Children's Hospital between July 2012 and October 2018. We compared AT (AT group; n=25) against no treatment (AT-free group; n = 18). RESULTS No significant differences in anthropometric and laboratory parameters were shown between the 2 groups at baseline and every study evaluation (1, 3, and 6 months). The incidences of clinical complications of liver disease were similar. Six months post-KP, the achievement of serum total bilirubin ≤1.5 mg/dL and satisfactory Pediatric End-Stage Liver Disease scores were not significantly different between the 2 groups. Cholangitis was observed in 30% of patients in the first 6 months postoperatively: 33% and 28% in the AT-free and AT groups, respectively (P = 0.18). Survival to LT listing at 12 months and without LT at 24 months were not significantly different between the 2 groups (P > 0.05). CONCLUSIONS AT after KP confirmed conflicting results; therefore, multicentered, prospective, randomized control studies are needed to better understand its utility after KP, especially in the multidrug resistance spread era.
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