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Diagnostics
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New Insights into the Diagnosis of Pediatric Cholestasis
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New Insights into the Diagnosis of Pediatric Cholestasis

A Special Issue of Diagnostics (ISSN 2075-4418) belonging to the section "Clinical Diagnosis and Prognosis".

Deadline for manuscript submissions: 31 January 2027 | Viewed by 7972

Editor

Dr. Paola Francalanci

E-Mail Website
Guest Editor
Pathology Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
Interests: liver; liver transplantation; diagnosis

Special Issue Information

Dear Colleagues,

Hyperbilirubinemia occurs in approximately 50% of neonates as an expression of physiological jaundice in the vast majority of cases. Prolonged jaundice (defined as jaundice lasting more than 2 weeks), termed neonatal/infantile cholestasis (NIC), occurs in up to 15% of all neonates and should raise suspicion of cholestasis, prompting further investigation. Rapid etiological definition is of primary importance to initiate appropriate surgical or medical treatment. The broad spectrum of potential causes of NIC requires a complex diagnostic approach that depends on the comprehensive clinical picture. For practical purposes, the causes of cholestasis are divided into surgical (extrahepatic cholestasis) and medical (intrahepatic cholestasis) conditions. The most common surgical cause of NIC is biliary atresia, while medical causes include defects in bile canalicular transport and bile development, inborn errors of bile acid synthesis, and inherited metabolic conditions.

The aim of this Special Issue, titled “New Insights into the Diagnosis of Pediatric Cholestasis”, is to support pediatricians working in primary and secondary care in the initial management of neonatal cholestasis (NIC), alongside pediatric neonatologists and hepatologists working in tertiary referral centers for further diagnostic work-up. We have decided to organize this issue into four sections: the clinical aspect, the surgical approach, diagnostic imaging, and the histological–molecular characteristics of NIC.

Dr. Paola Francalanci
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Diagnostics is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • extrahepatic cholestasis
  • intrahepatic cholestasis
  • biliary atresia
  • genetic liver disease
  • inborn errors of metabolism
  • jaundice
  • monogenic liver disease

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Published Papers (4 papers)

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Review

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26 pages, 8402 KB  
Review
Use of Next-Generation Sequencing and Whole-Exome Sequencing in the Diagnosis of Adult-Onset Familial Intrahepatic Cholestasis: Challenges in Interpreting Variants of Uncertain Significance
by Amalia Conti, Filippo Gabrielli, Simona Ferrari, Alessandro Vaisfeld, Claudia De Masi, Francesco Azzaroli, Fabio Piscaglia and Giovanni Vitale
Diagnostics 2026, 16(15), 2335; https://doi.org/10.3390/diagnostics16152335 - 25 Jul 2026
Viewed by 505
Abstract
Progressive Familial Intrahepatic Cholestasis (PFIC) is a rare liver disorder that, although typically present in childhood, can also occur in adulthood. Early diagnosis is crucial for appropriate clinical management, prognostic assessment, and therapeutic decision-making; however, it remains challenging due to phenotypic variability and [...] Read more.
Progressive Familial Intrahepatic Cholestasis (PFIC) is a rare liver disorder that, although typically present in childhood, can also occur in adulthood. Early diagnosis is crucial for appropriate clinical management, prognostic assessment, and therapeutic decision-making; however, it remains challenging due to phenotypic variability and the frequent identification of genetic variants of uncertain significance (VUS). Advances in next-generation sequencing (NGS) and whole-exome sequencing (WES) have improved the detection of disease-associated variants, revealing that the same genetic variants—often in a heterozygous state—may lead to adult-onset cholestatic disease, with milder or atypical presentations, while still conferring a significant risk of progressive liver injury and related complications. To assess the diagnostic yield and clinical utility of NGS panels and WES in adults with suspected PFIC or unexplained cholestatic liver disease, focusing on variant interpretation, emerging disease-associated genes, and clinical significance of VUS. A literature review was conducted to assess molecular diagnostics in adult cryptogenic cholestasis, with a focus on studies employing targeted NGS panels and WES. Selected studies were examined for diagnostic yield, variant classification, interpretive challenges, including VUS, and integration with clinical data. Data on patient demographics, sequencing techniques, and variant interpretation strategies were extracted to evaluate the current capabilities and limitations of genomic testing. From an initial search of 211 publications, 15 studies met the inclusion criteria, comprising five large adult cohorts and ten single-patient or trio-based reports. Across 72 patients, sequencing technologies identified 75 pathogenic or likely pathogenic variants, predominantly missense mutations, demonstrating high genetic heterogeneity. The most implicated genes included ABCB4, ABCB11, ATP8B1, TJP2, and USP53, with diagnostic yields ranging from 13.2% in large heterogeneous cohorts to substantially higher rates in carefully selected individual cases. VUS were identified in up to 67% of cases, highlighting the need for multidisciplinary interpretation integrating clinical, biochemical, and genetic data. Emerging evidence also implicated ciliopathy-associated genes such as DCDC2, NPHP3, PKHD1, TULP3, and TTC21B, expanding the genetic spectrum of adult cholestasis. Clinically, presentations ranged from mild biochemical abnormalities to progressive cholestasis, with pruritus being a common feature across studies. Comprehensive genetic testing significantly enhances diagnostic accuracy, informs prognosis, and guides individualized management in adults with cryptogenic cholestasis. Emerging evidence suggests that ciliopathy-associated genes may contribute to the genetic architecture of adult cholestatic disorders, further expanding the spectrum of disease-associated genes. However, the high prevalence of VUS remains a major challenge, highlighting the need for functional studies, longitudinal follow-up, and improved variant interpretation frameworks. As genomic technologies and analytical approaches continue to evolve, genetic testing is expected to play an increasingly central role in precision hepatology. Full article
(This article belongs to the Special Issue New Insights into the Diagnosis of Pediatric Cholestasis)
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31 pages, 9845 KB  
Review
Pediatric Cholestasis: A Practical Approach to Histological Diagnosis
by Francesca Arienzo, Silvia Vallese, Isabella Giovannoni, Andrea Pietrobattista, Marco Spada, Rita Alaggio and Paola Francalanci
Diagnostics 2026, 16(6), 878; https://doi.org/10.3390/diagnostics16060878 - 16 Mar 2026
Viewed by 4369
Abstract
Pediatric (neonatal and infantile) jaundice resulting from underlying cholestasis (caused by conjugated hyperbilirubinemia) is always pathological and requires prompt evaluation. Pediatric cholestasis can be caused by medical or surgical factors and, if left untreated, can lead to irreversible liver damage. Timely recognition of [...] Read more.
Pediatric (neonatal and infantile) jaundice resulting from underlying cholestasis (caused by conjugated hyperbilirubinemia) is always pathological and requires prompt evaluation. Pediatric cholestasis can be caused by medical or surgical factors and, if left untreated, can lead to irreversible liver damage. Timely recognition of pediatric cholestasis and identification of the underlying etiology are paramount to improve outcomes. The broad spectrum of causes potentially underlying pediatric cholestasis requires a multidisciplinary diagnostic approach, and each aspect must be interpreted in the concomitant clinical picture. A liver biopsy is one component of a complex diagnostic puzzle. However, interpreting a liver biopsy performed on a newborn/infant with conjugated/direct hyperbilirubinemia can be a challenging task, as these biopsies are rarely encountered in general hospitals. The aim of this review is to provide a practical and simplified approach to pediatric cholestasis with examples of real clinical cases we have encountered and discuss key features, both histological and clinical, that can help narrow the differential diagnosis and identify treatable causes. Full article
(This article belongs to the Special Issue New Insights into the Diagnosis of Pediatric Cholestasis)
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24 pages, 2972 KB  
Review
Beyond the Pump: The Evolving Molecular Landscape of Intrahepatic Cholestasis
by Ilaria Ziccardi, Michela Zorzi and Adamo Pio d’Adamo
Diagnostics 2026, 16(5), 726; https://doi.org/10.3390/diagnostics16050726 - 28 Feb 2026
Cited by 1 | Viewed by 1867
Abstract
Cholestasis encompasses a broad spectrum of hepatobiliary disorders characterized by impaired bile formation or flow. Historically classified based on clinical onset and severity, the landscape of cholestatic liver disease has been revolutionized by the advent of high-throughput genomic technologies. This review elucidates the [...] Read more.
Cholestasis encompasses a broad spectrum of hepatobiliary disorders characterized by impaired bile formation or flow. Historically classified based on clinical onset and severity, the landscape of cholestatic liver disease has been revolutionized by the advent of high-throughput genomic technologies. This review elucidates the critical role of genetics in redefining the pathophysiology, diagnosis, and management of cholestasis, framing pediatric Progressive Familial Intrahepatic Cholestasis (PFIC) and Adult-Onset Cholestatic Disease (AOCD) as a continuous phenotypic spectrum. We discuss the expansion of the molecular nosology to include 13 distinct PFIC types, highlighting how defects in canalicular transporters, tight junctions, and nuclear receptors underpin clinical heterogeneity. Furthermore, we examine the paradigm shift in the diagnostic flowchart, where Next-Generation Sequencing (NGS) has largely superseded liver biopsy for etiological definition. Finally, we address the therapeutic implications of this molecular precision, demonstrating how specific genotypes dictate eligibility for novel targeted therapies, such as IBAT inhibitors, marking the transition from supportive care to personalized medicine. Full article
(This article belongs to the Special Issue New Insights into the Diagnosis of Pediatric Cholestasis)
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Other

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12 pages, 4083 KB  
Case Report
A Rare Coexistence of Biliary Atresia and Alagille Syndrome in a Neonate: Clinical Implications of Dual Etiology in Neonatal Cholestasis
by Wan-Ning Wu, Hung-Chang Lee, Hsiang-Yu Lin, Nien-Lu Wang, Wai-Tao Chan, Shu-Chao Weng and Chuen-Bin Jiang
Diagnostics 2026, 16(12), 1752; https://doi.org/10.3390/diagnostics16121752 - 6 Jun 2026
Cited by 1 | Viewed by 630
Abstract
Background and Clinical Significance: Biliary atresia (BA) and Alagille syndrome (ALGS) represent distinct anatomic and genetic causes of neonatal cholestasis. Their overlapping clinical, biochemical, and early histological features present a formidable diagnostic challenge in early infancy, and their simultaneous coexistence is exceedingly [...] Read more.
Background and Clinical Significance: Biliary atresia (BA) and Alagille syndrome (ALGS) represent distinct anatomic and genetic causes of neonatal cholestasis. Their overlapping clinical, biochemical, and early histological features present a formidable diagnostic challenge in early infancy, and their simultaneous coexistence is exceedingly rare. This report documents a unique case of dual diagnosis to highlight the associated diagnostic pitfalls and implications for surgical management. Case Presentation: We present the case of a Taiwanese male neonate who manifested prolonged jaundice and acholic stools. Preoperative imaging and intraoperative cholangiography confirmed biliary atresia, for which the patient underwent a Kasai portoenterostomy. The patient subsequently exhibited an atypical postoperative course characterized by persistent hyperbilirubinemia and intractable pruritus. This atypical trajectory prompted an extensive, multisystem evaluation and molecular genetic analysis, revealing a concurrent genetic diagnosis of Alagille syndrome. To our knowledge, this dual diagnosis is rarely reported in the literature, which creates a significant challenge in determining surgical candidacy and predicting long-term liver health outcomes. Discussions: Early differentiation is complicated by the fact that some ALGS patients can initially mimic BA. Beyond its exceptional rarity, this case holds profound clinical significance for the evaluation of neonatal cholestasis, serving as a stark reminder of the risks of “diagnostic premature closure.” In diagnostically challenging cases of neonatal cholestasis, intraoperative biliary exploration remains the gold standard for the timely diagnosis of BA. Genetic testing should be considered an adjunctive tool when clinical and histological findings are inconclusive. Conclusions: This case highlights a critical clinical caveat in neonatal cholestasis: while a confirmed diagnosis of anatomical BA typically stands alone as a solitary pathology, clinicians should remain mindful of the remote possibility of a concurrent genetic etiology like ALGS in highly atypical presentations. Persistently unexpected postoperative jaundice or the accumulation of multisystem anomalies should prompt an expansion of the differential diagnosis. Recognizing this rare coexistence is crucial for effective multidisciplinary management, informed surgical decision-making, and accurate genetic counseling. Full article
(This article belongs to the Special Issue New Insights into the Diagnosis of Pediatric Cholestasis)
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