Title: Pediatric cholestasis: a practical approach to histological diagnosis

Source: Diagnostics 2026, 16 (6): 878

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Date of publication: March 2026

Publication type: Review article

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 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.

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Title: Prevalence of liver disease and liver transplantation in pediatric ZZ alpha-1 antitrypsin deficiency: a systematic review and meta-analysis

Source: Digestive and Liver Disease 2026, Mar 5. [E–publication]

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Date of publication: March 2026

Publication type: Systematic review and meta-analysis 

Abstract: Background: Pediatric Pi*ZZ alpha-1 antitrypsin deficiency (A1ATD) can cause hepatocyte A1AT polymer retention and progressive liver injury, but estimates of childhood liver morbidity vary across studies and remain poorly defined.

Aim: To quantify liver-specific outcomes in pediatric Pi*ZZ A1ATD.

Methods: We systematically reviewed studies reporting liver-specific outcomes in children with confirmed Pi*ZZ/ZZ A1ATD (PROSPERO CRD42022335666). We extracted prevalence of fibrosis and cirrhosis, elevated liver enzymes, and liver transplantation. Random-effects meta-analysis pooled logit-transformed proportions (with sensitivity analyses assessing robustness to model assumptions).

Results: Thirteen studies including 398 children met inclusion criteria. Pooled prevalence was 41.3% (95% CI 29.6-54.0) for fibrosis and 17.3% (7.2-35.9) for cirrhosis, with substantial heterogeneity for cirrhosis (I² 78.6%). Liver transplantation prevalence was 10.7% (6.3-13.0). Elevated liver enzymes occurred in 43.0% (19.2-70.5) with high heterogeneity (I² 89.4%). Across cohorts, the proportion with elevated liver enzymes declined with increasing mean age, despite ongoing liver disease in reported histology-based outcomes.

Conclusions: Clinically important liver disease occurs in a substantial subset of children with Pi*ZZ A1ATD. Declining rates of elevated liver enzymes with age should not be interpreted as disease resolution. Standardized registries are needed for longitudinal surveillance, to identify disease modifiers, and to guide early intervention in this high-risk population.

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Title: Prospective multicenter longitudinal measurement of liver stiffness in school-age children with cholestatic liver disease

Source: Gastro Hep Advances 2025, 4 (10): 100788 

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Date of publication: September 2025

Publication type: Multicenter prospective longitudinal study

Abstract: Background and aims: A multicenter prospective longitudinal study of vibration-controlled transient elastography (VCTE) in school-age children with biliary atresia (BA), alpha-1 antitrypsin deficiency (a1-AT) and Alagille syndrome (ALGS) was undertaken to test the hypothesis that there would be measurable disease progression over 2 years.

Methods: Vibration-controlled transient elastography was performed annually for 2 years in children with BA, a1-AT and ALGS.

Results: Valid liver stiffness measurement (LSM) was determined at baseline/second follow-up in 254/180 (71%), 104/58 (56%) and 100/61 (61%) participants (mean elapsed time 2.27 years) with BA, a1-AT and ALGS, respectively. Modeling did not reveal a relationship between LSM and time since baseline: BA 1.2% (-1.6, 4.2%), a1-AT 0.1% (-3.8, 4.2%), and ALGS 3.6% (-2.9, 10.5%) LSM (% change/year; mean [95% confidence interval]). Similarly, mean LSM did not change significantly from baseline to visit 2 (BA 13.6 + 11.0 vs 15.1 + 12.8; a1-AT 7.8 + 5.1 vs 8.5 + 7.6; ALGS 10.6 + 9.4 vs 12.2 + 12.1 kPa, mean + standard deviation). Albumin and total bilirubin levels did not change in these participants. Platelet counts dropped at rates that were similar to a national representative sample, the National Health and Nutrition Examination Survey (ie, 5000 to 7000/μL per year).

Conclusion: Surprisingly, longitudinal measurement of LSM and laboratory parameters of liver disease severity over 2 years in school-age children with compensated BA, a1-AT, and ALGS did not reveal significant change, consistent with slow progression of cholestatic liver disease in this age group. These findings have implications for both clinical care and interventional trials in this patient population.

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Title: Plasma proteome correlations with liver stiffness in pediatric cholestasis implicate epithelial to mesenchymal transition 

Source: Hepatology Communications 2025, 9 (10): e0796

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Date of publication: September 2025  

Publication type: Article

Abstract: Background: Pediatric cholestatic liver diseases can be characterized by rapidly progressive fibrosis. A multicenter cross-sectional analysis of vibration-controlled elastography in biliary atresia (BA), alpha-1 antitrypsin deficiency (A1AT), and Alagille syndrome (ALGS) was leveraged to interrogate the plasma proteome relative to liver stiffness measurements (LSM).

Methods: Slow off-rate modified aptamer scanning profiling of >7000 proteins in plasma from 187 children with BA (n=93), A1AT (n=31), ALGS (n=46), and healthy pediatric controls (n=17) was performed, and correlations with LSM were undertaken.

Results: There was an abundance of LSM correlated proteins (BA n=2720, A1AT n=694, ALGS n=5968). Interestingly, a distinct plasma proteome was found in ALGS relative to BA and A1AT. Weighted Correlation Network Analysis identified groups of proteins with strong LSM correlation (eg, in a BA module of interest, Pearson correlation coefficient 0.79, p=5´0-21). Machine learning developed models predicting LSM as a continuous variable (median R2=0.62 for BA). For BA, time to transplant could be predicted equally well by the proteome or clinical parameters (elastic net models achieved a C-index using proteome 0.91, clinical parameters 0.91, proteome and clinical parameters 0.90). Single-cell transcriptomics predicted the potential hepatic cell of origin for the most informative proteins, which included macrophage, mesenchymal, mesothelial, and endothelial cells. The epithelial-to-mesenchymal transition pathway was enriched in LSM correlated proteins in all 3 diseases.

Conclusions: The plasma proteome is highly correlated in a disease-specific fashion with LSM in BA, A1AT, and ALGS. These correlations provide unique opportunities to identify biomarkers and focus attention on epithelial-to-mesenchymal transition in pediatric cholestasis.

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Title: Alpha-1 antitrypsin deficiency-associated liver disease: From understudied disorder to the poster child of genetic medicine

Source: Hepatology Communications 2025, 9 (5): e0699

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Date of publication: April 2025

Publication type: Review article  

Abstract: Alpha-1 antitrypsin deficiency (AATD) constitutes an inborn disorder arising due to mutations in alpha-1 antitrypsin (AAT), a secreted protease inhibitor produced primarily in hepatocytes. It leads to diminished serum AAT levels, and this loss-of-function predisposes to chronic obstructive pulmonary disease and lung emphysema. The characteristic Pi*Z mutation results in hepatic Z-AAT accumulation. In its homozygous form (Pi*ZZ genotype), it is responsible for the majority of severe AATD cases and can cause both pediatric and adult liver disease, while the heterozygous form (Pi*MZ) is considered a disease modifier that becomes apparent primarily in the presence of other comorbidities or risk factors. In the current review, we collate conditions associated with AATD, introduce typical AAT variants, and discuss our understanding of disease pathogenesis. We present both cross-sectional and longitudinal data informing about the natural disease history and noninvasive tools that can be used for disease stratification as well as a basis for disease monitoring. Given that AATD-associated liver disease is highly heterogeneous, we discuss the risk factors affecting disease progression. While the loss-of-function lung disease is treated by weekly intravenous administration of purified AAT, recombinant modified AAT and oral protease inhibitors are currently in clinical trials. Among the liver candidates, small interfering RNA fazirsiran efficiently suppresses AAT production and is currently in phase 3 clinical trial, while several other genetic approaches, such as RNA editing, are at earlier stages. In summary, AATD represents a systemic disorder increasingly seen in the hepatologic routine and requiring thorough interdisciplinary care, since the currently ongoing clinical trials often address only one of the organs it affects.

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Title: Retrospective database analysis of liver-related clinical events in adult and pediatric patients with alpha-1 antitrypsin deficiency in the United States  

Source: Hepatology Medicine 2024, 16: 55-64

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Date of publication: July 2024

Publication type: Retrospective observational study

Abstract: Background and aims: Real-world analyses on burden of illness in patients with alpha-1 antitrypsin deficiency (AATD) are limited. We investigated the real-world burden of liver-related clinical events among adult and pediatric patients with AATD in the USA.

Methods: This was a retrospective, observational analysis of administrative claims data from the IQVIA PharMetrics^® Plus and Ambulatory Electronic Medical Records databases from 2011 to 2022. Patients had a diagnosis of liver and/or lung disease with ≥180 days of continuous enrollment in the IQVIA PharMetrics Plus database before and ≥90 days after their first diagnosis. Follow-up time was assigned to the AATD with liver disease health state or AATD with both liver and lung disease health state (for patients aged ≥18 years only). Baseline demographic characteristics and liver-related clinical events of interest were reported.

Results: Of 5136 eligible patients, 771 adult and 123 pediatric patients contributed time to the AATD with liver disease health state; 541 adults contributed time to the AATD with both liver and lung disease health state. Among adults, patients with both liver and lung disease had higher rates of liver-related clinical events than patients with liver disease alone. Ascites was the most frequently observed clinical event among adults in both health states, and the median time to the composite of any liver-related clinical event was 26.5 days among all adults combined. Across all pediatric age groups, ascites, gastrointestinal bleed and hepatic encephalopathy were more common than spontaneous bacterial peritonitis and hepatocellular carcinoma, but median time to liver-related clinical event varied by age group at index date and type of event. No liver transplantations occurred in patients aged 6-17 years.

Conclusion: Diagnosed AATD with liver disease carries a substantial burden on adult and pediatric patients; new treatment options are warranted to avoid disease progression to decompensating events.

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Title: Alpha-1-antitrypsin deficiency in children – unmet needs concerning the liver manifestation

Source: Children 2024, 11 (6): 694

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Date of publication: June 2024

Publication type: Article

Abstract: Objectives: This study aimed to analyse the clinical course of 45 children with severe alpha-1-antitrypsin deficiency (AATD) registered in our clinic to detect possible predictors of poor outcomes.

Methods: The clinical and biological data of 45 patients with homozygous or compound heterozygous AATD were analysed. The data were collected retrospectively going back to 2005 and prospectively from May 2020 until October 2021. It was based on questionnaires, laboratory values, sonography, and biopsy findings. Liver disease was classified into four grades depending on the grade of liver disease: mild or no liver disease, moderate disease, severe disease, and liver transplantation.

Results: Thirty-nine patients (86.7%) had a Pi*ZZ and five (11.1%) a Pi*SZ genotype. One patient showed a new, not-yet-described compound heterozygous genotype (Pi*Z + Asp95Asn). A total of 66.7% of the cohort showed mild or no liver disease, 20% moderate, and 13.3% severe. AATD was diagnosed in most cases because of liver abnormalities, such as the elevation of transaminases (42.2%). A total of 29.4% of the patients with neonatal icterus prolongatus developed severe liver disease, and 25.7% were born small for their gestational age (SGA). Diseases of the atopic type were reported in 47.4% of the cases.

Conclusions: The presence of neonatal icterus prolongatus in the first weeks of life was significantly more likely in severe courses of liver disease (r = 0.371, p = 0.012). A tendency toward atopic comorbidity in AAT-deficient children needs to be further evaluated.

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Title: EASL clinical practice guidelines on genetic cholestatic liver diseases  

Source: Journal of Hepatology 2024, Jun 8. [E–publication]

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Date of publication: June 2024  

Publication type: Guidance 

Abstract: Genetic cholestatic liver diseases are caused by (often rare) mutations in a multitude of different genes. While these diseases differ in pathobiology, clinical presentation and prognosis, they do have several commonalities due to their cholestatic nature. These Clinical Practice Guidelines (CPGs) offer a general approach to genetic testing and management of cholestatic pruritus, while exploring diagnostic and treatment approaches for a subset of genetic cholestatic liver diseases in depth. An expert panel appointed by the European Association for the Study of the Liver has created recommendations regarding diagnosis and treatment, based on the best evidence currently available in the fields of paediatric and adult hepatology, as well as genetics. The management of these diseases generally takes place in a tertiary referral centre, in order to provide up-to-date approaches and expertise. These CPGs are intended to support hepatologists (for paediatric and adult patients), residents and other healthcare professionals involved in the management of these patients with concrete recommendations based on currently available evidence or, if not available, on expert opinion.  

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Title: Neonatal cholestasis in children with Alpha-1-AT deficiency is a risk for earlier severe liver disease with male predominance

Source: Hepatology Communications 2023, 7 (12): e0345

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Date of publication: December 2023

Publication type: Article

Abstract: Background: Our objective was to better understand the natural history and disease modifiers of Alpha-1-antitrypsin deficiency (AATD), a common genetic liver disease causing hepatitis and cirrhosis in adults and children. The clinical course is highly variable. Some infants present with neonatal cholestasis, which can resolve spontaneously or progress to cirrhosis; others are well in infancy, only to develop portal hypertension later in childhood.

Methods: The Childhood Liver Disease Research Network has been enrolling AATD participants into longitudinal, observational studies at North American tertiary centers since 2004. We examined the clinical courses of 2 subgroups of participants from the several hundred enrolled; first, those presenting with neonatal cholestasis captured by a unique study, enrolled because of neonatal cholestasis but before specific diagnosis, then followed longitudinally (n=46); second, separately, all participants who progressed to liver transplant (n=119).

Results: We found male predominance for neonatal cholestasis in AATD (65% male, p=0.04), an association of neonatal gamma-glutamyl transpeptidase elevation to more severe disease, and a higher rate of neonatal cholestasis progression to portal hypertension than previously reported (41%) occurring at median age of 5 months. Participants with and without preceding neonatal cholestasis were at risk of progression to transplant. Participants who progressed to liver transplant following neonatal cholestasis were significantly younger at transplant than those without neonatal cholestasis (4.1 vs. 7.8 years, p=0.04, overall range 0.3-17 years). Neonatal cholestasis had a negative impact on growth parameters. Coagulopathy and varices were common before transplant, but gastrointestinal bleeding was not.

Conclusions: Patients with AATD and neonatal cholestasis are at risk of early progression to severe liver disease, but the risk of severe disease extends throughout childhood. Careful attention to nutrition and growth is needed.

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Title: Alpha-1 antitrypsin deficiency

Source: Medicina Clinica 2023, Nov 21. [E-publication]

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Date of publication: November 2023

Publication type: Review article

Abstract: Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition caused by decreased plasma and tissue levels of alpha-1 antitrypsin (AAT) that can lead to serious lung and liver disease in children and adults. AATD patients face challenges such as under diagnosis, clinical variability, and limited treatment options for liver disease. Early detection and biomarkers for predicting outcomes are needed to improve patient outcome. Currently, the only approved pharmacological therapy is augmentation therapy, which can delay the progression of emphysema. However, alternative strategies such as gene therapy, induced pluripotent stem cells, and prevention of AAT polymerization inside hepatocytes are being investigated. This review aims to summarize and update current knowledge on AATD, identify areas of controversy, and formulate questions for further research.

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