Hepatocellular carcinoma in an adult with Alagille syndrome: case report and literature review

Schoen, Karla; Ribeiro, Cristiane Maria; Gonçalves, Marianne Castro; Souza, Anthony; Porta, Gilda; Horvat, Natally

doi:10.1016/j.radcr.2020.09.027

Cited by 4 publications

(2 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among the bleeding events, the predominantly reported type was intracranial bleeding (25/150, 16.7%) 24,38,39,51,64,65,67,79,[85][86][87][88][89][90][91] , followed by pulmonary hemorrhage (15/150, 10%) 45,92 . Other bleeding events included gastrointestinal (10/150, 6.7%) 9,26,73,74,76,77,[93][94][95][96] , nasal (2/150, 1.3%) 61,73 intrathoracic 97 , intraperitoneal 98 , renal 60 , and ocular 89 bleeding, as well as hematochezia 73 , hematuria 48 and hematemesis 61 (each 1/150, 0.7%) (Figure 1D). Intracranial bleeds included hematoma (generally induced by a head trauma due to thin skull), and hemorrhages (Figure 1E).…”

Section: Resultsmentioning

confidence: 99%

Sex differences and risk factors for bleeding in Alagille syndrome

Hankeová

Hul

Laznovsky

et al. 2021

Preprint

View full text Add to dashboard Cite

Alagille syndrome (ALGS) is generally thought of as a pediatric cholestatic liver disease, but spontaneous bleeds are a major cause of death. Here, we investigated bleeding in patients and a mouse model for ALGS (Jag1Ndr/Ndr mice) and asked whether phenotypes identified in mice could be detected in patients non-invasively. Jag1Ndr/Ndr mice spontaneously bled, exhibiting a thin skull and vascular defects. Vascular abnormalities included artery-vein crossings, tortuous vessels, and capillary breakdown. Furthermore, Jag1Ndr/Ndr arteries had sparse vascular smooth muscle cell coverage, which was further aggravated by hypertension. Retinographs from patients with ALGS, biliary atresia, or CADASIL confirmed tortuous blood vessels and artery-vein crossings in ALGS. We also identified sex-specific differences: fewer major vessels in female Jag1Ndr/Ndr mice, and four-fold more female than male patients with intracranial hemorrhage. In conclusion, dysfunctional Jag1 disrupted vascular growth and homeostasis, with sex-specific differences. The mouse model for Alagille syndrome demonstrated multiple bleeding risk factors and vascular defects that can be identified in patients non-invasively.

show abstract

Section: Resultsmentioning

confidence: 99%

Sex differences and risk factors for bleeding in Alagille syndrome

Hankeová

Hul

Laznovsky

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…By way of comparison, the rate of HCC in pediatric liver diseases ranges from 0.8% in biliary atresia [38], to 2% in Hepatitis B infections, to 14% in Progressive familial intrahepatic cholestasis (PFIC) [39,40], and 13-17% for tyrosinemia type 1 [41]. Further, only 5 out of the 9 ALGS patients with HCC from the cohort of 1433 developed fibrosis [37], which combined with the fact that, despite cholestasis, only ~12-14% of ALGS patients develop cirrhosis [36,42], suggests that JAG1 haploinsufficiency confers, via unknown mechanism, protection against HCC. Interestingly, fibrosis in ALGS, when present, is atypical, with a pericellular "chicken-wire" appearance, rather than bridging fibrosis [43], suggesting the inflammation-fibrosis-cirrhosis-HCC axis is likely disrupted in ALGS, with unclear consequences for progression to HCC.…”

Section: Introductionmentioning

confidence: 99%

Jag1 Insufficiency Disrupts Neonatal T Cell Differentiation and Impairs Hepatocyte Maturation, Leading to Altered Liver Fibrosis

Mašek

Filipovic

Hankeová³

et al. 2022

Preprint

View full text Add to dashboard Cite

Background and Aims: Alagille syndrome (ALGS) is a pediatric genetic disorder, caused by mutations in the Notch ligand JAGGED1, presenting with cholestasis due to intrahepatic bile duct paucity. Despite chronic liver disease, few patients develop severe fibrosis or liver cancer, compared to other chronic liver diseases. In contrast, about 1/3 of ALGS patients suffer from reoccurring infections. Notch signaling regulates both liver and immune system development, but how immune system defects interact with liver pathology in ALGS to influence disease course is not known. Here, we aimed to determine whether a mouse model of ALGS mimics fibrosis and liver cancer, and whether ALGS immune system compromise could positively modulate inflammation or liver disease course. Methods: We used single cell RNA sequencing and 25-color flow cytometry to characterize cell populations in embryonic and postnatal liver in an ALGS mouse model (Jag1Ndr/Ndr mice). We analyzed liver cancer prevalence in Jag1Ndr/Ndr mice, in a cancer-prone genetic background, and thymic and spleen cell composition using flow cytometry. Finally, to test the functionality of the Jag1Ndr/Ndr immune system we performed adaptive immune cell transfer experiments into Rag1-/- mice and assessed inflammatory capacity in an ulcerative colitis model and in a DDC model of hepatocellular damage. Results: Adult Jag1Ndr/Ndr mice do not develop liver tumors (0%) while 45% of control mice do. Interestingly, Jag1Ndr/Ndr mice display ALGS-like chicken-wire hepatocellular fibrosis concomitant with mild inflammation shortly after the onset of liver cholestasis. Comprehensive single cell analysis revealed that liver CD4+ and CD8+ T cells of Jag1Ndr/Ndr mice are dysregulated in favor of CD4+, and Regulatory T-cells (Tregs) manifest reduced activation. Trans-plantation experiments show no difference between Jag1Ndr/Ndr and Jag1+/+ lymphocytes in DDC-induced liver damage. In contrast, Jag1Ndr/Ndr lymphocytes do not mount an inflammatory response to bacterial infection. Conclusion: Here we report immune dysregulation and cancer protection in the hypomorphic Jag1 mouse model of ALGS. Disrupted thymocyte differentiation coincides with limited activation of hepatocytes, blunting the inflammatory response to cholestasis. This may contribute to the pericellular fibrosis and prevent carcinogenesis. These results prompt the question of the relative contribution of Jag1 to liver cell pathology vs immune system in ALGS and high-light the need of future studies focused on dissecting apart how Jag1 modulates susceptibility to infection versus cancer risk.

show abstract

Alagille syndrome and risk for hepatocellular carcinoma: Need for increased surveillance in adults with mild liver phenotypes

Schindler

Gilbert

Piccoli

et al. 2020

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Alagille syndrome (ALGS) is a multisystem autosomal dominant developmental disorder caused predominantly by pathogenic variants in JAGGED1 (JAG1), and also by pathogenic variants in NOTCH2 in a much smaller number of individuals. Clinical presentation is highly variable and includes liver, heart, eye, skeleton, and facial abnormalities, with a subset of individuals also presenting with kidney, vascular, and central nervous system phenotypes. Hepatocellular carcinoma (HCC) is a rare complication of ALGS, though little is known about its incidence or etiology among affected individuals. Previous reports have identified HCC occurrence in both pediatric and adult cases of ALGS. We present a case report of HCC in a 58‐year‐old woman with a pathogenic JAG1 variant and no overt hepatic features of ALGS. Through a comprehensive literature review, we compile all reported pediatric and adult cases, and further highlight one previously reported case of HCC onset in an adult ALGS patient without any hepatic disease features, similar to our own described patient. Our case report and literature review suggest that ALGS‐causing variants could confer risk for developing HCC regardless of phenotypic severity and highlight a need for a cancer screening protocol that would enable early detection and treatment in this at‐risk population.

show abstract

Hepatocellular carcinoma in an adult with Alagille syndrome: case report and literature review

Cited by 4 publications

References 6 publications

Sex differences and risk factors for bleeding in Alagille syndrome

Sex differences and risk factors for bleeding in Alagille syndrome

Jag1 Insufficiency Disrupts Neonatal T Cell Differentiation and Impairs Hepatocyte Maturation, Leading to Altered Liver Fibrosis

Alagille syndrome and risk for hepatocellular carcinoma: Need for increased surveillance in adults with mild liver phenotypes

Contact Info

Product

Resources

About