HPHS Journal Watch Nov Dec 2024
Hepatology
Genetic variation in severe cystic fibrosis liver disease is associated with novel mechanisms for disease pathogenesis.
Stonebraker JR, Pace RG, Gallins PJ, et al. Hepatology. 2024 Nov 1;80(5):1012-1025. PMID: 38536042.
https://pubmed.ncbi.nlm.nih.gov/38536042
This is a multicenter international study designed to identify genes and pathways involved in the pathogenesis of severe cystic fibrosis (CF) liver disease (CFLD) to improve understanding of disease mechanisms including whole-genome sequencing of 516 patients with severe CFLD, as well as genome-wide association study (GWAS), transcriptome-wide association (TWAS), and pathway analyses, comparing patients with severe CFLD to a control population. Z allele was significantly associated with severe CFLD. GWAS analysis identified 2 SNPs with genome-wide significance in the PKD1 and FNPB1 genes, while TWAS identified 3 genes (CXCR1 and AAMP in chr 2q35 and TRBV24-1 in chr 7q34). The authors outline the association between CXCR1 with several physiologic mechanisms, including fibrosis development, neutrophil recruitment, macrophage accumulation, and upregulation of natural killer cells.
Pseudouridine synthase 1 promotes hepatocellular carcinoma through mRNA pseudouridylation to enhance the translation of oncogenic mRNAs.
Hu YX, Diao LT, Hou YR, et al. Hepatology. 2024 Nov 1;80(5):1058-1073. PMID: 38015993.
https://pubmed.ncbi.nlm.nih.gov/38015993
In this study, the authors utilize in vitro and in vivo mouse models of hepatocellular carcinoma (HCC) to evaluate the biological role of pseudouridine synthase (PUS) RNA epitranscriptomics. Pseudouridine (PU) is one of the most abundant RNA modifications, and it has emerged as a potential biomarker for HCC. High expression of Pseudouridine synthase 1 (PUS1) in clinical HCC sampled was associated with poorer overall survival and disease-free survival. The authors showed that PUS1 enhanced the protein levels of a set of oncogenes, including IRS1 and c-MYC, by means of pseudouridylation-mediated mRNA translation to promote HCC tumorigenesis. The study also demonstrated that pseudouridylation of mRNA lead to overexpression of PUS1- promoting HCC cell growth and development in vitro and in vivo. On the other hand, depletion of PUS1 significantly suppressed HCC cell proliferation and tumorigenesis. In the mouse model histological analysis confirmed that the expression of PUS1 was significantly decreased in the PUS1 knockout group and revealed that tumors in the PUS1 knockout group exhibited significantly lower Ki67 immunoreactivity. The study offers new insights into the regulation of mRNA pseudouridylation by PUS1 in HCC and offer a molecular basis for potential therapeutic strategies based on RNA modification.
Histopathology
Diagnostic approach to hepatic vascular lesions: a pediatric perspective
Putra J and Kim GE. Histopathology. 2024 Dec;85(6):835-845. PMID: 38924138
https://pubmed.ncbi.nlm.nih.gov/38924138
The pathological evaluation of hepatic vascular lesions in children requires special consideration. Inconsistent terminology, rarity of pathology specimens and overlapping pathological features between various lesions may pose a serious diagnostic challenge. This review article highlights the importance of using the International Society for the Study of Vascular Anomalies (ISSVA) classification scheme to characterize these lesions. Selected entities are discussed, including hepatic vascular tumors exclusively seen in the pediatric age group, such as hepatic infantile hemangioma and hepatic congenital hemangioma. Vascular malformations, with emphasis on their syndromic associations (venous malformation in blue rubber bleb naevus syndrome) and complications (hepatocellular nodules in Abernethy malformation) are also covered.
Histopathological assessment of the viability of hepatic alveolar echinococcosis
Robers S, Reinehr M, Haibach L, et al. Histopathology. 2024 Dec;85(6):857-867. PMID: 39044671
https://pubmed.ncbi.nlm.nih.gov/39044671
Infections by the larval stage of the tape worms Echinococcus multilocularis and Echinococcus granulosus s.l. are potentially fatal zoonoses affecting humans as dead-end hosts. Histopathological evaluation of hepatic echinococcosis is an integral part of patient management, including the distinction between alveolar (AE) and cystic echinococcosis (CE), which are associated with different disease courses and treatments. In this study, histomorphological criteria for determining parasitic viability based on the morphology of parasite structures and different stages of their decay were defined based on a clinically and molecularly defined cohort comprising 138 specimens from 112 patients (59 AE and 53 CE); 618 AE lesions were assessed for histopathological viability comparing H&E staining with mAbEm18 and mAbEm2G11 immunostaining. Histomorphological criteria for viability included delimited germinal layer, basophile laminated layer, presence of nuclei, and no debris. Protoscoleces in CE and AE displayed variable states of degeneration. Albendazole had no significant effect on the morphology of parasite structures. Viability assessment revealed high agreement between H&E and mAbEm18, but not mAbEm2G11 staining, suggesting mAbEm18 staining as reliable for parasite viability assessment. H&E and mAbEm18 staining displayed a central-peripheral gradient of parasite viability and decay across parasitic lesions, with decayed cystic lesions located more towards the lesion center while the most viable cystic lesions were located more peripherally. In conclusion, histopathological criteria corroborated by mAbEm18 staining provide a simple and reliable tool to assess the viability of AE lesions.
Human Pathology
Glutamine synthetase staining patterns in cirrhosis.
Nguyen ED, Ding CC, Umetsu SE, Ferrell LD, Wen KW. Hum Pathol. 2024 Nov;153:105655. PMID: 39245221
https://pubmed.ncbi.nlm.nih.gov/39245221
An aberrant periportal glutamine synthetase (GS) immunohistochemical staining pattern has been proposed as a marker of regression in cirrhotic livers. In this study, the authors analyzed GS expression in 88 liver resection and explant specimens from various etiologies. Cirrhosis was classified as progressive, indeterminate, or regressive according to the Beijing P-I-R classification, while aberrant GS staining patterns were categorized as perivenular, periseptal, or perinodular (circumferential/complete). The findings revealed that although aberrant periportal GS staining was commonly observed in regressed cirrhosis, it lacked specificity, as similar patterns were identified in indeterminate and progressive cases. This underscores the limitations of GS immunohistochemistry compared to trichrome and orcein staining in characterizing cirrhosis. Notably, the study also identified an association between the perinodular staining pattern and chronic cholestatic liver disorders.
Gastroenterology
Gut Pathobiont-Derived Outer Membrane Vesicles Drive Liver Inflammation and Fibrosis in Primary Sclerosing Cholangitis-Associated Inflammatory Bowel Disease.
Dorner H, Stolzer I, Mattner J, et al. Gastroenterology. 2024 Nov;167(6):1183-1197.e16. PMID: 38992449
https://pubmed.ncbi.nlm.nih.gov/38992449
This study explores the role of bacterial outer membrane vesicles (OMVs) from gut microbes in driving liver inflammation and fibrosis in the context of primary sclerosing cholangitis and inflammatory bowel disease (PSC-IBD). OMVs were observed to traverse the intestinal barrier and target liver-resident cells, such as hepatocytes and biliary epithelial cells, without the involvement of intact bacteria. Through mouse models and ductal organoids, researchers demonstrated that OMVs contribute to PSC-IBD by activating immune pathways, including Toll-like receptor 4, the NLRP3 inflammasome, and gasdermin-D–mediated pyroptosis. These vesicles were found to locally trigger inflammation and accelerate fibrosis in genetically predisposed mice. The findings further suggest that OMVs could serve as diagnostic markers of barrier dysfunction and as potential therapeutic targets for fibrosis in patients with PSC-IBD.
Gut
Circulating tumour DNA in patients with hepatocellular carcinoma across tumour stages and treatments
Campani C, Imbeaud S, Couchy G, et al. Gut. 2024 Oct 7;73(11):1870-1882. PMID: 39054058
https://pubmed.ncbi.nlm.nih.gov/39054058
This study investigates circulating tumor DNA (ctDNA) as a prognostic tool in early-stage hepatocellular carcinoma (HCC) and a dynamic biomarker for treatment response across various HCC stages. 772 plasma samples from 173 hepatocellular carcinoma (HCC) patients, collected at diagnosis or treatment (n=502), 24 hours after locoregional treatment (n=154), and during follow-up (n=116) were analyzed. ctDNA was most frequently detected in patients with advanced-stage HCC, particularly those with larger tumors, vascular invasion, and higher histopathological grades. Elevated baseline ctDNA levels were associated with worse clinical outcomes, including reduced overall survival (OS) and progression-free survival (PFS). ctDNA provided early signals of relapse, often preceding radiological evidence of disease recurrence. The findings of this study suggest that ctDNA could serve as an important adjunct to conventional imaging and clinical markers in the management of HCC.
Modern Pathology
ARX, PDX1, ISL1, and CDX2 Expression Distinguishes 5 Subgroups of Pancreatic Neuroendocrine Tumors With Correlations to Histology, Hormone Expression, and Outcome
Moser E, Ura A, Vogel L et al. Mod Pathol. 2024 Nov;37(11):100595. PMID: 39147030
https://pubmed.ncbi.nlm.nih.gov/39147030
The authors evaluated 185 PanNETs using a transcription factor panel (ARX, PDX1, ISL1, and CDX2) to search for new subgroups and correlate with morphology and hormone expression. They found that PanNETs can be classified into 5 subgroups (designated A1, A2, B, C, and D) according to histologic features and hormone expression. Subtype D (PDX1+/CDX2+/ISL1−/ARX−) was the least common, showing solid histology and expressing ACTH/serotonin, and is an independent prognosticator of poor outcome in multivariate analysis.
Prepared by:
Dana Balitzer, MD (Editor); University of California San Francisco
Clifton Fulmer, MD, PhD; Cleveland Clinic
Nigar Anjuman Khurram, MD; University of Pittsburgh
Yuanxin Liang, MD, PhD; Yale School of Medicine
Juan Putra, MD; Boston Children’s Hospital
Daniel Roberts MD; Cleveland Clinic
Camila Simoes MD; UAMS College of Medicine
Angela R. Shih, MD; Massachusetts General Hospital
Xuefeng Zhang, MD; Cleveland Clinic