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. 2024 Jan;28(2):e18035.
doi: 10.1111/jcmm.18035. Epub 2023 Nov 15.

Mitochondrial dysfunction is associated with the severity of liver fibrosis in patients after the Fontan operation

Saviga Sethasathien  1 , Krit Leemasawat  2 , Suchaya Silvilairat  1 , Rekwan Sittiwangkul  1 , Krit Makonkawkeyoon  1 , Apinya Leerapun  3 , Sarawut Kongkarnka  4 , Nakarin Inmutto  5 , Supanai Suksai  6   7 , Nattayaporn Apaijai  6   7   8 , Siriporn C Chattipakorn  6   7   9 , Nipon Chattipakorn  6   7   8
Affiliations

Mitochondrial dysfunction is associated with the severity of liver fibrosis in patients after the Fontan operation

Saviga Sethasathien et al. J Cell Mol Med. 2024 Jan.

Abstract

The gold standard for determining the severity of liver disease in Fontan patients is now liver biopsy. Since it is an invasive procedure, this study determined the possibility of applying mitochondrial function from isolated peripheral blood mononuclear cells (PBMCs) as a non-invasive indicator of liver fibrosis. Fontan patients (n = 37) without known liver disease were analysed cross-sectionally. Patients were classified according to their histology using the METAVIR score as follows; F0/F1-no/mild fibrosis; F2-moderate fibrosis; and F3/F4-cirrhosis. Peripheral blood mononuclear cells were assessed for mitochondrial activity and apoptosis. This study did not find any significant differences in cardiac function among the groups according to liver histology. Interestingly, our findings indicated a significant decrease in maximal respiration and spare respiratory capacity, in both the moderate (F2) and cirrhosis (F3/F4) groups compared with the group without significant fibrosis (F0/F1). Moreover, the cirrhosis group exhibited higher levels of apoptosis and lower levels of live cells, compared with both the moderate and no significant fibrosis groups. In conclusion, the degree of liver fibrosis in Fontan patients is strongly correlated with mitochondrial dysfunction in PBMCs. Mitochondrial function and apoptosis could potentially serve as novel markers for tracking the progression of liver fibrosis in these patients.

Keywords: Fontan operation; liver biopsy; liver fibrosis; mitochondrial function.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Fibrosis staging of FALD according to METAVIR scoring system. F1, portal fibrous expansion; F2, portal fibrosis with few septa (bridging fibrosis); F3, bridging fibrosis and distorted architecture; F4, probable or definite cirrhosis with nodule formation (mallory trichrome stain). FALD, Fontan‐associated liver disease.
FIGURE 2
FIGURE 2
Mitochondrial function in PBMCs from Fontan patients with No/Mild fibrosis, moderate fibrosis, and cirrhosis. *p < 0.05 versus No/Mild fibrosis in Maximal respiration and Spare respiratory capacity. One‐way anova test was used.
FIGURE 3
FIGURE 3
Proportion of cell death patterns in PBMCs from Fontan patients with No/Mild fibrosis, moderate fibrosis, and cirrhosis. *p < 0.05 versus No/Mild fibrosis. † p < 0.05 versus moderate fibrosis. Both in % Live cells and % Apoptosis cells. One‐way anova test was used.
FIGURE 4
FIGURE 4
The analysis of proton leak in PBMCs in different stages of liver fibrosis in patients after the Fontan operation. (A) Proton leak, (B) ratio of proton leak/oxidative phosphorylation respiration, (C) ratio of proton leak/uncoupled synthesis, (D) oxidative phosphorylation/uncoupled respiration. OXPHOS, oxidative phosphorylation.
See this image and copyright information in PMC

References

    1. Rychik J, Atz AM, Celermajer DS, et al. Evaluation and management of the child and adult with Fontan circulation: a scientific statement from the American Heart Association. Circulation. 2019;140(6):e234‐e284. doi:10.1161/CIR.0000000000000696 - DOI - PubMed
    1. Cowgill LD. The Fontan procedure: a historical review. Ann Thorac Surg. 1991;51(6):1026‐1030. doi:10.1016/0003-4975(91)91044-v - DOI - PubMed
    1. Ohuchi H. Adult patients with Fontan circulation: what we know and how to manage adults with Fontan circulation? J Cardiol. 2016;68(3):181‐189. doi:10.1016/j.jjcc.2016.04.001 - DOI - PubMed
    1. Tellez L, Rodriguez‐Santiago E, Albillos A. Fontan‐associated liver disease: a review. Ann Hepatol. 2018;17(2):192‐204. doi:10.5604/01.3001.0010.8634 - DOI - PubMed
    1. Liu M, Liu H, Dudley SC Jr. Reactive oxygen species originating from mitochondria regulate the cardiac sodium channel. Circ Res. 2010;107(8):967‐974. doi:10.1161/CIRCRESAHA.110.220673 - DOI - PMC - PubMed

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