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Delicate and thin fibrous septa indicate a regression tendency in metabolic dysfunction-associated steatohepatitis patients with advanced fibrosis

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Abstract

Background and aims

Metabolic dysfunction-associated steatohepatitis (MASH)-related fibrosis is reversible. However, the dynamic morphology change in fibrosis regression remains unclear. We aim to explore the morphological characteristics of fibrosis regression in advanced MASH patients.

Methods

Clinical and histological data of 79 biopsy-proved MASH patients with advanced fibrosis (F3–F4) were reviewed. The second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) image technology was used to quantitatively identify the R (regressive) septa from P (progressive) septa and PS (perisinusoidal) fibrosis. Non-invasive tests were used to compare the fibrosis level with and without R septa groups. Transcriptomics was used to explore hub genes and the underlying mechanism of the formation of R septa.

Results

The R septa were different from the P septa and PS fibrosis in detail collagen quantitation identified by SHG/TPEF technology. The R septa were found in MASH fibrosis-regressed patients, which met the definition of the “Beijing classification”. Therefore, patients were divided into two groups according to septa morphology: with R septa (n = 10, 12.7%), and without R septa (n = 69, 87.3%). Patients with R septa had lower values in most non-invasive tests, especially for liver stiffness assessed by TE (12.3 vs. 19.4 kPa, p = 0.010) and FAST (FibroScan®-AST) score (0.43 vs. 0.70, p = 0.003). Transcriptomics analysis showed that the expressions of five hub fibrogenic genes, including Col3A1, BGN, Col4A1, THBS2, and Col4A2 in the R septa group, were significantly lower.

Conclusions

The R septa can be differentiated from the P septa and PS fibrosis by quantitative assessment of SHG/TPEF, and it represents a tendency of fibrosis regression in MASH patients.

Trial registration: NCT03386890, 29/12/2017.

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Data availability

No additional data are available.

Abbreviations

BMI:

Body mass index

T2D:

Type 2 diabetes

CHD:

Coronary heart disease

PNPLA3 :

Patatin-like-phospholipase domain-containing protein 3

TM6SF2 :

Transmembrane 6 superfamily member 2

PLT:

Platelet

ALB:

Albumin

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

ALP:

Alkaline phosphatase

GGT:

Gamma-glutamyl transpeptidase

FBG:

Fasting blood glucose

FINS:

Fasting insulin

HOMA-IR:

Homeostatic model assessment for insulin resistance

TG:

Triglyceride

CHOL:

Cholesterol

HDL-C:

High-density lipoprotein cholesterol

LDL-C:

Low-density lipoprotein cholesterol

TBIL:

Total bilirubin

UA:

Uric acid

NAS score:

MAFLD activity score

LSM:

Liver stiffness measurement

VCTE:

Vibration-controlled transient elastography

MRE:

Magnetic resonance elastography

FAST score:

FibroScan®-AST score

MAST score:

MRI-based score

FIB-4:

Fibrosis-4 score

APRI:

AST-to-PLT ratio index

H&E:

Hematoxylin and eosin

IQR:

Interquartile range

SD:

Standard deviation

MAFLD:

Metabolic dysfunction-associated fatty liver disease

MASH:

Metabolic dysfunction-associated steatohepatitis

NASH-CRN:

Non-alcoholic steatohepatitis-clinical research network

NITs:

Non-invasive tests

SNPs:

Single-nucleotide polymorphisms

DEGs:

Differentially expressed genes

NA:

Not applicable

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Funding

This study was supported by the “Beijing Hospitals Authority Clinical Medicine Development of special funding support (Award No. ZLRK202301)” and the “National Natural Science Foundation of China (Award No. 82130018)”.

Author information

Authors and Affiliations

  1. Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, China

    Xiaofei Tong, Yameng Sun, Qianyi Wang, Xinyan Zhao, Wei Chen, Mengyang Zhang, Xiaoning Wu, Jingjie Zhao, Chenglin Sun, Xiaojuan Ou, Jidong Jia & Hong You

  2. HistoIndex Pte Ltd, Singapore, Singapore

    Yayun Ren

  3. Clinical Epidemiology and EBM Unit, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, China

    Xinyu Zhao

  4. MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

    Minghua Zheng

  5. Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China

    Minghua Zheng

  6. Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China

    Hao Ren & Zhenghan Yang

Authors
  1. Xiaofei Tong
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  2. Yameng Sun
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  17. Hong You
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Contributions

Study design: HY and XFT. Data collection: XFT, YMS, QYW, MYZ, XNW, CLS, JJZ, MHZ, and XJO. Liver biopsy assessment: XYZ and YMS. MRE assessment: HR and ZHY. Statistical analysis: XFT and XYZ. Manuscript writing: XFT. Genotype analysis: XFT and QYW. Critical revision of the manuscript: HY and JDJ.

Corresponding author

Correspondence to Hong You.

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Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical approval

The study was conducted by the principles enshrined in the Declaration of Helsinki and the Good Clinical Practices. The Ethics Committee of Beijing Friendship Hospital, Capital Medical University approved the study protocol (Approval No. 2015-P2-070–01).

Informed consent

All patients gave written informed consent prior to their enrollment.

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All authors had access to the study data and reviewed and approved the final manuscript.

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Supplementary Information

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12072_2024_10719_MOESM1_ESM.jpg

Supplementary file1 Diagnosis values for qFibrosis® parameters to identify R and P septa (AUROC > 0.7, p < 0.001), R septa and PS fibrosis (all AUROC > 0.9, p < 0.001). (JPG 541 KB)

12072_2024_10719_MOESM2_ESM.jpg

Supplementary file2 Non-invasive tests between F3 patients with and without R septa; Non-invasive tests between F3 patients without R septa and F4 patients without R septa. (A) The FAST score in F3 patients with R septa was significantly lower than in F3 patients without R septa (p = 0.002). The liver stiffness (LSM) assessed by TE, LSM assessed by MRE, MAST score, FIB-4 score, and APRI score in F3 patients with R septa show a lower trend but no significance. (B) The LSM assessed by TE (p = 0.001), LSM assessed by MRE (p ＜ 0.001), and FIB-4 score (p = 0.044) were significantly lower in F3 patients without R septa than in F4 patients without R septa. The FAST score, MAST score, and APRI score showed no difference in the two groups (JPG 363 KB)

Supplementary file3 (DOCX 15 KB)

Supplementary file4 (DOCX 21 KB)

Supplementary file5 (DOCX 15 KB)

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Tong, X., Sun, Y., Wang, Q. et al. Delicate and thin fibrous septa indicate a regression tendency in metabolic dysfunction-associated steatohepatitis patients with advanced fibrosis. Hepatol Int (2024). https://doi.org/10.1007/s12072-024-10719-w

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