Ballooning degeneration and fibrosis are responsible for high liver stiffness in human alcohol-related liver disease

Background Liver complications due to alcohol-related liver disease (ALD) are mainly driven by liver fibrosis. In everyday clinical practice, liver stiffness measurement (LSM) is a widely used non-invasive technique (1). However, LSM might be influenced by other pathological features of disease progression independently of fibrosis such as steatosis or ballooning, especially in ALD considering the impact of alcohol itself on stiffness (2). Aims To evaluate the impact of steatosis, ballooning and fibrosis histologically assessed on LSM in a cohort of patients with early ALD. Patients and Methods Patients with ALD based on the steatotic liver disease consensus definition (3) were prospectively recruited in the alcohol withdrawal unit of the Cliniques universitaires Saint-Luc. Inclusion criteria for liver biopsy was a significantly increased LSM (≥ 7.8 kPa) on transient elastography (Fibroscan®) suggesting fibrotic ALD. Patients with cirrhosis were excluded. Steatosis was quantified on hematoxylin and eosin-stained slides and fibrosis on picrosirius red stained slides using computer assisted morphometry (Visiopharm®). Steatosis and fibrosis areas were normalized by the tissue area and expressed as percentages. Ballooned hepatocytes were positively stained using anti-sonic hedgehog (SHH) immunohistochemistry and manually counted at 40-fold magnification. Normality was checked using the Shapiro-Wilk test. Continuous variables are expressed as medians and IQR. Statistical significance was defined by a p-value < 0.05. Results Thirty patients with ALD were recruited between April 2022 and December 2024. Median LSM was 11.9 kPa (10-15.8). Median weekly alcohol consumption was 80 units/week (52-119). Liver biopsies were mainly transjugular (93%) and of good quality (median biopsy size: 30 mm (21-37) – median number of portal tracts: 15 (7-21)). Median steatosis area was 6.3 % (3.6-10.0) and median fibrosis area was 6.2 % (3.8-9.3). Median SHH positive cells per field was 0.33 (0.04-1.20x). LSM correlated with both fibrosis area (r = 0.54; p=0.003) and SHH positive cells (r = 0.39; p=0.038), but not with steatosis (p>0.05). Multiple linear regression highlighted fibrosis as the only significant predictor of LSM after adjustment for age, gender, BMI, weekly alcohol consumption, steatosis area and SHH positive cells/fields (estimate for fibrosis area: r = 0.56; p=0.042). This model showed no multicollinearity (variation inflation factor for lobular inflammation and ballooning = 2.04). Conclusion In human fibrosing steatohepatitis, LSM is impacted by two key histological factors of ALD severity in univariate analysis: ballooning degeneration evidenced by immunohistochemistry and fibrosis evaluated by picrosirius red staining. Fibrosis remains the best predictor of LS even after adjustment for potential influencing co-factors confirming LSM validity in early ALD.

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Henin, G., Declerck, S., Goffaux, A., André-Dumont, S., Baldin, P., Starkel, P., & Lanthier, N. (2025). Ballooning degeneration and fibrosis are responsible for high liver stiffness in human alcohol-related liver disease. ESBRA, Cliniques universitaires Saint-Luc, Brussels, Belgium. https://hdl.handle.net/2078.5/273617