In this study, we proposed a histological parameter (GS-index) to quantify hepatic lobular architecture restoration in CHB patients in the era of antiviral therapy. Patients in the restored group were characterized by better clinical and morphological improvements than in the non-restored group. In addition, we observed through the GS-index that reverse patients attain more significant hepatic architecture restoration than non-reverse patients.
The GS-index was measured by the proportion of normal HVs in all HVs. Recently, Wanless updated the observation of the parenchymal extinction sequence (PE sequence), which consists of 9 levels in the natural history of parenchymal extinction lesions (PELs)16; this can be easily quantified by GS staining. Based on PELs, he proposed the VPA index which was defined as the proportion of PTs attaching to adjacent HVs. Thus, both the GS-index and the VPA index indicate that the approximation of HVs and PT is a key histological feature of advanced liver fibrosis.
Loss of normal lobular architecture is one of crucial functional consequences of liver fibrosis progression leading to portal hypertension and liver decompensation.1,2 In a study of HCV cirrhotic patients with paired liver biopsies, D'Ambrosio et al. observed that the proportion of patients with normal lobular metabolic zonation was increased by 50% (19/38) after 61 months of sustained virological response (SVR), when compared to pretreatment biopsies.17 For CHB patients with advanced liver fibrosis, our investigations revealed that hepatic lobular architecture restoration and clinical characteristics, such as liver function and LSM, can both be improved by efficacious antiviral treatment.
It is well documented that liver fibrosis can be reversed after successful suppression of HBV replication by antiviral treatment18,19. Our study illustrated the relationship between hepatic lobular architecture restoration and fibrosis regression. There is corresponding improvement in the health of the patients with degradation of collagen fibers and elongation of the distance between HVs and PT to achieve hepatic lobular zonation restoration. We also observed that the extent of restoration is different between reverse and non-reverse patients during longitudinal follow-up period.
In this study, the definition of normal lobular architecture is that HVs do not approximate PTs. The results of our analysis indicated that the elongation of the distance between HVs and PTs is a key histological feature of hepatic lobular architecture restoration and liver fibrosis regression. Hadi et al. proposed that PT-HVs approximation remains after fibrosis regression, manifesting as fibrous septa resorption.20 The enrollment criteria for this study included regression cases with the morphological feature of veno-portal approximation, which may lead to selection bias. In comparison with this cross-sectional study, our research is based on a national and multicenter cohort of patients in which sequential liver biopsies were performed during longitudinal follow-up period, making our results more robust.
The GS-index≥ 50% threshold of lobular restoration was proposed after long deliberation based on the following considerations: i) based on this cutoff value, restored patients can attain additional improvement in both clinical and histological characteristics compared to non-restored patients; ii) since there is no gold standard of hepatic lobular restoration assessment, in analogy with the previous semi-quantification assessment of liver fibrosis (Ishak system), which defined the “quantitative” indicators (“few”, “some” and “most”) based on the threshold of half of the portal tract or central area in routine practice,23 we attempted to defined lobular restoration as the half of the HVs in the whole liver biopsy not approximating to PT at week 78. The definition of hepatic lobular restoration needs to be confirmed in further investigation with the data of longer prospective follow up and clinical endpoints.
The novelty of this study is the type of insight being proposed. The GS-index has two important clinical implications. Firstly, the utility of GS-index facilitates the quantification of hepatic lobular zonation restoration. Secondly, the dynamic changes of GS-index add a new dimension, which is independent of fibrosis severity and inflammatory activity, for disease evolution assessment.
Our study has certain limitations. First, loss of GS expression following loss of endothelium-hepatocyte proximity or contact was observed in severe cirrhosis, especially Laennec 4B or 4C, leading to underestimation of HVs.8,21−24 Second, thick collagen fibers and contiguous liver parenchymal collapse can interfere with the perception of HVs and PTs. Third, the opening up of new HVs in cirrhosis regression is uncertain; therefore, we may have to approach this dilemma by counting the increase in the number of new veins rather than separating them from PTs. Last, overstaining in some parts of the specimens might lead to confusion in terms of identifying the HVs.
In conclusion, our study draws attention to the hepatic lobular architecture restoration assessment for CHB patients and the relationship to liver fibrosis regression. Restored patients can achieve greater improvements in histological and clinical features than non-restored patients. Hepatic lobular architecture can be restored through liver fibrosis regression.