Abstract
Post-transplant sinusoidal fibrosis (SF) and pericellular fibrosis (PCF) have not been extensively investigated in adults. Fifty-two post-transplant liver biopsies from 28 consented patients (12 men, mean age 49, range 33–67 years) were studied. Tissue morphology, including an arbitrary summative fibrosis score was assessed in detail. Collagen proportionate area (CPA) and alpha-smooth muscle actin (α-SMA) immunostain were evaluated by digital image analysis (DIA). Anti-keratin 7, anti-C4d and anti-sonic hedgehog (Shh) immunostains were scored semi-quantitatively. SF was observed in 36/52 (69.2%) biopsies and most of these (20/36, 55.6%) had centrilobular fibrosis (CLF). PCF was seen in 7/52 (13.5%) biopsies exclusively in cases with CLF. CPA was significantly correlated with time since liver transplantation (p = 0.043), summative fibrosis score and its main components but not with α-SMA. α-SMA-positive area significantly correlated with the Banff rejection score (p = 0.022) and centrilobular inflammatory changes were more severe in cases with CLF (p = 0.003). Hepatocyte ballooning of cholestatic type was associated with PCF (p = 0.016) and Shh expression (p < 0.001). Sinusoidal fibrosis is a frequent occurrence in post-transplant adult livers, with predilection toward centrilobular areas. Graft age and oxidative stress may contribute to SF development, while hepatocyte ballooning may be implicated in PCF development. Hepatic stellate cell (HSC) activation is likely affected by centrilobular inflammation.
Highlights
Sinusoidal fibrosis (SF) and pericellular fibrosis (PCF) are frequently observed in steatohepatitis of alcoholic and nonalcoholic aetiology [40]
The results of collagen proportionate area (CPA), percentage of α-SMA-stained area and summative fibrosis score are summarised in Table 3 along with significant correlations associated with each variable
SF has previously been reported in a variety of liver disorders, post-transplant SF was rarely mentioned in adult post-transplant liver: periportal SF in the context of recurrent hepatitis C has been reported as a marker of accelerated post-transplant recurrence [30], and as one of the suggested criteria for diagnosing fibrosing cholestatic hepatitis C [45]
Summary
Sinusoidal fibrosis (SF) and pericellular fibrosis (PCF) are frequently observed in steatohepatitis of alcoholic and nonalcoholic aetiology [40]. They have been reported as a frequent feature in the early phase of fibrosing cholestatic hepatitis C [10]. Hepatic stellate cells (HSCs) are the main liver cells responsible for extra-cellular matrix deposition and their activation plays a role in the development of SF, CLF and PCF [3]. The role of HSCs has not been studied in detail in post-transplant liver [5, 16, 43] and their activation has mainly been assessed in association with fibrosis progression in recurrent hepatitis C [5, 16]. In non-alcoholic steatohepatitis (NASH), sonic hedgehog (Shh), a member of the hedgehog signalling pathway expressed in ballooned hepatocytes, is involved in HSC activation with subsequent PCF [44]
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