Histologic features of allograft livers in patients treated for rejection before biopsy

Abstract

Liver biopsy is essential for management in liver transplant patients with clinical features suspicious for acute cellular rejection (ACR). As more patients are transplanted for noninfectious indications, it has become increasingly common for them to receive treatment for presumed ACR before biopsy. The effect of pretreatment on the classic histologic triad of ACR's mixed portal inflammation, endothelialitis, and bile duct damage is not well described. Here we report a retrospective study of 70 liver transplant biopsies performed on 53 patients for suspected ACR between 2018 and 2021. Thirty-seven biopsies had a clinical diagnosis of ACR after biopsy. Pretreatment with steroids, antithymocyte globulin, or other increased immunosuppression was given before biopsy in 17 of 37 cases; 20 not-pretreated cases acted as controls. A representative hematoxylin and eosin-stained slide from each biopsy was reviewed independently in a blinded fashion by 3 hepatic pathologists, graded according to the Banff system, assigned a Rejection Activity Index (RAI), and assessed for other histologic features. We found that pretreated biopsies had significantly less portal inflammation (P < .001), less endothelialitis (P < .001), lower RAI (P < .001), and less prominent eosinophils (P = .048) compared to not-pretreated biopsies. There was no significant difference for the other examined variables, including bile duct inflammation/damage (P = .32). Our findings suggest that portal inflammation and endothelialitis become less prominent with pretreatment, whereas bile duct inflammation/damage may take longer to resolve. When evaluating biopsies for suspected ACR, the finding of bile duct inflammation/damage should raise the possibility of partially treated ACR, even in the absence of endothelialitis and portal inflammation.

Keywords: Acute cellular rejection; Gastrointestinal pathology; Hepatic pathology; Liver.

Figure 1:. Histologic features following treatment for rejection in paired biopsies are similar to those in pretreated biopsies.

(A-C) Patient 1, who had a history of liver transplantation performed at another institution about three years prior, presented with AST 761 U/L, ALT 269 U/L, and Alk Phos 2687 U/L. After her initial biopsy showed features of severe acute cellular rejection (A), she was treated with IV steroids followed by an oral steroid taper and started on anti-thymocyte globulin. Repeat biopsy 13 days after first biopsy showed improvement in portal inflammation and endothelialitis (B), but bile ducts demonstrated residual damage/inflammation (C) including disrupted architecture, vacuolated cytoplasm, and intraepithelial lymphocytes (arrowheads). Laboratory values the day before the second biopsy included AST 487 U/L, ALT 749 U/L, and Alk Phos 1456 U/L. (D-F) Patient 2, who had a history of liver transplantation 8 months prior, presented with AST 159 U/L, ALT 247 U/L, and Alk Phos 881 U/L. After his initial biopsy showed features of mild acute cellular rejection (D), he was treated with IV steroids followed by an oral steroid taper. Repeat biopsy 14 days after first biopsy showed improvement of mixed portal inflammation and endothelialitis (E), but bile ducts demonstrated residual damage/inflammation (F) including disrupted architecture and intraepithelial lymphocytes (arrowheads). Laboratory values the day before the second biopsy included AST 45 U/L, ALT 119 U/L and Alk Phos 268 U/L. (G-H) Patient 3, who had a history of liver transplantation 3 months prior, presented with AST 52 U/L, ALT 198 U/L and Alk Phos 198 U/L. She was treated with increased tacrolimus and oral steroids before biopsy. Biopsy showed mostly lymphocytic inflammation involving a minority of portal tracts (score = 1) and no endothelialitis (score = 0) (G), while a minority of bile ducts demonstrated cuffing and infiltration by lymphocytes (score = 1) (arrowheads) (H). All biopsies are from patients with clinically confirmed ACR. Biopsies were obtained before treatment (A and D) and after treatment (B, C, E, F, G, and H) as part of clinical care. Hematoxylin-and-eosin stains.