COVID-19-Related Cholangiopathy: Histological Findings

Abstract

Cholangiopathy has been described in survivors of severe COVID-19, presenting significant clinical parallels to the pre-pandemic condition of secondary sclerosing cholangitis in critically ill patients (SSC-CIP). We aimed to examine the liver histopathology of individuals with persistent cholestasis after severe COVID-19.

Methods: We subjected post-COVID-19 cholestasis liver samples to routine staining techniques and cytokeratin 7 immunostaining and semi-quantitatively analyzed the portal and parenchymal changes.

Results: All ten patients, five men, had a median age of 56, an interquartile range (IQR) of 51-60, and required intensive care unit and mechanical ventilation. The median and IQR liver enzyme concentrations proximal to biopsy were in IU/L: ALP 645 (390-1256); GGT 925 (664-2169); ALT 100 (86-113); AST 87 (68-106); and bilirubin 4 (1-9) mg/dL. Imaging revealed intrahepatic bile duct anomalies and biliary casts. We performed biopsies at a median of 203 (150-249) days after molecular confirmation of infection. We found portal and periportal fibrosis, moderate-to-severe ductular proliferation, and bile duct dystrophy in all patients, while we observed hepatocyte biliary metaplasia in all tested cases. We observed mild-to-severe parenchymal cholestasis and bile plugs in nine and six cases. We also observed mild swelling of the arteriolar endothelial cells in five patients. We observed a thrombus in a small portal vein branch and mild periductal fibrosis in one case each. One patient developed multiple small biliary infarctions. We did not observe ductopenia in any patient.

Conclusions: The alterations were like those observed in SSC-CIP; however, pronounced swelling of endothelial cells, necrosis of the vessel walls, and thrombosis in small vessels were notable.

Keywords: COVID-19; bile duct diseases; cholangiopathy; cholestasis; pathology; post-COVID-19 cholangiopathy; sclerosing cholangitis; secondary sclerosing cholangitis in critically ill patients.

Figure 1

(A) Fibrous widening of interconnected portal tracts. Discrete to moderate inflammatory infiltration of mononuclear cells and ductular reaction was observed (H&E, ×100); (B) Fibrous widening of portal spaces with ductular reaction and discrete inflammatory infiltration of mononuclear cells. Dystrophic bile duct and a ductule with necrosis of cholangiocytes containing bile in the lumen can be observed (arrows) (H&E, ×200); (C) Same area as shown in (A), stained with Sirius red to demonstrate portal fibrosis. The ductular reaction can be observed more easily (Sirius red, ×100); (D) Immunohistochemical staining with anti-cytokeratin 7 antibody highlights intense ductular reaction and dystrophic bile duct in the center of the portal tract (×100); (E) Portal tract containing a bile duct with evident vacuolization of cholangiocyte cytoplasm (arrows) (H&E, ×200); (F) Portal tract exhibiting altered bile ducts. Long arrows indicate ducts with necrosis of cholangiocytes. Short arrows indicate dystrophic bile ducts. Discrete inflammatory infiltration of mononuclear cells and some eosinophils can be observed (H&E, ×200).

Figure 2

(A) Portal tract showing dystrophic bile ducts with infiltration of some lymphocytes in the wall (arrows) (H&E, ×200); (B) Expansion of the portal tract due to fibrosis with slight mononuclear inflammatory infiltration. The arrow indicates dystrophic ducts with some lymphocytes in the wall (arrow) (H&E, ×200); (C) The arrow indicates an artery with vacuolization of endothelial cell cytoplasm (H&E, ×200); (D) An arteriole can be observed with vacuolization of endothelial cells and infiltration of the wall by PAS+ material, resistant to diastase. Above the arteriole, there is a dystrophic bile ductule with irregularly arranged cholangiocytes, hyperchromatic nuclei, and slight vacuolization of the cytoplasm can be observed (PAS with diastase, ×200); (E) Portal tract with slight mononuclear inflammatory infiltration, ductular reaction, and in the center (arrow) a blood vessel occluded by a recent fibrinous thrombus (H&E, ×200); (F) Small portal tract, exhibiting a vessel with wall necrosis. The arrow points to a necrotic vessel with two cells displaying pyknotic nuclei and increased cytoplasmic eosinophilia (H&E, ×200).

Figure 3

(A) The portal tract with dystrophic duct and mild mononuclear inflammatory infiltration. The arrows indicate hepatocytes in the periportal region with cytoplasmic bile impregnation, some slightly ballooned (H&E, ×200); (B) The centrolobular area of the hepatic parenchyma (zone 3) and zone 2 showing biliary thrombi in the bile canaliculi and hepatocytes, with wider and clearer cytoplasm. A focus of necrosis of isolated hepatocytes with inflammatory cell infiltration can be observed (H&E, ×200); (C) Immunostaining with anti-cytokeratin 7 antibody, showing more intense staining of the bile ducts. The lighter staining in the parenchyma corresponds to hepatocytes with biliary metaplasia (×100).