Post-COVID-19 Cholestasis: A Case Series and Review of Literature

Abstract

Background: Coronavirus disease-2019 (COVID-19) cholangiopathy is a recently known entity. There are very few reports of liver transplantation (LT) for COVID-19-induced cholangiopathy. It is well known that vaccines can prevent severe disease and improve outcomes. However, there are no reports on the impact of COVID-19 vaccines on cholestasis. Therefore, we aimed to compare the course and outcome of patients who developed cholestasis following COVID-19 infection among vaccinated and unvaccinated individuals. Methods: Patients diagnosed with post-COVID cholestasis during the pandemic were included in the study after excluding other causes of cholestasis.

Results: Eight unvaccinated and seven vaccinated individuals developed cholestasis following COVID-19 infection. Baseline demographics, presentation, severity, and management of COVID-19 were similar in both groups. However, patients in the unvaccinated group had a protracted course. The peak ALP was 312 (239-517) U/L in the vaccinated group and 571.5 (368-1058) U/L in the unvaccinated group (P = 0.02). Similarly, the peak γ-glutamyl transpeptidase values were lower in the vaccinated (325 [237-600] U/L) than in the unvaccinated group (832 [491-1640] U/L; P = 0.004). However, the peak values of total bilirubin, transaminases, and INR were similar in both groups. Five patients developed ascites gradually in the unvaccinated group whereas none in the vaccinated group developed ascites. Plasma exchange was done in five patients, and two were successfully bridged to living donor LT in the unvaccinated group. Only two patients recovered with conservative management in the unvaccinated group, whereas all recovered with conservative management in the vaccinated group. The other four patients in the unvaccinated group were planned for LT.

Conclusion: Post-COVID-19 cholestasis is associated with high morbidity and mortality, meriting early identification and appropriate management. Vaccination can modify the course of severe COVID-19 infection and improve outcomes.

Keywords: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; COVID-19, coronavirus disease-2019; DDLT, deceased donor living transplantation; GGT, γ-glutamyl transpeptidase; LDLT, living donor liver transplantation; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; UDCA, ursodeoxycholic acid; ULN, upper limit of normal; liver function test; liver transplantation; plasma exchange; vaccination.

Figure 1

Management of COVID-19-induced cholestasis. Hepatotropic viruses-hepatitis A IgM, hepatitis B surface antigen, anti-hepatitis C antibody, hepatitis E IgM. Non-hepatotropic viruses-cytomegalovirus deoxyribonucleic acid (DNA), Epstein–Barr virus IgM, herpes simplex virus ribonucleic acid (RNA), dengue (IgM or NS1). ¶signs of liver cell failure-INR >1.5 or development of ascites or encephalopathy.‖ Plasma exchange was offered for patients with serum bilirubin >20 mg/dl and INR >1.5 with or without pruritus.‡ LT was suggested when the serum bilirubin, and INR did not subside despite plasma exchange with or without the development of ascites/hepatic encephalopathy. Medical management included UDCA (15 mg/kg) and steroid therapy was initiated when the enzyme elevation (>2 ULN) persisted three consecutive times, with liver biopsy demonstrating inflammatory infiltrates. Footnotes: MV, mechanical ventilation; TB, total bilirubin; ALP, alkaline phosphatase; GGT-γ, glutamyl transpeptidase; MRCP, magnetic resonance cholangiopancreatography; ERCP, endoscopic retrograde cholangiopancreatography; INR, international normalized ratio; LT, liver transplantation; PLEX, plasma exchange.

Figure 2

Liver explant histopathology of case #1. A: Light microscopy (40x) using Hematoxylin and Eosin stain demonstrating intracytoplasmic cholestasis (orange arrow). B: Light microscopy (40x) using Hematoxylin and Eosin stain demonstrating bile ductular proliferation (black arrow) with moderate portal inflammation (red arrow). C: Light microscopy (20x) using Hematoxylin and Eosin stain demonstrating profound bile ductular reaction (blue arrow). D: Light microscopy (40x) using Hematoxylin and Eosin stain demonstrating portal tract with arteriole (red arrow) and vein (blue arrow) and absence of bile duct. E: Immunohistochemistry (20x) targeting cytokeratin (CK) 7 stain demonstrating lack of bile ducts. F: Light microscopy (20x) using Hematoxylin and Eosin stain demonstrating incomplete nodule formation surrounded by fibrous septae (purple arrow).

Figure 3

Liver explant histopathology of case #2. A: Light microscopy (40x) using Hematoxylin and Eosin stain demonstrating intracytoplasmic and canalicular cholestasis with bile plugs (orange arrow: golden yellow pigment). B: Light microscopy (40x) using Hematoxylin and Eosin stain demonstrating macrovesicular steatosis (red arrow). C: Light microscopy (40x) using Hematoxylin and Eosin stain demonstrating the absence of lobular inflammation. D: Light microscopy (40x) using Hematoxylin and Eosin stain demonstrating minimal portal inflammation (blue arrow). E: Light microscopy (20x) using Hematoxylin and Eosin stain demonstrating architectural distortion with nodule formation surrounded by fibrous septae (black arrow). F: Light microscopy (20x) using Masson Trichrome stain demonstrating bridging fibrosis with complete nodule formation (black arrow).

Figure 4

Magnetic resonance cholangiopancreatography (MRCP) of case #7. (A) T2 weighted imaging and (B) MRCP-3D Maximum intensity projection (MIP) images demonstrate normal biliary ducts at the initial presentation (C) T2 weighted imaging and (D) MRCP-3D MIP images demonstrated ascites with normal biliary ducts at the last follow-up.