Acute liver chemistry elevations occur frequently in patients with coronavirus disease 2019 (COVID-19) (1,2). Aspartate aminotransferase elevations are the most common, can be severe, and are associated with worse outcomes (1,2). Cholangiocyte epithelial expression of angiotensin converting enzyme-2 (ACE2) (3), the host receptor for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), may lead to direct viral damage to cholangiocytes and eventual chronic liver disease. We describe 3 cases of a novel severe cholangiopathy arising during recovery from critical COVID-19 with potential for long-term hepatic morbidity.
We identified 3 young adults who underwent liver biopsy for evaluation of prolonged and severe cholestasis during recovery from critical COVID-19. None had preexisting chronic liver disease. Each patient had a prolonged hospitalization because of acute hypoxemic respiratory failure requiring mechanical ventilation and additional complications from COVID-19 (Table 1), confirmed by nasopharyngeal swab polymerase chain reaction testing for SARS-CoV-2. As of September 26, 2020 (range of follow-up: 167–189 days), 2 were discharged home and one remained hospitalized.
On admission, liver chemistries were normal or mildly elevated. Early during their hospitalization, each patient had severe but brief aminotransferase elevations (Figure 1a,b) believed to have been secondary to ischemic hepatitis. Subsequently, each patient developed marked cholestasis with associated jaundice that persisted long after cardiopulmonary and renal recovery (Table 1, Figure 1c,d). Laboratory studies for non–SARS-CoV-2 acute or chronic viral infections and autoimmune serologies were negative. Liver imaging showed no evidence of cirrhosis in any patient. Magnetic resonance cholangiography was abnormal for 2 patients (Table 1, Figure 2a,b), prompting endoscopic retrograde cholangiography with removal of biliary sludge and, for patient 2, extraction of small extrahepatic duct stones. Biliary casts were not seen. Jaundice did not resolve with biliary interventions.
Percutaneous liver biopsies were performed, and Figure 2c–f illustrates the key histological features observed, further described in Table 1. All 3 biopsies exhibited at least moderate portal and periportal fibrosis; the biopsy from patient 1 exhibited bridging portal-to-portal and portal-to-central fibrosis with focal fibrotic obliteration of terminal hepatic veins. Interlobular bile ducts were preserved in patient 2 but exhibited mild and moderate paucity in patients 1 and 3, respectively. All 3 biopsies exhibited extensive degenerative cholangiocyte injury, with prominent cholangiocyte vacuolization, regenerative change, apoptosis, and necrosis of the cholangiocyte epithelial layer of terminal bile ducts and marginal ductules. Immunohistochemistry demonstrated metaplastic expression of cytokeratin 7 in periportal hepatocytes of patient 3 only. In all 3 biopsies, portal tract hepatic arteries showed endothelial swelling with luminal narrowing, and there was portal vein endophlebitis. The biopsy from patient 2 exhibited focal features of sinusoidal obstructive syndrome (veno-occlusive disease) with pericentral confluent necrosis. For the biopsies from patients 1 and 2, immunohistochemistry and in situ hybridization for SARS-CoV-2 were negative.
We describe the first cases of a unique and profound post–COVID-19 cholangiopathy in patients who recovered from critical COVID-19 and went on to develop chronic cholestasis and liver injury. Histopathologically, these patients have predominant cholangiocyte injury with accompanying microvascular changes. Bile duct paucity, the presence of cytokeratin 7 metaplasia of periportal hepatocytes (characteristic of obstructive cholestasis) in one patient, and evidence of bridging fibrosis all indicate a risk of progression to a secondary biliary cirrhosis.
The differential diagnosis for these findings includes extra- or intra-hepatic biliary obstruction, a vanishing bile duct syndrome, and secondary sclerosing cholangitis of the critically ill patient (SSC-CIP) (4). Cholestasis persisted after biliary interventions in the 2 patients with biliary abnormalities on imaging, and all 3 patients' liver biopsies lacked the portal tract edema and neutrophilic inflammation characteristic of biliary obstruction. The vanishing bile duct syndromes of drug-induced, ischemic, or immunologic injury (as from graft-vs-host disease) exhibit bile duct atrophy and loss, but without the degree of cholangiocyte cytoplasmic vacuolization observed in these cases (5–7). The greatest resemblance of the current cases is to SSC-CIP because the following features are shared in common: imaging and endoscopic findings of damage to the extra- and intra-hepatic biliary tree, cholangiocyte necrosis and destruction of the biliary epithelium, ductular reaction and progressive fibrosis of portal tracts, and, in some cases, progression to secondary biliary cirrhosis (8–10). Cholangiocyte vacuolization has been noted (10,11) but is not a prominent histopathologic feature. Our cases have an extreme degree of cholangiocyte cytoplasmic vacuolization and regenerative change not previously described for SSC-CIP. The microvascular features of hepatic artery endothelial swelling, portal vein phlebitis, and sinusoidal obstruction syndrome also are unique.
We believe the post–COVID-19 cholangiopathy described herein represents a confluence of SSC-CIP and direct hepatic injury from COVID-19. The latter involves an intrahepatic microangiopathy affecting all 3 microvascular compartments in keeping with autopsy observations from patients succumbing to COVID-19 during their initial illness (12,13), with potential superimposed injury to cholangiocytes after their exposure to SARS-CoV-2. This last point is underscored by the sustained and extreme elevations of serum alkaline phosphatase levels observed at the upper limits of what has been reported for SSC-CIP (4,9–11) and far above what would be expected for the other conditions in the differential diagnosis. However, our attribution of the current findings to SARS-CoV-2 is indirect because polymerase chain reaction was not used to identify the presence of SARS-CoV-2 in the liver (14) and immunohistochemistry and in situ hybridization (13,15) were negative.
We thus believe that these cases constitute a novel cholangiopathy arising as a postacute condition after critical COVID-19. Although elements of the pathobiology may be shared with SSC-CIP, critical COVID-19 is the unique element of these patients' clinical course and seems to be associated with unique cholangiopathic features not previously observed in SSC-CIP or the broader spectrum of cholangiopathies. The pathobiology of this cholangiopathy requires further investigation, noting that extensive discussion has been given to potential mechanisms of liver injury from SARS-CoV-2, including the fact that biliary epithelia express ACE2, and hence should be susceptible to viral infection (3). Our concern is that this post-COVID cholangiopathy may lead to progressive liver injury with the potential need for liver transplantation. Further work is needed to better understand the development and possible prevention and treatment of this newly described condition associated with COVID-19.
CONFLICTS OF INTEREST
Guarantor of article: Nitzan C. Roth, MD, PhD.
Specific author contributions: N.C.R. – Study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript. A.K. – Study concept and design, acquisition of data, analysis and interpretation of data, and critical revision of the manuscript. T.V. – Acquisition of data, analysis and interpretation of data, and critical revision of the manuscript. J.X. – Acquisition of data and critical revision of the manuscript. G.R. – Acquisition of data and critical revision of the manuscript. D.B. – Study concept and design, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript. J.C. – Study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript
Financial support: None to report.
Conflicts of interest: None to report
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