Pathophysiological Mechanisms of Liver Injury in COVID-19

Alexander D. Nardo; Mathias Schneeweiss-Gleixner; May Bakail; Emmanuel D. Dixon; Sigurd F. Lax; Michael Trauner

Disclosures

Liver International. 2021;41(1):20-32. 

In This Article

Sirs-induced Cholestasis and Bile Duct Alterations in COVID-19

Cholestatic features such as bile duct proliferation, portal inflammatory infiltrates, and in some cases, canalicular/ductular bile plugs have been reported in post-mortem evaluations on COVID-19 patients.[49,119] The cytokine storm characteristic of the SARS-CoV-2-associated viral sepsis[120] may be a major contributing factor, since cytokines like TNF-alpha, IL-1 and IL-6 can induce hepatocellular cholestasis by down-regulating hepatobiliary uptake and excretory systems,[121,122] resembling the pathomechanisms seen in sepsis-induced cholestasis.[121–125] Further studies will have to explore whether—similar to sepsis—serum bile acids as the most accurate indicators of cholestasis may be relevant prognostic parameters in COVID-19.[122,126] Sustained systemic IL-6 signalling initiated by SARS-CoV-2 infection induces a C/EBPβ-dependent suppression of albumin synthesis.[127] In addition to hypo-albuminaemia, cholestasis in SIRS as a result of repressed hepatobiliary excretory function could be viewed as part of the negative acute phase response in COVID-19.

In addition to hepatocellular features, bile duct changes, such as ductular proliferation have been observed in postmortem studies.[49] Notably, IL-6 is a strong cholangiocellular mitogen factor[128] and induces a proliferative and pro-inflammatory phenotype.[74,129] Bile ducts from patients with COVID-19 could therefore be exposed to a 'triple hit' from (i) hypoxia from respiratory failure (potentially aggravated by obliteration of the peribiliary arterial plexus through vasculitic/thrombotic changes); (ii) systemic SIRS resulting in a reactive cholangiocyte phenotype or senescence-associated secretory phenotype, thus actively propagating inflammation as well as fibrosis and (iii) potential viral infection of cholangiocytes themselves. Thus, the hepatobiliary system may become an important target for adverse long-term hepatic outcomes of COVID-19. Secondary sclerosing cholangitis of critical ill patients (SSC-CIP) is a rare but clinically relevant complication in critically ill patients with severe trauma, burn injury, suffering from severe respiratory failure or requiring vasopressor therapy due to hemodynamic instability.[130,131] Malperfusion and hypoxia, as well as recurrent inflammatory stimuli, are the main triggers for the destruction of the biliary epithelium in SSC-CIP,[122] all conditions present in severe COVID-19 patients.

Therefore, hepatic long-term follow-up for COVID-19 survivors who experienced a severe disease course, such as ARDS with ECMO and prolonged ICU admission might be considered. Early diagnosis is paramount to best manage symptoms and disease progression of SSC-CIP, which could be counteracted with anti-cholestatic, cholangio-protective drugs such as UDCA or more recently norUDCA.[132–134]

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