COVID-19 and the Liver: A 2021 Update

Catherine W. Spearman; Alessio Aghemo; Luca Valenti; Mark W. Sonderup


Liver International. 2021;41(9):1988-1998. 

In This Article

COVID-19 and Chronic Liver Disease

Chronic liver disease (CLD) and particularly cirrhosis is associated with alterations in both innate and adaptive immunity leading to increased susceptibility to infections and aberrant systemic responses during infections. This is referred to as cirrhosis-associated immune dysfunction (CAID) and includes macrophage activation, impaired neutrophil and lymphocyte function, Toll-like receptor dysfunction, impaired complement system and importantly increased gut permeability with alterations in the gut microbiome.[23,51,52]

Data on the prevalence of CLD in COVID-19 studies are limited, but it is estimated that 1%-11% have associated CLD. The stage of the CLD and associated co-morbidities influence outcomes with progressive increase in morbidity and mortality with increasing Child–Pugh (CP) class.[53–57] COVID-19 can precipitate hepatic decompensation, and this is associated with increased mortality: 63.2% vs 26.2% without decompensation.[54]

In a systemic review and meta-analysis of 73 studies of 24 299 patients, CLD prevalence was 3% amongst all COVID-19 patients. No increased risk of COVID-19 noted, but CLD was associated with more severe infection [pooled OR 1.48; 95% CI 1.17–1.87, P = .001] and overall increased mortality [pooled OR 1.78; 95% CI 1.09–2.93, P = .02].[58]

In USA, the Centres for Disease Control study of 122 653 COVID-19 patients, where only 5.8% of patients had clear data, 37.6% had at least one underlying condition or risk factor predicting for severe disease and poor outcomes. Of these, 41 patients (0.6%) had CLD, including 7 who required ICU admission.[59] Given the known high prevalence of fatty liver disease in the US population, the estimated CLD prevalence is likely underestimated. In another US cohort of 2780 COVID-19 patients, CLD was associated with significantly higher mortality [RR 2.8, 95% CI 1.9–4.0]. Cirrhotics carried the highest mortality risk [RR 4.6, 95% CI 2.6–8.3]. Fatty liver disease and non-alcoholic steatohepatitis (NASH) were the most common aetiologies in the liver disease group. Mortality risk was independent of risk factors such as BMI, hypertension and diabetes.[53]

A large United Kingdom review of electronic health record data of more than 17 million patients suggested that 114 796 patients with CLD had an elevated mortality from COVID-19 with a fully adjusted HR of 1.68 [95% CI 1.34–2.10].[60]

The collaborating International Registries of SECURE-Cirrhosis and COVID-Hep (29 countries) have confirmed increasing frequency of ICU admission, ventilation support, renal replacement therapy and mortality with increasing Child–Pugh class.[54] Overall mortality for CP-A is 19%, CP-B (35%) and CP-C (51%). The odds ratio (OR) for death was for CP-A [OR 1.90; 1.03–3.52], CP-B [OR 4.14; 2.4–7.65] and CP-C [OR 9.32; 4.80–18.08]. In CP-C, the mortality was 79% on admission to ICU and 90% once on mechanical ventilation. Acute hepatic decompensation occurred in 46% of patients with cirrhosis, of whom 21% had no respiratory symptoms. Half of those with hepatic decompensation had acute-on-chronic liver failure (ACLF).[54] COVID-19 can be a trigger for ACLF, and COVID-19 case fatality rates are associated with a rising ACLF SCORE.[54,55]

Reported overall mortality rates for cirrhotics hospitalized with COVID-19 range between 30% and 34% with respiratory complications being the main cause of death.[54,55,57]

Viral Hepatitis and COVID-19

To date, no evidence has demonstrated that individuals with chronic hepatitis B (HBV) or hepatitis C (HCV) infection, without advanced fibrosis or cirrhosis, are at any greater risk for acquiring or having a worse outcome with COVID-19.[32,38,61–63] No independent association with death has been documented for HBV or HCV.[63–65] Although a population-based study using electronic health record data suggested that HCV-infected individuals with SARS-CoV-2 were more likely to be hospitalized, but were not at increased risk of death.[63]

Although guidance has recommended that direct acting antiviral (DAA) therapy for HCV could be delayed in patients with COVID-19, some data suggested a potentially beneficial effect of DAAs in COVID-19.[66–68] A meta-analysis of three trials point towards clinical recovery within 14 days of randomization being higher in the sofosbuvir/daclatasvir arms compared with control arms [RR 1.34; 95% CI 1.05–1.71, P = .02]. Sofosbuvir/daclatasvir improved time to clinical recovery [HR = 2.04; 95% CI 1.25–3.32, P = .004] with a significantly lower pooled risk of all-cause mortality [RR = 0.31; 95% CI 0.12–0.78, P = .013]. However, the sample size for analysis was 176 patients, one trial was not randomized, and the designs were not standardized, so data remains disappointing and no recommendation exists.[69] HBV reactivation remains a risk with COVID-19-specific therapies including tocilizumab and corticosteroids, and nucleos(t)ide analogues to prevent HBV flares are advisable. In summary, no contraindication exists to initiating anti-HBV or HCV DAA therapy during the pandemic and treatment initiation should be clinically guided.

Fatty Liver Disease and COVID-19

Metabolic dysfunction-associated fatty liver disease (MAFLD), independent of BMI, is epidemiologically associated with an increased risk of severe COVID-19 requiring hospitalization.[70,71] Initial data suggest that MAFLD may mediate the impact of obesity on COVID-19.[72] The mechanism encompasses the promotion of inflammation by facilitation of liver injury, which is a frequent feature of severe COVID-19, increased release of cytokines and procoagulant mediators. Several studies now demonstrate that MAFLD is associated with an increased risk of developing severe COVID-19. Outcomes are worse, especially in those with advanced liver fibrosis.[73–76] A systematic review and meta-analysis confirmed an increased risk of severe COVID-19 and ICU admission, but no observable difference in mortality between patients with and without MAFLD.[77] A comprehensive evaluation of the literature detected a >2-fold higher risk of COVID-19 in individuals with MAFLD, independent of BMI.[74] MAFLD also increases viral shedding time, 17.5 ± 5.2 days vs 12.1 ± 4.4 days, P < .0001, compared to patients without MAFLD.[76] Furthermore, genetic data suggest that metabolic dysfunction rather than hepatic fat accumulation itself may facilitate COVID-19 progression.[71] The mechanism linking obesity and MAFLD with severe COVID-19 is probably not mediated by increased hepatic fat, but includes more severe insulin resistance, hypoxia and alterations of gut permeability and the gut-liver axis[78] (Figure 2). Although additional data are required to elucidate the relationship between hepatic fat and SARS-CoV-2, the presence of MAFLD can be considered a marker of increased susceptibility to develop severe COVID-19.

Figure 2.

Mechanisms linking fatty liver disease and metabolic dysfunction with severe COVID-19

Alcohol-related Liver Disease and Alcohol-use Disorders and COVID-19

The large international registry (SECURE-Cirrhosis, COVID-Hep) study of 745 patients with CLD and cirrhosis from 130 different institutions in 29 countries identified alcohol-related liver disease (ArLD) as a risk factor for COVID-19-related mortality [OR 1.79; 1.03–3.13].[54] A US multicentre retrospective cohort study confirmed ArLD as an independent risk factor for COVID-19-related death [HR 2.42; 95% CI 1.29–4.55].[65] The higher mortality in ArLD may relate to the presence of advanced disease and CAID. This immune dysregulation, especially alterations in the gut-liver axis, is exaggerated in ArLD with increased endotoxaemia and Kupffer cell activation leading to the transcription of proinflammatory cytokines (TNF-α) and superoxide production.[23,51,52] In addition, chronic alcohol exposure also interferes with the normal functioning of all aspects of the adaptive immune response, including both cell-mediated and humoral responses.[79]

Importantly, psychosocial stressors have led to increased alcohol abuse, and social distancing has limited participation in substance use disorder supports groups increasing the risk for alcohol relapse in patients.[80]

Autoimmune Liver Disease and COVID-19

Immunosuppressed patients have higher SAR-CoV-2 viral titres, are more infectious and have prolonged viral shedding but seem not to be at increased risk of complications such as ARDS.[81,82] Registry data (SECURE-Cirrhosis, COVID-Hep and ERN RARE-LIVER) on 70 autoimmune hepatitis (AIH) patients have noted despite the use of immunosuppression in 86% of cases, no differences in the rates of major outcomes between AIH and non-AIH CLD patients including hospitalization (76% vs 85%; P = .06), ICU admission (29% vs 23%; P = .240) and death (23% vs 20%; P = .643). Propensity score-matched analysis of patients with AIH vs non-CLD (769 patients) demonstrated an increased risk of hospitalization with AIH [+18.4%; 5.6%-31.2%], but equivalent risk of all other outcomes including death [+3.2%; 9.1%-15.6%].[83] This suggests that, in stable patients, immunosuppression should not be reduced as a strategy to reduce the risk of COVID-19 infection. Steroid dosage may however warrant adjusting to manage severe COVID-19 or address adrenal insufficiency.[66]

Despite the increased ACE-2 expression on cholangiocytes, it is unclear whether patients with primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC), without underlying cirrhosis, are at increased risk of COVID-19 or if the virus exacerbates chronic cholestatic liver disease.[11] Ascending cholangitis must be excluded in PSC patients presenting with fever and deteriorating liver tests.