In our study of 45,360 COVID-19 positive patients, hepatopancreatic derangement was observed in 28,495 patients. To our knowledge till date this is the largest retrospective cohort study evaluating the hepatopancreatic injury in COVID-19 patients. Several studies have focused on the role of COVID-19 in hepatic injury(3, 6, 7). Liver injury was seen in 62.4% of our patient population. This is less than the incidence 78% incidence reported by Zhang et al. (6). Their sample size was significantly smaller (0.2%, n = 82) than ours. Huang et al. observed hepatic abnormalities in 31% of 41 patients admitted for COVID-19 infection with higher incidence in severe patients(7). In contrast to hepatic injury, pancreatic injury was observed in only a small subset of patients (1.8%). Multiple studies have reported mild increase in lipase (< 180 U/L) in a small percentage (12–17%) of COVID-19 patients(8, 9). The smaller percentage in our study could be due to higher cutoff value for lipase (400 U/L). Liu et al. reported 7.5% of severe patients who died had pancreatic injury. They also noted focal enlargement or dilation of pancreatic duct in these patients(4). Wang et al. observed hepatic injury and pancreatic injury in 29% and 17% of patients respectively(10).
The magnitude of hepatopancreatic injury increased with increase in disease severity. Critically sick patients have a significant elevation of transaminases, AlkP, PT, bilirubin, LDH and lipase in comparison to patients with mild/moderate disease. This difference was also significant between ICU patients who required mechanical ventilation and/or vasopressor use and those who did not. Hypoalbuminemia was significantly worse in the critically sick population as compared to the other two groups. Guan et al. reviewed the clinical characteristics of 1099 COVID-19 patients in China and noted that increased levels of AST was found in 18% and 39.4% patients with non-severe disease and severe disease respectively. They also found that levels of ALT were elevated in 19.8% of non-severe disease and 28.1% of severe disease patients(11). Several metanalysis also concluded that there is a higher incidence of liver injury in COVID-19 patients with severe disease as compared to non-severe disease(12, 13). Barlass et al. pointed out that patients who require ICU admission also have a higher level of lipase(14).
We observed that COVID-19 positive patients who had hepato-pancreatic injury have higher mortality and severity of disease. Lei et al. observed that increase in ALT, AST, AlkP and total bilirubin was associated with increased mortality in a retrospective cohort of 5771 COVID-19 positive individuals. Increase in AST was much more commonly associated with higher disease severity as well as confers highest risk for death amongst all markers(15).
Hepatic injury in COVID-19 can be caused by multiple pathophysiologic mechanisms including direct virus-induced effects, immune system mediated damage due to excessive inflammatory responses, and drug induced injury. SARS-CoV2 can exert direct cytopathic effect on liver resulting in hepatic injury. Postmortem biopsy of COVID-19 patient showed microvesicular steatosis, necrosis and cellular infiltration in liver tissue. SARS-CoV2 binds to membrane bound angiotensin converting enzyme 2 (ACE2) receptor to enter the cells(16). ACE2 receptors have a considerably higher expression on cholangiocytes (59.7%) as compared to hepatocytes (2.6%). Expression of ACE2 receptors on cholangiocytes is similar to that on Type 2 alveolar cells(17). Thus, COVID-19 can potentially cause liver injury of the same degree that is seen in the lungs. ACE2 receptors are also expressed on pancreatic cells (exocrine glands and islets) and this expression is mildly increased in contrast to the lungs(4).
Cytokine storm syndrome induced by COVID-19 is also likely to be blamed for hepatopancreatic injury. Several studies have reported elevated levels of hepatic enzymes and pro-inflammatory markers in association with severe cases of COVID-19(2). Multiple antiviral medications including Remdesivir, lopinavir, ritonavir and corticosteroids can cause drug induced hepatic injury. Other medications that can also cause hepatotoxicity including hydroxychloroquine, acetaminophen, tocilizumab and multiple antibiotics(16). Corticosteroids and non-steroidal anti-inflammatory drugs can also cause drug induced pancreatitis(18). Liu et al. pointed that the abnormalities in the laboratory markers are likely due to the medical treatments rather than COVID-19 itself (19).
Chronic liver disease mainly liver cirrhosis was present in 4.8% of our patient subset. We observed a significant increase in mortality, length of stay and disease severity in patients who had underlying liver cirrhosis. Several studies have reported chronic liver conditions in 1–11% of COVID-19 patients with hepatic injury(2). Kovalic et al. noticed a low (3%) prevalence of chronic liver disease in a metanalysis of 24,299 COVID-19 patients. They also outlined a noteworthy association of chronic liver disease with increased severity and mortality in COVID-19 patients(20). SECURE (surveillance epidemiology of coronavirus under research exclusion) Cirrhosis Registry and European association for the study of the liver Covid-hep registry have been created to assess the effects of COVID-19 on patients with chronic liver disease and those post-liver transplantations.
Study limitations include first, this is an observational retrospective cohort study, thus any associations found can’t be taken as causal relationship between COVID-19 and hepatopancreatic injury. Second, oropharyngeal and nasopharyngeal swabs were used in COVID-19 detection and both tests have different sensitivity and specificity which might result in variation in number of false positives or negatives. Third, the cutoffs for AST, ALT and Lipase might have influenced the results.