Our study showed that patients in the NAFLD group had a worse clinical course as compared to those in the non-NAFLD group. A higher proportion of NAFLD patients required the administration of anti-viral medications, had higher levels of LDH and CRP, required ICU admission, and had prolonged hospitalization. This supports the current evidence that patients with NAFLD do worse with COVID-19 as compared to non-NAFLD patients4,12. SARS-CoV-2 enters host cells via angiotensin I converting enzyme 2 (ACE2) receptors present in abundance in adipose tissues which can serve as a viral reservoir13. In addition, NAFLD patients may be more vulnerable to increased cytokine production associated with COVID-1914. We note that despite a poorer clinical course, patients in the NAFLD group had mild transaminitis with no persistent deterioration in liver function. Studies looking at LFT in COVID-19 patients have also found that the majority had mild LFT abnormalities that were self-limiting15–17. Thus, other factors such as associated metabolic co-morbidities may contribute to the increased risk of severe COVID-19 infection in NAFLD patients18. We found that more patients in the NAFLD group had hyperlipidaemia as compared to those in the non-NAFLD group.
Ji et al4. reported that COVID-19 patients who had illness progression had significantly higher BMI levels (26.6 ± 2.2 kg/m2), with 87% of these patients having NAFLD. However, we found that the median BMI in our NAFLD group who had a more severe clinical course, was lower than expected (24.3 kg/m2). Thus, it is unclear if weight or the underlying aetiology of fatty liver disease plays a bigger role in determining a patient’s clinical course in COVID-19. NAFLD is traditionally associated with central obesity but can also occur in lean subjects, especially in the Asian population. Body fat distribution is more important than total body fat content in the development of non-obese NAFLD19–23. Though Asians with NAFLD may have a lower BMI, they are still at an increased risk for adverse cardiometabolic outcomes. This has been attributed primarily to alterations in body fat distribution, in particular visceral adiposity which can be measured by waist circumference or waist-to-hip ratio24. Recently, sagittal abdominal diameter (SAD) - measured by the anteroposterior diameter of the abdomen in the supine position, has emerged as the preferred anthropometric indicator for visceral adiposity. SAD is clinically feasible and is an independent measurement with high reproducibility and correlation to adverse metabolic outcomes25–26. Genetic susceptibility of Asians to non-obese NAFLD has been postulated to be via predisposition to Type 2 diabetes mellitus, patatin-like phospholipase domain-containing-3 (PNPLA3) gene / Sterol regulatory element-binding factor 2 (SREBF) single nucleotide polymorphisms (SNP) and polymorphisms in apolipoprotein25,27−29. More studies will be needed to identify the factors that causally drive COVID-19 progression in individuals with obese and non-obese NAFLD.
One out of three of our cirrhotic patients had worsening LFT and decompensation, though none required ICU admission or died. Multiple mechanisms involved in liver injury in COVID-19 have been described. These include immune-mediated damage, direct cytotoxicity, anoxia due to respiratory failure, drug-induced liver injury, and reactivation of pre-existing liver disease30. In addition, the presence of cirrhosis associated immune dysfunction syndrome (CAIDS) can predispose cirrhotic patients to severe infection31 and result in more severe liver injury32. A recent study looking at cirrhotic patients with COVID-19 infection showed that mortality correlated strongly with baseline CTP class and MELD score, with a greater proportion of patients with CTP-C liver cirrhosis dying7. Other authors have found that patients with advanced liver cirrhosis did poorer with COVID-19 infection33–34. We postulate that our 3 cirrhotic patients ran a milder COVID-19 clinical course possibly from the absence of NAFLD and that 2 of 3 were CTP-A at baseline. This may explain why they had better outcomes in terms of not requiring ICU admission and not dying.
Our study had some limitations during the process of data acquisition due to missing clinical information, resulting in a smaller sample size of identifiable CLD patients. The majority of patients who were admitted and found to be overweight or have abnormal LFT, did not undergo liver imaging which could have picked up more patients with fatty liver. We also did not have baseline laboratory values of most patients prior to their admission. These values could have been used to calculate fibrosis scores as elevated Fibrosis-4 (FIB-4) scores have been shown to increase the likelihood of severe COVID-19 illness5,35.