NAFLD is a predictor of liver injury in COVID-19 hospitalized patients but not of mortality, disease severity on the presentation or progression – The debate continues

Abstract

To the Editor: We read with great interest the letter by Ji et al. 1 Obesity is a well-recognized risk factor for the development of non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated liver disease (MAFLD) and is associated with adverse outcomes in COVID-19 patients. 2 , 3 Qatar's population has a high prevalence of obesity 4 and also has one of the highest rates of COVID-19 cases per million population, with one of the lowest mortality rates. 5 We hypothesized that NAFLD is an independent risk factor for worse outcomes in hospitalized COVID-19 patients in our population. Methods We studied 589 patients with confirmed symptomatic COVID-19 who were hospitalized from May 2020 to June 2020 to COVID-19 facilities in the state of Qatar. We categorized them into 2 groups; NAFLD and no NAFLD, based on the hepatic steatosis index (HSI). 6 People with an HSI index of 36 and above were considered as having NAFLD. The lowest aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values within the last 1 year before the COVID-19 diagnosis, and, when unavailable, the lowest values at the time of recovery were used for calculation of HSI index. The primary outcome was mortality, and secondary outcomes were disease severity on presentation, and disease progression, and liver injury. Development of acute respiratory distress syndrome (ARDS), requirement for intensive care unit (ICU) admission, and mechanical ventilation were regarded as markers of disease progression. Disease severity was defined using the WHO classification into severe and non-severe. 7 Liver injury was classified as borderline if ALT or AST were less than twice the upper limit of normal (ULN), mild if elevated 2–5×, moderate if 5–15×, and severe if more than 15× the ULN. 8 There were no patients with excessive use of alcohol in our study. The Medical Research Center of Hamad Medical Corporation approved the study (MRC-01-20-631). Results Univariate regression analysis showed that age, gender, diabetes mellitus, and increased BMI were significantly associated with mortality (Table 1 ). NAFLD was significantly associated with increased disease severity on admission, ICU admission, and requirement for mechanical ventilation (Table 1). We performed multivariate regression analysis using all the statistically significant variables. Age above 50 years was the only predictor of increased mortality (odds ratio [OR] 8.88; 95% CI 3.61–21.84; p <0.000∗). For disease severity on presentation, only the presence of diabetes mellitus was a statistically significant predictor (OR 2.2; 95% CI 1.5–3.19; p <0.000). Age above 50 years and a BMI above 25 kg/m2 were the only 2 significant predictors of all 3 markers of disease progression in our study: development of ARDS, ICU admission, and mechanical ventilation. Age was associated with increased risk of ARDS (OR 2.57; 95% CI 1.80–3.66; p <0.000∗), ICU admission (OR 2.36; 95% CI 1.67–3.33; p <0.000∗) and mechanical ventilation (OR 2.03; 95% CI 1.42–2.90; p <0.000∗). Obesity was associated with increased risk of ARDS (OR 1.97; 95% CI 1.32–2.94; p = 0.001), ICU admission (OR 1.83; 95% CI 1.26–2.65; p = 0.001) and mechanical ventilation (OR 1.89; 95% CI 1.25–2.87; p = 0.002). The presence of NAFLD was not an independent predictor of increased mortality, disease severity on presentation, or disease progression. However, the presence of NAFLD was a predictor of the development of mild liver injury (OR 2.99; 95% CI 1.62–4.37; p = 0.000) and moderate liver injury (OR 5.104; 95% CI 3.21–6.99; p = 0.000). Table 1 Comparative results of patients with and without NAFLD on univariate analysis. No NAFLD (n = 269) NAFLD (n = 320) p value Age (years) [±SD] 44.5 [13.85] 47.78 [13.4] 0.0073 Gender (male percentage) 242, (Male 89.6%) 257, (Male 80.8%) 0.016 Diabetes mellitus 75 (27.78%) 160 (50.3%) 0.000 Hypertension 70 (25.93) 135 (42.45%) 0.000 Smoking 31 (11.56%) 37 (11.86%) 0.764 BMI [±SD] 25.61 [7.47] 30.76 [4.9] 0.000 Coronary artery disease 19 (7.04%) 30 (9.43%) 0.224 Chronic kidney disease 17 (6.32%) 33 (10.38%) 0.062 Cirrhosis 7 (2.59%) 3 (0.95 %) 0.516 Malignancy 12 (4.46%) 4 (1.25%) 0.067 Lung disease 15 (5.56%) 25 (7.85%) 0.252 Use of Immunosuppressive drugs 11 (4.07%) 14 (4.39%) 0.556 Severe disease on presentation 60 (22.3%) 95 (29.87%) 0.041 ARDS 77 (28.9%) 128 (40.3%) 0.004 ICU admission 102 (38.64%) 157 (49.68%) 0.008 Mortality 15 (5.68%) 19 (6.01%) 0.866 Mechanical ventilation 70 (26.62%) 114 (36.31%) 0.013 Multiorgan failure 19 (7.04%) 29 (9.21%) 0.382 Liver failure 1 (0.38%) 6 (1.9%) 0.095 Liver injury 132 (49.4%) 186 (59%) 0.018 Borderline elevation (<2× ULN) 95 (35%) 121 (38.4%) Mild (2–5×) 30 (11.3%) 55 (17.4%) Moderate(5–15×) 5 (1.87%) 10 (3.1%) Severe (>15×) 2 (0.7%) 0 (0%) The continuous variables are normally distributed and expressed as mean ±SD, and were compared using Student’s t test. normally distributed. The categorical variables were presented as numbers (percentage) and compared by the chi-square test or Fisher’s exact test. ARDS, acute respiratory distress syndrome; BMI, body mass index; ICU, intensive care unit; NAFLD, non alcoholic fatty liver disease; ULN, upper limit of normal. Discussion The presence of NAFLD has been associated with poor outcomes in patients with COVID-19. 1 , 3 , 9 However, our results conflict with these reports. We used similar inclusion criteria and used the HSI index as a surrogate marker for the presence of NAFLD like Ji et al. 1 We found that NAFLD is an independent predictor of the development of mild to moderate liver injury, like the authors described. However, when controlled for covariates in multivariate analysis, NAFLD was not a predictor of mortality, disease severity, or markers of disease progression in our study. We used the development of ARDS, ICU admission requirements, and the need for mechanical ventilation as surrogate markers of disease progression while the authors used the development of tachypnea and the requirement for supplemental oxygenation as surrogates of disease progression . Our observation was that in hospitalized patients using tachypnea and need for supplemental oxygen even once was quite common, so they are probably not the best markers for disease progression. The difference in our results could be due to a much larger sample size of patients with NAFLD from heterogeneous ethnic populations in our study. Although the HSI index has a high specificity (93%) and positive predictive value (99%), it is affected by inflammation and potentially could overestimate the prevalence of NAFLD. 10 There is a need to study the outcomes in large scale studies with histologically confirmed cases of NAFLD and COVID-19. Conclusion The presence of NAFLD is an independent predictor of mild to moderate liver injury in hospitalized patients with COVID-19. However, NAFLD was not an independent predictor of mortality, disease severity on presentation, or disease progression in patients with COVID-19. Financial support Funding for publications costs are covered by Hamad Medical Corporation. Authors' contribution KM and MUK conceived and designed the study, did data analysis, literature review and manuscript writing. FI, DHA, HSC, FA, PI, KEN GB, MA, KA, SA, YMK did data collection, data analysis, manuscript writing and literature review. All authors verified the final version of the study. Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.