Non-alcoholic fatty liver disease and COVID-19: Harmless companions or disease intensifier?

Table 1 Studies with data regarding the risk of non-alcoholic fatty liver disease/metabolic syndrome-associated fatty liver disease for severe coronavirus disease 2019

Ref.	Study type and number of NAFLD patients	Results	Appraisal
Zhou et al[45], 2020	Retrospective, matched cohorts, n = 55 per group	More severe COVID-19 in MAFLD OR = 4.07	Poor matching regarding metabolic status, more male pat in MAFLD group
Targher et al[46], 2020	Retrospective, cohort study n = 94 (216 w/o MAFLD)	More severe COVID-19 with higher FIB-4 or NFS	No matching, no full paper
Ji et al[47], 2020	Retrospective, cohort study n = 202	NAFLD 87 % in progressive COVID-19 (n = 39) vs 26 % in stable COVID-19 (n = 163)	Comorbidities highly different between groups, no full paper, NAFLD definition only via HSI
Hashemi et al[48], 2020	Retrospective, CLD cohort with 55 NAFLD patients (294 w/o CLD/NAFLD)	Presence of CLD and NAFLD higher risk for mechanical ventilation (OR = 2.15) and ICU admission (OR = 2.3), cirrhosis risk factor for mortality	Imbalance in metabolic status, NAFLD diagnosis relying on prior imaging
Huang et al[49], 2020	Retrospective, cohort n = 86 (194 w/o NAFLD)	Only higher ALT in NAFLD patients, course of disease comparable to controls	NAFLD only defined by HSI, imbalance in metabolic status
Forlano et al[50], 2020	Retrospective, cohort n = 61 (132 w/o NAFLD)	NAFLD pat with higher CRP, younger age. Fibrosis or cirrhosis no risk for more severe COVID-19	Only hospitalized patients, higher BMI in NAFLD, diagnosis by imaging (US or CT)
Lopez-Mendez et al[51], 2021	Retrospective, cohort study n = 66 (89 w/o steatosis)	Presence of steatosis (and/or liver fibrosis) not related to severity or mortality of COVID-19	Steatosis only defined by HSI, imbalance on metabolic status
Zheng et al[52], 2020	Retrospective, cohort study n = 66 (45 with and 21 w/o obesity)	Obesity risk factor for COVID severity in MAFLD patients (OR = 6.3)	Diagnosis of MAFLD by CT and clinical criteria, no controls w/o MAFLD, no full paper
Zhou et al[53], 2020	Retrospective, cohort study n = 93 (out of 327 total patients)	Younger MAFLD patients with relatively higher risk for severe COVID	No full paper, small number of older patients, CT data
Valenti et al[54], 2020	Retrospective, United Kingdom Biobank cohort (Mendelian randomization), total n > 500000	No evidence for NAFLD as risk factor for severe COVID-19	Data errors possible, partly little characterization of patients, no full paper
Mahamid et al[55], 2021	Retrospective, cohort study n = 22 (49 w/o MAFLD)	8/22 with severe COVID-19 vs 5/49 w/o MAFLD	CT data, large differences in metabolic status between groups
Chen et al[56], 2021	Retrospective, cohort study n = 178 (164 w/o hepatic steatosis)	More intubation and vasopressors in steatosis, but lower mortality	Only hospitalized patients, HSI or imaging, rel. high percentage of steatosis in cohort, metabolic status not balanced
Gao et al[57], 2021	Retrospective, matched cohorts, n = 65	OR = 4.07 for severe COVID-19 only in non-diabetic patients	Poor matching regarding metabolic status, NAFLD diagnosis by CT and clinical criteria, duplicate patients with Zhou et al[45]
Marjot et al[58], 2021	Retrospective CLD cohort with 322 NAFLD patients	No higher mortality for NAFLD patients in multivariate analysis	Control group matched only to complete CLD cohort, not specifically to NAFLD patients. Unclear definition of NAFLD
Parlak et al[59], 2021	Retrospective, cohort study n = 55 (288 w/o fatty liver)	Presence of fatty liver risk factor (OR = 3.9) for severe COVID-19	CT data, no data regarding BMI, no data comparison NAFLD vs non-NAFLD
Mushtaq et al[60], 2021	Retrospective, cohort study n = 320 (269 w/o NAFLD)	NAFLD predictor for mild or moderate liver injury, but not for disease severity or mortality	NAFLD only defined by HIS, imbalance on metabolic status, no full paper
Campos-Murguía et al[61], 2021	Retrospective, cohort study n = 176 (256 w/o MAFLD)	Liver fibrosis, not MAFLD alone, predictor for severity and mortality of COVID-19	CT data, relatively good obesity matching to controls
Kim et al[62], 2021	Retrospective, CLD cohort with 456 NAFLD patients	NAFLD no risk factor for severe course or mortality of COVID-19	No control cohort w/o liver disease, tertiary centers only, NAFLD ICD-diagnosis
Simon et al[63], 2021	Large Swedish CLD cohort (total n = 42320), biopsy confirmed, with unclear number of NAFLD patients	CLD presence as risk factor for hospitalization, but not for severe COVID (including cirrhosis)	Historic cohort with possible drop-outs, underlying CLD in controls may have been missed
Roca-Fernández et al[64], 2021	United Kingdom Biobank cohort, with prospective data on infection and hospitalization for COVID	Fatty liver with increased risk for testing COVID-positive, obesity and fatty liver with higher risk for hospitalization, but not obesity alone	Data errors possible, little characterization of patients, small number of patients with severe COVID
Ziaee et al[65], 2021	Retrospective Iranian cohort n = 218 (357 patients w/o NAFLD, additional control group w/o COVID)	Fatty liver significant more prevalent in COVID group compared to control group (38% vs 9%). Longer hospital stay and larger pulmonal involvement in NAFLD patients	Very low percentage of fatty liver in control group. Control group with missing data
Liu et al[66], 2022	COVID-19 HGI and United Kingdom Biobank cohorts (Mendelian randomization), retrospective data, total n > 2500000	No evidence for NAFLD as risk factor for severe COVID-19	Data errors possible, little characterization of patients, no full paper
Chang et al[67], 2022	South Korean COVID-19 cohort with FLI score (total n = 3122)	Highest FLI tertile with higher risk for severe COVID-19, but not for higher mortality	No NAFLD-specific case definition, FLI score tertile cutoff low
Vrsaljko et al[68], 2022	Prospective cohort study n = 120 (96 w/o NAFLD)	NAFLD with higher risk for severe COVID-19 including pulmonary thrombosis	No data regarding fibrosis
Tripon et al[69], 2022	Retrospective French cohort n = 311 (408 w/o NAFLD)	NAFLD with higher risk for hospitalization, high FIB-4 with higher risk for severe COVID-19	NAFLD only defined by NFS, important data missing in cohort patients
Moctezuma-Velázquez et al[70], 2022	Retrospective Mexican cohort n = 359 (111 w/o NAFLD)	NAFLD associated with mortality, ICU admission and mechanical ventilation, but CT-determined liver steatosis was not	NAFLD definition based on DSI, small number of control patients, only hospitalized patients
Okuhama et al[71], 2022	Retrospective Japanese cohort n = 89 (133 w/o fatty liver)	Fatty liver associated with severe COVID-19	CT data, no data regarding dyslipidemia, only hospitalized patients

BMI: Body mass index; CLD: Clinical liver disease; CT: Computed tomography; DSI: Dallas steatosis index; FLI: Fatty liver index; HIS: Hepatic steatosis index; MAFLD: Metabolic syndrome-associated fatty liver disease; NFS: Non-alcoholic fatty liver disease fibrosis score; pat: Patients; US: Ultrasound; NAFLD: Non-alcoholic fatty liver disease; OR: Odds ratio; ICU: Intensive care unit; COVID-19: Coronavirus disease 2019; HGI: Haemoglobin glycation index; ICD: International Classification of Diseases; CRP: C-reactive protein; ALT: Alanine aminotransferase.