Clinical perspectives, assessment, and mechanisms of metabolic-associated fatty liver disease in patients with COVID-19

Table 1 Studies evaluating metabolic-associated fatty liver disease in coronavirus disease 2019 patients

Ref.	Type of study and population	MAFLD/non-MAFLD patients (n)	MAFLD diagnosis	Liver fibrosis criteria	Clinical outcomes	Results
Gao et al[61]	Cohort, n = 130 pts, China	65/65	Hepatic steatosis by CT and MAFLD consensus criteria	N/A	COVID-19 severity	MAFLD: Increased risk of severe COVID-19 (OR 4.07, 95%CI: 1.1-15.09, P = 0.003)
Ji et al[52]	Cohort, n = 202 pts, China	76/126	HSI > 36 points and/or abdominal US	N/A	Liver injury and COVID-19 severity	MAFLD: Increased risk of severe COVID-19 (44.7% vs 6.6%, P < 0.0001), abnormal liver function tests from admission to discharge (70% vs 11.1%, P < 0.0001) and longer viral shedding time (17.5 vs 12.1 d, P < 0.0001)
Targher et al[53]	Cohort, n = 310 pts, China	94/216	Hepatic steatosis by CT and MAFLD consensus criteria	FIB-4, NFS	COVID-19 severity	MAFLD: Intermediate/high FIB-4 increased risk of severe COVID-19 (OR 2.95, 95%CI: 1.37-6.34, P < 0.005), intermediate/high NFS increased risk of severe COVID-19 (OR 2.91, 95%CI: 1.20-7.06)
Huang et al[83]	Cohort, n = 280 pts, China	86/194	HSI >36 points	N/A	Laboratory abnormalities, liver injury, COVID-19 severity, clinical outcomes	MAFLD: Increased levels of white blood cells (5.5 vs 4.7, P < 0.001), lymphocytes (1.4 vs 1.2, p 0.041), ALT (34.5 vs 23, P < 0.0001) and GGT (34 vs 21, P < 0.001). No difference in severity, complications and clinical outcomes
Mahamid et al[84]	Case control, n = 71 pts, Israel	22/49	Hepatic steatosis by CT and MAFLD consensus criteria	N/A	COVID-19 severity	MAFLD: Increased risk of severe COVID-19 (men: OR 3.29, 95%CI 3.28-3.58, P = 0.001; women: 3.25, 95%CI: 3.09-3.47, P = 0.002)
Zhou et al[85]	Cohort, n = 327 pts, China	59/268	Hepatic steatosis by CT and MAFLD consensus criteria	N/A	COVID-19 severity in younger (< 60 yr of age) and elderly (< 60 yr of age) patients	MAFLD: Younger patients increased risk of severe COVID-19 (OR 2.67, 95%CI: 1.13-6.34, P = 0.03). Elderly patients no difference in COVID-19 severity
Chen et al[86]	Cohort, n = 342 pts, United States	178/164	HSI > 36 points for Asians and HSI > 39 points for non-Asians or imaging evidence of hepatic steatosis	N/A	Liver injury and COVID-19 severity	MAFLD: Increased risk of transaminitis (ALT > 5 × ULN) (OR 2.12, 95%CI: 1.03-4.37, P = 0.04), ICU admission (OR 1.60, 95%CI: 1.00-2.57, P = 0.05), intubation (OR 2.51, 95%CI: 1.52-4.16, P ≤ 0.001), and vasopressor use (OR 1.22, 95%CI: 1.11-1.34, P ≤ 0.001)
Zhou et al[87]	Cohort, n = 110 pts (all patients < 60 yr of age), China	55/55	Hepatic steatosis by CT and MAFLD consensus criteria	N/A	COVID-19 severity	MAFLD: Increased risk of severe COVID-19 (OR 4.07, 95%CI: 1.20-13.79, P = 0.02)
Pan et al[88]	Meta-analysis, n = 110 pts (all patients < 60 yr of age), China	401/892	Hepatic steatosis plus one of the following: overweight, type 2 diabetes mellitus or metabolic dysregulation	N/A	Pooled prevalence of MAFLD and COVID-19 severity	MAFLD: Prevalence of MAFLD in COVID-19 patients (OR 0.31, 95%CI: 0.28-0.35, I2 = 38.8%, P = 0.1799). Increased risk of severe COVID-19 (OR 2.93, 95%CI: 1.87-4.60, I2 = 34.3%, P = 0.166)
Bramante et al[75]	Cohort, n = 6700 pts, United States	373	ICD codes for NAFLD or NASH or BMI 30 kg/m2 and elevated ALT	N/A	Admission or hospitalization for COVID-19	MAFLD: Increased risk of hospitalization (OR 1.43, 95%CI: 1.09-1.88, P < 0.01). Patients who had undergone bariatric surgery decreased risk of hospitalization (OR 0.22, 95%CI: 0.05-0.98, P < 0.05)
Lopez-Mendez et al[76]	Cross sectional, n = 155 pts, Mexico	66/89	HSI > 36 points	APRI, NFS and/or FIB-4	Prevalence of liver steatosis and fibrosis in COVID-19 patients, COVID-19 severity	MAFLD: Prevalence of steatosis 42.6% (66/155) and of advanced fibrosis 44.5% (69/155). Advanced liver fibrosis by FIB-4 increased risk of ICU admission (OR 1.74, 95%CI: 1.74-2.68, P = 0.023) and mortality (OR 6.45, 95%CI: 2.01-20.83, P = 0.002). No difference in disease severity
Forlano et al[77]	Cohort, n = 193 pts, United Kingdom	61/132	Imaging evidence of hepatic steatosis or previous diagnosis of MAFLD	FIB-4	ICU admission and in-hospital mortality	MAFLD: No difference in rates of ICU admission (OR 1.14, 95%CI: 0.53-2.5, P = 0.69) and in-hospital mortality (OR 0.86, 95%CI: 0.44-1.69, P = 0.67), regardless of the FIB-4 values (low <1.45, intermediate 1.45-3.25 or high > 3.25 risk of advanced fibrosis)
Mushtaq et al[78]	Cross sectional	320/269	HSI > 36 points	N/A	Mortality, COVID-19 severity, COVID-19 progression and liver injury	MAFLD: Increased risk of mild (OR 2.99, 95%CI: 1.62-4.37, P = 0.000) and moderate (OR 5.104, 95%CI: 3.21-6.99, P = 0.000) liver injury. No difference in disease severity, progression or mortality
Targher et al[79]	Cohort, n = 589 pts, Qatar	94/216	Hepatic steatosis by CT and MAFLD consensus criteria	N/A	COVID-19 severity according to NLR	MAFLD: MAFLD+NLR 2.8 (OR 5.32, 95%CI: 0.98-29.9, P = 0.053), non-MAFLD+NLR > 2.8 (OR 17.7, 95%CI: 3.89-80.6, P < 0.001), MAFLD+NLR>2.8 (OR 25.9, 95%CI: 5.32-127, P < 0.001) compared to those with non-MAFLD+NLR2.8. Patients with MAFLD and high NLR values have increased risk of severe COVID-19
Ji et al[46]	Cohort, n = 200 pts, China	125/75	HSI > 36 points and/or abdominal US	N/A	D-dimer levels	MAFLD: Increased D-dimer values at admission (0.72 vs 0.38 g/mL, P = 0.003) and peak levels (1.81 vs 0.63 g/mL, P = 0.003)
Ji et al[46]	Cohort, n = 81 pts (DVT 21 pts and non-DVT 60 pts), China	43/38	HSI > 36 points and/or abdominal US + Doppler US	N/A	Prevalence of MAFLD in DVT and non-DVT patients	MAFLD: Increased prevalence in patients with DVT compared to those without DVT (76% vs 45%, P = 0.01)
Sachdeva et al[80]	Systematic review and meta-analysis, n = 8142 pts, 8 studies (7 studies from China and 1 study from Israel)	833/7309	Imaging evidence of hepatic steatosis and MAFLD consensus criteria	N/A	COVID-19 severity	MAFLD: Increased risk of severe COVID-19 (OR 2.358, 95%CI: 1.902-2.923, P < 0.001)
Hashemi et al[81]	Cohort, n = 363 pts, United States	55/308 (69 w/CLD)	Imaging evidence or biopsy evidence of hepatic steatosis	N/A	Clinical outcomes	MAFLD: Increased risk of ICU admission (OR 2.30, 95%CI: 1.27-4.17, P = 0.03) and need of mechanical ventilation (OR 2.15, 95%CI: 1.18-3.91, P = 0.02). No difference in mortality rates

ALT: Alanine aminotransferase; BMI: Body mass index; CLD: Chronic liver disease; COVID-19: Coronavirus disease; 2019; CT: Computed tomography; DVT: Deep vein thrombosis; HSI: Hepatic steatosis index; MAFLD: Metabolic-associated fatty liver disease; N/A: Not available; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; NLR: Neutrophil/lymphocyte ratio; US; Ultrasound.

Table 2 Histological findings from liver biopsies of coronavirus disease 2019 patients

Ref.	Inclusion criteria	Population characteristics n (%)	Histopathological results
Sonzogni et al[89]	Postmortem SARS-CoV-2- positive patients. (n = 48)1; Male/Female (n): 35/131; Age (yr): 71 (32-86)	No comorbidities: 6 (13.3); Hypertension 24 (53.3); Cardiovascular Disease (different than hypertension) 17 (37.8); Diabetes 13 (28.9); Obesity 7 (15.6); Kidney disease 10 (22.2); Pulmonary disease 5 (11.1)	Portal vein parietal fibrosis	Absent 39%; Focal 29%; Multifocal 22%; Diffuse 8%
			Herniated portal vein in periportal parenchyma	Absent 25%; Focal 37%; Multifocal 27%; Diffuse 10%
			Periportal abnormal vessels	Focal 56%; Multifocal 37%; Diffuse 6%
			Fibrosis	Absent 24%; Portal fibrosis 60%; Incomplete fibrous septa 16%
			Lobular inflammation	Absent 50%; Mild 48%; Moderate 2%; Severe 0%
			Portal inflammation	Absent 33%; Mild 66%; Moderate 0%; Severe 0%
			Vascular thrombosis	Partial portal 50%; Complete portal 23%; Incomplete sinusoidal 14%; Complete sinusoidal 12%
			Parenchymal confluent necrosis	Absent 65%; Mild 11%; Moderate 15%; Severe 12%
			Steatosis	Absent 46%; Small droplets 6%; Large droplets 2%; Mixed small and large 46%
Lagana et al[90]	Patients who died from illness related to COVID-19. (n = 40)1; Male/Female (n): 28/121; Age (yr): 70 (66-80)	BMI, N = 32 mean (range) 26.5 (23.9-32.0); Chronic liver disease: 2 (13); Diabetes: 18 (50); Hypertension: 29 (76); Chronic kidney disease: 7 (22); Cardiac disease: 10 (36)	Lobular necroinflammation	20 (50%)
			Portal inflammation	20 (50%)
			Lobular apoptosis (individual hepatocytes)	10 (25%)
			Fat 0%–5%; 6%–33%; 34%–66%; 67%–100%	10 (25%); 19 (48%); 6 (15%); 5 (12%)
			Cholestasis	15 (38%)
Bradley et al[91]	Patients with a positive antemortem or post- mortem SARS-CoV-2. (n = 14)1; Male/Female: 6/81; Age (yr): 73.5 (42-84)	-	Periportal lymphocytic inflammation	2 (14%)
			Centrilobular necrosis	4 (28%)
			Steatosis	9 (64%)
			Congestion	11 (78%)
Falasca et al[92]	Postmortem SARS-CoV-2- positive patients. (n = 22)1; Male/Female: 15/71; Age (yr): 67.9 (27-92)	Chronic obstructive pulmonary disease: 6 (27.2); Cardiac disease: 8 (36.3); Malignancy: 5 (22.7); Hypertension: 4 (18.2); Diabetes: 4 (18.2); Kidney disease: 2 (9.1)	Inflammatory infiltrate	11 (50%)
			Congestion	10 (45.5%)
			Steatosis	12 (54.5%)

¹Age was reported as median (interquartile range). SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; BMI: Body mass index.