COVID-19 and pediatric fatty liver disease: Is there interplay?

Table 1 Main findings regarding the association between fatty liver disease and coronavirus disease 2019 in adults

Ref.	Study design	Population	NAFLD	Main findings
Mahamid et al[34]	Retrospective case-control study, SZMC, Jerusalem	71 hospitalized patients with COVID-19 infection, both genders, age ≥ 18.0 yr (mean age 51.0 ± 21.7), 22 NAFLD, 49 non-NAFLD	CT within hospitalization or recently made	Significant association between NAFLD and severity of COVID-19 even after adjustments for obesity, hypertension, metabolic syndrome, diabetes, and smoking. This association was independent of metabolic syndrome and/or its components. NAFLD patients have an increased risk of severe COVID-19 in both genders, in particular in males (Male: P = 0.001 Female: P = 0.002)
Ji et al[28]	Retrospective case-control study. Patients of two COVID Hospital in China	202 patients with COVID-19 (hospitalized and follow-up within 12 mo of the diagnosis). Median age 44.5 (34.8-54.1), 163 patients with stable disease (37.6% of patients with NAFLD), 39 patients with progressive disease (25.8% of patients with NAFLD)	NAFLD defined as hepatic steatosis index: 8 × (ALT/AST) + BMI (+ 2 if type 2 diabetes, + 2 if female) > 36 and/or US	Male patients aged > 60 yr, with higher BMI, underlying comorbidities, and NAFLD were associated with COVID-19 progression. Patients with NAFLD had higher risk of disease progression, longer viral shedding times, and higher likelihood of abnormal liver function from admission to discharge than patients without NAFLD
Zhou et al[31]	Cohort study, Asian ethnicity	55 MAFLD patients with COVID-19 were 1:1 matched by age (± 5 yr), sex, and BMI (± 1 unit) to COVID-19 patients without MAFLD. Age < 60 yr	CT	The presence of MAFLD was associated with severity of COVID-19 even after full adjustment (age, sex, smoking status, obesity, diabetes, hypertension) and a trend to increased duration of hospitalization. MAFLD patients had higher levels of CRP, ALT, AST, GGT, fasting blood glucose, and triglycerides
Medeiros et al[27]	Retrospective case-control study. Radiology Departments of Hospital Beneficiencia Portuguesa, San Paolo- Brasil	316 patients clinically suspected of having COVID-19 infection: -n.204: RT-PCR positive; -n.112: RT-PCR and chest CT negative pattern. Age > 18 yr	CT: Attenuation value of ≤ 40 HU, measured in the region of interest (commonly in the right hepatic lobe) in non-enhanced phase	Higher prevalence of steatosis in affected patients, even after adjustments for sex and age
Forlano et al[29]	Retrospective cohort study. Imperial College Healthcare NHS Trust (London, United Kingdom)	193 hospitalized, adult patients with COVID-19 infection and CT imaging, NAFLD: 61 (31%); Non-NAFLD: 132 (66%), excluded: 5 (3%)	US or CT dated within 1 yr from the admission for COVID-19 or a known diagnosis of NAFLD. FIB-4 index for fibrosis	No difference in terms of admission to ICU and in mortality between NAFLD and non-NAFLD patients. NAFLD patients were significantly younger at presentation
Gao et al[30]	Cohort study. Four hospitals in China	130 nondiabetic patients with COVID-19: 65 MAFLD and 65 controls were 1:1 matched by age (± 5 yr) and sex	CT	MAFLD presence in nondiabetic patients was associated with a 4-fold increased risk of severe COVID-19, even after adjusting for age, sex, and coexisting comorbidities. The risk of severe COVID-19 increased with increasing numbers of metabolic risk factors
Targher et al[33]	Retrospective cohort study. Four hospitals in China	310 hospitalized, adult patients with COVID-19 infection	CT: FIB-4 index and NFS used to categorize liver fibrosis in low, intermediate, or high	In patients with MAFLD the presence of intermediate or high fibrosis (FIB-4 or NFS) was associated with a higher risk of severe COVID-19, even after adjusting for sex, obesity, and diabetes
Sharma et al[32]	Review	Adult patients	CT/FIB-4 index and NFS	Patients with MAFLD had higher risk of disease progression, longer viral shedding times, higher likelihood of abnormal liver function, and 4-6-fold increased risk of severe disease than patients with no MAFLD. Younger patients (age < 60 yr) were also at greater risk for increased severity of COVID-19

ALT/AST: Alanine aminotransferase/aspartate aminotransferase; BMI: Body mass index; COVID-19: Coronavirus disease 2019; CRP: C-reactive protein; CT: Computed tomography; FIB-4: Fibrosis-4; GGT: Gamma-glutamyl transferase; ICU: Intensive care unit; MAFLD: Metabolic-associated fatty liver disease; NAFLD: Nonalcoholic fatty liver disease; NFS: Nonalcoholic fatty liver disease fibrosis score; NHS: National Health Service; RT-PCR: Real-time reverse transcription polymerase chain reaction; US: Ultrasound.

Table 2 Main findings regarding the association between fatty liver disease and coronavirus disease 2019 in children

Ref.	Study design	Population	NAFLD	Main findings
Qiu et al[36]	Cohort study. Three hospitals in Zhejiang Province, China	36 pediatric patients (aged 0-16 yr) with laboratory confirmed COVID-19 infection; mild cases (n = 17); moderate cases (n = 19) compared with adults with COVID-19 (n = 175); Children with SARS (n = 44); Children with H1N1 influenza (n = 167)	Increased liver enzymes	Elevated ALT in two patients (mild cases) and AST in three patients (two mild and one moderate case), 6% of cases with elevated liver enzymes, 18% of cases with elevated liver enzymes, 48% of cases with elevated liver enzymes, 17% of cases with elevated liver enzymes
Sun et al[37]	Retrospective analysis. Intensive Care Unit, Wuhan Children’s Hospital	8 severe or critically ill COVID-19 patients admitted to the ICU. Age: 2 mo-15 yr	Increased liver enzymes	Elevated ALT levels in 4 out of 8 patients. Total bilirubin level in all patients was normal
Wang et al[39]	Retrospective study. Children from six provinces (autonomous region) in northern China.	31 cases of COVID-19. Age: 6 mo-17 yr	Increased liver enzymes	Elevation of liver enzyme (22%)
Xia et al[38]	Retrospective study. Wuhan Children’s Hospital	20 COVID-19 pediatric patients. Age: 1 d-14 yr, 7 mo (median age: 2 yr and 1.5 mo)	No NAFLD screening. CT was performed for pneumonia	Elevated ALT (> 40 U/L) in 25% of cases
Jiehao et al[40]	Case series. Children’s Hospital in Shanghai, Hainan, Hefei in Anhui province, and Qingdao in Shandong province	10 patients aged 3-131 mo (mean: 74 mo). Male: female 1:1.5	No NAFLD screening. CT was performed for pneumonia	Median ALT: 18.5 U/L, AST: 27.7 U/L. One patient had ALT: 100 U/L and AST: 142 U/L
Tan et al[41]	Retrospective study. North Hospital of Changsha First Hospital	10 children with confirmed COVID-19 infection. Mean age of 7 yr (1-12 yr)	Increased liver enzymes	Elevated AST in two patients

ALT/AST: Alanine aminotransferase/aspartate aminotransferase; CT: Computed tomography; COVID-19: Coronavirus disease 2019; H1N1: Influenza A; ICU: Intensive care unit; NAFLD: Nonalcoholic fatty liver disease; SARS: Severe acute respiratory syndrome.