Non-alcoholic fatty liver diseases in patients with COVID-19: A retrospective study
Authors: Dong Ji, Enqiang Qin, Jing Xu, Dawei Zhang, Gregory Cheng, Yudong Wang, George Lau
Journal: Journal of Hepatology (2020)

Reply to: 'Younger patients with MAFLD are at increased risk of severe COVID-19 illness: A multicenter preliminary analysis'Journal of HepatologyVol. 73Issue 3PreviewWe read with interest the letter by YJ Zhou et al. stressing the finding that, in their own series, metabolic-associated fatty liver disease (MAFLD, also termed non-alcoholic fatty liver disease [NAFLD]) is associated with an increased risk of severe COVID-19 illness in younger but not older patients.1 As pointed out by the authors, a notable limitation of the study was the smaller sample size of the cohort of older patients, which might influence the validity of the results. Actually, if both age groups were combined together and analyzed as a whole, patients with MAFLD had a high likelihood of severe disease compared to those without MAFLD (26.9% vs. Full-Text PDF Is the increased risk for MAFLD patients to develop severe COVID-19 linked to perturbation of the gut-liver axis?Journal of HepatologyVol. 74Issue 2PreviewTwo recent studies in the Journal of Hepatology suggest that metabolic dysfunction-associated fatty liver disease (MAFLD) is a risk factor for progression to severe COVID-19. A Chinese study of 202 patients with COVID-19 found that those with indicators of MAFLD had a higher risk of respiratory disease progression than patients without MAFLD.1 A subsequent study of 327 patients, also from China, found increased risk for COVID-19 progression in younger (<60 years old) patients with MAFLD but not in older ones. Full-Text PDF No evidence for an increased liver uptake of SARS-CoV-2 in metabolic-associated fatty liver diseaseJournal of HepatologyVol. 73Issue 3PreviewWe read with interest the research article published by Ji and colleagues, in the Journal of Hepatology, showing that patients with metabolic-associated fatty liver disease (MAFLD) have a higher risk of COVID-19 disease progression and higher likelihood of abnormal liver blood tests from admission to discharge than patients without MAFLD.1 Given the absence of data on medical history of these patients, this persistence of liver blood test abnormalities could be either a mere reflection of pre-existing abnormalities related to MAFLD or could alternatively be due to a higher susceptibility of the fatty liver to SARS-CoV-2 infection. Full-Text PDF Reply to: 'No evidence for an increased liver uptake of SARS-CoV-2 in metabolic-associated fatty liver disease'Journal of HepatologyVol. 73Issue 3PreviewWe read with interest the letter by Biquard et al.1 In their study, mRNA expression of SARS-CoV-2 infection critical genes, such as angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), phosphatidylinositol 3-phosphate 5-kinase (PIKFYVE) and cathepsin L were found not to be enhanced in patients with metabolic-associated fatty liver disease (MAFLD, previously called non-alcoholic fatty liver disease [NAFLD]) or obesity. This finding is of potential added value to our observation that patients with COVID-19 had worse outcomes if they had underlying MAFLD. Full-Text PDF NAFLD or comorbidities, that is the questionJournal of HepatologyVol. 73Issue 3PreviewIn this study,1 Ji et al. describe the implication of non-alcoholic fatty liver disease (NAFLD) on clinical outcomes in patients with SARS-CoV-2 infection. They reported that the prevalence NAFLD was 37.6%, which is a high percentage with respect to the population included in the study. Indeed, the prevalence of NAFLD in China ranges from 15% to 40%,2 with a high variability between different regions. In northeastern China, where the study was conducted, the reported prevalence is 26.9%.3 Full-Text PDF Reply to: "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"Journal of HepatologyVol. 74Issue 2PreviewWe read with interest the article by Mushtaq et al.1 Both their study and ours1,2 used similar inclusion criteria and the hepatic steatosis index as a surrogate marker for the presence of NAFLD. We found that NAFLD is an independent predictor of disease progression. However, their study showed that when controlled for covariates in multivariate analysis, NAFLD was not a predictor of mortality, disease severity, or markers of disease progression. Mushtaq et al. correctly pointed out the different conclusions may be due to the different criteria used to define COVID-19 disease progression, development of tachypnea and requirement of oxygen supplements in our study as opposed to development of acute respiratory distress syndrome, intensive care unit (ICU) admission, and the need for mechanical ventilation in their study. Full-Text PDF Younger patients with MAFLD are at increased risk of severe COVID-19 illness: A multicenter preliminary analysisJournal of HepatologyVol. 73Issue 3PreviewWe read with great interest the article by Ji et al. on liver injury patterns and the clinical implications of metabolic-associated fatty liver disease (MAFLD) in patients with COVID-19.1 Metabolic and cardiovascular comorbidities like diabetes and hypertension aggravate the severity of COVID-19.2 Another comorbidity, MAFLD, also affects COVID-19 severity, as pointed out by Ji et al.1 Since excess liver fat is seen in up to a quarter of people,3 we hypothesized that its impact on severity might be modulated by age. Full-Text PDF 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 continuesJournal of HepatologyVol. 74Issue 2PreviewWe 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 obesity4 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. Full-Text PDF Reply to: 'NAFLD or comorbidities, that is the question'Journal of HepatologyVol. 73Issue 3PreviewWe thank Ponziani et al. for their interest in our manuscript and for their thoughtful comments.1 They raised the concern that the 37.6% prevalence of non-alcoholic fatty liver disease (NAFLD) in our cohorts was rather high compared to the 26.9% reported in Northeastern China and suggested that we may have over-diagnosed NAFLD. If NAFLD was over-diagnosed, the prevalence should be similar in the stable and progressive groups, as opposed to the marked difference, 25.8% vs. 87.2 %, respectively, observed in our study. Full-Text PDF Liver injury has been observed in patients with COVID-19, at an incidence ranging from 14–53%.1Xu L. Liu J. Lu M. Yang D. Zheng X. Liver injury during highly pathogenic human coronavirus infections.Liver Int. 2020; ([Epub ahead of print])https://doi.org/10.1111/liv.14435Crossref Scopus (613) Google Scholar, 2Wang D. Hu B. Hu C. Zhu F. Liu X. Zhang J. et al.Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA. 2020 Feb 7; ([Epub ahead of print])https://doi.org/10.1001/jama.2020.1585Crossref Scopus (16385) Google Scholar, 3Xu X.W. Wu X.X. Jiang X.G. Xu K.J. Ying L.J. Ma C.L. et al.Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series.BMJ. 2020; 368: m606Crossref PubMed Scopus (1461) Google Scholar We examined the liver injury patterns and implication of non-alcoholic fatty liver diseases (NAFLD) on clinical outcomes in Chinese patients with COVID-19. From January 20 through February 17, 2020, consecutive patients admitted to 2 designated COVID-19 Hospitals in China with confirmed COVID-19 and information on NAFLD status were studied. The diagnosis and clinical management of patients with COVID-19 were conducted in accordance with the practice guidelines issued by The Chinese National Health Commission.4Chinese Clinical Guidance for COVID-19 Pheumonia Diagnosis and Treatment.http://kjfy.meetingchina.org/msite/news/show/cn/3337.htmlDate accessed: January 23, 2020Google Scholar COVID-19 was confirmed by the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequences in the throat swab by reverse transcription PCR. Liver injury was defined as hepatocellular if the alanine aminotransferase (ALT) level was >30 IU/L for males and >19 IU/L for females5Park J.H. Choi J. Jun D.W. Han S.W. Yeo Y.H. Nguyen M.H. Low alanine aminotransferase cut-off for predicting liver outcomes; a nationwide population-based longitudinal cohort study.J Clin Med. 2019; 8: 1445Crossref Scopus (13) Google Scholar; ductular if alkaline phosphatase (ALP) was >the upper limit of normal (ULN) accompanied by gamma-glutamyltransferase (GGT) >ULN; mixed if both hepatocellular and ductular enzymes were raised >ULN. NAFLD was identified as hepatic steatosis index (HSI = 8 × [ALT/AST] + BMI [+ 2 if type 2 diabetes yes, + 2 if female]) >36 points and/or by abdominal ultrasound examination.6Lee J.H. Kim D. Kim H.J. Lee C.H. Yang J.I. Kim W. et al.Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease.Dig Liver Dis. 2010; 42: 503-508Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar The ALT/AST value used for HSI was taken either at complete recovery on discharge or from records of the patients before and within 12 months of the diagnosis of COVID-19. The patients were followed till discharged with recovery or disease progression. The study was approved by the Ethics Committees of FYSPH (20200303006) and the Fifth Medical Center of PLAGH (2020005D). The significance of clinical characteristics on admission were assessed by univariate and multivariate logistic regression analysis to investigate the independent risk factors of disease progression. p values <0.05 were considered significant. Two hundred and two consecutive patients with confirmed COVID-19 and information relating to NAFLD status were studied. Liver injury was observed in 101 (50%) and 152 (75.2%) patients on admission and during hospitalization, respectively. Almost all liver injury was mild with hepatocellular pattern, only 2.6% (4/152) had ductular or mixed pattern. Sixty-seven (33.2%) patients had persistent abnormal liver function from admission to last follow-up. Thirty-nine (19.3%) and 163 (80.7%) had progressive and stable disease, respectively. Patients with progressive disease were older, had higher BMI, and a higher percentage of comorbidity and NAFLD (Table 1). Univariate and multivariate logistic regression analysis showed that male sex (odds ratio [OR] 3.1; 95% CI 1.1–9.4), age >60 years (OR 4.8; 95% CI 1.5–16.2), higher BMI (OR 1.3; 95% CI 1.0–1.8), underlying comorbidity (OR 6.3; 95% CI 2.3–18.8) and NAFLD (OR 6.4; 95% CI 1.5 - 31.2), were associated with COVID-19 progression.Table 1Baseline characteristics of patients with COVID-19 on admission.Clinical characteristics on admissionOverallStableProgressiveaProgression of illness was defined as development of at least one of the following: respiratory rate ≥30 breaths/min, resting oxygen saturation ≤93% and PaO2/FiO2 ≤300 mmHg or worsening of lung CT findings, during the hospitalization period.p valuesn = 202n = 163n = 39Male sex (n, %)113 (55.9)86 (52.8)27 (69.2)0.093Age (years)44.5 (34.8–54.1)42.9 (32.6–51.8)55.1 (43.7–71.8)<0.001Age >60 years (n, %)31 (15.3)14 (8.6)17 (43.6)<0.001BMI (kg/m2)24.0 ± 2.823.4 ± 2.526.6 ± 2.2<0.001Smoke (n, %)19 (9.4)15 (9.2)4 (10.3)1.000Drink (n, %)6 (3.0)5 (3.1)1 (2.6)1.000Comorbidity (n, %)47 (23.3)23 (14.1)24 (61.5)<0.001NAFLD (n, %)76 (37.6)42 (25.8)34 (87.2)<0.001HBsAg positive (n, %)7 (3.5)5 (3.1)2 (5.1)0.885Epidemiology (n, %)0.866 No contact history46 (22.8)36 (22.1)10 (25.6) Travel to Wuhan100 (49.5)82 (50.3)18 (46.2) Close contact56 (27.7)45 (27.6)11 (28.2)Severity (n, %)<0.001 Mild5 (2.5)4 (2.5)1 (2.6) Moderate168 (83.2)146 (89.6)22 (56.4) Severe28 (13.9)12 (7.4)16 (41.0) Critical1 (0.5)1 (0.6)0 (0.0)Elevated ALT (n, %)101 (50.0)82 (50.3)19 (48.7)0.859Elevated ALP (n, %)5 (2.5)5 (3.1)0 (0)0.585Elevated AST (n, %)34 (16.8)24 (14.7)10 (25.6)0.102Elevated GGT (n, %)46 (22.8)31 (19.0)15 (38.5)0.009Elevated TBIL (n, %)17 (8.4)13 (8.0)4 (10.3)0.747Elevated GGT plus ALP∗The continuous variables were expressed as median (IQR), and compared using the Mann-Whitney U test, categorical variables were presented as numbers (percentage) and compared by the chi-square test or Fisher's exact test.† Comorbidity included hypertension, diabetes, cardiovascular disease, chronic lung disease and HIV infections. One patient had elevated ALP and GGT on admission. Another 3 developed during hospitalization. (n, %)1 (0.5)1 (0.6)0 (0)1.000Viral shedding daysbViral shedding period was defined as the time to undetectable SARS-CoV-2 from admission.13.0 (10.0–17.0)12.0 (10.0–16.0)17.0 (16.0–19.5)<0.001Hospitalization dayscThe criteria of discharge include all the following conditions: body temperatures remain normal over 3 days, significant improvement of respiratory symptoms, resolution of pulmonary imaging of inflammation, and repeated tests at least 24 hours apart confirms SARS-CoV-2 clearance.16.0 (12.0–22.0)15.0 (12.0–20.0)21.0 (16.5–27.0)0.001ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; GGT, gamma-glutamyltransferase; NAFLD, non-alcoholic fatty liver disease; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TBIL, total bilirubin.∗ The continuous variables were expressed as median (IQR), and compared using the Mann-Whitney U test, categorical variables were presented as numbers (percentage) and compared by the chi-square test or Fisher's exact test.† Comorbidity included hypertension, diabetes, cardiovascular disease, chronic lung disease and HIV infections. One patient had elevated ALP and GGT on admission. Another 3 developed during hospitalization.a Progression of illness was defined as development of at least one of the following: respiratory rate ≥30 breaths/min, resting oxygen saturation ≤93% and PaO2/FiO2 ≤300 mmHg or worsening of lung CT findings, during the hospitalization period.b Viral shedding period was defined as the time to undetectable SARS-CoV-2 from admission.c The criteria of discharge include all the following conditions: body temperatures remain normal over 3 days, significant improvement of respiratory symptoms, resolution of pulmonary imaging of inflammation, and repeated tests at least 24 hours apart confirms SARS-CoV-2 clearance. Open table in a new tab ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; GGT, gamma-glutamyltransferase; NAFLD, non-alcoholic fatty liver disease; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TBIL, total bilirubin. Patients with NAFLD had a higher risk of disease progression (6.6% [5/126] vs. 44.7% [34/76] p <0.0001), higher likelihood of abnormal liver function from admission to discharge (70% [53/76] vs. 11.1% [14/126]; p <0.0001) and longer viral shedding time (17.5 ± 5.2 days vs. 12.1 ± 4.4 days p <0.0001) compared to patients without NAFLD. Similar to other reports, our study showed that liver injury in patients with COVID-19 was frequent but mild in nature.1Xu L. Liu J. Lu M. Yang D. Zheng X. Liver injury during highly pathogenic human coronavirus infections.Liver Int. 2020; ([Epub ahead of print])https://doi.org/10.1111/liv.14435Crossref Scopus (613) Google Scholar, 2Wang D. Hu B. Hu C. Zhu F. Liu X. Zhang J. et al.Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA. 2020 Feb 7; ([Epub ahead of print])https://doi.org/10.1001/jama.2020.1585Crossref Scopus (16385) Google Scholar, 3Xu X.W. Wu X.X. Jiang X.G. Xu K.J. Ying L.J. Ma C.L. et al.Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series.BMJ. 2020; 368: m606Crossref PubMed Scopus (1461) Google Scholar The pattern of liver injury was mostly hepatocellular rather than cholestatic. This is of interest as it had been shown that biliary cells have high expression of angiotensin-converting enzyme (ACE2) receptor with a high affinity for the spike protein of SARS-CoV-2.7Zou X. Chen K. Zou J. Han P. Hao J. Han Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection.Front Med. 2020; ([Epub ahead of print])https://doi.org/10.1007/s11684-020-0754-0Crossref PubMed Scopus (1640) Google Scholar In other respiratory viral infection, hepatitis has been related to the collateral damage mediated by virus-specific effector cells generated in response to the pulmonary infection.8Polakos N.K. Cornejo J.C. Murray D.A. Wright K.O. Treanor J.J. Crispe I.N. et al.Kupffer cell-dependent hepatitis occurs during influenza infection.Am J Pathol. 2006; 168: 1169-1178Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar The postmortem liver biopsy in one of our patients showed only microvesicular steatosis, accompanied by overactivation of T cells, suggesting that liver injury in COVID-19 is likely immune mediated rather than being the result of direct cytopathic damage, as described for other viral respiratory diseases.9Xu Z. Shi L. Wang Y. Zhang J. Huang L. Zhang C. et al.Pathological findings of COVID-19 associated with acute respiratory distress syndrome.Lancet Respir Med. 2020; 8: 420-422Abstract Full Text Full Text PDF PubMed Scopus (6406) Google Scholar The majority of patients in our series with persistent liver injury had NAFLD and high BMI. Patients with NAFLD also had a higher risk of progression to severe COVID-19 and longer viral shedding time. With increasing global prevalence of NAFLD, this may suggest a large proportion of our population could be at risk of severe COVID-19. The underlying mechanism is unknown but might be related to impaired innate immunity to the virus. In particular, there are abundant ACE2 receptors in the small intestine and clinically, patients complain of abdominal pain and diarrhea. Circulation of the virus via the hepatic reticular system is expected, given the rich supply of blood to the liver from the small bowel. The liver contains the largest number of macrophages (Kupffer cells) in the body and is a potent cytokine producer. Impaired hepatic innate immune status might play a critical role in COVID-19 outcome. We postulate that in patients with NAFLD, the polarization status of hepatic macrophages might be skewed from inflammation-promoting M1 macrophages to inflammation-suppressing M2 macrophages, leading to progression of COVID-19.10Lefere S. Tacke F. Macrophages in obesity and non-alcoholic fatty liver disease: crosstalk with metabolism.JHEP Rep. 2019; 1: 30-43Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar However, a better understanding of the role of NAFLD in COVID-19 may have therapeutic implications. This work is funded by the Capital characteristic clinic project of Beijing Municipal Science and Technology Commission (Z181100001718034). We acknowledge all health-care workers involved in the diagnosis and treatment of patients with COVID-19 in our hospital. DJ, DZ, JX, and EQ treated the patients.DJ, GC, YW and GL processed statistical data and drafted the manuscript. DJ and GL had the idea for and designed the study. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. Download .pdf (.2 MB) Help with pdf files disclosures.pdf