1016567 research-article20212021 TAG0010.1177/17562848211016567Therapeutic Advances in GastroenterologyI Campos-Varela, A Villagrasa Therapeutic Advances in Gastroenterology Original Research The role of liver steatosis as measured with Ther Adv Gastroenterol 2021, Vol. 14: 1–14 transient elastography and transaminases DOI: 10.1177/ https://doi.org/10.1177/17562848211016567 https://doi.org/10.1177/17562848211016567 17562848211016567 on hard clinical outcomes in patients with © The Author(s), 2021. Article reuse guidelines: sagepub.com/journals- COVID-19 permissions Correspondence to: Isabel Campos-Varela , Ares Villagrasa, Macarena Simon-Talero , Salvador Augustin Mar Riveiro-Barciela, Meritxell Ventura-Cots, Lara Aguilera-Castro, Liver Unit, Department of Internal Medicine, Hospital Patricia Alvarez-Lopez, Emilie A Nordahl, Adrian Anton, Juan Bañares, Claudia Barber, Universitari Vall d’Hebron, Ana Barreira-Diaz, Betina Biagetti, Laura Camps-Relats, Andrea Ciudin, Raul Cocera, Pg. Vall d’Hebron, 119-129, Barcelona, 08035, Spain Cristina Dopazo, Andrea Fernandez, Cesar Jimenez, Maria M Jimenez, Mariona Jofra, saugustin@vhebron.net Clara Gil, Concepción Gomez-Gavara, Danila Guanozzi, Jorge A Guevara, Beatriz Lobo, Isabel Campos-Varela Carolina Malagelada, Joan Martinez-Camprecios, Luis Mayorga, Enric Miret, Liver Unit, Department of Internal Medicine, Hospital Elizabeth Pando, Ana Pérez-Lopez, Marc Pigrau, Alba Prio, Jesus M Rivera-Esteban, Universitari Vall d’Hebron, Alba Romero, Stephanie Tasayco, Judit Vidal-Gonzalez, Laura Vidal, Beatriz Minguez, Pg. Vall d’Hebron, 119-129, Barcelona, 08035, Spain Salvador Augustin and Joan Genesca Centro de Investigación Biomédica en Red de Enfermedades Hepáticas Abstract: Liver injury has been widely described in patients with Coronavirus disease 2019 y Digestivas (CIBERehd), Instituto de Salud Carlos (COVID-19). We aimed to study the effect of liver biochemistry alterations, previous liver III, Madrid, Spain disease, and the value of liver elastography on hard clinical outcomes in COVID-19 patients. icampos@vhebron.net Ares Villagrasa We conducted a single-center prospective observational study in 370 consecutive patients Patricia Alvarez-Lopez admitted for polymerase chain reaction (PCR)-confirmed COVID-19 pneumonia. Clinical and Adrian Anton Juan Bañares laboratory data were collected at baseline and liver parameters and clinical events recorded Ana Barreira-Diaz Laura Camps-Relats during follow-up. Transient elastography [with Controlled Attenuation Parameter (CAP) Cesar Jimenez measurements] was performed at admission in 98 patients. All patients were followed up Clara Gil Joan Martinez-Camprecios until day 28 or death. The two main outcomes of the study were 28-day mortality and the Alba Prio occurrence of the composite endpoint intensive care unit (ICU) admission and/or death. Jesus M Rivera-Esteban Alba Romero Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated at Judit Vidal-Gonzalez Liver Unit, Hospital admission in 130 patients (35%) and 167 (45%) patients, respectively. Overall, 14.6% of patients Universitari Vall d’Hebron, presented the composite endpoint ICU and/or death. Neither ALT elevations, prior liver Vall d’Hebron Institut of Reseach (VHIR), Vall disease, liver stiffness nor liver steatosis (assessed with CAP) had any effect on outcomes. d’Hebron Barcelona Hospital Campus, However, patients with abnormal baseline AST had a higher occurrence of the composite Universitat Autònoma de ICU/death (21% versus 9.5%, p = 0.002). Patients ⩾65 years and with an AST level > 50 U/ml Barcelona, Barcelona, Spain at admission had a significantly higher risk of ICU and/or death than those with AST ⩽ 50 U/ Macarena Simon-Talero ml (50% versus 13.3%, p < 0.001). In conclusion, mild liver damage is prevalent in COVID-19 Mar Riveiro-Barciela Meritxell Ventura-Cots patients, but neither ALT elevation nor liver steatosis influenced hard clinical outcomes. Beatriz Minguez Elevated baseline AST is a strong predictor of hard outcomes, especially in patients ⩾65 years. Joan Genesca Liver Unit, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut Keywords: ALT, AST, controlled attenuation parameter, CAP, liver injury of Reseach (VHIR), Vall d’Hebron Barcelona Hospital Campus, Received: 19 October 2020; revised manuscript accepted: 12 April 2021. Universitat Autònoma de Barcelona, Barcelona, Spain Centro de Investigación Introduction least 1,074,817 deaths have been reported to the Biomédica en Red de Coronavirus disease 2019 (COVID-19) was World Health Organization.1 The most common Enfermedades Hepáticas y Digestivas (CIBERehd), declared a pandemic in March 2020; by 13 symptoms of COVID-19 are fever and cough; Instituto de Salud Carlos October 2020, 37,423,660 cases resulting in at some patients can develop pneumonia, with rapid III, Madrid, Spain journals.sagepub.com/home/tag 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Gastroenterology 14 Lara Aguilera-Castro acute respiratory failure or acute respiratory dis- explore the prognostic value of liver elastography, Claudia Barber Danila Guanozzi tress syndrome.2–4 Aside from lung damage, there including steatosis measurement, in COVID-19 Beatriz Lobo is wide evidence of other organ involvement, patients. Carolina Malagelada Luis Mayorga including liver disease, with an increased related Stephanie Tasayco mortality.5–11 Department of Gastroenterology, Vall Methods d’Hebron Hospital Different aspects of liver involvement have been Universitari, Vall d’Hebron Barcelona Hospital described. Liver injury is present in between 14– Patient data Campus, Barcelona, Spain 76% of affected patients. There may be several dif- After the beginning of the COVID-19 pandemic Emilie A Nordahl ferent causes and patients with severe COVID-19 in Spain on January 31th, the first cases were Department of Clinical Pharmacology, Vall seem to have higher levels of aminotransfera admitted in our hospital during the first week of d’Hebron Barcelona ses.2–6,12,13 In addition, liver damage has been related March 2020. The Liver Unit of Hospital Hospital Campus, Barcelona, Spain to a prolonged hospital stay;14,15 however, this was Universitari Vall d’Hebron started to take care of Betina Biagetti not confirmed in another multicenter study.16 COVID-19 patients from March 16th in progres- Andrea Ciudin sively increasing numbers, peaking on March Department of Endocrinology, Vall The effect of previous liver disease has also been 31st with five hospital wards and around 150 d’Hebron Barcelona evaluated in an American registry study where patients. We started a prospective database of all Hospital Campus, Barcelona, Spain 250 patients were compared by propensity match- admitted patients from the emergency room on Raul Cocera ing to patients without known liver disease.7 17 March 2020, with it ending on 17 April 2020. Enric Miret Department of Urology, Patients with previous liver disease (including cir- All patients had COVID-19 pneumonia and were Vall d’Hebron Barcelona rhotic and non-cirrhotic patients) experienced confirmed positive by in-house polymerase chain Hospital Campus, Barcelona, Spain higher levels of hospitalization and mortality rates reaction (PCR) tests. No exclusions were deter- Cristina Dopazo compared with patients without previous liver mined. At that time, the standard drug therapy Andrea Fernandez disease. for COVID-19 during the whole study period in Mariona Jofra Concepción Gomez-Gavara our hospital was the combination of lopinavir- Elizabeth Pando Other studies have focused on the effect of meta- ritonavir (400 mg bid × 7 days) + hydroxychloro- Laura Vidal Department of bolic associated fatty liver disease (MAFLD) on quine (400 mg bid × 5 days) + azithromycin Hepatobiliar Surgery COVID-19 clinical outcomes in Asian popula- (500 mg qd × 3 days). Other off-label drugs (cor- and Liver Transplant, Vall d’Hebron Barcelona tions.8–10 Different approaches have been used, ticosteroids, cyclosporine, tocilizumab) were Hospital Campus, combining computed tomography (CT) and con- administered on an individual basis by patients’ Barcelona, Spain sensus diagnostic criteria,9,10,17 or the clinical physicians in some of the more severe cases; res- Maria M Jimenez Ana Pérez-Lopez index, hepatic steatosis index (HIS) and ultra- piratory and circulatory supportive therapy was Department of sound examination.8 All these studies have shown administered when necessary. All patients were Hematology, Vall d’Hebron Barcelona that patients with MAFLD are at higher risk of followed-up until day 28 or death. Hospital Campus, severe COVID-19, but that there are key differ- Barcelona, Spain Jorge A Guevara ences between patient subgroups. In the Zhou et The database included epidemiological, clinical, Marc Pigrau al.9 study, the risk was only present in younger laboratory, and outcome parameters that were Department of Endoscopy, patients; while for Zheng et al.,10 in a study evalu- gathered by all members of the Liver Unit Vall d’Hebron Barcelona Hospital Campus, ating only patients with MAFLD, the risk of COVID-teams. Collected laboratory parameters Barcelona, Spain severe COVID-19 was greater in obese patients. at admission included total lymphocyte count, However, the limited number of patients, the use platelet count, ferritin, lactate dehydrogenase of different diagnostic criteria, and the selection (LDH), D-Dimer (DD), interleukin-6 (IL-6), of the laboratory values to build the diagnostic total bilirubin, aspartate aminotransferase (AST), scores obtained up to one year before the COVID- alanine aminotransferase (ALT), gamma-gluta- 19 episode make the results difficult to interpret. myltransferase (GGT), alkaline phosphatase In that sense, the incorporation of liver elastogra- (AP) and albumin. In addition, follow-up param- phy to objectively explore liver disease might be a eters for patients with liver alterations were useful tool in the evaluation of liver injury in recorded. The final database was re-checked by COVID-19 patients. each person responsible for entering the data, while a final check was performed by four mem- The aims of our present study were: (1) to bers of the team. describe the characteristics of liver alterations in COVID-19 patients; (2) to assess the prognostic Given the exceptional circumstances in which the significance of preexisting liver disease; and (3) to study was conducted, informed consent was 2 journals.sagepub.com/home/tag I Campos-Varela, A Villagrasa et al. obtained verbally, and incorporated to the elec- or intubation (depending on ICU resources, tronical medical records for each patient. The which were constantly adapting) and the absence study was approved by the ethics committee of of any other conditions that might associate a our institution (PR(AG)184/2020). poor short-term prognosis. Definitions and outcomes Transient elastography Prior liver disease was defined by prior clinical Transient elastography (TE) was used to study history data (before the index admission) indicat- the potential role of liver stiffness measurements ing a previous diagnosis of a chronic liver disease. (LSMs) and liver steatosis on outcomes and their Cirrhosis was defined as per usual clinical, histo- potential value for prediction of the composite logical or elastography criteria. endpoint death/ICU. For this specific purpose, LSMs were carried out only in consecutive admit- Liver steatosis was evaluated by the Hepatic ted patients during the first 48 hrs after admission Steatosis Index [HSI = 8 × (ALT/AST) + body who were in stable condition without oxygen sup- mass index (BMI) (+2 if type 2 diabetes yes, +2 port or with mild-moderate O2 needs (Sa: if female)], using clinical and laboratory data at FiO2 > 300). The number of LSMs performed admission. The usual HSI categories were used to was not preplanned and we tried to complete as estimate the presence (HSI > 36) or absence many as possible. The TE device utilized (HSI < 30) of steatosis. In patients undergoing (Fibroscan 502 Touch) came available with M transient elastography (TE) (see below), steatosis and XL probes, which were used based on device was defined when the Controlled Attenuation requirements. The usual quality criteria [at least Parameter (CAP) value was above the usual 10 valid measurements and an interquartile range 250 dB/m threshold. In addition, a sensitivity (IQR)/mean (M) ⩽ 30%] were applied. analysis defining steatosis as CAP > 300 dB/m was conducted. Statistics Aminotransferase elevations were defined by Differences between categorical variables were AST or ALT values above the upper limit of nor- assessed by Chi–square test or Fisher’s exact test mality (ULN) (ULN, >50 U/ml for men, >35 U/ when necessary. Continuous variables were com- ml for women). Moderate AST/ALT alteration pared using the Student’s t test or Mann–Whitney was categorized in those cases with AST/ALT test as appropriate. A two-sided p-value < 0.05 over 4 times ULN, or acute hepatitis if values of was considered statistically significant. ALT were above 10 times ULN. In patients with at least a moderate increase in transaminase val- In order to adjust the weight of AST by other ues, a comprehensive work-up was carried out, well-known risk factors on COVID-19 outcomes, including viral serologies [hepatitis B surface anti- two approaches were taken. Firstly, an explora- gen (HBsAg), anti-hepatitis B core antigen (anti- tory adjustment using logistic regression analysis HBc) immunoglobulin M (IgM), anti-Hepatitis was performed. The selection of variables used to C virus, anti-Hepatitis E virus IgM, anti-cyto- enter the logistic regression models was based on megalovirus IgM and anti-Epstein Barr virus currently available literature, as well as on the IgM), and serum proteinogram, immunoglobulin results of univariate analyses. For this specific G levels, and antinuclear autoantibodies for the purpose, the composite death and/or ICU was assessment of autoimmune hepatitis. Concomitant preferred over death. This is due to the larger medications were reviewed, and the Roussel number of events and because it was regarded as Uclaf Causality Assessment Method was used to a more realistic and complete representation of assess the causal relationship with medications in the whole effect of COVID-19; both for the indi- cases with potential drug-induced liver injury.18 vidual patient and more globally for healthcare systems. Age and O2 saturation at admission were The two main outcomes of the study were death maintained as the main covariates for adjustment at 28 days and composite endpoint intensive care based on their observed weight on outcomes, as unit (ICU) admission or and/or death at 28 days. well as on available literature; and, most specially, ICU admission criteria included the need for ven- on their potential utility for rapid and objective tilator support in the form of high-flow cannulas triage, even in community settings. In order to journals.sagepub.com/home/tag 3 Therapeutic Advances in Gastroenterology 14 further adjust the weight of AST with other well- and main outcomes of this cohort. As seen, there documented blood prognostic markers available was an even distribution between men and at admission (lymphocyte count, ferritin, LDH, women. Their median age was 56 (range 21–88), IL-6, and DD), several combinations of these two-thirds were of white European origin, and biomarkers were introduced in blocks of three most of the remaining patients had Latin-Ameri- (while always keeping age and O2 saturation in can origin. the model). Relevant comorbidities with p < 0.10 at univariate analyses (hypertension, type-2 dia- betes) were also tested (keeping the other main Hepatic involvement covariates in the model). In order to avoid overfit- Only 33 patients (9%) had previously known liver ting and given the total number of events of the disease. The etiology of the previous liver disease composite endpoint, the two most stable variables was MAFLD in 20 (of these four had a mixed were used to further adjust odd’s ratio (OR) esti- etiology with alcohol liver disease), five chronic mates for AST on the composite endpoint. hepatitis C, five alcohol (four mixed with MAFLD), three chronic hepatitis B, one primary Secondly, a classification and regression tree biliary cholangitis (PBC), one biliary tract atresia, (CART) analysis was conducted in order to study one cryptogenic, and one iron deposition disease. and illustrate the interaction between the same Seven of the 33 patients had liver cirrhosis, and variables studied in the logistic regression analy- only one had decompensated cirrhosis before ses, as well as to identify the best cut-offs for con- admission. tinuous variables. The method has been previously used by our group and others and has been TE was performed in 101 patients, from whom described extensively elsewhere.19–21 In brief, the three determinations were non-valid. Among the method allows for the construction of inductive 98 patients with valid TE measurements, the decision trees through strictly binary splitting. median liver stiffness was 4.7 kPa (range 2.1– This method is especially adept at detecting rele- 22.5) and only two patients had liver stiffness vant interactions between variables and allows for >10 kPa. The median CAP was 252 (range 100– the identification of subgroups of patients that 397) and 47 patients (48%) had a CAP value share a specific combination of clinical character- >250 dB/m indicative of steatosis. The HSI was istics and a similar prognosis. In our study, the calculated for the whole cohort, and 46% had a number of patients in terminal nodes was set to a value of HSI > 36, suggestive of liver steatosis. minimum of 25 in order to maximize the stability of estimates. Age was forced (as continuous vari- ALT and AST were elevated at admission in 130 able) as a first node variable for the reasons men- patients (35%) and 167 (45%) patients, respec- tioned above. Cut-off points for continuous and tively; while 253 patients (69%) presented with ordinal variables were generated automatically by AST greater than ALT. Twenty-five (6.8%) the model based on statistical cost assumptions. patients presented a moderate ALT elevation during admission: 15 (60%) were male and the Finally, correlation between continuous variables median age was 55 years (range 23–73). The peak was studied by linear regression, and logarithmic ALT value of these patients was 268 U/ml (range transformations were applied when required by 160–470). Two (8.3%) patients had a history of differences in scale of variables in order to allow underlying liver disease (one MAFLD, one PBC). for a better visual interpretation of results. All Seven (28%) presented a moderate increase in analyses were performed using PAWS Statistics ALT at admission to hospital and the rest devel- (version 19.0; SPSS Inc., Hong Kong) software. oped it during hospitalization. In 11 cases (44%), the ALT increase was attributed to COVID-19 infection due to negative findings at the compre- Results hensive work-up of other causes. In the remaining 14 patients, the liver alteration was considered Baseline characteristics and main outcomes multi-factorial and probably related to different Demographics. During the study period, 370 treatments. The most commonly reported medi- patients with confirmed COVID-19 were consec- cations were parenteral nutrition with three cases utively admitted to the Liver Unit-COVID wards. and tocilizumab with two. Only two patients met Table 1 summarizes the baseline characteristics the criteria of acute hepatitis (10 × ULN): in one 4 journals.sagepub.com/home/tag I Campos-Varela, A Villagrasa et al. Table 1. Main characteristics of the entire cohort. Variable N = 370 Male 181 (49.0%) Age (years) (%) 56 (21–88) Origin Europe (%) 252 (68.1%) South America (%) 102 (27.6%) Africa (%) 10 (2.7%) Asia (%) 6 (1.6%) Diabetes mellitus (%) 58 (15.7%) Hypertension (%) 121 (33.7%) Dyslipidemia (%) 89 (24.1%) BMI (kg/m2) 28.6 (18.2–42.7) Days of fever before admission 7 (0–30) Obese (%) 129 (34.9%) Previous liver disease (%) 33 (8.9%) Cirrhosis (%) 7 (1.9%) Risk alcohol consumption† (%) 16 (4.3%) AST at admission (U/l) 39 (11–413) ALT at admission (U/l) 31 (5–420) AST elevation at admission (%) 167 (45.1%) ALT elevation at admission (%) 130 (35.1%) Moderate AST elevation anytime during admission‡ (%) 17 (4.6%) Moderate ALT elevation anytime during admission‡ (%) 25 (6.8%) Lymphocyte count (/l) at admission 1000 (100–5800) IL-6 (pg/ml) at admission 37.5 (1.5–4079) Ferritin (μg/l) at admission 518 (10–5503) D-Dimer (μg/ml) at admission 252 (50–34144) Lactate dehydrogenase (U/l) at admission 306 (139–1014) HSI index <30 (%) 29 (7.8%) 30–36 (%) 102 (27.6%) >36 (%) 169 (45.7%) (continued) journals.sagepub.com/home/tag 5 Therapeutic Advances in Gastroenterology 14 Table 1. (continued) Variable N = 370 Missing (%) 70 (18.9%) CAP (dB/m)§ 252 (100–397) >250 (dB/m)§ (%) 47 (48%) >300 (dB/m)§ (%) 24 (25%) LSM (kPa)§ 4.7 (2.1–22.5) >10 kPa§ (%) 2 (2%) O2 saturation with pulse-oximeter (%) at admission 97 (71–100) Need for O2 at admission (%) 147 (39.7%) Need for FiO2 > 30% at admission (%) 54 (14.6%) Peak GGT (U/l) anytime during admission 83 (11–1691) Peak AP (U/l) anytime during admission 91 (48–809) Peak Bilirubin (mg/dl) anytime during admission 0.64 (0.20–5.20) Lowest Albumin (g/dl) anytime during admission 3.3 (1.7–4.5) Lowest platelet count (10E9/l) anytime during admission 202 (29–697) Hospital length of stay (days) 7 (2–28) ICU admission (%) 39 (10.5%) Death (%) 17 (4.6%) Death/ICU (%) 54 (14.6%) Data are presented as median (range) or n (%). ALT: alanine aminotransferase (elevated ALT > 35 U/l for women and >50 U/l for men); AST: aspartate transaminase (elevated ALT > 35 U/l for women and >50 U/l for men); AP: Alkaline phosphatase; BMI: body mass index; CAP: controlled attenuation parameter; GGT: gamma-glutamyl transferase; HSI: hepatic steatosis index; ICU: intensive care unit; IL-6: Interleucine-6; LSM: Liver Stiffness Measurement. †Defined as >30 mg/d for men and 20 g/d for women. ‡Moderate AST/ALT elevations were defined as values >4 × x upper limit of normal (i.e. 140 U/l for women and 200 U/l for men). §Values correspond to 98 patients with elastography data. ALT, alanine aminotransferase (elevated ALT > 35 U/l for women and >50 U/l for men); AP, alkaline phosphatase; AST, aspartate transaminase (elevated ALT > 35 U/l for women and >50 U/l for men); BMI, body mass index; CAP, controlled attenuation parameter; GGT, gamma-glutamyl transferase; HIS, hepatic steatosis index; ICU, intensive care unit; IL-6, interleucine-6; LSM, liver stiffness measurement. patient it was considered directly as COVID-19 patients (10.5%) were transferred to the ICU and related and the other was multifactorial during two of them died. Mortality at 28 days in the over- the ICU admission. all cohort was 4.6%, and during that 28-day interval, 54 patients (14.6%) experienced the composite endpoint ICU and/or death. COVID-19 severity and outcomes In terms of COVID-19 severity, 147 (39%) Table 2 shows the comparison in key characteristics required oxygen support at admission, 54 (15%) according to occurrence or not of the main two out- of whom at a FiO2 > 30%. During admission, 39 comes. As expected, patients who died or experienced 6 journals.sagepub.com/home/tag I Campos-Varela, A Villagrasa et al. Table 2. Main characteristics of patients and univariate comparisons according to main outcomes. Variable Death p-value Death/ICU p-value Yes (n = 17) No (n = 353) Yes (n = 54) No (n = 316) Male (%) 11 (64.7%) 170 (48.2%) 0.18 32 (59.3%) 149 (47.2%) 0.10 Age (years) 75 (70–80) 55 (46–65) <0.0001 64 (53–72) 55 (45–65) <0.0001 Origin 0.03 0.53 Europe (%) 14 (82.4%) 238 (67.4%) 40 (74.1%) 212 (67.1%) South America (%) 1 (5.9%) 101 (28.6%) 12 (22.2%) 90 (28.5%) Africa (%) 2 (11.8%) 8 (2.3%) 2 (3.7%) 8 (3.5%) Asia (%) 0 6 (1.7%) 0 6 (1.9%) Diabetes mellitus (%) 5 (29.4%) 53 (15.1%) 0.11 13 (24.1%) 45 (14.3%) 0.07 Hypertension (%) 11 (64.7%) 110 (31.3%) 0.004 27 (50%) 94 (29.8%) 0.004 Dyslipidemia (%) 6 (35.3%) 83 (23.6%) 0.27 15 (28.3%) 74 (23.5%) 0.45 BMI (kg/m2) 29.6 (27.3–31.2) 28.6 (25.3–32.4) 0.58 29.6 (26.0–36.9) 28.5 825.3–32.3) 0.64 Obesity (%) 5 (38.5%) 124 (28.5%) 1.0 19 (40.4%) 110 (38.2%) 0.77 Previous liver disease (%) 1 (5.9%) 32 (9.1%) 0.65 4 (7.4%) 29 (9.2%) 0. 80 Cirrhosis (%) 1 (5.9%) 6 (1.7%) 0.28 2 (3.7%) 5 (1.6%) 0. 27 Risk Alcohol Consumption† (%) 0 16 (4.5%) 0.37 0 16 (5.1%) 0.14 ALT (U/L) at admission 39 (23–53) 31 (20–52) 0.57 35 (24–55) 30 (20–52) 0.18 ALT elevation at admission (%) 7 (41.2%) 123 (34.8%) 0.59 23 (42.6%) 107 (33.9%) 0.21 ALT elevated anytime during 11 (64.7%) 168 (47.6%) 0.17 26 (48.1%)† 135 (42.7%)† 0.46 admission‡ (%) Moderate ALT anytime during 1 (5.9%) 24 (6.8%) 1.0 4 (7.4%)† 9 (2.8%)† 0.11 admission‡ (%) AST (U/L) at admission 55 (38–83) 38 (29–54) 0.03 52 (36–73) 37 (29–52) 0.001 AST elevated at admission (%) 12 (70.6%) 155 (44.3%) 0.03 35 (64.8%) 132 (42.2%) 0.002 AST elevated anytime during 14 (82.4%) 197 (56.0%) 0.03 43 (79.6%)† 163 (51.7%)† <0.0001 admission‡ (%) Moderate AST elevation anytime 1 (5.9%) 16 (4.5%) 0.56 4 (7.4%)† 7 (2.2%)† 0.06 during admission‡ (%) Lymphocyte (/L) at admission 600 (500–1250) 1100 (800–1500) 0.03 800 (600–1100) 1100 (800–1500) <0.0001 IL-6 (pg/ml) at admission 96.7 (64.3–157.2) 36.8 (21.1–69.3) <0.0001 75.8 (52.0–125.5) 33.6 (19.5–63.1) <0.0001 Ferritin (μg/l) at admission 1055 (587–1574) 488 (253–834) 0.004 742 (488–1114) 450 (234–777) <0.0001 D-Dimer (μg/ml) at admission 536 (269–1578) 246 (152–391) 0.003 335 (216–609) 243 (147–381) 0.003 Lactate dehydrogenase (U/l) at 512 (280–699) 305 (262–378) 0.01 384 (296–517) 300 (260–364) <0.0001 admission HSI index at admission 0.38 (continued) journals.sagepub.com/home/tag 7 Therapeutic Advances in Gastroenterology 14 Table 2. (continued) Variable Death p-value Death/ICU p-value Yes (n = 17) No (n = 353) Yes (n = 54) No (n = 316) <30 (%) 0 29 (10.1%) 4 (9.8%) 25 (9.7%) 0.99 30–36 (%) 6 (46.2%) 96 (33.4%) 14 (34.1%) 88 (34.0%) >36 (%) 7 (53.8%) 162 (56.4%) 23 (56.1%) 146 (56.4%) CAP (dB/m)§ - 249 (202–297) - 226 (187–288) 249 (204–300) 0.45 CAP > 250 (dB/m)§ (%) 0 0 1.0 2 (40%) 44 (47.8%) 1.0 LSM (kPa)§ 4.1 (3.5–5.1) 4.4 (3.8–5.0) 4.4 (3.5–5.2) 0.77 LSM > 10 kPa§ 0 0 1.0 0 1 (1.1%) 1.0 Fever before admission (days) 5.5 (2.8–9) 7 (4–10) 0.26 7 (3–7) 7 (4–10) 0.06 Sat O2 (%) at admission 92 (89–98) 97 (95–98) 0.005 95 (90–97) 97 (95–98) <0.0001 Need for O2 at admission (%) 13 (76.5%) 134 (38.0%) 0.002 40 (74.1%) 107 (33.9%) <0.0001 Need for FiO2 > 30% at 10 (58.8%) 44 (12.5%) <0.0001 27 (50%) 27 (8.6%) <0.0001 admission Hospital length of stay (days) 6 (4–12) 7 (5–12) 0.09 19 (9–28) 6 (5–9) <0.0001 Data are presented as median (interquartile range) or n (%). ALT, alanine aminotransferase; AST, aspartate transaminase; BMI, body mass index; CAP, controlled attenuation parameter; HIS, hepatic steatosis index; ICU, intensive care unit; IL-6, interleukin-6; IQR, interquartile range; LSM: liver stiffness measurement. †: defined as >30 g/day for men and 20 g/day for women. ‡Anytime before ICU admission (patients for whom AST elevated once at ICU were excluded for this calculations). §Performed in 98 consecutive patients without oxygen support or with mild-moderate O needs (Sa: FiO > 300). 2 2 the composite endpoint were significantly older and disease or cirrhosis (Table 2). Only one patient were more frequently hypertensive; they also had who developed decompensation after COVID-19 lower baseline lymphocyte counts and higher ferritin, infection died. D-Dimer, and IL-6 values, showing the characteristic serum biomarker profile of severe COVID-19. Among the 98 patients undergoing TE, only 5 Type-2 diabetes was associated with worse outcomes, (5%) experienced the composite endpoint, and both in univariate (Table 2) and multivariate analysis none of them died. As seen in Table 2, the median (Supplemental Table 4), although neither of these liver stiffness was similar between patients experi- reached statistical significance. Obesity was not asso- encing or not the composite endpoint. ciated with either death or the composite endpoint. Liver steatosis The association between liver parameters Liver steatosis did not have any significant role in and Covid-19 outcomes the outcomes of COVID-19 patients in our cohort. As seen in Table 2, when steatosis was Previous liver disease and transient addressed with the hepatic HSI, no differences in elastography outcomes were detected at any HSI category. The presence of pre-existing liver disease (includ- More specifically, patients with HSI > 36 had the ing cirrhosis) was relatively uncommon (Table 1) exact same incidence of the composite endpoint in the whole cohort; therefore, significant differ- as patients with HSI < 30 (no steatosis) or HSI ences in the main outcomes could be detected 30–36 (Supplemental Table 1). In addition, the between patients with or without previous liver occurrence of death was similar between the three 8 journals.sagepub.com/home/tag I Campos-Varela, A Villagrasa et al. categories. These outcomes did not change in 95% CI 0.698–2.220, p = 0.46; 16.1%, 26/161 in those patients in whom the HSI could not be cal- patients with elevated ALT at any time before culated because of missing parameters ICU admission versus 13.4%, 28/209 in patients (Supplemental Table 1). with normal ALT, p = 0.46). When steatosis was assessed with CAP in the 98-patient cohort, the results were similar. As AST seen in Table 2, the median CAP was not signifi- On the other hand, AST elevations were strongly cantly different between patients experiencing or associated with outcomes in our cohort. As shown not the composite endpoint (no patients under- in Table 2, median AST (either at admission or at going CAP measurements died). When stratify- any time point during admission) was signifi- ing using either a 250 dB/M or a 300 sB/M cantly higher in patients who died or reached the threshold, the incidence of the composite end- composite endpoint. In addition, when compared point remained unchanged (Supplemental Table with patients with normal AST values at admis- 1). When CAP was assessed as a continuous vari- sion, those with abnormal baseline AST had a able through logistic regression, no significant significantly higher occurrence of death (7.2% association with the composite endpoint was versus 2.5%, respectively, p = 0.03) and the com- detected [OR 0.996, 95% confidence interval posite ICU/death endpoint (21% versus 9.5%, (CI) 0.981–1.010, p = 0.551]. p = 0.002) (Supplemental Table 2). All these dif- ferences remained significant, even after exclu- sion of patients with previously known liver ALT disease (data not shown) or with AST elevations As seen in Table 2, ALT elevations (analyzed occurring once admitted to the ICU (Table 2). either as continuous or dichotomous variables) Moderate AST elevations, either at admission or were not associated with death at 28 days. When before ICU, were uncommon (N = 7 and 11, the association was analyzed through logistic respectively) and did not affect outcomes sub- regression (ALT elevations at admission or peak stantially (differences in outcomes remained ALT at any time point during the episode, intro- unchanged after excluding these patients, data duced as a continuous or dichotomous variable), not shown). the results remained unchanged (data not shown). In order to adjust the weight of AST by other When applying the same analysis for the composite well-known risk factors on COVID-19 outcomes, death and/or admission to ICU, elevated ALT at two approaches were taken. admission (either as continuous or dichotomous variable) was not associated with this outcome Firstly, an exploratory adjustment using logistic (Table 2 and logistic regression univariate analy- regression analysis was performed (see Methods ses, data not shown). Both peak ALT (as a con- for details). Age and O2 saturation at admission tinuous variable considering the whole follow-up were maintained as the main covariates for adjust- time: OR 1.011, 95% CI 1.007–1.015, p < 0.001) ment. As seen in Table 3, both the OR and and elevated ALT at any time point during admis- p-value of AST remained unchanged after adjust- sion (as a dichotomous variable: 24%, 43/179 in ment with those two clinical variables. To further patients with elevated ALT versus 5.8%, 11/191 in adjust the weight of AST with other blood prog- patients with normal ALT, p < 0.001) were signifi- nostic markers available at admission, several cantly associated with the composite endpoint. combinations of these biomarkers were studied. Lymphocyte count and DD showed as the two However, among the 54 patients experiencing more stable and consistent variables, and thus this outcome, the ALT elevation occurred after were used to further adjust OR estimates for AST the patient was admitted to the ICU in 36% on the composite endpoint. As seen in (15/41) of the cases. Indeed, if ALT elevations Supplemental Table 3, AST lost stability when happening after admission to the ICU were introduced with those two variables, most likely excluded from the analysis (i.e. only ALT values due to the loss of linearity and discriminative abil- before ICU admission were considered), the ity for normal values. However, AST remained association of ALT elevations with the composite highly significant when kept as a dichotomous endpoint death/ICU disappeared (OR 1.245, variable. When the age-O2-AST block was journals.sagepub.com/home/tag 9 Therapeutic Advances in Gastroenterology 14 Table 3. Logistic regression adjustment of the weight of AST on the composite endpoint death and/or ICU. Univariate models Multivariable models OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) p-value AST (U/l) 1.007 (1.001–1.013) 0.03 1.007 (1.001–1.014) 0.02 1.007 (1.001–1.014) 0.02 Age (years) 1.041 (1.021–1.069) <0.001 1.042 (1.019–1.066) <0.001 1.031 (1.006–1.056) 0.01 O2 saturation 0.882 (0.832–0.936) <0.001 0.906 (0.850–0.964) 0.002 (pulse- oximeter) (%) AST, aspartate aminotransferase; CI, confidence interval; ICU, intensive care unit; OR, odd’s ratio. adjusted by the presence of hypertension, the lat- was a modest but significant linear correlation ter was not found to remain significantly associ- between AST and LDH at admission. ated with the composite endpoint (see Supplemental Table 3). Interestingly, when both parameters were plotted highlighting the occurrence or not of the primary Secondly, CART analysis was used to explore rel- endpoint, it could be observed that LDH eleva- evant, non-parametric interactions between all tions without AST increase were very common, these pre-selected variables and to obtain dis- but remained poorly predictive of the outcome, criminative cut-off values for continuous varia- suggesting a higher discriminative hierarchy of bles. Age was forced as first node based on the AST over LDH. AST and ALT were highly cor- reasons stated above (clinical relevance, available related both at admission and when comparing literature, and potential utility for rapid triage at peak values for each patient during the whole epi- all healthcare levels). Interestingly, an AST value sode (R square 0.743, p < 0.001 and 0.630, at admission of 50 U/l was identified as the most p < 0.001, respectively). discriminative and stable parameter to identify a high-risk population in the cohort (Figure 1). Discussion As seen here, patients of age 65 or older had a 2.5 In this prospective observational study in a large increase in risk of the composite endpoint when cohort of consecutive patients admitted for compared with patients below that age threshold COVID-19, we used a comprehensive diagnostic (26/107, 24.3% versus 28/263 10.6%, respec- approach (using clinical variables, blood tests, tively, p = 0.001). In that population of 65 or and TE) to evaluate the hepatic involvement of older, patients with AST ⩽ 50 U/l at admission liver disease in COVID-19 outcomes. In contrast had a similar risk to that of patients < 65 (10/75, to previous reports, we did not find any signifi- 13.3%), while 50% (16/32) of these older patients cant association of either previous liver disease, with AST > 50 U/l either were admitted to the liver steatosis or ALT elevations with hard clinical ICU and/or died, a risk almost 5 times higher outcomes; however, this study was not powered than for the other categories (p < 0.001). for this.5–10,14,15 We observed a strong association between baseline AST values an outcomes, espe- Finally, given the lack of association between cially in older patients. ALT, TE, and pre-existing liver disease with out- comes, the association between AST and LDH One of the main results in our study is that, in was further explored, under the hypothesis that contrast to previous reports by other groups,8–10 both elevations could be consequence of muscu- we did not find any association between liver stea- lar micro-damage [creatinine phosphokinase tosis and worse outcomes in COVID-19. The (CPK), aldolase, and other muscular enzymes evaluation of steatosis in previous reports has were not routinely available through the study been made based either on indirect serum scores period) and thus linked in terms of predictive based on transaminase ratios (such as HSI) ultra- ability. As seen in Supplemental Figure 1, there sound, or CT scan, which have suboptimal 10 journals.sagepub.com/home/tag I Campos-Varela, A Villagrasa et al. Figure 1. Classification and Regression Tree (CART) analysis of covariates associated to the composite endpoint death and/or ICU in the cohort. ALT, alanine aminotransferase; AST, aspartate transaminase; ICU, intensive care unit. sensitivity for steatosis detection.17 To the best of tools to detect steatosis; therefore, the latter tech- our knowledge, this is the first report on the use of nique might be selecting a higher-risk population. TE to evaluate the involvement and predictive In our view, this reason is unlikely given, on the value of liver disease in patients with COVID-19. one hand, the very low frequency of events even Fibroscan CAP is widely used for steatosis quan- in patients with higher CAP values; on the other tification and was evaluated in the present study hand, the lack of association in our cohort as an early prognostic tool in 98 consecutively between obesity or diabetes (which are generally admitted patients with mild-to-moderate associated with a higher degree of steatosis) with COVID-19. In this sub-cohort, patients, with-or- outcomes. Regarding HSI, previous reports used without steatosis, had the exact same incidence of varied timeframes to select the values entered in the composite endpoint death/ICU, and compari- the calculation of the score, which may justify to son of the CAP value distribution in the two some degree the difference in results. In any case, groups did not differ. In addition, we used HSI given the characteristic changes of ALT and AST (using only values at admission) to further study in patients with COVID-19, the transferability of the association in the whole cohort of 370 patients, the diagnostic accuracy for steatosis or fibrosis of with similar results. The reasons for this discrep- transaminase-based scores derived from chronic ancy with previous reports are not clear. As liver disease to this peculiar setting (in which referred above, CAP is more sensitive than other ALT/AST dynamics seem to be different to that journals.sagepub.com/home/tag 11 Therapeutic Advances in Gastroenterology 14 from chronic liver disease) should be put into Given the lack of association between ALT eleva- question. tion an outcomes, the origin of AST in these patients remains as an intriguing question. In a Our study was not able to confirm previous stud- recent paper, Bloom et al.12 observed a strong ies that suggest that prior liver disease had an correlation between ALT and AST elevations effect on COVID-19.7,22 However, the present (with no predictive effect on neither ICU admis- study is not suited to tackle this question, given sion nor death) and based on these data the the limited number of patients with previous liver authors suggested an effect of direct hepatic injury disease in our cohort. This question should be on COVID-19. Our results suggest otherwise. addressed through large registry-based studies, Despite the linear correlation between AST and ideally including adequate control groups. ALT in our study, there was a distinct effect of each transaminase on outcomes. The difference Nonetheless, the present study provides clinically in sample size (370 versus 60) and follow-up time relevant data on the association of ALT eleva- (28 versus 14 days) between both studies may tions in patients with COVID-19. Liver injury account for some of these differences, but a rea- (assessed with different transaminase-based cri- sonable alternative is assuming a different origin teria) and its relationship with COVID-19 have for AST elevations in COVID-19. Since other been evaluated in several studies, with conflicting viral hepatitis are led by ALT elevations and conclusions.5,6,11,12,14,15,23–25 In our large, prospec- many viral diseases associate different degrees of tively collected cohort, we did not observe a signifi- muscular damage, the predominant AST eleva- cant association between baseline ALT elevations tion observed in COVID-19 has been suggested and outcomes. In addition, both moderate ALT to be related to muscular micro-damage. We elevations and acute hepatitis were rare and found a modest correlation between AST and occurred mostly in patients already at the ICU. LDH at admission, but the discriminative ability The only associations between ALT and outcomes of AST is definitively higher than that of LDH. observed in our cohort were mostly due to the The results by Bloom and colleagues suggest that occurrence of ALT elevations once the patient was the correlation between AST and muscular admitted to the ICU, defeating the purpose of enzymes is low in these patients.12 Therefore, fur- using ALT elevations as predictor of hard clinical ther studies are needed to clarify whether the dif- outcomes. Our results suggest that most often it is ferent meaning of AST elevation in COVID-19 is ICU admission that anticipates ALT elevations, due to a particular form of liver damage (inde- rather than vice versa, pointing out at an adequate pendent of ALT elevations) or to micro-damage analysis of timing of ALT elevations as of critical in other tissues. relevance in order to provide a correct interpreta- tion of causality.23 Our study has some limitations. Firstly, elastogra- phy was only performed in a subset of patients Finally, the most relevant result of our study was and results cannot be extrapolated to the whole the observation of the association of AST eleva- population. The initial aim of TE evaluation was tions with worse COVID-19 outcomes. In our to study its role as a prognostic tool; therefore, the cohort, patients with abnormal AST at admis- focus is on less sick patients. For this aim, TE sion had twice the risk of death/ICU admission does not seem useful, but at least it allows for the than those with normal values. AST remained as observation of a lack of association between stea- a strong predictor of the composite endpoint, tosis (as defined both by CAP and HSI), which even after adjustment with other key clinical var- remains valid. iables like age or O2 saturation at admission. In this regard, AST was only discriminative in older Secondly, the low number of patients with previ- patients. In patients younger than 65, AST ele- ous liver disease preclude us from evaluating its vations did not seem to associate with worse out- impact on COVID-19 outcomes, as described comes. However, in patients older than 65, an above. However, it is possible that within the AST value at admission above 50 allowed the cohort there were patients with chronic liver dis- identification of a high-risk population with a ease (NASH, alcohol-related) not previously 50% risk of evolving to either ICU admission or identified. Another limitation was that we did not death. account for the use of drugs during admission or 12 journals.sagepub.com/home/tag I Campos-Varela, A Villagrasa et al. ICU stay; however, as the main focus and results Conflict of interest statement of the present study are baseline variables, we IC-V: Travel and conference grant from MSD, believe this limitation can be neglected. Astellas and Chiesi. SA: consulting fees from Boehringer Ingelheim, Ferrer, Gilead, Intercept, Finally, this study was not aimed at developing IQVIA, Novartis, Pfizer; speaking fees from comprehensive prognostic tools, but rather to Allergan, Gilead, MSD and Novartis; travel study the role of liver parameters on hard out- expenses from Gilead, MSD, Janssen, Genfit, comes. The correlation of AST with other rele- Bayer and Ferring; grant support from Gilead. vant prognostic markers of COVID-19 outcomes could be further developed, but it was out of the Funding scope of the present work, which was centered on The authors disclosed receipt of the following the liver involvement in COVID-19. Nonetheless, financial support for the research, authorship, and/ we think that the potential utility of AST as a or publication of this article: JG is a recipient of a prognostic marker in COVID-19 should be fur- Research Intensification grant from the Instituto ther studied, given its simplicity and wide de Salud Carlos III, Spain. MST and MVC are availability. recipients of a Juan Rodés grant from the Instituto de Salud Carlos III. The work was partially funded Despite these limitations, the study has clear by grants PI17/00310, PI18/00947, PI18/00961, strengths. This is the largest cohort reported to and PI19/00330 from Instituto de Salud Carlos III date focusing on the role of liver biochemistry and and co-funded by European Union (ERDF/ESF, steatosis on COVID-19 outcomes, and the first “Investing in your future” – Una manera de hacer one to study steatosis adequately. The study was Europa). CIBERehd is supported by Instituto de prospective, with data collected in almost real Salud Carlos III. The work was independent of all time, limiting the loss of information. Finally, one funding. of the main strengths of the present study is the long follow-up of patients and its focus on hard Guarantor of the article clinical outcomes, which make the observed asso- Joan Genesca ciations significantly more robust and relevant to clinical practice. ORCID iDs Isabel Campos-Varela https://orcid.org/ In conclusion, mild liver damage is very preva- 0000-0001-6597-3151 lent in COVID-19 patients, but neither the Macarena Simon-Talero https://orcid.org/ presence of ALT elevations nor prior hepatic 0000-0002-1409-3936 steatosis carry worse outcomes. Elevated AST at admission is a strong predictor of hard clini- cal outcomes, especially in patients older than Supplemental material 65 years. Supplemental material for this article is available online. Author contributions Study concept and design: IC-V, SA, JG. Patient enrollment and acquisition of data: AV, MS-T, MR-B, MV-C, LA-C, PA-L, EA, AA, JB, CB, References AB-D, BB, LC, AC, RC, CD, AF, CJ, MJ, CG, 1. World Health Organization. WHO Coronavirus CG-G, DG, JAG, BL, CM, JM-C, LM, EM, Disease (COVID-19) dashboard. Geneva: WHO, MMJ, EP, AP, MP, AP, JR, AR, ST, JV-G, LV, 2021. BM. Analysis and interpretation of data: SA, 2. Guan WJ, Ni ZY, Hu Y, et al. Clinical IC-V. Drafting of the manuscript: IC-V, SA, JG. characteristics of coronavirus disease 2019 in Critical revision of the manuscript: AV, MS-T, China. N Engl J Med 2020; 382: 1708–1720. MR-B, MV-C, LA-C, PA-L, EA, AA, JB, CB, AB-D, BB, LC, AC, RC, CD, AF, CJ, MJ, CG, 3. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus CG-G, DG, JAG, BL, CM, JM-C, LM, EM, in Wuhan, China. Lancet 2020; 395: 497–506. MMJ, EP, AP, MP, AP, JR, AR, ST, JV-G, LV, BM. 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