Increased Diagnosis of Hepatocellular Carcinoma in Hospitalized Patients with Alcohol Related Hepatitis after the Covid-19 Outbreak: A Global Multi-Center Propensity Matched Analysis
Authors: Abhilash Perisetti, Randeep Kaur, Ragesh Thandassery
Journal: Clinical Gastroenterology and Hepatology (2021)

We have read the recent article by Kim et al1Kim D. et al.Clin Gastroenterol Hepatol. 2021; 19: 1469-1479Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar with interest. We extended our study into the course of hepatocellular carcinoma (HCC) in patients with alcohol-related hepatitis post COVID-19 pandemic. The Coronavirus 2019 (COVID-19) pandemic has posed significant challenges in the management of chronic liver disease. Missed or delayed diagnosis of HCC is anticipated due to temporary interruption in standard surveillance protocols during the pandemic, although no large studies have documented these results. We attempted to study the baseline characteristics and outcomes in patients hospitalized with alcohol-related hepatitis, before and after the COVID-19 outbreak, and analyze the impact on outcomes including the diagnosis of HCC and inpatient mortality. A federated cloud-based network (TriNetX) data from fifty health care organizations across the globe was analyzed retrospectively.2https://www.trinetx.com/Google Scholar Patients admitted with alcohol-related hepatitis between January 2019 and December 2020 were studied. They were categorized into 2 groups including post-COVID outbreak (group 1, January 1, 2020 to December 1, 2020) and pre-COVID outbreak (group 2, January 1, 2019 to December 1, 2019). Patient characteristics and outcomes related to hospitalization were compared between these groups. Of 23,201 patients studied, 4383 patients were included in post-COVID, and 18,818 pre-COVID group. The 2 groups had comparable demographic features and occurrence of other comorbid diseases (Table 1), none of which had a COVID-19 diagnosis. After propensity matched analysis, we found that post-COVID group had a tendency to have higher total bilirubin levels (P = .05) during hospitalization. Similarly, the post-COVID group had a higher proportion of patients with underlying cirrhosis (P = 0.02). Patients had a similar course during hospitalization including most of the variables compared among the 2 groups except the occurrence of hepatorenal syndrome (higher in the post-COVID group; P < .001). Among the outcome variables studied, the post-COVID group had an increased occurrence of HCC (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.08–1.32; P < .001), however occurrence of ascites (OR, 0.72; 95% CI, 0.45–1.17; P = .18), hepatic encephalopathy (OR, 0.74; CI, 0.49–1.11; P = .15), need for steroid use (OR, 1.13; CI, 0.91–1.41; P = .24) and inpatient death (OR, 0.93; CI, 0.72–1.20; P = .59) were comparable among both groups.Table 1Propensity Matched Comparison of Groups With Alcohol-Related Hepatitis After and Before COVID-19 OutbreakBefore matchingP valueaPropensity matched analysis was performed and P < .05 was significant.After matchingP valuePost-COVID (group 1) n = 4383Pre-COVID (group 2) n = 18,818Post-COVID (group 1) n = 4383Pre-COVID (group 2) n = 4383Age, y (± SD)49.7 ± 12.350.2 ± 12.3.0149.7 ± 12.349.7 ± 12.2.09Gender, male, %63.964.7.3363.963.7.82BMI, kg/m2 (± SD)28.1 ± 5.927.7 ± 5.8.0228.2 ± 5.927.7 ± 5.8.09Comorbid diseases, %Hypertension65.565.6.8966.566.6.26Diabetes mellitus21.522.5.1421.520.9.56Obesity27.323.9< .00127.326.7.58Chronic kidney disease11.110.5.2511.19.9.08Coronary artery disease18.118.3.7518.117.8.73COPD18.920.3.3918.918.7.80Cerebrovascular disease11.012.7.00311.010.8.68Laboratory valuesHbA1c (± SD)6.3 ± 2.36.3 ± 2.2.716.3 ± 2.36.2 ± 1.9.89Hemoglobin, g/dL (± SD)13.1 ± 2.111.4 ± 2.6.01aPropensity matched analysis was performed and P < .05 was significant.Platelet count, per mL (± SD)214.5 ± 123.2214.2 ± 100.8.96214.5 ± 123.2213.7 ± 104.2.94Serum sodium, mEq/dL (± SD)138.4 ± 3.6138.5 ± 3.8.66138.4 ± 3.6138.4 ± 4.1.54Creatinine, mg/dL (± SD)2.08 ± 10.11.98 ± 10.5.892.08 ± 10.11.2 ± 4.4.33Bilirubin, total, mg/dL (± SD)1.4 ± 2.91.5 ± 3.8.720.71 ± 0.31.4 ± 2.9.05Alanine transaminase, U/L (± SD)56.5 ± 53.057.8 ± 101.5.8656.5 ± 53.054.5 ± 56.0.72Aspartate transaminase, U/L (± SD)77.2 ± 81.382.4 ± 207.6.7466.5 ± 69.582.3 ± 207.6.21Albumin, g/dL (± SD)3.8 ± 0.83.9 ± 0.8.293.8 ± 0.83.8 ± 0.8.79INR (± SD)1.2 ± 0.21.4 ± 0.7.941.2 ± 0.241.2 ± 0.4.60Prothombin time, s (± SD)13.8 ± 3.313.5 ± 4.5.6913.8 ± 3.313.2 ± 4.9.47Course of illness, %Underlying cirrhosis33.830.8< .00133.831.5.02Esophageal varices14.313.4.1114.313.7.40Hepatorenal syndrome3.82.7< .0013.82.2< .001Steroid therapy21.720.3.0421.721.0.48BMI, body mass index; COPD, chronic obstructive pulmonary disease; HbA1c, hemoglobin A1c; INR, international normalized ratio; SD, standard deviation.a Propensity matched analysis was performed and P < .05 was significant. Open table in a new tab BMI, body mass index; COPD, chronic obstructive pulmonary disease; HbA1c, hemoglobin A1c; INR, international normalized ratio; SD, standard deviation. These results might indicate decreased outpatient diagnosis of HCC, likely from delay or discontinuity in standard HCC surveillance as a result of the COVID-19 outbreak. We may infer that higher bilirubin levels and higher diagnosis of cirrhosis in the post-COVID group are consequent to general patient behavior of seeking medical care only with increased symptoms during the pandemic, however this did not translate to increased mortality. HCC is a slow growing tumor with a tumor doubling time of 6 months and we anticipate that the clinical impact of a missed diagnosis will be more remarkable in long term follow up in the post pandemic phase, and our results probably indicate only the tip of an iceberg. A larger study including the hospitalized and outpatient population might address this issue more appropriately. Tapper et al described 3 waves of the impact of COVID-19 on cirrhosis care; (1) an early high acuity phase with delayed routine care, (2) a challenging 'return to normal' phase, and (3) a final phase of missed diagnoses and progressive disease.1Kim D. et al.Clin Gastroenterol Hepatol. 2021; 19: 1469-1479Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar Our study testifies these predictions, and we recommend a greater caution as we encounter patients at risk for HCC in clinics, to confirm that they have not missed their scheduled ultrasound surveillance. Data on TriNetX network were obtained from academic medical centers, specialty physician services, and community hospitals. The data used is acquired from TriNetX (https://www.trinetx.com/). TriNetX has received a waiver from the institutional review board because it does not contain any protected health information or the HCO Information. It only includes aggregated counts and statistical summaries of deidentified information. Using TriNetX analytics platform, COVID-19 patients were identified based on Centers for Disease Control and Prevention coding guidelines. Patients were included if they had 1 or more of the following International Classification of Diseases, Ninth and Tenth Revisions, Clinical Modifications (ICD-10-CM) codes in the electronic medical records: U07.1 COVID-19; B34.2 coronavirus infection, unspecified; and B97.29 other coronavirus as the cause of disease classified elsewhere.1Harrison S.L. et al.PLoS Med. 2020; 17: e1003321Crossref PubMed Google Scholar ICD-10 codes K74.60 (unspecified cirrhosis of liver), K74.69 (other cirrhosis of liver), and K74.6 (other and unspecified cirrhosis of liver) were included to identify patients with cirrhosis of the liver. These COVID-19 patients with cirrhosis were divided into 2 groups: COVID-19 patients without cirrhosis (group A), and COVID-19 with cirrhosis (group B). Comorbidities were identified using codes I10 (essential hypertension), I20-25 (ischemic heart disease), N18 (chronic kidney disease), E08-13 (diabetes mellitus), J44.9 (chronic obstructive pulmonary disease, unspecified), and E65-E68 (overweight, obesity, and hyperalimentation).1Harrison S.L. et al.PLoS Med. 2020; 17: e1003321Crossref PubMed Google Scholar,2Quan H. et al.Med Care. 2005; 43: 1130-1139Crossref PubMed Scopus (7806) Google Scholar The data are susceptible to coding or data entry errors when patient information is translated into the ICD-10 codes. Only age of death was available. Date of death is not available. Underreporting of the data could be possible from HCO's. We could not report the influence of different HCOs because of privacy restriction. Recording of ICD codes in administrative data may vary in comorbidities, severity of illness, length of hospitalization, and whether in-hospital death occurred.3Chong W.F. et al.BMC Health Serv Res. 2011; 11: 105Crossref PubMed Scopus (45) Google Scholar However, the data collection errors are minimized because TriNetx aggregates the data directly from the electronic medical records. ICD 10 codes used: Corona virus U07.1, B34.2, B97.29, J12.81 Exclusion: B34.2, B97.2 Cirrhosis, Moon et al.4Moon A.M. et al.J Hepatol. 2020; 73: 705-708Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar K70.30, K70.31, K74.60, K74.69, K74.3, K74.4, K74.5 cirrhosis Varices: I85.0, I 85.01, I85.10, I85.11, 86.4 Ascites: K70.31, K70.11, R18.8, K65.2 HE: K70.41, K72.11, K72.91, B15, B16, B17.11, B19.0, B19.11, B19.21 HCC: C22.0, C22.8, C22.9 Cause of liver disease K83.1 PSC 76.9 other specified diseases of liver K76.89 other specified diseases of liver K76.9 liver disease unspecified K72.9 Hepatic failure K71 Toxic liver disease K75.81: NASH K76.9 Fatty liver not elsewhere specified B18 Chronic viral hepatitis B19.1 unspecific viral hepatitis K73. Chronic hepatitis not elsewhere classified K75.3 Granulomatous hepatitis K75.4 autoimmune hepatitis K75.89 other specified inflammatory liver disease K76.81- HPS K76.7- HRS Other comorbidities CV diseases ICD 10 I60-69 Substance abuse F10-F19 Predictors of Outcomes of COVID-19 in Patients With Chronic Liver Disease: US Multi-center StudyClinical Gastroenterology and HepatologyVol. 19Issue 7PreviewChronic liver disease (CLD) represents a major global health burden. We undertook this study to identify the factors associated with adverse outcomes in patients with CLD who acquire the novel coronavirus-2019 (COVID-19). Full-Text PDF