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Severe COVID-19 in chronic liver disease linked with cholestasis and secondary sclerosing cholangitis

NEW YORK 30/06 - Severe COVID-19 increases the risk for cholestasis and secondary sclerosing cholangitis (SSC) in patients with chronic liver disease (CLD), researchers say.

Among 65 patients with preexisting CLD who were hospitalized for COVID-19, 23% developed cholestatic liver failure (cholestasis plus bilirubin at least 6mg/dL) and 15.4% developed SSC on the basis of cross-sectional imaging or endoscopic retrograde cholangiopancreatography, according to Dr. Lukas Hartl and colleagues from the Medical University of Vienna.

Nineteen of the 65 had advanced liver disease, including seven with decompensated disease prior to SARS-CoV-2 infection, the researchers reported in Hepatology. The most common etiologies were non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) in 60%, followed by alcoholic liver disease (ALD; 15.4%) and viral hepatitis (7.7%). There was no difference in etiology between those with CLD and those with advanced CLD.

During a median follow-up period of 34.5 days (IQR 107.0) days, median aspartate aminotransferase (AST) levels rose from 26.5 U/L to 46.5 U/L and then dropped to 37.0 U/L at last measurement (p<0.001). Alanine aminotransferase (ALT) increased progressively from 25.0 U/L to 30.0 U/L to 36.0 U/L (p=0.080). Alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) levels also increased progressively, reaching mean highs of 175.0 U/L and 202.0 U/L, respectively.

While there was no significant difference in median bilirubin levels during SARS-CoV-2 infection (p=0.813), the rate of patients with bilirubin more than twice the upper limit of normal (ULN) doubled over time (from 9.2% to 10.8% to 21.5%, p=0.086).

Non-CLD patients had similar liver enzyme elevations during early stages of COVID-19, with subsequent decreases to normal levels, while parameters of cholestatic liver injury rose steadily, with significant elevation of ALP at the time of last available values.

Thirty-one patients with CLD (47.7%) exhibited severe cholestasis (ALP/GGT >5xULN) during follow-up and 15 patients (23.1%) had laboratory signs of cholestatic liver failure during COVID-19. Moreover, 10 CLD patients (15.4%) were diagnosed with SSC during follow-up, and one patient with preexisting primary sclerosing cholangitis showed radiological and laboratory signs of disease progression after COVID-19.

Five of the 19 patients with advanced CLD had a decompensation event during follow-up (ascites: n=1; hepatic encephalopathy, n=1; and acute-on-chronic liver failure, n=3). Mortality was significantly higher in CLD patients with vs without advanced disease (57.9% vs 41.5%, p=0.085).

Compared to 431 hospitalized COVID-19 patients without CLD, the CLD patients did not have more ICU admissions or intubations or longer hospital stays, but they did have higher rates of death (41.5% vs. 28.8%; p=0.037) and liver-related death (15.4% vs. 3.5%; p<0.001).

Among CLD patients, those with elevated bilirubin after first positive SARS-CoV-2 PCR test were more frequently admitted to the ICU (91.7% vs. 32.1%; p<0.001) and intubated (91.7% vs. 26.4%; p<0.001) and had longer median hospital stay (58.0 vs. 21.0 days; p=0.022), ICU stay (47.0 vs. 21.0 days; p=0.120) and intubation duration (41.0 vs. 19.5 days; p=0.047).

By log-rank test, elevated bilirubin levels after the first positive SARS-CoV-2 PCR test were associated with shorter time to liver-related death. There was no link between liver-related mortality and elevated ALP, GGT, AST or ALT. A higher MELD score (Model for End-Stage Liver Disease) after a first positive SARS-CoV-2 PCR test also independently predicted liver-related related mortality among CLD patients.

When comparing CLD patients with COVID-19 pneumonia to a matched group of 65 CLD patients with non-COVID pneumonia, there was no difference in need for extracorporeal membrane oxygenation, prevalence of severe cholestasis, or cholestatic liver failure. However, CLD patients with COVID-19 developed SSC more often (15.4% vs. 4.6%; p=0.040), suggesting, according to the authors, "that progressive cholestasis and bile duct alterations are indeed distinct for COVID-19 in critically ill CLD patients, as these occur more frequently than in CLD patients with non-COVID-19 pneumonia."

"The sustained elevation of cholestatic parameters and bile duct alterations may be explained by multifactorial liver and bile duct injury in critically ill CLD patients with COVID-19," they wrote, adding that "development of SSC after SARS-CoV-2 infection is a relevant risk, particularly in CLD patients with metabolic risk factors and/or NAFLD/NASH etiology."

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