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Yale: Strong link between abnormal liver tests and poor COVID-19 outcomes

Researchers at the Yale Liver Centre found that patients with COVID-19 presented with abnormal liver tests at much higher rates than suggested by earlier studies. They also discovered that higher levels of liver enzymes – proteins released when the liver is damaged – were associated with poorer outcomes for these patients, including ICU admission, mechanical ventilation, and death.

Previous studies in China found that approximately 15% of patients with COVID-19 had abnormal liver tests. The Yale study, which looked retrospectively at 1,827 COVID-19 patients who were hospitalised in the Yale New Haven Health system between March and April, found that the incidence of abnormal liver tests was much higher – between 41.6% and 83.4% of patients, depending on the specific test.

In all, the Yale researchers examined five liver tests, looking at factors such as elevations in aspartate aminotransferase (AST) and alanine transaminase (ALT), which indicate liver cell inflammation; an increase in bilirubin, which indicates liver dysfunction; and increased levels of alkaline phosphatase (ALP), which may indicate inflammation of bile ducts.

Although the researchers do not know why the incidence of abnormal liver tests was so much higher than in previous studies from China, senior author Dr Joseph Lim, professor of medicine and director of the Yale Viral Hepatitis Programme, said other health differences between the Chinese and US populations could account for it. "We can speculate that US patients may have an increased rate of other risk factors such as alcoholic or non-alcoholic fatty liver disease," he said.

Liver disease is widespread in the US population. Dr Michael Nathanson, the Gladys Phillips Crofoot professor of medicine (digestive diseases), professor of cell biology, director of the Yale Liver Centre, and a co-author of the study, said: "In the US, close to one-third of people have fatty liver disease, and several million people have chronic hepatitis B or C."

Because the Yale researchers had access to patients' health records, they were also able to look at their liver tests prior to being diagnosed with COVID-19. Approximately one-quarter of patients in the study had abnormal liver tests prior to being admitted for the virus. But regardless of whether patients came to the hospital with existing liver problems or developed them during their COVID-19-related hospitalisation, a strong association was observed between abnormal liver tests and the severity of the COVID-19 cases, the researchers said.

Rather than the liver itself driving poorer outcomes in COVID-19 patients, the organ is more likely "a bystander" affected by the hyperinflammation associated with COVID-19 and by the side effects of related treatments, Nathanson said.

The study noted a relationship between drugs used to treat severe COVID-19 and liver damage, most significantly the drug tocilizumab.

"We observed a strong association between the use of COVID-19 medications and abnormal liver tests," said Lim, but added that they could not confidently tease out that the abnormal tests were due to "drug-induced liver injury" as opposed to the disease.
The researchers have additional clinical and lab-based studies underway to further understand COVID-19's impact on liver pathology. Nathanson noted that as one of only four National Institutes of Health-sponsored liver centres in the country, the Yale Liver Centre is uniquely positioned to advance this research.

Additional Yale researchers involved in the study include lead author and internal medicine resident Dr Melanie Hundt; biostatistician Yanhong Deng, co-director of analytics at the Yale Centre for Analytical Sciences; and Maria Ciarleglio, associate professor at the Yale School of Public Health.

The COVID‐19 pandemic, caused by the SARS‐CoV‐2 virus, is associated with significant morbidity and mortality due to pneumonia, acute respiratory distress syndrome (ARDS) and multiorgan failure. Liver injury has been reported as a non‐pulmonary manifestation of COVID‐19 but characterization of liver test abnormalities and their association with clinical outcomes is incomplete. We conducted a retrospective cohort study of 1827 patients with confirmed COVID‐19 who were hospitalized within the Yale‐New Haven Health System (YNHHS) between March 14, 2020 and April 23, 2020. Clinical characteristics, liver tests (AST, ALT, ALP, TBIL, albumin) at three time points (pre‐infection baseline, admission, peak hospitalization), and hospitalization outcomes (severe COVID‐19, ICU admission, mechanical ventilation, death) were analyzed. Abnormal liver tests were commonly observed in hospitalized patients with COVID‐19, both at admission (AST 66.9%, ALT 41.6%, ALP 13.5%, TBIL 4.3%) and peak hospitalization (AST 83.4%, ALT 61.6%, ALP 22.7%, TBIL 16.1%). Most patients with abnormal liver tests at admission had minimal elevations 1‐2x ULN (AST 63.7%, ALT 63.5%, ALP 80.0%, TBIL 75.7%). A significant proportion of these patients had abnormal liver tests pre‐hospitalization (AST 25.9%, ALT 38.0%, ALP 56.8%, TBIL 44.4%). Multivariate analysis revealed an association between abnormal liver tests and severe COVID‐19, including ICU admission, mechanical ventilation, and death; associations with age, male gender, BMI, and diabetes mellitus were also observed. Medications used in COVID‐19 treatment (lopinavir/ritonavir, hydroxychloroquine, remdesivir, and tocilizumab) were associated with peak hospitalization liver transaminase elevations >5x ULN.
Conclusion: Abnormal liver tests occur in most hospitalized patients with COVID‐19 and may be associated with poorer clinical outcomes.

Melanie A Hundt, Yanhong Deng, Maria M Ciarleglio, Michael H Nathanson, Joseph K Lim


[link url=""]Yale University material[/link]


[link url=""]Hepatology abstract[/link]

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