Mortality in COVID-19 Does Not Appear to Be Driven by Liver Failure
The FLARE Four
- Elevated liver function tests are common in hospitalized patients with COVID-19 and are associated with more severe disease in observational studies
- Transaminases are far more likely to be elevated than alkaline phosphatase or total bilirubin, with aspartate transaminase often greater than alanine transaminase; these elevations are generally mild
- There are numerous hypotheses about why liver function tests become elevated, but it's not known exactly how COVID-19 influences the liver
- It appears that severe liver injury from COVID-19 is rare and that liver failure does not drive mortality
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Elevated liver function tests (LFT) are common in patients hospitalized with COVID-19, and occasionally the values are high enough to trigger clinical concern. In a fast literature update posted on May 6, 2020, Patricia P. Bloom, MD, a fellow in Gastroenterology at Massachusetts General Hospital, reviews what's known so far about the causes and consequences of abnormal LFTs in COVID-19.
Patterns of LFT Results
On admission, transaminases are by far the values most likely to be elevated, with aspartate transaminase (AST) often greater than alanine transaminase (ALT). These elevations are often mild and may even fall within the normal range.
In the largest COVID-19 study that investigated LFTs, 5,771 adults had elevated AST on admission and throughout hospitalization. ALT peaked above the upper limit of normal within 10 to 15 days of admission in the group with severe disease. Alkaline phosphatase rose but generally stayed normal; fluctuations in total bilirubin were mild.
Possible Causes of Elevated LFTs
- Muscle injury — Case reports have described rhabdomyolysis with elevated AST in COVID-19
- Hepatic steatosis — The single published liver biopsy of a COVID-19 patient showed microvesicular steatosis
- Microthrombosis — Abnormal coagulation markers have been seen in COVID-19. Ischemia is a known cause of AST-predominant LFT elevation, and microthrombotic events could contribute to liver injury
- Direct viral infection — ACE2, the major receptor for SARS-CoV-2, is expressed in the liver
- Hepatotoxic drugs — Many COVID-19 patients are started on potentially hepatotoxic therapies (e.g., acetaminophen, azithromycin, lopinavir/ritonavir, remdesivir, statins); the series of 5,771 patients showed a significant association between peak liver enzymes and use of antibiotics, antivirals or antifungals
LFTs and Outcomes
In nearly every cohort reported, admission LFTs were higher in COVID-19 patients who did poorly. Still, elevation was often mild.
Two published cases describe severe liver injury in COVID-19 patients:
- One patient's transaminases reached ALT 7590 U/L and AST 1445 U/L, but the paper does not report the clinical context, presence of overt liver failure or outcomes
- A patient with HIV infection presented with AST 1230 U/L and ALT 697 U/L; these abnormalities could only be attributed to COVID-19 but resolved spontaneously
No case of liver failure or dysfunction leading to death has been attributed directly to COVID-19.
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