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Page 6 of 10 Ramadori. Hepatoma Res 2020;6:28 I http://dx.doi.org/10.20517/2394-5079.2020.43

Figure 4. Autoradiographs of SDS-PAGE-analysis of a biosynthetically, radio-actively labelled major positive acute-phase-protein (SAA),
a minor positive acute-phase (factor B) and of the major negative acute-phase protein (albumin) immunoprecipitated from the same
sample of supernatant from hepatocyte cultures treated with different amounts of recombinant IL1. Line 5 in panel A and lines 7-9 are
negative controls. The relative abundance of the different proteins released into the supernatant is demonstrated by the time of exposure
of the film to the filter containing the immunoprecipitated radioactive protein. The shortest time of exposure time was for albumin (24 h)
and the longest was SAA (21 days). While synthesis of albumin was inhibited by increasing doses of human recombinant IL-1, synthesis
of factor B and of SAA were increased at the same time in the hepatocyte reproducing the process taking place in the liver in vivo during
an acute phase situation. It is understandable that the serum concentrations of the acute-phase cytokines produced at extrahepatic sites
has to be quite high to induce changes of protein synthesis in the liver until these can become measurable. This is also the case for those
proteins whose constitutive gene-expression is almost undetectable, as is the case for SAA or CRP in humans. SAA: serum amyloid A.
1985;162:930-42. (reprinted with permission) [49]

In summary, two main mechanisms act in reducing albumin serum concentration in patients with severe
COVID-19-infection: (1) reduction in albumin synthesis due to reduced food intake; (2) inhibition of
specific mRNA-synthesis in the hepatocellular nuclei induced by the direct interaction of the cell with the
acute-phase cytokines.

The acute-phase cytokines induce up-regulation of gene-expression of several positive hepatic acute-phase
[63]
proteins, and in extrahepatic organs [Figure 5], but the changes in serum level are influenced by their
[45]
synthesis in liver cells . This mechanism is not only active in cases of tissue damage caused by bacterial, but
[64]
also by viral infections . The order of magnitude of variations in the serum level of the acute-phase proteins
caused by viral infections is lower than that induced by bacterial infections.