Today, Italian pathologists released the liver findings from the first large series of COVID-19 autopsies as a preprint.* Their findings suggest the liver is not a major site of inflammation, but suffers from extensive effects of blood clotting, probably driven by fundamental problems with the blood clotting process or the function of the cells that make up the inner lining of the blood vessels, known as endothelial cells.
These findings come on the heels of earlier research from Italian autopsies showing that blood clots in the small arteries of the lungs appear to drive the low blood oxygen found in this disease.
Between February 1 and March 25, 230 patients died of COVID-19 in Bergamo Hospital in Bergamo, Italy. 48 of them had autopsies that included analysis of their livers. 33 out of these 48 had one or more significant preexisting condition, mainly obesity, chronic heart failure, or hypertension. They all died of respiratory failure, and none of them developed a liver disease during their hospital stay.
There were very few immune cells that had invaded the liver, consisting mainly of scattered helper T cells. This is inconsistent with a serious viral infection of the liver, and is in marked contrast to the large number of inflammatory cells that infiltrate the lungs.
The liver normally contains a large number of specialized immune cells known as Kupffer cells. These are a type of macrophage (a big cell that eats things). Kupffer cells can be activated mainly in two ways: either to be highly inflammatory, producing lots of oxidative stress to kill microbes; or to engage in a much less inflammatory process of tissue remodeling, laying down collagen in scar tissue, creating new blood cells, and cleaning up the debris of dead and dying cells. The Kupffer cells in this post-mortem analysis were highly activated along the second pathway, with many new blood vessels found in certain areas of the liver, and the Kupffer cells full of the debris of dead and dying cells.
Judging inflammation on a three point scale of mild, moderate and severe, none of the patients had severe inflammation and only one had moderate inflammation. Where inflammation existed they divided their analysis between two anatomical features of the major functional unit in the liver, the lobule, where much of the energy and detoxification occurs, and which has within it a portal area, where major blood vessels, lymph vessels, and bile ducts are clustered. 32 patients had mild portal inflammation and 23 had mild lobular inflammation. 16 patients didn't have any portal inflammation and 24 didn't have any lobular inflammation.
All of them had blood clots (thrombi) in their liver's blood vessels or clear evidence of recent blood clots.
All of them had fibrosis, the laying down of collagen-rich scar tissue, in the liver tissue as well as in the walls of the veins.
All of them had the growth of new, abnormal blood vessels.
The blood vessels were very dilated, and often herniated.
This picture is consistent with blood clots (thrombosis) blocking blood flow, causing many cells to die and get cleaned up by the Kupffer cells, and causing compensation through production of new blood vessels and abnormal dilation of existing blood vessels as an attempt to keep adequate blood flowing. Fibrosis is likely a means of poor healing of damaged tissue or structural reinforcement of tissue subject to high pressure and significant risk of damage.
The features were reminiscent of those seen in genetic defects of clotting factors and conditions of impaired blood flow within the liver.
It is possible that the virus could be impacting the endothelial cells directly, but I believe the totality of the evidence is most consistent with severe inflammation in the lung that drives systemic inflammation sufficiently to increase systemic clotting risk. However, more research is needed to clarify what might be happening in the endothelial lining of the blood vessels and other mechanisms by which the virus could be impacting organs outside the lung.
These findings underscore the major importance of blood clotting in this disease, and offer a further reason to drive attention in that direction for prevention and treatment.
Stay safe,
Chris
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*Footnotes
* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.