Dear Colleagues,

This Special Issue is the actualized continuation of our 2019 Special Issue “Liver Damage and Repair”.

The nonalcoholic fatty liver disease (NAFLD) "pandemic" and the possible development of liver fibrosis, cirrhosis and liver cancer underline the need to study the mechanisms of liver tissue damage and repair mechanisms, which is more urgent than it has ever been before. In fact, although the development of effective antiviral drugs has reduced the role of hepatitis viruses in liver damage, the incidence of liver cancer is growing worldwide.

The liver is a “frontier” organ located between two different “worlds”. The first world is the “external world”, which comprises all the nutrients necessary for normal growth and functioning of the body.

Special mention should be given to the importance of the liver and its relationship with nutritional proteins. In fact, the liver has a vital need for amino acids delivered by the portal blood and produces most plasma proteins. The most vital of them is albumin, which makes up 50–60% of the serum proteins, but it is even more abundant in the interstitial fluid (60% of the total amount in the body). On the other hand, the liver has to control potentially dangerous components, such as excess calorie intake, alcoholic beverages, bacteria, bacterial components, viruses, xenobiotics, etc., introduced daily into the body via food through the alimentary tract. The second world is the “internal world”, which depends on the delivery of energy sources, hormones and minerals to keep the body functioning under normal and “emergency” conditions. Under normal conditions, the liver (hepatocytes) takes up the elements from the nutrients absorbed through the small intestine and the waste (Kupffer cells) from the large intestine, both reaching the liver through the portal blood. From the arterial blood of the systemic circulation, the liver takes up xenobiotics (hepatocytes) and “waste” material such as aged erythrocytes, corpuscular matter and microorganisms reaching systemic circulation through the blood (Kupffer cells) and hormones from the adrenal glands, thyroid and from the hypophysis (hepatocyte). The most important cells physiologically involved in liver function are the hepatocytes and the liver macrophages—the Kupffer cells. Although the functional “plasticity” of the liver is such that it can clear large amounts of noxious material, when the quality or quantity of the “waste” overcomes the intracellular defense mechanisms, it can lead to recruitment of inflammatory cells and to hepatocellular damage. We have learned a great deal about the function of liver cells not only by establishing primary cultures of the different cell populations from the liver but also by studying different changes in gene expression in the liver during acute-phase situations induced at extrahepatic sites but also in the liver itself. Under acute-phase conditions, genes controlling structural or secretory proteins temporarily but dramatically change their expressions. Interactions between the liver and the bone marrow or the endocrine network become evident and their modulation return to normal after the emergency situation is under control. There are situations where the liver defense mechanisms are overwhelmed and inflammatory cells are recruited through the release of chemokines, and hepatocytes die.

The damaged cells are then cleared by the mononuclear phagocytes and restitutio ad integrum takes place. In cases of continuous exposure of the liver to the noxious agents and to inflammatory cells, replacement of the damaged cells with healthy ones is no longer possible and structural tissue changes become necessary; liver fibrosis progresses to cirrhosis. As a consequence, the hepatic blood supply switches from mainly portal blood to arterial blood from the hepatic artery. This leads to the capillarization of the sinusoids in the remaining “restructured” liver tissue. Portal blood then reaches the vena cava through collateral vessels of the portal venous system, which develop into true varices in the lower esophagus and stomach. This means that there is reduction in the blood flow in the portal vein and an increase in blood volume in the portal system, leading to a reduction in the systemic blood volume.

However, if the noxious agent(s) is eliminated, a partially reversible stage, accompanied by a partial functional recovery, can follow. If not, cirrhosis can further progress to irreversible shrinkage of the organ. Functional activity is then strongly reduced to a minimum (rest), which is provided by the maximally engaged remaining parenchymal and nonparenchymal cells. This functional capacity can be further reduced by the persistence of inflammatory infiltration and ongoing cellular damage. Under this condition, the risk of cancer development reaches 5–8%/year and decompensation symptoms become apparent.

Suggested topics:

1. Nutrition and the liver: how can we decide alcoholic and nonalcoholic?
2. The liver, proteins and blood
3. Iron, copper, the liver and bone marrow.
4. The liver and the endocrine system in health and
5. Hepatotropic viruses and liver diseases: clinics and liver pathology.
6. Liver and radiobiology: just another damaging agent?
7. Intracellular defense mechanisms in liver cells (hepatocytes, Kupffer cells).
8. Cellular pathology in acute and chronic liver damage of different origins in human liver.
9. Mechanisms of inflammation in acute and in “chronic” liver
10. Mechanisms of damage and repair: ischemia-ripe fusion
11. Fibrosis and cirrhosis: mechanisms of development and clinical consequences.
12. Change in the portal and systemic blood volumes in the sick
13. How can we stop fibrosis development and when does it make sense?
14. Tumor development: what is special about the liver?

Prof. Dr. Giuliano Ramadori
Guest Editor

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