Figure 16.2 The pathophysiological chain of HCC development in hemochromatosis different mutations in the HFE alleles) develop hemochromatosis. In fact, not all do, and only a fraction of these progress towards cirrhosis and hepatocellular cancer (Figure 16.2). This demonstrates that further factors modulate the risk of inflammation and cancer. Nowadays, patients with early signs of hemochromatosis disease can be treated with iron chelators to prevent organ damage, cirrhosis, and cancer.

Figure 16.3 The (standard) Fenton reaction

Hemochromatosis is a comparatively rare disease, but its pathophysiology is well understood. It provides an example for other, more prevalent, but less well understood factors that cause liver cancer by a basically similar pathway through chronic inflammation and cirrhosis. The most important ones are the hepatitis viruses HBV and HCV, and alcohol abuse (Table 16.1). In a typical Central European population, «3% of all HCC cases might be associated with hemochromatosis, and 30% each with HBV, HCV, and alcohol, the remainder with other known or unknown causes. A rising incidence of HCC in industrialized countries over the last decades is mainly caused by an according increased prevalence of HCV infections. Tellingly, the rise in cancer incidence is delayed by «15 years compared to that of the viral hepatitis. So, this is the period required for development of cirrhosis and cancer.

HBV persists as a chronic infection in «10% and HCV in >50% of infected persons. In chronic viral hepatitis, hepatocytes are continuously destroyed by cytotoxic T-cells attempting to eliminate the virus and need to be replaced. Replacement of hepatocytes is partly achieved by proliferation of differentiated hepatocytes and partly, especially during continuous damage, by recruitment of liver

Table 16.1. Causes of human hepatocellular cancer

Individual factors causing hepatocellular cancer in humans* Alcohol

Hepatitis virus B Hepatitis virus C Steatosis (fatty liver)

Inherited diseases leading to chronic liver damage Hemochromatosis and other diseases leading to iron or copper overload Other causes of liver cirrhosis Aflatoxins

* Several factors may interact, often in a synergistic fashion.

stem cells. These are thought to reside in the ducts of Herring at the origin of the bile duct. Their activation can be recognized by spreading of undifferentiated small epithelial-like cells with oval nuclei ('oval cells') into the hepatic parenchymal structure. During chronic alcohol abuse, hepatocyte destruction is initiated by the substance and its metabolites.

During chronic tissue damage and inflammation, nonepithelial cells in the liver become activated and proliferate. While their activation and proliferation initially serves to support the immune response and the regeneration of the tissue, during chronic liver damage and with increasing inflammation their expansion predominates and they gradually replace epithelial structures in the organ. This process eventually manifests as cirrhosis, in which the well-organized parenchymal tissue is displaced by more disorganized and dysfunctional fibrotic tissue.

In this disturbed tissue, hepatocellular cancer may develop from liver stem cells or from more differentiated hepatocytes that are more resistant to the adverse conditions in the organ. Hepatic cancer cells are typically more resistant to viral infection, store less iron, or are less easily triggered to apoptosis by cytotoxic immune cells. So, they may be selected for their ability to survive in the cirrhotic tissue environment. Specifically, their increased resistance to apoptosis, e.g. by the CD95 pathway (^7.2), may be one reason for the primary resistance of HCC to chemotherapy (^22.2).

Hepatocellular carcinoma is preceded by several morphological alterations in the parenchymal epithelium. These were initially identified in experimental animals (Box 16.1), and later confirmed in humans. In some cases, the proliferation of liver stem cells can actually be observed. Otherwise, the first morphological stage are small dysplastic foci, which increase in size to form nodules with progressively aberrant cells. While these precursor stages remain restricted to the epithelial parenchyma, actual HCC invades interstitia and vessels and may form metastases in distant parts of the liver or in other organs. A critical stage, both biologically and clinically, appears to be reached at a tumor volume of «1 cm3. Here, angiogenesis by branches of the hepatic artery and capillaries appears to become activated and the tumor cells become more invasive. This transition is quickly followed by spreading of the cancer cells through the liver, and later to other organs.

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