The Histopathology of Regeneration in Massive Hepatic Necrosis

Abstract

Massive hepatic necrosis (MHN) is a condition that offers an opportunity to study the remarkable ability of the liver to become repopulated with hepatocytes. A maximal regenerative stimulus is expected in cases of MHN (Roskams et al. APMIS Suppl 1991;23:32-39). Sequential chronological observations, after a severe degree of liver cell loss, permit study of the human equivalent of the situation in animal models in which circulating and bone marrow-derived stem and liver progenitor cells are recruited to the hepatopoietic process. To date, the bone marrow and circulating precursors have not been identified morphologically in human material. We present data that suggest that the circulating liver progenitor could have a lymphoblastoid morphological appearance. Similar cells are seen among the cellular infiltrate of MHN. We have found that combinations of markers, such as CD117/CD133 positive CD45/tryptase negative are useful to isolate these cells using cell-sorting technology. This may facilitate their expansion in vitro and the development of their use for therapeutic purposes. In MHN, the residual portal tracts and ductular reaction with the associated lymphoid infiltrate (some of which are probably liver cell progenitors derived from the circulation) constitute the fundamental regenerative community unit in which hepatopoiesis takes place. Defining the hepatopoietic process is hindered by the lack of morphological transitional forms in the period between the progenitors within the circulation and when they assume recognizable hepatocytic form as "metaplastic" hepatocytes associated with the ductular reaction. By achieving a better comprehension of these processes of liver cell restoration, we will be better placed to accelerate liver recovery in MHN, for example by the administration of granulocyte colony stimulating factor (GCSF). Thus, more patients will be able to restore their own livers and avoid liver transplantation.

Two sides of one coin: massive hepatic necrosis and progenitor cell-mediated regeneration in acute liver failure

“…Massive hepatic necrosis is a morphological concept. The core characteristic of MHN is extensive multilobular/panacinar hepatocyte necrosis (Craig et al, 2004). MHN was previously defined according to the extent of necrosis.…”

“…MHN has many synonymous terms, for example, massive hepatic loss, acute yellow atrophy, fulminant massive necrosis, panacinar necrosis, confluent necrosis, multilobular necrosis et al (Kalk, 1959; Horney and Galambos, 1977; Craig et al, 2004). Clinically, MHN is a critical event underlying acute liver failure (ALF), a serious clinical syndrome associated with a high mortality (Sugawara et al, 2012).…”

Bromodomain and extraterminal (BET) proteins regulate biliary-driven liver regeneration

“…However, recent lineage tracing studies in mice reveal that pre-existing hepatocytes are the main source of regenerated hepatocytes in current oval cell activation models [3, 4], raising a controversy about BEC-driven liver regeneration. Detailed marker analyses of human livers with cirrhosis [5] and massive hepatic necrosis [6] strongly suggest BEC contribution to regenerated hepatocytes in the human livers. However, the origin of regenerated hepatocytes in humans is still inconclusive due to a lack of cell-lineage tracing data.…”

Massive hepatic necrosis with large regenerative nodules

“…Acute viral hepatitis is the most common and important cause of acute fulminant liver failure worldwide 1. Its prognosis varies according to the underlying etiology; for example, patients with acute hepatitis A have a more favorable outcome compared to those with acute hepatitis B, autoimmune hepatitis or Wilson's disease 2…”

“…Massive hepatic necrosis (MHN) is characterized by extensive panlobular and multilobular hepatocyte necrosis, and is the morphological counterpart of acute fulminant liver failure 1. Histopathologic examination of explanted liver specimens reveals a wide spectrum of morphological changes in the parenchyma, from areas of extensive hepatocyte loss and parenchymal collapse to areas of hepatocytic regeneration with the appearance of regenerating nodules.…”