Immunolocalization of regenerating cells after submassive liver necrosis using PCNA staining

Abstract

Little data exist on the proliferative state of liver cells and its relationship with various morphological findings in acute liver failure (ALF) in man. In this study we used the monoclonal antibody NCL-PCNA (clone PC-10) against the proliferating cell nuclear antigen (PCNA) to detect cycling cells in paraffin sections of 3 normal livers, 14 post-mortem needle-specimens of submassive hepatic necrosis (SHN) due to paracetamol overdosage (POD), and 10 hepatectomy specimens obtained at transplantation in patients with acute or subacute liver failure of presumed viral aetiology. In normal livers, only occasional sinusoid-lining cells were stained, whereas in SHN following POD or presumed viral hepatitis, hepatocytes of variable morphology showed significant immunoreactivity. Following POD, immunoreactivity was higher in samples taken within 5-6 days than in those obtained at 9-11 days, a pattern reminiscent of the decrease in the rate of regeneration, previously documented after partial hepatectomy in humans. Immunolabelled hepatocytes were aggregated in multiacinar 'nodules' in cases with a map-like distribution of collapsed and non-collapsed parenchyma. Ductules demonstrated comparatively less staining, but extensive labelling was exceptionally found in areas of complete hepatocellular dropout. In these areas, small elongated cells with strongly PCNA-positive ovoid nuclei, forming periportal sprouting cords or incorporated into the lining of ductules, were most remarkable in that they closely resembled 'oval cells' described in animal studies.

Auxiliary transplantation for acute liver failure: Histopathological study of native liver regeneration

“…This confirms previous observations in humans. [7][8][9][10][11] Ductular reaction tends to be mild in degree and fades over a period of approximately 1 to 2 weeks. Hepatocytes derived from hepatic progenitors do not appear involved in the regenerative process.…”

“…14 Although in acetaminophen-induced injury proliferation of mature hepatocytes seems to be the main regenerative mechanism, this cannot be accurately assessed in seronegative liver failure because of the patchy nature of the initial damage leading to considerable sampling variation in subsequent core needle specimens. Assessment of cell proliferation by proliferating cell nuclear antigen immunostaining of explanted livers with map-like injury 7 has shown that in the nodular areas of parenchyma, hepatocellular nuclear staining is heterogeneous and maximal in areas adjacent to confluent cell loss or to portal tracts. This ranges from 10% to 50%, whereas in areas of multiacinar cell dropout, 10% to 35% of ductular epithelial cells are cycling; this suggests that expansion of a stem cell or progenitor cell compartment may be the regenerative response in areas of complete hepatocyte loss.…”

Parenchymal and Nonparenchymal Cellular Responses in Human Hepatic Regeneration

“…The marked increase in PCNA-positive hepatocytes in early hepatic regeneration indicates that they are activated to repair intracellular damage as well as prepare to replicate because PCNA is involved in DNA repair and replication (13,(19)(20)(21). Sinusoidal PCNA-positive cells are considered to be activated Kupffer cells or macrophages on the basis of their location and nuclear shape as indicated previously (19).…”

“…However, it was impossible in human cases ethically as well as practically due to the limitation of obtaining the samples. Thus broad spectrum of histopathologic changes during hepatic regeneration have been rarely documented in human livers (4,11,13,14).…”

Relationship between hepatocyte proliferative activity and liver functional reserve in human cirrhosis

“…7,15,[33][34][35] This correlates with the low PCNA-LI observed in normal livers. The current study shows a dramatic increase of hepatocyte proliferative activity in most cases of cirrhosis.…”