Bernard Portmann

A panel of recognized experts in liver transplantation pathology, hepatology, and surgery was convened for the purpose of developing a consensus document for the grading of acute liver allograft rejection that is scientifically correct, simple, and reproducible and clinically useful. Over a period of 6 months pertinent issues were discussed via electronic communication media and a consensus conference was held in Banff, Canada in the summer of 1995. Based on previously published data and the combined experience of the group, the panel agreed on a common nomenclature and a set of histopathological criteria for the grading of acute liver allograft rejection, and a preferred method of reporting. Adoption of this internationally accepted, common grading system by scientific journals will minimize the problems associated with the use of multiple different local systems. Modifications of this working document to incorporate chronic rejection are expected in the future.

BACKGROUND: End-stage cirrhosis related to hepatitic C virus (HCV) is a common reason for liver transplantation, although viremia ia known to persist in most cases. We investigated the impact of persistent HCV infection after liver transplantation on patient and graft survival and the effects of the HCV genotype and the degree of HLA matching between donor and recipient on the severity of recurrent hepatitis. METHODS: A group of 149 patients with HCV infection who received liver transplants between January 1982 and April 1994 were followed for a median of 36 months; 623 patients without HCV infection who underwent liver transplantation for end-stage chronic liver disease were used as a control group. A total of 528 liver-biopsy specimens from the HCV-infected recipients were reviewed, including 82 obtained one year after transplantation as scheduled and 39 obtained at five years as scheduled. In addition, biopsy specimens were obtained from 91 of the HCV-negative patients five years after transplantation. RESULTS: Cumulative survival rates for the 149 patients with HCV infection were 79 percent after one year, 74 percent after three years, and 70 percent after five years, as compared with rates of 75 percent, 71 percent, and 69 percent, respectively, in the HCV-negative transplant recipients (P=0.12). Of the 130 patients with hepatitis C infection who survived more than 6 months after transplantation, 15 (12 percent) had no evidence of chronic hepatitis on their most recent liver biopsy (median followup, 20 months), 70 (54 percent) had mild chronic hepatitis (median, 35 months), 35 (27 percent) had moderate chronic hepatitis (median, 35 months), and 10 (8 percent) had cirrhosis (median, 51 months). Graft loss occurred after a median of 303 days in 27 of the 149 patients, including 5 with HCV-related cirrhosis and 3 with HCV-related cholestatic hepatitis. Infection with HCV genotype 1b was associated with more severe graft injury, whereas the primary immunosuppressive regimen used and the extent of HLA mismatching between donors and recipients had no significant effect on this variable. CONCLUSIONS: After liver transplantation for HCV-related cirrhosis, persistent HCV infection can cause severe graft damage, and such damage is more frequent in patients infected with HCV genotype 1b than with other genotypes. After five years, the rates of graft and overall survival are similar between patients with and those without HCV infection.

The work of liver stem cell biologists, largely carried out in rodent models, has now started to manifest in human investigations and applications. We can now recognize complex regenerative processes in tissue specimens that had only been suspected for decades, but we also struggle to describe what we see in human tissues in a way that takes into account the findings from the animal investigations, using a language derived from species not, in fact, so much like our own. This international group of liver pathologists and hepatologists, most of whom are actively engaged in both clinical work and scientific research, seeks to arrive at a consensus on nomenclature for normal human livers and human reactive lesions that can facilitate more rapid advancement of our field.

Small, extraportal, hepatic parenchymal cells, positive for biliary-type cytokeratins, may represent hepatic stem cells, canals of Hering (CoH), and/or ductal plate remnants. We evaluated these cells 3 dimensionally in normal human liver and massive necrosis. Tissues from normal human livers and from 1 liver with acetaminophen-induced massive necrosis were serially sectioned, immunostained for cytokeratin 19 (CK19), and sequentially photographed. Images were examined to determine 3-dimensional relationships among CK19-positive cells. Immunostains for other hepatocyte and progenitor cell markers were examined. In normal livers, intraparenchymal CK19-positive cells lined up as linear arrays in sequential levels. One hundred of 106 (94.3%) defined, complete arrays within levels examined, most having 1 terminus at a bile duct, the other in the lobule, beyond the limiting plate. In massive necrosis, there were 767 individual CK19-positive cells or clusters around a single portal tract, 747 (97.4%) of which were spatially related forming arborizing networks connected to the interlobular bile duct by single tributaries. C-kit was positive in normal CoH. CK19 co-expressed with HepPar1, c-kit, and alpha-fetoprotein (AFP) in parenchymal cells in massive necrosis. Small, extraportal, biliary-type parenchymal cells represent cross-sections of the CoH that radiate from the portal tract, usually extending past the limiting plate into the proximate third of the hepatic lobule. The 3-dimensional structure of ductular reactions in massive necrosis suggests that these reactions are proliferations of the cells lining the CoH. Therefore, the CoH consist of, or harbor, facultative hepatic stem cells in humans.