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Acer tegmentosum Maxim., commonly known as Manchurian stripe maple, is a deciduous tree belonging to the family of Aceraceae and has been traditionally used in folk medicine for its remedial effects in liver diseases and traumatic bleedings. With a growing body of experimental evidence for its pharmacological efficacies, such as neuroprotective, hepatoprotective, antioxidant, and anti-inflammatory activities, A. tegmentosum has gradually gained popularity as a health supplement and functional food. However, the large part of essential toxicity information still remained lacking despite the possibility of mutagenic potentials as previously suggested, posing safety concerns for human consumption. In this study, we evaluated 90-day repeated oral toxicity of A. tegmentosum Maxim. water extract (ATWE) in SD rats with acute toxicity assessment in beagle dogs, and reevaluated genotoxicity using a combination of in vitro and in vivo assays. During the oral study period, ATWE did not cause toxicity-related clinical signs and mortality in rodents without adverse effects observed in the analysis of hematology, serum biochemistry, and histopathology, establishing >5,000 mg/kg BW as the NOAEL. In addition, doses up to 5,000 mg/kg BW did not cause acute toxicity in beagle dogs. When assessed for genotoxicity using bacterial reverse mutation, chromosome aberration, and micronucleus formation, ATWE showed lack of mutagenicity and clastogenicity. These results demonstrated that AWTE was safe in the present preclinical study for systemic toxicity and genotoxicity at the tested doses, providing a guideline for safe use in humans.

Although it is known that steatotic livers have a reduced ability to regenerate, most individuals with steatosis show generally benign prognosis. We hypothesized that a proliferative blockade in steatotic hepatocytes results in the compensatory expansion of hepatic progenitor cells (HPC) during fatty liver regeneration. Fifty-four cases of living donor liver transplantation (LDLT) with a liver biopsy performed at the postoperative 10th day were examined. HPC were counted by immunofluorescence histochemical dual-staining technique using cytokeratin 7 and Ki-67, and the replicative arrest of hepatocytes was assessed by p21 immunohistochemistry. The degree of ductular proliferation during regeneration 10 days after LDLT correlated both with the degree of steatosis and the number of HPC ( P < 0.001). There was no difference in the average number of HPC and the replicative arrest index between donors with or without steatosis before LDLT ( P = 0.111 and P = 0.062). However, degree of steatosis correlated with both the expansion of HPC and the replicative arrest index during liver regeneration 10 days after LDLT ( P < 0.001 and P < 0.001, respectively). Moreover, increased replicative arrest was strongly associated with HPC expansion ( P < 0.001). In conclusion, the compensatory expansion of HPC as a result of impaired hepatocyte replication occurred during steatotic liver regeneration after LDLT. [ABSTRACT FROM AUTHOR]

There is no agreement regarding the treatment of early allograft rejection (EAR) in adult living donor liver transplantation (LDLT). A protocol biopsy was performed in 62 adult LDLT recipients. Twenty-one patients (33.9%) had histological evidence of EAR. Of these, 14 patients had biochemical abnormalities and seven patients had no associated biochemical abnormalities. None of the seven patients with subclinical EAR (11.3% of the entire study population) were treated, and no subsequent rejection was observed. Gender mismatch (female-to-male) was the single independent risk factor for histological EAR [odds ratio (OR) = 13.458; 95% confidence interval (CI), 1.836–98.649] and the cumulative probability for a subsequent rejection was higher in patients with EAR (OR = 11.085; 95% CI, 1.221–100.654). However, the actuarial 1 year patient and graft survival rate in patients with EAR (81.0% and 85.5%) were similar to those without EAR (92.7% and 97.25%; P = 0.127 and 0.302, respectively). The presence of an initial biochemical abnormality was an independent risk factor for both a decreased patient survival (OR = 5.827; 95% CI, 1.095–31.017; P = 0.039) and graft loss (OR = 20.646; 95% CI, 2.044–208.524; P = 0.010). Subsequent rejection developed more frequently in patients with EAR. However, the survival is not determined by the presence of EAR but by the presence of a biochemical abnormality. [ABSTRACT FROM AUTHOR]

A clear understanding of the mechanisms in steatotic livers that trigger cholestasis or hyperbilirubinemia after living donor liver transplantation (LDLT) remains elusive. We hypothesized that microarchitectural disturbance might occur within regenerating steatotic livers without impairment of hepatic proliferative activity. Liver biopsy specimens from 67 LDLT recipients taken at the 10th postoperative day were scored for the numbers of portal tracts per area (nPT/A) of liver tissue and for intrahepatic cholestasis, and immunostained by proliferating cell nuclear antigen (PCNA) and Ki-67. The preoperative degree of macrovesicular steatosis (MaS) was independently associated with cholestasis after LDLT ( P < 0.001). Serum total bilirubin results on the 1st, 3rd, and 7th days post-LDLT in MaS+ (5–30% of MaS; n = 37) patients were significantly higher than those in MaS− (<5% of MaS; n = 30) patients ( P = 0.030, 0.042, and 0.019, respectively). Mean numbers of positively stained hepatocytes were 53.1 ± 12.0 in patients with MaS and 48.0 ± 17.1 in those without MaS by PCNA ( P = 0.390), and 24.4 ± 10.5 and 24.0 ± 14.0 by Ki-67 ( P = 0.940). However, a significant negative correlation was found between the degree of MaS and nPT/A ( P = 0.013), and nPT/A was correlated with the grade of histological cholestasis ( r = 0.350, P = 0.039). Intrahepatic cholestasis and hyperbilirubinemia after LDLT could be caused by scanty morphologic change of portal tract during steatotic liver regeneration. [ABSTRACT FROM AUTHOR]

The efficacy of auxiliary partial orthotopic liver transplantation (APOLT) to overcome the problems associated with a markedly steatotic graft in a living donor has not been fully explored. We have recently performed APOLT in a patient with alcoholic liver disease, where the only potential candidate donor was affected by 50% macrovesicular steatosis and 30% microvesicular steatosis. The recipient's left liver was resected and the donor's left liver, corresponding to a 0.46% graft-to-recipient weight ratio, was orthotopically transplanted. The postoperative course of this patient was uneventful, except for a transient large amount of ascites. Native liver volume in the recipient serially decreased, and the volume of the graft serially increased after transplantation. Four months after transplantation, the donor and recipient are doing well with a normal liver function. In conclusion, APOLT may be a feasible solution for a markedly steatotic living donor graft in patients with alcoholic liver disease. [ABSTRACT FROM AUTHOR]