Journal of Pathology and Translational Medicine

Original Articles

Chemotherapy-Associated Hepatopathy in Korean Colorectal Cancer Liver Metastasis Patients: Oxaliplatin-Based Chemotherapy and Sinusoidal Injury: Soo Jeong Nam, Jai Young Cho, Hye Seung Lee, Gheeyoung Choe, Ja June Jang, Yoo-Seok Yoon, Ho-Seong Han, Haeryoung Kim; Korean J Pathol. 2012;46(1):22-29. Published online February 23, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.1.22

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Background

Although chemotherapy-related hepatic injury has been reported in colorectal cancer liver metastasis (CRLM) patients, the morphologic changes caused by chemotherapeutic agents and the effect of chemotherapy on postoperative outcome remain ill-defined. A comprehensive review of the morphologic changes in the post-chemotherapy non-neoplastic liver was performed and the clinical effect of preoperative chemotherapy in CRLM patients was analyzed.

Methods

Hematoxylin-eosin, Masson's trichrome and reticulin-stained slides from non-neoplastic livers obtained from 89 CRLM patients were analyzed, and the clinicopathologic features were correlated with the status of chemotherapy exposure.

Results

Histopathologic features of sinusoidal injury (sinusoidal dilatation, centrilobular perivenular fibrosis, parenchymal extinction lesions, small vessel obliteration, and hepatocyte plate disruption) were significantly more frequent in oxaliplatin-exposed livers (p<0.05). The extent of sinusoidal dilatation was positively correlated with increasing numbers of chemotherapy cycles (p=0.022). Abnormal preoperative liver function tests were more frequently seen (p<0.05) and postoperative total bilirubin was higher in the chemotherapy group (p=0.008). Postoperative morbidity was more common in the chemotherapy group (p=0.044).

Conclusions

Sinusoidal injury is frequently seen in oxaliplatin-treated livers, and its presence, especially when extensive, should be documented in surgical pathology practice. The recognition of sinusoidal injury may provide helpful guidelines for surgeons in deciding the extent of hepatic resection.

Citations

Citations to this article as recorded by

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Correlation between Transforming Growth Factor-beta and Procollagen III with Regenerative Activity in Acute Liver Injury, and the Effect of Prostaglandin E2.: Nam Hoon Cho, Chan Il Park; Korean J Pathol. 1996;30(5):367-387.

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Abstract PDF: Transforming growth factor-beta (TGF-beta) plays an important role in hepatic fibrogenesis. It is thought to inhibit regeneration of the hepatocytes. The aim of this present study was to clarify the correlation of TGF-beta, collagen type III (PIIINP) and the regenerating activity of hepatocytes, and the effect of prostaglandin E2 (PgE2) on them in acute liver injury. Two hundred and sixteen male Sprague-Dawley rats, weighing 200g on average, were divided into six experimental groups and two control groups; group I-CCl4 only administration, group II-partial hepatectomy(PH) only, group III-PH following CCl4 administration, group IV-olive oil only administration, group V-sham operation, group VI-CCl4 administration with pretreatment of PgE2, group VII- PH with pretreatment of PgE2, and group VIII- PH following CCl4 administration with pretreatment of PgE2. Five rats were sacrificed at 12, 24, 36, 48, 96 and 168 hours after the administration of CCl4 or PH in each experimental group. The liver was tested with immunohistochemical stain for proliferating cell nuclear antigen (PCNA) and in situ hybridization for TGF-beta. Radioimmunoassay for serum PIIINP was also performed. The results were as follows: TGF-beta was expressed mainly in the perisinusoidal cells and periportal mesenchymal cells. The TGF-beta positive cells were most numerous in the combined group of CCl4 plus PH. TGF-beta expression tended to have an inverse relation, with the PCNA index in all experimental groups. The PCNA index was highest in the CCl4 only group and lowest in the combined group of CCl4 plus PH. The PH only group showed a peak PCNA index at 48 hours. In the CCl4 only group and the combined group of CCl4 plus PH, serum PIIINP appeared to increase at 12 hours or more after the expression of hepatic TGF-beta. Pretreatment of PgE2 revealed that TGF-beta precipitously disappeared at 48-96 hours after insult. PgE2 influenced the vanishing period, not the emerging time of TGF-beta and had a remarkable effect on the amount of TGF-beta especially in the PH following CCl4 administration group, which resulted in significant accentuation of PCNA indices. In conclusion, PH of the prior injured liver induces a marked increase of TGF-beta followed by a significant suppression of regeneration of the remaining liver, and PgE2 overtly suppresses the expression of TGF-beta.

Effects of Active Hexose Correlated Compounds on Drug Induced Liver Injury in Mice.: Ki Ouk Min, Hi Jeong Kwon, Eun Joo Seo, Jeana Kim, Seok Jin Kang, Byung Kee Kim; Korean J Pathol. 2000;34(7):509-515.

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Abstract PDF: AHCC (Active Hexose Correlated Compounds), which was at first extracted from cultured broth of Basidiomycotina, is known to be one of the Biological Response Modifiers (BRM). We examined the protective effects of AHCC on carbon tetrachloride (CCl4) and thioacetamide (TAA)-induced liver injury in mice. The AHCC pretreatment prevented the suppression of several physiological and biochemical parameters in the mice injected with CCl4 or TAA for 5 days. The liver weights and serum ALT and AST levels were increased by CCl4 or TAA, the degree of which was significantly reduced with the AHCC pretreatment. The AHCC pretreatment induced increasing activity of GST (glutathione s-transferase) and showed an increasing tendency of P450 and EROD (ethoxyresorufin o-dealkylation). The AHCC pretreatment also showed negative effects against the suppression of drug metabolizing enzymes, such as P450, EROD, and GST induced by CCl4 or TAA. AHCC pretreatment showed protective effects with significant inhibition of fatty change, inflammation, and necrosis in CCl4 and TAA intoxicated mice liver. The present study suggests that the protective effect of AHCC pretreatment might be related to the protection of liver from the drug induced liver injury in mice model.

The effects of Broad Spectrum Antibiotics and Endotoxin to the Carbon Tetrachloride-induced Liver Injury.: Hyun Ho Shin, O Joon Kwon, Yoon Kyung Sohn, In Soo Suh, Tae Joong Sohn; Korean J Pathol. 1992;26(4):329-337.

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Abstract PDF: This study was performed to investigate the effect of endotoxin to the CCl4-induced liver injury. Twelve Sprague-Dawley rats were intraperitoneally injected 1.6 g/kg CCl4 as control group. Another 24 rats were orally administrated 300 mg/kg of neomycin at 16 and 3 hours prior to CCl4 injection as experimental group. Twelve among them were intraperitoneally infected 1.0 mg/kg of endotoxin(E-Coli, 0111:B4, No L-2630, lipopolysaccharide, Sigma, USA) and CCl4 simultaneously for offsetting neomycin effect. The rats were sacrificed at 1, 4, 10, and 24 hours after CCl4 injection. The liver tissues from all experimental groups were observed by light and electron microscopy. The results obtained were summarized as follows: In the CCl4 only group, the hepatocytes revealed sweling of ER and mitochondria with many lipid droplet in the cytoplasm. Focal cellular necrosis was seen at the later phase. The Kupffer cells were activated and showed many cytoplasmic processes, secondary lysosomes, and vaculoles. The endothelial cells were edematous. Several neutrophils, platelets, and microthrombi were scattered in the sinusoid. In the neomycin-CCl4-endotoxin administrated group, both hepatocytic destruction and intrasinusoidal microthrombi formation were more pronounced. In the neomycin pretreated group, the hepatocytes revealed mild cellular destruction without necrosis. There is no intrasinusoidal microthrombi. According to these results, it would be concluded that the small dosage of gastrointestinal tract-derived endotoxin affects to the liver injury caused by CCl4. The synergistic effects of CCl4 and gastrointestinal tract-derived endotoxin which can not be detoxified by damaged Kupffer cells, may be more important in the pathogenesis of CCl4-induced liver injury.

Serochemical and Histopathological Observations on the Effect of Malotilate in Chronic Liver Injury Induced by Carbon Tetrachloride with or without Ethanol.: Hyoung Chun Kim, Eon Sub Park, Jae Hyung Yoo, Kye Yong Song; Korean J Pathol. 1989;23(2):223-234.

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Abstract PDF: An experimental studies were carried out to observe the protective effects of malotilate, a new antihepatotoxic agent, on the chronic hepatic injury induced by CCl4 with or without ethanol. The rats used weighed about 200g were divided into 2 groups, 4 weeks & 8 weeks. Each group was given by orally with malotilate, 100 mg/kg, once a day, and was injected by subcutaneously with CCl4 1.5 mg/kg in a mixture with olive oil twice a week. Aqueous ethanol (20%) was administered in drinking water daily. The serochemical and histopathological studies were carried out in each experimental group. The results were as follows: 1. The chronic liver injuries induced by CCl4 with or without ethanol were significantly ameliorated by normalize serum values GOT, GPT. Alkaline phosphatase, Cholesterol, HDL-Cholesterol, and gamma glutamyl transpeptidase. 2. In Group of 4 weeks, malotilate manifested protective effects by significant inhibition of fatty changes, spotty necrosis and fibrosis in CCl4-intoxicated liver with or without additional ethanol. 3. In group of 8 weeks, malotilate significantly imoproved fatty changes, fibrogenic activity in the group administered with CCl4, followed by ethanol.

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