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ABSTRACT: The carcinogenic process can be modulated by exposure to endogenous or environmental substance(s) acting as carcinogens or protocarcinogens. Polymorphic enzymes of cytochrome P450 (CYP) that play a role in detoxication/toxication of such substances via metabolization may account for the interpatient variability of clinical course in cancers such as hepatocellular carcinoma (HCC). Many CYP genetic polymorphisms, which may change enzyme activity, are known to exist in Japanese. The aim of the present study was to compare the frequencies of CYP polymorphisms between hepatitis C virus (HCV)-related HCC patients and healthy subjects.
Seven mutant alleles and related genotypes of CYP in 44 HCV-positive HCC patients were chosen as follows: *1C heterozygous, *1C homozygous and *1F homozygous for CYP1A2, *4A homozygous for CYP2A6, *2A or *3 heterozygous, *2A or *3 homozygous and *2A and *3 heterozygous for CYP2C19, and *10/*5 homozygous for CYP2D6. These mutant alleles have been reported to change the CYP enzyme activity in Japanese. The frequencies of the mutant alleles and genotypes were then compared with those reported in healthy Japanese.
There is no statistically significant difference in genetic mutant alleles between the two groups, except for the genotype of CYP2A6*4A homozygous. The frequency of this genotype in the HCC patients (0.144) is significantly higher than that in healthy Japanese (0.034; P < 0.05; odds ratio 3.36). The clinical significance related to HCC is unknown. Further evaluation of CYP2A6*4A (deletion type) in HCV-related HCC patients is required.
Journal of Gastroenterology and Hepatology 09/2005; 20(8):1191-7. DOI:10.1111/j.1440-1746.2005.03808.x · 3.50 Impact Factor
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ABSTRACT: Thrombocytopenia typically worsens with the progression of liver disease and can become a major clinical complication. Several mechanisms that contribute to thrombocytopenia have been proposed, including hypersplenism accompanied by increased platelet sequestration, platelet destruction mediated by platelet-associated immunoglobulins (PAIgG), and diminished platelet production stimulated by thrombopoietin (TPO). The purpose of the present study was to evaluate the role of each of these mechanisms in patients with liver disease-associated thrombocytopenia.
Twenty-nine patients with liver cirrhosis (LC), 20 of whom were hepatitis C virus (HCV)-seropositive, 29 chronic hepatitis (CH) patients, 24 of whom were HCV-seropositive, and 16 control patients without liver or hematopoetic disease were enrolled in this study. Serum TPO levels, PAIgG, and liver-spleen volumes were determined and correlation analyses were performed.
No differences in serum TPO levels were observed among the three groups. The PAIgG levels were significantly elevated in CH and LC patients (mean +/- SD: 56.5 +/- 42.3 and 144.6 +/- 113.6 ng/107 cells, respectively) compared with the controls (18.9 +/- 2.5 ng/107 cells, P < 0.001 for both). Spleen volume was significantly higher only in LC (428 +/- 239) compared with CH (141 +/- 55) and control (104 +/- 50 cm3) (P < 0.001), while liver volume was not significantly different between the three groups. Correlation analyses demonstrated a significant negative correlation between platelet count with PAIgG (r = - 0.517, P < 0.001) and spleen volume (r = - 0.531, P < 0.001), and no relationship between platelet count and serum TPO level (r = 0.076).
Serum TPO level may not be directly associated with thrombocytopenia in patients with chronic hepatitis and liver cirrhosis. In contrast, spleen volume and PAIgG are associated with thrombocytopenia in such patients, suggesting that hypersplenism and immune-mediated processes are predominant thrombocytopenic mechanisms.
Journal of Gastroenterology and Hepatology 06/2003; 18(6):638-44. DOI:10.1046/j.1440-1746.2003.03026.x · 3.50 Impact Factor
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ABSTRACT: A tendency to bleed and local vasodilation in the portal circulation are exacerbatory clinical factors in patients with liver cirrhosis. Esophageal variceal bleeding, in particular, is a frequent complication in these patients. Cirrhotic patients have been reported to show impairment of platelet aggregation and an activated fibrinolytic state, possibly with consequential lengthening of the bleeding time. Our previous study has demonstrated enhanced generation of PGI(2), a vasodilating and anti-platelet aggregating hormone, in the portal circulation of cirrhotic patients. In the present study, we compared the platelet aggregation and coagulation and fibrinolytic profiles in portal circulation with those in systemic circulation in twenty cirrhotic patients complicated with hepatocellular carcinoma. A portal blood sample was collected through a fine needle inserted percutaneously and guided ultrasonographically to the intrahepatic portal vein. Simultaneously, venous blood was drawn from a forearm vein as the systemic blood sample. Coagulation and fibrinolytic profiles were assessed by examining the extrinsic fibrinolytic system (tissue plasminogen activator (tPA), t-PA-plasminogen activator inhibitor complex), fibrinogen degeneration product, fibrinogen euglobulin lysis time, platelet count, and platelet aggregation elicited by ADP and collagen. Although fibrinolytic factors were activated in patients in the present study, there were no significant differences between the portal and systemic blood samples in all the coagulation and fibrinolytic parameters examined except for platelet aggregation. The curve of platelet aggregation response to collagen (1, 2, 10 µg/ml), but not that to ADP, shifted significantly more to the right in the portal blood compared to the systemic blood (P<0.05). This result suggested that the difference in prostaglandin generation reported previously, may cause the dissociation between collagen and ADP elicitation of platelet response in portal blood while there is no effect on other parameters in the coagulation and fibrinolytic profiles.
Hepatology Research 01/2001; 19(1):52-59. DOI:10.1016/S1386-6346(00)00078-4 · 2.74 Impact Factor
Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 08/2000; 97(7):920-4.
Gastroenterology 04/1995; 108(4). DOI:10.1016/0016-5085(95)28955-0 · 16.72 Impact Factor