Hepatitis: Park YN

Park YN, Roncalli M. · Department of Pathology, Center for Chronic Metabolic Disease, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea. · J Hepatol. · Pubmed #16982109 No free full text.

Abstract: Large cell change (LCC) is a noncommittal term used today to indicate liver cell dysplasia of the large cell type. Dysplasia was deleted from the original definition because not enough evidence has been collected over time to support premalignancy. LCC is a microscopically well-defined lesion, usually found in cirrhosis, whose origin, natural history, and fate are still debated. Different morphologic, phenotypic, molecular and clinical studies have been performed to address the issue of the dysplastic versus reactive nature of this lesion. The aim of this review is to critically evaluate the contributions to the topic and to underline that the heterogeneity of the lesion is an important issue to be taken into account for our biological understanding of it. While LCC has important morphologic analogies in experimental liver carcinogenesis, no comparable lesions are known in solid non-liver parenchymal human tissues that morphologically feature dysplasia, but in which it is uncertain whether the lesions are reactive or preneoplastic. The debate over the lesion may be useful in learning the actual limits of morphology and how additional information can be gained by looking inside the cells.

Kim do Y, Kim SU, Ahn SH, Park JY, Lee JM, Park YN, Yoon KT, Paik YH, Lee KS, Chon CY, Han KH. · Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea. · Dig Dis Sci. · Pubmed #19005758 No free full text.

Abstract: BACKGROUND: It is difficult to differentiate early compensated cirrhosis from chronic hepatitis solely by clinical features. The aim of this study was to assess the usefulness of liver stiffness measurement (LSM) for detection of early compensated liver cirrhosis in chronic hepatitis B (CHB). METHODS: Ninety-one consecutive CHB patients who underwent liver biopsy (LB) and LSM were recruited. All patients did not fulfill the clinical criteria for cirrhosis. The cutoff of LSM for cirrhosis was 10.3 kPa. RESULTS: All patients were divided into either group A (cirrhosis) or group B (CHB) according to LB result. The median LSM values of groups A and B were 11.8 and 7.6 kPa, respectively (P < 0.001). The sensitivity, specificity, positive predictive value, and negative predictive value of LSM in predicting cirrhosis were 0.59, 0.78, 0.68, and 0.72, respectively. The area under the receiver operating characteristics curve (AUROC) of LSM was 0.803, whereas the AUROCs of aspartate to alanine aminotransferase ratio (AAR) and aspartate aminotransferase to platelet ratio index (APRI) were 0.488 and 0.723, respectively. CONCLUSIONS: LSM showed an acceptable diagnostic accuracy for detecting early compensated cirrhosis in CHB.

Kim HR, Rha SY, Cheon SH, Roh JK, Park YN, Yoo NC. · Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seodaemun-Ku, Seoul, Korea. · Ann Oncol. · Pubmed #19179547 No free full text.

Abstract: BACKGROUND: Primary hepatic angiosarcoma is a very rare malignancy with a poor prognosis. While surgical resection has been validated as curative choice, most cases are diagnosed too late for resection. Nonetheless, treatment protocols have not been established and also there are very few reports on the clinical features and treatment outcomes. PATIENTS AND METHODS: Among 11,939 patients diagnosed with primary hepatic tumors from January 1985 to December 2007 at two centers, five patients were diagnosed with primary hepatic angiosarcoma. We analyzed patients' demographics, tumor characteristics, treatment modality, and outcomes using imaging, serology, and pathology. RESULTS: All five patients were diagnosed at advanced stage with distant metastases. The most common symptom was abdominal pain. The levels of the tumor markers were within the normal range and serological tests were negative for hepatitis B and C viruses. Two of four patients who received chemotherapy died <3 months after diagnosis, but the other two patients survived >6 months. CONCLUSIONS: A combination of chemotherapy resulted in an improved outcome for two of four patients, suggesting the potential usefulness of palliative chemotherapy to improve survival. This case study may aid in planning chemotherapy for patients with advanced hepatic angiosarcoma.

Kim SU, Ahn SH, Park JY, Kang W, Kim do Y, Park YN, Chon CY, Han KH. · Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. · J Clin Gastroenterol. · Pubmed #18987556 No free full text.

Abstract: GOAL: To investigate the performance of liver stiffness measurement (LSM) in combination with available noninvasive markers in hepatitis B virus-related chronic liver disease. BACKGROUND: Few noninvasive methods are available for predicting liver cirrhosis in chronic hepatitis B (CHB). STUDY: Between January 2006 and June 2007, we studied 130 consecutive treatment-naive CHB patients who underwent liver biopsy (LB) and LSM. The aspartate to alanine aminotransferase ratio, age-platelet index (API), aspartate aminotransferase to platelet ratio index (APRI), LSM, and their combinations were compared with liver histology. RESULTS: The API, APRI, and LSM, but not the aspartate to alanine aminotransferase ratio, correlated significantly with liver cirrhosis (all P<0.001). The diagnostic accuracy of LSM and API exceed that of the other diagnostic methods for predicting liver cirrhosis (area under the receiver operating characteristic curve=0.840 and 0.818). When LSM was combined with API and APRI, the diagnostic accuracy was improved markedly (area under the receiver operating characteristic curve =0.871, and 0.846). When both LSM and API results were in agreement, LB confirmed them in 89.1% (41/46) of cases for liver cirrhosis. LB could have been avoided in 41 (31.5%) of the 130 patients who were examined for the potential diagnosis of liver cirrhosis. CONCLUSIONS: The combination of LSM and API can avoid unnecessary invasive LB procedures in CHB patients.

Lee JE, Oh BK, Choi J, Park YN. · Department of Pathology, Center for Chronic Metabolic Disease, Institute of Gastroenterology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-gu, Seoul, 120-752, Korea. · Int J Cancer. · Pubmed #18449889 No free full text.

Abstract: Telomeric 3' overhang is a key component of telomere structure, but little is known about its role in hepatocarcinogenesis. We examined the 3' overhang and telomere length, mRNA levels of hTERT, POT1, TRF1 and cytokeratin 19 (CK19) in 41 hepatitis B virus (HBV)-related hepatocellular carcinomas (HCCs) and adjacent non-HCCs of B viral chronic hepatitis/cirrhosis. 3' overhang length was positively correlated with telomere length (p < 0.001). In non-HCCs, the 3' overhang shortened with increasing age (p = 0.043). Twenty-six HCCs had shorter and 15 HCCs had longer 3' overhangs than the adjacent non-HCCs. The mRNA levels of hTERT, POT1 and TRF1 were upregulated in HCCs than in non-HCCs. HCCs with lengthened 3' overhangs expressed higher hTERT mRNA levels than those with shortened 3' overhangs, when compared to 3' overhangs in non-HCCs (p = 0.044). POT1 and TRF1 showed no significant difference according to the 3' overhangs. HCCs with long 3' overhangs had higher mitosis (p = 0.046) and more frequent multipolar mitosis compared to those with short 3' overhangs (p = 0.034). HCCs with high cytokeratin 19 mRNA levels, a marker for hepatic progenitor cells, had longer 3' overhangs than HCCs with low cytokeratin 19 mRNA levels (p= 0.019). In conclusion, the 3' overhang erosion might be closely related to the number of cell divisions in telomerase-negative hepatocytes of chronic hepatitis/cirrhosis. In telomerase-positive HCCs, an altered 3' overhang are involved in HBV-related hepatocarcinogenesis and hTERT might be involved in regulation of 3' overhang.

Choi GH, Ju MK, Kim JY, Kang CM, Kim KS, Choi JS, Han KH, Park MS, Park YN, Lee WJ, Kim BR. · Department of Surgery, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul, Korea. · J Korean Med Sci. · Pubmed #18437023 links to  free full text

Abstract: We report on a case of hepatic splenosis. A 32-yr-old man underwent a splenectomy due to trauma at the age of 6. He had been diagnosed as being a chronic hepatitis B-virus carrier 16 yr prior to the surgery. The dynamic computer tomography (CT) performed due to elevated serum alpha-fetoprotein (128 ng/mL) demonstrated two hepatic nodules, which were located near the liver capsule. A nodule in Segment IVa had a slight enhancement during both the arterial and portal phases, and another nodule in Segment VI showed a slight enhancement only in the portal phases. Dynamic magnetic resonance imaging (MRI) of the mass in Segment VI showed enhanced development in the arterial phases and slight hyperintensivity to the liver parenchyma in the portal phases. These imaging findings suggested a hypervascular tumor in the liver, which could be either focal nodular hyperplasia, adenoma, or hepatocellular carcinoma (HCC). Even though these lesions were diagnosed as HCC, some of the findings were not compatible with typical HCC. On dynamic CT and MRI, all lesions showed a slight arterial enhancement and did not show early venous washout. All lesions were located near the liver capsule. These findings, along with a history of splenectomy, suggested a diagnosis of hepatic splenosis.

Koo JS, Kim H, Park BK, Ahn SH, Han KH, Chon CY, Park C, Park YN. · Department of Pathology, Brain Korea 21 Project for Medical Science, Seoul, Korea. · J Clin Gastroenterol. · Pubmed #18277883 No free full text.

Abstract: GOALS: We aimed to determine whether the presence of large liver cell dysplasia (LLCD) and/or small LCD (SLCD) in chronic hepatitis B is a risk factor for hepatocellular carcinoma (HCC) development. BACKGROUND: A close relationship between LLCD/SLCD and hepatitis B virus has been observed and SLCD has been proposed to be a putative precursor of HCC, whereas the significance of LLCD is still controversial. STUDY: One hundred eighty-one patients with chronic hepatitis B who underwent needle liver biopsy were evaluated for the presence of LLCD/SLCD. The predictive value of LLCD/SLCD for HCC development was assessed. RESULTS: LLCD and SLCD were present at initial biopsy in 82 (45%) and 17 (9%) patients, respectively. During the mean follow-up of 115+/-48 months, 19 (10%) cases were diagnosed of HCC, of which 13 (76%) and 3 (17%) cases had demonstrated LLCD and SLCD, respectively, at initial evaluation. The patients with LLCD showed a significantly higher cumulative probability of HCC development than those without LLCD (P=0.016). The risk of HCC development in the presence of LLCD was approximately 3-fold, with positive and negative predictive values of 15.9% and 94.9%, respectively. The patients with SLCD showed no significant difference in cumulative probability of HCC development compared with those without (P>0.05). CONCLUSIONS: LLCD in chronic hepatitis B is considered to be one of the risk factors for HCC development and its presence may help to identify a high-risk subgroup of patients requiring more intensive screening for HCC.

Kang JK, Cheong JY, Cho SW, Cho JH, Park JS, Kim YB, Kim DJ, Hwang SG, Yang JM, Park YN. · Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea. · Korean J Hepatol. · Pubmed #18159150 links to  free full text

Abstract: BACKGROUND AND AIMS: FibroScan is a new medical device that noninvasively measures liver stiffness. The aim of this study was to assess the accuracy of the liver stiffness measurement by FibroScan for making the diagnosis of liver fibrosis in patients with chronic viral hepatitis. METHODS: We studied 103 patients with chronic viral hepatitis B or C and they underwent FibroScan and liver biopsy between October 2005 and August 2006. Liver fibrosis was staged on a 0-4 scale according to the Korean Society of Pathologists Scoring System. The diagnostic accuracy was assessed by analysis of the receiver operator characteristics (ROC). RESULTS: The liver stiffness was 3.5-57.1 kPa (mean: 11.8, SD: 8.9). The mean value of liver stiffness in each fibrosis stage group (F1, F2, F3 and F4) was 5.8+/-1.8 kPa, 11.3+/-6.8 kPa, 11.8+/-6.0 kPa and 23.4+/-16.5 kPa, respectively. Liver stiffness measured by FibroScan showed reliable correlation with the liver fibrosis stage as confirmed by liver biopsy (r=0.56, p<0.001). The AUROC (95% CI) of > or = F2, > or = F3 and F4 was 0.93 (0.86-0.99), 0.72 (0.62-0.82) and 0.80 (0.67-0.92), respectively. The sensitivity and specificity of 7.5 kPa, which was the cutoff value for > or = F2, was 84% and 90%, respectively. CONCLUSIONS: FibroScan is a reliable method for the diagnosis of significant fibrosis (> or =F2) and cirrhosis in patients with chronic liver disease. The liver stiffness measurement by FibroScan showed good diagnostic performance for significant fibrosis.

Oh BK, Kim H, Park YN, Yoo JE, Choi J, Kim KS, Lee JJ, Park C. · Cancer Metastasis Research Center, Yonsei University College of Medicine, Seoul, Korea. · Lab Invest. · Pubmed #18158557 links to  free full text

Abstract: Telomerase reactivation and telomere maintenance are crucial in carcinogenesis and tumor progression. In this study, the relationships between telomere parameters, chromosomal instability and clinicopathological features were evaluated in hepatocellular carcinomas (HCCs). Telomere length (TL), telomerase activity (TA) and human telomerase reverse transcriptase (hTERT) mRNA levels were measured in 49 hepatitis B virus (HBV)-related HCCs and corresponding non-tumorous tissues. The results were compared with clinicopathological data, including differentiation, multipolar mitosis (MM), anaphase bridge, immunohistochemical stain results for cytokeratin 19 (CK19) and patient outcome. TL of HCCs ranged from 4.7 to 13.1 kb, and 44.4% of HCCs showed telomere lengthening. hTERT mRNA levels and TA were closely related (P=0.008), and were significantly higher in HCCs than non-tumorous tissues. TL was significantly higher in HCCs with strong TA (P=0.048), high hTERT mRNA levels (P=0.001) and poor differentiation (P=0.041). Frequent MM was associated with poor differentiation (P=0.007) and advanced stage (P<0.001). TA was positively correlated with MM, anaphase bridges and advanced stage (P=0.019, P=0.017 and P=0.029). Thirteen (28.3%) HCCs were CK19+ and demonstrated longer telomeres than CK19- HCCs (P=0.046). Overall survival was poor in HCCs with MM >0.4 per field (P=0.016), high TA (P=0.009) and high TL ratio (HCC/non-HCC) >0.8 (P=0.044). Our results show that long telomeres, high TA and high mitotic instability are poor prognostic markers for HBV-related HCCs and their close association suggests that telomere maintenance may be important for the progression of HCCs with high chromosomal instability to more aggressive ones.

Yoon YJ, Ahn SH, Park JY, Chon CY, Kim do Y, Park YN, Han KH. · Department of Internal Medicine, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-gu, Seoul 120-752, Korea. · J Gastroenterol. · Pubmed #18008032 No free full text.

Abstract: BACKGROUND: Diagnostic laparoscopy is known to be a relatively safe invasive procedure. However, its use has decreased owing to the development of imaging techniques, and fewer gastroenterologists now practice diagnostic laparoscopy. Our aim was to examine the role of diagnostic laparoscopy in a gastroenterology unit in the era of advanced imaging techniques. METHODS: We retrospectively reviewed 855 diagnostic laparoscopy cases. Its safety and efficacy were evaluated for various indications. RESULTS: No mortality was observed, and complications were noted in ten patients (1.2%). Among the indications were evaluation of chronic liver disease (n = 673), liver tumor (n = 15), ascites of unknown origin and peritoneal disease (n = 142), and staging of intra-abdominal malignancy (n = 25). In patients with chronic liver disease, 461 were diagnosed as having chronic viral hepatitis, based on clinical data including imaging studies, but the diagnosis was changed to cirrhosis after a laparoscopic exam in 69 patients (15.0%). In patients with ascites of unknown origin and peritoneal disease, the diagnostic yield was 87.2% (123/141). In 24 (19.5%) of the 123 patients, the diagnosis changed or the less probable diagnosis was confirmed after laparoscopic examination. The confirmed diagnoses were mainly primary peritoneal disease, including peritoneal tuberculosis, in 17 patients, peritoneal metastatic carcinoma in five, and mesothelioma in two. CONCLUSIONS: Diagnostic laparoscopy in a gastroenterology unit is safe and useful, especially for confirmation of liver cirrhosis and primary peritoneal disease evaluation.

Kim BK, Kim SA, Park YN, Cheong JY, Kim HS, Park JY, Cho SW, Han KH, Chon CY, Moon YM, Ahn SH. · Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. · Liver Int. · Pubmed #17696936 No free full text.

Abstract: OBJECTIVES: Few noninvasive models of chronic hepatitis B (CHB) to predict liver cirrhosis have been studied. The aim of the current study is to investigate the diagnostic accuracy of two simple novel models of spleen-platelet ratio index (SPRI) and age-spleen-platelet ratio index (ASPRI) in patients with CHB. PATIENTS AND METHODS: A total of 346 consecutive treatment-naïve patients with CHB were retrospectively studied. The aspartate to alanine aminotransferase ratio (AAR), age-platelet index (API), aspartate aminotransferase to platelet ratio index (APRI), SPRI, and ASPRI were compared with liver histology. RESULTS: AAR, APRI, SPRI, API, and ASPRI correlated significantly to fibrosis stage (all P<0.001). The diagnostic accuracy of ASPRI was the highest among five tests for prediction of cirrhosis (area under receiver operating characteristic curve, AUROC=0.893). Using a cutoff score of ASPRI>12, the presence of cirrhosis could be correctly identified with a high accuracy (96.3% positive predictive value) in 35 (10.1%) of 346 patients. Similarly, using a cutoff of <5, the presence of cirrhosis could be totally excluded with 100% of negative predictive value in 120 (34.7%) of 346 patients. CONCLUSION: ASPRI was accurate in predicting cirrhosis and screening with ASPRI has the potential to reduce the number of liver biopsies in CHB patients.

Oh BK, Kim H, Park HJ, Shim YH, Choi J, Park C, Park YN. · Cancer Metastasis Research Center, Yonsei University College of Medicine, Seoul, Korea. · Int J Mol Med. · Pubmed #17549390 No free full text.

Abstract: Aberrant DNA methylation on CpG islands is one of the most consistent epigenetic changes in human cancers, and the methylation process is catalyzed by DNA methyltransferase (DNMT). We evaluated i) the mRNA levels of three DNMTs; DNMT1, DNMT3a and DNMT3b, in 25 hepatocellular carcinomas (HCCs), in their corresponding non-cancerous liver tissues and in 7 normal livers by using real-time reverse transcriptase-polymerase chain reaction; ii) nuclear expression of DNMT1 and DNMT3a proteins in the HCCs by immunohistochemistry, iii) the methylation status of 5 genes; p16, p15, E-cadherin, HIC-1 and RASSF1A in the same tissues, and iv) the relationships between the above results and the clinicopathological characteristics, including prognosis. The differences in mRNA expression levels for DNMT1, DNMT3a and DNMT3b were statistically significant between HCC and normal livers (p<0.001), HCC and chronic hepatitis (p<0.001) and HCC and cirrhosis (p<0.001). An increase in mRNA expression levels of >4-fold for DNMT3b in HCCs was significantly associated with a poorer overall survival (p=0.027) and shorter metastasis-free survival (p=0.0299). A poorer recurrence-free survival was noted in HCCs with a >4-fold increase in DNMT3a mRNA (p=0.0120). The average numbers of methylated genes were 0, 1.27, 1.38 and 2.72 for normal livers, chronic hepatitis, cirrhosis and HCCs, respectively, and this progressive increase from normal livers to chronic hepatitis/cirrhosis through HCC may suggest that tumor suppressor gene methylation is an early event in hepatocarcinogenesis. These results first suggest that hepatocarcinogenesis involves an increased expression of DNMT1, DNMT3a and DNMT3b mRNA and a progressive increase in the number of methylated genes from normal liver, chronic hepatitis/cirrhosis to HCC and secondly that an increase in the DNMT3a and DNMT3b mRNA levels in HCCs relative to their non-cancerous tissues may be a predictor of poor survival.

Park BK, Park YN, Ahn SH, Lee KS, Chon CY, Moon YM, Park C, Han KH. · Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea. · J Gastroenterol Hepatol. · Pubmed #17295771 No free full text.

Abstract: BACKGROUND AND AIM: This study evaluated the long-term outcome and prognostic factors of chronic hepatitis B, based on histological grade and stage. METHODS: A total of 188 patients with chronic hepatitis B were followed for a mean 119.8 months. Ultrasonography and clinical assessment were performed regularly. In addition, liver biopsy specimens were re-evaluated based on histological grade and stage. RESULTS: During follow-up, cirrhosis developed in 62 patients, decompensation in 20 patients, and hepatocellular carcinoma (HCC) in 21 patients. The serum alanine aminotransferase (ALT) level at the time of liver biopsy was significantly correlated with the grades of lobular and porto-periportal activity. The development of cirrhosis correlated well with the grade of porto-periportal activity and stage of fibrosis. The probabilities of developing cirrhosis, decompensation and HCC were significantly higher in patients whose ALT levels were persistently elevated without flares or flared-up without normalization than in patients whose ALT levels flared-up then normalized or were normally sustained. By multivariate analysis, age and biochemical profile during follow-up were independent prognostic factors for chronic hepatitis B. CONCLUSIONS: The results demonstrate that histological grade and stage, and biochemical profile during follow-up in patients with chronic hepatitis B are important prognostic factors. Therefore, effective control of hepatitis activity might improve the long-term outcome of chronic hepatitis B patients.

Moon JH, Ahn CM, Chung HS, Ahn SH, Park YN. · Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. · Yonsei Med J. · Pubmed #17191321 links to  free full text

Abstract: Most hypervascular nodules in a cirrhotic liver are hepatocellular carcinomas (HCCs); however, some are benign hypervascular hyperplastic nodules. We report a case of benign hypervascular hyperplastic nodules in a 41-year-old male patient without hepatitis B or C virus infection, with a history of alcohol abuse, and diagnosed with an aortic aneurysm. The dynamic computerized tomography of the liver demonstrated multiple nodular lesions on both liver lobes with arterial enhancement and delayed washout. The hepatic angiography showed multiple faint nodular staining of both lobes in the early arterial phase. Magnetic resonance imaging revealed numerous nodules showing high signals on T1 weighted images, with some nodules showing a low central signal portion. The clinical impression was HCC. The ultrasonography-guided liver biopsy, which was performed on the largest nodule (2.5 cm in size), revealed hepatocellular nodules with slightly increased cellularity, unpaired arteries, increased sinusoidal capillarization, and focal iron deposition. However, both cellular and cytological atypia were unremarkable. Although the clinical impression was HCC, the pathological diagnosis was hypervascular hyperplastic nodules in alcoholic cirrhosis. Differential diagnosis of hypervascular nodules in cirrhosis and HCC is difficult with imaging studies; thus, histological confirmation is mandatory.

Kim JH, Han KH, Lee KS, Park YN, Ahn SH, Chon CY, Moon YM. · Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. · Yonsei Med J. · Pubmed #17191307 links to  free full text

Abstract: Combination therapy with interferon alpha (IFN-alpha) and ribavirin for 24 or 48 weeks according to HCV genotype has improved the overall sustained virological response (SVR) rates to approximately 40%. The aim of this study was to investigate the long-term efficacy of combination therapy with IFN-alpha and ribavirin for chronic hepatitis C in Koreans. One hundred thirty-eight patients with chronic hepatitis C who received this combination therapy between 1995 and 2003 were analyzed retrospectively. All patients were treated with IFN-alpha 3-6 million units three times weekly in combination with 900-1200 mg/day of ribavirin for 24 weeks. The overall SVR rate was 41.3%. Patients were followed up for a median of 41 months (range, 12-105 months) after completion of therapy. In all of the SVR patients (57 patients), SVR was conserved during the follow-up period. None of the patients progressed to decompensated liver disease or hepatocellular carcinoma (HCC). However, 5 of the 81 non-SVR patients (6.2%) progressed to decompensated liver disease or HCC. In conclusion, combination therapy with IFN-alpha and ribavirin shows good long-term efficacy in patients with chronic hepatitis C in Korea, one of the highest endemic areas of hepatitis B virus (HBV) infection.

Oh BK, Kim YJ, Park YN, Choi J, Kim KS, Park C. · Department of Pathology, Center for Chronic Metabolic Disease Research and Yonsei Biomedical Science and Technology Initiative, Yonsei University College of Medicine, Seoul, Korea. · Am J Gastroenterol. · Pubmed #16494581 No free full text.

Abstract: BACKGROUND: Telomerase reverse transcriptase (hTERT) is the rate-limiting determinant of telomerase, which is critical for carcinogenesis. Dysplastic nodules (DNs) appear to be preneoplastic lesions of hepatocellular carcinomas (HCCs). In this study, in order to characterize DNs, hTERT mRNA, hTERT gene dosage, and mRNA for c-myc, a transcriptional activator of hTERT were studied in human multi-step hepatocarcinogenesis. METHODS: Fifty four hepatic nodules including 5 large regenerative nodules, 14 low-grade DNs, 7 high-grade DNs, 11 DNs with HCC foci and 17 HCCs, 23 livers with chronic hepatitis/cirrhosis, and 6 normal livers were examined. Transcript levels were measured by real-time quantitative RT-PCR and gene dosages by real-time PCR and Southern blotting. RESULTS: The hTERT mRNA levels increased with the progression of hepatocarcinogenesis, and a significant induction in the transition between low- and high-grade DNs was seen. Most high-grade DNs strongly expressed hTERT mRNA at levels similar to those of HCCs. Twenty-one percent of low-grade DNs had high levels of hTERT mRNA, up to those of high-grade DNs and there was no difference in the pathological features between low-grade DNs with and without increased hTERT mRNA levels. No correlation was found between hTERT mRNA levels, hTERT gene dosage, and c-myc mRNA levels. CONCLUSIONS: These results suggest that the induction of hTERT mRNA is an important early event and that its measurement by real-time quantitative RT-PCR is a useful tool to detect premalignant/malignant tendencies in hepatic nodules. However, hTERT gene dosage and c-myc expression are not the main mechanisms regulating hTERT expression in hepatocarcinogenesis.

Koo JS, Seong JK, Park C, Yu DY, Oh BK, Oh SH, Park YN. · Department of Pathology, Institute of Gastroenterology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. · Intervirology. · Pubmed #15785085 No free full text.

Abstract: OBJECTIVES: Large liver cell dysplasia (LCD) is frequently associated with hepatitis B virus (HBV), but it remains uncertain whether it is reactive, senescent or preneoplastic. METHODS: The HBX transgenic mice and normal control mice were sacrificed at 1, 3, 5, 7, 9, 11, 13 and 15 months after birth. Twenty-three cases of human B viral chronic hepatitis/cirrhosis with prominent LCD were selected. The immunohistochemical stain of proliferating cell nuclear antigen (PCNA), transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and senescence-associated beta-galactosidase (SA-beta-Gal) were evaluated. RESULTS: In HBX transgenic mice, LCD was developed since 3 months and formed small nodules of hepatocellular adenoma, which progressed to hepatocellular carcinoma. The hepatocytes with LCD in HBX transgenic mice showed significantly higher PCNA-labeling index (LI) and lower TUNEL-LI than normal hepatocytes of control mice (p < 0.05). In the majority of human B viral chronic hepatitis/cirrhosis, the hepatocytes with LCD revealed higher PCNA-LI and lower TUNEL-LI than those without, when compared in each case using the same tissue block. SA-beta-Gal staining showed no difference between hepatocytes with and without LCD. CONCLUSION: It is suggested that LCD, related to HBV, might not be just an innocent bystander, but closely related to hepatocarcinogenesis.

Ahn SH, Park YN, Park JY, Chang HY, Lee JM, Shin JE, Han KH, Park C, Moon YM, Chon CY. · Department of Internal Medicine, Yonsei University College of Medicine, C.P.O. Box 8044, Seoul, South Korea. · J Hepatol. · Pubmed #15664243 No free full text.

Abstract: BACKGROUND/AIMS: During the natural course of hepatitis B virus (HBV) infection, the long-term clinical and histological outcomes following spontaneous hepatitis B surface antigen (HBsAg) seroclearance remain unclear. METHODS: Between 1984 and 2003, 49 (9.5%) out of 432 inactive HBsAg carriers had no detectable level of circulating HBsAg. Fifteen of 49 patients had undergone paired peritoneoscopic liver biopsies. RESULTS: During a mean follow-up period of 19.6 months after HBsAg seroclearance, 5 of 49 (10.2%) patients were noted to have HCC. Liver cirrhosis (P=0.040), a history of perinatal infection (P=0.005) and long-standing duration (at least 30 years) of HBsAg positivity (P=0.002) were associated with a significantly higher risk of developing HCC. Despite HBsAg seroclearance, HBV DNA was detected in the liver tissues from all 15 patients who underwent paired liver biopsies. Necroinflammation was significantly ameliorated (P<0.0001). On the other hand, amelioration of the fibrosis score did not reach a statistically significant level (P=0.072). Interestingly, aggravation of liver fibrosis was evident in 2 patients (13.3%) including one who had rapidly progressed to overt cirrhosis. CONCLUSIONS: In patients with spontaneous HBsAg seroclearance, necroinflammation was markedly improved and liver fibrosis was unchanged or regressed despite occult HBV infection. However, HCC developed in a minority of cases.

Oh BK, Kim YJ, Park C, Park YN. · Department of Pathology, and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, CPO Box 8044, Seoul, Korea. · Am J Pathol. · Pubmed #15632001 links to  free full text

Abstract: The telomeric repeat-binding factor 1 (TRF1), TRF2, and the TRF1-interacting nuclear protein 2 (TIN2) are involved in telomere maintenance. We describe the regulation of expression of these genes along with their relationship to telomere length in hepatocarcinogenesis. The transcriptional expression of these genes, TRF1 protein, and telomere length was examined in 9 normal livers, 14 chronic hepatitis, 24 liver cirrhosis, 5 large regenerative nodules, 14 low-grade dysplastic nodules (DNs), 7 high-grade DNs, 10 DNs with hepatocellular carcinoma (HCC) foci, and 31 HCCs. The expression of TRF1, TRF2, TIN2 mRNA, and TRF1 protein was gradually increased according to the progression of hepatocarcinogenesis with a marked increase in high-grade DNs and DNs with HCC foci and a further increase in HCCs. There was a gradual shortening of telomere during hepatocarcinogenesis with a significant reduction in length in DNs. Most nodular lesions (52 of 67) had shorter telomeres than their adjacent chronic hepatitis or liver cirrhosis, and the telomere lengths were inversely correlated with the mRNA level of these genes (P </= 0.001). This was more evident in DNs and DNs with HCC foci. In conclusion, TRF1, TRF2, and TIN2 might be involved in multistep hepatocarcinogenesis by playing crucial roles in telomere shortening.

Oh BK, Chae KJ, Park C, Park YN. · Department of Pathology, Institute of Gastroenterology, Center for Chronic Metabolic Disease Research, and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. · Oncol Rep. · Pubmed #15375513 No free full text.

Abstract: PinX1 is located at 8p23, a region with frequent loss of heterozygosity in hepatocellular carcinomas (HCCs). Overexpression of PinX1 is known to inhibit telomerase activity, shorten telomeres and induce crisis while its depletion increases tumorigenesis in nude mice. These results suggest that PinX1 might be critical for hepatocarcinogenesis. In this study, we assessed transcript expression of PinX1, the correlation between PinX1 mRNA level and telomere length and telomerase activity, as well as sequence alteration, in 24 HCCs and their adjacent non-HCC tissues from patients with B viral chronic hepatitis/cirrhosis. There was no significant difference between the levels of PinX1 mRNA in HCCs and those in non-HCCs. The PinX1 mRNA tended to increase as the telomere shortened in the HCCs (p=0.067, R(2)=0.166), but no correlation was found in non-HCCs. The PinX1 level revealed no significant relationship with telomerase activity in HCCs and non-HCCs. The missense mutations of PinX1, at the 254 and 265 residues, were found in 17% of the HCCs and their adjacent non-HCCs. The mutations were located in the non-conserved region and revealed no relation with PinX1 expression, telomere length and telomerase activity, suggesting that they are likely polymorphisms. Our findings suggest that PinX1 may not play a major role in hepatocarcinogenesis as a target tumor suppressor gene. PinX1, however, might be involved in the telomere length regulation of HCCs.

Park YN, Chae KJ, Kwon KW, Oh BK, Lee KS, Lee WJ, Park C. · Department of Pathology and Brain Korea, 21 Project for Medical Science, Yonsei University College of Medicine, CPO Box 8044, Seoul, Korea. · Hepatogastroenterology. · Pubmed #14571721 No free full text.

Abstract: BACKGROUND/AIMS: This study was undertaken to determine the expression p21WAF1/CIP1 and p53, the main regulator of G1 restriction point, in hepatitis B virus related hepatocarcinogenesis and their role in regulation of cell dynamics. METHODOLOGY: Immunohistochemistry for p21WAF1/CIP1, p53 and Ki-67 and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling were preformed in 8 low grade dysplastic nodules, 7 high grade dysplastic nodules, 58 hepatocellular carcinomas, and 62 chronic hepatitis/cirrhosis. In 33 hepatocellular carcinomas with fresh frozen tissue, p21WAF1/CIP1 mRNA was studied by reverse transcriptase polymerase chain reaction. RESULTS: Immunostaining for p21WAF1/CIP1 and p53 was positive in 28% and 38% of hepatocellular carcinomas and higher in poorly differentiated hepatocellular carcinomas, whereas it was negative in all of chronic hepatitis/cirrhosis and dysplastic nodules. In hepatocellular carcinomas with p21WAF1/CIP1 mRNA amplified, 31% showed the protein expression indicating post-transcriptional regulation. The rate of apoptosis and proliferation showed significant correlation with p53 status, however not with p21WAF1/CIP1 in hepatocellular carcinomas. Induction of p21WAF1/CIP1 was regulated by both p53 dependent and independent pathway. CONCLUSIONS: In hepatitis B virus related hepatocarcinogenesis, p21WAF1/CIP1 and p53 are suggested to be involved in late stage of tumor progression rather than in early stage of dysplastic nodules and p53 is considered to be the main regulator of the cell dynamics.

Ding X, Park YN, Taltavull TC, Thung SN, Jin X, Jin Y, Trung NS, Edamoto Y, Sata T, Abe K. · Department of Pathology, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan. · Jpn J Infect Dis. · Pubmed #12711820 links to  free full text

Abstract: We investigated the relationship of infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) to p53 mutation in hepatocellular carcinomas (HCC) from six countries, including Japan, China, Korea, Vietnam, Spain, and the Unites States. For this purpose, we used formalin-fixed, paraffin-embedded liver tissues obtained from 449 patients with HCC to detect the viral and p53 genes by polymerase chain reaction (PCR). HBV was the most prevalent in Korea (69.1%), China (66.1%), Vietnam (60.5%), and Spain (38.6%). In contrast, HCV was the most prevalent in Japan (59.8%) and in the United States (41.5%). Type C of HBV was the most common genotype (78.6%) encountered in HCC in these countries. Importantly, among 125 intrahepatic HBV DNA-positive patients, 44 (35.2%) were serologically negative for HBsAg (occult hepatitis B). Based on PCR, immunohistochemical, serological, and clinical findings, 4.8% of HCC patients were diagnosed with non-B, non-C. A point mutation at exon 7 of p53 was detected in 20 of the 239 HCC samples examined, including those from 9 Chinese, 5 American, 2 Japanese, 2 Korean, and 2 Spanish patients, respectively. Interestingly, a point mutation with an amino acid substitution at codon 251 (Ile-->Asn) was detected frequently in 11 of 20 (55%) cases. A specific mutation induced by Aflatoxin B1 at codon 249 was seen in two patients, both Chinese. Our results suggest that genotype C of HBV may play an important role in hepatocarcinogenesis in different geographic regions, and that in situ detection of HBV genomes could be important for clarifying the agent(s) of unknown etiology related to HCC.

Tan J, Hytiroglou P, Wieczorek R, Park YN, Thung SN, Arias B, Theise ND. · Department of Pathology, New York University Medical Center, New York, NY 10016, USA. · Liver. · Pubmed #12390471 No free full text.

Abstract: BACKGROUND/AIM: Proliferative bile ductular reactions occur in a variety of liver diseases in humans. It is a matter of debate whether such reactions result from progenitor cell proliferation with biliary and hepatocytic differentiation, versus biliary metaplasia of damaged hepatocytes. We investigated bile ductular reactions in liver diseases, paying particular attention to the presence of cells with intermediate (hepatocytic/biliary) features (oval-like cells). METHODS: Five specimens each were selected of submassive hepatic necrosis and cirrhosis due to hepatitis B, hepatitis C, autoimmune hepatitis, alcohol injury, primary biliary cirrhosis and primary sclerosing cholangitis. Immunohistochemical stains were performed for biliary markers (cytokeratins [CKs] 7 and 19), as well as hepatocytic markers (HepParl and alpha-fetoprotein[AFP]) in sequential sections. The degree of staining of each cell type (biliary, hepatocytic, intermediate) was graded semiquantitatively. RESULTS: Hepatocytes always stained diffusely for HepParl, occasionally for CK7, and rarely for CK19. Biliary cells were always diffusely positive for CK7 and CK19, and rarely for HepParl. Intermediate cells were identified in all cases and showed widespread staining for both HepParl and CK7, and less commonly for CK19. AFP was not expressed in any cell type. The morphologic and immunohistochemical features of bile ductular reactions were similar in the different diseases. CONCLUSIONS: Proliferating hepatic parenchymal cells with intermediate (hepatocytic/biliary) morphologic features and combined immunophenotype can be identified in a variety of acute and chronic liver diseases. The similarity of bile ductular reactions among chronic hepatitic, alcoholic and biliary diseases suggests that they result from proliferation of oval-like progenitor cells.

Lee SC, Chung HW, Chung JB, Park YN, Ahn SH, Park SW, Chun CY, Moon YM, Kang JK, Park IS. · Department of Internal Medicine, Yonsei University College of Medicine, C.P.O. Box 8044, Seoul 120-752, Korea. · Yonsei Med J. · Pubmed #11854943 links to  free full text

Abstract: Spontaneous total necrosis of hepatocellular carcinoma is extremely rare, with only 15 cases reported to date in the English literature, and the involved mechanism remains unresolved. This paper describes a case of spontaneous necrosis of hepatocellular carcinoma in a 70-year-old man with chronic hepatitis. The patient suffered epigastric pain on admission and computed tomography revealed a 4 cm mass with low density in the left lobe of the liver. Fine needle aspiration biopsy revealed a few scattered, naked and irregular nuclei exhibiting nuclear hyperchromasia in the dirty necrotic background, a finding highly suggestive of malignancy. The lobectomized liver revealed a 3.5 cm, well encapsulated, round, and nearly totally necrotic mass. On microscopic examination, the tumor was found to be composed of thick trabeculae of necrotic tumor cells, supporting the diagnosis of hepatocellular carcinoma. After surgery and throughout 13 months of follow up the patient has recovered well.

Kim MJ, Mitchell DG, Ito K, Hann HW, Park YN, Kim PN. · Department of Radiology, Thomas Jefferson University Hospital, 1096 Main Building, 132 S 10th Street, Philadelphia, PA 19107, USA · Abdom Imaging. · Pubmed #11178691 No free full text.

Abstract: BACKGROUND: To evaluate the relationship between magnetic resonance (MR) imaging grading of iron deposition and serial serum ferritin concentration in patients with chronic viral liver diseases. METHODS: In 80 patients with viral hepatitis and cirrhosis, MR images including T2*-weighted gradient echo images (echo time > or = 6.5 ms) were reviewed. The grades of parenchymal iron deposition and iron-containing nodules in the liver and spleen and the liver-to-muscle and spleen-to-muscle signal intensity ratios were compared with the most recent, the mean, the lowest, and the highest values from all available serum ferritin levels. RESULTS: The serum ferritin concentration was significantly correlated with the grades of iron deposition in liver and spleen and with the grades of iron-containing nodules seen on MR images (p < 0.05). Liver-to-muscle signal intensity ratio was weakly correlated with the ferritin concentrations. Among categories of ferritin concentration, correlation with MR grades was highest for mean ferritin concentration (r = 0.487, p < 0.001). CONCLUSION: MR imaging grades of hepatic iron and siderotic nodules correlate with serum ferritin, especially with the mean levels.