Journal of Pathology and Translational Medicine

Original Articles

C-reactive Protein Overexpression in the Background Liver of Hepatitis B Virus–Associated Hepatocellular Carcinoma Is a Prognostic Biomarker: Jin Ho Shin, Eunsil Yu, Eun Na Kim, Chong Jai Kim; J Pathol Transl Med. 2018;52(5):267-274. Published online July 27, 2018; DOI: https://doi.org/10.4132/jptm.2018.07.14

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Background
Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC). Peripheral blood C-reactive protein (CRP) concentration and CRP overexpression in HCC cells are proven to be prognostic markers for HCC, but the significance of CRP expression in non-neoplastic hepatocytes, which are the primary origin of CRP, has not been studied. This study was conducted to determine the clinicopathologic significance of CRP immunoreactivity in the background liver of HBV-associated HCC.
Methods
CRP immunostaining was done on tissue microarrays of non-neoplastic liver tissues obtained from surgically resected, treatment-naïve HBV-associated HCCs (n = 156). The relationship between CRP immunoreactivity and other clinicopathologic parameters including cancer-specific survival was analyzed. CRP immunoreactivity was determined using a 4-tier grading system: grades 0, 1, 2, and 3.
Results
CRP was positive in 139 of 156 cases (89.1%) of non-neoplastic liver in patients with HCCs: grade 1 in 83 cases (53.2%); grade 2 in 50 cases (32.1%); and grade 3 in six cases (3.8%). The patients with diffuse CRP immunoreactivity (grade 3) had decreased cancer-specific survival (p = .031) and a tendency for shorter interval before early recurrence (p = .050). The degree of CRP immunoreactivity correlated with serum CRP concentration (p < .001).
Conclusions
CRP immunoreactivity in non-neoplastic liver is a novel biomarker for poor cancer-specific survival of HBV-associated HCC and correlates with serum CRP concentration.

Citations

Citations to this article as recorded by

Analysis of Inflammatory and Thyroid Hormone Levels Based on Hepatitis A and B Virus Immunity Status: Age and Sex Stratification
Hyeokjun Yun, Jae-Sik Jeon, Jae Kyung Kim
Viruses.2024; 16(8): 1329. CrossRef
Ferritin and procalcitonin serve as discriminative inflammatory biomarkers and can predict the prognosis of severe fever with thrombocytopenia syndrome in its early stages
Keping Chen, Huidi Sun, Yu Geng, Chuankun Yang, Chun Shan, Yuxin Chen
Frontiers in Microbiology.2023;[Epub] CrossRef
Evaluation of Serum Ferritin, Procalcitonin, and C-Reactive Protein for the Prediction of Severity and Mortality in Hemorrhagic Fever With Renal Syndrome
Lihe Che, Zedong Wang, Na Du, Liang Li, Yinghua Zhao, Kaiyu Zhang, Quan Liu
Frontiers in Microbiology.2022;[Epub] CrossRef
Hepatocellular adenomas: recent updates
Haeryoung Kim, Young Nyun Park
Journal of Pathology and Translational Medicine.2021; 55(3): 171. CrossRef
A prospective follow-up study of the relationship between high-sensitivity C-reactive protein and primary liver cancer
Sarah Tan Siyin, Tong Liu, Wenqiang Li, Nan Yao, Guoshuai Xu, Jun Qu, Yajun Chen
BMC Cancer.2020;[Epub] CrossRef
CRP Levels in Viral Hepatitis: A Meta-Analysis Study
Sukhpal Singh, Abhishek Bansal, Pardeep Kumar
International Journal of Infection.2020;[Epub] CrossRef

Characterization of Histopathological Features that Differentiate Hepatitis B Virus Infection from Acute Cellular Rejection.: Dong Eun Song, Dong Hwan Jung, Shin Hwang, Bong Hee Park, Eunsil Yu; Korean J Pathol. 2009;43(6):535-541.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.6.535

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Abstract PDF

BACKGROUND
Differentiation of viral hepatitis from acute cellular rejection (ACR) after liver transplantation can be difficult because of overlapping histological features. Here we investigated clinicopathologic characteristics of 311 liver allograft biopsies and searched for characteristic histopathological features that would facilitate the differential diagnosis between hepatitis B virus (HBV) infection and ACR. METHODS: A retrospective clinicopathologic examination of 311 liver allograft biopsies consisting of clinically proven ACR or HBV infection was performed. Immunohistochemical staining for HBcAg and HBsAg was done for 64 allograft biopsies showing HBV infection. RESULTS: Moderate to severe bile duct damage, diffuse centrilobular necrosis and centrilobular inflammation (p<0.000, for each) were more frequently observed in cases of ACR, whereas diffuse acidophilic bodies and spotty necrosis (p<0.000, for each) were more prevalent in cases of HBV infection. Immunopositivity for HBcAg (n=60, 93.8%) was higher than that for HBsAg (n=14, 21.9%) CONCLUSIONS: The presence of moderate to severe bile duct damage, diffuse centrilobular necrosis and centrilobular inflammation was a characteristic feature of ACR, whereas diffuse distribution of acidophilic bodies or spotty necrosis was the only characteristic feature of HBV infection. HBcAg was a more sensitive immunohistochemical marker than HBsAg for detecting HBV infection in liver allograft biopsies.

Citations

Citations to this article as recorded by

Analysis of S Gene Mutation of the Hepatitis B Virus in Adult Liver Transplant Recipients Showing Resistance to Hepatitis B Immunoglobulin Therapy
G.-C. Park, S. Hwang, C.-S. Ahn, K.-H. Kim, D.-B. Moon, T.-Y. Ha, G.-W. Song, D.-H. Jung, Y.W. Shin, S.-H. Kim, K.-H. Chang, J.-M. Namgoong, C.-S. Park, H.-W. Park, Y.-H. Park, S.-H. Kang, B.-H. Jung, S.-G. Lee
Transplantation Proceedings.2013; 45(8): 3047. CrossRef
Posttransplantation prophylaxis with primary high-dose hepatitis B immunoglobulin monotherapy and complementary preemptive antiviral add-on
Shin Hwang, Chul-Soo Ahn, Gi-Won Song, Ki-Hun Kim, Deok-Bog Moon, Heung-Bum Oh, Young-Suk Lim, Han Chu Lee, Tae-Yong Ha, Dong-Hwan Jung, Young-Hwa Chung, Sung-Gyu Lee
Liver Transplantation.2011; 17(4): 456. CrossRef
Posttransplantation Prophylaxis with Primary High-dose Hepatitis B Immunoglobulin Monotherapy and Complementary Preemptive Antiviral Add-on. Liver Transpl 2011;17:456-465
Dong-Hwan Jung, Shin Hwang
The Korean Journal of Gastroenterology.2011; 57(5): 330. CrossRef

Relationship between Proliferative Activity and Expression of HBcAg and p53 Protein in Hepatocellular Carcinoma and Surrounding Nontumorous Liver.: So Ya Paik, Ho Guen Kim, Chan Il Park; Korean J Pathol. 1997;31(8):773-781.

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Abstract PDF: In an attempt to discover the factors contributing to the increased proliferative activity in hepatocytes and subsequent development of HCC, the proliferative activity of hepatocytes was compared with the size of regenerative nodules and HBcAg expression status in the surrounding nontumorous liver of 45 surgically resected hepatocellular carcinomas, including 34 HBV related ones. In the tumor, the difference in proliferative activity and the histological grade was analyzed in terms of p53 gene alteration. The proliferative activity was assessed by immunohistochemical methods using Ki-67 monoclonal antibody. HBcAg expression in the surrounding nontumorous liver correlated with both the inflammatory and proliferative activity of hepatocytes (p<0.05). p53 overexpression was associated with high proliferative activity and aggressive phenotype of tumor. No correlation was observed between the proliferative activity of hepatocytes and the size of regenerative nodules in cirrhosis (p>0.05). p53 overexpression was not evident in surrounding nontumorous liver including cirrhosis. In conclusion, the above results are in line with the view that hepatic carcinogenesis is a mutistep, progressive process. In the initial stage, chronic cellular injury incurred by immumologic reaction against HBcAg seems to play a pivotal role in increased cellular regeneration. However, once transformation of hepatocytes occur the major contributor to tumor growth seems to be alteration in p53 tumor suppresor gene.

Case Report

Combined IgA Nephropathy and Membranous Glomerulonephritis : A Report of Six Cases.: Ji Han Jung, Yeong Jin Choi, Yong Soo Kim, Yoon Sik Chang, Byung Kee Bang, Sang In Shim, Chang Suk Kang; Korean J Pathol. 2005;39(4):278-283.

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Abstract PDF: IgA nephropathy (IgAN) and membranous glomerulonephritis (MGN) are common in adults. However, it is unlikely that these two distinct glomerulonephrites coexist in a renal biopsy. Here, we report clinical and pathological data of six patients with concomitant existence of IgAN and MGN in renal biopsy specimens from 1990 to 2004. Five patients were male and one was female, and their ages ranged from 29 to 71 years. Four patients had microscopic hematuria, five had nephrotic range proteinuria, three had hepatitis B virus infections, three had rheumatoid factors, one had antinuclear antibodies. Two cases were developed after kidney transplant. Immunofluorescence microscopy showed characteristic findings of mesangial IgA deposits and granular IgG deposits on the capillary walls. These were confirmed by electron microscopic findings of immune-type electron-dense deposits in the mesangium and subepithelial capillary basement membranes. The pathogenesis and prognosis of the patients are discussed in this report.

Original Articles

Biologic Significance of Hepatocyte Hepatitis B Core Antigen Expression in Chronic Hepatitis B Virus Infection II.: Hye Kyung Lee, Kwang Min Lee, Dong Kyu Chung; Korean J Pathol. 1992;26(4):355-359.

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Abstract PDF: Routine use of commercially available antisera against hepatitis B core antigen(HBcAg) has permitted a reevaluation of the histochemical distribution of the antigen in liver tissue. HBcAg, classically described almost exclusively in the nucleus, was found with a very high frequency in the cytoplasm of liver cells as well. To elucidate the biologic significance of HBcAg expression and its relation to the natural course of hepatitis B virus(HBV) infection, the patterns of activity in 33 needle liver biopsies of HBsAg carriers were analysed. A good correlation of liver HBcAg with disease activity was demonstrated. HBcAg was present in the hepatocyte nuclei(nHBcAg) or cytoplasm(cHBcAg), or in both(mixed). Pure nHBcAg was seen mainly in non-aggressive reactive liver tissue and cHBcAg was predominantly associated with chronic active hepatitis(95%). The results suggest that expression of HBcAg correlates with the liver pathology and the possibility of HBcAg to be an immunological target for T cell mediated hepatocyte damage.

Clinico-pathological Study on Hepatitis B virus-Associated Nephropathy.: Moon Hyang Park, Hae Sun Ahn; Korean J Pathol. 1992;26(3):215-228.

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Abstract PDF: To clarify the characteristics of HBV-associated renal lesions, renal biopsies obtained from 22 HBsAg seropositive patients(M:F=32:1) were studied. Other than two(age 4 and 12), all were adults(17-77 y.o.). Twelve of the patients had nephrotic syndrome(NS), 5 NS and hematuria(H), 10 proteinuria and H, one gross H, one microscopic H, and 4 normal urinalysis at the time of biopsy. Light microscopy showed minimal change lesion(MCL) in 9 cases, mesangial proliferative glomerulonephritis(MSPGN) in 6, MPGN type I in 7, MPGN type III in 6, and mebranous nephropathy(MGN) in 5 cases. There were variable immunofluorescent(IF) findings of 25 cases studied; IF staining were predominant with IgG in 10 cases, with IgA in 5 and with IgM in 2 cases. Complements tended to be more strong for C1 &/or C4 than C3. In electron microscopic(EM) studies of MCL group, rare mesangial deposits were noted(3/5). In MSPGN, aside from mesangial deposits, there were occasional subendothelia(2/4) or subepithelial(1/4) deposits. In MPGN type I, in addition to the usual EM features of MPGN, some subepithelial deposits were also observed in 5 cases. In MGN, 3 out of 4 showed subendothelial deposits. Among 7 cases stained for HBsAg all were negative with IF and 2 were positive with PAP method. It is concluded that clinico-pathological findings of HBV-associated nephropathy are variable and partly show lupus-like features, different from primary glomerulopathy.

Expression pattern of Hepatitis B Viral Core Antigen (HBcAg) and Surface Antigen (HBsAg) in Liver of the Inactive HBsAg Carriers.: Hee Jeong Ahn, Kyoung Ho Kim, Young Nyun Park, Ho Guen Kim, Chan Il Park; Korean J Pathol. 1990;24(2):120-127.

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Abstract PDF: To understand better the complex natural course of HBV infection, the expression patterns of HBcAg and HBsAg in the liver of 51 inactive serum HBsAg carriers (24 CPH and 27 NPD) were studied by immunohistochemical methods. The inactive serum HBsAg carriers were devided into 3 groups by the following expression patterns of serum HBeAg/anti-HBe status and tissue HBcAg and HBsAg. Pattern A (18 cases) : HBeAg+, cHBcAg+ (94.4%), mHBsAg+ (61.1%), pATTERN B (14 cases) : anti-HBe+, nHBcAg+, cHBsAg+, Pattern C (19 cases) : anti-HBe+, HBcAg-, cHBsAg+ (89.5%). There were no significant differences between CPH and NPD, lthough the core free pattern was more common in the latter. The cHBcAg was expressed in 17 of 18 (94.4%) HBeAg seropositive cases but only one of 33 cases with serum anti-HBe, suggesting that the cHBcAg is intimately related to HBeAg. Since the inactive HBsAg carriers also expressed cHBcAg and/or mHBsAg, the necro-inflammatory activity of HBV infected liver is assumed to depend on the host immune response rather than their presence alone

Occurrence of Hepatitis B-Virus Antigens in a Consecutive Material of 112 Liver Biopsies.: S P Kim, C H Kim, S S Lee, C H Chung; Korean J Pathol. 1988;22(4):404-414.

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Abstract PDF: The frequency and occurrence of HBsAg and HBcAg in 112 consecutive, HBsAg sero-positive, liver biopsies were determined using immunoperxidase staining, HBsAg and HBcAg were demonstrated in 35 (31.3%) and 71 (63.4%) biopsies, respectively. HBsAg in liver was found in the cytoplasm as diffuse granules, mostly in the form of cytoplasmic inclusions. There was also perinuclear and membranous patterns. HBcAg in liver was found mostly in the cytoplasm and occasionally confined to the nucleus. The highest correspondence between HBsAg positivity in serum and liver was found in cases with normal histology morphology (80%). The frequency of HBs and HBcAg in liver in chronic liver disease was 23.1~50% and 36.4~69.2%. According to the variable expression pattern of HBs & c Ags in liver cells, 47 cases (42%) showed only HBcAg in liver. Twenty-nine cases (25.6%) failed to demonstrate any HBV Ags in liver and 24 cases showed boty antigens in liver. No correlation was found between liver disease groups and HBV Ag expression patterns. However, 11 cases (9.8%) showed only HBsAg in liver; predominant HBsAg pattern was observed in 80% of "normal histology group". 73.2% of HBsAg positive patients had anti-HBc in serum and 57.7% of them had HBeAg. 70.3% of anti-HBc positive and 70.7% of HBeAg sero-positive patients had HBcAg in liver cells. These findings strongly suggest that the presence of HBcAg. Serum HBeAg and anti-HBc can be used as a reliable indicator of active viral replication. The overall results further suggest an interplay of both hepatitis B virus and host immune response in the development and pathogenesis of hepatitis, including different degrees of accumulation of HBsAg and HBcAg in the liver and the various histological types of hepatitis.

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