Factors Associated With The Risk Of Hcc Development During The Follow
The baseline characteristics of the patients are listed in Supplementary Table S2. Patients with HCC had a higher median age , frequency of males , diabetes , hypertension , and cirrhosis , and a higher median total bilirubin level and lower median serum albumin level and platelet count compared with those without HCC .
Univariate analyses to identify factors associated with the risk of HCC development during follow-up showed that the total bilirubin and serum albumin levels and the platelet count were significantly predictive of HCC development. Next, these three variables were converted to binary variables using the Contal and O’Quigley method . The optimal cutoff points for prediction of HCC were as follows: total bilirubin level of 0.82 mg/dL, serum albumin level of 4.0 g/dL, and platelet count of 131 à 103/μL . Thus, patients with a total bilirubin level of â¥0.82 mg/dL, serum albumin level of < 4.0 g/dL, and platelet count of < 131 à 10³ μLâ1 have a significantly higher risk of HCC development , 2.59 , and 4.36 , respectively. Male gender was also associated with a higher risk of HCC development and the risk of HCC increased stepwise with increasing age.
A multivariate Cox-regression analysis indicated that cirrhosis , a low serum albumin level , and low platelet count were independent risk factors for HCC development and the risk of HCC also independently increased stepwise with increasing age.
Viral Hepatitis And Hepatocellular Carcinoma: Etiology And Management
Philippe J. Zamor, Andrew S. deLemos, Mark W. Russo
Division of Hepatology, Carolinas Medical Center, Charlotte, USA
Contributions: Conception and design: All authors Administrative support: None Provision of study materials or patients: None Collection and assembly of data: None Data analysis and interpretation: All authors Manuscript writing: All authors Final approval of manuscript: All authors.
Correspondence to:
Abstract: Chronic hepatitis B virus and chronic hepatitis C virus are associated with hepatic fibrosis and development of hepatocellular carcinoma . There are differences and variation with the incidence of HCC worldwide. Additionally, HCC develops via different pathways with these viral hepatitides. This review outlines the various mechanisms and pathophysiology that contributes to this process. There will also be a review on the recommended screening for HCC. Treatment considerations, which are different for these viruses, will be outlined in this review.
Keywords: Hepatocellular carcinoma chronic hepatitis C chronic hepatitis B cirrhosis sustained virologic response
Submitted Jan 02, 2017. Accepted for publication Mar 20, 2017.
doi: 10.21037/jgo.2017.03.14
Hbv Induces Gp73 Expression In Clinical Hcc Tissues
It has been reported that viral invasion can induce the expression of GP73 in hepatocytes . The concentration of serum GP73 is significantly increased in patients with liver injury caused by virus infection . Human carcinoma tissues were analyzed to validate the role of GP73 in HBV-related HCC. Immunohistochemistry analysis showed that the expression of GP73 was higher in HBVpositive HCC tissues than in HBV-negative HCC tissues . Western blot analysis also showed that HBV-positive HCC tissues had higher GP73 expression levels than HBV-negative HCC tissues . These results suggest that HBV infection induces GP73 expression in HCC tissues.
Fig. 1
HBV infection facilitates GP73 expression in HCC tissues. A Immunohistochemical staining of GP73 in HCC samples . B Western blot analysis of GP73 in HCC samples . Western blot band intensity was quantified using ImageJ software . The graphs show the means±SDs, n=6. *P< 0.05 compared with the control group
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Regardless Of Etiology Chronic Inflammation And Fibrosis Are Major Factors Favoring Liver Cell Clonal Expansion
Cirrhosis is the long-term histologic consequence of chronic inflammation and fibrosis and is found to be present in most patients who present with HCC. A number of in vivo studies, particularly those using transgenic mice, have now allowed for the dissection of the relative roles of chronic inflammation and cytokines in development of fibrosis and liver cell proliferation and malignant transformation expansion.1 In addition, there is now solid evidence for the synergistic effects of HBV with
Acute Immune Tolerant Phase
In the acute phase of infection with HBV, the immune tolerant phase is HBeAg with high viral loads, normal serum alanine aminotransferase , and near normal liver histology . When HBV is acquired in adulthood, this phase is very short however, perinatal and early childhood infection lead to a long immune-tolerant phase . The risk of progression to chronic carrier state differs greatly between those infected perinatally and as an adult . At the current time, antiviral treatment is not recommended during the immune-tolerant phase but rather for the immune clearance phase. Interestingly, some recent reports have shown evidence of immune reactivity during the immune-tolerant stage . As was presented by Zoulim and Mason, there is an argument to consider earlier treatment of CHB in order to prevent HCC .
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Towards Therapeutics And A Better Understanding Of Hdv
A better understanding of the molecular events underlying HCC development following HDV infection is vital to not only the approach to the virus but also for the development of new drugs, which can target specific parts of the pathways involved if not the virus itself and prevent development of HCC in patients infected with HDV. For example the targeted inhibition of STAT3 with a decoy 15-mer double-stranded oligonucleotide, which corresponds to the STAT3 response element in the c-fos promoter region, has been experimentally proven to abrogate head and neck cancer growth and could eventually be used to prevent or treat HCC as well.
Cyclophilins are a class of proteins localized in various cellular compartments, involved in metabolism and homeostasis and are upregulated during inflammation and cancer. Cyclophilin A , in the cytoplasm, is involved in the virus life cycle, while extracellular CypA and CypB are pro-inflammatory in nature. Cyclosporins are potential cyclophilin inhibitors and could have therapeutic potential for the treatment of virus induced liver diseases. Indeed cyclosporin A has been shown to inhibit HBV and HDV entry via sodium taurocholate co-transporting polypeptide. There is a direct interaction between the drug and the NTCP receptor , with overlap at the preS1 domain . CsA also has immunosuppressive effects, exercised via cyclophilin dependent inhibition of calcineurin.
Using Epidemiologic Findings To Determine Hcc Risk In The Clinic
Investigators from Taiwan examined the potential use of noninvasive clinical and laboratory measures, which have been demonstrated in epidemiological studies to be associated with HCC risk, to construct clinically usable nomograms to predict HCC risk in patients with chronic HBV infection65. A number of risk factors, including sex, age, family history of HCC, heavy alcohol consumption, serum levels of ALT, HBeAg sero-status, serum levels of HBV DNA, and HBV genotype were used to created predictive models based on data from 2435 subjects in the REVEAL-HBV study these were validated in an analysis of 1218 subjects. The models have shown very good to excellent predictive and discriminant abilities. However, it is not clear whether these can be applied to the clinical setting and to non-Taiwanese populations. There is no such model for predicting HCC among HCV-infected patients.
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Hbv And Epigenetic Modification
In addition, epigenetic mechanisms are involved in the regulation of HBV replication. The presence of HBV cccDNA is an important reason for the difficulty in curing HBV infection. The acetylation of histones binding to cccDNA in HCC can promote the transcription of cccDNA at the epigenetic level, thereby promoting HBV replication. By interacting with lncRNA-DLEU2, HBx can regulate viral cccDNA transcription, viral replication, and host cancer-related gene expression at the epigenetic level.72
Stress Inflammation & Chronic Liver Diseases
Stress describes a state of behavioral, physiological and psychological responses to environmental demands that exceed a persons natural regulatory capabilities . Acute stress responses are generally considered physiologic, eliciting physiological changes that lead to tissue injuries. Conversely, chronic psychosocial stress, which includes adverse life experiences, history of childhood trauma and poor social support , can have pathological effects that culminate in chronic inflammation.
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Hepatitis B Virus Hbx Mutants And Their Role In Hepatocellular Carcinoma
Correspondence to: Ishtiaq Qadri, PhD, Professor, Head Medical Biotechnology, Head Liver Biology, Head Translational Research, Department of Medical Biotechnology, King Fahd Medical Research Center, King Abdul Aziz University, PO Box 80216, Jeddah 21589, Saudi Arabia.
Telephone: +966-640-1000 Fax: +966-6952-5321
Different Pres Mutants Induce Various Mechanisms That Contribute To Hcc
The preS1/preS2/S sequence encodes a transcriptional activator with potentially transforming properties. These transcriptional effects can activate the protein kinase C-dependent c-Raf-1/MAP1-kinase signal pathway, thus promoting transcription factors to increase the proliferation rate of hepatocytes. Only the carboxy-terminal truncation of LHBs or MHBs has transactivating properties. The truncated LHB protein expressed in transgenic mice resulted in the development of HCC. The transactivating effects of MHBs are mediated via sequence-specific binding to DNA, thereby stimulating promoter sequences of the c-myc, c-fos, and c-Ha-ras oncogenes. Both LHBs and MHBs proteins have the same transcriptional effects.
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Hcc And Viral Hepatitis In The United States
In the United States, the age-adjusted incidence rates for HCC have tripled since the early 1980s. Incidence rates are 2â3-fold lower among Caucasians than African Americans, and 2â3-fold lower among African Americans than Asians, Pacific Islanders, or Native Americans. Asian men have the highest age-adjusted incidence rates . However, the largest proportional increases have occurred among whites , whereas the lowest proportional increases have occurred among Asians. In addition, the age distribution of HCC patients has shifted to younger ages, with the greatest proportional increases among individuals 45â60 years old.
Hepatitis B Virus Infection And Hepatocellular Carcinoma
Volume 17, Issue 6, 2017
Page: Pages: 7
Abstract
Background: Hepatocellular carcinoma is the most deadly form of liver cancer.Chronic hepatitis and subsequent liver fibrosis and cirrhosis are the major causes of HCC. HBV infectionresults not only in HCC but also extra-hepatic cancers. However, the importance and approachesfor HCC screening in HBV infected individuals, the risk factors of HCC, the possiblemechanisms leading to HCC and the potential therapeutic approaches of HBV-related HCC haveless been systematic reviewed.
Title:Hepatitis B Virus Infection and Hepatocellular Carcinoma- New Insights for an Old Topic
Volume: 17Issue: 6
Shi-Yan Yan, Jian-Gao Fan*Liang Qio*
Affiliation:
Keywords:Hepatitis B virus, infection, hepatocellular carcinoma, liver fibrosism, cancer, serum AFP.
Abstract: Background: Hepatocellular carcinoma is the most deadly form of liver cancer.Chronic hepatitis and subsequent liver fibrosis and cirrhosis are the major causes of HCC. HBV infectionresults not only in HCC but also extra-hepatic cancers. However, the importance and approachesfor HCC screening in HBV infected individuals, the risk factors of HCC, the possiblemechanisms leading to HCC and the potential therapeutic approaches of HBV-related HCC haveless been systematic reviewed.
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Hepatocellular Carcinoma Risk Steadily Persists Over Time Despite Long
Corresponding Authors: 0000-0002-4944-4396*Corresponding Authors:
#S.U. Kim and Y.S. Seo contributed equally to this work as co-first authors.
Corresponding Authors:
Cancer Epidemiol Biomarkers Prev 2020 29:832â7
Cancer Epidemiol Biomarkers Prev
Seung Up Kim, Yeon Seok Seo, Han Ah Lee, Mi Na Kim, Eun Ju Lee, Hye Jung Shin, Yu Rim Lee, Hye Won Lee, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Kwang-Hyub Han, Soon Ho Um, Won Young Tak, Young Oh Kweon, Beom Kyung Kim, Soo Young Park Hepatocellular Carcinoma Risk Steadily Persists over Time Despite Long-Term Antiviral Therapy for Hepatitis B: A Multicenter Study. Cancer Epidemiol Biomarkers Prev 1 April 2020 29 : 832â837.
Evidence For A Role Of Hepatitis B Virus In The Aetiology Of Hepatocellular Carcinoma
An aetiological association between cirrhosis and HCC was suspected as early as the beginning of the 20th Century . By the 1950s it was realized that it was posthepatitic cirrhosis that was most closely linked to tumour formation . Following the introduction of serological tests for HBV in the late 1960s it soon became evident that chronic HBV infection was a major risk factor for the development of HCC. Refinements of molecular techniques for identifying viral DNA, availability of HCC cell lines harbouring integrated HBV DNA, and a variety of animal models, either infected with viruses belonging to the same family as HBV or transgenically propagated with specific HBV genes, has made it possible to investigate in depth the role of chronic HBV infection in the pathogenesis of HCC.
Geographical correlation between the prevalence of hepatitis B virus carriage and hepatocellular carcinoma
Global maps showing the close similarity between the geographical distributions of chronic hepatitis B virus infection and hepatocellular carcinoma.
Hepatitis B virus markers in serum and tissues of patients with hepatocellular carcinoma
Cohort studies
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Hbv And Intestinal Microbiota
The intestinal flora plays an important role in human metabolism and physiological functions. Because of the existence of the liver-gut axis, intestinal flora and their metabolites can also influence the progression of liver disease. Chronic viral infection or cirrhosis remains a major cause of liver cancer. The disturbance of intestinal flora was higher in patients with CHB.119 Changes in intestinal flora composition and function in patients with early CHB suggest the potential role of intestinal flora in the progression of CHB.120 Changes in intestinal microbiota composition and diversity have also been detected in patients with HBV-associated HCC, and these microbiota have been shown to be involved in the regulation of different body functions.120,121 As an important pathogen-associated molecular pattern, LPS plays an important role in the progression of liver disease caused by the liver-gut axis. LPS promotes the secretion of inflammatory factors by activating TLR4/NF-B, regulates the responses of hepatocytes, Kupffer cells, and hepatic stellate cells, and then promotes the occurrence of HCC.122 Regulating the composition of the intestinal flora has been proposed as an adjunct therapy to reduce bacterial translocation and prevent HCC progression. However, the pathogenesis of HBV-associated chronic liver disease and HCC caused by changes in the intestinal microbiota is still not fully understood.
Direct Acting Agents For Hcv And Hcc
Use of IFN-free DAA for the treatment of HCV has been quite a revolution for the field of hepatology and virology. Traditional cure rates have risen from ~50% range to well above 90% in most groups of patients. Long term data is not yet available as to the impact of these newer agents and the incidence of HCC. It has been recognized that liver related complications such as hepatic encephalopathy and variceal hemorrhage are reduced and there is an improvement in hepatic function as demonstrated by the reduction in the Model for End-Stage Liver Disease score . A retrospective study from Japan recently reported that HCV genotype 1b infected patients that were cured by DAA as compared to those cured by IFN had similar rates of HCC development after cure . This study compared 77 DAA treated patients with a historical database of 528 patients.
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Factors Associated With Hbv
Thanks to the advances in the molecular biology of HBV, the pathogenesis of HBV-related HCC is largely clarified . The pathogenesis of HCC in patients with CHB can be divided according to HBV-related direct and indirect mechanisms. Direct oncogenic effects of HBV include HBV-host genome integration and HBV-encoded oncogenic protein. The integration of HBV DNA into the host genome induces both host chromosomal instability and insertional mutagenesis of HCC-related genes. This integration in the host genome most frequently happens in the telomerase reverse transcriptase region and myeloid/lymphoid or mixed-lineage leukemia 4 gene. Dysregulation of telomerase and histone methyltransferase expression subsequently increase the risk of hepatocarcinogenesis. Truncated HBV pre-S/S mutation induces surface protein synthesis imbalance and may increase endoplasmic reticulum stress and decrease tumor suppressor gene expression, and thus, it may play a primary role in oncogenesis. Among HBV-encoded proteins, HBV X protein has the most oncogenic effect in hepatocarcinogenesis. HBV X protein is a multifunctional regulator, and it is involved in several cancer-related molecular mechanisms, including alteration of signal pathways , DNA repair , apoptosis , mitochondrial function , and expression of noncoding RNA . Through these mechanisms, HBV X protein directly contributes to HCC development.
Pres2 Mutants Induce Er Stress
The preS2 mutant protein accumulated in the ER can trigger the ER stress-dependent vascular epithelial growth factor/Akt/mTOR and nuclear factor kappa B/COX-2 signal pathway. Through this signal pathway, HBx and envelope proteins that accumulate simultaneously in GGHs can enhance the oncogenic effects in transgenic and human HCCs. mTOR can suppress autophagy and regulate cellular metabolism. The suppression of autophagy by mTOR is in contrast to the induction of autophagy during UPR. This might result in contradictory treatment for HCC and HBV infection.
The LHBs protein with preS2 mutants may also activate an ER stress-independent pathway, ultimately leading to a growth advantage in type II GGHs. The pathway includes c-Jun activation domain binding protein 1 nuclear translocation and activation of p27/retinoblastoma/Cdk2/cyclin A, D pathways, which results in cell cycle progression, cell proliferation, and centrosome over-duplication.
Together, the data show that the preS2 mutant protein is a promising gene transactivator and an ER stress inducer, resulting in host genomic instability and HCC development.
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Hbv Involved In Activation Of Tumor
The carcinogenicity of HBV is closely related to the activation of multiple cancer-related signaling pathways in their host cells . The above described HBV mutations and integrations lead to the abnormal expression of multiple molecules in host cells, most of which are located in key locations of oncogenic signaling pathways. HBV structural proteins are also involved in disease progression by regulating multiple signaling pathways through mechanisms such as regulation of miRNAs or epigenetics.