Hepatitis Monthly
Volume:12 Issue: 10, Oct 2012

Context: Hepatocellular carcinoma (HCC) is a fatal disease. Chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection is the major cause of HCC. High viral replication rate and related hepatic/systematic inflammation are the major risk factors in HCC recurrence after hepatectomy or liver transplantation..Evidence Acquisition: Some of the carcinogenesis-related HBV mutations are also associated with poor prognosis for HCC patients. Antiviral therapy is an option for improving HCC prognosis after surgery. In case of HBV-associated HCC, treatment with interferon and nucleos(t)ide analogues (NAs), especially interferon, is effective in improving the prognosis. However, long-term use of NAs increases the possibility of developing drug-resistant viral mutations such as the HBV rtA181T/sW172 mutation, which increases the risk of HCC recurrence.. In cases of HCV-associated HCC, standard interferon with or without ribavirin therapy is effective in improving the prognosis of HCV-associated HCC; however, some HCV mutations, such as the amino acid substitution M91L, are associated with treatment failure and a poor prognosis. Therapeutic efficacy needs to be confirmed using largescale, randomized, placebo-controlled clinical trials.. Surveillance of viral mutations during antiviral treatment and a better understanding of the associations of HCC recurrence with viral load, inflammation-associated signaling, and environmental factors can aid the development of more effective strategies for the prevention of HCC recurrence after surgery.

Context: Studies on experimental animals have shown liver is a common target of chemical carcinogens; this might suggest that occupational exposure to chemicals is another risk factor for HCC. However, the relationship between occupation and liver cancer has not been extensively studied, with the exception of the known association between vinyl chloride and angiosarcoma of the liver..Evidence Acquisition: A MEDLINE and conventional search of the past 50 years of the medical literature was performed to identify relevant articles on incidence and mechanisms of HCC due to occupational exposure to chemicals. Several important edited books and monographs were also identified and reviewed.. While laboratory data clearly indicate that the liver is an important target of chemical carcinogenesis, epidemiological studies provide very limited evidence on occupational risk factors for HCC. Nevertheless, we found some case reports and epidemiological data showing a moderately increased risk of HCC development in people exposed to vinyl chloride, organic solvents, pesticides, polychlorinated biphenyls, and arsenic.. Occupational exposure to chemicals may be another risk factor for HCC development, but the interpretation of currently available findings is limited by the small number of studies, questionable accuracy of the diagnosis of liver cancer, and potential confounding or modifying factors such as chronic hepatitis virus infection and alcohol consumption. Further relevant investigations are required for clarifying the actual contribution of occupational exposure to chemicals in HCC development.

Context: Primary liver cancer is one of the most common and deadly malignant neoplasms worldwide. The incidence and mortality rates for hepatocellular carcinoma (HCC) are virtually identical, reflecting the poor overall survival of patients with this kind of tumor. Effective therapies mostly achieved if the HCC diagnosis is made at early stages of the tumor. Surveillance tests include serologic and radiologic examinations..Evidence Acquisition: In this review, an overview of biomarkers for the diagnosis of HCC and future challenges in this popular field has been presented.. Serum tumor markers, such as alpha-fetoprotein (AFP) and des-gammacarboxy prothrombin (DCP) are commonly used for the surveillance, but their roles have been intensely debated despite the existence of sensitive radiologic tests. Most HCC-related cancer biomarkers are involved in chronic inflammation and cancer. These biomarkers, according to their biologic characteristics are primarily divided into three groups including onco-foetal protein, stress protein, and post-translational modification.. Because of the limitations of traditional HCC biomarkers, exploration for novel biomarkers for the diagnosis of HCC is an evolving process.

Context: Clinical and experimental studies have suggested a link between S100 gene ex­pression and neoplastic disorders, however, the molecular mechanisms of this associa­tion are not well understood. The aim of this review was to conduct a comprehensive literature search in order to understand the possible underlying molecular mechanisms of this association. We also discuss their application as diagnostic and prognostic mark­ers in colorectal and hepatocellular carcinoma..Evidence Acquisitions: We searched Pubmed (NLM) and Web of Science (ISI Web of Knowledge).. S100 genes display a complex expression pattern in colorectal and hepatocel­ lular carcinoma. They are expressed in tumor and/or tumor stroma cells, and they exert both pro- and antitumorigenic actions. In view of this complexity, it becomes clear that S100 proteins might act as both friend and foe. The biological role of the S100 genes is predicted to depend on the relative contributions of the different cell types at specific stages of tumor progression.. Further research is required in order to uncover the functional role of S100 genes in tumorigenesis. Answers to this issue are needed before we can more fully un­derstand the clinical relevance of S100 protein expression within epithelial tumors, with regard to their potential applicability as biomarkers for diagnosis and therapy decisions.

Currently, there is a remarkable lack of genetic epidemiological studies on alpha 1-antitrypsin (AAT) deficiency in about half of the 193 countries of the World. This fact impedes the establishment of a true prevalence pattern of this deleterious hereditary disorder in extensive regions of human population.. The aim of the present study was to generate detailed maps of the frequency distribution of the two most frequent AAT deficiency alleles (i.e., PI*S and PI*Z) in all areas of the World.. Available data provided by epidemiological studies performed in 94 of 193 countries worldwide was used to develop detailed maps of these two alleles, We employed an informatics mathematical approach, namely: the ArcMap [a component of ESRI’s ArcGIS Geographical Information System (GIS), for Microsoft Windows], based on the inverse distance weighting (IDW) multivariate interpolation method, which creates new numerical points from known data, using a simple logarithm based in the distance existing between them. In this method, PI*S and PI*Z frequencies were represented by colored scales, where qualitative colors were converted into quantitative data, providing information on their distribution in all parts of the world. This approach not only confirmed our previous data, but also provided digital images of the remaining regions of all continents.. By using this approach, striking differences were found among regions, and unsuspected significant values of the PI*S and PI*Z alleles frequencies were obtained for several geographic regions where have not been studied yet. In fact, some of these regions might be considered as priority targets for further screening studies on AAT deficiency, in order to identify, and properly manage, individuals at risk for the diverse adverse health effects associated with AAT deficiency.

Contexts: Hepatocellular carcinoma (HCC) is one of the most common malignant diseases in the world. Because less than 20% of patients with HCC are resectable, various types of non-surgical treatment have been developed..Evidence Acquisition: At present, radiofrequency ablation (RFA) is accepted as the standard local treatment for patients with HCC because of its superior local control and overall survival compared to other local treatments.. New devices for RFA and combination treatments of RFA with other procedures have been developed to improve anti-tumoral effects.. This review mainly focuses on the status of RFA in the management of HCC and recent advances in RFA treatment technology.

Context: From the 1970s till the mid 1990s, hepatitis B was the most common etiological factor for hepatocellular carcinoma (HCC) in Pakistan. Afterwards, a shift in HCC etiology was observed with a steady rise in hepatitis C virus (HCV) related HCC cases. HCV-3a, which is the most prevalent genotype, is also most frequent in HCV related HCC. There was an increase in the proportion of non-B non-C (NBNC) HCC cases as well, which might be attributed to an increase in non-alcoholic fatty liver disease..Evidence Acquisition: The age-standardized rate for HCC is 7.64/100 000 in males and 2.8/100 000 in females. Male to female ratio is 3.6:1. Usual age of presentation is in the fifth and sixth decade. Most patients present with advanced disease, as they are not in a regular surveillance program. This is more so for patients with NBNC chronic liver disease. As many sonologists in Pakistan are practicing without sufficient training to pick up early lesions, alpha-fetoprotein is still recommended to compliment ultrasound in the surveillance of HCC.. Majority of HCC patients present with nonresectable disease. Interventions such as transarterial chemoembolization, radiofrequency ablation, resection and chemotherapy including sorafenib are available in selected centers. Pakistan appears to be in an area of intermediate endemicity for HCC. There is a need for population based epidemiological studies to estimate the exact disease burden.. Measures to prevent the spread of hepatitis C and B can slow down the epidemic rise in the incidence of HCC in the coming decades. There is a need to implement a proper surveillance program to identify HCC cases at an early stage..

Context: Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections constitute a major global health problem. About 60,000 and 350,000 deaths occur as the results of HBV and HCV infections, respectively. Chronic hepatitis B and C infections are leading causes of cirrhosis and hepatocellular carcinoma (HCC) which are considered as the third cancer-associated cause of deaths worldwide. Iran suffers from the same problem but to a lesser extent as it is considered as a low endemic area for HBV and HCV infections and also as a low incidence area of HCC. This study was conducted to assess and provide a clear picture about epidemiology of HBV and HCV infections in Iran and worldwide, with the consequence on HCC distribution all over the world including Iran, and to analyze current literature regarding the modes of transmission and risk factors of HBV and HCV infections..Evidence Acquisition: In this review, we performed electronic and manual searches on available databases such as MEDLINE, PubMed, Ovid, Embase, and the Iranian databases such as IranMedex. We also performed a Google search to find related articles.. HBV and HCV infections are the most common risk factors of hepatocellular carcinoma. The epidemiology of HCC usually follows that of HBV and HCV infections. With the introduction of HBV national vaccine in Iran and worldwide, there is a noticeable effect on reduction in HBV prevalence in most countries, and we expect that HCV will replace HBV as a major risk factor of HCC in Iran and worldwide. Alcohol plays a minor role as a risk factor for cirrhosis and HCC in Iran, Asia, and Africa, despite its noticeable role in Europe and the USA.. Vaccination against HBV remains the most effective approach against HBV infection with consequence decrease in HBV-related HCC. There is a need to improve the awareness about epidemiology of HBV and HCV infections, modes of transmission, and their complications, specifically HCC among population.

Context: Alpha-1-antitrypsin (A1AT) is the most abundant liver-derived, highly polymorphic, glycoprotein in plasma. Hereditary deficiency of alpha-1-antitrypsin in plasma (A1ATD) is a consequence of accumulation of polymers of A1AT mutants in endoplasmic reticulum of hepatocytes and other A1AT-producing cells. One of the clinical manifestations of A1ATD is liver disease in childhood and cirrhosis and/or hepatocellular carcinoma (HCC) in adulthood. Epidemiology and pathophysiology of liver failure in early childhood caused by A1ATD are well known, but the association with hepatocellular carcinoma is not clarified. The aim of this article is to review different aspects of association between A1AT variants and hepatocellular carcinoma, with emphasis on the epidemiology and molecular pathogenesis. The significance of A1AT as a biomarker in the diagnosis of HCC is also discussed..Evidence Acquisitions: Search for relevant articles were performed through Pub Med, HighWire, and Science Direct using the keywords “alpha-1-antitrypsin”, “liver diseases”, “hepatocellular carcinoma”, “SERPINA1”. Articles published until 2011 were reviewed.. Epidemiology studies revealed that severe A1ATD is a significant risk factor for cirrhosis and HCC unrelated to the presence of HBV or HCV infections. However, predisposition to HCC in moderate A1ATD is rare, and probably happens in combination with HBV and/or HCV infections or other unknown risk factors. It is assumed that accumulation of polymers of A1ATD variants in endoplasmic reticulum of hepatocytes leads to damage of hepatocytes by gain-of-function mechanism. Also, increased level of A1AT was recognized as diagnostic and prognostic marker of HCC.. Clarification of a carcinogenic role for A1ATD and identification of proinflammatory or some still unknown factors that lead to increased susceptibility to HCC associated with A1ATD may contribute to a better understanding of hepatic carcinogenesis and to the development of new drugs..

Context: Hepatocellular carcinoma (HCC) is one of the most common cancers in the world but with a striking geographical variation in incidence; most of the burden is in developing countries. This geographic variation in HCC incidence might be due to geographic differences in the prevalence of various etiological factors..Evidence Acquisition: Here, we review the epidemiological evidence linking dietary exposure to aflatoxin B1 (AFB1) and risk of HCC, possible interactions between AFB1 and hepatitis B virus (HBV) or polymorphisms of genes involved in AFB1-related metabolism as well as DNA repair.. Ecological, case-control and cohort studies that used various measures of aflatoxin exposure including dietary questionnaires, food surveys and biomarkers are summarized.. Taken together, the data suggest that dietary exposure to aflatoxins is an important contributor to the high incidence of HCC in Asia and sub-Saharan Africa, where almost 82% of the cases occur.

Context: Hepatitis B and Hepatitis C (HBV and HCV) infections are both major causes of hepatocellular carcinoma (HCC). However, HCC caused by each of these two viruses has unique characteristics that should be studied independently to that of another one. While HBV- and HCV-related HCCs share similar host and environmental risk factors such as male gender, age above 50 years old, family history of HCC, cirrhosis, obesity, and concomitant alcohol/tobacco use, they differ in their viral risk factors..Evidence Acquisition: The actual level of HBV DNA, the presence of HBV e antigen (HBeAg), and mutations in the viral genome are important predisposing factors to HCC development in HBV, whereas in HCV, viremia of any amount denotes an elevated risk. HBV and HCV also differ in their mechanisms of carcinogenesis. For example, HBV can integrate into the host genome and induce many different genetic alterations/mutations. Ultimately, though, both viruses act on similar pathways to produce HCC.. HBV and HCV are often transmitted differently - vertically (HBV) and horizontally (HCV), which may play a role in their distinct clinical presentations: HBV patients are younger and more frequently have larger/ bilobar tumors as opposed to HCV patients, who have worse liver function on diagnosis of HCC. Even the way they respond to treatment seems to be different. HBV-related HCC patients tend to progress faster after sorafenib treatments.. Future studies should investigate the ways in which these differences between HBV- and HCV-related HCC can translate into more tailored treatment strategies for each etiology of HCC in order to improve outcomes of both..

Context: Since the introduction of highly active anti-retroviral regimen for human immunodeficiency virus-1 infection, a significant increase in the incidence of hepatocellular carcinoma has been reported in patients already chronically infected with hepatitis B virus and then given this form of regimen for their retroviral infection.. Evidence Acquisition: This phenomenon was initially attributed to the far more prolonged survival of those patients who received this new regimen, which provided sufficient time, allowing hepatitis B virus-induced hepatocellular carcinoma to develop.. The current belief is that the increased incidence of hepatocellular carcinoma is because of co-infection with the two viruses, one known to be hepatocarcinogenic and the other suspected to increase the carcinogenic potential of the other. Because both hepatitis B virus and human immunodeficiency virus -1 are endemic in the Black population of sub-Saharan Africa and are transmitted in similar ways, as many as 20% of this population are co-infected with the two viruses. In this way, the already high risk of Black African patients developing hepatitis B virus-induced hepatocellular carcinoma is further increased.. The pathogenetic mechanism or mechanisms involved in the carcinogenic interaction between the hepatitis B virus and the human immunodeficiency virus-1 in sub-Saharan Black Africans and other populations co-infected with these viruses have yet to be determined..

Context: Several risk factors play the role in the development of hepatocellular carcinoma (HCC) from which chronic hepatitis B and C infections are the most important ones. DNA integration of hepatitis viruses alters the function of critical genes promoting malignant transformation of virus-infected liver cells..Evidence Acquisition: There are remarkable geographic differences in prevalence of chronic viral hepatitis and incidence of HCC. Middle Eastern countries are characterized by a moderate to high prevalence rate of chronic viral hepatitis in the population. This review discusses about epidemiologic findings of hepatitis B and C infections, and HCC, as well as focuses on Middle East countries, particularly Iran. We provide an overview about risk factors, prevention and treatment, and bring up the role of HCC induced by chronic viral hepatitis.. Vaccination against hepatitis B virus (HBV) in the early childhood is highly effective to lower infection rates, substantially. For hepatitis C, adequate hygiene when dealing with human blood and screening programs for blood donors can mainly reduce infection rates. As HCC is strongly associated with chronic viral hepatitis, prevention against the infection is crucial for preventing against HCC too.. Although prevention and treatment of chronic hepatitis B and C have improved within the last decades even in high-risk countries, effective and sustainable reduction of these infections still needs more actions..

Hepatocellular carcinoma (HCC) is the fifth most common fatal cancer and an important healthcare problem worldwide. There are many studies describing the prognostic and predictive effects of epidermal growth factor receptor 2 (c-erb-B2) and epidermal growth factor receptor 1 (EGFR), transmembrane tyrosine kinases that influence cell growth and proliferation in many tumors.. The current study aimed to investigate the expression levels of c-erb-B2, EGFR, PTEN, mTOR, PI3K, p27, and ERCC1 in hepatocellular carcinoma (HCC) and their correlation with other clinicopathologic features..Patients and Fifty HCC cases were stained immunohistochemically with these markers. Correlations between the markers and clinicopathologic characteristics and survival rates were analyzed.. No membranous c-erb-B2 staining was seen, whereas cytoplasmic positivity was present in 92% of HCC samples, membranous EGFR was observed in 40%, PI3K was found in all samples, and mTOR was seen in 30%, whereas reduced or absent PTEN expression was observed in 56% of samples and loss of p27 was seen in 92% of the cases. c-erb-B2 and mTOR overexpression, as well as reduced expression of p27, all correlated with multiple tumors (P = 0.041, P < 0.001, and P < 0.001, respectively). P27 loss, and mTOR and EGFR positivity were significantly correlated with AFP (P = 0.047, P = 0.004, and P = 0.008, respectively). Angiolymphatic invasion was more commonly seen in EGFR- and ERCC1-positive cases (P = 0.003 and P = 0.005). EGFR was also correlated with histological grade (P = 0.039). No significant correlations were found among PTEN, PI3K, and the clinicopathological parameters. Disease-free or overall survival rates showed significant differences among therapy modalities, AFP levels, angiolymphatic or lymph node invasions, and ERCC1 and p27 expression levels (P < 0.05).. c-erb-B2, EGFR, mTOR, ERCC1 overexpression levels, and loss of p27 may play roles in hepatocarcinogenesis and may be significant predictors of aggressive tumor behavior. These markers were found to be correlated with certain clinicopathologic features, therapy modalities, and survival rates in the current study. These findings may help in planning new, targeted treatment strategies. .

Coincidental occurrence of hepatocellular carcinoma (HCC) and cholangiocarcinoma, known as “collision tumors”, within a cirrhotic liver is rare. Herein, we report a case of liver transplantation (LT) in a patient with such collision tumors. Our patient was a 56-year-old woman with hepatitis C virus-related cirrhosis and 2 focal hepatic lesions, measuring 1.5 and 3 cm, in the liver segments 8 and 5, respectively. The lesion on segment 8 showed the typical radiological characteristics of HCC; however, the lesion in segment 5 showed an atypical vascular pattern and was closely associated with the inferior vena cava. Serum alpha-fetoprotein level was normal and serum carbohydrate antigen 19-9 (CA19-9) level was slightly elevated (63 U/mL); the extrahepatic spread of HCC was ruled out. The patient underwent an uneventful deceased-donor LT. Histopathological examination of the explant confirmed that the lesion on segment 8 was an HCC, but surprisingly, the lesion on segment 5 was found to be a cholangiocarcinoma. Six months after LT, the serum CA19-9 level was markedly elevated (255 U/mL), and the patient began experiencing abdominal pain. Magnetic resonance imaging showed enlarged hilar and paraaortic lymph nodes that were suggestive of metastases; histopathological analysis using ultrasound (US)-guided biopsy confirmed recurrent cholangiocarcinoma. Unfortunately, the patient died because of tumor recurrence 9 months after LT. Collision tumor resulting from the co-existence HCC and cholangiocarcinoma in a cirrhotic liver is rare and has a negative impact on the outcome of LT. Atypical vascular pattern and elevated serum CA19-9 levels are suggestive of such tumors; patients with these findings should undergo a targeted biopsy to rule out the coincidental occurrence of HCC and cholangiocarcinoma..