Hepatocellular carcinoma (HCC) is a growing health problem in humans. HCC is considered the most common of internal malignancy which cause the death of human, but in the developed Western world, HCC is less common accompanied by increasing essentially in incidence, due to it occurs specially in chronic liver disease. HCC associated with various risk factors including hepatitis B virus infection; hepatitis C virus infection; prolonged aflatoxin exposure; and alcoholic cirrhosis. Overall, one-third of cirrhosis patients will develop HCC during their life time. Also, chemical carcinogens cause tumor promotions through free radical metabolites result in many biochemical and molecular changes that induces oxidative stress. The identify of HCC stage and underlying liver status then choosing the most appropriate line of therapy (surgical, loco regional, radiological and medical) can be improve the survival and/or the quality of life of the patient. Taken into the account of the nutritional value of some natural antioxidant agents that support the function of the body resulting an improvement of the health and protection from different diseases, our review will provide an up-dated status of the different aspects of HCC management through covering the efficacy and the beneficial effects of different natural agents and their mechanism of action against HCC for the future therapy modalities.

As obligate intracellular parasites, viruses need a host cell to provide a milieu favorable to viral replication. Consequently, viruses often adopt mechanisms to subvert host cellular signaling processes. While beneficial for the viral replication cycle, virus-induced deregulation of host cellular signaling processes can be detrimental to host cell physiology and can lead to virus-associated pathogenesis, including, for oncogenic viruses, cell transformation and cancer progression. Included among these oncogenic viruses is the hepatitis B virus (HBV). Despite the availability of an HBV vaccine, 350-500 million people worldwide are chronically infected with HBV, and a significant number of these chronically infected individuals will develop hepatocellular carcinoma (HCC). Epidemiological studies indicate that chronic infection with HBV is the leading risk factor for the development of HCC. Globally, HCC is the second highest cause of cancer-associated deaths, underscoring the need for understanding mechanisms that regulate HBV replication and the development of HBV-associated HCC. HBV is the prototype member of the Hepadnaviridae family; members of this family of viruses have a narrow host range and predominately infect hepatocytes in their respective hosts. The extremely small and compact hepadnaviral genome, the unique arrangement of open reading frames, and a replication strategy utilizing reverse transcription of an RNA intermediate to generate the DNA genome are distinguishing features of the Hepadnaviridae. In this review, the authors provide a comprehensive description of HBV biology, summarize the model systems used for studying HBV infections, and highlight potential mechanisms that link a chronic HBV-infection to the development of HCC. For example, the HBV X protein (HBx), a key regulatory HBV protein that is important for HBV replication, is thought to play a cofactor role in the development of HBV-induced HCC, and the authors highlight the functions of HBx that may contribute to the development of HBV-associated HCC.

A selection of patients with hepatocellular carcinoma (HCC) for surgical resection is crucial and algorithms/staging systems help surgeons to decide on a standard treatment for each patient and each HCC stage. However, there are always difficulties in remembering and/or recalling the contents of the algorithms/staging systems. Moreover, most algorithms/staging systems don’t include data about the extent of hepatectomy, intra-hepatic distribution of tumor(s), and technical feasibility of resection, all of which are vital in the surgeons’ decision-making process. Here, we aimed to present a simple and handy mnemonic acronym for selecting resectable HCCs in surgical practice. This was reproduced from the existing well-known staging systems. The designed mnemonic acronym is a phrase “PERISH” and it includes asking for Performance of patient, Extra-hepatic disease, Reserve of liver, Intra-hepatic distribution, Stratifying risk factors, and Hepatectomy size in order. Performance based on whether the patient is mostly bedridden or not, should be the first step of evaluation. Next, asking for suspicious metastasis as bone pain and radiological evaluation of abdomen/thorax is mandatory. The calculation of Child-Pugh score is only the third step. Good candidates for surgical resection should be Child-Pugh “A” with normal bilirubin levels. Technical feasibility of resection according to the intra-hepatic distribution of tumor(s) should be done later and the candidates preferably should not have portal hypertension (no splenomegaly, no thrombocytopenia). If the patient fulfils all the previous steps, the surgeon may perform indo-cyanine green clearance test. Consequently, following the PERISH flowchart may prevent “perish” of the surgeons while selecting the appropriate resectable HCCs.

Hepatocellular carcinoma (HCC) arising in non-cirrhotic livers is relatively rare. Compared with HCC arising in cirrhotic livers they have some quirks. HCC in healthy livers are large tumors at diagnosis, and are detected due to the onset of abdominal symptoms, outside of any scheduled monitoring program. In non-cirrhotic patients, HCC has the same appearance as the classic image of cirrhotic HCC substrate. The presence of capsule, extensive intratumoral necrosis and typical behavior in the dynamic study after administration of intravenous contrast are present in most of the non-cirrhotic livers. In the presence of a suspicious lesion of HCC, we must assess the existence of underlying chronic liver disease. Ultrasound, computed tomography, and conventional magnetic resonance are imaging techniques that have a high specificity for the diagnosis of cirrhosis, but exhibit low sensitivity for diagnosis in the early stages of the disease. In recent years, new imaging methods are being developed to assess emerging liver fibrosis. In particular, in patients without chronic liver disease it is imperative to consider the differential diagnosis with other tumors that may settle in healthy livers with similar radiological characteristics as HCC. Therefore, in the presence of a lesion with pathognomonic radiological characteristics of HCC in the absence of cirrhosis, biopsy is required.

Cytokines are soluble extracellular small molecular weight protein or peptide. They are produced by virtually every nucleated cell type in response to injurious stimuli to control body metabolism, infection, inflammation and tissue or neuronal damage; therefore acting as messengers between tissues and the immune system; and participating in many physiological processes through their either anti-inflammatory or pro-inflammatory characteristics. Many cytokines have multiple cellular sources and targets, as well as many natural inducers and inhibitors. In pathophysiological conditions and during the early phase of chronic liver diseases, agent like virus, bacteria, parasites, ethanol, or toxins, induce secretion of cytokines at high levels. The presence of cytokine antagonists and soluble cytokine receptors, often released in concert with their respective cytokine agonist, presents additional complexity to interpretation.

As obligate intracellular parasites, viruses need a host cell to provide a milieu favorable to viral replication. Consequently, viruses often adopt mechanisms to subvert host cellular signaling processes. While beneficial for the viral replication cycle, virus-induced deregulation of host cellular signaling processes can be detrimental to host cell physiology and can lead to virus-associated pathogenesis, including, for oncogenic viruses, cell transformation and cancer progression. Included among these oncogenic viruses is the hepatitis B virus (HBV). Despite the availability of an HBV vaccine, 350-500 million people worldwide are chronically infected with HBV, and a significant number of these chronically infected individuals will develop hepatocellular carcinoma (HCC). Epidemiological studies indicate that chronic infection with HBV is the leading risk factor for the development of HCC. Globally, HCC is the second highest cause of cancer-associated deaths, underscoring the need for understanding mechanisms that regulate HBV replication and the development of HBV-associated HCC. HBV is the prototype member of the Hepadnaviridae family; members of this family of viruses have a narrow host range and predominately infect hepatocytes in their respective hosts. The extremely small and compact hepadnaviral genome, the unique arrangement of open reading frames, and a replication strategy utilizing reverse transcription of an RNA intermediate to generate the DNA genome are distinguishing features of the Hepadnaviridae. In this review, the authors provide a comprehensive description of HBV biology, summarize the model systems used for studying HBV infections, and highlight potential mechanisms that link a chronic HBV-infection to the development of HCC. For example, the HBV X protein (HBx), a key regulatory HBV protein that is important for HBV replication, is thought to play a cofactor role in the development of HBV-induced HCC, and the authors highlight the functions of HBx that may contribute to the development of HBV-associated HCC.

Systemic therapy for hepatocellular carcinoma (HCC) has been disappointing. The only drug approved by Food and Drug Administration recently has been sorafenib. Sorafenib has modest benefits with a low response rate and an improvement in time to progression of only 2-3 months. Multiple randomized trials, which compare the new agent to sorafenib as either first line or second line therapy, have been negative, showing no improved clinical benefit. Recently, in a large phase III randomized trial, regorafenib has shown superiority to placebo as a second line treatment for HCC. However, this drug has multiple side effects and is not well tolerated by many patients. The clinical benefit is also modest. Clearly, new approaches to treat advanced HCC are still needed. There is data showing that HCC is immunogenic and the immune system can be stimulated to attack these cancer cells. This article will briefly review immunotherapy as a promising treatment for HCC.

Over the past few years, despite improvement in screening and diagnosis of hepatocellular carcinoma (HCC), advanced stage remains the most common presentation at diagnosis, with limited management options, especially options available to patients in limited resource countries. There is currently no effective systemic chemotherapy, targeted, or immunologic therapy for advanced stage HCC. Sorafenib is the only approved front-line molecular-targeted treatment,with slight survival benefit. Regorafenib has recently been approved as second line therapy for HCC after failure of sorafenib. Ongoing research on molecular agents targeting different pathways, combination therapies, and immunotherapy, represent hope for new treatment modalities. This manuscript reviews current treatment, ongoing research, and potential future treatments for advanced HCC.

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that could develop at any level from the biliary tree. CCA is currently classified into intrahepatic (iCCA), perihilar and distal on the basis of its anatomical location. Of note, these three CCA subtypes have common features but also important inter-tumor and intra-tumor differences that can affect the pathogenesis and outcome. A unique feature of iCCA is that it recognizes as origin tissues, the hepatic parenchyma or large intrahepatic and extrahepatic bile ducts, which are furnished by two distinct stem cell niches, the canals of Hering and the peribiliary glands, respectively. The complexity of iCCA pathogenesis highlights the need of a multidisciplinary, translational and systemic approach to this malignancy. This review will focus on the advances of iCCA epidemiology, histo-morphology, risk factors, molecular pathogenesis, revealing the existence of multiple subsets of iCCA.

Hepatorenal syndrome is not an uncommon life-threatening complication arising from liver cirrhosis. The diagnostic criteria for this syndrome have been revised throughout the years, with recent revisions aimed at improving earlier diagnosis and treatment. Liver transplantation remains the only definitive treatment for hepatorenal syndrome. Due to the scarcity of liver grafts, many patients die waiting. This review focuses on the different strategies to bridge patients to liver transplantation and to improve the postoperative outcome.

Cytokines are soluble extracellular small molecular weight protein or peptide. They are produced by virtually every nucleated cell type in response to injurious stimuli to control body metabolism, infection, inflammation and tissue or neuronal damage; therefore acting as messengers between tissues and the immune system; and participating in many physiological processes through their either anti-inflammatory or pro-inflammatory characteristics. Many cytokines have multiple cellular sources and targets, as well as many natural inducers and inhibitors. In pathophysiological conditions and during the early phase of chronic liver diseases, agent like virus, bacteria, parasites, ethanol, or toxins, induce secretion of cytokines at high levels. The presence of cytokine antagonists and soluble cytokine receptors, often released in concert with their respective cytokine agonist, presents additional complexity to interpretation.

As obligate intracellular parasites, viruses need a host cell to provide a milieu favorable to viral replication. Consequently, viruses often adopt mechanisms to subvert host cellular signaling processes. While beneficial for the viral replication cycle, virus-induced deregulation of host cellular signaling processes can be detrimental to host cell physiology and can lead to virus-associated pathogenesis, including, for oncogenic viruses, cell transformation and cancer progression. Included among these oncogenic viruses is the hepatitis B virus (HBV). Despite the availability of an HBV vaccine, 350-500 million people worldwide are chronically infected with HBV, and a significant number of these chronically infected individuals will develop hepatocellular carcinoma (HCC). Epidemiological studies indicate that chronic infection with HBV is the leading risk factor for the development of HCC. Globally, HCC is the second highest cause of cancer-associated deaths, underscoring the need for understanding mechanisms that regulate HBV replication and the development of HBV-associated HCC. HBV is the prototype member of the Hepadnaviridae family; members of this family of viruses have a narrow host range and predominately infect hepatocytes in their respective hosts. The extremely small and compact hepadnaviral genome, the unique arrangement of open reading frames, and a replication strategy utilizing reverse transcription of an RNA intermediate to generate the DNA genome are distinguishing features of the Hepadnaviridae. In this review, the authors provide a comprehensive description of HBV biology, summarize the model systems used for studying HBV infections, and highlight potential mechanisms that link a chronic HBV-infection to the development of HCC. For example, the HBV X protein (HBx), a key regulatory HBV protein that is important for HBV replication, is thought to play a cofactor role in the development of HBV-induced HCC, and the authors highlight the functions of HBx that may contribute to the development of HBV-associated HCC.

Aim: Worldwide, hepatocellular cancer (HCC) is the fourth leading cause of cancer death and occurs 3 times more commonly in males than females. Current surveillance practices do not fully address gender differences in HCC.

Methods: Clinical characteristics and survival were compared between males and females using a prospectively collected database of HCC patients.

Results: In a cohort of 1206 patients, 307 (25%) were female who presented with older age, more non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), family history of HCC, and hypertension. Males (75%) were more likely to use alcohol and cigarettes. Females were more likely to undergo HCC surveillance, have smaller tumor size at diagnosis, and less vascular involvement. Males who met Milan criteria were more likely to undergo liver transplant than women who met the criteria. Median/mean survival was similar between the genders. Multivariate analysis showed that NAFLD/NASH was predictive of mortality for both males and females, age and smoking were predictive of mortality for males, and transplant was predictive of survival for males.

Conclusion: Gender differences in HCC appear related to both behavioral risk factors and biologic factors. Older females with HCC have more NAFLD/NASH and may be overlooked by current surveillance guidelines. These gender disparities may lend support to future studies of gender-based HCC screening.

Aim: This study aimed to explore the potential of detecting hepatocellular carcinoma (HCC)-associated DNA markers, TP53 249T mutations and aberrant methylation of RASSF1A and GSTP1 genes, for monitoring HCC recurrence. HCC remains a leading cause of death worldwide, with one of the fastest growing incidence rates in the US. While treatment options are available and new ones emerging, there remains a poor prognosis of this disease mostly due to its late diagnosis and high recurrence rate. Although there are no specific guidelines addressing how HCC recurrence should be monitored, recurrence is usually monitored by serum-alpha fetal protein and imaging methods such as magnetic resonance imaging (MRI). However, early detection of recurrent HCC remains limited, particularly at the site of treated lesion.

Methods: Here, the authors followed 10 patients that were treated for a primary HCC, and monitored for months or years later. At these follow-up visits, urine was collected and tested retrospectively for 3 DNA biomarkers that associate with HCC development.

Results: This 10-patient study compared detection of urine DNA markers with MRI for monitoring HCC recurrence. Five patients were confirmed by MRI for recurrence, and all 5 had detectable DNA biomarkers up to 9 months before recurrence confirmation by MRI.

Conclusion: Overall, this suggests that detection of HCC-associated DNA markers in urine could provide a promising tool to complement detection of recurrent HCC by imaging.

The liver is an essential organ for nutrient and drug metabolism - possessing the remarkable ability to sense environmental and metabolic stimuli and provide an optimally adaptive response. Early growth response 1 (Egr1), an immediate early transcriptional factor which acts as a coordinator of the complex response to stress, is induced during liver injury and controls the expression of a wide range of genes involved in metabolism, cell proliferation, and inflammation. In support of an important role of Egr1 in liver injury and repair, deficiency of Egr1 delays liver regeneration process. The known upstream regulators of Egr1 include, but are not limited to, growth factors (e.g. transforming growth factor β1, platelet-derived growth factor, epidermal growth factor, hepatocyte growth factor), nuclear receptors (e.g. hepatocyte nuclear factor 4α, small heterodimer partner, peroxisome proliferator-activated receptor-γ), and other transcription factors (e.g. Sp1, E2F transcription factor 1). Research efforts using various animal models such as fatty liver, liver injury, and liver fibrosis contribute greatly to the elucidation of Egr1 function in the liver. Hepatocellular carcinoma (HCC) represents the second leading cause of cancer mortality worldwide due to the heterogeneity and the late stage at which cancer is generally diagnosed. Recent studies highlight the involvement of Egr1 in HCC development. The purpose of this review is to summarize current studies pertaining to the role of Egr1 in liver metabolism and liver diseases including liver cancer.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. There are two major challenges for HCC, the first being that early detection is generally not applicable, and secondly, it is usually fatal within several months after diagnosis. HCC is an inflammation-induced cancer. It is known that chronic inflammation leads to oxidative/nitrosative stress and lipid peroxidation, generating excess oxidative stress, together with aldehydes which can react with DNA bases to form promutagenic DNA adducts. In this review, the evidence between oxidative stress and liver carcinogenesis is summarized. We focused on the potential of using DNA adducts as oxidative stress biomarkers for liver carcinogenesis.

Liver diseases are most common disorders in the world and characterized by rapid changes from steatosis to chronic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Natural products that attained great attention is to be used in the prevention and treatment of multiple diseases in humans. Several researches have been reported numerous natural and phytochemical compounds that may counteract or prevent the hepatic injury and primary liver cancer. The conservative treatment of liver toxicity and HCC may face awkward challenges in chemotherapy such as therapeutic failure or drug resistance. Accordingly, there is an actual need for safe and effective therapeutic and preventive modalities for liver disorders. The present review aims to focus on the potential protective and therapeutic effects of natural compounds in prevention and treatment of hepatotoxicity and HCC. It also demonstrates the mechanism of the natural products in enzymatic regulation of antioxidants and its role in apoptosis and proliferation of cancerous lesions of hepatocytes. Accordingly, it highlights the promising role of natural bioactive compounds and provides the rational for further transitional researches, and emphasize on the scientific validation of natural compounds for therapeutic portfolio for clinical use in liver diseases.

Hepatocellular carcinoma (HCC) is the fifth commonest cause of malignancy and the third cause of cancer mortality. There are different treatment options for HCC ranging from loco-regional therapy to surgical treatment. Different regimen of systemic chemotherapy has been tried with a poor response. Several studies aimed at discovering more molecules for the management of HCC. Those studies aimed at recognizing and targeting several signalling and molecular pathways that lead to cellular proliferation and tumour formation. In this review, we discussed the role of several agents found in natural and dietary products such as curcumin, resveratrol, flavonoids, Rubus aleaefolious Poir total alkaloids, Livistona chinesis seed, and crocetin. We had used the names of the above-mentioned products as key words in addition to “Hepatocellular Carcinoma” on PubMed to find studies that discussed their roles in HCC. Articles were downloaded for reviewing and discussing natural products that had adequate studies in treating HCC.

Aim: The present study was conducted to investigate the protective effect of chamomile flowers (CFME) and fennel seeds methanolic (FSME) extracts on azathioprine (AZA), an immunosuppressant drug, which induced liver injury and oxidative stress in rats.

Methods: Rats were divided into 6 groups (8 rats each) and treated orally for 28 consecutive days as follows. Group 1: rats were given normal saline and used as controls; group 2: rats treated with CFME (200 mg/kg); group 3: rats treated with FSME (200 mg/kg); group 4: rats treated with AZA (25 mg/kg); groups 5 and 6: rats treated with CFME (200 mg/kg) or FSME (200 mg/kg) 15 min prior to AZA (25 mg/kg) treatment. At the end of experimental period, blood and liver samples were collected from all groups for the biochemical analysis and histological examination.

Results: The obtained data revealed that AZA induced hepatic injury in the rats as evidenced by the significant increase in serum aspartate aminotransferase, alanine aminotransferase, alkaline phospatase, cholesterol, and direct bilirubin as well as hepatic malondialdehyde level accompanied with significant decrease in reduced glutathione content and total antioxidant capacity in the liver. Moreover, body weight gain showed significant decrease and relative liver weight showed significant increase on AZA treatment. The sequential significant changes in biochemical parameters were accompanied by severe histological changes in the liver tissue, including hepatocytes disorganization with pyknotic nuclei, fatty degeneration, congestion, fibrosis and bile duct necrosis around the portal tract. Areas of hemorrhages in blood vessels and in between hepatocytes were also seen. However, the results showed potential hepatoprotective effects of CFME and FSME against AZA-induced liver injury and oxidative stress. They succeeded to restore the biochemical parameters and improve the histological picture of the liver. This improvement was more pronounced in the rats pretreated with FSME.

Conclusion: It could be concluded that CFME and FSME have hepatoprotective potentials against AZA probably due to their antioxidant properties and radical scavenging activity.

Aim: Protective effects of aqueous extract of Amaranthus hybridus against aflatoxin B₁ (AFB₁) and/or fumonisin B₁ (FB₁) on the H4IIE-luc cell line were determined by use of the methyl thiazol tetrazolium viability assay and disruption of DNA integrity.

Methods: H4IIE-luc cells were incubated with different concentrations of AFB₁ and/or FB₁ for 24 and 48 h with or without aqueous extract of A. hybridus.

Results: AFB₁ decreased viability of cells after 24 and 48 h of exposure. EC₅₀ values for AFB₁ were 10.5 and 1.8 µmol/L for the two periods respectively. When the 48 h exposure to mycotoxin repeated with a pre-treatment of 20 and 40 µg/mL extract of A. hybridus, the EC₅₀ changed to 3.88 and 7.67 µmol/L, respectively. H4IIE-luc cells exposed to FB₁ for 24 h responded more than those incubated for 48 h. Cells treated with a combination of AFB₁ and FB₁ were less viable with a significant decrease at the greater concentration. The mixture of AFB₁ and FB₁ resulted in a significant threat to H4IIE-luc as indicated by the absence or appearance of new bands in random amplified polymorphic DNA analysis, which demonstrated damage to DNA. The protective effects were probably due to greater content of total phenolics, carotenoids, β-carotene, folic-, linolenic-, linoleic and palmitic acids, as well as calcium, magnesium, iron, zinc, and selenium observed in the extract.

Conclusion: Exposure to 40 μg/ml of extract of A. hybridus protected cells from damage to DNA by stabilizing DNA.