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1.  Role of anti-angiogenesis therapy in the management of hepatocellular carcinoma: The jury is still out 
World Journal of Hepatology  2014;6(12):830-835.
As the leading cause of disease-related deaths, cancer is a major public health threat worldwide. Surgical resection is still the first-line therapy for patients with early-stage cancers. However, postoperative relapse and metastasis remain the cause of 90% of deaths of patients with solid organ malignancies, including hepatocellular carcinoma (HCC). With the rapid development of molecular biology techniques in recent years, molecularly targeted therapies using monoclonal antibodies, small molecules, and vaccines have become a milestone in cancer therapeutic by significantly improving the survival of cancer patients, and have opened a window of hope for patients with advanced cancer. Hypervascularization is a major characteristic of HCC. It has been reported that anti-angiogenic treatments, which inhibit blood vessel formation, are highly effective for treating HCC. However, the efficacy and safety of anti-angiogenesis therapies remain controversial. Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti-angiogenic effects and is the first molecular target drug approved for the treatment of advanced HCC. While sorafenib has shown promising therapeutic effects, substantial evidence of primary and acquired resistance to sorafenib has been reported. Numerous clinical trials have been conducted to evaluate a large number of molecularly targeted drugs for treating HCC, but most drugs exhibited less efficacy and/or higher toxicity compared to sorafenib. Therefore, understanding the mechanism(s) underlying sorafenib resistance of cancer cells is highlighted for efficiently treating HCC. This concise review aims to provide an overview of anti-angiogenesis therapy in the management of HCC and to discuss the common mechanisms of resistance to anti-angiogenesis therapies.
doi:10.4254/wjh.v6.i12.830
PMCID: PMC4269901  PMID: 25544869
Hepatocellular carcinoma; Management; Molecularly targeted therapy; Anti-angiogenesis; Sorafenib
2.  Role of hepatectomy for recurrent or initially unresectable hepatocellular carcinoma 
World Journal of Hepatology  2014;6(12):836-843.
As a result of donor shortage and high postoperative morbidity and mortality after liver transplantation, hepatectomy is the most widely applicable and reliable option for curative treatment of hepatocellular carcinoma (HCC). Because intrahepatic tumor recurrence is frequent after loco-regional therapy, repeated treatments are advocated provided background liver function is maintained. Among treatments including local ablation and transarterial chemoembolization, hepatectomy provides the best long-term outcomes, but studies comparing hepatectomy with other nonsurgical treatments require careful review for selection bias. In patients with initially unresectable HCC, transarterial chemo-or radio-embolization, and/or systemic chemotherapy can down-stage the tumor and conversion to resectable HCC is achieved in approximately 20% of patients. However, complete response is rare, and salvage hepatectomy is essential to help prolong patients’ survival. To counter the short recurrence-free survival, excellent overall survival is obtained by combining and repeating different treatments. It is important to recognize hepatectomy as a complement, rather than a contraindication, to other nonsurgical treatments in a multidisciplinary approach for patients with HCC, including recurrent or unresectable tumors.
doi:10.4254/wjh.v6.i12.836
PMCID: PMC4269902  PMID: 25544870
Hepatocellular carcinoma; Hepatectomy; Repeat hepatectomy; Conversion therapy; Multidisciplinary treatment
3.  Transarterial chemoembolization for hepatocellular carcinoma: A review of techniques 
World Journal of Hepatology  2014;6(12):844-850.
Hepatocellular carcinoma (HCC) is one of the most common malignant diseases worldwide. While curative therapies, including resection, liver transplantation, and percutaneous ablation (percutaneous ethanol injection and radiofrequency ablation), are applicable for only a portion of the HCC population, transcatheter arterial chemoembolization (TACE) has been recognized as an effective palliative treatment option for patients with advanced HCC. TACE is also used even for single HCCs in which it is difficult to perform surgical resection or locoregional treatment due to systemic co-morbidities or anatomical problems. TACE has become widely adopted in the treatment of HCC. By using computed tomography-angiography, TACE is capable of performing diagnosis and treatment at the same time. Furthermore, TACE plays an important role in the multidisciplinary treatment for HCC when combined with other treatment. In this review, we first discuss the history of TACE, and then review the previous findings about techniques of achieving a locoregional treatment effect (liver infarction treatment, e.g., ultra-selective TACE, balloon-occluded TACE), and the use of TACE as a drug delivery system for anti-cancer agents (palliative, e.g., platinum complex agents, drug-eluting beads) for multiple lesions.
doi:10.4254/wjh.v6.i12.844
PMCID: PMC4269903  PMID: 25544871
Hepatocellular carcinoma; Transcatheter arterial chemoembolization; Balloon-occluded transcatheter arterial chemoembolization; Drug-eluting bead
4.  How did hepatitis B virus effect the host genome in the last decade? 
World Journal of Hepatology  2014;6(12):851-859.
The principal reason of chronic liver disease, cirrhosis and hepatocellular carcinoma is chronic viral hepatitis all over the world. Hepatitis B virus (HBV) has some mutagenic effects on the host genome. HBV may be exhibiting these mutagenic effects through integrating into the host genome, through its viral proteins or through some epigenetic mechanisms related with HBV proteins. This review aims to summarize the molecular mechanisms used by HBV for effecting host genome determined in the last decade. The focus will be on the effects of integration, HBV proteins, especially HBV X protein and epigenetic mechanisms on the host genome. These interactions between HBV and the host genome also forms the underlying mechanisms of the evolution of hepatocellular carcinoma.
doi:10.4254/wjh.v6.i12.851
PMCID: PMC4269904  PMID: 25544872
Hepatitis B virus; Host genome; Integration; Hepatitis B virus proteins; Epigenetic
5.  Occult hepatitis B virus infection 
World Journal of Hepatology  2014;6(12):860-869.
Occult hepatitis B virus (HBV) infection (OBI) refers to the presence of HBV DNA in the absence of detectable hepatitis B surface antigen. Since OBI was first described in the late 1970s, there has been increasing interest in this topic. The prevalence of OBI varies according to the different endemicity of HBV infection, cohort characteristics, and sensitivity and specificity of the methods used for detection. Although the exact mechanism of OBI has not been proved, intra-hepatic persistence of viral covalently closed circular DNA under the host’s strong immune suppression of HBV replication and gene expression seems to be a cause. OBI has important clinical significance in several conditions. First, OBI can be transmitted through transfusion, organ transplantation including orthotopic liver transplantation, or hemodialysis. Donor screening before blood transfusion, prophylaxis for high-risk organ transplantation recipients, and dialysis-specific infection-control programs should be considered to reduce the risk of transmission. Second, OBI may reactivate and cause acute hepatitis in immunocompromised patients or those receiving chemotherapy. Close HBV DNA monitoring and timely antiviral treatment can prevent HBV reactivation and consequent clinical deterioration. Third, OBI may contribute to the progression of hepatic fibrosis in patients with chronic liver disease including hepatitis C. Finally, OBI seems to be a risk factor for hepatocellular carcinoma by its direct proto-oncogenic effect and by indirectly causing persistent hepatic inflammation and fibrosis. However, this needs further investigation. We review published reports in the literature to gain an overview of the status of OBI and emphasize the clinical importance of OBI.
doi:10.4254/wjh.v6.i12.860
PMCID: PMC4269905  PMID: 25544873
Occult hepatitis B virus infection; Transmission; Reactivation; Chronic liver disease; Hepatocellular carcinoma
6.  Functional foods effective for hepatitis C: Identification of oligomeric proanthocyanidin and its action mechanism 
World Journal of Hepatology  2014;6(12):870-879.
Hepatitis C virus (HCV) is a major cause of viral hepatitis and currently infects approximately 170 million people worldwide. An infection by HCV causes high rates of chronic hepatitis (> 75%) and progresses to liver cirrhosis and hepatocellular carcinoma ultimately. HCV can be eliminated by a combination of pegylated α-interferon and the broad-spectrum antiviral drug ribavirin; however, this treatment is still associated with poor efficacy and tolerability and is often accompanied by serious side-effects. While some novel direct-acting antivirals against HCV have been developed recently, high medical costs limit the access to the therapy in cost-sensitive countries. To search for new natural anti-HCV agents, we screened local agricultural products for their suppressive activities against HCV replication using the HCV replicon cell system in vitro. We found a potent inhibitor of HCV RNA expression in the extracts of blueberry leaves and then identified oligomeric proanthocyanidin as the active ingredient. Further investigations into the action mechanism of oligomeric proanthocyanidin suggested that it is an inhibitor of heterogeneous nuclear ribonucleoproteins (hnRNPs) such as hnRNP A2/B1. In this review, we presented an overview of functional foods and ingredients efficient for HCV infection, the chemical structural characteristics of oligomeric proanthocyanidin, and its action mechanism.
doi:10.4254/wjh.v6.i12.870
PMCID: PMC4269906  PMID: 25544874
Hepatitis C virus; Blueberry leaves; Functional foods; Oligomeric proanthocyanidin; Heterogeneous nuclear ribonucleoproteins
7.  Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies 
World Journal of Hepatology  2014;6(12):880-893.
Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease around the world. It includes a spectrum of conditions from simple steatosis to non-alcoholic steatohepatitis (NASH) and can lead to fibrosis, cirrhosis, liver failure, and/or hepatocellular carcinoma. NAFLD is also associated with other medical conditions such as obesity, diabetes mellitus (DM), metabolic syndrome, hypertension, insulin resistance, hyperlipidemia, and cardiovascular disease (CVD). In diabetes, chronic hyperglycemia contributes to the development of both macro- and microvascular conditions through a variety of metabolic pathways. Thus, it can cause a variety of metabolic and hemodynamic conditions, including upregulated advanced glycation end-products (AGEs) synthesis. In our previous study, the most abundant type of toxic AGEs (TAGE); i.e., glyceraldehyde-derived AGEs, were found to make a significant contribution to the pathogenesis of DM-induced angiopathy. Furthermore, accumulating evidence suggests that the binding of TAGE with their receptor (RAGE) induces oxidative damage, promotes inflammation, and causes changes in intracellular signaling and the expression levels of certain genes in various cell populations including hepatocytes and hepatic stellate cells. All of these effects could facilitate the pathogenesis of hypertension, cancer, diabetic vascular complications, CVD, dementia, and NASH. Thus, inhibiting TAGE synthesis, preventing TAGE from binding to RAGE, and downregulating RAGE expression and/or the expression of associated effector molecules all have potential as therapeutic strategies against NASH. Here, we examine the contributions of RAGE and TAGE to various conditions and novel treatments that target them in order to prevent the development and/or progression of NASH.
doi:10.4254/wjh.v6.i12.880
PMCID: PMC4269907  PMID: 25544875
Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Advanced glycation end-products; Toxic advanced glycation end-products; Receptor for advanced glycation end-products; Toxic advanced glycation end-products-receptor for advanced glycation end-products system; Diabetes mellitus; Cardiovascular disease; Dietary fructose; Dietary advanced glycation end-products
8.  Transitions of histopathologic criteria for diagnosis of nonalcoholic fatty liver disease during the last three decades 
World Journal of Hepatology  2014;6(12):894-900.
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and is the most common type of chronic liver diseases in the majority of developed countries. NAFLD shows a wide spectrum of disorders including simple steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis. While simple steatosis is recognized to be benign and stable, NASH is considered to be an aggressive form of the disease progressing to cirrhosis. Currently, differentiation between NASH and simple steatosis can be done only by liver biopsy. Despite many proposals and revisions, the histological criteria for the differentiation have not been perfected yet. In this review article, the changes in the histopathologic criteria of NAFLD during the last three decades are summarized, and perspectives of the future changes are demonstrated. The discussion focuses on how pathologists have been dealing with “hepatocellular ballooning”. Loose criteria, in which hepatocellular ballooning was not required for the diagnosis of NASH, were applied in many clinical studies published in around 2000’s, whereas a strict criterion based on the presence/absence of hepatocellular ballooning was approved recently. Hence, simple and reliable methods of identifying ballooned hepatocytes are being sought. Clinical and pathological predictors of NAFLD-related hepatocarcinogenesis will also be sought in the future.
doi:10.4254/wjh.v6.i12.894
PMCID: PMC4269908  PMID: 25544876
Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Hepatocellular ballooning; Cirrhosis; Hepatocellular carcinoma
9.  Vitamin D deficiency in chronic liver disease 
World Journal of Hepatology  2014;6(12):901-915.
Vitamin D is an important secosteroid hormone with known effect on calcium homeostasis, but recently there is increasing recognition that vitamin D also is involved in cell proliferation and differentiation, has immunomodulatory and anti-inflammatory properties. Vitamin D deficiency has been frequently reported in many causes of chronic liver disease and has been associated with the development and evolution of non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) virus infection. The role of vitamin D in the pathogenesis of NAFLD and CHC is not completely known, but it seems that the involvement of vitamin D in the activation and regulation of both innate and adaptive immune systems and its antiproliferative effect may explain its importance in these liver diseases. Published studies provide evidence for routine screening for hypovitaminosis D in patients with liver disease. Further prospectives studies demonstrating the impact of vitamin D replacement in NAFLD and CHC are required.
doi:10.4254/wjh.v6.i12.901
PMCID: PMC4269909  PMID: 25544877
Cholecalciferol; Vitamin D; Hepatitis C; Liver fibrosis; Liver disease; Interferon; Sustained virological response; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis
10.  Recombinase polymerase amplification as a promising tool in hepatitis C virus diagnosis 
World Journal of Hepatology  2014;6(12):916-922.
Hepatitis C virus (HCV) infection represents a significant health problem and represents a heavy load on some countries like Egypt in which about 20% of the total population are infected. Initial infection is usually asymptomatic and result in chronic hepatitis that give rise to complications including cirrhosis and hepatocellular carcinoma. The management of HCV infection should not only be focus on therapy, but also to screen carrier individuals in order to prevent transmission. In the present, molecular detection and quantification of HCV genome by real time polymerase chain reaction (PCR) represent the gold standard in HCV diagnosis and plays a crucial role in the management of therapeutic regimens. However, real time PCR is a complicated approach and of limited distribution. On the other hand, isothermal DNA amplification techniques have been developed and offer molecular diagnosis of infectious dieses at point-of-care. In this review we discuss recombinase polymerase amplification technique and illustrate its diagnostic value over both PCR and other isothermal amplification techniques.
doi:10.4254/wjh.v6.i12.916
PMCID: PMC4269910  PMID: 25544878
Hepatitis C virus; Nucleic acid testing; Polymerase chain reaction; Point-of-care; Recombinase polymerase amplification
11.  Palliative external-beam radiotherapy for bone metastases from hepatocellular carcinoma 
World Journal of Hepatology  2014;6(12):923-929.
The incidence of bone metastases (BMs) from hepatocellular carcinoma (HCC) is relatively low compared to those of other cancers, but it has increased recently, especially in Asian countries. Typically, BMs from HCC appear radiologically as osteolytic, destructive, and expansive components with large, bulky soft-tissue masses. These soft-tissue masses are unique to bone metastases from HCC and often replace the normal bone matrix and exhibit expansive growth. They often compress the peripheral nerves, spinal cord, or cranial nerves, causing not only bone pain but also neuropathic pain and neurological symptoms. In patients with spinal BMs, the consequent metastatic spinal cord compression (MSCC) causes paralysis. Skull base metastases (SBMs) with cranial nerve involvement can cause neurological symptoms. Therefore, patients with bony lesions often suffer from pain or neurological symptoms that have a severe, adverse effect on the quality of life. External-beam radiotherapy (EBRT) can effectively relieve bone pain and neurological symptoms caused by BMs. However, EBRT is not yet widely used for the palliative management of BMs from HCC because of the limited number of relevant studies. Furthermore, the optimal dosing schedule remains unclear, despite clinical evidence to support single-fraction radiation schedules for primary cancers. In this review, we outline data describing palliative EBRT for BMs from HCC in the context of (1) bone pain; (2) MSCC; and (3) SBMs.
doi:10.4254/wjh.v6.i12.923
PMCID: PMC4269911  PMID: 25544879
Hepatocellular carcinoma; Metastasis; Radiotherapy; Palliative therapy; Spinal cord compression; Skull base metastasis
12.  Evaluation of hepatocellular carcinoma development in patients with chronic hepatitis C by EOB-MRI 
World Journal of Hepatology  2014;6(12):930-938.
AIM: To evaluate the efficacy of ethoxibenzyl-magnetic resonance imaging (EOB-MRI) as a predictor of hepatocellular carcinoma (HCC) development.
METHODS: Between August 2008 and 2009, we studied 142 hepatitis C virus-infected patients (male 70, female 72), excluding those with HCC or a past history, who underwent EOB-MRI in our hospital. The EOB-MRI index [liver-intervertebral disc ratio (LI)] was calculated as: (post-liver intensity/post-intervertebral disc intensity)/(pre-liver intensity/pre-intervertebral disc intensity).
RESULTS: The median follow-up period was 3.1 years and the patients were observed until the end of the study period (31 December, 2012). In the follow-up period, HCC occurred in 21 patients. The cumulative occurrence rates were 2.1%, 9.1%, and 14.1% at 1, 2, and 3 years, respectively. Using the optimal cut-off value of LI 1.46, on univariate analysis, age, aspartate amino transferase (AST), α-fetoprotein (AFP) ≥ 10, albumin, total cholesterol, prothrombin time, platelets, and LI < 1.46 were identified as independent factors, but on multivariate analysis, LI < 1.46: risk ratio 6.05 (1.34-27.3, P = 0.019) and AFP ≥ 10: risk ratio 3.1 (1.03-9.35, P = 0.045) were identified as independent risk factors. LI and Fib-4 index have higher area under the receiver operating characteristic curves than other representative fibrosis evaluation methods, such as Forn’s index and AST-to-platelet ratio index.
CONCLUSION: LI is associated with the risk of HCC occurrence in hepatitis C patients. LI may be a substitute for liver biopsy when evaluating this risk and its combined use with Fib-4 is a better predictive method of HCC progression.
doi:10.4254/wjh.v6.i12.930
PMCID: PMC4269912  PMID: 25544880
Ethoxibenzyl-magnetic resonance imaging; Hepatocellular carcinoma; Risk factor; Fibrosis
13.  Management of “very early” hepatocellular carcinoma on cirrhotic patients 
World Journal of Hepatology  2014;6(11):766-775.
Due to the advances in screening of cirrhotic patients, hepatocellular carcinoma (HCC) is being diagnosed in earlier stages. For this reason the number of patients diagnosed of very early HCC (single tumors ≤ 2 cm) is continuously increasing. Once a patient has been diagnosed with this condition, treatment strategies include liver resection, local therapies or liver transplantation. The decision on which therapy should the patient undergo depends on the general patients performance status and liver disease. Anyway, even in patients with similar conditions, the best treatment offer is debatable. In this review we analyze the state of the art on the management of very early HCC on cirrhotic patients to address the best treatment strategy for this patient population.
doi:10.4254/wjh.v6.i11.766
PMCID: PMC4243150  PMID: 25429314
Hepatocellular carcinoma; Very early; Liver resection; Liver transplantation; Local therapies
14.  Mammalian target of rapamycin inhibition in hepatocellular carcinoma 
World Journal of Hepatology  2014;6(11):776-782.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is the only available systemic agent for treatment of HCC that improves overall survival for patients with advanced stage disease; unfortunately, an effective second-line agent for the treatment of progressive or sorafenib-resistant HCC has yet to be identified. This review focuses on components of the mammalian target of rapamycin (mTOR) pathway, its role in HCC pathogenesis, and dual mTOR inhibition as a therapeutic option with potential efficacy in advanced HCC. There are several important upstream and downstream signals in the mTOR pathway, and alternative tumor-promoting pathways are known to exist beyond mTORC1 inhibition in HCC. This review analyzes the relationships of the upstream and downstream regulators of mTORC1 and mTORC2 signaling; it also provides a comprehensive global picture of the interaction between mTORC1 and mTORC2 which demonstrates the pre-clinical relevance of the mTOR pathway in HCC pathogenesis and progression. Finally, it provides scientific rationale for dual mTORC1 and mTORC2 inhibition in the treatment of HCC. Clinical trials utilizing mTORC1 inhibitors and dual mTOR inhibitors in HCC are discussed as well. The mTOR pathway is comprised of two main components, mTORC1 and mTORC2; each has a unique role in the pathogenesis and progression of HCC. In phase III studies, mTORC1 inhibitors demonstrate anti-tumor activity in advanced HCC, but dual mTOR (mTORC1 and mTORC2) inhibition has greater therapeutic potential in HCC treatment which warrants further clinical investigation.
doi:10.4254/wjh.v6.i11.776
PMCID: PMC4243151  PMID: 25429315
Mammalian target of rapamycin; hepatocellular carcinoma; Mammalian target of rapamycin complex 1; Mammalian target of rapamycin complex 2; PI3K/AKT/mTOR signaling pathway; Sorafenib; Everolimus; Sirolimus; Liver transplantation; CC-223
15.  Problem of hepatocellular carcinoma in West Africa 
World Journal of Hepatology  2014;6(11):783-792.
The incidence of hepatocellular carcinoma (HCC) is known to be high in West Africa with an approximate yearly mortality rate of 200000. Several factors are responsible for this. Early acquisition of risk factors; with vertical or horizontal transmission of hepatitis B (HBV), environmental food contaminants (aflatoxins), poor management of predisposing risk factors and poorly-managed strategies for health delivery. There has been a low uptake of childhood immunisation for hepatitis B in many West African countries. Owing to late presentations, most sufferers of HCC die within weeks of their diagnosis. Highlighted reasons for the specific disease pattern of HCC in West Africa include: (1) high rate of risk factors; (2) failure to identify at risk populations; (3) lack of effective treatment; and (4) scarce resources for timely diagnosis. This is contrasted to the developed world, which generally has sufficient resources to detect cases early for curative treatment. Provision of palliative care for HCC patients is limited by availability and affordability of potent analgesics. Regional efforts, as well as collaborative networking activities hold promise that could change the epidemiology of HCC in West Africa.
doi:10.4254/wjh.v6.i11.783
PMCID: PMC4243152  PMID: 25429316
Liver cancer; West Africa; Aflatoxin; Surveillance; Hepatitis B
16.  Role of vaptans in the management of hydroelectrolytic imbalance in liver cirrhosis 
World Journal of Hepatology  2014;6(11):793-799.
Ascites and hyponatremia are the most common complications in patients with liver cirrhosis and develop as a consequence of a severe impairment of liver function and portal hypertension. Increasing evidences support the central role of renal function alterations in the pathogenesis of hydroelectrolytic imbalances in cirrhotic patients, thus implying a dense cross-talk between liver and kidney in the systemic and splanchnic vascular homeostasis in such subjects. Since Arginin Vasopressin (AVP) hyperincretion occurs at late stage of cirrhosis and plays an important role in the development of refractory ascites, dilutional hyponatremia and finally hepato-renal syndrome, selective antagonists of AVP receptors V2 (vaptans) have been recently introduced in the therapeutic algorithm of advanced cirrhotic patients. Despite the promising results of earlier phase-two studies, randomized controlled trials failed to find significant results in terms of efficacy of such drugs both in refractory ascites and hyponatremia. Moreover, concerns on their safety profile arise, due to the number of potentially severe side effects of vaptans in the clinical setting, such as hypernatremia, dehydration, renal impairment, and osmotic demyelination syndrome. More robust data from randomized controlled trials are needed in order to confirm the potential role of vaptans in the management of advanced cirrhotic patients.
doi:10.4254/wjh.v6.i11.793
PMCID: PMC4243153  PMID: 25429317
Cirrhosis; Vaptans; Portal hypertension; Arginin vasopressin; Liver
17.  Pathogenesis and therapeutic approaches for non-alcoholic fatty liver disease 
World Journal of Hepatology  2014;6(11):800-811.
Non-alcoholic fatty liver disease affects approximately one-third of the population worldwide, and its incidence continues to increase with the increasing prevalence of other metabolic disorders such as type 2 diabetes. As non-alcoholic fatty liver disease can progress to liver cirrhosis, its treatment is attracting greater attention. The pathogenesis of non-alcoholic fatty liver disease is closely associated with insulin resistance and dyslipidemia, especially hypertriglyceridemia. Increased serum levels of free fatty acid and glucose can cause oxidative stress in the liver and peripheral tissue, leading to ectopic fat accumulation, especially in the liver. In this review, we summarize the mechanism underlying the progression of hepatic steatosis to steatohepatitis and cirrhosis. We also discuss established drugs that are already being used to treat non-alcoholic fatty liver disease, in addition to newly discovered agents, with respect to their mechanisms of drug action, focusing mainly on hepatic insulin resistance. As well, we review clinical data that demonstrate the efficacy of these drugs, together with improvements in biochemical or histological parameters.
doi:10.4254/wjh.v6.i11.800
PMCID: PMC4243154  PMID: 25429318
Non-alcoholic fatty liver disease; Insulin resistance; Drugs; Pathogenesis
18.  Perceptions of post-transplant recidivism in liver transplantation for alcoholic liver disease 
World Journal of Hepatology  2014;6(11):812-817.
Although alcoholic liver disease (ALD) is regarded as a common indication for liver transplantation (LT), debatable issues exist on the requirement for preceding alcoholic abstinence, appropriate indication criteria, predictive factors for alcoholic recidivism, and outcomes following living-donor LT. In most institutions, an abstinence period of six months before LT has been adopted as a mandatory selection criterion. Data indicating that pre-transplant abstinence is an associated predictive factor for alcoholic recidivism supports the reasoning behind this. However, conclusive evidence about the benefit of adopting an abstinence period is yet to be established. On the other hand, a limited number of reports available on living-donor LT experiences for ALD patients suggest that organ donations from relatives have no suppressive effect on alcoholic recidivism. Prevention of alcoholic recidivism has proved to be the most important treatment after LT based on the resultant inferior long-term outcome of patients. Further evaluations are still needed to establish strategies before and after LT for ALD.
doi:10.4254/wjh.v6.i11.812
PMCID: PMC4243155  PMID: 25429319
Abstinence; Alcoholic liver disease; Liver transplantation; Six-month rule
19.  Circulating microRNA, miR-122 and miR-221 signature in Egyptian patients with chronic hepatitis C related hepatocellular carcinoma 
World Journal of Hepatology  2014;6(11):818-824.
AIM: To explore the potential usefulness of serum miR-122 and miR-221 as non-invasive diagnostic markers of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).
METHODS: This prospective study was conducted on 90 adult patients of both sex with HCV-related chronic liver disease and chronic hepatitis C related HCC. In addition to the 10 healthy control individuals, patients were stratified into; interferon-naïve chronic hepatitis C (CH) (n = 30), post-hepatitis C compensated cirrhosis (LC) (n = 30) and treatment-naïve HCC (n = 30). All patients and controls underwent full clinical assessment and laboratory investigations in addition to the evaluation of the level of serum miRNA expression by RT-PCR.
RESULTS: There was a significant fold change in serum miRNA expression in the different patient groups when compared to normal controls; miR-122 showed significant fold increasing in both CH and HCC and significant fold decrease in LC. On the other hand, miR-221 showed significant fold elevation in both CH and LC groups and significant fold decrease in HCC group (P = 0.01). Comparing fold changes in miRNAs in HCC group vs non HCC group (CH and Cirrhosis), there was non-significant fold elevation in miR-122 (P = 0.21) and significant fold decreasing in miR-221 in HCC vs non-HCC (P = 0.03). ROC curve analysis for miR-221 yielded 87% sensitivity and 40% specificity for the differentiation of HCC patients from non-HCC at a cutoff 1.82.
CONCLUSION: Serum miR-221 has a strong potential to serve as one of the novel non-invasive biomarkers of HCC.
doi:10.4254/wjh.v6.i11.818
PMCID: PMC4243156  PMID: 25429320
MiRNA; Hepatocellular carcinoma; Serum
20.  Hemodynamic effects of ambrisentan-tadalafil combination therapy on progressive portopulmonary hypertension 
World Journal of Hepatology  2014;6(11):825-829.
Intravenous epoprostenol is recommended for World Health Organization functional class (WHO-FC) IV patients with pulmonary arterial hypertension (PAH) in the latest guidelines. However, in portopulmonary hypertension (PoPH) patients, advanced liver dysfunction and/or thrombocytopenia often makes the use of intravenous epoprostenol challenging. Here we report the cases of two WHO-FC IV PoPH patients who were successfully treated with a combination of two oral vasodilators used to treat PAH: ambrisentan and tadalafil. Oral vasodilator therapy using a combination of ambrisentan and tadalafil may be a safe and effective therapeutic option for WHO-FC IV PoPH patients and should be considered for selected patients with severe and rapidly progressing PoPH.
doi:10.4254/wjh.v6.i11.825
PMCID: PMC4243157  PMID: 25429321
Portopulmonary hypertension; Ambrisentan; Tadalafil; Thrombocytopenia
21.  Severe alcoholic hepatitis-current concepts, diagnosis and treatment options 
World Journal of Hepatology  2014;6(10):688-695.
Alcoholic hepatitis (AH) is an acute hepatic manifestation occurring from heavy alcohol ingestion. Alcoholic steatohepatitis (ASH) is histologically characterized by steatosis, inflammation, and fibrosis in the liver. Despite the wide range of severity at presentation, those with severe ASH (Maddrey’s discriminant function ≥ 32) typically present with fever, jaundice, and abdominal tenderness. Alcohol abstinence is the cornerstone of therapy for AH and, in the milder forms, is sufficient for clinical recovery. Severe ASH may progress to multi-organ failure including acute kidney injury and infection. Thus, infection and renal failure have a major impact on survival and should be closely monitored in patients with severe ASH. Patients with severe ASH have a reported short-term mortality of up to 40%-50%. Severe ASH at risk of early death should be identified by one of the available prognostic scoring systems before considering specific therapies. Corticosteroids are the mainstay of treatment for severe ASH. When corticosteroids are contraindicated, pentoxifylline may be alternatively used. Responsiveness to steroids should be assessed at day 7 and stopping rules based on Lille score should come into action. Strategically, future studies for patients with severe ASH should focus on suppressing inflammation based on cytokine profiles, balancing hepatocellular death and regeneration, limiting activation of the innate immune response, and maintaining gut mucosal integrity.
doi:10.4254/wjh.v6.i10.688
PMCID: PMC4209414  PMID: 25349640
Alcoholic steatohepatitis; Infection; Renal failure; Corticosteroids; Pentoxifylline
22.  Difficulties in diagnosing acute kidney injury post liver transplantation using serum creatinine based diagnostic criteria 
World Journal of Hepatology  2014;6(10):696-703.
Renal function in patients with advanced cirrhosis is an important prognostic factor for survival both prior to and following liver transplantation. The importance of renal function is reflected by the introduction of the model for end stage liver disease (MELD) score, which includes serum creatinine. The MELD score has been shown to predict the short term risk of death for transplant wait listed patients and is currently used by many countries to allocate liver transplants on the basis of severity of underlying illness. Changes in serum creatinine are also used to stage acute kidney injury. However prior to liver transplantation the serum creatinine typically over estimates underlying renal function, particularly when a colorimetric Jaffe based assay is used, and paradoxically then under estimates renal function post liver transplantation, particularly when immunophyllins are started early as part of transplant immunosuppression. As acute kidney injury is defined by changes in serum creatinine, this potentially leads to over estimation of the incidence and severity of acute kidney injury in the immediate post-operative period.
doi:10.4254/wjh.v6.i10.696
PMCID: PMC4209415  PMID: 25349641
Serum creatinine; Acute kidney injury; Liver transplantation
23.  Laser ablation for small hepatocellular carcinoma: State of the art and future perspectives 
World Journal of Hepatology  2014;6(10):704-715.
During the last two decades, various local thermal ablative techniques for the treatment of unresectable hepatocellular carcinoma (HCC) have been developed. According to internationally endorsed guidelines, percutaneous thermal ablation is the mainstay of treatment in patients with small HCC who are not candidates for surgical resection or transplantation. Laser ablation (LA) represents one of currently available loco-ablative techniques. In this article, the general principles, technique, image guidance, and patient selection are reported. Primary effectiveness, long-term outcome, and complications are also discussed. A review of published data suggests that LA is equivalent to the more popular and widespread radiofrequency ablation in both local tumor control and long-term outcome in the percutaneous treatment of early HCC. In addition, the LA technique using multiple thin laser fibres allows improved ablative effectiveness in HCCs greater than 3 cm. Reference centres should be equipped with all the available techniques so as to be able to use the best and the most suitable procedure for each type of lesion for each patient.
doi:10.4254/wjh.v6.i10.704
PMCID: PMC4209416  PMID: 25349642
Liver; Hepatocellular carcinoma; Minimally invasive procedures; Laser; Laser ablation
24.  Targeting the insulin-like growth factor pathway in hepatocellular carcinoma 
World Journal of Hepatology  2014;6(10):716-737.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Only 30%-40% of the patients with HCC are eligible for curative treatments, which include surgical resection as the first option, liver transplantation and percutaneous ablation. Unfortunately, there is a high frequency of tumor recurrence after surgical resection and most HCC seem resistant to conventional chemotherapy and radiotherapy. Sorafenib, a multi-tyrosine kinase inhibitor, is the only chemotherapeutic option for patients with advanced hepatocellular carcinoma. Patients treated with Sorafenib have a significant increase in overall survival of about three months. Therefore, there is an urgent need to develop alternative treatments. Due to its role in cell growth and development, the insulin-like growth factor system is commonly deregulated in many cancers. Indeed, the insulin-like growth factor (IGF) axis has recently emerged as a potential target for hepatocellular carcinoma treatment. To this aim, several inhibitors of the pathway have been developed such as monoclonal antibodies, small molecules, antisense oligonucleotides or small interfering RNAs. However recent studies suggest that, unlike most tumors, HCC development requires increased signaling through insulin growth factor II rather than insulin growth factor I. This may have great implications in the future treatment of HCC. This review summarizes the role of the IGF axis in liver carcinogenesis and the current status of the strategies designed to target the IGF-I signaling pathway for hepatocellular carcinoma treatment.
doi:10.4254/wjh.v6.i10.716
PMCID: PMC4209417  PMID: 25349643
Hepatocellular carcinoma; Insulin; Insulin-like growth factor; Insulin-like growth factor receptor; Therapy; Tyrosine kinase inhibitor; Antibody therapy
25.  Lipid-lowering agents in the management of nonalcoholic fatty liver disease 
World Journal of Hepatology  2014;6(10):738-744.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed countries and is associated not only with increased risk for liver disease-related complications but also with higher cardiovascular morbidity. Accordingly, lipid-lowering agents are frequently considered in these patients to reduce cardiovascular risk. However, there have been concerns regarding the safety of these agents in patients with chronic liver diseases. In the present review, we discuss the safety of lipid-lowering agents in patients with NAFLD as well as their effects on both cardiovascular and liver disease in this population. Accumulating data suggest that statins are safe in patients with NAFLD and that they reduce the increased cardiovascular morbidity of this population. However, it is still unclear whether statins are also useful as a treatment for NAFLD per se, since there are very limited and conflicting data on their effects on liver histology. There is also very scarce evidence regarding the safety and efficacy of other lipid-lowering agents in patients with NAFLD. Randomized controlled studies are needed to evaluate the role of lipid-lowering agents and particularly statins for the prevention of both cardiovascular and liver disease-related complications in this high-risk population.
doi:10.4254/wjh.v6.i10.738
PMCID: PMC4209418  PMID: 25349644
Nonalcoholic fatty liver disease; Statins; Fibrates; Ezetimibe; Colesevelam; Omega-3 fatty acids; Nicotinic acid; Cardiovascular disease; Transaminases; Nonalcoholic steatohepatitis

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