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1.  Hepatic metastatic disease in pediatric and adolescent solid tumors 
World Journal of Hepatology  2015;7(14):1807-1817.
The management of hepatic metastatic disease from solid tumors in adults has been extensively described and resection of metastatic liver lesions from colorectal adenocarcinoma, renal adenocarcinoma, breast cancer, testicular cancer, and neuroendocrine tumors (NET) have demonstrated therapeutic benefits in select patients. However, there are few reports in the literature on the management of hepatic metastatic disease in the pediatric and adolescent populations and the effectiveness of hepatic metastasectomy. This may be due to the much lower incidence of pediatric malignancies and the higher chemosensitivity of childhood tumors which make hepatic metastasectomy less likely to be required. We review liver involvement with metastatic disease from the main pediatric solid tumors, including neuroblastoma and Wilms tumor focusing on the management and treatment options. We also review other solid malignant tumors which may have liver metastases including germ cell tumors, gastrointestinal stromal tumors, osteosarcoma, desmoplastic small round cell tumors and NET. However, these histological subtypes are so rare in the pediatric and adolescent populations that the exact incidence and best management of hepatic metastatic disease are unknown and can only be extrapolated from adult series.
PMCID: PMC4506938  PMID: 26207162
Hepatic metastatic disease; Pediatric and adolescent solid tumors; Neuroblastoma; Wilms tumor
2.  Spontaneous bleeding or thrombosis in cirrhosis: What should be feared the most? 
World Journal of Hepatology  2015;7(14):1818-1827.
The more modern and accurate concept of a rebalanced hemostatic status in cirrhosis is slowly replacing the traditional belief of patients with cirrhosis being “auto-anticoagulated”, prone only to bleeding complications, and protected from thrombotic events. With greater attention to clinical thrombotic events, their impact on the natural history of cirrhosis, and with the emergence and increased use of point-of-care and global assays, it is now understood that cirrhosis results in profound hemostatic alterations that can lead to thrombosis as well as to bleeding complications. Although many clinical decisions are still based on traditional coagulation parameters such as prothrombin (PT), PT, and international normalized ratio, it is increasingly recognized that these tests do not adequately predict the risk of bleeding, nor they should guide pre-emptive interventions. Moreover, altered coagulation tests should not be considered as a contraindication to the use of anticoagulation, although this therapeutic or prophylactic approach is not at present routinely undertaken. Gastroesophageal variceal bleeding continues to be one of the most feared and deadly complications of cirrhosis and portal hypertension, but great progresses have been made in prevention and treatment strategies. Other bleeding sites that are frequently part of end-stage liver disease are similar to clinical manifestations of thrombocytopenia, with gum bleeding and epistaxis being very common but fortunately only rarely a cause of life-threatening bleeding. On the contrary, manifestations of coagulation factor deficiencies like soft tissue bleeding and hemartrosis are rare in patients with cirrhosis. As far as thrombotic complications are concerned, portal vein thrombosis is the most common event in patients with cirrhosis, but venous thromboembolism is not infrequent, and results in important morbidity and mortality in patients with cirrhosis, especially those with decompensated disease. Future studies and the more widespread use of point-of-care tests in evaluating hemostasis will aid the clinician in decision making when facing the patient with bleeding or with thrombotic complications, with both ends of a continuum being potentially fatal.
PMCID: PMC4506939  PMID: 26207163
Bleeding; Hemorrhage; Thromboembolism; Portal vein thrombosis; Coagulation; Cirrhosis
3.  Voriconazole and the liver 
World Journal of Hepatology  2015;7(14):1828-1833.
Voriconazole is an azole useful for the prophylaxis and the treatment of aspergillosis and other fungal infections in immunosuppressed subjects, as those found in aplasia after aggressive polychemotherapy treatments, after hematopoietic stem cell, liver or lung transplantation. Its administration in therapeutic doses lead to extremely varied serum levels from patient to patient and even to the same patient. The explanations are varied: nonlinear pharmacokinetics, certain patient-related factors, including genetic polymorphisms in the cytochrome P450 2C19 gene, the kidney and liver function, simultaneous administration with other drugs metabolised by the same cytochrome. It is recommended to maintain the serum concentrations of voriconazole between 1.5 and 4 μg/mL. At lower values its efficacy decreases and at higher values the risk of neurological toxicity increases. Even at these concentrations it is not excluded the possible appearance of a variety of toxic effects, including on the liver, manifested by cholestasis, hepatocytolisis, or their combination. It is recommended to monitor the clinical and laboratory evolution of all patients treated with voriconazole, and of the serum levels of the drug of those who belong to risk groups, even if there is still no consensus on this issue, given the lack of correlation between the serum level and the occurrence of adverse effects in many patients.
PMCID: PMC4506940  PMID: 26207164
CYP2C19; Pharmacokinetics; Liver toxicity; Therapeutic drug monitoring; Voriconazole
4.  Circulating biomarkers of hepatocellular carcinoma response after locoregional treatments: New insights 
World Journal of Hepatology  2015;7(14):1834-1842.
Hepatocellular cancer is the 5th most common cancer in the world and the third cause of death by malignant disease. Locoregional therapies are the most usual treatment of choice for patients with early or intermediate stage of disease. The main diagnostic tools for the detection of recurrence are the radiological techniques such as 4-phase computed tomography or dynamic contrast enhanced magnetic resonance imaging. However, in order to achieve best evaluation of treatment outcome and recurrence rates, there is a great need for the identification of specific and easily measured circulating biomarkers. The aim of this review is to analyze the existing data considering the prognostic significance of changes of serum diagnostic markers such as alpha-fetoprotein, des-gamma-carboxy prothrombin, alpha-fetoprotein-L3, angiogenetic factors (vascular endothelial growth factor, hypoxia inducible factor-1a) and immune parameters before and after radiofrequency ablation or transarterial chemoembolization.
PMCID: PMC4506941  PMID: 26207165
Radiofrequency ablation; Transarterial chemoembolization; Hepatocellular cancer; Circulating biomarkers; Prognosis
5.  Hepatitis C cirrhosis: New perspectives for diagnosis and treatment 
World Journal of Hepatology  2015;7(14):1843-1855.
Chronic hepatitis C infection is the leading cause of chronic liver disease, cirrhosis, hepatocellular carcinoma as well as the primary indication for liver transplantation in the United States. Despite recent advances in drugs for the treatment of hepatitis C, predictive models estimate the incidence of cirrhosis due to hepatitis C infection will to continue to rise for the next two decades. There is currently an immense interest in the treatment of patients with fibrosis and early-stage cirrhosis as treatment can lead to decrease in the rates of decompensated cirrhosis, hepatocellular carcinoma and need for liver transplantation in these patients. The goal of this paper is to provide clinicians and health care professionals further information about the treatment of patients with hepatitis C infection and cirrhosis. Additionally, the paper focuses on the disease burden, epidemiology, diagnosis and the disease course from infection to treatment. We provide an overview of multiple studies for the treatment of chronic hepatitis C infection that have included patients with cirrhosis. We also discuss the advantages and disadvantages of treatment in cirrhotic patients and focus on the most up to date guidelines available for treatment.
PMCID: PMC4506942  PMID: 26207166
Cirrhosis; Diagnosis; Treatment; Simeprevir; Sofosbuvir; Ledipasvir; Liver transplantation; Hepatitis C virus
6.  Spectrum of biliary complications following live donor liver transplantation 
World Journal of Hepatology  2015;7(14):1856-1865.
Liver transplantation is the optimal treatment for many patients with advanced liver disease, including decompensated cirrhosis, hepatocellular carcinoma and acute liver failure. Organ shortage is the main determinant of death on the waiting list and hence living donor liver transplantation (LDLT) assumes importance. Biliary complications are the most common post operative morbidity after LDLT and occur due to anatomical and technical reasons. They include biliary leaks, strictures and cast formation and occur in the recipient as well as the donor. The types of biliary complications after LDLT along with their etiology, presenting features, diagnosis and endoscopic and surgical management are discussed.
PMCID: PMC4506943  PMID: 26207167
Liver transplantation; Biliary stricture; Bile leak
7.  Usefulness of contrast enhanced ultrasound in monitoring therapeutic response after hepatocellular carcinoma treatment 
World Journal of Hepatology  2015;7(14):1866-1874.
In the last years, the development in the oncology field has been huge and rapid. In particular, the evaluation of response to anti-tumour treatments has been being object of intense research, producing significant changes. Response assessment after therapy in solid neoplasias has always used radiological imaging techniques, with tumour size reduction representing a presumed therapeutic efficacy. However, with the introduction of anti-angiogenetic drugs the evaluation of tumour size has become unsuitable because some tumours, under treatment, show only tumour perfusion changes rather than lesion shrinkage. Between different imaging techniques with contrast-enhancement, contrast-enhanced ultrasound (CEUS) and, in particular, dynamic CEUS have arisen as a promising and non-invasive device for monitoring cancer treatments. Moreover, the introduction of perfusion software has even more refined the technique since it is able to provide quantitative parameters related to blood flow and blood volume that can be associated with tumour response and clinical outcome such as the progression free survival and the overall survival. Here, we give an overview of the current status of CEUS in monitoring hepatocellular carcinoma response to different kind of treatments.
PMCID: PMC4506944  PMID: 26207168
Dynamic contrast-enhanced ultrasound; Hepatocellular carcinoma; Ablative treatment; Anti-angiogenetic drugs; Time-intensitive curve
8.  Cartilage oligomeric matrix protein: A novel non-invasive marker for assessing cirrhosis and risk of hepatocellular carcinoma 
World Journal of Hepatology  2015;7(14):1875-1883.
AIM: To assess serum cartilage oligomeric matrix protein (COMP) as a marker of cirrhosis and risk of progression to hepatocellular carcinoma (HCC).
METHODS: A COMP enzyme-linked immunosorbent assay was used to test 187 patients with chronic liver diseases at the time point of first evaluation. The selected patients included 72 with chronic hepatitis B infection, 75 with chronic hepatitis C infection, 22 with primary biliary cirrhosis, 7 with autoimmune hepatitis type 1, and 11 with alcoholic liver disease. Demographic, biochemical, histological and clinical characteristics of the patients were recorded at the first evaluation. One hundred and forty-seven patients were followed for a median [interquartile range (IQR)] duration of 96.5 (102) mo. The clinical, biochemical and histological data, as well as the development of cirrhosis, HCC according to internationally accepted criteria and in case of death, a liver-related cause during the follow-up period, were recorded at the electronic database of our clinic. COMP determination was also performed in 43 healthy individuals who served as the control study group.
RESULTS: COMP positivity (> 15 U/L) was detected in 22%-36% among chronic liver disease groups. Strikingly, almost 83% of COMP-positive patients were cirrhotic at baseline, independently of cause of liver disease. Among the patients who developed HCC during follow-up, 73.7% (14/19) were COMP positive at baseline. COMP positivity was significantly associated with older age (P < 0.001), advanced fibrosis (P = 0.001) and necroinflammatory activity (P = 0.001), higher aspartate aminotransferase (P < 0.001), alanine aminotransferase (P < 0.02), γ-glutamyl transpeptidase (P = 0.003), alkaline phosphatase (P = 0.001), bilirubin (P < 0.05), international normalized ratio (P = 0.002) and alpha-fetoprotein levels (P < 0.02), and lower albumin (P < 0.001), and platelet count (P = 0.008). COMP levels [median (IQR)] were significantly higher in cirrhotics compared to non-cirrhotics [13.8 (7.9) U/L vs 9.8 (4.6) U/L, respectively; P < 0.001]. On multivariate logistic regression analysis, COMP-positivity was independently associated only with cirrhosis (OR = 4.40, 95%CI: 1.33-14.69, P = 0.015). Kaplan-Meier analysis showed that COMP positivity was significantly associated with HCC development (P = 0.007) and higher incidence of liver-related death (P < 0.001).
CONCLUSION: Elevated COMP levels are strongly associated with cirrhosis and HCC progression. Serum COMP is a new promising non-invasive biomarker for HCC risk assessment in surveillance programs.
PMCID: PMC4506945  PMID: 26207169
Hepatic fibrosis; Hepatocellular carcinoma; Viral hepatitis; Enzyme-linked immunosorbent assay; Biomarker; Cirrhosis
9.  Utility of liver biopsy in predicting clinical outcomes after percutaneous angioplasty for hepatic venous obstruction in liver transplant patients 
World Journal of Hepatology  2015;7(14):1884-1893.
AIM: To determine utility of transplant liver biopsy in evaluating efficacy of percutaneous transluminal angioplasty (PTA) for hepatic venous obstruction (HVOO).
METHODS: Adult liver transplant patients treated with PTA for HVOO (2003-2013) at a single institution were reviewed for pre/post-PTA imaging findings, manometry (gradient with right atrium), presence of HVOO on pre-PTA and post-PTA early and late biopsy (EB and LB, < or > 60 d after PTA), and clinical outcome, defined as good (no clinical issues, non-HVOO-related death) or poor (surgical correction, recurrent HVOO, or HVOO-related death).
RESULTS: Fifteen patients meeting inclusion criteria underwent 21 PTA, 658 ± 1293 d after transplant. In procedures with pre-PTA biopsy (n = 19), no difference was seen between pre-PTA gradient in 13/19 procedures with HVOO on biopsy and 6/19 procedures without HVOO (8 ± 2.4 mmHg vs 6.8 ± 4.3 mmHg; P = 0.35). Post-PTA, 10/21 livers had EB (29 ± 21 d) and 9/21 livers had LB (153 ± 81 d). On clinical follow-up (392 ± 773 d), HVOO on LB resulted in poor outcomes and absence of HVOO on LB resulted good outcomes. Patients with HVOO on EB (3/7 good, 4/7 poor) and no HVOO on EB (2/3 good, 1/3 poor) had mixed outcomes.
CONCLUSION: Negative liver biopsy greater than 60 d after PTA accurately identifies patients with good clinical outcomes.
PMCID: PMC4506946  PMID: 26207170
Hepatic venous outflow obstruction; Liver transplantation; Post-transplant biopsy; Angioplasty
10.  Is there a role for adaptive immunity in nonalcoholic steatohepatitis? 
World Journal of Hepatology  2015;7(13):1725-1729.
The growing diffusion of nonalcoholic fatty liver disease (NAFLD) is a consequence of the worldwide increase in the prevalence of obesity. Oxidative stress is widely recognized to play a pivotal role in NAFLD evolution to nonalcoholic steatohepatitis (NASH). Here we review recent evidence suggesting that oxidative stress-derived antigens originating within fatty livers stimulate both humoral and cellular adaptive immune responses and the possible mechanisms involved in sustaining hepatic inflammation in NASH.
PMCID: PMC4491900  PMID: 26167244
Liver; Adaptive immunity; Nonalcoholic steatohepatitis; Hepatic inflammation; Nonalcoholic fatty liver disease
11.  Changing common sense: Anti-platelet/coagulation therapy against cirrhosis 
World Journal of Hepatology  2015;7(13):1730-1734.
Until recently, anti-platelet/coagulation therapy had not been recommended for patients with cirrhosis. Although venous thrombosis is one of the representative complications of cirrhosis and ischemic disorders associated with atherosclerosis are not infrequent in cirrhotic patients, many clinicians have tended to hesitate to introduce anti-platelet/coagulation therapy to their patients. Undoubtedly, this is due to the increased risk of hemorrhagic diathesis in cirrhotic patients. However, accumulating evidence has revealed the benefits of anti-platelet/coagulation therapy for cirrhotic patients. In addition to the safety of the therapy carried out against cardiovascular diseases in cirrhotic patients, some clinical data have indicated its preventive effect on venous thrombosis. Moreover, the efficacy of anti-platelet/coagulation therapy against cirrhosis itself has been demonstrated both clinically and experimentally. The conceptual basis for application of anti-platelet/coagulation therapy against cirrhosis was constructed through two pathologic studies on intrahepatic thrombosis in cirrhotic livers. It may be better to use thrombopoietin-receptor agonists, which have been tested as a treatment for cirrhosis-related thrombocytopenia, in combination with anti-platelet drugs to reduce the risk of venous thrombosis. During the last decade, the World Journal of Gastroenterology, a sister journal of World Journal of Hepatology, has been one of the main platforms of active discussion of this theme.
PMCID: PMC4491901  PMID: 26167245
Anti-platelet/coagulation therapy; Cirrhosis; Hemorrhagic diathesis; Thrombosis; Thrombocytopenia
12.  Pancreaticobiliary reflux as a high-risk factor for biliary malignancy: Clinical features and diagnostic advancements 
World Journal of Hepatology  2015;7(13):1735-1741.
Pancreaticobiliary junction is composed of complex structure with which biliary duct and pancreatic duct assemble and go out into the ampulla of Vater during duodenum wall surrounding the sphincter of Oddi. Although the sphincter of Oddi functionally prevents the reflux of pancreatic juice, pancreaticobiliary reflux (PBR) occurs when function of the sphincter of Oddi halt. The anatomically abnormal junction is termed pancreaticobiliary maljunction (PBM) and is characterized by pancreatic and bile ducts joining outside of the duodenal wall. PBM is an important anatomical finding because many studies have revealed that biliary malignancies are related due to the carcinogenetic effect of the pancreatic back flow on the biliary mucosa. On the other hand, several studies have been published on the reflux of pancreatic juice into the bile duct without morphological PBM, and the correlation of such cases with biliary diseases, especially biliary malignancies, is drawing considerable attention. Although it has long been possible to diagnose PBM by various imaging modalities, PBR without PBM has remained difficult to assess. Therefore, the pathological features of PBR without PBM have not been yet fully elucidated. Lately, a new method of diagnosing PBR without PBM has appeared, and the features of PBR without PBM should soon be better understood.
PMCID: PMC4491902  PMID: 26167246
Pancreaticobiliary maljunction; Pancreas juice; Reflux; Flow; Magnetic resonance imaging
13.  Nucleos(t)ide analogs in the prevention of hepatitis B virus related hepatocellular carcinoma 
World Journal of Hepatology  2015;7(13):1742-1754.
Hepatocellular carcinoma (HCC) is among the most common cancer types and causes of cancer related mortality worldwide. Almost 50% of all HCC cases globally are attributable to chronic hepatitis B virus (HBV) infection. The incidence rates of HCC in untreated Asian subjects with HBV infection was estimated to be 0.2% in inactive carriers, 0.6% for those with chronic hepatitis without cirrhosis, and 3.7% for those with compensated cirrhosis. In Western populations, HCC incidences are reported to be 0.02% in inactive carriers, 0.3% in subjects with chronic hepatitis without cirrhosis, and 2.2% in subjects with compensated cirrhosis. Despite effective antiviral treatment options which are able to transform chronic hepatitis into an inactive carrier state, the risk of HCC cannot be fully ruled out to exclude those patients from surveillance. Newer nucleos(t)ide analogues (NAs) as entecavir and tenofovir are very potent in terms of sustained virological suppression which leads to improved liver histology. However, they do not have any influence on the cccDNA or integrated DNA of HBV in the liver. Nonetheless, viral replication is the only modifiable component among the established risk factors for HBV-related HCC with the current treatment options. In this review, it was aimed to summarize cumulative evidence behind the concept of prevention of HBV related HCC by NAs, and to discuss remaining obstacles to eliminate the risk of HCC.
PMCID: PMC4491903  PMID: 26167247
Hepatitis B virus; Hepatocellular carcinoma; Prevention; Nucleos(t)ide analogues; Risk factors
14.  Surgical treatment of intra hepatic recurrence of hepatocellular carcinoma 
World Journal of Hepatology  2015;7(13):1755-1760.
Recurrence after hepatocellular carcinoma (HCC) is frequent. Currently, there are no recommendations on therapeutic strategy after recurrence of HCC. Whereas the 5 year-recurrence rate after resection of HCC is 100%, this drops to 15% after primary liver transplantation. Repeat hepatectomy and salvage liver transplantation (SLT) could be performed in selected patients to treat recurrent HCC and enable prolonged overall survival after treatment of recurrence. Other therapies such as local ablation, chemoembolization or sorafenib could be proposed to those patients unable to benefit from resection or SLT. A clear definition of the place of SLT and “prophylactic” liver transplantation is required. Indeed, identifying risks factors for recurrence at time of primary liver resection of HCC may help to avoid recurrence beyond Milan criteria and non-resectable situations. In this review, we summarize the recent data available in the literature on the feasibility and outcomes of repeat hepatectomy and SLT as treatment for recurrent HCC.
PMCID: PMC4491904  PMID: 26167248
Hepatocellular carcinoma; Liver resection; Survival; Intrahepatic recurrence; Liver transplantation
15.  Drug- and herb-induced liver injury: Progress, current challenges and emerging signals of post-marketing risk 
World Journal of Hepatology  2015;7(13):1761-1771.
Drug-induced liver injury (DILI) and herb-induced liver injury is a hot topic for clinicians, academia, drug companies and regulators, as shown by the steadily increasing number of publications in the past 15 years. This review will first provide clues for clinicians to suspect idiosyncratic (unpredictable) DILI and succeed in diagnosis. Causality assessment remains challenging and requires careful medical history as well as awareness of multifaceted aspects, especially for herbs. Drug discontinuation and therapy reconciliation remain the mainstay in patent’s management to minimize occurrence of acute liver failure. The second section will address novel agents associated with liver injury in 2014 (referred to as “signals”), especially in terms of clinical, research and drug development implications. Insights will be provided into recent trends by highlighting the contribution of different post-marketing data, especially registries and spontaneous reporting systems. This literature scrutiny suggests: (1) the importance of post-marketing databases as tools of clinical evidence to detect signals of DILI risk; and (2) the need for joining efforts in improving predictivity of pre-clinical assays, continuing post-marketing surveillance and design ad hoc post-authorization safety studies. In this context, ongoing European/United States research consortia and novel pharmaco-epidemiological tools (e.g., specialist prescription event monitoring) will support innovation in this field. Direct oral anticoagulants and herbal/dietary supplements appear as key research priorities.
PMCID: PMC4491905  PMID: 26167249
Hepatotoxicity; Liver damage; Herb; Signal; Safety; Predictivity
16.  Relevance of ADAMTS13 to liver transplantation and surgery 
World Journal of Hepatology  2015;7(13):1772-1781.
A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) specifically cleaves unusually-large von Willebrand factor (VWF) multimers under high shear stress, and down-regulates VWF function to form platelet thrombi. Deficiency of plasma ADAMTS13 activity induces a life-threatening systemic disease, termed thrombotic microangiopathy (TMA) including thrombotic thrombocytopenic purpura (TTP). Children with advanced biliary cirrhosis due to congenital biliary atresia sometimes showed pathological features of TMA, with a concomitant decrease of plasma ADAMTS13 activity. Disappearance of their clinical findings of TTP after successful liver transplantation suggested that the liver is a major organ producing plasma ADAMTS13. In situ hybridization analysis showed that ADAMTS13 was produced by hepatic stellate cells. Subsequently, it was found that ADADTS13 was not merely responsible to development of TMA and TTP, but also related to some kinds of liver dysfunction after liver transplantation. Ischemia-reperfusion injury and acute rejection in liver transplant recipients were often associated with marked decrease of ADAMTS13 and concomitant formation of unusually large VWF multimers without findings of TMA/TTP. The similar phenomenon was observed also in patients who underwent hepatectomy for liver tumors. Imbalance between ADAMTS13 and VWF in the hepatic sinusoid might cause liver damage due to microcirculatory disturbance. It can be called as “local TTP like mechanism” which plays a crucial role in liver dysfunction after liver transplantation and surgery.
PMCID: PMC4491906  PMID: 26167250
A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13; Thrombocytopenia; Microcirculation; Liver dysfunction; von Willebrand factor; Liver transplantation; Acute rejection; Ischemia-reperfusion injury; Hepatectomy; Liver surgery; Local thrombotic thrombocytopenic purpura like mechanism
17.  Impact of geography on organ allocation: Beyond the distance to the transplantation center 
World Journal of Hepatology  2015;7(13):1782-1787.
AIM: To illustrate the application and utility of Geographic Information System (GIS) in exploring patterns of liver transplantation. Specifically, we aim to describe the geographic distribution of transplant registrations and identify disparities in access to liver transplantation across United Network of Organ Sharing (UNOS) region 1.
METHODS: Based on UNOS data, the number of listed transplant candidates by ZIP code from 2003 to 2012 for Region 1 was obtained. Choropleth (color-coded) maps were used to visualize the geographic distribution of transplant registrations across the region. Spatial interaction analysis was used to analyze the geographic pattern of total transplant registrations by ZIP code. Factors tested included ZIP code log population and log distance from each ZIP code to the nearest transplant center; ZIP code population density; distance from the nearest city over 50000; and dummy variables for state residence and location in the southern portion of the region.
RESULTS: Visualization of transplant registrations revealed geographic disparities in organ allocation across Region 1. The total number of registrations was highest in the southern portion of the region. Spatial interaction analysis, after adjusting for the size of the underlying population, revealed statistically significant clustering of high and low rates in several geographic areas could not be predicted based solely on distance to the transplant center or density of population.
CONCLUSION: GIS represents a new method to evaluate the access to liver transplantation within one region and can be used to identify the presence of disparities and reasons for their existence in order to alleviate them.
PMCID: PMC4491907  PMID: 26167251
Health geographic’s; Healthcare disparities; Outcome research
18.  Non-alcohol fatty liver disease in Asia: Prevention and planning 
World Journal of Hepatology  2015;7(13):1788-1796.
AIM: To review all of epidemiological aspects of non-alcoholic fatty liver disease (NAFLD) and also prevent this disease is examined.
METHODS: We conducted a systematic review according to the PRISMA guidelines. All searches for writing this review is based on the papers was found in PubMed (MEDLINE), Cochrane database and Scopus in August and September 2014 for topic of NAFLD in Asia and the way of prevention of this disease, with no language limitations. All relevant articles were accessed in full text and all relevant materials was evaluated and reviewed.
RESULTS: NAFLD is the most common liver disorder in worldwide, with an estimated with 20%-30% prevalence in Western countries and 2%-4% worldwide. The prevalence of NAFLD in Asia, depending on location (urban vs rural), gender, ethnicity, and age is variable between 15%-20%. According to the many studies in the world, the relationship between NAFLD, obesity, diabetes mellitus, and metabolic syndrome (MS) is quiet obvious. Prevalence of NAFLD in Asian countries seems to be lower than the Western countries but, it has increased recently due to the rise of obesity, type 2 diabetes and MS in this region. One of the main reasons for the increase in obesity, diabetes and MS in Asia is a lifestyle change and industrialization. Today, NAFLD is recognized as a major chronic liver disease in Asia. Therefore, prevention of this disease in Asian countries is very important and the best strategy for prevention and control of NAFLD is lifestyle modifications. Lifestyle modification programs are typically designed to change bad eating habits and increase physical activity that is associated with clinically significant improvements in obesity, type 2 diabetes and MS.
CONCLUSION: Prevention of NAFLD is very important in Asian countries particularly in Arab countries because of high prevalence of obesity, diabetes and MS.
PMCID: PMC4491908  PMID: 26167252
Non-alcoholic fatty liver disease; Metabolic risk factors; Asian countries; Prevention
19.  Transjugular intrahepatic portosystemic stent shunt for medically refractory hepatic hydrothorax: A systematic review and cumulative meta-analysis 
World Journal of Hepatology  2015;7(13):1797-1806.
AIM: To assess the effectiveness of transjugular intrahepatic portosystemic stent shunt (TIPSS) in refractory hepatic hydrothorax (RHH) in a systematic review and cumulative meta-analysis.
METHODS: A comprehensive literature search was conducted on MEDLINE, EMBASE, and PubMed covering the period from January 1970 to August 2014. Two authors independently selected and abstracted data from eligible studies. Data were summarized using a random-effects model. Heterogeneity was assessed using the I2 test.
RESULTS: Six studies involving a total of 198 patients were included in the analysis. The mean (SD) age of patients was 56 (1.8) years. Most patients (56.9%) had Child-Turcott-Pugh class C disease. The mean duration of follow-up was 10 mo (range, 5.7-16 mo). Response to TIPSS was complete in 55.8% (95%CI: 44.7%-66.9%), partial in 17.6% (95%CI: 10.9%-24.2%), and absent in 21.2% (95%CI: 14.2%-28.3%). The mean change in hepatic venous pressure gradient post-TIPSS was 12.7 mmHg. The incidence of TIPSS-related encephalopathy was 11.7% (95%CI: 6.3%-17.2%), and the 45-d mortality was 17.7% (95%CI: 11.34%-24.13%).
CONCLUSION: TIPSS is associated with a clinically relevant response in RHH. TIPSS should be considered early in these patients, given its poor prognosis.
PMCID: PMC4491909  PMID: 26167253
Cirrhosis; Portal hypertension; Hepatic hydrothorax; Transjugular intrahepatic portosystemic stent shunt; Meta-analysis
20.  Liver ultrasound elastography: More than staging the disease 
World Journal of Hepatology  2015;7(12):1595-1600.
Ultrasound elastography is perhaps the most important breakthrough in the evolution of ultrasonography in the last 15 years. Since transient elastography was introduced, many other methods have been developed and became more and more widely available. The value of ultrasound elastography in staging a chronic liver disease has been established by numerous studies. There have been many studies that have shown that using liver elastography it is possible to predict the presence of the complications of cirrhosis: portal hypertension, presence of esophageal varices (and even their risk of bleeding) and hepatocellular carcinoma. It has been shown that liver elastography can predict the progression of liver fibrosis and also the survival (hepatic events - free) of the patients with chronic liver diseases. These are the real quests of the clinicians, this is the ultimate scope of any medical investigation - to predict the outcome of a patient and to help making therapeutic decisions. I brought together only a small amount of the data that has already been written on this subject to support my affirmation that liver ultrasound elastography is more than a tool for staging the liver disease, but it is also comparable to a crystal ball which in the hands of a skilled clinician can reveal the future of the patient and can help to improve this future.
PMCID: PMC4483541  PMID: 26140079
Liver ultrasound elastography; Transient elastography; Fibrosis; Hepatitis; Survival; Cirrhosis
21.  Treatment of ectopic varices with portal hypertension 
World Journal of Hepatology  2015;7(12):1601-1605.
Ectopic varices are unusual with portal hypertension and can involve any site along the digestive tract outside the gastroesophageal region. Hemorrhage from ectopic varices generally are massive and life threatening. Diagnosis of ectopic varices is difficult and subsequent treatment is also difficult; the optimal treatment has not been established. Recently, interventional radiology and endoscopic treatments have been carried out successfully for hemorrhage from ectopic varices.
PMCID: PMC4483542  PMID: 26140080
Portal hypertension; Endoscopic injection sclerotherapy; Balloon-occluded retrograde transvenous obliteration; Ectopic varices; Endoscopic band ligation; Percutaneous transhepatic obliteration; Transjugular intrahepatic portosystemic shunts
22.  Treatment of chronic hepatitis C in liver transplant candidates and recipients: Where do we stand? 
World Journal of Hepatology  2015;7(12):1606-1616.
The first generation direct antiviral agents (DAAs) highlighted substantial prognosis improvement among liver transplant (LT) candidates and recipients with recurrent hepatitis C virus (HCV) infection. During 2014, second generation DAAs are associated with high sustained virological response rates (> 95%), shortened duration courses and relatively few toxicities. In keeping with the currently available data, patients with decompensated cirrhosis awaiting LT is preferable to be treated with interferon-free, new generation DAAs, with or without ribavirin combinations. Although data about the safety of new DAAs combinations in this patient population are limited, sofosbuvir and daclatasvir pharmacokinetics do not appear to change significantly in moderate or severe liver impairment, while other new DAAs (simeprevir, asunaprevir) seem to be contraindicated in patients with severe liver impairment (Child-Pugh class C). On the other hand, sofosbuvir should not be given in patients with glomerular filtration rate ≤ 30 mL/min, but ongoing trials will clarify better this issue. With the objective that newer antiviral combinations will yield safer and more efficient manipulation of HCV recurrence post-transplant, the European Association for the Study of the Liver has recently updated its recommendations towards this direction. Nevertheless the new antivirals’ high cost may be the biggest challenge to their implementation worldwide.
PMCID: PMC4483543  PMID: 26140081
Liver transplantation; Decompensated cirrhosis; Hepatitis C; New antiviral agents; Sofosbuvir; Simeprevir; Daclatasvir; Recurrent hepatitis C
23.  Predictive factors associated with hepatitis C antiviral therapy response 
World Journal of Hepatology  2015;7(12):1617-1631.
Hepatitis C virus (HCV) infection may lead to significant liver injury, and viral, environmental, host, immunologic and genetic factors may contribute to the differences in the disease expression and treatment response. In the early 2000s, dual therapy using a combination of pegylated interferon plus ribavirin (PR) became the standard of care for HCV treatment. In this PR era, predictive factors of therapy response related to virus and host have been identified. In 2010/2011, therapeutic regimens for HCV genotype 1 patients were modified, and the addition of NS3/4a protease inhibitors (boceprevir or telaprevir) to dual therapy increased the effectiveness and chances of sustained virologic response (SVR). Nevertheless, the first-generation triple therapy is associated with many adverse events, some of which are serious and associated with death, particularly in cirrhotic patients. This led to the need to identify viral and host predictive factors that might influence the SVR rate to triple therapy and avoid unnecessary exposure to these drugs. Over the past four years, hepatitis C treatment has been rapidly changing with the development of new therapies and other developments. Currently, with the more recent generations of pangenotipic antiviral therapies, there have been higher sustained virologic rates, and prognostic factors may not have the same importance and strength as before. Nonetheless, some variables may still be consistent with the low rates of non-response with regimens that include sofosbuvir, daclatasvir and ledipasvir. In this manuscript, we review the predictive factors of therapy response across the different treatment regimens over the last decade including the new antiviral drugs.
PMCID: PMC4483544  PMID: 26140082
Hepatitis C; Direct acting antivirals; Antiviral therapy; Interferon; Sustained virologic response
24.  Guide for diagnosis and treatment of hepatocellular carcinoma 
World Journal of Hepatology  2015;7(12):1632-1651.
Hepatocellular carcinoma (HCC) is ranked as the 5th common type of cancer worldwide and is considered as the 3rd common reason for cancer-related deaths. HCC often occurs on top of a cirrhotic liver. The prognosis is determined by several factors; tumour extension, alpha-fetoprotein (AFP) concentration, histologic subtype of the tumour, degree of liver dysfunction, and the patient’s performance status. HCC prognosis is strongly correlated with diagnostic delay. To date, no ideal screening modality has been developed. Analysis of recent studies showed that AFP assessment lacks adequate sensitivity and specificity for effective surveillance and diagnosis. Many tumour markers have been tested in clinical trials without progressing to routine use in clinical practice. Thus, surveillance is still based on ultrasound (US) examination every 6 mo. Imaging studies for diagnosis of HCC can fall into one of two main categories: routine non-invasive studies such as US, computed tomography (CT), and magnetic resonance imaging, and more specialized invasive techniques including CT during hepatic arteriography and CT arterial portography in addition to the conventional hepatic angiography. This article provides an overview and spotlight on the different diagnostic modalities and treatment options of HCC.
PMCID: PMC4483545  PMID: 26140083
Diagnosis of hepatocellular carcinoma; Surgical resection; Hepatocellular carcinoma; Liver transplantation; Radiofrequency ablation; Microwave ablation; Percutaneous ethanol or acetic acid ablation; Radio-embolisation; Systemic chemotherapy; Trans-arterial chemoembolisation
25.  Systematic review: Preventive and therapeutic applications of metformin in liver disease 
World Journal of Hepatology  2015;7(12):1652-1659.
Metformin, a biguanide derivative, is the most commonly prescribed medication in the treatment of type 2 diabetes mellitus. More recently, the use of metformin has shown potential as a preventive and therapeutic agent for a broad spectrum of conditions, including liver disease and hepatic malignancies. In this systematic review, we critically analyze the literature behind the potential use of metformin across the spectrum of liver disease and malignancies. The PubMed and Ovid MEDLINE databases were searched from 2000 to March 2015, using a combination of relevant text words and MeSH terms: metformin and mammalian target of rapamycin, hepatitis B virus (HBV), hepatitis B virus (HCV), non-alcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC) or cholangiocarcinoma. The search results were evaluated for pertinence to the issue of metformin in liver disease as well as for quality of study design. Metformin has a number of biochemical effects that would suggest a benefit in treating chronic liver diseases, particularly in the context of insulin resistance and inflammation. However, the literature thus far does not support any independent therapeutic role in NAFLD or HCV. Nonetheless, there is Level III evidence for a chemopreventive role in patients with diabetes and chronic liver disease, with decreased incidence of HCC and cholangiocarcinoma. The use of metformin seems to be safe in patients with cirrhosis, and provides a survival benefit. Once hepatic malignancies are already established, metformin does not offer any therapeutic potential. In conclusion, there is insufficient evidence to recommend use of metformin in the adjunctive treatment of chronic liver diseases, including NAFLD and HCV. However, there is good evidence for a chemopreventive role against HCC among patients with diabetes and chronic liver disease, and metformin should be continued in patients even with cirrhosis to provide this benefit.
PMCID: PMC4483546  PMID: 26140084
Non-alcoholic fatty liver disease; Metformin; Chemoprevention; Hepatocellular carcinoma; Hepatitis C

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