Hepatocellular Carcinoma In Non-cirrhotic Patients Research Articles

Hepatic Pecoma versus Hepatocellular Carcinoma In The Noncirrhotic Liver on Gd-EOB-DTPA-Enhanced MRI: A Diagnostic Challenge.

Hepatic perivascular epithelioid cell tumors (PEComa) often mimic hepatocellular carcinoma (HCC) in patients without cirrhosis. This study aimed to develop a nomogram using imaging characteristics on Gd-EOB-DTPA-enhanced MRI and to distinguish PEComa from HCC in a noncirrhotic liver. Forty patients with non-cirrhotic Gd-EOB-DTPA-enhanced magnetic resonance imaging(MRI) were included in our study. A multivariate logistic regression model was used to select significant variables to distinguish PEComa from HCC. A nomogram was developed based on the regression model. The performance of the nomogram was assessed with respect to the ROC curve and calibration curve. Decision curve analysis (DCA) was performed to evaluate the clinical usefulness of the nomogram. Two significant predictors were identified: the appearance of an early draining vein and the T1D value of tumors. The ROC curve showed that the area under the curve (AUC) of the model to predict the risk of PEComa was 0.91 (95% CI: 0.80~1) and showed that the model had high specificity (92.3%) and sensitivity (88.9%). The nomogram incorporating these two predictors showed favorable calibration, which was validated using 1000 resampling procedures, and the corrected C-index of this model was 0.90. Furthermore, DCA analysis showed that the model had clinical practicability. In conclusion, the nomogram model showed favorable predictive accuracy for distinguishing PEComa from HCC in non-cirrhotic patients and may aid in clinical decision-making.

Development and Validation of a Novel Prognosis Model Based on a Panel of Three Immunogenic Cell Death-Related Genes for Non-Cirrhotic Hepatocellular Carcinoma.

The accurate prediction of non-cirrhotic hepatocellular carcinoma (NCHCC) risk facilitates improved surveillance strategy and decreases cancer-related mortality. This study aimed to explore the correlation between immunogenic cell death (ICD) and NCHCC prognosis using The Cancer Genome Atlas (TCGA) datasets, and the potential prognostic value of ICD-related genes in NCHCC. Clinical and transcriptomic data of patients with NCHCC patients were retrieved from TCGA database. Weighted gene co-expression network analysis was performed to obtain the NCHCC phenotype-related module genes. Consensus clustering analysis was performed to classify the patients into two clusters based on intersection genes among differentially expressed genes (DEGs) between cancer and adjacent tissues, NCHCC phenotype-related genes, and ICD-related genes. NCHCC-derived tissue microarray was used to evaluate the correlation of the expression levels of key genes with NCHCC prognosis using immunohistochemical staining. Cox regression analyses were performed to construct a prognostic risk score model comprising three genes (TMC7, GRAMD1C, and GNPDA1) based on DEGs between two clusters. The model stratified patients with NCHCC into two risk groups. The overall survival (OS) of the high-risk group was significantly lower than that of the low-risk group. Univariable and multivariable Cox regression analyses revealed that these signature genes are independent predictors of OS. Functional analysis revealed differential immune status between the two risk groups. Next, a nomogram was constructed, which demonstrated the potent distinguishing ability of the developed model based on receiver operating characteristic curves. In vitro functional validation revealed that the migration and invasion abilities of HepG2 and Huh7 cells were upregulated upon GRAMD1C knockdown but downregulated upon TMC7 knockdown. This study developed a prognostic model comprising three genes, which can aid in predicting the survival of patients with NCHCC and guide the selection of drugs and molecular markers for NCHCC.

Screening and interventions to prevent nonalcoholic fatty liver disease/nonalcoholic steatohepatitis-associated hepatocellular carcinoma.

Liver cancer is the sixth most commonly diagnosed cancer worldwide, with hepatocellular carcinoma (HCC) comprising most cases. Besides hepatitis B and C viral infections, heavy alcohol use, and nonalcoholic steatohepatitis (NASH)-associated advanced fibrosis/cirrhosis, several other risk factors for HCC have been identified (i.e. old age, obesity, insulin resistance, type 2 diabetes). These might in fact partially explain the occurrence of HCC in non-cirrhotic patients without viral infection. HCC surveillance through effective screening programs is still an unmet need for many nonalcoholic fatty liver disease (NAFLD) patients, and identification of pre-cirrhotic individuals who progress to HCC represents a substantial challenge in clinical practice at the moment. Patients with NASH-cirrhosis should undergo systematic HCC surveillance, while this might be considered in patients with advanced fibrosis based on individual risk assessment. In this context, interventions that potentially prevent NAFLD/ NASH-associated HCC are needed. This paper provided an overview of evidence related to lifestyle changes (i.e. weight loss, physical exercise, adherence to healthy dietary patterns, intake of certain dietary components, etc.) and pharmacological interventions that might play a protective role by targeting the underlying causative factors and pathogenetic mechanisms. However, well-designed prospective studies specifically dedicated to NAFLD/NASH patients are still needed to clarify the relationship with HCC risk.

Recurrence of hepatocellular carcinoma in noncirrhotic patients with nonalcoholic fatty liver disease versus hepatitis B infection.

This study aimed to compare the long-term cumulative recurrence rates of hepatocellular carcinoma (HCC) and prognosis after curative resection for HCC in noncirrhotic patients with nonalcoholic fatty liver disease (NAFLD) versus hepatitis B virus (HBV) infection. We retrospectively analyzed the data of 791 patients without recurrence within 1 year after curative resection for HCC from January 2005 to December 2015. Of these, 63 and 728 were NAFLD and HBV patients without cirrhosis, respectively. Recurrence of HCC was observed in 6 (9.5%) and 210 (28.8%) patients in the NAFLD and HBV groups, respectively, during median follow-ups of 69.9 and 85.2 months. Cumulative recurrence rates in the NAFLD group at 2, 4, 6, 8 and 10 years (3.6, 9.4, 12.4, 12.4 and 12.4%, respectively) were significantly lower than in the HBV group (1.7, 16.9, 27.2, 37.1 and 44.4%, respectively) ( P = 0.008). Cumulative overall survival (OS) rates in the NAFLD group at 2, 4, 6, 8 and 10 years (98.2, 96.0, 84.0, 84.0 and 84.0 %, respectively) were significantly lower than in the HBV group (99.3, 98.4, 97.3, 95.7 and 93.6%, respectively) ( P = 0.003). HBV infection, with or without fatty liver compared to NAFLD, were significant predictors for the recurrence of HCC ( P < 0.05 for all) and OS ( P < 0.05 for all), respectively. Noncirrhotic NAFLD patients showed lower recurrence rates of HCC but poorer survival outcomes than noncirrhotic HBV patients with or without fatty liver. The recurrence risk of HCC remains even in noncirrhotic NAFLD patients.

Advanced Hepatocellular Carcinoma in Adults Without Cirrhosis: A Single-Institution Retrospective Review.

Although up to one in five cases of hepatocellular carcinoma (HCC) occurs in patients without cirrhosis, there is scarce literature characterizing non-cirrhotic HCC (NCHCC). Existing NCHCC research is primarily limited to surgical case series and there is a lack of data on unresectable NCHCC. The purpose of this retrospective review was to compare the characteristics of unresectable NCHCC and cirrhotic hepatocellular carcinoma (CHCC). A retrospective chart review of adult patients with unresectable HCC treated from 2007 to 2017 was performed at the University of Florida Shands Hospital. The data set was stratified into two cohorts: NCHCC and CHCC. Continuous variables were compared using Wilcoxon-Mann-Whitney tests and Kruskal-Wallis rank-sum tests. Categorical variables were compared using Pearson's Chi-squared tests and Fisher's exact tests. Overall survival was explored utilizing the Kaplan-Meier and log-rank method. There were 1494 adult patients included in the final analysis, including 264 patients (17.7%) with NCHCC and 1230 patients (82.3%) with CHCC. Median age was 61.0 years old and median follow-up time was 30.2 months. NCHCC patients were older than CHCC patients (66.3 years vs 61.9 years; p < 0.0001). NHCC tumors were larger than CHCC tumors (7.92 ± 4.85 vs 4.38 ± 3.12 cm; p < 0.0001) and more likely to be associated with distant metastases (23.35% vs 15.91%; p = 0.0055). There was no difference in overall survival, with a median of 23.5 months in NCHCC and 22.4 months in CHCC (p = 0.9196). Our findings suggest that unresectable NCHCC and CHCC have unique characteristics but similar overall survival. To the best of our knowledge, this is the largest comparison of CHCC and NCHCC.

Neutrophil-to-Lymphocyte Ratio Can Distinguish Patients with Liver Cirrhosis from Healthy People but Cannot Distinguish Patients with Cirrhotic Hepatocellular Carcinoma from Patients with Liver Cirrhosis.

Identifying cirrhotic hepatocellular carcinoma (HCC) during liver cirrhosis (LC) stage is pivotal for improving the clinical outcomes of cirrhotic HCC patients. Inflammation-driven markers play a crucial role in tumorigenesis and tumor progression. Neutrophil-to-lymphocyte ratio (NLR) is an inflammatory response marker. This study aimed to evaluate the ability of NLR to distinguish cirrhotic HCC from LC. Data of healthy control (HC) people, LC patients, cirrhotic HCC patients, and non-cirrhotic HCC patients were retrospectively analyzed. Mann-Whitney U test and Chi-squared test were used to compare demographic and clinical parameters in different groups. Spearman correlation analysis was used to assess correlations. Receiver operating characteristic (ROC) curves were performed to determine diagnostic accuracy. A total of 419 participants were enrolled in this study, including 152 HC people, 131 LC patients, 96 cirrhotic HCC patients, and 40 non-cirrhotic HCC patients. Level of NLR was elevated significantly in LC compared with HC (P < 0.001). No significant differences were found for NLR between LC and cirrhotic HCC (P = 0.083), as well as between cirrhotic HCC and non-cirrhotic HCC (P = 0.729). NLR was positively correlated with platelet-to-lymphocyte ratio (r = 0.33, P < 0.001). The area under the ROC curve (AUC) value for NLR to distinguish LC from HC was 0.759 (P < 0.001), and AUC value to distinguish cirrhotic HCC from LC was 0.567 (P = 0.083), and AUC value to distinguish non-cirrhotic HCC from cirrhotic HCC was 0.519 (0.415-0.623) (P = 0.729). NLR can distinguish LC from HC but cannot not distinguish cirrhotic HCC from LC.

Comparison of prognoses between cirrhotic and noncirrhotic patients with hepatocellular carcinoma and esophageal varices undergoing surgical resection

Esophageal varices (EV) is common and is a poor prognostic factor for patients with hepatocellular carcinoma (HCC). However, the outcomes between cirrhotic and noncirrhotic HCC patients with EV is not well studied. The present study aimed to investigate the clinical manifestations and prognoses of HCC patients after surgical resection stratified by the cirrhosis status. A total of 111 patients with HCC and EV, who underwent surgical resection, were retrospectively enrolled between July 2003 and July 2019. The diagnosis of liver cirrhosis was established using the Ishak fibrosis score F5 or F6 in the nontumor part of liver specimens. Prognostic factors were analyzed using the Cox proportional hazards model. There were 85 (76.6%) and 26 (23.4%) patients with and without cirrhosis, respectively. Compared with those without cirrhosis, there were more females, less seropositive rate of hepatitis B surface antigen (HBsAg), more seropositive rate of antibody against to hepatitis C virus (HCV), less albumin-bilirubin (ALBI) grade 1, lower platelet count, and more had tumor burden within the Milan criteria in cirrhotic patients. Cirrhotic patients had a higher risk of posthepatectomy decompensation compared to noncirrhotic patients (hazard ratio 9.577, p = 0.017). No difference was observed in overall survival and recurrence-free survival between patients with or without cirrhosis. Compared with patients without cirrhosis, cirrhotic patients with HCC and EV are vulnerable to posthepatectomy decompensation. However, cirrhosis is not a poor prognostic factor of overall survival and recurrence for HCC patients after surgical resection.

S2859 Metastatic Hepatocellular Carcinoma After Sustained Virologic Response to Hepatitis C in a Non-Cirrhotic

Introduction: Hepatitis C has long been one of the most common causes of cirrhosis and resultant hepatocellular carcinoma (HCC). There is evidence demonstrating an increased risk of development of HCC in non-cirrhotic patients who have had sustained virologic response (SVR) after direct acting antiviral (DAA) treatment of hepatitis C. We present a case of a non-cirrhotic 72-year-old male who attained SVR with DAA treatment in 2018. After presenting to the hospital two years later with significant weight loss and fatigue, he was found to have metastatic HCC. Case Description/Methods: A 71-year-old male with a history of tobacco use, hypertension, diabetes mellitus type 2, and chronic hepatitis C who completed Harvoni in 2017 was admitted due to unintentional weight loss of fifty-five pounds associated with early satiety, epigastric pain, and weakness. He was found to have hepatitis C antibodies in 1993 and underwent a liver biopsy in 2001 that showed stage one fibrosis. In 2015, he underwent a second liver biopsy that again showed stage one portal fibrosis. In July 2017, he underwent treatment and was found to have an undetectable viral load. During his 2021 admission, CT abdomen/pelvis showed heterogeneous enhancement throughout the right lobe of the liver with scattered hyper-enhancing foci. He underwent liver biopsy showing HCC. He was offered the option of immunotherapy versus hospice care. He then opted for hospice care. Discussion: While HCC can develop in patients who achieved sustained virologic response following HCV eradication, 20% of cases can develop in non-cirrhotics. Surveillance is not performed in these cases, so HCC can present at more advanced stages. Risk factors for HCC development after HCV clearance are older age at eradication, male sex, advanced fibrosis stage, AFP levels following IFN treatment, heavy alcohol use, diabetes mellitus, hypertension, and hyperlipidemia. Clearance by DAAs had no impact on short term development of HCC but noted sofosbuvir-based treatment without Ribavirin as adding additional risk. Other guidelines proposed following the level of fibrosis and SVR but acknowledged that implementation of this strategy cannot presently be achieved in clinical practice. Although abdominal ultrasound remains the gold standard, associating the development of HCC in patients with SVR and various SNPs could identify patients at increased risk. Our case further enforces the need for increased surveillance in this patient population.

Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cause of cancer with an increasing incidence. The major HCC risk factor in 80 % of all patients is liver cirrhosis followed by chronic hepatitis B infection or non-alcoholic steatohepatitis (NASH) in non-cirrhotic HCC patients. In early BCLC stages curative treatment applying liver resection, liver transplantation or local ablation is feasible, but, despite increased usage of surveillance programmes two-thirds of HCC patients are diagnosed in advanced BCLC stages. Transarterial chemoembolization (TACE) and selective internal radiation therapy (SIRT) show improved tumor control in BCLC stage B. In fact, major advances in HCC therapy concern medical treatment with the implementation of immunotherapy. The combination of atezolizumab with bevacizumab comprises the new first-line treatment in BCLC stage C. Tyrosine kinase inhibitors (TKI) are indicated in case of contraindications or as second line therapy.

Non-invasive imaging criteria for the diagnosis of hepatocellular carcinoma in non-cirrhotic patients with chronic hepatitis B

Background & AimsCriteria defined by the European Association for the Study of the Liver (EASL) and Liver Imaging Reporting and Data System (LI-RADS) enable hepatocellular carcinoma (HCC) diagnosis based on imaging in cirrhosis. Non-cirrhotic patients require biopsy given the lower pre-test probability of HCC. The objective of our study was to assess the performance of EASL and LI-RADS criteria for the diagnosis of HCC in non-cirrhotic patients with chronic HBV infection.MethodsThis was a cross-sectional study performed at a referral center. We included all patients with HBV without cirrhosis with focal liver lesions who underwent contrast-enhanced CT or MRI at our clinic between 2005-2018. Studies were reviewed by 2 radiologists blinded to the diagnosis.ResultsWe included 280 patients, median age was 56.8 (IQR 48.2-65.45) years and 223 (80%) were male. In 191 (79%) cases the lesion was found as a result of screening. Cirrhosis was excluded based on pathology in 252 (90%) cases. We assessed 338 nodules: 257 (76%) HCC, 40 (12%) non-HCC malignant lesions, and 41 (12%) benign lesions. EASL criteria and LR-5/LR-tumor-in-vein (TIV) categories had a 100% agreement in categorizing lesions as HCC, and 226 nodules (67%) were classified as HCCs. The sensitivity, specificity, positive predictive value, and negative predictive value were 82.1 (76.9-86.6), 81.5 (71.3-89.2), 93.4 (89.3-96.2), and 58.9 (49.2-68.1), respectively. When the pre-test probability of HCC is >70%, estimated as a PAGE-B score above 9, and EASL or LR-5/LR-TIV criteria are met, post-test probability would be >90%.ConclusionsEASL criteria and LR-5/LR-TIV categories show a positive predictive value in patients with HBV without cirrhosis that is comparable to that seen in patients with cirrhosis. These criteria can be used when the pre-test probability of HCC is >70%.Lay summaryCurrent guidelines recommend performing a biopsy to confirm the diagnosis of presumed hepatocellular carcinoma (HCC) in patients without cirrhosis. We showed that specific imaging criteria had a 100% agreement for categorizing lesions as HCC, with a positive predictive value of 93.4%. These imaging criteria could be used to diagnose HCC in HBV patients without cirrhosis with a pre-test probability of HCC of ≥70%, avoiding the need for a liver biopsy.

Preoperative Alpha-Fetoprotein Has No Prognostic Role in Small Hepatocellular Carcinoma in Non-Cirrhotic Patients After Surgical Resection

Alpha-fetoprotein (AFP) has been widely used as a tumor marker in the treatment of hepatocellular carcinoma (HCC) in patients with cirrhosis. However, a large number of HCC patients are diagnosed without cirrhosis, and the prognostic capability of AFP was unclear in HCC patients without cirrhosis. Our purpose was to investigate the prognostic efficiency of AFP in patients with non-cirrhosis, single, and small HCC who were treated with surgical resection.Among the 111 374 liver cancer patients included in the Surveillance, Epidemiology, and End Results database, we selected 224 patients without cirrhosis with a single HCC ≤3 cm in diameter who were identified at diagnosis and treated with surgical resection. The AFP test results were recorded as AFP-positive and AFP-negative levels.Kaplan-Meier method showed that there was no significant survival difference between the AFP-positive and AFP-negative groups (P = .566). The same results were found in the subgroups of patients with tumor size ≤2 cm and 2-3 cm (P = .710 and .687, respectively). Receiver operating characteristic (ROC) curve analysis showed that AFP had inadequate accuracy to discriminate survivors and deceased patients in subgroups of patients with tumor size ≤3 cm, 2-3 cm, or ≤2 cm (area under the ROC curve = 0.449, 0.458, 0.443; 95% confidence interval = 0.366-0.533, 0.346-0.571, 0.317-0.569, respectively).AFP levels have no predictive value in well-compensated non-cirrhosis patients with single, small HCC (≤3 cm) treated with surgical resection for curative intent.

Hepatocellular Carcinoma in Cirrhotic Versus Non-Cirrhotic Patients: A Retrospective Study of 483 Patients

Background and Aim: Although cirrhosis is a classical risk factor for the development of hepatocellular carcinoma (HCC), its absence does not exclude this risk. We aimed to assess the clinical characteristics and outcomes of cirrhotic HCC (C-HCC) and non-cirrhotic HCC (NC-HCC) patients. Methods: Patients consecutively included in a prospective HCC cohort (University Hospital Bern) were analysed. They were categorised into two groups, based on the basis of histology or combined radiological and laboratory characteristics. Results: 20.4% of patients were NC-HCC. This group was characterized by a higher median age and a higher female prevalence compared to the C-HCC group. Non-alcoholic fatty liver disease (NAFLD) (25.7%) and HBV infection (14.9%) were the main risk factors in this group, whereas alcohol abuse (26%) and HCV (21.6%) in C-HCC, P&lt;0.001. 19.4% of them were diagnosed during a screening programme. Resection was performed in 54.5% of NC HCC patients despite the advanced stage (BCLC stage B and C). No statistically significant difference in survival rate was observed between C and NC-HCC patients (24 months vs. 33.9 months, P=0.162). In multivariate analysis, in the NC-HCC group each unit increase in BMI was associated with mortality while liver transplantation and resection were positively associated with survival. In the C-HCC group, the BCLC stage C was negatively associated with survival while all the therapeutic lines were negative factors for mortality. Conclusion: NC-HCC patients were diagnosed more often outside a screening programme. The patients were older, with a higher female prevalence and despite an advanced stage, were often amenable to surgery.

Deoxycholic Acid Upregulates Serum Golgi Protein 73 through Activating NF-κB Pathway and Destroying Golgi Structure in Liver Disease

Golgi protein 73 (GP73) is upregulated in a variety of liver diseases, yet the detailed mechanism is poorly characterized. We analyzed GP73 in a retrospective cohort including 4211 patients with chronic liver disease (CLD) or hepatocellular carcinoma (HCC). The effect of deoxycholic acid (DCA) and nuclear factor-kappa B (NF-κB) on expression and release of GP73 in Huh-7 and SMMC7721 cells were studied. A mouse study was used to confirm our findings in vivo. A positive correlation was found between serum GP73 and total bile acid (TBA) in cirrhotic patients (r = 0.540, p < 0.001), higher than that in non-cirrhotic CLD (r = 0.318, p < 0.001) and HCC (r = 0.353, p < 0.001) patients. In Huh-7 and SMMC7721 cells, DCA upregulated the expression and release of GP73 in a dose- and time-dependent manner. After overexpressing NF-κB p65, the promoter activity, GP73 messenger RNA (mRNA) level, and supernatant GP73 level were increased. The promotion effect of DCA on GP73 release was attenuated after inhibiting the NF-κB pathway. Mutating the binding sites of NF-κB in the sequence of the GP73 promoter led to a declined promoting effect of DCA on GP73. The upregulation role of DCA in GP73 expression through the NF-κB pathway was confirmed in vivo. In addition, exposure to DCA caused disassembly of Golgi apparatus. In summary, DCA upregulates the expression and release of GP73 via activating the NF-κB pathway and destroying the Golgi structure.

The characteristics and risk factors of hepatocellular carcinoma in nonalcoholic fatty liver disease without cirrhosis.

We evaluated the characteristics of hepatocellular carcinoma (HCC) in patients who had non-alcoholic fatty liver disease (NAFLD) without cirrhosis. We prospectively followed NAFLD patients at our University hospital. NAFLD was diagnosed from detection of steatosis by histology or imaging, no alcohol intake, and exclusion of other liver diseases. Cirrhosis was defined by histological features, imaging data, and symptoms. We compared NAFLD-related HCC with or without cirrhosis and non-cirrhotic NAFLD with or without HCC. There were 48 non-cirrhotic HCC patients and 71 cirrhotic HCC patients. Multiple logistic regression analysis revealed that other than liver function factors, male gender (OR: 5.603, 95%CI: 1.577-19.900), light drinker (OR: 2.797, 95%CI: 1.031-7.589), and tumor size (OR: 1.031, 95%CI 1.009-1.055) differ significantly between these two groups. The recurrence rate was significantly lower in the non-cirrhotic HCC group than the cirrhotic HCC group, with risk factors being des-γ-carboxy prothrombin and the number of HCCs. The non-cirrhotic HCC group showed significantly better survival because of absence of non-cancerous liver failure. Comparison between non-cirrhotic NAFLD patients with or without HCC (n=612) revealed the following risk factors for HCC: male gender (OR: 7.774, 95%CI: 2.176-27.775), light drinker (OR: 4.893, 95%CI: 1.923-12.449), and high FIB4 index (OR 2.634, 95%CI: 1.787-3.884). In patients with non-cirrhotic NAFLD, important risk factors for HCC were male gender, alcohol consumption, and the FIB4 index. HCC recurrence and survival were only influenced by the tumor stage. We should be aware of alcohol consumption as a modifiable risk factor for HCC.

Hyperlipidemia and Nonalcoholic Steatohepatitis Predispose to Hepatocellular Carcinoma Development Without Cirrhosis.

Hepatocellular carcinoma (HCC) accounts for 90% of primary hepatic malignancies. With the exception of chronic hepatitis B (CHB), other etiologies of chronic liver disease require progression to cirrhosis before HCC development. Case reports have described HCC in noncirrhotic patients with hepatitis C (HCV) and nonalcoholic fatty liver disease. The aim of this study was to determine the prevalence of patients without cirrhosis and CHB who developed HCC among a large cohort of HCC patients and to identify independent variables that are associated with no cirrhosis among patients with HCC. From 2005 to 2015, hepatobiliary cancer patients seen in our liver cancer and liver transplant clinics were evaluated. Patients were included if above18 years old and had histologically confirmed HCC from liver biopsy, resection specimen, or explanted livers. Patients with CHB, non-HCC tumors, or missing paired tumor and nontumor liver histology were excluded. Demographic information, pertinent laboratory values, and comorbid conditions were recorded. Potential predictors were evaluated using both backward stepwise logistic regression model and classification tree model. Of the 1927 patients screened, 545 HCC patients (411 transplanted, 43 resected, 74 transarterial chemoembolization/radiofrequency ablation, 17 untreated) included, 29 (5.3%) patients had no cirrhosis histologically. Eleven patients had HCV, 3 had alcoholic liver disease, 3 had nonalcoholic fatty liver, and 12 had cryptogenic liver disease. Logistic regression models show that patients with hyperlipidemia and elevated serum alanine aminotransferase are more likely to develop HCC without cirrhosis (odds ratio, 1.73 and 0.40; P<0.05). This large cohort, histology-confirmed case-controlled study shows that patients with nonalcoholic fatty liver disease and hyperlipidemia with elevated serum alanine aminotransferase (most likely nonalcoholic steatohepatitis) are significantly associated with the development of HCC in the absence of cirrhosis.

Hepatocellular carcinoma in non-cirrhotic liver: A comprehensive review.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which in turns accounts for the sixth most common cancer worldwide. Despite being the 6th most common cancer it is the second leading cause of cancer related deaths. HCC typically arises in the background of cirrhosis, however, about 20% of cases can develop in a non-cirrhotic liver. This particular subgroup of HCC generally presents at an advanced stage as surveillance is not performed in a non-cirrhotic liver. HCC in non-cirrhotic patients is clinically silent in its early stages because of lack of symptoms and surveillance imaging; and higher hepatic reserve in this population. Interestingly, F3 fibrosis in non-alcoholic fatty liver disease, hepatitis B virus and hepatitis C virus infections are associated with high risk of developing HCC. Even though considerable progress has been made in the management of this entity, there is a dire need for implementation of surveillance strategies in the patient population at risk, to decrease the disease burden at presentation and improve the prognosis of these patients. This comprehensive review details the epidemiology, risk factors, clinical features, diagnosis and management of HCC in non-cirrhotic patients and provides future directions for research.

Long-term follow-up after cure from chronic hepatitis C virus infection shows occult hepatitis and a risk of hepatocellular carcinoma in noncirrhotic patients.

Curing of hepatitis C virus (HCV) infection primarily aims to prevent severe liver complications. Our objectives were to investigate the long-term presence and impact of occult HCV infection (OCI) and to study the outcomes in terms of liver disease after virological cure. A total of 97 patients with achieved sustained virological response (SVR) during 1990-2005 were followed either by a clinical follow-up (FU) visit with blood sampling and liver elastography (n=54) or through national registries for outcomes (n=43). To diagnose OCI among patients with SVR, a highly sensitive method was used to detect HCV-RNA traces in whole blood. The FU duration was a median of 10.5 years, with samples up to 21.5 years after the end of treatment (EOT). The majority of patients [52 (96%)] were HCV-RNA negative at FU, and regression of fibrosis was statistically significant. OCI was found in two (4%) of them at 8 and 9 years after EOT. These patients had F1 and F2 fibrosis before treatment and F2 at FU, but no other abnormal findings. Three previously noncirrhotic men were diagnosed with hepatocellular carcinoma 8-11 years after EOT. Occult infection could be detected many years after the achievement of SVR but was not associated with serious liver disease. The majority had persistent viral eradication and regression of fibrosis after SVR. However, an increased risk of hepatocellular carcinoma may persist in the long term after SVR even in noncirrhotic patients. Further studies with FU after direct-acting antiviral therapy and on the long-term impact after cure are needed.

Incidence and Survival Trends of Hepatocellular Carcinoma in Non-Cirrhotics With Ishak Fibrosis Score of 0-4 Between 2005-2014: A SEER Analysis

Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and one of the leading causes of cancer related deaths. Although HCC occurs most commonly in cirrhotic livers, there is growing concern about HCC in non-cirrhotics, especially those with metabolic syndrome and NAFLD. However, there are limited data regarding HCC incidence and survival among non-cirrhotic patients in the United States. Methods: The Surveillance, Epidemiology, and End Results (SEER) registry was utilized to obtain data for HCC in non-cirrhotic patients with Ishak fibrosis scores of 0-4 from 2005-2014. Results: Overall incidence from 2005-2014 was 0.30 cases per 100,000 persons per year, with higher incidence in males (0.49, 95% CI: 0.47-0.51) compared to females (0.13, 95% CI: 0.12-0.14). For race, incidence was greatest among Asian or Pacific Islanders (APIs) (0.83, 95% CI: 0.77-0.90), but annual percent change (APC) was highest among whites (APC 3.29) and blacks (APC 6.53) (figure 1). APC in APIs has been stable (0.56)(table 1). Incidence analysis by HCC stage (localized, regional, and distant) shows that localized disease has the greatest incidence (0.18, 95% CI: 0.17-0.18) and localized and regional disease have the highest APC (3.24 and 6.51, respectively). Survival analysis showed that females had a higher five-year survival (42.8%, 95% CI: 37.2%-48.2%) than males (36.6%, 95%CI: 33.6%-39.5%). For race, APIs had the highest five-year survival (46.5%, 95% CI: 41.5%-51.2%) and blacks had the lowest (25.3%, 95% CI: 17.9%-33.3%) (figure 2). For stage and AFP levels, survival was highest for localized disease (51.7%, 95%CI: 48.2%- 55.1%) and negative/normal AFP levels (54.06%, 95%CI: 48.44%-59.34%), respectively. Conclusion: The incidence of HCC in non-cirrhotic patients in the US with Ishak fibrosis scores of 0-4 is increasing. Moreover, our findings correlate well with obesity trends in the US, where lower rates of obesity are observed among non-Hispanic Asians (11.7%) than among non-Hispanic white (34.5%), Hispanic (42.5%), and non-Hispanic black (48.1%)[1]. Survival is influenced by gender, race, AFP level, and stage of disease. These findings may help to identify at-risk populations as well as risk factors for improving surveillance for HCC in non-cirrhotics.832_A Figure 1. Incidence Rate, Race 2005-2014; decimal place indicates number of months in year832_B Figure 2. Count, Annual Percent Change and Hazard Ratios for HCC In Non-Cirrhotics with Ishak Fibrosis 0-4832_C Figure 3. Survival Based on Race

Identifying Differentially Expressed MicroRNAs Between Cirrhotic and Non-Cirrhotic Hepatocellular Carcinoma and Exploring Their Functions Using Bioinformatic Analysis

Background/Aims: Few studies have been designed to directly investigate the exact mechanisms underlying the different phenotypes between cirrhotic and non-cirrhotic hepatocellular carcinoma (HCC). This study aimed to illuminate the incidence and developmental mechanisms for both types of HCC through differentially expressed microRNAs (miRNAs) using bioinformatic analysis. Methods: The miRNA-seq data and clinical data of patients (from The Cancer Genome Atlas (TCGA) database) were utilized to determine differentially expressed miRNAs between cirrhotic and non-cirrhotic HCC. Afterwards, the function of the selected miRNAs was predicted with online tools. Furthermore, the miRNA expression and clinical significance were validated by external datasets and our experiment. Results: The present study included 135 non-cirrhotic and 80 cirrhotic patients to find differentially expressed miRNAs. Among them, four miRNAs (mir-1296, mir-23c, mir-149, and mir-95) were finally selected for further validation and analysis. Correlation analysis found that two miRNAs are greatly associated with the non-cirrhotic HCC patients’ clinical traits, such as the T, M, and N tumor stages. However, only mir-23c was associated with the cirrhotic HCC patients’ tumor T and N stages. Furthermore, survival analysis revealed that increased mir-149 in non-cirrhotic HCC, patients’ age and the existence of vessels in the tumor in cirrhotic HCC were independent risk factors for the patients’ postoperative overall survival. Functional and interaction analyses also supported the notion that these miRNAs function through some pathways that influence the behavior of the HCC. These results are strongly supported by analysis of extra datasets and our experiment. Conclusions: The cirrhotic and non-cirrhotic HCC types involve differentially expressed miRNAs, which are correlated with distinctive pathological traits. To some extent, non-cirrhotic HCC seems more dependent on miRNA network regulation, but additional studies are needed to confirm this conclusion.

Proton pump inhibitors are associated with accelerated development of cirrhosis, hepatic decompensation and hepatocellular carcinoma in noncirrhotic patients with chronic hepatitis C infection: results from ERCHIVES

Proton pump inhibitors are among the most commonly prescribed medications in the United States. Their safety in cirrhosis has recently been questioned, but their overall effect on disease progression in noncirrhotic patients with chronic liver disease remains unclear. To determine the impact of proton pump inhibitors on the progression of liver disease in noncirrhotic patients with hepatitis C virus (HCV) infection. Using the electronically retrieved cohort of HCV-infected veterans (ERCHIVES) database, we identified all subjects who received HCV treatment and all incident cases of cirrhosis, hepatic decompensation and hepatocellular carcinoma. Proton pump inhibitor use was measured using cumulative defined daily dose. Multivariate Cox regression analysis was performed after adjusting univariate predictors of cirrhosis and various indications for proton pump inhibitor use. Among 11 526 eligible individuals, we found that exposure to proton pump inhibitors was independently associated with an increased risk of developing cirrhosis (hazard ratio [HR]: 1.32; 95% confidence interval: [1.17, 1.49]). This association remained robust to sensitivity analysis in which only patients who achieved sustained virologic response were analysed as well as analysis excluding those with alcohol abuse/dependence. Proton pump inhibitor exposure was also independently associated with an increased risk of hepatic decompensation (HR: 3.79 [2.58, 5.57]) and hepatocellular carcinoma (HR: 2.01 [1.50, 2.70]). In patients with chronic HCV infection, increasing proton pump inhibitor use is associated with a dose-dependent risk of progression of chronic liver disease to cirrhosis, as well as an increased risk of hepatic decompensation and hepatocellular carcinoma.