BACKGROUND Given the lack of long-term prospective studies, it is challenging for clinicians to make informed decisions about screening and treatment decisions regarding the risk of hepatocellular carcinoma (HCC) in patients with non-alcoholic steatohepatitis (NASH) who do not have cirrhosis. AIM To characterise the pooled risk of HCC in the non-cirrhosis population. METHODS Published studies were identified through April 2016 in MEDLINE, Scopus, Science Citation Index, AMED and the Cochrane Library. Two independent reviewers screened citations and extracted data. Random effect odds ratios (OR) were calculated to obtain aggregate estimates of effect size between NASH and non-NASH groups. Between-study variability and heterogeneity were assessed. RESULTS Nineteen studies with 168 571 participants were included. Eighty-six per cent of included subjects had cirrhosis. The prevalence of HCC in non-cirrhotic NASH was 38.0%; among other aetiologies in non-cirrhotics, it was 14.2% (P < 0.001). Non-cirrhotic NASH subjects were at greater odds of developing HCC than non-cirrhotic subjects of other aetiologies (OR 2.61, 95% CI 1.27-5.35, P = 0.009). When examining all NASH subjects either with or without cirrhosis, those with NASH as the underlying liver disease did not have a significantly increased risk of HCC (OR 1.43, 95% CI 0.77-2.65, P = 0.250). CONCLUSIONS In non-cirrhotic subjects, those with NASH have a higher risk of HCC compared to other aetiologies of liver disease. Further study investigating the risk factors of HCC among non-cirrhotic NASH patients is needed.

Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. An increasing number of reports describe HCC in the setting of obesity and diabetes, two major risk factors for non-alcoholic fatty liver disease (NAFLD). The increasing incidence of these conditions and the emerging evidence of HCC in non-cirrhotic NAFLD prioritize a better understanding of NAFLD-related HCC epidemiology and pathogenesis in order to target screening policies and develop preventive-therapeutic strategies. In this review, we focus on the epidemiological impact of this condition, suggesting a possible link between HCC in cryptogenic cirrhosis and NAFLD. Furthermore, we analyse the suggested pathogenic mechanisms and the possible preventive-therapeutic strategies.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/liv.13031

The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment

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.

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

Somatostatin (SST) deficits are common pathological features in depression and other neurological disorders with mood disturbances, but little is known about the contribution of SST deficits to mood symptoms or causes of these deficits Here we show that mice lacking SST (Sst(KO)) exhibit elevated behavioral emotionality, high basal plasma corticosterone and reduced gene expression of Bdnf, Cortistatin and Gad67, together recapitulating behavioral, neuroendocrine and molecular features of human depression Studies in Sst(KO) and heterozygous (Sst(HZ)) mice show that elevated corticosterone is not sufficient to reproduce the behavioral phenotype, suggesting a putative role for Sst cell-specific molecular changes Using laser capture microdissection, we show that cortical SST-positive interneurons display significantly greater transcriptome deregulations after chronic stress compared with pyramidal neurons Protein translation through eukaryotic initiation factor 2 (EIF2) signaling, a pathway previously implicated in neurodegenerative diseases, was most affected and suppressed in stress-exposed SST neurons We then show that activating EIF2 signaling through EIF2 kinase inhibition mitigated stress-induced behavioral emotionality in mice Taken together, our data suggest that (1) low SST has a causal role in mood-related phenotypes, (2) deregulated EIF2-mediated protein translation may represent a mechanism for vulnerability of SST neurons and (3) that global EIF2 signaling has antidepressant/anxiolytic potential

Somatostatin, neuronal vulnerability and behavioral emotionality.

The incidence of hepatocellular carcinoma (HCC) has increased significantly in United States over the last few decades in parallel with the epidemic of nonalcoholic fatty liver disease (NAFLD). Limited data suggests that HCC could arise in steatotic liver without the presence of cirrhosis. The present study was conducted to characterize patients with NAFLD presenting with HCC in non-cirrhotic liver (NCL) compared to the NAFLD- HCC patients in association with cirrhotic liver (CL). A retrospective analysis of all patients diagnosed with HCC and NAFLD diagnosis seen at our institution between 2003 and 2012 was done. The patients were characterized based on demographic and clinical variables as well as histological and tumor features. Comparisons between the NCL and CL groups were done using analysis of variance (ANOVA) or the non-parametric Kruskal–Wallis tests and Pearson's chi-square tests or Fisher's Exact tests as appropriate. P value of 5 cm) (77.8 % vs. 10.6 %), and receive hepatic resection as the modality of HCC treatment (66.7 % vs. 17 %); and were less likely to receive loco-regional therapy (22.3 % vs. 61.7 %) or orthotopic liver transplantation (OLT) (0 % vs. 72.3 %), with p value 0.05). Patients with HCC in the absence of liver cirrhosis are more likely to present at an older age with larger tumor and have higher rates of tumor recurrence. Studies to assess the cost-effectiveness of HCC surveillance in this group should be conducted.

Characterization of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) patients without cirrhosis

HCC predominantly develops in the condition of chronic inflammation that has led to liver cirrhosis. A small proportion of patients with HCC is diagnosed in the non-cirrhotic liver (NCL). Data on patients with HCC in NCL in advanced stages are scarce. A retrospective analysis was performed comparing 93 patients with HCC in NCL to 571 patients with HCC in liver cirrhosis (LC) with respect to clinical and demographic characteristics. Also factors influencing survival in patients with HCC in NCL were analyzed. Patients with HCC in NCL were diagnosed at older age and in more advanced tumor stages than patients with LC. More than 25% of patients with HCC in NCL presented with extrahepatic metastases. Only a minority of patients with HCC in NCL lacked any sign of hepatic damage. Risk factors for LC and risk factors for NAFLD are present in the majority of patients with HCC in NCL. The BCLC classification corresponded with the survival of patients with HCC in NCL although the therapeutic options differ from those for patients with liver cirrhosis. It will be one of the major challenges in the future to awake awareness of carrying a risk of hepatic malignancies in patients with chronic liver diseases apart from liver cirrhosis, especially in NAFLD. Surveillance programs need to be implemented if these are cost-effective.

/pdf/characterization-and-prognosis-of-patients-with-1mrxfebbvu.pdf

Characterization and prognosis of patients with hepatocellular carcinoma (HCC) in the non-cirrhotic liver

Pharmacological evidence suggests that the neuropeptide somatostatin (SST) exerts anxiolytic action via the amygdala, but findings concerning the putative role of endogenous SST in the regulation of emotional responses are contradictory. We hypothesized that an endogenous regulation of SST expression over the course of the day may determine its function and tested both SST gene expression and the behavior of SST knock out (SST-/-) mice in different aversive tests in relation to circadian rhythm. In an open field and a light/dark avoidance test, SST-/- mice showed significant hyperactivity and anxiety-like behavior during the second, but not during the first half of the active phase, failing to show the circadian modulation of behavior that was evident in their wild type littermates. Behavioral differences occurred independently of changes of intrinsically motivated activity in the home cage. A circadian regulation of SST mRNA and protein expression that was evident in the basolateral complex of the amygdala of wild type mice may provide a neuronal substrate for the observed behavior. However, fear memory towards auditory cue or the conditioning context displayed neither a time- nor genotype-dependent modulation. Together this indicates that SST, in a circadian manner and putatively via its regulation of expression in the amygdala, modulates behavior responding to mildly aversive conditions in mice.

/pdf/circadian-modulation-of-anxiety-a-role-for-somatostatin-in-2sy7wqq6jy.pdf

Janine Poranzke

Papers

Characterization and prognosis of patients with hepatocellular carcinoma (HCC) in the non-cirrhotic liver

Circadian Modulation of Anxiety: A Role for Somatostatin in the Amygdala