Liver cancer has a high incidence and mortality rate worldwide, with hepatocellular carcinoma (HCC) being the most common histological type. With the decrease in the number of newly infected patients and the spread of antiviral therapy, hepatitis virus-negative chronic liver diseases including steatohepatitis are increasingly accounting for a large proportion of HCC, and an important clinical characteristic is the high prevalence of metabolic syndrome including hypertension, type 2 diabetes (T2D), dyslipidemia, and obesity. Since patients with steatohepatitis are less likely to undergo surveillance for early detection of HCC, they may be diagnosed at an advanced stage and have worse prognosis. Therefore, treatment strategies for patients with HCC caused by steatohepatitis, especially in advanced stages, become increasingly important. Further, hypertension, T2D, and dyslipidemia may occur as side effects during systemic treatment, and there will be increasing opportunities to prescribe metabolic syndrome medications, not only for originally comorbid diseases, but also for adverse events during HCC treatment. Interestingly, epidemiological studies have shown that patients taking some metabolic syndrome medications are less likely to develop various types of cancers, including HCC. Basic studies have also shown that these drugs have direct antitumor effects on HCC. In particular, angiotensin II receptor blockers (a drug group for treating hypertension), biguanides (a drug group for treating T2D), and statins (a drug group for treating dyslipidemia) have shown to elucidate antitumor effects against HCC. In this review, we focus on the antitumor effects of metabolic syndrome medications on HCC and their mechanisms based on recent literature. New therapeutic agents are also increasingly being reported. Analysis of the antitumor effects of metabolic syndrome medications on HCC and their mechanisms will be doubly beneficial for HCC patients with metabolic syndrome, and the use of these medications may be a potential strategy against HCC.

Background: The treatment of the hepatitis C virus (HCV) has reduced the risk of hepatocellular carcinoma (HCC)-related mortality. Many patients with advanced HCC have achieved longer survival through systemic chemotherapy. However, survivors of HCC may develop liver cancer during and after treatment. Therefore, the present study investigated prognostic factors for survival in patients with HCV-related HCC in the new era of molecular targeted therapy. Methods: A total of 359 patients with HCV-related HCC treated with first-line chemotherapy were reviewed. A Cox proportional hazards model and Kaplan−Meier curve were used to identify prognostic factors associated with survival outcomes. Results: The median follow-up duration was 16.0 months (range, 1.0−115.7) and the median duration of first-line systemic therapy was 3.73 months (range, 0.7−86.9). The achievement of a sustained virological response (SVR) (p  <  0.001), albumin−bilirubin (ALBI) grade II/III (p  <  0.001), Barcelona Clinic Liver Cancer (BCLC) stage C (p  =  0.005), extrahepatic spread (p < 0.001), baseline AFP (alpha-fetoprotein) level ≥ 90 (p = 0.038), baseline DCP (des-γ-carboxy prothrombin) level ≥ 500 (p < 0.001), and a fibrosis-4 (FIB-4) index ≥ 4 (p  =  0.003) were identified as prognostic factors for overall survival. Conclusions: The achievement of SVR was most strongly associated with overall survival. Other factors, such as the BCLC stage, extrahepatic spread, baseline tumor marker (AFP/DCP) levels, ALBI grade, and FIB-4 index need to be considered in the management of patients with HCV-related HCC.

Neoangiogenesis is one of the key pathogenetic mechanisms in hepatocellular carcinoma (HCC). Modulation of the renin-angiotensin system (RAS) by angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) seems to be a possible adjuvant therapy for HCC, due to the anti-angiogenic and anti-fibrogenic activity of these drugs.

To elucidate the role of ARBs and ACE-Is in HCC.

We performed an electronic search of the literature using the most accessed online databases (PubMed, Cochrane library, Scopus and Web of Science), entering the query terms "angiotensin-converting enzyme inhibitors" OR "ACE inhibitors" OR "ACE-I" AND "hepatocarcinoma*" OR "hepatocellular carcinoma; moreover "angiotensin II type 1 receptor blockers" OR "ARBs" AND "hepatocarcinoma*" OR "hepatocellular carcinoma". Eligibility criteria were: (1) prospective or retrospective clinical studies; (2) epidemiological studies; and (3) experimental studies conducted in vivo or in vitro. Abstracts, conference papers, and reviews were excluded a priori. We limited our literature search to articles published in English, in peer-reviewed journals.

Thirty-one studies were selected. Three interventional studies showed that ACE-Is had a significant protective effect on HCC recurrence only when used in combination with vitamin K or branched chain aminoacids, without a significant increase in overall survival. Of six retrospective observational studies, mainly focused on overall survival, only one demonstrated a prolonged survival in the ACE-Is group, whereas the two that also evaluated tumor recurrence showed conflicting results. All experimental studies displayed beneficial effects of RAS inhibitors on hepatocarcinogenesis. Numerous experimental studies, conducted either on animals and cell cultures, demonstrated the anti-angiogenetic and antifibrotic effect of ACE-Is and ARBs, thanks to the suppression of some cytokines such as vascular endothelial growth factor, hypoxia-inducible factor-1a, transforming growth factor-beta and tumor necrosis factor alpha. All or parts of these mechanisms were demonstrated in rodents developing fewer HCC and preneoplastic lesions after receiving such drugs.

In humans, RAS inhibitors - alone or in combination - significantly suppressed the cumulative HCC recurrence, without prolonging patient survival, but some limitations intrinsic to these studies prompt further investigations.

Neovascularization is a marker of plaque vulnerability that can be assessed noninvasively using contrast-enhanced ultrasound (CEUS). The presence and extent of plaque neovascularization and their relation to cardiovascular risk factors and treatments were assessed in asymptomatic patients with carotid stenosis of intermediate severity and no indication for revascularization.

Sixty-six patients aged 69 ± 8 years (59% men) were prospectively enrolled. Plaque neovascularization was assessed using CEUS with sulfur hexafluoride contrast in each of the four carotid segments bilaterally (a total of 528 segments). In each plaque, the presence or absence of contrast enhancement was assessed semiquantitatively as CEUS grade 1 (no signal or signal confined to the adventitia and/or shoulder of the plaque) or CEUS grade 2 (signal within the plaque).

Plaques were detectable in 289 of 528 carotid segments (54.7%). CEUS grade 2 was present in at least one plaque in 48 of 66 patients (72.7%) and was not influenced by stenosis severity or morphology. The highest CEUS grade 2 prevalence was observed in patients with diabetes and the lowest in those treated with angiotensin-converting enzyme inhibitors and statins, especially when low-density lipoprotein cholesterol was <100 mg/dL. Patients with multiple CEUS grade 2 plaques (20 of 66 [30%]) had both higher low-density lipoprotein and higher C-reactive protein.

Intraplaque neovascularization is frequent in asymptomatic patients with intermediate carotid stenosis and is more prevalent in those with diabetes. Low-density lipoprotein cholesterol < 100 mg/dL and treatment with angiotensin-converting enzyme inhibitors seem to confer protection from neovascularization, although larger interventional studies are necessary to confirm these data.

The single nucleotide polymorphism (SNP) of the vascular endothelial growth factor (VEGF) gene -634 G/C (rs2010963) influences the progression of hepatocellular carcinoma (HCC). There have been no studies on the role of VEGF SNP -634 G/C in chronic liver disease (CLD). The aim of the present study was to analyse the correlation between VEGF SNP -634 and the clinical severity of CLD and HCC.

A cross sectional study was conducted on 182 subjects (46 HCC, 39 liver cirrhotic/LC, 38 chronic hepatitis/CH; and 57 healthy subjects). The study was conducted from 2010 to 2014 at the Dr. Sardjito Hospital Yogyakarta, Indonesia. All subjects submitted blood serum for DNA sequencing examination using primer. The clinical data of CLD and HCC were assessed, and sVEGFR-2 was examined in 149 subjects. All data were analysed using STATA programme 11.0.

Significant differences were observed in genotypic frequency (GG/GC/CC) between HCC, LC, CH and healthy subjects (p=0.004), but though no significant differences were observed between the G>G and C>G genotypic frequencies (p=0.337). The frequency of genotype GG was significantly higher than genotype GC or CC in HCC and was associated with declining of clinical conditions (p<0.05). No significant difference in the distribution genotypes was observed with respect to the level of sVEGFR-2 in the serum. However, we observed a significant correlation between sVEGFR-2 and clinical characteristics in LC and CH (p<0.05).

Genotype GG of the VEGF SNP -634 is the dominant genotype in severe CLD and HCC. sVEGFR-2 correlates with the disease severity but is not directly associated with the SNP -634 genotype.