Background & Aims: The influence of HFE gene mutations and liver iron overload on hepatocellular carcinoma (HCC) occurrence in patients with cirrhosis is subjected to controversial results. The aim of this work was to clarify this influence in a large cohort of prospectively followed-up cirrhotic patients classified according to the cause of their liver disease. Methods: Three hundred one consecutive cirrhotic patients (162 alcoholics and 139 HCV-infected patients) were included at time of diagnosis of cirrhosis and followed-up. Liver iron overload on initial biopsy according to modified Deugnier’s score and C282Y/H63D HFE gene mutations were assessed. Results: In patients with alcoholic cirrhosis (mean iron score, 2.0 ± 3.0; mean time of follow-up, 66.1 ± 45.1 months), 40 (24.6%) developed HCC. Thirteen (8.02%) were heterozygotes for C282Y HFE gene mutation and had higher hepatic iron scores (3.6 ± 3.8 vs 1.9 ± 2.8, respectively, P = .05). In univariate analysis, liver iron overload as a continuous variable (HR, 1.23 [1.13–1.34], P < .001) or in binary coding with an optimal threshold of iron score ≥2.0 (HR, 4.1 [2.1–7.3], P < .0001) and C282Y mutation carriage (HR, 2.7 [1.2–6.3], P = .01) were risk factors for HCC. In multivariate analysis, liver iron and C282Y mutation carriage remained independent risk factors for HCC. In patients with HCV-related cirrhosis (C282Y mutation carriage, 17 [12.23%]; mean liver iron score, 0.9 ± 1.9; mean time of follow-up, 85.5 ± 42.1 months; HCC, 63 [45.32%] patients), C282Y mutation carriage and liver iron were not associated with HCC occurrence. Conclusions: Liver iron overload and C282Y mutation are associated with a higher risk of HCC in patients with alcoholic but not HCV-related cirrhosis.
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Patients
The present study was part of an ongoing prospective study aiming to assess the rates of HCC development in the course of various liver diseases. In the present study, we compiled all new patients who were consecutively referred to our liver unit for diagnosis and management of cirrhosis between January 1, 1990, and December 31, 2000, and who fulfilled the following inclusion criteria: (1) biopsy-proven cirrhosis; (2) no infection by the human immunodeficiency virus or hepatitis B virus; (3) no
Baseline Characteristics of Patients and Follow-up
Clinical and biochemical features of the 301 patients recorded at inclusion are summarized in Table 1 according to the etiology of cirrhosis. Along with parameters reflecting iron metabolism, parameters estimating the severity of liver disease such as Child-Pugh score or known risk factors for HCC occurrence are displayed in Table 1. Regarding HFE gene mutations, none of the studied patients were homozygotes for the C282Y mutation, 3 patients with alcoholic cirrhosis were homozygotes for the
Discussion
By independently analyzing iron metabolism parameters in 2 distinct cohorts of cirrhotic patients according to the cause of their liver disease, our results suggest that liver iron overload and HFE gene mutations may not participate equally in alcohol- or HCV-induced hepatocarcinogenesis. In our study, patients with HCV-related cirrhosis had lower hepatic iron scores than patients with alcoholic cirrhosis even if older. As a possible consequence, this lower iron accumulation did not influence
The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma
Liver Transpl
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F. Lodato et al.
Hepatocellular carcinoma prevention: a worldwide emergence between the opulence of developed countries and the economic constraints of developing nations
2020, Clinics and Research in Hepatology and Gastroenterology
Genome wide association study has identified chromosome 6p21.33 as a risk locus of hepatocellular carcinoma (HCC). MiR-877 is located on this region, functioning as a tumor suppressor. The aim of this study was to investigate the association between rs1264440 in the promoter of miR-877 and HCC risk.
A total of 352 HCC patients and 359 age, gender, ethnicity and living area matched controls were enrolled in this study. The rs1264440 was genotyped using the TaqMan allelic discrimination assay. MiR-877 expression in HCC tissues was examined using quantitative PCR.
After Adjustment for age, sex, smoking status, drinking status and HBsAg status, this study showed a significant association between the rs1264440 and HCC risk. Subjects with the rs1264440 TT genotype and T allele showed a 2.20- and 1.44-fold increased risk to develop HCC, respectively (TT vs. CC: 95% CI, 1.18–4.11, P = 0.01; T vs. C: 95% CI, 1.07–1.94, P = 0.02). The increased risk was also observed in smokers and nondrinkers subgroup. The rs1264440 TT carriers had lower levels of miR-877.
The rs1264440 in the promoter region of miR-877 may regulate miR-877 expression and serve as an independent biomarker for the risk of HCC.
Hepatocellular carcinoma (HCC) arises from hepatocytes through the sequential accumulation of multiple genomic and epigenomic alterations resulting from Darwinian selection. Genes from various signalling pathways such as telomere maintenance, Wnt/β-catenin, P53/cell cycle regulation, oxidative stress, epigenetic modifiers, AKT/mTOR and MAP kinase are frequently mutated in HCC. Several subclasses of HCC have been identified based on transcriptomic dysregulation and genetic alterations that are closely related to risk factors, pathological features and prognosis. Undoubtedly, integration of data obtained from both preclinical models and human studies can help to accelerate the identification of robust predictive biomarkers of response to targeted biotherapy and immunotherapy. The aim of this review is to describe the main advances in HCC in terms of molecular biology and to discuss how this knowledge could be used in clinical practice in the future.
Alcoholic liver disease (ALD) is one of the most common liver diseases worldwide. However, the exact mechanisms underlying ALD remain unclear. Previous studies reported that sphingosine kinase 2 (SphK2) plays an essential role in regulating hepatic lipid metabolism. In the current study, we demonstrate that compared to wild-type (WT) mice, SphK2 deficient (SphK2−/−) mice exhibited a greater degree of liver injury and hepatic lipid accumulation after feeding with an alcohol diet for 60 days. This is accompanied by a down-regulation of steroid 7-alpha-hydroxylase (Cyp7b1) and an up-regulation of pro-inflammatory mediators (Tnfα, F4/80, Il-1β). In vitro experiments showed that alcohol induced SphK2 expression in mouse primary hepatocytes and cultured mouse macrophages. Furthermore, alcohol feeding induced a more severe intestinal barrier dysfunction in SphK2−/− mice than WT mice. Deficiency of SphK2 impaired the growth of intestinal organoids. Finally, SphK2 expression levels were down-regulated in the livers of human patients with alcoholic cirrhosis and hepatocellular carcinoma compared to healthy controls. In summary, these findings suggest that SphK2 is a crucial regulator of hepatic lipid metabolism and that modulating the SphK2-mediated signaling pathway may represent a novel therapeutic strategy for the treatment of ALD and other metabolic liver diseases.
Alcohol-related liver disease is the most prevalent type of chronic liver disease worldwide, accounting for 30% of hepatocellular carcinoma (HCC) cases and HCC-specific deaths. Alcohol has been associated with an increased risk of several malignancies, this risk starting at doses as low as 10 g/1 unit/day. The carcinogenic process includes direct acetaldehyde toxicity through the formation of protein and DNA adducts, an increased production of reactive oxygen species, changes to lipid peroxidation and metabolism, inflammation and an impaired immune response and modifications to DNA methylation. A high annual incidence of HCC has been observed in large European cohorts of patients with alcoholic cirrhosis, reaching 2.9%, with numerous host factors modulating this risk (age, gender, liver failure, genetic polymorphisms affecting oncogenic pathways). Because of impaired surveillance and poor patient compliance, HCC is often detected late in patients with chronic liver disease of alcoholic aetiology. This delay in detection, which is frequently made in the context of advanced liver cirrhosis rather than in surveillance programmes, results in more advanced HCC that is less amenable to curative treatment. Consequently, patients with alcohol-related HCC generally have a worse prognosis than those with non-alcoholic HCC.
Patients who develop chronic fibrotic liver disease, caused by viral or metabolic aetiologies, are at a high risk of developing hepatocellular carcinoma (HCC). Even after complete HCC tumour resection or ablation, the carcinogenic tissue microenvironment in the remnant liver can give rise to recurrent de novo HCC tumours, which progress into incurable, advanced-stage disease in most patients. Thus, early detection and prevention of HCC development is, in principle, the most impactful strategy to improve patient prognosis. However, a “one-size-fits-all” approach to HCC screening for early tumour detection, as recommended by clinical practice guidelines, is utilised in less than 20% of the target population, and the performance of screening modalities, including ultrasound and alpha-fetoprotein, is suboptimal. Furthermore, optimal screening strategies for emerging at-risk patient populations, such as those with chronic hepatitis C after viral cure, or those with non-cirrhotic, non-alcoholic fatty liver disease remain controversial. New HCC biomarkers and imaging modalities may improve the sensitivity and specificity of HCC detection. Clinical and molecular HCC risk scores will enable precise HCC risk prediction followed by tailoured HCC screening of individual patients, maximising cost-effectiveness and optimising allocation of limited medical resources. Several aetiology-specific and generic HCC chemoprevention strategies are evolving. Epidemiological and experimental studies have identified candidate chemoprevention targets and therapies, including statins, anti-diabetic drugs, and selective molecular targeted agents, although their clinical testing has been limited by the lengthy process of cancer development that requires long-term, costly studies. Individual HCC risk prediction is expected to overcome the challenge by enabling personalised chemoprevention, targeting high-risk patients for precision HCC prevention and substantially improving the dismal prognosis of HCC.
