Obesity-associated mechanisms of hepatocarcinogenesis

Obesity has been recognized as a key component of the metabolic syndrome, a cluster of risk factors associated with diabetes and cardiovascular morbidity. In addition, obesity has been linked to higher frequency of cancers in a variety of tissues including the liver. Liver cancer most often occurs as hepatocellular carcinoma (HCC) complicating cirrhosis due to chronic viral infection or toxic injury and remains the third leading cause of cancer death in the world. However, HCC is increasingly diagnosed among individuals with obesity and related disorders. As these metabolic conditions have become globally prevalent, they coexist with well-established risk factors of HCC and create a unique challenge for the liver as a chronically diseased organ. Obesity-associated HCC has recently been attributed to molecular mechanisms such as chronic inflammation due to adipose tissue remodeling and pro-inflammatory adipokine secretion, ectopic lipid accumulation and lipotoxicity, altered gut microbiota, and disrupted senescence in stellate cells, as well as insulin resistance leading to increased levels of insulin and insulin-like growth factors. These mechanisms synergize with those occurring in chronic liver disease resulting from other etiologies and accelerate the development of HCC before or after the onset of cirrhosis. Increasingly common interactions between oncogenic pathways linked to obesity and chronic liver disease may explain why HCC is one of the few malignancies with rising incidence in developed countries. Better understanding of this complex process will improve our strategies of cancer prevention, prediction, and surveillance.     

HCC and NASH: How strong is the clinical demonstration?

Obesity and the metabolic syndrome (MS) are growing epidemics associated with an increased risk for many types of cancer. In the liver, in?ammatory and angiogenic changes due to insulin resistance and fatty liver disease are associated with an increased incidence of liver cancer. Regardless of underlying liver disease, cirrhosis remains the most important risk factor for hepatocellular carcinoma (HCC) although rare cases of HCC arising without cirrhosis raise the possibility of a direct carcinogenesis secondary to nonalcoholic fatty liver disease (NAFLD). Moreover, MS and its different features may also increase the risk of HCC in the setting of chronic liver diseases of other causes such as viral hepatitis or alcohol abuse. Taking into account all these data, it is necessary to better determine the risk of developing HCC in patients with MS to improve the screening guidelines and develop prophylactic treatments in this setting.     

Chronic liver diseases as liver tumor precursors

Liver cancer is a major global health problem and hepatocellular carcinoma (HCC) accounts for 75% of all liver carcinoma. HCC occurs more often in men than in women and mostly in people 50 to 60 years old. The disease is more common in parts of sub-Saharan Africa and Asia than in North and South America and Europe. Nevertheless its incidence increased over the past 4 decades in some Western countries. Worldwide, liver carcinoma is the 5th most common cancer and 3rd most common cause of cancer mortality (behind only lung and colorectal cancer) with approximately 680,000 annual deaths. Unlike most of the other malignancies, HCC almost entirely develops in the context of inflammation and organ injury and is related to cirrhosis in about 85% of the cases. Among underlying etiologies of liver cirrhosis, most frequent are viral infection and toxic substances, mostly alcohol. The main HCC risk factor in Eastern Asia and Africa is hepatitis B virus infection. Hepatitis C virus infection is the main risk factor in Western countries. Hereditary hemochromatosis is not a very frequent cause of liver cirrhosis, but these patients are at higher risk for HCC compared with other etiologies of cirrhosis. Aflatoxins, cancer-causing substances made by a type of plant mold, can play a role in some countries in Asia and Africa, and can have a synergistic effect with hepatitis B infection.     

Mutations of the HFE gene in patients with hepatocellular carcinoma

OBJECTIVE: Hepatocellular carcinoma (HCC) is a late consequence of severe liver disease. Patients with genetic hemochromatosis may be at risk for HCC, but limited information is available on the relationship of HCC and heterozygosity for the HFE gene mutations. METHODS: HFE mutations (C282Y and H63D) were assessed in 162 consecutive patients (131 men/31 women) with HCC. A total of 159 patients had cirrhosis. The most common etiologies of cirrhosis were chronic viral hepatitis (hepatitis C 39%, hepatitis B 9%) and alcoholic liver disease (36%). RESULTS: Five patients were C282Y homozygotes, four C282Y/H63D compound heterozygotes, and three H63D homozygotes. The C282Y and H63D allele frequencies in HCC were 8.3 (95% confidence limit = 5.3-11.3) and 11.1 (7.8-14.6), respectively, and not different from previously published data in healthy subjects or patients with chronic hepatitis C in Austria. Furthermore, there was no difference in the age at diagnosis in patients with or without HFE gene mutations. C282Y homozygotes had a 19-fold increased risk to develop HCC. In contrast, all other HFE allele constellations were not associated with such a risk. CONCLUSIONS: Except for C282Y homozygotes, HFE gene mutations do not increase the risk to develop HCC in patients with cirrhosis.     

Telomere and telomerase in chronic liver disease and hepatocarcinoma

The pathogenesis of liver cirrhosis is not completely elucidated. Although in the majority of patients, the risk factors may be identified in B and C viral hepatitis, alcohol intake, drugs or fatty liver disease, there is a small percentage of patients with no apparent risk factors. In addition, the evolution of chronic liver disease is highly heterogeneous from one patient to another. Among patient with identical risk factors, some rapidly progress to cirrhosis and hepatocellular carcinoma (HCC) whereas others have a benign course. Therefore, a genetic predisposition may contribute to the development of cirrhosis and HCC. Evidence supporting the role of genetic factors as a risk for cirrhosis has been accumulating during the past years. In addition to the results from epidemiological studies, polymorphisms studies and data on twins, the concept of telomere shortening as a genetic risk factor for chronic liver disease and HCC has been proposed. Here we review the literature on telomerase mutations, telomere shortening and liver disease including hepatocellular carcinoma.     

Hepatocellular carcinoma in patients with autoimmune hepatitis

AIM： To evaluate and confirm the low incidence of hepatocellular carcinoma （HCC） in patients with autoimmune hepatitis （AIH）. At present only very few cases of HCC in patients with AIH and definite exclusion of chronic viral hepatitis have been published, suggesting that HCC due to AIH is rare. METHODS： In order to further investigate the incidence of HCC in patients with AIH, we reviewed our large cohort of 278 patients with AIH. RESULTS： Eighty-nine patients （32%） were diagnosed with liver cirrhosis, a preneoplastic condition for HCC. We studied a total of 431 patient years of cirrhosis in these patients, an average 4.8 years per patient. During this period none of the patients of our own study cohort developed HCC. However, three patients with HCC due to AIH associated liver cirrhosis were referred to our department for further treatment of HCC. In all three patients chronic viral hepatitis was excluded. CONCLUSION： We conclude that HCC may under rare circumstances develop due to chronic AIH dependent liver cirrhosis. Compared to other causes of liver cirrhosis such as chronic viral hepatitis, alcohol, or hemochromatosis, the incidence of HCC is significantly lower. Pathophysiological differences between AIH and chronic viral hepatitis responsible for differences in the incidence of HCC are yet to be further characterized and may lead to new therapeutic concepts in prevention and treatment of liver cancer.     

Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment

Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.     

Hepatocellular carcinoma associated with hereditary hemochromatosis occurring in non-cirrhotic liver

The occurrence of primary hepatocellular carcinoma (HCC) in patients with hereditary hemochromatosis (HH) is well known. Thereby, the development of liver cirrhosis seems to be a prerequisite. Whether or not a hepatic iron overload in the context of hereditary hemochromatosis is an independent risk factor for HCC remains unclear. To date there are only a few reports about HCC arising in non-cirrhotic livers in the presence of HH. We report the case of a 64-year-old man who presented to our outpatient clinic with HCC. Liver cirrhosis could be excluded. Detailed exploration of the patient's history revealed that he had been treated by venesection for about 10 years up to 15 years ago. Subsequent investigations showed an elevated serum ferritin and transferrin saturation. The diagnosis of HH was confirmed by genetic testing, with homozygosity for the Cys282Tyr mutation. The patient received palliative chemotherapy and finally died 15 months after initial diagnosis of HCC.     

NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States

The incidence of hepatocellular carcinoma (HCC) in the United States is increasing, but the clinical characteristics of American patients with HCC have not been well described. The aims of this study were to determine the etiology of liver disease and short-term outcome among HCC patients presenting to a single center in the United States. One hundred five consecutive patients with HCC were studied; mean age was 59 years, 67% were men, and 76% were non-Hispanic white. The most common etiology of liver disease was hepatitis C (51%) and cryptogenic cirrhosis (29%). Half of the patients with cryptogenic cirrhosis had histologic or clinical features associated with nonalcoholic fatty liver disease (NAFLD). Fifty-three (50%) patients had HCC detected during surveillance (group I), whereas the remaining patients had symptomatic tumors (group II). Group I patients had smaller tumors (P =.01), were more likely to be eligible for surgical treatment (P =.005), and had a better median survival compared with patients in group II (P =.001). Patients with cryptogenic cirrhosis were less likely to have undergone HCC surveillance and had larger tumors at diagnosis. In conclusion, hepatitis C and cryptogenic liver disease are the most common etiologies of diseases in our patients with HCC. NAFLD accounted for at least 13% of the cases. Patients who underwent surveillance had smaller tumors and were more likely to be candidates for surgical or local ablative therapies. Because of the increasing incidence of NAFLD, further studies are needed to determine the risk of HCC in patients with NAFLD.     

Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease

Hepatocellular carcinoma (HCC) is on the rise globally, causing more than 800 thousand deaths annually, with an estimated annual percent change of 0.51 for causes other than viral hepatitis, including nonalcoholic fatty liver disease (NAFLD). The incidence of NAFLD-related HCC is peaking in several Far East regions (6–12% vs. 2–3% in Western Europe and USA), HCC risk being mainly driven by the epidemic of obesity and diabetes, both favored by an unhealthy diet and sedentary lifestyle. Under inherited susceptibility outlined by such genetic markers as variants in PNPLA3, TM6SF2 and MBOAT7, neoplastic transformation of NAFLD is driven by sublethal lipotoxicity consequent to hepatocyte lipid overload, whereas a myriad of factors spanning from subverted circadian homeostasis and gut dysbiosis to alcohol abuse and tobacco may interact as risk modifiers. At variance with viral HCC, NAFLD-HCC shows a frequent association with cardiovascular co-morbidities, absence of cirrhosis in up to half of patients and an association with persistently normal transaminase values. All these misleading features of NAFLD-related HCC account for the low uptake of surveillance and linkage to curative treatments that has been reported in patients with this cancer, a downside that could be attenuated when scores for cost-effective risk stratification become available.     

Nonalcoholic fatty liver disease,metabolic risk factors,and hepatocellular carcinoma: An open question

Non-alcoholic liver disease(NAFLD) defines liver abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis with or without cirrhosis development, occurring in the absence of significant alcohol consumption, use of teratogenic medication, or hereditary disorders. The association between NAFLD and metabolic syndrome is well documented and widely recognized. Obesity, type 2 diabetes mellitus(T2DM), and dyslipidemia are the most common metabolic risk factors associated with NAFLD. Among the components of metabolic syndrome, current evidence strongly indicates obesity and diabetes as hepatocellular carcinoma(HCC) risk factors. There is also growing evidence that suggests an increased risk of HCC in NAFLD patients, even surpassing other etiologies in some high-income countries. Epidemiologic data demonstrate a parallel rise in prevalence of obesity, diabetes, NAFLD, and HCC. As obesity and its related diseases have steadily afflicted larger populations, HCC incidence is expected to increase in the future. Pathophysiologic mechanisms that underlie NAFLD development and subsequent progression to nonalcoholic steatohepatitis and cirrhosis(insulin resistance and hyperinsulinemia, oxidative stress, hepatic stellate cell activation, cytokine/adipocytokine signaling pathways, and genetic and environmental factors) appear to play a significant role in the development of NAFLD-related HCC. However, a comprehensive view of molecular mechanisms linking obesity, T2 DM, and NAFLD-related HCC, as well as the exact sequence of molecular events, is still not understood in its entirety. Good-quality data are still necessary, and efforts should continue towards better understanding the underlying carcinogenic mechanisms of NAFLD-related HCC. In this paper, we aimed to centralize the most important links supporting these relationships, focusing on obesity, T2 DM, and NAFLD-related HCC, as well as point out the major gaps in knowledge regarding the underlying molecular mechanisms behind them.     

2002例肝硬化患者的病因及并发症分析

目的探讨近年重庆医科大学附属第二医院肝硬化病因及并发症特点。方法回顾性分析本院2002年1月-2011年12月2002例肝硬化住院患者病因及相关资料。计数资料以百分数表示,不同组间率的比较采用χ2检验。结果病因构成方面,乙型肝炎1213例（60.6%）,酒精性脂肪肝133例（6.6%）,乙型肝炎合并酒精性脂肪肝332例（16.6%）,自身免疫性肝病136例（6.7%）,非酒精性脂肪肝34例（1.7%）。以2007年1月1日为界,将时期分为前后两段比较分析,显示乙型肝炎肝硬化人数构成比由64.1%下降到59.3%（P〈0.05）,乙型肝炎合并酒精性肝硬化由13.6%增至17.7%（P〈0.05）,自身免疫性肝硬化由3.5%增至7.1%（P〈0.05）。肝硬化主要并发症发生率依次为原发性肝癌（22.1%）、自发性腹膜炎（21.3%）、上消化道出血（19.3%）、肝性脑病（7.3%）、肝肾综合征（4.0%）。有乙型肝炎家族史的肝硬化患者肝癌发生率明显高于无家族史者（31.1%vs.22.2%,P〈0.05）,高HBV载量的肝硬化患者肝癌发生率也明显增加（χ2=10.88,P〈0.05）。结论乙型肝炎仍然是我院肝硬化主要病因,但酒精因素及自身免疫性肝病所致肝硬化明显增加,原发性肝癌为肝硬化最常见并发症,乙型肝炎合并酒精性肝硬化的预后最差。     

Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease: Current Progresses and Challenges

The rising global prevalence of metabolic diseases has increased the prevalence of non-alcoholic fatty liver disease (NAFLD), leading to an increase in cases of NAFLD-related hepatocellular carcinoma (HCC). To provide an updated literature review detailing epidemiology, risk factors, pathogenic pathways, and treatment strategies linked to NAFLD-related HCC, we conducted a literature search on PubMed from its inception to December 31, 2021. About 25% of the global population suffers from NAFLD. The annual incidence of HCC among NAFLD patients is approximately 1.8 per 1,000 person-years. Older age, male sex, metabolic comorbidities, unhealthy lifestyle habits (such as smoking and alcohol consumption), physical inactivity, genetic susceptibility, liver fibrosis, and degree of cirrhosis in NAFLD patients are important risk factors for NAFLD-related HCC. Therefore, low-calorie diet, moderate-intensity exercise, treatment of metabolic comorbidities, and cessation of smoking and alcohol are the main measures to prevent NAFLD-related HCC. In addition, all patients with advanced NAFLD-related fibrosis or cirrhosis should be screened for HCC. Immune suppression disorders and changes in the liver microenvironment may be the main pathogenesis of NAFLD-related HCC. Hepatic resection, liver transplantation, ablation, transarterial chemoembolization, radiotherapy, targeted drugs, and immune checkpoint inhibitors are used to treat NAFLD-related HCC. Lenvatinib treatment may lead to better overall survival, while immune checkpoint inhibitors may lead to worse overall survival. Given the specific risk factors for NAFLD-related HCC, primary prevention is key. Moreover, the same treatment may differ substantially in efficacy against NAFLD-related HCC than against HCC of other etiologies.     

Molecular targets for prevention of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the world with an extremely poor prognosis. The major etiologic risk factors for HCC development include toxins (alcohol, aflatoxin B1), androgens and estrogens, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection as well as various inherited metabolic disorders, such as alpha-1-antitrypsin deficiency and hemochromatosis. The molecular pathogenesis of HCC development is very complex and involves alterations in the structure or expression of several tumor suppressor genes, oncogenes and, possibly, mechanisms leading to a genetic instability due to mismatch repair deficiency or chromosomal instability and aneuploidy due to defective chromosomal segregation. Central to the molecular pathogenesis of HCCs are mutations of various genes and a genetic instability which in most cases result from chronic liver disease and the associated enhanced liver cell regeneration and mitotic activity. The prognosis of HCC patients is generally very poor. Most studies report a five year survival rate of less than 5% in symptomatic HCC patients. Furthermore, these tumors have been shown to be quite resistant to radio- or chemotherapy. Investigations of the natural history and clinical course of HCCs revealed long-term survival of patients only with small asymptomatic HCCs that could be treated surgically or by non-surgical interventions. Apart from exploring and refining new HCC treatment strategies, the implementation of existing and the development of novel measures to prevent HCC development are most important. Primary HCC prevention includes among others universal hepatitis B vaccination, antiviral therapy of patients with chronic hepatitis B or C, reduction of food contamination with aflatoxins, elimination of excessive alcohol etc. Also for some genetic diseases there is the potential for HCC prevention by identifying affected family members at risk, such as patients with precirrhotic hemochromatosis. Reduction of iron overload by phlebotomy has been shown to eliminate the progression hemochromatosis to liver cirrhosis and HCC. Preventive measures, therefore, should have a major impact on the incidence of HCCs in patients with acquired and inherited liver diseases. Further, the prevention of a local recurrence or the development of new HCC lesions in patients after successful surgical or non-surgical HCC treatment (secondary prevention) is of paramount importance and is expected to significantly improve disease-free and overall patient survival. Based on rapid scientific advances, molecular diagnosis, gene therapy and molecular prevention are becoming increasingly part of our patient management and will eventually complement and in part replace existing diagnostic, therapeutic and preventive strategies. Overall, this should result in a reduction of the incidence of HCCs, one of the most devastating malignancies worldwide.     

Alcohol use disorder and the liver

Alcohol use disorders (AUD) cause a range of physical harms, but the major cause of alcohol-related mortality is alcohol-related liver disease (ALD), in some countries accounting for almost 90% of alcohol-related deaths. The risk of ALD has an exponential relationship with increasing alcohol consumption, but is also associated with genetic factors, other life-style factors and social deprivation. ALD includes a spectrum of progressive pathology, from liver steatosis to fibrosis and liver cirrhosis. There are no specific treatments for liver cirrhosis, but abstinence from alcohol is key to limit progression of the disease. Over time, cirrhosis can progress (often silently) to decompensated cirrhosis and hepatocellular carcinoma (HCC). Liver transplantation may be suitable for patients with decompensated liver cirrhosis and may also be used as a curative intervention for HCC, but only for a few selected patients, and complete abstinence is a prerequisite. Patients with AUD are also at risk of developing alcoholic hepatitis, which has a high mortality and limited evidence for effective therapies. There is a strong evidence base for the effectiveness of psychosocial and pharmacological interventions for AUD, but very few of these have been trialled in patients with comorbid ALD. Integrated specialist alcohol and hepatology collaborations are required to develop interventions and pathways for patients with ALD and ongoing AUD.     

Hepatocellular carcinoma prevention： A worldwide emergence between the opulence of developed countries and the economic constraints of developing nations

INTRODUCTION Hepatocellular carcinoma (HCC) is the fifth most common neoplasm, the major cause of death in patients with liver cirrhosis, and the third most common cause of cancer- related death in the world[1,2]. Every year, 560 000 people in the world d…     

Incidence and clinical presentation of portal vein thrombosis in cirrhotic patients

BACKGROUND: Portal vein thrombosis (PVT) is due to many risk factors, but its pathogenesis is still not clearly understood. To identify the risk factors for PVT, we analyzed the clinical characteristics and complications associated with PVT in cir-rhotic patients.
METHODS: We studied patients with liver cirrhosis who were admitted to our unit from April 2009 to December 2014. The patients were divided into the PVT and non-PVT groups, and were compared by variables including gender, age, the etiology of cirrhosis, stage of cirrhosis, complications, imaging, and treatment.
RESULTS: PVT was found in 45 (9.8%) of 461 cirrhotic pa-tients admitted to our hospital. Most patients (45.9%) had hepatitis B virus (HBV)-related cirrhosis, with a similar dis-tribution of etiologies between the groups. However, there was no positive relationship between PVT and etiologies of cirrhosis. Most patients (71.5%) were in the stage of hepatic decompensation. No statistically signiifcant differences were found in complications including esophageal varices, ascites, and hepatic encephalopathy between the groups. However, there was a signiifcant positive correlation between hepatocel-lular carcinoma (HCC) and PVT (P<0.01). In 30 patients with PVT, thrombosis occurred in the portal vein and/or portal branches, 37.8% were diagnosed on ultrasound.
CONCLUSIONS: The incidence of PVT was 9.8%, mainly in patients with HBV-related cirrhosis. The development of PVT was associated with the severity of liver disease and HCC.     

Hepatocellular carcinoma in the post-hepatitis C virus era: Should we change the paradigm?

Hepatocellular carcinoma (HCC) is a common and deadly malignancy. The disease usually develops on a background of chronic liver disease. Until recently, the most common etiology was infection with the hepatitis C virus (HCV). The advent of direct-acting antiviral (DAA) therapies has been a major breakthrough in HCV treatment. Sustained virologic response can now be achieved in almost all treated patients, even in patients with a high risk for the development of HCC, such as the elderly or those with significant fibrosis. Early reports raised concerns of a high risk for HCC occurrence after DAA therapy both in patients with previous resection of tumors and those without previous tumors. As the World Health Organization’s goals for eradication of HCV are being endorsed worldwide, the elimination of HCV seems feasible. Simultaneous to the decrease in the burden of cirrhosis from HCV, non-alcoholic fatty liver disease (NAFLD) incidence has been increasing dramatically including significant increased incidence of cirrhosis and HCC in these patients. Surprisingly, a substantial proportion of patients with NAFLD were shown to develop HCC even in the absence of cirrhosis. Furthermore, HCC treatment and potential complications are known to be influenced by liver steatosis. These changes in etiology and epidemiology of HCC suggest the beginning of a new era: The post–HCV era. Changes may eventually undermine current practices of early detection, surveillance and management of HCC. We focused on the risk of HCC occurrence and recurrence in the post–HCV era, the surveillance needed after DAA therapy and current studies in HCC patients with NAFLD.     

Occupational exposure to vinyl chloride and liver diseases

Portal hypertension,liver fibrosis,and angiosarcoma of the liver(ASL)have been reported among workers exposed to vinyl chloride monomer(VCM)since the 1970s.In 2007,the International Agency for Research on Cancer established the association of VCM with hepatocellular carcinoma(HCC),though only on the basis of the few cases available.Thereafter,recent reports from the United States cohort and a European sub-cohort of vinyl chloride workers provided compelling evidence of a strong association between cumulative VCM exposure and HCC risk.Further areas of research include the risk of liver cancer at lower levels of exposure and different patterns of risk of ASL and HCC with the time since exposure.The evidence of interaction between VCM exposure and other known liver carcinogens such as alcohol and chronic viral infection provides clues for the health surveillance of exposed workers.Notably,also the risk of VCM-associated chronic liver disease is modulated by alcohol consumption,viral infection,and genetic polymorphism.A counter-intuitive finding from cohort studies of exposed workers is the lower mortality from liver cirrhosis with respect to the general population;this can be attributed to the healthy worker effect and to the selection of liver cancer as the cause of death in the presence of concomitant chronic liver disease.Studies designed to overcome these intricacies confirmed an association between cumulative VCM exposure and the risk of liver cirrhosis.     

Hepatocellular carcinoma in patients with metabolic dysfunction-associated fatty liver disease: Can we stratify at-risk populations?

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new nomenclature recently proposed by a panel of international experts so that the entity is defined based on positive criteria and linked to pathogenesis, replacing the traditional non-alcoholic fatty liver disease (NAFLD), a definition based on exclusion criteria. NAFLD/MAFLD is currently the most common form of chronic liver disease worldwide and is a growing risk factor for development of hepatocellular carcinoma (HCC). It is estimated than 25% of the global population have NAFLD and is projected to increase in the next years. Major Scientific Societies agree that surveillance for HCC should be indicated in patients with NAFLD/ MAFLD and cirrhosis but differ in non-cirrhotic patients (including those with advanced fibrosis). Several studies have shown that the annual incidence rate of HCC in NAFLD-cirrhosis is greater than 1%, thus surveillance for HCC is cost-effective. Risk factors that increase HCC incidence in these patients are male gender, older age, presence of diabetes and any degree of alcohol consumption. In non-cirrhotic patients, the incidence of HCC is much lower and variable, being a great challenge to stratify the risk of HCC in this group. Furthermore, large epidemiological studies based on the general population have shown that diabetes and obesity significantly increase risk of HCC. Some genetic variants may also play a role modifying the HCC occurrence among patients with NAFLD. The purpose of this review is to discuss the epidemiology, clinical and genetic risk factors that may influence the risk of HCC in NAFLD/MAFLD patients and propose screening strategy to translate into better patient care.