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 6 th 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.     

Endoscopic ultrasound and fine needle aspiration for the diagnosis of hepatocellular carcinoma

Liver cancer is one of the most frequent solid cancers. The major risk factor associated with the development of hepatocellular carcinoma (HCC) is cirrhosis caused by hepatitis B, hepatitis C virus or chronic alcohol consumption. The overall prognosis of patients with HCC is very poor and this is mainly due to the advanced stages of cancer at presentation and also because of underlying cirrhosis. When HCC is diagnosed at early stages, prognosis is better with five-year disease free survival of around 50% with resection, or local ablative treatments such as radio-frequency ablation or percutaneous ethanol injection, and 70-80% with liver transplantation. Therefore, systematic screening of all the high-risk patients is the key to an early diagnosis of small HCC and the use of an appropriate treatment modality. The currently available tools for the screening, surveillance and diagnosis of HCC in the presence of cirrhosis remain sub-optimal. The advancements made in the past 10 years, however, have made HCC a potentially curable disease in a highly selected group of patients. This review will briefly discuss the current guidelines for surveillance and diagnosis of HCC in high-risk subjects and then review the potential role of endoscopic ultrasound and fine needle aspiration for the diagnosis of small HCC.     

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.     

De novo Hepatocellular Carcinoma after Liver Transplantation

Liver transplantation is the definitive therapy for patients with advanced liver disease and its complications. Patients who are transplanted with a diagnosis of hepatocellular carcinoma (HCC) are at risk of recurrent cancer, and these patients are monitored on a regular basis for recurrence. In contrast, de novo HCC following liver transplantation is a very rare complication, and recipients without HCC at the time of transplantation are not screened. We describe the clinical features of de novo HCC over a decade after achieving a sustained viral response with treatment of hepatitis C and two decades after liver transplantation. Our case highlights the necessity of screening for HCC in the post-transplant patient with advanced liver disease even after viral clearance.     

Advanced hepatocellular carcinoma. Review of targeted molecular drugs

Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world in terms of incidence, accounting for approximately 630 thousand new cases per year; in addition, HCC is the third most common cause of cancer death. Worldwide, the greatest risk factors for HCC are the infections caused by hepatitis B and C viruses, which increase the risk of developing the disease by about 20 times. The standard treatment in the early stages of the disease, such as surgical resection, local ablation and liver transplantation, are able to cure a proportion of patients, but most cases of HCC present in advanced stages, precluding the use of such treatments with curative intent. In these advanced stages, systemic treatments are commonly used. Unfortunately, chemotherapy with conventional cytotoxic agents is ineffective and does not seem to modify the natural history of disease. Treatment options for patients with advanced HCC are extremely limited, but the identification of signaling pathways, and the recognition of the role of these pathways in the pathogenesis of the disease resulted in the development of drugs directed at specific therapeutic targets. One such drug is Sorafenib, a kinase inhibitor with antiangiogenic and antiproliferative properties. In conclusion, Sorafenib has demonstrated survival benefits in patients with advanced HCC, thus representing a new standard reference for systemic treatment in these cases.     

Hepatitis C and Hepatocellular Carcinoma

With the significant burden of hepatocellular carcinoma (HCC) attributable to hepatitis C (HCV), prevention of HCC should first and foremost include treatment of hepatitis C. At the very least, any patient who is at risk for liver disease progression to advanced fibrosis should have HCV treated. This is potentially one of the single most important interventions that can be employed long-term to decrease the incidence of HCV-related HCC. Furthermore, efforts should be made in proactively treating HCV in patients listed for liver transplant with HCC and those HCC patients with limited tumor burden treated with curative intent. Studies exploring more specifically which patients with HCC receiving liver-directed therapy should also have HCV treated need to be performed. The overall cost effectiveness of treating those with significant HCC tumor burden needs to be better understood. With new direct acting antivirals for the treatment of HCV, it is becoming increasingly difficult to find reasons to leave virtually any patient with hepatitis C untreated who is at risk for HCC or with HCC. Although there are limited data directly linking the treatment of HCV with the incidence of HCC, this is a tremendous opportunity to change the epidemiology of HCC by utilizing treatment for hepatitis C.     

Hepatocellular carcinoma: an Asian perspective

Hepatocellular carcinoma (HCC) is one of the most frequently occurring malignancies in Asia. The incidence exceeds 30 cases/100,000/year in the east Asian region. Worldwide, it accounts for almost 1 million deaths/year. The high incidence in Asia is due to the high prevalence of chronic viral hepatitis, mainly chronic hepatitis B. With the introduction of universal vaccination for hepatitis B in some Asian countries in the mid 1980s, some of these countries are experiencing a decline in the incidence of HCC. This probably underscores the point that HCC caused by hepatitis B is a malignancy preventable by vaccine. Due to the relative paucity of symptoms in the early stages and the rapid doubling time of the tumor, most HCCs are discovered late in advanced stages at presentation. Most Asian countries have adopted a screening program for patients at risk. Earlier and smaller HCCs are detected through such programs but these programs have yet to demonstrate improved patient survival. Physicians managing patients with HCC are faced with two main challenges, the malignancy itself and the underlying liver disease. The extent of the tumor and the existing liver function limits the therapeutic choices available. Hepatic resection remains the treatment of choice. However, the majority of patients present with nonresectable tumors. Transarterial chemoembolization, percutaneous ethanol injection and radiofrequency ablation are the other treatment modalities. In patients with small tumors (<5 cm) and poor liver function, liver transplant offers a viable treatment alternative. In summary, the risk factor for HCC in Asia is predominantly chronic hepatitis B. Universal vaccination against hepatitis B is likely to reduce the incidence. The prognosis and outcome of treatment remains poor with a 5-year survival of 35% for patients treated surgically and less than 10% for nonresectable tumors. Current management is aimed at earlier detection and more effective treatment of early HCC. In future, the challenge will be managing HCC in the premalignant stage.     

Inherited hepatocellular carcinoma

Inherited liver disorders that cause chronic inflammation, fibrosis, and cirrhosis can lead to the development of liver cancer. Because of the rarity and diversity of some of these syndromes, the relative risk of developing HCC in these patients and the age at which tumours typically arise cannot be accurately estimated. Among patients with hereditary hemachromatosis (HH), the annual incidence of HCC is 4% once cirrhosis has been established. Fibrosis and portal hypertension associated with HH can be partially reversed with therapeutic phlebotomy, but it is unclear whether this treatment alters the incidence of HCC in these patients. Importantly, it seems likely that coincidence of these genetic disorders with known HCC risk factors such as alcoholism and viral hepatitis would amplify their oncogenic potential. For this reason, patients with known genetic disorders of the liver should be repeatedly counselled to avoid environmental and toxic injury to the liver. Treatment of HCC in patients with inherited liver disease mirrors that of HCC associated with other etiologies. Unfortunately, there are case series which suggest these patients with inherited liver disease and HCC tend to present at more advanced stages and are therefore not eligible for curative therapies, causing overall decreased survival relative to patients with HCC of viral or other etiologies.     

Hepatocellular carcinoma: epidemiology, risk factors, and screening

In this article, the epidemiology of hepatocellular carcinoma (HCC), risk factors for the development of HCC, and how these factors affect the decision about whether an individual should or should be entered into a screening program are considered. The factors determining the risk for HCC include age, male gender, and the nature of the underlying liver disease. In particular, cirrhosis is associated with a significant risk for HCC. However, in hepatitis B HCC also occurs in noncirrhotic liver. Decision analysis can be used to identify patients at greatest risk for HCC and who might be candidates for screening. Screening itself should be developed in a programmatic manner to ensure that appropriate target populations are identified, that appropriate screening tests are chosen, and that appropriate recall and enhanced follow-up are instituted for patients who have positive screening test results. Screening should be by ultrasonography at 4- to 12-month intervals. Patients with abnormal screening tests require additional investigation using computed tomography scanning, magnetic resonance imaging, or liver biopsy. Negative results do not exclude the possibility of cancer and further follow-up is necessary.     

Nucleos(t)ide analogs in the prevention of hepatitis B virus related hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is among the most common cancer types and causes of cancer related mortality worldwide.Almost 50% of all HCC cases globally are attributable to chronic hepatitis B virus(HBV) infection.The incidence rates of HCC in untreated Asian subjects with HBV infection was estimated to be 0.2% in inactive carriers,0.6% for those with chronic hepatitis without cirrhosis,and 3.7% for those with compensated cirrhosis.In Western populations,HCC incidences are reported to be 0.02% in inactive carriers,0.3% in subjects with chronic hepatitis without cirrhosis,and 2.2% in subjects with compensated cirrhosis.Despite effective antiviral treatment options which are able to transform chronic hepatitis into an inactive carrier state,the risk of HCC cannot be fully ruled out to exclude those patients from surveillance.Newer nucleos(t)ide analogues(NAs) as entecavir and tenofovir are very potent in terms of sustained virological suppression which leads to improved liver histology.However,they do not have any influence on the ccc DNA or integrated DNA of HBV in the liver.Nonetheless,viral replication is the only modifiable component among the established risk factors for HBV-related HCC with the current treatment options.In this review,it was aimed to summarize cumulative evidence behind the concept of prevention of HBV related HCC by NAs,and to discuss remaining obstacles to eliminate the risk of HCC.     

Role of innate immunity in the development of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the most common form of liver cancer worldwide.It is caused by a variety of risk factors,most common ones being infection with hepatitis viruses,alcohol,and obesity.HCC often develops in the background of underlying cirrhosis,and even though a number of interventional treatment methods are currently in use,recurrence is fairly common among patients who have had a resection.Therefore,whole liver transplantation remains the most practical treatment option for HCC.Due to the growing incidence of HCC,intense research efforts are being made to understand cellular and molecular mechanisms of the disease so that novel therapeutic strategies can be developed to combat liver cancer.In recent years,it has become clear that innate immunity plays a critical role in the development of a number of liver diseases,including HCC.In particular,the activation of Toll-like receptor signaling results in the generation of immune responses that often results in the production of proinflammatory cytokines and chemokines,and could cause acute inflammation in the liver.In this review,the current knowledge on the role of innate immune responses in the development and progression of HCC is examined,and emerging therapeutic strategies based on molecular mechanisms of HCC are discussed.     

Risk factors of acute hepatic failure during antituberculosis treatment: two cases and literature review

Hepatotoxicity is a well-known side effect of antituberculosis treatment (ATT). If not recognised in time, drug-induced hepatitis can develop, which may rapidly progress to acute liver failure. We describe two patients with acute hepatic failure caused by ATT, whose pretreatment liver function had been normal. Both patients successfully underwent liver transplantation. Possible risk factors predisposing towards ATT-induced hepatic failure were evaluated, and at least four risk factors were present in these patients. Although available guidelines do not advocate routine monitoring of liver function during ATT unless baseline values are elevated or in the case of pre-existent liver disease, this is nevertheless common practice. Liver function should always be measured in patients who develop symptoms during ATT, and rising liver function parameters should prompt immediate action to prevent the occurrence of liver failure. This report underscores that regular monitoring of liver function parameters and adherence to guidelines is especially important in patients with risk factors for ATT-induced liver disease. An evaluation of chronic viral hepatitis in risk groups before starting ATT could be worthwhile.     

Liver Imaging Reporting and Data System criteria for the diagnosis of hepatocellular carcinoma in clinical practice: A pictorial minireview

Hepatocellular carcinoma (HCC) is the sixth most common cancer. The main risk factors associated with HCC development include hepatitis B virus, hepatitis C virus, alcohol consumption, aflatoxin B1, and nonalcoholic fatty liver disease. However, hepatocarcinogenesis is a complex multistep process. Various factors lead to hepatocyte malignant transformation and HCC development. Diagnosis and surveillance of HCC can be made with the use of liver ultrasound (US) every 6 mo. However, the sensitivity of this imaging method to detect HCC in a cirrhotic liver is limited, due to the abnormal liver parenchyma. Computed tomography (CT) and magnetic resonance imaging (MRI) are considered to be most useful tools for at-risk patients or patients with inadequate US. Liver biopsy is still used for diagnosis and prognosis of HCC in specific nodules that cannot be definitely characterized as HCC by imaging. Recently the American College of Radiology designed the Liver Imaging Reporting and Data System (LI-RADS), which is a comprehensive system for standardized interpretation of CT and MRI liver examinations that was first proposed in 2011. In 2018, it was integrated into the American Association for the Study of Liver Diseases guidance statement for HCC. LI-RADS is designed to ensure high sensitivity, precise categorization, and high positive predictive value for the diagnosis of HCC and is applied to “high-risk populations” according to specific criteria. Most importantly LI-RADS criteria achieved international collaboration and consensus among liver experts around the world on the best practices for caring for patients with or at risk for HCC.     

Hepatitis C virus and hepatocellular carcinoma

The sequential development of cirrhosis and hepatocellular carcinoma (HCC) in patients with transfusion-associated hepatitis was a clue leading to the identification of hepatitis C virus (HCV) as a risk factor for HCC. The incidence of HCV-related liver cancer is increasing in many developed countries: tumours arise in older patients, are almost invariably associated with cirrhosis and often have a less aggressive course than is seen in HCC related to other aetiological factors. Most HCCs grow as a single hepatic nodule for several years before generating satellite or distant tumour nodules. Tumour progression and hepatic failure are the leading causes of death. HCV might promote cancer through cirrhosis, which is per se an important risk factor for this tumour. HCV might also have oncogenic properties by interacting with cellular genes that regulate cell growth and differentiation. The primary prevention of HCC through vaccination against HCV is not yet available. The treatment of patients with chronic hepatitis C with interferon might attenuate the risk of HCC.     

New advances in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the leading cause of deaths in cirrhotic patients and the third cause of cancer related deaths.Most HCC are associated withwell known underlying risk factors,in fact,HCC arise in cirrhotic patients in up to 90%of cases,mainly due to chronic viral hepatitis and alcohol abuse.The worldwide prevention strategies are conducted to avoid the infection of new subjects and to minimize the risk of liver disease progression in infected patients.HCC is a condition which lends itself to surveillance as at-risk individuals can readily be identified.The American and European guidelines recommended implementation of surveillance programs with ultrasound every six months in patient atrisk for developing HCC.The diagnosis of HCC can be based on non-invasive criteria(only in cirrhotic patient)or pathology.Accurately staging patients is essential to oncology practice.The ideal tumour staging system in HCC needs to account for both tumour characteristics and liver function.Treatment allocation is based on several factors:Liver function,size and number of tumours,macrovascular invasion or extrahepatic spread.The recommendations in terms of selection for different treatment strategies must be based on evidence-based data.Resection,liver transplant and interventional radiology treatment are mainstays of HCC therapy and achieve the best outcomes in well-selected candidates.Chemoembolization is the most widely used treatment for unresectable HCC or progression after curative treatment.Finally,in patients with advanced HCC with preserved liver function,sorafenib is the only approved systemic drug that has demonstrated a survival benefit and is the standard of care in this group of patients.     

The diagnostic approach to hepatocellular carcinoma

Risk factors and symptoms of hepatocellular carcinoma (HCC): The main risk factors of HCC include infection with hepatitis B or C virus, as well as alcohol consumption. There are no specific symptoms of HCC, making early diagnosis and detection of the disease difficult. When HCC presents with specific clinical symptoms, the tumour is typically very far advanced. Surveillance in liver cirrhosis: The most common serological marker used in HCC diagnosis is alpha-fetoprotein (AFP), but other tumour markers such as the des-gamma-carboxyprothrombin (DGCP) or fractions of AFP (AFP-L3) exist and there use is discussed in this context. Surveillance should be done by sonography at 6 (to 12) months intervals. The single nodule in the cirrhotic liver: Ultrasound is the most commonly used imaging modality for detecting HCC tumour nodules with a large range of reported sensitivities. HCC may appear as a hypoechoic, isoechoic, or hyperechoic round or oval lesion with intratumoural flow signals on Doppler or power Doppler sonography. The differentiation of smaller malignant lesions in cirrhotic livers can be improved by contrast-enhanced ultrasound (CEUS). Spiral computed tomography (CT) and magnetic resonance imaging (MRI) with and without contrast enhancement play an important role in the diagnosis and staging of HCC. If the vascular pattern on imaging is not typical, biopsy becomes necessary. The patient with known HCC: Different tumour markers are used in the evaluation of tumour progression, prediction of patient outcome and treatment efficacy. Among the various staging systems used in the context of HCC, the Barcelona-Clinic-Liver-Cancer (BCLC) staging system is currently the only staging system that takes into account tumour stage, liver function, physical status and cancer-related symptoms. Beside surgical resection, non-surgical treatments such as percutaneous ethanol injection (PEI), radiofrequency thermoablation (RFTA) and trans-arterial chemoembolisation (TACE) are used. Successful tumour "bridging" with ablative therapy methods can be achieved in carefully selected patients on the waiting list for orthotopic liver transplantation. Contrast-enhanced sonography is able to control the ablation treatment of HCC.     

Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace

Hepatocellular carcinoma (HCC) is a common cancer worldwide that primarily develops in cirrhosis resulting from chronic infection by hepatitis B virus and hepatitis C virus, alcoholic injury, and to a lesser extent from genetically determined disorders such as hemochromatosis. HCC has recently been linked to non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of obesity and related metabolic disorders such as diabetes. This association is alarming due to the globally high prevalence of these conditions and may contribute to the rising incidence of HCC witnessed in many industrialized countries. There is also evidence that NAFLD acts synergistically with other risk factors of HCC such as chronic hepatitis C and alcoholic liver injury. Moreover, HCC may complicate non-cirrhotic NAFLD with mild or absent fibrosis, greatly expanding the population potentially at higher risk. Major systemic and liver-specific molecular mechanisms involved include insulin resistance and hyperinsulinemia, increased TNF signaling pathways, and alterations in cellular lipid metabolism. These provide new targets for prevention, early recognition, and effective treatment of HCC associated with NAFLD. Indeed, both metformin and PPAR gamma agonists have been associated with lower risk and improved prognosis of HCC. This review summarizes current evidence as it pertains to the epidemiology, pathogenesis, and prevention of NAFLD-associated HCC.     

Natural history of chronic hepatitis C

The natural history of chronic hepatitis C is one of a slow progression from early stage chronic hepatitis without fibrosis to cirrhosis or hepatocellular carcinoma (HCC). The disease progresses to advanced stage chronic hepatitis C over 10–30 years. Data from Japan indicate that mortality associated with chronic hepatitis C results mainly from the development of HCC. We studied 186 patients referred between 1968 and 1994. The mean follow‐up interval was 8.6 (2–23) years. HCC developed in 34 patients (18%). The cumulative probability of HCC development was 4% at 5 years, 18% at 10 years and 45% at 15 years. Univariable analysis indicated that age at entry, fibrosis stage, inflammation activity and the status of IFN treatment (treated vs untreated) were predictive risk factors for developing HCC in patients with chronic hepatitis C. Multivariable analysis of these risk factors indicated that age at entry (> 50 vs < 50; Risk Ratio = 3.2, P < 0.005) and fibrosis stage (F3 vs F0; Risk Ratio = 5.6, P < 0.005) are independent risk factors for HCC. From these results it was concluded that (1) 20% of patients referred to liver clinics with chronic hepatitis C in Japan can be expected to develop HCC over a 10 year period; (2) the risk of HCC increases with progression of liver fibrosis (F3, F4) and age (greater than 50 years old) at the time of diagnosis and (3) the degree of liver fibrosis is a critical predictive factor for the occurrence of HCC.     

Non-viral factors contributing to hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide, accounting for over half a million deaths per year. The geographic pattern of HCC incidence is parallel to exposure to viral etiologic factors. Its incidence is increasing, ranging between 3% and 9% annually depending on the geographical location, and variability in the incidence rates correspond closely to the prevalence and pattern of the primary etiologic factors. Chronic infections with hepatitis B viruses or hepatitis C viruses have both been recognized as human liver carcinogens with a combined attributable fraction of at least 75% of all HCC cases. Multiple non-viral factors have been implicated in the development of HCC. Increased body mass index and diabetes with subsequent development of non-alcoholic steatohepatitis represent significant risk factors for HCC. Other non-viral causes of HCC include iron overload syndromes, alcohol use, tobacco, oral contraceptive, aflatoxin, pesticides exposure and betel quid chewing, a prevalent habit in the developing world. Wilson disease, α-₁ antitrypsin deficiency, Porphyrias, autoimmune hepatitis, Schistosoma japonicum associated with positive hepatitis B surface antigen, and thorotrast-ray are also contributing hepatocellualar carcinoma. In addition, primary biliary cirrhosis, congestive liver disease and family history of liver cancer increase the risk of HCC incident. In conclusion, clarification of relevant non-viral causes of HCC will help to focus clinicians on those risk factors that are modifiable. The multilevel preventative approach will hopefully lead to a reduction in incidence of non-viral HCC, and a decrease in the patient morbidity and mortality as well as the societal economic burden associated with HCC.     

Economic growth leads to increase of obesity and associated hepatocellular carcinoma in developing countries

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer related death worldwide. In recent years, the prevalence of HCC has increased in both developing and developed countries. Most HCC cases develop in the presence of advanced chronic liver disease related to viral hepatitis. In particular hepatitis B virus and hepatitis C virus infections are considered as major HCC risk factors worldwide. However, current studies provide strong evidence for increasing numbers of HCC in nonalcoholic fatty liver disease (NAFLD). NAFLD represents the hepatic manifestation of metabolic syndrome which is based on obesity and insulin resistance. Epidemiologic data clearly demonstrates that NAFLD and obesity-related disorders are significant risk factors for tumor development in general and HCC in particular. As a consequence of life style changes towards higher calorie intake and less exercise, obesity and metabolic syndrome are spreading all over the world. Due to this increase in obesity and metabolic syndrome NAFLD-related HCC will become a major health care problem in the future. In conclusion, better understanding of the impact of NAFLD and obesity in the development of HCC will improve our treatment strategies of HCC and allow preventive measures.