Hepatocellular carcinoma (HCC): An update on risk factors, surveillance, diagnosis and treatment strategies

Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?

Liver disease refers to a wide spectrum of both acute conditions caused by various injurious agents, such as viruses, toxins, alcohol and pharmacological agents, as well as chronic liver diseases, which may over time lead to cirrhosis. Cirrhosis, from whatever cause, predisposes to hepatocellular carcinoma, a primary liver cancer, particularly if the cirrhosis is caused by hepatitis B or C infection. Most acute liver diseases can be managed conservatively or by withdrawing the hepatotoxic agent responsible. Severe acute liver damage may result in liver failure, or be so overwhelming as to induce irreversible liver damage (fulminant liver failure), which is associated with significant mortality rates. A proportion of acute infections and diseases may cause ongoing liver injury, resulting in chronic liver disease and cirrhosis. Like acute liver damage, chronic disease often goes undiagnosed during the early stages of the condition. Many cases only present to practitioners when substantial permanent damage has already occurred, at which time signs of liver failure and or cirrhosis are apparent. A minority of cases are detected at an earlier stage, either as a result of screening of families for inherited liver disease or as a result of abnormal liver function being found on blood tests performed during a routine medical examination. The liver is the major organ involved in a number of key metabolic processes. Damaged or reduced functional capacity can result in jaundice, hypoglycaemia, prolonged blood clotting, protein malnutrition, increased risk of infection, confusion, impaired lung and kidney function, fluid retention and fatigue. In addition, severe liver disease is often linked to vague symptoms such as malaise and fatigue, all of which results in significant morbidity, greatly impairing an individual's quality of life. Liver failure of any degree, once present, is associated with a significantly increased risk of premature death. The major liver diseases from a public health perspective are hepatitis C and B infection, alcoholic liver disease, primary liver cancer and haemochromatosis. The substantial public health impact of chronic liver disease can be gauged from the reported death rate per 100 000 population, although the figures may not be truly representative as mortality figures are underestimated in some countries. Data are available for the current EU states (Table 1). The differences observed between countries mainly reflect regional variations in the incidence of hepatitis B and hepatitis C infection (1, 2). Unfortunately, comparative figures for countries on the eastern and southern borders of the European Union are not available. However, World Health Organization data on the incidence of viral hepatitis per 100 000 population clearly shows the very great burden of hepatitis, even with the likelihood of under-reporting. The incidence of hepatitis C is reported as: Czechoslovakia 3.11, Estonia 26.65, Latvia 12.52, Russia 22.12, Ukraine 9.46, Croatia 3.38, Macedonia 1.28, Albania 4.37; and of hepatitis B: Romania 12.01, Russia 44.18, Ukraine 18.85, Belarus 9.34, Georgia 10.22, Moldavia 17.58, Yugoslavia 3.68. These data are relevant as several of these states are joining the European Union in the near future, and in addition many economic migrants and asylum seekers who journey to the European Union originate from this part of the world. It would therefore appear that both hepatitis B- and C-induced liver damage are conditions that will account for significantly more morbidity and mortality in the European Union in the future. Incidence of hepatitis B infection per 100 000 people in Europe. Prevalence of hepatitis C as a percentage of the total population of a region. There are an estimated 5 million carriers of hepatitis C in western Europe, with a higher but not well-documented carriage rate in eastern Europe. In western Europe, hepatitis C accounts for 70% of all cases of chronic hepatitis, 40% of cases of cirrhosis, and 60% of cases of hepatocellular carcinoma. End-stage liver disease resulting from infection now represents the major indication for liver transplant surgery in western Europe. The major route of infection is through blood and blood products. New infections are asymptomatic in 80% of cases. While blood-bank screening is reducing the incidence in western Europe, and universal precautions are also helping, this is not the case in eastern Europe. Occupational and perinatal exposure remain important routes of infection. A large percentage of new cases in western Europe are related to intravenous drug abuse and to the increased prevalence of hepatitis C infection in economic migrants and asylum seekers from eastern Europe and the ex-Soviet republics (Table 2). Unfortunately, 40% of those with an acute infection face life-long chronic infection. Approximately 20% of these develop cirrhosis. Indeed, of the causes of death in those who develop chronic hepatitis, 80% are due to cirrhosis or its complications. Co-infection with hepatitis B is an added risk factor, with chronic hepatitis B being more common in eastern Europe and southern Balkan countries. Once cirrhosis develops, 1–4% of patients per year develop hepatocellular carcinoma. Hepatitis B infection and chronic hepatitis C are both premalignant diseases. Vaccination has been proven to reduce infection rates and the incidence of hepatocellular carcinoma as a result of hepatitis B, following seminal studies in Taiwan. Unfortunately, optimal vaccination schedules have not been achieved in eastern Europe, mainly due to economic restrictions. In the case of hepatitis C, vaccination is not a possibility, and a reliable vaccine is not on the horizon. Treatment for chronic hepatitis C is not yet as effective as could be wished. In all, only 40% of those with genotype 1, prevalent in most countries, respond to combination therapy. Treatment is expensive (several thousand Euro per patient) and lengthy (minimum 6 months). Consequently, prevention is the key to reducing the burden of disease caused by hepatitis C. Even allowing for a slowly falling prevalence of hepatitis C infection in western Europe, there remains a large cohort of currently infected individuals progressing to cirrhosis and primary liver cell cancer, who represent an enormous future health and financial burden to Europe, considering the costs of anti-viral therapy, monitoring tests and treatment of the complications of chronic liver disease. The situation in eastern Europe is worse. Education, public health measures and identification of individuals at pre-cirrhotic stages represent means to diminish overall costs while increasing the benefits of treatment. Hepatocellular carcinoma is a type of primary liver cell cancer whose major risk factors are hepatitis B infection, and cirrhosis due to any cause. Thus, the incidence of hepatocellular carcinoma is linked both to the prevalence of chronic viral hepatitis and to other major additional causes of cirrhosis such as excessive alcohol consumption. Calculations based on reasonable estimates indicate that the current age-adjusted incidence figures will sharply increase during the next few decades. Cancer registry data document annual rates in males in the Mediterranean regions of 10 cases per 100 000, with an estimated incidence in northern Europe of half this figure. Consequently, the number of new cases in Europe as a whole is at least 25 000 per year. Only 50% survive for 1 year if untreated. Smaller diameter tumours and single tumours have improved survival after therapy. However, detection of early tumours suitable for resection and alternative treatments requires surveillance programmes of groups most at risk; hepatitis B-infected individuals and those with cirrhosis, particularly due to hepatitis C and alcohol. Surveillance currently relies on ultrasound techniques in combination with serological markers of hepatocellular carcinoma development. Even though relatively inexpensive, there are no structured, nationally based, surveillance programmes for individuals most at risk and even then the cost–benefit analysis has to be clearly demonstrated. Diseases attributable directly or indirectly to excessive alcohol intake are placing a great burden on healthcare systems. German and UK studies have shown that in 25–40% of all acute medical admissions, alcohol plays a contributory role. A report from the Royal College of Physicians in the UK has estimated that up to 12% of all hospital costs are related to harmful alcohol consumption. Precise figures in Europe are not available but Eurostat does publish death rates per 100 000 related to alcohol abuse, the majority attributable to alcoholic liver disease. In the European Union states these are (in males): Austria 6.3, Belgium 3.6, Denmark 8.5, Finland 7.7, France 6.9, Germany 10.8, Greece 0.9, Ireland 3.2, Italy 0.6, Luxembourg 8.7, Netherlands 1.7, Portugal 1.4, Spain 1.3, Sweden 5, UK 1.1. In addition, in northern Italy, the Dionysos Study reported that 4% of the population had alcoholic liver disease of varying severity. After hepatitis C infection, alcoholic liver disease is currently the second most common indication for liver transplantation throughout European member states. There is concern that alcohol consumption is increasing in adolescents and young adults in many countries, whilst overall per capita consumption is increasing in eastern Europe (Figure 3). Percentage of 15-year-olds consuming alcohol at least once a week by country. Increasing consumption is likely to result in larger numbers of people suffering from associated liver disease in the future. There is an urgent need to identify risk factors, other than total consumption, for the development of significant alcoholic liver disease, cirrhosis and subsequent hepatocellular carcinoma, to allow for the development of targeted healthcare. However, as with hepatitis C infection, public-health promotion and increasing public awareness of the serious complications of excessive alcohol consumption are likely to be key factors in the future reduction of the rates of alcohol-related liver disease. Haemochromatosis is an inherited condition common in northern European countries. The cardinal feature of the disease is iron overload, characterized by deposition of excessive iron in tissues and organs throughout the body, resulting in damage and organ failure over time. The spectrum of conditions associated with iron overload includes liver disease, diabetes, impotence, abnormal skin pigmentation, joint damage and heart disease, including heart failure. Excessive iron overload is associated with a documented increased risk of premature death, with cirrhosis, liver failure, liver cancer and diabetes contributing most to this risk. Many patients with haemochromatosis remain undiagnosed as gradual iron overload occurs for years before patients present with end-organ damage and related symptoms. Increased awareness of the disease has led to an increased incidence, primarily as a result of improved diagnosis and recognition. Early diagnosis is vital as a simple, cost-effective treatment, venesection, is available for patients. Regular removal of units of blood prevents iron deposition and is associated with long-term improved patient survival. Unfortunately, neither diabetes nor cirrhosis, once present, responds to this treatment. Nevertheless, recognition of iron overload in those patients is of vital importance to additional family members who can be screened for the condition by means of a simple blood test, hopefully prior to significant tissue damage occurring. Hereditary haemochromatosis has been estimated to affect between 1 : 1000 and 1 : 3000 people in northern Europe (Figure 4).1–9 The condition becomes less frequent in eastern or southern countries. In 1996, the genetic abnormality responsible for 80–100% of cases was discovered. Identification of the gene has enabled estimation of the gene frequency and therefore those at risk of the condition to be calculated (Table 3).10–19 The genetic data suggests that hereditary haemochromatosis is among one of the most common inherited conditions worldwide, and has led to suggestions that population-based screening would be cost-effective. However, there is some discrepancy between the numbers who carry the genetic risk for the disease and those with actual abnormalities in iron load, consistent with the condition. It is possible that additional unknown genetic factors as well as environmental factors account for this disparity. Until such time as we have a better mean of identifying those who will develop the disease, arguments against the introduction of screening will persist. Prevalence of haemachromatosis in Europe: % population. Acute liver failure, fortunately relatively uncommon, is associated with high mortality rates, despite often multidisciplinary management in an intensive-care setting. Recent data from both Europe and the USA have confirmed that paracetamol overdose remains the most common cause of acute liver failure despite restrictions on its use and the addition of clear warnings on packaging, accounting for almost 40% of cases.20, 21 Additional frequent causes include drug reactions and viral hepatitis. Spontaneous survival rates for acute liver failure vary according to aetiology from between 60 and 70% for paracetamol overdose to as low as 18% for patients with viral hepatitis. Many patients require extreme measures to improve survival; in all 30–40% require emergency liver transplantation. Overall mortality rates for those unable to undergo urgent transplantation have been reported to be as high as 35–57%.21, 22 Similarly, chronic liver diseases, in particular cirrhosis, has a poor prognosis, Recent evidence suggests that cirrhosis reduces the estimated life expectancy by 37 years and by 20 years among 30 and 50-year-olds, respectively.23 In addition, the incidence of hepato-cellular carcinoma in European patients with cirrhosis has been reported to be in the order of 5–6% per annum.24 As well as high mortality rates, chronic liver disease typically results in a significant reduction in the quality of life of the patient. One recent study revealed that patients with moderate to severe liver disease reported similar reductions in all aspects of quality of life to patients recovering from a stroke.25 Such data confirm the significant social impact of liver disease on patients and their families. The financial burden of direct costs alone for liver disease is considerable and set to increase. It has been documented that just over 2% of all hospital discharges in America in 1998 cited a hepatitis C-related diagnosis.26 The estimated direct medical costs for hepatitis C alone during that year was US$1 billion. Medical treatment employing combination interferon-alpha therapy costs €4000−5000 per quality-adjusted year of life gained, and is effective in only about 40% of cases.27 Over one-third of all liver transplants are currently performed for hepatitis C-related conditions, which represents a five-fold increase on figures from 1990. The estimated cost per liver transplant reported in the literature varies from an average of €33 000 to €94 000.28, 29 Another regularly used benchmark of cost, length of hospital stay, is also prolonged for individuals with chronic liver disease, with a reported average of 10.2 days, although specialist gastroenterology consultation can reduce this.30 With future epidemiological projections predicting a four-fold increase in the number of people at risk of chronic liver disease over the next 10–15 years, the enormous financial implications for health services throughout Europe are only too apparent, if significant steps are not taken in attempt to reduce transmission of infective hepatitis and the regular abuse of alcohol among European populations. The costs of treating end-stage liver disease and hepatocellular carcinoma superimposed on cirrhosis are high. Prevention of cirrhosis and thus hepatocellular carcinoma is the key to reducing health care costs and overall disease burden. Prevention of hepatitis B and C infection by vaccination and universal precautions, as well as identification and treatment of chronic hepatitis C patients and reduction of alcohol consumption would all contribute to this objective.

Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality and healthcare expenditure in patients with chronic liver disease. There are no consensus guidelines on diagnosis and management of HCC in India. The Indian National Association for Study of the Liver (INASL) set up a Task-Force on HCC in 2011, with a mandate to develop consensus guidelines for diagnosis and management of HCC, relevant to disease patterns and clinical practices in India. The Task-Force first identified various contentious issues on various aspects of HCC and these issues were allotted to individual members of the Task-Force who reviewed them in detail. The Task-Force used the Oxford Center for Evidence Based Medicine-Levels of Evidence of 2009 for developing an evidence-based approach. A 2-day round table discussion was held on 9th and 10th February, 2013 at Puri, Odisha, to discuss, debate, and finalize the consensus statements. The members of the Task-Force reviewed and discussed the existing literature at this meeting and formulated the INASL consensus statements for each of the issues. We present here the INASL consensus guidelines (The Puri Recommendations) on prevention, diagnosis and management of HCC in India.

Diabetes and hepatocellular carcinoma: Associations, biologic plausibility, and clinical implications

More than 18 million adults in the United States abuse alcohol, a prevalence 5 times higher than that of hepatitis C. Chronic alcohol use of greater than 80 g/day for more than 10 years increases the risk for hepatocellular carcinoma (HCC) approximately 5-fold; alcohol use of less than 80 g/day is associated with a nonsignificant increased risk for HCC. The risk for HCC in decompensated alcohol induced cirrhosis approaches 1% per year. The risk does not decrease with abstinence, and HCC can occur in a noncirrhotic liver. Alcohol use in chronic hepatitis C doubles the risk for HCC as compared with the risk in hepatitis C alone. Furthermore, there may be synergism between alcohol and hepatitis C in the development of HCC, and in these patients HCC may occur at an earlier age and the HCC may be histologically more advanced. Studies in the United States and Italy suggest that alcohol is the most common cause of HCC (accounting for 32%-45% of HCC). The mechanisms by which alcohol causes HCC are incompletely understood, but may include chromosomal loss, oxidative stress, a decreased retinoic acid level in the liver, altered DNA methylation, and genetic susceptibility. Alcohol use is increasing in many countries, suggesting that alcohol will continue to be a common cause of HCC throughout the world.

Time-dependent events in natural history of occult hepatitis B virus infection: the importance of population-based long-term follow-up study with repeated measurements

Reducing the incidence of hepatocellular carcinoma (HCC) in HIV-infected patients has become a serious problem when managing these patients. There are many explanations for this disease evolution, which notably include their longer survival under effective antiviral therapy and also the more rapid evolution of chronic liver disease. Despite recent advances in the management of hepatitis B (HBV) and hepatitis C (HCV) viral diseases, which will probably increase the number of patients achieving a virological response, HIV-infected patients with cirrhosis are still at risk of the onset of HCC. This evolution to HCC is also correlated to other comorbidities such as excessive alcohol consumption and nonalcoholic steatohepatitis (NASH). HCC thus remains a public health issue in this population. The poor prognosis and aggressiveness of HCC have been fully demonstrated, but the mechanisms underlying this aggressiveness are not yet well defined. As well as underlying mechanisms that contribute to accelerating hepatocarcinogenesis in HIV-infected patients, there are other reasons why HIV-infected patients should be considered a higher risk population. This review discusses the principal epidemiological determinants; the mechanisms of pathogenesis; and the treatment of HCC in HIV/HBV and HIV/HCV coinfected patients. It also discusses the probable need to develop a specific screening policy for HCC in this population in order to prevent the rapid development and to make them more amenable to a curative treatment.

The changing epidemiology of liver diseases in Asia.

Coffee Consumption and Risk of Liver Cancer: A Meta-Analysis

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the fourth leading cause of cancer deaths globally with increasing incidence. In most cases, HCC develops as a result of an underlying chronic liver disease. The stage at the time of diagnosis is closely correlated with prognosis with a 5-year survival of more than 70% for patients with early-stage HCC. These patients are generally suitable for curative treatment, such as resection, ablation or liver transplantation. In contrast, 5-year survival may be as low as 5% for patients in advanced stages of the disease. Due to organ shortage and the risk of mortality for patients on the waiting list for liver transplantation, survival in patients undergoing transplantation due to HCC should be comparable to those with benign indications. However, there is an ongoing debate concerning the best criteria for the selection of patients with HCC for transplantation, as the current criteria may rule out patients with a good prognosis. Liver resection may be performed in patients with HCC in non-cirrhotic livers and cirrhotic livers with preserved liver function. However, careful selection of patients is crucial due to high recurrence risk (>50%) and severe complications in >10% of liver resections for HCC. The aims of this thesis were to identify prognostic biomarkers in and improve the selection of patients undergoing transplantation and resection for HCC, respectively. Yet another aim was to improve upon the existing early detection of recurrence. The seven studies included in this thesis provided novel insights into prognostic biomarkers and selection of surgical patients with HCC. Firstly, the literature was reviewed regarding biomarkers to detect recurrence after transplantation for HCC. Next, two novel tumour-related prognostic biomarkers were identified and the applicability of circulating tumour DNA (ctDNA) was evaluated. Moreover, using data from the European Liver Transplant Registry (ELTR), vascular invasion and locoregional treatment were identified as important prognostic markers. Lastly, using propensity score calibration, prognostic differences between HCC in cirrhotic and non-cirrhotic livers were clarified. The studies included in this thesis add important knowledge towards better selection of patients for transplantation and resection of HCC, respectively. In future guidelines, alpha-fetoprotein, radiological markers of vascular invasion and response to locoregional treatment may be included in selection criteria for transplantation of patients with HCC. In addition, the novel biomarkers identified may add important prognostic information and improve the selection of patients. For resected patients, a proper balance between survival benefit and risk of recurrence and complications may be ensured. For transplanted patients, optimized selection means that the utility of donor organs is maximized by more accurately selecting patients with favourable tumour biologies.

Alcohol and cancer.

Most cases of hepatocellular carcinoma (HCC) are associated with cirrhosis related to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Changes in the time trends of HCC and most variations in its age-, sex-, and race-specific rates among different regions are likely to be related to differences in hepatitis viruses that are most prevalent in a population, the timing of their spread, and the ages of the individuals the viruses infect. Environmental, host genetic, and viral factors can affect the risk of HCC in individuals with HBV or HCV infection. This review summarizes the risk factors for HCC among HBV- or HCV-infected individuals, based on findings from epidemiologic studies and meta-analyses, as well as determinants of patient outcome and the HCC disease burden, globally and in the United States.

Focus

Preface

New frontiers in liver resection for hepatocellular carcinoma.