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).
Table 1. Standard death rates for men and women per 10 000 from chronic liver disease in Europe
The differences observed between countries mainly reflect regional variations in the incidence of hepatitis B and hepatitis C infection (Figure 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.
Hepatitis c and hepatitis b infection
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).
Table 2. Life time prevalence of all drug abuse and percentage intravenous drugs
% intravenous opiate abuse
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.
Alcoholic liver disease
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).
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.
Table 3. Hereditary haemochromatosis-associated gene frequency by country as a percentage
Economic and social burden of liver disease
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.