Based on Presidential Lecture given at the Shanghai–Hong Kong International Liver Congress 2006.
Potential conflict of interest: Nothing to report.
Immigration, cheap air travel, and globalization are all factors contributing to a worldwide spread of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. End-stage chronic liver disease (ESLD) as a result of co-infection with HBV/HCV is now the major cause of death for individuals who have been infected with the HIV virus. The high incidence of HCV infection in Egypt—the legacy left from the mass use of tartar emetic to eradicate schistosomiasis, as in other high prevalence areas—will take years to reduce. Steatohepatitis due to non-alcoholic fatty liver disease is developing into a new and major health problem as a result of rising levels of obesity in populations worldwide. Hepatic steatosis also has an adverse influence on the progression of other liver diseases including chronic HCV infection and alcoholic liver disease. In many countries, considerable public concern is on the rise due to increased levels of alcohol consumption adversely affecting younger and affluent age groups. With the rising prevalence of cirrhosis, primary hepatocellular carcinoma (HCC) is increasing in frequency as is that of primary intrahepatic cholangiocarcinoma. Finally, despite the successes of liver transplantation, many deserving patients are not getting transplants due to low levels of cadaver organ donation in many countries, thereby increasing pressures on the use of living donor liver transplantation. Only through a concerted effort from governments, health agencies, healthcare professionals at all levels, and the pharmaceutical industry can this grim outlook for liver disease worldwide be reversed. (HEPATOLOGY 2006;44:521–526.)
Chronic disease constitutes a fast increasing burden to society. The World Health Organization (WHO) estimates that 46% of global disease and 59% of mortality is due to chronic diseases. Thirty-five million individuals in the world die each year from chronic disease and the numbers are increasing steadily.1 The progressive increase in the cost for healthcare in recent decades is expected to continue, in fact accelerate. According to the Office for National Statistics in the United Kingdom, liver disease is now the fifth most common cause of death after heart disease, stroke, chest disease and cancer.2 However, unlike other major causes of mortality, liver disease rates are increasing rather than declining. A recent UK study showed that mortality rates in Scotland for subjects with cirrhosis have more than doubled for men and have increased by almost half for women.3
For hepatologists worldwide, there have never been more challenges faced, yet never more tools available to overcome them. But, stemming the rising tide of global ill health from liver disorders will require the harnessing of resources and long-term strategies through governments, international agencies and those with experience of public health at all levels. Estimated numbers of HBV and HCV infected subjects worldwide are staggering (370 and 130 million subjects respectively) and of the 40 million known HIV positive subjects, 3 million are co-infected with HBV and 4.5 million with HCV4 (Fig. 1).
Universal vaccination at birth in high prevalence areas for HBV has been shown to be highly effective in reducing carrier rates in children as well as the incidence of chronic liver disease including hepatocellular carcinoma (HCC). First reported from Taiwan,5 data is now available from Singapore, China, Malaysia, Thailand, South Korea and elsewhere in the Far East. Vaccination coverage is more than 90% in cities but is thought to be much lower in rural areas. Achieving adequate coverage in rural areas of many high endemic countries is a logistical as well as an economic challenge. Although 182 countries are now including hepatitis B in national immunization programs,6 large areas of the world with a moderate or high prevalence of HBV remain without immunization strategies. For instance, most of central Africa and the Indian Subcontinent (although India has recently started a process of implementation) provide little to no immunization, largely due to cost constraints. Even with a cost of less than $1 for developing countries, a series of 3 doses costs more than the other 6 childhood vaccines. Even with the initiation of infant immunization programs, it will take a long time to reduce the massive adult carrier pools around the world and the severe consequences that arise from such infections.
In lower prevalence areas of the West, infection rates have not been substantially decreased despite the targeting of high risk groups. The effects of current large scale immigration are a persistent causative factor for infection. In the UK, it has been estimated that 90,220 people come into the country through legal immigration each year (the number probably doubles if those entering illegally are counted). Coming from areas of high prevalence (>7%), an estimated 6,300 additional chronic HBV carriers enter the country each year. These numbers are small in comparison to those found in the United States where a recent study found that 15% of East Asians in New York (as many as 100,000 people) are chronic HBV carriers. Immigrants from China have a rate of infection 35 times higher than in the general population, with liver cancer rates 6 to 10 times as high as that of Caucasians.7
The very high rate of HCV infection in Egypt, an estimated 7%-14%, is a sad story in terms of a public health measure commendable in itself, but with unfortunate consequences. Major efforts by the Ministry of Health in Egypt were taken from the mid 1950s to the 1980s to eradicate schistosomiasis which was then the major health problem in the country and main cause of liver disease. Millions of people were treated in the mass treatment campaigns in rural communities8 with intravenous tartar emetic, the only agent at that time known to be effective against the schistosomiasis worm. Disposable needles and syringes were not available 40-50 years ago and the dangers of exposure to human blood were much less appreciated. As schistosomiasis infection rates lessened, those for HCV increased. Frank et al.,9 in 1995, recorded a direct relationship between the parenteral treatment of schistosomiasis and the country-wide prevalence of antibodies to HCV. Interestingly, (in relation to the different natural histories of HCV and HBV infection) as many people were infected with HBV as with HCV during this period but, as is well known, acquisition of HBV infection in adult life leads to chronic infection in only a small percentage of cases and the HBV carriage rate in Egypt was not increased. Of particular interest is the relation of more severe disease and co-infection or co-disease. For example, evidence exists showing that chronic schistosomiasis leads to a more severe and progressive liver disease from HCV infection, possibly as a result of a change in the balance of HCV-specific T cell responses.
Another area of major health concern is non-alcoholic fatty liver disease (NAFLD) related to the rising levels of obesity around the world promoted by increasing affluence and more sedentary occupations. Even regions previously exempt, such as the Far East and China, are being affected by adoption of Western lifestyles and habits. Rising rates of alcohol consumption fueled by the same sort of affluence and by greater accessibility to supplies (through supermarkets and now in the UK even petrol stations), is adding to the burden of liver disease worldwide. What is perhaps not sufficiently appreciated are the additive effects of steatosis from NAFLD or alcoholic excess on liver disease from other etiologies initiating a more severe and rapid course of disease. The adverse effects of viral co-infection are also of considerable scientific interest and clinical importance, as considered below.
Co-infection of HBV/HCV With HIV
Any reduction in the overall burden of HBV and HCV infection from immunization and screening programs is outweighed by the number of co-infected HBV/HCV cases resulting from the estimated 4.9 million new cases of HIV each year.10 The rapid rise in the number of HIV infections in Asia, the Far East and Eastern Europe and the continuing high frequency of infection in Sub-Saharan Africa have influences far beyond their own countries. Large scale emigration movements and the greater general ability for people to travel across the globe makes the spread of disease much easier. A recent public health report on HIV in the UK documented that 3,138 of the 4,287 new HIV infections from heterosexual contacts newly diagnosed in 2004 had acquired their infection in Africa.11 With similar routes for acquisition of HCV as for HIV, those countries faced with major problems of drug abuse and addiction such as Thailand and Malaysia are also experiencing greater numbers of HCV infected subjects. Because of the long natural history of HCV infection, the influence of new infections will continue for decades. In the UK it is predicted that the peak for the number of cases will not be apparent until 2010-2020. An example of how quickly lifestyle issues such as these can affect life survival comes from Russia, where high alcohol consumption, drug abuse and tuberculosis have reduced healthy life expectancy at birth (2002) to 52.8 years.12
Specific Disease Interactions—HBV, HCV and HIV.
With the effectiveness of highly active antiretroviral therapy (HAART) against AIDS-related illness, ESLD due to HBV and HCV co-infection has become a major cause of death in HIV-positive subjects. In one series, 44% of deaths were from liver disease in a group of patients with cirrhosis infected with both HBV and HCV.13 The most common co-infection was HCV alone, present in 29% of the cases and accounted for 31% of the liver-related deaths (Fig. 2). Alcohol abuse was another factor contributing to mortality and was recorded in 59% of liver-related deaths compared with 24% of those not developing ESLD.
The immunosuppression resulting from HIV infection is known to lead to more rapid progression of HCV related liver pathology. Cirrhosis develops within 5 years rather than over the usual 20-30 years. Of clinical importance also is the observation that adverse reactions to interferon therapy, particularly depression, are greater in HCV co-infected subjects, possibly related to the known presence of viral particles from both infections in brain tissue. Immune reconstitution following HAART therapy in those with HCV and HBV co-infection can lead to so called “hepatitis flares”. Less commonly, the very severe liver lesion of fibrosing cholestatic hepatitis is precipitated. The same mechanism is likely to be responsible for the reported increased risk of fulminant hepatic failure in HIV-positive HCV co-infected subjects treated in the HAART era, as compared with the pre-HAART period.14 In HIV/HBV co-infected subjects, the chances of spontaneous clearance of HBV are decreased and the likelihood of the patient developing resistance to lamivudine is increased.15 Whether the disease manifestations of HIV are adversely affected by HBV/HCV co-infection is the subject of conflicting reports, but there is good evidence to show an increased rate of toxicity from HAART therapy in such cases.16
HBV, hepatitis B virus; HCV, hepatitis C virus; ESLD, end-stage liver disease; HCC, hepatocellular carcinoma; NAFLD, nonalcoholic fatty liver disease; HAART, highly active antiretroviral therapy; BMI, body mass index; IHC, intrahepatic cholangiocarcinoma.
Body Mass Index and Nonalcoholic Fatty Liver Disease
Although only a small percentage, possibly 5% of those with severe hepatic steatosis, will progress over many years to significant fibrosis and even cirrhosis,17 the sheer size of the numbers falling into the overweight/obese category with a body mass index (BMI) of > 25 is the basis for the American description of a new epidemic of cirrhosis. One study in the United States using proton magnetic resonance spectroscopy showed that 1 in 3 adults had steatosis as defined by a hepatic triglyceride content of >5.5%; a finding which if applied to the whole population would translate to more than 60 million potential sufferers from NAFLD.18 In Italy, where the population is usually considered to be at low risk, a recent cohort study showed 1 in 4 or 5 to be suffering from NAFLD.19 Figures are lower in China and Japan where incidence of the disease is 15% and 14% respectively,20, 21 but these numbers will only worsen with the increasing adoption of a Western lifestyle. Indeed, in China the number of obese subjects has doubled in 10 years. The first comprehensive national survey in 2004 on Diet, Nutrition and Disease found that an estimated 200 million of the Chinese population of around 1.3 billion were overweight. Twenty million had diabetes and 160 million hypertension.22 In the UK, recent surveys have shown 25% of the population to be obese. Most worryingly are the numbers of children falling into this category with documented instances of NAFLD leading to severe hepatic fibrosis even cirrhosis in the late teens.
In the context of a high BMI, NAFLD is correlated particularly with central (truncal) obesity and is part of what has been termed the metabolic X syndrome. This includes hypertriglyceridemia, decreased high density lipoprotein cholesterol, hypertension and most importantly insulin resistance. The latter is of central importance in the pathogenesis of NAFLD with progression to impairment of glucose tolerance in many cases.23
Effects of Steatosis in the Progression of Other Liver Disease.
The presence of steatosis in the liver is increasingly recognized as an additional risk factor for the development of additional injury. Excess body weight in subjects with heavy alcohol consumption markedly increases the severity of steatosis and is a risk factor for the development of acute alcoholic hepatitis and cirrhosis.24, 25 Similarly, in hemochromatosis, the odds of having liver fibrosis increase by 3.9% when steatosis is present.26 The pathogenesis and effects of steatosis have been extensively studied in chronic HCV infection. Usually, if only to a slight or moderate degree, the presence of steatosis and insulin resistance is correlated with central obesity, except in genotype 3 infections where there may be an additional viral induced mechanism.27 An association with the metabolic syndrome is sufficient explanation for the many reports describing a significantly increased prevalence of type 2 diabetes mellitus in chronic HCV hepatitis. In a case-controlled study of patients without cirrhosis on liver biopsy, a third of the HCV infected patients had type 2 diabetes mellitus, a remarkably increased prevalence not found in patients with chronic hepatitis B or matched controls.28 The presence of steatosis and particularly the progression of insulin resistance to diabetes mellitus adversely affect the course of chronic hepatitis C leading to an increase in steatohepatitis and higher annual rates in the progression of fibrosis.29–31 In patients with non-genotype 3 infection, the presence of steatosis is a predictor of treatment failure with antiviral agents. Obesity appears to be independently associated with the reduced response rates, though as the majority of cases also have steatosis, the inter-relationships are difficult to separate.32
Global Issues of Alcoholic Liver Disease and Disease Interactions.
Developing countries are experiencing rising levels of alcohol consumption and alcoholic liver disease is becoming even more of a global problem. The rising mortality rates from alcoholic cirrhosis already referred to in the UK can be correlated with an increase in consumption. The latter in turn is inversely related to the curve relating price of alcohol to income (Fig. 3). Another important factor is the greater number of outlets selling alcohol as well as the longer licensing hours recently introduced in the UK.33 Of particular concern is the younger age at which people are beginning to drink. The number of 14-year-old children buying alcohol illicitly, ie, under the age of 18, in the UK has doubled over the past 15 years. Eleven million adults are estimated to binge drink regularly in the UK, and there are an increasing number of hospital admissions from acute alcoholic hepatitis.
Alcohol abuse has also been shown to be an adverse risk factor in the progression of severe fibrosis/cirrhosis from HCV infection. Interactions between alcohol consumption and hepatitis B and C infections are also seen in the context of primary HCC. Although this tumor will develop in cirrhosis of any etiology, hepatitis B and alcohol account for 80% of cases worldwide. Epidemiological studies have also shown a rising incidence in the West. A recent study on the influence of alcohol and other non-viral risk factors in HCC cases as compared to cirrhotic controls showed that the risk of HCC was increased 6-fold for alcohol, 5-fold for tobacco and 4-fold for obesity. Dose-dependent relationships were demonstrable between alcohol, tobacco exposure and the risk of HCC with significant interactions between the three factors as evidenced by synergistic indices of >1.34
Interestingly, there is evidence that the frequency of intrahepatic cholangiocarcinoma (IHC) (a tumor seen considerably less frequently than primary HCC in the West) is also increasing. A recent case-controlled study of all patients with IHC aged 65 or older identified during 1993-1999 in population based registries in the United States (equivalent to 14% of population) identified a number of significant risk factors.35 These included nonspecific cirrhosis (adjusted odds ratio 27.2), alcoholic liver disease (7.4), hepatitis C (6.1), HIV (5.9), and diabetes (2.0).
Organ Donation and Liver Transplantation
Another challenge and again one with global implications, is organ donation. There is a failure to keep up with the need for transplantation of those with end-stage liver disease. As a result, a substantial number of patients are dying on waiting lists worldwide before an organ becomes available for them. Among the various approaches being pursued to increase the number of available grafts is the use of marginal donors, namely those in which the cadaver graft has been adversely affected by factors such as pressor requirement, hypernatremia, and (relevant to this paper) hepatic steatosis. Steatosis has been shown to increase sensitivity of liver to ischemic and reperfusion injury and the use of marginal grafts and those obtained from non-heart beating donors are accompanied by a higher incidence of primary nonfunction and early graft impairment as well as a poorer long-term outcome.
Estimates of steatosis in cadaver organ grafts are staggeringly high and range from 37%-51% with 21% having levels greater than 30%, at which point graft function can be severely affected.36, 37 In grafts from living donors who by selection represent a relatively healthy group, steatosis of some degree is found in one third to one half with 5%-15% of cases having more than 30% of hepatocytes affected.38, 39 The steatosis, as in other situations, is closely correlated to BMI. Overall, this means that a substantial number of grafts, whether from cadaver or from living donor, cannot currently be used. Impaired rates of hepatic regeneration with steatosis can also have an impact on the recovery of the living donor.40 According to a recent systematic review there have been an estimated 12-13 donor deaths following adult living donor liver transplantation.41 With donation of the right lobe carrying greater risks for the donor than that of the left lobe, a good argument can be made for greater use of left lobe grafts, particularly now that graft congestion which is the basis of the small-for-size syndrome, can be controlled by restricting arterial inflow and ensuring an adequate hepatic outflow.42
The value of regulatory interventions by governments in maximizing organ donation can be substantial. Spain sets the greatest example where the cadaver organ donation rate in 2005 was 35.1 per million population, compared with a miserable 12.8 per million in the UK, and corresponding liver transplant rates of 24.3 and 10.3 per million, respectively. The Spanish system is based on a statutory responsibility placed on hospital authorities to maximize organ donation with a senior authority appointed to oversee its implementation. Its introduction into Australia and South America was also successful in raising donation rates. Another example of effective organizational change brought about by government action comes from Italy where organ donation was increased from 15.3 to 21.1 per million population over a 2-year period with corresponding increases in liver transplantation rate from 12.6 to 18.2 per million.43
In conclusion, the pace and technological advances of modern day research are such that many of the previously intractable problems encountered in liver disease are being unraveled. Techniques recently reported for culturing the HCV virus should lead to rapid advances in the production of an effective vaccine, and more effective antiviral drug regimes are in the pipeline. Hepatologists can also do much more for individual patients in terms of better managing the major complications of ESLD, ascites, variceal bleeding, and hepatic encephalopathy. Also, perhaps with albumin dialysis we are at last getting nearer to developing an effective liver support device.44, 45
Public health organizations and government involvement can help to counteract pressures of lifestyle and to get currently available and effective drugs to those who need them most in deprived areas of the world. Government immunization programs are critical in limiting the spread of hepatitis B worldwide. The cost of antiviral drugs for AIDS and antiviral drug regimes for HCV infection are way beyond the health budgets of African and other developing countries with high prevalence rates for these infections. The efforts of the Bill & Melinda Gates Foundation and other charitable organizations, as well as increasing government aid from the richer West, will go some way to contain the rising tide of infection and disease, but much will also depend on the cooperation of the pharmaceutical industry in making available therapeutic agents at an affordable price to those countries in need.Truly, these are global issues from which there can be no recoil.