Recognizing and preventing death from compensated cirrhosis in the community

Cirrhosis remains a major global public health problem, accounting for an estimated 800 000 deaths each year 1. In the majority of countries worldwide, mortality from cirrhosis has been steadily declining since the mid or late 1970s 2. However, in other regions of the world, such as Central and Eastern Europe and the UK, mortality rates among those with cirrhosis have been rising 2-4, suggesting an increasing public health burden caused by liver disease. Cirrhosis marks the end stage of any chronic liver disease. The natural history of cirrhosis consists of an initially asymptomatic phase (compensated cirrhosis) followed by a rapidly progressive phase characterized by the development of liver dysfunction and/or complications of portal hypertension, including jaundice, variceal haemorrhage, ascites or encephalopathy (decompensated cirrhosis) 5. This two-stage model of the natural history of cirrhosis has been further refined to include four stages 5, including compensated cirrhosis with no ascites or oesophageal varices (stage 1, 1% mortality at 1 year), compensated cirrhosis with oesophageal varices without bleeding and no ascites (stage 2, 3% mortality at 1 year), decompensated cirrhosis with ascites with or without oesophageal varices (stage 3, 20% mortality at 1 year) and decompensated cirrhosis with variceal bleeding with or without ascites (stage 4, 57% mortality at 1 year) 5. This model has been validated 6 and evidence supporting this classification is reviewed elsewhere 7. However, the majority of the studies performed to date have only considered mortality rates stratified by the two-stage model, with a cumulative 1 year survival of 95% in those with compensated disease when compared to 61% in those with decompensated disease 5. Despite an increased understanding of the natural history of cirrhosis, studies investigating mortality in those with cirrhosis are limited by the inclusion of non-consecutive patients, incomplete reporting of inclusion criteria, incompleteness of follow-up and the inclusion of patients at differing disease stages without stratifying by disease stage 5. Most of what is known about mortality in the setting of cirrhosis comes from hospital-based clinical studies 5, although more recently, several studies have been performed using large hospital-based databases 3, 10. However, there are few population-based studies comparing mortality among participants with cirrhosis to the general population, particularly taking into consideration those with compensated and decompensated disease and other co-morbidities. Given the trends of increasing cirrhosis observed in many countries, it is important to better understand the impact of cirrhosis on all-cause mortality to characterize the burden of liver disease. In this issue of the Journal, Fleming et al., determined the overall survival in patients aged 25 and over with cirrhosis (n = 4537) compared with the general population (n = 44 403, matched by registration at the same general practice, by gender and by age) in a large longitudinal database of general practice records in the UK between 1987 and 2002 8. Patients with cirrhosis were included based on the presence of a diagnostic or therapeutic code for cirrhosis, oesophageal varices and/or portal hypertension. Cirrhotic patients were then stratified based on decompensated disease (based on a code for ascites, gastrointestinal bleed or a prescription for spironolactone) and compensated disease. The authors demonstrated that patients with compensated and decompensated cirrhosis had a five-fold [adjusted hazards ratio (AHR), 4.7; 95% CI 4.4, 5.0] and 10-fold (AHR, 9.7; 95% CI 8.9, 10.6) increased risk of all-cause mortality, respectively, when compared with the general population, while adjusting for age and gender. These findings were not explained by differences in co-mordibity in those with cirrhosis, given that even those with cirrhosis and no recorded co-morbidity had considerable excess mortality when compared with the general population. Compared with those with compensated cirrhosis, patients with decompensated cirrhosis had lower overall survival at 1 (75% vs. 87%) and 5 years (45% vs. 67%). Furthermore, mortality in patients with alcoholic cirrhosis was substantially greater than those non-alcohol related cirrhosis in the first year following diagnosis and subsequently thereafter. One limitation of this study, common to large population-based studies, is the inability to adjust for other unmeasured factors which may have also contributed to increased all-cause mortality in this population (e.g. body mass index, hepatocellular carcinoma and modest alcohol consumption). This important study by Fleming et al., demonstrates that cirrhosis is associated with a considerable health burden when compared with the general population, particularly in those with decompensated disease. As we move forward, any efforts to reduce liver-related mortality will require systematic strategies to improve the surveillance, detection, prevention and treatment of cirrhosis and reduce the proportion of patients progressing to decompensated disease, where the risk of mortality is highest. In terms of surveillance and detection of chronic liver disease, the use of simple (i.e. serum ALT measurement) and complex (i.e. serum markers or elastography imaging) techniques for assessing general populations has been proposed 9, 10 yet the low prevalence rates of clinically significant disease within populations limits the ability for health systems to allocate resources for this endeavour 11. For individuals with established cirrhosis, there remains an opportunity to improve adherence with screening and surveillance for hepatocellular carcinoma (HCC) as this complication is becoming more prominent as a leading cause of death in patients with compensated disease. Emphasis should also be placed on how systems of care handle the subsequent assessment of abnormalities identified during HCC surveillance (recall procedures) so that the eventual identification of HCC lesions is performed when the malignancy is still in an early stage 12. From a population perspective, however, the ability to influence lifestyle behaviours would have the greatest impact on preventing cirrhosis as well as reducing the risk of death from this condition. Several large-scale observational cohort studies have documented the relationship between obesity and the incidence of cirrhosis. Furthermore, there is also empiric evidence that obesity influences the rate of disease progression and is associated with the need for hospitalization and/or death from cirrhosis 13, 14. Determining the reasons why progression to decompensated cirrhosis occurs more frequently in the setting of obesity is of great interest within the hepatology research community. While alcohol consumption remains a major risk factor in the development of significant liver disease, the continued use of alcohol in high doses following the development of cirrhosis has clearly exacted a significant risk for death even among middle-aged persons within general populations 15. Thus, continued efforts should also be aimed at developing new methods for teaching individuals with chronic liver disease how to control and prevent alcohol abuse. It is also likely that the combination of obesity and excessive alcohol use synergistically increase the risk of decompensated cirrhosis and mortality 16. Finally, a positive relationship between cigarette smoking and progressive liver fibrosis has been identified as well 17. Verifying this association in additional long-term observational studies would help support more active interventions towards smoking cessation in patients with cirrhosis as well. As mentioned by Fleming et al., the application of interventions to prevent overt complications of portal hypertension from cirrhosis appears to be having an impact in reducing and now maintaining the overall mortality rate from cirrhosis as the prevalence of the condition increases with time 18. For patients affected by chronic liver diseases where treatments have been identified, there is also a growing body of evidence supporting the concept that fibrosis can be reversed after successful therapy even when histological cirrhosis is observed. For conditions where specific and effective pharmacological therapies are unavailable (i.e. NAFLD) or among patients unresponsive to established therapies, there remains a gap in the ability to provide therapies for regressing fibrosis in cirrhosis where novel breakthroughs are greatly awaited 19. Subsequent investigations like those from Fleming et al., are eagerly awaited to demonstrate the global burden of disease associated with the development of cirrhosis and its complications. Greater awareness regarding the worldwide prevalence of this disease should assist researchers in collaborating to determine which interventions will improve health-related quality of life and healthcare utilization for affected individuals. The authors would like to thank Gregory Dore (The Kirby Institute for infection and immunity in society, University of New South Wales) for review and input into the first draft of this manuscript. Funding sources: The Kirby Institute for infection and immunity is funded by the Australian Government Department of Health and Ageing and is affiliated with the Faculty of Medicine, University of New South Wales. Partly funded by the National Institutes of Health grant EB 10393 (J. A. T). Conflict of interest: The authors have no conflict of interest related to this manuscript.

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