Fleming, Catherine Mary
(2010)
The epidemiology of cirrhosis and abnormal liver function in the general population of the UK.
PhD thesis, University of Nottingham.
Abstract
Background
Liver disease is a serious problem both in the UK and globally. While the incidence and mortality from several chronic diseases are decreasing, mortality from liver disease is increasing. As well as the medical sequelae for an individual with liver disease, in the UK the increase in chronic liver disease poses particular problems with respect to increasing hospital admissions, mortality and significant costs to the public both in terms of treatment and in loss of productivity. The increase in society of several risk factors for chronic liver disease, notably alcohol intake, obesity and type 2 diabetes, mean that these problems are likely to increase in the future.
Despite these apparent problems there are surprisingly few reliable sources of data on the occurrence of chronic liver disease (cirrhosis) in the general population of the UK and the rate and consequence of disease progression particularly among ambulatory patients. Nor are their robust estimates of the prevalence of abnormal liver function tests (which may represent undiagnosed liver disease) and their associations with mortality.
This thesis utilises two distinct datasets to examine separate areas of interest in the epidemiology of liver disease in the UK. The first three studies contained within this thesis are concerned with the epidemiology of cirrhosis in the general population of the UK. The second group of three studies focuses on the prevalence of elevated liver function tests in a population of older people in the UK, the demographic, clinical and lifestyle factors associated with such and the mortality following an elevated liver function test.
Objectives
1. To estimate the incidence and prevalence of cirrhosis in the population of the UK
2. To describe the mortality associated with cirrhosis compared with the general population and the disease progression of cirrhosis
3. To estimate the prevalence of elevated liver function tests among people aged 75 and over in the UK
4. To describe the association between elevated liver function test and demographic, lifestyle, clinical characteristics and mortality among people aged 75 and over.
Methods
To examine objectives 1 and 2 I utilised the General Practice Research Database (GPRD) constructing a population based cohort of 4537 subjects with cirrhosis and 44,403 age, sex and practice matched controls. I used Poisson regression to estimate incidence rate ratios and describe trends in alcoholic and non-alcohol-related cirrhosis. Using Cox regression within an historical matched cohort design I estimated the absolute excess mortality rates and hazard ratios for mortality in people with cirrhosis compared to the general population. I described the probability of progressing from one disease state to another.
To examine objectives 3 and 4 I accessed data from one arm of the Medical Research Council (MRC) Trial of Assessment and Management of Older People in the Community, a representative sample of community dwelling people aged 75 and over, totalling 15,308 participants. The prevalence of abnormal liver function was described as the proportion of study participants with elevated aspartate transaminase, alkaline phosphatase or serum bilirubin. Associations between elevated liver function and demographic, lifestyle and clinical factors were examined using multivariable logistic regression. I determined the absolute mortality rates and hazard ratios for all-cause and cause-specific mortality using a Cox proportional hazards model.
Findings
Epidemiology of cirrhosis (GPRD)
These studies have shown an increasing trend in both the incidence and prevalence of cirrhosis in the UK with an estimated 45% increase in incidence of cirrhosis in the 10-year period studied. I estimate that 76 per 100,000 people were living with cirrhosis in 2001. Just over half of all cirrhosis was associated with alcoholism. Disease progression with cirrhosis among this mainly ambulatory population was rapid with a rate of decompensation in people with compensated disease of 5% per year and 1 in 10 dying in the first year following diagnosis. This figure increased to 25% of people dying within one year for those with decompensated disease. Mortality in subjects with compensated and decompensated cirrhosis was 93.4 and 178.0 per 1000 person years compared with only 19.2 per 1000 person years in the general control population. Following adjustment for age and sex people with compensated and decompensated disease were respectively 5 and 10 times more likely to die than the general population.
Epidemiology of abnormal liver function tests (MRC cohort)
Abnormalities in liver function were common with roughly 1 in 6 people aged 75 and over having at least one elevated liver enzyme, although most of these elevations were mild. A single elevated measurement of aspartate transaminase was associated with an increased consumption of alcohol and a lower age in contrast with that of a single measurement of alkaline phosphatase which showed an association with higher age and lower alcohol consumption. An elevated bilirubin measurement was strongly associated with being male. Having a single elevated liver function test was associated with a modest increase in the hazard of death compared with people with normal liver function tests (adjusted hazard ratio for death 1.27 (95% CI[1.19, 1.36]). As well as an unsurprising increase in the hazard ratio for death from liver disease, elevated aspartate transaminase or alkaline phosphatase were both associated with modest increases in the hazard of death from cancer (adjusted hazard ratios of 1.56 (95%CI[1.21, 2.01]) and 1.61 (95%CI[1.39, 1.86]) respectively). Elevated alkaline phosphatase was additionally associated with increases in the hazard of death from respiratory disease (adjusted hazard ratio 1.58 (95%CI[1.32, 1.90])) and cardiovascular disease (adjusted hazard ratio 1.34 (95%CI[1.17, 1.55])).
Conclusions
From my work on the incidence and prevalence of cirrhosis I estimate that a minimum of 31,000 people in the UK are living with cirrhosis, a figure which is likely to rise given increasing trends in the incidence of cirrhosis described in this thesis. The significant mortality and disease progression associated with cirrhosis means that more needs to be done to combat both the incidence and progression of this disease both on an individual and population level.
Elevations in enzymes regarded as reflecting liver function are common in people aged 75 and over and in most people these abnormalities are less than 2x the upper limit of normal for the assays used. These elevations I observed are associated with both a modest increase in all-cause mortality and also with an increase in death due to specific causes. Rather than simply a marker of liver function the investigation of people with elevated liver function tests, particularly those with severely elevated tests, may lead to the identification of potentially treatable conditions that underlie death.
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