Obesity has risen at an epidemic rate during the past 20 years. It is well established that higher levels of body fat are associated with an increased risk for the development of type 2 diabetes, hypertension and dyslipidemia. More recently there has been a surge of interest in the effect of excess body weight on the liver. Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognised condition that is often seen in patients who are overweight in the absence of significant alcohol use. Obesity and hepatic steatosis also contribute to the acceleration of other liver diseases such as chronic hepatitis C (HCV). The mechanisms by which obesity and steatosis contribute to the development and progression of liver injury remain to be determined.
The principle aims of the studies described in this thesis were to examine the role of obesity and related metabolic factors in the progression of chronic HCV. In addition, the effect of weight reduction and increased physical activity on the biochemical, metabolic and histological features of chronic liver disease in overweight patients with steatosis was determined.
Host metabolic factors associated with increased BMI such as elevated insulin levels may play a role in disease progression. The relationship between obesity-related metabolic profiles and fibrosis was investigated in 160 patients with chronic HCV.
Patients with HCV genotype 3 had more severe steatosis (p=0.0001) and developed stage 1 and 2 fibrosis at a younger age (p<0.05) than patients with viral genotype 1. For both genotypes, overweight patients had significantly more steatosis and increased circulating insulin and leptin levels. In overweight but not lean patients, there was a statistically significant increase in circulating insulin levels with increasing fibrosis (p=0.03). Following multivariate analysis, insulin was independently associated with fibrosis (p=0.046) but not inflammation (p=0.83). There was no association between leptin and fibrosis.
Although obesity is a risk factor for fibrosis in both chronic HCV and NAFLD, the use of weight reduction as a treatment option for these diseases had not been previously investigated.
The effect of weight reduction and increased physical activity was examined in 50 patients with hepatic steatosis (HCV, n=33; non-HCV, n=17). The intervention consisted of two phases; an initial three month intensive weight loss program followed by a 12 month weight maintenance program.
On completion, 68% of patients had achieved and maintained weight loss with a mean reduction of 9.4 ± 4.0% body weight and decrease in waist circumference of 13.0 ± 5.0 cm. Thirty-two percent of patients had regained weight. In this latter group there was a mean increase of 8.6 ± 5.3% body weight relative to the end of the three month intensive period.
Paired pre- and post-intervention liver biopsy specimens were available for 17 patients (HCV genotype 1, n=6; HCV genotype 3, n=8; non-HCV, n=3). Overall there was a striking improvement in hepatic steatosis after weight loss (p<0.0001). The degree of reduction in steatosis was significantly associated with the amount of weight loss (rs=0.72, p=0.001). In some patients there was also a significant improvement in stage of fibrosis (p=0.008). Activated stellate cells, detected by a-smooth muscle actin staining, were assessed in biopsies from 10 patients and were significantly reduced following weight reduction in both portal tracts (p=0.01) and acini (p=0.02).
Improvements in serum ALT levels were correlated with the amount of weight loss (r=0.35, p=0.04). In patients who maintained weight loss, mean ALT levels at 15 months remained significantly lower than values at enrolment (p=0.004), while in regainers, mean ALT levels at 15 months were no different to values at enrolment (p=0.79). Improvements in fasting serum insulin levels were also correlated with weight loss (r=0.46, p=0.04) and subsequent weight maintenance sustained this improvement.
Co-morbid obesity significantly contributed to decreased feelings of well being in patients with chronic liver disease. Weight reduction produced significant improvements in both physical and mental aspects of quality of life which were sustained with weight maintenance.
In conclusion, abnormal metabolic profiles associated with obesity, such as elevated insulin levels, may contribute to the progression of chronic liver disease. Weight reduction in overweight patients with steatosis is an effective method of reducing steatosis and in some patients decreases the severity of fibrosis. Maintenance of weight loss and physical activity in overweight patients with liver disease results in a sustained improvement in liver enzymes, serum insulin levels and quality of life. Treatment of overweight should form an important component of the management of patients with chronic liver disease.