icon-folder.gif   Conference Reports for NATAP  
  American Association for the Study of Liver Diseases 2003 Conference
Boston, MA
Oct 24-28, 2003
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  Reported by Jules Levin
This report is about fatty liver, how it can accelerate progression of fibrosis in individuals with or without hepatitis C, and what you can do about it. Fatty liver may be more worrisome in individualswith HCV or HBV because they already may have advanced fibrosis.
Leon Adams (Mayo Clinic, Rochester, MN) reported study results in an oral presentation on the “Time Course of Fibrosis Progression in Patients with Nonalcoholic Fatty Liver Disease (NASH)”.
Fatty liver (steatosis) is the deposition of fat in the liver and it has been reported to accelerate liver disease and reduce response rates to interferon/ribavirin therapy for HCV. Fatty liver can result from drinking alcohol but NASH (nonalcoholic fatty liver) can also develop, and is associated with elevated lipids. In a poster at AASLD, Adams reported on the correlation between lipids and fatty liver and liver disease. Hypertriglyceridemia and low HDL cholesterol levels are common in NAFLD (fatty liver). Hypertriglyceridemia becomes less severe as NAFLD progresses, in part due to hepatic synthetic dysfunction. Triglyceride levels are independently associated with severity of steatosis in patients with simple steatosis and cirrhotic stage NASH and with inflammatory grade in patients with non-cirrhotic NASH. HDL levels are inversely correlated with inflammatory grade in non-cirrhotic NASH patients.
The natural history of nonalcoholic fatty liver disease (NAFLD) is not well defined, although it is known occasionally to progress to cirrhosis. Liver fibrosis represents one of the most worrisome feature on liver biopsy in patients with NAFLD, but the rate of fibrosis progression over time remains undefined. Small studies report 8% to 50% of patients, on average 29%, experience progressive fibrosis over the course of 5-10 years.
The aim of this study is to describe the histological course of liver fibrosis in patients with NAFLD, and to examine whether clinical, laboratory or histological features routinely determined in patients with NAFLD could be predictive of fibrosis progression.
They reviewed their experience in 100 patients with well-defined NAFLD that underwent more than one liver biopsy in the absence of treatment. These patients were seen at Mayo Clinic in Rochester, Minnesota, between January 1990 and December 2000. Patients with other liver disease and those with secondary causes of NAFLD were excluded. Clinical and laboratory data at time of initial biopsy were retrieved. Liver biopsies were reviewed by liver pathologists and severity of fibrosis staged according to the scoring proposed by Brunt et al. (Am J Gastroenterol 1999;94:2467-74). Univariate and multivariate linear regression analyses were used to identify predictors of fibrosis progression.
The 100 patients underwent a mean of 2.3 liver biopsies (range 2 to 4, total 226) with a mean interval between first and last biopsy of 36 ± 39 months, (range 9-288). Mean age was 45 ±10 years (range 18-68), 34 were male, 41 diabetic, 31 hypertensive and 77 were obese (body mass index ≥30). Mean ALT was 98 (range 13-258) and mean fibrosis stage on initial biopsy was 1.7 ±1.4 (range 0-4). Cirrhosis was present in 17 patients on initial biopsy. Age, body mass index, diabetes, ALT, albumin, glucose and platelet count were all significantly associated with fibrosis stage on initial biopsy (p<0.05). There was no change in BMI between biopsies (32 vs 33 kg/m2). 62 patients had hypertryigliceridemia (>150 mg/dl). 57 had low HDL (<40 mg/dl for men and <50 mg/dl for women).
Progression of fibrosis was observed in 29%, stable fibrosis in 55% and improvement in 16%. When cirrhotics were excluded, progression of fibrosis was seen in 35%, stable fibrosis in 48% and improvement in fibrosis in 16%. Among patients with worsening fibrosis, 18 (62%) had a one stage increase and 11 (38%) had 2 or more stage increases. Progression to cirrhosis was seen in 6% overall.
Among patients who improved, 12 (75%) had one stage decrease and 4 (25%) had two or more fibrosis stage improvement. The mean rate of fibrosis progression was variable, overall being 0.08 ± 0.54 (range -1.71 to 2.30) fibrosis stage/year (Graph one). Patients with progressive disease had a rate of 0.65 ±0.51 (range 0.02 to 2.30) fibrosis stage/year. Excluding cirrhotics, the mean rate of progression was 0.11 stage/year (range –1.71 to 2.30). Rate of fibrosis progression was significantly associated with fibrosis stage on initial biopsy by univariate linear regression, F3/F4 stage fibrosis was predictive of increased fibrosis rate. This association remained significant when cirrhotics (p=0.001). Having diabetes was also predictive of increased progression rate of fibrosis. Age and initial BMI were not significantly associated with rate of change of fibrosis.
The study authors concluded that liver fibrosis remains stable over a number of years in the majority of patients with NAFLD, but worsening or spontaneous improvement is however observed in a number of patients. Overall liver fibrosis in patients with NAFLD follows a progressive course over time. The presence of diabetes and a lower stage of fibrosis at initial biopsy appears to be predictive of a higher rate of fibrosis progression. Routinely determined clinical and biochemical variables do not predict changes in liver fibrosis over time.
Weight Loss and Exercise Can Improve Fibrosis
Ingrid Hickman and Australian researchers presented results from this study showing that weight loss can improve fibrosis (stage of liver disease) in overweight individuals with fatty liver (NAFLD or steatosis).
Obesity is a risk factor for the progression of fibrosis in chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD) and hepatitis C (HCV). The aim of this study was to investigate the longer-term effect of weight loss on liver biochemistry, serum insulin levels and quality of life in overweight patients with liver disease and the effect of subsequent weight maintenance or regain and to determine factors associated with successful weight maintenance.
Thirty-one patients (NAFLD, n=13; HCV and steatosis, n=18) completed a 15 month lifestyle intervention consisting of a 3 month weight loss program followed by a 12 month weight maintenance program.
On completion, 21 patients (68%) had achieved and maintained weight loss with a mean weight loss of 9.4 ± 4.0% body weight and decrease in waist circumference of 13.0 ± 5.0 cm.
Serum alanine aminotransferase (ALT) levels decreased significantly with weight reduction (p=0.001) and the decrease in ALT was associated with the amount of weight lost (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 patients who regained weight, mean ALT levels at 15 months were no different to values at enrolment (p=0.79).
Improvements in fasting serum insulin levels were also associated with the amount of weight loss (r=0.46, p=0.04) and subsequent weight maintenance sustained this improvement. Fourteen patients consented to a repeat liver biopsy 3-6 months after weight reduction. There was a striking improvement in grade of steatosis after weight loss (p<0.0001) and in 7 patients there was also an improvement in the stage of fibrosis (p=0.02).
At enrolment, lower quality of life scores as measured by the short form-36 questionnaire, were associated with a higher body mass index and quality of life scores significantly improved after weight loss. Weight maintainers were more likely to sustain recommended levels of physical activity and have higher fasting insulin levels (p=0.03) at enrolment compared with patients who regained weight.
In conclusion, these findings demonstrate that lifestyle interventions reduced risk factors associated with progression of liver disease, decreased abnormal liver enzymes, improved quality of life and in a proportion of patients improved histological features of liver injury. Importantly, these changes were achievable and sustainable with relatively small but persistent changes in lifestyle. Treatment of overweight should form an important component of the management of patients with chronic liver disease.