Thank you for your interest in CCO content. As a guest, please complete the following information fields. These data help ensure our continued delivery of impactful education.
Become a member (or login)? Member benefits include accreditation certificates, downloadable slides, and decision support tools.
Patients with NAFLD or NASH seldom present with liver-specific symptoms. Many are still identified on the basis of tests performed in the investigation and management of other related conditions such as hypertension and type 2 diabetes mellitus. Nonetheless, even before liver disease is advanced, it is clear that such patients have a constellation of symptoms related to the presence of NAFLD or NASH itself. Those with NAFLD or NASH are typically middle-aged and possess some feature of metabolic syndrome (eg, obesity).[32,33] Although many patients are asymptomatic, the most common symptoms are fatigue and pain or dullness in the right upper quadrant. Laboratory testing may also detect mild to moderate elevations in aminotransferases and gamma-glutamyltranspeptidase. Hepatomegaly is present in approximately 10% of those with NASH.
The typical natural history of NAFLD is that of a slowly progressive disease, yet approximately 20% of patients will exhibit rapid fibrosis progression. A meta-analysis of 11 observational studies in 411 patients with NAFLD and paired biopsies reported that the rate of fibrosis progression is approximately 1 fibrosis stage per 14 years in those with nonalcoholic fatty liver compared with 7 years in NASH.
The most common causes of death in patients with NASH are cardiovascular disease and non–liver-related malignancy, highlighting the importance of holistic management of such patients. It remains to be determined if successful treatment of liver inflammation in the future will have an impact on these extrahepatic outcomes. An initial analysis of 129 Swedish patients diagnosed with NAFLD after referral due to elevated liver enzymes reported that those with NASH, but not simple steatosis, were at a significantly increased risk for overall and liver-related mortality compared with age-matched and sex-matched controls. After a mean follow-up of 13.7 years, the overall survival rate among those with NASH was 70% vs 80% in the reference population (P = .01), and the rate of liver-related mortality was 2.8% vs 0.2%, respectively (P = .04). This finding resonated with the view then that progression to NASH was a critical step in the development of disease. However, a more recent analysis after a mean follow-up of 26.4 years has cast some doubt on this inference, suggesting instead that it is the presence of fibrosis rather than NASH that drives overall and liver-related mortality in this population. In this more recent analysis, overall mortality was significantly increased in those with fibrosis stage 3/4, regardless of NAFLD activity score, compared with the reference population (HR: 3.28; P < .001). In comparison, overall mortality did not differ between the reference population and those with fibrosis stage 0-2, regardless of NAFLD activity score. These data from retrospective studies suggest that outcomes in the setting of NAFLD reflect not only the presence of inflammation but also a differential susceptibility to the development of liver fibrosis.