The face of clinical hepatology is currently experiencing a major shift: away from (increasingly well-treatable viral) infections as prominent etiologies to non-alcoholic fatty liver disease (NAFLD). NAFLD consists of a disease spectrum that is associated and overlapping with obesity, dyslipidemia, cardiovascular disease, and insulin resistance/type 2 diabetes, that is features of the metabolic syndrome, a major cause of morbidity in developed and developing societies (Fig. 1). Ninety percent of NAFLD patients exhibit at least one of these risk factors, and one third exhibits three or more (Table 1). The exact numbers of patients with NAFLD can only be estimated due to the lack of reliable non-invasive markers and the need for histological definition of disease stage. In a recent study from the United States involving 400 volunteers at an army medical center with a mean age of 54.6 years and 45% obese subjects, the reported prevalence of NAFLD was 46%. Non-alcoholic steatohepatitis (NASH), that is histological necroinflammation, was diagnosed in 12% and twice as frequently in Hispanics versus Caucasians. Patients with NASH mostly (80%) exhibited a body mass index (BMI) > 30, had a mean alanine aminotransferase (ALT) of 50 U/L, and a higher quantitative insulin-sensitivity check index. Already in 2004, the Dallas Heart study that examined 2287 adults in a population-based setting showed a 31% prevalence of NAFLD, as confirmed by magnetic resonance imaging (MRI) in 31%. In this Texan cohort, the average age was 45 years, and the highest prevalence of hepatic steatosis was observed in the Hispanic cohort despite, on average, being 5 years younger than non-Hispanics. Likewise, in US populations with a BMI below 25, Hispanic origin and hypertension were significantly correlated with the presence of NAFLD on ultrasound. In Asian populations, despite a historically lower prevalence of metabolic risk factors and NAFLD, the incidence of NASH has increased dramatically, and the prevalence of the disease is growing rapidly.[6, 7] Additionally, a marked difference between rural and urban areas exists, indicating that lifestyle and education are contributing to NAFLD and NASH in Asia. However, the underlying mechanisms appear too complex. Even in a non-obese, non-affluent, rural population in India (n = 1991), with an average age of 35.5 years and a mean BMI of 19.6, the prevalence of NAFLD was 8.7%. In this study, the group with hepatic steatosis as determined by ultrasound and computed tomography scan exhibited a mean age of 39 and a mean BMI of 23, well below that of similar Western populations, perhaps due to a higher predisposition to accumulate visceral fat. Therefore, with the increasing prevalence of environmental risk factors of NAFLD in Asia recently and a comparable genetic predisposition, NAFLD is likely soon to rise to similar prevalence in most Asian countries as in the West despite a lower frequency of adiposity. In high-risk Western populations with diabetes and obesity, the prevalence of NAFLD can reach up to 75%,[10, 11] but the overall incidence of NASH is difficult to assess due to reliance on biopsy, especially in follow-up. A study from Hong Kong derived from a hospital cohort reported histological progression in 58% and fibrosis progression in 28% during a 3-year follow-up of patients at risk but with a low NAFLD activity score of < 3. In the absence of fibrosis or inflammation, the course of hepatic steatosis appears to be more benign. Thus, in a cohort of 144 patients with alcoholic and non-alcoholic fatty liver, regression as determined by ultrasound was observed in nearly every second case.[13, 14]
Apart from a waxing and waning course of disease activity, which may in part depend on (minor) lifestyle changes, the factors that determine disease progression in individual patients remain poorly defined. A meta-analysis on 10 studies comprising 221 patients found that over a mean time of 5.3 years, 21% of patients improved, 41% had unchanged liver histology, and 38% showed fibrosis progression by at least one histological stage (out of four stages). The strongest predictor of NASH progression was the degree of necroinflammation on initial biopsy. Sedentary lifestyle and overnutrition feed into the genetic predisposition of the “thrifty phenotype” that is partly determined by race, gender, and epigenetic changes, as reflected by a positive family history of NAFLD and the metabolic syndrome.[16-18] Notably, advanced fibrosis is prominent in patients older than 45 years, and liver-related mortality is increased approximately ninefold in patients suffering from NASH. Moreover, NASH is a key contributor to mortality from cardiovascular disease independent of traditional risk factors, and advanced stages of NAFLD predict carotid intima-media thickness and carotid plaques. Exploration of the underlying pathomechanism has led to a concept in which a pro-inflammatory state, including increased levels of pro-inflammatory cytokines, decreased protective adipokines, enhanced oxidant stress, emanating from the expanding and inflamed adipose tissue of obese patients, induces the release of atherogenic and prothrombotic factors from the liver. Certain studies even suggest that the liver is the prime driver of adipose inflammation and atherogenesis.
The incidence of hepatocellular carcinoma (HCC) in NAFLD remains controversial, since the association of NASH with cryp togenic cirrhosis as cause of HCC is difficult to prove. Patients with NASH can develop HCC even in the absence of cirrhosis, influenced by risk factors that contribute to the development of HCC. A systematic review of epidemiology studies including a total of 35 cohort, case control, and cross-sectional studies, as well as case reports, reported a cumulative HCC mortality rate during a follow-up of up to 20 years in non-cirrhotic NASH below 3%. In cirrhotic NASH, the cumulative incidence ranged from 2.4% to 12.8% in 3–12 years. Overall, this is considerably lower compared with virus-associated HCCs. In Hepatitis B surface antigen-positive patients with compensated cirrhosis, the 5-year cumulative HCC risk reaches 15% in endemic areas.