Non-alcoholic Fatty Liver Disease
Steatosis is defined by the accumulation of fat in the hepatocytes.7 Other than in cases of mitochondrial toxicity (e.g. acute fatty liver of pregnancy, Reye’s syndrome) where bipolar lipids accumulate in micelles (often called microvesicular steatosis),8 steatosis mainly consists of fat-filled vacuoles delineated by a bi-layer lipid membrane and predominantly accumulating triglycerides.9 The fat vacuoles may differ in size, from small vesicles up to large vacuoles that fill the cytoplasm and displace the nucleus towards the border of the cell. This results in the term macrovesicular steatosis.7,10 If smaller vacuoles are present, the term mesovesicular is often used. If the dimensions of the vacuoles vary, steatosis is often called mixed type steatosis, although this implies the presence of typical fat vacuoles of varying diameter, and not necessarily the concomitant presence of macrovesicular steatosis and micelles as seen in acute mitochondrial toxicity.8
Steatosis can be secondary to several causes, such as the use of alcohol and certain drugs (e.g. furadantin, methotrexate, amiodarone, corticosteroids) to chronic hepatitis C (especially genotype 3).4 In the absence of these causes, steatosis is called NAFLD.7,11 NAFLD thus not only necessitates the absence of significant alcohol use (defined as >20 g/day in women and >30 g/day in men) but also the exclusion of all other causes of secondary steatosis, making the term NAFLD not an ideal denominator of this entity.11,12 The term has, however, been widely adopted.
NAFLD comprises a wide spectrum of histological liver lesions. If steatosis is the only histological abnormality, it is called non-alcoholic fatty liver (NAFL).12 However, if steatosis is accompanied by inflammation and signs of hepatocyte degeneration (ballooning or swelling of hepatocytes because of cytoskeleton damage), it is called NASH.4,7 NASH requires the combination of steatosis, lobular inflammation (portal inflammation is not included in the diagnosis) and ballooning of any degree.7,12 These features can only be reliably assessed by liver histology, implying NASH to be a histological diagnosis.10,12,13 NAFLD can be accompanied by fibrosis, which can progress to cirrhosis and its inherent complications. It is generally accepted that the risk of fibrosis and progression to cirrhosis is confined to patients with NASH (but fibrosis is not part of the definition of NASH), whereas NAFL is believed to run a benign course, at least in terms of liver disease.10,14,15 Typical features of NASH and even steatosis can disappear in the cirrhotic stage, making it difficult to establish an aetiological diagnosis in some cases of cryptogenic cirrhosis, part of which are considered burned-out NASH based on the presence of metabolic risk factors for NAFLD and NASH.14
Despite extensive research conducted so far, the pathophysiology of NAFLD and NASH remains poorly understood. Epidemiologically, NAFLD and NASH are closely related to obesity, to dyslipidaemia, to disturbances of glycaemic control and to the metabolic syndrome (MetS).16 Therefore, NAFLD is sometimes considered as the hepatic manifestation of the MetS.3,17 For some time NAFLD was considered to be secondary to these metabolic features, but insight is growing in the aetiological role of NAFLD in the development of the MetS or type 2 diabetes mellitus (T2DM), which it often precedes.17,18 Currently the pathophysiology of NASH is considered to be a parallel multi-hit process involving nutrients, the gut microbiome, the intestinal barrier, the adipose tissue (producing adipokines), the immune system and the liver, together with genetic and environmental factors.19
Although exact data vary because of differences in modes of diagnosis and selection of patients, NAFLD seems to affect about 15–30 % of the adult population in western countries, making it the most prevalent liver disease worldwide.1,2 The prevalence of NASH is estimated at 2–5 %, with progressive fibrosis in about 45–50 %, with a risk of ultimately developing cirrhosis in 10–20 %.2,15 The risk of hepatocellular carcinoma (HCC) is not well-defined, and some concern has risen about the risk of HCC in non-cirrhotic NAFLD.20,21