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Non - Alcoholic Fatty Liver Disease

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Non - Alcoholic Fatty Liver Disease NON - ALCOHOLIC FATTY LIVER DISEASE Author: Nicolene Naidu Bachelor of Biological Science (Cellular Biology), Bachelor of Medical Science (Medical Microbiology) (Honours) Non - Alcoholic Fatty Liver Disease (termed NAFLD for short) is a condition characterized by the significant accumulation of lipids in the hepatocytes of the liver parenchyma. While non - alcoholic fatty liver disease and alcoholic liver disease are pathologically similar, unlike alcoholic liver disease, non - alcoholic fatty liver disease occurs in patients who do not have a history of excessive alcohol intake. Another term closely related to NAFLD but more histologically and clinically specific is Non - Alcoholic Steatohepatitis(NASH). It was coined by Ludwig et al in 1980 and is characterised by a fatty liver accompanied by inflammation and hepatocyte injury (“Ballooning”). Fibrosis may or may not be present. It should be noted that the histological appearance of non – alcoholic steatohepatitis is identical to that of alcoholic liver disease. Distinction between the two is based on the amount of alcohol intake. Non - alcoholic fatty liver disease is the loose term used to describe a wide spectrum of liver damage ranging from hepatic steatosis (simple benign fatty liver), non - alcoholic steatohepatitis, chronic fibrosis and cirrhosis (P Angulo, 2002). Figure 1: Showing a drawing of the various stages of liver damage, including a normal liver; fatty liver in which deposits of fat cause liver enlargement; liver fibrosis in which scar tissueforms and more liver cell injury occurs and cirrhosis in which scar tissue makes the liver hard and unable to work properly.(www.liverfoundation.org). 1 Pseudo-alcoholic liver disease, non - alcoholic Laennec’s disease, alcohol-like hepatitis, diabetic hepatitis and steatonecrosis are among the terms that have been used to refer to non – alcoholic fatty liver disease (Shethet al, 1997). While non - alcoholic fatty liver diseasehas no age or sex predilectionand affects all racial and ethnic groups, overweight and obese individuals, individuals with type 2 diabetes mellitus, those with elevated blood lipids like triglyceride and cholesterol (hyperlipidemia)and those with ‘metabolic syndrome’’ are most likely at risk of developing non – alcoholic fatty liver disease(Vernon et al, 2011).Recently, patients with hypothalamic or pituitary dysfunction (Adams et al, 2004), impaired glucose tolerance and dyslipidemia were also found to progressively develop non – alcoholic fatty acid liver disease. Epidemiologically, it has been reported worldwide with evidence of geographic variations in prevalence and is estimated to be the most common liver disease in the Western world. PATHOGENESIS While the exact mechanisms involved in the pathogenesis of non – alcoholic liver disease are not fully elucidated (Ramesh et al, 2005), scientists propose a ‘2 hit’ theory (Day et al, 1998). One “hit” that causes an accumulation of excess fat in the liver and then a second “hit” or further injury that causes hepatic steatosis to lead to hepatic inflammation. (Rouviere O, Yin M, Dresner MA, et al. MR elastography of the liver: preliminary results. Radiology 2006; 240:440–448) 2 THE FIRST HIT – The accumulation of fats in the hepatocytes (hepatic steatosis): Closely related to the metabolic changes associated with insulin resistance and obesity (Hubsher, 2006). Impaired fatty acid metabolism in the liver cells and an increase in free fatty acid delivery to the liver lead to the accumulation of trigylcerides in the liver hepatocytes (Hubsher, 2006).When the supply of fatty acids to the liver is greater than the demand for the synthesis of cholesterol, triglyceride and phospholipid as well as mitochondrial oxidation, hepatic steatosis occurs. In the presence of insulin resistance, the amount of free fatty acids available exceeds the mitochondrial capacity for oxidation. It is thought that the impaired mitochondrial β-oxidation function that results in insulin resistance results in decreased fatty acid disposal (Reid, 2001). The hepatic steatosis that occurs in this stage is a form of ectopic lipid accumulation. NOTE:It hasrecently been recognised that a fatty liver may exacerbate insulin resistance. The accumulation of fat in the liver interferes with phosphorylation of insulin receptor substrates (Samuel et al, 2004) which may be mediated by increased microsomal cytochrome P450 2E1expression at the hepatocellular level (Schattenberg et al,2005). This process could potentiate a cycle whereby fatty change in the liver could be initiated by the metabolic syndrome and vice versa (Adams et al, 2005). THE SECOND HIT – Oxidative stress The second hit involves oxidative stress causing the lipids accumulated in the hepatocytes to undergo peroxidation (Day et al, 1998). A process which is promoted by the formation of reactive oxygen species as a result ofmitochondrial dysfunction, along with the induction of microsomal cytochrome P450 2E1(Chitturi et al, 2001). Oxidative stress also causes disease progression by resulting in cytokine production (Pessayre et al,2001). Disease progression which is also mediated byelevated levels of pro- inflammatory cytokines like Tumour Necrosis Factor α and a decrease in anti- inflammatory cytokines like adiponectin (Diehl et al, 2005 ), which are bothcharacteristic of the metabolic syndrome, further suggest the influence of the metabolic syndrome in non – alcoholic fatty liver disease progression. Both the first and second “hit” (Day et al, 2002). Biopsies of livers with non- alcoholic steatohepatitis (NASH) have shown a significant reduction the expression of the cytokine adiponectin and its receptors in NASH as compared to simple steatosis (Kaser et al, 2005). 3 Progression to fibrosis and cirrhosis among the above factors requires an interplay between inflammatory cells, Kuppfer cells, fatty liver cells and hepatic stellate cells (while the exact role of iron in NAFLD is uncertain, iron can lead to stellate cell activation and collagen deposition – Younossi et al, 1999). We will not go into detail on the exact interactions involved between the above mentioned cells, but will note that leptin, interleukin – 10 (pro-inflammatory cytokine), transforming growth factor β (also a pro-inflammatory cytokine) are among the elements that play a role in activating and regulating this process. Table 1: Shows the numerous conditions associated with fatty liver disease. (David A. Sass MD,* Parke Change, MD,†and Kapil B. Chopra, MD. Nonalcoholic Fatty Liver Disease:A Clinical Review. Digestive Diseases and Sciences, Vol. 50, No. 1 (January 2005), pp. 171–180) 4 SIGNS AND SYMPTOMS Because most patients with non – alcoholic fatty liver disease present with no symptoms (asymptomatic), it is often called a “silent killer”. Some patients do however present with non- specific symptoms like vague upper right quadrant abdominal pain, malaise and fatigue. DIAGNOSIS Patients suffering from non –alcoholic fatty liver disease are often discovered by “accident” during routine laboratory testing, when the liver function panel shows elevated liver enzyme levels or when abdominal imaging incidentally detects a fatty liver. Generally the most common and usually the first abnormality found in non – alcoholic fatty liver disease patients is a slight elevation of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (Angulo P, 2002). Patients with non – alcoholic fatty liver disease usually present with an AST/ALT ratio of < 1. This differs from patients with alcoholic liver disease who typically exhibit increases in ALT and AST that are disproportionate to each other.However,there is not enough diagnostic difference between alcoholic and non- alcoholic fatty liver disease for elevated liver enzymes alone to be used to make a positive diagnosis for either disease. It should be noted that the degree of serum aminotransferase elevation does not have a significant histological correlation with the severity of hepatic inflammation or fibrosis (Sonsuz et al, 2000). Other laboratory findings may include elevated serum alkaline phosphatase (AlkP), bilirubin, glucose and lipid levels, although these may only present once the disease is established. A physical exam may show hepatomegaly due to fatty infiltration of the liver. Because Hepatitis C (HCV) can cause histological changes that closely resemble those associated with non-alcoholic fatty liver disease, serological testing to 5 exclude viral hepatitis should be a prerequisite for the diagnosis of non – alcoholic fatty liver disease. Before a diagnosis of non- alcoholic fatty liver disease is even considered, the patient must consume less than 20 - 30 grams (approx. 2 drinks) of alcohol a day and all the other possible causes for liver disease must first be eliminated (eg. viral, metabolic, autoimmune markers, drugs or toxins, hepatobiliary obstructions, tumours, etc. ) Imaging techniques are a valuable tool in the diagnosis of non – fatty liver disease. Techniques that can identify hepatic steatosis include ultrasonography (US), Computed Tomography (CT), and Magnetic Resonance Imaging (MRI). ULTRASONOGRAPHY Most commonly used least expensive method Can be used to subjectively diagnose moderate to severe steatosis. This technique ishowever, poor at detecting smaller amounts of fat in the liver. Findings of diffuse fatty liver change include increased acoustic attenuation, vascular blurring and an increased echogenicity of the liver (ie. hyperechogenicity).
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