Non-alcoholic Fatty Liver Disease (NALFD)
Introduction and Facts
Non-alcoholic fatty liver disease (NAFLD) is hepatic steatosis, inflammation, and hepatocyte damage (ballooning degeneration). In Western countries and various countries in Asia, changes in lifestyle and diet increase the prevalence of obesity and metabolic syndrome, which is in line with the increase in NAFLD incidence.
The condition of NAFLD is not only considered a primary liver disease. Still, it is also part of the metabolic syndrome or insulin resistance conditions and lifestyle-related diseases such as diabetes, dyslipidemia, and hypertension. NAFLD has become a global problem with the prevalence of 10-50%, which is also influenced by ethnicity to gender and is estimated to increase in line with the increasing problems of obesity and metabolic syndrome globally.
Pathophysiology
Insulin resistance, oxidative stress, and inflammation are believed to play a role in the pathogenesis and progression of NAFLD. The 'multi-hit hypothesis (formerly known as the 'two-hit) has been used to explain the pathogenesis of NAFLD. Insulin resistance causes an increase in free fatty acids that are absorbed by the liver, resulting in a state of first-hit steatosis. This is followed by various complex interactions (multiple second hits) involving liver cells, stellate cells, adipose cells, Kupffer cells, inflammatory mediators, and reactive oxygen species that can cause inflammation (NASH) or progress to cirrhosis.
Insulin resistance initiates the first hit. The state of insulin resistance causes adipose cells and muscle cells to oxidize lipids, leading to free fatty acids. The fatty acids are then absorbed by the liver, resulting in a state of steatosis. The liver's free fatty acids can be bound to triglycerides or oxidized in mitochondria, peroxisomes, or microsomes.
The oxidation products are dangerous and can cause injury to the liver, which can then progress to fibrosis. Lipid peroxidation and oxidative stress increase the production of hydroxyneonenal (HNE) and malondialdehyde (MDA) which increase liver fibrosis through activation by stellate cells leading to increased production of transforming growth factor-beta (TGF-ß).
Inflammatory mediators play a role in the progression of NAFLD. Proinflammatory transcription factors such as nuclear factor kappa beta (NF-) are frequently found to be elevated in NASH patients. Adiponectin and tumor necrosis factor-alpha (TNF-a) are two proinflammatory proteins associated with the pathogenesis of NAFLD. Adiponectin is a hormone released by adipose cells that reduce fatty acid oxidation and inhibits hepatic gluconeogenesis. Both humans and mice showed low adiponectin levels and were associated with increased severity of inflammation. The breakdown of adiponectin in mice showed a significant increase in the degree of steatosis and inflammation. TNF-a is an inflammatory mediator produced mainly by macrophages and produced by adipose cells and hepatocytes. TNF-a causes liver injury by inhibiting mitochondrial electron transport and releasing reactive oxygen species that stimulate lipid peroxidation.
Kupfer cell inactivation is also associated with NAFLD and decreased liver cell regeneration capacity. Kupfer cell elimination is associated with an increased degree of NASH. Kupffer cell function is impaired in increased liver fat, possibly due to over 'full' hepatic sinusoids, prolonged antigen exposure to Kupffer cells, and decreased Kupffer cell outflow, leading to a persistent inflammatory response.
Clinical Symptoms and Complications
As with other chronic liver diseases, most patients with NAFLD are asymptomatic. NAFLD is usually found incidentally on routine laboratory tests or follow-up examinations of other conditions, such as hypertension, diabetes, and severe obesity. Elevated ALT levels or sonographic evidence of NAFLD may also be found on examination of gallstones.
Symptoms that may appear are usually non-specific. Fatigue was the most frequently reported and did not correlate with the severity of histologic lesions. Another common symptom is discomfort in the right upper abdomen that is vague and cannot be categorized as a specific pain.
There are no pathognomonic signs for NASH. Obesity is the most common abnormality found on physical examination and occurs in 30-100% of patients. Hepatomegaly is the most common finding in patients with liver disorders. A small proportion of patients also show stigmata signs of chronic liver disease, of which palmar erythema and spider nevi are the most common. Jaundice, ascites, asterixis, and symptoms of portal hypertension may be seen in patients with advanced cirrhosis. Muscle wasting can also be discovered as the disease progresses but is often masked by a pre-existing state of edema or obesity.
Diagnosis
1. Laboratory Examination
a. Concentrations of ALT (SGPT) and/or AST (SGOT) are usually mild to moderate, reaching 1-4 times the upper limit of normal with an AST/ALT ratio of less than 1. This ratio is typical for NAFLD, although it depends on the severity of the disease. In contrast, on the other hand, an AST/ALT ratio of more than one was associated with fibrosis and disease progression. However, the less severe alcoholic fatty liver also has an AST/ALT ratio of less than 1; therefore, it can help differentiate alcoholic fatty liver from non-alcoholic fatty liver disease but requires careful interpretation.
b. Gamma-glutamyltranspeptidase (GGT) is almost always elevated. Alkaline Phosphatase (AP) can increase up to 2 times the upper standard limit. The results of liver function tests such as albumin, bilirubin, and prothrombin time are usually normal, except in the presence of cirrhosis and liver failure. Some studies have also been conducted to find non-invasive predictors in diagnosing advanced fibrosis and cirrhosis in NAFLD patients, including FibroTest, Hepascore, and APRI (AST-to-platelet Ratio Index).
2. Imaging
Abdominal imaging is often performed to confirm the suspicion of NAFLD. The presence of fat in the liver can be identified through a variety of non-invasive imaging. In daily practice, steatosis is often detected by ultrasonography (USG), computerized axial tomography (CT), and magnetic resonance imaging (MRI) when the amount of fat exceeds 25-30% of the liver's weight.
3. Liver Biopsy
Liver biopsy is the only way to diagnose the presence and severity of the histologic spectrum of NAFLD. Liver biopsy is required when imaging techniques fail to diagnose and confirm the presence of NASH, fibrosis, and/or cirrhosis.
Management and Treatment
The management strategy for NAFLD starts from lifestyle modification, which can be continued with therapy targeting the components of the metabolic syndrome, pharmacotherapy, and cirrhosis management. In general, NAFLD/NASH management goals are to increase patient survival and reduce complication rates. In addition, short-term goals are to resolve NASH conditions, correct or prevent worsening of fibrosis, and improve metabolic syndrome or other risk conditions.
a. Lifestyle modification
Lifestyle changes, including weight loss, dietary changes, and physical exercise, resulted in NAFLD patients' improvements. Weight loss = 7% of total initial body weight reduced steatosis, inflammation, ballooning, and NAFLD activity score (NAS).
b. Pharmacotherapy
a. Insulin Sensitizing Drugs (Insulin-Sensitizing Drugs). Insulin resistance plays a central role in the pathogenesis of NAFLD. Observations on rats with insulin resistance and fatty liver, after being given metformin or thiazolidinediones, experienced improvements for both conditions.
b. Antioxidant. Oxidative stress is a key mechanism of liver cell injury and NAFLD progression. Vitamin E is one of the antioxidants that is often researched as an alternative to NAFLD treatment.
c. Lipid-Lowering Drugs (Lipid-Lowering Drugs). Considering NAFLD as a disorder of liver fat homeostasis, the administration of fat-lowering drugs is also a consideration.
d. Ursodeoxycholic Acid (UDCA) and Omega-3 Fatty Acids. Several studies have attempted to examine the use of UDCA (conventional and high-dose). The use of omega-3 fatty acids is approved in the United States to treat hypertriglyceridemia and is being investigated for use in treating NAFLD.
Reference:
1. Setiawan SI, Kurniawan J. Treatment options for non-alcoholic fatty liver disease (NAFLD). Mirror of the World of Medicine 2021;293:48(3):173-5.
2. Non-alcoholic fatty liver disease (NAFLD) [Internet]. [cited 2021 Aug 26]. Available from: http://eprints.undip.ac.id/44142/3/BAB_2.pdf
