Nonalcoholic, fatty liver disease (NAFLD) is defined as the ectopic accumulation of fat in the liver (hepatic steatosis) when no other causes of secondary liver fat accumulation are present. Although, minor deposition of fat can occur in the liver of healthy adults, deposition of fat in at least 5% of hepatocytes is considered pathologic. NAFLD includes both nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) which is diagnosed when there is evidence of inflammatory activity and hepatocyte injury in a steatotic liver tissue. The diagnosis of NAFLD should not be made in a patient who has a history of significant alcohol consumption. The acceptable level of daily alcohol consumption is considered to be less than 20 g/day in men and 10 g/day in women. These cutoff values are not accurately defined, especially in patients with prior history of heavy alcohol use and those who are prone to NASH. NASH can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma with about 30% to 40% of patients developing fibrosis. NASH is not a diagnosis of exclusion and can be associated with other liver conditions such as chronic hepatitis C. NASH is classified into two types, primary; which is related to obesity and diabetes in the absence of excessive alcohol intake, and secondary; which is toxin or drug induced. This article will focus on primary NASH.
Certain conditions have been associated with NAFLD and NASH. Obesity has a strong association with NAFLD. Metabolic syndrome (which comprises of obesity, type 2 diabetes mellitus or hyperinsulinemia, hypertension, and dyslipidemia) is strongly associated with NAFLD. About three-quarter of patients with insulin resistance and type 2 diabetes mellitus have fatty liver disease with a higher prevalence of cirrhosis. Other metabolic and genetic conditions that are associated with NAFLD are polycystic ovary disease, lipodystrophies, mitochondrial diseases, Weber-Christian disease and Wilson disease. Both nutritional overload states such as total parenteral nutrition and malnutrition (as in Kwashiorkor and celiac disease) are associated with NAFLD.
People of African American origins have lower rates of NAFLD compared to Hispanic Americans despite having higher rates of obesity and diabetes. Their genetic variation can explain this. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) also known as adiponutrin is a protein that mediates the break down of fat and can increase hepatic fat levels based on its expression. Polymorphisms in the gene coding this protein have been linked to the ethnic variation of NAFLD as Hispanic Americans were found to have higher levels of this protein.
NAFLD; including both NAFL and NASH, is the most common cause of abnormal liver enzymes in the developed countries. The prevalence of NAFLD and NASH in adults in the United States is 30% to 40% and 3% to 12% respectively, and it has been increasing given the increasing prevalence of the predisposing conditions. There is also ethnic variation in prevalence as mentioned before, with Hispanics having the highest prevalence, followed by Caucasians than African-Americans. It can develop at any age, and its prevalence increases with aging.
NAFL and NASH are in the spectrum of NAFLD. They both involve steatosis which is defined as more than 5% liver fat. The mechanism of NAFLD can be explained by the "two-hit" hypothesis that involves steatosis (first hit), followed by oxidative stress and injury (second hit). Increased hepatic fat deposition results from an imbalance between energy supply and consumption. NAFLD is thus the hepatic manifestation of adipose tissue dysfunction secondary to energy surplus.
The three main sources of free fatty acid (FFA) in the liver are plasma nonesterified fatty acids (NEFAs) from adipose tissue (60%), de novo lipogenesis in the liver (25%), and dietary free fatty acids from chylomicrons (15%). The liver gets rid of the fat either via beta-oxidation of FFA (which predominantly occurs in the mitochondria, and in peroxisomes and cytochrome P-450 when there is energy surplus) or via exporting them as very low-density lipoproteins (VLDLs).
The NEFAs in plasma increase when the adipocyte is overtaxed leading to increased lipolysis. The adipose tissue releases FFAs in response to hormones such as glucagon, epinephrine, and adrenocorticotropic hormone. Insulin inhibits adipose tissue lipolysis after meals. When there is adipocyte insulin resistance, there is inappropriate postprandial lipolysis in adipose tissue. Prolonged starvation causes an appropriate release of fat from adipocytes which may cause NASH if the hepatocyte's ability to handle the fat is overwhelmed. Excess calorie intake and parenteral nutrition cause hepatic lipotoxicity due to increased de novo lipogenesis by the liver in an attempt to discard the excess carbohydrates. Monounsaturated fatty acids (MUFAs) are needed to synthesize triglycerides, which prevents cellular injury by keeping excess fatty acids in the liver in the esterified, inert form. Deficient synthesis of MUFAs in the liver or any impairment in the secretion of VLDLs can cause toxic fat accumulation within the hepatocyte. Mitochondrial dysfunction can also cause steatosis due to impaired beta-oxidation of fatty acids (as in alcoholic steatosis, NASH, acute fatty liver of pregnancy and use of medications such as valproic acid).
Different lipids have different potential to cause toxicity. Accumulation of liver triglycerides helps to buffer toxic lipids to lipid droplets enriched with inert triglycerides. Thus, hepatic triglyceride accumulation, which typically manifests as hepatic steatosis, is perhaps a defense mechanism to handle energy surplus in the liver. Toxic fat accumulation in the hepatocytes is caused by nontriglyceride metabolites of free fatty acids. Triglyceride in the lipid droplet form is a non-toxic mechanism to store fatty acids in the inert form. The lipotoxic metabolites of FFA have not been fully identified yet; these likely include saturated fatty acids, free cholesterol, ceramides, lysophosphatidylcholine, and diacylglycerol. The linearity of the two hit hypothesis is questionable as it has not always been shown that isolated steatosis precedes NASH, and the type of fat that typically accumulates in the liver with isolated steatosis (neutral fat or triglyceride) is different from the toxic fat (accumulation of which leads to NASH). The two-hit model does not explain why the first hit (steatosis) occurs. The presence of steatosis in itself might be a marker of hepatotoxic stress, and it is likely that NASH follows when the adaptive responses to the hepatocyte stress fail to maintain hepatocyte viability.
The cascade of events results in mitochondrial dysfunction which impairs oxidate phosphorylation and the ability of the cells to synthesize ATP and provide the energy they need to maintain their structure and function. This leads to the production of reactive oxygen species (ROS), leading to injury of the endoplasmic reticulum and lipid peroxidation. In turn, lipid peroxidation damages DNA, proteins, and membranes with the result of cell ballooning and disruption of its cytoskeleton, driving cells to go into apoptosis and local necrosis. In response to cell injury and necrosis, inflammatory cytokines are released which causes inflammation and activate stellate cells which deposit collagen resulting in fibrosis. Thus the hepatic lipotoxicity secondary to energy surplus leads to other injurious processes such as adipose tissue dysfunction, oxidative stress, endoplasmic reticulum stress, ineffective autophagy and dysbiosis of the gut flora, all of which cause sterile hepatocyte inflammation. Apoptosis, necrosis, and necroptosis of the hepatocyte is the net result of eventual progression to fibrosis and liver cirrhosis.
Most patients with NAFLD and NASH are asymptomatic, and the disease is usually diagnosed incidentally on routine blood work. However, some people with NASH can present with right upper quadrant pain or discomfort, perhaps due to liver capsular stretching from hepatomegaly. A physical exam is non-specific and can show hepatomegaly secondary to steatosis, acanthosis nigricans (increased pigmentation around the neck and joints) due to insulin resistance or stigmata of liver cirrhosis such as palmar erythema, spider telangiectasias, muscle wasting, jaundice, splenomegaly, and ascites if the patient has cirrhosis.
The diagnosis of NAFLD/NASH is often made incidentally when routine lab tests show abnormal liver biochemical tests or imagining tests show hepatic steatosis or hepatomegaly. Imaging modalities include ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI). Ultrasonography, however, is most widely used as it is the least expensive and most available modality. A diagnosis of NAFLD should be made only in the absence of excessive alcohol intake (defined as alcohol consumption of more than 20 g/day for men and more than 10 g/day for women), and other causes of liver disease such as viral hepatitis, autoimmune hepatitis, hereditary or drug-induced liver disease. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are usually mildly elevated at two to five times the upper level of normal with ALT greater than AST in a 2:1 ratio. This pattern of serum aminotransferase elevation helps distinguish NAFLD from alcoholic hepatitis, as the AST is usually greater than ALT in alcoholic hepatitis in a greater than 2:1 ratio. Please note that this pattern flips in NASH with advanced fibrosis or cirrhosis and the AST is usually greater than ALT in such cases. Serum alkaline phosphatase can be mildly elevated, usually up to twice the upper limit of normal. Bilirubin, albumin, and INR are usually within the normal limits but will be elevated in patients who develop cirrhosis. Ferritin can be elevated in up to 60% of patients and usually indicates more advanced disease given it is a marker of inflammation. Autoimmune antibodies such as antinuclear antibody (ANA) can be detected in low titers.
Liver biopsy is often needed to confirm the diagnosis of NASH and stage the fibrosis when patients present with a chronic unexplained elevation of serum aminotransferases. Liver biopsy is often not indicated when aminotransferases are normal, and the only abnormality is a hepatic steatosis on imaging. Liver biopsy is the gold standard for diagnosis but is not always accurate due to observer-related bias and sampling error (only 1/50,000 of the liver volume is sampled with a biopsy, and the features of NAFLD are not always uniformly present throughout the liver). The histologic features on liver biopsy can be classified as steatosis, steatohepatitis, and fibrosis. Steatosis is the accumulation of lipid droplets in hepatocytes. It is pathologic when it involves more than 5% of the hepatocytes. Steatosis is termed macrovesicular when the lipid droplets are large and displace the nucleus to the periphery of the cell, and microvesicular when the droplets are small and accumulate without causing any nuclear displacement. Both mixed and macrovesicular steatosis is seen in NAFLD, but a pure microvesicular pattern is not seen in NAFLD (but is seen with alcoholic hepatitis and various other conditions). NASH is present when there is steatosis, inflammation (chronic mononuclear cell inflammatory infiltrate composed of lymphocytes, rare plasma cells, and monocytes) and hepatocyte ballooning. The NAS (NAFLD activity score) ranging from 0 to 8 points is the most widely used grading and staging system for histological features on the biopsy. It scores and grades NASH based on steatosis, lobular inflammation, hepatocyte ballooning with a score of 5 or higher correlating with NASH and less than 3 as unlikely to be NASH. There is a separate fibrosis score ranging from 0 to 4 with this system. While this a valuable tool for research, its use in an individual patient to diagnose, prognosticate or exclude NASH remains controversial.
Various non-invasive tests are used for predicting the severity of fibrosis in NAFLD patients. These include both serologic tests and imaging techniques. The serologic tests include AST to Platelet Ratio Index (APRI) score, Fibrosis-4 (Fib-4) calculator and NAFLD fibrosis score (NFS). A score of greater than 1 with APRI less than 0.676 with NFS and greater than 2.67 with Fib-4 predicts the presence of advanced fibrosis, while NFS less than -1.455 and Fib-4 score less than 1.3 suggests a low risk for advanced fibrosis. Commercial fibrosis marker panels such as enhanced liver fibrosis (ELF) test and FibroTest are also helpful to predict/exclude advanced fibrosis. Radiologic techniques such as FibroScan (using ultrasound transient elastography), acoustic radiation force impulse imaging and magnetic resonance elastography are also useful. Of these, FibroScan is more widely used, and a score greater than 9.3 kPa with XL probe or greater than 9.6 kPa with M probe predicts advanced fibrosis and scores less than 7.2 kPa and less than 7.9 kPa with respective probes reliably exclude advanced fibrosis.
In summary, a diagnosis of NAFLD should be considered in patients with features of metabolic syndrome, radiological evidence of steatosis, and/or abnormal liver biochemical test results, if there are no risk factors for alcoholic liver disease or other chronic liver diseases. A combination of the serologic non-invasive scores or imaging test scores may be used to predict the risk for advanced fibrosis. Such a prognostic methodology offers us the option to reserve liver biopsy for only those patients who are at either intermediate or high-risk for advanced fibrosis.
The mainstay of treatment is lifestyle modification with the goal to achieve at least 5% to 10% of weight loss. Both biochemical and histological improvement was seen in patients who had weight loss, which is accomplished via calorie reduction combined with exercise. One to two cups of caffeinated drip coffee may be considered as part of the lifestyle modification measure, given the reported association of caffeinated drip coffee with decreased liver fibrosis and decreased incidence of hepatocellular carcinoma. Studies have shown that eliminating high fructose corn syrup and increasing omega three fats in the diet is beneficial. Thiazolidinediones appear to be beneficial in improving adipocyte insulin sensitivity and preventing inappropriate lipolysis. Their side effect profile (weight gain, congestive heart failure exacerbation, and osteoporosis), however, limits their use. Antioxidants such as vitamin E are of modest benefit and likely safe in non-diabetic patients; a dose of 800 units per day may be offered in such patients after explaining the risks of increased all-cause mortality with high dose vitamin E therapy. In patients with diabetes, we do not recommend giving a dose higher than 400 units per day. Bariatric surgery is an effective treatment and may be considered in patients with morbid obesity who would otherwise meet the criteria for bariatric surgery. Statins should not be withheld in patients with NAFLD due to pre-existing abnormal liver biochemical tests. Liver transplantation is the last resort in patients with decompensated cirrhosis, with the caveat that NAFLD can recur after transplant.
Patients with NAFLD especially NASH are at an increased risk of developing cirrhosis and hepatocellular carcinoma. Up to 10% of patients with NASH will eventually develop cirrhosis, which is the third most common causes of death in NAFLD after cardiovascular disease and cancer.
The management of NAFLD is multidisciplinary; each healthcare professional who encounters these patients must encourage changes in lifestyle to lower the morbidity of the disorder. The mainstay of treatment is lifestyle modification with the goal to achieve at least 5% to 10% of weight loss. Both biochemical and histological improvement was seen in patients who had weight loss, which is accomplished via calorie reduction combined with exercise. Thiazolidinediones appear to be beneficial in improving adipocyte insulin sensitivity and preventing inappropriate lipolysis. Their side effect profile (weight gain, congestive heart failure exacerbation, and osteoporosis), however, limits their use. Antioxidants such as vitamin E are of modest benefit and likely safe in non-diabetic patients; Bariatric surgery is an effective treatment and may be considered in patients with morbid obesity who would otherwise meet the criteria for bariatric surgery. Statins should not be withheld in patients with NAFLD due to pre-existing abnormal liver biochemical tests. Liver transplantation is the last resort in patients with decompensated cirrhosis, with the caveat that NAFLD can recur after transplant.
The outlook for Patients with NAFLD especially NASH is guarded because many are at an increased risk of developing cirrhosis and hepatocellular carcinoma. Up to 10% of patients with NASH will eventually develop cirrhosis, which is the third most common causes of death in NAFLD after cardiovascular disease and cancer. (Level V)
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