Non-alcoholic fatty liver disease
|Non-alcoholic fatty liver disease|
|Classification and external resources|
Micrograph of non-alcoholic fatty liver disease, demonstrating marked macrovesicular steatosis. Trichrome stain
Non-alcoholic fatty liver disease (NAFLD) is one cause of a fatty liver, occurring when fat is deposited (steatosis) in the liver not due to excessive alcohol use. It is related to insulin resistance and the metabolic syndrome and may respond to treatments originally developed for other insulin-resistant states (e.g. diabetes mellitus type 2) such as weight loss, metformin and thiazolidinediones. Non-alcoholic steatohepatitis (NASH) is the most extreme form of NAFLD, and is regarded as a major cause of cirrhosis of the liver of unknown cause.
Signs and symptoms 
Most patients with NAFLD have few or no symptoms. Patients may complain of fatigue, malaise, and dull right-upper-quadrant abdominal discomfort. Mild jaundice may be noticed although this is rare. More commonly NAFLD is diagnosed following abnormal liver function tests during routine blood tests. By definition, alcohol consumption of over 20 g/day (about 25 ml/day) excludes the condition.
NAFLD can also be caused by some medications:
- Antiviral drugs (nucleoside analogues)
- Aspirin rarely as part of Reye's syndrome in children
Soft drinks 
Soft drinks have been linked to NAFLD through the presence of high fructose corn syrup which may cause increased deposition of fat in the abdomen although the consumption of sucrose shows a similar effect (likely due to its breakdown into fructose).
Indian men have a high prevalence of non-alcoholic fatty liver disease. Two genetic mutations for this susceptibility have been identified, and these mutations provided clues to the mechanism of NASH and related diseases.
Polymorphisms (genetic variations) in the single-nucleotide polymorphisms (SNPs) T455C and C482T in APOC3 are associated with fatty liver disease, insulin resistance, and possibly hypertriglyceridemia. 95 healthy Asian Indian men and 163 healthy non-Asian Indian men around New Haven, Connecticut were genotyped for polymorphisms in those SNPs. 20% homogeneous wild both loci. Carriers of T-455C, C-482T, or both (not additive) had a 30% increase in fasting plasma apolipoprotein C3, 60% increase in fasting plasma triglyceride and retinal fatty acid ester, and 46% reduction in plasma triglyceride clearance. Prevalence of non-alcoholic fatty liver disease was 38% in carriers, 0% wild (normal). Subjects with fatty liver disease had marked insulin resistance.
NAFLD is considered to cover a spectrum of disease activity. This spectrum begins as fatty accumulation in the liver (hepatic steatosis). A liver can remain fatty without disturbing liver function, but by varying mechanisms and possible insults to the liver may also progress to become NASH, a state in which steatosis is combined with inflammation and fibrosis. NASH is a progressive disease: over a 10 year period, up to 20% of patients with NASH will develop cirrhosis of the liver, and 10% will suffer death related to liver disease. Cigarette smoking is not associated with an increased risk of developing NASH.
The exact cause of NAFLD is still unknown. However, both obesity and insulin resistance probably play a strong role in the disease process. The exact reasons and mechanisms by which the disease progresses from one stage to the next are not known.
One debated mechanism proposes a "second hit", or further injury, enough to cause change that leads from hepatic steatosis to hepatic inflammation. Oxidative stress, hormonal imbalances, and mitochondrial abnormalities are potential causes for this "second hit" phenomenon.
Common findings are elevated liver enzymes and a liver ultrasound showing steatosis. An ultrasound may also be used to exclude gallstone problems (cholelithiasis). A liver biopsy (tissue examination) is the only test widely accepted as definitively distinguishing NASH from other forms of liver disease and can be used to assess the severity of the inflammation and resultant fibrosis.
Non-invasive diagnostic tests have been developed, such as FibroTest, that estimates liver fibrosis, and SteatoTest, that estimates steatosis, however their use has not been widely adopted. Apoptosis has been indicated as a potential mechanism of hepatocyte injury as caspase-cleaved cytokeratin 18 (M30-Apoptosense ELISA) in serum/plasma is often elevated in patients with NASH; however, as the role of oncotic necrosis has yet to be examined it is unknown to what degree apoptosis acts as the predominant form of injury.
Other diagnostic tests are available. Relevant blood tests include erythrocyte sedimentation rate, glucose, albumin, and renal function. Because the liver is important for making proteins used in coagulation some coagulation related studies are often carried out especially the INR (international normalized ratio). Blood tests (serology) are usually used to rule out viral hepatitis (hepatitis A, B, C and herpes viruses like EBV or CMV), rubella, and autoimmune related diseases. Hypothyroidism is more prevalent in NASH patients which would be detected by determining the TSH.
It has been suggested that in cases involving overweight patients whose blood tests do not improve on losing weight and exercising that a further search of other underlying causes be undertaken. This would also apply to those with fatty liver who are very young or not overweight or insulin-resistant. In addition those whose physical appearance indicates the possibility of a congenital syndrome, have a family history of liver disease, have abnormalities in other organs, and those that present with moderate to advanced fibrosis or cirrhosis.
A large number of treatments for NAFLD have been studied. While many appear to improve biochemical markers such as alanine transaminase levels, most have not been shown to reverse histological abnormalities or reduce clinical endpoints:
- Treatment of nutrition and excessive body weight:
- Nutritional counseling: Diet changes have shown significant histological improvement. Specifically, avoiding food containing High-fructose corn syrup and trans-fats is recommended.
- Weight loss: gradual weight loss may improve the process in obese patients; rapid loss may worsen NAFLD. Specifically, walking or some form of aerobic exercise at least 30–45 minutes daily is recommended. The negative effects of rapid weight loss are controversial: the results of a meta-analysis showed that the risk of progression is very low.
- A recent meta-analysis presented at the Annual Meeting of American Association for Study of Liver Diseases (AASLD) reported that weight-loss surgery leads to improvement and or resolution of NASH in around 80% of patients.
- Insulin sensitisers (metformin and thiazolidinediones) have shown efficacy in some studies.
- ursodeoxycholic acid and lipid-lowering drugs, have little benefit.
- Vitamin E: Vitamin E can improve some symptoms of NASH and was superior to insulin sensitizer in one large study. In the Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial, for patients with NASH but without diabetes mellitus, the use of very high dosages of vitamin E (800 IU/day) for four years was associated with a significantly higher rate of improvement than placebo (43% vs. 19%) in the primary outcome. The primary outcome was an improvement in certain histological features as measured by biopsy—but it did not improve fibrosis. Pioglitazone, an insulin sensitizer, improved some features of NASH but not the primary outcome, and resulted in a significant weight gain (mean 4.7 kilograms) which persisted after pioglitazone was discontinued.
- Statin: Improvements in liver biochemistry and histology in patients with NAFLD through treatment with statins have been observed in numerous cases, although these studies were carried out on a relatively small sample of patients. Statins have also been recommended for use in treating dyslipidemia for patients with NAFLD.
- Modest wine drinking: In a study using the NHANES III dataset, it has been shown that mild alcohol consumption (one glass of wine a day) reduces the risk of NAFLD by half.
The prevalence of non-alcoholic fatty liver disease ranges from 9 to 36.9% of the population in different parts of the world. Approximately 20% of the United States population suffers from non-alcoholic fatty liver, and the prevalence of this condition is increasing. The prevalence of non-alcoholic fatty liver disease is higher in Hispanics, which can be attributed to high rates of obesity and type 2 diabetes in Hispanic populations. Non-alcoholic fatty liver disease is also more common among men than women in all age groups until age 60, where the prevalence between sex equalize. This is due to the protective nature of estrogen.
In children 
Pediatric Nonalcoholic Fatty Liver Disease (NAFLD) was first reported in 1983. It is currently the primary form of liver disease among children. NAFLD has been associated with the metabolic syndrome, which is a cluster of risk factors that contribute to the development of cardiovascular disease and type 2 diabetes mellitus. Studies have demonstrated that abdominal obesity and insulin-resistance in particular are thought to be key contributors to the development of NAFLD. Because obesity is becoming an increasingly common problem worldwide, the prevalence of NAFLD has been increasing concurrently. Moreover, boys are more likely to be diagnosed with NAFLD than girls with a ratio of 2:1. Studies have suggested that progression toward a more advance stage of disease among children is dependent on age and presence of obesity. This finding is consistent with previous studies in adults demonstrating the same association between age and obesity, and liver fibrosis. Early diagnosis of NAFLD in children may help prevent the development of liver disease during adulthood. This is challenging as most children with NAFLD are asymptomatic with few showing abdominal pain. Currently, liver biopsy is considered the gold standard for diagnosing NAFLD. However, this method is invasive, costly and bears greater risk for children, and noninvasive screening and diagnosing methods would have significant public health implications for children with NAFLD. The only treatment shown to be truly effective in childhood NAFLD is weight loss.
See also 
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