| Non-alcoholic fatty liver disease | |
|---|---|
| Classification and external resources | |
Micrograph of non-alcoholic fatty liver disease, demonstrating marked macrovesicular steatosis. Trichrome stain. |
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| ICD-10 | K76.0 |
| ICD-9 | 571.8 |
| DiseasesDB | 29786 |
| eMedicine | med/775 |
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.[1] Non-alcoholic steatohepatitis (NASH) is the most extreme form of NAFLD this being regarded as a major cause of cirrhosis of the liver of unknown cause.[2]
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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.[1]
NAFLD is associated with insulin resistance and metabolic syndrome (obesity, combined hyperlipidemia, diabetes mellitus (type II) and high blood pressure).[1][2]
NAFLD can also be caused by some medications:[1]
Common findings are elevated liver enzymes and a liver ultrasound showing steatosis. An ultrasound may also be used to exclude gallstone problems (cholelithiasis). A biopsy (tissue examination) of the liver 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.[1]
Non-invasive diagnostic tests have been developed, such as FibroTest, that estimates liver fibrosis,[3] and SteatoTest, that estimates steatosis,[4] however their use has not been widely adopted.[5] Apoptosis has been shown to be the mechanism of hepatocyte destruction and caspase-cleaved cytokeratin 18 (M30-Apoptosense ELISA) in serum/plasma is often elevated in patients with NASH.[6][7]
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, EBV, CMV and herpes viruses), rubella, and autoimmune related diseases. Hypothyroidism is more prevalent in NASH patients which would be detected by determining the TSH.[8]
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 that 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.[9]
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 outright inflammation of the liver. When inflammation occurs in this setting, the condition is then called NASH. Over time, up to 20 percent of patients with NASH may develop cirrhosis. 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.[1]
Soft drink (SD) consumption—specifically high-fructose corn syrup SD consumption—has become a major concern in public health. 80% of NAFLD patients with or without metabolic syndrome had excessive intake of SD (>500 cm3/day or >12 teaspoons/day added sugar) compared to the 17% healthy controls (P-value <0.001; Confidence Interval=95%).[10] This included Coca-Cola (both regular and diet) and fruit juices as the most common SD sources. Another study suggests that 31 g/day in SD sugar intake raises the odds ratio for NAFLD to 1.45 times with 95% confidence.[11] Metabolically, phosphorylation of fructose by fructokinase is specific and not rate-limited causing human hepatic ATP depletion.[12] Ultimately, this leads to lipogenesis, which increases NAFLD risk.
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.[13]
Pediatric Nonalcoholic Fatty Liver Disease (NAFLD) was first reported in 1983.[14] It is currently the primary form of liver disease among children.[15] 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.[16][17][18][19][20] Because obesity is becoming an increasingly common problem worldwide, the prevalence of NAFLD has been increasing concurrently.[21] Moreover, boys are more likely to be diagnosed with NAFLD than girls with a ratio of 2:1.[22][23] Studies have suggested that progression toward a more advance stage of disease among children is dependent on age and presence of obesity.[18] This finding is consistent with previous studies in adults demonstrating the same association between age and obesity, and liver fibrosis.[24][25] Early diagnosis of NAFLD in children may help prevent the development of liver disease during adulthood.[18][26] This is challenging as most children with NAFLD are asymptomatic with few showing abdominal pain.[26] Currently, liver biopsy is considered the gold standard for diagnosing NAFLD.[15] 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.[15] The only treatment shown to be truly effective in childhood NAFLD is weight loss.[27][28]
The prevalence of non-alcoholic fatty liver disease ranges from 9 to 36.9% of the population in different parts of the world.[29][30][31] Approximately 23% of the United States population suffers from non-alcoholic fatty liver, and continues to trend upward.[32] 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.[33] Non-alcoholic fatty liver disease is also more common among men than women in all ages groups until age 60, where the prevalence between sex equalize. This is due to the protective nature of estrogen.[34]
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:.[1]
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.[38]
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.[39]