Non-alcoholic fatty liver disease (NAFLD) is one of the types of fatty liver which occurs when fat is deposited (steatosis) in the liver due to causes other than excessive alcohol use. Non-alcoholic steatohepatitis (NASH) is the most extreme and fast progressing subtype of NAFLD. NAFLD is the most common liver disorder in developed countries.
NAFLD 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. Up to 80% of obese people have the disease and up to 20% normal-weight people might develop it. It is estimated that 24% of the worldwide population is affected in 2017. While largely unknown in the 2000's, NASH and NAFLD are the leading cause of chronic liver disease as of 2017. Most people have a good outcome if the condition is caught in its early stages.
About 12 to 25% of people in the United States have NAFLD, while NASH affects between 2 and 5% of people in the United States. The annual economic burden was estimated at US$103 billion in the USA in 2016.
Official guidelines are provided since 2016 by a few institutions such as the American Association for the Study of Liver Diseases (AASLD) and the United Kingdom's National Institute for Health and Care Excellence (NICE).
Video Non-alcoholic fatty liver disease
Signs and symptoms
Most people 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 of net ethanol) excludes the condition.
Maps Non-alcoholic fatty liver disease
Risk factors
NAFLD is associated with insulin resistance and metabolic syndrome (obesity, combined hyperlipidemia, diabetes mellitus (type II), and high blood pressure), as well as insulin resistance, persistently elevated transaminases, increasing age and BMI, panhypopituitarism and hypoxia caused by obstructive sleep apnea, with some of them being strong predictors of disease progression.
In particular, non-obese people affected by NAFLD ("lean NAFLD") have been found to have impaired insulin sensitivity, to be frequently sedentary, to have increased cardiovascular risk and increased liver lipid levels, being the consequence of decreased capacity for storing fat and reduced mitochondrial function in adipose tissue and increased hepatic de novo lipogenesis.
Genetics
Genetic risk factors of NAFLD are also known. 66.67% T2DM family reported more than one family member have NAFLD. In addition, Hispanic persons have higher prevalence of NAFLD than white individuals, whereas the lowest susceptibility is observed in black individuals. Two genetic mutations for this susceptibility have been identified and validated in large cohorts, the non-synonymous single-nucleotide polymorphisms (SNPs) in PNPLA3 (encoding patatin-like phospholipase domain-containing protein 3) and TM6SF2 (encoding transmembrane 6 superfamily member 2).
Polymorphisms (genetic variations) in the 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.
Although NAFLD has a genetic component, the AASLD does not recommend screening family members as there is no confirmation of heritability.
Drugs
NAFLD can also be caused by some medications (drug-induced illness):
- Amiodarone
- Antiviral drugs (nucleoside analogues)
- Aspirin rarely as part of Reye's syndrome in children
- Corticosteroids
- Methotrexate
- Tamoxifen
- Tetracycline
Pathophysiology
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, it may also progress to become non-alcoholic steatohepatitis (NASH), a state in which steatosis is combined with inflammation and fibrosis (steatohepatitis). 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.
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.
Diagnosis
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 (gold standard) as definitively distinguishing NASH from other forms of liver disease and can be used to assess the severity of the inflammation and resultant fibrosis. For children and young people, liver ultrasonography is advised.
According to NICE guidelines, it is disadvised to test enzymes levels to rule out NAFLD, as they are often within the normal range even in advanced disease.
Some biomarker-based blood tests have been developed but as of 2011 their use had not been widely adopted.
Some blood tests are useful to confirm diagnosis or rule out others. They include erythrocyte sedimentation rate, glucose, albumin, and kidney function. Because the liver is important for making proteins used in blood clotting some coagulation related studies are often carried out especially the INR (international normalized ratio). In people with fatty liver with associated inflammatory injury (steatohepatitis) blood tests are usually used to rule out viral hepatitis (hepatitis A, B, C and herpesviruses such as EBV or CMV), rubella, and autoimmune diseases. Low thyroid activity 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 is 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.
According to AASLD guidelines, liver biopsy should be considered in patients with NAFLD who are at increased risk of having steatohepatitis and/or advanced fibrosis, but only when all other competing chronic liver diseases are excluded (such as alcoholic liver disease). The presence of a metabolic syndrome, NAFLD Fibrosis Score or FIB-4, or liver stiffness measured by VCTE or MRE may be used to identify the patients who are at higher risk of steatohepatitis or advanced fibrosis. Also, NAFLD patients should be considered for screening for HCC (liver cancer) and gastroesophageal varices.
Management
Weight loss is the most effective way to decrease liver fat. Several randomized studies found that intense changes in lifestyle, including diet, exercise and cognitive-behavioral therapy, allowed to attain 7-10% of weight loss, which was associated with reduced fat liver, NASH remission and reduction of fibrosis, as lower weight loss of 3-5% body weight provide much more limited improvements. Similar results were found for NAFLD in children and teenagers. A combination of both diet and exercise appear to be the most efficient in improving NAFLD and weight loss. The motivational support, such as with cognitive-behavioral therapy, is not to be overlooked, as most NAFLD people do not perceive their condition as a disease, and thus have a low motivation to change.
Other recommendations include improving metabolic risk factors and reducing alcohol intake.
No pharmacological treatment had received approval as of 2015, although antiglycemic drugs may help in liver fat loss. While many treatments appear to improve biochemical markers such as alanine transaminase levels, most have not been shown to reverse histological abnormalities or reduce clinical endpoints.
Bariatric surgery seems to be an effective method for obese NAFLD people to provoke weight loss and reduce NASH inflammation.
Medical nutrition therapy
Treatment of NAFLD typically involves counseling to improve nutrition and consequently body weight and composition. Diet changes have shown significant histological improvement. People with NAFLD might benefit from a moderate to low-carbohydrate diet and low-fat diet, as there is evidence that high intake of fructose increases the proportion of fat in the liver. The Mediterranean diet also showed promising results in a 6-weeks scheme in reduction of NASH induced inflammation and fibrosis, independently from weight loss, which might be due to the richness in polyphenols.
The NICE guidelines do include recommandations for Vitamin E, although not all NAFLD people are receptive. The NICE does not recommend omega-3 fatty acid supplementation since randomized trials were inconclusive, although previous systematic reviews found that omega-3 fatty acid supplementation in those with NAFLD/NASH using doses approaching or higher than 1 gram daily (median dose 4 grams/day with median duration 6 months treatment) has been associated with improvements in liver fat. According to AASLD guidelines, « omega-3 fatty acids should not be used as a specific treatment of NAFLD or NASH, but they may be considered to treat hypertriglyceridemia in patients with NAFLD ».
Coffee and tea appear to have beneficial effects, although more studies are needed.
Alcohol is an aggravating factor and should be avoided by people with NAFLD or NASH.
Physical activity therapy
Weight loss may improve the process in obese patients, particularly for obese or overweight people. Similar physical activities and diets are advisable for obese and overweight people and NAFLD people if they are overweight. Although physical activity is less important for weight loss than dietary adaptations (to reduce calories intake), the NICE advises physical activity to reduce liver fat even if there is no weight reduction. Indeed, weight loss, through exercise or diet, was shown to be the most effective way to reduce liver fat and help NASH and fibrosis remission. Exercise alone can prevent or reduce hepatic steatosis, but it remains unkwnown whether it can improve all other aspects of the liver, hence a combined approach with exercise and diet is advised. Aerobic exercise may be more effective than resistance training, although there are contradictory results. Exercise and diet have been shown to reduce insulin resistance. Vigorous training is preferable to moderate training, as only high intensity exercising was shown to reduce chances of NASH developing into a steatohepatitis or advanced fibrosis.
Medication
Various medications are explored but none yet has proven efficacy for the whole population, with molecules being effective for some while not at all for others. AASLD and NICE guidelines recommend that pharmacological treatments should be primarily aimed at improving liver disease and should generally be limited to those with biopsy-proven NASH and fibrosis.
Insulin sensitizers (metformin and thiazolidinediones, such as pioglitazone) are commonly used to reduce insulin resistance in those with NAFLD, with several randomized trials showing that they can improve all histological features of NASH, lead to resolution of steatohepatitis and may improve hepatic fibrosis. However, the side-effects associated with these drugs, which include osteopenia, increased fracture risk, fluid retention, congestive heart failure and bladder cancer and long-term weight gain, have limited their adoption. Due to these side-effects, AASLD recommend the use of pioglitazone only in patients with biopsy-proven NASH. However, AASLD disadvise the use of metformin as studies were inconclusive about the improvement of the liver histological condition, although there was an improvement in insulin resistance and serum aminotransferases, as this did not translate into NASH improvements. NICE provides similar guidelines regarding pioglitazone, which should be administered in secondary care to adults with advanced liver fibrosis, whether or not they have diabetes.
According to AASLD and NICE, Vitamin E is an effective treatment that can be administered in patients with biopsy-proven NASH.
Improvements in liver biochemistry and histology in patients with NAFLD through treatment with statins. NAFLD patients are at a higher risk of cardiovascular disease, hence statins treatement is indicated. Indeed, NAFLD patients are not at higher risk for serious liver injury from statins according to AASLD. However, even if statins can be used with patients with NASH cirrhosis, they should be avoided in case of decompensated cirrhosis. Statins have also been recommended for use in treating dyslipidemia for patients with NAFLD. Treatment with pentoxifylline has demonstrated improvements in the histological appearance of fatty liver tissue under the microscope in many small trials. According to NICE guidelines, statins can be continued to be consumed unless liver enzyme levels double within 3 months of starting statins.
Surgical intervention
Weight-loss surgery such as bariatric surgery leads to improvement or remission from NASH and NAFLD.
Outcomes
The progression rate of fibrosis in humans with NASH is estimated to 7 years, compared to 14 years with NAFLD, and with a dynamically, exponentially increasing rate along as more stages are reached. Fibrosis in humans with NASH progressed more rapidly than in humans with NAFLD. The exact causes of the disease and mechanisms by which the disease progresses from one stage to the next are not fully understood, although some very recent findings provide new insights into the mechanisms.
NAFLD is a risk factor for hypertension, chronic kidney disease, atrial fibrillation, myocardial infarction, ischaemic stroke and death from cardiovascular causes based on very low to low quality evidence from observational studies.
NAFLD and NASH increase the risk of hepatocellular carcinoma (HCC). Cirrhosis and HCC induced by NAFLD are the second cause of liver transplantation in the US in 2017. Liver cancer develops in NASH in the absence of cirrhosis in 45% in the cases,, and people with NASH cirrhosis have increased risk of liver cancer. Indeed, the rate of liver cancer associated with NASH has increased fourfold between 2002 and 2012 in the USA, which is more than any other cause of liver cancer. NAFLD constitutes the third most common risk factor for liver cancer.
NAFLD is also thought to be a precursor of the metabolic syndrome, although a bidirectional influence is not excluded.
Epidemiology
The percentage of people with non-alcoholic fatty liver disease ranges from 9 to 36.9% in different parts of the world. Approximately 20% of the United States population have non-alcoholic fatty liver, and the number of people affected is increasing. This means about 75 to 100 million people in the United States are affected. Similar prevalence can be found in Europe and Asia-Pacific countries although less data is available. In children from 1-year-old to 19-years-old teenagers, prevalence was found to be approximately 8% in the general population up to 34% in studies with data from child obesity clinics.
The rates 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. It is the most common chronic liver disease in children and teenagers just as for adults.
Although the disease is commonly associated with obesity, a significant proportion are normal-weight or lean. Lean NAFLD affects between 10-20% of the Americans and European, although some countries have a higher incidence (e.g., India has a very high proportion of lean NAFLD and almost no obese NAFLD). Lean NAFLD people are at the same or higher risks, with a poorer median survival rate (free of liver transplantation) than for obese NAFLD people, according to an international cohort study including 483 patients with biopsy-diagnosed NAFLD with a mean follow-up period of over 11 years. PNPLA3 may be relevant for the progression of NAFLD in lean people. Thus, people suffering from NAFLD should be considered as a potential population for treatment regardless of obesity.
Worldwide, about 25% of the total population seems to be affected by NAFLD or NASH, according to ultrasonography or proton NMR spectroscopy, as studies based on elevated liver enzymes systematically underestimated the true prevalence.
History
Cases now understood as NAFLD were first described in the Japanese literature in the mid-1970s, followed by case reports in English. The term "nonalcoholic steatohepatitis" was first published by Jurgen Ludwig and co-authors from the Mayo Clinic in 1980, and the broader NAFLD started to be used around 2002.
The 1980 paper was mostly ignored at the time but came to be seen as a landmark paper, and starting in the mid-1990s the condition began to be intensively studied, and a series of international meetings were held on the topic starting in 1998.
Diagnostic criteria began to be worked out; in 2005 the Pathology Committee of the NIH NASH Clinical Research Network proposed a scoring system that as of 2006 had not been validated.
Children
Pediatric nonalcoholic fatty liver disease (NAFLD) was first reported in 1983. It is the primary form of liver disease among children since at least 2007. 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. 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. Overweight, or even weight gain, in childhood and adolescence was associated with an increased risk of NAFLD later in life, with adult NAFLD predicted in a 31-year follow-up study by risk factors during childhood including BMI, plasma insulin levels, male sex, genetic background (PNPLA3 and TM6SF2 variants) and low birth weight, an emerging risk factor for adulthood NAFLD.
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.
Intensive lifestyle modification should be the first line of treatment according to AASLD as it improves the liver histology and aminotransferases levels. In terms of pharmacological treatment, metformin should be avoided but Vitamin E at 800 IU/day offers histological benefits on a case by case basis.
Research
Diagnosis
Because diagnosis based on a biopsy makes it difficult to estimate epidemiology, accurate and inexpensive methods of diagnosing and monitoring NAFLD disease progression are a research priority.
As of 2015 magnetic resonance elastography, which was found to have excellent accuracy to detect of fibrosis in NAFLD regardless of BMI and inflammation.
Management
As of 2016, clinical trials were underway for pentoxifylline, obeticholic acid, GFT505, exenatide, liraglutide, metreleptin, and others. The use of prebiotics and probiotics to correct the gut microbiota balance is also being investigated.
Clinical training
A 2018 study on a medical and nursing staff observed that only a few recognized NAFLD symptoms, none knew NAFLD could be asymptomatic, and 12.5% knew that weight loss could reverse NAFLD.
Animal studies
The cafeteria diet was reported by a study to reproduce the metabolic syndrome and liver inflammation in rats.
See also
- Alcoholic liver disease
- Fatty liver (includes both non-alcoholic and alcoholic liver disease)
References
External links
- NIH page on Nonalcoholic Steatohepatitis
Source of article : Wikipedia
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