Non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease
Micrograph of non-alcoholic fatty liver disease, demonstrating marked steatosis (fatty liver appears white). Trichrome stain
Specialty Gastroenterology

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.[1] NAFLD is the most common liver disorder in developed countries.[2]

NAFLD is related to insulin resistance and the metabolic syndrome; as of 2017 a combination of improved diet and exercise appeared to be the most efficient way to manage NAFLD and reduce insulin resistance.[3] It may respond to treatments originally developed for other insulin-resistant states (e.g. diabetes mellitus type 2) such as metformin, and thiazolidinediones.[4] Up to 80% of obese people have the disease and up to 20% normal-weight people might develop it.[5] It is estimated that 24% of the worldwide population is affected in 2017.[5] While largely unknown in the 2000s,[6] NASH and NAFLD are the leading cause of chronic liver disease as of 2017.[5]

About 12 to 25% of people in the United States have NAFLD,[7] while NASH affects between 2 and 12% of people in the United States.[8][9][7] The annual economic burden was estimated at US$103 billion in the USA in 2016.[5]

The prevalence of NAFLD/NASH is expected to increase to the point of becoming the leading cause of liver transplantation by 2020.[10]

Official guidelines are provided since 2016 by a few institutions such as the American Association for the Study of Liver Diseases (AASLD), the United Kingdom's National Institute for Health and Care Excellence (NICE) and the European Association for the Study of the Liver (EASL).[4][11][12][13]

Signs and symptoms

NAFLD can cause liver dysfunction related symptoms. NAFLD can be incidentally diagnosed following abnormal liver function tests during routine blood tests or after a hepatic steatosis is detected by biopsy. Indeed, in cases of symptoms or signs attributable to liver disease or when tests show abnormal liver chemistries, NAFLD should be suspected and investigated. However, when no symptoms or signs attributable to liver disease are reported or when the tests show normal liver chemistries, but a hepatic steatosis is detected, other metabolic risk factors (e.g., obesity, diabetes mellitus, dyslipidemia) and alternate causes such as alcohol should be investigated.[11]

Patients may complain of fatigue, malaise, and dull right-upper-quadrant abdominal discomfort. Mild jaundice may be noticed, although this is rare.

People with NAFLD are likely to be asymptomatic.[4]

The AASLD define NAFLD as: evidence of hepatic steatosis, and absence of another factor that could explain the fat accumulation in the liver, such as alcohol (over 21 g/week for men and 14 g/week for women), drug-induced steatosis, heredity or by deficiencies in parenteral nutrition such as choline.[11] The NICE and EASL consider excessive alcohol use (over 30g for men and 20g for women), drug-induced steatosis, hepatitis C and endocrine conditions as alternative causes of fatty liver unrelated to NAFLD.[4][12]

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.[1][5][14][15]

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.[5]

Although controversial, NAFLD was observed to be 2 times more prevalent in men than women.[11]

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).[5]

Although NAFLD has a genetic component, the AASLD does not recommend screening family members as there is not enough confirmation of heritability,[11] although there is some evidence from familial aggregation and twin studies.[5]

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).

According to EASL, NAFLD can include either a steatosis alone ; a steatosis concurrent with lobular or portal inflammation without ballooning ; or a steatosis with ballooning but without inflammation. In NASH, other histological features can appear but are not necessary for diagnosis, such as portal inflammation, polymorphonuclear infiltrates, Mallory-Denk bodies, apoptotic bodies, clear vacuolated nuclei, microvacuolar steatosis, megamitochondria and perisinusoidal fibrosis.[12]

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

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. However, since most people affected by NAFLD are likely to be asymptomatic, liver biopsy represent a too high risk for routine diagnosis, so that other methods might be preferred, such as liver ultrasonography. Routine liver function blood tests are not sensitive enough to detect NAFLD. For children and young people, liver ultrasonography is advised.[11][4] Biopsy is also the only procedure that can reliably differenciate NAFLD from NASH.[12]

Common findings are elevated liver enzymes and a liver ultrasound showing steatosis. An ultrasound may also be used to exclude gallstone problems (cholelithiasis). 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.[1][5][4] The EASL recommend screening for a steatosis whenever a NAFLD is suspected as this is a key predictor of the disease evolution and predicts future diabetes type II, cardiovascular events and hypertension.[12]

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.[16]

Some biomarker-based blood tests have been developed but as of 2011 their use had not been widely adopted.[17]

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 (FIB-4), or liver stiffness (as 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.[11]

The EASL recommend to assess dietary and physical activities, as unhealthy lifestyles influence the development and progression of NAFLD. The FLIP algorithm is recommended by the EASL to grade the ballooning, and the use of the NAFLD Activity Score (NAS) to grade the severity of NASH rather than for its diagnosis. They also consider the steatosis, activity and fibrosis (SAF) score to be an accurate and reproducible scoring system.[12]

The cardiovascular system screening is considered mandatory by the EASL, as NAFLD outcomes often result in cardiovascular complications.[12]

Monitoring

To monitor the evolution of NAFLD, the NICE advise to offer regular NAFLD screening for advanced liver fibrosis every three years to adults and every two years for children using the enhanced liver fibrosis (ELF) blood test.[4] According to EASL, follow-up is mandatory in obesity and insulin-resistant people by using the homeostasis model assessment of insulin resistance (HOMA-IR). NASH patients with a fibrosis and hypertension should have a closer monitoring as there is a higher risk of disease progression.[12]

Management

Lifestyle modification

A combination of improved diet and exercise appears to be the most efficient way to manage NAFLD and reduce insulin resistance.[11][12][3][18] Motivational support, such as with cognitive-behavioral therapy, is helpful, as most people with NAFLD do not perceive their condition as a disease, and thus have a low motivation to change.[11][4][12][19][1]

Diet

Treatment of NAFLD typically involves counseling to improve nutrition.[20][1] People with NAFLD might benefit from a moderate to low-carbohydrate diet and low-fat diet.[21][1] The Mediterranean diet also showed promising results in a 6-weeks scheme in reduction of NASH induced inflammation and fibrosis, independently from weight loss.[12][1][19][22][23]

The EASL recommend energy restriction of 500-1000 kcal/week less than the daily diet, a target of 7-10% weight loss for obese/overweight NAFLD, a low to moderate fat and moderate to high carbohydrate diet or a low carbohydrate ketogenic or high protein diet such as the Mediterranean diet and avoiding all fructose-containing beverages and food.[12] Indeed, there is some evidence that a high intake of fructose increases the proportion of fat in the liver, so food or beverages high in fructose, sucrose or high fructose corn syrup should be avoided.[19]

The NICE guidelines include recommendations for Vitamin E, although it is not useful for all people with NAFLD.[4][1] The NICE does not recommend omega-3 fatty acid supplementation since randomized trials were inconclusive,[1][4] 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.[24][19] 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 ».[11]

Coffee and tea appear to have beneficial effects, although more studies are needed.[12][25][23] For the EASL, there is no liver-related limitations to the consumption of coffee.[12]

Alcohol is an aggravating factor and should be avoided by people with NAFLD or NASH.[11][4][1][26] The EASL allow alcohol consumption below 30g/day for men and 20g/day for women.[27]

Physical activity

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.[4] Although physical activity is less important for weight loss than dietary adaptations (to reduce calories intake),[19] the NICE advises physical activity to reduce liver fat even if there is no weight reduction.[4][1] 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.[19] Exercise alone can prevent or reduce hepatic steatosis, but it remains unknown whether it can improve all other aspects of the liver, hence a combined approach with exercise and diet is advised.[11][3] Aerobic exercise may be more effective than resistance training, although there are contradictory results.[1][28] 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.[1][29]

The EASL recommend between 150 to 200 min/week in 3 to 5 sessions of moderate intensity aerobic physical activity or resistance training. Since both effectively reduce liver fat, the choice of activity should be tailored to fit the individual's preferences with the goal of maintaining in the long-term: « Any engagement in physical activity or increase over previous levels is however better than continuing inactivity ».[12]

Medication

AASLD, NICE and EASL 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.[11][4][12]

No medicines specifically for NAFLD or NASH 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.,[30]

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.[1][31] 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.[11] 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.[4]

According to AASLD and NICE, Vitamin E is an effective treatment that can be administered in patients with biopsy-proven NASH.[11][4][1]

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 and EASL. However, even if statins can be used with patients with NASH cirrhosis, they should be avoided in case of decompensated cirrhosis.[11][12][32] 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.[31] According to NICE guidelines, statins can be continued to be consumed unless liver enzyme levels double within 3 months of starting statins.[4]

Surgical intervention

According to EASL, bariatric surgery is an effective method for obese and diabetic individuals with NAFLD to induce weight loss and reduce or resolve NASH inflammation, including fibrosis.[12][19][1] For the AASLD, bariatric surgery can be considered only for NASH on a case-by-case basis by an experienced bariatric surgery program.[11]

For NASH patients with an end-stage liver disease, liver failure or liver cancer, liver transplantation is an accepted procedure according to the EASL. The overall survival is comparable to transplantation following other diseases.[12]

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.[33][5] Fibrosis in humans with NASH progressed more rapidly than in humans with NAFLD.[1] An international study showed that NAFLD patients had a 10‐year survival rate of 81.5%.[11]

NAFLD is a risk factor for fibrosis, 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.[4][34][35]

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,[36] 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.[37] NAFL and NASH were found to develop into cirrhosis in respectively 2-3% and 15-20% of the patients over a 10–20 years time period.[1]

NAFLD is also thought to be a precursor of the metabolic syndrome, although a bidirectional influence is not excluded.[38][39]

The presence and stage of fibrosis was found to be the strongest prognostic factor for liver-related events and mortality, in particular for NAFLD.[5][40]

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.[41][19][42]

Epidemiology

The percentage of people with non-alcoholic fatty liver disease ranges from 9 to 36.9% in different parts of the world.[43][44] Approximately 20% of the United States population have non-alcoholic fatty liver.[45] Similar prevalence can be found in Europe and Asia-Pacific countries although less data is available.[5] 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.[46]

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.[5][47] It is the most common chronic liver disease in children and teenagers just as for adults.[5]

NAFLD was observed to be 2 times more prevalent in men than women.[11]

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.[5][48][19]

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.[5]

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.[49][50]

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.[49]

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.[49]

Children

Pediatric nonalcoholic fatty liver disease (NAFLD) was first reported in 1983.[51] It is the primary form of liver disease among children since at least 2007.[5][52] 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.[53][54][55][56][57]

Boys are more likely to be diagnosed with NAFLD than girls.[46] Overweight, or even weight gain, in childhood and adolescence is 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.[5]

Early diagnosis of NAFLD in children may help prevent the development of liver disease during adulthood.[55][58] This is challenging as most children with NAFLD are asymptomatic with few showing abdominal pain.[58] Liver biopsies for diagnosis in children should be done when the diagnosis is unclear or before starting a potentially hepatotoxic medical therapy according to AASLD.[11] The EASL suggest using fibrosis tests such as elastometry, acoustic radiation force impulse imaging and serum biomarkers in order to reduce the number of biopsies.[12] In followup, children should be offered a regular NAFLD screening for advanced liver fibrosis every two years using the enhanced liver fibrosis (ELF) blood test according to NICE.[4]

The only treatment shown to be truly effective in childhood NAFLD is weight loss.[59]

Intensive lifestyle modifications, including physical activity and dietary changes, should be the first line of treatment according to AASLD and EASL as it improves the liver histology and aminotransferases levels. In terms of pharmacological treatment, metformin should be avoided but Vitamin E may improve liver health for some children.[11][12] The NICE advises the use of Vitamin E for children with advanced liver fibrosis, whether they have diabetes or not.[4]

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.[60]

As of 2015 magnetic resonance elastography, which was found to have excellent accuracy to detect of fibrosis in NAFLD regardless of BMI and inflammation.[61]

Management

As of 2016, clinical trials were underway for pentoxifylline, obeticholic acid, GFT505, exenatide, liraglutide, metreleptin, and others.[1] The use of prebiotics and probiotics to correct the gut microbiota balance is also being investigated.[62]

Alternative day modified fasting has shown a significant effect on weight loss and insulin sensitivity, and is thus suggested as potential treatment to investigate.[23]

See also

References

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Classification
External resources
  • NIH page on Nonalcoholic Steatohepatitis
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