Seong Hee Kang, Hye Won Lee, Jeong-Ju Yoo ,Yuri Cho, and Seung Up Kim equally contributed to this work as co-first authors.
The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing rapidly worldwide as the obese and diabetic populations increase, and it has been estimated to be 20–30% in Korea. Considering the increased popularity of a westernized diet and lifestyle, lack of exercise, and the resulting increase in obesity and diabetes, NAFLD is predicted to become more prevalent in the future and to become a major cause of chronic liver disease. In some patients, NAFLD progresses to end-stage liver diseases such as cirrhosis and hepatocellular carcinoma (HCC), and it is an independent cardiovascular risk factor.
In 2013, the Korean Association for the Study of the Liver (KASL) enacted a clinical practice guideline for the diagnosis and treatment of NAFLD to improve understanding of the disease and provide useful clinical information and direction for healthcare providers. The research results that have accumulated since then necessitate a revision. Accordingly, the clinical practice guidelines committee began revising the guidelines to reflect the results of Korean and international research and develop new recommendations based on a systematic approach that reflects evidencebased medicine and expert opinions. However, evidence remains insufficient, and many studies are currently being conducted. As medical evidence and new findings accumulate in the future, these guidelines will require ongoing supplementation and revision.
Patients diagnosed with NAFLD based on clinical, biochemical, radiological, or pathological findings in the absence of significant alcohol consumption and liver diseases such as viral hepatitis were the primary research population involved in the development of these guidelines. These guidelines are also based on data from pediatric and adolescent NAFLD patients, whose unique findings distinguish them from adult NAFLD patients.
The aim of these guidelines is to provide useful clinical information and direction to healthcare providers involved in the diagnosis and treatment of NAFLD patients. Moreover, these guidelines are intended to provide definite and practical information to resident physicians, practitioners, and trainers.
The Clinical Practice Guideline Committee for the Management of NAFLD (Committee) was organized in accordance with proposals by the approval of the KASL Board of Executives and consists of 16 gastroenterologists, one pathologist, one radiologist, and two pediatricians specializing in hepatology. All expenses were paid by KASL. Each committee member collected and analyzed the source data in his or her own field, and the members then wrote the manuscript together.
The committee systematically collected and reviewed the international and domestic literature published in PubMed, MEDLINE, KoreaMed, and other databases. The literature was limited to research papers published in the English and Korean languages. The keywords used were ‘nonalcoholic fatty liver disease,’ ‘nonalcoholic fatty liver,’ ‘nonalcoholic steatohepatitis,’ ‘fatty liver,’ ‘hepatic steatosis,’ and ‘steatohepatitis.’ In addition, keywords related to specific clinical questions were included.
The literature gathered for data collection was analyzed in a systematic review, and the quality of evidence was classified based on the modified Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system (
The strength of each recommendation was suggested according to the GRADE system. In addition to the level of evidence, the results of studies were considered based on aspects of clinical multipliers and socio-economic factors, such as cost. Grading of the recommendations was performed as follows: 1, strong recommendation or 2, weak recommendation. A strong recommendation indicated, for example, that the interventions could be applied in most patients with strong certainty, there was a greater possibility of desirable effects, and there was high-quality evidence, as well as presumed patient-important outcomes, cost-effectiveness, preference, and compliance. A weak recommendation indicated a suggestion made with less certainty but that could be considered favorable for many patients. Alternative interventions could be chosen for “weak recommendations”, according to cost and the preferences of the patients or medical practitioners.
These Clinical Practice Guidelines for the Management of NAFLD have been developed through the reviews of medical experts to be used practically for treatment, research, and education. These recommendations are not absolute standards for treatment, and adoption of these guidelines in clinical practice can differ for individual patients.
The committee considered the following clinical questions as key components to be covered in the guidelines.
1. What are the definition and categories?
2. What are the incidence rate and prevalence rate?
3. How does NAFLD progress?
4. What causes NAFLD-related deaths?
5. What are the risk factors of NAFLD?
6. What are NAFLD’s comorbidities?
7. Who should be targeted for NAFLD screening, and how is screening conducted?
8. Which non-invasive surrogates are available to diagnose hepatic steatosis?
9. Which non-invasive surrogates are available to diagnose NASH?
10. Which non-invasive surrogates are available to assess liver fibrosis?
11. Which differential tests are available for advanced fibrosis?
12. What are the indications for liver biopsy?
13. What are the histopathological features of NAFLD?
14. Is surveillance for HCC necessary?
15. How can HCC be prevented?
16. Who should be treated, and what is the aim of the treatment?
17. What do lifestyle modifications include?
18. What is the effect of moderate or less alcohol consumption?
19. What are the types, indications, effects, and side effects of medications for NAFLD?
20. What are the indications for and post-operative management of bariatric surgery?
21. What are the indications for liver transplantation (LT) and post-LT management?
Regarding NAFLD in children and adolescents:
1. What is the prevalence rate?
2. How does NAFLD progress?
3. What genetic diseases are associated with risk factors?
4. Is related NAFLD related to family history and genetic predisposition?
5. Who should be targeted for NAFLD screening, and how is screening conducted?
6. What are the diagnostic methods?
7. Who should be treated, and how?
The manuscripts written by the committee members were reviewed and approved through meetings of the committee. The quality of the manuscripts was evaluated based on the integrity of the contents and the standards of Appraisal of Guidelines for Research and Evaluation II (AGREE II). The guidelines were also reviewed at a meeting of an external review board consisting of 11 specialists in the field of hepatology and at a symposium open to all KASL members, and they were then further modified prior to publication. The final manuscript was endorsed by the Board of Executives of KASL.
The Korean version of the KASL Clinical Practice Guideline for the Management of NAFLD was released at Liver Week 2021 (May 15, 2021), and published in the
NAFLD is a condition characterized by finding fat infiltration of the liver on radiological exams or biopsy without significant alcohol intake, viral hepatitis, medication intake that would cause a fatty liver, or other obvious cause. NAFLD is defined as a disease with findings suitable for clinical, biochemical, imaging, and pathological examinations. NAFLD is a generic term that encompasses the spectrum of nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), and NASH cirrhosis (
The term NAFLD was introduced by Schaffner in 1986 [
In 2007, researchers published results from tracking 5,237 men for more than 4 years and reported for the first time that the annual incidence of NAFLD was 74.1 cases per 1,000 persons [
The prevalence of NAFLD varies depending on the study population, definition of NAFLD, and diagnostic modality. In 2002, the prevalence among 1,074 people receiving health checkups and diagnosed by abdominal ultrasound was 48.6% [
The prevalence diagnosed using the fatty liver index (FLI) was 12.6–16.1% [
People with normal body weight (body mass index [BMI; kg/m2] of less than 23 kg/m2 for Asians, less than 25 kg/m2 for Westerners) or non-obese weight (BMI of less than 25 kg/m2 for Asians, less than 30 kg/m2 for Westerners) can also be diagnosed with NAFLD, but data on the incidence rate among those people in Korea are limited. In 2004, the prevalence of NAFLD was 16.1% among 460 people with a BMI between 18.5 kg/m2 and 25 kg/m2 who received domestic health checkups [
1. The annual incidence of NAFLD in Korea is about 45 cases per 1,000 persons.
2. The prevalence of NAFLD in Korea is approximately 30%.
3. The prevalence of nonalcoholic fatty liver disease in the domestic non-obese population is about 19%.
Because the natural course of NAFLD can only be confirmed through repeated liver biopsy, it has been reported only in small studies. The incidence of NASH was reported to vary from 8.5% to 64.0% over a 3.0–6.6 years follow-up period, a large variation that appears to result from differences in the number of patients, various follow-up periods, and diagnostic criteria [
In a meta-analysis comparing NAFL and NASH, the percentage of patients who progressed to more than one stage of liver fibrosis were similar at 39.1% and 34.5%, respectively, but the time it took those patients to progress more than one stage was 14.3 years and 7.1 years, respectively. NASH thus showed faster progression [
In a cohort study of NASH patients, the incidence of cirrhosis varied by race and region, with an average of 21–26% of patients progressing to cirrhosis in eight years [
Recently, HCC caused by NAFLD has rapidly increased, becoming the third most common cause of HCC development in United States, and that number is expected to increase by 9% per year [
According to data from the U.S. National Vital Statistics System, the mortality rate of NAFLD has increased in the past decade [
1. Liver fibrosis can progress faster in NASH than in NAFL.
2. The incidence of liver cirrhosis and HCC associated with NAFLD is increasing, and HCC can develop even in the absence of liver cirrhosis.
3. The main causes of death among patients with NAFLD are CVD, malignant tumors, and liver diseases, and liver diseaserelated mortality increases when steatohepatitis and liver fibrosis are present.
NAFLD is closely related to obesity, diabetes, dyslipidemia, and metabolic syndrome (
In the presence of hypothyroidism, the prevalence of NAFLD increases by 1.6 times [
Decreased physical activity and sarcopenia increase the risk of NAFLD [
Genetic factors play a major role in the occurrence of NAFLD. Typically, the patatin-like phospholipase domain-containing 3 (
1. Major risk factors for NAFLD include obesity, diabetes, dyslipidemia, and metabolic syndrome.
NAFLD is closely related to systemic metabolic diseases [
In a retrospective cohort study of 1,804 patients with NAFLD in Denmark in the 2000s, the mortality rate from CVD was higher than that in the normal control group [
T2DM and NAFLD influence each other [
Metabolic syndrome is a major risk factor for the occurrence of NAFLD and is a common comorbid disease. A prospective Korean cohort study of 46,874 men reported that patients with mild and moderate NAFLD (diagnosed by abdominal ultrasound) had a risk of metabolic syndrome 1.5 and 2 times higher, respectively, than the control group [
CKD and NAFLD share risk factors such as T2DM and hypertension [
Arrhythmia, osteoporosis, colon adenoma, colon cancer, and breast cancer all have increased incidence in patients with NAFLD [
1. NAFLD is often associated with comorbidities such as cardiovascular disease, T2DM, metabolic syndrome, CKD, and malignant tumors.
Screening for NAFLD should be considered in cases of persistent liver enzyme elevation. Because the cost effectiveness of screening in diabetic patients has been confirmed [
The primary screening test for NAFLD is ultrasonography. When NAFLD is suspected in the ultrasonography results, other tests (computed tomography [CT], magnetic resonance imaging [MRI], serologic tests, transient elastography, etc.) can be performed.
1. Subjects who have persistent liver enzyme elevation or diabetes should be screened for NAFLD. (A1)
2. Subjects with metabolic syndrome (which is closely associated with insulin resistance, obesity, and other risk factors for NAFLD) can be considered for screening. (B1)
3. Abdominal ultrasonography is the primary screening modality. (B1)
Because the prognosis of NAFLD differs significantly depending on the histological findings, the diagnosis of hepatic steatosis and fibrosis and assessment of their severity are clinically crucial. To date, liver biopsy is the gold standard in assessing hepatic necroinflammation, steatosis, and fibrosis. However, liver biopsy is expensive, invasive, carries a risk of complications, is subject to intra-/inter-observer interpretational variability, and can suffer from sampling errors when an insufficient amount of liver tissue is collected [
Abdominal ultrasonography is the first-line imaging modality for screening asymptomatic patients with abnormal liver enzyme levels. However, it suffers from subjective interpretation, examination difficulties in obese patients, and low sensitivity when the amount of hepatic steatosis is less than 30%. Moreover, ultrasonography cannot distinguish NASH from NAFL [
Controlled attenuation parameter (CAP) is a feature of transient elastography that can quantify the degree of fat deposition in the liver parenchyma by measuring ultrasound attenuation [
Hepatic steatosis is associated with low attenuation on CT scans, which can be used for the quantitative assessment of hepatic steatosis. Because the attenuation of enhanced CT is affected mainly by the amount of blood flow, unenhanced CT is favored for the measurement of hepatic steatosis, and the attenuation of liver and spleen parenchyma are frequently compared. For moderate to severe steatosis, the specificity of CT was reported to be high, but its sensitivity and positive predictive value were low [
MRI is superior to ultrasonography for measuring a small amount of fat in the liver, and it is the most precise imaging tool for evaluating NAFLD. Quantitative MRI measurements of hepatic fat deposition using the Dixon technique can be classified into MRS and MRI proton density fat fraction (MRI-PDFF) [
In addition to radiological examinations, various panels of serological tests have been proposed to diagnose hepatic steatosis and assess its severity (
The FLI was proposed by Bedogni et al. [
The NAFLD liver fat score (NLFS) was proposed by Kotronen et al. [
The HSI was proposed by Lee et al. [
The noninvasive surrogates just described show acceptable accuracy in most cross-section studies and have been used to trace changes in hepatic steatosis in certain studies. However, the usefulness of those noninvasive surrogates in monitoring disease progression and evaluating treatment response should be further investigated.
1. Abdominal ultrasonography, CAP, unenhanced CT, MRS, and MRI-PDFF are acceptable modalities for diagnosing hepatic steatosis. (A1)
2. If radiological examinations are infeasible, panels for hepatic steatosis can be used to assess hepatic steatosis. (B1)
NASH is significantly associated with liver fibrosis progression and HCC. Non-invasive modalities to diagnose NASH are limited, but a prediction model based on liver stiffness, CAP (assessed using transient elastography), and ALT levels was recently proposed by a Korean study [
Recently, multiparametric MR indices, which score the results from various MRI techniques, have been under investigation. A recent Korean study found that a multiparametric MRI index using MRE, MRS, and T1 mapping to differentiate NASH from NAFL showed sensitivity of 80%, specificity of 85.2%, and an AUC of 0.883 [
1. Non-invasive diagnosis of NASH remains limited, so it should be diagnosed by liver biopsy. (A1)
The assessment of liver fibrosis is crucial in patients with NAFLD because the degree of liver fibrosis is significantly associated with long-term outcomes such as the development of HCC and liver-related death [
Ultrasound-based measurement techniques for liver fibrosis take advantage of shear wave elastography (SWE). They can be divided into two categories: 1) measuring the elasticity of the liver parenchyma using SWE without acquiring imaging data (transient elastography) and 2) image-based sonoelastography that acquires both elasticity and 2D image data (point SWE and 2D SWE). Transient elastography is widely used in clinical practice, and many researchers have reported its high performance in quantifying liver fibrosis in NAFLD patients. In a recent meta-analysis, transient elastography showed high sensitivity and specificity for evaluating the degree of liver fibrosis in NAFLD patients [
MRE shows high diagnostic accuracy for liver fibrosis [
In addition to radiological examinations, various panels of serological tests have been proposed to diagnose liver fibrosis (
Of the noninvasive panels for liver fibrosis, the NFS has been studied the most. The NFS was proposed in a US study by Angulo et al. [
The fibrosis-4 index (FIB-4) was proposed by Sterling et al. in a study comprising 832 subjects with human immunodeficiency virus/hepatitis C virus co-infection. FIB-4 is calculated using the platelet count, age, AST, and ALT. The AUC of FIB-4 for advanced liver fibrosis was 0.765. When the FIB-4 is less than 1.30, advanced liver fibrosis can be excluded (accuracy, 90%), and when FIB-4 is more than 2.67, advanced liver fibrosis can be diagnosed (accuracy, 80%) [
The enhanced liver fibrosis (ELF) panel has recently been used to assess liver fibrosis in Europe. ELF was proposed by Guha et al. [
Other serological surrogates for liver fibrosis, such as M2BPGi and AsAGP, have been proposed [
1. Radiological examinations such as transient elastography, point SWE, 2D SWE, and MRE are helpful in assessing hepatic fibrosis. (A1)
2. If radiological examinations are infeasible, panels such as NFS or FIB-4 can be used to diagnose liver fibrosis. (B1)
In NAFLD, liver fibrosis testing uses serologic tests, image tests, or liver biopsy. Because liver biopsy cannot be performed in all patients, an algorithm can be used to differentiate advanced fibrosis (
When subjects are classified as intermediate risk by transient elastography, FIB-4, or the NFS, additional tests such as M2BPGi, AsAGP, ELF, SWE, or MRE can be performed. If the algorithms suggest advanced fibrosis, additional tests to re-evaluate the liver fibrosis or a liver biopsy should be considered.
1. Non-invasive methods such as transient elastography, FIB-4, and NFS are prioritized to discriminate advanced liver fibrosis. (A1)
2. Serological tests, imaging tests, and liver biopsies may be performed as additional liver fibrosis evaluations. (B1)
Non-invasive tests to replace liver biopsy have been developed and shown high accuracy [
Liver biopsy has several limitations. First, sampling error is a concern because only a small portion of the liver tissue is sampled during liver biopsy. Second, intra- and inter-observer variability occurs [
1. Liver biopsy should be considered in patients suspected of having NASH or advanced liver fibrosis. (B1)
2. Liver biopsy should be considered when the presence or severity of coexisting chronic liver disease cannot be excluded. (B1)
The role of liver biopsy in NAFLD diagnosis lies in differentiating simple steatosis (NAFL) from NASH, evaluating the extent of fibrosis (stage), and excluding the possibility of other liver diseases. NAFL is defined as the presence of ≥5% steatotic hepatocytes without evidence of hepatocellular injury in the form of hepatocyte ballooning [
Because the incidence of liver cirrhosis and HCC associated with NAFLD is increasing rapidly, the risk of HCC should be assessed and surveillance should be established in all NAFLD patients. Because the incidence of HCC in patients with NAFLD-related cirrhosis is more than 1.5% per year [
Although the incidence of HCC in patients with NAFLD was 10 times higher than that in the normal control group [
Abdominal ultrasound is the primary surveillance test for HCC. However, in overweight or obese patients, it can be difficult to perform accurately [
Smoking is associated with liver fibrosis and is known to be a risk factor for the development of HCC. In meta-analyses and cohort studies, smoking increased the risk of developing HCC by 1.5 and 1.8 times, respectively [
In a 32-year cohort study, diabetes increased the incidence of HCC by 4.6 times [
Dyslipidemia is associated with NASH and CVD, but the relationship with liver disease-related mortality or HCC is still lacking. In a meta-analysis, statin use reduced the risk of developing HCC by 37% [
Obesity is associated with both liver fibrosis and HCC [
1. Patients with liver cirrhosis associated with NAFLD need HCC surveillance. (A1)
2. To reduce the development of HCC in patients with NAFLD, smoking cessation, alcohol abstinence, and weight loss are recommended. (B1)
NAFLD is commonly associated with metabolic diseases such as obesity, diabetes, and insulin resistance. Given that NAFLD is associated with increased mortality from CVD and liver-related complications [
The most important histologic marker indicating long-term prognosis is the severity of fibrosis [
1. Patients with NAFLD need lifestyle modifications and treatment for comorbidities. (A1)
2. Patients with NASH or hepatic fibrosis need management or treatment for histologic improvement. (A1)
Among overweight or obese (BMI >25.0 kg/m2) NAFLD patients, weight loss through lifestyle changes significantly reduced their liver fat content as revealed by imaging [
In NAFLD patients with obesity, the rate of weight loss affects steatohepatitis. A study showed that weight reduction that targeted a gradual decrease (maximum of 1 kg/week of body weight) improved both NASH and NAS [
Reducing the intake of total energy and controlling food intake are crucial aspects of NAFLD treatment. In prospective, randomized, controlled studies, reductions in energy intake caused weight loss, decreased intrahepatic fat content, decreased liver enzyme levels, and decreased insulin resistance [
Recently, the association between the ratio of macronutrients (carbohydrates, fats, and proteins) and the development of obesity and NAFLD has been studied. Carbohydrate intake was associated with metabolic syndrome and the severity of intrahepatic inflammation [
The Mediterranean diet pattern emphasizes vegetables, fruits, whole grains, and legumes, and the principal source of dietary lipids is olive oil. It also includes the moderate consumption of fish and shellfish, white meat, eggs, and dairy products, with red meat and processed meats eaten rarely and in small quantities [
Dietary control along with weight loss can help reduce hepatic fat content. However, studies of specific nutrients and dietary habits have been conducted on only small numbers of patients, and few have shown histologic improvement to hepatic inflammation or fibrosis. It is difficult to maintain adherence to appropriate dietary habits in the long run. Therefore, it is necessary to study an appropriate diet to which patients can maintain adherence for a long time that produces histological improvement. In addition, dietary effects can vary depending on genetic predisposition [
NAFLD is associated with a low level of physical activity. In large-scale Korean cohort studies, prolonged sitting time and decreased physical activity were positively associated with the prevalence of NAFLD regardless of BMI [
It is unclear which exercise is most effective. Some randomized controlled studies comparing aerobic exercise and resistance exercise have shown that aerobic exercise more effectively reduces liver fat content than resistance exercise [
1. In overweight or obese NAFLD patients, weight loss of more than 5–7% results in decreased intrahepatic fat content, and weight loss of more than 7–10% is required to improve hepatic inflammation and fibrosis. (A1)
2. To reduce intrahepatic fat content, a reduction in the total energy intake of more than 500 kcal/day is required. (A1)
3. To reduce intrahepatic fat content, at least moderate-intensity exercise for more than 30 minutes more than 3 times per week is required. (B1)
The effects of moderate or less alcohol consumption should be considered because NAFLD, by definition, includes patients whose alcohol consumption is insignificant. However, alcohol consumption is not easy to distribute randomly, so the effects of alcohol consumption on NAFLD can be evaluated only through longitudinal observational studies. Significant alcohol consumption (male ≥210 g/week, female ≥140 g/week) can cause alcohol-related liver disease and should be avoided. However, the effects of light or moderate drinking vary. In some studies, light or moderate drinking (male <210 g/week, female <140 g/week) appears to be protective against fatty liver and hepatic fibrosis [
1. Moderate or less alcohol use in NAFLD patients requires attention. (B1)
Pioglitazone, a PPAR-γ agonist, reduces insulin resistance in the liver, muscle, and adipose tissue, and also reduces the amount of fat in the liver and hepatocellular injury by alleviating hepatic mitochondrial oxidative dysfunction [
However, weight gain [
Metformin, a commonly prescribed drug for T2DM, was expected to be beneficial in treating NASH patients, as it reduces insulin resistance in the liver and muscles. Moreover, metformin inhibits hepatic fat accumulation and glucose excretion by activating adenosine monophosphate-activated protein kinase, and also decreases the expression of tumor necrosis factor-α [
Liraglutide, a synthetic long-acting GLP-1 receptor agonist, has been approved to treat diabetes mellitus and obesity. In a small phase 2 clinical trial of 52 patients with biopsy-proven NASH, patients receiving subcutaneous injections of liraglutide (1.8 mg/day for 48 weeks) achieved greater weight loss and resolution of NASH than those receiving placebo [
In a phase 2 trial of semaglutide, a GLP-1 analogue, 320 patients with NASH were randomized to receive daily subcutaneous semaglutide (0.1 mg, 0.2 mg, or 0.4 mg) or placebo for 72 weeks. The proportions of patients who experienced NASH resolution without the exacerbation of hepatic fibrosis were 40%, 36%, and 59%, respectively, in the treatment groups and 17% in the placebo group (
1. Pioglitazone is effective in improving steatohepatitis in NASH confirmed by liver biopsy, regardless of diabetes mellitus, but safety concerns about long-term treatment should be considered. (B1)
2. Metformin can be used as a first-line treatment for diabetes mellitus in patients with concomitant NAFLD who also have diabetes mellitus. (B1)
Vitamin E decreases oxidative stress (which worsens NASH) and improves liver inflammation [
However, the long-term use of vitamin E also carries safety concerns because of the increased risk of prostate cancer or hemorrhagic stroke [
1. High-dose vitamin E (800 IU/day) can improve NASH confirmed by liver biopsy in non-diabetic patients, but safety should be considered for long-term administration. (B1)
CVD is the most common cause of death for NAFLD patients, so it is important to modify its risk factors [
1. Because the incidence and mortality rate of CVD in NAFLD are high, it is necessary to actively control the risk factors of CVD. (A1)
2. In the case of dyslipidemia in NAFLD, a statin can be used to prevent CVD. (B1)
3. Omega-3 fatty acids are not recommended as a treatment for NASH, but they can be used in NAFLD with hypertriglyceridemia. (B1)
The pathophysiology of NASH is complicated, and its interactions with other metabolic diseases have not been fully elucidated. Therefore, NASH treatments are currently under development for a wide range of targets. The main targets are changes in intestinal microflora and intestinal permeability, oxidative stress, insulin resistance, apoptosis, lipotoxicity, inflammation, bile acid metabolism, and liver fibrosis. At the time of this writing, six new drugs are in phase 3 clinical trials or have published intermediate results (
Bariatric surgery has been performed in NASH patients with obesity who did not respond to medical treatment for weight loss. In Western countries, bariatric surgery is considered to be indicated for patients with a BMI greater than 35 kg/m2 that is accompanied by hypertension or diabetes mellitus or a BMI greater than 40 kg/m2 [
In a 5-year follow-up study of biopsy-confirmed NASH patients who underwent bariatric surgery, BMI, the amount of fat in the liver, and NAS were all found to be reduced, and histological improvement in the fibrosis stage was noted after surgery [
1. Bariatric surgery can be considered for NASH patients with obesity who do not respond to medical treatment and lifestyle modification. (B1)
2. The effectiveness and safety of bariatric surgery have not been established in patients with cirrhosis. (B1)
LT can be considered in patients with end-stage liver disease caused by NAFLD-associated cirrhosis, liver failure, or HCC, according to the clinical practice guideline for LT. NASH patients experience a high risk of mortality from cardiovascular complications, so a meticulous pretransplant cardiovascular evaluation is needed [
Posttransplant management is similar to that for other NASH patients. Maintaining a healthy weight and diet is important, especially given that weight gain is common following LT [
1. Liver transplantation could be considered in NASH patients with end-stage liver disease or HCC, according to the clinical practice guideline for LT. (A1)
The National Health and Nutrition Survey conducted between 2015 and 2017 defined cases with ALT of 26 IU/L (boys) and 22 IU/L (girls) as NAFLD, and the estimated prevalence of this disease in children was 11.2% (14.7% for boys and 7.4% for girls) [
1. The prevalence of NAFLD among children and adolescents in Korea is increasing as their obesity rate increases.
The natural course and prognosis of NAFLD in children and adolescents are not well known. Unlike NAFL, NASH can progress to cirrhosis in children and adolescents [
1. NASH in children and adolescents can progress to end-stage liver disease, including cirrhosis, in young adults.
The risk factors for NAFLD in children and adolescents are obesity, adolescent age, and being male [
Unlike in adults, in children and adolescents, steatosis sometimes appears as a phenotype of genetic disease. Therefore, through medical history, examination, and testing, Wilson’s disease, Bardet-Biedl syndrome, polycystic ovary syndrome, Prader-Willi syndrome, Turner syndrome, Cohen syndrome, alpha1-antitrypsin deficiency, glycogen storage disease, genetic tyrosinemia type 1, homocystinuria, Refsum disease, citrullinemia, and lysosomal acid lipase deficiency should be differentiated [
1. Obesity, adolescent age, and being male are risk factors for nonalcoholic fatty liver disease in children and adolescents.
2. If steatosis is found in children and adolescents, potential accompanying genetic diseases should be considered.
Children and adolescents with a family history of NAFLD are at high risk of developing it. In children and adolescents diagnosed with NAFLD, 59% of their siblings and 78% of their parents also had NAFLD. On the other hand, in obese children and adolescent patients without NAFLD, NAFLD was found in only 17% of their siblings and 37% of their parents [
In a genome-wide association study, an increase in liver fat mass was associated with mutations in the
1. Children and adolescents are at increased risk of NAFLD if there is a family history of it.
2. NAFLD in children and adolescents can be associated with genetic variations and genetic polymorphism.
NAFLD is common in children and adolescents who are overweight (above the 85th percentile and below the 95th percentile of BMI) or obese (above the 95th percentile of BMI). Therefore, screening is necessary for those groups. Overweight and obesity are checked during school health checkups in the 4th and 6th grades of elementary school, the 1st grade of middle school, and the 1st grade of high school in Korea. In overweight young people, screening tests are performed using liver enzyme levels [
ALT is used as a screening method for NAFLD in overweight and obese children and adolescents. In 2007, the US Expert Committee also recommended AST and ALT as screening tests [
1. NAFLD screening tests can be performed in overweight and obese children and adolescents. (B1)
2. The preferred screening test for NAFLD in children and adolescents is ALT, and abdominal ultrasound can also be performed. (B1)
The standard test for diagnosing NAFLD is liver biopsy. However, because that method is invasive, its application to children and adolescents is limited. The pathologic findings of NAFLD in children and adolescents can differ from those found in adults. Representative differences are that steatosis is more widely observed, balloon degeneration of hepatocytes and hepatic lobular inflammation are milder, and inflammation and fibrosis of the portal region are often present. Sinusoid fibrosis in zone 3, which is commonly observed in adults, is relatively rare in NAFLD in children and adolescents.
As a non-invasive method for diagnosing NAFLD, a method using cytokeratin-18, which is produced during hepatocyte death, can be used [
1. In addition to liver biopsy, non-invasive tests such as abdominal ultrasound, liver fibrosis scans, and MRI-PDFF can be performed. (B1)
Overweight and obese children and adolescents with NAFLD are subject to treatment, and these patients are recommended to correct their lifestyle habits first. There are insufficient studies on the long-term prognosis of NAFLD in children and adolescents, and few prospective randomized controlled studies have been done. However, when the disease is diagnosed at an early age, the possibility of long-term complications is high.
Most of children and adolescents with NAFLD are associated with obesity, so it is important to correct lifestyle habits to improve obesity. Various studies have been conducted on the correction of lifestyle habits. Based on randomized controlled studies, the North American Society of Pediatric Gastrointestinal Nutrition recommended in 2017 that simple sugar-added beverages be restricted, moderate physical activity be increased, and screen time (time exposed to the screens of electronic devices such as TVs, computers, and smartphones) be reduced to less than 2 hours per day [
According to the TONIC trial, a large multicenter randomized controlled study comparing vitamin E, metformin, and placebo in NAFLD patients aged 8–17 years, the three groups did not differ in terms of a sustained decrease in ALT. In the vitamin E group, histological improvement was observed. However, long-term use of high-dose vitamin E is not recommended because of concerns about side effects [
Although there is no guideline for surgical treatment of NAFLD, it can be performed in cases of severe obesity (BMI 97th percentile or higher) based on the results of research in adults [
1. In NAFLD in children and adolescents who are overweight or obese, lifestyle correction such as improvement of dietary habits, increase in physical activity, and restriction of screen time is needed first. (A1)
This study was supported by the Korean Association for the Study of the Liver (KASL).
This manuscript was reviewed by native speakers for English proof readings (Eworld Editing; KASL2104-01).
Study conception and design: Seong Hee Kang, Hye Won Lee, Jeong-Ju Yoo, Yuri Cho Seung Up Kim and Yong Kyun Cho; Report writing: Seong Hee Kang, Hye Won Lee, Jeong-Ju Yoo, Yuri Cho Seung Up Kim, Tae Hee Lee, Byoung Kuk Jang, Sang Gyune Kim, Sang Bong Ahn, Haeryoung Kim, Dae Won Jun, Joon-Il Choi, Do Seon Song, Won Kim, Soung Won Jeong, Moon Young Kim, Hong Koh, Sujin Jeong, Jin-Woo Lee and Yong Kyun Cho; Review: Seong Hee Kang, Hye Won Lee, Jeong-Ju Yoo, Yuri Cho Seung Up Kim and Yong Kyun Cho; Final approval of the submission of the manuscript: Seong Hee Kang, Hye Won Lee, Jeong-Ju Yoo, Yuri Cho Seung Up Kim, Tae Hee Lee, Byoung Kuk Jang, Sang Gyune Kim, Sang Bong Ahn, Haeryoung Kim, Dae Won Jun, Joon-Il Choi, Do Seon Song, Won Kim, Soung Won Jeong, Moon Young Kim, Hong Koh, Sujin Jeong, Jin-Woo Lee and Yong Kyun Cho.
Yong Kyun Cho is a speaker for Samil Pharm, Bukwang and DaeWoong. He has received a research grant from DaeWoong, Dong-A, Celltrion and Ildong.
Seung Up Kim has served as an advisory committee member of Gilead Sciences, Bayer, Eisai, Novo Nordisk, and GreenCross. He is a speaker for Gilead Sciences, GSK, Bayer, Eisai, Abbvie, EchoSens, MSD, Eisai, Otsuka, Bristol-Myers Squibb, Yuhan, Samil Pharm, Ildong, Celltrion, PharmaKING, DaeWoong, Samjin, DongA, Hanmi, BuKwang, Echme medical, Hanwha, Sysmax, and ChongKunDang. He has also received a research grant from Abbvie, Bristol-Myers Squibb, ChongKunDang, DaeWoong, Hanmi, Samil Pharm, and Echme Medical.
Jeong-Ju Yoo is a speaker for DaeWoong, Ildong, Pharmaking, Dong-A, BMS, Samil Pharm and Bukwang.
Tae Hee Lee is a speaker for Abbvie, Gilead, Samil Pharm and Yuhan. He has received a research grant from Eisai, Celltrion, PharmaKING and GC Wellbeing.
Byoung Kuk Jang is a speaker for Gilead. He has received a research grant from PharmaKING, Novo Nordisk Pharma, Vaccitech and GC Wellbeing.
Sang Gyune Kim has received grants from GE healthcare, Samsung Medison, BMS, Samil, Ildong; received honoraria from BMS, MSD, Gilead, Daewoog, Hanwha; consulted Samsung Medison.
Sang Bong Ahn has received grants from Hanwha, Samjin, Ildong, and Hanmi.
Dae Won Jun has served as an advisory committee member of Sysmax, J2H, and Future medicine. He is a speaker for Gilead Sciences, Bristol-Myers Squibb, Yuhan, Chong Kun Dang, Ildong, Donga, Samil, Phamaking, Celltrion, and Daewoong. He has also received a research grant from Yuhan.
Joon-Il Choi previously received grants from Bayer Healthcare, Guerbet Korea, Bracco Korea and Samsung Medison. He previously received honorariums from Bayer Healthcare, Guerbet Korea and Bracco Korea.
Won Kim has served as an advisory committee member of Boehringer-Ingelheim, HK inno.N, GreenCross, Standigm, Pharmaking, KOBIOLABS, Eisai, Zydus and Novonordisk. He is a speaker for Gilead, Boehringer-Ingelheim, Samil, Il-dong, LG chemistry and Bukwang. He has also received a research grant from Gilead, Il-dong, GreenCross, Bukwang, Roche, Galmed, Novartis, Pfizer, Springbank, Altimmune, MSD, BMS, Novonordisk, Hitachi Aloka, JW medical, Dicerna and Enyo.
Soung Won Jeong is a speaker for Daewoong, Samil and Pharmaking. He has received a research grant from Dong-A ST, Ildong and Chongkundang.
Moon Young Kim is a speaker for Samjin and Gilead. He has received a research grant from Yuhan.
Jin-Woo Lee has served as an advisory committee member of Abbvie and Novo Nordisk. He has received a research grant from Galectin Therapeutics Inc, BMS, MSD and Ipsen.
The other authors declare that they have no competing interests.
Appraisal of Guidelines for Research and Evaluation II
alanine aminotransferase
aspartate aminotransferase
area under the receiver operating characteristic curve
body mass index
controlled attenuation parameter
chronic kidney disease
computed tomography
cardiovascular disease
enhanced liver fibrosis
fibrosis-4 index
fatty liver index
glucagon-like peptide-1
Grading of Recommendations
GREek Atorvastatin and Coronary-heart-disease Evaluation
hepatocellular carcinoma
hepatic steatosis index
the Korean Association for the Study of the Liver
low density lipoprotein cholesterol
liver transplantation
metabolic (dysfunction)-associated fatty liver disease
metabolic equivalents of task
magnetic resonance elastography
MRI proton density fat fraction
magnetic resonance imaging
MR spectroscopy
nonalcoholic fatty liver
nonalcoholic fatty liver disease
NAFLD activity score
nonalcoholic steatohepatitis
NAFLD fibrosis score
NAFLD liver fat score
Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis
the patatin-like phospholipase domain–containing 3
peroxisome proliferator activated receptor gamma
sorting and assembly machinery component 50
shear wave elastography
type 2 diabetes mellitus
transmembrane 6 superfamily
Risk factors for nonalcoholic fatty liver disease.
Algorithm to differentiate advanced fibrosis. TE, transient elastography; FIB-4, fibrosis-4 index; NFS, nonalcoholic fatty liver disease fibrosis score.
The grading of recommendations, assessment, development, and evaluation (GRADE) system
Criteria | ||
---|---|---|
Quality of evidence | ||
High quality | Further research is very unlikely to change our confidence in the estimate of the effect. | A |
Moderate quality | Further research is likely to have an important impact on our confidence in the estimate of the effect and may change the estimate. | B |
Low quality | Further research is very likely to have an important impact on our confidence in the estimate of the effect and is likely to change the estimate. Any change of estimate is uncertain. | C |
Strength of recommendation | ||
Strong | Factors influencing the strength of the recommendation include the quality of the evidence, presumed patient-important outcomes, and cost. | 1 |
Weak | Variability in preference and values or greater uncertainty. The recommendation is made with less certainty, higher cost or resource consumption. | 2 |
Definition of nonalcoholic fatty liver disease-related terms
Term | Definition |
---|---|
NAFLD | NAFLD is a generic term encompassing a spectrum of liver disorders, including nonalcoholic fatty liver, NASH, and NASH cirrhosis. Fat accumulation of more than 5% of the liver’s weight in a biopsy is defined as fat infiltration. |
NAFL (simple steatosis) | This condition is characterized by fat infiltration of the liver without findings of ballooning degeneration or fibrosis. |
NASH | This condition is characterized by fat infiltration of the liver along with findings of inflammation associated with ballooning degeneration. It is occasionally associated with fibrosis. |
NASH cirrhosis | This condition is characterized by cirrhosis associated with NAFL or NASH, or cirrhosis occurring in patients with NAFL or NASH as proven by past histology. |
NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NAFL, nonalcoholic fatty liver.
Panels for hepatic steatosis
Panels | Equations | Cutoff | Diagnostic tools (cohort) | Validated in Korean population |
---|---|---|---|---|
Fatty liver index (FLI) [ |
= (e 0.953×loge (triglycerides) + 0.139*BMI + 0.718×loge (GGT) + 0.053×waist circumference - 15.745) / (1 + e 0.953×loge (triglycerides) + 0.139×BMI + 0.718×loge (GGT) + 0.053×waist circumference - 15.745) × 100 | ≥60, <30 | Ultrasonography (Italy) | Yes |
NAFLD liver fat score (NLFS) [ |
= -2.89 + 1.18 × metabolic syndrome (yes = 1/no = 0) + 0.45 × diabetes (yes = 2/no = 0) + 0.15 × (fasting insulin, μU/L) + 0.04 × AST + 0.94 × AST/ALT ratio | >-0.64 | MRS (Finland) | Yes |
Hepatic steatosis index (HSI) [ |
= 8 × ALT/AST + BMI (+2, if diabetes; +2, if female) | ≥36, <30 | Ultrasonography (Korea) | Yes |
BMI, body mass index; GGT, gamma-glutamyl transpeptidase; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
Panels for liver fibrosis
Panels | Equations | Cutoff | Diagnostic tools (cohort) | Validated in Korean population |
---|---|---|---|---|
NAFLD fibrosis score (NFS) | = -1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × impaired fasting glucose or diabetes (yes=1, no=0) + 0.99 × AST/ALT ratio - 0.013 × platelet count (×109/L) - 0.66 × serum albumin (g/dL) | <-1.455, >0.676 | Liver biopsy | Yes |
Fibrosis-4 index (FIB-4) [ |
= Age (years) × AST [U/L] / (platelets [109/L] × (ALT [U/L])1/2 | <1.3, >2.67 | Liver biopsy | Yes |
Enhanced liver fibrosis (ELF) [ |
Patented (hyaluronic acid, tissue inhibitor of metalloproteinase 1, amino terminal peptide of procollagen III as constituent variables) | 0.3576 | Liver biopsy | Yes |
NAFLD, nonalcoholic fatty liver disease; BMI, body mass index; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
Examples of moderate and vigorous physical activity
Moderate-intensity physical activity | Vigorous-intensity physical activity |
---|---|
(3–6 METs) | (>6 METs) |
Brisk walking | Running |
Dancing | Walking/climbing briskly up a hill |
Slow cycling | Fast cycling |
Gardening | Aerobics |
Recreational swimming | Fast swimming |
Active involvement in games and sports with children | Competitive sports and games (e.g., football, volleyball, basketball) |
General building tasks (e.g., roofing, painting) | Digging or shoveling |
Carrying/moving objects of less than 20 kg | Carrying/moving objects of more than 20 kg |
Walking domestic animals |
METs, metabolic equivalents of task.
NASH treatment drugs in phase 3 clinical trials
Drug | Clinical trial | Chemical type | Therapeutic target |
---|---|---|---|
Obeticholic acid | REGENERATE REVERSE | Synthetic bile acid derivative | Farnesoid X receptor |
Selonsertib | STELLAR-3, 4 (discontinued development) | Antifibrotic agents | Apoptosis signal-regulating kinase 1 |
Elafibranor | RESOLVE-IT (discontinued development) | PPAR agonist | PPAR-α/δ |
Cenicriviroc | AURORA | Chemokine receptor antagonist | CCR2, 5 |
Resmetirom | MAESTRO-NASH | Hepatic thyroid hormone receptor β-selective agonist | THRβ |
Aramchol | ARMOR | Synthetic fatty acid/bile acid conjugate | Stearoyl coenzyme A desaturase 1 |
PPAR, peroxisome proliferator-activated receptor; CCR, chemokine receptor; THR, thyroid hormone receptor.