Evidence‐based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020

Nonalcoholic fatty liver disease (NAFLD) has become a serious public health issue not only in Western countries but also in Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease that often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma (HCC). While a definite diagnosis of NASH requires liver biopsy to confirm the presence of hepatocyte ballooning, hepatic fibrosis is the most important prognostic factor in NAFLD. With so many NAFLD patients, it is essential to have an effective screening method for NAFLD with hepatic fibrosis. As HCC with non‐viral liver disease has increased markedly in Japan, effective screening and surveillance of HCC are also urgently needed. The most common death etiology in NAFLD patients is cardiovascular disease event. Gastroenterologists must, therefore, pay close attention to CVD when examining NAFLD patients. In the updated guidelines, we propose screening and follow‐up methods for hepatic fibrosis, HCC, and CVD in NAFLD patients. Several drug trials are ongoing for NAFLD/NASH therapy, however, there is currently no specific drug therapy for NAFLD/NASH. In addition to vitamin E and thiazolidinedione derivatives, recent trials have focused on sodium glucose co‐transporter 2 (SGLT2) inhibitors and glucagon‐like peptide‐1 (GLP‐1) analogues, and effective therapies are expected to be developed. These practical guidelines for NAFLD/NASH were established by the Japanese Society of Gastroenterology in conjunction with the Japan Society of Hepatology. Clinical evidence reported internationally between 1983 and October 2018 was collected, and each clinical and background question was evaluated using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. This English summary pro‐ vides the core essentials of these clinical practice guidelines, which include the definition and concept, screening systems for hepatic fibrosis, HCC and CVD, and current therapies for NAFLD/NASH in Japan.


INTRODUCTION
Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent cause of chronic liver disease worldwide 1 and is now the fastest-growing indication for liver transplantation among waitlist registrants. 2 There are more than 20 million NAFLD patients in Japan, and it is feared that this number will increase in the future. 3 In recent years, hepatocellular carcinoma (HCC) based on non-viral liver disease has increased, and the need for a screening method has become urgent.
The Japanese NAFLD/NASH guidelines were established in 2014. 4 These clinical guidelines have received considerable attention and been widely used. However, new knowledge has since been reported relating to their concepts, diagnostic imaging methods, and treatment methods. Therefore, a joint committee of the Japanese Society of Gastroenterology and the Japanese Society of Hepatology has reviewed and revised these guidelines.
The current guidelines summarize reports from 1983 to the end of October 2018, focusing on the following: (1) concept and clinical significance of liver fibrosis, (2) screening and follow-up systems for liver fibrosis, (3) surveillance of HCC, (4) a system for consultation with specialists regarding cardiovascular risk in NAFLD, and (5) new therapeutics. We hope that these guidelines will be used widely in clinical practice, and also hope to discuss and improve any problems that may arise in the clinical field so that further revisions may be made as necessary.

THE CONCEPT AND DEFINITION OF NAFLD
In the 2014 guidelines, 4 NAFLD was characterized by evidence of hepatic steatosis by either imaging or histology and the appropriate exclusion of other liver diseases. NAFLD is histologically characterized by macrovesicular steatosis and further categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). In the revised guidelines, the concept and diagnosis of NAFLD are essentially the same (Table 1). NAFLD is characterized by evidence of hepatic steatosis as determined by either imaging or histology, associated with any metabolic factor. Other liver diseases, such as alcoholic liver disease, viral liver disease, and drug-induced liver disorder, are excluded.
The European Association for the Study of the Liver (EASL) defines NAFLD as being characterized by ''excessive hepatic fat accumulation associated with insulin resistance (IR)''. 5 In Japan, 60%-70% of NAFLD cases are complicated with diabetes mellitus or IR, while others may be complicated with obesity, hypertension, or dys lipidemia without IR. 6,7 Therefore, we defined NAFLD as "hepatic steatosis associated with any metabolic factor." Another issue is NAFL progression. McPherson et al. 8 report that of 27 NAFL patients, 12 (44%) had progressed to NASH at the second biopsy. NAFL and NASH are not completely different diseases; there is a certain amount of overlap. Therefore, we specifically state in the guidelines that "NAFL and NASH are not completely different diseases. Some NAFL patients show slow progression of hepatic fibrosis." In addition, the American Association for the Study of Liver Diseases 9 and EASL management guidelines 5 state that hepatic steatosis induced by drugs should be excluded from NAFLD. We, therefore, specify that "hepatic steatosis induced by drugs is treated as a drug-induced liver disorder, not as NAFLD." After the publication of the 2014 guidelines, many cohort studies demonstrated that hepatic fibrosis, but no other histological features of NAFLD, was associated independently with long-term overall mortality, liver transplantation, and liver-related events in NAFLD patients. [10][11][12] Therefore, we added the following statement to the revised guidelines: "the most important factor in the prognosis is hepatic fibrosis, and follow-up and treatment methods should be selected depending on the degree of hepatic fibrosis." We also added new clinical questions (CQs).

CQ. Which histological factor is most important in assessing survival?
� The stage of hepatic fibrosis is strongly associated with both total and liver-related mortalities. It is important to evaluate the grade of hepatic fibrosis in NAFLD patients. (Evidence Level A, Strength 1) 1014 -TOKUSHIGE ET AL.

FLOWCHART FOR THE FOLLOW-UP AND SCREENING OF HEPATIC FIBROSIS, HCC, AND CARDIOVASCULAR DISEASE
There is currently no overall flowchart for the screening and followup of hepatic fibrosis, HCC, or cardiovascular disease (CVD). As noted, the most important factor in the prognosis is hepatic fibrosis.
We, therefore, propose that the first step on the flowchart be a Following Castera et al. 13 we propose a screening method for NAFLD with hepatic fibrosis by a general physician (Figure 1). At the first screening for NAFLD, physicians are recommended to measure serum hepatic fibrosis markers, such as hyaluronic acid, Type IV collagen 7S, Mac-binding protein glycosylation isomer, and to use a fibrosis scoring system such as the FIB-4 index, NFS, or platelet count. If any data indicate liver fibrosis, consultation with a gastroenterology specialist should be considered. Screening for HCC should be considered in patients with LC or advanced fibrosis. In the revised guidelines, we have added new CQs regarding HCC follow-up and screening in NAFLD/NASH patients.

CQ. How should NAFLD/NASH patients be followed up?
� Depending on the grade of hepatic fibrosis, it is important to follow-up not only liver-related events, but also CVD and extrahepatic malignancies. (Evidence Level A, Strength 1)

CQ. How should NAFLD/NASH patients be screened for HCC?
� HCC screening should be performed depending on the stage of hepatic fibrosis and risk factors for HCC. However, the best screening method in terms of cost and manpower remains to be determined. (Evidence Level C, Strength 2) In terms of HCC risk factors, old age, male, advanced fibrosis, diabetes, and moderate alcohol intake have been reported to be risk factors for NAFLD-HCC. [15][16][17] CVD, the most common death etiology in NAFLD patients, is another issue. Francque et al. 18 reported the screening method for CVD in NAFLD patients. It is important to note that NASH and NAFLD T A B L E 1 New definition and concept of NAFLD NAFLD is characterized by evidence of hepatic steatosis as determined by either imaging or histology, associated with metabolic factors. Other liver diseases, such as alcoholic liver disease, viral liver disease, and drug-induced liver disorder are excluded. NAFLD is categorized into NAFL and NASH. NAFL is a mostly benign, nonprogressive clinical entity, while NASH can progress to cirrhosis or even hepatocellular carcinoma 1. Fat deposition in the liver is histologically significant at 5% or more 2. NASH is histologically characterized by hepatic steatosis associated with evidence of liver cell injury (ballooning degeneration) and inflammation 3. NAFL and NASH are not completely different diseases. Some NAFL patients show slow progression of hepatic fibrosis 4. The upper limit of alcohol drinking is 30 g/day in males and 20 g/day in females 5. Hepatic steatosis induced by drugs is treated as a drug-induced liver disorder 6. Reye's syndrome and acute fatty liver of pregnancy, which show microvesicular steatosis, are excluded from NAFLD 7. In NASH cirrhosis, certain histological characteristics of NASH, such as hepatic steatosis and ballooning degeneration, are sometimes lost and this is known as "burned-out NASH" Note: The most important factor in the prognosis is hepatic fibrosis, and follow-up and treatment methods should be selected depending on the degree of hepatic fibrosis.

PATHOGENESIS AND GENOMIC BACKGROUND
Given the important role of IR and oxidative stress in the pathophysiology of NAFLD/NASH, [29][30][31] several studies have attempted to investigate their effects.
The I148M variant of patatin-like phospholipase domaincontaining 3 (PNPLA3) is widely known to be associated with the occurrence and progression of NAFLD/NASH worldwide. [32][33][34] The mechanism remains unknown, however, it has been suggested that the 148M variant disrupts ubiquitylation and proteasomal degradation of PNPLA3, resulting in an accumulation of PNPLA3-148M and impaired mobilization of triglycerides from lipid droplets (LDs). [35][36][37] There is known to be a significant association between HCC and the 148M variant. 38,39 TM6SF2, GCKR, GATAD2A and DYSF have been reported as genomic background candidates. [39][40][41][42][43] In addition, there has been a recent focus on the relationship between NAFLD and gut dysbiosis. 44,45 Henao-Mejia et al. 46 found that inflammasome-mediated dysbiosis regulates the progression of NAFLD and obesity, however, a more detailed analysis using human samples is needed. Sarcopenia has also been examined. 47

DIAGNOSIS AND IMAGING
The diagnosis of NAFLD is described as part of the concept and definition of NAFLD (Table 1). "Nonalcoholic" is defined as an upper limit of alcohol drinking of 30 g/day in males and 20 g/day in females.
NASH is diagnosed from liver biopsy on the basis of the presence of steatohepatitis, however, liver biopsy has several drawbacks. It is an expensive and invasive procedure and there is potential for sampling error and variability in interpretation by pathologists. 48 Figure 4 is a flowchart of therapy for NAFLD patients. It is similar to that in the previous guidelines. 4 NAFLD is usually associated with metabolic disturbance such as visceral obesity, IR, type 2 diabetes mellitus, or dyslipidemia, and these underlying conditions play a crucial role in its pathogenesis. Therefore, it makes sense to treat not only the liver disease itself but also these associated metabolic morbidities, and it is likewise essential to prevent stimulation or pathogenesis of these diseases, so-called "2nd hits," in the management of NAFLD/NASH. 61 Treatments for these associated conditions

PHARMACOLOGICAL TREATMENTS
Vitamin E and pioglitazone have been shown to improve liver function and liver histological findings. [73][74][75][76] However, their safety over the long-term remains to be evaluated.

CQ. Is vitamin E effective for patients with NAFLD/NASH?
�  Nevertheless, the trials for NAFLD/NASH had several problems.
First, even in placebo groups, about 20% of patients improved due to lifestyle improvements. Second, to confirm improvement of liver fibrosis, which associated with prognosis, an observation period of 5 years or more is necessary. In addition, histological evaluation differs among pathologists. It is also problematic that NAFLD is a syndrome, and therefore, includes many pathogeneses. The effects of drugs are, therefore, not always constant. Finally, the prevalence 1020 -TOKUSHIGE ET AL.
HEPATOLOGY RESEARCH of the PNPLA3 variant, which is a risk factor of progression of NASH, is different among races. It is expected that these problems will be resolved, and that new drugs will be approved for NASH therapy.
Elucidating the pathogenesis of NAFLD/NASH and developing therapies are now worldwide issues, and it is important that Japanese medical studies of NAFLD/NASH advance. For that purpose, these guidelines were prepared by searching for relevant evidence worldwide without regard to ethnic characteristics, and the obtained evidence was then summarized from a Japanese perspective. Of course, ethnic differences correlate with susceptibility to metabolic syndrome-related diseases including NAFLD/ NASH, 109

APPENDIX
The members of the Guidelines Committee who created and evaluated the Japanese Society of Gastroenterology ''Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/ nonalcoholic steatohepatitis 2020″ are listed below.