Asia–Pacific Working Party on Non‐alcoholic Fatty Liver Disease guidelines 2017—Part 1: Definition, risk factors and assessment

Abstract

Since the publication of the guidelines for the assessment and management of non‑alcoholic fatty liver disease (NAFLD) by the Asia–Pacific Working Party on NAFLD in 2007,1 our understanding of the clinical characteristics and natural history of NAFLD has improved, and there have been developments in the assessment and treatment of NAFLD. It is therefore timely to update the guidelines in light of new evidence. This document presents the recommendations of the Asia–Pacific Working Party on NAFLD. The exercise was supported by the Journal of Gastroenterology and Hepatology Foundation. Members performed a systematic review of the literature on specified domains of interest, thereby allowing them to provide recommendations on different aspects of the clinical assessment and management of patients with NAFLD. The contents and statements were then discussed through face-to-face meetings and e-mail communications. The statements in this document follow the Grading of Recommendation Assessment, Development, and Evaluation approach (Table 1).2 The final grading of evidence and recommendations was determined by majority vote. These guidelines cover various aspects in the management of NAFLD, including diagnosis, screening, assessment, and treatment. While most evidence came from studies on adults identified to be at risk of metabolic disorder and after exclusion of other liver diseases, two special populations are included in this document. NAFLD in children and adolescents is becoming increasingly prevalent and may have devastating consequences owing to the long duration of fatty liver disease. In addition, chronic viral hepatitis is highly prevalent in Asia–Pacific countries, and the impact of concomitant fatty liver, a much discussed topic both for hepatitis B and C, is re-evaluated here for its long-term clinical significance and implications for patient care. A clear, reproducible definition of NAFLD is required for clinical practice and epidemiological studies because there are several causes of fatty liver and steatohepatitis, each with differing management implications and clinical outcomes. An unresolved definitional and semantic challenge is that two or more etiological factors commonly interact to influence the incidence, severity, and outcome of fatty liver. The current established “negative” definition of NAFLD requires (i) evidence of hepatic steatosis by either imaging or histology and (ii) absence of other causes of hepatic fat accumulation from conditions such as significant alcohol consumption, hepatitis C, medication use, or hereditary disorders. While it has been acknowledged that “in the majority of patients” NAFLD is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidemia, this fails to identify overnutrition (as opposed to established obesity) as pivotal, or to account for the approximately 25% of patients in Asian cohorts who have fatty liver but are not obese. However, the vast majority of such “non-obese NAFLD” patients exhibit insulin resistance. In this respect, it is also critical to note that family history of diabetes (genetic predisposition) and prediabetes as well as established diabetes are commonly associated with NAFLD. Finally, it has now been clearly demonstrated that loss of 10% of bodyweight (in overweight persons) completely reverses all elements of non-alcoholic steatohepatitis (“NASH”) pathology, including liver fibrosis. This cements the role of overnutrition in the causation of NAFLD. Review articles from Europe have tended towards a more positive definition of NAFLD, as did the original Asia–Pacific Guidelines of 2007. The recommended definition for the 11th Revision of the International Classification of Diseases is “NAFLD is characterized by fatty liver (defined as earlier) related to over-nutrition in the absence of excessive alcohol consumption.” The majority of cases of NAFLD show steatosis with no or minimal liver inflammation. The term favored by the American Association for the Study of Liver Diseases (AASLD) for this, non-alcoholic fatty liver, has not been adopted by the 11th Revision of the International Classification of Diseases as it seems ambiguous. Specifically, all NAFLD cases have fatty liver, whether steatohepatitis (NASH) is present or not. Instead, if the pathology is known, the terminology should be “NAFLD without NASH” or “simple steatosis,” “NASH,” and “with or without fibrosis or cirrhosis” for either category. Between 10% and 25% of NAFLD cases show steatohepatitis, that is, NASH. The hallmarks are conspicuous hepatocyte injury (especially ballooning and apoptosis) and substantial liver inflammation. NASH is more likely to be associated with liver fibrosis than cases showing only steatosis. Notwithstanding the likely importance of NASH in leading to fibrosis, it is the presence of fibrosis (with or without NASH) that predicts progression to cirrhosis in clinical outcome studies. Hepatocellular carcinoma (HCC) is a complication of NAFLD, but not exclusively among cases that progressed to cirrhosis (including cases of “cryptogenic cirrhosis”). Besides, it is unclear if a patient must have NASH before progressing to NAFLD-related HCC. No more than one standard drink per day (i.e. 70 g ethanol per week) for women and no more than two standard drinks per day (i.e. 140 g ethanol per week) for men have been used by the National Institutes of Health NASH clinical research network and widely adopted for clinical studies. The relevance of this standard to the populations in the Asia–Pacific region was discussed in the 2007 Guidelines. The proposed levels of alcohol intake are based on evidence about daily alcohol intake and risk of cirrhosis. The “cut-off” values have been set lower than the apparent “threshold levels” so as to avoid the issue of overlap between alcoholic liver disease and obesity, type 2 diabetes (T2DM), and metabolic syndrome in progression to cirrhosis. Patients who may be drinking at safe levels at the time of presentation with liver disease may have a past history of chronic excessive alcohol intake for a prolonged period of time and may have cirrhosis. Lifetime alcohol intake is therefore important and needs to be incorporated into history taking. Over the past three decades, changing Western lifestyles and dietary habits, in addition to relatively high rates of genetic predisposition in several community groups, have increased the prevalence of NAFLD in the Asia–Pacific region. On the basis of hepatic imaging, recent studies suggest that a quarter (95% confidence interval [CI]: 23.3–31.9%) of the general population in Asia has NAFLD, but the proportion of patients with advanced liver fibrosis diagnosed by transient elastography (TE) appears to be low (3.7% among NAFLD patients).3 Obesity, dyslipidemia, T2DM, and metabolic syndrome are established risk factors for developing NAFLD. In addition, several other risk factors for NAFLD have been identified in the Asia–Pacific region. These include hypothyroidism, polycystic ovary syndrome, obstructive sleep apnea, hypopituitarism, and hypogonadism. There may be subtle differences in the phenotype distribution of NAFLD between Asia–Pacific and Western countries. Of particular interest are more frequent “lean NAFLD” and the urban–rural differences of prevalence rates of NAFLD in Asia.4 In addition, Asian people are particularly susceptible, partly owing to body composition differences in fat and muscle and genetic susceptibility via predisposition to T2DM, PNPLA3 SNPs, and polymorphisms in apolipoprotein 3.5 On the other hand, the natural history of NAFLD and its progression to cirrhosis and HCC (when this occurs) is over several decades; the fact that NAFLD in Asian countries may be more recent than in North and South America, for example, may also influence the present distribution of disease phenotypes towards the milder end of the pathological spectrum. There are limited studies evaluating the incidence of NAFLD and the prevalence of NASH in the general population. In Japan, pooled regional NAFLD incidence rate estimates are 52.3 (95%CI: 28.1–96.8) per 1000 person-years.6 Incident NAFLD is not uncommon among Chinese people who are not obese; for instance, 8.9% of lean subjects developed NAFLD during a 5-year follow-up.6 Because the diagnosis of NASH requires a liver biopsy, the population prevalence of NASH in Asia is currently unknown. Among Asian liver biopsy series, NASH can be found in 63.5% (95%CI: 47.7–76.8). In natural history studies involving paired liver biopsies, around 25% of patients may progress from simple steatosis to NASH in 3 years.7 Non-alcoholic steatohepatitis is the most common cause of cirrhosis and HCC in patients without other known etiological causes of liver disease worldwide. Thus, 63.3% of formerly designated cryptogenic cirrhosis cases could finally be attributed to NAFLD because cryptogenic cirrhosis is more associated with metabolic syndrome than other causes of cirrhosis. A study from Japan found that 17 of 320 HCC cases (5.3%) were either associated with NASH or had unknown (“cryptogenic”) etiology.8 “Cryptogenic” HCC also accounted for 5.4% of all HCCs in Korea. syndrome and its (i.e. and are common in cryptogenic cirrhosis and HCC literature from Asia also a between NAFLD and HCC in The majority of HCC patients either did not have cirrhosis or cirrhosis was well with B and cirrhosis with other However, from long-term studies from this with of liver are required to the prevalence and incidence of HCC in NAFLD in NASH patients in general is to the importance of and factors in the prevalence of NAFLD and its liver in different of the vast Asia–Pacific region. of the prevalence of NAFLD in children and adolescents widely between studies. liver that the prevalence of NAFLD was in children to study from the prevalence was in to in the prevalence of NAFLD in children (defined as the body by and that of children and adolescents had However, the prevalence of NAFLD may be by this because liver is relatively for cases with hepatic fat is used to NAFLD The prevalence of levels was in adolescents to in the National Health and A study of children a prevalence of of for in the general population is likely to be in and in There are as a for NAFLD as the of is not well established and levels not the of NAFLD in children or The standard diagnosis of NASH on liver There were no studies to NASH prevalence by this in the Asia–Pacific region. In the used to liver steatosis. found that the prevalence of NAFLD and NASH was and among of the cause of study in children was by of NAFLD and NASH were and cirrhosis has been in children as as of A recent that the pooled prevalence estimates did not by region in the general population among children and In in clinical studies of the prevalence estimates by in the studies from Asia than studies from Europe and North It should be that used in different studies could NAFLD prevalence and insulin are risk factors for the of NAFLD (Table The of genetic and by and may the susceptibility to NAFLD. the prevalence of NAFLD with and with the the among and susceptibility to NAFLD liver can also be by factors including and the liver pathology in such cases may be from NAFLD to overnutrition and or such as excessive intake excessive fat insulin and bodyweight intake excessive fat intake also to increased of both and fatty insulin by and muscle and the of in hepatic of fatty and of the majority of liver is also increased by to increased of to fatty in the Thus, insulin with with the increased of both and fatty to excessive accumulation of in the It is widely that is the most significant risk for However, that has not to is also important of NAFLD Thus, bodyweight after of as well as bodyweight from to are both risk factors for NAFLD, in both and studies in that the both of the by to and metabolic hepatic and could a be in NAFLD, no has been about The of PNPLA3 is associated with the of hepatic the of PNPLA3 is associated with lower hepatic The of is associated with the hepatic A between the polymorphisms of and hepatic has been but so have a found no significant between polymorphisms and risk of NAFLD is associated with in the with the general population because of increased The most common causes of in patients with NAFLD are disease and by disease. NAFLD appears to be with and in a of The risk factors for the of advanced fibrosis or cirrhosis are advanced obesity, and studies for the incidence and of NAFLD in the general population that the incidence rate of NAFLD was around during a to and of patients with NAFLD had during that It is well known that is related to NAFLD and loss is associated with NAFLD It is that simple steatosis is a clinical NASH can progress to in cases to HCC. However, recent studies have demonstrated that simple steatosis has the to progress to NASH with the of and that the presence and of fibrosis, of the diagnosis of the long-term to a review and of the fibrosis progression rate in patients with simple steatosis was with in patients with in of A risk for such progression is more on liver The of NASH in advanced a to as studies have that patients with a rate to patients with cirrhosis by the hepatitis the rate of of HCC was lower HCC about 5-year fatty liver disease can to cirrhosis and in to of HCC can be to cryptogenic the majority of such cases are to be to studies in Asian countries such as Japan, and suggest that the of NASH to HCC is lower than in the and is in the region of The incidence of HCC in NAFLD is in patients who have cirrhosis. In the incidence of developing HCC among NAFLD patients was but it was more likely among with advanced fibrosis. Among the incidence of HCC was in In addition, and diabetes are risk factors for HCC and the risk of HCC with other hepatitis B and The and diabetes has a in incidence of has now the most cause for liver in the from South the NAFLD HCC has from to over the There is evidence that HCC can in patients with NASH without of liver have that of NASH HCC cases not show evidence of liver and the risk of HCC appears to be with NAFLD with other Recommendation fatty liver disease should be as the cause of liver disease in patient who is overweight and in hepatitis B or C, alcoholic liver liver diseases, and metabolic have been Liver disease may present with liver in and a between and in bodyweight is a to imaging should be used to steatosis. other such as by may provide history for and current alcohol A including of bodyweight and habits, and of is a to NAFLD A or family history of T2DM, and high fatty liver, and cirrhosis is In diagnosis could be with positive of risk factors for NAFLD, exclusion of other and of fatty liver by hepatic with and a diagnosis of NAFLD is On the other hand, for liver biopsy on the of confidence that other conditions have been as hepatitis and liver and whether to NAFLD other than by or are such as into a clinical of for risk factors are discussed in the on of (TE) or other may be used to liver the for NASH not NASH and for various of fibrosis have not been can be a basis for the of by including of liver In addition, is approach to steatosis as discussed in in the In patients with liver liver the are liver biopsy or after This is in in the on of liver fibrosis. fatty liver disease is the most common cause of chronic liver disease and is to to of the general However, only a proportion of the general population has liver disease because of NAFLD. In a study on subjects in NAFLD on was in advanced fibrosis on liver was found in only subjects found to have NAFLD on population may from as well as assessment and treatment other of the metabolic syndrome to the risk of disease. However, the of such approach is unknown. On the other hand, the prevalence of NAFLD and liver disease is high among patients with diabetes and In a study on patients with diabetes the of patients with increased with and liver with advanced was and In a the prevalence of NAFLD on and advanced fibrosis on liver was and among In study on patients with NAFLD, and advanced fibrosis were in and These of patients most of the for While the current of treatment is a to community all or with risk the of with of 10% of bodyweight are now such that it can be that by NAFLD, with increased to disease and common to be of the and importance of the consequences of NAFLD. levels are not for for NAFLD as may be in patients with liver disease to and may be increased in patients with only simple steatosis. is a a was found to have and for the diagnosis of However, it is and may be for fatty The has been to be for the of significant hepatic steatosis and may be as a for NAFLD, as well as for progress to and liver is performed allowing assessment of the of liver disease at the the there in the natural history of long-term of and of (Table These a on for Recommendation Liver biopsy is for the diagnosis of as opposed to the other liver phenotypes of NAFLD. However, it is and with a low risk of and and in by may in with a of patients or in a community a liver biopsy is not as a general liver may be for patients with NAFLD who are to have chronic liver there is a to NASH from other chronic liver diseases, The and of new imaging and can the clinical for liver Non-alcoholic steatohepatitis is as the presence of hepatic and hepatocyte injury steatosis steatosis or steatosis with inflammation. 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It is important to note that steatosis not include but this is in the this is because the of steatosis is not a of liver on the On the basis of the a NAFLD been for of children clinical and clinical and uncommon be used as a with subtle with steatosis steatosis No in but not as with steatosis than on patients imaging time of common clinical and have been used in clinical studies. While of of liver fat to simple for to the presence of NAFLD. 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The hepatocyte through the of a of In both and through the of both and is increased in It has demonstrated for NAFLD but for NASH simple The is the in clinical The was also for limited at a of it as a for A of studies that had of to NASH other with or for NASH in patients with NAFLD. the is is to be used but either as the with a low or of a is that is exclusively by with in and is associated with NAFLD and the in levels in different studies it to be the in is that is with a and was used to NASH or its with NASH or with of liver including and may be of but are to as on is by the as and levels of and It has for NASH and NASH It has with and so be are highly of that at the can of have been increasingly in the and diagnosis of NAFLD and The and levels were in NASH with patients with simple Because fibrosis is the most the only for in NAFLD, including HCC and fibrosis assessment is of clinical for and HCC should be in of cirrhosis. Because of the of liver biopsy discussed in the Liver histology and have been developed to liver fibrosis. Over the past several decades, of with clinical including NAFLD fibrosis and liver fibrosis and have used to the of liver In addition, of long-term such as the risk of diabetes and and However, each of the studies appears to have used its as a of no widely values to patients at low and high risk have been to liver include and elastography A recent that had high and used to identify fibrosis in patients with However, to of among patients with high The of can the rate of in but is elastography has also in patients with NAFLD was the most of the assessment However, is not widely and is used in clinical practice because of the high studies in this region have the of of liver biopsy among Asian patients with have that the of and can more than that by either However, and as a the implications of various values have not been Thus, at the present the clinical of such to avoid liver biopsy A of is that most have been performed in studies a Thus, the of the to the natural history of disease and to or to The incidence of developing HCC in NASH cirrhosis is and the of such cases is over from the suggest that for HCC is the risk of developing HCC is per all NASH patients with cirrhosis should HCC to patients with cirrhosis from other is the most the and of in the fatty liver is not This may in for imaging and the of The of The issue of HCC in of patients with NAFLD was in the on HCC. However, the risk for each fibrosis is so it is not to of HCC for patients in the Asian or The risk of developing HCC in patients with without advanced fibrosis is low with population studies showing that the incidence of HCC HCC after that increased risk of HCC in NASH include PNPLA3 obesity, and family These factors may risk for screening, thereby However, as there is or to and this is important for is to the of both NAFLD and metabolic studies have demonstrated that patients with NAFLD have a prevalence of of metabolic syndrome including obesity, T2DM, and In Asian NAFLD the risk of diabetes by to The of diabetes with NAFLD metabolic and studies of NAFLD patients show that advanced fibrosis (NASH) have increased from Asian studies have that NAFLD is risk for as well as However, the of for NAFLD in patients with disease or disease in NAFLD patients is to be fatty liver is associated with a prevalence of chronic the of this between different cohorts of NAFLD among Asian NAFLD patients by or liver a with to in risk has been found Asian studies have increased risk of in NAFLD In both and the risk of and carcinoma in NAFLD patients is to and with patients without NAFLD. These in NASH patients than among with simple steatosis. However, no in NAFLD patients have been performed to the current fatty liver disease is associated with obstructive sleep and A of studies to obstructive sleep found a to increased risk of NAFLD including NASH and advanced fibrosis with obstructive sleep the risk of obstructive sleep among NAFLD patients is not women with NAFLD have been to have lower than without the prevalence of in Chinese men was increased among with Recommendation The to for The of this was supported by the Journal of Gastroenterology and Hepatology Foundation.